Enantioselective halocyclization using reagents tailored for chiral anion phase-transfer catalysis

Article abstract of DOI:10.1021/ja305795x

A chiral anion phase-transfer system for enantioselective halogenation is described. Highly insoluble, ionic reagents were developed as electrophilic bromine and iodine sources, and application of this system to o-anilidostyrenes afforded halogenated 4H-3,1-benzoxazines with excellent yield and enantioselectivity.

Full text of DOI:10.1021/ja305795x

Communication
pubs.acs.org/JACS
Enantioselective Halocyclization Using Reagents Tailored for Chiral
Anion Phase-Transfer Catalysis
Yi-Ming Wang, Jeffrey Wu, Christina Hoong, Vivek Rauniyar, and F. Dean Toste*
Department of Chemistry, University of California, Berkeley, California 94720, United States
S
* Supporting Information
insoluble nature of the fluorinating reagent, nonselective
ABSTRACT: A chiral anion phase-transfer system for
enantioselective halogenation is described. Highly in-
soluble, ionic reagents were developed as electrophilic
bromine and iodine sources, and application of this system
to o-anilidostyrenes afforded halogenated 4H-3,1-benzox-
azines with excellent yield and enantioselectivity.
background reaction is minimal. We hypothesized that other
electrophilic functionalization reactions should be amenable to
chiral anion phase-transfer catalysis, thereby extending the
applicability of the concept to a general approach for catalysis.
Toward this goal, novel electrophilic reagents needed to be
developed where insolubility, normally detrimental, is a
required feature. We report herein the synthesis of a new
brominating reagent (1d) for use in anionic phase-transfer
bromination, as well as an analogous reagent (5d) for
iodination.
Given the lack of methods for enantioselective synthesis of
4H-3,1-benzoxazines,10 we chose the 6-exo-trig cyclization of
amide 3a to examine the utility of the cationic brominating
reagents in chiral anion phase-transfer catalysis. (Bis)amine-
halonium reagents have long been known and employed as
electrophilic halonium sources in reactions with alkenes;11
however, attempts to use the known oligomeric DABCO-
bromine complex or bis(sym-collidine)bromine(I) hexafluor-
ophosphate under chiral anion phase-transfer conditions
resulted in rapid conversion to 4a with poor enantioselectivity,
reflecting a significant amount of uncatalyzed background
reaction (Table 1, entries 1 and 2).12
he enantioselective synthesis of halogenated compounds
T
is an important target for the synthetic community.1 In
particular, electrophilic halogenation of alkenes offers direct
access to bifunctionalized molecules with the concomitant
formation of up to two stereocenters. There are, however, only
a limited number of approaches for the induction of
enantioselectivity in this class of electrophilic addition
reactions, especially in a catalytic sense.2 In addition to
transition metal-catalyzed alkene halogenations,3 organocata-
lytic methods have recently been reported using modified
cinchona alkaloids,4 aminourea5 and bis(amidine) derivatives,6
C3-symmetric imidazoline derivatives,7 and phosphoric acids8 as
catalysts. While high enantioselectivities can been achieved, low
temperatures and/or high catalyst loading are often required to
overcome the uncatalyzed background reaction.
The lack of success using these monocationic reagents led us
to consider the monoalkylated-DABCO scaffold as a starting
point, in analogy to Selectfluor, for the generation of more
highly charged reagents for phase-transfer bromination. To that
end, treatment of monoalkyl DABCO tetrafluoroborates with
elemental bromine in the presence of AgBF4 resulted in the
formation of tricationic brominating reagents 1, which could be
isolated by precipitation (Figure 1). These brominating
reagents could be stored in an airtight vial at −20 °C for at
least a month without deterioration. Moreover, 1a was found to
mediate the bromocyclization of amide 3a almost instanta-
neously under homogeneous conditions in acetonitrile. In
contrast, 1a was insoluble in organic solvents of low or
moderate polarity, including hexanes, toluene, and dichloro-
methane, and exposure of amide 3a to 1a in toluene did not
result in significant formation of the cyclized product.
Encouragingly, when 3a was combined with 1a in the presence
of chiral phosphoric acid 2a (10 mol %) and Na2CO3, desired
product was obtained in moderate enantioselectivity (Table 1,
entry 3).
Very recently, our laboratories reported an enantioselective
fluorocyclization of olefins using chiral anion phase-transfer
catalysis,9 (Scheme 1) by taking advantage of the low solubility
Scheme 1. Application of Chiral Anion Phase Transfer
a
Catalysis to Bromo- And Iodocyclization
a
Phos*− = chiral phosphate anion, E = Br or I.
of the cationic fluorinating reagent Selectfluor in nonpolar
solvents. Exchange of the tetrafluoroborate anions from the
reagent with lipophilic chiral phosphate anions brings the active
electrophile into solution as a chiral ion pair, resulting in
efficient, chemo- and enantioselective fluorination of the
substrate at or near room temperature. Notably, due to the
With these promising results, we sought to optimize the
structure of the brominating reagent. To increase the phase-
Received: June 14, 2012
Published: July 25, 2012
© 2012 American Chemical Society
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Communication
Table 1. Optimization of Enantioselective Bromocyclization
a
b
entry
“Br+”
cat.
solv
toluene
base
time
conv.
ee
1
DABCO·2Br2
(coll)2Br+PF6
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2c
2c
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
0.5 h
0.5 h
24 h
24 h
24 h
24 h
16 h
16 h
16 h
17 h
17 h
17 h
17 h
4 h
100%
100%
82%
39%
1%
−
2
toluene
3
1a
1b
1c
1d
1d
1d
1d
1d
1d
1d
1d
toluene
59%
70%
20%
83%
86%
89%
60%
89%
91%
90%
92%
94%
4
toluene
67%
5
toluene
30%
6
toluene
67%
7
p-xylene
62%
c
8
xyl/hex (1:1)
hexanes
90%
9
21%
c
c
c
c
c
10
11
12
13
14
xyl/hex (1:1)
xyl/hex (1:1)
xyl/hex (1:1)
xyl/hex (1:1)
xyl/hex (1:1)
90%
90%
d
100%
100%
100%
d
Na3PO4
e
f
,g
d
h
1d
2c
Na3PO4
a
b
c
d
1
Estimated from H NMR of the crude product. Determined by chiral HPLC. p-Xylene and hexanes. Finely ground and dried overnight.
e
f
g
h
Reprecipitated from MeNO2. 5 mol %. 0.025 M. 82% isolated yield.
with no loss in enantioselectivity observed when catalyst
loading was decreased to 5 mol % (entry 12−14).
With optimized reaction conditions in hand, we explored the
substrate scope of our bromination reaction (Table 2). We
were pleased to find good tolerance for substituents of varying
steric bulk at the α position of the styrenyl system. Potentially
problematic functional groups including a silyl ether (4e), an
unprotected alcohol (4f), and a tertiary amine (4o) did not
significantly impact the reactions. Notably, a substrate with a
pyridyl backbone gave desired product in excellent yield and
enantioselectivity (4n). Electron-withdrawing (4q) and elec-
tron-donating (4r) substitution at the para position, as well as
ortho substitution (4p) of the benzamide aryl were tolerated. A
slight modification of reaction conditions also afforded
benzoxazine 4s with t-butyl substitution at the 2-position.
Gratifyingly, heteroarylamides (3t−3v) were also suitable
substrates under standard reaction conditions. These examples,
all run at room temperature without precaution to exclude air
and moisture, demonstrate the mildness and operational
simplicity of the reaction conditions.
Figure 1. Synthesis of cationic halogenating reagents and ORTEP
diagram of 1d (ellipsoids at 50% probability level, counterions and H’s
omitted for clarity).
transfer efficiency and electrophilicity of the brominating
reagent, we synthesized the more lipophilic and electron-
deficient reagent 1b. Indeed, treatment of 3a with 1b resulted
in product formation in improved enantioselectivity. While a
further increase in electron-deficiency (1c) was detrimental, the
use of more lipophilic reagent 1d afforded 4a with increase in
enantioselectivity to 83% ee (Table 1, entries 3−6). A decrease
in the polarity of the solvent to 1:1 p-xylene/hexanes resulted
in better conversion and enantioselectivity (entries 7, 8). While
commercially available TRIP (2b) catalyzed the reaction with
nearly identical efficiency and selectivity, a more highly
lipophilic phosphoric acid with 6,6′-TIPS substituents (2c,
TIPS-TRIP) resulted in further improvements (entries 10, 11).
Use of 1d reprecipitated from nitromethane (see Supporting
Information) shortened reaction time without affecting
enantioselectivity, and optimization of base and concentration
improved enantioselectivity to 94% ee in 82% isolated yield
We next explored substrates bearing substitution at both the
α and the β positions of the styrenyl system. In the event,
subjection of these substrates to standard reaction conditions
furnished desired products in excellent yields and enantiose-
lectivities. In all cases, only one diastereomer was observed in
1
the H NMR of the crude product. Notably, substituents of
varying steric and electronic properties were tolerated (4g−4i).
For example, enantioenriched gem-bromochloro adduct 4h was
formed in 88% yield and 96% ee from the corresponding vinyl
chloride. Cyclic substrates, including conjugated (4k) and
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Journal of the American Chemical Society
Communication
1d, reagent 5d was obtained as an off-white solid of similar
stability. We were pleased to find that treatment of 3b, 3j, and
3n with 5d (in place of 1d) for 16 h without otherwise
modifying reaction conditions furnished the corresponding
iodinated products 6b, 6j, and 6n in similarly high yields and
enantioselectivities (Scheme 2).
Table 2. Scope of Enantioselective Bromocyclization
Scheme 2. Enantioselective Electrophilic Iodocyclization
To provide some evidence that the reaction is proceeding
through the proposed anionic phase-transfer process, we
subjected 3a to optimized reaction conditions but in the
absence of base, which is required for the formation and
regeneration of the chiral phosphate anion. After 2 h reaction
time, the product was obtained in moderate conversion. The
enantioselectivity observed, however, was greatly diminished
(eq 1). On the other hand, use of base alone without 2c did not
result in rate acceleration. Thus, the observed rate and
enantioselectivity enhancement in the presence of base cannot
be attributed to deprotonation of the amide substrate. These
experiments strongly suggest that the chiral phosphate anion is
the active catalytic species in our optimized system (and not the
phosphoric acid). Moreover, a nonlinear effect study (see
Supporting Information) showed significant deviation from
linearity. This study, combined with the observation that
monoalkyl DABCO-derived reagents provide products with
increased enantioselectivity, suggests that the occurrence of
highly charged intermediates may be advantageous for
enantioinduction in chiral phosphate phase-transfer catalysis.
In summary, an anionic phase-transfer protocol for
enantioselective bromination was developed and applied to
the 6-exo-trig bromocyclization of styrenyl amides. To realize
this system, an insoluble cationic brominating reagent was
developed, with optimal results delivered with 6,6′-silyl
substituted TRIP phosphoric acid as an anionic phase-transfer
precatalyst. Enantioselective iodination was achieved with an
analogous cationic iodinating reagent. The resulting methods
furnished a broad range of enantioenriched 4H-3,1-benzox-
azines under mild and operationally simple reaction conditions.
The highly insoluble nature of the halogenating reagents in
nonpolar solvents effectively suppressed the noncatalyzed
background reaction and led to halocyclization reactions with
excellent enantioselectivity, even at low catalyst loading. For
a
Conditions: 1d (1.3 equiv), TIPS-TRIP (5 mol %), Na3PO4 (4.0
equiv), p-xylene/hexanes (1:1, 0.025 M), 4 h, rt. Relative and absolute
stereochemistry assigned by analogy to that of 4l, determined by X-ray
crystallography. Yields after chromatographic purification and
enantioselectivities determined by chiral HPLC. 1.5 equiv 1d in
mesitylene/hexanes (1:1).
b
remote dienes (4l), afforded desired product with excellent
chemo- and enantioselectivity. Similarly, benzothiophene
substituted substrate 3m provided dearomatized product in
excellent yield and enantioselectivity. These results highlight
the extraordinary tolerance of this catalyst system for
substitution on the alkene moiety.
We speculated that enantioselective iodination might also be
achieved through an analogous reagent. Thus, we prepared
iodination reagent 5d as a further test of the robustness and
generality of the anionic phase-transfer approach. Through a
procedure nearly identical to the one used in the preparation of
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Journal of the American Chemical Society
Communication
(k) Zhang, W.; Liu, N.; Schienebeck, C. M.; Decloux, K.; Zheng, S.;
Werness, J. B.; Tang, W. Chem. Eur. − J. 2012, 18, 7296.
Bromoamination: (l) Zhou, L.; Chen, J.; Tan, C. K.; Yeung, Y.-Y. J.
Am. Chem. Soc. 2011, 133, 9164. (m) Chen, J.; Zhou, L.; Yeung, Y.-Y.
Org. Biomol. Chem. 2012, 10, 3808.
example, reaction of cyclohexenyl substrate 3j with 1d with
catalyst loading reduced of 0.1 mol % afforded the desired
product in 87% yield and 90−93% ee.13 These methods extend
the utility of the chiral anion phase-transfer approach and serve
as a starting point for the design of other reagents for use in this
paradigm.
(5) Iodolactonization: Veitch, G. E.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2010, 49, 7332.
(6) (a) Iodolactonization: Dodish, M. C.; Johnston, J. N. J. Am.
Chem. Soc. 2012, 134, 6068. After submission of this work, the use of a
BINOL-derived amidine-catalyzed bromolactonization was reported:
(b) Paull, D. H.; Fang, C.; Donald, J. R.; Pansick, A. D.; Martin, S. F. J.
Am. Chem. Soc. 2012, 134, 11129.
ASSOCIATED CONTENT
* Supporting Information
Experimental details, characterization data for new compounds,
and crystallographic data (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
■
S
(7) Bromolactonization: (a) Murai, K.; Matsushita, T.; Nakamura, A.;
Fukushima, S.; Shimura, M.; Fujioka, H. Angew. Chem., Int. Ed. 2010,
49, 9174. (b) Murai, K.; Nakamura, A.; Matsushita, T.; Shimura, M.;
Fujioka, H. Chem. Eur.J. 2012, 18, 8448.
AUTHOR INFORMATION
Corresponding Author
fdtoste@berkeley.edu
Notes
■
(8) (a) Huang, D.; Wang, H.; Xue, F.; Guan, H.; Li, L.; Peng, X.; Shi,
Y. Org. Lett. 2011, 13, 6350. (b) Hennecke, U.; Muller, C. H.;
̈
Frohlich, R. Org. Lett. 2011, 13, 860. Use of a Lewis basic cocatalyst:
̈
(c) Denmark, S. E.; Burke, M. T. Org. Lett. 2012, 14, 256. Earlier
study of Lewis base catalysis: (d) Denmark, S. A.; Burke, M. T. Proc.
Natl. Acad. Sci. U.S.A. 2010, 107, 20655. (e) While this manuscript
was under preparation, an enantioselective bromoamination of
enamides with chiral phosphoric acids was reported: Alix, A.; Lalli,
C.; Retailleau, P.; Masson, G. J. Am. Chem. Soc. 2012, 134, 10389.
(9) (a) Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D.
Science 2011, 334, 1681. (b) Phipps, R. J.; Hiramatsu, K.; Toste, F. D.
J. Am. Chem. Soc. 2012, 134, 8376. See also: (c) Hamilton, G. L.;
Kanai, T.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 14984. For a
review see: (d) Phipps, R. J.; Hamilton, G. L.; Toste, F. D. Nature
Chem. 2012, 4, 613.
(10) No enantioselective catalytic approaches to 4H-3,1-benzoxazines
have been reported. For an elegant approach to the asymmetric
synthesis of 4H-3,1-benzoxazin-2-ones in the context of HIV-1 reverse
transcriptase inhibitor Efavirenz (Sustiva), see: Pierce, M. P.; Parsons,
R. L., Jr.; Radesca, L. A.; Lo, Y. S.; Silverman, S.; Moore, J. R.; Islam,
Q.; Choudhury, A.; Fortunak, J. M. D.; Nguyen, D.; Luo, C.; Morgan,
S. J.; Davis, W. P.; Confalone, P. N.; Chen, C.; Tillyer, R. D.; Frey, L.;
Tan, L.; Xu, F.; Zhao, D.; Thompson, A. S.; Corley, E. G.; Grabowski,
E. J. J.; Reamer, R.; Reider, P. J. J. Org. Chem. 1998, 63, 8538. For an
enantioselective catalytic synthesis of oxazines by 6-endo-trig
chlorocyclization, see ref 4f.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the University of California Berkeley and to
Amgen for financial support. V.R. thanks the NSERC for a
postdoctoral fellowship. We gratefully acknowledge William J.
Wolf for obtaining X-ray crystallographic data for 1d.
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experiments.
NOTE ADDED AFTER ASAP PUBLICATION
■
This paper was published ASAP on July 25, 2012. Due to a
production error, Table 2 was incorrect. The revised version
was posted on July 26, 2012.
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