An efficient reduction of N-substituted carbonylimidazolides into formamides by NaBH4

Article abstract of DOI:10.1016/j.tetlet.2017.04.072

A novel, simple and versatile protocol was investigated for highly efficient synthesis of formamides through reducing N-substituted carbonylimidazolides by NaBH₄ under mild reaction conditions. By this method, not only carboxylic acids or isocyanates, but also amines can readily access formamides with high yields.

Full text of DOI:10.1016/j.tetlet.2017.04.072

Accepted Manuscript
An efficient reduction of N-substituted carbonylimidazolides into formamides
by NaBH4
Zhiyong Chen, Yiming Cao, Zeyu Tian, Xuan Zhou, Wenjin Xu, Jia Yang,
Hanbing Teng
PII:
S0040-4039(17)30526-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.072
TETL 48864
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 March 2017
21 April 2017
24 April 2017
Please cite this article as: Chen, Z., Cao, Y., Tian, Z., Zhou, X., Xu, W., Yang, J., Teng, H., An efficient reduction
of N-substituted carbonylimidazolides into formamides by NaBH4, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.04.072
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Tetrahedron Letters
An efficient reduction of N-substituted carbonylimidazolides into formamides by
NaBH4
Zhiyong Chen, Yiming Cao, Zeyu Tian, Xuan Zhou, Wenjin Xu, Jia Yang, Hanbing Teng*
School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, People's Republic of China.
*Corresponding author, wdthb@163.com.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel, simple and versatile protocol was investigated for highly efficient synthesis of
formamides through reducing N-substituted carbonylimidazolides by NaBH4 under mild
reaction conditions. By this method, not only carboxylic acids or isocyanates, but also amines
can readily access formamides with high yields.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
N-substituted carbonylimidazolide
formamide
reduction
sodium borohydride
N-formyl derivatives serve as a valuable class of compounds
having a wide range of applications in medicinal and organic
chemistry. They are important pharmaceutical intermediates and
some have been used as drugs.1,2 In the field of organic
chemistry, formamides are vital raw material in the synthesis of
formamidines,3 isocyanides,4 Vilsmeier reagents5 and fungicide.6
Furthermore, as Lewis bases, they are excellent catalysts in
allylation7 and hydrosilylation8 of carbonyl compounds and other
transformations.9 In addition, the formyl group is a conventional
amino protecting group especially in peptide synthesis.10
In this work, we reported a novel protocol of synthesis of
various formamides in high yield by reduction of N-substituted
carbonylimidazolide with NaBH4 at room temperature. As
important reagents, N-substituted carbonylimidazolides had good
stability and played a particularly role in the preparation of
ureas17, carbamates18 and thiocarbamates19. They could be
conveniently prepared by treatment of isocyanates with
imidazole, which made our method suitable for the synthesis of
formamides from carboxylic acids because isocyanate group
could be readily converted from carboxyl group. (Scheme 1,
Route A). It was to be noted that N-substituted
carbonylimidazolide could also be obtained by reaction of amines
with commercially available and inexpensive N,N'-
carbonyldiimidazole (CDI) (Scheme 1, Route B). Therefore, our
method was appliable to prepare formamides from amines as
well. To the best of our knowledge, there was no any report
available about the preparation of formamides from both
carboxylic acids or isocyanates and amines.
Hence, a great deal of research has focused on the synthesis of
N-formyl derivatives. In most cases, Amines were acted as
starting materials, various N-formylating agents and methods
were developed for the preparation of formamides.11
Alternatively, few studies have been devoted to synthesis of
formamides starting from carboxylic acids12 or its derivative such
as isocyanate13 and carbamoyl azide14. These protocols had an
advantage that N-protected amino acids were adaptable to the
preparation of N-protected gem-diamines, which were
particularly useful for the synthesis of retro-inverso peptides.15
However, synthesis of formamides from carboxylic acids
often involved in converting carboxyl group into isocyanate, then
reaction of it with formic acid.12 It might be unfavorable for the
raw materials of N-Boc protected amino acids or peptides
because formic acid was sometimes used as N-Boc deprotection
agent.16 Direct reduction of isocyanates to formamides required a
special reducing agent.13 Although reduction of carbamoyl azide
with NaBH4 could also provide formamides.14 However,
carbamoyl azides had poor stability and were difficult to purify
and store, which would greatly limit their application.
Scheme 1 Synthesis of formamides from both carboxylic acids or
isocyanates and amines

2
Tetrahedron
In our initial experiment, the N-cyclohexyl and N-phenyl
(equiv.)
3.0
(%)
90
carbonylimidazolide were chosen to represent the N-aliphatic and
N-aromatic substituted carbonylimidazolides, respectively. A
common reaction condition was employed, e.g. room temperature
(RT) and THF/H2O mixed solvent system. The reaction was
investigated only by regulation of the amount of NaBH4. The
reduction of N-cyclohexyl and N-phenyl carbonyl-imidazolide
with various equivalents of NaBH4 was performed as model
reaction. The results were listed in Table 1.
1
2
3
1.0
3.0
91
93
Table 1. Model Reaction: Optimization of the amount of
NaBH4
Timea
(min)
200
25
Yieldb
(%)
90
NaBH4
(equiv.)
Entry
Starting material
4
5
3.0
3.0
96
90
1
2
3
4
5
1a
2a
1a
2a
1a
1.0
1.0
2.0
2.0
3.0
91
86
91
23
91
50
90
a Monitored by TLC. b Isolated yield
6
3.0
84
As shown in Table 1, the amount of NaBH4 had a great
influence on the reaction time. For N-phenyl carbonylimidazolide,
it was sufficient to reduce it in about 25 minutes with 1.0 equiv
of NaBH4 and offered an excellent yield. The reaction efficiency
cannot be significantly improved by increasing the amount of
NaBH4 to 2.0 equiv. However, for N-cyclohexyl counterpart, it
took above three hours to carry out the reaction if only 1.0 equiv
of NaBH4 was used. When the amount of NaBH4 was increased
to 3.0 equiv, the reaction time was shortened to 50 minutes. No
attempt had been made to further increase the amount of NaBH4
or to adjust other parameters since these results were completely
satisfactory.
7
8
3.0
3.0
86
87
With these optimized conditions in hand, we explored the
scope of the reaction including N-alkyl carbonylimidazolides
(entries 3-12, 22) and N-aryl carbonylimidazolide (entries 13-21,
23) (Table 2). All selected N-substituted carbonylimidazolides
had been conveniently prepared by widely used methods.
Compounds (1a, 9a, 13a-16a) were readily prepared by Route
A,20 Compounds (2a-4a, 10a-12a, 17a-18a) were directly
synthesized by Route B,21 and Compounds (5a-8a) were obtained
by Route A after converting carboxylic acids to corresponding
isocyanates according to the conventional methods we reported.22
For the N-alkyl and N-aryl carbonylimidazolides, 3.0 equiv and
1.0 equiv of NaBH4 was used respectively. Both N-alkyl and N-
aryl carbonylimidazolides reacted smoothly and provided the
corresponding formamides in good to excellent yields and for the
most of cases, the reaction was completed in 25-50 minutes.23
9
3.0
93
10
11
12
3.0
3.0
3.0
90
88
90
Table 2. Synthesis of formamides
Entry
Substrate
Product
NaBH4
Yielda

heterocyclic substituted carbonylimidazolides were applicable to
this reaction and all three N-heterocyclic substituted
carbonylimidazolides (6a, 12a, 21a) did not compromise the
efficiency of the methodology. In addition, two different
characteristic methyl esters had been also tested, aliphatic ester (8a)
and aromatic ester (19a) offered corresponding desired products in
87% and 95% yield respectively.
Reduction of 22a and 23a, bearing two N-substituted
carbonylimidazolide functionalities, became elusive under the
standard conditions. For 22a, it took 36 minutes to compete the
reaction when 2.0 equiv of NaBH4 was used. For 23a, however,
if the amount of NaBH4 was 6.0 equiv, the reaction cannot yet be
completed over 4 hours. By increasing the amount of NaBH4 to
10.0 equiv, the reaction time was shortened to 120 minutes.
13
1.0
1.0
93
90
14
15
1.0
1.0
1.0
86
92
88
It is known that the general urea functionality was not
susceptible to reducing agent NaBH4 because of the poor
electrophilic character of the amide carbonyl group. However,
the urea functionality on the N-substituted carbonyl-imidazolides
had displayed excellent reactivity. Two key factors could
contribute to it. First, by the formation of acylimidazoles, the
electron-withdrawing effect of imidazole made the carbonyl
carbon more electrophilic to increase its reactivity to nucleophilic
attack. Second, as a sufficiently good leaving group24, the
dissociation of the imidazole anion provided the significant
driving force. Like the common reaction of N-substituted
carbonylimidazolides with nucleophiles such as amines, thiols
and alcohols, the dissociation of imidazole anion was also
conducive to the reaction.17-19
16
17
18
19
1.0
1.0
92
95
Scheme 2 The possible reaction mechanism
The possible reaction mechanism was shown in Scheme 2.
Initially, as an excellent nucleophile, hydrogen anion (H-)
provided by NaBH4 attacked carbonyl carbon atom on urea
functionality to form alkoxide intermediate M. Subsequently,
accompanying by the dissociation of imidazole anion, the
unstable alkoxide intermediate converted to carbonyl again and
formed the target formamide, which constituted a good amide
conjugation system and was stable enough for mild reducing
agent NaBH4. The requirement of a less amount of NaBH4 for N-
aromatic substituted carbonylimidazolides was closely related to
not only the increased electrophilic of N-aromatic substituted
carbonylimidazolides by the electron-withdrawing effect of aryl
group, but also the easy formation of stronger conjugation system
of the resulting N-aromatic formamide products. Different from
N-substituted carbonylimidazolides, the carboxylic acid
imidazolides were readily reduced into primary alcohols by
NaBH4,25 because the formed intermediate aldehyde was highly
reactive and tended to be further reduced by NaBH4 after the
carbonyl carbon was attacked by H- ion and the imidazole anion
was removed. When a stronger reducing agent such as LiAlH4
was used, formamides would be over-reduced into N-
methylamines.26
20
21
1.0
1.0
88
89
22
23
10.0
2.0
84 b
89
a Isolated yield.
b Reaction time: 2h.
N-Boc and N-Fmoc protected amino acids (entries 5-8) were
both adaptable to this method. Sterically hindered N-substituted
carbonylimidazolides also provided the desired products with
satisfied yield not only in the case of aliphatic analogues (entries 9-
12) but also for aromatic substituents (entries 20, 21). The
substitution on the aromatic ring had no negative influence on the
reaction outcome: both electron-releasing (alkyl e.g., entry 13) and
electron-withdrawing
Trifluoromethoxy(entry 16), nitro (entry 17), Trifluoromethyl
(entry 18), ester (entry 19)] functionalities were tolerated. N-
In summary, we have developed a more versatile method than
the previously reported for the preparation of formamides. By our
method, not only carboxylic acids or isocyanates, but also amines
can readily access formamides. In addition, our method is
economical and no expensive catalyst or special reagent is
employed. Moreover, the reaction is simple, mild, fast and shows
good applicability.
[halogen
(entries
14,
15),

4
Tetrahedron
19. Duspara, P. A.; Islam, M . S.; Lough, A. J.; Batey, R. A. J. Org.
Chem. 2012, 77, 10362.
Acknowledgments
20. Christian, J.; Christoph, N.; Therese, S.; Lionel, R.; Christian, D.
K. J. Med. Chem. 2014, 57, 7590.
We are grateful for financially supported by the National
Training Programs of Innovation and Entrepreneurship for
Undergraduates (No. 20161049720020).
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Giuseppone, N. Langmuir 2015, 31, 7738. (b) Velavan, A.;
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23. General procedure for the synthesis of formamides (b) from
N- substituted carbonylimidazolides (a)
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To a solution of compound a 1.0mmol in THF (8 mL) at room
temperature, NaBH4 (3.0mmol for N-aliphatic substituted
carbonylimidazolides and 1.0mmol for N-aromatic substituted
carbonylimidazolides) in 1 mL H2O was added with vigorous
stirring. The progress of the reaction was monitored by TLC. After
the reaction was complete, the reaction mixture was cooled with
ice water, 1 M HCl was added carefully till pH=2-3. The solution
was extracted with dichloromethane (3×20 mL) and the organic
layers were combined. The organic extract was washed with brine,
dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The crudes were purified by silica gel column
chromatography.
(6b) yield 84% of white solid; Rf = 0.6 (CH2Cl2/MeOH, 9:1, v/v);
1H NMR (400 MHz, CDCl3) (trans/cis= 35/65) δ 8.31 (d, J = 10.8
Hz, 1H, trans), 8.20 – 7.98 (m, 1H, cis), 7.24 (br s, 1H, cis), 6.51
(br s, 1H, trans), 5.76 – 5.40 (m, 1H, trans), 5.34 – 5.06 (m, 1H,
cis), 3.53 – 3.16 (m, 2H, trans, 2H, cis), 2.41 – 1.73 (m, 4H, trans,
4H, cis), 1.43 (s, 9H, trans), 1.40 (s, 9H, cis). 13C NMR (100 MHz,
CDCl3) δ 165.85, 165.07, 154.12, 153.61, 80.84, 80.30, 65.72,
45.62, 33.47, 32.30, 28.38, 23.07, 22.23. ESI-MS, m/z calcd. for
C10H18N2O3Na+ [M+Na]+ 237.132; found 237.105.
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(8b) yield 87% of white solid; Rf = 0.65 (CH2Cl2/MeOH, 9:1,
v/v);1H NMR (400 MHz, CDCl3) (trans/cis= 30/70) δ 8.26 (d, J =
11.7 Hz, 1H, trans), 8.09 (s, 1H, cis), 6.94 (br s, 1H, cis), 6.78 (br
s, 1H, trans), 5.86 (br s, 1H, cis), 5.78 (br d, J = 8.7 Hz, 1H, trans),
5.65 (s, 1H, cis), 5.40 (s, 1H, trans), 3.72 (s, 3H, trans), 3.69 (s,
3H, cis), 2.91 (s, 2H, cis), 2.81 (s, 2H, trans), 1.41 (s, 9H, trans,
9H, cis). 13C NMR (100 MHz, CDCl3) δ 171.26, 164.42, 160.58,
154.69, 80.47, 53.96, 52.35, 52.06, 39.47, 38.51, 28.29. ESI-MS,
m/z calcd. for C10H18N2O5Na+ [M+Na]+ 269.122; found 269.094.
(21b) yield 89% of pale green solid; Rf = 0.5 (PE/EtOAc, 5:1,
1
v/v); H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.74 (d, J = 8.0
Hz, 1H), 7.34 (ddd, J = 18.3, 15.0, 8.4 Hz, 5H), 7.25 – 7.19 (m,
2H). 13C NMR (100 MHz, CDCl3) δ 161.09, 137.39, 135.20,
130.93, 129.46, 127.79, 127.72, 127.54, 127.17, 127.08, 125.66,
121.91. ESI-MS, m/z calcd. for C13H10NOS [M+H]+ 228.040;
found 228.031.
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(22b) 10.0mmol NaBH4 was used; yield 89% of white solid; Rf =
0.35 (CH2Cl2/MeOH, 10:1, v/v); H NMR (400 MHz, DMSO-d6)
1
(trans/cis= 85/15) δ 7.97 (s, 2H, trans), 7.91 (d, J = 11.9 Hz, 2H,
cis), 3.05 (q, J = 6.4 Hz, 4H, trans, 4H, cis), 1.47 – 1.31 (m, 4H,
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Characterization data of compounds including NMR and MS
spectra are available as supplementary material.

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An efficient reduction of N-substituted
carbonylimidazolides into formamides by
NaBH4
Leave this area blank for abstract info.
Zhiyong Chen , Yiming Cao, Zeyu Tian , Xuan Zhou , Wenjin Xu , Jia Yang , Hanbing Teng *

Carboxylic acids, isocyanates and amines are all easy to access formamides by this method.
The method is economical and no expensive catalyst or special reagent is employed.
The reaction is simple, mild, fast and shows good applicability.