Free-radical-mediated [2 + 2 + 1] cycloaddition of acetylenes, amidines, and CO leading to five-membered α,β-unsaturated lactams

Article abstract of DOI:10.1021/ja312654q

A free-radical-mediated [2 + 2 + 1] cycloaddition reaction comprising acetylenes, amidines, and CO was achieved by radical chain reaction to give five-membered α,β-unsaturated lactams in good yields. Both acyclic and cyclic amidines reacted with a variety of terminal acetylenes to afford monocyclic, bicyclic, and tricyclic lactams. We propose that vinyl radical carbonylation and nucleophilic addition of the amidine onto the resulting α-ketenyl radical give stable intermediates that are ready to undergo five-membered ring closure with elimination of tin radical.

Full text of DOI:10.1021/ja312654q

Communication
pubs.acs.org/JACS
Free-Radical-Mediated [2 + 2 + 1] Cycloaddition of Acetylenes,
Amidines, and CO Leading to Five-Membered α,β-Unsaturated
Lactams
Takahide Fukuyama, Nao Nakashima, Takuma Okada, and Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
S
* Supporting Information
Scheme 2. Three-Component Coupling Reactions of
Acetylenes, Imines, and CO
a
ABSTRACT: A free-radical-mediated [2 + 2 + 1]
cycloaddition reaction comprising acetylenes, amidines,
and CO was achieved by radical chain reaction to give five-
membered α,β-unsaturated lactams in good yields. Both
acyclic and cyclic amidines reacted with a variety of
terminal acetylenes to afford monocyclic, bicyclic, and
tricyclic lactams. We propose that vinyl radical carbon-
ylation and nucleophilic addition of the amidine onto the
resulting α-ketenyl radical give stable intermediates that
are ready to undergo five-membered ring closure with
elimination of tin radical.
a
Conditions: 1a (0.5 mmol), 2 (5 mmol), 1,1′-azobis(cyclohexane-1-
carbonitrile) (V-40) (30 mol %), CO (80 atm), Bu3SnH (1.2 equiv),
C6H6 (10 mL), 110 °C, 6 h.
ycloaddition reactions incorporating CO provide a
Table 1. Radical-Mediated [2 + 2 + 1] Cycloaddition of 1-
Octyne, CO, and DBU
C
powerful means to access a wide range of cyclic and
heterocyclic carbonyl compounds, and many efforts have been
directed to transition-metal-catalyzed carbonylation reactions.1
Previously, we found that acyl radicals generated by the
addition of alkyl radicals to CO2 undergo N-philic acyl radical
cyclization onto the imine nitrogen, providing an annulation
method for the synthesis of lactams.3,4 The N-philic acyl radical
cyclization can be rationalized by dual orbital interactions
between the π* orbital of the acyl radical and the lone pair of
the imine nitrogen and the singly occupied molecular orbital of
the acyl radical and the π* orbital of the imine.5 With successful
examples of the intramolecular reaction using imines in hand,
we then embarked on the challenge of intermolecular trapping
of acyl radicals by N−C double bonds in the hope of
developing a novel multicomponent radical reaction.6 Herein
we report that the intermolecular [2 + 2 + 1] cycloaddition
reaction of acetylenes, amidines, and CO leading to five-
membered α,β-unsaturated lactams proceeds efficiently under
free-radical reaction conditions (Scheme 1), representing the
first radical-mediated aza-Pauson−Khand reaction.7,8
a
b
entry
equiv of 4a
equiv of Bu3SnH
time (h)
yield (%)
1
2
3
4
5
2.0
5.0
5.0
5.0
5.0
1.2
1.2
0.6
0.3
0.3
3
3
3
3
6
39
60
68
62
66
a
Conditions: 1a (0.5 mmol), 4a, AIBN (15−20 mol %), CO (80 atm),
b
Bu3SnH, C6H6 (10 mL), 80 °C. Isolated yields as determined by flash
chromatography.
intermolecular trapping reaction with acyl radicals was very
modest. For example, the reaction of 1-octyne (1a), CO, and
10 equiv of imine 2a gave the unusual [2 + 2 + 1] cycloaddition
product 3a in only 15% yield (Scheme 2). Imine 2b having a
methoxy group at the para position of the benzene ring gave a
better yield of lactam 3b (31%), and interestingly, p-
dimethylamino-substituted imine 2c gave lactam 3c in a further
improved yield of 51%. These trends led us to consider the use
of amidines rather than imines as the acyl radical trap.
In our initial efforts, we focused on imines as the acyl radical
trap. Unfortunately, however, the reactivity of imines in the
Scheme 1. Strategy for Lactam Synthesis by Radical-
Mediated [2 + 2 + 1] Cycloaddition
As a model reaction, we examined the intermolecular [2 + 2
+ 1] cycloaddition reaction using 1a, CO, and 1,8-
Received: December 28, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja312654q | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 2. Three-Component Reactions of 1, 4, and CO
Scheme 3. Radical Chain Mechanism for the [2 + 2 + 1]
Cycloaddition
Scheme 4. [2 + 2 + 1] Cycloaddition Using Dihydrooxazine
7
increased the yield of 5a to 60% (entry 2). Since the product
does not contain a tributyltin moiety, we examined the reaction
with a decreased amount of Bu3SnH. Gratifyingly, the results
when 0.6 or 0.3 equiv of Bu3SnH was used were essentially
equivalent to those when a stoichiometric amount was used
(entries 3−5).
To examine the generality of the present [2 + 2 + 1]
cycloaddition reaction, a variety of acetylenes 1 and amidines 4
were exposed to similar radical carbonylation conditions (Table
2). The reactions of acetylenes bearing acetoxy, silyloxy, or
amino functional groups all worked well to give the
corresponding lactams, each having the desired functionality
intact (entries 2−4). Arylacetylenes 1e−g also participated in
the three-component reaction to give the corresponding 2-aryl-
substituted lactams 5e−g (entries 5−7). The reaction of 1a
with 4b having a 6,6-fused ring system also gave a good yield of
the corresponding tricyclic lactam 5h (entry 8). We also tested
monocyclic amidines 4c and 4d. The reactions of 1a and 1b
with six-membered amidine 4c gave the corresponding lactams
5i and 5j having a bicyclo[4.3.0] skeleton (entries 9 and 10). In
contrast, the reaction of 1a with five-membered amidine 4d
gave the uncyclized three-component product 6 as the major
product (entry 11). The very low yield of lactam 5k in this case
may be due to the steric demands of the bicyclo[3.3.0] system,
which could prevent the cyclization. Amidine 4e gave bicyclic
lactam 5l in 69% yield (entry 12). The reaction using acyclic
amidine 4f was also successful (entry 13).
A possible reaction mechanism for the present radical-
mediated [2 + 2 + 1] cycloaddition is shown in Scheme 3, using
entry 13 of Table 2 as the specific example. The addition of a
tributyltin radical to the acetylene terminus of 1a would
generate a β-stannylated vinyl radical, which would undergo
carbonylation to generate α,β-unsaturated acyl radical A and
the isomeric α-ketenyl radical B.9 Intermolecular trapping of
the α-ketenyl radical10 by amidine 4f would then afford
intermediate C, which can be drawn in several canonical forms,
including D. 5-Endo cyclization of C to give E11 followed by β-
a
Conditions; 1 (0.5 mmol), 2 (2.5 mmol), AIBN (15−30 mol %), CO
(80 atm), Bu3SnH (0.3 equiv for entries 1 and 3; 0.6 equiv for entries
2, 4−10, 12, and 13; 1.2 equiv for entry 11), C6H6 (10 mL), 80 °C, 6
b
h. Isolated yields as determined by flash chromatography on silica gel
c
d
and/or recycling preparative HPLC. 1e (0.01 M). 1f or 1g (0.02 M).
e
4c (8.8 equiv).
diazabicyclo[5.4.0]undec-7-ene (DBU, 4a) as the amidine
(Table 1). When 1-octyne (0.05 M) was treated with DBU
(2 equiv) under CO pressure (80 atm) in the presence of
tributyltin hydride (1.2 equiv) and 2,2′-azobis(isobutyronitrile)
(AIBN) (20 mol %) at 80 °C for 3 h, the expected five-
membered α,β-unsaturated lactam 5a was obtained in 39%
yield (entry 1). Using a larger excess of DBU (5 equiv)
B
dx.doi.org/10.1021/ja312654q | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Trans. 1 2002, 2747. (d) Minozzi, M.; Nanni, D.; Spagnolo, P.
Chem.Eur. J. 2009, 15, 7830. (e) Rowlands, G. J. Tetrahedron 2010,
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fission would lead to the formation of α,β-unsaturated lactam
5m and regenerate the tributyltin radical.
The proposed key intermediate C should be highly stabilized
by the two nitrogen atoms originating from the amidine starting
material. In support of the importance of doubly donating
groups, dihydrooxazine 7 reacted smoothly to give the
corresponding bicyclic lactam ring 8 in good yield (Scheme 4).
In summary, we have developed a novel method for
constructing five-membered α,β-unsaturated lactam rings by a
[2 + 2 + 1] cycloaddition reaction between acetylenes,
amidines, and CO, which is accomplished by a free-radical
chain reaction. In this reaction, intermolecular trapping of α-
ketenyl radicals by the nitrogen of the amidine gives a highly
conjugated, highly stabilized radical species, which then
undergoes five-membered-ring closure leading to unique
heterocyclic ring systems. Thus, polarity-controlled radical
reactions clearly represent a promising strategy for exploring
multicomponent radical sequences, and we are continuing our
efforts along this line.
(5) For theoretical studies of dual orbital interactions, see:
(a) Schiesser, C. H.; Wille, U.; Matsubara, H.; Ryu, I. Acc. Chem.
Res. 2007, 40, 303. (b) Falzon, C. T.; Ryu, I.; Schiesser, C. H. Chem.
Commun. 2002, 2338. (c) Schiesser, C. H.; Matsubara, H.; Ritsner, I.;
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(e) Kyne, S. H.; Schiesser, C. H.; Matsubara, H. J. Org. Chem. 2008,
73, 427.
(6) C-philic additions to N−C double bonds are well-documented.
See: (a) Kim, S.; Kim, S.; Otsuka, N.; Ryu, I. Angew. Chem., Int. Ed.
2005, 44, 6183. (b) Miyabe, H.; Yamaoka, Y.; Takemoto, Y. J. Org.
Chem. 2006, 71, 2099. (c) Akindele, T.; Yamamoto, Y.; Maekawa, M.;
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and sample spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
(7) For recent reviews of Pauson−Khand reactions, see ref 1 and:
(a) Gibson, S. E.; Stevenazzi, A. Angew. Chem., Int. Ed. 2003, 42, 1800.
(b) Lee, H.-W.; Kwong, F.-Y. Eur. J. Org. Chem. 2010, 789.
(8) For Ru-catalyzed aza-Pauson−Khand reactions, see: (a) Chatani,
N.; Morimoto, T.; Kamitani, A.; Fukumoto, Y.; Murai, S. J. Organomet.
Chem. 1999, 579, 177. (b) Chatani, N.; Tobisu, M.; Asaumi, T.; Murai,
S. Synthesis 2000, 925.
AUTHOR INFORMATION
Corresponding Author
ryu@c.s.osakafu-u.ac.jp
■
Notes
(9) Matsubara, H.; Ryu, I.; Schiesser, C. H. J. Org. Chem. 2005, 70,
3610.
The authors declare no competing financial interest.
(10) For trapping of α-ketenyl radicals by amines, see: (a) Tojino,
M.; Uenoyama, Y.; Fukuyama, T.; Ryu, I. Chem. Commun. 2004, 2482.
(b) Uenoyama, Y.; Fukuyama, T.; Nobuta, O.; Matsubara, H.; Ryu, I.
Angew. Chem., Int. Ed. 2005, 44, 1075. (c) Uenoyama, Y.; Fukuyama,
T.; Ryu, I. Org. Lett. 2007, 9, 935. (d) Ryu, I.; Fukuyama, T.; Tojino,
M.; Uenoyama, Y.; Yonamine, Y.; Terasoma, N.; Matsubara, H. Org.
Biomol. Chem. 2011, 9, 3780.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, and
Technology (MEXT), Japan, and the Japan Society for the
Promotion of Science (JSPS).
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dx.doi.org/10.1021/ja312654q | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX