Innovative synthesis of 4-carbaldehydepyrrolin-2-ones by zwitterionic rhodium catalyzed chemo- and regioselective tandem cyclohydrocarbonylation/CO insertion of α-imino alkynes

Article abstract of DOI:10.1021/ja011710n

The tandem cyclohydrocarbonylative/CO insertion of α-imino alkynes employs CO, H₂, and catalytic quantities of zwitterionic rhodium complex (η⁶-C₆H₅ BPh₃)^-Rh⁺(1,5-COD) and triphenyl phosphite affording aldehyde substituted pyrrolinones in 67-82% yields. This unique transformation is readily applied to imino alkynes containing alkyl, alkoxyl, vinyl, and aryl substituents. The ability to prepare highly functionalized pyrrolinones makes this an attractive route to these important and versatile pharmaceuticals.

Full text of DOI:10.1021/ja011710n

10214
J. Am. Chem. Soc. 2001, 123, 10214-10220
Innovative Synthesis of 4-Carbaldehydepyrrolin-2-ones by
Zwitterionic Rhodium Catalyzed Chemo- and Regioselective Tandem
Cyclohydrocarbonylation/CO Insertion of R-Imino Alkynes
Bernard G. Van den Hoven and Howard Alper*
Contribution from the Centre for Catalysis Research and InnoVation, Department of Chemistry,
UniVersity of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
ReceiVed July 13, 2001
Abstract: The tandem cyclohydrocarbonylative/CO insertion of R-imino alkynes employs CO, H2, and catalytic
quantities of zwitterionic rhodium complex (η6-C6H5BPh3)-Rh+(1,5-COD) and triphenyl phosphite affording
aldehyde substituted pyrrolinones in 67-82% yields. This unique transformation is readily applied to imino
alkynes containing alkyl, alkoxyl, vinyl, and aryl substituents. The ability to prepare highly functionalized
pyrrolinones makes this an attractive route to these important and versatile pharmaceuticals.
Introduction
protease.10 The versatility of pyrrolinones is extended upon
hydrogenation to their pyrrolidinone analogues. Additional
biological activities have been described, including HIV protease
inhibition,11 cognitive performance enhancement,12 selective
estrogen receptor modulation (SERM),13 anticonvulsant activi-
ties,14 renin inhibition,15 and amnesia reversal activity.16
Pyrrolinones have been prepared from catalytic methods
which include the ruthenium catalyzed Alder-ene reaction17 and
ring closing metathesis,18 the rhodium catalyzed hydrocarbo-
nylation of alkenamides,19 and the iron catalyzed carbonylation
of allenyl imines.20 Though many catalytic processes result in
limited chirality, racemic pyrrolinones have been efficiently
resolved by enzymatic kinetic resolution to their enantiomeric
counterparts.21
It has been our goal in recent years to discover and develop
rhodium catalyzed transformations of functionalized alkynes
utilizing the zwitterionic rhodium complex (η6-C6H5BPh3)-Rh+-
(1,5-COD (1) in the presence of CO and H2. A fascinating aspect
to this research concerns the chemo- and regioselectivity effects
directed by functional groups adjacent to a triple bond. We have
demonstrated the regioselective hydroformylation of both
enynes1 and acetylenic thiophenes2 to their R,â-unsaturated
aldehydes and the chemo- and regioselective cyclohydrocarbo-
nylation of R-keto alkynes and acetylenic thiazoles to furanones3
and thiazepinones.4
It was anticipated that the use of R-imino alkynes as
functionalized alkynes for the reaction with CO/H2 and 1 would
(10) Smith, A. B., III; Hirschmann, R.; Pasternak, A.; Guzman, M. C.;
Yokoyama, A.; Sprengeler, P. A.; Darke, P. L.; Emini, E. A.; Schleif, W.
A. J. Am. Chem. Soc. 1995, 117, 11113.
(11) Spaltenstein, A.; Almond, M. R.; Bock, W. J.; Cleary, D. G.; Furfine,
E. S.; Hazen, R. J.; Kazmierski, W. M.; Salituro, F. G.; Tung, R. D.; Wright,
L. L. Bioorg. Med. Chem. Lett. 2000, 10, 1159.
(12) (a) Ogiso, T.; Iwaki, M.; Tanino, T.; Ikeda, K.; Paku, T.; Horibe,
Y.; Suzuki, H. J. Pharm. Sci. 1998, 87, 594. (b) Pinza, M.; Farina, C.;
Cerri, A.; Pfeiffer, U.; Riccaboni, M. T.; Banfi, S.; Biagetti, R.; Pozzi, O.;
Magnani, M.; Dorigotti, L. J. Med. Chem. 1993, 36, 4214.
(13) Grese, T. A.; Pennington, L. D.; Sluka, J. P.; Adrian, M. D.; Cole,
H. W.; Fuson, T. R.; Magee, D. E.; Phillips, D. L.; Rowley, E. R.; Shetler,
P. K.; Short, L. L.; Venugopalan, M.; Yang, N. N.; Sato, M.; Glasebrook,
A. L.; Bryant, H. U. J. Med. Chem. 1998, 41, 1272.
(14) (a) Reddy, P. A.; Hsiang, B. C. H.; Latifi, T. N.; Hill, M. W.;
Woodward, K. E.; Rothman, S. M.; Ferrendelli, J. A.; Covey, D. F. J. Med.
Chem. 1996, 39, 1898. (b) Yong, A. K.; Stemp, G.; Blackburn, T. P.;
Buckingham, R. E.; Chan, W. N.; Evans, J. M.; Hadley, M. S.; Thompson,
M.; Upton, N.; Stean, T. O. Bioorg. Med. Chem. Lett. 1995, 5, 1163.
(15) Williams, P. D.; Perlow, D. S.; Payne, L. S.; Holloway, M. K.;
Siegl, P. K. S.; Schorn, T. W.; Lynch, R. J.; Strouse, J. F.; Vlasuk, G. P.;
Hoogsteen, K.; Springer, J. P.; Bush, L.; Halgren, T. A.; Richards, A. D.;
Kay, J.; Veber, D. F. J. Med. Chem. 1991, 34, 887.
Pyrrolinones, especially enantiomerically pure forms, are
pharmacologically active materials that are important synthons
in the preparation of γ-amino acids,5 various alkaloids,6 and
natural products.7 These five-membered rings express antitumor
properties,8 as well as inhibition of COX-29 and HIV-1
(1) Van den Hoven, B. G.; Alper, H. J. Org. Chem. 1999, 64, 3964.
(2) Van den Hoven, B. G.; Alper, H. J. Org. Chem. 1999, 64, 9640.
(3) Van den Hoven, B. G.; El Ali, B.; Alper, H. J. Org. Chem. 2000,
65, 4131.
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(5) (a) Ma, D.; Ma; J.; Ding, W.; Dai, L. Tetrahedron: Asymmetry 1996,
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2845.
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62, 1206.
(17) Trost, B. M.; Roth, G. J. Org. Lett. 1999, 1, 67.
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C.; Ferna´ndez, A. G.; Miquel, I.; Ferna´ndez-Serrat, A.; Farrerons, C. Bioorg.
Med. Chem. Lett. 2000, 10, 1745.
(18) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 7324.
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(20) Sigman, M. S.; Eaton, B. E. J. Org. Chem. 1994, 59, 7488.
10.1021/ja011710n CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/27/2001

Synthesis of 4-Carbaldehydepyrrolin-2-ones
J. Am. Chem. Soc., Vol. 123, No. 42, 2001 10215
afford pyrrolinones. We now describe a novel chemo- and
regioselective route to 4-carbaldehydepyrrolin-2-ones in 67-
82% yields by the zwitterionic rhodium complex (1) and
triphenyl phosphite catalyzed cyclohydrocarbonylation/CO in-
sertion of trisubstituted acetylenic imines.
zwitterionic rhodium complex (1) and triphenyl phosphite
affords the pyrrolin-2-one (8) and the 4-carbaldehydepyrrolin-
2-one (9) (eq 4). The reaction is both temperature and pressure
dependent. The use of 1.5 mmol of 7 with 2 mol % of 1, 8 mol
% of (PhO)3P, 10 mL of CH2Cl2, and total pressures of 21 and
42 atm at optimum CO/H2 ratios of 5:1 and 11:1 affords various
mixtures of 8 and 9. Temperatures between 70 and 100 °C favor
the production of 9 over 8 with some residual polymeric
material. The longer the reaction takes place at these elevated
temperatures, the greater the abundance of 9. The temperature
and time dependence of 9 has lead us to reason that 9 likely
arises from 8 or an intermediate closely related to 8.
Results and Discussion
There are many approaches to the preparation of alkynyl
imines. In our study, we utilized two routes: (a) the direct
amination/dehydration of alkynones (eq 1 and Table S1;
throughout the text, the S refers to Supporting Information)22
and (b) the cross coupling reaction between imidoyl chlorides
(5) and terminal alkynes (6) using catalytic amounts of
Pd(PPh3)2Cl2 and CuI (eq 2, Table S4).23 Imidoyl chlorides (eq
3) were prepared by the direct reaction of secondary amides
(4) with SOCl2 (Table S2)24 or by the reaction of acyl chlorides
(2) with aza-Wittig reagents (3) (Table S3).25 In this manner,
hex-3-yn-2-one was reacted with primary amines to form Schiff
bases in 66-78% yields, while imino alkynes (7) were formed
in 65-96% yields, obtained from the terminal alkyne to imidoyl
chloride (5) coupling reaction. These trisubstituted alkynyl
imines (7) readily incorporate alkyl, alkoxyl, vinyl, and aryl
groups in the R1, R2, and R3 positions.
The tandem cyclohydrocarbonylation/CO insertion of imino
alkynes was evaluated by determining the dependence on R2
(Table 1), R3 (Table 2), and R1 (Table 3). To initiate our
investigation, imino alkynes with R1 ) methyl, R3 ) ethyl, and
R2 groups containing n-butyl, isopropyl, cyclohexyl, and ethyl
phenyl were determined to react best by treating 1.5 mmol of
7 with 2 mol % of the zwitterionic rhodium complex (1), 8
mol % of triphenyl phosphite, 10 mL of CH2Cl2, 18.5 atm of
CO, and 3.5 atm of H2 in a 45 mL autoclave for 18-36 h at
100 °C. Placement of a minimum two carbon spacer between
the imino nitrogen and a substituent within R2 removes possible
steric interference and allows the reaction to 9 to be complete
within 18 h (Table 1, entries 1 and 5). The addition of
substituents to C1 of R2 required an increased reaction time of
24 h when R2 is isopropyl (Table 1, entry 2) and 36 h when R2
is cyclohexyl (Table 1, entry 3). Utilizing 2-methyltetrahydro-
furan as R2 (7d) preferentially leads to 9d at 80 °C instead of
100 °C. Higher temperatures result in a dark discoloration of
the reaction mixture and inhibiton of 9d. The placement of allyl
(7f), benzyl (7g), and methylbenzyl (7h) groups at R2 results
in products with no CO incorporation. Aromatic R2 groups such
as phenyl (7w), tolyl (7x), and 4-chlorophenyl (7y) revealed a
complicated reaction mixture where 8 was minor and 9 was no
longer present.
The unique transformation of 7 to 9 (eq 5) may be extended
to R-imino alkynes where R1 contains an aromatic unit. These
unsaturates preferentially react at 90 °C with a total pressure
of 42 atm and a CO/H2 ratio of 11/1. To determine the scope at
(21) (a) Cuiper, A. D.; Kouwijzer, M. L. C. E.; Grootenhuis, P. D. J.;
Kellogg, R. M.; Feringa, B. L. J. Org. Chem. 1999, 64, 9529. (b) van der
Deen, H.; Cuiper, A. D.; Hof, R. P.; van Oeveren, A.; Ferimha, B. L.;
Kellogg, R. M. J. Am. Chem. Soc. 1996, 118, 3801.
(22) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc.
2001, 123, 2074.
(23) (a) Lin, S.-Y.; Sheng, H.-Y.; Huang, Y.-Z. Synthesis 1991, 235.
(b) Faust, R.; Go¨belt, B. Tetrahedron Lett. 1997, 38, 8017.
(24) Kantlehner, W.; Mergen, W. W. In ComprehensiVe Organic
Functional Group Transformations; Katritzky, A. R., Meth-Cohn, O., Rees,
C. W., Eds.; Pergamon: Tarrytown, NY, 1995; Vol. 5, Chapter 17.
(25) (a) Shi, C.; Wang, K. K. J. Org. Chem. 1998, 63, 3517. (b) Shi, C.;
Zhang, Q.; Wang, K. K. J. Org. Chem. 1999, 64, 925.
The reaction of an alkynyl imine (7) with carbon monoxide
and hydrogen in the presence of catalytic quantities of the

10216 J. Am. Chem. Soc., Vol. 123, No. 42, 2001
Van den HoVen and Alper
Table 1. Tandem Cyclohydrocarbonylation/CO Insertion of R-Imino Alkyne with Different R2 Groupsa
a Reaction conditions: 7, 1.5 mmol; 1, 0.03 mmol (2 mol %); (PhO)3P, 0.12 mmol (8 mol %); CH2Cl2, 10 mL; CO, 17.5 atm; H2, 3.5 atm. b The
reactions proceeded to full conversion (obtained by NMR), and the products were isolated by silica gel chromatography using 33:67 to 50:50 ethyl
acetate/hexane as eluant.
the alkynyl unit (R3), we evaluated imino alkynes with R1 )
phenyl and R2 ) n-butyl. The R3 group employed alkyl, alkoxyl,
pylidenepyrrolin-2-one 9k in 67% yield, as expected from our
recent study on alkynones (Table 2, entry 3).4 Aromatic R3 units
consisting of phenyl (7o) and 4-methoxyphenyl (7p) favor five-
membered pyrrolinones where the R2 group (n-butyl) is cleaved
and replaced by hydrogen.
To evaluate the effect of substitution on the aromatic R1 unit,
the R2 and R3 substituents used were isopropyl and n-butyl,
respectively, while the aromatic unit varied from phenyl (7q)
to 4-tolyl (7r) and 4-anisolyl (7s), forming 9q-s with 78-81%
yields (Table 3, entries 1-3). Placement of an electron
withdrawing group on the ring reduces the reactivity of 7.
Utilizing a 4-chlorophenyl substituted at R1 (7t) gives 9t in 72%
yield after 36 h (Table 3, entry 4), and 4-nitrophenyl (7v) affords
8v (64% yield) as the major product after reacting for 18 h. If
7v is permitted to react for additional time, the hydrogenation
of the nitro group to an amine begins to compete with the
production of 9, leading to a complicated reaction mixture.
Increasing the size of the aryl group from phenyl (7q) to
naphthyl (7u) requires a reaction time of 36 h to obtain 9u in
75% yield (Table 3, entry 5).
vinyl, and aryl groups (Table 2). Interestingly, increasing the
size of R3 to n-butyl (7i), isopropyl (7l), and methylcyclohexyl
(7m) has little influence on 9, as all reactions are complete
within 24 h and have comparable yields ranging from 75 to
79% (Table 2, entries 1, 4, and 5). Utilizing the tert-butyl
substituted R-imino alkyne (7n) causes the reaction to take place
very slowly (Table 2, entry 6), even at temperatures exceeding
110 °C, while placement of a methoxy methyl group (7j) and
a vinyl group (7k) at R3 favors a reaction temperature of 75
°C. In particular, 7j gives the demethoxylated product 9j in 72%
yield (Table 2, entry 2), and 7k gives the conjugated 3-isopro-
Certain criteria appear to be evident for the preparation of
4-carbaldehydepyrrolin-2-ones (9). The R1 unit may be alkyl
or aryl, while R2 and R3 preferentially give 9 when strong
electron donating groups are used, as well as groups that are
nonconjugating to the imino alkyne. Increasing the size of the
R1 and R2 groups decreases the reactivity toward cyclization.
Primary and secondary substituted R3 groups have minimal

Synthesis of 4-Carbaldehydepyrrolin-2-ones
J. Am. Chem. Soc., Vol. 123, No. 42, 2001 10217
Table 2. Tandem Cyclohydrocarbonylation/CO Insertion of R-Imino Alkyne with Different R3 Groupsa
a Reaction conditions: 7, 1.5 mmol; 1, 0.03 mmol (2 mol %); (PhO)3P, 0.12 mmol (8 mol %); CH2Cl2, 10 mL; CO, 38.5 atm; H2, 3.5 atm. b The
reactions proceeded to full conversion (obtained by NMR), and the products were isolated by using silica gel chromatography using 33:67 to 50:50
ethyl acetate/hexane as eluant.
reactivity differences, but placement of tertiary substituted
groups appreciably reduce the reactivity of the imino alkyne.
In 1995, it was observed that catalytic amounts of the
zwitterionic rhodium complex (1) and bisdiphenylphosphinobu-
tane readily hydrogenate imines in the presence of hydrogen
and methanol.26 In our reaction system, we have placed an imine
under hydroformylation conditions. As a result, there is potential
for formamides to be produced which may lead to the cyclization
we have observed. To determine whether the imine functional
group initiated the cyclization with the alkyne in a CO and H2
atmosphere, we prepared sec-butylideneisopropylamine and
isopropyl(1-phenylethylidene)amine and reacted them under our
conditions. After 24 h, neither imine generated the expected
formamides, and only trace amounts of the hydrogenated
counterparts were observed. The lack of formamides implied
that cyclization to the core pyrrolinone ring must originate from
the rhodium addition to the triple bond and a consequential acyl
rhodium intermediate or that the presence of a triple bond
adjacent to the imine functionality alters its reactivity to allow
the rhodium to initially add to the imine.
whether 9 originated from 8, we placed a number of pyrrolinones
8 (isolated prior to substrate optimization) back under a carbon
monoxide/hydrogen atmosphere or a complete carbon monoxide
atmosphere. Reintroduction of 8 utilizing the conditions noted
for 7,27 under a CO/H2 or a CO atmosphere, resulted in low
conversions to 9 after 24 h. These results indicate for the
conversion of R-imino alkynes to 4-carbaldehydepyrroli-2-ones
that 8 is the minor and not the major route to 9.
A possible mechanism is outlined in Scheme 2. The active
rhodium complex (10), generated from 1 (Scheme 2), binds to
the acetylenic imine via the triple bond and the imine (11) or
directly to the imine (12). Intramolecular hydrorhodation leads
to 13, and subsequent carbonylation gives 14. Reorientation of
14 to 15 promotes intramolecular cyclization across the triple
bond to the 4-rhodiumpyrrolinone (16). Hydrogen addition to
15 creates the trisubstituted pyrrolinone 8 and regenerates the
rhodium complex 10. Alternatively, 16 undergoes CO insertion
to generate 17. Addition of H2 generates the aldehyde substituted
pyrrolinone ring 9 and regenerates the rhodium complex 10.
In conclusion, we have described a unique preparation of
tetrasubstituted pyrrolinones. The unexpected tandem cyclohy-
drocarbonylation/CO insertion catalyzed by zwitterionic rhodium
In our reaction system, the presence of both 8 and 9 leads us
to speculate that 9 may originate from 8 or that an intermediate
related to 8 may lead to both 8 and 9 (Scheme 1). To test
(27) Please see the Supporting Information for procedures used to
(26) Zhou, Z.; James, B. R.; Alper, H. Organometallics 1995, 14, 4209.
reintroduce 8 to a CO or CO/H2 atmosphere.

10218 J. Am. Chem. Soc., Vol. 123, No. 42, 2001
Van den HoVen and Alper
Table 3. Tandem Cyclohydrocarbonylation/CO Insertion of R-Imino Alkyne with Substituted Aromatic R1 Groupsa
a Reaction conditions: 7, 1.5 mmol; 1, 0.03 mmol (2 mol %); (PhO)3P, 0.12 mmol (8 mol %); CH2Cl2, 10 mL; CO, 38.5 atm; H2, 3.5 atm. b The
reactions proceeded to full conversion (obtained by NMR), and the products were isolated by silica gel chromatography using 33:67 to 50:50 ethyl
acetate/hexane as eluant.
Scheme 1. Possible Route to 8 and 9
complex 1 (η6-C6H5BPh3)-Rh+(1,5-COD) and triphenyl phos-
liner and stirring bar was placed zwitterionic rhodium complex 1 (0.03
mmol), triphenyl phosphite (0.12 mmol), acetylenic imine 7 (1.5 mmol),
phite is both electronically and sterically controlled within the
and CH2Cl2 (10 mL). The autoclave was flushed three times with carbon
acetylenic imine. Utilizing a reasonable degree of control, these
monoxide, pressurized from 17.5 to 38.5 atm followed by the
4-carbaldehydepyrrolin-2-ones are readily prepared and have
introduction of hydrogen to a total pressure of 21-42 atm. The
potential use as precursors toward important pharmacological
applications.
autoclave was placed in an oil bath at 75-100 °C for 18-36 h and
then allowed to cool to room temperature. The autoclave was depres-
surized, the reaction mixture filtered through Celite, and the solvent
Experimental Section
removed by rotary evaporation. The resulting residue was purified by
silica gel chromatography using an ethyl acetate/hexanes gradient
ranging from 33:67 to 50:50 as the eluant to afford 9 (Tables 1-3).
Materials. All acyl chlorides, primary amines, and terminal alkynes
were purchased from commercial sources. The zwitterionic rhodium
complex, (η6-C6H5BPh3)-Rh+(1,5-COD) (1), was prepared according
to the procedure of Schrock and Osborn.28 All solvents were dried and
distilled under N2 prior to use.
1-Butyl-4-carbaldehyde-3-ethyl-5-methyl-3-pyrrolin-2-one (9a).
1
Colorless liquid; IR ν1(CdO) 1727 cm-1, ν2(CdO) 1644 cm-1; H
NMR (500 MHz, CDCl3) δ 9.71 (s, 1H), 3.55 (t, 1H, J ) 7.7 Hz),
3.45 (t, 1H, J ) 7.7 Hz), 3.30 (m, 1H), 2.38 (br, 3H), 2.01 (m, 2H),
1.52 (q, 2H, J ) 7.7 Hz), 1.32 (sextet, 2H, J ) 7.7 Hz), 0.92 (t, 3H,
J ) 7.4 Hz), 0.71 (t, 3H, J ) 7.5 Hz); 13C NMR (200 MHz, CDCl3)
δ 182.9, 180.1, 159.9, 118.8, 46.0, 40.5, 31.9, 22.5, 20.7, 14.3, 11.4,
General Procedure for the Cyclohydrocarbonylative/CO Inser-
tion of Acetylenic Imines. In a 45 mL autoclave containing a glass
(28) Schrock, R. R.; Osborn, J. A. Inorg. Chem. 1970, 9, 2339.

Synthesis of 4-Carbaldehydepyrrolin-2-ones
J. Am. Chem. Soc., Vol. 123, No. 42, 2001 10219
Scheme 2. Proposed Mechanism
9.6; EI MS (m/z) 209 [M+]; HRMS calculated for C12H19NO2 [M+],
209.141 58; found, 209.141 73.
11.0, 9.1; EI MS (m/z) 237 [M+]; HRMS calculated for C13H19NO3
[M+], 237.136 49; found, 237.135 25.
4-Carbaldehyde-3-ethyl-1-isopropyl-5-methyl-3-pyrrolin-2-one (9b).
4-Carbaldehyde-3-ethyl-5-methyl-1-phenethyl-3-pyrrolin-2-one
(9e). Yellow liquid; IR ν1(CdO) 1725 cm-1, ν2(CdO) 1642 cm-1; 1H
NMR (200 MHz, CDCl3) δ 9.61 (s, 1H), 7.10-7.27 (m, 5H), 3.62-
3.79 (m, 2H), 2.90 (m, 1H), 2.86 (t, 2H, J ) 6.6 Hz), 1.99 (q, 2H, J )
7.4 Hz), 1.95 (br, 3H), 0.74 (t, 3H, J ) 7.4 Hz); 13C NMR (200 MHz,
CDCl3) δ 182.4, 179.5, 159.4, 137.8, 129.8, 128.9, 127.0, 118.0, 45.4,
42.1, 35.1, 21.8, 10.3, 9.3; EI MS (m/z) 257 [M+]; HRMS calculated
for C16H19NO2 [M+], 257.141 58; found, 257.143 01.
1
Colorless liquid; IR ν1(CdO) 1725 cm-1, ν2(CdO) 1641 cm-1; H
NMR (300 MHz, CDCl3) δ 9.61 (s, 1H), 4.05 (septet, 1H, J ) 6.5
Hz), 3.17 (m, 1H), 2.32 (br, 3H), 1.92 (m, 2H), 1.35 (d, 3H, J ) 6.2
Hz), 1.33 (d, 3H, J ) 6.3 Hz), 0.61 (t, 3H, J ) 7.5 Hz); 13C NMR
(300 MHz, CDCl3) δ 182.3, 179.6, 159.6, 118.1, 45.4, 21.7, 20.1, 19.9,
11.1, 8.5; EI MS (m/z) 195 [M+]; HRMS calculated for C11H17NO2
[M+], 195.125 93; found, 195.127 07.
4-Carbaldehyde-1-cyclohexyl-3-ethyl-5-methyl-3-pyrrolin-2-
one (9c). Colorless liquid; IR ν1(CdO) 1723 cm-1, ν2(CdO) 1642
cm-1; 1H NMR (200 MHz, CDCl3) δ 9.67 (s, 1H), 3.59 (m, 1H), 3.23
(m, 1H), 2.36 (br, 3H), 1.57-2.22 (m, 8H), 1.18-1.30 (m, 4H), 0.65
(t, 3H, J ) 7.6 Hz); 13C NMR (200 MHz, CDCl3) δ 182.5, 179.8,
159.8, 118.2, 54.1, 45.5, 29.9, 29.7, 26.0, 24.9, 21.9, 11.4, 8.6; EI MS
(m/z) 235 [M+]; HRMS calculated for C14H21NO2 [M+], 235.157 23;
found, 235.155 58.
1,3-Dibutyl-4-carbaldehyde- -5-phenyl-4-pyrrolin-2-one (9i). Yel-
1
low liquid; IR ν1(CdO) 1727 cm-1, ν2(CdO) 1649 cm-1; H NMR
(300 MHz, CDCl3) δ 9.12 (s, 1H), 7.44-7.48 (m, 3H), 7.32-7.38 (m,
2H), 3.31-3.43 (m, 3H), 1.98 (q, 2H, J ) 7.2 Hz), 1.18-1.28 (m,
6H), 1.03 (sextet, 2H, J ) 7.7 Hz), 0.79 (t, 3H, J ) 7.1 Hz), 0.65 (t,
3H, J ) 7.3 Hz); 13C NMR (300 MHz, CDCl3) δ 184.6, 179.3, 161.7,
130.3, 128.8, 128.5, 126.9, 119.9, 44.6, 40.1, 30.3, 28.3, 26.7, 22.3,
19.3, 13.5, 13.0; EI MS (m/z) 299 [M+]; HRMS calculated for C19H25-
NO2 [M+], 299.188 53; found, 299.187 08. Anal. Calcd for C19H25-
NO2: C, 76.22; H, 8.42; N, 4.68. Found: C, 76.10; H, 8.30; N, 4.46.
1-Butyl-4-carbaldehyde-3-methyl-5-phenyl-4-pyrrolin-2-one (9j).
Yellow liquid; IR ν1(CdO) 1730 cm-1, ν2(CdO) 1648 cm-1; 1H NMR
(300 MHz, CDCl3) δ 9.20 (s, 1H), 7.51-7.53 (m, 3H), 7.39-7.41 (m,
2H), 3.39-3.42 (m, 3H), 1.47 (d, 3H, J ) 7.6 Hz), 1.32 (q, 2H, J )
4-Carbaldehyde-3-ethyl-5-methyl-1-(tetrahydrofuran-2-ylmethyl)-
3-pyrrolin-2-one (9d). Yellow liquid; IR ν1(CdO) 1726 cm-1
,
ν2(CdO) 1642 cm-1; 1H NMR (200 MHz, CDCl3) δ 9.67 (s, 1H), 3.95
(m, 1H), 3.59-3.82 (m, 3H), 3.26-3.46 (m, 2H), 2.39 (br, 3H), 1.75-
2.09 (m, 6H), 0.68 (t, 3H, J ) 7.4 Hz); 13C NMR (200 MHz, CDCl3)
δ 182.6, 179.8, 160.6, 118.0, 77.1, 68.0, 45.4, 44.1, 29.0, 25.5, 21.8,

10220 J. Am. Chem. Soc., Vol. 123, No. 42, 2001
Van den HoVen and Alper
7.4 Hz), 1.08 (sextet, 2H, J ) 7.3 Hz), 0.72 (t, 3H, J ) 7.3 Hz); 13C
NMR (300 MHz, CDCl3) δ 185.0, 180.3, 161.7, 130.7, 129.2, 128.9,
127.2, 122.2, 40.4, 40.0, 30.7, 19.6, 14.9, 13.4; EI MS (m/z) 257 [M+];
HRMS calculated for C16H19NO2 [M+], 257.141 58; found, 257.140 55.
1-Butyl-4-carbaldehyde-3-isopropylidene-5-phenyl-4-pyrrolin-2-
3H, J ) 6.9 Hz), 1.10-1.26 (m, 4H), 0.84 (t, 3H, J ) 7.2 Hz); 13C
NMR (300 MHz, CDCl3) δ 185.3, 180.1, 163.2, 140.9, 129.5, 129.3,
128.9, 124.6, 120.2, 46.8, 45.3, 28.7, 26.7, 22.6, 21.4, 20.0, 19.6, 13.8;
EI MS (m/z) 299 [M+]; HRMS calculated for C19H25NO2 [M+],
299.188 53; found, 299.187 09.
3-Butyl-4-carbaldehyde-1-isopropyl-5-(4-methoxyphenyl)-4-pyr-
rolin-2-one (9s). Yellow liquid; IR ν1(CdO) 1725 cm-1, ν2(CdO) 1646
cm-1; 1H NMR (300 MHz, CDCl3) δ 9.13 (s, 1H), 7.25-7.27 (m, 2H),
7.00 (d, 2H, J ) 8.9 Hz), 3.85 (s, 3H), 3.76 (septet, 1H, J ) 6.9 Hz),
3.39 (m, 1H), 2.00 (m, 2H), 1.37 (d, 3H, J ) 6.9 Hz), 1.31 (d, 3H, J
) 6.8 Hz), 1.10-1.26 (m, 4H), 0.84 (t, 3H, J ) 7.3 Hz); 13C NMR
(300 MHz, CDCl3) δ 185.3, 180.1, 163.0, 161.3, 130.9, 130.5, 120.3,
119.5, 114.3, 55.4, 46.7, 45.4, 28.7, 26.8, 22.6, 20.0, 19.7, 13.9; EI
MS (m/z) 315 [M+]; HRMS calculated for C17H25NO3 [M+], 315.183 44;
found, 315.181 92. Anal. Calcd for C17H25NO3: C, 72.35; H, 7.99; N,
4.44. Found: C, 72.17; H, 7.93; N, 4.36.
one (9k). Yellow liquid; IR ν1(CdO) 1730 cm-1, ν2(CdO) 1648 cm-1
;
1H NMR (300 MHz, CDCl3) δ 9.16 (s, 1H), 7.46-7.49 (m, 3H), 7.33-
7.36 (m, 2H), 3.43 (t, 2H, J ) 7.5 Hz), 2.50 (s, 3H), 2.46 (s, 3H), 1.33
(quintet, 2H, J ) 7.5 Hz), 1.10 (sextet, 2H, J ) 7.6 Hz), 0.70 (t, 3H,
J ) 7.3 Hz); 13C NMR (300 MHz, CDCl3) δ 184.3, 167.3, 161.3, 160.8,
130.2, 129.5, 128.6, 128.0, 127.7, 121.6, 115.3, 40.6, 30.9, 28.0, 23.7,
19.7, 13.3; EI MS (m/z) 283 [M+]; HRMS calculated for C18H21NO2
[M+], 283.157 23; found, 283.155 25.
1-Butyl-4-carbaldehyde-3-isopropyl-5-phenyl-4-pyrrolin-2-one (9l).
Yellow liquid; IR ν1(CdO) 1726 cm-1, ν2(CdO) 1649 cm-1; 1H NMR
(300 MHz, CDCl3) δ 9.18 (s, 1H), 7.46-7.52 (m, 3H), 7.35-7.38 (m,
2H), 3.47 (m, 1H), 3.35 (d, 1H, J ) 3.3 Hz), 2.63 (septet, 1H, J ) 6.9
Hz), 1.36 (m, 1H), 1.28 (quintet, 2H, J ) 6.9 Hz), 1.18 (d, 3H, J )
7.0 Hz), 1.07 (sextet, 2H, J ) 7.5 Hz), 0.86 (d, 3H, J ) 7.0 Hz), 0.67
(t, 3H, J ) 7.3 Hz); 13C NMR (300 MHz, CDCl3) δ 185.0, 178.5,
162.9, 130.6, 129.1, 128.8, 127.3, 119.8, 50.5, 40.3, 30.7, 29.2, 19.7,
19.4, 17.5, 13.3; EI MS (m/z) 285 [M+]; HRMS calculated for C18H23-
NO2 [M+], 285.172 88; found, 285.171 65. Anal. Calcd for C18H23-
NO2: C, 75.76; H, 8.12; N, 4.91. Found: C, 75.61; H, 8.08; N, 4.74.
1-Butyl-4-carbaldehyde-3-cyclohexylmethyl-5-phenyl-4-pyrrolin-
2-one (9m). Yellow liquid; IR ν1(CdO) 1727 cm-1, ν2(CdO) 1649
cm-1; 1H NMR (300 MHz, CDCl3) δ 9.20 (s, 1H), 7.47-7.54 (m, 3H),
7.34-7.38 (m, 2H), 3.29-3.50 (m, 3H), 1.78-1.94 (m, 2H), 1.51-
1.68 (m, 7H), 0.90-1.36 (m, 8H), 0.71 (t, 3H, J ) 7.3 Hz); 13C NMR
(300 MHz, CDCl3) δ 185.0, 179.9, 161.5, 130.6, 129.1, 128.8, 127.4,
121.3, 43.0, 40.0, 36.8, 34.7, 33.9, 32.9, 30.6, 26.4, 26.2, 26.1, 19.7,
13.4; EI MS (m/z) 339 [M+]; HRMS calculated for C22H29NO2 [M+],
339.219 83; found, 339.218 33. Anal. Calcd for C22H29NO2: C, 77.84;
H, 8.61; N, 4.13. Found: C, 77.64; H, 8.75; N, 4.01.
3-Butyl-4-carbaldehyde-1-isopropyl-5-phenyl-4-pyrrolin-2-one (9q).
Yellow liquid; IR ν1(CdO) 1726 cm-1, ν2(CdO) 1648 cm-1; 1H NMR
(300 MHz, CDCl3) δ 9.08 (s, 1H), 7.46-7.51 (m, 3H), 7.31-7.36 (m,
2H), 3.69 (septet, 1H, J ) 6.9 Hz), 3.38 (t, 1H, J ) 5.5 Hz), 2.00 (m,
2H), 1.34 (d, 3H, J ) 6.9 Hz), 1.28 (d, 3H, J ) 6.9 Hz), 1.11-1.26
(m, 4H), 0.82 (t, 3H, J ) 7.2 Hz); 13C NMR (300 MHz, CDCl3) δ
185.0, 179.9, 162.8, 130.5, 129.3, 129.0, 128.8, 127.6, 120.2, 46.8,
45.3, 28.6, 26.7, 22.5, 20.0, 19.6, 13.8; EI MS (m/z) 285 [M+]; HRMS
calculated for C18H23NO2 [M+], 285.172 88; found, 285.171 36. Anal.
Calcd for C18H23NO2: C, 75.76; H, 8.12; N, 4.91. Found: C, 75.91;
H, 7.92; N, 4.84.
3-Butyl-4-carbaldehyde-1-isopropyl-5-(4-chlorophenyl)-4-pyrro-
lin-2-one (9t). Yellow oil; IR ν1(CdO) 1726 cm-1, ν2(CdO) 1649
1
cm-1; H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 7.50 (d, 2H, J )
8.7 Hz), 7.28-7.33 (m, 2H), 3.69 (septet, 1H, J ) 6.9 Hz), 3.41 (t,
1H, J ) 5.4 Hz), 1.97-2.07 (m, 2H), 1.36 (d, 3H, J ) 6.9 Hz), 1.31
(d, 3H, J ) 6.9 Hz), 1.10-1.27 (m, 4H), 0.84 (t, 3H, J ) 7.2 Hz); 13
C
NMR (300 MHz, CDCl3) δ 184.6, 179.8, 161.3, 137.0, 130.7, 130.4,
129.8, 129.3, 126.1, 120.7, 46.9, 45.4, 28.7, 26.8, 22.6, 20.1, 19.8, 13.9;
EI MS (m/z) 319 [M+]; HRMS calculated for C18H22NO2Cl [M+],
319.133 91; found, 319.134 76.
3-Butyl-4-carbaldehyde-1-isopropyl-5-(2-naphthalenyl)-4-pyrro-
lin-2-one (9u). Yellow oil; IR ν1(CdO) 1725 cm-1, ν2(CdO) 1647
cm-1; 1H NMR (300 MHz, CDCl3) δ 9.17 (s, 1H), 7.88-7.99 (m, 4H),
7.53-7.63 (m, 2H), 7.36-7.42 (m, 1H), 3.77 (septet, 1H, J ) 6.8 Hz),
3.44-3.51 (m, 1H), 2.00-2.14 (m, 2H), 1.16-1.45 (m, 10H), 0.89 (t,
1.5H, J ) 6.7 Hz), 0.87 (t, 1.5H, J ) 6.6 Hz); 13C NMR (300 MHz,
CDCl3) δ 185.3, 185.1, 180.0, 162.9, 162.8, 133.7, 132.5, 129.8, 129.6,
128.9, 128.8, 128.3, 127.9, 127.4, 125.4, 125.0, 124.9, 120.6, 47.1,
47.0, 45.5, 28.9, 28.7, 26.9, 26.8, 22.6, 20.1, 20.0, 19.8, 19.6, 13.9; EI
MS (m/z) 335 [M+]; HRMS calculated for C22H25NO2 [M+], 35.188 53;
found, 335.189 05. Anal. Calcd for C22H25NO2: C, 78.77; H, 7.51; N,
4.18. Found: C, 79.00; H, 7.15; N, 3.87.
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council of Canada for support of
this research.
Supporting Information Available: Experimental proce-
dures for the synthesis of 4, 5, and 7. 1H and 13C NMR spectra
for 5a-5j, 7a-7y, 8e, 8k, 8t-8v, and 9a-9u (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
3-Butyl-4-carbaldehyde-1-isopropyl-5-p-tolyl-4-pyrrolin-2-one (9r).
Yellow liquid; IR ν1(CdO) 1727 cm-1, ν2(CdO) 1648 cm-1; 1H NMR
(300 MHz, CDCl3) δ 9.10 (s, 1H), 7.30 (d, 2H, J ) 8.2 Hz), 7.23-
7.25 (m, 2H), 3.73 (septet, 1H, J ) 6.9 Hz), 3.40 (t, 1H, J ) 5.2 Hz),
2.42 (s, 3H), 1.98-2.07 (m, 2H), 1.36 (d, 3H, J ) 6.9 Hz), 1.30 (d,
JA011710N