A new modification of the Passerini reaction: A one-pot synthesis of α-acyloxyamides via sequential Kornblum oxidation/Passerini reaction

Article abstract of DOI:10.1016/j.tetlet.2015.02.007

Abstract A novel approach for the synthesis of α-acyloxyamides is described. Benzylic substrates (halides or tosylates), under mild Kornblum conditions, are oxidized to give the corresponding aldehydes, which undergo a Passerini reaction with carboxylic acids and isocyanides to produce the corresponding α-acyloxyamides in excellent yields.

Full text of DOI:10.1016/j.tetlet.2015.02.007

Accepted Manuscript
A new modification of the Passerini reaction: a one-pot synthesis of α-acylox-
yamides via sequential Kornblum oxidation/Passerini reaction
Mehdi Adib, Ehsan Sheikhi, Marjan Azimzadeh
PII:
S0040-4039(15)00250-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.02.007
TETL 45870
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 September 2014
26 December 2014
1 February 2015
Please cite this article as: Adib, M., Sheikhi, E., Azimzadeh, M., A new modification of the Passerini reaction: a
one-pot synthesis of α-acyloxyamides via sequential Kornblum oxidation/Passerini reaction, Tetrahedron Letters
(2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.02.007
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A new modification of the Passerini reaction: a one-pot synthesis of
α-acyloxyamides via sequential Kornblum oxidation/Passerini
reaction
Mehdi Adib*, Ehsan Sheikhi, Marjan Azimzadeh
School of Chemistry, College of Science, University of Tehran, PO Box 14155-6455,
Tehran, Iran
Abstract-A novel approach for the synthesis of α-acyloxyamides is described.
Benzylic substrates (halides or tosylates), under mild Kornblum conditions, are
oxidized to give the corresponding aldehydes, which undergo a Passerini reaction
with carboxylic acids and isocyanides to produce the corresponding α-acyloxyamides
in excellent yields.
Keywords: Kornblum oxidation, Passerini reaction, α-acyloxyamides, benzylic
substrates, dimethyl sulfoxide, carboxylic acids, isocyanides.
*Corresponding author. Tel./fax: +98(21)66495291; E-mail: madib@khayam.ut.ac.ir
1

Multicomponent reactions (MCRs) have become important tools in synthetic
chemistry due to their ability to provide efficient access to complex molecules from
readily available starting materials, and their utility for the construction of interesting
biologically active organic compounds and the rapid generation of drug-like molecule
libraries.1 Isocyanide-based MCRs are especially important in this area.2,3
The high efficiency of isocyanides in MCRs is due to their divalent C-atom and its
distinct reactivity towards C(sp2 or sp) electrophilic centers. In transformations
involving these entities, this divalent C-atom is converted into a tetravalent state,
which makes the addition irreversible. It must be remembered that this property of
isocyanides was essential in the successful development of classical MCRs such as
the Passerini three-component reaction (P-3CR) as the first MCR involving
isocyanides,4 which combines an aldehyde, a carboxylic acid and an isocyanide to
give an α-acyloxyamide (Scheme 1).
O
R3
R2
O
R2CO2H
R1CHO
R3NC
+
+
N
H
R1
O
Scheme 1. The Passerini three-component reaction.
The Passerini reaction has been the subject of extensive research. Several
modifications of the classic P-3CR have been described, including variation of one of
the components or introduction of a linkage between two of them.5 Some cases
involve a catalyst such as Cu(II),6 Al(III),7 aluminum-organophosphate,8 SiCl4,9
Bi(OTf)3,10 Ti(i-PrO)4,11 etc., or occur in the presence of an ionic liquid.12 Through
the application of these MCRs, interesting potential drug-like derivatives of the
original α-acyloxyamide product and many different skeletons are now readily
accessible.5–13
Although a large number of modifications of P-3CRs have been successfully
explored, to the best of our knowledge, only one oxidative Passerini reaction has been
reported, by Zhu et al., in which reactions between alcohols, isocyanides, and
carboxylic acids in toluene in the presence of a catalytic amount of cupric chloride,
sodium nitrite, and TEMPO, under an oxygen atmosphere, resulted in the formation
of P-3CR adducts in good yields.14
Considering the pharmacological significance of α-acyloxyamides, and as part of our
continuing efforts on the development of new routes for the preparation of
2

biologically active organic compounds,15 herein, we describe a new approach for the
synthesis of α-acyloxyamides, which is initiated by an in situ oxidation of benzylic
substrates to the corresponding aldehydes. This procedure develops the flexibility of
the Passerini reaction, while not limiting one of the substrates to being an aldehyde. It
has additional advantages such as the use of more commercially accessible benzylic
substrates compared to aldehydes, and the intermediate aldehydes do not need
separation. This should be especially valuable in cases where the aldehydes are
unstable (e.g., volatile, or susceptible to polymerization or hydrolysis).
Thus, under mild Kornblum oxidation conditions,16 a solution of a benzylic substrate
1 in dimethyl sulfoxide in the presence of sodium bicarbonate at 90 C was converted
into the corresponding aldehyde within three hours,17 as was indicated by TLC
monitoring. Subsequently, the aldehyde prepared in situ was treated with a carboxylic
acid 2 and an isocyanide 3 at 90 C for two hours to afford the corresponding
Passerini reaction products, α-acyloxyamides 4, in 86–96% yields (with respect to the
benzylic substrate 1) (Table 1). All the reactions went to completion within five
1
hours. H NMR analysis of the reaction mixtures clearly indicated formation of the
corresponding α-acyloxyamides 4 in excellent yields.18 All the products were
characterized by melting point determination and from their 1H and 13C NMR spectral
data.
3

Table 1 Direct synthesis of α-acyloxyamides 4 via sequential Kornblum oxidation/Passerini reaction.a
O
R2
R1
NaHCO3
O
R2NC
(CH3)2S
+
R1CO2H +
Ar
X
(CH3)2SO
+ +
N
90 °C, 5 h
H
Ar
O
1
2
3
4
Entry ArCH2X
R1
CH3
R2
4, Yield (%)b mp (°C)
Lit. mp (°C)
7719
Cl
1
4a, 93c
4b, 92
4c, 94
4d, 93
4e, 91
75–76
Cl
Cl
2
3
104–105
149–150
122–124
151
10419
148–15020
122–12421
151–15320
Cl
Cl
Me
Me
4
Me
5
Cl
Br
Cl
MeO
6
4f, 92
150–152
150–15122
Cl
MeO
7
4g, 90
4h, 96
4i, 93
4j, 86
4k, 93
4l, 89
4m, 90
4n, 87
125–127
197
125–12622
196–19823
198–20021
184–18620
148–15024
210–21220
114–11621
199–20120
Cl
Cl
Cl
Cl
Cl
8
Cl
Cl
9
199–200
184–185
149–150
210–212
114–115
199–200
Cl
MeO
10
Cl
11
Cl
O2N
12
Cl
Cl
O2N
O2N
13
O2N
MeO
14
Br
Br
15
4o, 91
113
112–11424
16
17
4p, 90
4b, 93
115–116
104–105
115–11724
Br
10419
4

Br
18
19
20
21
22
23
4c, 95
4e, 92
4n, 89
4b, 95
4c, 96
4e, 94
149–150
151
148–15020
151–15320
199–20120
10419
Br
Me
Br
O2N
MeO
199–200
104–105
149–150
151
OTs
OTs
148–15020
151–15320
OTs
Me
aThe reaction conditions were optimized for the synthesis of α-acyloxyamide 4c as a model reaction (entry 3),
which were used for the preparation of all the other α-acyloxyamides:
reaction temperature of 90 ºC for both the Kornblum oxidation and the Passerini reaction;
reaction time of 3 h for the Kornblum oxidation and 2 h for the Passerini reaction;
use of benzyl chloride, NaHCO3, benzoic acid and tert-butyl isocyanide in a molar ratio of 1:1.1:1.2:1.2;
DMSO volume of 0.75 mL for 1 mmol of benzyl chloride.
bIsolated yields.
cα-Acyloxyamide 4a was purified by column chromatography and α-acyloxyamides 4b–p were purified through
precipitation by adding water to the reaction mixture.18
A mechanistic explanation for this reaction is depicted in Scheme 2. At first, reaction
of the benzylic substrate
1
with dimethyl sulfoxide gives the
alkoxydimethylsulfonium intermediate 5, which in the presence of NaHCO3
undergoes elimination of dimethyl sulfide to form the corresponding aldehyde 6. The
next step involves the reaction between aldehyde 6, carboxylic acid 2 and isocyanide
3 through a presumed cyclic transition state 7 to give intermediate 8. Finally, an
irreversible Mumm-type rearrangement (a transacylation) leads to the α-acyloxyamide
4 (Scheme 2).
R1
_
_
R1CO2H (2)
R2NC (3)
R1
or
_
_
Me2S
C
6
1
5
R2
R1
R2
R1
7
Mumm-type
rearrangement
R1
R2
R2
8
4
Scheme 2. Proposed mechanism.
5

In conclusion, we have developed a new and straightforward approach for the
synthesis of α-acyloxyamides of potential synthetic and pharmacological interest, via
sequential Kornblum oxidation/Passerini reaction between benzylic substrates,
dimethyl sulfoxide, carboxylic acids and isocyanides. The use of benzylic substrates
in place of aldehydes, the good to excellent yields of the products and the easy work-
up procedure are the main advantages of this method. To the best of our knowledge,
this is the first report on the use of benzyl halides or benzyl tosylates instead of
aldehydes as substrates for the preparation of α-acyloxyamides via the Passerini
reaction.
Acknowledgement
This research was supported by the Research Council of the University of Tehran.
References and notes:
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Marcaccini, S.; Torroba, T. Post-condensation Modifications of the Passerini and
Ugi Reactions; Zhu, J., Bienaymé, H., Eds.; Wiley-VCH: Weinheim, 2005; pp
33–75, and references therein.
6

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16. (a) Kornblum, N.; Jones, W. J.; Anderson, G. J. J. Am. Chem. Soc. 1959, 81,
4113–4114; (b) Kornblum, N.; Powers, J. W.; Anderson, G. J.; Jones, W. J.;
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17. Bratulescu, G. Rev. Chim. (Bucharest) 2010, 61, 815–816.
18. General procedure for the preparation of compounds 4a–p: A mixture of the
appropriate benzylic substrate (1 mmol) and NaHCO3 (0.092 g, 1.1 mmol) in
DMSO (0.75 mL) was stirred for 3 h at 90 ºC. Next, the appropriate carboxylic
acid (1.2 mmol) and isocyanide (1.2 mmol) were added to the mixture and stirring
was continued at 90 ºC for 2 h. After completion of the reaction, the mixture was
cooled to ambient temperature. Next, H2O (2 mL) was added to the mixture and
stirring was continued for 15 min at ambient temperature. The resulting precipitate
was filtered, washed with H2O, dried, and recrystallized from n-hexane/EtOAc
7

(3:1) to afford the pure product 4. [α-Acyloxyamide 4a was purified by column
chromatography using n-hexane-EtOAc (4:1) as eluent].
Selected NMR spectral data:
1
2-(tert-Butylamino)-2-oxo-1-phenylethyl benzoate (4c) H NMR (300.1 MHz,
DMSO-d6): δ 1.22 [9H, s, C(CH3)3], 6.09 (1H, s, OCH), 7.35 (1H, t, J = 7.2 Hz,
CH), 7.42 (2H, dd, J = 7.4, 7.1 Hz, 2CH), 7.53 (2H, dd, J = 7.5, 7.4 Hz, 2CH),
7.61 (2H, d, J = 7.6 Hz, 2CH), 7.65 (1H, t, J = 7.1 Hz, CH), 7.97 (1H, s, NH),
8.04 (2H, d, J = 7.5 Hz, 2CH). 13C NMR (75.5 MHz, DMSO-d6): δ 28.32
[C(CH3)3], 50.41 [C(CH3)3], 75.45 (OCH), 127.16 (2CH), 128.37 (CH), 128.38
(2CH), 128.73 (2CH), 129.33 (C), 129.34 (2CH), 133.50 (CH), 136.21 (C),
164.91 and 167.00 (2C=O). 2-(Cyclohexylamino)-1-(4-methylphenyl)-2-
oxoethyl 4-methylbenzoate (4d): 1H NMR (300.1 MHz, DMSO-d6): δ 1.00‒1.76
[10H, m, CH(CH2)5], 2.29 and 2.37 (6H, 2s, 2CH3), 3.45‒3.55 (NCH), 6.00 (1H,
s, OCH), 7.20 (2H, d, J = 7.9 Hz, 2CH), 7.33 (2H, d, J = 8.0 Hz, 2CH), 7.45 (2H,
d, J = 7.9 Hz, 2CH), 7.91 (2H, d, J = 8.0 Hz, 2CH), 8.14 (1H, d, J = 7.7 Hz, NH).
13C NMR (75.5 MHz, DMSO-d6): δ 20.72 and 21.15 (2CH3), 24.36, 24.44, 25.10,
32.02 and 32.20 (5CH2), 47.61 (NCH), 75.24 (OCH), 126.60 (C), 127.11 (2CH),
128.93 (2CH), 129.26 (2CH), 129.41 (2CH), 133.18, 137.80 and 143.86 (3C),
164.92 and 166.94 (2C=O). 2-(tert-Butylamino)-2-oxo-1-phenylethyl 4-
chlorobenzoate (4h): 1H NMR (300.1 MHz, DMSO-d6): δ 1.21 [9H, s, C(CH3)3],
6.08 (1H, s, OCH), 7.48 (2H, d, J = 8.4 Hz, 2CH), 7.53 (2H, t, J = 7.6 Hz, 2CH),
7.62 (2H, d, J = 8.4 Hz, 2CH), 7.66 (1H, t, J = 7.4 Hz, CH), 8.00 (1H, s, NH),
8.02 (2H, d, J = 7.8 Hz, 2CH). 13C NMR (75.5 MHz, DMSO-d6): δ 28.26
[C(CH3)3], 50.45 [C(CH3)3], 74.69 (OCH), 128.45 (2CH), 128.72 (2CH), 128.95
(2CH), 129.18 (C), 129.34 (2CH), 133.15 (C), 133.55 (CH), 135.16 (C), 164.80
and 166.67 (2C=O). 2-(Cyclohexylamino)-1-(4-methoxyphenyl)-2-oxoethyl 4-
1
chlorobenzoate (4j): H NMR (300.1 MHz, DMSO-d6): δ 0.99‒1.77 [10H, m,
CH(CH2)5], 3.45‒3.51 (1H, NCH), 3.82 (3H, s, OCH3), 6.05 (1H, s, OCH), 7.05
(2H, d, J = 8.5 Hz, 2CH), 7.47 (2H, d, J = 8.2 Hz, 2CH), 7.61 (2H, d, J = 8.2 Hz,
13
2CH), 7.99 (2H, d, J = 8.5 Hz, 2CH), 8.24 (1H, d, J = 7.7 Hz, NH). C NMR
(75.5 MHz, DMSO-d6): δ 24.32, 24.41, 25.09, 31.98 and 32.18 (5CH2), 47.68
(NCH), 55.49 (OCH3), 74.46 (OCH), 114.01 (2CH), 121.29 (C), 128.45 (2CH),
128.88 (2CH), 131.58 (2CH), 133.16 and 135.24 (2C), 163.42 (C‒O) 164.49 and
166.63 (2C=O). 2-(Cyclohexylamino)-2-oxo-1-phenylethyl 4-chlorobenzoate
8

1
(4k): H NMR (300.1 MHz, DMSO-d6): δ 0.99‒1.78 [10H, m, CH(CH2)5],
3.46‒3.53 (1H, NCH), 6.08 (1H, s, OCH), 7.48 (2H, d, J = 8.5 Hz, 2CH), 7.53
(2H, t, J = 7.7 Hz, 2CH), 7.62 (2H, d, J = 8.5 Hz, 2CH), 7.66 (1H, t, J = 7.4 Hz,
CH), 8.03 (2H, dd, J = 7.2, 1.1 Hz, 2CH), 8.27 (1H, d, J = 7.8 Hz, NH). 13C NMR
(75.5 MHz, DMSO-d6): δ 24.30, 24.39, 25.08, 31.96 and 32.17 (5CH2), 47.69
(NCH), 74.75 (OCH), 128.47 (2CH), 128.73 (2CH), 128.93 (2CH), 129.12 (C),
129.40 (2CH), 133.23 (C), 133.60 (CH), 135.02 (C), 164.83 and 166.46 (2C=O).
2-(Cyclohexylamino)-1-(4-methoxyphenyl)-2-oxoethyl 4-nitrobenzoate (4n):
1H NMR (300.1 MHz, DMSO-d6): δ 1.00‒1.77 [10H, m, CH(CH2)5], 3.43‒3.54
(1H, NCH), 3.81 (3H, s, CH3), 6.21 (1H, s, OCH), 7.05 (2H, d, J = 8.5 Hz, 2CH),
7.88 (2H, d, J = 8.4 Hz, 2CH), 8.02 (2H, d, J = 8.5 Hz, 2CH), 8.27 (2H, d, J = 8.4
Hz, 2CH), 8.39 (1H, d, J = 7.6 Hz, NH). 13C NMR (75.5 MHz, DMSO-d6): δ
24.26, 24.34, 25.05, 31.91 and 32.13 (5CH2), 47.78 (NCH), 55.45 (OCH3), 74.35
(OCH), 113.99 (2CH), 121.04 (C), 123.54 (2CH), 128.05 (2CH), 131.63 (2CH),
143.37 and 147.40 (2C), 163.48 (C‒O) 164.33 and 165.98 (2C=O).
19. Ngouansavanh, T.; Zhu, J. Angew. Chem. Int. Ed. 2006, 45, 3495–3497.
20. Fan, X.; Li, Y.; Zhang, X.; Qu, G.; Wang, J. Can. J. Chem. 2006, 84, 794–799.
21. Mahyari, M.; Shaabani, S.; Shaabani, A.; Ng, S. W. Comb. Chem. High
Throughput Screening 2013, 16, 858–864.
22. Karimi, B.; Farhangi, E. Adv. Synth. Catal. 2013, 355, 508–516.
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Bhogayta, N. P. RSC Adv. 2013, 3, 10867–10874.
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9

A new modification of the Passerini reaction: a one-pot
synthesis of α-acyloxyamides via sequential
Kornblum oxidation/Passerini reaction
Mehdi Adib, Ehsan Sheikhi, Marjan Azimzadeh
O
R2
R1
NaHCO3
O
R1CO2H
Ar
X
(CH3)2SO
R2NC
(CH3)2S
+
+
+
+
N
90 °C, 5 h
H
Ar
O
10