Nitrogen-philic cyclization of acyl radicals onto N = C bond. New synthesis of 2-pyrrolidinones by radical carbonylation/annulation method [17]

Full text of DOI:10.1021/ja980731n

5838
J. Am. Chem. Soc. 1998, 120, 5838-5839
Scheme 1
Nitrogen-philic Cyclization of Acyl Radicals onto
NdC Bond. New Synthesis of 2-Pyrrolidinones by
Radical Carbonylation/Annulation Method
Ilhyong Ryu,* Kazutoshi Matsu, Satoshi Minakata, and
Mitsuo Komatsu*
Department of Applied Chemistry
Faculty of Engineering, Osaka UniVersity
Suita, Osaka 565-0871, Japan
ReceiVed March 5, 1998
Radical cyclization reactions have become part of the repertoire
of the synthetic organic chemist, even for the synthesis of
nitrogen-containing heterocycles such as alkaloids.1,2 As for five-
membered ring formation, however, the strategic flexibility of
the systems reported thus far is still insufficient, since useful
strategies are limited to straightforward extensions of the 5-hex-
enyl radical cyclization in which a carbon atom at the 2, 3, or 4
position is replaced by a nitrogen atom (type 1, Scheme 1). In
pursuit of alternate radical cyclization methodologies for the
synthesis of nitrogen heterocycles, radical cyclizations onto N-C
double bonds have been examined by Takano,3 Warkentin,4
Bowman,5 and their co-workers (type 2, Scheme 1).6 Unfortu-
nately, this type of alkyl radical cyclization is often plagued by
poor selectivities giving mixtures of nitrogen-containing hetero-
cycles via 5-exo and 6-endo cyclizations. This suggests that the
rates of both modes of cyclization are too close to be controlled,
limiting the synthetic utility of this otherwise unique strategy.
It occurred to us that the introduction of a polar component
into radical cyclization chemistry would create new selective
cyclization systems. The use of an acyl radical which is δ+/δ-
polarized should increase the selectivity by matching with the
δ-/δ+ character of the N-C acceptor double bond.7 This would
create an “N-philic” acyl radical cyclization (eq 1). With this
(1) For leading reviews including radical cyclizations, see: (a) Beckwith,
A. L. J. Tetrahedron 1981, 37, 3073. (b) Hart, D. J. Science 1984, 223, 4639.
(c) Curran, D. P. Synthesis 1988, 417, 489. (d) Jasperse, C. P.; Curran, D. P.;
Fevig, T. L. Chem. ReV. 1991, 91, 1237. (e) Motherwell, W. B.; Crich, D.
Free-Radical Chain Reactions in Organic Synthesis; Academic: London, 1992.
(f) Beckwith, A. L. J. Chem. Soc. ReV. 1993, 143. (g) Curran, D. P.; Porter,
N.; Giese, B. Stereochemistry of Radical Reactions; VCH: Weinheim, 1996.
(h) Giese, B.; Kopping, B.; Go¨bel, T.; Dickhaut, J.; Thoma, G.; Kulicke, K.
J.; Trach, F. Org. React. 1996, 48, 301.
(2) For recent reviews, see: (a) Sibi, M. P.; Ji, J. In Progress in Heterocyclic
Chemistry; Suschitzky, H., Gribble, G. W., Eds.; Pergamon Press: Oxford,
1996; Vol. 8. (b) Renaud, P.; Giraud, L. Synthesis 1996, 913. (c) Fallis, A. G.
Brinza, I. M. Tetrahedron 1997, 53, 17543. For selected recent examples on
the synthesis of nitrogen heterocycles using radical cyclizations, see: (d)
Parsons, P. J.; Penkett, C. S.; Cramp, M. C.; West, R. I.; Warrington, J.;
Saraiva, M. C. Synlett 1995, 507. (e) Curran, D. P.; Josien, H.; Ko, S.-B.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2683. (f) Boger, D. L.; McKie, J. A.
J. Org. Chem. 1995, 60, 1271. (g) Sato, T.; Kugo, Y.; Nakaumi, E.; Ishibashi,
H.; Ikeda, M. J. Chem. Soc., Perkin Trans. 1 1995, 1801. (h) Minisci, F.;
Fontana, F.; Coppa, F.; Yan, Y. M. J. Org. Chem. 1995, 60, 5430. (i) Yuasa,
Y.; Ando, J.; Shibuya, S. J. Chem. Soc., Perkin Trans. 1 1996, 465. (j) Kizil,
M.; Lampard, C.; Murphy, J. A. Tetrahedron Lett. 1996, 37, 2511. (k)
Czernecki, S.; Ayadi, E.; Xie, J. Tetrahedron Lett. 1996, 37, 9193. (l) Clive,
D. L. J.; Coltart, D. M. Tetrahedron Lett. 1998, 39, 2519. (m) Aurrecoechea,
J. M.; Fernandez-Acebes, A. Synlett 1996, 39. (n) Della, E. W.; Knill, A. M.
J. Org. Chem. 1996, 61, 7529. (o) Robertson, J.; Peplow, M. A.; Pillai, J.
Tetrahedron Lett. 1996, 37, 5825. (p) Pandey, G.; Reddy, G. D.; Chakrabarti,
D. J. Chem. Soc., Perkin Trans. 1 1996, 219.
working hypothesis in mind, we examined the 5-exo/6-endo
cyclization of acyl radicals onto imine N-C bonds and found
that indeed the cyclization proceeds with complete selectiVity for
the nitrogen-philic mode (5-exo). We report herein a novel
synthesis of 2-pyrrolidinones using a 4 + 1 type carbonylation/
annulation method in which polarity is a key factor in controlling
the selectivity of the radical cyclization.
The reaction of 3-bromopropylimine 1a with carbon monoxide
was carried out in the presence of tributyltin hydride and a
catalytic amount of AIBN (2,2′-azobisisobutyronitrile) using an
autoclave equipped with a glass liner. Under the conditions
shown in eq 2, the desired 2-pyrrolidinone 2a was obtained in
81% yield after isolation by flash chromatography on silica gel.8
(3) (a) Takano, S.; Suzuki, M.; Kijima, A.; Ogasawara, K. Chem. Lett.
1990, 315. (b) Takano, S.; Suzuki, M.; Ogasawara, K. Heterocycles 1994,
37, 149.
(4) (a) Tomaszewski, M. J.; Warkentin, J. Tetrahedron Lett. 1992, 33, 2123.
(b) Tomaszewski, M. J.; Warkentin, J. J. Chem. Soc., Chem. Commun. 1993,
966. (c) Tomaszewski, M. J.; Warkentin, J.; Werstiuk, N. H. Aust. J. Chem.
1995, 48, 291.
(5) (a) Bowman, W. R.; Stephenson, P. T.; Terrett, N. K.; Young, A. R.
Tetrahedron Lett. 1994, 35, 6369. (b) Bowman, W. R.; Stephenson, P. T.;
Terrett, N. K.; Young, A. R. Tetrahedron 1995, 51, 7959. (c) Bowman, W.
R.; Stephenson, P. T.; Young, A. R. Tetrahedron 1996, 52, 11445.
(6) Nitrogen radical cyclizations constitute the third type of strategy for
the synthesis of nitrogen-containing heterocycles, see: (a) Beckwith, A. L.
J.; Maxwell, B. J.; Tsanakatsidis, J. Aust. J. Chem. 1991, 44, 1809. (b) Esker,
J. L.; Newcomb, M. AdV. Heterocycl. Chem. 1993, 58, 1. (c) Bowman, W.
R.; Clark, D. N.; Marmon, R. J. Tetrahedron 1994, 50, 1275. (d) Bowman,
W. R.; Clark, D. N.; Marmon, R. J. Tetrahedron 1994, 50, 1295. (e) Bowman,
W. R.; Broadhurst, M. J.; Coghlan, D. R.; Lewis, K. A. Tetrahedron Lett.
1997, 38, 6301. (f) Maxwell, B. J.; Tsanaktsidis, J. J. Am. Chem. Soc. 1996,
118, 4276. (g) Tokuda, M.; Fujita, H.; Suginome, H. J. Chem. Soc., Perkin
Trans. 1 1994, 777. (h) Togo, H.; Hoshina, Y.; Yokoyama, M. Tetrahedron
Lett. 1996, 37, 6129. (i) Zard, S. Z. Synlett 1996, 1148. (j) Kaim, L. E.; Meyer,
C. J. Org. Chem. 1996, 61, 1556. Also see a unique strategy based on radical
cyclization onto azide functionality: (k) Kim, S.; Joe, G. H.; Do, J. Y. J. Am.
Chem. Soc. 1994, 116, 5521. (l) Kizil, M.; Murphy, J. A. J. Chem. Soc., Chem.
Commun. 1995, 1409.
Acyl radical cyclization took place at the nitrogen atom selec-
tively. None of the corresponding six-membered ring product
resulting from “carbon-attack” was observed.
As shown in Table 1, this 2-pyrrolidinone synthesis by a 4 +
1 annulation method is quite general and the yields are good to
(7) The polar nature of acyl radical is acknowledged in the slow rate of
decarbonylation in polar solvents, see: (a) Tsentalovic, Y. P.; Fischer, H. J.
Chem. Soc., Perkin Trans. 2 1994, 729. (b) Linazzi, L.; Ingold, K. U.; Scaiano,
J. C. J. Phys. Chem. 1983, 87, 529. (c) Turro, N. J.; Gould, I. R.; Baretz, B.
H. J. Phys. Chem. 1983, 87, 531.
(8) For typical experimental procedure, see the Supporting Information.
S0002-7863(98)00731-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/02/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 23, 1998 5839
Table 1. Synthesis of 2-Pyrrolidinones by 4 + 1 Type
2-pyrrolidinone (run 6). The aminoalkyl radical resulting from
N-philic cyclization can be designed such that it will participate
in a second cyclization or an intermolecular C-C bond forming
reaction (runs 10, 11). The N-philic acyl radical cyclization can
be extended to the synthesis of 2-piperidinone by a 5 + 1 type
annulation method, and eq 3 demonstrates such an example.
Carbonylation/Annulationa
The origin of the unusual selectivity of the acyl radical
cyclization, contrasted with that of the corresponding alkyl radical
cyclizations,5 brings up intriguing mechanistic issues. It is well-
known that acyl radicals are considered to be nucleophilic in the
context of additions to C-C double bonds having electron-
withdrawing groups.12 In this regard, the present results seem to
be contradictory, since the only products observed come from
attack of the acyl radical at the nucleophilic nitrogen of the N-C
double bond. One rationale for this may be that the carbon-philic
attack (6-endo) is the kinetic process and it is followed by
subsequent isomerization to the thermodynamically more favor-
able R-amido radical (5-exo).13 However, the reaction of 1f
performed at a high tin hydride concentration (0.1 M) gave only
the product of 5-exo cyclization (2f), together with a comparable
amount of the uncyclized reduction product, suggesting that the
5-exo radical might be kinetically formed. A possible explanation
for the selective N-philic cyclization may involve nucleophilic
attack of nitrogen on the carbonyl group, which would give the
5-exo radical via a resonance organization. The role of nitrogen
lone pair on the selectivity should be evaluated properly, and we
are now addressing the mechanistic issues surrounding this new
type of cyclization.
In summary, we have demonstrated the first intramolecular
addition of acyl radicals onto N-C double bonds which occurs
with complete selectivity for N-philic cyclization. The products
of this cyclization, 2-pyrrolidinones, are capable of further
transformations, and this new reaction provides a basis for the
synthesis of five-membered nitrogen-containing heterocycles with
incorporation of carbon monoxide in the heterocyclic rings. We
believe that “polarity governed” radical reactions such as that
reported in this study will be a key feature in the design of
selective radical cyclization systems.
a Reaction conditions: For runs 1-5, 10, and 11, [RX] ) 0.015-
0.020 M, AIBN, CO (78-90 atm), Bu3SnH, C6H6, 80 °C, 2-3 h; for
runs 6-9, [RX] ) 0.017-0.022 M, V-40 (1,1′-azobis(cyclohexane-1-
carbonitrile)), CO (70-90 atm), Bu3SnH, C6H6, 110 °C, 3-5 h.
b Isolated yields by flash chromatography on silica gel. c By NMR.
d Obtained as a 53:47 mixture of diastereomers (by GC).
high. In every case, only one carbonylation product was observed
and neither the six-membered product9 nor the uncyclized
carbonylation/reduction product (aldehyde) was formed. The
absence of aldehydes suggests that the present N-philic acyl
radical/imine cyclization should be very rapid. Both aldimines
and ketimines can be used for this reaction, but the benzaldehyde
imine cyclization is complicated by the formation of the homo-
coupling dimers at the benzylic position, which causes chain
cleavage (run 4).10 This is presumably due to the very slow
hydrogen abstraction of the cyclized R-amido benzyl radical,
which is expected to be very stable. On the other hand, systems
containing aryl radicals do not tolerate aldiminyl C-H bonds
because of an undesirable radical translocation,11 but the use of
a ketimine-type substrate gives an excellent yield of 3,4-benzo-
Acknowledgment. We are grateful to Professor Noboru Sonoda and
Dr. Cathleen M. Crudden for helpful discussions during the course of
this work. I.R. thanks the Sumitomo Foundation for financial support.
This work was supported by Grant-in-Aid for Scientific Research from
the Ministry of Education, Science, Sports, and Culture of Japan.
Supporting Information Available: Experimental procedures and
spectral data for compounds 2a-j (33 pages, print/PDF). See any current
masthead page for ordering information and Web access instructions.
(9) This selective cyclization to form five-membered rings is generally not
observed in related acyl radical cyclizations onto CdC bonds. For leading
references on the kinetic and mechanistic studies, see: (a) Chatgilialoglu, C.;
Ferreri, C.; Lucarini, M.; Venturini, A.; Zavitsas, A. Chem. Eur. J. 1997, 3,
376. (b) Ryu, I.; Fukushima, H.; Okuda, T.; Matsu, K.; Kambe, N., Sonoda,
N.; Komatsu, M. Synlett 1997, 1265. For selective cyclization onto CdN,
see: (c) Brinza, I. M.; Fallis, A. G. J. Org. Chem. 1996, 61, 3580.
(10) The corresponding cyclization of all carbon systems onto styryl double
bonds does not suffer from this type of radical/radical coupling, see: (a)
Schwartz, C. E.; Curran, D. P. J. Am. Chem. Soc. 1990, 112, 9272. (b) Ryu,
I.; Kusano, K.; Hasegawa, M.; Kambe, N.; Sonoda, N. J. Chem. Soc., Chem.
Commun. 1991, 1018. (c) Nagahara, K.; Ryu, I.; Kambe, N.; Komatsu, M.;
Sonoda, N. J. Org. Chem. 1995, 60, 7384.
JA980731N
(12) For reviews involving acyl radicals, see: (a) Brown, C. E.; Neville,
A. G.; Rayner, D. M.; Ingold, K. U.; Lusztyk, J. Aust. J. Chem. 1995, 48,
363. (b) Ryu, I.; Sonoda, N. Angew. Chem., Int. Ed. Engl. 1996, 35, 1050. (c)
Crich, D.; Yuan, H. In AdVances in Free Radical Chemistry; Rawal, V. H.,
Ed.; JAI Press: Greenwich, CT, 1998; Vol. 2, in press. (d) Ryu, I.; Sonoda,
N.; Curran, D. P. Chem. ReV. 1996, 96, 177.
(13) Preliminary ab initio MO calculations at UHF 3-21G level suggested
that 5-exo radical A is 17.2 kcal/mol more stable than the corresponding 6-endo
radical B (eq 1).
(11) For similar observation, see ref 4b.