Palladium-catalyzed oxidative cycloaddition through C-H/N-H activation: Access to benzazepines

Article abstract of DOI:10.1002/anie.201208076

Rings beget rings: Benzazepines, well-known structural design elements in medicinal chemistry, are readily prepared by a one-pot palladium-catalyzed oxidative cycloaddition of isatins with various alkynes. Copyright

Full text of DOI:10.1002/anie.201208076

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DOI: 10.1002/anie.201208076
Benzazepine Synthesis
À
À
Palladium-Catalyzed Oxidative Cycloaddition through C H/N H
Activation: Access to Benzazepines**
Lei Wang, Jiayao Huang, Shiyong Peng, Hui Liu, Xuefeng Jiang,* and Jian Wang*
The biological applications of many nitrogen-containing
heterocycles have encouraged chemists to develop efficient
methods for their synthesis.[1] Recently, chemists have turned
their attention to solving the problem of finite chemical
feedstocks coupled with the negative impact of manufacturing
structures based on nitrogen-containing heterocycles through
a similar strategy.[6] Recently, a one-pot Pd-catalyzed C H/
À
À
N H activation of alkynes was reported to facilitate isoqui-
nolinone synthesis, which includes the formation of a nitro-
gen-containing six-membered ring.[7] Although these methods
have been shown to be highly efficacious in the construction
of five- or six-membered N-heterocyclic systems, there are
very few reports on the direct synthesis of more challenging
higher-order nitrogen-containing seven-membered rings by
Pd-catalyzed oxidative cyclization (Scheme 1c).
waste.[2] In this regard, directed C H activation towards the
À
À
formation of C C and C-heteroatom bonds has received the
most attention owing to its sustainable and environmentally
benign features.[3] In particular, the Pd-catalyzed oxidative
À
À
cycloaddition of alkynes by C H/N H bond cleavage has
proven reliable in forming the corresponding nitrogen-
containing heterocycles in an atom- and step-economical
synthetic manner.[4] In recent reports, Jiao et al. described an
elegant approach to constructing indoles from anilines and
Benzazepines are well-known seven-membered nitrogen-
containing heterocycles that form the structural scaffold of
many pharmaceutical compounds; therefore, they are often
used as structural elements in medicinal chemistry.[8] For
example, Mozavaptan (Figure 1) is used as an orally effective,
À
À
alkynes using Pd-catalyzed oxidative C H/N H activation,
involving a five-membered ring cyclization (Scheme 1a).[5]
Other transition metals (such as Ru and Rh) have been
applied to assembling indole and other five-membered-ring
Scheme 1. Pd-catalyzed oxidative cycloaddition for five- to seven-mem-
Figure 1. Examples of benzazepine pharmaceuticals.
À
À
bered ring formation involving C H/N H activation. a) Indole syn-
thesis. b) Isoquinolone synthesis. c) Benzazepine synthesis.
nonpeptide arginine vasopressin V-2 receptor antagonist.[9]
Lotensin is a prescription medication licensed for treating
high blood pressure (hypertension), congestive heart failure,
and chronic renal failure by inhibiting angiotensin-converting
enzyme (ACE) in human subjects.[10] Anafranil is identified as
an antiobsessional drug that belongs to the class of pharma-
cologic agents known as tricyclic antidepressants.[11] In
addition to Anafranil, its analogues, Tienopramine and
Amezepine, are also classified as antidepressants.[12]
Preparation of such benzazepine-containing compounds
generally requires multiple synthetic steps.[13] A direct syn-
thetic method utilizing simple and readily available starting
materials, would not only enable the construction of a new
class of scaffolds, but would also facilitate late-stage modifi-
cation of existing compounds that are biologically active. To
[*] L. Wang, J. Y. Huang, S. Y. Peng, Prof. Dr. J. Wang
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
E-mail: chmwangj@nus.edu.sg
Dr. H. Liu, Prof. Dr. X. f. Jiang
Shanghai Key Laboratory of Green Chemistry and Chemical Process,
East China Normal University
3663N, Zhongshan Road, Shanghai, 200062 (China)
E-mail: xfjiang@chem.ecnu.edu.cn
[**] Financial support from Singapore through the National University
of Singapore, the Singapore Ministry of Education, and the National
Research Foundation (R14300080112, R143000443112, and NRF-
CRP7-2010-03), as well as from China through an NSFC grant
(21272075) is greatly appreciated.
À
À
address this limitation, we devised a direct C H/N H
activation method to construct a benzazepine scaffold. We
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208076.
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envisioned that this strategy could be applied to the produc-
tion of valuable benzazepine heterocycles from simple and
readily available alkynes and isatins by a direct oxidative
cycloaddition.
Our investigation began with the Pd-catalyzed oxidative
cycloaddition of isatin 1a and diphenylacetylene 2a to give
the corresponding benzazepine 3aa (Table 1). Based on
Table 1: Optimization of reaction conditions.[a]
Entry
Oxidant
Solvent
T [8C]
Yield [%][b]
1
2
3
4
5
6
7
8
–
CuI
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN/1,4-dioxane
MeCN/1,4-dioxane
MeCN/1,4-dioxane
MeCN/1,4-dioxane
MeCN/1,4-dioxane
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
80
<5
16
AgOAc
AgOAc
AgCO2CF3
AgSbF6
CuBr2
Cu(OAc)2
BQ
(NH4)2S2O8
PhI(OAc)2
oxone
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
77
38[c]
28
<5
<5
40
15
<5
24
Scheme 2. Scope of isatins. Reaction conditions: MeCN/1,4-dioxane
9
(v/v=1:1; 2 mL), 1b–o (0.2 mmol, 1.0 equiv), 2a (1.0 mmol,
5.0 equiv), Pd(OAc)2 (10 mol%), 1008C, 24 h, under N2. For the crystal
structure of compound 3da, see the Supporting Information.
10
11
12
13
14
15
16
17
<5
83
55[d]
81
After identifying the optimized conditions, we examined
the scope of isatins 1. Scheme 2 illustrates the substitution
pattern on the istains we validated. Electron-withdrawing,
electron-neutral, and electron-donating substituents at the
C5 position were tolerated and gave high yields (3ba–fa, 3ja–
ka).[14] Substrates with electron-withdrawing and/or electron-
donating substituents at the C4 or C7 positions also showed
moderate to high reactivity and afforded the corresponding
benzazepine products (Scheme 2, 3ga–ha, 3la–oa).[15]
56
18
60
[a] Reaction conditions: MeCN/1,4-dioxane (v/v=1:1; 2 mL), 1a
(0.2 mmol, 1.0 equiv), 2a (1.0 mmol, 5.0 equiv), Pd(OAc)2 (10 mol%),
AgOAc (2.0 equiv), 24 h, under N2. [b] Yield of isolated product after
purification by column chromatography. [c] 1a/2a=1:3. [d] Reaction
conducted in air. Ac=acetyl, BQ=1,4-benzoquinone, DMF=dimethyl-
formamide.
We investigated a range of different alkynes 2 that could
potentially react with 1a to study the generality of the method
for further synthetic exploitation. The reaction showed broad
substrate tolerance among internal alkynes. Electron-rich
tolanes reacted to give products in high yield (Scheme 3, 3ab–
ac, 3ae–af) while electron-deficient systems were less facile
(Scheme 3, 3ad and 3ah). Heteroaryl, ester-containing and
aliphatic alkynes were also tolerated (3ak, 3am, 3al). When
asymmetrical internal alkynes were employed, two regioisom-
ers were usually observed (3ae–ak). In the event that the
internal alkynes were highly electron-rich (2 f) or electron-
deficient (2h, 2i, 2m), the major stereoisomers formed
followed Markovnikovꢀs rule for both alkyne additions.[19]
The minor isomer formed differed from the major product
as a result of anti-Markovnikov addition in the second alkyne
addition step.[19] However, when the asymmetrical internal
alkynes were less electron-rich (2e, 2g), less electron-
deficient, or electron-neutral (2j, 2k) by virtue of their
functional groups, steric considerations became predominant
and the least sterically-encumbered product was formed as
the major stereoisomer.[19] An exception was 2-butyne, which
optimization experiments, the best results were obtained
using Pd(OAc)2 as catalyst with stoichiometric amounts of
AgOAc as the oxidant in a mixed solvent of MeCN/1,4-
dioxane (v/v = 1:1) (Scheme 2, entry 13). Under these con-
ditions, conversion was complete within 24 h at 1208C
(entry 13, 83% yield of isolated product). Variation of
oxidants (Table 1, entries 2–12), or solvents (see the detailed
solvent screening in the Supporting Information) led to
a decrease in chemical yield. The effects of temperature were
summarized in Table 1 (entries 13–17), and a similar yield was
achieved at lower temperature (entry 15, 1008C, 81%).
However, further lowering of the temperature led to slow
conversion (entries 16–17, 56% and 18%, respectively).
Moreover, product formation was also highly sensitive to
the ratio of starting materials (1a/2a) used. When the ratio of
2a was decreased from 1:5 (1a/2a, entry 3) to 1:3 (1a/2a,
entry 4), a significant decrease in yield was observed. An inert
atmosphere (N2) was found to be essential to the reaction.
When the reaction was carried out in air, only moderate yield
was obtained (entry 14, 55%).
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reaction, a combination of one phenyl ring, one carbon atom,
and one oxygen atom were eliminated from the desired
structure. Surprisingly, when a carbazole 1p reacted with
diphenylacetylene 2a, the corresponding carbazole-fused
azepine 3pa was obtained in 87% yield [Eq. (1)]. This finding
greatly enriches the diversity of our synthetic applications.
The versatility of this palladium-catalyzed oxidative
cycloaddition can be exploited in chemoselective transforma-
tions to access various frameworks with high degrees of
molecular complexity. As outlined in Scheme 5, the oxidative
Scheme 3. Scope of alkynes. Reaction conditions: MeCN/1,4-dioxane
(v/v=1:1; 2 mL), 1a (0.2 mmol, 1.0 equiv), 2b–m (1.0 mmol,
5.0 equiv), Pd(OAc)2 (10 mol%), 1008C, 24 h, under N2. [a] Ratio of
regioisomers (r.r.) was determined by NMR spectroscopy.
generated an unknown structure (not shown) under these
conditions. When the naphthalene-based isatin 1t was used,
a series of unique and unexpected pyrrole-fused 3-indolinone
structures were obtained through a currently unknown
reaction mechanism (Scheme 4). Notably, although two
molecules of diphenylacetylene 2a played a part in the
Scheme 5. Synthetic transformations of benzazepine 3aa. Reaction
conditions: a) 3aa (0.1 mmol), m-CPBA (0.2 mmol), CH2Cl2 (2 mL),
RT, 0.5 h, 85%; b) 3aa (0.1 mmol), 10% Pd/C, H2 (balloon), THF
(2 mL), RT, 0.5 h, 95%; c) 3aa (0.1 mmol), FeCl3 (0.5 mmol), TMSN3
(2 mmol), DCE (3 mL), 608C, 6 h, 57%; d) 3aa (0.1 mmol), Cu(OTf)2
(4.5 mmol), AlCl3 (5 mmol), CS2 (10 mL), RT, 24 h, 61%. For crystal
structures of compounds 4,5,7, and 8, see the Supporting Information.
DCE=1,2-dichloroethane, Tf=trifluoromethanesulfonyl, TMS=tri-
methylsilyl.
adduct 3aa was readily converted into polysubstituted
quinoline 4 through the use of 2.0 equivalents of meta-
chloroperoxybenzoic acid (m-CPBA). Polysubstituted quino-
line 4 was structurally characterized by single crystal X-ray
diffraction analysis.[16] Under standard Pd-catalyzed hydro-
genation conditions (10 mol% Pd/C, 1 atm H2), 3aa unex-
pectedly afforded dimer 5 in 0.5 h, which was structurally
confirmed by X-ray diffraction analysis.[17] C1 C2 bond
À
Scheme 4. Synthesis of pyrrole-fused 3-indolinones. [a] Ratio of
regioisomers (r.r.) was determined by NMR spectroscopy. [b] Value in
parentheses is the yield of isolated product based on recovered
starting material. For the crystal structure of compound 3ta, see the
Supporting Information.
cleavage could also be carried out in the presence of an
FeCl3 catalyst to yield 7 and 8 (55:45),[18] which bear acyl
chloride and acyl azide functional groups on the N atom,
respectively. Notably, using Cu(OTf)2 and AlCl3 to promote
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dehydrogenation, benzazepine 3aa was converted into 6,
which could potentially be used in pigments and dyes, owing
to its extended p-conjugated system.
To gain some mechanistic insight into the reaction
mechanism,
control
experiments
were
conducted
(Scheme 6). To address the importance and irreplaceability
À
À
À
À
of C7 H and N H bonds, substrates 1q (C7 Cl vs. C7 H), 1r
Scheme 6. Control experiments. Reaction conditions: MeCN/1,4-diox-
ane (v/v=1:1; 2 mL), 1q–s (0.2 mmol, 1.0 equiv), 2a (1.0 mmol,
5.0 equiv), Pd(OAc)2 (10 mol%), 1008C, 24 h, under N2.
Scheme 8. Proposed catalytic cycle.
In summary, we have developed a synthesis of benzaze-
pine heterocycles that utilizes simple and readily available
isatins and alkynes, and employs direct PdII-catalyzed oxida-
tive cycloaddition. Heterocycles are well tolerated in the
reaction, which allows access to a number of unique
molecular structures. The significance of the benzazepine
scaffold as a structural element should render this method
attractive for both synthetic and medicinal chemistry, thus
paving the way for the synthesis of other complex biologically
active heterocyclic systems.
À
À
(N Me vs. N H) and 1s (oxindole vs. isatin 1a) were tested
and the desired cycloaddition adducts were not detected
À
À
(Scheme 6). This result reveals that C7 H and N H are both
vital reaction sites. To further understand the effects of the
functional group, two comparative experiments were con-
ducted (Scheme 7). Electron-rich isatin 1 f reacted more
rapidly than electron-deficient isatin 1j (Scheme 7; 3 fa/3ja =
19:11). Similarly, electron-rich alkyne 2c is favored in this
oxidative cycloaddition as electron-deficient alkyne 2d failed
to generate the targeted product 3ad in the presence of 2c.
Instead, a new oxidative adduct, 3ax, was obtained.
Received: October 8, 2012
Revised: November 26, 2012
Published online: December 23, 2012
Keywords: benzazepine · C-H activation · N-H activation ·
.
oxidative cycloaddition · palladium
[1] a) J. A. Joule, K. Mills, Heterocyclic Chemistry, 4th ed., Black-
well, Oxford, 2000; b) T. Eicher, S. Hauptmann, The Chemistry
of Heterocycles, Wiley-VCH, Weinheim, 2003; c) A. R. Katrizky,
A. F. Pozharskii, Handbook of Heterocyclic Chemistry, 2nd ed.,
Pergamon, Amsterdam, 2000.
[2] a) C.-J. Li, B. M. Trost, Proc. Natl. Acad. Sci. USA 2008, 105,
13197; b) B. M. Trost, Science 1991, 254, 1471; c) B. M. Trost,
Angew. Chem. 1995, 107, 285; Angew. Chem. Int. Ed. Engl. 1995,
34, 259; d) P. T. Anastas, J. C. Warner, Green Chemistry Theory
and Practice, Oxford University Press, New York, 1998.
À
[3] For selected recent reviews on C H functionalization, see: a) C.
Scheme 7. Competition experiments.
Zhu, R. Wang, J. R. Falck, Chem. Asian J. 2012, 7, 1502; b) G.
Song, F. Wang, X. Li, Chem. Soc. Rev. 2012, 41, 3651; c) J. F.
Hartwig, Chem. Soc. Rev. 2011, 40, 1992; d) J. Wencel-Delord, T.
Drçge, F. Liu, F. Glorius, Chem. Soc. Rev. 2011, 40, 4740; e) L.
Ackermann, Chem. Rev. 2011, 111, 1315; f) R. Jazzar, J. Hitce, A.
Renaudat, J. Sofack-Kreutzer, O. Baudoin, Chem. Eur. J. 2010,
16, 2654; g) T. Satoh, M. Miura, Chem. Eur. J. 2010, 16, 11212;
h) D. A. Colby, R. G. Bergman, J. A. Ellman, Chem. Rev. 2010,
À
On the basis of known transition-metal-catalyzed C H
activation/oxidative cycloaddition reactions, we propose
a mechanism to account for product formation (Scheme 8).
Formation of benzazepine 3aa presumably commences with
the palladation of isatin 1a to yield the palladium intermedi-
ate 9 (Scheme 8). This is followed by syn-addition of
intermediate 9 to diphenylacetylene (2a) to generate vinyl-
palladium intermediate 10. Insertion of another 2a affords
butadienylpalladium intermediate 11. Finally, intramolecular
palladation of 11 leads to the formation of palladabenzocy-
cloheptatriene 12, which can subsequently undergo reductive
elimination to yield benzazepine 3aa.
À
110, 624; i) “C H Activation”: J.-Q. Yu, Z.-J. Shi, Topics in
Current Chemistry, Vol. 292, Springer, Berlin, 2010; j) C.-J. Li,
Acc. Chem. Res. 2009, 42, 335; k) I. V. Seregin, V. Gevorgyan,
Chem. Soc. Rev. 2007, 36, 1173; l) K. R. Campos, Chem. Soc. Rev.
2007, 36, 1069.
À
[4] For selected recent reviews and examples of Pd-catalyzed C H
activations, see: a) O. Daugulis, H.-Q. Do, D. Shabashov, Acc.
Chem. Res. 2009, 42, 1074; b) X. Chen, K. M. Engle, D.-H. Wang,
Angew. Chem. Int. Ed. 2013, 52, 1768 –1772
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.
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Communications
J.-Q. Yu, Angew. Chem. 2009, 121, 5196; Angew. Chem. Int. Ed.
2009, 48, 5094; c) K. MuÇiz, Angew. Chem. 2009, 121, 9576;
Angew. Chem. Int. Ed. 2009, 48, 9412; d) L.-M. Xu, B.-J. Li, Z.
Yang, Z.-J. Shi, Chem. Soc. Rev. 2010, 39, 712; e) P. Sehnal,
R. J. K. Taylor, I. J. S. Fairlamb, Chem. Rev. 2010, 110, 824;
f) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147; g) C. S.
Yeung, V. M. Dong, Chem. Rev. 2011, 111, 1215; h) R. Shintani,
H. Otomo, Haruka, K. Ota, T. Hayashi, J. Am. Chem. Soc. 2012,
134, 7305.
[9] a) G. Decaux, A. Soupart, G. Vassart, Lancet 2008, 371, 1624;
b) A. K. Ghose, T. Herbertz, H. Torsten, L. Robert, B. D.
Dorsey, J. P. Mallamo, ACS Chem. Neurosci. 2012, 3, 50; c) G. L.
Robertson, Nat. Rev. Endocrinol. 2011, 7, 151.
[10] a) F. Hou, X. Zhang, G. Zhang, D. Xie, P. Chen, W. Zhang, J.
Jiang, M. Liang, G. Wang, Z. Liu, R. Geng, N. Engl. J. Med. 2006,
354, 131; b) R. N. Nicolas, R. Hernandez-Gallego, Cardiovasc.
Ther. 2012, 30, 193.
[11] a) P. K. Gillman, Br. J. Pharmacol. 2007, 151, 737; b) S. Stahl,
Stahlꢀs Essential Psychopharmacology: The Prescriberꢀs Guide,
Cambridge University Press, New York, 2009; c) U. Albert, E.
Aguglia, G. Maina, F. Bogetto, J. Clin. Psychiatry 2002, 63, 1004.
[12] C. R. Ganellin, D. J. Triggle, Dictionary of Pharmacological
Agents, Chapman & Hall/CRC, London, 1996.
[13] For selected examples and reviews, see: a) Y. Onozaki, N.
Kurono, H. Senboku, M. Tokuda, K. Orito, J. Org. Chem. 2009,
74, 5486; b) S. W. Gerritz, J. S. Smith, S. S. Nanthakumar, D. E.
Uehling, J. E. Cobb, Org. Lett. 2000, 2, 4099; c) V. Kouznetsov,
A. Palma, C. Ewert, Curr. Org. Chem. 2001, 5, 519.
[14] CCDC 849053 (3da) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[15] CCDC 857373 (3ta) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[16] CCDC 903588 (4) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[17] CCDC 894859 (5) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[5] Z.-Z. Shi, C. Zhang, S. Li, D.-L. Pan, S.-T. Ding, Y.-X. Cui, N.
Jiao, Angew. Chem. 2009, 121, 4642; Angew. Chem. Int. Ed. 2009,
48, 4572.
[6] For selected reviews and examples of Rh- or Ru-catalyzed
reactions, see: a) N. Guimond, C. Gouliaras, K. Fagnou, J. Am.
Chem. Soc. 2010, 132, 6908; b) N. Guimond, K. Fagnou, J. Am.
Chem. Soc. 2009, 131, 12050; c) N. Umeda, H. Tsurugi, T. Satoh,
M. Miura, Angew. Chem. 2008, 120, 4083; Angew. Chem. Int. Ed.
2008, 47, 4019; d) L. Li, W. W. Brennessel, W. D. Jones, J. Am.
Chem. Soc. 2008, 130, 12414; e) P. A. Evans, P. A. Inglesby, J.
Am. Chem. Soc. 2008, 130, 12838; f) Y.-F. Wang, K. K. Toh, J.-Y.
Lee, S. Chiba, Angew. Chem. 2011, 123, 6049; Angew. Chem. Int.
Ed. 2011, 50, 5927; g) D. R. Stuart, P. Alsabeh, M. Kuhn, K.
Fagnou, J. Am. Chem. Soc. 2010, 132, 18326; h) R. K. Chinna-
golla, M. Jeganmohan, Chem. Commun. 2012, 48, 2030; i) L.
Ackermann, L. Wang, A. V. Lygin, Chem. Sci. 2012, 3, 177; j) L.
Ackermann, A. V. Lygin, Org. Lett. 2012, 14, 764; k) K.
Parthasarathy, N. Senthilkumar, J. Jayakumar, C.-H. Cheng,
Org. Lett. 2012, 14, 3478; l) L. Ackermann, A. V. Lygin, N.
Hofmann, Angew. Chem. 2011, 123, 6503; Angew. Chem. Int. Ed.
2011, 50, 6379; m) B. Li, H. Feng, S. Xu, B. Wang, Chem. Eur. J.
2011, 17, 12573; n) L. Ackermann, S. Fenner, Org. Lett. 2011, 13,
6548; o) E. Ferrer Flegeau, C. Bruneau, P. H. Dixneuf, A.
Jutand, J. Am. Chem. Soc. 2011, 133, 10161.
[7] For a recent example of Pd-catalyzed isoquinolinone synthesis,
see: a) H.-B. Zhong, D. Yang, S.-Q. Wang, J.-H. Huang, Chem.
Commun. 2012, 48, 3236; for a selected recent example of Rh-
catalyzed isoquinolinone synthesis, see: T. K. Hyster, T. Rovis, J.
Am. Chem. Soc. 2010, 132, 10565.
[18] CCDC 894859 (7 and 8) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[8] For selected books, see: a) M. Shamma, The Alkaloids, Aca-
demic Press, New York, 1972; b) B. Renfroe, C. Harrington,
G. R. Proctor, Heterocyclic Compounds: Azepines, Wiley &
Interscience, New York, 1984.
[19] To determine the regioselectivity of asymmetric internal alkynes,
the regioisomers of compound 3ag and 3ah were established by
X-ray crystal analysis. For details, see the Supporting Informa-
tion.
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