Carbamate-Catalyzed Enantioselective Bromolactamization

Article abstract of DOI:10.1002/anie.201504724

A highly facile, efficient, and enantioselective bromolactamization of olefinic amides was effected by a carbamate catalyst and ethanol additive. The amide substrates underwent N-cyclization predominantly to give a diverse range of enantioenriched bromolactam products containing up to two stereogenic centers.

Full text of DOI:10.1002/anie.201504724

.
Angewandte
Communications
International Edition: DOI: 10.1002/anie.201504724
German Edition: DOI: 10.1002/ange.201504724
Asymmetric Catalysis
Carbamate-Catalyzed Enantioselective Bromolactamization
Yi An Cheng, Wesley Zongrong Yu, and Ying-Yeung Yeung*
Abstract: A highly facile, efficient, and enantioselective
bromolactamization of olefinic amides was effected by a car-
bamate catalyst and ethanol additive. The amide substrates
underwent N-cyclization predominantly to give a diverse range
of enantioenriched bromolactam products containing up to
two stereogenic centers.
when the electron-withdrawing 3,5-bis(trifluoromethyl) sub-
stituent was introduced into the N-Ar ring. The thiocarba-
mate 3c gave lower enantioselectivity than 3a, while carba-
mate 3d delivered an enhanced 56% ee (entries 3 and 4). It is
noteworthy that the carbamate catalysts 3b and 3d gave
higher enantioselectivities than their corresponding thiocar-
bamate catalysts 3a and 3c. This discovery stands in stark
contrast to our earlier studies on halolactonization reactions,
where the thiocarbamate catalysts gave much higher enan-
tioselectivities than the corresponding carbamates, thus
suggesting that the reaction mechanism of carbamate catal-
ysis in halocyclization might be different from that of
thiocarbamate.[10] The enantioselectivity did not improve
further when either the urea catalyst 3e, or thiourea 3 f, or
carbamate catalysts with other cinchona alkaloid scaffolds
C
atalytic enantioselective halocyclization of olefinic sub-
strates has been the subject of intensive research interest in
recent years.[1] Elegant halocyclization strategies which span
various classes of reactions have been documented, including
halolactonizations,[2] haloaminocyclizations,[3] and haloether-
ifications.[4] In contrast, a feasible catalytic and enantioselec-
tive halolactamization protocol (i.e. from olefinic amide to
lactam) has proven highly elusive to date.[5] A major hurdle
lies in the tendency of olefinic amides to undergo O-
cyclization, instead to N-cyclization to give the lactam;
a consequence of the higher electronegativity of O compared
to that of N.[6] Indeed, a handful of enantioselective halo-O-
cyclizations of olefinic amides giving oxazine-type products
have been reported.[7] Attempts to develop a successful
catalytic enantioselective halolactamization protocol thus has
to overcome the dual challenge of: 1) overriding the inherent
preference for O-cyclization of the amide substrates to give
lactams; 2) attaining a suitable catalytic protocol which offers
a useful level of enantioselectivity for the lactam products.
Herein, we are pleased to report a highly enantioselective
bromolactamization promoted by a combination of carba-
mate catalyst and ethanol additive. This report also represents
the first case of an asymmetric reaction catalyzed effectively
by a carbamate organocatalyst.[8]
Table 1: Bromolactamization of 1a using catalysts with various chiral
scaffolds.[a]
At the initial stage of the investigation, we targeted the
cyclization of the olefinic amide 1a, using N-bromosuccin-
imide (NBS) as the halogen source in CH2Cl2 at À788C
(Table 1). The resultant N-cyclized product 2a contains
a tricyclic amide core which is found in a wide variety of
pharmaceutically important molecules.[9] 4-Methoxyphenyl
thiocarbamate (3a), a well-studied catalyst for asymmetric
bromocyclization,[10] gave a modest 33% ee (entry 1). The
enantioselectivity improved when the catalyst was switched to
the carbamate 3b, the oxygen analogue of 3a (entry 2).
Interestingly, the enantioselectivities were markedly altered
Entry
Catalyst
Yield [%][b]
ee [%]
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3 f
3g
3h
3i
90
57
89
88
71
84
89
77
79
33
41
19
56
[*] Dr. Y. A. Cheng, W. Z. Yu, Prof. Dr. Y.-Y. Yeung
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
E-mail: chmyyy@nus.edu.sg
À14
À22
43
À22
Prof. Dr. Y.-Y. Yeung
Department of Chemistry, The Chinese University of Hong Kong
Shatin, Hong Kong (China)
À47
[a] Reactions were carried out with olefinic amide 1a (0.1 mmol), catalyst
(0.0033 mmol), NBS (0.24 mmol) in CH2Cl2 (2.0 mL). [b] Yield of
isolated 2a. Ts=4-toluenesulfonyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201504724.
12102
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 12102 –12106

Angewandte
Chemie
(3g–i) were used (entries 5–9). Carbamate catalysts with
other N-Ar substituents generally also led to lower enantio-
selectivities.[11]
Investigation into other reaction parameters followed and
Table 3 summarizes the results obtained. Analytical reagent
grade (AR) CHCl3 based solvent blends delivered enhance-
ments to the enantioselectivity (entries 2 and 3). In an
unexpected twist, replacing AR grade CHCl3 with high-
performance liquid chromatography (HPLC) grade CHCl3
resulted in deterioration in both the reaction rate and the
ee value (entry 4). After extensive investigations, we sus-
pected that the key to this difference might lie in the EtOH
additive (0.6–1.0% v/v) present in AR grade CHCl3. To
confirm our suspicion, the EtOH additive was removed by
filtering the AR grade CHCl3 through a column of activated
molecular sieves or alumina, and the rate and enantioselec-
tivity were found to be low (entries 5 and 6). The yield and
ee value were restored when 1.0% v/v EtOH was added to the
HPLC grade CHCl3 (entry 7), thus indicating the crucial role
played by the EtOH additive in mediating the reaction.[12]
It is worth noting that the carbamate catalyst displayed
high potency in controlling the N-/O-selectivity when com-
pared to several common catalysts used in halogenation
reactions. Intriguingly, 3d gave exclusively the N-cyclized
product 2a (Table 2, entry 1). In sharp contrast, the N-/O-
selectivity was much poorer when other common catalysts for
bromocyclization such as Lewis-basic PPh3 and PPh3S were
used (entries 2 and 3). When the Lewis-acidic catalyst BF3-
THF was employed, the O-cyclized product 2a’ was formed
exclusively (entry 4).
Table 2: Reaction of 1a with NBS using various catalysts.[a]
Table 4: Substrate scope of bromolactamization of 1 catalyzed by 3d.[a]
Entry
Catalyst
2a/2a’[b]
1
2
3
4
3d
PPh3
Ph3PS
BF3-THF
100:0
60:40
60:40
0:100
[a] Reactions were carried out with olefinic amide 1a (0.1 mmol), catalyst
(0.0033 mmol), NBS (0.24 mmol) in CH2Cl2 (2.0 mL). [b] Determined by
1H NMR analysis of the crude reaction mixture upon completion of
reaction. THF=tetrahydrofuran.
Table 3: Optimization of the 3d-catalyzed bromolactamization reac-
tion.[a]
Entry
2
R1
t [h]
Yield [%]
ee [%]
1
2
2a
2b
ent-2b
2c
H
Ph
Ph
18
18
18
22
20
45
42
22
18
19
48
18
18
18
42
18
19
19
18
94
89
80
79
86
62
82
92
93
92
81
95
98
89
72
83
80
79
96
68
94
À92
91
93
90
86
90
90
95
97
93
96
91
86
90
94
94
97
3[b]
4
3-MeOC6H4
4-MeC6H4
4-vinyl-C6H4
4-CF3C6H4
4-ClC6H4
Me
iPr
tBu
cyclopentyl
cyclohexyl
–
–
–
–
–
Entry
R1
Solvent
Yield [%]
ee [%]
5
6
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
1
H
H
H
H
H
H
H
H
CH2Cl2
AR CHCl3
88
91
92
8
14
11
89
93
44
74
89
56
63
68
46
50
50
68
70
85
86
94
7[c]
8[c]
9
2[b]
3
AR CHCl3/PhMe (3:1)
HPLC CHCl3/PhMe (3:1)
AR CHCl3/PhMe (3:1)
AR CHCl3/PhMe (3:1)
HPLC CHCl3/PhMe (3:1)
AR CHCl3/PhMe (1:1)
AR CHCl3/PhMe (1:1)
AR CHCl3/PhMe (1:1)
AR CHCl3/PhMe (2:1)
4
5[c]
6[d]
7[e]
8
10
11
12
13
14
15[d]
16
17
18
19
9[f]
10[f,g]
11[g,h]
Ph
Ph
Ph
[a] Reactions were carried out with olefinic amide 1 (0.1 mmol), catalyst
(0.0033 mmol), NBS (0.24 mmol) in solvent (2.0 mL). [b] The reaction
was conducted at À628C. [c] The CHCl3 was treated with microwave-
dried 5 Š molecular sieves before use. [d] The CHCl3 was passed through
activated neutral Al2O3 before use. [e] 15 mL EtOH added. [f] Reaction
time was 42 h. [g] 10 mol% 3d was used. [h] Total amount of solvent was
3 mL and reaction time was 18 h. AR=analytical reagent grade,
HPLC=high-performance liquid chromatography grade.
cyclohexyl
[a] Reactions were carried out with olefinic amide 2 (0.1 mmol), 3d
(0.01 mmol), NBS (0.24 mmol) in 2:1 AR grade CHCl3/PhMe (3.0 mL).
[b] 3i (0.01 mmol) was used as the catalyst. [c] The reaction was
conducted at À508C. [d] 1.2 mmol NBS was used. Ns=4-nitrobenze-
nesulfonyl.
Angew. Chem. Int. Ed. 2015, 54, 12102 –12106
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 12103

.
Angewandte
Communications
This catalytic protocol could also be applied to the bulkier
phenyl-substituted substrate 1b after fine-tuning the reaction
conditions, and delivered the product 2b in 89% yield and
94% ee (entries 8–11).
The scope of the bromolactamization was probed and the
product diversity is laid out in Table 4. Notably, a switch of
catalyst from 3d to its pseudoenantiomeric form 3i furnished
the antipode of bromolactam 2b in excellent enantioselec-
tivity of 92% ee (entry 3). The reaction proceeded smoothly
with electron-rich aryl substituents (entries 4–6). The high
ee value was maintained even with the inclusion of a vinyl
substituent (entry 6). In contrast, substrates with electron-
deficient aryl substituents required a relatively higher tem-
perature of À508C to attain an appreciable reaction rate,
albeit with modestly lower enantioselectivities (entries 7 and
8). Alkyl substituents were exceptionally well-tolerated
(entries 9–13). Good enantioselectivities were also obtained
for substrates with indole ring substituents (entries 14–17).
When the Ts group at the amide functionality was replaced
with a 4-nitrobenzenesulfonyl (Ns) group (i.e. substrates 1q
and 1r), the corresponding lactam products 2q and 2r could
still be obtained with high ee values (entries 18 and 19).
In addition to the 1,1-disubstituted alkene substrates in
Table 4, the current protocol could be readily adapted to the
bromolactamization of trans-1,2-disubstituted olefinic amides
with little or no change to the reaction conditions (Table 5).
The reaction resulted in the formation of bromolactams with
two stereogenic centers with excellent diastereoselectivities
(entries 1–4). The absolute configurations of 2h and 5b
(Figure 1) were determined by X-ray crystallographic stud-
ies[13] and the stereochemistry of all the other bromolactams 2
and 5 were assigned by analogy. Following the success of the
reaction with various disubstituted olefins, we attempted to
cyclize the more sterically hindered, trisubstituted olefinic
amide 6 as an added challenge (Scheme 1). To our delight, the
lactam 7 was furnished in 91% ee under the optimized
reaction conditions.
Figure 1. Molecular structure of compounds 2h (left) and 5b (right) in
the solid state. Thermal ellipsoids are shown at 50% probability.
Scheme 1. Bromolactamization of the trisubstituted olefinic amide 6.
The usefulness of the current protocol in medicinal
chemistry applications is illustrated in Scheme 2. Cyclization
Table 5: Bromolactamization of trans-1,2-disubstituted olefinic amide
4.[a]
Entry
5
R1
Yield [%]
ee [%]
1
2
5a
5b
5c
5d
Me
Et
Pr
72
97
88
90
91
92
90
88
Scheme 2. Direct synthesis of pharmaceutically important lactam core
2s and subsequent transformations. DMF=N,N-dimethylformamide.
3[b]
4[b]
C5H11
of 1s gave 2s, which has a tricyclic lactam core that commonly
occurs in bioactive molecules, such as the highly potent
histamine H3 receptor agonist 8[9b] and the H3 receptor
modulator 9.[9f] 2s contains two Br handles, each of which
[a] Reactions were carried out with olefinic amide 4 (0.1 mmol), 3d
(0.01 mmol), NBS (0.24 mmol) in 2:1 AR grade CHCl3/PhMe (3.0 mL).
[b] 3:1 AR grade CHCl3/PhMe (3.0 mL) was used as the solvent
combination.
12104 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 12102 –12106

Angewandte
Chemie
could be selectively modified. For instance, palladium-cata-
lyzed coupling reaction of 2s could functionalize the C3
position of the indole moiety to give 10. In contrast,
substitution with azide on the methylene bromide of 2s
yielded 11, in which the alkyl azide handle is a common click
partner for bioimaging uses.[14] These reactions are thus
valuable in the rapid synthesis of a large diversity of bioactive
molecule analogues for the drug screening process.
To obtain insight into the reaction mechanism, a 1H NMR
study was performed on a 1:1 mixture of 3d and NBS. Close
examination of the NMR spectrum revealed a distinctly new
species.[11] When a sample of this mixture was subjected to
high-resolution mass spectrometry (HRMS), the mass of the
new species was found to be equal to that of brominated 3d.
In addition, when subjecting the new species in aqueous
Na2SO3, 3d could be regenerated quantitatively, thus suggest-
ing that the Br in the new species is electrophilic in
bromination reaction. As 3d contains a relatively acidic N-
H proton, we speculated that one possibility is that the N-H
might exchange with NBS to form the N-Br species, that is,
3d-Br (Scheme 3).[15,16]
To gain a better understanding on the reaction, 3d was
mixed with the stronger brominating agent 2,4,4,6-tetra-
bromo-2,5-cyclohexadienone (TBCO) (1:1),[17] and the same
mass value corresponding to the new species could also be
detected by HRMS. In a further experiment, we subjected 1i
to a stoichiometric amount of 3d-Br which was generated
in situ from a 1:1 mixture of 3d and TBCO (Scheme 3). After
19 h, 2i was formed with the same ee value as that of the
reaction performed using a catalytic amount of 3d and
stoichiometric halogen source NBS (Table 4, entry 10).[11]
Based on these observations, we suspected that 3d-Br
could be the active brominating species in the reaction. This
process is different from the mechanistic proposals in our
previous studies on thiocarbamates, where the Lewis-basic
sulfur could interact with the Br on NBS during the process of
the enantioselective bromocyclization reactions.[10] Although
the establishment of a very detailed mechanistic picture
demands further experimentation, we attempted to construct
a preliminary proposal of the catalytic cycle by piecing our
Scheme 4. A plausible reaction mechanism.
current data together. This mechanistic proposal is depicted
in Scheme 4. At this stage, we believe that the first step might
involve a halogen exchange between 3d and NBS to give the
chiral brominating species 3d-Br. The amide in 1, which
contains an acidic proton, as a result of the electron-with-
drawing Ts group, might then hydrogen bond to the
quinuclidine nitrogen atom of 3d-Br to give species A.[16]
We speculated that the OH in the imidic acid (tautomer of
amide) of the substrate 1 might be a better hydrogen-bond
donor to the hard base quinuclidine,[6] thus allowing the softer
imidic nitrogen base to attack the bromonium and yield the
lactam product 2. The role of ethanol, however, remains
unclear and will be the subject of further investigations.[12]
In summary, we have developed an enantioselective
bromolactamization using a carbamate as the catalyst, thus
resulting in the formation of lactams with up to two
stereogenic centers. The reaction rate and enantioselectivity
was promoted by EtOH additive. The antipode of the lactam
product could be obtained by a simple switch to the
pseudoenantiomeric form of the catalyst. To the best of our
knowledge, this represents the first case of organocatalytic
enantioselective bromolactamization that proceeds with N-
cyclization, thus leading to the formation of highly enan-
tioenriched bromolactams.[18] This report also details the first
effective use of a carbamate as an organocatalyst. Intensive
studies on the mechanism of the carbamate catalysis are
underway.
Acknowledgements
We thank the NEA-ETRP (grant no. 143-000-547-490),
A*STAR-Public Sector Funding (grant no. 143-000-536-
305), GSK-EDB (grant no. 143-000-564-592), and National
University of Singapore Tier 1 Funding (grant no. 143-000-
605-112) for financial support. We are also grateful for
scholarships to Y.A.C. (NGS Scholarship) and W.Z.Y. (NUS
Research Scholarship).
Scheme 3. Bromine exchange between 3d and NBS.
Angew. Chem. Int. Ed. 2015, 54, 12102 –12106
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 12105

.
Angewandte
Communications
P. M. Pihko), Wiley-VCH, Weinheim, 2009, chap. 6; d) Y. Xi, X.
Shi, Chem. Commun. 2013, 49, 8583.
Keywords: asymmetric catalysis · cyclizations · lactams ·
organocatalysis · reaction mechanisms
[9] a) Z. Xiong, D. A. Gao, D. A. Cogan, D. R. Goldberg, M.-H.
Hao, N. Moss, E. Pack, C. Pargellis, D. Skow, T. Trieselmann, B.
Werneburg, A. White, Bioorg. Med. Chem. Lett. 2008, 18, 1994;
b) H. G. F. Richter, C. Freichel, J. Huwyler, T. Nakagawa, M.
Nettekoven, J.-M. Plancher, S. O. Roche, F. Schuler, S. Taylor, C.
Ullmer, R. Wiegand, Bioorg. Med. Chem. Lett. 2010, 20, 5713;
c) R. R. Forseth, E. M. Fox, D. W. Chung, B. J. Howlett, N. P.
Keller, F. C. Schroeder, J. Am. Chem. Soc. 2011, 133, 9678; d) R.
Sekonyela, J. M. Palmer, J.-W. Bok, S. Jain, E. Berthier, R.
Forseth, F. Schroeder, N. P. Keller, Plos One 2013, 8, e62591;
e) D. Goldberg, A. Abeywardane, C. Miller, T. Morwick, M.
Netherton, R. Snow, J. Wang, J.-P. Wu, Z. Xiong, US Pat. Appl.
US 2006/0276453A1, 2006; f) M, Nettekoven, J.-M. Plancher,
H. Richter, O. Roche, S. Taylor, PCT Int. Appl. WO 2007/
065820A1, 2007.
How to cite: Angew. Chem. Int. Ed. 2015, 54, 12102–12106
Angew. Chem. 2015, 127, 12270–12274
[1] For reviews on halocyclization, see: a) A. Castellanos, S. P.
Fletcher, Chem. Eur. J. 2011, 17, 5766; b) C. K. Tan, L. Zhou, Y.-
Y. Yeung, Synlett 2011, 1335; c) U. Hennecke, Chem. Asian J.
2012, 7, 456; d) S. E. Denmark, W. E. Kuester, M. T. Burk,
Angew. Chem. Int. Ed. 2012, 51, 10938; Angew. Chem. 2012, 124,
11098; e) S. R. Chemler, M. T. Bovino, ACS Catal. 2013, 3, 1076;
f) K. Murai, H. Fujioka, Heterocycles 2013, 87, 763; g) C. K. Tan,
Y.-Y. Yeung, Chem. Commun. 2013, 49, 7985; h) C. K. Tan, W. Z.
Yu, Y.-Y. Yeung, Chirality 2014, 26, 328; i) Y. A. Cheng, W. Z.
Yu, Y.-Y. Yeung, Org. Biomol. Chem. 2014, 12, 2333.
[10] a) See Ref. [4b]; b) Y. Zhao, X. Jiang, Y.-Y. Yeung, Angew.
Chem. Int. Ed. 2013, 52, 8597; Angew. Chem. 2013, 125, 8759;
c) L. Zhou, D. W. Tay, J. Chen, G. Y. C. Leung, Y.-Y. Yeung,
Chem. Commun. 2013, 49, 4412; d) X. Jiang, C. K. Tan, L. Zhou,
Y.-Y. Yeung, Angew. Chem. Int. Ed. 2012, 51, 7771; Angew.
Chem. 2012, 124, 7891; e) C. K. Tan, C. Le, Y.-Y. Yeung, Chem.
Commun. 2012, 48, 5793; f) L. Zhou, J. Chen, C. K. Tan, Y.-Y.
Yeung, J. Am. Chem. Soc. 2011, 133, 9164; g) C. K. Tan, L. Zhou,
Y.-Y. Yeung, Org. Lett. 2011, 13, 2738; h) L. Zhou, C. K. Tan, X.
Jiang, F. Chen, Y.-Y. Yeung, J. Am. Chem. Soc. 2010, 132, 15474.
[11] The details appear in the Supporting Information.
[12] The ee value of the bromolactamization product was highly
dependent on the size of the alcohol additive, and much lower
conversion was observed when a sterically bulky alcohol was
used. In addition, the use of Et2O in place of EtOH as the
additive led to a significant reduction in ee value, thus suggesting
that the hydroxy group of EtOH might play a crucial role in the
reaction. Thus, we speculate that the ethanol might involve in the
enantiodetermining step with the involvement of hydrogen
bonding. For details, see the Supporting Information.
[13] CCDC 1063550 (2h) and 1063551 (5b) contain the supplemen-
tary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre.
[14] J. D. Crowley, D. A. McMorran, Top. Heterocycl. Chem. 2012, 28,
31.
[15] S. M. Ahmad, D. C. Braddock, G. Cansell, S. A. Hermitage, J. M.
Redmonda, A. J. P. White, Tetrahedron Lett. 2007, 48, 5948.
[16] Since carbamate can undergo tautomerization, we cannot rule
out the possibility that 3d-Br might exist as the form of O-Br
species instead of N-Br species.
[2] For selected recent efforts on the development of catalytic
enantioselective halolactonization, see: a) K. Murai, J. Naka-
jima, A. Nakamura, N. Hyogo, H. Fujioka, Chem. Asian J. 2014,
9, 3511; b) K. Murai, N. Shimizu, H. Fujioka, Chem. Commun.
2014, 50, 12530; c) H. Nakatsuji, Y. Sawamura, A. Sakakura, K.
Ishihara, Angew. Chem. Int. Ed. 2014, 53, 6974; Angew. Chem.
2014, 126, 7094; d) M. Wilking, C. G. Daniliuc, U. Hennecke,
Synlett 2014, 1701; e) T. Arai, N. Sugiyama, H. Masu, S. Kado, S.
Yabe, M. Yamanaka, Chem. Commun. 2014, 50, 8287; f) X. Han,
C. Dong, H.-B. Zhou, Adv. Synth. Catal. 2014, 356, 1275.
[3] For selected recent efforts on the development of catalytic
enantioselective haloaminocyclization, see: a) C. B. Tripathi, S.
Murkherjee, Org. Lett. 2014, 16, 3368; b) Y. Cai, P. Zhou, X. Liu,
J. Zhao, L. Lin, X. Feng, Chem. Eur. J. 2015, 21, 6386; c) W. Xie,
G. Jiang, H. Liu, J. Hu, X. Pan, H. Zhang, X. Wan, Y. Lai, D. Ma,
Angew. Chem. Int. Ed. 2013, 52, 12924; Angew. Chem. 2013, 125,
13162.
[4] For selected recent efforts on the development of catalytic
enantioselective haloetherification, see: a) C. H. Müller, C.
Rçsner, U. Hennecke, Chem. Asian J. 2014, 9, 2162; b) D. W.
Tay, G. Y. C. Leung, Y.-Y. Yeung, Angew. Chem. Int. Ed. 2014,
53, 5161; Angew. Chem. 2014, 126, 5261; c) Z. Ke, C. K. Tan, F.
Chen, Y.-Y. Yeung, J. Am. Chem. Soc. 2014, 136, 5627.
[5] For elegant reports of enantioselective bromo-N-cyclization of
olefinic carbamate substrates using a metal catalysts, see: a) D.
Huang, X. Liu, L. Li, Y. Cai, W. Liu, Y. Shi, J. Am. Chem. Soc.
2013, 135, 8101; b) H. Huang, H. Pan, Y. Cai, M. Liu, H. Tian, Y.
Shi, Org. Biomol. Chem. 2015, 13, 3566.
[6] a) G. Cardillo, M. Orena, Tetrahedron 1990, 46, 3321; b) K. E.
Harding, T. H. Tiner in Comprehensive Organic Synthesis, Vol. 4
(Ed.: B. M. Trost), Pergamon, New York, 1991, p. 363.
[7] a) A. Jaganathan, A. Garzan, D. C. Whitehead, R. J. Staples, B.
Borhan, Angew. Chem. Int. Ed. 2011, 50, 2593; Angew. Chem.
2011, 123, 2641; b) A. Jaganathan, R. J. Staples, B. Borhan, J.
Am. Chem. Soc. 2013, 135, 14806; c) Q. Yin, S.-L. You, Org. Lett.
2014, 16, 2426; Q. Yin, S.-L. You, Org. Lett. 2013, 15, 4266; d) Y.-
M. Wang, J. Wu, C. Hoong, V. Rauniyar, F. D. Toste, J. Am.
Chem. Soc. 2012, 134, 12928; e) V. Rauniyar, A. D. Lackner,
G. L. Hamilton, F. D. Toste, Science 2011, 334, 1681; f) Y.
Kawato, A. Kubota, H. Ono, H. Egami, Y. Hamashima, Org.
Lett. 2015, 17, 1244.
[17] Although the reaction rate between 3d and NBS was slow, the
reaction rate between 3d and bromine source could be greatly
enhanced by replacing NBS with TBCO.
[8] Organocatalysts such as thioureas have been widely utilized in
various asymmetric reactions. In contrast, carbamates have not
been used as catalysts in organic transformations. For references
on thiourea organocatalysts, see: a) M. S. Sigman, E. N. Jacob-
sen, J. Am. Chem. Soc. 1998, 120, 4901; b) H. B. Jang, J. W. Lee,
C. E. Song, Cinchona Alkaloids in Synthesis and Catalysis:
Ligands, Immobilization and Organocatalysis (Ed.: C. E. Song),
Wiley-VCH, Weinheim, 2009, chap. 8; c) M. Kotke, P. R.
Schreiner in Hydrogen Bonding in Organic Synthesis (Ed.:
[18] We also attempted to cyclize an olefinic amide with a benzene
core instead of an indole. The corresponding bromolactam could
be obtained in good yield and appreciable enantioselectivity. For
details, see the Supporting Information.
Received: May 25, 2015
Revised: July 5, 2015
Published online: August 28, 2015
12106 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 12102 –12106