Enantioselective chlorocyclization of indole derived benzamides for the synthesis of spiro-indolines

Article abstract of DOI:10.1021/ol4020943

(DHQD)₂PHAL catalyzed enantioselective chlorocyclization of indole derived benzamides was realized. Spiro-indolines containing a continuous quaternary carbon center and tertiary carbon center were obtained in good yields with excellent enantioselectivity (up to 90% yield and 96% ee).

Full text of DOI:10.1021/ol4020943

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Enantioselective Chlorocyclization
of Indole Derived Benzamides for the
Synthesis of Spiro-indolines
Qin Yin and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
slyou@sioc.ac.cn
Received July 24, 2013
ABSTRACT
(DHQD)2PHAL catalyzed enantioselective chlorocyclization of indole derived benzamides was realized. Spiro-indolines containing a continuous
quaternary carbon center and tertiary carbon center were obtained in good yields with excellent enantioselectivity (up to 90% yield and 96% ee).
Chiral halogenated compounds are ubiquitous in nat-
uralproductsand among the mostversatile buildingmotifs
in the construction of molecular complexity.1 Stereoselec-
tive incorporation of halogen atoms, therefore, has re-
ceived tremendous interests. Enantioselective electrophilic
halogenation of alkene, a straightforward strategy to
obtain functionalized halogenated compounds, has thus
far eluded organic chemists until recently.2 An efficient
Co-salen catalyzed enantioselective iodoetherification reac-
tion has been developed by Kang and co-workers in 2003.3
Later, Gao and co-workers reported the first organocata-
lytic enantioselective iodolactonization reaction with qua-
ternary ammonium salts derived from cinchonidine.4 In
2010, Tang and co-workers reported an elegant enantio-
selective bomolactonization of enynes by a cinchona
alkaloid derived urea.5 Since then, notable advances have
been achieved in enantioselective iodocyclization6 and
bromocyclization reactions.7ꢀ9 However, efficient enan-
tioselective chlorocyclizations remain rare due to the
highly reactive nature of chloronium ions. Recently, with
(DHQD)2PHAL as the catalyst, Borhan and co-workers
have realized asymmetric chlorocyclization reactions of
4-substituted 4-pentenoic acids and unsaturated amides to
construct chiral lactones or oxazolines and dihydrooxa-
zines, respectively.10ꢀ12 Meanwhile, catalytic asymmetric
dearomatization reactions have recently emerged as effi-
cient methods converting aromatics to enantiopure spir-
ocyclic compounds.13 Asymmetric dearomatization of
indoles represents an intriguing protocol to synthesize
(5) Zhang, W.; Zheng, S.; Liu, N.; Werness, J. B.; Guzei, I. A.; Tang,
W. J. Am. Chem. Soc. 2010, 132, 3664.
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Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445, 900. (b) Veitch,
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Chem. Sci. 2013, 4, 2100.
r
10.1021/ol4020943
XXXX American Chemical Society

chiral indolines and related alkaloids. In this regard, indole
substrateswithpreinstallednucleophilesattheC3-position
are generally utilized. Gouverneur and co-workers have
developed an enantioselective fluorocyclization of indoles
bearing an embedded heteronucleophile tethered at the C3
or N1 position.14 As a continuation of our interest in the
catalytic asymmetric dearomatization reaction,15 we envi-
saged that enantioselective electrophilic chlorocyclization
of indoles bearing a nucleophile at the C2 position could
lead to a spiro-indoline containing a continuous spiro
quaternary carbon center and tertiary carbon center
(Scheme 1). Herein, we report the results from this study.
Scheme 1. Chlorocyclization of Indoles Bearing an Embedded
Nucleophile
(7) For recent examples on enantioselective bromocyclization, see:
(a) Murai, K.; Matsushita, T.; Nakamura, A.; Fukushima, S.; Shimura,
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X.; Li, L.; Cai, Y.; Liu, W.; Shi, Y. J. Am. Chem. Soc. 2013, 135, 8101. (u)
We began our studies by testing the reactions of indole-
derived benzamide 1a with different halogen sources. For-
tunately, the reactions could all proceed smoothly via a6-exo-
trig cyclization to generate spiro benzoxazines (Table 1).
To our delight, with 1,3-dichloro-5,5-diphenylhydantoin
(DCDPH) as the halogen source and (DHQD)2PHAL
as the catalyst, the chlorocyclization of 1a led to 2a
in excellent yields with moderate enantioselectivity
at ꢀ30 °C using DCM or CH3CN as the solvent respectively
(85ꢀ94% yields, 75ꢀ77% ee, entries 1 and 2, Table 1).
Product 2a could be obtained in 89% yield and 90% ee
when mixed solvents (DCM/CH3CN: 2/1) were employed
(entry 3, Table 1). Reactions with several other halogen
sources gave much lower activity or enantioselectivity. For
example, only 10% conversion was obtained when NCS
was used (entry 4, Table 1). 1,3-Dichloro-5,5-dimethylhy-
dantoin (DCDMH) gave the desired product with a full
conversionand85%ee(entry5, Table1). Furtherscreening
of solvents revealedCHCl3 is the optimal one, affording the
desired product in 82% yield with 95% ee (entries 6ꢀ10,
Table 1). Elevating the reaction temperature to ꢀ10 °C led
to a slightly decreased yield and enantioselectivity (entry 11,
Table 1). The absolute configuration of the product was
determined by a single crystal X-ray analysis of enantiopure
2a (see the Supporting Information).
€
Wilking, M.; Muck-Lichtenfeld, C.; Daniliuc, C. G.; Hennecke, U.
J. Am. Chem. Soc. 2013, 135, 8133.
(8) For recent enantioselective fluorocyclization reactions, see: (a)
Wilkinson, S. C.; Lozano, O.; Schuler, M.; Pacheco, M. C.; Salmon, R.;
Gouverneur, V. Angew. Chem., Int. Ed. 2009, 48, 7083. (b) Rauniyar, V.;
Lackner, A. D.; Hamilton, G. L.; Toste, F. D. Science 2011, 334, 1681.
(c) Cochrane, N. A.; Nguyen, H.; Gagne, M. R. J. Am. Chem. Soc. 2013,
135, 628.
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tion and bromination reactions, see: (a) Phipps, R. J.; Hiramatsu, K.;
Toste, F. D. J. Am. Chem. Soc. 2012, 134, 8376. (b) Honjo, T.; Phipps,
R. J.; Rauniyar, V.; Toste, F. D. Angew. Chem., Int. Ed. 2012, 51, 9684.
(c) Alix, A.; Lalli, C.; Retailleau, P.; Masson, G. J. Am. Chem. Soc. 2012,
134, 10389. (d) Zhang, W.; Liu, N.; Schienebeck, C. M.; Zhou, X.; Izhar,
I. I.; Guzei, I. A.; Tang, W. Chem. Sci. 2013, 4, 2652.
(10) For recent examples on enantioselective chlorocyclization, see:
(a) Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B. J. Am.
Chem. Soc. 2010, 132, 3298. (b) Jaganathan, A.; Garzan, A.; Whitehead,
D. C.; Staples, R. J.; Borhan, B. Angew. Chem., Int. Ed. 2011, 50, 2593.
(c) Yousefi, R.; Whitehead, D. C.; Mueller, J. M.; Staples, R. J.; Borhan,
B. Org. Lett. 2011, 13, 608.
Under the optimized reaction conditions, various sub-
stituted indole-derived benzamides were tested to probe
the generality of the reaction. The results are summarized
in Scheme 2. Either an electron-donating group (2bꢀ2d,
80ꢀ87% yields, 91ꢀ95% ee) or an electron-withdrawing
group (2e, 70% yield, 95% ee) at the meta or para position
of the benzamide (R3) were well tolerated. In addition, 1f
containing heteroarylamide was also a suitable substrate
(2f, 86% yield, 94% ee). A decreased ee, however, was
obtained when the benzamide was replaced with an piva-
lamide (2g, 76% yield, 80% ee). The substrates bearing an
electron-donating group (2h, 90% yield, 96% ee) or an
electron-withdrawing group (2i, 82% yield, 90% ee) on the
indole core were well tolerated.
(11) During the preparation of this manuscript, an enantioselective
chloroetherification of homoallylic alcohols was reported; see: Zeng, X.;
Miao, C.; Wang, S.; Xia, C.; Sun, W. Chem. Commun. 2013, 49, 2418.
(12) For a selected recent example of enantioselective dichlorination
of olefin, see: (a) Nicolaou, K. C.; Simmons, N. L.; Ying, Y.; Heretsch,
P. M.; Chen, J. S. J. Am. Chem. Soc. 2011, 133, 8134. For enantiose-
lective chloroamination reaction of activated alkene, see: (b) Cai, Y.;
Liu, X.; Jiang, J.; Chen, W.; Lin, L.; Feng, X. J. Am. Chem. Soc. 2011,
133, 5636. For enantioselective halogenative semipinacol rearrange-
ment, see: (c) Chen, Z.-M.; Zhang, Q.-W.; Chen, Z.-H.; Li, H.; Tu,
Y.-Q.; Zhang, F.-M.; Tian, J.-M. J. Am. Chem. Soc. 2011, 133, 8818.
(13) For a recent review, see: Zhuo, C.-X.; Zhang, W.; You, S.-L.
Angew. Chem., Int. Ed. 2012, 51, 12662.
(14) Lozano, O.; Blessley, G.; Martinez del Campo, T.; Thompson,
A. L.; Giuffredi, G. T.; Bettati, M.; Walker, M.; Borman, R.; Gouverneur,
V. Angew. Chem., Int. Ed. 2011, 50, 8105.
(15) For selected examples of the dearomatization reaction from this
group, see: (a) Wu, Q.-F.; He, H.; Liu, W.-B.; You, S.-L. J. Am. Chem.
Soc. 2010, 132, 11418. (b) Cai, Q.; Zheng, C.; Zhang, J.-W.; You, S.-L.
Angew. Chem., Int. Ed. 2011, 50, 8665. (c) Yin, Q.; You, S.-L. Org. Lett.
2012, 14, 3526.
Substrates varying the substituents on aniline were also
carried out to further examine the reaction scope. In all
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scope for Chlorocyclization of 1
time
yield
(%)b
ee
entrya
solvent
DCM
Xþ, product
(h)
(%)c
1
2
3
DCDPH, 2a
DCDPH, 2a
DCDPH, 2a
16
2
85
94
89
75
77
90
CH3CN
DCM/CH3CN
(2/1)
12
4
5
DCM/CH3CN
(2/1)
NCS, 2a
24
12
<10
92
86
85
DCM/CH3CN
(2/1)
DCDMH, 2a
6
DCE
DCDPH, 2a
DCDPH, 2a
DCDPH, 2a
DCDPH, 2a
DCDPH, 2a
DCDPH, 2a
12
12
12
3
93
88
55
88
82
67
53
58
54
78
95
91
7
CCl4
8
toluene
CF3CH2OH
CHCl3
9
10
11d
30
30
CHCl3
a Reactions were performed with 1a (0.1 mmol), Xþ (0.15 mmol), and
10 mol % of (DHQD)2PHAL at ꢀ30 °C. b Isolated yield. c Determined
by HPLC. d Reaction was performed at ꢀ10 °C.
Scheme 3. Substrate Scope for Chlorocyclization of 3
cases, good yields and enantioselectivity were achieved
(2jꢀ2k, 77ꢀ82% yields, 84ꢀ92% ee). When the protecting
group of the indole N1 position was changed from Ac to
Boc, the corresponding chlorocyclization product 2l was
obtained in 74% yield with 88% ee.
To further broaden the structural diversity of the pro-
ducts, indol-2-yl benzamide substrates were also tested to
afford the corresponding oxazolines (Scheme 3).
Under slightly revised reaction conditions, substrates
with an electron-withdrawing group on the indole core
could be well tolerated in good yields with excellent en-
antiocontrol (4aꢀ4d, 75ꢀ81% yields, 93ꢀ96% ee). Benz-
amides containing various substituents on the benzene
ring were also suitable substrates to give the corresponding
chlorocyclization products with excellent enantioselectiv-
ity (4eꢀ4h, 76ꢀ81% yields, 92ꢀ94% ee). In addition,
N-Boc indole and 2-thienyl derived substrates could both
be well tolerated (4iꢀ4j, 75ꢀ86% yields, 90ꢀ93% ee).
The products obtained here containing a chiral CꢀCl
bond provide an opportunity for diverse transformations
(Scheme 4). For instance, when 2a (92% ee) was treated
with silver nitrate in aqueous phase, nitrate 5a was ob-
tained with good stereochemical integrity (74% yield, 93%
ee). The alcohol 6a could be obtained in good yield after
subjecting nitrate 5a to Pd/C hydrogenation conditions
(91% yield, 92% ee). The relative stereochemistry of
product 6a was established by NOESY NMR analysis
(see the Supporting Information). Furthermore, product
4i (93% ee) could be converted to enantioenriched indo-
line-3-one 7a via a hydrolysis and Ley oxidation reaction
sequence. Notably, 7a has a skeleton similar to that of
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Transformations of Products
Figure 1. Proposed working model.
continuous spiro quaternary carbon center and tertiary
carbon center by enantioselective chlorocyclization of
indole derived benzamides. With (DHQD)2PHAL as the
catalyst, dearomatization products were obtained in good
yields and excellent enantioselectivity under mild reaction
conditions with operationally simple procedures.
natural product erucalexin, which shows antifungal activ-
ity against S. sclerotiorum and R. solani.16
As for the working model of this reaction, we speculate
that, on the one hand, the phthalazine nitrogen in the
catalyst forms a hydrogen bond with the benzamide NH in
the substrate to increase the nucleophilic property of the
amide group; on the other hand, the tertiary amine nitro-
gen in the catalyst acts as a Lewis base to activate the
chloronium species to provide a chiral environment to
induce high enantioselectivity (a). It seems that, in our
system, the dichlorohydantoin was not activated by the
hydrogen-bond interaction with the protonated amino-
group (b), as a racemic product was obtained when BzOH
(1 equiv) was added as an additive (Figure 1).10a
Acknowledgment. We thank the National Basic Re-
search Program of China (973 Program 2010CB833300),
the National Natural Science Foundation of China
(20923005, 21025209, 21121062), and the Chinese Acad-
emy of Sciences for generous financial support.
Supporting Information Available. Detailed experi-
mental procedures and spectroscopic data for all new
compounds and X-ray crystal data of 2a. This material
is available free of charge via the Internet at http://
pubs.acs.org.
In summary, we have developed an efficient method
for the construction of chiral indoline skeletons with a
(16) Pedras, M. S. C.; Suchy, M.; Ahiahonu, P. W. K. Org. Biomol.
Chem. 2006, 4, 691.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX