Mild oxidation of tosylmethylisocyanide to tosylmethylisocyanate: Utility in synthetic and medicinal chemistry

Article abstract of DOI:10.1016/j.tetlet.2014.02.016

A convenient and efficient (one-step) oxidation is reported of commercially available tosylmethylisocyanide (TOSMIC) to form tosylmethylisocyanate, making this highly reactive bifunctional molecule a readily available synthetic reagent. Besides engaging in nucleophilic addition reactions with alcohols, amines, and thiols, tosylmethylisocyanate also reacts with carboxylic acids to form tosylmethylamides, which undergo substitution reactions in the presence of organocopper and organomagnesium reagents.

Full text of DOI:10.1016/j.tetlet.2014.02.016

Tetrahedron Letters 55 (2014) 2003–2005
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Mild oxidation of tosylmethylisocyanide to tosylmethylisocyanate:
utility in synthetic and medicinal chemistry
⇑
Hoang V. Le, Bruce Ganem
Department of Chemistry & Chemical Biology, Baker Laboratory, Cornell University, Ithaca, NY 14853-1301, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and efficient (one-step) oxidation is reported of commercially available tosylmethylisocyanide
(TOSMIC) to form tosylmethylisocyanate, making this highly reactive bifunctional molecule a readily avail-
able synthetic reagent. Besides engaging in nucleophilic addition reactions with alcohols, amines, and thiols,
tosylmethylisocyanate also reacts with carboxylic acids to form tosylmethylamides, which undergo substi-
tution reactions in the presence of organocopper and organomagnesium reagents.
Received 25 January 2014
Revised 6 February 2014
Accepted 8 February 2014
Available online 18 February 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Isonitrile-based Multicomponent reactions
Tosylmethylisocyanide
p-Toluenesulfonylmethyl isocyanate
Tosylmethylisocyanate
Tosylmethylamide
Our laboratory recently reported a mild and efficient method
for preparing isocyanates in high yield from the corresponding iso-
nitriles by oxidation using dimethylsulfoxide (DMSO) in the pres-
ence of catalytic quantities of trifluoroacetic anhydride (TFAA).1
The mild, workup-free conditions seemed ideal for the synthesis
of reactive or multifunctional isocyanates. One particularly inter-
esting example that attracted our attention was p-toluenesulfo-
nylmethyl isocyanate (TsCH2N@C@O), whose compact molecular
framework combines a strongly acidic methylene group and a
reactive tosyl leaving group together with a highly electrophilic
isocyanate group.
The literature on TsCH2N@C@O consists of two published papers,
although the compound is often confused with the much more well-
known isonitrile TsCH2N@C: (tosylmethylisocyanide, or TOSMIC).2
Tosylalkylisocyanates have previously been synthesized by the Cur-
tius rearrangement of alkanesulfonylacetyl azides,3 and by the chlo-
rination of S-ethyl N-(1-tosylalkyl)thiocarbamates.4 The latter
publication also described addition reactions of the isocyanates
with methanol, ethanol, benzylamine, and dibenzylamine. Here
we report an efficient one-step synthesis of TsCH2N@C@O from
commercially available TOSMIC that makes the compound much
more accessible. We also present more general findings on the
reaction of TsCH2N@C@O with alcohols and amines, as well as
new results with thiols and carboxylic acids. Besides being of gen-
eral utility, our findings may be of particular interest to medicinal
chemists seeking to introduce hydrophobic pharmacophores (such
as tosyl) at the site of common nucleophilic functional groups.
Following our published procedure,1 treatment of TOSMIC with
DMSO (1.1 equiv) and TFAA (0.05 equiv) at low temperature
(CH2Cl2, ꢀ60 °C to rt, 10 min) resulted in a ꢁ1:1 mixture of starting
material and TsCH2N@C@O. Superior results were obtained using
excess catalyst, leading to the optimal procedure depicted below
(Eq. 1), which was routinely conducted on a 1–2 g scale in yields
ranging from 50% to 60% after recrystallization. The clean oily crude
product decomposed at rt, with a half-life of approximately 20 h,
but crystallization from ether/hexanes afforded 2 as a white crystal
(mp = 69–70 °C) that could be stored at ꢀ90 °C for several weeks.
DMSO (1.0 equiv)
TFAA (0.6 equiv)
TsCH2
N C O
TsCH2
N C
CH2Cl2
-78 oC (5 min)
rt (5 min)
ð1Þ
1
2
Consistent with earlier reports, isocyanate 2 formed the corre-
sponding tosylmethylcarbamates in good yield when dissolved in
neat primary and secondary alcohols and stirred at rt (Eq. 2).
R-XH
neat
TsCH2NHCO–XR
2
ð2Þ
3
Reaction of 1.0 equiv of cyclohexanol or cholesterol with 3.0
equiv of 2 (rt, CH Cl3 solution) also gave the expected carbamate,
although only in ca. 30% yield. Reaction of 2 with butanethiol affor-
ded the corresponding S-thiocarbamate in lower yield. Table 1
summarizes the synthesis of 3a–e.
⇑
Corresponding author. Tel.: +1 607 255 7360.
E-mail address: bg18@cornell.edu (B. Ganem).
http://dx.doi.org/10.1016/j.tetlet.2014.02.016
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2004
H. V. Le, B. Ganem / Tetrahedron Letters 55 (2014) 2003–2005
Condensation of 2 with various primary and secondary amines
O
O
O O
H
N
n-Bu2CuLi
or
n-BuMgCl
S
S
N
(1 equiv) successfully afforded the corresponding N-tosylmethylu-
reas 4 (Eq. 3), although the desired ureas could only be obtained by
addition of a solution of 2 to a cold (ꢀ78 °C) stirred solution of the
amine in THF. The inverse addition of amine to the isocyanate at
any temperature led to the formation of insoluble polymeric mate-
rial, possibly by deprotonation of the active methylene group in 2.
Consistent with that hypothesis, the most basic amine (pyrroli-
dine) furnished carbamate in the lowest yield (Table 2).
O
O
5a
7
O
O
S
S
O
N
N
O
O
O
9
8
RR'NH
TsCH2NHCONRR'
2
ð3Þ
4
O
n-Bu2CuLi
or n-BuMgCl
H
N
N
O
Isocyanates have long been known to undergo condensation
reactions with carboxylic acids that proceed under certain condi-
tions with loss of CO2 to afford carboxamides.5 Efforts to synthesize
the corresponding tosylmethylamides 5 (Eq. 4) by condensing iso-
cyanate 2 with benzoic acid were unsuccessful. However, by adapt-
ing the modification of Sasaki and Crich in which the carboxylic
acid was first transformed into its salt using Hoenig’s base,6 a ser-
ies of tosylmethylcarboxamides 5a–e was prepared under mild
conditions (Table 3).
O
O
10
6
Scheme 1.
with pKa values. However, a competition experiment in which
equimolar quantities of benzoic and p-nitrobenzoic ammonium
salts reacted with 2 afforded the benzamide 5a (39% yield), ruling
out any interfering side reactions of 2 with the nitro group.
Besides presenting a potentially useful pharmacophore, tosylm-
ethylamides 5 may undergo carbon-carbon bond-forming substi-
tution reactions of the tosyl group using various organometallic
reagents. To our surprise, an initial test coupling of amide 5a with
di-n-butylcopperlithium (2.2 equiv) afforded not N-pentylbenza-
mide as expected, but furnished instead N-(n-butoxymethyl)benz-
amide 6 as the only detectable product in 72% yield (Eq. 5).
Particularly characteristic was the sharp doublet for the O–CH2–
N methylene group as well as the –CH2–O triplet in 1H NMR spec-
trum. The same product was obtained using n-BuMgCl (2.2 equiv,
52% yield) in place of the organocuprate. Compound 6 was also
formed when the reaction was conducted using n-BuLi, but in
much lower yield.
RCO2 HNEt(i-Pr)2
TsCH2NHCOR
2
ð4Þ
5
Reactions of 2 with the salt of p-nitrobenzoic acid, as with salts
of aliphatic carboxylic acids (hydrocinnamic acid, cyclohexanecar-
boxylic acid) afforded none of the corresponding tosylmethyla-
mides, affording instead only decomposition products derived
from 2. This unexpected lack of reactivity does not appear to trend
Table 1
Reaction of 2 with alcohols and a thiol
RXH
Tosylmethylcarbamate 3
% Yielda
EtOH (excess)
i-PrOH (excess)
cyclohexanol (1 equiv)
cholesterol (1 equiv)
n-BuSH (1 equiv)
n-BuSH (3 equiv)
3a RX = EtO
3b RX = iPrO
3c RX = cyclohexyl–O
3d RX = cholesteryl–O
3e RX = n-BuS
71
60
30
32
12
22
(n-Bu)2CuLi
or n-BuMgCl
TsCH2NHCOPh
BuOCH2NHCOPh
ð5Þ
5a
3e RX = n-BuS
6
THF, -78 o
C
a
Conditions: stirring 16 h at rt, followed by concentration and purification by
One plausible mechanism for this unusual transformation is de-
picted in Scheme 1 below.
flash column chromatography.
Metallation of amide 5a followed by elimination of toluenesulf-
inate anion from 7 would afford intermediate imine 8. Back-addi-
tion of ArSOꢀ2 to form 9 followed by cyclization would lead to
acyloxaziridine 10. Attack of the organometallic reagent at the
oxaziridine oxygen in 10, which finds precedent in the work of
Davis et al.7 would furnish the N-(n-butoxymethyl)benzamide 6.
These preliminary findings indicate a convenient new route to
alkoxymethylamides, a rare class of compounds that has proven
challenging to be prepared by other methods.7 The only alternative
access to these compounds involves electrolysis of N-acylglycines
(RCONHCH2COOH) in methanol, ethanol, or 2-propanol, as noted
by Linstead et al.8
Table 2
Reaction of 2 with Amines RR0NH
RR0NH
Tosylmethylurea 4
% Yielda
n-BuNH2
t-BuNH2
Pyrrolidine
Aniline
o-Phenylenediamine
4a R = H, R0 = n-Bu
4b R = H, R0 = t-Bu
4c R,R0 = (CH2)4
61
55
21
72
54
4d R = H, R0 = Ph
4e R = H, R0 = (o-NH2Ph)
a
Conditions: THF, -78 °C, 0.5 h; then stirring 1 h at rt, followed by concentration
and purification by trituration or flash column chromatography.
In summary, we report an easy and efficient one-step synthesis
of TsCH2N@C@O (2), making it a readily available synthetic reagent
for nucleophilic addition reactions with various O, N, and S nucle-
ophiles. We also report that N-tosylmethylbenzamides such as 5a
(formed by the reaction of 2 with benzoic acid) undergo an unusual
substitution reaction in the presence of organocopper and organo-
magnesium reagents to afford N-(alkoxymethyl)benzamides like 6.
Table 3
Conversion of 2 into Carboxamides 5
Carboxylate salt (1.2 equiv)
Tosylmethylamide 5
% Yielda
R = Ph
5a
5b
5c
5d
5e
5f
56
40
23
53
37
0
R = p-(OCH3)-C6H4
R = o-(F)-C6H4
R = 2-naphthyl
R = cinnamyl
R = p-(NO2)-C6H4
Acknowledgments
a
Conditions: DMF, -40 °C, 0.5 h; then stirring 2 h at rt, followed by partitioning
between ethyl acetate and water, and purification by flash column chromatography.
Support of the Cornell NMR Facility has been provided by NSF
(CHE 7904825; PGM 8018643) and NIH (RR02002).

H. V. Le, B. Ganem / Tetrahedron Letters 55 (2014) 2003–2005
2005
2. Online literature searches on TsCH2N@C@O returned many hits, but only two
citations were relevant. The rest concerned TOSMIC, not TsCH2N@C@O.
3. Strating, J.; van Oven, H. O.; van Leusen, A. M. Rec. Trav. Chim. Pays-Bas 1966, 85,
631–633.
4. Olijnsma, T.; Engberts, J. B. F. N.; Strating, J. Rec. Trav. Chim. Pays-Bas 1970, 89,
897–906.
5. Schuemacher, A. C.; Hoffmann, R. W. Synthesis 2001, 243–246.
6. Sasaki, K.; Crich, D. Org. Lett. 2011, 13, 2256–2259.
7. Davis, F. A.; Mancinelli, P. A.; Balasubramanian, K.; Nadir, U. K. J. Am. Chem. Soc.
1979, 101, 1044–1045.
Supplementary data
Supplementary data (representative experimental procedures
and complete spectroscopic data for new reactants and products
shown in Tables 1–3) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.02 .016.
References and notes
8. Linstead, R. P.; Shephard, B. R.; Weedon, B. C. L. J. Chem. Soc. 1951, 2854–2858.
1. Le, H. V.; Ganem, B. Org. Lett. 2011, 13, 2584–2585.