Organic Reactions, Volume 111 E-Book
269,99 €
Mehr erfahren.
- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Serie: Organic Reactions
- Sprache: Englisch
The 111th volume in this series for organic chemists in academia and industry presents critical discussions of widely used organic reactions or particular steps of a reaction. The material is treated from a preparative viewpoint, with emphasis on limitations, interfering influences, effects of structure and the selection of experimental techniques. The work includes tables that contain all possible examples of the reaction under consideration. Detailed procedures illustrate the significant modifications of each method. Volume contents: RING-OPENING REACTIONS OF EPOXIDES WITH TITANIUM(III) REAGENTS T. V. (Babu) RajanBabu, William A. Nugent, and Sandipan Halder REDUCTIVE CYCLIZATION OF 2-NITRO- AND beta-NITROSTYRENES, 2-NITROBIPHENYLS, AND 1-NITRO-1,3-DIENES TO INDOLES, CARBAZOLES, AND PYRROLES Bjorn C. G. Soderberg and William F. Berkowitz
Sie lesen das E-Book in den Legimi-Apps auf:
Seitenzahl: 579
Veröffentlichungsjahr: 2022
Ähnliche
Table of Contents
COVER
TITLE PAGE
COPYRIGHT
INTRODUCTION TO THE SERIES BY ROGER ADAMS, 1942
INTRODUCTION TO THE SERIES BY SCOTT E. DENMARK, 2008
PREFACE TO VOLUME 111
CHAPTER 1 RING‐OPENING REACTIONS OF EPOXIDES WITH TITANIUM(III) REAGENTS
ACKNOWLEDGMENTS
INTRODUCTION
MECHANISM AND STEREOCHEMISTRY
SCOPE AND LIMITATIONS
APPLICATIONS TO SYNTHESIS
COMPARISON WITH OTHER METHODS
EXPERIMENTAL CONDITIONS
EXPERIMENTAL PROCEDURES
TABULAR SURVEY
REFERENCES
SUPPLEMENTAL REFERENCES
CHAPTER 2 REDUCTIVE CYCLIZATION OF 2‐NITRO‐ AND β‐NITROSTYRENES, 2‐NITROBIPHENYLS, AND 1‐NITRO‐1,3‐DIENES TO INDOLES, CARBAZOLES, AND PYRROLES
ACKNOWLEDGEMENTS
INTRODUCTION
MECHANISM
SCOPE AND LIMITATIONS
APPLICATIONS TO SYNTHESIS
COMPARISON WITH OTHER METHODS
EXPERIMENTAL CONDITIONS
EXPERIMENTAL PROCEDURES
TABULAR SURVEY
REFERENCES
NOTE
CUMULATIVE CHAPTER TITLES BY VOLUME
AUTHOR INDEX, VOLUMES 1‐111
CHAPTER AND TOPIC INDEX, VOLUMES 1‐111
END USER LICENSE AGREEMENT
List of Illustrations
Chapter 1
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Scheme 7
Figure 1 The original structure proposed for the adduct of Cp
2
TiCl with coll...
Scheme 8
Figure 2 The structure of the titanium(III)‐epoxide complex.
Scheme 9
Scheme 10
Scheme 11
Scheme 12
Scheme 13
Scheme 14
Scheme 15
Scheme 16
Scheme 17
Scheme 18
Scheme 19
Scheme 20
Scheme 21
Scheme 22
Scheme 23
Scheme 24
Scheme 25
Scheme 26
Scheme 27
Scheme 28
Figure 3 Energy minima for titanium(III)‐activation of water for HAT. The BD...
Scheme 29
Scheme 30
Scheme 31
Scheme 32
Scheme 33
Scheme 34
Scheme 35
Scheme 36
Scheme 37
Scheme 38
Scheme 39
Scheme 40
Scheme 41
Figure 4 Transition states for the cyclization of radical
49
.
Figure 5 Analogues of
48
that cyclize with lower diastereoselectivities.
Figure 6 Intermediates in “template catalysis” of cyclobutane formation.
Scheme 42
Scheme 43
Scheme 44
Scheme 45
Scheme 46
Scheme 47
Scheme 48
Scheme 49
Scheme 50
Scheme 51
Scheme 52
Scheme 53
Scheme 54
Scheme 55
Scheme 56
Scheme 57
Scheme 58
Scheme 59
Scheme 60
Scheme 61
Scheme 62
Scheme 63
Scheme 64
Scheme 65
Scheme 66
Scheme 67
Scheme 68
Scheme 69
Scheme 70
Scheme 71
Scheme 72
Scheme 73
Scheme 74
Scheme 75
Scheme 76
Scheme 77
Scheme 78
Scheme 79
Scheme 80
Scheme 81
Scheme 82
Figure 7 Chiral analogues of Cp
2
TiCl
2
for use in asymmetric catalysis.
Scheme 83
Scheme 84
Scheme 85
Scheme 86
Scheme 87
Scheme 88
Figure 8 β‐Titanoxy radicals derived from cycloalkene oxides.
Scheme 89
Scheme 90
Scheme 91
Scheme 92
Scheme 93
Scheme 94
Scheme 95
Scheme 96
Scheme 97
Scheme 98
Scheme 99
Scheme 100
Scheme 101
Scheme 102
Scheme 103
Scheme 104
Scheme 105
Scheme 106
Scheme 107
Scheme 108
Scheme 109
Scheme 110
Scheme 111
Scheme 112
Scheme 113
Scheme 114
Scheme 115
Scheme 116
Scheme 117
Scheme 118
Scheme 119
Scheme 120
Scheme 121
Scheme 122
Scheme 123
Scheme 124
Scheme 125
Scheme 126
Scheme 127
Scheme 128
Scheme 129
Scheme 130
Scheme 131
Scheme 132
Scheme 133
Scheme 134
Figure 9 Example of an unreactive epoxide.
Scheme 135
Figure 10 An unreactive β,γ‐epoxy alcohol.
Scheme 136
Scheme 137
Scheme 138
Scheme 139
Scheme 140
Scheme 141
Scheme 142
Scheme 143
Scheme 144
Scheme 145
Scheme 146
Scheme 147
Scheme 148
Scheme 149
Scheme 150
Scheme 151
Scheme 152
Scheme 153
Scheme 154
Scheme 155
Scheme 156
Scheme 157
Scheme 158
Scheme 159
Scheme 160
Scheme 161
Scheme 162
Scheme 163
Scheme 164
Scheme 165
Scheme 166
Scheme 167
Scheme 168
Scheme 169
Scheme 170
Figure 11 Substrate in unsuccessful dehydroxylation.
Scheme 171
Scheme 172
Scheme 173
Scheme 174
Scheme 175
Figure 12 Possible intermediates in the epoxide opening of
234
at either C2 ...
Scheme 176
Figure 13 Relative reactivities of HAT reagents.
Scheme 177
Scheme 178
Scheme 179
Figure 14 HAT reagents γ‐terpinine (
253
) and
tert
‐dodecanethiol (
254
).
Scheme 180
Figure 15 Titanium complex for “template catalysis”.
Scheme 181
Scheme 182
Scheme 183
Scheme 184
Scheme 185
Scheme 186
Scheme 187
Scheme 188
Scheme 189
Scheme 190
Scheme 191
Scheme 192
Scheme 193
Scheme 194
Scheme 195
Scheme 196
Scheme 197
Scheme 198
Scheme 199
Scheme 200
Scheme 201
Scheme 202
Scheme 203
Scheme 204
Scheme 205
Scheme 206
Scheme 207
Scheme 208
Scheme 209
Scheme 210
Scheme 211
Scheme 212
Scheme 213
Scheme 214
Scheme 215
Scheme 216
Scheme 217
Scheme 218
Scheme 219
Scheme 220
Scheme 221
Scheme 222
Scheme 223
Scheme 224
Scheme 225
Scheme 226
Scheme 227
Scheme 228
Scheme 229
Scheme 230
Scheme 231
Scheme 232
Scheme 233
Scheme 234
Scheme 235
Scheme 236
Scheme 237
Scheme 238
Scheme 239
Scheme 240
Scheme 241
Scheme 242
Scheme 243
Scheme 244
Scheme 246 The radical formed from transannular cyclization.
Scheme 245
Scheme 246
Scheme 247
Scheme 250 Substrates that demonstrate functional‐group compatibility in the...
Scheme 248
Scheme 249
Scheme 250
Scheme 251
Scheme 252
Scheme 253
Scheme 254
Scheme 255
Scheme 256
Scheme 257
Scheme 258
Scheme 259
Scheme 260
Scheme 261
Scheme 262
Scheme 263
Scheme 264
Scheme 265
Scheme 266
Scheme 267
Scheme 268
Scheme 269
Figure 18 General structure of furanofuran lignans.
Scheme 270
Scheme 271
Scheme 272
Scheme 273
Scheme 274
Scheme 275
Scheme 276
Scheme 277
Figure 19 Adducts of Cp
2
TiCl with MCl
2
salts.
Scheme 278
Scheme 279
Scheme 280
Scheme 284 Complexes formed between a δ‐hydroxy ester and either Cp
2
TiCl
2
or...
Scheme 281
Figure 21 The putative structure of the adduct formed from collidine and Me
3
Scheme 282
Scheme 283
Scheme 284
Scheme 285
Scheme 286
Scheme 287
Scheme 288
Scheme 289
Scheme 290
Scheme 291
Scheme 292
Chapter 2
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Scheme 7
Scheme 8
Scheme 9
Scheme 10
Scheme 11
Scheme 12
Scheme 13
Scheme 14
Scheme 15
Scheme 16
Scheme 17
Scheme 18
Scheme 19
Scheme 20
Scheme 21
Scheme 22
Scheme 23
Scheme 24
Scheme 25
Scheme 26
Scheme 27
Scheme 28
Scheme 29
Scheme 30
Scheme 31
Scheme 32
Scheme 33
Scheme 34
Scheme 35
Scheme 36
Scheme 37
Scheme 38
Scheme 39
Scheme 40
Scheme 41
Scheme 42
Scheme 43
Scheme 44
Scheme 45
Scheme 46
Scheme 47
Scheme 48
Scheme 49
Scheme 50
Scheme 51
Scheme 52
Scheme 53
Scheme 54
Scheme 55
Scheme 56
Scheme 57
Scheme 58
Scheme 59
Scheme 60
Scheme 61
Scheme 62
Scheme 63
Scheme 64
Scheme 65
Scheme 66
Scheme 67
Scheme 68
Scheme 69
Scheme 70
Scheme 71
Scheme 72
Scheme 73
Scheme 74
Scheme 75
Scheme 76
Scheme 77
Scheme 78
Scheme 79
Scheme 80
Scheme 81
Scheme 82
Scheme 83
Scheme 84
Scheme 85
Scheme 86
Scheme 87
Scheme 88
Scheme 89
Scheme 90
Scheme 91
Scheme 92
Scheme 93
Scheme 94
Scheme 95
Scheme 96
Scheme 97
Scheme 98
Scheme 99
Scheme 100
Scheme 101
Scheme 102
Scheme 103
Scheme 104
Scheme 105
Scheme 106
Scheme 107
Scheme 108
Scheme 109
Scheme 110
Scheme 111
Scheme 112
Scheme 113
Scheme 114
Scheme 115
Scheme 116
Scheme 117
Scheme 118
Scheme 119
Scheme 120
Scheme 121
Scheme 122
Scheme 123
Scheme 124
Scheme 125
Scheme 126
Scheme 127
Scheme 128
Scheme 129
Scheme 130
Scheme 131
Guide
COVER PAGE
TABLE OF CONTENTS
ORGANIC REACTIONS
TITLE PAGE
COPYRIGHT
INTRODUCTION TO THE SERIES BY ROGER ADAMS, 1942
INTRODUCTION TO THE SERIES BY SCOTT E. DENMARK, 2008
PREFACE TO VOLUME 111
Begin Reading
AUTHOR INDEX, VOLUMES 1‐111
CHAPTER AND TOPIC INDEX, VOLUMES 1‐111
END USER LICENSE AGREEMENT
Pages
ii
iii
iv
v
vi
vii
viii
ix
x
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
339
340
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
383
384
385
386
387
388
389
390
391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
427
428
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
459
460
461
462
463
464
465
466
467
468
469
470
471
472
473
474
475
476
477
478
479
480
481
482
483
484
485
486
487
488
489
490
491
492
493
494
495
496
497
498
499
500
501
502
503
504
505
506
507
508
509
510
511
512
513
514
515
516
517
518
519
520
521
522
523
524
525
526
527
528
529
530
531
532
533
534
535
536
537
538
539
540
541
542
543
544
545
546
547
548
549
550
551
552
553
554
555
556
557
558
559
560
561
562
563
564
565
566
567
568
569
570
571
572
573
574
575
576
577
578
579
580
581
582
583
584
585
586
587
588
589
590
591
592
593
594
595
596
597
598
599
600
601
602
603
604
605
606
607
608
609
610
611
612
613
614
615
616
617
618
619
620
621
622
623
624
625
626
627
628
629
630
631
632
633
634
635
636
637
638
639
640
641
642
643
644
645
646
647
648
649
650
651
652
653
654
655
656
657
658
659
660
661
662
663
664
665
666
667
668
669
670
671
672
673
674
675
676
677
678
679
680
681
682
683
684
685
686
687
688
689
690
691
692
693
694
695
696
697
698
699
700
701
702
703
704
705
706
707
708
709
710
711
712
713
714
715
716
717
718
719
720
721
722
723
724
725
726
727
728
729
730
731
732
733
734
735
736
737
738
739
740
741
742
743
744
745
746
747
748
749
750
751
752
753
754
755
756
757
758
759
760
761
762
763
764
765
766
767
768
769
771
772
773
774
775
776
777
778
779
780
781
782
783
784
785
786
787
788
789
790
791
792
793
794
795
796
797
799
800
801
802
803
804
805
806
807
808
809
810
811
812
813
814
815
816
817
FORMER MEMBERS OF THE BOARD OF EDITORS AND DIRECTORS
JEFFREY
AUBÉ
MARISA
C.
KOZLOWSKI
JOHN
E.
BALDWIN
STEVEN
V.
LEY
DALE
L.
BOGER
JAMES
A.
MARSHALL
ANDRÉ
B.
CHARETTE
MICHAEL
J.
MARTINELLI
ENGELBERT
CIGANEK
STUART
W.
McCOMBIE
DENNIS
CURRAN
SCOTT
J.
MILLER
SAMUEL
DANISHEFSKY
JOHN
MONTGOMERY
HUW
M. L.
DAVIES
LARRY
E.
OVERMAN
SCOTT
E.
DENMARK
ALBERT
PADWA
VICTOR
FARINA
T. V.
RAJANBABU
PAUL
FELDMAN
JAMES
H.
RIGBY
JOHN
FRIED
WILLIAM
R.
ROUSH
JACQUELYN
GERVAY
‐
HAGUE
TOMISLAV
ROVIS
STEPHEN
HANESSIAN
SCOTT
D.
RYCHNOVSKY
LOUIS
HEGEDUS
MARTIN
SEMMELHACK
PAUL
J.
HERGENROTHER
CHARLES
SIH
JEFFREY
S.
JOHNSON
AMOS
B.
SMITH
, III
ROBERT
C.
KELLY
BARRY
M.
TROST
LAURA KIESSLING
PETER
WIPF
FORMER MEMBERS OF THE BOARD NOW DECEASED
ROGER
ADAMS
HERBERT
O.
HOUSE
HOMER
ADKINS
JOHN
R.
JOHNSON
WERNER
E.
BACHMANN
ROBERT
M.
JOYCE
PETER
BEAK
ANDREW
S.
KENDE
ROBERT
BITTMAN
WILLY
LEIMGRUBER
A. H.
BLATT
FRANK
C. Mc
GREW
VIRGIL
BOEKELHEIDE
BLAINE
C. Mc
KUSICK
GEORGE
A.
BOSWELL
,
JR
.
JERROLD
MEINWALD
THEODORE
L.
CAIRNS
CARL
NIEMANN
ARTHUR
C.
COPE
LEO
A.
PAQUETTE
DONALD
J.
CRAM
GARY
H.
POSNER
DAVID
Y.
CURTIN
HANS
J.
REICH
WILLIAM
G.
DAUBEN
HAROLD
R.
SNYDER
LOUIS
F.
FIESER
MILÁN
USKOKOVIC
HEINZ
W.
GSCHWEND
BORIS
WEINSTEIN
RICHARD
F.
HECK
JAMES
D.
WHITE
RALPH
F.
HIRSCHMANN
Organic Reactions
VOLUME 111
EDITORIAL BOARD
P. ANDREWEVANS, Editor‐in‐Chief
STEVEN M. WEINREB, Executive Editor
DAVID
B.
BERKOWITZ
STEFAN LUTZ
PAUL
R.
BLAKEMORE
BO
QU
JIN K. CHA
JENNIFER
M.
SCHOMAKER
REBECCA L. GRANGE
KEVIN
H.
SHAUGHNESSY
DENNIS G. HALL
STEVEN
D.
TOWNSEND
DONNA M. HURYN
CHRISTOPHER
D.
VANDERWAL
JEFFREY
N.
JOHNSTON
MARY
P.
WATSON
BARRY B. SNIDER, Secretary
JEFFERY B. PRESS, Treasurer
DANIELLESOENEN, Editorial Coordinator
DENALINDSAY, Secretary and Processing Editor
LANDY K.BLASDEL, Processing Editor
TINAGRANT, Processing Editor
ENGELBERTCIGANEK, Editorial Advisor
ASSOCIATE EDITORS
WILLIAM F. BERKOWITZ
SANDIPAN HALDER
William A. Nugent
T. V. (BABU) RAJANBABU
BJÖRN C. G. SÖDERBERG
Copyright © 2022 by Organic Reactions, Inc. All rights reserved.
Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada
No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750‐8400, fax (978) 750‐4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748‐6011, fax (201) 748‐6008, or online at http://www.wiley.com/go/permission.
Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.
For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762‐2974, outside the United States at (317) 572‐3993 or fax (317) 572‐4002.
Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com.
Library of Congress Cataloging‐in‐Publication Data:
ISBN: 978‐1‐119‐98221‐0
Printed in the United States of America
INTRODUCTION TO THE SERIES BY ROGER ADAMS, 1942
In the course of nearly every program of research in organic chemistry, the investigator finds it necessary to use several of the better‐known synthetic reactions. To discover the optimum conditions for the application of even the most familiar one to a compound not previously subjected to the reaction often requires an extensive search of the literature; even then a series of experiments may be necessary. When the results of the investigation are published, the synthesis, which may have required months of work, is usually described without comment. The background of knowledge and experience gained in the literature search and experimentation is thus lost to those who subsequently have occasion to apply the general method. The student of preparative organic chemistry faces similar difficulties. The textbooks and laboratory manuals furnish numerous examples of the application of various syntheses, but only rarely do they convey an accurate conception of the scope and usefulness of the processes.
For many years American organic chemists have discussed these problems. The plan of compiling critical discussions of the more important reactions thus was evolved. The volumes of Organic Reactions are collections of chapters each devoted to a single reaction, or a definite phase of a reaction, of wide applicability. The authors have had experience with the processes surveyed. The subjects are presented from the preparative viewpoint, and particular attention is given to limitations, interfering influences, effects of structure, and the selection of experimental techniques. Each chapter includes several detailed procedures illustrating the significant modifications of the method. Most of these procedures have been found satisfactory by the author or one of the editors, but unlike those in Organic Syntheses, they have not been subjected to careful testing in two or more laboratories. Each chapter contains tables that include all the examples of the reaction under consideration that the author has been able to find. It is inevitable, however, that in the search of the literature some examples will be missed, especially when the reaction is used as one step in an extended synthesis. Nevertheless, the investigator will be able to use the tables and their accompanying bibliographies in place of most or all of the literature search so often required. Because of the systematic arrangement of the material in the chapters and the entries in the tables, users of the books will be able to find information desired by reference to the table of contents of the appropriate chapter. In the interest of economy, the entries in the indices have been kept to a minimum, and, in particular, the compounds listed in the tables are not repeated in the indices.
The success of this publication, which will appear periodically, depends upon the cooperation of organic chemists and their willingness to devote time and effort to the preparation of the chapters. They have manifested their interest already by the almost unanimous acceptance of invitations to contribute to the work. The editors will welcome their continued interest and their suggestions for improvements in Organic Reactions.
INTRODUCTION TO THE SERIES BY SCOTT E. DENMARK, 2008
In the intervening years since “The Chief” wrote this introduction to the second of his publishing creations, much in the world of chemistry has changed. In particular, the last decade has witnessed a revolution in the generation, dissemination, and availability of the chemical literature with the advent of electronic publication and abstracting services. Although the exponential growth in the chemical literature was one of the motivations for the creation of Organic Reactions, Adams could never have anticipated the impact of electronic access to the literature. Yet, as often happens with visionary advances, the value of this critical resource is now even greater than at its inception.
From 1942 to the 1980's the challenge that Organic Reactions successfully addressed was the difficulty in compiling an authoritative summary of a preparatively useful organic reaction from the primary literature. Practitioners interested in executing such a reaction (or simply learning about the features, advantages, and limitations of this process) would have a valuable resource to guide their experimentation. As abstracting services, in particular Chemical Abstracts and later Beilstein, entered the electronic age, the challenge for the practitioner was no longer to locate all of the literature on the subject. However, Organic Reactions chapters are much more than a surfeit of primary references; they constitute a distillation of this avalanche of information into the knowledge needed to correctly implement a reaction. It is in this capacity, namely to provide focused, scholarly, and comprehensive overviews of a given transformation, that Organic Reactions takes on even greater significance for the practice of chemical experimentation in the 21st century.
Adams' description of the content of the intended chapters is still remarkably relevant today. The development of new chemical reactions over the past decades has greatly accelerated and has embraced more sophisticated reagents derived from elements representing all reaches of the Periodic Table. Accordingly, the successful implementation of these transformations requires more stringent adherence to important experimental details and conditions. The suitability of a given reaction for an unknown application is best judged from the informed vantage point provided by precedent and guidelines offered by a knowledgeable author.
As Adams clearly understood, the ultimate success of the enterprise depends on the willingness of organic chemists to devote their time and efforts to the preparation of chapters. The fact that, at the dawn of the 21st century, the series continues to thrive is fitting testimony to those chemists whose contributions serve as the foundation of this edifice. Chemists who are considering the preparation of a manuscript for submission to Organic Reactions are urged to contact the Editor‐in‐Chief.
PREFACE TO VOLUME 111
We will have rings and things and fine array
William Shakespeare
The Taming of the Shrew, 1590–1592
The two chapters in this volume of Organic Reactions describe the reductive ring‐opening reactions of epoxides with titanium(III) reagents and the reductive cyclization reactions of nitroaryl and nitroalkenyl derivatives. Both chapters feature the generation and synthetic utility of a specific reactive intermediate, a free radical and a nitrene, respectively. Interestingly, despite the wide variety of processes that proceed through reactive intermediates, there are only a limited number of different types of such species, i.e., carbanions, radicals, carbocations, carbenes, carbynes, and nitrenes. These are usually high energy, short‐lived, and therefore have significant reactivity to permit an array of transformations. Hence, a critical component in developing a new reaction that deploys a specific type of reactive intermediate is the ability to generate it in a controlled and selective manner, thereby taming the inherent reactivity to facilitate the desired bond‐forming event in the desired manner. A particularly compelling aspect of Organic Reactions chapters is the delineation of so‐called Black‐Swan Events that provides the insight for accessing a specific reactive intermediate with new chemical reactivity. Notably, both chapters feature different types of ring‐forming reactions, albeit this is the entire focus of the latter chapter. The first chapter also delineates other things and fine array to illustrate the synthetic utility of the reductive opening of epoxides. Another contrasting feature of the chapters is that while the first is almost entirely centered around a specific method to generate a free‐radical intermediate, the second compares two different ways to access the same reactive intermediate, both of which constitute named reactions. Hence, this volume of the Organic Reactions series represents another stellar contribution that outlines the seminal developments in the generation and productive reactions of reactive intermediates to construct important synthetic motifs embedded in functional molecules.
The first chapter by T. V. (Babu) RajanBabu, William A. Nugent, and Sandipan Halder provides an outstanding treatise on the ring opening of epoxides with titanium(III) reagents. The authors concisely describe the historical events that led to the discovery of the reduction of epoxides by single‐electron transfer using titanocene monochloride, which is ascribed to a series of Black‐Swan Events (vide supra). For instance, Davies and Gibson reported the first example of the conversion of cyclohexene oxide to cyclohexene with titanocene monochloride in 1984; however, this work was preceded by several seemingly unrelated reports. For instance, Linnemann described probably the first epoxide cleavage by an SET process in 1866 using sodium amalgam in water, followed by contributions from Percy Julian in 1954 and mechanistic studies by Kochi in the late 1960s using chromium(II) salts. The culmination of these developments paved the way for the catalytic and stoichiometric titanium(III) reactions with epoxides outlined herein.
The Mechanism and Stereochemistry section describes the critical features associated with the generation of β‐titanoxy radicals from epoxides, including the impact of the titanium complex and the mechanistic details for the carbon‐oxygen bond cleavage. A particularly valuable feature of this section is the insight into the regeneration of the titanium reagent to facilitate the catalytic version. The authors also delineate the various mechanistic pathways to the β‐titanoxy radicals, essential for planning a reaction sequence, including different methods deployed to trap the radicals formed after an initial cyclization. The section then culminates with a discussion of various aspects of regio‐ and stereocontrol, in which the diastereoselective processes are further subdivided into inter‐ and intramolecular variations. For example, the cyclization reaction section is organized by the type of Baldwin process, namely, 5‐exo‐trig, 5‐exo‐dig, 6‐endo‐trig, 6‐exo‐trig, and 6‐exo‐dig and includes sections on tandem cyclization reactions and the reactions of β,γ‐epoxy alcohols.
The Scope and Limitation section starts with a survey of suitable epoxides to provide the reader with a sense of what types of transformations are feasible, followed by an important section on functional‐group compatibility and the effects of substrate structure on reactivity. Each section is critical to anyone contemplating utilizing this reaction in complex synthesis. The intramolecular addition reactions and the associated termination strategies comprise a sizable component of this section, including transannular cyclization reactions and the construction of polycyclic products via cascade‐type cyclization reactions. The Applications to Synthesis section is organized by the type of transformation, which permits a strategic analysis of these reactions. Hence, each sub‐section delineates how this process has been deployed in the synthesis of a target of value to illustrate its impact in useful applications. Notably, this process has been utilized to prepare nearly two hundred natural products and advanced intermediates, making it a “formidable tool” for target‐directed synthesis. The Comparison with Other Methods section delineates two critical limitations of the current process that can be mitigated to some degree by using alternative protocols, which thus provides a complementary picture of how to manipulate these types of epoxy alcohols. Additionally, the chapter provides detailed Experimental Conditions, which will be particularly insightful for anyone wishing to understand the nuances of this type of process. The Tabular Survey incorporates reactions reported up to October 2021. The tables mirror the Scope and Limitations section, making identifying examples of a particular process straightforward. Overall, this is an outstanding chapter on a very interesting and powerful synthetic transformation that has been widely deployed in organic synthesis.
The second chapter by Björn C. G. Söderberg and the late William F. Berkowitz outlines the reductive cyclization of 2‐nitro‐ and β‐nitrostyrenes, 2‐nitrobiphenyls, and 1‐nitro‐1,3‐dienes to prepare indoles, carbazoles, and pyrroles with a particular emphasis on indoles. Notably, the indole core is arguably one of the oldest and most widely studied heterocyclic motifs. For instance, early studies on the synthesis of indigo dye inspired the first chemical synthesis of indole itself by von Baeyer in 1866 by reducing oxindole with zinc dust. The importance of the indole motif in dyes, medicinal chemistry, bioactive natural products, bacterial physiology, and neurotransmitters, such as serotonin and melatonin, make it an important structural array. Thus, methods to prepare this heterocycle have inspired many innovative synthetic approaches. Ironically, the two methods reported herein utilize nitro aromatics as the nitrogen source in the heterocyclic product, which is analogous to the method employed by von Baeyer and Emmerling in 1869 for the conversion of 2‐nitrocinnamic acid to indole using iron filings under basic conditions. Interestingly, this approach remained dormant for nearly a century until the development of the Cadogan‐Sundberg process and then the related Watanabe‐Cenini‐Söderberg reaction to convert nitrostyrenes to indoles using trivalent phosphorus reagents and palladium catalysts, respectively.
The Mechanism and Stereochemistry section is organized by the named reaction and the type of product formed. For example, some general mechanistic considerations delineate the importance of forming a nitroso derivative en route to the putative nitrene in the Cadogan‐Sundberg process. DFT calculations support a concerted [3+1] cycloaddition followed by a retro [2+2] cycloaddition to generate the nitrosoarene, which undergoes a second deoxygenation via an oxazaphosphiridine to afford the nitrene to initiate cyclization. The remainder of the section deals with the caveats that have evolved with this mechanistic proposal in constructing carbazoles, indoles and pyrroles. The format for the Watanabe–Cenini–Söderberg reaction is similar, albeit, in this case, the cyclization is proposed to occur through either the nitroso or the nitrene intermediate. The initiation is thought to involve the formation of a radical anion that reacts with carbon monoxide to form a series of metallacycle intermediates. The recognition that both of these processes undergo cyclization via an equivalent nitroso/nitrene intermediate provides a unifying theme for these reactions.
The Scope and Limitations section commences with the methods used to prepare the substrates for both types of reactions. The remainder of the section is then organized by the type of reaction, namely, 2‐nitrostyrenes to form indoles and β‐nitrostyrenes to produce indoles in the context of the specific named reaction. Additional sections describe the conversion of 1‐nitro‐1,3‐dienes to pyrroles and the synthesis of heterocyclic analogs of indoles and carbazoles. A particularly useful feature is the direct comparison of the two methods, which gives the reader advice in selecting a specific set of reaction conditions. There is also a section on using other transition‐metal catalysts and the applications of elemental sulfur and selenium as reductants. The final component of this section delineates the corresponding reactions of nitro and nitrosobenzenes for comparison. The Applications to Synthesis section provides examples using both methods to target some important compounds, including a few examples of closely related processes. The Comparison with Other Methods section discusses several alternative methods that focus on the N1‐C2 cyclization reactions of nitro‐ and amino‐substituted alkenes, alkynes and aryl groups. The organization of the Tabular Survey mirrors the Scope and Limitations, thereby making it easy for the reader to identify a specific transformation. Overall, this is an excellent chapter on two variants of a critical process that will be a valuable resource to a broad cross‐section of the synthetic community, given the importance and ubiquity of these types of nitrogen heterocycles.
I would be remiss if I did not acknowledge the entire Organic Reactions Editorial Board for their collective efforts in steering this volume through the stages of the editorial process. I thank Dr. Jin K. Cha (Chapter 1) and Dr. Donna M. Huryn (Chapters 1 and 2), who served as the Responsible Editors to marshal the chapters through the various phases of development. I am also deeply indebted to Dr. Danielle Soenen for her continued and heroic efforts as the Editorial Coordinator; her knowledge of Organic Reactions is critical to maintaining consistency in the series. Dr. Dena Lindsay (Secretary to the Editorial Board) is thanked for coordinating the authors', editors', and publisher's contributions. In addition, the Organic Reactions enterprise could not maintain the quality of production without the efforts of Dr. Steven M. Weinreb (Executive Editor), Dr. Engelbert Ciganek (Editorial Advisor), Dr. Landy Blasdel (Processing Editor), and Dr. Tina Grant (Processing Editor). I would also like to acknowledge Dr. Barry B. Snider (Secretary) for keeping everyone on task and Dr. Jeffery Press (Treasurer) for his fiscal diligence.
I am also indebted to past and present members of the Board of Editors and Board of Directors for ensuring the enduring quality of Organic Reactions. The specific format of the chapters, in conjunction with the collated tables of examples, makes this series of reviews both unique and exceptionally valuable to the practicing synthetic organic chemist.
P. Andrew Evans
Kingston
Ontario, Canada
CHAPTER 1 RING‐OPENING REACTIONS OF EPOXIDES WITH TITANIUM(III) REAGENTS
T. V. (BABU) RAJANBABU, WILLIAM A. NUGENT
Department of Chemistry and Biochemistry, The Ohio State University, 100 west 18th Avenue, Columbus, OH 43210, USA
SANDIPAN HALDER
Department of Chemistry, Visvesvaraya National Institute of Technology (VNIT), South Ambazari Road, Nagpur, INDIA, 440010
Edited by JIN K. CHA AND DONNA M. HURYN
CONTENTS
ACKNOWLEDGMENTS
INTRODUCTION
MECHANISM AND STEREOCHEMISTRY
Generation of β‐Titanoxy Radicals from Epoxides
Nature of the Reagent
Mechanism of Epoxide Carbon–Oxygen Bond Cleavage
Regeneration of Cp
2
TiCl During Catalysis
MECHANISTIC PATHWAYS OF β‐TITANOXY RADICALS
Epoxide Deoxygenation
Elimination of β‐Hydrogen
Elimination of Cyanide and Carboxylates
Rearrangement of β‐Titanoxy Radicals
Reduction by Hydrogen‐Atom Transfer
Intermolecular Addition
Arylation of β‐Titanoxy Radicals via Cross‐Coupling
Dimerization of Vinyl and Aryl Epoxides
Cyclization via Intramolecular Arylation
Cyclization of Epoxy Alkenes and Epoxy Alkynes
RADICAL TERMINATION STEPS FOLLOWING CYCLIZATION
Trapping by a Second Equivalent of Cp
2
TiCl
Formation of Organotitanium Species Followed by Elimination
Radical Addition–Elimination
Loss of a β‐Hydrogen Atom
Reduction by Hydrogen‐Atom Transfer
Intermolecular Addition to an Alkene Acceptor
Homolytic Substitution of the Titanium–Oxygen Bond to Afford a Tetrahydrofuran
Additional Intramolecular Addition (Tandem Cyclization)
ORIGINS OF SELECTIVITY
Regioselectivity of Epoxide Opening
Enantioselective Ring‐Opening of Epoxides
Stereochemical Course of Intermolecular Addition of β‐Titanoxy Radicals
Carbon–Carbon Bond‐Forming Reactions
Hydrogen‐Atom‐Transfer Reactions
Stereochemistry of Intramolecular Addition Reactions
5‐
exo
‐trig and 5‐
exo
‐dig Cyclization
Construction of Fused Cyclopentanes via 5‐
exo
‐trig Cyclization
6‐
endo
‐trig Cyclization
6‐
exo
‐trig Cyclization
6‐
exo
‐dig Cyclization
Stereochemistry of Tandem Polycyclization Reactions
Reactions Involving β,γ‐Epoxy Alcohols
Mechanistic Models
Possible Role of Hydrogen Bonding
SCOPE AND LIMITATIONS
Scope of Suitable Epoxide Substrates
Functional‐Group Compatibility
Nitro Compounds and Other One‐Electron Oxidants
Activated Organic Halides
Aldehydes and Ketones
α,β‐Unsaturated Carbonyl Compounds
Nitriles
Alcohol O–H and Amide N–H Functional Groups
Amines
Carbon–Oxygen Bond Cleavage of Oxetanes and Alcohols
Ring‐Opening of Aziridines
Effect of Substrate Structure on Reactivity
Deoxygenation of Epoxides
Rearrangement of Trisubstituted Epoxides to Allylic Alcohols
β‐Elimination of Hydroxide, Cyanide, or Carboxylate Leaving Groups
Reduction of Epoxides to Alcohols
Intermolecular Addition of Epoxides to C=C Double Bonds
Addition to Nitriles
Cross‐Coupling to Aryl Halides
Homodimerization of Vinyl and Aryl Epoxides
Intramolecular Addition (Cyclization)
Intramolecular Arylation of Epoxides
3‐
exo
and 4‐
exo
Cyclizations
Cyclizations Leading to Five‐ to Eight‐Membered Rings
5‐
exo
‐trig and 5‐
exo
‐dig Cyclizations of Hex‐5‐enyl Radicals
Cyclization Followed by Nonreductive Termination
Termination by Loss of a β‐Hydrogen Atom
Termination by Loss of a β‐Carbonate Group or Fluoride
Termination by Addition–Elimination to a Phosphinoyl, Sulfoximyl, or Trialkylstannyl Alkene
Cyclization Followed by an Intramolecular S
H
2 Reaction
Cyclization Followed by Intermolecular Addition
6‐
endo
‐trig Cyclization
6‐
exo
‐trig Cyclization
6‐
exo
‐dig Cyclizations
7‐
endo
‐trig Cyclization
7‐
exo
‐trig, 8‐
endo
‐trig, and 8‐
endo
‐dig Cyclizations
Transannular Cyclizations
Polycyclic Compounds via Tandem Cyclizations
APPLICATIONS TO SYNTHESIS
Deoxygenation of Epoxides
Reduction of Epoxides to Alcohols
Intermolecular Addition Reactions
Intramolecular Addition (Cyclization) Reactions
Terpenoids as a Testing Ground
COMPARISON WITH OTHER METHODS
EXPERIMENTAL CONDITIONS
Safety Considerations
Stoichiometric Reactions
Isolation of Cp
2
TiCl
In situ Generation of Cp
2
TiCl
Catalytic Reactions
Protic Catalysis
Aprotic Catalysis
Photoredox Catalysis
Reaction Conditions
Effect of Temperature
Selection of Solvent
Normal Versus Inverse Addition
Effect of Additives
Aqueous Workup Procedures
EXPERIMENTAL PROCEDURES
Anhydrovinblastine from Leurosine [Deoxygenation of an Epoxide].
(
S
)‐3‐Hydroxyoct‐1‐ene [Deoxygenative Rearrangement for the Synthesis of an Allyl Alcohol from a Chiral β,γ‐Epoxy Alcohol].
N
‐
Benzoyl‐5‐
O
‐(
tert
‐butyldimethylsilyl)‐3′‐deoxyadenosine [Chemo‐ and Regioselective Radical‐Mediated Reduction of an Epoxide].
(2
R
,3
R
,4
S
)‐1‐(Benzyloxy)‐3‐methylpentane‐2,4‐diol [Diastereoselective Radical‐Mediated Reduction of a Chiral β,γ‐Epoxy Alcohol].
(
S
)‐1,4‐Dipropoxybutan‐2‐ol [Catalytic Enantioselective Reductive Ring‐Opening of a
meso
Epoxide].
Methyl (1
S
,2
S
,4a
R
,6
S
,8a
S
)‐6‐(Benzoyloxy)‐2‐(hydroxymethyl)‐5,5,8a‐trimethyldecahydronaphthalene‐1‐carboxylate [Radical‐Mediated Reduction of an Epoxide Using Titanium(III)‐Coordinated Water as a Hydrogen Source].
(2
R
*,1′
R
*,3′
S
*,5′
R
*)‐2‐(5′‐Acetoxy‐3′‐hydroxy‐2′‐methylenecyclohexyl)‐2‐
tert
‐butyldimethylsiloxyacetic Acid Methyl Ester [Radical‐Mediated Rearrangement of an Epoxide into an Allylic Alcohol].
9‐Methylene‐
cis
‐bicyclo[4.3.0]non‐1‐ylmethanol [Catalytic 5‐
exo
‐dig Cyclization of a 1,2‐Epoxyalk‐6‐yne].
Diethyl (3a
S
,6a
R
)‐1,1‐Diethyltetrahydro‐1
H
‐cyclopenta[
c
]furan‐5,5(3
H
)‐dicarboxylate [Radical Cyclization Followed by Homolytic Substitution to Form a Tetrahydrofuran].
((1
S
,4a
R
,6
S
,8a
S
)‐6‐Hydroxy‐5,5,8a‐trimethyl‐2‐methylenedecahydronaphthalen‐1‐yl)methyl Acetate [Tandem 6‐
endo
‐trig/6‐
endo
‐trig Cyclization Followed by Termination via Loss of a β‐Hydrogen Atom].
((1
S
,2
S
,4a
R
,6
S
,8a
S
)‐6‐Hydroxy‐2,5,5,8a‐tetramethyldecahydronaphthalen‐1‐yl‐2‐
d
)‐methyl Acetate [Tandem 6‐
endo
‐
trig/6‐
endo
‐trig Cyclization Followed by Termination via Deuterium‐Atom‐Transfer Reduction].
2‐(Hydroxymethyl)‐2‐methylcyclobutan‐1‐one [Cyclization of a γ,δ‐Epoxy Nitrile to a Small‐Size Ring].
2‐(Hydroxymethyl)‐2,3,3‐trimethylcyclobutylacetic Acid
tert
‐Butyl Ester [Catalytic 4‐
exo
‐trig Cyclization to an α,β‐Unsaturated Ester].
(6
R
,7
R
)‐7‐(((
tert
‐Butyldimethylsilyl)oxy)methyl)‐8,8‐dimethyl‐2‐oxaspiro[5.5]undecan‐3‐one [Enhanced Reactivity in the Intermolecular Addition of an Epoxide‐Derived Radical to Trifluoroethyl Acrylate].
1‐(2‐Hydroxycyclohexyl)ethanone [Intermolecular Addition of an Epoxide‐Derived Radical to a Nitrile].
3‐Methyl‐1‐phenylindolin‐3‐yl methanol [Intramolecular Arylation of an Epoxide‐Derived Radical].
(1‐(4‐(3
R
,4
S
)‐1‐Benzyl‐4‐hydroxypyrrolidin‐3‐yl)phenyl)ethanone [Radical‐Mediated, Nickel‐Catalyzed Cross‐Coupling of an Epoxide with an Aryl Halide].
TABULAR SURVEY
Chart 1. Titanium Reagents Used in the Tables
Chart 2. Photoredox Catalysts and Ligands Used in the Tables
Chart 3. Cobalt Catalysts Used in the Tables
Table 1. Reduction of Epoxides
A. Using Cp
2
TiCl
B. Using Cp
2
TiCl and Water as a Hydrogen Atom Donor
C. Use of 1,4-Cyclohexadiene Analogs
D. Use of Silanes
E. Use of Hydrogen
F. Use of Ti(Oi-Pr)
4
/TMSCl/Mg
G. Stereoselective Reactions
Table 2. Epoxide Opening Followed by Elimination to Form Allylic Alcohols
Table 3. Alkenes from Epoxides via Deoxygenation
Table 4. Intermolecular Additions
A. α,β-Unsaturated Carbonyl Compounds
B. α,β-Unsaturated Nitriles
C. α,β-Unsaturated Sulfones
D. α,β-Unsaturated Metal Carbenes
Table 5. Intermolecular Substitution via Cross-Coupling with Aryl and Vinyl Halides
Table 6. Miscellaneous Reactions Following Epoxide Opening
A. Radical Dimerization
B. Translocation of Radical
C. Wagner‐Meerwein Rearrangement
D. Elimination of Fluoride
E. Isomerization to Allylic Alcohols
Table 7. Cyclopropanes via Epoxide Opening Followed by Cyclization/Rearrangement
Table 8. Cyclobutanes via Epoxide Opening Followed by Cyclization
Table 9. Cyclopentanes via Epoxide Opening
A. Followed by 5-exo-trig Cyclization
B. Followed by 5-exo-trig Cyclization to a Carbonyl Compound
C. 5-exo-trig Cyclization Followed by Elimination
D. 5-exo-trig Cyclization Followed by Radical Substitution
E. Followed by 5-exo-dig Cyclization to an Alkyne
Table 10. Cyclopentanones via Epoxide Opening Followed by 5-exo-dig Cyclization to a Nitrile
Table 11. Cyclohexanes
A. Via 6-exo-trig Cyclization Followed by Reduction or Elimination
B. Via 6-endo-trig Cyclization Followed by Elimination or Reduction
C. Via exo-dig Cyclization
Table 12. Cycloheptanes and Cyclooctanes via Cyclization of Epoxide-Derived Radicals
Table 13. Radical Arylation of Epoxides Initiated by Cp
2
TiCl or Analogs
Table 14. Bicyclo[3.3.0]octanes and Bicyclo[4.2.0]octanes via Tandem Reactions
Table 15. Bicyclo[4.3.0]nonanes and Bicyclo[5.3.0]decanes via Tandem Reactions
Table 16. Bicyclo[4.4.0]decanes via Tandem Reactions
Table 17. Bicyclo[5.4.0]undecanes via Tandem Reactions
Table 18. Tricyclic Products via Tandem Reactions
Table 19. Tetracyclic Products via Tandem Reactions
Table 20. Miscellaneous Tandem Reactions Initiated by Reactions of Epoxides with Cp
2
TiCl
Table 21. Reactions Initiated by Cp
2
TiCl Generated under Photoredox Catalysis
A. Reductions
B. Cyclizations
C. Intramolecular Arylations
Table 22. Cross-Coupling of Epoxides and Aryl Iodides via Ti/Ni/Photoredox Catalysis
REFERENCES
SUPPLEMENTAL REFERENCES
ACKNOWLEDGMENTS
We thank Jin Cha, Linda Press, Danielle Soenen, Landy Blasdel, and several members of the Editorial Board of Organic Reactions for many suggestions to improve the content and presentation of this article. We thank Professor Andreas Gansäuer and Dr. Sven Hildebrandt for critically reading portions of the manuscript prior to publication. Thanks are also due to Professor Alfonso Fernàndez‐Mateos for helpful discussions regarding his published and unpublished work. During the few years it took to complete this chapter, research at The Ohio State University was generously supported by the US National Institutes of Health (most recently through the grant R01 GM108762 and R35 GM139545‐01) and the US National Science Foundation (CHE‐1900141). The authors would also like to thank the Department of Chemistry at The Ohio State University for hosting Dr. William Nugent and for providing academic and computer resources.
INTRODUCTION
This chapter delineates the ring‐opening reactions of epoxides with titanium(III) reagents and catalysts. As shown in Scheme 1, these reactions proceed by a single‐electron transfer (SET) mechanism. Using epoxide 1 as an example, this process requires the initial complexation of the epoxide oxygen atom to the titanium atom (structure 2). Complex 2 then undergoes SET, resulting in the homolysis of one epoxide carbon–oxygen bond to afford a β‐titanoxy radical represented by 3.
Scheme 1
β‐Titanoxy radicals, such as 3, can undergo a variety of subsequent transformations, four of which are depicted as pathways A–D in Scheme 2. Pathway A involves trapping the carbon‐centered radical with a second equivalent of titanium(III), which ultimately results in deoxygenation of the epoxide.1 Pathway B is a reduction process, wherein the presence of a suitable donor (QH) enables a hydrogen‐atom transfer (HAT) to the radical center; hydrolysis of the resulting alkoxide releases the corresponding alcohol.1 In pathway C, intermolecular addition of radical 3 to an activated vinyl compound (exemplified here by methyl acrylate) leads to the formation of a carbon–carbon bond; trapping the new radical intermediate with a second equivalent of titanium(III) affords a titanium(IV) enolate.2 Finally, pathway D is a cyclization reaction: intramolecular addition of the radical to the pendant alkene is followed by trapping the radical with a second equivalent of titanium(III), to afford the cyclization product as a titanium(IV) organometallic species.3
Scheme 2
By far, the most common titanium(III) reagent used for the transformations in Scheme 2 is titanocene monochloride, which is represented herein as Cp2TiCl. In most cases Cp2TiCl is generated in situ by the reduction of commercial titanocene dichloride (Cp2TiCl2) with zinc or manganese metal powder.4 Prior to 1999, the reactions depicted in Scheme 2 were invariably carried out utilizing a stoichiometric amount of Cp2TiCl. A pivotal breakthrough occurred with the invention of catalytic versions of this chemistry. Gansäuer and coworkers developed a catalytic protocol using the Brønsted acid 2,4,6‐collidine hydrochloride. Protonolysis of the intermediate titanium alkoxide intermediate regenerates Cp2TiCl2, closing the catalytic cycle.5 In another approach, Oltra and coworkers reported a catalytic process using aprotic conditions that employ a combination of chlorotrimethylsilane and 2,4,6‐collidine.6
Using these catalytic protocols, the amount of the titanium complex can sometimes be reduced by two or even three orders of magnitude. Workup is greatly simplified and the utilization of Cp2TiCl chemistry in automated synthesis is now feasible.7 In some applications, a low steady‐state concentration of titanium(III) is actually beneficial in suppressing undesired side‐reactions.8 In addition to these advantages, the enantioselective ring‐opening of epoxides using chiral titanium catalysts can now be realized.
Free‐radical chemistry dates back to the observation of triphenylmethyl radical by Gomberg in 1900.9 However, many decades would pass before applications of free‐radical chemistry in organic synthesis were pursued. (After all, free‐radical processes underlie the chemistry of combustion, the very embodiment of a nonselective organic reaction). However, by the 1980s many of the underlying principles of the kinetic and thermodynamic behavior of radicals had been delineated.10 Applications of free‐radical chemistry in natural‐product synthesis, as in the synthesis of hirsutene (Scheme 3), began to emerge.11
Scheme 3
Radical‐based synthetic methods have several advantages, including functional‐group compatibility and access to unconventional reaction conditions compared with traditional ionic methods. Radical reactions provide unique reactivity patterns, including a tolerance for steric effects: they are well suited to the formation of highly congested, chiral 4° and vicinal, contiguous stereogenic centers. Cyclic structures can often be assembled with predictable control of the configuration at the newly created stereocenters; however, some limitations remain with this approach. Many early radical‐based methods involve termination by HAT from reagents such as tributyltin hydride. When HAT results in the formation of an sp3 carbon, the subsequent functionalization of this center can be challenging. Moreover, the nature of the radical‐chain reaction dictates that there are limited opportunities for reagent control, and selectivity is most often a consequence of substrate control.
The titanium(III)‐mediated ring‐opening of epoxides provides a method for addressing the issue of reagent control. The intermediacy of a titanium(III)–epoxide complex such as 2 means that the regio‐ and stereoselectivity of epoxide opening via SET can be influenced by the ligands on titanium. Moreover, the titanium atom remains bound to the oxygen atom in 3 after carbon–oxygen bond homolysis and can thus influence the course of subsequent chemical events as depicted in Scheme 2.
As is often the case with novel chemistry, the discovery of the reduction of epoxides by SET utilizing titanocene monochloride was anticipated by several “Black Swan Events”12 in the chemical literature. The reduction of propylene oxide to 2‐propanol by sodium amalgam in the presence of water (Scheme 4) was first reported in 1866 when organic chemistry was in its infancy.13 This may well represent the first report of an epoxide cleavage by SET. The first example of an epoxide ring‐opening using a transition‐metal reductant involved the use of chromium(II) salts and was reported by the renowned African‐American chemist Percy Julian in 1954.14 Kochi would later provide the key insight that reduction of epoxides by chromium(II) proceeds by discrete one‐electron steps.15 Davies and Gibson reported in 1984 that the treatment of cyclohexene oxide with titanocene monochloride affords cyclohexene in 70% yield along with the titanium oxo complex [Cp2TiCl]2O.16 Thus, the stage was set for the following developments.
Scheme 4
The four pathways shown in Scheme 2 represent the state of art in titanium(III) chemistry ca. 1994. Since then, a profusion of novel, alternative reaction pathways for β‐titanoxy radicals have been imagined and reduced to practice. These include the loss of a β‐hydrogen atom to afford an allylic alcohol,17 elimination of a suitable leaving group,18 radical substitution at oxygen,19 intramolecular arylation,20 and cross‐coupling reactions,21 to name just a few. The rapid evolution of the field is further illustrated by Scheme 5. This remarkable tandem polycyclization affords the tetracyclic product 4 as a single diastereomer.22 Neither the final radical cyclization into a nitrile acceptor nor the formation of a strained four‐membered ring could have been anticipated based on the understanding of radical reactions in 1994.
Scheme 5
As a result of such advances, titanium(III)‐mediated epoxide opening has emerged as a formidable synthetic tool.23,24 As of this writing (October 2021) these reactions have been applied in the synthesis of over 170 natural products, drugs, and advanced intermediates. Several review articles have been devoted to these synthetic applications.25–27 Moreover, it has been suggested that Cp2TiCl represents a nearly ideal reagent for “green chemistry,”28 which should further increase interest in using these methods for large‐scale synthetic applications.
This chapter focuses on epoxide‐opening reactions involving well‐defined titanium(III) reagents, especially titanocene monochloride and its congeners. Both stoichiometric and catalytic reactions are considered. Additionally, there exist a number of ill‐defined (and in some cases unstable) formulations obtained by reduction of Cp2TiCl2 with alternative metals such as sodium amalgam,29 magnesium,30 or indium powder.31 These will be mentioned principally as a point of comparison with the chemistry of titanium(III). As noted in the “Comparison with Other Methods” section, the observed products from such reactions often are significantly different from those obtained using Cp2TiCl, and consequently, such examples are not included in the Tabular Survey.
In addition to epoxides, titanocene monochloride reacts with a variety of other functional groups. Although several of these reactions (such as those with aromatic aldehydes and organic halides) are useful, a detailed discussion of such chemistry is outside the scope of the current chapter. Such reactions will be addressed to some extent in the context of functional‐group compatibility in the “Scope and Limitations” section with the aim to familiarize the reader with these alternative reactions to avoid potential side reactions.
Several conventions are used throughout the chapter in the interest of consistency and clarity. Throughout our discussion, “normal addition” will refer to the addition of a solution of titanium(III) to a solution of an epoxide; conversely “inverse addition” implies addition of an epoxide to a titanium(III) solution. 2,4,6‐Collidine (2,4,6‐trimethylpyridine) is frequently used as a co‐reagent in reactions of Cp2TiCl. In all cases where collidine or its hydrochloride salt (abbreviated coll•HCl) appears in schemes, it specifically refers to the 2,4,6‐isomer. Finally, all the reactions described in this chapter are followed by an aqueous hydrolysis step. In the interest of clarity, the hydrolysis step is indicated in schemes only when an unusual protocol is employed or there is a didactic purpose for its inclusion. In all schemes, the symbol “R” is used exclusively to represent hydrocarbyl substituents, whereas the symbol “Q” is used where substituents may additionally contain heteroatoms (NO2, CO2Me, etc.). All available diastereomeric and enantiomeric ratios are reported in the schemes. The literature up to October 2021 is covered. Insights gleaned while writing the current chapter are described in a recent essay, which provides solutions to several longstanding “mechanistic mysteries” in titanium(III) chemistry.8
MECHANISM AND STEREOCHEMISTRY
Generation of β‐Titanoxy Radicals from Epoxides
Nature of the Reagent Titanocene monochloride is typically prepared by reduction of commercial bis(cyclopentadienyl)titanium(IV) dichloride in THF (Scheme 6). In the solid state, this titanium(III) reagent forms a bis‐chloride‐bridged dimer, 5, as confirmed by X‐ray crystallographic analysis.32,33
Scheme 6
In contrast to the solid‐state dimer 5, when dissolved in the donor solvent tetrahydrofuran, the reagent exists in an equilibrium between the monomer 6 and the “open” dimer 7. The dimerization equilibrium constant for the reaction shown in Scheme 7 is 3 × 103 M–1.34 Each titanium atom in 6 and 7 possesses a singly occupied orbital35,36 and, consistent with the availability of this unpaired electron, both 6 and 7 function as reducing agents. Dimer 7 is a slightly stronger reductant than 6, as revealed by cyclic voltametric studies.33,34
Scheme 7
Because titanocene monochloride is usually generated by in situ reduction of Cp2TiCl2 with either zinc or manganese metal (Scheme 6), other metal salts (ZnCl2 or MnCl2) are generated and will be present in solution. These salts have no effect upon the redox potential of 6 and 7 or upon the dimerization equilibrium constant.34 It is significant that, unlike in 5, both structures 6 and 7 possess a potentially vacant coordination site. In the absence of a reactant, this site is generally occupied by a molecule of THF as shown in Scheme 7. The presence of ZnCl2 or MnCl2 may actually serve a protective function, especially for (C5H4R)2TiCl analogues bearing an electron‐withdrawing substituent on the Cp ring. For instance, when these species are generated under electrochemical conditions the loss of the cyclopentadienyl ligand is the major pathway, but not when zinc or manganese is used as reductant. This is attributed to efficient chloride abstraction from [(C5H4R)2TiCl2]– by Zn2+ or Mn2+.37
When reactions with Cp2TiCl are carried out under catalytic conditions, 2,4,6‐collidine hydrochloride is often added as a mild acid, thus providing a stoichiometric source of chloride for MCl2. Although primarily intended to promote protonolysis of titanium alkoxide species,38 two additional roles have been identified for this reactant. Kinetic studies indicate that collidine hydrochloride can activate the manganese powder that is used as the stoichiometric reductant. This effect significantly reduces the induction period for some catalytic reactions.39 The presence of collidine hydrochloride also protects the catalyst from decomposition by forming the titanium(III) ate complex 8 (Figure 1). It has been proposed that the presence of collidine hydrochloride disrupts the usual monomer–dimer equilibrium by the formation of an equilibrium mixture of monomeric Cp2TiCl and 8.40
Figure 1 The original structure proposed for the adduct of Cp2TiCl with collidine hydrochloride.
Recent DFT studies have demonstrated that the energy of complex 8 is 18.4 kcal/mol lower than that of the two separate species.41 However, in the minimized structure, the second chlorine atom is not coordinated to the titanium atom. Thus, the titanium atom is accessible for epoxide binding and subsequent inner‐sphere electron transfer, so that the rate of this process is essentially unchanged from that involving uncomplexed Cp2TiCl.41
Assigning a redox potential to Cp2TiCl in THF is complicated by issues of solution speciation.34,42 The most readily oxidizable component of such solutions is Cp2TiCl2– (E° = –1.27 V versus Fc+/Fc), but this anion does not react with epoxides because it lacks an open coordination site for inner‐sphere electron‐transfer. Moreover, such solutions contain both monomeric Cp2TiCl and dimeric (Cp2
