Facile reaction of carboxylic acids with isonitriles in toluene

Article abstract of DOI:10.1016/j.tetlet.2011.03.122

Isonitriles react with low concentrations of carboxylic acids in toluene at 110 °C to give N-formylamides in yields generally above 70%. These concentrations can be obtained either by syringe pump addition of a toluene solution of the acid, or by using a suspension of the acid if it has limited solubility in toluene at room temperature.

Full text of DOI:10.1016/j.tetlet.2011.03.122

Tetrahedron Letters 52 (2011) 2933–2934
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile reaction of carboxylic acids with isonitriles in toluene
⇑
Jason G. Polisar, Ling Li, Jack R. Norton
Department of Chemistry, Columbia University, Havemeyer Hall, 3000 Broadway, New York, NY 10027, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Isonitriles react with low concentrations of carboxylic acids in toluene at 110 °C to give N-formylamides
in yields generally above 70%. These concentrations can be obtained either by syringe pump addition of a
toluene solution of the acid, or by using a suspension of the acid if it has limited solubility in toluene at
room temperature.
Received 16 February 2011
Accepted 23 March 2011
Available online 7 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Isonitriles
N-Formylamides
Two component coupling
Peptide synthesis
Treatment of carboxylic acids (1) with isonitriles (2) has re-
cently been shown to produce N-formylamides (3).1 Experi-
ments1,2 and calculations3 support the mechanism in Scheme 1,
in which 1 and 2 initially form a formimidate carboxylate mixed
anhydride, or FCMA (4); a 1,3 O ? N acyl transfer then gives 3.
The original reports involved halogenated solvents with micro-
wave heating, at or above 150 °C. In order to determine appropriate
conditions for kinetic studies we have examined the reaction in
several solvents at various temperatures, and have found that it
proceeds readily in toluene at 110 °C with conventional heating.
However, with benzoic acid (1a) and cyclohexyl isonitrile (2a) each
0.02 M in toluene (1:1 ratio), we obtained only a 43% yield of the N-
formylamide and observed two major side products:4 benzoic
anhydride (5a) and N-cyclohexylformamide (6a). On the hypothe-
sis1f that they arose from interception by 1a of the intermediate 4a,
as depicted in Scheme 2, we used a syringe pump to add the acid
slowly. A 61% yield of the N-formylamide 3a was isolated when a
0.02 M stock solution of 1a was added to 2 equiv of 2a in 2 mL tol-
uene over the course of 45 h at 110 °C.
The applications of RCO2H/RNC coupling have largely been in
peptide synthesis.1a–d,5 Relatively few simple aliphatic isonitriles
have been employed, and to our knowledge no aromatic ones.
We have therefore tried our toluene/110 °C conditions on the com-
binations in Tables 1 and 2.
The results show the reaction to be remarkably tolerant of func-
tional groups, for example, nitro (3m and 3n), halo (3i, 3n, 3o, 3u),
cyano (3t–3x), pyridyl (3o), thienyl (3h and 3i), carbomethoxy (3j),
and acetyl (3p–3s). It does not affect the isolated double bond in 3f
CHO
N
O
O
R1
+
R2
R2 N+ C–
R2
R1
OH
R1
O
N
O
3
2
1
4, FCMA
Scheme 1. Reaction of carboxylic acids with isonitriles.
O
O
O
O
O
+
Cy
H
N
H
Cy
Ph
O
Ph
Ph
OH
Ph
O
N
5a
6a
1a
4a
Scheme 2. Proposed mechanism of side product formation.
⇑
Corresponding author. Tel.: +1 212 854 7644; fax: +1 212 854 7660.
E-mail address: jrn11@columbia.edu (J.R. Norton).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.122

2934
J. G. Polisar et al. / Tetrahedron Letters 52 (2011) 2933–2934
Table 1
Table 2
Preparation of N-formylamides (3) by the syringe pump addition of acids (1) to
isonitriles (2)
Preparation of N-formylamides (3) from isonitriles (2) and acids (1) that are not
soluble in toluene at room temperature
Product
Acid, R1
=
Isonitrile, R2
=
Yield (%)
Product
Acid, R1
=
Isonitrile, R2
=
Yield (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph (1a)
PhCH2CH2 (1b)
1b
1b
cyclo-Hex (2a)
2a
n-C5H11 (2b)
4-MeC6H4 (2c)
2,6-Xylyl (2d)
2d
61
72
55
68
61
66
75
74
65
57
72
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
3x
4-NO2C6H4 (1i)
1i
Picolinic (1j)
4-Me(O)C-C6H4 (1k)
1k
1k
1k
cyclo-Hex (2a)
3-BrC6H4 (2g)
2-Cl-6-MeC6H3 (2e)
cyclo-Hex (2a)
4-MeOC6H4 (2f)
4-MeC6H4 (2c)
4-Et2NC6H4 (2h)
cyclo-Hex (2a)
3-CF3C6H4 (2i)
Ph (2j)
70
67
68
70
80
89
79
84
63
83
94
65
1b
CH2CHCH2 (1c)
PhCHCH (1d)
2-Thiopheneacetic (1e)
1e
MeO2C(CH2)6 (1f)
MeOCH2CH2OCH2 (1g)
2d
2d
4-NCC6H4 (1l)
2-Cl-6-MeC6H3 (2e)
2,6-Xylyl (2d)
4-MeOC6H4 (2f)
1l
1l
1l
1l
3j
3k
4-Et2NC6H4 (2h)
2-Naphthyl (2k)
O
S
R
N
H
H
N
O
H
+
S
R
O
CO2H
S
O
R
+
N+ C–
7
6
Not Observed
2d
2e
R=2, 6-xylyl
R=2-Cl, 6-MePh
CHO
N
1e
S
R
O
3h 74%
3i 65%
Scheme 3.
or the conjugated one in 3g, the ether linkage in 3k, or the tertiary
amine nitrogens in 3s and 3w. Addition of the acid 1e to the isoni-
triles 2d and 2e produced only the expected products 3h and 3i,
and no 7 (Scheme 3). (Alkenes such as 7 are the exclusive products
when many arylacetic acids are treated with isonitriles under
microwave conditions.6)
Acknowledgements
We thank Professor S. Danishefsky and his group for helpful dis-
cussions. A 400 MHz NMR spectrometer used in this work was ac-
quired with support from the NSF (CHE-0840451). This work was
supported by the NSF (CHE-0749537).
Of course a syringe pump is impractical with acids that are not
soluble in toluene at room temperature. With acids that dissolve
completely in toluene at 110 °C, that is, 4-methoxybenzoic acid
(1h), 4-nitrobenzoic acid (1i), and picolinic acid (1j), mixed results
were obtained. Treating 1i with 2a or 2g gave a good isolated yield
of the N-formyl amide 3m or 3n, whereas treating 1h with 2a gave
a substantial amount of the anhydride 5b (about 3:1 relative to the
N-formyl amide 3l). Presumably the more basic 1h is more nucle-
ophilic and better at intercepting the FCMA. The medicinally rele-
vant7 acid 1j reacts very slowly with isonitrile 2e, requiring 3 days;
we speculate that formation of the corresponding FCMA is slow.
Acids with limited solubility in toluene even at 110 °C mimic
the effect of slow addition. Their concentrations remain low, which
limits their ability to attack the FCMA; yields of the N-formyl
amide are thus high. Examples are offered by the reaction of 1k
(0.05 M in toluene) with the isonitrile 2a, 2c, 2f, or 2h for 48 h, giv-
ing 3p–3s (Table 2). Likewise, the reaction of 1l with 2a, 2h, 2i, 2j,
or 2k for 24 h gives 3t–3x in good to excellent yields, although
longer reaction times result in significant decarbonylation of the
formyl groups in these products.
Supplementary data
Supplementary data (experimental details, characterization
data and copies of 1H and 13C NMR spectra) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.03.122.
References and notes
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In summary, we have found (1) that aromatic as well as ali-
phatic isonitriles react with carboxylic acids in toluene at 110 °C
to give good yields of N-formylamides, and (2) that either slow
addition or limited solubility of the acid suppresses the formation
of an anhydride as a byproduct.
6. Basso, A.; Banfi, L.; Galatini, A.; Guanti, G.; Rastrelli, F.; Riva, R. Org. Lett. 2009, 11,
4068.
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