Reaction products of activated aromatic and heteroaromatic chlorides with n,n-disubstituted formamides

Article abstract of DOI:10.1080/00397910903136118

Several N,N-disubstituted aromatic amines (3a-g) was obtained in very good yield by the reaction of adequate doubly activated aromatic or heteroaromatic halides (1a-e) with N,N-disubstituted formamides (2a-c). Analogously, starting from 4-chloro-3-pyridin

Full text of DOI:10.1080/00397910903136118

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Reaction Products of Activated Aromatic
and Heteroaromatic Chlorides with N,N-
Disubstituted Formamides
Zdzisław Brzozowski a & Jarosław Sławiński b
a Department of Chemical Technology of Drugs , Medical University
of Gdańsk , Gdańsk, Poland
b Department of Organic Chemistry , Medical University of Gdańsk ,
Gdańsk, Poland
Published online: 06 May 2010.
To cite this article: Zdzisław Brzozowski & Jarosław Sławiński (2010) Reaction Products of
Activated Aromatic and Heteroaromatic Chlorides with N,N-Disubstituted Formamides, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:11, 1639-1645, DOI: 10.1080/00397910903136118
To link to this article: http://dx.doi.org/10.1080/00397910903136118
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Synthetic Communications1, 40: 1639–1645, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903136118
REACTION PRODUCTS OF ACTIVATED AROMATIC
AND HETEROAROMATIC CHLORIDES WITH
N,N-DISUBSTITUTED FORMAMIDES
1
Zdzisław Brzozowski and Jarosław Sławinski
2
´
1Department of Chemical Technology of Drugs, Medical University of
´
Gdansk, Gdansk, Poland
´
2
´
Department of Organic Chemistry, Medical University of Gdansk,
´
Gdansk, Poland
Several N,N-disubstituted aromatic amines (3a–g) was obtained in very good yield by the
reaction of adequate doubly activated aromatic or heteroaromatic halides (1a–e) with N,N-
disubstituted formamides (2a–c). Analogously, starting from 4-chloro-3-pyridinesulfonamide,
the appropriate 4-dialkylamino-1Hþ-pyridinium-3-(N-formyl)sulfonamidates (5a,b) were
obtained in 52–60% yield. Mechanisms of the reactions are discussed.
Keywords: Activated aromatic chlorides; amination and formylation reaction products; N,N-disubstituted
formamides
INTRODUCTION
Compounds containing dimethylamino functionality have attracted much
attentions because of their wide range of biological activity.[1,2] For example,
6-dimethylamino-purine derivatives bearing 2-phosphonomethoxyethyl groups
attached to the N7 or N9 positions of the purine ring were shown to possess anti-EBV
(Epstein–Barr virus) activity,[3] whereas 6-dimethylamino-purine alone acts as a
cyclin-dependent kinases inhibitor.[4] The dimethylamino moiety is also found in a
number of heterocyclic and aromatic compounds such as clanfenur (antitumor),[5]
metesind (thymidylate synthase inhibitor),[6] 6-dimethylamino-8-azaadenosine
(antitumor),[7] glyparamide (antidiabetic),[8] aditoprim (antibacterial),[9] and other
important drugs, for example, methadone (narcotic analgesic),[1,10] ampyzine (central
stimulant),[1] triampyzine (anticholinergic),[1] and diphenhydramine (antihistaminic,
sedative).[1] In addition to their usefulness as drugs, the reactivity of their amino
groups also makes them popular starting compounds in organic synthesis.[2]
Application of N,N-dimethylformamide (DMF) as an equivalent of dimethyla-
mine in the nucleophilic substitution of active halogen atoms is not unknown in the
literature. Dimetylamination of 2-chloroquinoline, 4-chloro-2-phenylquinoline,
Received April 3, 2009.
Address correspondence to Jarosław Sławinski, Department of Organic Chemistry, Medical
´
University of Gdansk, Al. Gen. J. Hallera 107, 80-416 Gdansk, Poland. E-mail: jaroslaw@amg.gda.pl
´
´
1639

´
Z. BRZOZOWSKI AND J. SŁAWINSKI
1640
2-chloro-5-nitropyridine, and halogenated anthraquinones was reported when those
halides were refluxed in DMF.[11–13] Use of DMF or N-methylformamide in the
presence of a base (KOH, K2CO3) or nucleophiles (secondary alkylamines or
aminoalcohols, 1.0–2.5 molar equiv) with some activated aromatic=heteroaroamtic
halides at an elevated temperature (130–190 ꢀC), which provides aminated com-
pounds, has been reported also.[14–18] A convenient dimethylamination of activated
aromatic chlorides was achieved by using DMF and diethanolamine. Several
dimethylamination products were prepared in 74–86% yields by the reactions of
p-nitrochlorobenzene, 2-chloropyridine, 2-chloroquinoline, and 2-chloropyrimidine
with DMF in the presence of diethanolamine (2.5 molar equiv.) at 130 ꢀC; however,
the authors[18] reported that the reaction with 2-chloropyrazine under the same
conditions failed.[18]
RESULTS AND DISCUSSION
We have found in our studies that the combination of DMF and diethanola-
mine (DEA) with doubly activated halogenated aromatics, such as 1-chloro-2,4-
dinitrobenzene or 4-chloro-3-pyridinesulfonamide, at 130–150 ꢀC could not be
recommended as a better way to produce such dimethylaminoaromatic compounds
because of the formation of an intractable mixture of products. It is to be supposed
that under these conditions, competition reactions between the nucleophile (DEA)
and DMF took place. These observations prompted us to investigate the possibilities
of aminating some doubly activated aromatic and heteroaromatic chlorides with
neat DMF or other amide solvents. To the best of our knowledge, these reactions have
never been reported. Although the compounds (3a,[19] 3b,[20] 3c,[20] 3d,[21] 3e,[22] and
3f[23]) are known, they were synthesized by a different manner.
For the initial amination studies, 1-chloro-2,4-dinitrobenzene was used with
DMF, N,N-diethylformamide (DEF), and N-methylformanilide at 150–155 ꢀC.
The reaction gave the corresponding amination products in 87, 69, and 86% yields,
respectively (3a, 3b, and 3c) as shown in Scheme 1.
For further investigation, we applied the various substituted benzenes or
pyridines involving 2-chloro-1,3-dinitrobenzene (3d), 4-chloro-3-nitrobenzonitrile
(3e), 2-chloro-5-nitrobenzonitrile (3f), and 2-chloro-3-cyano-4,6-dimethylpyridine
(3g) with DMF under the same conditions to obtain the corresponding amination
products in 57–86% yields (3d, 3e, 3f, and 3g; see Scheme 1). The best isolation yields
were obtained by using substituted benzene (83–86%, 3d–f) rather then pyridine
(57%, 3g).
According to the proposed mechanism (Scheme 1), the initial step would
consist of the formation of aluminium chloride of type A, followed by elimination
of formyl chloride, to give the expected amination products (3a–g). To get more
insight into the reaction mechanism, the analogous reaction of 4-chloro-3-pyridine-
sulfonamide (4) with N,N-dimethylformamide and N,N-diethylformamide (2a–b)
was carried out under the same conditions. The reaction gave the corresponding
betaine products (5a and 5b) in 52–60% yields as a result of further reaction of inter-
mediate 4-diakylamino-3-pyridinesulfonamide C with nascent formyl chloride to
provide intermediate D and then finally tautomerization (Scheme 2).

PRODUCTS OF ACTIVATED AROMATIC AND HETEROAROMATIC CHLORIDES 1641
Scheme 1.
In conclusion, we have developed a new amination method by treating
substituted benzene (1a–d) and pyridine (1e) derivatives with various substituted
amides including N,N-dimethylformamide, N,N-diethylformamide, and N-
methylformanilide. Moreover, it is demonstrated that the presence of a sulfonamide
moiety in the 4-chloropyridine ring (4) makes it susceptible to the further reaction
with nascent formyl chloride to produce simultaneously amination and a formyla-
tion product, which tautomerized to the stable betaine of type 5, under exactly the
same conditions.
Scheme 2.

´
Z. BRZOZOWSKI AND J. SŁAWINSKI
1642
EXPERIMENTAL
Melting points were taken on a Buchi 535 apparatus and are uncorrected.
¨
Infrared (IR) spectra in KBr pellets were recorded on a Perkin-Elmer 1600 Fourier
1
transform (FT)–IR spectrometer. H and 13C NMR spectra were recorded on a
Varian Gemini (200-MHz) instrument (chemical shifts are expressed as d values
relative to Me4Si as standard).
General Procedure for the Amination of Doubly Activated
Aromatic and Heteroaromatic Chlorides (1a–f) Using
N-R1, N-R2-Formamides (2a–c)
A solution of the corresponding aromatic or heteroaromatic compound
containing the doubly activated chloro substituent (0.02 mol) in adequate N,N-
disubstituted formamides (7 mL) was heated with stirring for 8–32 h (see Scheme 1).
After cooling to room temperature, the reaction mixture was stirred for 4 h, and
then water (50 mL) was added dropwise. The suspension obtained was left overnight.
The precipitate was collected by suction and purified by crystallization from 99.9%
ethanol.
2,4-Dinitro-N,N-dimethylaniline (3a)
Starting from 1-chloro-2,4-dinitrobenzene (4.05 g) and DMF, the title
compound 3a was obtained: 3.7 g, 87%; mp 74–75 ꢀC; IR (KBr) 2975, 2915, 2815,
1605, 1335 cmꢁ1
;
1H NMR (CDCl3) d 3.06 (s, 6H, CH3NCH3), 7.01 (d,
Jortho ¼ 9.5 Hz, 1H, H-6), 8.20 (dd, Jortho ¼ 9.5 Hz, Jmeta ¼ 2.7 Hz, 1H, H-5), 8.68
(d, Jmeta ¼ 2.7 Hz, 1H, H-3) ppm; 13C NMR (CDCl3) d 42.92, 117.11, 124.65,
128.25, 136.20, 136.48, 149.62 ppm. Anal. calcd. for C8H9N3O4: N, 19.89. Found:
N, 19.92.
2,4-Dinitro-N,N-diethylaniline (3b)
Starting from 1-chloro-2,4-dinitrobenzene (4.05 g) and N,N-diethylforma-
mide, the title compound 3b was obtained: 3.3 g, 69%; mp 77–78 ꢀC; IR (KBr)
;
2980, 2970, 2925, 2870, 2850, 1605, 1320 cmꢁ1 1H NMR (CDCl3) d 1.25 (t,
J ¼ 7.1 Hz, 6H, 2 ꢂ CH3 of Et2N), 3.37 (J ¼ 7.1 Hz, 4H, 2 ꢂ CH2 of Et2N), 7.07
(d, Jortho ¼ 9.3 Hz, 1H, H-6), 8.19 (dd, Jortho ¼ 9.3 Hz, Jmeta ¼ 2.4 Hz, 1H, H-5),
8.62 (d, Jmeta ¼ 2.4 Hz, 1H, H-3) ppm; 13C NMR (CDCl3) d 12.66, 46.68, 118.55,
124.20, 127.85, 136.30, 137.88, 148.27 ppm. Anal. calcd. for C10H13N3O4: N,
17.56. Found: N, 17.70.
2,4-Dinitro-N-methyl-N-phenylaniline (3c)
Starting from 1-chloro-2,4-nitrobenzene (4.05 g) and N-methylformanilide, the
title compound 3c was obtained: 4.7 g, 86%; mp 168–169 ꢀC; IR (KBr) 2980, 2900,
;
1610, 1320, 1585, 1530 cmꢁ1 1H NMR (CDCl3) d 3.48 (s, 3H, CH3), 7.1 (d,
Jortho ¼ 7.8 Hz, 1H, H-6), 7.21–7.28 (m, 3H, PhN), 7.38 (t, J ¼ 7.8 Hz, 2H, PhN),

PRODUCTS OF ACTIVATED AROMATIC AND HETEROAROMATIC CHLORIDES 1643
8.28 (dd, Jortho ¼ 7.8 Hz, Jmeta ¼ 2.4 Hz, 1H, H-5), 8.62 (d, Jmeta ¼ 2.4 Hz, 1H, H-3)
ppm; 13C NMR (CDCl3) d 42.77, 121.40, 123.34, 126.42, 128.09, 130.33, 138.45,
139.39, 146.45, 147.56 ppm. Anal. calcd. for C13H11N3O4: N, 15.38. Found: N, 15.49.
2,6-Dinitro-N,N-dimethylaniline (3d)
Starting from 2-chloro-1,3-dinitrobenzene (4.05 g) and DMF, the title com-
pound 3d was obtained: 3.6 g, 85%; mp 77.5–78.5 ꢀC; IR (KBr) 2940, 2805, 1610,
1
1350 cmꢁ1; H NMR (CDCl3) d 2.80 (s, 6H, CH3NCH3), 7.04 (t, J ¼ 8.0 Hz, 1H,
H-4), 7.82 (d, J ¼ 8.0 Hz, 2H, H-3 and H-5) ppm; 13C NMR (CDCl3) d 42.65,
120.78, 129.81, 140.28, 140.62 ppm. Anal. calcd. for C8H9N3O4: N, 19.87. Found:
N, 19.94.
4-Dimethylamino-3-nitrobenzonitrile (3e)
Starting from 4-chloro-3-nitrobenzonitrile (3.2 g) and DMF, the title
compound 3e was obtained: 3.2 g, 83%; mp 113–114 ꢀC; IR (KBr) 2965, 2925,
1
2815, 2220, 1615, 1345 cmꢁ1; H NMR (CDCl3) d 3.01 (s, 6H, CH3NCH3), 7.03
(d, Jortho ¼ 8.8 Hz, 1H, H-5), 7.53 (dd, Jortho ¼ 8.8 Hz, Jmeta ¼ 1.9 Hz, 1H, H-6),
8.06 (d, Jmeta ¼ 1.9 Hz, 1H, H-2) ppm; 13C NMR (CDCl3) d 42.42, 98.26, 118.02,
118.25, 131.98, 135.68, 148.11 ppm. Anal. calcd. for C9H9N3O2:N, 21.97. Found:
N, 22.11.
2-Dimethylamino-5-nitrobenzonitrile (3f)
Starting from 2-chloro-5-nitrobenzonitrile (3.65 g) and DMF, the title com-
pound 3f was obtained: 3.3 g, 86%; mp 107–108 ꢀC; IR (KBr) 2915, 2820, 2215,
1615, 1330 cmꢁ1
;
1H NMR (CDCl3) d 3.33 (s, 6H, CH3NCH3), 6.79 (d,
Jortho ¼ 9.5 Hz, 1H, H-3), 8.16 (dd, Jortho ¼ 9.5 Hz, Jmeta ¼ 2.6 Hz, 1H, H-4), 8.39
(d, Jmeta ¼ 2.6 Hz, 1H, H-5) ppm. Anal. calcd. for C9H9N3O2: N, 21.98. Found:
N, 22.04.
3-Cyano-4,6-dimethyl-2-dimethyaminopyridine (3g)
Starting from 2-chloro-3-cyano-4,6-dimethylpyridine (3.33 g) and DMF, the
title compound 3g was obtained: 2.0 g, 57%; mp 48–48.5 ꢀC; IR (KBr) 2925, 2845,
1
2800, 2200, 1580, 1560, 1515, 1400, 1240 cmꢁ1; H NMR (CDCl3) d 2.35 (s, 3H,
CH3-4), 2.38 (s, 3H, CH3-6), 3.24 (s, 6H, CH3NCH3), 6.40 (s, 1H, H-5) ppm;
13C NMR (CDCl3) d 21.19, 25.23, 41.05, 89.83, 114.39, 118.84, 154.76, 160.93,
161.08 ppm. Anal. calcd. for C10H13N3: C, 68.54; H, 7.47; N, 23.98. Found: C,
68.86; H, 7.40; N, 24.11.
Procedure for the One-Pot Dialkylamination and Formylation of
4-Chloropyridine-3-sulfonamide Using N,N-Dialkylformamides
A solution of 4-chloro-3-pyridinesulfonamide 4 (7.7 g, 0.04 mol) in N,N-
dimethylformamide (15 mL) or N,N-diethylformamide (18 mL) was refluxed with

´
Z. BRZOZOWSKI AND J. SŁAWINSKI
1644
stirring for 26 or 18 h, respectively. After cooling to room temperature, the reaction
mixture was left to stand for 48 h. The precipitate was collected by filtration, washed
with ethanol (2 ꢂ 2 mL), and recrystallized from ethanol.
4-Dimethylamino-1Hþ-pyridinium-3-(N-formyl)sulfonamidate (5a)
Starting from DMF, the title compound 5 was obtained: 5.5 g, 60%; mp
272–273 ꢀC; IR (KBr) 2760, 2655, 2630, 1990, 1920, 1630, 1335, 1150, 1130 cmꢁ1
;
1H NMR (DMSO-d6) d 2.85 (s, 3H, N-CH3), 3.13 (s, 3H, N-CH3), 6.20 (d,
=
J ¼ 7.4 Hz, 1H, H-5), 7.24 (d, J ¼ 7.4 Hz, H-6), 8.22 (s, 1H, H-C O), 8.26 (s, 1H,
H-2), 11.82 (br.s, 1H, NHþ) ppm; 13C NMR (DMSO-d6) d 35.04, 41.22, 120.17,
128.22, 138.86, 139.57, 162.83, 173.13 ppm. Anal. calcd. for C8H11N3O3S: C,
41.91; H, 4.83; N, 18.32. Found: C, 41.98; H, 4.80; N, 18.40.
4-Diethylamino-1Hþ-pyridinium-3-(N-formyl)sulfonamidate (5b)
Starting from N,N-diethyformamide, the title compound 6 was obtained: 5.4 g,
52%; mp 241–243 ꢀC; IR (KBr) 2965, 2930, 2850, 2810, 2770, 2470, 2370, 2115, 1640,
1355, 1345, 1145, 1130 cmꢁ1
;
1H NMR (DMSO-d6) d 1.04 (t, J ¼ 7.0 Hz, 3H,
CH2CH3), 2.17 (t, J ¼ 7.0 Hz, 3H, CH2CH3), 3.34 (q, J ¼ 7.0 Hz, 2H, CH2CH3),
3.48 (q, J ¼ 7.0 Hz, 2H, CH2CH3), 6.26 (d, J ¼ 7.3 Hz, 1H, H-5), 7.76 (d, J ¼þ7.3 Hz,
=
1H, H-6), 8.26 (s, 1H, H-C O), 8.31 (s, 1H, H-2), 11.84 (s, 1H, NH ) ppm;
13C NMR (DMSO-d6) d 12.12, 14.55, 46.63, 120.14, 128.16, 138.88, 139.46, 162.13,
173.09 ppm. Anal. calcd. for C10H15N3O3S: C, 66.67; H, 5.87; N, 16.33. Found: C,
66.60; H, 5.97; N, 16.30.
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