Modular one-pot synthesis of tetrasubstituted pyrroles from α-(alkylideneamino)nitriles

Article abstract of DOI:10.1021/jo070426x

(Chemical Equation Presented) 2,3,4,5-Tetrasubstituted pyrroles have been prepared with high regioselectivity by a formal cycloaddition of α-(alkylideneamino)nitriles and nitroolefins followed by elimination of HCN and HNO₂. The reaction allows

Full text of DOI:10.1021/jo070426x

Modular One-Pot Synthesis of Tetrasubstituted Pyrroles from
r-(Alkylideneamino)nitriles‡
Ines Bergner and Till Opatz*,†
Institute of Organic Chemistry, UniVersity of Mainz, Duesbergweg 10-14, D-55128 Mainz, Germany
opatz@chemie.uni-hamburg.de
ReceiVed March 1, 2007
2,3,4,5-Tetrasubstituted pyrroles have been prepared with high regioselectivity by a formal cycloaddition
of R-(alkylideneamino)nitriles and nitroolefins followed by elimination of HCN and HNO2. The reaction
allows the convergent construction of the pyrrole ring in four steps from a nitroalkane and three aldehydes.
Introduction
example is the top-selling drug atorvastatin (Lipitor), which is
applied as an antihyperlipidemic agent.14 Consequently, a large
number of synthetic methods for the construction of the pyrrole
ring have been developed, for example, the Knorr,15 Paal-
Knorr,16,17 and Hantzsch syntheses,18 [3 + 2]-cycloadditions,19-21
multicomponent reactions,22-24 and ring contractions25 or
cyclizations.26-29 Here, we describe facile access to highly
Pyrroles are found as key structural elements in a vast number
of natural products, for example, the marine and terrestrial
pyrrole alkaloids, pyrrole-imidazole alkaloids, and the ubiquitous
porphyrins.1-7 In addition, pyrrole derivatives have found broad
application in medicine and materials science.8-13 A well-known
† Present address: Institute of Organic Chemistry, University of Hamburg,
Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany.
‡ Dedicated to Prof. Herbert Waldmann on the occasion of his 50th birthday.
(1) Bailly, C. Curr. Med. Chem.sAnti-Cancer Agents 2004, 4, 363-
378.
(2) Christophersen, C. In Alkaloids; Brossi, A., Ed.; Academic Press:
New York, 1985, Vol. 24, pp 25-111.
(3) Le Quesne, P. W.; Dong, Y.; Blythe, T. A. In Alkaloids: Chemical
and Biological PerspectiVes; Pelletier, S. W., Ed.; Pergamon: Oxford, U.K.,
1999; Vol. 13, pp 237-287.
(13) Guernion, N. J. L.; Hayes, W. Curr. Org. Chem. 2004, 8, 637-
651.
(14) Roth, B. D. (Warner-Lambert Co.) EP Patent 409281, 1991.
(15) Knorr, L. Ber. Dtsch. Chem. Ges. 1884, 17, 1635-1642.
(16) Paal, C. Ber. Dtsch. Chem. Ges. 1885, 18, 367-371.
(17) Braun, R. U.; Mueller, T. J. J. Synthesis 2004, 2391-2406.
(18) Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474-1476.
(19) Van Leusen, A. M.; Siderius, H.; Hoogenboom, B. E.; Van Leusen,
D. Tetrahedron Lett. 1972, 5337-5340.
(4) Fuerstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582-3603.
(5) Faulkner, D. J. Nat. Prod. Rep. 1998, 15, 113-158.
(6) Milgrom, L. R. The Colors of Life: an Introduction to the Chemistry
of Porphyrins and Related Compounds; Oxford University Press: Oxford,
U.K., 1997.
(7) The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard,
R., Eds.; Academic Press: San Diego, CA, 2000.
(8) Kashman, Y.; Koren-Goldshlager, G.; Gravalos, M. D. G.; Schleyer,
M. Tetrahedron Lett. 1999, 40, 997-1000.
(9) Pindur, U.; Kim, Y. S.; Mehrabani, F. Curr. Med. Chem. 1999, 6,
29-69.
(20) Gribble, G. W.; Saulnier, M. G.; Pelkey, E. T.; Kishbaugh, T. L.
S.; Liu, Y.; Jiang, J.; Trujillo, H. A.; Keavy, D. J.; Davis, D. A.; Conway,
S. C.; Switzer, F. L.; Roy, S.; Silva, R. A.; Obaza-Nutaitis, J. A.; Sibi, M.
P.; Moskalev, N. V.; Barden, T. C.; Chang, L.; Habeski, W. M.; Pelcman,
B.; Sponholtz, W. R., III; Chau, R. W.; Allison, B. D.; Garaas, S. D.; Sinha,
M. S.; McGowan, M. A.; Reese, M. R.; Harpp, K. S. Curr. Org. Chem.
2005, 9, 1493-1519.
(21) Huisgen, R.; Gotthardt, H.; Bayer, H. O.; Schaefer, F. C. Chem.
Ber. 1970, 103, 2611-2624.
(22) St. Cyr, D. J.; Martin, N.; Arndtsen, B. A. Org. Lett. 2007, 9, 449-
452.
(23) Balme, G. Angew. Chem., Int. Ed. 2004, 43, 6238-6241.
(24) Shimizu, M.; Takahashi, A.; Kawai, S. Org. Lett. 2006, 8, 3585-
3587.
(25) Joshi, U.; Pipelier, M.; Naud, S.; Dubreuil, D. Curr. Org. Chem.
2005, 9, 261-288.
(10) Biava, M.; Fioravanti, R.; Porretta, G. C.; Deidda, D.; Maullu, C.;
Pompei, R. Bioorg. Med. Chem. Lett. 1999, 9, 2983-2988.
(11) Loya, S.; Rudi, A.; Kashman, Y.; Hizi, A. Biochem. J. 1999, 344,
85-92.
(12) MacDiarmid, A. G. Synth. Met. 1997, 84, 27-34.
10.1021/jo070426x CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/22/2007
J. Org. Chem. 2007, 72, 7083-7090
7083

Bergner and Opatz
SCHEME 1. General Reaction Course for the Formation of
Pyrroles
electrophile contains a potential leaving group, should allow
the preparation of polysubstituted pyrroles. Indeed, we found
that the reaction of R-(alkylideneamino)nitriles (1) with ni-
troolefins (2) under basic conditions directly furnishes 2,3,4,5-
tetrasubstituted pyrroles (9a-n) (Scheme 1, Table 3).
The course of the reaction presumably involves the conjugate
addition of the stabilized 2-azaallyl anion to the Michael
acceptor followed by nucleophilic attack of the resulting
nitronate to the imine carbon under formation of a 2-cyano-4-
nitropyrrolidine 5.31,38 Alternatively, compounds 5 could be
formed by a 1,3-dipolar cycloaddition of an azomethine ylide
equivalent derived from 1.38-40 Unfortunately, the regioisomeric
2-cyano-3-nitropyrrolidines 6 may be formed as well. Elimina-
tion of HCN from compounds 5 and 6 leads to the regioisomeric
nitropyrrolines 7 and 8, respectively, which exhibit different
behavior under the basic reaction conditions. In the 4-nitro-1-
pyrrolines 7, the potential leaving group is located in â-position
to the acidifying imine moiety and they readily eliminate HNO2
under formation of the pyrroles 9. In contrast, the 3-nitro-1-
pyrrolines 8 are more persistent, and elimination of HNO2 occurs
only under more drastic conditions, leading to the regioisomeric
pyrroles 10. Due to their different polarity, the chromatographic
separation of compounds 8 and 9 is much easier than the
separation of pyrroles 9 and 10. Therefore, it is advisable to
control the reaction conditions so that only the major addition
product is converted to the pyrrole. As the choice of base,
solvent, and temperature may also influence the regioselectivity
of the primary addition reaction, it is difficult to distinguish
between these effects only on the basis of yield and isomeric
ratio of the pyrrole fraction. When R-(alkylideneamino)nitrile
1a, nitroolefin 2a, and 2 equiv of KOtBu were heated in THF
to 60 °C, a mixture of the regioisomeric pyrroles 9a and 10a in
a ratio of 1.6:1 was isolated in 19% yield (entry 2, Table 1).
We tested several bases, solvents, and temperatures to optimize
yield as well as isomeric ratio and found out that isomerically
pure 9a (51% isolated yield) can be obtained with Cs2CO3 in
refluxing THF (see Tables 1 and 3).
substituted pyrroles by addition of R-(alkylideneamino)nitriles
to R,â-unsaturated nitro compounds under basic conditions.
Results and Discussion
R-(Alkylideneamino)nitriles (1) can be readily obtained by
condensation of Strecker products derived from ammonia with
aldehydes.30 The extended conjugation of their anions makes
them CH-acidic, so that even guanidine bases such as TBD or
amidine bases such as DBU suffice for their deprotonation. We
have recently demonstrated that the conjugate addition of
deprotonated R-(alkylideneamino)nitriles to R,â-unsaturated
ketones or esters31 can be used as the key step for the preparation
of highly substituted pyrrolidines32,33 and of γ-amino acid esters
and γ-lactams.34 In some cases, cyclization of the intermediate
enolates by means of a 5-endo-trig process cannot be
prevented.35-37 A similar reaction sequence, in which the
Reaction of imine 1b and nitroolefin 2a under these conditions
furnished pure pyrrole 9g in 36% yield along with the 3-nitro-
1-pyrroline 8g (31%), the relative configuration of which was
assigned by NOE experiments.
FIGURE 1. Isolated side product.
(26) Tejedor, D.; Gonzalez-Cruz, D.; Garcia-Tellado, F.; Marrero-Tellado,
J. J.; Rodriguez, M. L. J. Am. Chem. Soc. 2004, 126, 8390-8391.
(27) Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213-7256.
(28) Padwa, A.; Gruber, R.; Pashayan, D. J. Org. Chem. 1968, 33, 454-
455.
A different side product was obtained when 1b was reacted
with 1-nitrocyclohexene (2g) to pyrrole 9l. Examination of the
product by 2D NMR spectroscopy revealed the formation of
the 4-amino-5,6,7,8-tetrahydroisoquinoline 11 (17% yield). This
compound was presumably formed by attack of the benzylic
(29) Binder, J. T.; Kirsch, S. F. Org. Lett. 2006, 8, 2151-2153.
(30) Tsuge, O.; Ueno, K.; Kanemasa, S.; Yorozu, K. Bull. Chem. Soc.
Jpn. 1986, 59, 1809-1824.
(31) Tsuge, O.; Ueno, K.; Kanemasa, S.; Yorozu, K. Bull. Chem. Soc.
Jpn. 1987, 60, 3347-3358.
(37) Alva Astudillo, M. E.; Chokotho, N. C. J.; Jarvis, T. C.; Johnson,
C. D.; Lewis, C. C.; McDonnell, P. D. Tetrahedron 1985, 41, 5919-5928.
(38) Tatsukawa, A.; Kawatake, K.; Kanemasa, S.; Rudzinski, J. M. J.
Chem. Soc., Perkin Trans. 2 1994, 2525-2530.
(32) Meyer, N.; Opatz, T. Synlett 2004, 787-790.
(33) Meyer, N.; Werner, F.; Opatz, T. Synthesis 2005, 945-956.
(34) Bergner, I.; Opatz, T. Synthesis 2007, 918-928.
(35) Baldwin, J. E.; Cutting, J.; Dupont, W.; Kruse, L.; Silberman, L.;
Thomas, R. C. J. Chem. Soc., Chem. Commun. 1976, 736-738.
(36) Grigg, R.; Kemp, J.; Malone, J.; Tangthongkum, A. J. Chem. Soc.,
Chem. Commun. 1980, 648-650.
(39) Pearson, W. H.; Stoy, P. Synlett 2003, 903-921.
(40) Arrieta, A.; Otaegui, D.; Zubia, A.; Cossio, F. P.; Diaz-Ortiz, A.;
delaHoz, A.; Herrero, M. A.; Prieto, P.; Foces-Foces, C.; Pizarro, J. L.;
Arriortua, M. I. J. Org. Chem. 2007, 72, 4313-4322.
7084 J. Org. Chem., Vol. 72, No. 19, 2007

Modular One-Pot Synthesis of Tetrasubstituted Pyrroles
TABLE 1. Optimization of Reaction Conditions
entry
base (equiv)
solvent
temp, °C
time, h
product ratioa 9a:10a:8a
% 9aa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
KOtBu (1.05)
KOtBu (2.7)
KOtBu (2)
Me4NOH (2)
DBU (2)
THF
THF
THF
THF/MeOH 2:1
THF
THF
THF
THF
THF
60
60
60
25
25
25
25
25
25
25
25
25
25
25
25
25
60
60/25
120
16.5
3.5
18
18
18
18
18
18
23
23
23
23
23
23
23
8.5
7.5/16
1:0:0.7
1:0.9:0
1:0:0
1:0.5:0
1:0:1.7
nd
nd
nd
1:0:0.2
1:0:0.6
1:0:0.6
nd
33
19b
24c
17
23
KOtBu (2)
KOH (2)
ndd
nde
ndf
48
BaO (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2),
Bu4NHSO4 (0.1)
Cs2CO3 (2),
Bu4NHSO4 (0.1)
TBD (2)
MeCN
DMF
38
39
iPrOH/THF 3.5:1
dioxane
CH2Cl2
toluene
tBuOMe
THF
ndd
ndd
ndd
ndd
ndd
58
nd
nd
nd
nd
1:0:0.15
1:0.56:0.36
THF
39
19
THF
25
23.5
1:0:1.29
24
20
21
22
THF
MeOH
CH2Cl2
25
25
25
6
6
6
1:0.65:1.15
1:0:1.45
1:0.18:0.49
26
22
50
TBD (2)
TBD (2)
a Determined by 1H NMR spectroscopy (percentage: relative integral of 5-CH3 signal of 9a compared to all aromatic protons). b Combined isolated yield.
c Temperature was raised to 60 °C before the base was added. d Slow reaction with formation of side products. e Formation of side products. f No conversion.
SCHEME 2. Formation of Side Product 11
SCHEME 3. Pyrroles from â-Acetoxynitroalkanes
center of the 2-azaallyl anion on the â-carbon of the Michael
acceptor and subsequent nucleophilic attack of the resulting
nitronate on the nitrile carbon (Scheme 2).
4-cyanophenyl-substituted acceptor 2e led to the formation of
isomeric mixtures (entries 6 and 10). A rationale for this
behavior may be the enhanced acidity of H-4 in the correspond-
ing 3-nitro-1-pyrrolines (8), which accelerates the elimination
of HNO2 to form pyrroles 10.
Apart from nitroolefins, â-acetoxynitroalkanes can serve as
alternative electrophiles,42 although the resulting regioselectivi-
ties are lower. For instance, the reaction of 1a with acetate 12
So far, we could not identify conditions under which
compound 11 can be obtained as the major product. Microwave
irradiation increases the rate of the pyrrole synthesis compared
to conventional heating (complete conversion within 2 min).
However, the conditions had to be adapted to avoid formation
of the regioisomeric pyrroles. The best results were obtained
with DMF as the solvent at 100 °C (entry 8, Table 2). Again,
complete regioselectivity on the stage of the pyrrole was
observed with Cs2CO3 as a base.41
(41) While both conventional and microwave heating furnished crude
pyrroles with surprisingly clean NMR spectra, TLC also indicated the
formation of undefined polar (polymeric?) side products in all cases. This
largely accounts for the deviation of the combined yields of compounds 8
and 9 from unity.
Whereas the majority of the investigated nitroolefins could
be converted to isomerically pure pyrroles (Table 3), use of the
J. Org. Chem, Vol. 72, No. 19, 2007 7085

Bergner and Opatz
TABLE 2. Optimization of Reaction under Microwave Heating
entry
solvent
temp, °C
t (run), min
t (hold), min
product ratioa 9a:10a:8a
% 9aa
1
2
3
5
6
7
8
THF
67
81
79
150
150
100
100
1
2
2
2
2
2
2
2
2
2
2
2
2
2
nd
nd
nd
nd
1:0.22:0
1:0:0.4
1:0:0.34
ndb
ndb,c
ndb,c
ndb,d
39
CH3CN
EtOH
DMF
DMF
DMF
DMF
44
54e
1
a Determined by H NMR spectroscopy (percentage ) relative integral of CH3 signal at 2.34 ppm compared to all aromatic protons). b Formation of 9a
observed by TLC. c Complete conversion, formation of side products. d Complete conversion, formation of 9a and one side product. e Isolated yield.
TABLE 3. Preparation of Pyrroles 9
entry
imine
R1
2-Naph
2-Naph
2-Naph
2-Naph
2-Naph
2-Naph
2-Naph
R2
nitroolefin
R3
R4
Me
Me
Me
Et
n-Pent
Et
Ph
pyrrole
methoda
yield, %
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1d
1a
1b
1c
1c
1d
1d
Me
Me
Me
Me
Me
Me
Me
Bn
Bn
Ph
2a
2a
2b
2c
2d
2e
2f
2a
2a
2e
2f
2g
2g
2g
2g
2g
2g
4-Cl-C6H4
4-Cl-C6H4
3,4-(MeO)2C6H3
Me
9a
9a
9b
A
B
B
B
B
B
B
A
A
B
B
A
A
A
B
A
B
51
54
40
33
34
56
34
36
43
42
31
46
37
38
51
33
43
9c
Me
9d
4-CN-C6H4
Ph
4-Cl-C6H4
4-Cl-C6H4
4-CN-C6H4
Ph
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
9e/10e (7:1)
9f
2-Naph
Me
Me
Et
9g
9h
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
2-Naph
9i/10i (3:1)
Ph
Ph
9j
Me
Bn
Bn
Bn
Ph
9k
9l
9m
9m
9n
9n
2-Naph
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
3,4-(MeO)2C6H3
Ph
a Method A: 2 equiv of Cs2CO3, THF, reflux. Method B: 2 equiv of Cs2CO3, DMF, microwave heating, 100 °C.
with 3 equiv of Cs2CO3 in the microwave reactor furnished 9c
along with its regioisomer 10c (3.75:1) in 37% overall yield
(Scheme 3).
only acceptor-substituted products, our protocol also permits
the preparation of products devoid of an electron-withdrawing
substituent. On the other hand, compounds of this type can be
sensitive to aerial oxidation and their longer exposure to
halogenated solvents such as CDCl3 should also be avoided to
prevent the formation of intensely colored oxidation products.
Since the pronucleophiles 1 can be obtained from two
aldehydes and the electrophiles 2 can be prepared by condensa-
tion of an aldehyde and a nitroalkane, the reported method
represents a highly modular synthesis of the pyrrole ring that
is amenable to the combinatorial variation of all four substit-
uents.43 It is distantly related to the Barton-Zard reaction42 and
the Montforts synthesis,44 which furnish 3,4-disubstituted pyr-
role-2-carboxylates. In contrast to the Grob cyclization,45 the
reaction does not involve the formation of N2O by means of a
Nef process.46,47 While many reported pyrrole syntheses yield
Experimental Section
The R-(alkylideneamino)nitriles 1a-1d,32-34 the nitroolefins 2a-
2d,48-51 and the nitroacetate 1242 were prepared according to
literature procedures. Nitrostilbene 2f was prepared from a Schiff
(44) Haake, G.; Struve, D.; Montforts, F.-P. Tetrahedron Lett. 1994, 35,
9703-9704.
(45) Grob, C. A.; Camenisch, K. HelV. Chim. Acta 1953, 36, 49-58.
(46) Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017-1047.
(47) Nef, J. U. Liebigs Ann. Chem. 1894, 280, 263-291.
(48) Kawai, Y.; Inaba, Y.; Tokitoh, N. Tetrahedron: Asymmetry 2001,
12, 309-318.
(42) Barton, D. H. R.; Kervagoret, J.; Zard, S. Z. Tetrahedron 1990, 46,
7587-7598.
(43) Attempts to prepare 2,3,4,5-tetraalkyl-substituted pyrroles have so
far met with little success. The intermediate formation of enamines from
the pronucleophiles may account for this behavior.
(49) Alles, G. A. J. Am. Chem. Soc. 1932, 54, 271-274.
7086 J. Org. Chem., Vol. 72, No. 19, 2007

Modular One-Pot Synthesis of Tetrasubstituted Pyrroles
base of benzaldehyde and phenylnitromethane in acetic acid.52
Phenylnitromethane itself was obtained by reaction of benzyl
bromide with silver nitrite in aqueous medium.53
(method B) from 1a (99.5 mg, 0.478 mmol), 2a (94.3 mg, 0.477
mmol), and Cs2CO3 (311.5 mg, 0.956 mmol) in DMF (1 mL)]; mp
177-179.5 °C; Rf 0.42 (petroleum ether/ethyl acetate 5:1); IR (KBr)
ν ) 3447 (s, br), 1628 (m), 1603 (m), 1510 (m), 1490 (s), 1089
(m), 1003 (w), 862 (w), 836 (m), 751 (m) cm-1; 1H NMR, COSY,
HMBC (400 MHz, DMSO-d6) δ ) 11.05 (br s, 1H, NH), 7.92
(mc, 2H, H1′, H4′), 7.88 (mc, 2H, H5′, H8′), 7.70 (dd, J ) 8.6, 1.6
Hz, 1H, H3′), 7.52-7.40 (m, 4H, H6′, H7′, H3′′,5′′), 7.31 (BB′
part of AA′BB′ system, 2H, H2′′,6′′), 2.25 (s, 3H, 5-CH3), 2.20 (s,
3H, 3-CH3) ppm; transient NOE, irradiation at 2.20 ppm (3-CH3)
enhances the signals at 7.92 (H1′, 1.6%), 7.70 (H3′, 1.5%), and
7.31 (H2′′,6′′, 2.6%) ppm, whereas irradiation at 2.25 ppm (5-CH3)
enhances only the signals at 11.05 (NH, 0.9%) and 7.31 (H2′′,6′′,
2.9%) ppm; 13C NMR, HSQC, HMBC (100.6 MHz, DMSO-d6) δ
) 135.2 (C1′′), 133.3 (C8a′), 131.2 (C4a′), 131.1 (2C, C2′′,6′′),
131.0 (C4′′), 129.8 (C2′), 128.1 (2C, C3′′,5′′), 127.8 (C4′), 127.5
(C5′), 127.5 (C8′), 126.3 (C7′), 126.1 (C2), 125.7 (C5), 125.2 and
125.1 (C3′, C6′), 123.3 (C1′), 121.3 (C4), 113.9 (C3), 11.9 (5-
CH3), 11.8 (3-CH3) ppm. The HMBC spectrum showed correlations
between both methyl groups and C4 as well as C1′′. Anal. Calcd
for C22H18ClN: C, 79.63; H, 5.47; N, 4.22. Found: C, 79.62; H,
5.43; N, 4.24. ESI-MS (m/z) 331.1 (100) [M]+; ESI-HRMS calcd
for [C22H18ClN + H]+ 332.1206, found 332.1216.
3-(4-Chlorophenyl)-4,5-dimethyl-2-(2-naphthyl)-1H-pyrrole
(10a) and 9a were obtained as an isomeric mixture prepared
according to method A, starting from 1a (100 mg, 0.48 mmol) and
2a (94.9 mg, 0.48 mmol) with KOtBu (146.7 mg, 1.31 mmol)
instead of Cs2CO3. A portion (85.1 mg) of the crude product (152.2
mg) was purified by column chromatography (petroleum ether/ethyl
acetate 5:1) to yield a 1.6:1 isomeric mixture of 9a and 10a (27.4
mg, 0.083 mmol, 19%) as a slightly yellow foam.
NMR data for 10a (in CDCl3): 1H NMR (300 MHz, CDCl3) δ
) 8.03 (br s, 1H, NH), 7.75-7.64 (m, 5H, H1′, H3′, H4′, H5′,
H8′), 7.54-7.40 (m, 2H, H6′, H7′), 7.30 (AA′ part of AA′BB′
system, 2H, H3′′,5′′), 7.22 (BB′ part of AA′BB′ system, 2H,
H2′′,6′′), 2.33 (s, 3H, 5-CH3), 2.03 (s, 3H, 4-CH3); transient NOE,
irradiation at 2.03 ppm (4-CH3) enhances the signals at 7.30
(H3′′,5′′, 0.2%), 7.22 (H2′′,6′′, 1.3%), and 2.33 (5-CH3, 1.2%) ppm;
13C NMR (75.5 MHz, CDCl3) δ ) 135.0 (C1′′), 133.6 (C8a′), 131.8
(C4a′), 131.7 (C4′′), 131.7 (2C, C2′′,6′′), 130.7 (C2′), 130.3 (Cq),
128.4 (2C), 128.3, 128.0, 127.6 (2C), 126.2, 125.7, 125.2 (Cq),
124.1 (C1′), 121.7 (Cq), 115.4 (Cq), 11.3 and 9.7 (4-CH3, 5-CH3)
ppm.
(E)-4-(2-Nitro-but-1-enyl)benzonitrile (2e).54 4-Cyanobenzal-
dehyde (1.92 g, 14.6 mmol) and ammonium acetate (1.12 g, 14.6
mmol) were heated to reflux in 1-nitropropane (20 mL) overnight.
Excess 1-nitropropane was removed in vacuo. The oily residue was
dissolved in ethyl acetate (40 mL) and washed with saturated
NaHCO3 solution (40 mL), water (40 mL), and brine (40 mL). The
organic layer was dried (Na2SO4) and the solvent was removed in
vacuo to yield a brown solid (2.71 g). The material was recrystal-
lized from ethanol/petroleum ether to yield 2e as a slightly ochre
solid (0.34 g). A second crop (0.85 g) was obtained from the mother
liquor after it stood for 50 h at 4 °C. The remaining mother liquor
was concentrated in vacuo and purified by flash chromatography
(petroleum ether/ethyl acetate 10:1) to give pure 2e (0.27 g) as
yellow crystals. Combined yield 1.46 g, 50%; mp 109-110 °C; Rf
0.35 (petroleum ether/ethyl acetate 5:1); IR (KBr) ν ) 2230 (s),
1650 (m), 1517 (s), 1502 (m), 1456 (m), 1441 (m), 1326 (s), 1285
1
(m), 948 (m), 935 (m), 843 (m), 808 (m) cm-1; H NMR (300
MHz, CDCl3) δ ) 7.95 (s, 1H, â-CH), 7.73 (AA′ part of AA′BB′
system, 2H, H2,6), 7.48 (BB′ part of AA′BB′ system, 2H, H3,5),
2.80 (q, J ) 7.4 Hz, 2H, CH2), 1.25 (t, J ) 7.4 Hz, 3H, CH3);
transient NOE, irradiation at 2.80 ppm (CH2) enhances the signals
at 7.48 (H3,5, 1.0%) and 1.25 (CH3, 1.5%) ppm; 13C NMR (75.5
MHz, CDCl3) δ ) 155.4 (C-NO2), 137.0 (C4), 132.6 (2C, Ar),
130.6 (â-CH), 129.9 (2C, Ar), 118.0 and 113.3 (C1, CN), 20.7
(CH2), 12.5 (CH3) ppm; FD-MS (m/z): 202.1 (100%) [M]+. Calcd
for C11H10N2O2: C, 65.34; H, 4.98; N, 13.85. Found: C, 65.33;
H, 4.87; N, 13.86.
General Procedure for the Synthesis of Pyrroles (9a-9n):
Method A. A mixture of imine 1, nitroolefin 2 (1-1.5 equiv), and
cesium carbonate (2 equiv) in THF (1.8 mL/100 mg of imine) was
heated under reflux for several hours under argon atmosphere. After
complete conversion (TLC), ethyl acetate and saturated aqueous
NaHCO3 solution were added to the reaction mixture. After
separation of the organic layer, the aqueous layer was extracted
twice with ethyl acetate. The combined organic layers were washed
with water, dried over Na2SO4, and filtered and the solvent was
removed in vacuo. The crude product was purified by flash
chromatography or recrystallization.
Method B. A mixture of imine 1, nitroolefin 2 (1 equiv), and
cesium carbonate (2 equiv) in DMF (1 mL/100 mg of imine) was
heated to 100 °C in an argon-filled closed vial by irradiation with
microwaves for 2 min (CEM Discover, air cooling, IR temperature
control, maximum power 100 W). After pressure equilibration, the
mixture was quenched with water and extracted with ethyl acetate
(3×). The combined organic layers were washed with water (3×)
and with brine (1×) and dried over Na2SO4, and the solvent was
removed in vacuo. Purification of the crude products was carried
out as described for method A.
4-(4-Chlorophenyl)-3,5-dimethyl-2-(2-naphthyl)-1H-pyrrole
(9a) was prepared according to method A from 1a (500.5 mg, 2.40
mmol), 2a (474.9 mg, 2.40 mmol), and Cs2CO3 (1.56 g, 4.80 mmol)
in THF (9 mL). A portion (106.3 mg) of the crude product was
recrystallized from methanol to yield 9a (36.7 mg) as a slightly
beige solid. Another portion of 9a (17.6 mg) was obtained from
the mother liquor. Combined yield 54.3 mg, 51% [yield was
increased to 54% when 9a was prepared by microwave heating
4-(3,4-Dimethoxyphenyl)-3,5-dimethyl-2-(2-naphthyl)-1H-
pyrrole (9b) was prepared according to method B from 1a (100.9
mg, 0.484 mmol), 2b (108.2 mg, 0.485 mmol), and Cs2CO3 (314.2
mg, 0.964 mmol) in DMF (1 mL). A portion (206.4 mg) of the
crude product (220.0 mg) was purified by column chromatography
(petroleum ether/ethyl acetate 5:1) to yield 9b (64.6 mg, 40%) as
a slightly pink solid. mp 182-184 °C; Rf 0.15 (petroleum ether/
ethyl acetate 5:1); IR (KBr) ν ) 3383 (s, br), 1601 (m), 1506 (s),
1463 (m), 1254 (s), 1240 (m), 1136 (m), 1025 (m), 857 (m), 816
1
(m) cm-1; H NMR, HMBC, COSY (400 MHz, DMSO-d6) δ )
10.92 (br s, 1H, NH), 7.92-7.90 (m, 2H, H1′′, H4′′), 7.87 (mc,
2H, H5′′, H8′′), 7.70 (dd, J ) 8.7, 1.6 Hz, 1H, H3′′), 7.48 (ddd, J
) 8.1, 6.8, 1.1 Hz, 1H, H7′′), 7.42 (ddd, J ) 8.0, 6.8, 1.1 Hz, 1H,
H6′′), 6.98 (d, J ) 8.2 Hz, 1H, H5′), 6.85 (d, J ) 1.8 Hz, 1H,
H2′), 6.79 (dd, J ) 8.2, 1.8 Hz, 1H, H6′), 3.77 (2s, 2 × 3H, OCH3),
2.25 (s, 3H, 5-CH3), 2.21 (s, 3H, 3-CH3) ppm; 13C NMR, HMBC,
HSQC (100.6 MHz, DMSO-d6) δ ) 148.8 (C3′), 147.2 (C4′), 133.9
(C8a′′), 131.9 (C2′′), 131.3 (C4a′′), 129.4 (C1′), 128.3 (C4′′), 128.0
(2C, C5′′, C8′′), 126.7 (C7′′), 126.1 (C2), 125.7 (C5), 125.5 (C3′′),
125.5 (C6′′), 123.5 (C1′′), 123.1 (C4), 122.1 (C6′), 114.6 (C3), 114.1
(C2′), 112.3 (C5′), 56.0 (OCH3), 55.9 (OCH3), 12.5 (3-CH3), 12.3
(5-CH3) ppm; ESI-MS (m/z) 737.4 (37) [2M + Na]+, 714.4 (30)
[2M]+, 713.4 (100) [2M - H]+, 356.2 (18), [M - H]+. Anal. Calcd
for C24H23NO2: C, 80.64; H, 6.49; N, 3.92. Found: C, 80.54; H,
6.44; N, 4.00. ESI-HRMS calcd for [C24H23NO2 + H]+ 358.1807,
found 358.1806.
(50) Leroux, M. L.; Le Gall, T.; Mioskowski, C. Tetrahedron: Asym-
metry. 2001, 12, 1817-1823.
(51) Tamura, R.; Hayashi, K.; Kai, Y.; Oda, D. Tetrahedron Lett. 1984,
25, 4437-4440.
(52) Robertson, D. N. J. Org. Chem. 1960, 25, 47-49.
(53) Ballini, R.; Barboni, L.; Giarlo, G. J. Org. Chem. 2004, 69, 6907-
6908.
(54) Kraus, K. W.; Dolter, R. J.; Petrowski, G. E.; Bogan, R. T.; Buenker,
R. J.; Plamondon, J. E.; Miller, J. J.; Whalen, D. L.; Koopman, D. J. Proc.
Iowa Acad. Sci. 1970, 76, 127-134.
J. Org. Chem, Vol. 72, No. 19, 2007 7087

Bergner and Opatz
3-Ethyl-4,5-dimethyl-2-(2-naphthyl)-1H-pyrrole (9c) was pre-
pared according to method B from 1a (150.0 mg, 0.720 mmol), 2c
(83.0 mg, 0.721 mmol), and Cs2CO3 (470.2 mg, 1.44 mmol) in
DMF (1 mL). A portion (171.1 mg) of the crude product (181.1
mg) was purified by column chromatography (petroleum ether/ethyl
acetate 5:1) to yield 9c (56.6 mg, 0.227 mmol, 33%) as a slightly
brown oil. Rf 0.52 (petroleum ether/ethyl acetate 5:1); IR (NaCl,
film) ν ) 3430 (m), 2960 (s), 2926 (s), 2867 (m), 1628 (m), 1593
(m), 1525 (m), 1461 (m), 854 (m), 820 (m), 749 (s) cm-1; 1H NMR
(300 MHz, DMSO-d6) δ ) 10.49 (br s, 1H, NH), 7.88-7.80 (m,
4H, H1′, H4′, H5′, H8′), 7.59 (dd, J ) 8.6, 1.5 Hz, 1H, H3′), 7.43
(mc, 2H, H6′, H7′), 2.57 (q, J ) 7.4 Hz, 2H, CH2), 2.15 (s, 3H,
CH3), 1.91 (s, 3H, CH3), 1.14 (t, J ) 7.4 Hz, 3H, CH2CH3) ppm;
13C NMR (75.5 MHz, DMSO-d6) δ ) 133.6 (C8a′), 131.9 (C4a′),
130.9 (C2′), 127.9 (C4′), 127.6 (2C, C5′, C8′), 126.3 (C7′), 125.1
and 125.0 (C3′, C6′), 124.8, 124.4, 122.6 (C1′), 122.1, 113.9 (C4),
18.2 (CH2), 15.8 (CH3), 11.0 (CH3), 9.0 (CH3) ppm; ESI-HRMS
calcd for [C18H19N + H]+ 250.1596, found 250.1591.
(221.1 mg) was purified by column chromatography (toluene/
petroleum ether 2:1) to yield 9f (50.3 mg, 0.140 mmol, 34%) as a
slightly pink foam. Rf 0.47 (petroleum ether/ethyl acetate 5:1); IR
(KBr) ν ) 3392 (s), 1599 (m), 1499 (m), 864 (m), 825 (m), 772
(m), 759 (m), 739 (s), 700 (s) cm-1; 1H NMR (300 MHz, DMSO-
d6) δ ) 11.31 (br s, 1H, NH), 7.79-7.77 (m, 2H), 7.68-7.64 (m,
2H), 7.41 (mc, 2H), 7.23-7.16 (m, 6H), 7.12-7.07 (m, 1H), 7.03-
7.01 (m, 4H), 2.30 (s, 3H, CH3); 13C NMR (75.5 MHz, DMSO-d6)
δ ) 136.6 (Cq), 136.0 (Cq), 133.2 (Cq), 131.3 (Cq), 130.9 (Cq),
130.7 (2C), 129.9 (2C), 128.1 (2C), 127.8 (2C), 127.6, 127.5, 127.4,
126.3, 126.2 (Cq), 126.1 (Cq), 125.9, 125.7, 125.4, 125.2, 124.2,
121.7 (Cq), 121.3 (Cq), 11.8 (CH3) ppm; ESI-MS (m/z) 360.2 (32)
[M + H]+, 359.2 (100) [M]+, 358.2 (38) [M - H]+; ESI-HRMS
calcd for [C27H21N + H]+ 360.1752, found 360.1758.
5-Benzyl-3-(4-chlorophenyl)-4-methyl-2-(2-naphthyl)-4-nitro-
3,4-dihydro-2H-pyrrole (8g) and 5-benzyl-4-(4-chlorophenyl)-
3-methyl-2-(2-naphthyl)-1H-pyrrole (9g) were prepared according
to method A from 1b (99.7 mg, 0.351 mmol), 2a (69.5 mg, 0.352
mmol), and Cs2CO3 (231.1 mg, 0.709 mmol) in THF (1.8 mL). A
portion (133.0 mg) of the crude product (147.0 mg) was purified
by column chromatography (petroleum ether/ethyl acetate 5:1 +
1% Me2NEt) to yield 9g (47.2 mg, 0.116 mmol, 36%) as a slightly
beige solid. The side product 8g was isolated in 31% yield (44.4
mg, 0.098 mmol) as a slightly yellow oil.
4,5-Dimethyl-2-(2-naphthyl)-3-pentyl-1H-pyrrole (9d) was
prepared according to method B from 1a (60.9 mg, 0.292 mmol),
2d (45.9 mg, 0.292 mmol), and Cs2CO3 (189.7 mg, 0.582 mmol)
in DMF (0.6 mL). A portion (76.4 mg) of the crude product (86.9
mg) was purified by column chromatography (petroleum ether/ethyl
acetate 8:1) to yield 9d (25.5 mg, 0.087 mmol, 34%) as a reddish
oil. Rf 0.49 (petroleum ether/ethyl acetate 5:1); IR (NaCl, film) ν
) 3430 (br), 2955 (m), 2926 (s), 2857 (m), 1628 (m), 1593 (m),
Analytical data for 8g: Rf 0.26 (petroleum ether/ethyl acetate
5:1); IR (NaCl, film) ν ) 3060 (w), 1641(w), 1601 (w), 1542 (s),
1494 (m), 1455 (m), 1385 (w), 1347 (w), 1093 (m), 1015 (m), 857
1
1466 (m) 890 (w), 855 (m), 748 (m) cm-1; H NMR, HMBC,
1
(w), 820 (m), 750 (m), 731 (m), 705 (m) cm-1; H NMR, COSY,
COSY (400 MHz, DMSO-d6) δ ) 10.50 (br s, 1H, NH), 7.87 (d,
J ) 8.6 Hz, 1H, H4′), 7.83 (d, J ) 8.0 Hz, 1H, H5′), 7.81-7.79
(m, 2H, H1′, H8′), 7.60 (dd, J ) 8.6, 1.8 Hz, 1H, H3′), 7.46 (ddd,
J ) 8.2, 6.9, 1.3 Hz, 1H, H7′), 7.40 (ddd, J ) 8.0, 6.9, 1.3 Hz, 1H,
H6′), 2.54 (mc, 2H, R-CH2), 2.15 (s, 3H, 5-CH3), 1.90 (s, 3H,
4-CH3), 1.51 (mc, 2H, â-CH2), 1.35-1.30 (m, 4H, γ-,δ-CH2), 0.85
(mc, 3H, ꢀ-CH3) ppm; 13C NMR, HMBC, HSQC (100.6 MHz,
DMSO-d6) δ ) 133.9 (C8a′), 132.3 (C2′), 131.2 (C4a′), 128.2 (C4′),
127.9 (C5′), 127.8 (C8′), 126.7 (C7′), 125.4 (C3′), 125.3 (C6′), 125.1
(C5), 124.9 (C2), 122.9 (C1′), 121.2 (C3), 114.5 (C4), 32.0 (γ-C),
30.8 (â-C), 25.4 (R-C), 22.4 (δ-C), 14.5 (ꢀ-C), 11.4 (5-CH3), 9.5
(4-CH3) ppm; FD-MS m/z ) 291.5 (100) [C21H25N]+; ESI-HRMS
calcd for [C21H25N + H]+ 292.2065, found 292.2061.
HMBC (400 MHz, CDCl3) δ ) 7.82-7.75 (m, 3H, H4′, H5′, H8′),
7.70 (br s, 1H, H1′), 7.46-7.43 (m, 2H, H6′, H7′), 7.36-7.28 (m,
8H, H3′, H3′′,5′′, C6H5), 7.11-7.09 (m, 2H, H2′′,6′′), 5.45
(d-pseudo-t, Jd ) 9.1 Hz, Jt ≈ 1.7 Hz, 1H, H2), 4.32 (d, J ) 9.1
Hz, 1H, H3), 4.00 (dd, J ) 15.4, 1.3 Hz, 1H, CH2-Ha), 3.69 (dd,
J ) 15.4, 2.1 Hz, 1H, CH2-Hb), 1.22 (s, 3H, CH3) ppm; transient
NOE, irradiation at 1.22 ppm (CH3) enhances the signals at 7.36
(C6H5, 1.2%), 7.11 (H2′′,6′′, 3.0%), 5.45 (H2, 2.1%), 4.32 (H3,
0.5%), 4.00 (CH2-Ha, 0.6%), and 3.69 (CH2-Hb, 1.0%) ppm,
whereas irradiation at 4.32 ppm (H3) enhances the signals at 7.70
(H1′, 1.2%), 7.36-7.32 (H3′, 2.1%), 7.11 (H2′′,6′′, 6.4%), and 5.45
(H2, 1.0%) ppm; 13C NMR, HSQC, HMBC (100.6 MHz, CDCl3)
δ ) 172.1 (C5), 137.4 (C2′), 135.1 (C1′′′), 134.5 (C4′′), 133.2
(C8a′), 133.0 (C4a′), 132.2 (C1′′), 130.3 (2C, C2′′,6′′), 129.3 (2C)
and 129.2 (2C), (C3′′,5′′, C2′′′,6′′′), 128.8 (2C, C3′′′,5′′′), 128.7
(C4′′′), 128.0 (C8′), 127.7 and 127.3 (C4′, C5′), 126.3 and 126.0
(C6′, C7′), 125.9 (C1′), 124.5 (C3′), 102.6 (C4), 75.6 (C2), 63.7
(C3),36.7(CH2),17.8(CH3)ppm;ESI-HRMScalcdfor[C28H23N2O2-
Cl + Na]+ 477.1346, found 477.1364. The compound slowly
decomposes in solution.
4-(4-Cyanophenyl)-3-ethyl-5-methyl-2-(2-naphthyl)-1H-pyr-
role (9e) and 3-(4-Cyanophenyl)-4-ethyl-5-methyl-2-(2-naph-
thyl)-1H-pyrrole (10e). Compound 9e was prepared according to
method B, starting from 1a (150.7 mg, 0.724 mmol), 2e (146.1
mg, 0.723 mmol), and Cs2CO3 (473.4 mg, 1.453 mmol) in DMF
(1.5 mL). A portion (106.8 mg) of the crude product (261.8 mg)
was purified by column chromatography (petroleum ether/ethyl
acetate 8:1) to yield an isomeric mixture of 9e and 10e (2.5:1, 23.8
mg, 0.071 mmol, 24%) along with pure 9e (31.9 mg, 0.095 mmol,
32%) as an orange solid. mp 180-183 °C (decomp); Rf 0.41
(petroleum ether/ethyl acetate 5:1); IR (KBr) ν ) 3332 (s), 2226
(s), 1603 (s), 1508 (m), 1496 (m), 844 (m), 748 (m) cm-1; 1H NMR
(300 MHz, DMSO-d6) δ ) 11.12 (br s, 1H, NH), 7.95-7.83 (m,
6H), 7.67 (dd, J ) 8.5, 1.6 Hz, 1H), 7.53-7.73 (m, 4H), 2.71 (q,
J ) 7.4 Hz, 2H, CH2), 2.23 (s, 3H, CH3), 0.91 (t, J ) 7.4 Hz, 3H,
CH2CH3) ppm; 13C NMR, DEPT (75.5 MHz, DMSO-d6) δ ) 142.3
(Cq), 133.4 (Cq), 132.2 (2C, C2′′,6′′), 133.1 (Cq), 131.2 (Cq), 130.2
(2C, C3′′,5′′), 128.0, 127.7, 127.6, 126.7 (Cq), 126.5, 126.3 (Cq),
125.5, 125.5 (overlapping signals), 124.1, 120.8 (Cq), 120.5 (Cq),
119.4 (CN), 107.8 (Cq), 17.8 (CH2), 15.8, 11.8 (2 × CH3) ppm;
ESI-MS (m/z) 337.1 (28) [M + H]+, 336.1 (100) [M]+, 335.1 (30)
[M - H]+; ESI-HRMS calcd for [C24H20N2 + H]+ 337.1705, found
Analytical data for 9g: mp 155-157 °C; Rf 0.54 (petroleum
ether/ethyl acetate 5:1); IR (NaCl, film) ν ) 3420 (br), 1628 (m),
1602 (m), 1488 (s), 1452 (m), 1090 (m), 1003 (m), 832 (s), 820
1
(m), 748 (m), 728 (m) cm-1; H NMR (300 MHz, CDCl3) δ )
7.92 (br s, 1H, NH), 7.88-7.82 (m, 4H, H1′, H4′, H5′, H8′), 7.58
(dd, J ) 8.5, 1.7 Hz, 1H, H3′), 7.50-7.22 (m, 11H), 4.06 (s, 2H,
PhCH2), 2.30 (s, 3H, CH3) ppm; 13C NMR (75.5 MHz, CDCl3) δ
) 139.3 (C1′′′), 134.5 (Cq), 133.7 (C8a′), 131.9 (Cq), 131.8 (Cq),
131.3 (2C, C2′′, 6′′), 130.9 (Cq), 128.8 (2C), 128.7 (2C), 128.4
(2C), 128.3, 127.9 (Cq), 127.7 (partly overlapping signals, 3C),
126.6, 126.4, 125.6, 125.1, 124.5, 123.7 (C3), 115.2 (C4), 32.4
(CH2), 11.5 (CH3) ppm. Anal. Calcd for C28H22ClN: C, 82.44; H,
5.44; N, 3.43. Found: C, 82.60; H, 5.32; N, 3.61. ESI-MS (m/z)
407.3 (45) [M]+, 383.6 (72), 332.1 (90), 320.3 (45), 263.2 (100);
ESI-HRMS calcd for [C28H22ClN + H]+ 408.1519, found 408.1511.
5-Benzyl-4-(4-chlorophenyl)-2-(3,4-dimethoxyphenyl)-3-meth-
yl-1H-pyrrole (9h) was prepared according to method A from 1c
(100.3 mg, 0.341 mmol), 2a (67.2 mg, 0.341 mmol), and Cs2CO3
(223.0 mg, 0.684 mmol) in THF (1.8 mL). A portion (128.4 mg)
of the crude product (147.4 mg) was purified by column chroma-
tography (petroleum ether/ethyl acetate 5:1 + 1% Me2NEt) to yield
1
337.1707. Characteristic H NMR shifts of 10e: 1H NMR (300
MHz, DMSO-d6) δ ) 11.10 (br s, 1H, NH), 2.35 (q, J ) 7.4 Hz,
2H, CH2), 2.24 (s, 3H, CH3), 0.90 (t, J ) 7.4 Hz, 3H, CH3).
5-Methyl-2-(2-naphthyl)-3,4-diphenyl-1H-pyrrole (9f) was
prepared according to method B, starting from 1a (99.8 mg, 0.479
mmol), 2f (108.3 mg, 0.481 mmol), and Cs2CO3 (312.9 mg, 0.960
mmol) in DMF (1 mL). A portion (192.3 mg) of the crude product
7088 J. Org. Chem., Vol. 72, No. 19, 2007

Modular One-Pot Synthesis of Tetrasubstituted Pyrroles
9h (52.6 mg, 0.126 mmol, 43%) as a slightly yellow viscous oil.
Rf 0.28 (petroleum ether/ethyl acetate 3:1); IR (NaCl, film) ν )
3360 (br), 1601 (m), 1506 (s), 1453 (m), 1249 (s), 1221 (m), 1140
ether/ethyl acetate 5:1); IR (KBr) ν ) 3446 (m), 3430 (m), 2927
(s), 2846 (m), 1628 (m), 1601 (m), 1525 (m), 854 (m), 823 (m),
1
749 (s) cm-1. H NMR (300 MHz, CDCl3) δ ) 7.97 (br s, 1H,
(m), 1090 (m), 1027 (m) 834 (m) cm-1
;
1H NMR (300 MHz,
NH), 7.96-7.70 (m, 4H, H1′, H4′, H5′, H8′), 7.60 (dd, J ) 8.6,
1.5 Hz, 1H, H3′), 7.44 (mc, 2H, H6′, H7′), 2.88 (mc, 2H, H2-7),
2.55 (mc, 2H, H2-4), 2.26 (s, 3H, CH3), 1.83 (mc, 4H, H2-5, H2-6)
ppm; 13C NMR (75.5 MHz, CDCl3) δ ) 133.9 (C8a′), 131.3 (2C,
C2′, C4a′), 128.2 (C4′), 127.6 and 127.6 (overlapping signals, C5′,-
C8′), 126.2 and 124.9 (C6′, C7′), 123.9 (2C, C1′, Cq), 123.4 (Cq),
122.1, 118.7 (Cq), 117.9 (Cq), 24.2 (CH2), 23.9 (CH2), 23.6 (CH2),
21.7 (CH2), 11.0 (CH3) ppm; Anal. Calcd for C19H19N: C, 87.37;
H, 7.33; N, 5.36. Found: C, 87.34; H, 7.23; N, 5.33. ESI-MS (m/
z) 294.2 (18), 278.2 (40), 261.2 (100) [M]+; ESI-HRMS calcd for
[C19H19N + H]+ 262.1596, found 262.1586.
CDCl3) δ ) 7.75 (br s, 1H, NH), 7.40-7.18 (m, 9H), 6.94-6.89
(m, 3H), 4.02 (s, 2H, CH2Ph), 3.91 (s, 6H, OCH3), 2.20 (s, 3H,
CH3) ppm; 13C NMR (75.5 MHz, CDCl3) δ ) 149.0 (C3′), 147.7
(C4′), 139.4 (Cq), 134.6 (Cq), 131.7 (Cq), 131.2 (2C, C2′′, 6′′),
128.7 (2C), 128.5 (2C), 128.4 (2C), 127.9 (Cq), 126.7 (Cq), 126.6
(Cq), 126.5, 123.2 (C4), 119.2 (C6′), 113.8 (C3), 111.5 and 110.5
(C2′, C5′), 55.9 (2C, OCH3), 32.3 (CH2Ph), 11.2 (CH3) ppm; ESI-
MS (m/z) 434.3 (100), 417.3 (40) [M]+, 343.1 (70), 295.2 (54),
263.4 (38); ESI-HRMS calcd for [C26H24ClNO2 + H]+ 418.1574,
found 418.1574.
3-Benzyl-1-(2-naphthyl)-4,5,6,7-tetrahydro-2H-isoindole (9l)
and 4-Amino-3-benzyl-1-(2-naphthyl)-5,6,7,8-tetrahydroisoquin-
oline (11). Compound 9l was prepared according to method A from
1b (150.6 mg, 0.530 mmol), 2g (59.5 µL, 67.1 mg, 0.528 mmol),
and Cs2CO3 (343.6 mg, 1.055 mmol) in THF (2.6 mL). A portion
(162.9 mg) of the crude product (178.5 mg) was purified by column
chromatography (petroleum ether/ethyl acetate 5:1 + 1% i-PrNH2)
to yield 9l (59.7 mg, 0.177 mmol, 37%) as a pink solid. Side product
11 was isolated in 17% yield (29.1 mg) as a slightly yellow oil.
Analytical data for 9l: mp 106-107.5 °C; Rf 0.51 (petroleum
ether/ethyl acetate 5:1); IR (KBr) ν ) 3426 (s), 2926 (m), 2914
(m), 1626 (m), 1586 (w), 1510 (m), 1493 (w), 846 (m), 829 (m),
745 (m), 733 (m) cm-1; 1H NMR (300 MHz, CDCl3) δ ) 7.84 (br
s, 1H, NH), 7.79 (mc, 3H, H4′, H5′, H8′), 7.72 (s, 1H, H1′), 7.48-
7.24 (m, 8H, H3′, H6′, H7′, C6H5), 3.99 (s, 2H, PhCH2), 2.90, 2.60
3-(4-Cyanophenyl)-5-(3,4-dimethoxyphenyl)-4-ethyl-2-phenyl-
1H-pyrrole (9i) and 3-(4-Cyanophenyl)-2-(3,4-dimethoxyphe-
nyl)-4-ethyl-5-phenyl-1H-pyrrole (10i). Compound 9i was pre-
pared according to method B, starting from 1d (149.8 mg, 0.534
mmol), 2e (108.5 mg, 0.537 mmol), and Cs2CO3 (356.6 mg, 1.094
mmol) in DMF (1.5 mL). A portion (91.5 mg) of the crude product
(195.1 mg) was purified by column chromatography (petroleum
ether/ethyl acetate 2:1) to yield an isomeric mixture of 9i and 10i
(42.5 mg, 0.104 mmol, 42%) as a slightly yellow foam. Rf 0.12
(petroleum ether/ethyl acetate 5:1); IR (KBr) ν ) 3426 (s, br), 2226
(m), 1604 (s), 1516 (s), 1496 (s), 1464 (m), 1252 (s), 1225 (m),
1
1141 (m), 1025 (m), 847 (m), 767 (m), 699 (m) cm-1; H NMR
(300 MHz, DMSO-d6, ratio of isomers a:b ) 3:1) δ ) 11.2 (br s,
b
1H, NHa+b), 7.82-6.70 (m, 12H, Ara+b), 3.82 (s, 3H, OCH3 ), 3.78
b
a
a
(s, 3H, OCH3 ), 3.70 (s, 3H, OCH3 ), 3.56 (s, 3H, OCH3 ) 2.53 (q,
J ) 7.4 Hz, 2H, CH2a+b), 0.88-0.83 [partly overlapping signals;
(2 mc, 2 × 2H, H2-4, H2-7), 1.84 (mc, 4H, (H2-5, H2-6) ppm; 13
C
b
contains 0.86 (t, J ) 7.4 Hz, 3H, CH3 ), 0.83 (t, J ) 7.4 Hz, 3H,
NMR (75.5 MHz, CDCl3) δ ) 139.4 (C1′′), 133.8 (C8a′), 131.3
(C2′), 131.2 (C4a′), 128.7 (2C), 128.6 (2C), 128.2, 127.6, and 127.6
(partly overlapping signals), 126.4, 126.2, 126.0 (Cq), 125.0, 124.7
(Cq), 123.9, 122.3, 118.7 (Cq), 118.6 (Cq), 32.2 (PhCH2), 24.2
(CH2), 24.0 (CH2), 23.6 (CH2), 21.7 (CH2) ppm. Anal. Calcd for
C25H23N: C, 88.98; H, 6.87; N, 4.15. Found: C, 88.82; H, 6.78;
N, 4.08. ESI-MS (m/z) 370.3 (35), 354.3 (30), 337.2 (100) [M]+,
262.1 (100); ESI-HRMS calcd for [C25H23N + H]+ 338.1909, found
338.1921.
a
CH3 ] ppm; 13C NMR, DEPT (75.5 MHz, DMSO-d6, ratio of
isomers a:b ) 3:1) δ ) 149.0 (Cqb), 148.7 (Cqa), 147.9 (Cqa), 148.0
(Cqb), 143.2 (Cqa), 143.0 (Cqb), 133.6 (Cqa), 132.8 (Cqb), 132.6
(2Ca+b), 131.7 (2Ca), 131.6 (2Cb), 129.8 (Cqb), 129.7 (Cqa), 129.0
(2Ca+b), 128.9 (Cqa+b), 127.9 (2Cb), 127.8 (2Ca), 126.7a, 126.6b,
126.2 (Cqb), 125.3 (Cqa), 122.3 (Cqa), 121.7 (Cqb), 121.5 (Cqb),
120.9 (Cqa), 120.2a, 120.0b, 119.6 (CNa+b), 112.3b, 112.1a, 112.0b,
111.8a, 109.0 (Cqb), 108.9 (Cqa), 56.0 (OCH3 ), 55.9 (OCH3 ), 55.9
b
b
a
a
a
b
a+b
(OCH3 ), 55.5 (OCH3 ), 17.8 (CH2 ), 17.8 (CH2 ), 16.3 (CH3
)
Analytical data for 11: Rf 0.14 (petroleum ether/ethyl acetate
5:1); IR (NaCl, film) ν ) 3386 (w), 3057 (w), 2932 (m), 2858
(m), 1620 (m), 1605 (m), 1494 (m), 1440 (m), 1424 (s), 1330 (w),
ppm; ESI-MS (m/z) 425.1 (83), 409.1 (40) [M + H]+, 408.1 (100)
[M]+, 407.1 (60) [M - H-]+, 282.2 (50); ESI-HRMS calcd for
[C27H24N2O2]+ 408.1838, found 408.1851.
1
1266 (w), 897 (m), 821 (m), 736 (s), 704 (m) cm-1; H NMR,
2-(3,4-Dimethoxyphenyl)-3,4,5-triphenyl-1H-pyrrole (9j) was
prepared according to method B, starting from 1d (100.8 mg, 0.357
mmol), 2f (81.0 mg, 0.360 mmol), and Cs2CO3 (233.5 mg, 0.717
mmol) in DMF (1 mL). A portion (161.2 mg) of the crude product
(177.4 mg) was purified by column chromatography (petroleum
ether/ethyl acetate 5:1) to yield 9j (43.4 mg, 0.101 mmol, 31%) as
a slightly yellow solid. mp 198-201 °C; Rf 0.17 (petroleum ether/
ethyl acetate 5:1); IR (KBr) ν ) 3436 (m, br), 3342 (m), 1602
(m), 1512 (s), 1492 (m), 1461 (m), 1442 (m), 1252 (s), 1224 (m),
COSY, HMBC (400 MHz, CDCl3) δ ) 7.96 (br d, J ) 1.7 Hz,
1H, H1′), 7.91-7.86 (m, 3H, H4′, H5′, H8′), 7.67 (dd, J ) 8.4,
1.7 Hz, 1H, H3′), 7.51-7.47 (m, 2H, H6′, H7′), 7.33-7.31 (m,
4H, H2′′,6′′, H3′′,5′′), 7.25-7.21 (m, 1H, H4′′), 4.25 (s, 2H,
PhCH2), 3.51 (br s, 2H, NH2), 2.73 (t, J ) 6.2 Hz, 2H, H2-8), 2.49
(t, J ) 6.6 Hz, 2H, H2-5), 1.89 (mc, 2H, H2-6), 1.69 (mc, 2H, H2-
7) ppm; 13C NMR, HSQC, HMBC (100.6 MHz, CDCl3) δ ) 148.2
(C1), 141.5 (C3), 138.7 (2C, C2′, C1′′), 137.7 (C4), 133.3 (C8a′),
132.6 (C4a′), 130.4 (C4a), 129.6 (C8a), 128.7 (2C, C2′′,6′′), 128.5
(2C, C3′′,5′′), 128.2 (2C, C1′, Naph-CH), 127.8 (Naph-CH), 127.6
(C3′), 127.5 (Naph-CH), 126.5 (C4′′), 125.9 and 125.8 (C6′, C7′),
41.4 (PhCH2), 28.2 (C8), 24.2 (C5), 22.5 (C7), 22.2 (C6) ppm;
ESI-HRMS calcd for [C26H24N2 + H]+ 365.2018, found 365.2027.
3-Benzyl-1-(3,4-dimethoxyphenyl)-4,5,6,7-tetrahydro-2H-iso-
indole (9m) was prepared according to method A from 1c (150.0
mg, 0.510 mmol), 2g (86.2 µL, 97.2 mg, 0.764 mmol, 1.5 equiv),
and Cs2CO3 (331.0 mg, 1.019 mmol) in THF (2.6 mL). After the
mixture was refluxed for 2 h, another portion of 2g (57.5 µL, 64.8
mg, 0.510 mmol) was added. After 3 h, the same amount of 2g
was added and the reaction mixture was stirred overnight at 60 °C.
A portion (250.2 mg) of the crude product (263.6 mg) was purified
by column chromatography (CH2Cl2/petroleum ether/ethyl acetate
3:3:0.1) to yield 9m (63.5 mg, 38%) as a yellow solid. The yield
was increased to 51% when 9m was prepared according to the
general procedure (method B) from 1c (100.3 mg, 0.341 mmol),
2g (39.1 µL, 44.1 mg, 0.347 mmol), and Cs2CO3 (223.2 mg, 0.685
1
1026 (m), 766 (m), 700 (m) cm-1; H NMR (300 MHz, DMSO-
d6) δ ) 11.30 (br s, 1H, NH), 7.29-7.24 (m, 4H), 7.17-7.10 (m,
7H), 7.01 (mc, 4H), 6.86-6.83 (m, 3H), 3.70 (s, 3H, OCH3), 3.49
(s, 3H, OCH3); 13C NMR (75.5 MHz, DMSO-d6) δ ) 148.2 (C3′),
147.4 (C4′), 136.4 (Cq), 136.1 (Cq), 132.8 (Cq), 131.0 (2C), 130.8
(2C), 129.0 (Cq), 128.3 (Cq), 128.2 (2C), 128.1 (4C), 128.0 (2C),
126.2 and 125.9 (2C), 125.3 (Cq), 122.6 (Cq), 122.1 (Cq), 119.7
(C6′), 111.7 and 111.6 (C2′, C5′), 55.5 (OCH3), 55.0 (OCH3) ppm;
ESI-MS (m/z) 448.3 (72), 431.2 (100) [M]+; ESI-HRMS calcd for
[C30H25NO2]+ 431.1885, found 431.1891.
3-Methyl-1-(2-naphthyl)-4,5,6,7-tetrahydro-2H-isoindole (9k)
was prepared according to method A from 1a (150.1 mg, 0.721
mmol), 2g (81.3 µL, 91.6 mg, 0.720 mmol), and Cs2CO3 (468.2
mg, 1.437 mmol) in THF (2.6 mL). A portion (153.0 mg) of the
crude product (180.0 mg) was purified by column chromatography
(petroleum ether/ethyl acetate 5:1) to yield 9k (72.9 mg, 0.279
mmol, 46%) as a pink solid. mp 81-83 °C; Rf 0.64 (petroleum
J. Org. Chem, Vol. 72, No. 19, 2007 7089

Bergner and Opatz
mmol) in DMF (1 mL). The crude product was purified by column
chromatography with petroleum ether and ethyl acetate (3:1). mp
119-123 °C; Rf 0.18 (petroleum ether/ethyl acetate 5:1), Rf 0.23
(petroleum ether/CH2Cl2/ethyl acetate 3:3:0.1); IR (KBr) ν ) 3386
(s), 2939 (m), 2915 (m), 1528 (s), 1261 (m), 1219 (m), 1144 (m),
(1.2 mL). The crude product was purified by column chromatog-
raphy (petroleum ether/ethyl acetate 5:1). Rf 0.20 (petroleum ether/
ethyl acetate 5:1); IR (KBr) ν ) 3371 (m), 2929 (m), 1603 (m),
1528 (m), 1504 (s), 1463 (m), 1440 (m), 1252 (s), 1224 (m), 1142
1
(m), 1025 (m), 766 (m) cm-1; H NMR (300 MHz, DMSO-d6) δ
1
1023 (m), 737 (w), 700 (w) cm-1; H NMR (300 MHz, DMSO-
) 10.70 (br s, 1H, NH), 7.54 (d, J ) 7.7 Hz, 2H, H2′′,6′′), 7.38 (t,
J ) 7.7 Hz, 2H, H3′′,5′′), 7.18-7.13 (m, 2H, H4′′, H2′), 7.07 (dd,
J ) 8.4, 1.5 Hz, 1H, H6′), 6.97 (d, J ) 8.4 Hz, 1H, H5′), 3.81 (s,
3H, OCH3), 3.76 (s, 3H, OCH3), 2.69 (mc, 4H, H2-4, H2-7), 1.71
(mc, 4H, H2-5, H2-6) ppm; 13C NMR (75.5 MHz, DMSO-d6) δ )
148.8 (C3′), 146.9 (C4′), 133.6 (Cq), 128.5 (2C), 126.9 (Cq), 126.6
(Cq), 125.8 (Cq), 125.6 (2C), 125.0, 118.5 (Cq), 118.1, 117.5 (Cq),
112.1, 110.0, 55.7 (2C, OCH3), 23.9, 23.8, 23.7, 23.7 (partly
overlapping signals, CH2) ppm; ESI-MS (m/z) 350.3 (100), 333.2
(70) [M]+, 212.1 (49); ESI-HRMS calcd for [C22H23NO2 + H]+
334.1807, found 334.1811.
d6) δ ) 10.52 (br s, 1H, NH), 7.29-7.14 (m, 5H, C6H5), 7.03 (s,
1H, H2′), 6.93 (mc, 2H, H5′, H6′), 3.83 (s, 2H, PhCH2), 3.78 (s,
3H, OCH3), 3.73 (s, 3H, OCH3), 2.63 (mc, 2H, H2-7), 2.37 (mc,
2H, H2-4), 1.64 (mc, 4H, H2-5, H2-6) ppm; 13C NMR (75.5 MHz,
DMSO-d6) δ ) 148.9 (C3′), 146.2 (C4′), 140.8 (C1′′), 128.4 (2C,
C6H5), 128.3 (2C, C6H5), 127.4 (Cq), 125.8, 125.1 (Cq), 123.6 (Cq),
116.8, 116.6 (Cq), 115.9 (Cq), 112.4, 108.9, 55.7 (OCH3), 55.6
(OCH3), 31.6 (PhCH2), 24.1 (CH2), 23.9 (CH2), 23.4 (CH2), 21.6
(CH2) ppm; ESI-MS (m/z) 380.3 (20), 364.3 (33), 347.3 (100) [M]+,
272.1 (46); ESI-HRMS calcd for [C23H25NO2 + H]+ 348.1964,
found 348.1960.
1-(3,4-Dimethoxyphenyl)-3-phenyl-4,5,6,7-tetrahydro-2H-iso-
indole (9n) was prepared according to method A from 1d (150.4
mg, 0.537 mmol), 2g (66.4 µL, 64.6 mg, 0.589 mmol), and
Cs2CO3 (349.3 mg, 1.072 mmol) in THF (2.6 mL). A portion (183.4
mg) of the crude product (193.8 mg) was purified by column
chromatography (CH2Cl2/petroleum ether/ethyl acetate 3:3:0.1) to
yield 9n (56.0 mg, 0.168 mmol, 33%) as a slightly beige foam.
The yield was increased to 43% when 9n was prepared according
to method B from 1d (119.5 mg, 0.426 mmol), 2g (53.1 µL, 59.9
mg, 0.471 mmol), and Cs2CO3 (281.2 mg, 0.863 mmol) in DMF
Acknowledgment. This work was supported by the Deutsche
Forschungsgemeinschaft. We thank H. Kolshorn for the NMR
spectroscopic analyses.
Supporting Information Available: 1H and 13C NMR spectra
of all products. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO070426X
7090 J. Org. Chem., Vol. 72, No. 19, 2007