Convenient dimethylamino amination in heterocycles and aromatics with dimethylformamide

Article abstract of DOI:10.1081/SCC-200026634

A convenient dimethylamino amination of various heterocyclic and aromatic compounds having activated chloro group has been carried out in good yields using dimethyl formamide (DMF).

Full text of DOI:10.1081/SCC-200026634

This article was downloaded by: [University of Illinois at Urbana-
Champaign]
On: 18 August 2013, At: 07:54
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T
3JH, UK
Synthetic Communications:
An International Journal
for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Convenient Dimethylamino
Amination in Heterocycles
and Aromatics with
Dimethylformamide
Anu Agarwal a & Prem M. S. Chauhan a
a Medicinal and Process Chemistry Division,
Central Drug Research Institute, Lucknow, 226001,
India
Published online: 06 Jan 2011.
To cite this article: Anu Agarwal & Prem M. S. Chauhan (2004) Convenient
Dimethylamino Amination in Heterocycles and Aromatics with Dimethylformamide,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 34:16, 2925-2930, DOI: 10.1081/SCC-200026634
To link to this article: http://dx.doi.org/10.1081/SCC-200026634
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all
the information (the “Content”) contained in the publications on our
platform. However, Taylor & Francis, our agents, and our licensors
make no representations or warranties whatsoever as to the accuracy,
completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of
the authors, and are not the views of or endorsed by Taylor & Francis.

The accuracy of the Content should not be relied upon and should be
independently verified with primary sources of information. Taylor and
Francis shall not be liable for any losses, actions, claims, proceedings,
demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in
relation to or arising out of the use of the Content.
This article may be used for research, teaching, and private study
purposes. Any substantial or systematic reproduction, redistribution,
reselling, loan, sub-licensing, systematic supply, or distribution in any form
to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 16, pp. 2925–2930, 2004
Convenient Dimethylamino Amination in
Heterocycles and Aromatics with
Dimethylformamide
*
Anu Agarwal and Prem M. S. Chauhan
Medicinal and Process Chemistry Division, Central Drug Research Institute,
Lucknow, India
ABSTRACT
A convenient dimethylamino amination of various heterocyclic and aro-
matic compounds having activated chloro group has been carried out in
good yields using dimethyl formamide (DMF).
Key Words: Dimethyl amination; Dimethyl formamide; Dimethyl-
amino-purine.
INTRODUCTION
The new millennium has witnessed a gamut of drugs and chemical
reagents containing the dimethylamino group. It is present in ampyzine[1]
*
Correspondence: Prem M. S. Chauhan, Medicinal and Process Chemistry Division,
Central Drug Research Institute, Lucknow 226001, India; Fax: 91-0522-2223405 or 91-
0522-2223938; E-mail: prem_chauhan_2000@yahoo.com or premsc58@hotmail.com.
2925
DOI: 10.1081/SCC-200026634
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2926
Agarwal and Chauhan
(central stimulant), triampyzine[1] (anticholinergic), dimethirimol[2] (fungi-
cide), aminopyrine[3] (antipyretic), 6-dimethylamino-8-azaadenosine[4] (anti-
tumor), diphenhydramine[1] (antihistamine), methadone[5] (narcotic
analgesic), and various other drugs.
In addition to drugs, the dimethylamino group is present in important mole-
cules such as 6-dimethylamino-purine (6-DMAP), a very important chemical,
present in 0.78–0.08mol% in the DNA composition of algae.[6] The 6-DMAP
(inhibitor of cyclin dependant kinase [CDK]) is used to study the DNA endo-
reduplication during elongation and differentiation of primary roots.[7]
6-DMAP is also used to activate embryos and oocytes that give rise to cloned
rabbits that are produced by nuclear transfer from adult somatic cells.[8]
The dimethylamino group is mainly introduced by reacting chloro com-
pounds with dimethylamine. As this reaction involves elevated temperature
and pressure, it is not a convenient method for synthesis.[9] Most of the time,
dimethylamination ends up with very low yield.[10] Coppinger synthesized
N,N-dimethylbenzamide by refluxing benzoyl chloride with DMF.[11]
Chloro benzene substituted with nitro group at different positions was refluxed
with copper sulfate and DMF to obtain the corresponding dimethylamino
compounds.[12]
In this communication, a systematic study is done on the replacement of
an activated chloro group with the dimethylamino group in heterocyclic and
aromatic compounds by using DMF (Sch. 1).
Scheme 1.

Dimethylamino Amination in Heterocycles and Aromatics
2927
The dimethylamination of 2-chloro-4-piperidino pyrimidine (2), 2,4-
dichloro pyrimidine (3), 2,4-dichloro-6-piperidino triazene (4), 2-chloro-4,6-
dipiperidino triazene (5), and 4-chloro pyridine (6) with DMF yielded the
desired dimethylamino products in very good yields (70–96%). There was
no reaction in 2-amino-6-chloro pyrazine (7) due to the presence of deactiva-
ting amino group (Table 1).
The dimethylamino amination of aromatic compounds is temperature
dependant. The temperature at which chloro group is replaced depends on
the activation of the chloro group induced either by nitrogen atom of hetero-
cyclic ring or nitro group. As nitro group exerts its strong electron withdraw-
ing effect only at the ortho or para positions so only chloro groups at ortho or
para positions are replaced and those at meta positions (10) are unaffected.
This method of dimethylamino amination by DMF is of great importance
in chemical synthesis due to its wide applicability, easy reaction conditions,
and high yield. It is also very useful in synthesizing 6-DMAP and various
other chemicals of medicinal importance.
EXPERIMENTAL
IR spectra were recorded on Beckman Aculab-10, Perkin Elmer 881, and
FTIR 8210 PC, Shimadzu spectrophotometers either on KBr discs or in neat.
Nuclear Magnetic Resonance (NMR) spectra were recorded on either Bruker
Avance DRX-300 MHz or Bruker DPX 200 FT spectrometers using TMS as
an internal reference. FAB mass spectra were recorded on JEOL SX 102/
DA 6000 mass spectrometer using Argon/Xenon (6 KV, 10 mA) as the
FAB gas. Chemical analysis were carried out on Carlo-Erba-1108 instrument.
The melting points were recorded on an electrically heated melting point
apparatus and are uncorrected.
Dimethylamino Amination Procedure
0.5 gm of the chloro compounds were heated with 15 mL of DMF and
K2CO3 for 10 hr. The DMF was removed under reduced pressure and 5%
sodium hydrogen carbonate solution was added. The compound was extracted
with chloroform and dried over Na2SO4 and concentrated to afford the product
which on crystallization with chloroform and hexane afforded the pure
dimethylamino compounds.
2-N,N-Dimethylamino-4-piperidinopyrimidine (2). M.P. 76–788C,
1
MS 207 (Mþ1), IR (KBr) 3017, 2940, 2858, 1648, 1586, 1487 cm21; H
NMR (CDCl3, 200 MHz) d (ppm) 7.91 (d, 1H, J ¼ 6.12 Hz), 5.84 (d, 1H,

2928
Agarwal and Chauhan
Table 1. Dimethylamino amination of heterocyclic and activated nitro halo
compounds.
Temp
(8C)
Yield
(%)
Entry
1
Starting
Product
120
96
2
3
150
75
100
50
20
4
80
92
5
6
7
80
80
95
75
No reaction
(continued)

Dimethylamino Amination in Heterocycles and Aromatics
2929
Table 1. Continued.
Temp
(8C)
Yield
(%)
Entry
8
Starting
Product
140
95
9
25
96
10
No reaction
J ¼ 6.13 Hz), 3.59 (t, 4H, J ¼ 5.1 Hz), 3.12 (s, 6H), 1.62 (bs, 6H), 13C 162.2
(C), 162.0 (C), 156.2 (CH), 91.9 (CH), 44.8 (CH2), 36.8 (N–CH3), 25.5
(CH2), 24.7 (CH2). Anal. calcd for C11H18N4: C, 64.05; H, 8.79; N, 27.16.
Found: C, 64.38; H, 8.56; N, 26.88.
bis-2,4-(N,N-Dimethylamino)-6-piperidino-triazene (4). M.P. 72–
748C, MS 251 (Mþ1), IR (KBr) 3016, 2943, 2860, 1620, 1466, 1350 cm21
;
1H NMR (CDCl3, 200 MHz) d (ppm) 3.76 (t, 4H, J ¼ 5.2 Hz), 3.11 (s, 12H),
1.59 (m, 6H), 13C 170.2 (C), 163.60 (C), 45.5 (CH2), 36.32 (N–CH3), 25.8
(CH2), 24.3 (CH2). Anal. calcd. for C12H22N6: C, 57.57; H, 8.86; N, 33.57.
Found: C, 57.28; H, 8.94; N, 33.62.
2-N,N-Dimethylamino-4,6-bis-piperidino-triazene (5). M.P. 102–
1038C, MS 291 (Mþ1), IR (KBr) 3002, 2928, 2848, 1632, 1443, 1397 cm21
;
1H NMR (CDCl3, 200 MHz) d (ppm) 3.73 (t, 8H, J ¼ 5.1), 3.08 (s, 6H),
1.57 (bs, 12H), 13C 166.62 (C), 165.73 (C), 44.48 (CH2), 36.26 (N–CH3),
26.235 (CH2), 25.71 (CH2). Anal. calcd for C15H26N6: C, 62.04; H, 9.02;
N, 28.94. Found: C, 61.76; H, 8.94; N, 28.72.

2930
Agarwal and Chauhan
ACKNOWLEDGMENTS
A.A. thanks the Council of Scientific and Industrial Research (India) for
the award of fellowship. We are also thankful to S.A.I.F. Division, CDRI,
Lucknow for providing spectroscopic data.
REFERENCES
1. Dictionary of Organic Compounds, 5th Ed.; Chapman and Hall: London,
Vol. 2.
2. Elias, R.S.; Shephard, M.C.; Snell, B.K.; Stubbs, J. 5Butyl-2-dimethyl
amino-4-hydroxy-6 methyl pyrimidine: a systemic fungicide. Nature
1968, 219, 1160.
3. Takahashi, T.; Kenematsu, K. Study of analgesics (XVIII) antipyrine
derivatives. Chem. Pharm. Bull. 1958, 6, 98.
4. Hutzenlaub, W.; Tolman, R.L.; Robins, R.K. Azapurine nucleosides syn-
thesis and antitumor activity of certain 3-b-D-ribofuranosyl and 20-deoxy-
D-ribofuranosyl-n-triazolo[4,5-d]pyrimidines. J. Med. Chem. 1972, 15,
879.
5. Schultz, E.M.; Robb, C.M.; Sprague, J.M. The reaction of 1-dimethyl-
amino-2-chloropropane with diphenylacetonitrile: the structure of ami-
done. J. Am. Chem. Soc. 1947, 69, 2454.
6. Pakhomova, M.V. Nucleotide composition and content of methylated
bases in DNA of the White Sea algae. Biologiya 2002, 1, 18–21;
Chem. Abstr. 2002, 137, 275421f.
7. Rosiak, M.; Polit, J.T.; Maszewski, J. Inhibitors of cyclin dependant
kinases CDK. Biologia Plantarum 2002, 45, 205–211; Chem. Abstr.
2002, 137, 60354a.
8. Chesne, P.; Adenot, P.G.; Viglietta, C. Cloned rabbits produced by
nuclear transfer from adult somatic cells. Nat. Biotech. 2002, 20,
366–369.
9. Lurthy, N.G.; Bergstrom, F.W.; Mosher, H.S. Introduction of alkylamino
and diakyl-amino groups into the quinoline nucleus. J. Am. Chem. Soc.
1949, 71, 1109.
10. Albert, A.; Brown, D.J. Purine studies. Part I. Stability to acid and alkali.
Solubility. Ionization. Comparison with pteridines. J. Chem. Soc. 1954,
76, 2060.
11. Coppinger, G.M. J. Am. Chem. Soc. 1954, 76, 1372.
12. Deorha, D.S.; Sharma, H.L. J. Ind. Chem. Soc. 1963, 40, 819–820.
Received in India April 22, 2004