Surprising formylations with methylformamidopyridines and oxalyl chloride

Article abstract of DOI:10.1016/S0040-4039(00)00401-9

4-N-(Methylformamido)pyridine with (COCl)₂ gives the corresponding Vilsmeier reagent which reacts with 4-substituted dimethylanilines to produce 5-substituted-N-methylisatins. The corresponding 2-N- (methylformamido)pyridine under the same conditions generates benzo[2,3]pyrido[6,7-b][1,5]diazocines. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00401-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3475–3478
Surprising formylations with methylformamidopyridines and
oxalyl chloride
Ying Cheng,a,∗ Qing-Xiang Liu a and Otto Meth-Cohn b,∗
aChemistry Department, Beijing Normal University, Beijing 100875, China
bChemistry Department, University of Sunderland, Sunderland SR1 3SD, UK
Received 12 January 2000; accepted 7 March 2000
Abstract
4-N-(Methylformamido)pyridine with (COCl)2 gives the corresponding Vilsmeier reagent which reacts
with 4-substituted dimethylanilines to produce 5-substituted-N-methylisatins. The corresponding 2-N-
(methylformamido)pyridine under the same conditions generates benzo[2,3]pyrido[6,7-b][1,5]diazocines.
© 2000 Published by Elsevier Science Ltd. All rights reserved.
Recently, we have demonstrated1 that Vilsmeier reagents (hereinafter referred to as VRs; R2N+_CHCl
Cl−) are readily transformed into carbenes by the action of bases such as pyridine. These nucleo-
philic carbenes react with the unchanged VR to give an ethene (R2NCCl_CClNR2) which can be
isolated or further formylated to give products such as isatins, quindolines and 2,2-biindoles. In other
work,2 we have shown that when the base utilised to react with the VR is a 4-substituted dimethyl-
aniline, a dibenzo[1,5]diazocine results (Scheme 1). We herein examine the reactions of 2- and 4-
methylformamidopyridines (MFPs) in Vilsmeier formylations, since they combine the presence both
of an electrophilic formylating group and a basic centre, thereby hopefully enabling Vilsmeier→carbene
transformations.
It is surprising that no work has been reported on utilising MFPs in Vilsmeier reactions. Indeed,
while the 2-isomer is commercially available,3 the 4-isomer is previously unreported, but easily made
by NaH/MeI methylation of 4-formamidopyridine, itself made by HCO2H/Ac2O formylation of 4-
aminopyridine. Both isomers are readily and efficiently converted into solid VRs with oxalyl chloride.
Treatment of the VR of 4-MFP with various 4-substituted dimethylanilines proved most interesting.
While under a nitrogen atmosphere no definable product could be isolated, the interaction in air produced,
to our surprise, the corresponding N-methylisatin 1. Yields of the isatins from a 1:1 ratio of the two
reactants were moderate (30–52%) but perhaps this is not surprising in the light of our suggested
mechanism (Scheme 2). This envisages a formylation as in Scheme 1 followed by an aerial oxidation
∗
Corresponding authors. E-mail: yincheng@public2.east.net.cn (Y. Cheng), otto.meth-cohn@sunderland.ac.uk (O. Meth-
Cohn)
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00401-9
tetl 16681

3476
Scheme 1.
of the intermediate to an intermediate carbene which then cyclises. It is possible the the VR acts as an
intermolecular hydride abstractor but this is not borne out by attempts to abstract hydride from N,N-
dimethylbenzylamine (which remains unchanged). The simplicity of the reaction even with these yields
makes the method worthy of further optimisation, towards important, but presently not easily made,
isatins. In the formation of 1, X=Me, the yield increased to 41% if oxygen was slowly bubbled into the
reaction mixture during the interaction. We are currently examining other oxidants.
Scheme 2.
The corresponding 2-MFP behaved quite differently when treated with the same dimethylanilines
in the same manner. Again we were surprised, since despite the possibly deactivated pyridine ring,

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benzo[2,3]pyrido[6,7-b][1,5]diazocines 2, members of a new and interesting system,4 were isolated in
yields of 56–58%, no doubt exactly as depicted in Scheme 1.
It would appear that the 2-MFP VR is not significantly protonated on the ring nitrogen due to the
proximate (quaternised?) group, thus allowing cyclisation, while the more nucleophilic 4-isomer (cf.
DMAP) is protonated significantly, thus deactivating the system to diazocine formation. Clearly, these
two VRs are of some interest and deserve a fuller study to clarify their other potentials. Illustrative
examples of the above reactions are given below:
– Isatin 1 formation utilising 4-MFP: To 4-(methylformamido)pyridine (1.36 g, 0.01 M) was added
oxalyl chloride (2 mL) with stirring in an ice-bath, with gas evolution evident. The resulting red
mixture was stirred at room temperature for 30 min and the excess of oxalyl chloride was removed in
vacuo. Under ice-bath cooling, a solution of the dimethylaniline (0.01 M) in dry chloroform (30 mL)
was added dropwise. The resulting red solution was refluxed for 18 h and the solvent was removed,
the residue basified and then extracted with chloroform. The chloroform layer was dried, evaporated
and the residue purified by silica gel chromatography.5
– Diazocine 2 formation utilising 2-MFP: To 2-(methylformamido)pyridine (1.36 g, 0.01 M) was added
oxalyl chloride (2 mL) with stirring in an ice-bath, with gas evolution evident. The resulting yellow
mixture was stirred at room temperature for 30 min and the excess of oxalyl chloride was removed in
vacuo. Under ice-bath cooling, a solution of the dimethylaniline (0.01 M) in dry chloroform (30 mL)
was added dropwise. The resulting red solution was refluxed for 10 h and the solvent was removed.
The residue was basified and extracted with chloroform and the chloroform layer dried, evaporated
and the residue purified by silica gel chromatography.6
In conclusion, we have shown that the VR derived from 2-(methylformamido)pyridine and oxalyl
chloride formylates 4-substituted dimethylanilines to give benzopyrido[1,5]diazocines, while the 4-
isomer under the same conditions yields 5-substituted N-methylisatins.
Acknowledgements
We heartily thank the National Natural Science Foundation of China for a Grant (No. 29772003) to
Y.C. which made this work possible.
References
1. (a) Cheng, Y.; Goon, S.; Meth-Cohn, O. Chem. Commun. 1996, 1395–1396; (b) Meth-Cohn, O.; Goon, S. Tetrahedron Lett.
1996, 37, 9381–9384; (c) Cheng, Y.; Goon, S.; Meth-Cohn, O. J. Chem. Soc., Perkin Trans. 1 1998, 1619–1625.
2. (a) Meth-Cohn, O.; Taylor, D. L. J. Chem. Soc., Chem. Commun. 1995, 1463–1464; (b) Cheng, Y.; Meth-Cohn, O.
Tetrahedron Lett. 1996, 37, 2679–2682; (c) Meth-Cohn, O. Adv Het. Chem. 1996, 65, 1–39; (d) Cheng, Y.; Meth-Cohn, O.;
Taylor, D. L. J. Chem. Soc., Perkin Trans. 1 1998, 1257–1262.
3. From Aldrich; compound 23654-3.

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4. The corresponding dipyrido[2,3-b;20,30-j][1,5]diazocine is known as its 5,11-dione. See: Seide, K. Chem. Ber. 1924, 57,
1807–1812, and references cited therein.
5. The isatins are all known and mps together with 1H and 13C NMR spectroscopy are in accord with our own previous data;
see Ref. 1c.
6. All the products gave correct CHN analysis data. Some properties of the diazocines 2 are: Mps: 2, X=Me, 107–109°C;
X=F, 115–117°C; X=Cl, 125–127°C; X=Br, 124–126°C. 1H NMR (CDCl3): 2, X=Me: 8.11 (1H, dd, J=4.8 and 1.8), 7.31
(1H, dd, J=7.2 and 1.8), 7.02 (1H, dd, J=8.0 and 2.0), 6.96 (1H, d, J=2.0), 6.76 (1H, d, J=8.0), 6.60 (1H, dd, J=7.0 and
4.8), 3.90–4.50 (4H, br, 2×NCH2), 3.03 (3H, s, NMe), 2.77 (3H, s, NMe), 2.29 (3H, s, ArMe). 13C NMR (CDCl3): 2,
X=Me: 159.6, 147.9, 146.1, 138.9, 132.1, 128.7, 127.2, 125.6, 119.6, 115,4, 112.5, 58.1, 56.6, 38.9, 37.1, 20.1. MS 2,
1
X=Me: m/z 253 (100%, M+), 238 (87%). H NMR (CDCl3): 2, X=F: 8.11 (1H, dd, J=4.8 and 1.6), 7.32 (1H, dd, J=7.0
and 1.6), 6.73–6.94 (3H, m), 6.62 (1H, dd, J=7.4 and 5.2), 4.36 (2H, s, NCH2), 4.25 (2H, s, NCH2), 3.04 (3H, s, NMe),
2.74 (3H, s, NMe). 13C NMR (CDCl3): 2, X=F: 159.8, 157.6, 154.1, 146.7, 146.4, 139.2, 127.5, 119.5, 118.0, 117.6, 114.6,
114.3, 113.0, 58.2, 56.5, 39.3, 37.2. MS 2, X=F: m/z 257 (100%, M+), 242 (80%). 1H NMR (CDCl3): 2, X=Cl: 8.11 (1H,
dd, J=5.0 and 1.8), 7.31 (1H, dd, J=7.4 and 1.8), 7.08–7.16 (2H, m), 6.74 (1H, d, J=8.6), 6.61 (1H, dd, J=7.0 and 4.8),
4.10–4.50 (4H, br, 2×NCH2), 3.02 (3H, s, NMe), 2.76 (3H, s, NMe). 13C NMR (CDCl3): 2, X=Cl: 159.6, 148.8, 146.1,
139.2, 131.2, 128.0, 127.2, 122.6, 119.0, 112.9, 58.0, 56.4, 38.9, 37.1. MS 2, X=Cl: m/z 273/275 (100%, M+), 258/260
(80%). 1H NMR (CDCl3): 2, X=Br: 8.10 (1H, dd, J=4.8 and 1.6), 7.23–7.32 (3H, m), 6.68 (1H, d, J=8.2), 6.60 (1H, dd,
J=7.4 and 4.6), 4.10–4.50 (4H, br, 2×NCH2), 3.02 (3H, s, NMe), 2.75 (3H, s, NMe). 13C NMR (CDCl3): 2, X=Br: 159.6,
149.2, 146.5, 139.2, 134.0, 131.0, 127.6, 119.0, 116.8, 112.9, 109.8, 58.0, 56.4, 38.9, 37.2. MS 2, X=Br: m/z 317/319 (70%,
M+), 302/304 (47%).