Convenient N-Formylation of Secondary Amines: KF-Al2O 3-Promoted Synthesis of Formamide Derivatives via Dichlorocarbene Generated from Chloroform

Article abstract of DOI:10.1055/s-2003-41060

The treatment of secondary amines with chloroform in the presence of KF-Al₂O₃ in acetonitrile brought about highly facile and efficient N-formylation to give the corresponding formamides in good to excellent yields. The N-formylation reaction not only involves mild conditions, simple operations and high yields but high chemoselectivity as well.

Full text of DOI:10.1055/s-2003-41060

PAPER
2317
Convenient N-Formylation of Secondary Amines: KF–Al2O3-Promoted
Synthesis of Formamide Derivatives via Dichlorocarbene Generated from
Chloroform
N
-Formylation of Seco
a
ndary
A
min
s
es: Form
a
amide
D
eri
t
vatives
o
via
D
ichlor
o
s
carbene hi Mihara,a Yoshio Ishino,*a Satoshi Minakata,b Mitsuo Komatsu*b
a
Osaka Municipal Technical Research Institute, Morinomiya 1-6-50, Joto-ku, Osaka 536-8553, Japan
Fax +81(6)69638049; E-mail: ishino@omtri.city.osaka.jp
b
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan
Fax 81(6)68797402; E-mail: komatsu@chem.eng.osaka-u.ac.jp
Received 9 June 2003; revised 29 July 2003
tion conditions. Moreover, although formylation reactions
using dichlorocarbene are known, they also suffer from
drawbacks such as the need for an aqueous work-up and
its inapplicability to sterically hindered amines.7 In this
Abstract: The treatment of secondary amines with chloroform in
the presence of KF–Al2O3 in acetonitrile brought about highly facile
and efficient N-formylation to give the corresponding formamides
in good to excellent yields. The N-formylation reaction not only in-
volves mild conditions, simple operations and high yields but high paper, we wish to report on the facile and chemoselective
chemoselectivity as well.
N-formylation of secondary amines performed by the use
of KF–Al2O3 under extremely mild conditions.
Keywords: potassium fluoride, formylation, amines, amides, car-
benes
The reactions of N-methylaniline with chloroform in the
presence of KF–Al2O3 were examined under various reac-
tion conditions (Table 1). When potassium fluoride or
alumina (neutral) was used, desired N-methylformanilide
was not formed (entries 1 and 2). In contrast, the use of
commercially available KF–Al2O3 caused a smooth reac-
tion, providing the product in excellent yield (entry 3). Al-
though N-methylformanilide was produced in
chloroform, the desired reaction proceeded more smooth-
ly in acetonitrile (entries 4 and 5). As shown in entry 5, the
reaction was carried out in acetonitrile at reflux for 1.5
hours to give the best result. Furthermore, even at ambient
temperature, the product was formed in excellent yield
(entry 6). The solid–liquid biphasic reaction can be con-
ducted with simple and non-aqueous work-up, i.e., filtra-
tion of the inorganic oxides and evaporation of the
solvent. Accordingly, compared with conventional reac-
tions, the present method using readily available KF–
Al2O3 is characterized by operational simplicity, mild
conditions and high yields.
In recent years, the use of inorganic solid oxides as cata-
lysts, reagents and reaction media has received consider-
able attention because of their high level of
chemoselectivity and environmental compatibility as well
as simplicity of operation and their ready availability at
low cost. Thus, a number of heterogeneous reactions us-
ing inorganic oxides such as silica gel, alumina, clay and
zeolite under mild conditions have already been reported.1
In particular, KF–Al2O3 is known to be a useful solid-sup-
ported reagent for various base-induced organic reac-
tions.2 Since the exploitation of the versatile KF–Al2O3 by
Ando et al.,3 a number of reactions including addition,
elimination and coupling reactions have been reported.
On the other hand, KF–Al2O3 has also been shown to pro-
mote the -elimination of hydrogen chloride from chloro-
form, but the KF–Al2O3-promoted method is regarded as
being less efficient than the well known method that uses
phase transfer catalysts in addition reactions of dichloro-
carbene to cyclohexene.4 From these points of view, ap-
plications of the KF–Al2O3-promoted method for the
generation of dichlorocarbene to other transformations
are significant for developing convenient synthetic proce-
dures.
In addition, the formylation reaction was influenced, to a
considerable extent, by solvents and bases. Acetonitrile
and ethanol were found to be more favorable solvents than
DMF and hexane. Alumina (basic), MgO, KF–Celite and
KF–CaF2 were inefficient as a solid base for the reaction
under the conditions used.
Formamide dervatives are important intermediates in or-
ganic synthesis and, therefore, various methods for the N-
formylation of amines were reported.5 Recently, several
chemoselective N-formylation reactions using mixed an-
hydride methodologies have been developed.6 However,
the methods require the preparation of unsymmetrical
acid anhydrides, low temperature and/or anhydrous reac-
A plausible pathway is the reaction of secondary amines
with dichlorocarbene, generated from chloroform and
KF–Al2O3, followed by hydrolysis by water8 contained in
the latter to afford the N-formylated products.
Under the optimized conditions, various secondary
amines were treated with chloroform in the presence of
KF–Al2O3 to produce formamide derivatives in good to
excellent yields (Table 2). Both aromatic and aliphatic
secondary amines reacted smoothly with chloroform. For
a variety of secondary amines, e.g. a sterically hindered
SYNTHESIS 2003, No. 15, pp 2317–2320
x
x.
x
x
.
2
0
0
3
Advanced online publication: 23.09.2003
DOI: 10.1055/s-2003-41060; Art ID: F05303SS
© Georg Thieme Verlag Stuttgart · New York

2318
M. Mihara et al.
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a
Table 1 KF–Al2O3 -Promoted Synthesis of N-Methylformanilide
O
PhNCH
Me
base
+
CHCl3
PhNH
Me
solvent
(1 mmol)
Entry
Base
KF
Base (g)
CHCl3 (mL)
Solvent (mL)
CHCl3
Temp (°C)
reflux
reflux
reflux
reflux
reflux
r.t.
Time (h)
1.5
Yieldb (%)
1
2
3
4
5
6
7
2
5
5
2
2
2
2
10
10
10
4
0 (53)
0 (61)
91 (3)
74 (18)
93 (0)
93 (2)
71 (19)
Al2O3 (neutral)
KF–Al2O3
KF–Al2O3
KF–Al2O3
KF–Al2O3
KF–Al2O3
CHCl3
1.5
CHCl3
1.5
CHCl3
1.5
1
MeCN (3)
MeCN (3)
EtOH (3)
1.5
1
18
1
50
1.5
a KF–Al2O3: potassium fluoride, 40 wt% on alumina.
b In parentheses, recovery (%) of N-methylaniline is given.
a
Table 2 N-Formylation of Various Secondary Amines with Chloroform on KF–Al2O3
Entry
Amine
Temp (°C)
Time (h)
Product
Yield (%)
CHO
N
Me
X
NH
Me
X
1
2
3
X = H
r.t.
r.t.
18
24
X = H
93
81
X = OMe
X = Cl
X = OMe
X = Cl
r.t.
reflux
24
3
70b
86
4
5
Bu2NH
r.t.
reflux
24
1.5
Bu2NCHO
70
83
(c-C6H11)2NH
50
18
(c-C6H11)2NCHO
77c
Y
NH
Y
N CHO
6
7
8
Y = O
Y = S
r.t.
r.t.
18
18
Y = O
Y = S
80
75
r.t.
reflux
24
1.5
76d
85
HN
NH
OHC
N
N CHO
9
r.t.
18
67e
CHO
N
H
N
Et
Et
Et
N
Et
N
H
H
10
11
r.t.
r.t.
24
24
86
90
H
N
n-Bu
OH
PhNH
CHO
PhN
a Reaction conditions; entries 1–4, 6, 7 and 10: amine–CHCl3–(KF–Al2O3)–MeCN, 1 mmol–1 mL–2 g–3 mL; entries 5 and 8: amine–CHCl3–
(KF–Al2O3)–MeCN, 1 mmol–2 mL–4 g–6 mL; entry 9: amine–CHCl3–(KF–Al2O3)–MeCN, 1 mmol–1.2 mmol–2 g–3 mL; entry 11: amine–
CHCl3–(KF–Al2O3)–MeCN, 1 mmol–1.5 mL–3 g–4.5 mL.
b Recovery of p-chloro-N-methylaniline was 30%.
c Recovery of dicyclohexylamine was 5%.
d The monoformylated product was obtained in 6% yield.
e The diformylated product was obtained in 8% yield.
Synthesis 2003, No. 15, 2317–2320 © Thieme Stuttgart · New York

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N-Formylation of Secondary Amines: Formamide Derivatives via Dichlorocarbene
2319
MS (EI, 70 eV): m/z (%) = 144 (M+, 2), 100 (3), 71 (18), 58 (100).
amine (entry 5), heterocyclic amines (entries 6 and 7) and
a diamine (entry 8), the reaction showed good results
without any significant influence of their structures on the
product yields. It is interesting to note that the mono-
formylation of N,N -diethylethylenediamine occurred se-
lectively when chloroform (1.2 equiv) was used (entry 9).
Also, noteworthy is the fact that secondary amines with a
hydroxy group in the side chain (entry 10) and with allyl
group (entry 11) underwent chemoselective N-formyla-
tion in high yields. On the other hand, the reactions of pri-
HRMS: calcd for C7H16N2O: 144.1263; found: 144.1262.
2-(N-Butyl-N-formylamino)ethanol
Yield: 86%; colorless oil; E/Z ratio = 1:1.6.
IR (neat): 3396, 2971, 1661, 1434, 1062 cm–1.
1H NMR (300 MHz, CDCl3): = 0.90–0.97 (m, 3 H), 1.26–1.38 (m,
2 H), 1.47–1.60 (m, 2 H), 3.28–3.36 and 3.47 [(m) and (t, J = 5.3
Hz), 4 H], 3.5 (br s, 1 H), 3.70 and 3.75 (t, 2 H, J = 5.3 Hz), 8.04 and
8.08 (s, 1 H).
mary amines gave no formylated products and in the case 13C NMR (75 MHz, CDCl3): = 13.5, 13.7, 19.5, 20.0, 29.3, 30.7,
of n-octylamine, isonitrile9 was obtained as a major isol-
42.2, 46.2, 48.7, 49.7, 59.4, 61.0, 163.6, 164.1.
MS (EI, 70 eV): m/z (%) = 145 (M+, 23), 114 (98), 102 (47), 74 (70),
72 (100), 58 (29).
able product in 36% yield under the reaction conditions
used.10
HRMS: calcd for C7H15NO2: 145.1103; found: 145.1104.
In summary, we demonstrate that KF–Al2O3 is a useful
solid-supported reagent for generation of dichlorocarbene
from chloroform in the N-formylation reaction of second-
ary amines. The application of KF–Al2O3 to the N-formy-
lation of several secondary amines provides a new method
for the synthesis of formamide derivatives, which features
selectivity, mild reaction conditions and simple proce-
dures. The present method complements the existing syn-
thetic methods due to these advantages.
N-Allylformanilide15
Yield: 90%; colorless oil; E/Z ratio = 13:1.
IR (neat): 3064, 2872, 1680, 1597, 1497, 1356, 960, 926 cm–1.
1H NMR (300 MHz, CDCl3): = 4.28 and 4.42 [(d, J = 5.3 Hz) and
(d, J = 5.7 Hz), 2 H], 5.16–5.22 (m, 2 H), 5.79–5.92 (m, 1 H), 7.18–
7.42 (m, 5 H), 8.37 and 8.49 (s, 1 H).
13C NMR (75 MHz, CDCl3): = 47.8, 52.5, 117.6, 118.2, 123.5,
125.1, 126.6, 129.0, 129.5, 132.4, 133.4, 139.0, 141.1, 161.9, 162.4.
MS (EI, 70 eV): m/z (%) = 161 (M+, 97), 132 (100), 106 (71), 104
(61), 77 (73).
Amines, CHCl3 (98%) and MeCN (99%) from commercial sources
were used without further purification. KF–Al2O3, purchased from
Aldrich Chemical Co., Inc., was stored in a plastic bottle with a
screw cap in the air and used without further treatment. Mps were
measured with a Yanaco MP-I3 and are uncorrected. FT-IR spectra
HRMS: calcd for C10H11NO: 161.0841; found: 161.0833.
References
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C
NMR spectra were obtained on a JEOL JNM-AL300 (300 MHz,
75MHz) instrument. Chemical shifts were reported in ppm relative
to tetramethylsilane ( units). Mass and exact mass spectra were re-
corded on a JEOL JMS-600 spectrometer.
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N,N -Diethyl-N-formylethylenediamine
Yield: 67%; colorless oil; E/Z ratio = 1:1.
IR (neat): 3445, 2975, 1670, 1439, 1130 cm–1.
1H NMR (300 MHz, CDCl3): = 1.07–1.23 (m, 6 H), 1.5 (br s, 1 H),
2.67 (q, 2 H, J = 7.2 Hz), 2.75–2.81 (m, 2 H), 3.29–3.46 (m, 4 H),
8.05 and 8.11 (s, 1 H).
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47.5, 43.9, 47.0, 47.2, 47.5, 162.8.
Synthesis 2003, No. 15, 2317–2320 © Thieme Stuttgart · New York

2320
M. Mihara et al.
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Synthesis 2003, No. 15, 2317–2320 © Thieme Stuttgart · New York