Synthesis of lactams by radical substitution reaction of α,β-unsaturated acyl radicals at amine nitrogen

Article abstract of DOI:10.1021/ol070080c

(Chemical Equation Presented) Substitution at nitrogen by α,β-unsaturated acyl radicals took place accompanied by elimination of an α-phenethyl radical. This reaction led to the development of a new carbonylative annulation method for five- to seven-membe

Full text of DOI:10.1021/ol070080c

ORGANIC
LETTERS
2007
Vol. 9, No. 5
935-937
Synthesis of Lactams by Radical
Substitution Reaction of
r,â-Unsaturated Acyl Radicals at Amine
Nitrogen
Yoshitaka Uenoyama, Takahide Fukuyama, and Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture UniVersity,
Sakai, Osaka 599-8531, Japan
ryu@c.s.osakafu-u.ac.jp
Received January 11, 2007
ABSTRACT
Substitution at nitrogen by
r
,
â
-unsaturated acyl radicals took place accompanied by elimination of an
r-phenethyl radical. This reaction led
to the development of a new carbonylative annulation method for five- to seven-membered ring lactams.
Whereas radical cyclization reactions have become a power-
ful tool for creating heterocyclic rings,1,2 the potential of
intramolecular homolytic substitution (SHi) reactions to create
heterocyclic rings has remained underexploited. Examples
are restricted to mainly group 14 and 16 elements, such as
Si, Ge, Sn, S, Se, and Te,3,4 whereas SHi-type ring formation
reactions at nitrogen, an element in group 15, have been
scarcely reported.5 In pursuit of new radical-mediated
carbonylation processes,6 we recently reported that polarity-
matched acyl radical cyclization onto the nitrogen of imines
is a useful tool for the synthesis of lactams (the first equation
of Scheme 1).7,8 Herein, we report that the substitution
reaction of acyl radicals at the nitrogen of amines also
provides a useful route for the synthesis of nitrogen-
unsubstituted lactams (the second equation of Scheme 1).9
We envisioned that if an acyl radical bearing a benzyl-
amine moiety could be generated expulsion of a benzyl
Scheme 1. Two Types of [n + 1] Annulation Strategies to
Lactam Rings
(1) Renaud, P., Sibi, M. P., Eds. Radical in Organic Synthesis; Wiley-
VCH: Weinheim, Germany, 2001; Vols. 1 and 2.
(2) (a) Bowman, W. R.; Fletcher, A. J.; Potts, G. B. S. J. Chem. Soc.,
Perkin Trans. 1 2002, 2747. (b) McCarroll, A. J.; Walton, J. C. Angew.
Chem., Int. Ed. 2001, 40, 2224.
(3) For reviews, see: (a) Schiesser, C. H.; Wild, L. M. Tetrahedron 1996,
52, 13265. (b) Walton, J. C. Acc. Chem. Res. 1998, 31, 99. (c) Beckwith,
A. L. J. Chem. Soc. ReV. 1993, 143. (d) Schiesser, C. H. Chem. Commun.
2006, 4055.
10.1021/ol070080c CCC: $37.00
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Published on Web 01/30/2007

radical in an SHi manner would lead to the formation of a
lactam ring. When we examined the stannylcarbonylation
of (N-benzyl)pentynylamine (1a) with tributyltin hydride and
AIBN under CO pressure, we found that the envisaged six-
membered ring lactam 2a, which does not contain a benzyl
group on nitrogen, is formed, albeit in low yield together
with lactams containing a benzyl substituent on nitrogen
(Scheme 2).
smoothly from tributyltin hydride and instead permits dimer-
ization. N-t-Butylhexynylamine also gave the desired product
in good yield.10
We examined the generality of the lactam ring formation
using a variety of substituted N-R-phenethyl alkynylamines,
as summarized in Table 1. For example, N-unsubstituted
Table 1. Carbonylative SHi-Type Reaction Leading to
Nitrogen-Unsubstituted Lactamsa
Scheme 2. Effect of the Substituent at Amine Nitrogen for
Radical Substitution Reaction
This prompted us to examine several substituents at amine
nitrogen, including R-phenethyl, diphenylmethyl, and t-butyl.
To our delight, we found that 1b, which has an R-phenethyl
group, resulted in the formation of 2a in 74% yield after
isolation by silica gel chromatography. The diphenylmethyl
group gives excellent selectivity for the desired product 2a;
however, the yield of 2a was modest due to poor chain
propagation. In this case, tetraphenylethane was detected in
the crude reaction mixture, which suggests that the expelled
diphenylmethyl radical is too stable to abstract hydrogen
(4) For recent examples, see: (a) Studer, A.; Amrein, S.; Matsubara,
H.; Schiesser, C. H.; Doi, T.; Kawamura, T.; Fukuyama, T.; Ryu, I. Chem.
Commun. 2003, 1190. (b) Ryu, I.; Okuda, T.; Nagahara, K.; Kambe, N.;
Komatsu, M.; Sonoda, N. J. Org. Chem. 1997, 62, 7550. (c) Crich, D.;
Hutton, T. K.; Ranganathan, K. J. Org. Chem. 2005, 70, 7672. (d) Carland,
M. W.; Martin, R. L.; Schiesser, C. H. Org. Biomol. Chem. 2004, 2, 2612.
(e) Malmstro¨m, J.; Jonsson, M.; Cotgreave, I. A.; Hammarstro¨m, L.; Sjo¨din,
M.; Engman, L. J. Am. Chem. Soc. 2001, 123, 3434. (f) Coulomb, J.; Certal,
V.; Fensterbank, L.; Lacoˆte, E.; Malacria, M. Angew. Chem., Int. Ed. 2006,
45, 633 and references therein.
(5) (a) Depature, M.; Siri, D.; Grimaldi, J.; Hatem, J.; Faure, R.
Tetrahedron Lett. 1999, 40, 4547. (b) Zhang, L. M.; Koreeda, M. J. Am.
Chem. Soc. 2004, 126, 13190.
(6) For reviews on radical carbonylations, see: (a) Ryu, I.; Sonoda, N.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1050. (b) Ryu, I.; Sonoda, N.;
Curran, D. P. Chem. ReV. 1996, 96, 177. (c) Ryu, I. Chem. Soc. ReV. 2001,
30, 16. Also see a review on acyl radicals: (d) Chatgilialoglu, C.; Crich,
D.; Komatsu, M.; Ryu, I. Chem. ReV. 1999, 99, 1991.
a Reaction conditions: for entries 1-9, [RX] ) 0.01 M, AIBN (19-20
mol %), CO (74-90 atm), Bu3SnH (1.3-1.5 equiv), C6H6 (50 mL), 90 °C,
4 h; for entries 10 and 11, [RX] ) 0.01 M, V-40 (1,1′-azobis(cyclohexane-
1-carbonitrile)) (20 mol %), CO (90 atm), Bu3SnH (1.3 equiv), C6H6 (50
b
mL), 110 °C, 4 h. Isolated yields by flash chromatography on silica gel.
(7) (a) Ryu, I.; Matsu, K.; Minakata, S.; Komatsu, M. J. Am. Chem.
Soc. 1998, 120, 5838. (b) Ryu, I.; Miyazato, H.; Kuriyama, K.; Matsu, K.;
Tojino, M.; Fukuyama, T.; Minakata, S.; Komatsu, M. J. Am. Chem. Soc.
2003, 125, 5632. (c) Tojino, M.; Otsuka, N.; Fukuyama, T.; Matsubara,
H.; Schiesser, C. H.; Kuriyama, H.; Miyazato, H.; Minakata, S.; Komatsu,
M.; Ryu, I. Org. Biomol. Chem. 2003, 1, 4262. (d) Tojino, M.; Otsuka, N.;
Fukuyama, T.; Matsubara, H.; Ryu, I. J. Am. Chem. Soc. 2006, 128, 7712.
(8) For theoretical work, see: (a) Falzon, C. T.; Ryu, I.; Schiesser, C.
H. Chem. Commun. 2002, 2338. (b) Matsubara, H.; Falzon, C. T.; Ryu, I.;
Schiesser, C. H. Org. Biomol. Chem. 2006, 4, 1920.
γ-lactam 2e can be prepared from N-phenethyl homopro-
pargylamine 1e in 84% yield (entry 1). The reaction of
substituted alkynylamines 1j-l also proceeded smoothly to
(10) In this case, the lactam having t-butyl on nitrogen of the lactam 2a
and the N-t-butyl-R-methylene lactam were also obtained in 6% and 12%
yields, respectively. See: Tojino, M.; Uenoyama, Y.; Fukuyama, T.; Ryu,
I. Chem. Commun. 2004, 2484.
(9) (a) Georg, G. I.; He, P.; Kant, J.; Wu, Z. J. J. Org. Chem. 1993, 58,
5571. (b) Casadei, M. A.; Gessner, A.; Inesi, A.; Jugelt, W.; Moracci, F.
M. J. Chem. Soc., Perkin Trans. 1 1992, 2001.
936
Org. Lett., Vol. 9, No. 5, 2007

give the corresponding δ-lactams 2j-l in good yields (entries
7-9). In a similar way, seven-membered ring lactams 2m
and 2n were synthesized from 1m and 1n, respectively
(entries 10 and 11). The preparation of chiral γ-lactams was
also examined. A diastereomeric mixture of alkynylamines
1f and 1g was obtained by the condensation of R-phenethyl-
amine having an (R)-configuration with benzaldehyde, fol-
lowed by reaction with propargyl bromide in the presence
of zinc. This gave a mixture of diastereomers 1f and 1g,
which were separated by recrystallization of the HCl salt.
The resulting chiral alkynylamines 1f and 1g were subjected
to the standard reaction conditions, which gave the chiral
γ-substituted R-methylene-γ-butyrolactams 2f and 2g, re-
spectively (entries 2 and 3). In a similar way, chiral γ-methyl-
substituted γ-lactams 2h and 2i were prepared from the
corresponding alkynylamines 1h and 1i in good yields
(entries 4 and 5).
reduction of 4 and subsequent hydrogenation using Pd(OH)2
catalyst gave the alkaloid sibirine (6).13
Scheme 4. Carbonylative SHi-Type Reaction of a Tertiary
Alkynylamine 1o and Its Application to the Synthesis of
(()-Sibirine
For the present homolytic substitution reaction at N by
R,â-unsaturated acyl radicals, we propose a pathway which
involves the nucleophilic trap of R-ketenyl radicals, forming
intermediate A as the first event (Scheme 3). Thus formed
In conclusion, we have demonstrated that R,â-unsaturated
acyl radicals, generated by radical carbonylation of N-
substituted alkynylamines in the presence of tributyltin
hydride, undergo unusual substitution at the nitrogen atom.
According to the protocol, five- to seven-membered ring
lactams were prepared in good yields. Thus, in addition to
radical addition to imine N-C bonds, homolytic substitution
of acyl radicals at nitrogen is a useful tool for lactam ring
formation with incorporation of CO.
Scheme 3. Proposed Reaction Pathway
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformations of Carbon Resources” from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan. Y.U. acknowledges a Grant-in-Aid from JSPS
scholarship.
A would then undergo â-fission expelling the R-phenethyl
radical and yielding B, which is a canonical form of the
product C.11,12
Note Added after ASAP Publication. The stereochem-
istry of structures 4-6 in Scheme 4 and the Supporting
Information was incorrect in the version published ASAP
January 30, 2007; the revised version was published ASAP
February 5, 2007.
Although the present method is useful for the synthesis
of lactams unsubstituted at nitrogen, interestingly, the SHi-
type reaction at nitrogen is possible even in the case of a
tertiary amine. The carbonylative SHi-type reaction of 1o,
coupled with the subsequent protodestannylation procedure,
gave the corresponding N-methyl-substituted lactam 2o in
86% yield (Scheme 4). Thus prepared 2o was subjected to
a Diels-Alder reaction with siloxydiene 3, resulting in
spirocycle 4 in 50% yield. The lithium aluminum hydride
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL070080C
(11) Interestingly, the 6-aza-7-phenyloctanoyl radical did not undergo a
SHi-type reaction. This may suggest the importance of the ketenyl radical
structure.
(12) A preliminary MO calculation on the BHandHLYP/6-31+G*//
BHandHLYP/6-31G* predicted that this two-step pathway is possible.
(13) (a) Wanner, M. J.; Koomen, G. J. Tetrahedron Lett. 1989, 30, 2301.
(b) Deyine, A.; Poirier, J. M.; Duhamel, L.; Duhamel, P. Tetrahedron Lett.
2005, 46, 2491. (c) Koreeda, M.; Wang, Y.; Zhang, L. Org. Lett. 2002, 4,
3329.
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