A one-step protocol for the N-chloromethylation of heterocyclic imides

Article abstract of DOI:10.1081/SCC-100105876

A convenient single step methodology for the N-chloromethylation of heterocyclic imides using a mixture of formaldehyde sodium bisulfite adduct and thionyl chloride is described.

Full text of DOI:10.1081/SCC-100105876

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A ONE-STEP PROTOCOL FOR THE N-
CHLOROMETHYLATION OF HETEROCYCLIC IMIDES
Shu He a , Hongyi Yu a , Qinghong Fu a , Rongze Kuang a , Jeff B. Epp a & William C.
Groutas b
a Department of Chemistry , Wichita State University , Wichita, Kansas, 67260, U.S.A.
b Department of Chemistry , Wichita State University , Wichita, Kansas, 67260, U.S.A.
Published online: 16 Aug 2006.
To cite this article: Shu He , Hongyi Yu , Qinghong Fu , Rongze Kuang , Jeff B. Epp & William C. Groutas (2001) A ONE-
STEP PROTOCOL FOR THE N-CHLOROMETHYLATION OF HETEROCYCLIC IMIDES, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 31:20, 3055-3058, DOI: 10.1081/SCC-100105876
To link to this article: http://dx.doi.org/10.1081/SCC-100105876
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SYNTHETIC COMMUNICATIONS, 31(20), 3055–3058 (2001)
A ONE-STEP PROTOCOL FOR THE
N-CHLOROMETHYLATION OF
HETEROCYCLIC IMIDES
Shu He, Hongyi Yu, Qinghong Fu, Rongze Kuang,
Jeff B. Epp, and William C. Groutas*
Department of Chemistry, Wichita State University,
Wichita, Kansas 67260
ABSTRACT
A convenient single step methodology for the N-chloromethy-
lation of heterocyclic imides using a mixture of formaldehyde
sodium bisulfite adduct and thionyl chloride is described.
We have recently described the structure-based design of the 1,2,5-
thiadiazolidin-3-one 1,1 dioxide template I and have demonstrated that it
can serve as a general and flexible platform for the design of inhibitors
of clinically-relevant (chymo)trypsin-like serine proteases.1–5 We have
furthermore demonstrated that core structure I is amenable to the facile
construction of libraries for use in lead identification and optimization.
As part of a project focusing on the solution phase construction of libraries
*Corresponding author.
3055
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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3056
HE ET AL.
based on I, a chloromethylation protocol suitable for generating intermediate
Ia was desired.
Several procedures have been described in the literature for the direct
or indirect N-chloromethylation of imide type molecules, including chloro-
trimethylsilane/paraformaldehyde,6 N-alkylation with HBr/HCHO/HOAc,7
N-alkylation with chloromethyl pivalate8 or chloromethyl phenyl sulfide1–5
followed by treatment with HBr/HOAc or sulfuryl chloride, respectively,
and others. After extensive experimentation, it was observed that refluxing a
mixture of imide, sodium formaldehyde bisulfite adduct and thionyl chloride
yielded the desired N-chloromethylated product. To the best of our knowl-
edge, the use of these reagents and conditions for N-chloromethylation has
not been described before.
The scope of this methodology was investigated using a range of sub-
strates (Table 1). Thus, 4,5-disubstituted 1,2,5-thiadiazolidin-3-one 1,1 diox-
ide derivatives 1a and 2a yielded the corresponding N-chloromethylated
products 1b and 2b upon refluxing a mixture of the heterocyclic imide
with formaldehyde sodium bisulfite adduct and thionyl chloride. The reac-
tion proceeded uneventfully when a compound bearing an ester group (5a)
was used. The methodology was then extended to other heterocyclic systems
with mixed results. Thus, isothiazolidin-3-one 1,1 dioxide derivative 3a and
saccharin 4a yielded the desired products 3b and 4b in 64% and 73% yield,
respectively. In the case of phthalimide and succinimide starting materials
and minor amounts of unidentifiable products were recovered.
In summary, a convenient, one-step procedure for the N-chloromethy-
lation of heterocyclic imides that is suitable for the solution phase construc-
tion of libraries has been described.
Representative Synthesis: A mixture of compound 1a (2.47 g; 9.41 mmol),
formaldehyde sodium bisulfite adduct (6.31 g; 47.05 mmol) and thionyl
chloride (15 mL) was refluxed gently overnight. Excess thionyl chloride
was removed in vacuo and the residue taken up in methylene chloride
(80 mL). Saturated sodium bicarbonate (30 mL) was carefully added and

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N-CHLOROMETHYLATION OF HETEROCYCLIC IMIDES
Table 1. Synthesis of N-Chloromethyl Compound
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the organic layer was separated, washed with water (30 mL) and dried over
anhydrous sodium sulfate. Removal of the solvent yielded 1b (2.68 g; 91.0%
1
yield). H NMR(CDCl3): d 0.98–2.0 (m, 18H), 3.08 (m, 1H), 3.40 (m, 1H),
4.00 (t, H), 5.36 (s, 2H). Anal. Calculated: %C: 46.31; %H: 7.45; %N: 9.00.
Found: %C: 46.32; %H: 7.91; %N: 8.95.

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HE ET AL.
Compounds 2b, 3b, 4b and 5b were synthesized using a similar
procedure.
Compound 2b: d 0.68 (d, 3H), 0.80 (d, 3H), 1.55–1.78 (m, 3H), 3.92 (t,
1H), 4.28 (d, 1H), 4.53 (d, 1H), 5.5 (d, 2H), 7.38 (s, 5H). Anal. Calcd. %C:
50.78; %H: 5.79; %N: 8.47. Found: %C: 50.78; %H: 5.83; %N: 8.42.
Compound 3b: d 2.92 (1H, m), 3.36 (1H, m), 3.66 (1H, m), 3.80 (1H, m),
3.92 (1H, m), 5.50 (2H, q), 7.20–7.40 (5H, m). Anal. Calcd. %C: 48.22; %H:
4.42; %N: 5.12. Found: %C: 48.08; %H: 4.63; %N: 5.14. Compound 4b: d
5.58 (s, 2H), 7.26–7.93 (m, 3H), 8.14 (m, 1H), mp 140–2ꢀC (lit.9 mp
146–7ꢀC). Compound 5b: 2.70 (dd, 1H), 2.96 (dd, 1H), 4.31 (t, 1H), 4.50
(dd, 2H), 5.09 (dd, 2H), 5.26 (dd, 2H), 7.40 (m, 10H). Anal. Calcd. %C:
53.97; %H: 4.53; %N: 6.62. Found: %C: 54.06; %H: 4.73; %N: 6.76.
ACKNOWLEDGMENT
Financial support of this work by the National Institutes of Health
(HL 57788) is gratefully acknowledged.
REFERENCES
1. Groutas, W.C.; Kuang, R.; Venkataraman, R.; Epp, J.B.; Ruan, S.;
Prakash, O. Biochemistry 1997, 36, 4739–4750.
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Received in the USA December 4, 2000

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