Catalytic, enantioselective, and highly chemoselective bromocyclization of olefinic dicarbonyl compounds

Article abstract of DOI:10.1002/anie.201304107

Overriding preferences: An amine-thiocarbamate catalyst can mediate the facile, efficient, and highly enantioselective bromocyclization of olefinic 1,3-dicarbonyl compounds. In the presence of the bifunctional catalyst, the bromination occurs chemoselectively at the olefinic moiety rather than at the carbon atom in the α-position to the carbonyl units. Copyright

Full text of DOI:10.1002/anie.201304107

Angewandte
Chemie
DOI: 10.1002/anie.201304107
Asymmetric Catalysis
Catalytic, Enantioselective, and Highly Chemoselective
Bromocyclization of Olefinic Dicarbonyl Compounds**
Yi Zhao, Xiaojian Jiang, and Ying-Yeung Yeung*
Dedicated to Professor E. J. Corey on the occasion of his 85th birthday
Catalytic enantioselective halocyclization of olefinic sub-
strates attracted much attention over the past few years.[1] The
resulting enantioenriched heterocycles form the core of many
natural products and pharmaceutically important intermedi-
ates.[2] In addition, the halogen atoms can be manipulated
readily to give various functional building blocks.[3] Most of
the reported catalytic enantioselective halocyclization reac-
tions involve the use of a nitrogen- or an oxygen-containing
À
À
nucleophilic partner that has an N H or a O H moiety (e.g.,
amides or alcohols/carboxylic acids, respectively).[4] The
À
catalysts can then interact with the R H functionalities
(R = N, O) through hydrogen bonds and/or salt bridges. Such
interactions allow for an effective enantioinduction, resulting
in highly enantioselective transformations.
Scheme 1. Comparison of previous and present studies.
dicarbonyl compound 1a and N-bromosuccinimide (NBS)
were used as substrate and stoichiometric source of the
halogen atom, respectively. Reactions with simple catalysts,
including DABCO (4), DBU, and DMAP, gave significant
amounts of 2-bromo 1,3-dicarbonyl compound 2a, while the
reaction with NEt3 gave a mixture of unidentified products
(Table 1, entries 1–4).[8] In particular, when DBU was used as
the catalyst, cyclized product 3a was not obtained and 2a was
isolated in 98% yield.
During further investigations, we found that catalysts with
Lewis basic sulfur atoms preferably mediate the bromination
at the olefinic moiety instead of at the carbon atom in a-
position to the carbonyl functionalities, and thus facilitate the
cyclization process. The reaction with triphenylphosphine
sulfide (5) gave the desired product 3a with only trace
amounts of 2a (Table 1, entry 5). When the reaction was
catalyzed by thiocarbamate 6, 3a was obtained as the only
product in 78% yield (Table 1, entry 6). To our delight, 3a
was obtained in an excellent yield (92%) and with only
a negligible amount of 2a when amine–thiocarbamate
catalyst 7a was used (Table 1, entry 7). Encouraged by these
preliminary results, we proceeded to optimize the reaction
conditions and to develop the asymmetric version of the
reaction.
A systematic screening of various halogen sources and
solvents showed that toluene and NBS gave the best results
(see the Supporting Information for details). The influence of
the reaction temperature was also examined. At À608C, the
reaction of 1a with quinidine-derived amine–thiocarbamate
7a gave product 3a in 34% yield and 16% ee (Table 2,
entry 1, footnote c). The ee value and yield improved when
the reaction was conducted at À408C (Table 2, entry 1).
Unexpectedly, reactions with thiocarbamate catalysts that
contain other cinchona alkaloid frameworks, including qui-
nine, cinchonine, and cinchonidine, were sluggish and no
1,3-Dicarbonyl compounds 1, which contain an acidic
proton in a-position to the carbonyl funtionalities, are also
potential nucleophiles for halocyclizations (when R2 is an
olefinic side chain), furnishing highly functionalized cyclic
ethers 3 (Scheme 1).[5] However, this type of nucleophile is
also highly susceptible to halogenation in a-position to the
carbonyl functionalities, which is a well-known process.[6] The
resulting a-halogenated dicarbonyl compound 2 is not a good
halogenating reagent and not usually used in the halocycliza-
tion of olefinic substrate 1.[6b,m,7] Nonetheless, herein we
report an efficient, catalytic, and highly enantioselective
bromocyclization of olefinic 1,3-dicarbonyl compounds,
giving rise to highly functionalized furans (see below). A
protocol that employs an amine–thiocarbamate as catalysts
was developed for the chemoselective bromination at the
olefinic moiety over the carbon atom in a-position to the
carbonyl functionalities.
At the outset of this study, we screened several catalysts
that are commonly used in halocyclizations. Olefinic 1,3-
[*] Y. Zhao, Dr. X. Jiang, 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
Homepage: http://www.chemistry.nus.edu.sg/people/academi-
c_staff/yeungyy.htm
[**] We thank the National University of Singapore (grant no. 143-000-
509-112), ASTAR-Public Sector Funding (grant no. 143-000-536-
305), and GSK-EDB for financial support. We are also grateful for
scholarships to Y. Zhao and X. Jiang (NUS Research Scholarship).
Special thanks goes to Dr. J. Chen (NUS) for her assistance on the
mechanistic investigation and Dr. Ji’En Wu (CMMAC, NUS) for his
help on the NMR analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304107.
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Table 1: Reaction of 1a with NBS using various catalysts.[a]
cyclized products were detected after five days at À608C.
Reactions with an (S)-BINOL-derived phosphoric acid or
a proline-derived thiocarbamate as catalysts could not furnish
the desired product under the same conditions, either.[9]
Next, catalysts with different substituents at the thiocar-
bamate moiety were examined. Catalysts with electron-rich
(Table 2, entries 2–6), bulky (Table 2, entry 8), and electron-
deficient (Table 2, entry 9) aryl moieties did not lead to better
enantioselectivities than that obtained with 2,4-dimethoxy-
phenyl-substituted catalyst 7a. Surprisingly, 2,4,6-trimethoxy-
phenyl thiocarbamate 7j was an excellent catalyst and 3a was
furnished in 89% yield and 96% ee (Table 2, entry 10). These
results suggest that the substituents at the 2, 4, and 6 positions
of the aryl moiety of the catalyst might have a synergistic
effect in inducing high enantioselectivity, although the reason
for this effect remains unclear. The reaction with catalyst 7j
was readily scalable without loss of efficiency and enantiose-
lectivity (Table 2, entry 11).[10]
Entry
1
Catalyst
Yield [%][b]
1a
2a
3a
12
67
22
2[c]
3
NEt3
DBU
trace
0
trace
98
trace
0
60
4
DMAP
10
28
5
6
75
15
trace
trace
20
78
Once the optimized conditions were identified, we
examined the substrate scope of the reaction (Table 3). The
reactions of different olefinic 1,3-dicarbonyl compounds
1 proceeded smoothly to give aryl- and alkyl-substituted
products 3 with high yields and ee values. Dicarbonyl
substrates with electron-deficient aryl substituents gave
products with good to excellent enantioselectivity (from
98% to 84% ee; Table 3, entries 1–3). In comparison, sub-
strates with electron-rich aryl substituents generally gave
products with lower enantioselectivities, which could be
ascribed to the enhanced background reaction (Table 3,
7
0
trace
92
[a] Reactions were carried out with 1a (0.01 mmol), catalyst
(0.002 mmol), and NBS (0.011 mmol) in CDCl3 (0.3 mL) at 258C for 2 h
in the absence of light. [b] Determined by 1H NMR analysis. [c] Signifi-
cant amounts of other unidentified side products were detected. Entry in
bold marks optimized reaction conditions. DABCO=1,4-diazabicyclo-
[2.2.2]octane; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene; DMAP=N,N-
dimethylaminopyridine.
Table 3: Substrate scope of bromocyclization of 1 catalyzed by 7j.[a]
Table 2: Screening of catalysts with different thiocarbamate substi-
tuents.[a]
Entry
Subst.
R
Yield [%][b]
ee [%]
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1 f
1g
1h
1i
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
4-Me-C6H4
3-MeO-C6H4
2-naphthyl
Me
CH2OMOM
iPr
tBu
89
87
86
86
89
87
80
83
87
86
88
92
98
90
84
74
78
81
55
64
90
92
86
90
Entry
7
R
Yield [%][b]
ee [%]
1[c]
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7 f
7g
7h
7i
2,4-(MeO)2C6H3
4-MeOC6H4
82
67
72
74
78
57
75
64
32
89
85
20
6
14
7
18
4
8
0
0
96
94
9
1j
1k
1l
10
11
12
2,5-(MeO)2C6H3
3,4,5-(MeO)3C6H2
2,6-(EtO)2C6H3
2,6-(iPrO)2C6H3
C6H5
2-naphthyl
C6F5
2,4,6-(MeO)3C6H2
2,4,6-(MeO)3C6H2
cyclopentyl
cyclohexyl
1m
13
14
1n
1o
89
91
76
91
15
16
1p
1q
86
92
90
99
10
7j
7j
11[d]
[a] Reactions were carried out with 1a (0.03 mmol), catalyst 7
(0.006 mmol) and NBS (0.033 mmol) in toluene (1.0 mL) at À408C in
the absence of light. [b] Yields of isolated products. [c] When this
reaction was performed at À608C for 5 days, 3a was obtained in 34%
yield and 16% ee. [d] The reaction was conducted on a 0.3 mmol scale.
Entry in bold marks optimized reaction conditions.
[a] Reactions were carried out with 1 (0.03 mmol), catalyst 7j
(0.006 mmol), and NBS (0.033 mmol) in toluene (1 mL) in the absence
of light. [b] Yields of isolated products. Boc=tert-butoxycarbonyl,
MOM=methoxymethyl, TBS=tert-butyldimethylsilyl.
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entries 4–6). Notably, alkyl-substituted substrates gave prod-
ucts with good ee values in most cases (Table 3, entries 7–16).
This result is in sharp contrast with our previous studies and
some other reports, in which low to moderate ee values were
generally reported for alkyl-substituted substrates in asym-
metric halocyclization processes.[1,11] Moreover, this catalytic
protocol was compatible with various protecting groups,
including OTBS, OMOM, isopropyldene, and N-Boc (see
Table 3). The absolute configuration of 3 was established by
X-ray crystallography of compound 3a.[12]
After studying the substrate scope of this reaction, we
investigated the required catalyst loading of 7j. Interestingly,
the catalyst was highly efficient, and product 3a was obtained
with comparable yields and ee values, even when the catalyst
loading was reduced to 5 mol% (Scheme 2).
Scheme 3. Synthesis of 9 from 3q. TFA=trifluoroacetic acid.
a bifunctional interaction/activation of the substrate with/by
the catalyst, resulting in an efficient bromocyclization process
[Scheme 4, Eq. (1)].[14]
Scheme 4. Proposed mechanism of the cyclization.
Scheme 2. Examination of catalyst loading required for bromocycliza-
tion and crystal structure of compound 3a (thermal ellipsoids drawn
at 50% probability).
We speculate that the exceptionally strong preference for
the cyclization over the bromination in a-position to the
carbonyl functionalities can be attributed to the limited
pocket size of the bifunctional catalyst, and transition state A
might be energetically more favorable than transition state B
(with regard to steric demand; Scheme 4). We also examined
the bromination of dicarbonyl compound 10, a substrate that
is known to smoothly undergo asymmetric halogenation using
cinchona alkaloid catalysts.[6c] However, the reaction was
sluggish and only a trace amount of the product was detected
when amine–thiocarbamate catalyst 7j was used at À78 or
À508C in CH2Cl2 or toluene for 3 days. This result is in
agreement with the speculation that the pocket of the
bifunctional amine–thiocarbamate catalyst might not be
suitable for the bromination at the a-position of 1,3-dicar-
bonyl compounds. A possible explanation is that the carbonyl
anion might not come into close proximity to S-Br at the
thiocarbamate, thus not allowing for an effective bromination
through transition state B [Scheme 4, Eq. (2)]. The hypothesis
The cyclized products can be further manipulated to give
various functional building blocks. For instance, removal of
the Boc protecting group of 3q with TFA gave amine 8.
Treatment of 8 with NaHCO3 in toluene at reflux furnished
quinuclidine 9, which can potentially act as a chiral organo-
catalyst scaffold (Scheme 3).[13]
Based on our previous studies on thiocarbamate cataly-
sis,[11] we believe that the quinuclidine moiety of 7j might act
as a nitrogen base to deprotonate the 1,3-dicarbonyl unit,
while the Lewis basic sulfur atom of the thiocarbamate
moiety of 7j might coordinate to Br. We attempted to convert
2a into 3a with 7j as the catalyst, but the reaction did not
occur. This result implies that the Br atom in dicarbonyl
compounds 2 is not readily exchangeable under the reaction
conditions, thus suggesting that 2 and 3 might be formed
through two independent pathways. During the formation of
cyclized products 3, a possible transition state A might involve
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the ratio of cyclized product 3a over a-brominated dicarbonyl
compound 2a increases dramatically when an amine and
a thiocarbamate are used together in a bifunctional catalytic
system.
In summary, a facile and highly enantioselective bromo-
cyclization of olefinic dicarbonyl compounds has been
developed using an amine–thiocarbamate as the catalyst.
The use of such a catalyst resulted in the formation of the
desired cyclized products with high enantioselectivities and an
excellent ratio of cyclization to bromination in a-position to
the carbonyl functionalities.
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Received: May 13, 2013
Published online: July 14, 2013
Keywords: asymmetric catalysis · chemoselectivity · cyclization ·
.
furans · Lewis bases
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formation of 3a, but the reaction did not occur. For details, see
Scheme 4.
[8] DABCO and some other amine bases were used as catalysts in
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excellent diastereoselectivity. For an elegant example, see: W.
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[9] The structures of these catalysts are given in the Supporting
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[10] We have also examined the substrate with a 1,3-di-tert-butyl-
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1,3-dione. For details, see the Supporting Information.
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thiocarbamate catalyst was used).
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