A one-step route to azomethine ylides via chloroiminium salts

Article abstract of DOI:10.1016/j.tetlet.2003.11.095

A new, one-step procedure for the generation of azomethine ylides, 4 and 20, via chloroiminium salts, 3 and 19, is reported. The generation of the azomethine ylides was confirmed by their trapping with dimethyl acetylenedicarboxylate (DMAD) which, upon spontaneous 1,4-dehydrochlorination, gave the corresponding pyrroles 17 and 21.

Full text of DOI:10.1016/j.tetlet.2003.11.095

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 943–946
A one-step route to azomethine ylides via chloroiminium saltsq
Rosaleen J. Anderson,a Andrei S. Batsanov,b Natalia Belskaia,c
Paul W. Groundwater,a,* Otto Meth-Cohna and Andrey Zaytseva
aSunderland Pharmacy School––Drug Design and Synthesis, University of Sunderland, Wharncliffe Street, Sunderland SR1 3SD, UK
bDepartment of Chemistry, University of Durham, South Road, Durham DH1 3LE, UK
cLaboratory of Technology for Organic Synthesis, The Urals State Technical University, 19 Mira Street, Ekaterinburg 620002, Russia
Received 14 October 2003; revised 11 November 2003; accepted 21 November 2003
Abstract—A new, one-step procedure for the generation of azomethine ylides, 4 and 20, via chloroiminium salts, 3 and 19, is
reported. The generation of the azomethine ylides was confirmed by their trapping with dimethyl acetylenedicarboxylate (DMAD)
which, upon spontaneous 1,4-dehydrochlorination, gave the corresponding pyrroles 17 and 21.
ꢀ 2003 Elsevier Ltd. All rights reserved.
When amide 2c (R1 ¼ Ph, R2 ¼ Et) was reacted with
R2
R4
R2
R4
(COCl)2 in dry CHCl3 at room temperature, the product
of the reaction was an oxazolium salt 5, presumably
formed by the 1,5-electrocyclisation of the azomethine
ylide 4. This oxazolium salt 5 reacted with TMSCN9 in
the presence of CsF in acetonitrile to give the unstable
4-oxazoline 6, which as its azomethine isomer 7, could
then be trapped with dimethyl acetylenedicarboxylate
(DMAD) affording a mixture of the adduct 8 (26%
yield) and pyrrole 9 (15%). The adduct 8, which was
obtained as a single diastereoisomer, is unstable and
under the reaction conditions can aromatise, via the loss
of HCN, to give pyrrole 9 (Scheme 2).10 The interme-
diacy of the oxazolium salt 5 was confirmed when the
reaction between amide 2c and oxalyl chloride was
performed in an NMR tube in CDCl3. The complete
conversion of amide 2c to oxazolium salt 5 took 6 h at
50 ꢁC.
R1
R5
R1
R5
N
R3
N
R3
1
Azomethine ylides 1 are versatile intermediates for the
preparation of a wide range of heterocycles through
1,3-dipolar cycloadditions,1 1,5-electrocyclisations,2 or
1,7-electrocyclisations.3–5 There are many routes to
azomethine ylides, including the decarboxylation of
iminium salts,6 the ring-opening of aziridines,7 and the
1,2-prototropy of a-imino esters.8
We wish to describe here a new, one-step route to
chloro-substituted ÔstabilisedÕ azomethine ylides 4 via
chloroiminium salts (amide chlorides) 3 derived from
the amides of N-aroyl-N-methylamino acid esters 2
(Scheme 1), by their reaction with oxalyl chloride.
O
Cl
Cl
(COCl)2
R1
CO2R2
R1
CO2R2
R1
CO2R2
N
N
N
Me
Me
Me
4
3
2
Scheme 1.
Keywords: Azomethine ylides; Chloroiminium salts; Cycloadducts; Pyrroles; Furanones.
q Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tetlet.2003.11.095
* Corresponding author. Tel.: +44-191-515-2600; fax: +44-191-515-2502; e-mail: paul.groundwater@sunderland.ac.uk
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.095

944
R. J. Anderson et al. / Tetrahedron Letters 45 (2004) 943–946
A possible mechanism for the formation of furanone
16 is given in Scheme 3, in which the first step is
attack of the ester carbonyl oxygen of 2a on (COCl)2,
followed by the enolisation of the highly acidic methyl-
ene group of the oxonium ion 10. The subsequent
intramolecular cyclisation of enol 11 results in another
oxonium ion 12. The loss of methyl chloride leads to the
keto-anhydride 13, the tautomer 14 of which reacts with
(COCl)2 affording the disubstituted maleic anhydride 15.
Finally, the reaction between 15 and a third molecule of
oxalyl chloride gives furanone 16 (Scheme 3).
O
OEt
(COCl)2
CHCl3
Cl
Cl
Ph
N
CO2Et
Ph
N
2c
(R1 = Ph,
2 = Et)
Me
Me
R
4
3
TMSCN
CsF
CH3CN
CN
Cl
Ph
Ph
Ph
O
O
O
In order to prevent this chlorination (Scheme 3), the
reactions of the methyl esters of the amides 2 with oxalyl
chloride were repeated in dry dichloromethane, in the
presence of DMAD, and the pyrrole products 17 of the
trapping of the azomethine ylide 4 with DMAD, fol-
lowed by aromatisation (1,4-dehydrochlorination), were
obtained in poor to reasonable yields (Scheme 4 and
Table 1).
N
N
N
OEt
OEt
OEt
Me
Me
Me
5
6
CO2Me
CO2Et
CO2Me
O
N
OEt
MeO2C
Ph
MeO2C
CN
DMAD
H
Ph
Ph
N
CO2Et
Next, a series of substituted N-aroyl-N-methylbenzyl-
amines 18 were prepared and reacted with oxalyl chlo-
ride in the presence of DMAD in dry chloroform under
reflux, to give the pyrroles 21 (Scheme 5), in moderate
yields (Table 2). The structures of the pyrroles 21 were
again established by 1H and 13C NMR spectroscopy, IR
spectroscopy and high resolution mass spectrometry.
N
NC
Me
Me
Me
7
9
8
Scheme 2.
Initial attempts to carry out this reaction with the
methyl esters of amides 2a–c in dry chloroform failed so
it was decided to monitor the course of the reaction by
1H NMR spectroscopy, which showed that heating
the methyl ester 2a at 50 ꢁC was insufficient, since only
the signals of the starting materials were observed, where-
as refluxing the solutions led to unexpected results––
refluxing amide 2a with (COCl)2 in dry chloroform gave
furanone 16 in 88% yield (Scheme 3).
As before, formation of pyrrole 21 is proposed to pro-
ceed through formation of the chloroiminium salt 19,
which is subsequently deprotonated, affording azome-
thine ylide 20. This 1,3-dipole is stabilised by delocali-
sation of the negative charge into the aromatic ring of
the benzyl function. The subsequent cycloaddition with
DMAD leads to pyrrole 21 after 1,4-dehydrochlorina-
tion (Scheme 5). The delocalisation of the negative
charge depends upon the substituent (R2) in the para-
position of the benzyl function in the initial amide 18
The structure of furanone 16 was unequivocally es-
tablished by single crystal X-ray diffraction (Fig. 1).11
O
O
O
O
O
Cl
O
O
Cl
w
(COCl)2
O
O
N
N
CO2Me
N
Me
O
Me
2a
Me
OMe
MeO
Me
MeO
MeO
11
10
w
O
O
O
O
O
HO
O
N
O
N
O
14
O
O
O
O
N
Me
O
Me
O
Me
O
MeO
MeO
Me
MeO
12
13
(COCl)2
Cl
Cl
O
O
Cl
Cl
Cl
O
(COCl)2
MeO
O
O
N
N
Me
Me
O
MeO
16
15
Scheme 3.

R. J. Anderson et al. / Tetrahedron Letters 45 (2004) 943–946
Table 2. Yields of pyrroles 21 from amides 18
945
Entry
R1
R2
% Yield
a
b
c
H
NO2
NO2
NO2
Cl
31
29
29
17
11
NO2
MeO
H
d
e
H
H
and the expected stability of the azomethine ylides 20
correlates with the yields of the pyrroles. A substituent
in the para-position of the benzoyl group (R1) does not
appear to influence the yield of the pyrroles 21. One
possible explanation of this fact is that resonance
structure 20a is a stronger contributor to the electronic
distribution in the azomethine ylide than resonance
structure 20b.
Figure 1. Single crystal X-ray structure of furanone 16 (50% thermal
ellipsoids).
Cl
Cl
N
N
Me
Me
R1
R2
R1
R2
20a
20b
MeO2C
CO2Me
CO2Me
O
(COCl)2
DMAD
Once again, it was found that the polarity of the solvent
has an impact on the yield of the pyrrole. For example,
performing the reaction of amide 18a with oxalyl chlo-
ride in dry DCM afforded the pyrrole 21a in an
improved yield of 47%. This may be due to either the
deprotonation step in the suggested mechanism (see
Scheme 5) being more favourable in more polar sol-
vents, or the azomethine ylide being stabilised by better
solvation by the dichloromethane.
N
CO2Me
N
Me
Me
R1
R1
17a-c
2a-c
Scheme 4.
Table 1. Yields of pyrroles 17 from amides 2 (R2 ¼ Me)
Entry
R1
% Yield (RT)
% Yield (reflux)
In summary, azomethine ylides 4 and 20 (derived from
N-aroyl-N-methylamino acid esters 2 or N-aroyl-N-
methylbenzylamines 18) can be prepared in a simple
one-step procedure, via chloroiminium salts, 3 and 19,
and trapped with DMAD to give pyrroles, 17 and 21.
Excessive heating of this reaction leads to unexpected
products. For example, the amino acid methyl ester 2a
reacted with oxalyl chloride in the absence of DMAD to
give the novel trichlorofuranone 16.
a
b
c
p-CH3OC6H4
p-O2NC6H4
Ph
15
21
12
26
64
28
O
Cl
(COCl)2
CHCl3
N
N
Me
Me
19
R1
R2
R1
R2
18
References and notes
MeO2C
CO2Me
1. (a) Tsuge, O.; Kanemasa, S. In Advances in Heterocyclic
Chemistry; Katritzky, A. R., Ed.; Academic: 1989, Vol. 45,
p 232–349 (b) Grigg, R.; Sridharan, V. In Advances in
Cycloaddition; Curran, D. P., Ed.; JAI: 1993, Vol. 3, p 161.
2. (a) Taylor, E. C.; Turchi, I. J. Chem. Rev. 1979, 79, 181;
(b) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1980, 19, 947.
3. (a) Arany, A.; Groundwater, P. W.; Nyerges, M. Tetra-
hedron Lett. 1998, 38, 3267; (b) Arany, A.; Bendell, D.;
Groundwater, P. W.; Garnett, I.; Nyerges, M. J. Chem.
Soc., Perkin Trans. 1 1999, 2605.
Cl
N
Me
R1
R2
20
MeO2C
CO2Me
MeO2C
Cl
CO2Me
H
4. Marx, K.; Eberbach, W. Tetrahedron 1997, 51, 14687.
5. Groundwater, P. W.; Nyerges, M. In Advances in Hetero-
cyclic Chemistry; Katritzky, A. R., Ed.; Academic: 1999,
Vol. 73, p 97–129.
N
N
Me
Me
R1
R2
R1
R2
6. (a) Rizzi, G. P. J. Org. Chem. 1970, 35, 2069; (b) Grigg,
R.; Idle, J.; McMeekin, P.; Vipond, D. J. Chem. Soc.,
Chem. Commun. 1987, 49.
21
Scheme 5.

946
R. J. Anderson et al. / Tetrahedron Letters 45 (2004) 943–946
7. (a) Heine, H.; Peavy, R. Tetrahedron Lett. 1965, 3123; (b)
Huisgen, R.; Scheer, W.; Mader, H. Angew. Chem., Int.
Ed. Engl. 1969, 8, 602.
8. (a) Grigg, R.; Gunaratne, H. Q. N.; Kemp, J. J. Chem.
Soc., Perkin Trans. 1 1984, 41; (b) Grigg, R.; Gunaratne,
H. Q. N. Tetrahedron Lett. 1983, 24, 4457; (c) Grigg, R.
Chem. Soc. Rev. 1987, 16, 89.
9. Vedejs, E.; Grissom, J. W. J. Org. Chem. 1988, 53, 1876.
10. 8 White solid (0.052 g, 26%), mp 112–113 ꢁC (found: MHþ
373.139, calcd for C19H21N2O6: MHþ, 373.139); mmax
(KBr)/cmꢀ1 1741 and 1711 (ester C@O); dH (300 MHz;
CDCl3) 1.36 (3H, t, J 7.1, CH3CH2), 2.45 (3H, s, NCH3),
3.64 (3H, s, 4-CO2CH3), 3.86 (3H, s, 3-CO2CH3), 4.27–
4.40 (2H, m, OCH2CH3), 4.97 (1H, s, 2-H), 7.41–7.43 (3H,
m, Ar-H), 7.58–7.61 (2H, m, Ar-H); dC (75 MHz; CDCl3)
14.7 (C3CH2), 31.7 (NC3), 53.0 (CH3, 4-CO2C3), 53.3
(CH3, 3-CO2C3), 62.5 (OC2CH3), 72.3 (CH, C-2), 75.0
(quat, C-5), 115.5 (quat, CN), 127.4 (2 · CH), 129.2
(2 · CH), 130.1 (CH), 135.3 (quat, C-10), 139.0 (quat, C-
3), 139.5 (quat, C-4), 161.5 (quat, C@O), 162.4 (quat,
C@O), 168.0 (quat, C@O). The configuration of 8 has not
been established. 9 White solid (0.028 g, 15%), mp 117–
118 ꢁC (found: MHþ 346.129, calcd for C18H20NO6: MHþ,
346.1285); dH (270 MHz; CDCl3) 1.35 (3H, t, J 7.1,
CH3CH2), 3.60 (3H, s, OCH3), 3.66 (3H, s, NCH3), 3.95
(3H, s, OCH3), 4.31 (2H, q, J 7.1, OCH2CH3), 7.28–7.31
(2H, m, Ar-H), 7.45–7.50 (3H, m, Ar-H); dC (75 MHz;
CDCl3) 14.5 (CH3CH2), 34.9 (NCH ), 51.8 (OCH3), 53.1
3
(OCH3), 61.4 (OCH2CH3), 112.0 (quat, C-3 or C-4), 120.6
(quat, C-2), 126.0 (quat, C-3 or C-4), 128.7 (2 · CH), 129.8
(CH), 130.3 (quat, C-10), 130.7 (2 · CH), 143.6 (quat, C-5),
160.3 (quat, C@O), 163.4 (quat, C@O), 167.2 (quat,
C@O).
11. C13H10Cl3NO4, M ¼ 350:57, monoclinic, a ¼ 7:3651ð3Þ,
ꢀ
b ¼ 20:2855ð10Þ, c ¼ 10:1981ð5Þ A, b ¼ 103:019ð3Þꢁ, V ¼
3
ꢀ
1484:5ð1Þ A , T ¼ 120ð2Þ K, colourless crystal (0.42 · 0.28 ·
0.15 mm),spacegroupP21=n(no14),Z ¼ 4,l ¼ 0:63 mmꢀ1
.
¼
Reflections, 20,080 in number (4328 independent, Rint
0:031) with 60ꢁ were measured on a CCD area detector and
corrected for absorption. The structure was solved by direct
methods and refined on F 2 of all data by full-matrix least
squares (non-H atoms in anisotropic, H in isotropic approx-
imation) to R ¼ 0:034 [3820 reflections with I > 2rðIÞ] and
wRðF 2Þ ¼ 0:092 (all data), using SHELXL-97 software.
Full structural data have been deposited with the Cam-
bridge Crystallographic Data Centre, CCDC-221744.