A convenient one-pot synthesis of formamide derivatives using thiamine hydrochloride as a novel catalyst

Article abstract of DOI:10.1016/j.tetlet.2010.06.005

Formamide derivatives have been synthesized in excellent yields from amine and formic acid in the presence of a catalytic amount of thiamine hydrochloride (VB₁) at 80 °C. The advantages of this method are the use of a cheap, stable, non-toxic, and readily available catalyst, easy work-up, improved yields, and solvent-free conditions.

Full text of DOI:10.1016/j.tetlet.2010.06.005

Tetrahedron Letters 51 (2010) 4186–4188
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Tetrahedron Letters
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A convenient one-pot synthesis of formamide derivatives using thiamine
hydrochloride as a novel catalyst
Min Lei , Lei Ma a,*, Lihong Hu
a
a,b,*
a
School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, PR China
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Formamide derivatives have been synthesized in excellent yields from amine and formic acid in the pres-
Received 7 April 2010
Revised 26 May 2010
Accepted 1 June 2010
Available online 8 June 2010
1
ence of a catalytic amount of thiamine hydrochloride (VB ) at 80 °C. The advantages of this method are
the use of a cheap, stable, non-toxic, and readily available catalyst, easy work-up, improved yields, and
solvent-free conditions.
Ó 2010 Elsevier Ltd. All rights reserved.
Formylation of amines is one of the most important protocols in
organic synthesis and medicinal chemistry. Formamides are useful
intermediates in various organic syntheses as their skeletons are
Cl
NH3
Cl
N
N
S
1
present in different medicinally important compounds. Moreover,
H C
N
H C
3
3
the formyl group is an important amino-protecting group in pep-
2
tide synthesis. In recent years, formamides are also used as Lewis
OH
bases to promote several organic transformations.3
1
Figure 1. The structure of VB .
A number of formylation methods have been reported in recent
4
years. Some of the useful formylation reagents are chloral, formic
5
6
7
acid-DCC, formic acid-EDCI, formic acid-ZnCl
2
,
formic acid-PEG
R1
NH
R1
NCHO
8
9
10
VB1 2 mol %
HCOOH
4
00, formic acid esters, CDMT, and other formylation re-
+
1
1
agents. However, many of these procedures so far suffer from
disadvantages, such as expensive reagents, harsh reaction condi-
tions, prolonged reaction times, high reaction temperature, and
low isolation yields. Therefore, there is a need to develop a better
catalyst for the synthesis of formamide derivatives in terms of
operational simplicity and economic viability.
Solvent-free, 80 o
R
C
R
1
2
Scheme 1. Synthesis of formamides 2.
when a mixture of aniline 1a and formic acid was heated at
It is well known that thiamine hydrochloride (VB
non-toxic, stable, and can be recovered. VB contains a pyrimidine
ring and a thiazole ring linked by a methylene bridge (Fig. 1). VB
1
) is cheap,
7
1
00 °C for 4 h (Table 1, entry 1). However, we obtained the corre-
sponding product 2a in 84% yield by simply mixing aniline 1a and
formic acid in the presence of 1 mol % of VB at 80 °C for 15 min,
thus, highlighting the role of VB as a promoter. Further studies re-
vealed that the reaction was sluggish giving poor yields (<20%) in
various solvents, such as MeOH, EtOH, THF, DCM, and MeCN (Table
, entries 6–10). Moreover, we also found that 2 mol % of VB was
1
sufficient and an excessive amount of catalyst did not increase the
yields (Table 1, entries 2–5).
In terms of yields and reaction time, we achieved the best con-
1
ditions to synthesize formamide 2a by using 2 mol % VB under
solvent-free conditions. Having established the optimized reaction
conditions, we then successfully synthesized a variety of formam-
ide derivatives 2 (Scheme 1), and the results are summarized in
1
1
1
analogs have been used as powerful catalysts for many carbon–
carbon and carbon–heteroatom bond formation reactions in good
1
1
2
1
yields. As a part of the ongoing interest in VB -catalyzed reaction
13
for various organic transformations, we had the opportunity to
further explore its catalytic activity toward the synthesis of forma-
mides. In this Letter, we wish to report a simple but effective pro-
cedure for the synthesis of formamide derivatives from amines and
1
formic acid by employing VB
1
as a novel catalyst (Scheme 1).
for a model
Initially, we studied the catalytic efficiency of VB
1
reaction using aniline 1a and formic acid in different reaction con-
ditions (Table 1). It was reported that no reaction was observed
1
4
Table 2.
In all of the studied examples, the aromatic amines, primary
amines, and secondary amines could react smoothly to give the
*
Corresponding author. Tel.: +86 21 6425 3691; fax: +86 21 5027 2221.
E-mail address: malei@ecust.edu.cn (L. Ma).
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.005

M. Lei et al. / Tetrahedron Letters 51 (2010) 4186–4188
4187
Table 1
Table 2 (continued)
a
Optimization of the reaction conditions
Entry
Product 2
Time (min)
Yieldb (%)
Entry
Solvent
Catalyst
mol %)
Temp. (°C)
Time (min)
Yieldb of 2a (%)
NHCHO
O
(
2
q
1
2
3
4
5
6
7
8
9
None
None
None
None
None
MeOH
EtOH
THF
0
1
2
3
5
2
2
2
2
2
100
80
80
80
240
15
10
10
10
240
240
240
240
240
NRc,7
84
96
95
95
<20
<20
<15
<10
<20
18
OH
CHO
120
120
40
0
0
HN
2
r
80
Reflux
Reflux
Reflux
Reflux
Reflux
O
1
9
0
N
OH
CHO
DCM
MeCN
2s
1
0
O
a
Conditions: aniline 1a (5 mmol), formic acid (1 mL), solvent-free or solvent
3 mL).
Isolated yields.
2
O
85
(
HN
b
CHO
2
t
c
No reaction was observed.
O
O
Table 2
21
HN
40
85
CHO
a
Synthesis of formamides 2 catalyzed by VB
1
N
H
Entry
Product 2
Time (min)
10
Yieldb (%)
96
2u
a
1
Reaction conditions: amine 1 (5 mmol), formic acid (1 mL), VB (0.1 mmol,
mol %), solvent-free, 80 °C.
Isolated yields.
NHCHO
NHCHO
NHCHO
1
2
2
2
2
a
b
c
b
2
20
92
corresponding formamide derivatives 2 in good to excellent yields
(85–96%). Aromatic amines carrying either electron-donating or
electron-withdrawing groups could react efficiently giving good
yields (Table 2, entries 1–11).
Then, we examined the reactivity of aliphatic amines in the
1
presence of VB (Table 2, entries 12–17). It is interesting to note
3
4
10
10
95
95
NHCHO
2
d
Cl
that in the case of the aliphatic amines, we have achieved good
5
6
20
15
90
95
NHCHO
2
e
Cl
Table 3
NHCHO
a
Synthesis of amides 2 catalyzed by VB
1
2
f
H
NH2
R2
VB1
N
Cl
NHCHO
2
7
8
9
15
40
30
94
94
93
+
R COOH
2
g
O
O N
NHCHO
2
Entry
1
Product 2
Yieldb (%)
2
h
H
N
Br
NHCHO
90
2
i
O
O
O
OH
NHCHO
2v
H
N
1
0
30
88
2
3
84
80
2j
2
w
HO
NHCHO
1
1
1
2
20
20
90
93
H
N
2
k
CH NHCHO
2x
2y
2
2
l
H
N
4
5
0
0
NCHO
1
1
1
3
4
5
30
30
30
88
87
90
2
m
O
O
O
NCHO
H
N
2
n
NCHO
2z
2
o
a
1
Conditions: aniline 1a (5 mmol), acid (1 mL or 1 g for 2y and 2z), VB (0.1 mmol,
1
6
7
NHCHO
15
15
92
93
2 mol %), solvent-free, 100 °C, 4 h.
2
p
b
Isolated yields.
1

4
188
M. Lei et al. / Tetrahedron Letters 51 (2010) 4186–4188
R
R1
N
H
H
O
OH
Cl
H
N
NH3
Cl
N
Cl
H
H
Cl
O
N
+
S
N
N
H
OH
S
H C
N
3
H C
3
H C
N
3
H C
3
OH
OH
VB1
3
R
R1
R1
NCHO
-
H O
2
N
VB1
+
HO
OH
R
4
2
Scheme 2. A possible mechanism for the formation of compound 2.
to high yields (88–93%) by employing catalytic amount of VB
2 mol %), which normally show poor yields.7
As shown in Table 2, -amino acids ( -phenylananine and
line) were also examined in the presence of 2 mol % of VB
tunately, no reaction was observed as indicated by TLC.
1
90713046, 30772638, 30925040), and CAS Foundation (grant
KSCX2-YW-R-179).
(
a
L
L
-pro-
, unfor-
-Amino
1
References and notes
a
1
.
(a) Kobayashi, K.; Nagato, S.; Kawakita, M.; Morikawa, O.; Konishi, H. Chem.
Lett. 1995, 575; (b) Chen, B.-C.; Bendarz, M. S.; Zhao, R.; Sundeen, J. E.; Chen, P.;
Shen, Z.; Skoumbourdis, A. P.; Barrish, J. C. Tetrahedron Lett. 2000, 41, 5453; (c)
Jackson, A.; Meth-Cohn, O. J. Chem. Soc., Chem. Commun. 1995, 1319.
(a) Hartinez, J.; Laur, J. Synthesis 1982, 979; (b) Kraus, N. A. Synthesis 1973, 361.
Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 56, 6620.
acids could not be formylated under the conditions because the
-amino acids were easy to form intramolecular salts which re-
duced the nucleophilicity of the amino group. Then, we used the
carboxyl group-protected -amino acids ( -phenylalanine methyl
ester and -tryptophan methyl ester) as the starting materials, find-
ing that the reaction could proceed smoothly to give the desired
a
2.
3.
4.
a
L
L
Blicke, F. F.; Lu, C.-J. J. Am. Chem. Soc. 1952, 74, 3933.
5. Waki, J.; Meinhofer, J. J. Org. Chem. 1977, 42, 2019.
1
5
6
7
.
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Chen, F. M. F.; Benoiton, N. L. Synthesis 1979, 709.
Chandra Shekhar, A. C.; Kumar, A. R.; Sathaiah, G.; Paul, V. L.; Sridhar, M.; Rao,
P. S. Tetrahedron Lett. 2009, 50, 7099.
products in good yields.
The reaction that completed within 40 min with excellent
yields was an important finding regarding this reaction. The re-
ported methods pointed out that the reaction time was long (4–
8. Das, B.; Krishnaiah, M.; Balasubramanyam, P.; Veeranjaneyulu, B.;
Nandankumar, D. Tetrahedron Lett. 2008, 49, 2225.
9
.
(a) Yale, H. L. J. Org. Chem. 1971, 36, 3238; (b) Kisfaludy, L.; Laszlo, O. Synthesis
987, 510; (c) Duezek, W.; Deutsch, J.; Vieth, S.; Niclas, H. J. Synthesis 1996, 37.
0. Luca, L. D.; Giacomelli, G.; Porcheddu, A.; Salaris, M. Synlett 2004, 2570.
1
2 h) when using aromatic amines bearing strong electron-with-
1
drawing group (–NO ) or secondary amines as the starting materi-
2
1
7
als. However, the reaction could be completed within 40 min
using 2 mol % as the catalyst, much shorter than the reported
methods.
11. (a) Strazzolini, P.; Giumanimi, A. G.; Cauci, S. Tetrahedron 1990, 46, 1081; (b)
Reddy, P. G.; Kumar, G. D. K.; Baskaran, S. Tetrahedron Lett. 2000, 41, 9149; (c)
Mihara, M.; Ishino, Y.; Minakara, S.; Komatsu, M. Synthesis 2003, 2317; (d)
Desai, B.; Danks, T. N.; Wagner, G. Tetrahedron Lett. 2005, 46, 955; (e) Hosseini-
Sarvari, M.; Sharghi, H. J. Org. Chem. 2006, 71, 6652.
Furthermore, other carboxylic acids were selected to undergo
the amidation (Table 3).16 The results summarized in Table 3
12.
(a) Noonan, C.; Baragwanath, L.; Connon, S. J. Tetrahedron Lett. 2008, 49, 4003;
b) Dünkelmann, P.; Jung, D. K.; Nitsche, A.; Demir, A. S.; Siegert, P.; Lingen, B.;
(
clearly indicated that the reaction of acetic acid, propionic acid,
Baumann, M.; Pohl, M.; Müller, M. J. Am. Chem. Soc. 2002, 124, 12084; (c)
Orlandi, S.; Caporale, M.; Benaglia, M.; Annunziata, R. Tetrahedron: Asymmetry
2003, 14, 3827.
and butyric acid with aniline in the presence of 2 mol % in 90%,
7
8
4%, and 80% yields, respectively, at 100 °C for 4 h. However, no
13. Lei, M.; Ma, L.; Hu, L. Tetrahedron Lett. 2009, 50, 6393.
target products were obtained when using benzoic acid and cin-
namic acid as starting materials.
We have not established an exact mechanism for the formation
of this kind of compounds 2; however, a reasonable pathway is
14. General procedure for the preparation of formamides 2a–2q and 2t using VB
1
as a catalyst: A mixture of amine 1 (5 mmol), formic acid (1 mL), and VB1
(
(
0.1 mmol, 2 mol %) was heated at 80 °C under stirring for the appropriate time
Table 2). After completion of the reaction as indicated by TLC, 20 mL of EtOAc
2 3
was added and washed with aq HCl (concn 5%), aq Na CO (concn 5%), and
brine. Then, the organic layer was dried over MgSO4 and concentrated to afford
the compounds 2a–2q without further purification.
shown in Scheme 2. Formic acid is activated by VB
which reacts to produce the formamide derivatives 2.
In conclusion, VB has been employed here as an efficient cata-
1
to form 3,
1
5. General procedure for the preparation of formamides 2u using VB
catalyst: A mixture of -tryptophan methyl ester (5 mmol), formic acid (1 mL),
and VB (0.1 mmol, 2 mol %) was heated at 80 °C under stirring for 40 min.
After completion of the reaction as indicated by TLC, 20 mL of EtOAc was added
and washed with aq Na CO (concn 5%), brine, and concentrated in vacuum to
1
as a
1
L
lyst for the synthesis of formamide derivatives. A simple work-up
procedure, mild reaction conditions, and excellent yields make our
methodology a valid contribution to the existing methods in the
fields of formamide.
1
2
3
give a course product, which was chromatographed on silica gel and eluted
with DCM–MeOH (100:1) to give the pure product 2u.
Compound 2u: 1H NMR (400 MHz, CDCl
(
): d = 8.21 (br s, 1H), 8.16 (s, 1H), 7.54
d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.12 (t,
J = 8.0 Hz, 1H), 6.99 (s, 1H), 6.16 (br s, 1H), 5.03 (dd, J = 5.5 Hz, J = 13.0 Hz,
H), 3.72 (s, 3H), 3.33–3.34 (m, 2H).
6. General procedure for the preparation of amides 2v–2x using VB
A mixture of aniline 1a (5 mmol), acid (1 mL), and VB (0.1 mmol, 2 mol %) was
3
Acknowledgments
1
2
1
1
1
as a catalyst:
This work was supported by the Chinese National Science and
Technology Major Project ‘Key New Drug Creation and Manufac-
turing Program’ (Grants 2009ZX09301-001, 2009ZX09102), the
1
heated at 100 °C under stirring for 4 h. After completion of the reaction as
indicated by TLC, 20 mL of EtOAc was added and washed with aq HCl (concn
5
%), aq Na
MgSO and concentrated to afford the compounds 2v–2x without further
purification.
2 3
CO (concn 5%), and brine. Then, the organic layer was dried over
Chinese National High-Tech R&D Program
(Grants 2007AA
4
0
2Z147), the National Natural Science Foundation of China (Grants