Copper-catalyzed addition reactions of aromatics and ketones to 2-aza-2,4-cyclopentadienone: Facile and efficient transformation of carbonyl-ene-nitriles to 1H-pyrrolin-2(5H)-ones

Article abstract of DOI:10.1021/jo801776v

(Chemical Equation Presented) Copper-catalyzed reactions of carbonyl-ene-nitriles with carbon nucleophiles, such as aromatics and ketones, afforded pyrrolin-2-ones (γ-lactam) in excellent yield. The reaction mechanism involves addition reactions with a ke

Full text of DOI:10.1021/jo801776v

SCHEME 1
Copper-catalyzed Addition Reactions of
Aromatics and Ketones to
2-Aza-2,4-cyclopentadienone: Facile and Efficient
Transformation of Carbonyl-ene-nitriles to
1H-Pyrrolin-2(5H)-ones
Masahito Murai, Koji Miki, and Kouichi Ohe*
nucleophiles appear to be even more difficult.4 In particular,
addition reactions of aromatics5 and ketones to ketimines have
been much less explored. To the best of our knowledge, the
few existing examples are limited to the reactions of electroni-
cally activated ketimines that have electron-withdrawing groups
on the imine carbon,5a,b,d reactions mediated by stoichiometric
Brønsted or Lewis acids,5a,c,d or intramolecular reactions.5d,e
Thus, the development of effective catalytic addition reactions
of inactivated carbon nucleophiles to ketimines would be a
significant contribution to organic synthesis.
Department of Energy and Hydrocarbon Chemistry,
Graduate School of Engineering, Kyoto UniVersity, Katsura,
Nishikyo-ku, Kyoto 615-8510, Japan
ohe@scl.kyoto-u.ac.jp
ReceiVed August 14, 2008
In the course of our study on the reactivity of carbonyl-ene-
nitrile compounds (16) with alkenes, we found an unexpected
copper-catalyzed formation of pyrrolin-2-ones (3) (Scheme 1).7
The structure of 3 implies a reaction mechanism involving
vinylation of the ketimine moiety of 2-aza-2,4-cyclopenta-
dienone intermediate 2, which is formed via hydration of a nitrile
moiety followed by dehydrative cyclization. Although Gavin˜a
et al. have already reported that nonsubstituted 2-aza-2,4-
cyclopentadienone reacts with both enophiles and dienophiles
to give the corresponding Diels-Alder adducts,8 our report was
the first example of the reaction via 2-aza-2,4-cyclopentadienone
intermediate 29 as an electrophile. This result encouraged us to
initiate research on the catalytic addition reactions of C-H
Copper-catalyzed reactions of carbonyl-ene-nitriles with
carbon nucleophiles, such as aromatics and ketones, afforded
pyrrolin-2-ones (γ-lactam) in excellent yield. The reaction
mechanism involves addition reactions with a ketimine
moiety of the 2-aza-2,4-cyclopentadienone intermediate,
which is formed via hydration of a nitrile moiety followed
by dehydrative cyclization.
(3) Transition-metal catalyzed Strecker reactions of ketimines have been well-
studied. For recent examples, see: (a) Suto, Y.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2007, 129, 500. (b) Wang, J.; Hu, X.; Jiang, J.; Gou, S.; Huang, X.;
Liu, X.; Feng, X. Angew. Chem., Int. Ed. 2007, 46, 8468. (c) Kato, N.; Suzuki,
M.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2004, 45, 3147. (d) Kato, N.;
Suzuki, M.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2004, 45, 3153. (e)
Zhuang, W.; Saaby, S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 4476.
(f) Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2003, 125, 5634. (g) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002,
124, 10012. (h) Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867. (i) Hua,
D. H.; Lagneau, N.; Wang, H.; Chen, J. S. Tetrahedron: Asymmetry 1995, 6,
349.
Transition metal-catalyzed addition reactions of carbon nu-
cleophiles to imines represent one of the most direct methods
for the synthesis of various R-branched primary and secondary
amines through the formation of new carbon-carbon bonds.1
In contrast to the well-studied addition reactions of carbon
nucleophiles with aldimines, however, reactions with ketimines
are limited because of their poor electrophilicity and steric
hindrance.2,3 Therefore, most reported methods require strong
nucleophiles such as organometallic species2 and trimethylsilyl
cyanide.3 The direct addition reactions of C-H bonds of carbon
(4) Transition metal-catalyzed alkynylations of ketimines were restricted to
a few examples, see: (a) Luo, Y.; Li, Z. Li. C.-J. Org. Lett. 2005, 7, 2675. (b)
Jiang, B.; Shi, Y.-G. Angew. Chem., Int. Ed. 2004, 43, 216. (c) Fischer, C.;
Carreira, E. M. Synthesis 2004, 9, 1497.
(5) (a) Abid, M.; Teixeira, L.; To¨ro¨k, B. Org. Lett. 2008, 10, 933. (b) Skarpos,
H.; Vorob’eva, D. V.; Osipov, S. N.; Odinets, I. L.; Breuer, E.; Ro¨schenthaler,
G.-V. Org. Biomol. Chem. 2006, 4, 3669. (c) Rozas, M. F.; Piro, O. E.;
Castellano, E. E.; Mirifico, M. V.; Vasini, E. J. Synthesis 2002, 16, 2399. (d)
Bravo, P.; Crucianelli, M.; Farina, A.; Meille, S. V.; Volonterio, A.; Zanda, M.
Eur. J. Org. Chem. 1998, 435. (e) Spadoni, G.; Balsamini, C.; Bedini, A.; Duranti,
E.; Tontini, A. J. Heterocycl. Chem. 1992, 29, 305.
(6) Nozaki, K.; Sato, N.; Takaya, H. Bull. Chem. Soc. Jpn. 1996, 69, 1629.
(7) Murai, M.; Kawai, S.; Miki, K.; Ohe, K. J. Organomet. Chem. 2007,
692, 579.
(8) (a) Gavin˜a, F.; Costero, A. M.; Andreu, R.; Carda, M.; Luis, S. V. J. Am.
Chem. Soc. 1988, 110, 4017. (b) Gavin˜a, F.; Costero, A. M.; Andreu, M. R.;
Luis, S. V. J. Org. Chem. 1988, 53, 6112.
(9) 2-Aza-2,4-cyclopentadienone intermediates were proposed in nickel- and
iron-catalyzed tandem cyanation, cyclization, and carboxylation of alkynylketones
leading to pyrrolinone derivatives, see: (a) Rosas, N.; Sharma, P.; Arellano, I.;
Ram´ırez, M.; Pe´rez, D.; Herna´ndez, S.; Cabrera, A. Organometallics 2005, 24,
4893. (b) Arzoumanian, H.; Jean, M.; Nuel, D.; Garcia, J. L.; Rosas, N.
Organometallics 1997, 16, 2726.
* To whom correspondence should be addressed.
(1) For reviews, see: (a) Shibasaki, M.; Kanai, M. Chem. ReV. 2008, 108,
2853. (b) Tomioka, K.; Yamada, K. Chem. ReV. 2008, 108, 2874. (c) Kobayashi,
S.; Ishitani, H. Chem. ReV. 1999, 99, 1069. (d) Bloch, R. Chem. ReV. 1998, 98,
1407. (e) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895.
(2) For selected examples, see: (a) Notte, G. T.; Leighton, J. L. J. Am. Chem.
Soc. 2008, 130, 6676. (b) Perl, N. R.; Leighton, J. L. Org. Lett. 2007, 9, 3699.
(c) Rabbat, P. M. A.; Valdez, S. C.; Leighton, J. L. Org. Lett. 2006, 8, 6119. (d)
Saaby, S.; Nakama, K.; Lie, M. A.; Hazell, R. G.; Jørgensen, K. A. Chem.sEur.
J. 2003, 9, 6145. (e) Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67, 7819.
(f) Borg, G.; Chino, M.; Ellman, J. A. Tetrahedron Lett. 2001, 42, 1433. (g)
Davis, F. A.; Lee, S.; Zhang, H.; Fanelli, D. L. J. Org. Chem. 2000, 65, 8704.
(h) Cogan, D. A.; Liu, G.; Ellman, J. A. Tetrahedron 1999, 55, 8883. (i) Cogan,
D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268. (j) Tang, T. P.; Ellman,
J. A. J. Org. Chem. 1999, 64, 12. (k) Wang, D. K.; Dai, L. X.; Hou, X. L.;
Zhang, Y. Tetrahedron Lett. 1996, 37, 4187. (l) Davis, F. A.; Reddy, R. T.;
Reddy, R. E. J. Org. Chem. 1992, 57, 6387. (m) Ciganek, E. J. Org. Chem.
1992, 57, 4521.
9174 J. Org. Chem. 2008, 73, 9174–9176
10.1021/jo801776v CCC: $40.75 2008 American Chemical Society
Published on Web 10/17/2008

TABLE 1. Cu-catalyzed Arylation with Aromatics
cyclization. To gain insight into the reaction mechanism, isotopic
labeling experiment using the 18O-labeled water (98% 18O) was
carried out. Treatment of 1 with furan in the presence of 3 equiv
of the 18O-labeled water afforded the 18O-enriched product 4e
(Scheme 2). The high-resolution mass spectrum of the product
4e showed two sharp peaks at m/z ) 304.1244 (100% intensity)
and 302.1168 (94% intensity), indicating 52% 18O incorporation
in the product.11 This isotope-labeling experiment supports the
hypothesis that the reaction proceeds via both hydration of a
nitrile moiety and dehydrative cyclization between the resulting
amide and an original carbonyl group.12 Attempts to isolate
2-aza-2,4-cyclopentadienone intermediate 2 failed, probably due
to its high reactivity.
SCHEME 2
a Isolated yields. b 4a (X ) OMe, Y ) H): 4a′ (X ) H, Y ) OMe)
) 16:1. c In toluene at reflux. d 1 mol% of Cu(OTf)2 was used. e 4i
(3-): 4i′ (2-) ) 29:1.
bonds of various nucleophiles to intermediate 2. We report
herein copper-catalyzed addition reactions of carbon nucleo-
philes, such as aromatics and ketones, to a ketimine moiety of
2-aza-2,4-cyclopentadienone 2. The resulting pyrrolin-2-ones
are an important class of compounds found in a number of
naturally occurring alkaloids and are applicable to the synthesis
of indolizidine derivatives.
We initiated our investigation using various aromatics as
carbon nucleophiles to obtain the Fridel-Crafts type arylated
products. When we carried out the reaction of 1 with anisole in
the presence of Cu(OTf)2 (5 mol %) and H2O (0.1 equiv) in
ClCH2CH2Cl at 70 °C,10 we obtained 84% yield of the arylated
product 4a as the major product, together with a small amount
of the regio isomer 4a′ (Table 1, entry 1). Other electron-rich
aromatics, such as phenol and 1,3-dimethoxybenzene, also
reacted smoothly with 1 to afford 4b and 4c in good to excellent
yields, respectively (entries 2 and 3). With N,N-dimethylaniline,
the corresponding arylated product 4d was obtained in 77%
yield, although a prolonged reaction time and higher reaction
temperature were required (entry 4). When the reaction of 1
with several heteroaromatic compounds, such as furan, 2-me-
thylfuran, thiophene, 2-methylthiophene, and benzofuran were
attempted, the corresponding products 4e-4i were obtained in
excellent yields with high regio-selectivities (entries 5-10). In
addition, the reaction with furan proceeded successfully even
if the catalyst loading was decreased to 1 mol % (entry 6).
The present protocol was also extended to reactions with other
carbonyl-ene-nitrile compounds. For example, the reaction of
2-cyanobenzophenone 5 with furan gave the corresponding
adduct 6 in 74% yield (eq 1).
As demonstrated above, the ketimine moiety of the 2-aza-
2,4-cyclopentadienone 2 reacted effectively with various aro-
matics. To demonstrate the advantages of the present transfor-
mation, we next examined the Mannich-type reaction of 1 with
ketones (Table 2).13 When the reaction of 1 with acetophenone
TABLE 2. Cu-catalyzed Mannich-type Reaction with Ketones
entry
R
time (h)
product
yield (%)a
1
Ph
24
3
8
6
6
7a
7b
7c
7d
7e
95
quant
97
92
93
2
4-MeOC6H4
4-CF3C6H4
Me
3b
4
5
tBu
a Isolated yields. b 80 °C.
was carried out, ꢀ-aminoketone 7a was obtained in 95% yield
(entry 1). Both 4-methoxy and 4-trifluoromethylacetophenone
reacted with 1 to afford the corresponding products 7b and 7c
in excellent yields, respectively (entries 2 and 3). Surprisingly,
In our previous report,7 we proposed that the vinylation or
ene-type reaction proceeds via the 2-aza-2,4-cyclopentadienone
intermediate 2, which is formed by hydration and dehydrative
(11) Theoritical percentage of 18O incorporation would be 75%, when 3 equiv
of H218O to 1 was employed.
(10) Other transition metal complexes, such as Sc(OTf)2, [RuCl2(CO)3]2,
PtCl2, AuCl3, PdCl2, Cu(OTf)-benzene, CuCl, and CuCl2, GaCl3 were ineffective
for the reaction.
(12) No incorporation of 18O in 4e was observed upon admixture of 4e with
3 equiv of H218O in the presence of Cu(OTf)2, which indicates the 18O
incorporation during the transformation of 1.
J. Org. Chem. Vol. 73, No. 22, 2008 9175

the reaction with aliphatic ketones such as acetone and tert-
butyl methyl ketone also proceeded smoothly to give the
corresponding ꢀ-aminoketone 7d and 7e in 92 and 93% yields,
respectively (entries 4 and 5). Furthermore, 1 reacted with
2-butanone to give the single constitutional isomer 7f quanti-
tatively as a mixture of diastereomers (d/r ) 66:34) (eq 2). The
structure of 7f suggests that 2-aza-2,4-cyclopentadienone 2 from
1 reacts selectively with a thermodynamically stable enol
generated from 2-butanone.
reactions to the synthesis of N-heterocycles as natural products
including asymmetric transformations are now in progress.
Experimental Section
General Procedure for Copper-catalyzed Reactions of Car-
bonyl-ene-nitrile Compounds with Aromatics and Ketones
leading to 1H-Pyrrolin-2(5H)-ones. A flame-dried Schlemk flask
was charged with Cu(OTf)2 (7.2 mg, 0.020 mmol), carbonyl-ene-
nitrile 1 (93.3 mg, 0.40 mmol), distilled water (0.7 µL, 0.040 mmol),
and furan (136 mg, 2.0 mmol) in DCE (2.0 mL), and the resulting
reaction mixture was stirred at 70 °C for 3 h. The mixture was
diluted with diethyl ether and filtered through a short silica gel pad.
The organic solvent was removed under reduced pressure, and the
residue was subjected to flash column chromatography on silica
gel (hexane/AcOEt ) 7/1 to 4/1) afforded 3,5-diphenyl-5-(2-furyl)-
3-pyrrolin-2-one 4e as a white solid (112 mg, 93%): mp 141.3-142.5
°C; IR (KBr): 694, 746, 794, 894, 1076, 1153, 1236, 1361, 1446,
1491, 1599, 1687 (CdO), 2852, 3066, 3167 (N-H) cm-1. 1H NMR
(400 MHz, CDCl3): δ 6.33 (s, 1H), 6.35 (s, 1H), 7.29-7.42 (m,
9H), 7.48 (s, 1H), 7.62 (br, 1H), 7.90 (d, J ) 8.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3): δ 65.1, 107.7, 110.2, 126.1, 127.3, 128.2,
128.4, 128.7, 128.8, 130.7, 134.2, 138.8, 142.9, 143.7, 152.6, 171.8.
Anal. calcd for C20H15NO2: C, 79.72; H, 5.02. Found: C, 80.00; H,
5.02.
Having established that addition reactions of aromatics and
ketones to the ketimine moiety of 2-aza-2,4-cyclopentadienone
intermediate lead to substituted pyrrolin-2-ones, we next dem-
onstrated the synthetic application to azabicyclo[4.3.0]nonanone
(indolizidinone), which has recently received considerable
attention in view of its wide range of biological activities.14
When the reaction of 1 with 3-bromo-2,2-dimethylbutan-2-one
was attempted, the corresponding ꢀ-aminoketone was obtained
in 81% yield (Scheme 3). The subsequent intramolecular
cyclization of 7g using sodium hydride afforded azabicyclo-
[4.3.0]nonanone 8 in 81% yield. Furthermore, one-pot synthesis
of 8 from 1 and ꢀ-bromoketone was examined in the presence
of potassium carbonate as a base. We were delighted to find
that 8 was obtained in 74% yield from 1 and ꢀ-bromoketone in
one pot.
One-pot Synthesis of Azabicyclo[4.3.0]nonanone (6,6-dimeth-
yl-2,8a-diphenyl-5,6,7,8-tetrahydroindolizin-3,7-dione (8)). A
flame-dried Schlemk flask was charged with Cu(OTf)2 (7.2 mg,
0.020 mmol), 1 (93.3 mg, 0.40 mmol), distilled water (0.7 µL, 0.040
mmol), potassium carbonate (0.48 mmol), and 3-bromo-2,2-
dimethylbutan-2-one (358 mg, 2.0 mmol) in DCE (2.0 mL), and
the resulting reaction mixture was stirred at 70 °C for 20 h. The
mixture was poured into water (10 mL) and then extracted with
Et2O (20 mL × 3). The combined organic layer was dried over
MgSO4. The organic solvent was removed under reduced pressure,
and the residue was subjected to flash column chromatography on
silica gel (hexane/AcOEt ) 7/1 to 4/1) to afford 6,6-dimethyl-2,8a-
diphenyl-5,6,7,8-tetrahydro-indolizin-3,7-dione 8 as a pale yellow
viscous oil (98 mg, 0.30 mmol, 74% yield). IR (neat): 695, 789,
874, 1139, 1166, 1311, 1401, 1447, 1493, 1691 (CdO), 2867, 2929,
SCHEME 3
1
2969 cm-1. H NMR (400 MHz, CDCl3): δ 1.02 (s, 3H), 1.22 (s,
3H), 2.71 (d, J ) 13.6 Hz, 1H), 2.83 (d, J ) 14.8 Hz, 1H), 3.40
(d, J ) 14.8 Hz, 1H), 4.28 (d, J ) 13.6 Hz, 1H), 7.21-7.28 (m,
3H), 7.30-7.44 (m, 7H), 7.98 (d, J ) 6.8 Hz, 2H). 13C NMR (100
MHz, CDCl3): δ 20.8, 25.1, 44.1, 44.5, 46.9, 67.9, 126.3, 127.2,
128.5, 128.8, 129.0, 129.3, 130.9, 133.8, 135.7, 145.7, 168.7, 210.2.
HRMS (FAB, M + H+): calcd for C22H22NO2: 332.1651. Found:
332.1657.
Acknowledgment. This work was financially supported by
a Grant-in-Aid for Scientific Research (B) (Grant No. 19350093)
from the Japan Society for the Promotion of Science (JSPS).
M. M. thanks the JSPS Research Fellowships for Young
Scientists.
In conclusion, we have demonstrated Cu(OTf)2-catalyzed
addition reactions of C-H bonds of various aromatics and
ketones to the ketimine moiety of 2-aza-2,4-cyclopentadienone
intermediate. The reaction proceeds under mild conditions and
provides efficient access to synthetically useful pyrrolin-2-ones.
The present method might provide an efficient tool for the
synthesis of various natural products containing a γ-lactam
skeleton, such as salinosporamide A-C, omuralide, lactacystin,
PI-091, and lucilactaene.15 Further studies on application of these
Supporting Information Available: General procedures and
characterization of new compounds are provided as a PDF file.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO801776V
(13) For reviews on the Mannich reaction, see: (a) Sodeoka, M.; Hamashima,
Y. Pure. Appl. Chem. 2008, 80, 763. (b) Verkade, J. M. M.; van Hemert, L. J. C.;
Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Chem. Soc. ReV. 2008, 37, 29. (c)
Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 5797.
(15) (a) Reddy, L. R.; Fourn´ıer, J.-F.; Subba Reddy, B. V.; Corey, E. J. Org.
Lett. 2005, 7, 2699. (b) Reddy, L. R.; Fourn´ıer, J.-F.; Subba Reddy, B. V.; Corey,
E. J. J. Am. Chem. Soc. 2005, 127, 8974. (c) Williams, P. G.; Buchanan, G. O.;
Feling, R. H.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. J. Org. Chem. 2005,
70, 6196. (d) Fukuda, N.; Sasaki, K.; Sastry, T. V. R. S.; Kanai, M.; Shibasaki,
M. J. Org. Chem. 2006, 71, 1220. (e) Shiraki, R.; Sumino, A.; Tadano, K.-I.;
Ogawa, S. J. Org. Chem. 1996, 61, 2845. (f) Yamaguchi, J.; Kakeya, H.; Uno,
T.; Shoji, M.; Osada, H.; Hayashi, Y. Angew. Chem. In. Ed. 2005, 44, 3110.
(14) For reviews on the indolizidines, see: (a) Michael, J. P. Nat. Prod. Rep.
1999, 16, 675. (b) Nemr, A. E. Tetrahedron 2000, 56, 8579. (c) Asano, N.;
Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11,
1645. (d) Michael, J. P. Nat. Prod. Rep. 2003, 20, 458. (e) Michael, J. P. Nat.
Prod. Rep. 2005, 22, 603. (f) Pyne, S. G. Curr. Org. Synth. 2005, 2, 39 and
references therein.
9176 J. Org. Chem. Vol. 73, No. 22, 2008