Unprecedented one-pot, domino tertiary alcohol protection-michael type addition of halides to Morita-Baylis-Hillman adduct of isatin with RCOX/K 2CO3: Diastereoselective synthesis of oxindole appended β-halo esters

Article abstract of DOI:10.1021/ol303554c

A facile method utilizing RCOX/K₂CO₃ as a novel reagent for conjugate addition of hydrogen halide, in addition to tertiary (3)-hydroxyl protection that leads to the synthesis of functionalized β-halo Morita-Baylis-Hillman ester appended oxindoles, has been developed. The diastereoselective one-pot O-acylation-hydrohalogenation observed cannot otherwise be performed by treatment with hydrohalide. Deprotection of a 3 -hydroxyl protecting group has also been demonstrated by treatment with hydrochloric acid.

Full text of DOI:10.1021/ol303554c

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1186–1189
Unprecedented One-Pot, Domino Tertiary
Alcohol ProtectionꢀMichael Type
Addition of Halides to MoritaꢀBaylisꢀ
Hillman Adduct of Isatin with RCOX/
K2CO3: Diastereoselective Synthesis of
Oxindole Appended β‑Halo Esters
Rajarethinam Solaiselvi,† Ponnusamy Shanmugam,*,† and Asit Baran Mandal‡
Council of Scientific and Industrial Research (CSIR)-Central Leather Research
Institute (CLRI), Organic Chemistry Division, Chemical Laboratory, Adyar,
Chennai-600020, India
shanmu196@rediffmail.com
Received December 27, 2012
ABSTRACT
A facile method utilizing RCOX/K2CO3 as a novel reagent for conjugate addition of hydrogen halide, in addition to tertiary (3°)-hydroxyl protection
that leads to the synthesis of functionalized β-halo MoritaꢀBaylisꢀHillman ester appended oxindoles, has been developed. The
diastereoselective one-pot O-acylationꢀhydrohalogenation observed cannot otherwise be performed by treatment with hydrohalide.
Deprotection of a 3°-hydroxyl protecting group has also been demonstrated by treatment with hydrochloric acid.
Development of novel methods to functionalize an
oxindole nucleus has attracted much attention, since oxin-
dole is an integral structural unit in alkaloid natural
products and is widely found in heterocyclic compounds
withbiological and medicinal applications.1,2The Moritaꢀ
BaylisꢀHillman (MBH) adducts3 and their acetate deriv-
atives are useful precursors for the synthesis of diverse
and multifunctional molecules,4 and the MBH adduct of
isatin has been utilized for functionalization of an oxindole
† Organic Chemistry Division.
‡ Chemical Laboratory.
(3) (a) Baylis, A. B.; Hillman M. E. D. German Patent 2155113, 1972.
Chem. Abstr. 1972, 77, 34174q. (b) Morita, K.; Suzuki, Z.; Hirose, H.
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103, 811. (b) Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev. 2009,
109, 1. (c) Batra, S.; Singh, V. Tetrahedron 2008, 64, 4511. (d) Ciganek, E.
Organic Reactions; Paquette, L., Ed.; Wiley: New York, 1997; Vol. 51, p
201. (e) Ma, G. N.; Jiang, J. J.; Shi, M.; Wei, Y. Chem. Commun. 2009,
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110, 5447.
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(b) Viswambharan, B.; Selvakumar, K.; Suchithra, M.; Shanmugam, P.
Org. Lett. 2010, 12, 2108. (c) Selvakumar, K.; Vaithiyanathan, V.;
Shanmugam, P. Chem. Commun. 2010, 46, 2826.
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P. R.; Williams, R. M. Tetrahedron 2004, 60, 9503.
r
10.1021/ol303554c
Published on Web 03/05/2013
2013 American Chemical Society

Scheme 1. 3°-Hydroxyl Protection and Michael Type HCl
Addition to 1a with RCOCl/K2CO3
nucleus.5 β-Halo MBH esters6 are vital intermediates to
synthesize β-branched MBH esters.7 Nucleophilic substi-
tution of MBH adducts with various nucleophiles pro-
vided functionalized trisubstituted alkenes via an allylic
nucleophilic substitution reaction.8,9 In contrast to the
previous reports,10 we have observed conjugate addi-
tion of hydrogen halide along with tertiary alcohol
protection by reaction with acyl halides (RCOX) in
the presence of alkali carbonates, forming β-halo MBH
esters of oxindole.
The protectionꢀdeprotection sequences of hydroxyl
groups, particularly tertiary alcohol, is one of the essential
transformations for selective reactions.11 Hence, several
studies have been directed toward developing efficient,
simple methods to protect the hydroxyl group using a
variety of protecting reagents and catalytic conditions.12
However, manyofthemsufferfrom stringent experimental
conditions, usage of expensive chemicals, and/or prepara-
tion of catalysts.13 Against this background, and also in
continuation of our interest in the functionalization of
oxindole via BaylisꢀHillman chemistry,5b,c,8c we report
Figure 1. ORTEP diagram of compounds 3c, 3g, and 3f.14
here a facile one-pot tertiary alcohol protection and dia-
stereoselective hydrohalogenation (dr <95%) of MBH
adduct acrylates of isatin.
To avoid pyridine as a base, we examined the tertiary
(3°) alcohol protection ofMBH adduct1awithotheralkali
metal carbonate bases. Thus, adduct 1a in acetonitrile was
treated with acetyl chloride and potassium carbonate at rt.
We were gratified to observe that the 3°-hydroxyl protec-
tion took place with a 52% yield of 4a (Scheme 1).
To increase the yield of 4a, the above reaction was
monitored with increased amounts of acetyl chloride to
1.5 equiv. To our surprise, in addition to the formation of
4a in 75% yield, the 3°-OH protected, hydrochlorinated
MBH acetate 3a was found to be forming in the reaction
mixture in 20% yield. Compound 4a can be converted to
3a under similar reagent conditions.
(6) (a) Senapati, B. K.; Hwang, G. S.; Lee, S.; Ryu, D. H. Angew.
Chem., Int. Ed. 2009, 48, 4398. (b) Li, Q.; Shi, M.; Lyte, J. M.; Li, G.
Tetrahedron Lett. 2006, 47, 7699. (c) Lee, S.; Hwang, G. S.; Shin, S. C.;
Lee, T. G.; Jo, R. H.; Ryu, D. H. Org. Lett. 2007, 9, 5087.
(7) (a) Kataoka, T.; Kinoshita, H.; Kinoshita, S.; Iwamura, T.;
Watanabe, S. Angew. Chem., Int. Ed. 2000, 39, 2358. (b) Ramachandran,
P.; Rudd, M. T.; Burghardt, T. E.; Reddy, M. V. R. J. Org. Chem. 2003,
68, 9310. (c) Reynolds, T. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am.
Chem. Soc. 2006, 128, 15382. (d) Reynolds, T. E.; Scheidt, K. A. Angew.
Chem. 2007, 119, 7952. Angew. Chem., Int. Ed. 2007, 46, 7806. (e) Tarsis,
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Lett. 2008, 10, 4819. (f) Mueller, A. J.; Jennings, M. P. Org. Lett. 2008,
10, 1649.
The structure of 3a was unambiguously assigned by
spectroscopic data analyses (IR, 1H, 13C NMR, and mass),
and the relative stereochemistry was confirmed as (R,R) by
single crystal X-ray analysis of 3f (Figure 1).
With this promising result in hand, we then undertook
further optimization experiments, and the results are
summarized in Table 1. The conditions were optimized
for choice of base, solvent, and equivalents of acid halide
and base used. The yield of compound 3a increased with 1
equiv of base, and in 8 h, compound 3a and acetate 4a were
formed in 75% and 12% yield, respectively (Table 1,
entries 1ꢀ3), conferring high diastereoselectivity (95%)
for 3a. Although both K2CO3 and Na2CO3 lead tothe high
diastereoselectivity of product, potassium carbonate gave
a higher yield of 4a in a given reaction time. However,
reaction with organic bases such as pyridine, Et3N, and
DABCO lead to the formation of acetate 4a in good yield.
From the results it is clear that the reaction conditions
could be tuned for either the 3°-alcohol protected adduct
or 3°-alcohol protected conjugate addition product, and
the ideal conditions for the latter were found to include
1.5 equiv of acid halide and 1 equiv of potassium carbonate
in dichloromethane (Table 1, entry 5).
(8) (a) Basavaiah, D.; Kumaragurubaran, N.; Padmaja, K. Synlett
1999, 713. (b) Kim, H. S.; Kim, T. Y.; Lee, K. Y.; Chung, Y. M.; Lee,
H. J.; Kim, J. N. Tetrahedron Lett. 2000, 41, 2613. (c) Shanmugam, P.;
Rajasingh, P. Tetrahedron 2004, 60, 9283.
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Villieras, J. Synthesis 1998, 1765. (b) Ying, T. K.; Bao, W. L.; Wang,
Z. H.; Zhang, Y. M. J. Chem. Res. (S) 2005, 96. (c) Yadav, J. S.; Reddy,
B. V. S.; Madan, C. New J. Chem. 2001, 25, 1114.
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1985, 24, 94. (b) Buchholz, R.; Hoffmann, H. M. R. Helv. Chim. Acta
1991, 74, 1213. (c) Basavaiah, D.; Bakthadoss, M.; Pandiaraju, S.
J. Chem. Soc., Chem. Commun. 1998, 1639.
(11) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; Wiley: New York, 1991.
(12) (a) Schelhaas, M.; Waldmann, H. Angew. Chem., Int. Ed. 1996,
35, 2056. (b) Ramesh, R.; Bhat, R. G.; Chandrasekaran, S. J. Org. Chem.
2005, 70, 837. (c) Karimi, B.; Golshani, B. J. Org. Chem. 2000, 65, 7228.
(d) Paleo, M. R.; Aurrecoechea, N.; Jung, K.-Y.; Rapoport, H. J. Org.
Chem. 2003, 68, 130.
(13) (a) Poon, K. W. C.; Albiniak, P. A.; Dudley, G. B.; Berliner,
M. A.; Ragan, J. A. Org. Synth. 2007, 84, 295. (b) Yokoshima, S.; Ueda,
T.; Kobayashi, S.; Sato, A.; Kobayashi, T.; Tokuyama, H.; Fukuyama,
T. Pure Appl. Chem. 2003, 75, 29. (c) Shirakawa, E.; Hayashi, T. Chem.
Commun. 2006, 3927.
The surprising Michael type conjugate addition of HX
took place only under basic conditions. The reactions of
Org. Lett., Vol. 15, No. 6, 2013
1187

Table 1. Optimization for the Synthesis of 3a
Table 2. Synthesis of Tertiary Alcohol Protected β-Halo MBH
Esters 3aꢀj and Acetate Adducts 4aꢀj from MBH Adducts 1aꢀha
equiv
products
3a/4a
(yield %)a
equiv of
of
time
(h)
entry MeCOCl
base
base
solvent
1
2
3
4
5
6
7
8
1
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Na2CO3
K2CO3
pyridine
Et3N
0.5
0.5
0.5
1
1
1
1
1
1
1
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
4
4
8
8
8
8
8
8
8
8
8
3
0/52
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
20/75
30/56
75c/12
82c/5
80d/3
74c/8
12/30
5/55
9
10
11
12b
8/56
8/50
86/5
DABCO
K2CO3
1
1
a Isolated yield. b Acetyl bromide yielded the corresponding β-bromo
MBH ester. c Dr of 4a determined by 1H NMR of the crude product was
95%. d Dr of 4a was 80%.
MBH adduct
Z
productb
both the adduct 1a and the hydroxyl protected MBH
adduct of isatin 4a, with hydrogen halides, yielded only
the allylic substituted product.15 The hydrohalogenated
MBH acetate could not be accomplished by a stepwise ꢀOH
protection and reaction with a hydrogen halide which
yields only allylic halo substituted product 5 (Scheme 2).
The formation of the unexpected product with acetyl
chloride prompted us to generalize with other acyl halides
such as acetyl bromide for conjugate HBr addition with 1a
under optimal conditions. The reaction took place rapidly
and afforded the β-bromo MBH ester 3b (86%) in 3 h with
a traceof4a. The diastereoselectivity for bromocompound
3b was found to be 87% with the similar relative config-
uration (R, R) (Table 2, entry 2). Similarly, with acetyl
iodide generated in situ from treating acetyl chloride with
potassium iodide, the reaction proceeded smoothly to
provide the desired iodo compound 3c in 80% yield with
90% (R, R) diastereoselectivity (Table 2, entry 3). The
versatility of the method developed was evaluated by
screening other acyl halides. Propionyl chloride provided
the hydrochlorinated propionate product 3d in 60% yield
along with the tertiary hydroxyl protected product 4b in
29% yield, generalizing the method for acyl halides
(Table 2, entry 4). The relative stereochemistry of iodo deriv-
ative 3c and bromo derivative 3g was confirmed as (R, R)
by single crystal X-ray analysis (Figure 1). The synthesis of
the β-halo product was unsuccessful with the acrylonitrile
derived MBH adduct of isatin. When treated, only the pro-
tected adduct was formed up to 87% yield and no hydrogen
entry
R1
1
R3COX 3/4 (%)d dr (%)e
1
2
Me
Me
Me
Me
Me
Bn
Bn
Bn
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
1a
1a
1a
1a
1bg
1c
1c
1c
1d
1e
1f
2a
2b
2cf
2d
2b
2a
2b
2cf
2b
2b
2b
2b
2a
2b
2b
2e
3a (82)
3b (80)
3c (80)
3d (60)
3e (75)
3f (80)
3g (75)
3h (74)
3i (74)
3j (74)
3k (80)
3l (81)
4i (91)
4i (90)
4j (90)
4k (82)
95:05
87:13
90:10
90:10
80:20
95:05
85:15
85:15
84:16
80:20
88:12
88:12
ꢀ
3
4c
5
6
7
8
9
10
11
12
13h
14h
15h
16h
allyl
propargyl CO2Me
Me
Me
Me
Me
Bn
Bn
CO2Et
CO2nBu 1g
CN
CN
CN
CO2Me
1h
1h
1i
ꢀ
ꢀ
1c
ꢀ
a All reactions were performed with 1.5 equiv of RCOX and 1 equiv
of K2CO3 in CH2Cl2. b Unless stated otherwise the corresponding
3°-hydroxyl protected MBH adduct was isolated in <5% yield. c The
corresponding 3°-hydroxyl protected MBH adduct was isolated in
29% yield. d Isolated yield of the major diastereomer. e Diastereomeric
ratio was determined using 1H NMR of the crude product. f In situ
generation of acetyl iodide by treating acetyl chloride with KI. g R2 =
Me. h Only 3°-OH protected MBH adduct was obtained.
halide addition was noticed (Table 2, entries 13ꢀ15). The
method has been found to be versatile with acyl halides.
However, under optimized conditions, experiments with an
aromatic acid halide, for example benzoyl chloride, led only to
the tertiary hydroxyl protection (Table 2, entry 16).
To demonstrate the scope and limitation of the reaction,
experiments with an MBH adduct of N-substituted and
5-substituted isatins 1bꢀewere carried out, and they furnished
the hydrohalogenated MBH acetate as the major product
(Table 2, entries 5ꢀ10). To show the method is general for
Scheme 2. Reaction of MBH Ester of Isatin with Halides under
Acidic and Basic Conditions
(14) CCDC 915450, 911325, and 911324 contains the supplementary
crystallographic data of compounds 3c, 3g, and 3f, respectively. A copy
of the data can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (Fax: þ 44-1223/336-033;
E-mail: deposit@ccdc.cam.ac.uk).
(15) Shanmugam, P.; Vaithiyanathan, V.; Viswambharan, B. Tetra-
hedron 2006, 62, 4342.
1188
Org. Lett., Vol. 15, No. 6, 2013

Scheme 3. Synthesis of 3b in a One-Pot Sequential Manner,
3°-Hydroxyl Deprotection and Synthetic Transformation of 3b
Scheme 5. Plausible Mechanism of the Reaction
acrylate derived MBH adducts, under optimized conditions,
the reaction of ethyl acrylate and the n-butyl acrylate adduct of
N-methyl isatin gave the β-bromo compound in 80% and
81% yields, respectively (Table 2, entries 11, 12).
Scheme 6. Experimental Support for the Mechanism
The formation of an MBH adduct of isatin and the reaction
with acyl halide could also be achieved in a one-pot sequential
manner, however, in a lower yield of 3b (75%) (Scheme 3).
Compound 3b with mineral acids such as H2SO4 or HCl
in methanol at 65 °C for 3 h yielded deprotected product 6a
in 95% yield. Further synthetic transformation of 6a with
10 mol % of Cu(OTf)2 afforded unexpected, functionalized
bis-isatin compounds 7a and 7b, where the hydroxyl group
in 6a has been substituted with another molecule of 6a that
became dehydrated to 7a and 7b. Reductive cyclization of 7a
with sodium borohydride at rt led to the formation of
cyclopropane appended functionalized bis isatin 8a in
80% yield in a diastereoselective manner along with a
10% yield of other inseparable diastereomers (Scheme 3).
To widen the substrate scope, a methyl acrylate derived
MBH adduct of N-bridged isatin 1j was treated with acetyl
bromide and furnished the bis-tertiary alcohol protected
hydrogen halide addition product 3m in 50% yield
(Scheme 4). Thus, the method has versatility over the
substituents of acyl halides, isatins, and acrylates. Experi-
ments with the acrylate MBH adduct ofninhydrin and that
of benzaldehyde resulted only in the hydroxyl protected
compounds in 82 and 90% yields, respectively.
A mechanistic proposal for the diastereoselective for-
mation of the β-halo ester appended oxindole is outlined in
Scheme 5. The mechanism can be explained by invoking a
diastereoselective domino acylation/Michael type addition
pathway. In the initial step, the base triggers the alkoxide
ion resulting from adduct 1, to obtain acylated intermediate
A followed by the attack of the halide on the activated
double bond of the Michael acceptor, producing the enolate
ion B. A possible coordination of the partially negative amide
oxygen of oxindole with a metal enolate probably stabilizes
the intermediate and orients the path of protonation, ex-
plaining the observed acyclic stereocontrol in the product 3.
The acylation and the attack of the halide ion on the
activated double bond are consecutive under basic condi-
tions, as inference from the experimental support (Scheme 6)
that a reaction of the hydroxyl acetylated MBH adduct 4a
with propionyl bromide resulted in the formation of acetyl
protected product 3b in 70% yield along with a 5% yield of
corresponding propionyl protected compound 3d. Similarly,
the hydroxyl benzoylated adduct4k with acetyl bromide under
optimized conditions led to the formation of benzoate pro-
tected compound 3n as a major product and acetyl protected
product 3g in 8% yield, sustaining the above presumption.
In conclusion, we have demonstrated a facile and efficient
method that utilizes acyl halide for halogenation in addition
to 3°-hydroxyl protection that leads to the synthesis of
functionalized, β-halo MBH ester appended oxindoles. The
reaction itself features a simple experimental procedure under
benign conditions with acyclic stereocontrol and atom econ-
omy. Further studies with utilization of these β-halo MBH
esters for functionalization of an oxindole core are underway.
Acknowledgment. R.S. thanks the CSIR (New Delhi)
for the award of SRF.
Scheme 4. Synthesis of 3°-OH Protected β-Halo MBH-Ester of
N-Bridged Isatin 3m
Supporting Information Available. Detailed experimen-
tal procedure, compiled spectroscopic data of new com-
pounds, and scanned copies of spectra are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
1189