Unusual product from the reaction of 2-diazo-1-[5-(4-methoxybenzoyl)-2,3- dihydropyrrolizin-1-yl]ethanone with rhodium (II) acetate

Article abstract of DOI:10.3184/030823407X268944

The rhodium(II)-catalysed reaction of the diazoketone derived from 5-(4-methoxybenzoyl)-2,3-dihydropyrrolizin-1-carboxylic acid (anirolac) did not give the expected intramolecular cyclisation product but afforded the 2,3-dihydropyrrolizin-1-one only an el

Full text of DOI:10.3184/030823407X268944

670 RESEARCH PAPER
NOvEMBER, 670–672
JOURNAL OF CHEMICAL RESEARCH 2007
Unusual product from the reaction of 2-diazo-1-[5-(4-methoxybenzoyl)-
2,3-dihydropyrrolizin-1-yl]ethanone with rhodium (II) acetate
Erick Cuevas-Yañeza*, Simón Hernández-Ortegab, Aydeé Fuentes-Benitesa,
Carlos González-Romeroa and Raymundo Cruz-Almanzab†
aDepartamento de Química Orgánica, Facultad de Química, Universidad Autónoma del Estado de México. Paseo Colón esq.
Paseo Tollocan, 50120, Toluca, Mexico
bInstituto de Química, UNAM. Circuito Exterior, Ciudad Universitaria, Coyoacán, 05419, México, D.F.
The rhodium(II)-catalysed reaction of the diazoketone derived from 5-(4-methoxybenzoyl)-2,3-dihydropyrrolizin-
1-carboxylic acid (anirolac) did not give the expected intramolecular cyclisation product but afforded the
2,3-dihydropyrrolizin-1-one only an elimination product. X-ray studies confirmed the structure.
Keywords: anirolac [5-(4-methoxybenzoyl)-2,3-dihydropyrrolizin-1-carboxylic acid], pyrrole, diazoketone, rhodium (II) acetate,
carbenoid
The intermolecular reactions of carbenes with electron-rich
pyrroles are well known processes, with applications in the
C-alkylation of pyrroles for the synthesis of hygrine
derivatives.1 Similar intramolecular carbenoid insertions at
C-2 of pyrroles have been described in the literature, and these
reactions have been used in the synthesis of some indolizine-
based natural products.2 In contrast, the insertion of carbenoids
into the C-3H bond of pyrroles has rarely been documented.3
In connection with other synthetic investigations, some time
ago we initiated studies on the insertion of a-ketocarbenoids
into the C-3H bond of pyrroles and we have described the
efficient conversion of 2-pyrrolyl-a-diazo-b-ketoesters
and a-diazoketones into the corresponding bicyclic 5 and
6-membered ketones.4
Compounds 1, 2 and 3 were characterised by conventional
spectroscopic techniques. Since the bicylcic compound 3 was
a crystalline solid, it was studied by X-ray crystallography.
The structure of this compound is shown in Fig. 1 and some
important crystallographic data are given in Tables 1 and 2.
The X-ray study revealed some interesting features of
compound 3. First, the study confirmed that the product
structure which lost a two-carbon chain compared to the
original diazoketone 2; this agrees with prior NMR and
MS analyses, specially NMR and MS. In addition, an almost
planar bicyclic system of pyrrolizine is observed, where
the positions 2- and 5- of pyrrole moiety are substituted by
carbonyl groups, unlike molecule 2 which is substitued at C-2
by an alkyl group.
As a continuation of these studies, we attempted to
extend this methodology to pyrrolizine rings. We believed
that carbenoid insertions on pyrrolizines could be used for
the synthesis of strained azatriquinanes5 which are closely
related to the fenestranes.6 A potentially good starting
material to achieve this purpose is 5-(4-methoxybenzoyl)-2,3-
dihydropyrrolizin-1-carboxylic acid (anirolac) (1), a member
of the ketorolac group of analgesics, the synthesis of which has
been described previously.7 We found an alternative collateral
reaction which did not have a precedent in the pyrrole series
and which occurs instead of the carbenoid insertion. The
results in this area are now reported.
To the best of our knowledge, this is the first example of
a carbenoid extrusion from a pyrrole moiety. Although the
reaction mechanism is not clear, presumably this proceeds
via
a
carbenoid rearrangement10 and subsequent ipso
substitution at C-2 in the pyrrole ring.2e Note that this kind
of carbenoid rearrangements occurs only in pyrroles with
electron withdrawing groups, whereas electron-rich pyrroles
give carbenoid insertion products. On the other hand, It is
We have prepared the diazoketone 2, derived from anirolac 1
(Scheme 1). The carboxylic acid 1 did not give the desired
diazoketone using the coventional preparative method
through the acid chloride8 or the mixed carbonic–carboxylic
anhydride.2e Therefore, we used another method developed
by our group.9 Treatment of anirolac 1 with an equimolar
amount of triphenylphosphine, a slight excess of NBS
(1.2 equiv) and followed by excess ethereal diazomethane
gave the diazoketone 2 in 48% yield.
Exposure of diazoketone 2 to catalytic amounts of rhodium
(II) acetate in dichloromethane solution at room temperatures
afforded the bicyclic compound 3 in 45% yield (Scheme 2).
Fig. 1
H3CO
H3CO
O
O
1)Ph3P, NBS, 0 °C
OH
N
N
2) CH2N2
O
O
N2
2
1
Scheme 1
* Correspondent. E-mail: ecuevas@uaemex.mx
† Deceased
PAPER: 07/4920

JOURNAL OF CHEMICAL RESEARCH 2007 671
Table 1 Crystal data for compound 3
Table 2 Selected bond distances (Å) and angles (°) for
compound 3
Crystal data
Empirical formula
C15H13NO3
Bond
Distance (Å)
1.359(3)
1.397(3)
1.381(4)
1.378(3)
1.357(3)
1.445(4)
1.513(4)
1.215(3)
1.527(3)
1.469(3)
1.468(4)
1.487(3)
1.228(3)
1.386(3)
Formula weight
255.26
N(1)–C(2)
C(2)–C(3)
C(3)–C(4)
C(4)–C(5)
N(1)–C(5)
C(5)–C(6)
C(6)–C(7)
O(1)–C(6)
C(7)–C(8)
N(1)–C(8)
C(2)–C(9)
C(9)–C(10)
O(2)–C(9)
C(10)–C(11)
Crystal colour
Colourless needle
Orthorhombic
Pbca
Crystal system
Space group
a
11.323(1) a = 90°
7.8966(7) b = 90°
27.733(2) g = 90°
2479.6(4)
b
c,
Volume, cm3
Z
8
Density (calcd.),g/cm3
Absorption coefficient,
(mm-1)
1.368
0.096
1072
F(000)
Crystal size (mm)
0.42 ¥ 0.10 ¥ 0.08
Data collection
Temperature, K
Radiation, l ( )
q min, max,°
Bond
Angle (°)
106.3(2)
120.9(2)
108.5(2)
109.9(2)
106.8(2)
116.4(6)
109.3(2)
106.8(2)
106.9(2)
102.52(19)
128.0(3)
125.1(3)
114.4(2)
132.7(2)
291(2)
N(1)–C(2)–C(3)
N(1)–C(2)–C(9)
C(4)–C(3)–C(2)
C(5)–N(1)–C(2)
C(5)–C(4)–C(3)
N(1)–C(5)–C(6)
N(1)–C(5)–C(4)
C(5)–C(6)–C(7)
C(6)–C(7)–C(8)
N(1)–C(8)–C(7)
O(1)–C(6)–C(5)
O(1)–C(6)–C(7)
C(5)–N(1)–C(8)
C(3)–C(2)–C(9)
0.71073
2.32,24.99
–13<h<13,
–9 <k<9,
–32<l<32
18758
Index ranges
Reflections collected
Independent reflections
Observed reflects
[I>2.0s(1)]
2187(Rint = 0.0611)
R1 = 0.0589,wR2 = 0.1199
Refinement
Data-to-parameter ratio
R, wR2
2187/0/173
R1 = 0.0937,wR2 = 0.1345
1.001
G.O.F.
Largest diff. peak,
standard reflections every 97 reflections were used to monitor the
crystal stability. The structure was solved by direct methods, missing
atoms were found by difference-Fourier synthesis, and refined
on F2 by a full-matrix least-squares procedure using anisotropic
displacement parameters and using SHELX-97. Crystallographic
data for the structure reported in this paper have been deposited with
the Cambridge Crystallographic Data Centre (CCDC No.668508).
Copies of available materials can be obtained free of charge on
application to the Director, CCDC, 12 Union Road, Cambridge CB2
IEZ, UK (fax: (44) 01223 336033); e-mail: deposit@ccdc.ac.uk.
2-Diazo–1–[5-(4–methoxybenzoyl)–2,3–dihydropyrrolizin-1-yl]
ethanone (2): A precooled solution of N-bromosuccinimide (NBS,
0.21 g, 1.2 mmol) in THF (4 ml) in THF (5 ml) at 0°C was added
dropwise to a stirred solution of triphenylphosphine (0.262 g,
l mmol) and anirolac 1 (0.285 g, l mmol) under a nitrogen atmosphere.
The resulting mixture was stirred at 0°C under nitrogen atmosphere
for 15 min. The coolant was removed and the reaction mixture
was allowed to warm to room temperature for an additional
15 min. The reaction mixture was cooled to 0°C, then an ether
solution of diazomethane (5 mmol) from N–methyl-N-nitroso-4-
toluenesulfonamide (1.53 g, 7.14 mmol) was added; a vigorous
evolution of nitrogen occurred and the mixture was allowed to warm
to room temperature overnight. The solvent was removed in vacuo
and purification by column chromatography (SiO2, hexane/AcOEt
7:3) afforded diazocompound 2 as yellow oil (0.15 g, 48%). IR
hole,e-3
0.160,–0.163
possible that the product arises by auto-oxidation of the
initial diazocompound.11 The fission of a C–C bond with the
formation of a carbonyl group suggests that an oxidation is
taking place.
In conclusion, this report reveals
product which requires further experiments to elucidate the
mechanistic details of the reaction.
a novel reaction
Experimental
The starting materials were purchased from Aldrich Chemical Co.
and were used without further purification. Solvents were distilled
before use; ether and tetrahydrofuran (THF) were dried over sodium
using benzophenone as indicator. Diazomethane was prepared from
N-methyl-N-nitroso-p-toluenesulfonamide (Diazald®) using
a
minimum amount of water and ethanol as a co-solvent, and dried
over KOH pellets before use. Silica gel (230–400 mesh) and neutral
alumina were purchased from Merck. Silica plates of 0.20-mm
thickness were used for TLC. Melting points were determined with
a Fisher–Johns melting point apparatus and they are uncorrected.
1H and 13C NMR spectra were recorded using a varian Gemini 200,
the chemical shifts (d) are given in ppm relative to TMS as internal
standard (0.00). For analytical purposes the mass spectra were
recorded on a JEOL JMS-5X 10217 in the EI mode, 70 ev, 200°C
via direct inlet probe. Only the molecular and parent ions (m/z) are
reported. IR spectra were recorded on a Nicolet Magna 55-X FT
instrument. For the RX difraction studies, crystals of compound
3 were obtained by slow evaporation of a DMF solution, and the
reflections were acquired with a Nicolet P3/F diffractometer. Three
(CHCl3, cm-1) 2108, 1774; H NMR (CDCl3, 200 MHz) d 2.85 (m,
1
2H), 3.87 (s, 3H), 3.98 (t, 1H) 4.48 (m, 2H), 5.40 (s, 1H), 6.06 (d, 1H
J3-4 = 3.9 Hz), 6.83 (d, 1H, J4-3 = 3.9 Hz), 6.96 (d, 2H, J = 8.8 Hz), 7.85
(d, 2H, J = 8.8 Hz); 13C NMR (CDCl3, 50 MHz) d 31.7, 47.4, 47.8,
54.2, 55.3, 102.7, 113.4, 113.7, 124.0, 127.4, 131.0, 131.3, 131.6,
142.0, 162.4, 183.8, 192.3; MS [EI+] m/z (RI%); 309 [M] + (25), 281
[M-N2]+ (10), 240 [M- COCHN2]+ (100), 135 [CH3OC6H4CO]+ (85);
HRMS for C17H15N3O3 calcd. 309.1113, found 309.1011.
H3CO
H3CO
O
Rh2(OAc)2
CH2Cl2, R. T.
O
N
N
O
O
N2
2
3
Scheme 2
PAPER: 07/4920

672 JOURNAL OF CHEMICAL RESEARCH 2007
and R.L. Shriner, J. Am. Chem. Soc.,1933, 55, 3828; (j) C.D. Nenitzescu
and E. Solomonica, Chem Ber., 1931, 64, 1924.
5-(4-Methoxybenzoyl)-2,3-dihydropyrrolizin-1-one (3): A solution
of the diazocompound 2 (0.309 g, l mmol) in dry CH2Cl2 (5 ml)
was stirred with Rh2(OAc)4 (2 mg) under a nitrogen atmosphere at
room temperature. After 2 h, the mixture was evaporated in vacuo
and purified by column chromatography (SiO2, hexane/AcOEt 8 : 2)
to afford the compound 3 as white solid (0.11 g, 45%) m.p. 182°C,
2
(a)P. MullerandP. Polleaux, Helv. Chim.Acta, 1998, 81, 317;(b)C.W. Jefford
and J.B. Wang, Tetrahedron Lett., 1993, 34, 3119; (c) C.W. Jefford,
Q.TangandA.Zaslona,J.Am.Chem.Soc.,1991,113,3513;(d)C.W.Jefford,
Q. Tang and Zaslona,A. Helv. Chim. Acta, 1989, 72, 1749; (e) C.W. Jefford,
T. Kubota and A. Zaslona, Helv. Chim. Acta, 1986, 69, 2048;
(f) E. Galeazzi, A. Guzman, A. Piñedo, A. Saldaña, D. Torre and
J.M. Muchowski, Can. J. Chem., 1983, 61, 454.
A. Carpeta and M. Salim, Tetrahedron, 2000, 56, 8063.
E. Cuevas-Yañez, J.M. Muchowski and R. Cruz-Almanza, Tetrahedron,
2004, 60, 1505.
(a) v. Gelaso, J. Hansen and M. Mascal, TEOCHEM 1997, 392, 21;
(b) M. Mascal, N.M. Hext and O.v. Shishkin, Tetrahedron Lett., 1996, 37,
131; (c) T.J. Atkins, J. Am. Chem. Soc., 1980, 102, 6364; (d) J.M. Erhardt,
E.R. Grover and J.D. Wuest, J. Am. Chem. Soc., 1980, 102, 6365;
(e) A.G. Anderson and P.C. Wade, J. Org. Chem., 1978, 43, 54.
R. Keese, Chem. Rev., 2006, 106, 4787.
(a) J.M. Muchowski, Adv. Med. Chem., 1992, 1, 109; (b) J.M. Muchowski,
S.H. Unger, J. Ackrell, P. Cheung, G.F. Cooper, J. Cook, P. Gallegra,
O. Halpern, R. Koehler, A.F. Kluge, A.R. van Horn, Y. Antonio,
H. Carpio, F. Franco, E. Galeazzi, I. Garcia, R. Greenhouse,
A. Guzman, J. Iriarte, A. Leon, A. Peña, V. Perez, D. Valdez, N. Ackerman,
S.A. Ballaron, D.v. Krishna Murthy, J.R. Rovito, A.J. Tomolonis,
J.M. Young and W.H. Rooks II, J. Med. Chem., 1985, 28, 1037.
(a) J.N. Bridson and J. Hooz, Org. Synth. Coll.,1988, VI, 386; (b) L.T. Scott
and C.A. Sumpter, Org. Synth. Coll., 1993, VIII,196.
1
IR (CHCl3, cm-1) 1779, 1701; H NMR (CDCl3, 200 MHz) d 3.13
(t, 2H), 3.87 (s, 3H), 4.72 (t, 2H), 6.74 (d, 1H, J4-3 = 4.4 Hz), 6.99
(d, 2H, J3-4 = 4.4 Hz), 6.99 (d, 2H, J = 8.8 Hz), 7.87 (d, 2H, J = 8.8 Hz);
13C NMR (CDCl3, 50 MHz) d 38.9, 44.3, 55.4, 106.4, 113.7, 113.7,
123.6, 128.7, 130.6, 131.3, 131.8, 136.6, 163.2, 184.6, 191.2; MS
[EI+] m/z (RI%), 255 [M]+ (10), 135 [CH3OC6H4CO]+ (100); HRMS
for C15H13NO3 calcd. 255.0895, found 255.0898.
3
4
5
Financial support from SIEA-UAEMEX and CONACyT
(“repatriación” program grant for E.C.) is gratefully
acknowledged. The authors would like to thank Rocío Patiño,
Angeles Peña, Elizabeth Huerta, Javier Pérez and Luis Velasco
for the technical support
6
7
Received 29 October 2007; accepted 30 November 2007
Paper 07/4920
doi: 10.3184/030823407X268944
8
9
References
1
(a)S.MuthusamyandC.Gunanathan,Synlett.,2002,1783;(b)B.E.Maryanoff,
E. Cuevas-Yañez, M.A. Garcia, M.A. de la Mora, J.M. Muchowski and
R. Cruz-Almanza, Tetrahedron Lett., 2003, 44, 4815.
J. Org. Chem., 1982, 47, 3000; (c) B.E. Maryanoff, J. Org. Chem., 1979,
44, 4410; (d) B.E. Maryanoff, J. Heterocylc. Chem., 1977, 14, 177;
(e) J. R. Tammy, J. Grossman and F.W. Fowler, J. Am. Chem. Soc., 1972,
94, 6495; (f) J.F. Biellmann and M.P. Goeldner, Tetrahedron, 1971, 27,
2957; (g) H. Rapoport and E. Jorgensen, J. Org. Chem., 1949, 14, 664;
(h) F. Sorm, Collect. Czech. Chem. Commun., 1947, 17, 245; (i) W.E. Sohl
10 E. Cuevas-Yañez and R.J. Cruz-Almanza, Mex. Chem. Soc., 2004, 48, 46;
Chem. Abstr., 141, 349998.
11 (a) J.D. White and P. Hrnciar, J. Org. Chem., 1999, 64, 7271;
(b) K. Nakatani, K. Takada and S. Isoe, J. Org. Chem., 1995, 60, 2466.
PAPER: 07/4920