Synthesis of isocyanides through dehydration of formamides using XtalFluor-E

Article abstract of DOI:10.1016/j.tetlet.2014.11.128

The formation of isocyanides from formamides using XtalFluor-E, [Et₂NSF₂]BF₄, is presented. A wide range of formamides can be used to produce the corresponding isocyanides in up to 99% yield. In a number of cases, the crude products showed good purity (generally >80% by NMR) allowing to be used directly in multi-component reactions.

Full text of DOI:10.1016/j.tetlet.2014.11.128

Tetrahedron Letters 56 (2015) 461–464
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of isocyanides through dehydration of formamides using
XtalFluor-E
⇑
Massaba Keita, Mathilde Vandamme, Olivier Mahé, Jean-François Paquin
Canada Research Chair in Organic and Medicinal Chemistry, Department of Chemistry, PROTEO, CGCC, Université Laval, 1045 avenue de la Médecine, Québec G1V 0A6, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
The formation of isocyanides from formamides using XtalFluor-E, [Et NSF ]BF , is presented. A wide
2
2
4
Received 11 November 2014
Revised 24 November 2014
Accepted 28 November 2014
Available online 4 December 2014
range of formamides can be used to produce the corresponding isocyanides in up to 99% yield. In a num-
ber of cases, the crude products showed good purity (generally >80% by NMR) allowing to be used
directly in multi-component reactions.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Isocyanide
Isonitrile
Formamide
Dehydration
Diethylaminodifluorosulfinium
tetrafluoroborate
Introduction
reported the preparation of 1,3,4-oxadiazoles from 1,2-diacylhydr-
1
7a
azines (Fig. 1). As a potential extension of this work, we imagined
Isocyanides (also called isonitriles)1 are key building blocks in
organic synthesis. They are well known for their use in the Ugi
reaction (or other multicomponent reactions), but they are also
utilized in many other synthetic transformations. They can act
that if formamides (i.e., R = H) were used as starting substrate,
1
2
upon activation with XtalFluor-E and in the presence of a base,
isocyanides would be generated.
Herein, we report the feasibility of this transformation. A wide
range of formamides can be used to produce the corresponding
isocyanides in up to 99% yield. In a number of cases, the crude
3
4
5
as ligands for transition metals. Finally, a few natural products
contain this functionality.6
As isocyanides are somewhat unstable, they are normally pre-
pared just before their use, although some are commercially avail-
able. A straightforward approach for their preparation consists in
R1
O
R1
7
the dehydration of formamides. Numerous reagents can affect this
1
2
N N
R
R
= alkyl or aryl
= NHC(O)R
8
transformation including phosphoryl chloride, chlorophosphate
1
9
10
11
12
1,3,4-oxadiazoles
derivatives, Vilsmeier reagent, TsCl, Burgess reagents chloro-
1
0
13
,14 cyan-
3
dimethylformiminium chloride, phosgene, CCl
uric chloride,
4
/PPh
1
5
16
F F
and TfOH.
Unfortunately, some of these
[
Et
2
NSF
2
]BF
4
S
reagents are expensive and not available on a large scale, in addi-
tion most are either hygroscopic, moisture sensitive, highly toxic or
thermally unstable.
O
(XtalFluor-E)
O
NEt
2
2
R
R1
NHR2
R1
N
H
-
+ BF
4
We have recently described the synthesis of various N-contain-
1
7
ing heterocycles
through dehydration using diethylam
NSF ]BF ), XtalF luor-
1
R
R
= H
= alkyl or aryl
inodifluorosulfinium tetrafluoroborate ([Et
E, a crystalline solid initially developed as a deoxofluorinating
agent with enhanced thermal stability. In particular, we have
2
2
4
2
1
8
R2
C
N
base
isocyanides
This work
⇑
Corresponding author. Tel.: +1 418 656 2131x11430; fax: +1 418 656 7916.
E-mail address: jean-francois.paquin@chm.ulaval.ca (J.-F. Paquin).
Figure 1. Activation of amides with [Et
oxadiazoles and isocyanides.
2
NSF
2
]BF
4
for the synthesis of 1,3,4-
http://dx.doi.org/10.1016/j.tetlet.2014.11.128
040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
0

4
62
M. Keita et al. / Tetrahedron Letters 56 (2015) 461–464
products showed good purity (generally >80% by NMR) allowing to
be used directly in multi-component reactions.
Table 2
a
Scope of the dehydration of formamides with XtalFluor-E
XtalFluor-E (1.1 equiv)
O
3
Et N (1.5 equiv)
Results and discussion
R
R-NC
2-15
N
H
H
CH Cl (1 M), -40 ºC, 1 h
2
2
We optimized the reaction conditions using 1 as the formamide
and selected results are shown in Table 1. First, using 1 equiv of
NC
NC
NC
XtalFluor-E and Et
Et N was optimal (entries 1–3). Other organic bases (entries 4–5)
or an inorganic base (entry 6) was less effective. Using Et N as
the base, other solvents were examined but all proved less effec-
tive than CH Cl (entries 7–10). Using a slight excess of XtalFlu-
3
N as the base, it was found that 1.5 equiv of
3
MeO
O
2
N
I
3
2; 97% (85%)
3; 47%b
4; 51%b
2
2
or-E (1.1 equiv) provided almost a quantitative yield (entry 11).
Finally, fine-tuning of the reaction temperature (not shown)
revealed that running the transformation at À40 °C for 1 h pro-
vided a cleaner product (less side-products observed by 1H NMR
analysis of the crude product).
CH3
NC
NC
NC
COOEt
6; 39%b
5; 72% (92%)
7; 34%b
These optimized conditions were then used to examine the
scope of this reaction (Table 2). In a number of cases, the crude iso-
cyanide was pure enough so that it could be used directly in a sub-
sequent transformation (vide infra). In those cases, no further
purification was performed and the estimated NMR purity is indi-
NC
NC
MeO
8; 99% (94%)
9; 96% (93%)c
1
9
cated in parentheses.
When the crude isocyanides showed
CN
CN
NC
numerous impurities, purification using flash chromatography
was performed; this often resulted in lower yields due, most likely,
to the instability of the product on silica gel. Hence, a wide range of
isocyanides could be generated including ones derived from aro-
matic (2–7), benzylic (8–9), aliphatic (10–12) or amino acid-based
formamides (13–15). Also, these results show that various func-
tional groups including ether, ester, and protected amines (benzyl,
Cbz or Boc) are well tolerated. In the case of the phenylalanine-
based isocyanide (13), chiral HPLC analysis showed that complete
racemization occurred when starting from the enantioenriched
N
N
Bn
10; 83% (89%)
Cbz
F
F
b
11; 95% (93%)
12; 56%
F
F
NC
2
0
OMe
formamide. For the crude isocyanides with good purity, the crude
yield varied between 72% and 99%. For the isocyanides that
required purification, the isolated yields were lower, that is,
MeO
2
C
NC
N
CN
Boc
O
15; 60%b
1
3; 96% (71%)
14; 91% (86%)
between 34% and 60%. Surprisingly, for
a few formamides
a
Crude yield after work-up with purity estimated by 1H NMR analysis in
(Fig. 2), no desired product could be isolated. For N-pentylforma-
parenthesis.
b
mide and N-(4-trifluoromethylphenyl)formamide, complete degra-
dation was observed. With N-tert-butylformamide, no conversion
Isolated yield.
Reaction time was 2 h.
c
was observed (even at higher temperature) and the starting form-
amide could be fully recovered. Finally, for N-formylglycine ethyl
ester, the major product was not the desired isocyanide, although
we have not been able to isolate and characterize this compound.
We suspect an intramolecular reaction with the activated amide
similarly to what has been observed with 1,2-diacylhydrazines.1
Table 1
Selected optimization results for the dehydration of the formamide 1
XtalFluor-E (1 equiv)
MeO
MeO
base
O
7a
solvent (1 M)
N
H
H
NC
0 °C, 1 h then rt, 2 h
This side-reaction may be slowed down with an a-substituent (cf.
compounds 13–14).
1
2
Yielda (%)
With respect to the reaction mechanism, the formation of isocy-
anides would most likely proceed with a mechanism similar to that
which occurs for the cyclodehydration of 1,2-diacylhydrazines
Entry
Base
Solvent
1
2
3
4
5
6
7
8
9
Et
3
Et
3
Et
3
N (1.2 equiv)
N (1.5 equiv)
N (2.5 equiv)
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
64
90
92
23
<20
0
41
36
55
50
99
1
7a
(Figs. 1 and 3).
group to [Et NSF
Hence, nucleophilic attack of the amide carbonyl
]BF at the electrophilic sulfur would generate
iPr
2,4,6-Collidine (1.5 equiv)
CO (1.5 equiv)
2
EtN (1.5 equiv)
2
2
4
b
21
intermediate 16. Loss of HF and diethylaminosulfinyl fluoride
would lead to the protonated isocyanide (17) that would rapidly
c
K
2
3
Et
3
Et
3
Et
3
Et
3
Et
3
N (1.5 equiv)
N (1.5 equiv)
N (1.5 equiv)
N (1.5 equiv)
N (1.5 equiv)
THF
CH CN
Toluene
EtOAc
3
generate the isocyanide in the presence of Et N.
3
Finally, we explored the possibility of using the crude isocya-
1
1
0
1
nides directly in multi-component reactions. First, Passerini reac-
d
CH
Cl
2 2
22
tion
using crude isocyanides 2, 5, 8, 9, 11, or 14 with a
a
Determined by 1H NMR analysis of the crude using p-xylene as an internal
benzaldehyde and a carboxylic acid provided the corresponding
-acyloxyamide 18–25 in moderate to good yield from forma-
standard.
a
b
Estimated value as spectral interferences prevented
measurement.
a more accurate
mides over two steps (Table 3). Using this particular protocol, a
simple filtration allows the isolation of the final product. This reac-
tion is particularly effective with benzylic isocyanides. At this
c
Starting material was recovered.
d
1
.1 equiv of XtalFluor-E was used.

M. Keita et al. / Tetrahedron Letters 56 (2015) 461–464
463
O
O
O
H
N
H
H
a
b
N
H
H
N
Ph
crude 8 or 9
O
O
R
R
H
degradation
H
N
2
6; R = H (53%)
7; R = OMe (51%)
2
F3C
Scheme 1. Synthesis of N-formyl amides with crude isocyanides. Reagents and
conditions: (a) XtalFluor-E, Et N, CH Cl
(1 M), À40 °C, 1–2 h followed by an
aqueous work-up. (b) PhCO H, CHCl , 150 °C (MW), 30 min. Yields from products 26
3
2
2
O
H
2
3
H
N
H
and 27 are calculated from formamides (over two steps).
N
H
EtO
O
O
no reaction
major side-reaction
observed
NO
2
Figure 2. Unproductive formamides.
O
O
a
b
N
Ph
crude 8
N
H
H
N
H
F
S
F
+
Me
NEt
R
R
2
F
F
2
8; R = OMe (35%)
S
H
O
O
NEt
2
+
Scheme 2. Ugi-Smiles with
XtalFluor-E, Et N, CH Cl
(1 M), À40 °C, 1 h followed by an aqueous work-up. (b)
CH CHO, BnNH , 4-nitrophenol, rt, 16 h. The yield from products 28 is calculated
a crude isocyanide. Reagents and conditions: (a)
R
R +
N
H
R
N
C H
7
N
H
H
3
2
2
1
3
2
1
6
from the formamide (over two steps).
Et N
3
and purity of isocyanides and the fact that the Passerini is not a
2
2
+
-
quantitative reaction, even with pure isocyanide.
Then, synthesis of N-formyl amide under conditions reported by
R
N
C
2
4
À
Danishefsky with crude isocyanides 8 or 9 and benzoic acid gave
the desired products 26 and 27 in moderate yields over two steps
Figure 3. Mechanistic proposal for the dehydration reaction. The BF
4
counter-ion
has been omitted for clarity.
(Scheme 1).
Finally, a phenol Ugi–Smiles reaction25 with crude isocyanide 8
Table 3
is also possible albeit in moderate yield (Scheme 2).
Overall, the results obtained for those two multi-component
reactions show that the presence of minor impurities in the isocy-
anide does not affect significantly the subsequent transformation
and suggest that extension to other multi-component reactions
may be possible.
Synthesis of a
-acyloxyamide using crude isocyanidesa,b
i) XtalFluor-E
1
Et N
R CO
2
H
3
O
R
O
CH
2
Cl
2
, -40 °C
ArCHO
R1
R
O
R-CN
N
H
H
N
H
ii) work-up
H O, rt
2
crude
Ar
O
isocyanide
Conclusion
MeO
O
O
We have reported the synthesis of isocyanides from forma-
mides using XtalFluor-E. A number of isocyanides can be prepared
in up to 99% yield from readily available formamides. In a number
of cases, the crude products showed good purity (generally >80%
by NMR) allowing to be used directly in multi-component
reactions.
O
Ph
O
Ph
N
H
N
H
Ph
O
Me
R1
Ph
O
1
8 (33%)
19 (34%)
O
O
N
H
Ar
O
R
0; R = H, Ar = Ph, R1 = Ph (50%)
Acknowledgments
2
1
2
2
2
1; R = OMe, Ar = Ph, R = Ph (74%)
1
This work was supported by the Canada Research Chair Pro-
gram, the Natural Sciences and Engineering Research Council of
Canada, the Canada Foundation for Innovation, FRQ-NT Centre in
Green Chemistry and Catalysis (CGCC), FRQ-NT Research Network
on Protein Function, Structure and Engineering (PROTEO), Omega-
Chem and the Université Laval. OmegaChem is acknowledged for a
generous gift of N-t-BOC-4,4-difluoro-(2S)-aminomethylpyrroli-
dine benzensulfonate.
2; R = OMe, Ar = 4-NO -C H R
= Ph (74%)
6 4
2
6 4,
1
3; R = OMe, Ar = Ph, R = 4-NO -C H (75%)
2
O
O
O
Ph
O
Ph
N
H
MeOOC
N
H
CbzN
Ph
O
Ph
O
2
4 (39%)
25 (36%)
a
See Supplementary Material for details on the reaction conditions.
Isolated yield by filtration over two steps.
b
Supplementary data
point, no attempts were made to further improve the yield though
additional product may be present in the filtrate.23 This represents
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.1
1.128.
5
7–87% per step, which is satisfactory considering the crude yield

4
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M. Keita et al. / Tetrahedron Letters 56 (2015) 461–464
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1
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