N-Formylsaccharin: A new formylating agent

Article abstract of DOI:10.1055/s-0030-1260951

N-Formylsaccharin, a very cheap reagent, has been revealed to be an efficient and chemoselective formylating agent of amines. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1260951

1920
LETTER
N-Formylsaccharin: A New Formylating Agent
N
a
-Formylsaccha
h
rin:
A
N
ew
o
Formylating
m
Agent as Cochet,a Véronique Bellosta,a Alfred Greiner,b Didier Roche,b Janine Cossy*a
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 Rue Vauquelin, 75231 Paris Cedex 05, France
Fax +33(1)40794660; E-mail: janine.cossy@espci.fr
Edelris s.a.s., 115 Avenue Lacassagne, 69003 Lyon, France
b
Received 15 April 2011
Table 1 N-Formylation of Primary Amines 2
Abstract: N-Formylsaccharin, a very cheap reagent, has been re-
vealed to be an efficient and chemoselective formylating agent of
amines.
O
O
1) THF
O
r.t., 15 min
R
RNH2
N
O
+
H
N
H
Key words: formylation, amine, amino alcohol, saccharin
2) NaHCO3 aq
S
H
1
2
3
O
Entry Amine 2
N-Formamide 3
Yield (%)
quant.
Formamides are important intermediates in organic syn-
thesis and in the preparation of pharmaceuticals.1 More-
over, they are useful reagents for Vilsmeier formylation2
and for the synthesis of formamidines3 and isocyanides.4
As Lewis bases, formamides can also promote several
reactions such as allylation5 and hydrosilylation.6 In addi-
tion, the formyl group can be used as an amino-protecting
group or to functionalize the amino group of amino esters
in peptide synthesis.7 Furthermore, N-formyl derivatives
are useful precursors in the preparation of N-methyl com-
pounds.8 Due to the importance of the formamides, a great
number of methods or reagents have been reported for the
N-formylation of amines.9 Most of these formylation con-
ditions involve the use of either formic acid in the pres-
ence of an activating reagent such as DCC,10 EDCI,11
CDMT,12 PEG-400,13 Lewis acids,14 thiamine hydrochlo-
ride,15 sodium formate,16 inorganic oxides,17 metals,18
aqueous formic acid,19 formic acid derivatives (acetic for-
mic anhydride,20 formate esters7a,21 or ammonium for-
mate)22 as well as N-formyl derivatives.23 Choral,24
dichlorocarbene,25 paraformaldehyde,26 and solid-sup-
ported reagents27 have also been used for the N-formyla-
tion of amines. However, many of these methods suffer
from disadvantages such as lack of generality, or the use
of reagents or catalysts which are either expensive, not
easily accessible, instable, toxic, or not eco-friendly (use
of metals). Furthermore, strictly anhydrous conditions,
long reaction times, as well as heating are often required.
Some of the procedures lead to the formation of byprod-
ucts which can be difficult to eliminate or require acidic
or basic workup that can be detrimental with sensitive
substrate, in particular when racemization can occur.
Hence we report herein the use of N-formylsaccharin 1 as
a powerful formylating agent.
CHO
NH2
N
H
1
2a
3a
3b
3c
3d
H
NH2
N
CHO
2
84
77
93
2b
H
NH2
N
CHO
3
4
2c
H
NH2
N
CHO
2d
H
N
NH2
5
6
98
81
CHO
2e
2f
3e
3f
H
N
NH2
CHO
H
NH2
N
CHO
7
8
9
quant.
92
2g
3g
H
NH2
N
CHO
Br
Br
2h
3h
H
N
NH2
CHO
40
(conv.)
CO2Me
CO2Me
SYNLETT 2011, No. 13, pp 1920–1922
x
x
.x
x
.2
0
1
1
2i
3i
Advanced online publication: 14.07.2011
DOI: 10.1055/s-0030-1260951; Art ID: D12011ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
N-Formylsaccharin: A New Formylating Agent
1921
N-Formylsaccharin (1) was synthesized using formic acid served. The N-formylation of anilines was also very effec-
and acetic acid (60 °C, 2 h) to form acetic formic anhy- tive as both electron-rich and electron-poor anilines were
dride which reacted with saccharin (60 °C, 5 h) to produce N-formylated in excellent yields (Table 1, entries 6–9).
1 as crystals in 90–95% yield (Scheme 1).28
Secondary amines were also efficiently N-formylated by
N-formylsaccharin 1 as 4a–e were transformed to 5a–e,
respectively, in yields superior to 75% (Table 2), using
the same protocol as before.
O
O
HCO2H/Ac2O
(2 equiv)
O
H
O-Formylation of alcohols was also examined using N-
formylsaccharin 1 (THF, r.t., 15 min, then addition of an
aq sat. NaHCO3 solution). Under these conditions, the
conversion of octanol and the yield in isolated formyloc-
tanol were low. Thus, when substrates containing both
amino and hydroxy groups were treated with N-formyl-
saccharin (r.t., 15 min), a selective N-formylation was ob-
served. Due to the water solubility of N-formylamino
alcohols, the treatment of the reaction mixture by a sup-
ported base [(piperidinomethyl)polystyrene, 3 equiv, 10
min)] in order to trap the acidic byproducts was per-
formed. Compounds 7 were selectively obtained from
amino alcohols 6 in yields up to 90% (Table 3).30 Of note,
the N-formylation of optically active amino alcohols was
achieved without racemization (6b and 6c). Furthermore,
the formylation of hydroxyaniline was also chemoselec-
tive as 7d was obtained from 6d in 90% yield (Table 3).
NH
N
60 °C, 7 h
90–95%
S
S
O
O
O
O
saccharin
1
Scheme 1
When primary amines 2 (1 equiv) were treated with 1
(1 equiv) in THF for 15 minutes at room temperature, the
N-formamides 3 were isolated in excellent yield after a
saturated aqueous NaHCO3 workup. No purification was
required during isolation of 3 due to the acidic nature of
saccharin (pKa = 1.5) and to the high solubility of its
sodium salt in water.29 The results are reported in Table 1.
Primary N-alkylamines 2a–e were transformed to the cor-
responding N-formamides 3a–e in excellent yields and,
under these conditions, no epimerization of 3e was ob-
In conclusion, we have developed a convenient, efficient,
and chemoselective formylation of amines using N-formyl-
saccharin. This latter reagent has a great number of advan-
tages including low cost, availability, ease of handling,
stability, chemoselectivity, can react under mild reaction
Table 2 N-Formylation of Secondary Amines 4
O
O
1) THF
O
R1
r.t., 15 min
R1R2NH
N
O
+
H
N
R2
2) NaHCO3 aq
S
H
O
1
4
5
Table 3 Selective N-Formylation of Amino Alcohols 6
Entry Amine 4
N-Formamide 5
Yield (%)
77
1) 1, THF, r.t., 15 min
OH
NH
OH
NH2
2) (piperidinomethyl)polystyrene
6
H
O
NH
NCHO
1
7
Entry
1
Amino alcohol 6
Product 7
Yield (%)
90
5a
4a
OH
OH
2
97
N
CHO
5b
N
H
N
CHO
7a
N
H
4b
6a
3
quant.
OH
N
NH
OH
CHO
2
3
55
90
N
CHO
7b
N
H
4c
5c
O
6b
O
CHO
4
75
85
NH2
HN
N
N
H
OH
OH
CHO
4d
5d
Me
Me
N
6c
7c
N
OH
OH
5
N
CHO
N
H
4
90
N
H
NH2
CHO
4e
6d
5e
7d
Synlett 2011, No. 13, 1920–1922 © Thieme Stuttgart · New York

1922
T. Cochet et al.
LETTER
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Acknowledgment
EDELRIS s.a.s. is gratefuly acknowledged for financial support
(Grant to T. C.).
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Typical Procedure
Formic acid (20 mmol, 2 equiv) and Ac2O (20 mmol, 2
equiv) were stirred at 60 °C for 2 h and saccharin (1.83 g, 10
mmol, 1 equiv) was added in one portion. The reaction
mixture was stirred for 5 h at 60 °C. Water was added (10
mL), and the white precipitate was filtered to afford pure
N-formylsaccharin (1.9 g, 9 mmol, 90%).
(29) Typical Procedure for Amines
To a suspension of N-formylsaccharin (211 mg, 1 mmol, 1
equiv) in anhyd THF (1 mL) at r.t., the requisite primary or
secondary amine was added (1 mmol, 1 equiv). After 15 min
at r.t., the reaction mixture was diluted with CH2Cl2 (10 mL),
and a sat. aq NaHCO3 solution (10 mL) was added, the layers
were separated, and the aqueous layer extracted with CH2Cl2
(2 × 10 mL). The combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo to afford pure
N-formylated amines.
(30) Typical Procedure for Amino Alcohols
To a suspension of N-formylsaccharin (211 mg, 1 mmol,
1 equiv) in anhyd THF (1 mL) at r.t., the requisite amino
alcohol was added (1 mmol, 1 equiv). After 15 min at r.t., the
reaction mixture was diluted with CH2Cl2 (5 mL),
(piperidinomethyl)polystyrene (loading: 4 mmol/g, 750 mg)
was added, and the reaction mixture was stirred at r.t. After
10 min, the reaction mixture was filtered through Celite® and
concentrated in vacuo to afford pure N-formylated amino
alcohols.
Synlett 2011, No. 13, 1920–1922 © Thieme Stuttgart · New York