A novel type of N-formylation and related reactions of amines via cyanides and esters as formylating agents

Article abstract of DOI:10.1039/b810086a

A novel N-formylation and related reactions proceed from cyanides promoted by esters. The Royal Society of Chemistry.

Full text of DOI:10.1039/b810086a

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COMMUNICATION
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A novel type of N-formylation and related reactions of amines
via cyanides and esters as formylating agentsw
Kai Bao, Weige Zhang,* Xiujuan Bu, Zhichun Song, Liang Zhang and
Maosheng Cheng*
Received (in Cambridge, UK) 16th June 2008, Accepted 31st July 2008
First published as an Advance Article on the web 16th September 2008
DOI: 10.1039/b810086a
A novel N-formylation and related reactions proceed from
Table 1 Ester-promoted N-formylation of N-demethyl erythromycin
derivativesa
cyanides promoted by esters.
Cyanide ion catalysed aminolysis of esters is one of the useful
methods for the conversion of amines into amides.1 In our
tentative preparation of de(N-methyl)-N-benzoyl-6-O-methyl
erythromycin derivatives for the evaluation of their anti-
inflammatory activity,2 we applied this methodology by
treating de(N-methyl)-6-O-methyl erythromycin 1a with
substituted benzoate A, B or C (1.2 equiv.) in the presence
of potassium cyanide (1.0 equiv.) in methanol (containing
0.1% H2O) under reflux for 48 h. To our surprise, the desired
N-benzoyl derivatives were obtained in low yields (o10%).
Instead, a common major product was isolated in these
parallel reactions; the compound was subsequently confirmed
to be de(N-methyl)-N-formyl-6-O-methyl erythromycin 2a by
Entry Substrate MCN (eq)
Ester (eq) Product Yield (%)
1
the application of H NMR, 13C NMR and MS.
1
2
3
4
5
6
7
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
KCN (1.0)
KCN (1.0)
KCN (1.0)
KCN (2.0)
KCN (2.0)
KCN (2.0)
KCN (2.0)
KCN (2.0)
KCN (2.0)
KCN (2.0)
NaCN (2.0) C (0.3)
NaCN (2.0) E (0.3)
KCN (2.0)
KCN (2.0)
KCN (2.0)
KCN (2.0)
A (1.2)
B (1.2)
C (1.2)
A (0.3)
B (0.3)
C (0.3)
D (0.3)
E (0.3)
C (0.1)
E (0.1)
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
49
55
53
62
60
76
58
79
45
65
72
77
82
70
69
65
Intrigued by these results, we proceeded to repeat this
reaction under different conditions and found that: (1) neither
KCN nor benzoate alone could induce the reaction; (2) the
moisture content of methanol played a positive role in the
reaction; (3) the pH value of the reaction mixture rose from
7.5 to about 10.0 through the generation of an alkaline gas
during these reactions. Furthermore, with the idea of
optimizing the reaction conditions, we carried out the
reactions of 1a with KCN or NaCN and esters, including
aliphatic esters D and E, respectively.
10
11
12
13
14
15
16
17
a
E (0.3)
E (0.3)
E (0.3)
E (0.3)
As indicated in Table 1: (1) the use of either aromatic esters
or aliphatic esters in this reaction could generate the
N-formylation products; (2) by increasing the quantity of
KCN from 1 to 2 equiv. and decreasing of the amount of
ester from 1.2 to 0.3 equiv., the yield was clearly improved,
whereas further decreasing the amount of ester to 0.1 equiv.
led to a lower yield; (3) the reaction was equally effective when
KCN was replaced by NaCN. Our data also showed that
dicarboxylic acid ester, dimethyl malonate E, was more effi-
cient in promoting this reaction as compared with other
esters. We also noted that the reaction was influenced to a
considerable extent by the solvent utilized; methanol
Reactions performed in MeOH (containing 0.1% H2O) at 45 1C for
4 h, then under reflux for 48 h.
(containing 0.1% H2O), in particular, was found to be more
a favorable solvent than ethanol. The following reactions
using diverse N-demethyl erythromycin derivatives 1b–1e
as the substrates, under the standardized condition
[KCN (2.0 equiv.), dimethyl malonate E (0.3 equiv.)] were
efficiently transformed to give N-formyl erythromycin deriva-
tives 2b–2e, respectively. Taking the above results
into account, we realized that an unusual ester promoted
N-formylation of amines using cyanide as formylating agent,
instead of the normal N-acylation catalysed by KCN, had
occurred as the main reaction path.
School of Pharmaceutical Engineering, Shenyang Pharmaceutical
University, Shenyang, 110016, China.
E-mail: zhangweige2000@sina.com; mscheng@263.net;
Fax: +86(24)-23995043; Tel: +86(24)-23986422
w Electronic supplementary information (ESI) available: Experimental
procedures, spectroscopic data, and scans of NMR spectra. See DOI:
10.1039/b810086a
In order to assess its generality, the same reaction was
investigated for several other aliphatic secondary amines
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Table
amines
2
Ester-promoted N-formylation of aliphatic secondary
Table 3 Reactions of aliphatic primary amines
Substrate
Ester
Product
Yield (%)
Substrate
Ester
Product
Yield (%)
A
C
D
E
4a
4a
4a
4a
75
68
62
83
C
E
6a
6a
41
56
C
E
6b
6b
46
70
E
4b
57
E
6c
77
E
4c
62
C
D
E
6d
6d
6d
65
60
81
E
E
6e
6f
75
44
E
E
4d
4e
60
66
Aromatic primary amines, 7a–7c were also utilized in the
reaction, generating the expected N-formylation products
8a–8c at moderate to high yields (Table 4). Treatment of
o-phenylenediamine 7d gave the expected product, benzimida-
zole 8d, which could be regarded as an analog of formamidine
to a certain extent, at a 78% yield.
E
4f
55
Notably, the above reactions were highly insensitive for
ester A, B, C and D, and no N-formylation products or
N,N0-disubstituted formamidines were generated. In contrast,
the reaction of aromatic primary amines substituted by
3a–3f under the standardized conditions, and the results are
summarized in Table 2. The reactions of ephedrine 3a, a
b-hydroxyl secondary amine similar to the desosamine moiety
of erythromycin derivatives, with KCN promoted by
aromatic esters A, C or aliphatic esters D, E, furnished the
N-formylation product 4a at
a 62–83% yield. Other
Table 4 Reactions of aromatic primary amines
b-hydroxyl secondary amines, including pseudoephedrine 3b
and propranolol 3c, and five- or six-membered cyclic amines
3d–3f, were also employed in the reaction, successfully
generating the expected products. Unfortunately, any attempt
to transform hindered amines, dibenzylamine and dicyclo-
hexylamine into the corresponding N-formylation products
under our conditions failed, even under reflux for more than
96 h and only the unreacted starting materials were recovered.
Unexpectedly, standard treatment of aliphatic primary
amines 5a–5f (Table 3) did not form the desired N-formylation
products, rather a set of (E)-N,N0-disubstituted formamidines
6a–6e was encountered, with the exception that dimethyl
2-((tert-butylamino)methylene) malonate 6f was obtained at
a low yield (44%), which can be explained by the steric
hindrance of tert-butyl.
Substrate
Product
Yield (%)
7a R = H
8a
8b
8c
8d
66
82
85
78
7b R = p-OCH3
7c R = p-OCH2CH3
7d R = o-NH2
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56% yield) could form if 3a, 5d or 7a was subsequently added
to the reaction mixture, respectively. No N-formylation pro-
ducts were obtained when E was replaced by dimethyl
2,2-diethylmalonate, in the case of 7a. In addition, the unique
mechanism of E was indirectly supported by the formation of
6f (Table 3). To better understand the above reactions and the
role of E, we proposed the following reaction mechanism
(Scheme 1) to account for the N-formylation and related
reactions.
Accordingly, the existence of a trace amount of HCN that
acted as a formic acid equivalent, condensed with the
malonate to form intermediate I (8e), which then subjected
to a nucleophilic additon of amine, followed by elimination of
ammonia to give II. Hydrolysis or aminolysis of II would
afford the corresponding N-formylated product III or forma-
midine IV.
In summary, we describe a novel N-formylation and related
reactions proceed from cyanide promoted by dimethyl malonate
and other esters. These results led to a general and efficient
access to the synthesis of formamides, N,N0-disubstituted
formamidines, benzo-imidazole, 2-(aminomethylene) malonate
and its derivative. Efforts are currently underway in our research
group to apply this method to the construction of other
potentially valuable organic molecules.
Scheme 1 Mechanism of the N-formylation and related reactions.
electron-withdrawing groups, such as 4-chloroaniline,
3-nitroaniline, 3-aminopyridine and 2-aminothiazole, failed
to give the desired N-formylation products either the use of
aromatic esters A, B, C or that of aliphatic esters D, E; whereas
the same product dimethyl 2-(aminomethylene) malonate 8e,
was obtained exclusively in the presence of E and the
unreacted aromatic primary amines could be recovered.
These phenomena indicated that ester E exhibited a
behavior that deviated from esters A, B, C and D; E might
have utilized a unique mechanism, compared with the other
esters. We therefore carried out the following experiments to
gain some mechanistic insight into ester E. Treatment of E
with KCN in methanol (containing 0.1% H2O) at 45 1C for 3 h
gave 8e at a 86% yield, whereas 4a, 6d or 8a (63%, 52% or
We gratefully acknowledge the Shenyang Science
&
Technology Bureau Item (Nos. 1063223-3-00, 1053125-1-49)
for generous financial support.
Notes and references
1 Z. Kabouche, C. Bruneau and P. H. Dixneuf, Tetrahedron Lett.,
1991, 32, 5359.
2 A. Mereu, E. Moriggi, M. Napoletano, C. Regazzoni, S.
Manfredini, T. P. Mercurio and F. Pellacini, Bioorg. Med. Chem.
Lett., 2006, 16, 5801.
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Chem. Commun., 2008, 5429–5431 | 5431