Stereoselective halocyclization of alkenes with n-acyl hemiaminal nucleophiles

Article abstract of DOI:10.1002/chir.22219

Halocyclization of alkenes was realized using N-acylhemiaminal nucleophiles. High diastereoselectivity could be achieved for the formation of three stereogenic centers in this halogen-mediated cyclization reaction. We also demonstrated that enantioselecti

Full text of DOI:10.1002/chir.22219

CHIRALITY 25:805–809 (2013)
Stereoselective Halocyclization of Alkenes With N-Acyl
Hemiaminal Nucleophiles
1
1
1
2
3
2
1,3
*
*
NA LIU, HAO-YUAN WANG, WEI ZHANG, ZHI-HONG JIA, ILIA A. GUZEI, HUA-DONG XU, AND WEIPING TANG
1School of Pharmacy, University of Wisconsin, Madison, Wisconsin
2School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu Province, P.R. China
3Department of Chemistry, University of Wisconsin, Madison, Wisconsin
ABSTRACT
Halocyclization of alkenes was realized using N-acylhemiaminal nucleophiles. High
diastereoselectivity could be achieved for the formation of three stereogenic centers in this halogen-
mediated cyclization reaction. We also demonstrated that enantioselective bromocyclization of
alkenes using N-acylhemiaminal nucleophiles was possible. Chirality 25:805–809, 2013. © 2013 Wiley
Periodicals, Inc.
KEY WORDS: halocyclization; hemiaminal; stereoselective; alkene
INTRODUCTION
General Method for the Preparation of Hemiaminals
To a solution of the above imide (2 mmol) in methanol (20 mL) was
added NaBH4 (148 mg, 4 mmol) in several portions at 0 °C. The reaction
was monitored by TLC. After completion, the reaction was quenched with
water and diluted with dichloromethane. The organic layer was washed
with water, dried over Na2SO4, and concentrated under reduced
pressure. The hemiaminal product was purified by flash column chroma-
tography using hexane and EtOAc as the eluent.
The development of chemo-, regio-, and stereoselective
addition reactions to alkenes is of fundamental importance
in organic chemistry. Halogen-promoted addition of nucle-
ophiles to unsaturated C-C bonds represents one of the
most powerful methods in organic synthesis and is widely
used for the introduction of diverse functionalities to organic
compounds.1–4 The resulting carbon-halogen bonds are not
only present in numerous halogen-containing natural
products5–9 but also serve as useful handles for the introduction
of other functional groups. In addition to carbon-halogen
bonds, the halogen-promoted addition reactions may also
provide various other bond types (e.g., C-O, C-N, and C-C)
depending on the choice of nucleophiles. We herein introduce
hemiaminals as a new class of nucleophiles for halocyclization
of alkenes.
General Method for the Bromocyclization of Hemiaminals
To a solution of compound 12 or 15 (0.1 mmol) and TsOH (22.83 mg,
0.12 mmol) in chloroform (2 mL) at room temperature was added
N-bromosuccinimide (NBS) (21.4 mg, 0.12mmol). The reaction was stirred
at room temperature until the starting material disappeared as indi-
cated by TLC. The reaction was concentrated under vacuum. The
residue was purified by flash column chromatography on silica gel
(50% ethyl acetate in hexanes).
Method for the Catalytic Asymmetric Bromocyclization
of Hemiaminals
EXPERIMENTAL SECTION
Instruments and Materials
To a solution of compound 12a (0.05 mmol), (DHQD)2PHAL (7.8 mg,
0.01 mmol), and TsOH (1.9 mg, 0.01 mmol) in chloroform (1 mL) at room
temperature was added NBS (21.4 mg, 0.12 mmol). The reaction was
stirred at room temperature until the starting material disappeared as
indicated by TLC. The reaction was concentrated under vacuum. The
residue was purified by flash column chromatography on silica gel
(50% ethyl acetate in hexanes).
All reactions in nonaqueous media were conducted under a positive
pressure of dry argon in glassware that had been oven-dried prior to
use unless noted otherwise. Anhydrous solutions of reaction mixtures
were transferred via an oven-dried syringe or cannula. All solvents were
dried prior to use unless noted otherwise. Thin-layer chromatography
(TLC) was performed using precoated silica gel plates (EMD Chemical,
60, F254). Flash column chromatography was performed with silica gel
(Silicycle, 40-63 μm). Infrared spectra (IR) were obtained on a Bruker
RESULTS AND DISCUSSION
1
Equinox 55 Spectrophotometer. H and 13C nuclear magnetic resonance
Recently, significant progress has been made in the area
of catalytic asymmetric halocyclization of alkenes,10–18 in
particular, enantioselective halolactonizations.19–32 A num-
ber of reviews have been published in this area.33–38 The
more synthetically versatile enantioselective intermolecular
addition of nucleophiles and halogen electrophiles to alkenes,
however, remains largely unexplored.39–41 We recently
spectra (NMR) were obtained on a Varian Unity-Inova 400 MHz or
500 MHz recorded in ppm (δ) downfield of TMS (δ = 0) in CDCl3 unless
noted otherwise. Signal splitting patterns were described as singlet (s),
doublet (d), triplet (t), quartet (q), quintet (quint), or multiplet (m), with
coupling constants (J) in Hertz. High-resolution mass spectra (HRMS)
were performed by the Analytical Instrument Center at the School of
Pharmacy or Department of Chemistry on an Electron Spray Injection
(ESI) mass spectrometer.
General Method for the Preparation of Imides
Additional Supporting Information may be found in the online version of this article.
*Correspondence to: W. Tang, School of Pharmacy, University of Wisconsin,
Madison, WI 53705. E-mail: wtang@pharmacy.wisc.edu; Hua-Dong Xu,
School of Pharmaceutical Engineering and Life Science, Changzhou
University, 1 Gehu Road, Changzhou, Jiangsu Province, 213164, China.
E-mail: hdxu@cczu.edu.cn
Received for publication 8 June 2013; Accepted 19 June 2013
DOI: 10.1002/chir.22219
Published online 15 August 2013 in Wiley Online Library
(wileyonlinelibrary.com).
To a solution of allylic chloride or bromide 10 (3.6 mmol) in DMF
(10 mL) was added potassium phthalimide (998.9 mg, 5.4 mmol) and
stirred overnight at room temperature. The mixture was then diluted with
dichloromethane and the organic layer was washed with water and brine.
The organic phase was dried over Na2SO4 and concentrated under
reduced pressure. The imide product was purified by flash column
chromatography using hexane and EtOAc as the eluent.
© 2013 Wiley Periodicals, Inc.

806
LIU ET AL.
Br
N
NBS
-HBr
NBS
reported the first highly enantioselective intermolecular
bromoesterification of alkenes with up to 93% ee (eq. 1.).42
We found that the enantioselectivity correlated with the
acidity of the sulfonamide NH and the most acidic
trifluoromethanesulfonamide offered the highest ee. No
reaction occurred when the N-H group was replaced by
an N-Me group.
Ph
Ph
N
Ph
1
4
3
-H
Br
N
Ph
N
5
6
-H
Br
Br
Br
NBS
Ph
N
Ph
N
8
7
H2O
OH
Br
Br
NBS
We reasoned that the N-H bond in a protonated amine
might also direct the intermolecular haloesterification
reaction. To our surprise, tertiary amine 1 was oxidized to
hemiaminal under acidic conditions and the resulting
hemiaminal then served as a nucleophile for the subsequent
halocyclization to yield product 2 (eq. 2). The structure of
compound 2 was unambiguously assigned by x-ray analysis
(Fig. 1).
Ph
N
2
9
Scheme 1. Proposed mechanism for the formation of product 2.
NBS. We also tried to examine the scope of this tandem
oxidation-bromocyclization reaction. We observed a complex
mixture, however, when N,N-dimethyl cinnamyl amine or N,
N-diisopropyl cinnamyl amine was treated with NBS under
the same conditions.
Aminal is a common structural motif in many natural prod-
ucts and pharmaceutical agents, such as quinocarcin43,44 and
communesins.45,46 N-acylhemiaminal or N-acylhemiaminal
ether were also found in numerous natural products such
as zampanolide,47,48 echinocandin B,49 spergualin,50,51
mycalamides,52 tallysomycins,53 and perinadine A.54 To
the best of our knowledge, hemiaminal has not been used
as a general nucleophile in halogen-mediated addition reac-
tions for the preparation of hemiaminal ethers. We only
found one such example in a report by Chen and coworkers
using iodine as the electrophile as shown in eq. 3.55
The mechanism for the formation of bromocyclization prod-
uct 2 from allylic amine 1 is shown in Scheme 1. Oxidation of
allylic amine 1 by NBS followed by elimination of HBr may
produce iminium ion 4, which is in equilibrium with enamine
5. Bromination of this enamine would then afford iminium ion
6, which is in equilibrium with enamine 7. Bromination of
enamine 7 would generate iminium 8, which is in equilibrium
with hemiaminal 9. Bromocyclization of this hemiaminal
would yield final product 2. Apparently, it requires four equiv-
alents of NBS for the conversion of 1 to 2. The yield of product
2, however, could not be further improved with additional
The high diastereoselectivity for the formation of three
stereogenic centers in product 2 and the wide presence of
N-acylhemiaminals or N-acylhemiaminal ethers in natural
products encouraged us to study N-acylhemiaminal as a
general nucleophile for stereoselective halocyclizations.
N-Acylhemiaminals 12a-h could be easily prepared from
the corresponding allylic chlorides or bromides in two steps
through a sequence of substitution and reduction as shown
in Scheme 2. We also prepared N-acylhemiaminals 15a
and 15b from cinnamyl chloride 10a and the corresponding
5- or 6-membered cyclic imides.
We then treated hemiaminal 12a with 1.2 equivalents of
NBS. We found that the major product was actually imide
17 and the minor product was N-acylhemiaminal ether
16a (eq. 4). The hemiaminal was oxidized quickly by
Fig. 1. X-ray structure of compound 2 (CCDC 933536).
Chirality DOI 10.1002/chir

STEREOSELECTIVE HALOCYCLIZATION OF ALKENES
807
The structure and relative stereochemistry of product 16e was
unambiguously assigned by x-ray analysis (Fig. 2).
Under the standard conditions, good yields could also be
obtained for products 18a and 18b (eq. 5).
Finally, we tried to develop the enantioselective
bromocyclization of 12a using chiral catalyst. We first treated
hemiaminal 12a with chiral acid CSA (entry 1, Table 2). Only
racemic product was obtained. Addition of catalytic amount of
Scheme 2. Preparation of N-acylhemiaminal substrates.
NBS back to imide 11a, which then underwent
intermolecular addition of bromine and water to yield
product 17. No reaction occurred when we treated 12a
with NCS. Interestingly, only imide product was observed
when NIS was employed as the halogenation reagent.
The selectivity for bromocyclization product 16a could
be improved significantly in the presence of TsOH. An
84% yield of 16a was isolated under this condition (entry
1, Table 1). Other weaker acids such as benzoic acid led
to a complex mixture. The scope of bromocyclization of
hemiaminal 12 was then examined (Table 1). The R group
can also be an alkyl group (entry 2). No desired product
16c was observed for substrate 12c (entry 3). Various
substituted aryl groups could be tolerated (entries 4-7).
TABLE 1. Bromocyclization of hemiaminal 12a
Fig. 2. X-ray structure of compound 16e (CCDC 933537).
entry
Substrate 12
Yieldb (%)
1
2
12a, R = Ph
86
78
0
12b, R = Me
12c
TABLE 2. Conditions for enantioselective bromocyclization of
hemiaminal 12a
3
entry
1
conditions
Yield (%) Ee (%)
NBS (120 mol%), (+)-CSA
(100 mol%), CHCl3
86
86
47
51
0
0
4
5
6
7
12d, R = 4-Cl-C6H4
12e, R = 2,4-Cl2-C6H3
12f, R = 4-Ph-C6H4
12 g, R = CF3
71
67
63
96
2
3
4
NBS (120 mol%), (+)-CSA (100 mol%),
(DHQD)2PHAL (20 mol%), CHCl3
NBS (120 mol%), (+)-CSA (20 mol%),
(DHQD)2PHAL (20 mol%), CHCl3
NBS (120 mol%), TsOH (20 mol%),
(DHQD)2PHAL (20 mol%), CHCl3
74
64
aConditions: NBS (120 mol%), TsOH (100 mol%), CHCl3, rt.
bIsolated yield.
Chirality DOI 10.1002/chir

808
LIU ET AL.
(DHQD)2PHAL56–58 to the above system did not induce
any enantioselectivity (entry 2). Interestingly, a 74% ee
was observed when the amount of acid was reduced to
20 mol% (entry 3). The yield of product 16a, however,
was only 47%. Slightly lower ee and similar yield were
obtained when achiral acid was employed (entry 4). We
were not able to improve the enantioselectivity further by
running the reaction in other solvents.
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CONCLUSION
In summary, we have developed an efficient method for
the stereoselective synthesis of N-acylhemiaminal ethers
16 and 18 from readily available hemiaminals through
bromocyclizations. Three stereogenic centers in these
heterocycles were constructed in high diastereoselectivity.
Moderate enantioselectivity could also be achieved using
dimeric cinchona alkaloid catalysts. Efforts to further improve
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ACKNOWLEDGMENTS
W.T. thanks the University of Wisconsin for startup
funding to support this research. H.-D.X. thanks the Natu-
ral Science Foundation of China (21002032 and 21272077)
for financial support.
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Chirality DOI 10.1002/chir