Intramolecular radical acylation of 2-methylsulfonylpyrroles

Article abstract of DOI:10.1016/S0040-4039(00)00342-7

Primary alkyl radicals generated (AIBN/Bu₃SnH) from 1-(2- or 3- haloalkyl)-2-methylsulfonylpyrroles are intercepted by CO (80 atm), and the acyl radicals so produced undergo intramolecular oxidative cyclization at the α-position, giving bicyclic ketones with retention or loss of the sulfonyl moiety. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00342-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3035–3038
Intramolecular radical acylation of 2-methylsulfonylpyrroles
a,∗
a,∗
b
Luis D. Miranda, Raymundo Cruz-Almanza, Abraham Alvarez-García and
c
Joseph M. Muchowski
a
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria Coyoacan,
Coyoacan D. F. 04510, Mexico
Facultad de Química, Universidad Autónoma del Estado de México, Toluca Edo. de Méx. 05000, Mexico
b
c
Roche Bioscience, 3401 Hillview Ave., Palo Alto, CA 94304-1320, USA
Received 26 January 2000; accepted 24 February 2000
Abstract
Primary alkyl radicals generated (AIBN/Bu3SnH) from 1-(2- or 3-haloalkyl)-2-methylsulfonylpyrroles are
intercepted by CO (80 atm), and the acyl radicals so produced undergo intramolecular oxidative cyclization at
the α-position, giving bicyclic ketones with retention or loss of the sulfonyl moiety. © 2000 Elsevier Science Ltd.
All rights reserved.
Keywords: acylation; acyl radical; carbonylation; pyrroles; pyrrolizidones; indolizidinones.
Radical carbonylation is a useful procedure for constructing asymmetric ketones when the carbon-
ylation process is coupled with the inter- or intramolecular addition of the acyl radical to a double
1
bond. Recently, we reported a process in which such a radical carbonylation was combined with an
2
intramolecular addition onto indole and pyrrole systems. It is well known that systems bearing a sulfone
3
a
group are excellent radical acceptors and undergo formal radical aromatic substitutions in which the
3
b–g
sulfone group is usually, although not always, lost.
Also, the addition step may, or may not, occur at
3
g
the ipso position. We describe herein our recent findings on the radical carbonylation and cyclization
of the N-2 and 3-haloalkyl-2-methylsulfonylpyrroles 1 (Scheme 1).
The AIBN/Bu SnH-mediated radical reaction of 1 with CO was examined with the expectation that
3
the acyl radical 3, derived from 2, would add intramolecularly to C-2 of the heteroaromatic system giving
4, which, upon aromatization by loss of the methylsulfonyl radical, would produce the bicyclic ketone 5.
The required methylsulfonylpyrrole derivatives were synthesized as reported before from known
4
2
-methylthiopyrrole (6) which was acylated under Vilsmeier–Haack conditions and oxidized to the
corresponding sulfone (Scheme 2). The sulfones were alkylated with the appropriate dihaloalkane.
The methylsulfonylpyrroles were subjected to standard radical carbonylation conditions,2 i.e. 0.02
M benzene solution of the substrate, at 95°C under CO pressure (80 atm), portionwise addition of
,5
∗
Corresponding author. Tel: 52 56 22 44 28; fax: 52 56 16 22 17; e-mail: raymundo@servidor.unam.mx (R. Cruz-Almanza)
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00342-7
tetl 16622

3
036
Scheme 1.
3
Scheme 2. Conditions: (i) MCPBA, dichloromethane, 0°C; (ii) 1,2-dibromoethane, NaH, DMF, 0°C; (iii) POCl ,
N-acetylmorpholine, 2 h, then AcONa aq. 3 h; (iv) 1-bromo-3-chloropropane, NaH, DMF, 0°C; (v) NaI, CH CN reflux 26
3
h
2
Bu SnH/AIBN at 1 h intervals. Under such conditions, compound 7 gave the expected pyrrolizidone
1
3
5
2a in good yield, and a small amount of the reductive dehalogenation product 13a. When the 5-acyl
compound 9 was submitted to the same reaction conditions (five additions/0.4 equiv.) the diketone 12b
and reduction product 13b were obtained in moderate and low yield, respectively (Eq. (1)).
(1)

3
037
The homologous compound 11a also gave the expected indolizidinone 15 in moderate yield and the
pyrrolizidine 14, resulting from competitive 5-exo cyclization of the alkyl radical, in low yield (Eq. (2)).
The formation of 16, the product derived from radical attack at C-5, is interesting, and has precedence in
oxidative intramolecular radical alkylation of 11a and related compounds.3a
(2)
When pyrrole 11b was subjected to the usual reaction conditions, 17 was obtained as the major
product. The desired diketone 18 was isolated in very low yield together with a small amount of
the unexpected sulfone 14 (Eq. (3)). This compound is formed by alkyl radical addition at C-5, and
subsequent aromatization by the interesting loss of an acetyl radical. When 11b was reacted with n-
Bu SnH/AIBN in the absence of CO, 17 and 14 were isolated in 74 and 23% yields, respectively.
3
(3)
Finally, it is noteworthy that 1-(2-iodoethyl)pyrrole 19, under the usual radical carbonylation condi-
tions, gave 3-(1-pyrrolyl)propionaldehyde 20 (60%), and no 12a, a result which is not surprising given
that the electronically analogous alkyl radicals fail to add to pyrroles not activated by one or more electron
3
a
attracting substituents.
(4)
In conclusion, four different methylsulfonylpyrrole derivatives were studied in a tandem carbonyla-
tion/cyclization radical process. The methodology described herein is of interest since pyrrolizidones
and indolizidinones were synthesized by a novel process, usually in good to moderate yields.
Acknowledgements
Financial support from CONACYT (No. 27997E) is gratefully acknowledged. We also wish to thank
R. Patiño, J. Pérez, W. Matus and H. Rios for technical support.
References
1
. (a) Ryu, I.; Sonoda, N. Angew. Chem., Int. Ed. Engl. 1996, 35, 1050–1066. (b) Ryu, I.; Sonoda, N.; Curran, D. P. Chem. Rev.,
996, 96, 177–194.
1

3
038
2
3
. Miranda, L. D.; Cruz-Almanza, R.; Pavón, M.; Alva, E.; Muchowski, J. M. Tetrahedron Lett. 1999, 40, 7153–7157.
. (a) Ryu, I.; Kuriyama, H.; Minakata, S.; Komatsu, M.; Yoon, J.-Y.; Kim, S. J. Am. Chem. Soc. 1999, 121, 12190. (b) Caddick,
S.; Aboutayab, K.; West, R. I. J. Chem. Soc., Chem. Commun. 1995, 1353–1354. (c) Caddick, S.; Aboutayab, K.; Jenkins, K.;
West, R. I. J. Chem. Soc., Perkin Trans. 1 1996, 675–682. (d) Caddick, S.; Aboutayab, K.; West, R. I. Synlett 1993, 231–232.
(e) Aldabbagh, F.; Bowman, R. Tetrahedron Lett. 1997, 21, 3793–3794. (f) Aldabbagh, F.; Bowman, R. Tetrahedron 1999,
5
5, 4109–4122. (g) Antonio, Y.; De la Cruz, E.; Galeazzi, E.; Guzman, A.; Bray, B. L.; Greenhouse, R.; Kurz, L. J.; Lusting,
D. A.; Maddox, M. L.; Muchowski, J. M. Can. J. Chem. 1994, 72, 15
4. Franco, F.; Greenhouse, R.; Muchowski, J. M. J. Org. Chem. 1982, 47, 1682–1988.
5
. Typical procedure: A benzene solution 0.02 M of methylsulfonylpyrrole (1 equiv.), n-Bu SnH (0.4 equiv.) and AIBN (0.4
3
equiv.) under 80 atm of CO was heated at 95–100°C for 1 h. After this time the autoclave was cooled to room temperature
and another 0.4 equiv. of n-Bu SnH and 0.4 equiv. of AIBN was added, and heated at 95–100° for 1 h under 80 atm of CO.
3
This process was repeated until no starting material was present. The reaction was monitored by TLC analysis. The autoclave
was cooled and the solvent removed under reduced pressure and the residue partitioned between hexane and acetonitrile.
The polar layer was washed with hexane (five times). After, the solvent was evaporated and the crude product was purified
by flash column chromatography (Hex-EtOAc). Selected spectral data of final products: compound 12a: IR (CHCl ):νmax
3
−
1
1
(
1
cm ) 1695.4, 2925.9, 2958.7; H NMR (CDCl
3
, 300 MHz): δ 3.09 (t, 2H, J=6.3 Hz), 4.31 (t, 2H, J=6.3 Hz), 6.52 (dd,
H, J7,6=4.05, J6,5=2.25 Hz), 6.73 (dd, 1H, J7.6=4.05, J7,5=1.05 Hz), 7.04 (dd, 1H, J7,5=1.05, J6,5=2.25 Hz); EM (IE) m/z:
):νmax (cm ) 1153.3, 1315.4, 2854.5, 2927.8, 2958.7; H NMR (CDCl , 200
3
MHz): δ 2.56 (q, 2H, J=7.25 Hz), 2.88 (t, 2H, J=7.4 Hz), 3.07 (s, 3H), 4.19 (t, 2H, J=7.14 Hz), 5.92 (d, 1H, J=3.89 Hz), 6.87
):νmax (cm ) 1694.8, 2856.4, 2889.2, 2873.8,
, 200 MHz): δ 2.28 (q, 2H, J=6.0 Hz), 2.6 (t, 2H, J=6.35 Hz), 4.12 (t, 2H, J=5.84 Hz), 6.26
dd, 1H, J8,7=4.1, J7,6=2.38 Hz), 6.86 (dd, 1H, J7.6=2.38, J8.6=1.56 Hz), 7.02 (dd, 1H, J8,7=4.1, J8,6=1.56 Hz); EM (IE) m/z:
+
−1
1
M =121 (100%). Compound 14: IR (CHCl
3
+
−1
(
2
(
d, 1H, J=3.89 Hz); EM (IE) m/z: M =185 (100%). Compound 15: IR (CHCl
931.7, 2962.5; H NMR (CDCl
3
1
3
+
−1
1
M =135 (100%). Compound 16 IR (CHCl
3
):νmax (cm ) 1110.9, 1334.7, 1694.8, 2856.4, 2927.8, 2960.6; H NMR (CDCl
3
,
2
1
2
00 MHz): δ 2.37 (q, 2H, J=6.22 Hz), 2.67 (s, 3H), 2.67 (t, 2H, J=6.15 Hz), 3.16 (s, 3H), 4.47 (t, 2H, J=5.85 Hz), 6.92 (d,
+
−1
H, J=4.2 Hz), 7.0 (d, 1H, J=4.2 Hz). EM: M m/z=213 (100%). Compound 12b: IR (CHCl ):νmax (cm ) 1645.8, 1695.4,
3
1
925.9, 2958.7; H NMR (CDCl
J=4.5 Hz), 7.06 (d, 1H, J=4.5 Hz); EM (IE) m/z: M =163 (100%). Compound 17: IR (CHCl
927.8, 2960.6; H NMR (CDCl
3
, 300 MHz): δ 2.50 (s, 3H,), 3.09 (t, 3H, J=5.85 Hz), 4.61 (t, 2H, J=5.85 Hz), 6.69 (d, 1H,
+
−1
3
):νmax (cm ) 1637.4, 2854.5,
1
2
3
, 300 MHz): δ 2.50 (q, 2H, J=7.35 Hz), 2.36 (s, 3H), 2.83 (t, 2H, J=7.2 Hz), 4.29 (t, 2H,
+
J=7.05 Hz), 5.88 (d, 1H, J=3.89 Hz), 6.92 (d, 1H, J=3.89 Hz); EM (IE) m/z: M =149 (60%). Compound 18: IR (CHCl
3
):νmax
−1
1
(
(
cm ) 1638.4, 1662.6, 2856.4, 2927.8, 2960.6; H NMR (CDCl
3
, 300 MHz): δ 2.28 (q, 2H, J=6.43 Hz), 2.51 (s, 3H), 2.64
+
t, 2H, J=6.22 Hz), 4.58 (t, 2H, J=5.89 Hz), 6.93 (d, 1H, J=4.38 Hz), 6.97 (d, 1H, J=4.38 Hz); EM (IE) m/z: M =177 (95%).