An unusual ring expansion from the Zav'yalov pyrrole synthesis: Formation of oxacino[2,3-c]pyrroles

Article abstract of DOI:10.1039/a809033e

Enamino acids 2 and 5 undergo a facile cyclisation to afford the pyrrole 3 and isoindole 6 ring systems; a novel two atom ring expansion ensues when derivatives 5b,d are subjected to the cyclisation conditions, resulting in the formation of the new oxacin

Full text of DOI:10.1039/a809033e

An unusual ring expansion from the Zav’yalov pyrrole synthesis: formation of
oxacino[2,3-c]pyrroles
Christopher D. Gabbutt,a John D. Hepworth,a B. Mark Heron,*a Mark R. J. Elsegoodb and William Cleggb
a Department of Chemistry, University of Hull, Hull, UK HU6 7RX. E-mail: b.m.heron@chem.hull.ac.uk
b Department of Chemistry, University of Newcastle, Newcastle upon Tyne, UK NE1 7RU. E-mail: w.clegg@ncl.ac.uk
Received (in Liverpool, UK) 18th November 1998, Accepted 22nd December 1998
Enamino acids 2 and 5 undergo a facile cyclisation to afford
the pyrrole 3 and isoindole 6 ring systems; a novel two atom
ring expansion ensues when derivatives 5b,d are subjected to
the cyclisation conditions, resulting in the formation of the
new oxacino[2,3-c]pyrrole system, the structure of which is
confirmed by X-ray crystallography.
192.8 (CNO), respectively, when compared to the isoindoles 6a
and b. Elemental analysis and HRMS for 7 and 8 confirmed that
both contained an additional CO2 unit. The structure of 8‡ was
established as the oxacino[2,3-c]pyrrole by X-ray crystallog-
raphy (Fig. 1). The 1H NMR spectrum of 8§ displayed marked
broadening of the signals associated with the aliphatic functions
indicating that the molecule is undergoing conformational
interconversion. The resolution of the spectrum was improved
when it was recorded at low temperature (253 K).
The pyrrole unit1 occurs in a diversity of natural products,
pharmaceutical agents and polymers.2 The synthesis of this ring
system has been the subject of intense activity and has featured
in a number of review articles.3,4 Despite such activity, routes to
2,5-unsubstituted pyrroles and routes which involve the forma-
tion of the C-2–C-3 bond are particularly rare.4 There are
several routes to pyrroles that utilise 1,3-dicarbonyl compounds
and a-amino acids as the starting components, but in all of these
examples the resulting pyrrole retains a carboxylate function at
C-2.5 In 1973, Zav’yalov reported an efficient route to the
pyrrole system (Scheme 1),6 which has been scarcely utilised in
the last 25 years.7 We now report the application of this
methodology to the synthesis of some novel substituted pyrroles
and fused analogues and describe a unique ring expansion
reaction to afford the new oxacino[2,3-c]pyrrole system.
Dimethylaminomethylene ketones 1 and 4 were obtained by
standard protocols.8 Their addition–elimination reaction with a
range of a-amino acids in aq. EtOH containing NaOAc gave the
crystalline enamino acids 2 and 5 in high yields (Scheme 2).†
Heating a solution of enamino acids 2a,b and 5a,c in Ac2O
containing Et3N proceeded with the instantaneous formation of
a deep red colour which was accompanied by the vigorous
evolution of CO2 (lime water bubbler) as the internal reaction
temperature reached reflux. In the case of 5b,d, however,
evolution of CO2 was only slight. After ca. 30 min the reaction
mixture was allowed to cool and was subjected to an aqueous
work-up. TLC examination of the crude reaction mixtures
typically revealed the presence of a fast running major
component contaminated with dark base line material rendering
initial purification by flash chromatography easy.
It is evident from the 1H NMR data that the eight-membered
ring of 8 is in equilibrium between a number of conformers.10
However, 7 does not display this behaviour, probably as a
R1
R1
EtO2C
i
EtO2C
O
O
NHCH(R2)CO2H
NMe2
2a R1 = Me, R2 = Ph (73%)
b R1 = OEt, R2 = H (69%)
1a R1 = Me
b R1 = OEt
ii
R3
EtO2C
R1
O
R3
NMe2
R2
N
O
Ac
4a R3 = H
b R3 = Me
3a R1 = Me, R2 = Ph (48%)
b R1 = OAc, R2 = H (57%)
i
R2
R3
R3
R3
ii
O
R3
N
Ac
NHCH(R2)CO2H
O
OAc
The cyclisation of enamino acid 2a proceeded with the
expected regioselectivity of cyclisation on to the more electro-
philic ketonic carbonyl group rather than the ester function to
afford a single pyrrole, 3a, confirmed by the presence of signals
in its 1H NMR spectrum associated with the ethyl ester moiety.
Of particular note is the efficient preparation of 3b. Existing
routes to compounds of this type are often laborious and low
yielding.3c,f,h,4 Formation of the pyrroles 3 and isoindoles 6 and
9 is chemoselective, and in no instances did we observe the
presence of any a-amino ketones resulting from a Dakin–West
reaction.9
5a R3 = H, R2 = Ph (83%)
b R3 = H, R2 = (CH2)2SMe (85%)
c R3 = Me, R2 = Ph (81%)
d R3 = Me, R2 = Bui (94%)
6a R3 = H, R2 = Ph (69%)
b R3 = Me, R2 = Ph (72%)
O
O
(CH2)2SMe
Ac
Bui
ii
O
O
N
N
Ac
or
Me
Me
OAc
7 (45%)
O
The 13C NMR spectra of 7 (from 5b) and 8 (from 5d)
contained an additional low field signal at d 168.9 (OAc) and
8 (50%)
(CH2)2CO2Me
Ac
R
O
N
Ac2O
NH(CHR)CO2–K+
NAc
∆, 2 h
9 (64%)
R = H, Me
Scheme 2 Reagents and conditions: i, a-amino acid (1.05 equiv.)
NaOAc.3H2O (1.05 equiv.) eq. EtOH, D; ii, Ac2O, Et3N (1.1 equiv.), D.
Scheme 1
Chem. Commun., 1999, 289–290
289

In conclusion, this pyrrole synthesis is highly versatile and
permits access to 2,5-unsubstituted pyrroles, 3-hydroxypyrrole
derivatives, isoindoles and the novel oxacino[2,3-c]pyrroles.
We thank the EPSRC for the provision of a mass spectrome-
try service at the University of Wales, Swansea.
Notes and references
† All new compounds were fully characterised by 1H and 13C NMR, HRMS
and elemental analyses.
¯
‡ Crystal data for 8: C17H23NO4, M = 305.36, triclinic, space group P1, a
= 7.7540(11), b = 8.8328(12), c = 12.476(2) Å, a = 78.530(14), b =
89.250(12), g = 81.025(9)°, U = 827.0(2) Å3, Dc = 1.226 g cm23, Z = 2,
Cu-Ka radiation (l = 1.54184 Å), m = 0.71 mm21, T = 160 K, R1 =
0.0471 (F2 > 2s), wR2 = 0.1095 (all data) for 2778 unique data and 205
parameters. CCDC 182/1130. Crystallographic data is available in CIF
format from the RSC web site, see: http://www.rsc.org/suppdata/cc/
1999/289/
Fig. 1 X-Ray crystallographic structure of the oxacino[2,3-c]pyrrole 8.
consequence of the rigidity imparted to the ring by the enol
acetate function.
§ Selected data for 8: from 5d (49.5%) after elution from silica with 40%
Scheme 3 depicts a possible mechanism for the formation of
the isoindoles 6 and oxacinopyrrole 8. It is well established that
the acylation of N-substituted amino acids proceeds with the
formation of mesoionic 1,3-oxazolium-5-olates (munchnones)
and evidence has accrued that these are tautomeric with N-acyl
ketenes.11 The mesoionic heterocycle 10 may react by two
distinct pathways. We propose that, when R = phenyl, the
extended conjugation imparts stability to the munchnone
tautomer which then attacks the proximal CNO group. The
alkoxide species thus generated forms the lactone 11 with
concomitant oxazole ring cleavage. Cycloreversion of CO2 and
subsequent O-acylation completes the route to the dihydro-
isoindoles 6a,b. Conversely, 10 is destabilised when R = alkyl
and the munchnone undergoes ring–chain tautomerism to the N-
acyl ketene 12. Intramolecular acylation of the enamine
function affords the spirocycle 13. Oxetane ring formation and
subsequent ring cleavage of 14 effects the ring expansion to the
oxacinopyrrole system. It is noteworthy that the formation of
the oxacinopyrroles only occurs with the combination of an a-
alkyl amino acid and a cyclohexane-1,3-dione; replacement of
either one of these components results in the formation of the
pyrrole or isoindole as, for example, 9 which is derived from
2-hydroxymethylene-1-tetralone and glutamic acid 5-methyl
ester.
EtOAc in hexane, as colourless cubes from EtOAc–hexane, mp
=
152.5–153.5 °C, nmax(KBr)/cm21 2962, 1766, 1742, 1670, 1594, 1524,
1274, 1189 cm21; dH(CDCl3, 253 K) 0.82 (3H, d, J 6.6, CHCH3), 0.94 (3H,
d, J 6.6, CHCH3), 1.07 (3H, s, 7-CH3), 1.27 (3H, s, 7-CH3), 1.87 [1H, m, J
6.6, CH(CH3)2], 2.25 (1H, d, J 12.3, CH2), 2.37 (1H, d, J 12.3, CH2),
2.64–2.70 [1H, m, CH2CH(CH3)2], 2.65 (3H, s, NAc), 2.79–2.83 [1H, m,
CH2CH(CH3)2], 2.92 (1H, d, J 12.3, CH2), 2.99 (1H, d, J 12.3, CH2), 7.70
(1H, s, 1-H); dC(CDCl3, 299 K) 22.1, 23.5, 28.2, 29.4, 33.2, 34.6, 42.5, 53.4,
120.0, 122.3, 126.5, 137.4, 169.0, 169.4, 192.8. Found C, 66.85; H, 7.60; N,
4.55; M+ 305.1627. C17H23NO4 requires C, 66.85; H, 7.60; N, 4.60%; M+
305.1627.
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O
O
R
R
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O
O
R
–CO2
NAc
N
N
Ac
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OAc
O
O
6b R = Ph
11
O
O
O
O
R
O
C
O
R
O
R
N
N
N
Ac
O
O
Ac
O
10
12
13
O–
O
R
O
N
O
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NAc
R
O
O
Ac
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8 R = Bui
Scheme 3
14
Communication 8/09033E
290
Chem. Commun., 1999, 289–290