Facile access to α-acyloxyamides via epoxide rearrangement/three-component domino reaction catalyzed by indium(III) chloride

Article abstract of DOI:10.1080/00397911.2016.1201511

A simple and efficient Passerini reaction of epoxides involving highly regioselective rearrangement of epoxide to aldehyde/three-component Passerini reaction catalyzed by indium(III) chloride is described. In the present protocol, epoxides served as wonderful substrates to furnish a library of α-acyloxyamides under mild reaction conditions in shorter reaction times and in good yields.

Full text of DOI:10.1080/00397911.2016.1201511

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Facile Access to α -acyloxyamides via Epoxide
Rearrangement/Three Component Domino
Reaction Catalyzed by Indium(III) Chloride
Kadari Lingaswamy, Palakodety Radha Krishna & Y. Lakshmi Prapurna
To cite this article: Kadari Lingaswamy, Palakodety Radha Krishna & Y. Lakshmi Prapurna
(
2016): Facile Access to α -acyloxyamides via Epoxide Rearrangement/Three Component
Domino Reaction Catalyzed by Indium(III) Chloride, Synthetic Communications, DOI:
0.1080/00397911.2016.1201511
1
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1201511
View supplementary material
Accepted author version posted online: 17
Jun 2016.
Published online: 17 Jun 2016.
Submit your article to this journal
Article views: 5
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20
Download by: [Universite Laval]
Date: 25 June 2016, At: 02:04

Facile access to α-acyloxyamides via epoxide rearrangement/three component
domino reaction catalyzed by Indium(III) Chloride
1
1
1
Kadari Lingaswamy , Palakodety Radha Krishna , Y. Lakshmi Prapurna
1
D-207, Discovery Laboratory, Organic and Biomolecular Chemistry Division, CSIR-
Indian Institute of Chemical Technology, Hyderabad
Corresponding author Y. Lakshmi Prapurna D-207, Discovery Laboratory, Organic and
Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad- 500 007, E-mail: ylprapurna.iict@gov.in, prapurnay@gmail.com
Abstract
A simple and efficient Passerini reaction of epoxides involving highly regioselective
rearrangement of epoxide to aldehyde/three component Passerini reaction catalyzed by
Indium(III) Chloride is described. In the present protocol, epoxides served as wonderful
substrates to furnish a library of α-acyloxyamides under mild reaction conditions in
shorter reaction times and in good yields.
Graphical Abstract
KEYWORDS: Epoxides, TosMIC, Indium(III) Chloride,Tandem
rearrangement/Passerini condensation, Highly regioselective
1
. INTRODUCTION
1

Isocyanides have long proved themselves to be valuable building blocks in modern
[
1]
organic chemistry. The carbon center of the isocyanide group is formally divalent and
can react with electrophiles or nucleophiles. The isocyanide chemistry has drawn
[2]
enduring attention because of its ubiquitous applications in organometallics and in
combinatorial science, where isocyanides have proven to be highly prolific in the
[
3]
development of multicomponent reactions (MCRs). Speed, diversity, efficiency, atom
[4]
economy, and environmental friendliness are some of the notable features of MCRs. An
important class of MCRs is the isocyanide-based multicomponent reactions (IMCRs) and
[
5]
is extensively used in targeted oriented and diversity oriented organic synthesis. In
recent years, IMCRs experienced a renaissance, and they are now regularly used to
produce diversity-oriented compound libraries for pharmaceutical or material science.
The most widely known and best characterized of the IMCRs are the Passerini three-
[
6]
[7]
[8]
component reaction (Passerini 3CR) and the Ugi four component reaction (Ugi 4CR).
Indeed, the large number of different scaffolds now available mostly builds on these two
MCRs and their combination with other types of reactions.
The Passerini reaction is a three component reaction between a carboxylic acid, a
carbonyl compound and an isocyanide, that offers direct access to α-acyloxy amide.
Despite the similarities between Ugi and Passerini reactions, the Ugi reaction is relatively
more celebrated IMCR than Passerini, due to its poorer efficiency and requirement of
highly acidic conditions. The synthetic scope of the Passerini coupling is often limited to
the need of an efficient electrophilic activation of the carbonyl moiety and instability of
isocyanides under highly acidic conditions. In the past decade, substantial advances in
2

[
9]
this reaction have been witnessed. Recently, the Passerini three component reaction
starting from alcohols involving tandem oxidative process in which oxidation of alcohols
are combined with the subsequent elaboration of the carbonyl intermediates was
[
10]
developed. Various modifications of this reaction have already been developed
employing replacement of the carboxylic acid, for example with trimethylsilyl azide,
[11]
phenols, thioacids, or silanol. Although many variations of the second nucleophilic
component i.e. acid in such reactions have been reported, the alteration of electophilic
partner other than carbonyl component has received less attention. It was our intention to
investigate Passerini reaction involving electrophilic variant other than carbonyl
component. In this context, our literature review reveals the work by Motherwell, who
reported a novel multicomponent reaction featuring an epoxide, isocyanide and acid.
[
12]
However, initially the structures were wrongly identified and later rectified.
Furthermore, the protocol suffer from a number of drawbacks, including the need of
stoichiometric amount of Lewis acid catalyst, high temperature and comparatively lower
yields. The discovery of a catalytic method under ambient conditions would therefore be
a significant development in this field.
2
. RESULTS AND DISCUSSIONS
Considering the pharmacological significance of α-acyloxyamides, and as our research
[
13]
interest include p-Toluenesulfonylmethyl isocyanide (TosMIC) chemistry, herein, we
describe a new approach for the synthesis of α-acyloxyamides involving epoxides in
Passerini reaction (Scheme 1), which in general is known as homo-Passerini reactions.
This tandem reaction sequence offers several advantages from a synthetic point of view
3

including reduction of number of steps and waste as well as of the time and work
required and high atom economy. The notable feature of the present protocol is in-situ
formation of desired aldehyde as an intermediate, which in general are unstable and are
not readily accessible. The process offers an easy and efficient synthesis of α-
acyloxyamides in high yields under simple reaction conditions.
The reaction conditions for the synthesis of α-acyloxyamide from styrene oxide 1a and
TosMIC 2 and benzoic acid 3 were optimized, and the observed results are given in Table
1
. The test reaction using 1, 2 and 3 without any catalyst had failed (Table 1, entry 1),
which can be attributed to the poor electrophilcity of styrene oxide i.e. epoxide when
compared to the carbonyl compound. After more experimentation, we found that Lewis
acid catalyzed condensation of epoxide, acid and isocyanide was more effective.
Accordingly, the condensation of from styrene oxide 1a and TosMIC 2 and benzoic acid
3
was performed in presence of BF .Et O. Gratifyingly, the Passerini product 4a was
3 2
observed, albeit in low yield. In order to improve the yield, various Lewis acids such as
CuI, Zn(OTf) , InCl , Cu(OTf) , FeCl , and RuCl were screened and good yields were
2
3
2
3
3
observed when InCl was used. Next the reaction optimization studies were performed
3
using different solvents like THF, CH CN, THF:H O, CH Cl and EtOAc. Whereas
3
2
2
2
CH CN did not afford any product (Table 1, entry 9), among the other solvents our best
3
result was observed when THF was used as a solvent (Table 1, entry 5). The amount of
catalyst also has a crucial effect on the reaction. It was found that the yield of the product
increased significantly from 40% to 90% when the amount of catalyst increased from 10
mol% to 30 mol%. The yield of the product had no much change with the further increase
4

of catalyst amount. Next, we found that the effect of increase in reaction temperature is
not significant on the rate of the reaction and moreover it leads to the formation of
undesired products. These studies demonstrated that 0.3 equiv of InCl in THF at room
3
temperature was optimal for the synthesis of α-acyloxyamides.
The detailed analysis of the product 4a revealed the formation α-acyloxyamides from
[
14]
epoxides proceeded through tandem rearrangement of epoxides to aldehyde and
condensation of in situ derived aldehyde, acid and isonitrile component. Based on these
evaluation, we were intrigued to probe the feasibility of the present reaction using
[
14f]
catalytic AuCl /AgSbF system (Table 1, entry 13),
which was reported as an efficient
3
6
method for rearrangement of epoxides to carbonyl compounds. Nonetheless, InCl was
3
proved to be as the best choice of catalyst for the direct synthesis of α-acyloxyamides
from epoxides. As shown in Figure 1, InCl initially coordinates to oxygen of oxirane,
3
which leads to the C-O bond cleavage to generate stable carbocation intermediate II.
Next, the migration of hydrogen generates the corresponding aldehyde III
regioselectively. The aldehyde formed, then undergoes condensation with an acid and an
isonitrile component and form α-acyloxyamides as final products. The condensation was
believed to proceed via commonly admitted Passerini reaction mechanism. The
[
15]
mechanistic study of the Passerini reaction was on-going since its discovery. The rapid
access of α-acyloxyamides indicates that most probably the InCl remains coordinated to
3
the aldehyde after the hydride shift. The product 4a was characterized by its spectral data.
1
The HNMR spectrum revealed the characteristic protons CH-OBz at δ 5.50 as doublet of
doublet, methylene protons as doublet of doublets at δ 4.69 and δ 4.56, benzylic CH as a
2
5

multiplet at δ 3.18-3.07 and all other protons resonated at their appropriate values. This
1
3
was further supported by CNMR, IR and MS spectral analysis.
Using optimized conditions, the versatility of the present protocol is further examined
with different epoxides as summarized in Table 2. To our delight, the reactions proceeded
smoothly to afford the corresponding α-acyloxyamides in good yields. 1-Aryl, 1,1-diaryl,
1
,1-alkyl and aryl substituted epoxides furnished the corresponding α-acyloxyamides as
the only isolable products indicating the rearrangement of epoxide underwent by
exclusive hydride shift (Table 2, entries 1-9). On the other hand, the exclusive formation
of 4b from stilbene oxide 1j indicates predominant migration of phenyl group. However,
the pinene oxide (Table 2, entry 11) provided 4k, involving an additional alkyl shift is
[16]
both interesting and plausible. The compounds 4c, 4f and 4k were obtained as
1
diastereomeric mixtures. The diastereomeric ratio was measured from the HNMR
analysis based on relative integration of diastereomeric protons. The diastereomeric ratio
of 4c was identified as 1.3:1 from its spectral data, which revealed the characteristic
methyl protons at δ 1.34 as a doublet (J = 7.09 Hz) with an integration of 1.7H and at δ
1
1
.27 as a doublet (J = 7.21 Hz) with an integration of 1.3H. Whereas, the HNMR of 4f
shows the NH proton at δ 6.73 as a triplet (J = 6.60 Hz) with an integration of 0.6H and at
δ 6.55 as a triplet (J = 6.72 Hz) with an integration of 0.4H. Likewise, the protons due to
methyl group resonated as doublets at different chemical shifts that is δ 1.45 (J = 7.09
Hz) and δ 1.37 (J = 7.34 Hz) with the same integral ratio suggesting the diastereomeric
ratio of 3:2. However, the diastereomeric ratio of 4k could not be detected by its spectral
analysis. No product was observed when the attempts were made to extend the scope of
6

the method to nonaromatic epoxides. Presumably, incipient carbocation formed by the
initial cleavage of epoxide is much less stabilized in alkyl-substituted epoxides compared
to that in the aryl substituted one. But in case of entries 8 and 11, where the carbocation is
better stabilized on a tertiary center, the rearrangement underwent smoothly and provided
the corresponding α-acyloxyamides. Further, the scope of the reaction regarding the
isocyanide was demonstated with t-butyl isocyanide 2a (Table 2, entry 9). Even though,
there are two possible rearrangements for substituted epoxides, InCl was found be very
3
efficient in the rearrangement of epoxides to the corresponding carbonyl compounds very
selectively. In general Passerini reaction is slow and low yielding. It is noteworthy, to
mention that the present described protocol not only features epoxides as novel substrates
but also significant with respect to yield and time.
5
. CONCLUSION
In summary, an efficient synthesis of α-acyloxy amides in which epoxide as an
electrophilic variant in Passerini reaction catalyzed by InCl has been developed. The
3
direct utilization of epoxides under the present conditions illustrated a practical and atom
economical route for access to α-acyloxyamides. This reaction is highly regioselective
and can proceed under mild ambient reaction conditions in less reaction time. As a result,
the present reaction has the potential to be further applied in organic synthesis. The
ability to perform tandem rearrangement/MCR would widen significantly the versatility
and scope of these aldehyde-based MCRs.
EXPERIMENTAL
7

The chemicals used were obtained from Sigma-Aldrich and used without further
1
purification. All solvents were used as obtained from the commercial suppliers. H NMR
1
3
spectra were recorded at 400, and 500 MHz (using TMS as a reference), and C NMR
were recorded at 75 and 125 MHz (using the CDCl triplet centered at δ 77.0 Hz as
3
reference) in CDCl as solvent at ambient temperature. Chemical shifts (δ) were recorded
3
in ppm, coupling constants J were given in hertz (Hz), and multiplicity is reported as s
(singlet), d (doublet), dd (doublet of doublet), td (triplet of doublet), t (triplet), m
(multiplet), br. s, (broad singlet). IR spectra were recorded on at Perkin-Elmer IR-683
-1
spectrophotometer with NaCl optics and are reported in wavenumbers (cm ). Mass
spectra were recorded on Finnigan Mat 1210 double focusing mass spectrometers
operating at a direct inlet system. High Resolution Mass Spectra (HRMS) were
performed on a high resolution magnetic sector mass spectrometer. For low (MS) and
high (HRMS) resolution, m/z ratios are reported as values in atomic mass units. All the
reactions monitored by analytical thin layer chromatography (TLC) using E-Merck
silicagel plates (60G-254). All evaporations were carried out under reduced pressure on
Büchi rotary evaporator at below 40 °C. All crude reaction products were purified by
column chromatography silica gel (60-120 mesh) by using ethyl acetate and petroleum
ether solvent system. Melting points were recorded on Büchi 535 melting point apparatus
and are uncorrected.
GENERAL EXPERIMENTAL PROCEDURE FOR SYNTHESIS OF Α-
ACYLOXYAMIDES:
8

To a solution of styrene oxide 1 (100 mg, 0.80 mmol), TosMIC 2 (162 mg, 0.80 mmol)
and benzoic acid 3 (101mg, 0.80 mmol) in THF (2 mL/ mmol), InCl (55 mg, 0.24 mmol)
3
was added and stirred until completion (monitored by TLC). The reaction was diluted
with EtOAc (5 mL) and washed with water (5 mL). The resulting organic extract was
washed with brine (5 mL), separated, and the brine layer was extracted with EtOAc (5
mL). The combined organics were dried (Na SO ) and concentrated by rotary
2
4
evaporation. Flash chromatography (EtOAc: n-hexane, 1:9 to 2:8) yielded 4a as a white
solid (100mg, 90% yield).
ACKNOWLEDGMENTS
We are grateful to DST (GAP 0485), New Delhi for generous financial support. The
authors K.L. thank UGC, New Delhi for financial support in the form of fellowship.
REFERENCES
[
1]
For reviews on isocyanides in organic synthesis, see: (a) Dömling, A.; Ugi, I.
Angew. Chem., Int. Ed. 2000, 39, 3168; (b) Josien, H.; Ko, S.-B.; Bom, D.; Curran, D. P.
Chem. Eur. J. 1998, 4, 67; (c) Saegusa, T.; Ito, Y. Synthesis 1975, 291; (d) Isocyanide
Chemistry. Applications in Synthesis and Material Science, ed. V. G. Nenajdenko, Wiley-
VCH, Weinheim, Germany, 2012.
[
2]
515; (b) R. J. Angelici, M. Lazar. Inorg. Chem. 2008, 47, 9155.
3] (a) A. Dçmling, Comb. Chem. High Throughput Screening 1998, 1, 1; (b) C.
(a) L. Weber, Angew. Chem. 1998, 110, 1597; Angew. Chem. Int. Ed. 1998, 37,
1
[
Hulme, T. Nixey. Curr. Opin. Chem. Biol. 2003, 6, 921, and references therein.
9

Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Weinheim, 2005
and references therein.
[
4]
therein.
5]
Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083, and references
[
(a) Wilson, R. M.; Stockdill, J. L.; Wu, X.; Li, X.; Vadola, P. A.; Park, P. K.;
Wang, P.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2012, 51, 2834; (b) Vlaar, T.;
Ruijter, E.; Maes, B. U. W.; Orru, R. V. A. Angew. Chem., Int. Ed. 2013, 52, 7084.
[
6]
(a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126; (b) Riva, R.; Banfi, L. Org.
React. 2005, 65, 1; (c) Maeda, S.; Komagawa, S.; Uchiyama, M.; Morokuma, K. Angew.
Chem., Int. Ed. 2011, 50, 644. (d) Kazemizadeh, A. R.; Ramazani, A. Curr. Org. Chem.
2
012, 16, 418.
7] (a) Ugi, I. Isonitrile Chemistry; Academic Press: London, 1971; (b) Dömling, A.;
Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168; (c) Dömling, A. Chem. Rev. 2006, 106,
7–89; (d) Ugi, I. Angew. Chem., Int. Ed. Engl. 1982, 21, 810.
8] Bousquet, T.; Jida, M.; Soueidan, M.; Deprez-Poulain, R.; Agbossou-Niedercorn,
F.; Pelinski, L. Tetrahedron Lett. 2012, 53, 306.
9] Brioche, J.; Masson, G.; Zhu, J. Org. Lett. 2010, 12, 4341; (b) Ngouansavanh, T,
Zhu, J. Angew. Chem. Int. Ed. 2006, 45, 3495.
10] (a) Schremmer, E. S.; Wanner, K. T. Heterocycles 2007, 74, 661. (b) Nixey, T.;
[
1
[
[
[
Hulme, C. Tetrahedron Lett. 2002, 43, 6833. (a) El Kaim, L.; Gizolme, M.; Grimaud, L.
Org. Lett. 2006, 8, 5021; (b) El Kaim, L.; Gizolme, M.; Grimaud, L.; Oble, J. J. Org.
Chem. 2007, 72, 4169; (c) Dai, W. M.; Li, H. M. Tetrahedron 2007, 63, 12866
1
0

mling, A.; Illgen, K. Synthesis 2005, 662; (e) Soeta, T.; Kojima, Y.; Ukaji, Y.;
Inomata, K. Org. Lett. 2010, 12, 4341.
[
11] Kern, O. T.; Motherwell, W. B. Chem. Commun., 2003, 2988. Erratum in Chem.
Commun., 2005, 1787.
12] (a) Radha Krishna, P.; Raja Sekhar, E.; Prapurna, Y. L. Tetrahedron Lett. 2007,
8, 9048; (b) Radha Krishna, P.; Raja Sekhar, E. Adv. Synth. & Catal., 2008, 350, 2871;
c) Radha Krishna, P.; Lakshmi Prapurna, Y. Synlett 2009, 2613, and references cited
therein.
13] (a) Maruoka, K.; Murase, N.; Bureau, R.; Ooi, T.; Yamamoto, H. Tetrahedron
994, 50, 3663; (b) Ranu, B. C.; Jana, U. J. Org. Chem. 1998, 63, 8212; (c) Karamé, I.;
[
4
(
[
1
Tommasino, M. L.; Lemaire, M. Tetrahedron Lett. 2003, 44, 7687; (d) Banerjee, M.;
Roy, U. K.; Sinha, P.; Roy, S. J. Organomet. Chem. 2005, 690, 1422. (e) Procopio, A.;
Dalpozzo, R.; De Nino, A.; Nardi, M.; Sindona, G.; Tagarelli, A. Synlett 2004, 2633. (f)
Gudla, V.; Balamurugan, R. Tetrahedron Lett. 2012, 53, 5243.
[
[
14] Ramozzi, R.; Morokuma, K. J. Org. Chem. 2015, 80, 5652.
15] Lewis, J. B.; Hedrick, G. W. J. Org. Chem. 1965, 30, 4271.
1
1

a
Table 1. Optimization of the reaction conditions.
b
Entry Catalyst
Solvent
THF
THF
THF
THF
THF
THF
THF
THF
Time
24 h
Yiele[%]
0
1
2
3
4
5
6
7
8
9
1
1
1
-
BF Et O
40 min 65
3
2
CuI
1 h
1 h
0
Zn(OTf)2
InCl3
40
30 min 90
Cu(OTf)2
FeCl3
1 h
1 h
1 h
50
20
40
RuCl3
InCl3
CH CN
50 min 0
3
0
1
2
3
InCl3
THF:H O 40 min 55
2
InCl3
CH Cl
40 min 70
30 min 50
2
2
InCl3
EtOAc
c
1
AuCl /AgSbF Dioxane 30 min 42
3 6
a
Reaction conditions: epoxide (1.0 equiv), TosMIC (1.0 equiv), benzoic acid (1.0 equiv),
Lewis acid (0.3 equiv) and solvent.
b
The yields refer to isolated products purified by column chromatography.
c
The reaction was carried out with different mol% of AuCl /3AgSbF and the yield refer
3
6
to the product obtained with 5 mol% of AuCl and 15 mol% of AgSbF the maximum
3
6
amount of catalyst tested.
1
2

a
Table 2. Synthesis of α-acyloxyamides from epoxides catalyzed by InCl3
b
Entr Substrate
Isocyani Product
Diastereome Tim Yield[%
c
d
y
1
de
ric ratio
-
e
]
TosMIC
30
min
90
88
2
TosMIC
-
35
min
3
4
TosMIC
TosMIC
1.3:1
-
45
85
86
min
45
min
5
TosMIC
-
40
84
min
6
7
TosMIC
TosMIC
3:2
-
40
85
87
min
40
min
8
9
TosMIC
-
-
40
80
87
min
t-BuNC
40
min
1
3

1
1
a
0
1
TosMIC
TosMIC
-
40
92
84
min
not detected 40
min
Reaction conditions: Epoxide (1.0 equiv), TosMIC (1.0 equiv), InCl (0.3 equiv) in
3
THF.
b
All the products were characterized from spectral data.
c
1
Detected by H NMR spectra.
d
Isolated yields after purifications by column chromatography.
1
4

Scheme 1. Epoxides as electrophiles in Passerini reaction catalyzed by InCl3.
1
5

Figure 1. A plausible reaction pathway
1
6