Indium(III) Chloride Promoted Highly Efficient Tandem Rearrangement-α-Addition Strategy towards the Synthesis of α-Hydroxyamides

Article abstract of DOI:10.1055/s-0035-1561602

A new tandem process is reported that provides access to α-hydroxyamides from epoxides for the first time. Herein, we explore InCl₃-mediated tandem rearrangement of epoxides to aldehydes and α-addition of TosMIC to in situ derived aldehydes. An unprecedented C-C bond-forming reaction is disclosed that features mild conditions, high yields, and shorter reaction times.

Full text of DOI:10.1055/s-0035-1561602

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–F
letter
A
K. Lingaswamy et al.
Letter
Synlett
Indium(III) Chloride Promoted Highly Efficient Tandem Rear-
rangement–α-Addition Strategy towards the Synthesis of
α-Hydroxyamides
Kadari Lingaswamy
Dumpala Mohan
OH
H
InCl3
R2
R1
R2
R1
N
Tos
(0.5 equiv)
O
CN
Tos
Palakodety Radha Krishna
Y. Lakshmi Prapurna*
H
THF:H2O (9:1), rt
O
epoxide
TosMIC
a-hydroxy amide
R1, R2 = H,
aryl or alkyl
D-207, Discovery Laboratory, Organic and Biomolecular
Chemistry Division, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500007, India
C–C bond formation via tandem rearrangement/a-addition
ylprapurna.iict@gov.in
mild reaction conditions
high regioselectivity
shorter reaction times
high yields
O
R2
R1
H
H
Received: 20.10.2015
Accepted after revision: 10.03.2016
Published online: 07.04.2016
Bearing a formally divalent carbon, isocyanides are ca-
pable of engaging in carbon–carbon bond-forming reac-
tions known as α-additions. p-Toluenesulfonylmethyl iso-
cyanide (TosMIC), a unique isocyanide is widely used in the
synthesis of heterocycles.12 It is a densely functionalized
building block with three functional groups that can engage
in a multitude of reactions. In the course of our research
aimed at expanding the TosMIC chemistry,13,14 we attempt-
ed InCl3-mediated nucleophilic ring-opening of epoxides
with TosMIC. However, our results revealed the addition of
TosMIC to epoxide does not form the expected product 3a
but affords instead the α-hydroxyamides 2a–k through un-
precedented tandem rearrangement of epoxides to alde-
hydes and subsequent α-addition of TosMIC to aldehydes
(Scheme 1). To the best of our knowledge, this is the first
example of synthesis of α-hydroxyamides directly from ep-
oxides. Moreover, a full investigation on the literature re-
veals that TosMIC has not been used as an isonitrile compo-
nent in most of the α-additions of isocyanides to aldehydes
reported thus far. A few reported formation of byproducts
along with the desired product when TosMIC was employed
as a nucleophile in this reaction.11b
First, we examined the reaction of the styrene oxide
(1a) with TosMIC using various Lewis acids (Table 1). Nei-
ther BF3·OEt2 nor CuI gave the product (Table 1, entries 1
and 6). But the other Lewis acids like Zn(OTf)2, FeCl3,
Cu(OTf)2, and RuCl3 gave lower yields (Table 1, entries 2, 4,
5, and 7). InCl3 was found to be effective to furnish the
product 2a in less reaction time and high yield. It was also
found that THF–H2O (9:1) was the optimal solvent for this
reaction. To determine the optimal catalyst loading the re-
action using styrene oxide with TosMIC was conducted
with varying amounts of InCl3 (Table 2). A maximum yield
of 90% was obtained with 50 mol% of catalyst (Table 2, entry
4). Increase in catalyst loading to 100 mol% did not have any
DOI: 10.1055/s-0035-1561602; Art ID: st-2015-b0827-l
Abstract A new tandem process is reported that provides access to α-
hydroxyamides from epoxides for the first time. Herein, we explore
InCl3-mediated tandem rearrangement of epoxides to aldehydes and α-
addition of TosMIC to in situ derived aldehydes. An unprecedented C–C
bond-forming reaction is disclosed that features mild conditions, high
yields, and shorter reaction times.
Key words C–C bond formation, indium(III) chloride, epoxides, Tos-
MIC, tandem rearrangement, α-addition
The α-hydroxyamides are useful building blocks for the
synthesis of biologically active natural products,1 especially
depsipeptide compounds.2 They have been identified as in-
hibitors of methionine aminopeptidase-2 and HIV protease,
potent antitumor activity, and play an important role in
medicinal chemistry.3 Due to the significance of this core,
the convenient formation of this moiety has attracted much
attention in recent years. Classically, α-hydroxyamides have
been synthesized by condensation of lactic acid with an
amine and the most direct method is the Passerini-type re-
action.4–6 Since the early studies by Passerini,7 Ugi, and co-
workers8 the power of α-addition reaction in constructing
polyfunctional molecules has been well appreciated. The
Passerini-type reaction, that is, reaction of aldehydes with
isocyanides under acid-free conditions attracts chemists for
wider applications. Although the Lewis acid mediated α-
addition of isocyanides to aldehydes has been well studied,9
most of these methods suffer from formation of undesired
products and moreover, catalyst turnover for conventional
Lewis acid catalysis requires the cleavage of the Lewis acid
from the product.10 Later on, dramatic improvement has
been reported in the enantioselective α-addition of isocya-
nides to aldehydes.11
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

B
K. Lingaswamy et al.
Letter
Synlett
Table 2 Optimization of Catalyst Loading for the Synthesis of α-Hy-
droxyamides
OH
H
R2
R1
N
Tos
Tos
H
2a–k
Yield (%)a
O
Entry
InCl3
Time (min)
R2
O
InCl3 (0.5 equiv)
+
TosMIC
+
1
2
3
4
5
0
10
60
60
60
30
30
–
R1
1a–k
THF–H2O (9:1), r.t.
71
82
90
90
R1, R2 = H, aryl
or alkyl
R2
R1
30
H
N
50
OH
O
100
3a
a Yields refer to pure isolated products.
Scheme 1 InCl3-mediated synthesis of α-hydroxyamides from epox-
ides
2a wherein CH–OH proton appeared at δ = 4.21 ppm. The
same proton which otherwise would have appeared down-
field shifted in 3a than reported herein. Further, the forma-
tion of 2a was unambiguously demonstrated by 13C NMR
analysis, and the IR spectrum revealed characteristic
stretching frequencies at 3319 and 1675 cm–1 due to N–H
and C=O functional groups. Observation of α-substituted al-
cohols in these reactions can be explained by tandem rear-
rangement of epoxide to aldehyde16 followed by α-addition
of TosMIC to aldehyde. While the rearrangement and α-ad-
ditions are known separately, a simple method capable of
effecting both elementary steps has not been identified. In-
deed, the significance of this novel protocol is that it per-
forms both operations in a single pot to afford α-hydroxy-
amides from easily accessed epoxides and TosMIC. To our
delight, the test reaction between benzaldehyde 4 and Tos-
MIC furnished the corresponding α-hydroxyamide 4a in
high yield, which itself has the ability to open a new era of
InCl3-mediated Passerini-type reaction under mild condi-
tions. In Scheme 2, a plausible mechanism for InCl3-mediat-
ed facile synthesis of α-hydroxyamides is outlined. Even
though, the Lewis acid mediated rearrangement of epoxide
to aldehyde is already known in the literature, in order to
find the aldehyde formation, two parallel reactions of sty-
rene oxide with and without addition of TosMIC were per-
formed under standard conditions.17a Identification of alde-
hyde was done by comparing both the reaction sets, the re-
action mixture without TosMIC showed the corresponding
aldehyde,17b which was also seen in the reaction mixture
wherein TosMIC was present which was further consumed
(analysis by TLC) to give the α-hydroxyamide product.
significant effect on the yield of the product (Table 2, entry
5). Particularly noteworthy was the dependence of reaction
outcome on addition of water which facilitates easy hydro-
lysis. The reaction provided the α-substituted alcohol prod-
uct 2a instead of the expected β-substituted alcohol prod-
uct 3a, that is, the nucleophilic oxirane ring opening with
isonitrile functionality of TosMIC. Although the nucleophil-
ic ring opening of the epoxide is well established, the α-
substituted alcohol synthesis remains typically limited.15
Table 1 Optimization of Reaction Conditionsa
Entry
Catalyst
Solvent
Time (min)
Yield (%)b
1
2
BF3·OEt2
Zn(OTf)2
InCl3
THF
60
30
30
60
20
60
25
30
30
30
0
56
80
50
55
0
THF
3
THF
4
FeCl3
THF
5
Cu(OTf)2
CuI
THF
6
THF
7
RuCl3
InCl3
THF
55
75
90c
75
8
MeCN
THF–H2O
CH2Cl2
9
InCl3
10
InCl3
a Reaction conditions: epoxide (1.0 equiv), TosMIC (1.0 equiv), Lewis acid
(0.5 equiv), and solvent.
b The yields refer to isolated products purified by column chromatography.
c The best yield was obtained in THF–H2O (9:1).
1
Moreover, the H NMR analysis of the crude reaction mix-
ture showed a triplet at δ = 9.73 ppm (J = 2.32 Hz) indicat-
ing the aldehyde formation as an intermediate (see Sup-
porting Information).
The spectral analysis revealed 2a as the predominant
product. Thus, the H NMR spectrum of product 2a shows
1
characteristic N–H as a broad singlet at δ = 7.55 ppm, meth-
ylene protons at δ = 4.65 ppm as a doublet (J = 6.97 Hz),
CH–OH at δ = 4.21 ppm, two C–H protons as doublet of
doublets at δ = 3.04 and 2.62 ppm, and all other protons
resonated at their appropriate values. The possible forma-
tion of 3a was discounted in view of the 1H NMR analysis of
Encouraged by these results, we next turned our atten-
tion to investigate the scope of the reaction. Generally, vari-
ous epoxides (Table 3, entries 1a–k) containing different
substituents underwent the reaction under the standard
conditions to give the corresponding α-hydroxyamides
(2a–k) as the sole products. It indicates InCl3-mediated
isomerization of epoxides proceeded with complete regio-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

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K. Lingaswamy et al.
Letter
Synlett
1-Aryl-, 1,1-diaryl-, 1,1-dialkyl-, and aryl-substituted
epoxides underwent rearrangement to the corresponding
aryl-substituted acetaldehydes by exclusive hydride shift
(Table 3, entries 1 and 4–12). On the other hand, as ob-
served in the rearrangement of stilbene oxide, that is, 1,2-
diaryl epoxide, phenyl migration predominates the hydro-
gen shift (Table 3, entry 3). The formation of 2f (Table 3, en-
try 7) can be explained by the rearrangement of α-pinene
oxide to the expected aldehyde.18 However, the reaction
with 1l, which is a nonaromatic epoxide has proven unsuc-
cessful (Table 3, entry 13). Presumably, the incipient carbo-
cation formed by the initial cleavage of epoxide is much less
stabilized in alkyl-substituted epoxide compared to the
aryl-substituted one. But in case of 2f and 2k the product
formation can be explained by better stabilization of carbo-
cation on the tertiary center. These reactions are usually
fast and high-yielding. The spectral data of products 2b–k
further established the conclusive formation of the α-sub-
stituted alcohol product. However, the present protocol did
not furnish the desired product when tert-butyl isonitrile
and cyclohexyl isonitrile were used as isonitrile compo-
nents. The reason for this may be attributed to the higher
nucleophilicity of these compounds compared to TosMIC.19
InCl3
R2
O
R2
O
InCl3
InCl3
δ
δ
R2
O
R1
R1
H
R1
InCl3
InCl3
Tos
hydride
shift
O
Tos
O
C
N
N
R2
R1
H
R2
H
R1
H
InCl2
O
H
OH
H
hydrolysis
R2
R1
Cl
R2
R1
N
Tos
H
N
Tos
O
Scheme 2 A plausible reaction pathway
selectivity. InCl3 is a mild Lewis acid for complete regiose-
lective transformation and has a great functional-group tol-
erance.
Table 3 InCl3-Promoted Synthesis of α-Hydroxyamides from Epoxidesa
Entry
Substrate
Productb
Time (min)
30
Yield (%)c
90
O
O
Ph
N
H
Tos
1
Ph
1a
OH
2a
O
Ph
Ph CHO
4
2
3
4
5
30
40
30
30
90
92
94
92
N
H
Tos
OH
4a
Ph
O
O
O
O
Ph
Ph
N
H
Tos
Tos
Tos
Ph
1b
OH
OH
OH
2b
Ph
O
O
Ph
Ph
N
H
Ph
1c
2b
Ph
N
H
Ph
1d
2dd
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

D
K. Lingaswamy et al.
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Table 3 (continued)
Entry
Substrate
Productb
Time (min)
30
Yield (%)c
O
O
6
7
N
H
Tos
Tos
90
OH
1e
2e
O
O
60
45
85
89
N
H
OH
O
2fd
1f
O
N
H
Tos
8
OH
Br
Br
1g
2g
O
O
N
Tos
9
10
11
40
30
20
90
88
92
H
OH
F
F
1h
2h
O
O
N
Tos
H
OH
2id
1i
O
O
N
Tos
H
OH
MeO
1j
MeO
2j
O
O
12
13
90
80
N
Tos
H
OH
1k
2k
PMBO
n.d.f
180
0e
O
1l
O
O
HO
N
Tos
14
90
85
H
5
5a
a Reaction conditions: epoxide (1.0 equiv), TosMIC (1.0 equiv), InCl3 (0.5 equiv), and THF–H2O (9:1).
b All the products were characterized from spectral data.
c Isolated yields after purification by column chromatography.
d The products 2d,f,i were obtained as diastereomeric mixtures.
e Formation of unisolable products is observed.
f Not detected.
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K. Lingaswamy et al.
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Synlett
In general ketones are less reactive than aldehydes to-
wards nucleophilic attack. A simple method for the α-addi-
tion of isocyanides to carbonyl compounds is still lacking.
For instance, the susceptibility of the reaction with ketone,
that is, cyclohexanone (Table 2, entry 14) under the same
reaction conditions was next examined. It is noteworthy to
mention that the reaction of TosMIC with 5 under the pres-
ent conditions proceeded smoothly to afford 5a in good
yield. As far as we know, this is the first example of α-addi-
tion of TosMIC to ketone.
In conclusion, we have described for the first time a tan-
dem protocol that provides efficient synthesis of α-hy-
droxyamides directly from epoxides.20 A mechanistically
novel reaction pathway for the construction of C–C bond
formation was disclosed. Considering the mild reaction
conditions, tolerance of various functional groups, easy
availability of substrates, high regioselectivity, and shorter
reaction times, the methodology described here undoubt-
edly will find new applications in future synthetic endeav-
ors. The products obtained by the present protocol are
densely functionalized and can act as unique building
blocks.
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Acknowledgment
We are grateful to DST (GAP 0485), New Delhi for generous financial
support. The authors K.L. and D.M. thank UGC, New Delhi for financial
support in the form of a fellowship.
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561602.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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(17) (a) As suggested by one of the reviewers, a control experiment
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K. Chem. Commun. 2012, 48, 5497.
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(20) General Experimental Procedure (Table 3, Entry 1)
A solution of styrene oxide (120 mg, 1.0 mmol), TosMIC (195
mg, 1.0 mmol), and InCl3 (110 mg, 0.5 mmol) in THF–H2O (9:1,
2 mL) was stirred at ambient temperature until completion
(TLC). The resulting solution was partitioned between an equi-
molar ratio of Et2O (2 × 20 mL), the combined organic layers
were washed with brine (1 × 20 mL), dried (Na2SO4), evaporated
under vacuum, and the residue thus obtained was purified by
column chromatography (silica gel 60–120 mesh, EtOAc–n-
hexane, 3.0:7.0) to afford 2a.
2-Hydroxy-3-phenyl-N-(tosylmethyl)propanamide (2a)
Yellow solid (290 mg, 90% yield), mp 125–127 °C. 1H NMR (500
MHz, CDCl3): δ = 7.78 (d, J = 8.2 Hz, 2 H), 7.56 (br s, 1 H, NH),
7.39–7.15 (m, 7 H), 4.65 (d, J = 6.9 Hz, 1 H), 4.19 (dd, J = 9.4, 3.4
Hz, 1 H), 3.04 (dd, J = 13.9, 3.0 Hz, 1 H), 2.62 (dd, J = 14.0, 9.4 Hz,
1 H), 2.44 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 172.6, 145.5,
136.6, 133.7, 129.9, 129.4, 128.9, 128.7, 127.1, 72.8, 59.9, 40.5,
21.7. ESI-MS: m/z = 334 [M + H]+. HRMS: m/z calcd for
C
17H19O4NNaS [M + Na]+: 356.0927; found: 356.09226.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F