CuCN-Mediated O-Alkylation of N,N,-Dimethylformamide with Alkyl Halides

Article abstract of DOI:10.1080/00397910802696220

This article reports the CuCN-mediated O-alkylation of formamide with 2-bromomethylindole. In addition, the formyloxylation products have been successfully exploited in the synthesis of novel indol-2-ylmethyl ether derivatives.

Full text of DOI:10.1080/00397910802696220

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CuCN-Mediated O-Alkylation of
N,N,-Dimethylformamide with
Alkyl Halides
B. T. S. Thirumamagal a & Sureshbabu Narayanasamy
a
a Department of Organic Chemistry , University of
Madras , Guindy Campus, Chennai, India
Published online: 14 Jul 2009.
To cite this article: B. T. S. Thirumamagal & Sureshbabu Narayanasamy (2009) CuCN-
Mediated O-Alkylation of N,N,-Dimethylformamide with Alkyl Halides, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:16, 2917-2922, DOI: 10.1080/00397910802696220
To link to this article: http://dx.doi.org/10.1080/00397910802696220
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Synthetic Communications1, 39: 2917–2922, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802696220
CuCN-Mediated O-Alkylation
of N,N,-Dimethylformamide
with Alkyl Halides
B. T. S. Thirumamagal and Sureshbabu Narayanasamy
Department of Organic Chemistry, University of Madras,
Guindy Campus, Chennai, India
Abstract: This article reports the CuCN-mediated O-alkylation of formamide
with 2-bromomethylindole. In addition, the formyloxylation products have been
successfully exploited in the synthesis of novel indol-2-ylmethyl ether derivatives.
Keywords: O-Alkylation of amides, CuCN, formyloxylation, transition-metal
cyanide
INTRODUCTION
The formate esters can be synthesized by O-formylation of alcohols using
various formylating agents[1] including Vilsmeier–Haack reagent.[2]
A
more compelling alternative method for the synthesis of formate ester
derivatives is via an O-alkylation of amides with alkyl halides.[3] Reports
that exploit dimethylformamide (DMF) as a formate anion equivalent in
the synthesis of formate ester have also been revealed.[4] CuCN is a widely
renowned transition-metal cyanide in organometallic chemistry that has
valuable synthetic capabilities[5] and a cascade of catalytic activities.[6]
Herein we propose a method that could effectively make use of CuCN
in the O-alkylation of amides with alkyl halides.
Received October 9, 2008.
Address correspondence to B. T. S. Thirumamagal, Restorative and Prosthe-
tic, 305 W. 12th Avenue, The Ohio State University, Columbus, OH 43210, USA.
E-mail: srinivasaraghava.2@osu.edu
2917

2918
B. T. S. Thirumamagal and S. Narayanasamy
RESULTS AND DISCUSSION
Scheme 1 presents the strategies for the synthesis of the compounds of
interest. Transition-metal cyanide CuCN was used in the direct
O-alkylation of DMF with bromo compounds 1 and 2, leading to the
formation of formate esters 3 and 4, respectively. Bromo compounds 1
and 2 were prepared sequentially via an allylic bromination of the corre-
sponding methyl derivatives[7,8] using N-bromosuccinimide (NBS) in the
presence of a catalytic amount of benzoyl peroxide in dry CCl4 under
reflux. Reaction of 1 equiv of bromo compound 1 with 3.5 equiv of
CuCN in dry DMF followed by the conventional workup afforded for-
mate ester 3 as a white spongy solid in 65% yield after purification.
The 1H NMR spectrum of formate ester 3 displayed O–CO–H and
CH2 protons as two singlets at d 8.04 and d 5.8, respectively, besides
the aromatic protons. CuCN was also efficiently used with the other
bromo compound 2 under the same reaction conditions to afford formate
esters 4 in 51% yield after chromatographic purification (SiO2) using
hexanes=ethylacetate 6=4 as the eluting solvent. The utility of CuCN in
the formyloxylation reaction has also been established by a plausible
mechanism, which agrees with previous extensive reports,[9] although
no intermediates were isolated. The fundamental role of cuprous ions
has also been clearly demonstrated by the fact that the reaction was
unsuccessful in the absence of cuprous cyanide as well as the fact that
the bromo compounds 1 and 2 are stable in DMF.
Because there is no extensive report on the synthesis of ether deriva-
tives 5–9, it was therefore our interest to exploit the formate esters 3 and 4
in the synthesis of the former, which could be used as potential intermedi-
ates. The treatment of formate ester 3 in dry chloroform with thionyl
Scheme 1. CuCN-mediated synthesis of indol-2-ylmethylformate ester 3 and 4
and indol-2-ylmethyl ether derivatives 5–9. Reagents and conditions: (i) (a)
CuCN, DMF, 25–30ꢀC, 6–10 h; (b) H2O, yield 51–65%; (ii) SOCl2, ROH, CHCl3.
0–30ꢀC, 7 h, 60–78%.

O-Alkylation of N,N-Dimethylformamide
2919
chloride followed by the addition of methanol, ethanol, isobutyl alcohol,
and p-cresol at 0–30ꢀC afforded ether derivatives 5–8 respectively in
70–78% yield after chromatographic purification (SiO2) using hexanes=
1
ethylacetate (8=2) as the eluting solvent. The H NMR spectrum of the
ether derivative 5 displayed OCH3 and CH2 protons as two singlets at
d 3.3 and d 4.6 respectively, in addition to the aromatic protons. Reaction
of isobutyl alcohol with other formate ester 4 under the same reaction
conditions afforded ether derivative 9 in 60% yield (Scheme 1).
Though it was perceived that CuCN could be principally used in the
synthesis of nitrile derivatives, for the first time our study[10] has demon-
strated the utility of CuCN in the formate ester synthesis at room
temperature, which in turn has opened up an effective means for the
formyloxylation reactions because it is simpler than other methods. In
addition, we also report a synthesis of novel indol-2-ylmethyl ether
derivatives.
EXPERIMENTAL
DMF was distilled from calcium hydride and stored over molecular
˚
sieves (pore size 3 A). Chloroform was distilled from P2O5 and stored
˚
over molecular sieves (pore size 4 A). CuCN was purchased from Aldrich
Chemicals. 1H NMR and 13C NMR spectra were recorded in CDCl3, and
tetramethylsilane (TMS) was used as an internal standard. Merck silica
gel (ACME, l00–200 mesh) was used for column chromatography. All
the other reagents were purchased commercially and used as such unless
stated otherwise.
Synthesis of Formate Ester Derivatives: General Procedure
Cuprous cyanide (3.5 mmol) was added to a solution of 2-bromomethy-
lindole 1 and 2 (1 mmol) in dry DMF (10 mL) and stirred at 25–30ꢀC
for 6–10 h. The solution color was changed to green, and the course of
the reaction was followed by thin-layer chromatography (TLC). The
reaction mixture was poured into crushed ice. The solid obtained was
filtered and washed meticulously with ethylacetate (30–40mL). The filtrate
was extracted further with ethylacetate (3ꢁ 20mL) and brine (10 mL).
Both the organic layers were combined and then dried over anhydrous
Na2SO4. Solvent removal followed by the chromatographic (SiO2) purifi-
cation and recrystallization (absolute ethanol) of the residues afforded
formate esters 3 and 4 in 40–65% yield.

2920
B. T. S. Thirumamagal and S. Narayanasamy
Spectroscopic Data of Formate Ester Derivatives
Formic acid 1-benzenesulfonyl-3-phenylsulfanyl-1H-indol-2-
ylmethyl ester (3)
Yield 65%; mp 140–142ꢀC; IR (KBr) cmꢂ1 1722 (C¼O), 1328, 1163;
1H NMR (CDCl3) d 5.8 (s, 2H, CH2), 7.0–8.3 (m, 14H, aromatic), 8.04
(s, 1H, O–CO–H); 13C NMR (CDCl3) d 55.8, 103.1, 115.4, 120.0,
121.2, 122.1, 125.3, 126.5, 127.4, 128.2, 129.3, 129.1, 132.6, 134.1,
135.0, 138.5, 140.5, 165.0 m=z: 423 (Mþ). Anal. calcd. for C22H17NO4S2:
C, 62.39, H, 4.05; N, 3.31. Found: C, 62.09; H, 4.13; N, 3.11.
Formic acid 1-benzenesulfonyl-3-chloro-1H-indol-2-ylmethyl ester (4)
Yield 51%; mp 130–133ꢀC; IR (KBr) cmꢂ1 1726 (C¼O), 1331, 1160;
1H NMR (CDCl3) d 5.5 (s, 2H, CH2), 7.2–7.9 (m, 9H, aromatic), 8.1
(s, 1H, O–CO–H); 13C NMR (CDCl3) d 56.3, 114.1, 120.2, 121.5,
125.8, 126.4, 127.7, 128.0, 129.5, 130.8, 134.4, 138.5, 139.9, 165.0 m=z:
349 (Mþ), 351 (M þ 2). Anal. calcd. for C16H12ClNO4S: C, 54.94; H,
3.46; N, 4.00. Found: C, 54.88; H, 3.73; N, 4.12.
Synthesis of Ether Derivatives: General Procedure
Thionyl chloride (0.5 mL) was added to a solution of indol-2-ylmethylfor-
mate esters 3 and 4 (1 mmol) in dry chloroform (10 mL) and stirred at 0ꢀC
for 1 h. Further alcohol (5 mL) was added and stirred at 30ꢀC for 6 h. The
course of the reaction was followed by TLC. The excess alcohol was
removed, and the reaction mixture was poured into crushed ice and
extracted with chloroform (3 ꢁ 30 mL). The chloroform layer was dried
over anhydrous Na2SO4 and filtered. Solvent removal followed by the
chromatographic (SiO2) purification of the residue using hexanes=
ethylacetate (8=2) as the eluting solvent afforded indol-2-ylmethyl ether
derivatives 5–9.
Spectroscopic Data of Ether Derivatives
1-Benzenesulfonyl-2-methoxymethyl-3-phenylsulfanyl-1H-indole (5)
1
Viscous liquid; 75% yield; IR (KBr) cmꢂ1 1318, 1167, 1143; H NMR
(CDCl3) d 3.3 (s, 3H, CH3), 4.6 (s, 2H, CH2), 7.2–7.9 (m, 14H, aromatic);

O-Alkylation of N,N-Dimethylformamide
2921
13C NMR (CDCl3) d 58.8, 66.1, 115.4, 118.0, 120.5, 125.2, 127.0, 127.1,
127.5, 128.7, 129.2, 129.3, 130.4, 130.9, 134.0, 134.4, 138.5, 141.0; m=z:
409 (Mþ). Anal. calcd. for C22H19NO3S2: C, 64.52; H, 4.68; N, 3.42.
Found: C, 64.43; H, 4.53; N, 3.37.
1-Benzenesulfonyl-2-ethoxymethyl-3-phenylsulfanyl-1H-indole (6)
1
Viscous liquid; 78% yield; IR (KBr) cmꢂ1 1320, 1170, 1150; H NMR
(CDCl3) d 1.09–1.12 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 3.3–3.4 (q, J ¼ 7.6 Hz,
2H, OCH2), 4.7 (s, 2H, CH2O), 7.2–7.8 (m, 14H, aromatic); 13C NMR
(CDCl3) d 14.8, 65.7, 66.9, 114.1, 118.7, 120.0, 125.2, 126.1, 127.0,
127.5, 128.4, 129.2, 129.3, 129.4, 130.4, 134.0, 134.3, 138.5, 140.7; m=z
423 (Mþ). Anal. calcd. for C23H21NO3S2: C, 65.22; H, 5.00; N, 3.31.
Found: C, 65.52; H, 4.73; N, 3.23.
1-Benzenesulfonyl-2-isobutoxymethyl-3-phenylsulfanyl-1H-indole (7)
1
Viscous liquid; 70% yield; IR (KBr) cmꢂ1 1329, 1161, 1148; H NMR
(CDCl3) d 0.95 [d, J ¼ 6.9 Hz, 6H, (CH3)2], 1.8–1.9 (m, 1H, CH), 3.2
(d, J ¼ 7.0 Hz, 2H, OCH2), 4.6 (s, 2H, CH2O), 7.2–7.9 (m, 14H, aro-
matic); 13C NMR (CDCl3) d 20.0, 29.1, 65.8, 76.2, 114.3, 118.0, 120.5,
125.3, 126.9, 127.0, 128.9, 129.1, 129.2, 129.5, 130.4, 131.0, 134.0,
134.4, 138.5, 140.7; m=z: 451 (Mþ). Anal. calcd. for C25H25NO3S2: C,
66.49; H, 5.58; N, 3.10. Found: C, 66.32; H, 5.23; N, 2.98.
1-Benzenesulfonyl-3-phenylsulfanyl-2-p-tolyloxymethyl-1H-indole (8)
1
Mp 130–132ꢀC; 72% yield; IR (KBr) cmꢂ1 1321, 1180, 1153; H NMR
(CDCl3) d 2.2 (s, 3H, CH3), 5.3 (s, 2H, CH2), 6.8–7.8 (m, 18H, aromatic);
13C NMR (CDCl3) d 21.0, 65.2, 107.6, 116.2, 118.0, 120.5, 125.2, 125.7,
126.1, 126.7, 127.1, 127.8, 128.0, 128.3, 129.0, 129.4, 130.1, 131.6, 134.1,
135.0, 138.5, 141.0, 156.0; m=z 485 (Mþ). Anal. calcd. for C28H23NO3S2:
C, 69.25; H, 4.77; N, 2.88. Found: C, 69.02; H, 4.67; N, 2.35.
ACKNOWLEDGMENTS
B. T. S. T. acknowledges the University Grants Commission (UGC)–
Special Assistance Programme (SAP) for instrument grants to the depart-
ment and the University of Madras for a University Research Fund
(URF).

2922
B. T. S. Thirumamagal and S. Narayanasamy
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