Cyclocondensation of α-aminonitriles and enones: A short access to 3,4-dihydro-2H-pyrrole 2-carbonitriles and 2,3,5-trisubstituted pyrroles

Article abstract of DOI:10.1021/jo901759u

(Chemical Equation Presented) The reaction of α,β-unsaturated carbonyl compounds with aminoacetonitrile hydrochloride furnishes 3,5-disubstituted 3,4-dihydro-2H-pyrrole-2-carbonitriles in a one-pot reaction sequence. While these products can serve as starting materials for the preparation of polysubstituted pyrrolizidines, they are kinetically stable against the base-induced elimination of HCN. In contrast, their 2-substituted analogues obtained from α-substituted α-aminonitriles can be readily converted to the corresponding 2,3,5-trisubstituted pyrroles under microwave irradiation. The key step presumably involves the thermal electrocyclization of a stabilized 2-azapentadienyl anion formed by condensation of the reactants and subsequent deprotonation.

Full text of DOI:10.1021/jo901759u

pubs.acs.org/joc
Cyclocondensation of r-Aminonitriles and Enones: A Short Access to 3,4-
Dihydro-2H-pyrrole 2-carbonitriles and 2,3,5-Trisubstituted Pyrroles
Ines Bergner,†,§ Christine Wiebe,†,§ Nino Meyer,‡ and Till Opatz*,†
†Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg,
Germany, and ‡Institute of Organic Chemistry, University of Mainz, Duesbergweg 10-14, 55128 Mainz,
Germany. §These authors contributed equally to this work.
opatz@chemie.uni-hamburg.de
Received August 14, 2009
The reaction of R,β-unsaturated carbonyl compounds with aminoacetonitrile hydrochloride fur-
nishes 3,5-disubstituted 3,4-dihydro-2H-pyrrole-2-carbonitriles in a one-pot reaction sequence.
While these products can serve as starting materials for the preparation of polysubstituted
pyrrolizidines, they are kinetically stable against the base-induced elimination of HCN. In contrast,
their 2-substituted analogues obtained from R-substituted R-aminonitriles can be readily converted
to the corresponding 2,3,5-trisubstituted pyrroles under microwave irradiation. The key step
presumably involves the thermal electrocyclization of a stabilized 2-azapentadienyl anion formed
by condensation of the reactants and subsequent deprotonation.
4-7
€
Introduction
Wurthwein et al.,
the relative energy of the seco and
cyclo forms of azapentadienyl anions is determined by the
position of the nitrogen atom in the chain. For the nitrogen-
free system as well as for its 1- and 3-aza analogues, the seco
form is lower in energy while for the 2-azapentadienyl anion,
cyclization is energetically favored. This may be attributed to the
electronic perturbation exerted by the more electronegative
nitrogen atom which, if located at a nodal plane of the HOMO
in the seco form, promotes ring closure to maximize its HOMO
coefficient.
The anion-stabilizing capacity of the cyano group permits the
deprotonation of R-aminonitriles even in the presence of poten-
tially acidic NH protons. The resulting aminoketeniminate salts
can serve as readily available R-aminocarbanion equivalents for
the preparation of a variety of amines and N-heterocycles.8-11
The cyclization of open-chain compounds represents a
straightforward access to carbo- and heterocyclic compounds.
In contrast to the frequently employed amide bond formations,
intramolecular aldol condensations, or transition-metal-cata-
lyzed carbon-carbon bond formations, electrocyclizations in-
volve not only the termini of the seco precursor but also its entire
conjugated π-electron system. While the stereochemistry of
electrocyclic ring closure and its reversion is governed by orbital
symmetry,1 the thermodynamics of the reaction may depend on,
e.g., steric factors, ring strain, or charge stabilization in the
product. As demonstrated by Hunter and Steiner2,3 as well as by
*To whom correspondence should be addressed. Fax: þ49-40-42838-
4239.
€
(6) Wolf, G.; Wurthwein, E. U. Tetrahedron Lett. 1988, 29, 3647–3650.
(1) Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed. Engl. 1969, 8,
€
781–853.
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(2) Hunter, D. H.; Steiner, R. P. Can. J. Chem. 1975, 53, 355–365.
(3) Hunter, D. H.; Sim, S. K.; Steiner, R. P. Can. J. Chem. 1977, 55, 1229–
1241.
(8) Hauser, C. R.; Taylor, H. M.; Ledford, T. G. J. Am. Chem. Soc. 1960,
82, 1786–1789.
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(10) Opatz, T. Synthesis 2009, 1941–1959.
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5662–5664.
€
(4) Wolf, G.; Wurthwein, E. U. Chem. Ber. 1991, 124, 655–663.
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DOI: 10.1021/jo901759u
r
Published on Web 09/28/2009
J. Org. Chem. 2009, 74, 8243–8253 8243
2009 American Chemical Society

Bergner et al.
JOCArticle
Extension of the conjugated system by introduction of a CdN
double bond through formation of an imine further increases
the CH-acidity. Thus, R-(alkylidenenamino)nitriles can even be
deprotonated with amine or amidine bases to furnish stabili-
zed 2-azaallyl anions, which are known to undergo exception-
ally clean 1,4-additions to a variety of Michael acceptors
while 1,3-dipolar cycloadditions of their N-protonated or
N-metalated counterparts have been reported as well.12-15 If
Strecker products derived from ammonia are condensed with
R,β-unsaturated ketones, the resulting Schiff bases furnish
stabilized 2-azapentadienyl anions upon deprotonation. In
SCHEME 1. Proposed Reaction Mechanism
€
analogy to the unsubstituted parent system, these Huckel
aromatic anions may in turn undergo a disrotatory thermal
electrocyclization to furnish the anions of pyrroline-2-carboni-
triles.12,16 Herein, we report on the development of this reaction
as well as on its application to the synthesis of cyanopyrrolines
and pyrroles.
acidity of the proton in the 2-position, compounds 3 are
invariably obtained as thermodynamic mixtures of cis- and
trans-isomers (isomeric ratio trans/cis 1.2-3.3:1). The iso-
mers can be separated chromatographically, and reequili-
bration occurs under basic conditions. A similar reaction
has been described by Koch et al. for the formation of
3,5-diphenyl-3,4-dihydro-2H-pyrrole-2,2-dicarboxylic acid
diethyl ester from diethyl aminomalonate and chalcone,
although no mechanistic rationale for the ring closure was
given.18,19 Compounds of type 3 have been prepared by
Tasheva et al. by vinylogous addition of (diphenylmethyl-
eneamino)acetonitrile to enones and acidolysis of the pro-
ducts.20 However, the presented protocol compares favor-
ably with the latter reaction sequence in terms of simplicity
and atom economy. To evaluate the substrate scope of our
one-pot procedure, various acyclic R,β-unsaturated carbo-
nyl compounds were subjected to the optimized reaction
conditions. The results are summarized in Table 1.
While yields up to 90% could be achieved with chalcone
derivatives, neither cinnamaldehyde nor ethyl vinyl ketone
gave the reaction. Benzylideneacteone reacted in a yield of
49% which is reduced by increased steric bulk in the alkyl
portion. The isopropyl group is still tolerated while the tert
butyl substituent is not. The structures of the trans-isomers
of compounds 3f and 3g have been determined by X-ray
crystallography (see the Supporting Information). The high
mobility of H-2 in compounds 3 prevents the elimination of
HCN by treatment with strong bases and hampers their
direct conversion to 2,4-disubstituted pyrroles. Attempts to
react the salts of 3 with dienophiles in a 1,3-dipolar cyclo-
addition to furnish 7-azabicyclo[2.2.1]heptanes have so far
met with little success,21-24 whereas their oxidation to
pyrrole-2-carbonitriles proceeds in high yield. The vinylo-
gous addition of compounds 3 to enones can serve as the key
step for a short synthesis of 1,3,5-trisubstituted pyrrolizi-
dines (Scheme 2).
Results and Discussion
Aminoacetonitrile is unstable in pure form, but its hydro-
chloride and sulfate salts can be stored indefinitely at ambi-
ent temperature and are commercially available. When
aminoacetonitrile hydrochloride was heated with chalcone
in the presence of bases, a compound possessing diastereo-
topic methylene protons was detected in the NMR spectra of
the reaction mixtures. To improve the conversion, several
solvents were tested. The reaction was carried out in DMF,
DMSO, diglyme, glyme, xylene, and acetic acid in the
presence of DIPEA (2 equiv) as well as in neat DIPEA and
pyridine. TLC indicated that all other solvents except for
DIPEA led to the expected product with pyridine exhibiting
the least formation of byproducts. Variation of the tempera-
ture showed refluxing pyridine to be the best solvent for the
reaction. However, thermal decomposition of the aminoni-
trile is an issue, and higher yields can be obtained if super-
stoichiometric amounts (1.5-2 equiv) of the hydrochloride
are employed. Lower reaction temperatures did not lead to a
significant improvement, and below 80 °C, the reaction
ceased. Microwave heating led to diminished yields due to
extensive decomposition of aminoacetonitrile hydrochloride
which could be attributable to an efficient conversion of
microwave energy into heat by the polar salt.17 Variation
of the amount of solvent and addition of catalytic amount of
acids or bases had no noticeable effect on the rate of
conversion. The product could be identified as 3,5-diphenyl-
3,4-dihydro-2H-pyrrole-2-carbonitrile 3a. Presumably, the
reaction takes the course depicted in Scheme 1.
Condensation of the components furnishes imine 4, which
is deprotonated to 2-azapentadienyl anion 5. Electrocycliza-
tion furnishes the 1-azaallyl anion 6, which is reprotonated to
the thermodynamically more stable 3,4-dihydro-2H-pyrrole
3. However, a stepwise mechanism involving two molecules
of enone cannot be ultimately ruled out. Due to the high
Exhaustive reduction of the addition product 8 with an
excess of sodium cyanoborohydride furnished pyrrolizidine
(18) Koch, J.; Robert, J. F.; Panouse, J. J. C. R. Seances Acad. Sci. C 1978,
286, 95–98.
(19) Sammes, M. P.; Chung, M. W. L.; Katritzky, A. R. J. Chem. Soc.,
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(20) Tasheva, D.; Petrova, A.; Simova, S. Synth. Commun. 2007, 37,
3971–3979.
(21) Huisgen, R.; Gotthardt, H.; Bayer, H. O. Chem. Ber. 1970, 103,
2368–2387.
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Chem. 1994, 72, 1417–1423.
(12) Tsuge, O.; Ueno, K.; Kanemasa, S.; Yorozu, K. Bull. Chem. Soc.
Jpn. 1986, 59, 1809–1824.
(13) Tsuge, O.; Kanemasa, S.; Yorozu, K.; Ueno, K. Bull. Chem. Soc.
Jpn. 1987, 60, 3359–3366.
(14) Meyer, N.; Opatz, T. Synlett 2004, 787–790.
(15) Kanemasa, S.; Tsuge, O. Adv. Cycloaddit. 1993, 3, 99–159.
(16) Xiang, Y. B.; Drenkard, S.; Baumann, K.; Hickey, D.; Eschenmoser,
A. Helv. Chim. Acta 1994, 77, 2209–2250.
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8244 J. Org. Chem. Vol. 74, No. 21, 2009

Bergner et al.
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TABLE 1. Results of the Cyclization
entry
product
R1
R2
reaction time (h)
yield (%)
trans/cisa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
Ph
Ph
4-F-C6H4
Ph
4-Cl-C6H4
2-Naphth
2-Naphth
benzo[b]furan-2-yl
(E)-4-chlorostyryl
4-F-C6H4
Me
iPr
tBu
H
8
40
17
5
8
6
6
4
3.5
4
18
64
53
53
90
90
77
64
38
77
49
3.0:1
2.9:1
2.4:1
2.6:1
3.3:1
2.7:1
3.3:1
2.8:1
1.3:1
3.3:1
1.2:1
4-MeO-C6H4
4-CN-C6H4
3-NO2-C6H4
Ph
2-Br-C6H4
Ph
4-Cl-C6H4
2-Cl-C6H4
Ph
4-Cl-C6H4
4-Cl-C6H4
Ph
33c
b
b
b
H
Et
aDetermined by 1H NMR spectroscopy. bNo conversion. cContains impurities.
SCHEME 2. Preparation of Pyrrolizidines
SCHEME 3. General Reaction Course for the Formation of
Pyrroles
9 in 62% yield and more than 85% diastereoselectivity but
required elevated temperatures. The course of the reaction
presumably involves imine reduction, reductive cyclization,
and subsequent decyanation.14 If the reduction was con-
ducted at ambient temperature, bicyclic nitrile 10 was iso-
lated in 28% yield along with diastereomerically pure 9
(27%). The relative configuration of both pyrrolizidines
was deduced from the intense NOESY contacts between
the four pseudoaxial protons in positions 1, 3, 5, and 7
located on the concave side of the roof-shaped azabicyclo-
[3.3.0] framework.
The kinetic stability of compounds 3 under basic condi-
tions is dependent on the absence of a substituent in the
2-position. While the condensation of aminoacetonitrile
with suitable enones occurs spontaneously, the correspond-
ing reaction of Strecker products derived from aliphatic or
aromatic aldehydes requires the use of dehydrating agents
(Scheme 3).
The TiCl4/triethylamine system proved to be effective
for all tested cases, while combinations with other Lewis
acids such as BF3-etherate or zinc chloride or the use of
N-methylmorpholine instead of triethylamine gave inferior
results.25 The nature of the R-substituent turned out to have
a profound influence on the reactivity of the condensation
products 12. If aminonitriles derived from aromatic alde-
hydes were used as the starting materials, imines 12 cyclized
directly to the 2,3,5-trisubstituted 3,4-dihydro-2H-pyrrole-
2-carbonitriles 14. In contrast, R-substituents which do not
provide additional resonance stabilization had no such
accelerating effect and alkyl-substituted ketimines 12 could
be isolated as mixtures of geometric isomers. Presumably,
the enhanced CH-acidity of the R-aryl substituted condensa-
tion product accounts for this behavior. Since intermediates
12 are sensitive to hydrolysis, they were preferably cyclized
after an extractive workup without chromatographic purifi-
cation. Elimination of HCN from cyanopyrroline 14a with
Cs2CO3 in refluxing THF gave pyrrole 15a in a disappoint-
ingly low yield of only 15%, which could ultimately be
increased to 61% by switching to potassium tert-butoxide
in DMF under microwave heating to 100 °C. Under these
conditions, cyclization of intermediates 12 to pyrroles 15
occurred as well (Scheme 4).
While the isolation of pyrrolines 14 is possible, the overall
yield of the pyrrole synthesis was higher if the dehydrocyana-
tion was performed on the crude products. Unfortunately,
combination of the condensation and the cyclization/elimi-
nation in a one-pot protocol was unsuccessful as only slow and
incomplete formation of the pyrroles 15 was observed. Using
the optimized conditions for both steps, scope and limitations
of the novel pyrrole synthesis were evaluated (Table 2).
While their reaction modes differ, alkyl- and aryl-substi-
tuted R-aminonitriles roughly gave the same overall yields
for a given enone. An aliphatic substituent R3 was also
tolerated (compare entries 2 and 13) while changing R2 from
aryl to alkyl had a deleterious effect. This may be due to
the formation of enamines and concomitant C-C-bond
formations in the condensation step. Although the overall
(25) Saito, T.; Kobayashi, S.; Ohgaki, M.; Wada, M.; Nagahiro, C.
Tetrahedron Lett. 2002, 43, 2627–2631.
J. Org. Chem. Vol. 74, No. 21, 2009 8245

Bergner et al.
JOCArticle
TABLE 2. Synthesis of Pyrroles 15
entry
aminonitrile
R1
R2
R3
purified intermediate (dr, yield, %)
pyrrole yield, % (over two steps)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
11aa
11aa
11a
Ph
Ph
Ph
Ph
Ph
Ph
4-F-C6H4
4-F-C6H4
Ph
Ph
Ph
14a (1:1.45, 47)
15a
15b
15c
15d
15e
15f
41
50
45
44
38
34
4-MeO-C6H4
2-Cl-C6H4
Ph
Ph
3-NO2-C6H4
Ph
Ph
3-NO2-C6H4
4-MeO-C6H4
2-Cl-C6H4
Me
Ph
Ph
H
11aa
11b
4-F-C6H4
cyclohexyl Ph
cyclohexyl 4-Cl-C6H4
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
11c
11c
11da
11da
11da
11da
11da
11aa
11aa
11aa
11aa
11aa
Ph
Ph
4-Cl-C6H4
4-F-C6H4
4-F-C6H4
Ph
H
Me
Et
12g (1:4, 33)
15g
15h
15i
15j
15k
15l
43
40
40
30
31
21
b
b
2-benzylidenecyclohexanone
15m
19c
aAmino nitrile hydrochloride was used. bComplex mixture. cContains impurities.
General Procedure for the Preparation of Cyanopyrrolines 3.
SCHEME 4. Formation of Pyrrole 15a
Finely ground aminoacetonitrile hydrochloride (1.5 equiv)
and the corresponding R,β-unsaturated carbonyl compound
(1 equiv) were suspended in pyridine. The resulting mixture
was heated to reflux under stirring until the reaction was
complete. If the electrophile was still present after 2 h as judged
by TLC, another portion of aminoacetonitrile hydrochloride
(0.5 equiv) was added. The addition was repeated until TLC
indicated complete consumption of the starting material. The
reaction mixture was diluted with ethyl acetate, washed with
satd aq NaHCO3, and dried over Na2SO4. Evaporation of the
solvent in vacuo gave a crude product which was further purified
by silica gel flash chromatography.
3,5-Diphenyl-3,4-dihydro-2H-pyrrole-2-carbonitrile (3a)20
.
The title compound was prepared according to the general
procedure from aminoacetonitrile hydrochloride (3.20 g, 34.6
mmol), chalcone (4.98 g, 23.9 mmol), and pyridine (100 mL).
After a reaction time of 4 h, TLC indicated incomplete conversion,
and a second portion of aminoacetonitrile hydrochloride (1.07 g,
12.0 mmol) was added. After another 4 h, the reaction mixture was
worked up to yield a dark oil (7.45 g). Ratio of isomers: trans/cis=
3.0:1. Purification of the crude product by flash chromatography
(cyclohexane/ethyl acetate, 10:1) gave trans-3a as yellow crystals
(2.79 g, 47%): mp 69-70 °C dec (lit.20 mp 74-76 °C); Rf
(cyclohexane/ethyl acetate 2:1)=0.5 and cis-3a as yellow crystals
(1.00 g, 17%), mp 103-104 °C dec, Rf (cyclohexane/ethyl acetate
2:1)=0.33.
trans-Isomer: IR (film) ν=3062, 3030, 2244, 1611, 1576, 1496,
1449, 1346, 1028, 761, 693 cm-1; 1H NMR, COSY, HMBC (400
MHz, CDCl3) δ = 7.89-7.93 (m, 2H, phenyl), 7.54 (mc,
1H, phenyl), 7.50-7.45 (m, 2H, phenyl), 7.40-7.35 (m, 2H,
phenyl), 7.34-7.26 (m, 3H, phenyl), 4.94 (dt, 1H, Jd=7.2 Hz,
Jt=1.9 Hz, H-2), 3.94 (d-pseudo-t, 1H, Jd=9.5 Hz, Jt=7 Hz,
H-3), 3.69 (ddd, 1H, J=17.3, 9.5, 1.9 Hz, H-4a), 3.27 (ddd, 1H,
J=17.3, 7.6, 1.9 Hz, H-4b); 13C NMR, HMBC (100.6 MHz,
CDCl3) δ=176.7 (CdN), 140.1, 132.6 (C-10, C-100), 131.9 (1C),
129.2 (2C), 128.7 (2C), 128.1 (2C), 127.8 (1C), 126.7 (2C), 119.2
(CN), 68.9 (C-2), 48.8 (C-3), 43.7 (C-4); FD-MS (m/z)=246.1
(100) [M]þ; FAB-HRMS calcd for [C17H14N2þH]þ 247.1235;
found 247.1231. Anal. Calcd for C17H14N2 (246.31): C, 82.90;
H, 5.73; N, 11.37. Found: C, 82.44; H, 5.87; N, 11.19.
yield was somewhat lower, cinnamaldehyde turned out to be
a suitable substrate and could be converted to 2,3-diphenyl-
pyrrole (entry 14).
In summary, a facile and direct access to disubstituted
cyanopyrrolines from enones and aminoacetonitrile hydro-
chloride has been found. The products may serve as starting
materials for the preparation of various mono- and bicyclic
N-heterocycles. When higher N-unsubstituted R-amino
nitriles were used as the amine component, two- to tetra-
substituted pyrroles could be obtained in a two-step protocol
based on the same cyclization reaction. Neither procedure
involves expensive reagents or catalysts and all starting
materials are readily available.
Experimental Section
The R-aminonitriles 1a-e were prepared according to litera-
ture procedures.26-31
(26) Lagriffoul, P.-H.; Tadros, Z.; Taillades, J.; Commeyras, A. J. Chem.
Soc., Perkin Trans. 2 1992, 1279–1285.
(27) Kurtz, P.; Disselnkoetter, H. Justus Liebigs Ann. Chem. 1972, 764,
69–93.
cis-Isomer: IR (film) ν=3062, 2246, 1665, 1607, 1576, 1496,
1449, 1346, 762, 694 cm-1; 1H NMR, COSY (400 MHz, CDCl3)
δ=7.96-7.91 (m, 2H, phenyl), 7.54 (mc, 1H, phenyl), 7.51-7.46
(m, 2H, phenyl), 7.40-7.24 (m, 5H, phenyl), 5.33 (dt, 1H, Jd=
8.5 Hz, Jt=1.2 Hz, H-2), 3.96 (dt, 1H, Jt=8.5 Hz, Jt=6.4 Hz,
H-3), 3.52 (ddd, 1H, J=17.3, 8.5, 1.5 Hz, H-4a), 3.43 (ddd, 1H,
(28) Paventi, M.; Edward, J. T. Can. J. Chem. 1987, 65, 282–289.
(29) Pascal, R.; Taillades, J.; Commeyras, A. Tetrahedron 1980, 36, 2999–
3008.
(30) McKay, A. F.; Paris, G. Y.; Garmaise, D. L. J. Am. Chem. Soc. 1958,
80, 6276–6280.
(31) Severin, T.; Adhikary, P.; Dehmel, E.; Eberhard, I. Chem. Ber. 1971,
104, 2856–2863.
8246 J. Org. Chem. Vol. 74, No. 21, 2009

Bergner et al.
JOCArticle
J = 17.3, 6.4, 1.5 Hz, H-4b); 13C NMR, DEPT (75.5 MHz,
CDCl3) δ=177.7 (CdN), 138.6, 132.7 (C-10, C-100), 131.9 (1C),
128.9 (2C), 128.8 (2C), 128.1 (2C), 128.0 (1C), 127.5 (2C,
phenyl), 117.0 (CN), 67.3 (C-2), 46.1 (C-3), 42.4 (C-4); FD-
MS (m/z) = 246.1 (100) [M]þ. Anal. Calcd for C17H14N2
(246.31): C, 82.90; H, 5.73; N, 11.37. Found: C, 82.71; H,
5.70; N, 11.06.
(C-40), 68.5 (C-2), 48.7 (C-3), 43.5 (C-4); ESI-MS m/z (%) =
543.3 [2M þ H]þ (7), 313.1 [M þ H þ MeCN]þ (11), 272.1 [M þ
H]þ (62), 245.1 [M - CN]þ (100); ESI-HRMS calcd for [C18H13-
N3 þ H]þ 272.1188; found 272.1180.
cis-Isomer: IR (film) ν=3156, 2927, 2360, 2341, 2254, 2232,
1
1611, 1345, 1062, 908 cm-1. H NMR (300 MHz, CDCl3) δ=
7.89 (mc, 2H, H-200,600), 7.63 (mc, 2H, H-20,60), 7.44-7.57 (m,
3H, H-300,400,500), 7.34 (mc, 2H, H-30,50), 5.36 (dt, 1H, Jd=8.2 Hz,
Jt=1.5 Hz, H-2), 4.02 (d-pseudo-t, 1H, Jt ≈ 8 Hz, Jd=5.7 Hz, H-
3), 3.57 (ddd, 1H, J=17.4, 8.5, 1.5 Hz, H-4a), 3.40 (ddd, 1H, J=
17.4, 5.7, 1.5 Hz, H-4b); 13C NMR (75.5 MHz, CDCl3) δ=177.3
(C-5), 144.2 (C-10), 132.7 (C-30,50), 132.2 (C-400, 100), 128.8 (2C),
128.4 (2C), 128.2 (2C) (C-40,60, C-200,600, C-300,500), 118.4 (CN),
116.6 (CN), 112.0 (C-40), 67.0 (C-2), 46.0 (C-3), 42.5 (C-4); ESI-
MS m/z (%)=272.1 [M þ H]þ (24), 245.1 [M - CN]þ (100); ESI-
HRMS calcd for [C18H13N3 þ H]þ 272.1188; found 272.1186.
5-(4-Chlorophenyl)-3-(3-nitrophenyl)-3,4-dihydro-2H-pyrrole-
2-carbonitrile (3d). The title compound was prepared according
to the general procedure from aminoacetonitrile hydrochloride
(192 mg, 2.07 mmol), 40-chloro-3-nitrochalcone (397 mg, 1.38
mmol), and pyridine (5.8 mL). After 3 h, TLC indicated in-
complete conversion, and another portion of aminoaceto-
nitrile hydrochloride (65 mg, 0.70 mmol) was added. After
another 2 h, workup yielded a black oil (560 mg). Ratio of
isomers: trans/cis=2.6:1. Purification of the crude product by
flash chromatography (cyclohexane/ethyl acetate, 5:1) gave
trans-3d as yellow crystals (277 mg, 0.85 mmol, 62%), mp
169.5-170.5 °C (dec), Rf (cyclohexane/ethyl acetate 2:1) =
0.38 and cis-3d as orange crystals (80 mg, 0.38 mmol, 28%),
mp 178-179 °C (dec), Rf (cyclohexane/ethyl acetate 2:1)=0.15.
trans-Isomer: IR (film) ν=2958, 2919, 1611, 1597, 1530, 1351,
1093, 906, 735 cm-1; 1H NMR (400 MHz, CDCl3) 8.19 (dt, Jd=
7.7 Hz, Jt=1.7 Hz, 1H, H-40), 8.14 (t, J=1.7 Hz, 1H, H-20), 7.83
(AA0-part of AA0BB0-system, 2H, H-200,600), 7.62 (d, Jd=7.7 Hz,
1H, H-60), 7.59 (t, Jt =7.8 Hz, 1H, H-50), 7.44 (BB0-part of a
AA0BB0-system, 2H, H-300,500), 4.93 (dt, Jd=7.3 Hz, Jt=1.6 Hz,
1H, H-2), 4.06 (d-pseudo-t, Jd=9.2 Hz, Jt ≈ 7 Hz, 1H, H-3), 3.73
(ddd, J=17.2, 9.2, 1.6 Hz, 1H, H-4a), 3.25 (ddd, J=17.2, 7.7, 1.6
Hz, 1H, H-4b);13C NMR (400 MHz, CDCl3) δ=175.5 (C-5),
149.1 (aryl-Cq), 142.0 (aryl-Cq), 138.8 (aryl-Cq), 133.4 (aryl-
CH), 131.0 (aryl-Cq) 130.7 (aryl-CH), 129.8 (C-20,60), 129.4 (C-
30, 50), 123.3 (aryl-CH), 121.8 (aryl-CH), 118.6 (CN), 68.9 (C-2),
48.9 (C-3), 43.7 (C-4); FAB-MS (m/z) 325 (100) [M]þ, 176 (94);
ESI-HRMS calcd for [C17H12ClN3O2 þ H]þ 326.0696, found
326.0692.
5-(4-Fluorophenyl)-3-(4-methoxyphenyl)-3,4-dihydro-2H-pyr-
role-2-carbonitrile (3b). The title compound was prepared ac-
cording to the general procedure from aminoacetonitrile
hydrochloride (108 mg, 1.17 mmol), 4-methoxy-40-fluorochal-
cone (197 mg, 0.77 mmol), and pyridine (3.2 mL). After 19 h,
TLC did not indicate complete conversion, and another portion
of aminoacetonitrile hydrochloride (36 mg, 0.39 mmol) was
added. After another 21 h, workup produced a black oil (237
mg). Ratio of isomers: trans/cis=2.9:1. Purification of the crude
product by flash chromatography (cyclohexane/ethyl acetate,
10:1 þ 1% EtNMe2) gave trans-3c as a yellow oil (95 mg, 42%):
Rf (cyclohexane/ethyl acetate 10:1)=0.20 and cis-3c as a yellow
oil (26 mg, 11%), Rf (cyclohexane/ethyl acetate 10:1)=0.06.
trans-Isomer: IR (film) ν=3005, 2936, 2838, 2245, 1603, 1513,
1253, 1034, 838 cm-1; 1H NMR (300 MHz, CDCl3) δ=7.90 (mc,
2H, H-30,50), 7.11-7.21 (m, 4H, H-20,60, H-400,600), 6.90 (mc, 2H,
H-300,500), 4.86 (dt, 1H, Jd=7.1 Hz, Jt=1.9 Hz, H-2), 3.90 (d-
pseudo-t, 1H, Jd=9.4 Hz, Jt ≈ 7 Hz, H-3), 3.81 (s, 3H, OCH3),
3.63 (ddd, 1H, J=17.3, 9.4, 1.9 Hz, H-4a), 3.19 (ddd, 1H, J=
17.3, 7.4, 1.9 Hz, H-4b); 13C NMR (75.6 MHz, CDCl3) δ=175.4
(C-5), 166.5 (1JC,F=253.7 Hz, C-40), 159.1 (C-400), 131.8 (C-100),
130.4 (3JC,F=8.8 Hz, C-20,60), 129.1 (4JC,F=3.2 Hz, C-10), 127.7
(C-200, 600), 119.2 (CN), 115.8 (2JC,F=21.9 Hz, C-30, 50), 114.5 (C-
300, 500), 69.0 (C-2), 55.3 (OCH3), 48.3 (C-3), 43.7 (C-4); ESI-MS
m/z=336.1 [M þ H þ MeCN]þ (7), 295.1 [M þ H]þ (100), 268.0
[M - CN]þ (32); ESI-HRMS calcd for [C18H15FN2O þ H]þ
295.1247, found 295.1240.
1
cis-Isomer: H NMR (300 MHz, CDCl3) δ=8.02 (mc, 2H,
H-30,50), 7.36 (mc, 2H, H-20,60), 7.18 (mc, 2H, H-400,600), 6.91 (mc,
2H, H-300,500), 5.60 (br d, 1H, J=8.1 Hz, H-2), 3.98 (d-pseudo-t,
1H, Jt ≈ 8 Hz, Jd=6.3 Hz, H-3), 3.73 (s, 3H, OCH3), 3.52 (ddd,
2H, J=17.4, 8.5, 1.2 Hz, H-4a), 3.38 (ddd, 1H, J=17.4, 6.3, 1.2
Hz, 4b); 13C NMR (75.5 MHz, CDCl3) δ=176.6 (C-5), 164.3
(1JC,F = 249.7 Hz, C-40), 158.6 (C-400), 131.7 (C-100), 130.8
(3JC,F=9.0 Hz, C-20,60), 129.6 (4JC,F=3.0 Hz, C-10), 128.8 (C-
200, 600), 118.2 (CN), 116.0 (2JC,F=21.9 Hz, C-30, 50), 114.0 (C-300,
500), 66.9 (C-2), 55.1 (OCH3), 44.5 (C-3), 41.9 (C-4); ESI-MS
m/z=317.1 [M þ K]þ (20), 295.1 [M þ H]þ (20), 273.2 (100);
ESI-HRMS calcd for [C18H15FN2O þ H]þ 295.1247, found
295.1238.
cis-Isomer: IR (film) ν=2927, 1605, 1597, 1529, 1348, 1093,
907, 731 cm-1; 1H NMR (400 MHz, CDCl3) δ=8.18 (dt, Jt=2.3,
Hz, Jd=6.4 Hz, 1H, H-40), 8.11 (br s, 1H, H-20), 7.86 (mc, part of
a AA0BB0-system, 2H, H-200,600), 7.54-7.59 (m, 2H, H-50, 60),
7.47 (mc, part of a AA0BB0-system, 2H, H-300,500), 5.38 (dt, Jd=
8.4 Hz, Jt=1.5 Hz, 1H, H-2), 4.09 (d-pseudo-t, Jt ≈ 9 Hz, Jd=6.2
Hz, 1H, H-3), 3.57 (ddd, J=17.3, 8.8, 1.1 Hz, 1H, H-4a), 3.41
(ddd, J=17.3, 6.2, 1.1 Hz, 1H, H-4b); 13C NMR (101 MHz,
CDCl3) δ=176.5 (C-5), 148.6 (C-30), 140.8 (aryl-Cq), 138.9 (aryl-
Cq), 133.7 (aryl-CH), 131.0 (aryl-Cq), 130.4 (aryl-CH), 129.8 (C-
200,600), 129.5 (C-300,500), 123.5 (aryl-CH), 123.0 (aryl-CH), 116.6
(CN), 67.3 (C-2), 46.1 (C-3), 42.6 (C-4); FAB-MS (m/z) 326 (84)
[M þ H]þ, 178 (100); ESI-HRMS calcd for [C17H12ClN3O2 þ
Na]þ 348.0516, found 348.0519. Anal. Calcd for C17H12ClN3O2
(325.75): C, 62.68; H, 3.71; N, 12.90. Found: C, 62.35; H, 3.45;
N, 12.83.
5-Phenyl-3-(4-cyanophenyl)-3,4-dihydro-2H-pyrrole-2-carbo-
nitrile (3c). The title compound was prepared according to
the general procedure from aminoacetonitrile hydrochloride
(166 mg, 1.82 mmol), 4-cyanochalcone32 (205 mg, 0.88 mmol),
and pyridine (3.2 mL) in 17 h. Workup yielded a black oil
(245 mg). Ratio of isomers: trans/cis=2.4:1. Purification of the
crude product by flash chromatography (cyclohexane/ethyl
acetate, 10:1) gave trans-3c as a yellow oil (95 mg, 40%), Rf
(cyclohexane/ethyl acetate 10:1)=0.24 and cis-3c as a yellow oil
(32 g, 13%), Rf (cyclohexane/ethyl acetate 10:1)=0.09.
trans-Isomer: IR (film) ν=3068, 2926, 2360, 2341, 2254, 2232,
1
1612, 1345, 1074, 909 cm-1; H NMR (300 MHz, CDCl3) δ=
7.86 (mc, 2H, H-200,600), 7.65 (mc, 2H, H-20,60), 7.43-7.56 (m,
3H, H-300,400,500), 7.38 (mc, 2H, H-30,50), 4.92 (dt, 1H, Jd=7.0 Hz,
Jt=1.7 Hz, H-2), 4.00 (d-pseudo-t, 1H, Jd=9.5 Hz, Jt ≈ 7 Hz, H-
3), 3.74 (ddd, 1H, J=17.4, 9.5, 1.7 Hz, H-4a), 3.25 (ddd, 1H, J=
17.4, 7.4, 1.7 Hz, H-4b); 13C NMR (75.5 MHz, DMSO) δ=176.4
(C-5), 145.3 (C-10), 133.0 (C-30,50), 132.2 (C-400, C-100), 128.8
(2C), 128.2 (2C), 127.6 (2C), 118.5 (CN), 118.2 (CN), 111.9
5-(2-Naphthyl)-3-phenyl-3,4-dihydro-2H-pyrrole-2-carbo-
nitrile (3e). The title compound was prepared according to
the general procedure from aminoacetonitrile hydrochloride
(173 mg, 1.87 mmol), (E)-1-(2-naphthyl)-3-phenylpropenone33
(33) Robinson, T. P.; Hubbard, R. B.; Ehlers, T. J.; Arbiser, J. L.;
Goldsmith, D. J.; Bowen, J. P. Bioorg. Med. Chem. 2005, 13, 4007–4013.
(32) MacClean, I. S.; Widdows, S. T. J. Chem. Soc. 1914, 105, 2169–2175.
J. Org. Chem. Vol. 74, No. 21, 2009 8247

Bergner et al.
JOCArticle
(370 mg, 1.25 mmol), and pyridine (5.8 mL). After 2 h, TLC
indicated incomplete conversion, and another portion of ami-
noacetonitrile hydrochloride (60 mg, 0.65 mmol) was added.
This was repeated after 3 h. After a further 3 h, workup yielded a
black oil (475 mg). Ratio of isomers: trans/cis=3.3:1. Purifica-
tion of the crude product by flash chromatography (cyclo-
hexane/ethyl acetate, 15:1) gave trans-3e as a yellow oil
(46 mg, 0.16 mmol, 13%): Rf (cyclohexane/ethyl acetate 2:1)=
0.5, cis-3e as a brown oil (51 mg, 0.17 mmol, 14%), Rf
(cyclohexane/ethyl acetate 2:1) = 0.36 and a mixture of both
isomers (trans/cis=10/0.08, 235 mg, 63%).
67.8 (C-2), 47.7 (C-3), 43.4 (C-4); FAB-MS m/z 376.2/374.2 (90/
91) [M]þ, 349.1/347.1 (12/12) [M - HCN]þ, 323.2/321.2 (8/9),
293.2 (51), 192.2 (100), 127.2 (58) [C10H7]þ; FAB-HRMS calcd
for [C21H15BrN2 þ H]þ 375.0497, found 375.0484. Anal. Calcd
for C21H15BrN2 (374.04): C, 67.21; H, 4.03; N, 7.47. Found: C,
67.12; H, 4.02; N, 7.25.
1
Characteristic data of the cis-isomer: H NMR (400 MHz,
CDCl3) δ=8.25 (s, 1H, H-10), 5.55 (dt, Jd=8.5 Hz, Jt=1.2 Hz,
1H, H-2), 3.61 (dd, J=1.4, 4.1, 1H, H-4a), 3.59 (dd, J=1.4, 3.0,
1H, H-4b);13C NMR (101 MHz, CDCl3) δ=177.5 (C-5), 137.7
(aryl-Cq), 133.5 (aryl-CH), 133.0 (aryl-Cq),130.5 (aryl-Cq),
129.8 (aryl-CH), 129.7 (aryl-CH), 129.2 (aryl-CH), 128.9 (aryl-
CH), 128.4 (aryl-CH), 128.2 (aryl-CH), 128.1 (aryl-CH), 128.1
(aryl-CH), 127.7 (aryl-CH), 127.1 (aryl-CH), 124.5 (aryl-CH),
124.4 (C-10), 119.0 (CN), 66.2 (C-2), 45.5 (C-3), 41.4 (C-4).
5-(Benzo[b]furan-2-yl)-3-phenyl-3,4-dihydro-2H-pyrrole-2-
carbonitrile (3g). The title compound was prepared according to
the general procedure from aminoacetonitrile hydrochloride
(133 mg, 1.45 mmol), (E)-1-(benzo[b]furan-2-yl)-3-phenylpro-
penone (244 mg, 0.98 mmol), and pyridine (4.2 mL). After 2 h,
TLC indicated incomplete conversion, and another portion of
aminoacetonitrile hydrochloride (50 mg, 0.54 mmol) was added.
This was repeated after 2 h. After a further 2 h, workup yielded
a black oil (323 mg). Ratio of isomers: trans/cis = 3.3:1.
Purification of the crude product by flash chromatography
(cyclohexane/ethyl acetate, 5:1) gave trans-3g as yellow crystals
(123 mg, 0.42 mmol, 44%): mp 137-138 °C dec, Rf (petroleum
ether/ethyl acetate 2:1)=0.61 and cis-3g as a brown oil (58 mg,
0.20 mmol, 20%), Rf (petroleum ether/ethyl acetate 2:1)=0.54.
trans-Isomer: IR (film) ν=3050, 3032, 2243, 1616, 1052, 751,
699 cm-1; 1H NMR (400 MHz, CDCl3) δ=7.66 (d, J=7.8 Hz,
1H, H-40), 7.58 (d, J=8.4 Hz, 1H, H-70), 7.43 (t, J=7.8 Hz, 1H,
H-50), 7.25-7.38 (m, 7H, aryl-CH), 4.97 (dt, Jd=7.1 Hz, Jt=1.8
Hz, 1H, H-2), 3.96 (d-pseudo-t, Jd=9.3 Hz, Jt ≈ 7.4 Hz, 1H,
H-3), 3.69 (ddd, J=17.4, 9.5, 1.8 Hz, 1H, H-4a), 3.28 (ddd, J=
17.4, 7.7, 1.8 Hz, 1H, H-4b); 13C NMR (101 MHz, CDCl3) δ=
168.1 (C-5), 156.1 (C-7a0), 149.4 (C-20), 139.7 (C-100), 129.6 (2C,
Ph), 128.2 (aryl-CH), 127.7 (aryl-CH), 127.6 (C-3a0), 127.0 (2C,
Ph), 124.0 (aryl-CH), 122.6 (aryl-CH), 118.9 (CN), 112.4 (2C,
aryl-CH), 69.4 (C-2), 49.0 (C-3), 43.8 (C-4); FAB-MS m/z 286
(91) [M]þ, 259 (5) [M - HCN]þ, 233 (14), 182 (100); FAB-
HRMS calcd for [C19H14N2O þ H]þ 287.1184, found 287.1168.
Anal. Calcd for C19H14N2O (286.33): C, 79.70; H, 4.93; N, 9.78.
Found: C, 79.68; H, 4.81; N, 9.80.
trans-Isomer: IR (film) ν=3060, 3031, 2242, 1608, 752, 670
cm-1; 1H NMR (400 MHz, CDCl3) δ=8.21 (s, 1H, H-10), 8.12
(dd, J=8.7, 1.6 Hz, 1H, naphth), 7.94-7.84 (m, 3H, naphth),
7.55 (mc, 2H, naphth), 7.28-7.39 (m, 5H, Ph), 4.97 (dt, Jd =
7.1 Hz, Jt=1.7 Hz, 1H, H-2), 3.98 (d-pseudo-t, Jd=9.4 Hz, Jt ≈
7Hz,1H,H-3),3.81(ddd,J=17.2, 9.4, 1.7 Hz, 1H, H-4a), 3.38 (ddd,
J=17.2, 7.5, 1.7 Hz, 1H, H-4b); 13C NMR (125.75 MHz, CDCl3)
δ=176.9 (C-5), 140.3 (aryl-Cq), 135.2 (aryl-Cq), 132.9 (aryl-Cq),
130.4 (aryl-Cq), 129.7 (aryl-CH), 129.5 (2C, Ph-CH), 129.1 (aryl-
CH), 128.8 (aryl-CH), 128.2 (aryl-CH), 128.1 (aryl-CH), 128.1 (2C,
Ph-CH), 127.0 (aryl-CH), 126.9 (2C, Ph-CH), 124.5 (aryl-CH),
119.5 (CN), 69.2 (C-2), 49.1 (C-3), 43.9 (C-4); FAB-MS (m/z) 296
(57) [M]þ, 269 (32) [M - HCN]þ, 192 (100), 127 (72) [C10H7]þ;
ESI-HRMS calcd for [C21H16N2þ H]þ 297.1392, found 297.1398.
cis-Isomer: IR (film) ν=3060, 3031, 2956, 2924, 1608, 750,
1
699, 477 cm-1; H NMR (400 MHz, CDCl3) δ=8.25 (s, 1H,
H-10), 8.14 (dd, J=8.6, 1.6 Hz, 1H, naphth), 7.87-7.92 (m, 3H,
naphth), 7.56 (mc, 2H, naphth), 7.39-7.25 (m, 5H, Ph), 5.36 (dt,
Jd=8.2 Hz, Jt=1.5 Hz, 1H, H-2), 3.98 (d-pseudo-t, Jt ≈ 8 Hz,
Jd=6.4 Hz, 1H, H-3), 3.61 (ddd, J=17.2, 8.4, 1.5 Hz, 2H, H-4a),
3.54 (ddd, J=17.2, 6.4, 1.5 Hz, 1H); 13C NMR (100.75 MHz,
CDCl3) δ=177.9 (C-5), 139.0 (aryl-Cq), 135.2 (aryl-Cq), 133.0
(aryl-Cq), 130.5 (aryl-Cq), 129.7 (aryl-CH), 129.2 (C-300,500),
129.1 (aryl-CH), 128.8 (aryl-CH), 128.2 (aryl-CH), 128.2 (aryl-
CH), 128.1 (aryl-CH), 127.7 (C-200,600), 127.0 (aryl-CH), 124.5
(aryl-CH), 117.3 (CN), 67.6 (C-2), 46.4 (C-3), 42.6 (C-4); FAB-
MS (m/z) 296 (47) [M]þ, 269 (18) [M - HCN]þ, 192 (100), 127
(39) [C10H7]þ; FAB-HRMS calcd for [C21H16N2 þ H]þ
297.1392, found 297.1380.
3-(2-Bromophenyl)-5-(2-naphthyl)-3,4-dihydro-2H-pyrrole-2-
carbonitrile (3f). The title compound was prepared according to
the general procedure from aminoacetonitrile hydrochloride (135
mg, 1.46 mmol), 3-(2-bromophenyl)-1-(2-naphthyl)propenone34
(329 mg, 0.98 mmol), and pyridine (4 mL). After 3 h, TLC
indicated incomplete conversion and another portion of amino-
acetonitrile hydrochloride (45 mg, 0.48 mmol) was added. After a
further 3 h, workup yielded a black oil (381 mg). Ratio of isomers:
trans/cis = 2.7:1. Purification of the crude product by flash
chromatography (cyclohexane/ethyl acetate, 5:1) gave trans-3f
as yellow crystals (22 mg, 0.059 mmol, 6%): mp 148-149 °C
(dec), Rf (cyclohexane/ethyl acetate 2:1)=0.49 and a mixture of
cis- and trans-3f as yellow crystals (trans/cis=2.5/1, 261 mg, 0.70
mmol, 71%), Rf cis (cyclohexane/ethyl acetate 2:1)=0.43.
trans-Isomer: 1H NMR (400 MHz, CDCl3) δ=8.22 (s, 1H, H-
10), 8.12 (dd, J=8.6, 1.7 Hz, 1H, naphth), 7.94-7.84 (m, 3H,
naphth), 7.63 (dd, J = 8.0, 1.0 Hz, 1H, H-30), 7.55 (mc, 2H,
naphth), 7.27 (dt, Jt=6.4 Jd=1.0 Hz, 1H, H-50), 7.19-7.10 (m,
2H, H-40, H-60), 5.15 (dt, Jd=5.6 Hz, Jt=1.5 Hz, 1H, H-2), 4.48
(dt, Jd=9.6 Hz, Jt=5.6 Hz, 1H, H-3), 3.84 (ddd, J=17.5, 9.6, 1.5
cis-Isomer: IR (film) ν=3064, 3029, 2936, 2241, 1617, 753,
700 cm-1; 1H NMR (400 MHz, CDCl3) δ=7.67 (d, J=7.8 Hz,
1H, H-40), 7.59 (d, J=8.4 Hz, 1H, H-70), 7.43 (mc, 1H, H-50),
7.40-7.24 (m, 7H, aryl-CH), 5.36 (d-pseudo-t, Jd=8.2 Hz, Jt ≈
1.6 Hz, 1H, H-2), 3.97 (d-pseudo-t, Jt ≈ 8.3 Hz, Jd=6.4 Hz, 1H,
H-3), 3.52 (ddd, J=17.3, 8.5, 1.5 Hz, 1H, H-4a), 3.44 (ddd, J=
17.3, 6.4, 1.6 Hz, 1H, H-4b); 13C NMR, DEPT (101 MHz,
CDCl3) δ=169.0 (C-5), 156.1 (C-7a0), 149.5 (C-20), 138.3 (C-100),
129.2 (2C, Ph), 128.4 (aryl-CH), 127.7 (3C, aryl-CH), 127.6 (C-
3a0), 124.0 (aryl-CH), 122.6 (aryl-CH), 116.7 (CN), 112.5 (aryl-
CH), 112.4 (aryl-CH), 67.7 (C-2), 46.3 (C-3), 42.5 (C-4); FAB-
MS m/z 286 (100) [M]þ, 182 (89); FAB-HRMS calcd for
[C19H14N2O þ H]þ 287.1184, found 287.1190.
(E)-3-(4-Chlorophenyl)-5-(4-chlorostyryl)-3,4-dihydro-2H-
pyrrole-2-carbonitrile (3h). The title compound was prepared
according to the general procedure from aminoacetonitrile
hydrochloride (202 mg, 2.16 mmol), (E,E)-1,5-bis(4-chloro-
phenyl)-penta-1,4-dien-2-one35,36 (449 mg, 1.48 mmol), and
pyridine (6.3 mL). After 3 h, TLC did not indicate complete
conversion, and another portion of aminoacetonitrile hydro-
chloride (70 mg, 0.76 mmol) was added. Workup after 1 h
Hz, 1H, H-4a), 3.41 (ddd, J=17.5, 5.6, 1.5 Hz, 1H, H-4b); 13
C
NMR (101 MHz, CDCl3) δ=177.1 (C-5), 139.9 (aryl-Cq), 135.3
(aryl-Cq), 133.9 (aryl-Cq), 133.0 (aryl-Cq), 130.3 (aryl-Cq), 129.8
(aryl-CH), 129.5 (aryl-CH), 129.2 (aryl-CH), 128.9 (aryl-CH),
128.5 (aryl-CH), 128.2 (aryl-CH), 128.1 (aryl-CH), 127.7 (aryl-
CH), 127.1 (aryl-CH), 124.6 (aryl-CH), 124.4 (C-20), 119.0 (CN),
(35) Nadar, P. A.; Renuga, V. J. Indian Chem. Soc. 2006, 83, 1219–1222.
(36) Straus, F.; Ecker, O. Ber. Dtsch. Chem. Ges. 1906, 39, 2977–3006.
(34) Misra, S. S. J. Indian Chem. Soc. 1975, 52, 1095–1096.
8248 J. Org. Chem. Vol. 74, No. 21, 2009

Bergner et al.
JOCArticle
yielded a black oil (615 mg). Ratio of isomers: trans/cis =
2.8:1. Purification of the crude product by flash chromato-
graphy (cyclohexane/ethyl acetate, 5:1) gave trans-3h as
orange crystals (150 mg, 0.44 mmol, 30%): mp 134-136 °C
(dec), Rf (cyclohexane/ethyl acetate 2:1)= 0.38 and a mix-
ture of cis and trans-3h as red oil (40 mg, 0.12 mmol, 8%,
cis/trans=1.25:1), Rf (cyclohexane/ethyl acetate 2:1)=0.14.
trans-Isomer: IR (film) ν=3051, 3031, 2243, 1633, 1580, 1492,
benzylideneacetone (854 mg, 5.84 mmol), and pyridine (24 mL).
After 4 h, the reaction mixture was worked up to yield a black oil
(977 mg). Ratio of isomers: trans/cis= 3.3:1. Purification of a
portion (706 mg) of the crude product by flash chromatography
(cyclohexane/ethyl acetate, 10:1 þ 1% EtNMe2, alumina) gave
trans-3j as reddish crystals (57 mg, 33%): mp 82-83 °C dec, Rf
(cyclohexane/ethyl acetate 2:1)=0.52 and cis-3j as reddish oil (28
mg, 16%), Rf (cyclohexane/ethyl acetate 2:1) = 0.35. The cis-
isomer still contained impurities.
1
1407, 1352, 1091, 1013, 812, 731 cm-1; H NMR (400 MHz,
CDCl3) δ=7.43 (mc, 2H, aryl-H), 7.34 (mc, 4H, aryl-H), 7.17
(mc, 2H, aryl-H), 7.04 (br s, 2H, styryl-H), 4.79 (dt, Jd=7.0 Hz,
Jt=1.6 Hz, 1H, H-2), 3.83 (d-pseudo-t, Jd=9.3 Hz, Jt ≈ 7 Hz,
1H, H-3), 3.49 (ddd, J=17.1, 9.3, 1.6 Hz, 1H, H-4a), 3.01 (ddd,
J=17.1, 7.6, 1.6 Hz, 1H, H-4b); 13C NMR, DEPT (126 MHz,
CDCl3) δ=176.7 (C-5), 140.7 (styryl-C2), 138.4 (Cq), 136.0 (Cq),
133.8 (Cq), 133.4 (Cq), 129.4 (2C, aryl-CH), 129.3 (2C, aryl-CH),
128.8 (2C, aryl-CH), 128.1 (2C, aryl-CH), 123.5 (styryl-C1),
118.8 (CN), 68.5 (C-2), 48.1 (C-3), 42.4 (C-4); FAB-MS m/z 339
(100) [M - H]þ, 167 (60); FAB-HRMS calcd for [C19H14Cl2-
N2þ H]þ 341.0612, found 341.0597.
trans-Isomer: IR (film) ν=2921, 2243, 1714, 1642, 1495, 1456,
1
1430, 1381, 1318, 1021, 759, 701 cm-1; H NMR (300 MHz,
CDCl3) δ = 7.41-7.27 (m, 3H, phenyl), 7.24-7.16 (m, 2H,
phenyl), 4.69 (dsext, Jd=6.8 Hz, Jsext=1.6 Hz, 1H, H-2), 3.80
(d-pseudo-t, 1H, Jd=9.4 Hz, Jt ≈ 7 Hz, H-3), 3.22 (ddd, J=17.8,
9.6, 1.6 Hz, 1H, H-4a), 2.82 (ddd, 1H, J=17.8, 7.4, 1.6 Hz, H-
4b), 2.18 (d, 3H, J=1.6 Hz, CH3); 13C NMR (75.5 MHz, CDCl3)
δ=179.8 (CdN), 140.2 (C-10), 129.2 (2C, Ph), 127.7, 126.6 (2C,
Ph), 119.3 (CN), 68.8 (C-2), 49.1 (C-3), 47.5 (C-4), 19.8 (CH3);
EI-MS (m/z) 184 (32) [M]þ, 143 (19), 80 (100); FAB-HRMS
calcd for [C12H12N2 þ H]þ 185.1079, found 185.1072.
1
Characteristic data of the cis-isomer: H NMR (400 MHz,
cis-Isomer: IR (NaCl, film) ν=2924, 2244, 1708, 1641, 1495,
1455, 1429, 1381, 912, 760, 733, 700 cm-1. 1H NMR (300 MHz,
CDCl3) δ = 7.40-7.26 (m, 3H, phenyl), 7.22-7.16 (m, 2H,
phenyl), 5.07 (d-pseudosext, 1H, Jd =8.4, Jsext ≈ 1 Hz, H-2),
3.79 (dt, 1H, J=8.4 Hz, J=7.2 Hz, H-3), 3.03 (ddd, J=17.9, 8.4,
1.5 Hz, 2H, H-4a), 2.95 (ddd, J=17.9, 7.2, 1.5 Hz, 2H, H-4b),
2.20 (d, 3H, J=1.2 Hz, CH3); 13C NMR (75.5 MHz, CDCl3) δ=
180.8 (CdN), 138.3 (C-10), 129.1 (2C, Ph), 127.9, 127.4 (2C, Ph),
116.9 (CN), 67.0 (C-2), 46.4, 45.9 (C-3, C-4), 20.0 (CH3); EI-MS
m/z 184 (27) [M]þ, 143 (19), 80 (100); FAB-HRMS calcd for
[C12H12N2 þ H]þ 185.1079, found 185.1075.
CDCl3) δ=7.07 (s, 2H, styryl-H), 5.22 (dt, Jd=8.1 Hz, Jt=1.2
Hz, 1H, H-2), 3.30 (ddd, J=17.0, 8.6, 1.2 Hz, 1H, H-4a), 3.17
(ddd, J=17.0, 6.1, 1.2 Hz, 1H, H-4b); 13C NMR, DEPT (126
MHz, CDCl3) δ = 177.7 (C-5), 140.9 (styryl-C2), 137.1 (Cq),
136.0 (Cq), 134.0 (Cq), 133.4 (Cq), 129.3 (aryl-CH), 129.2 (aryl-
CH), 128.87, 128.84 (2 ꢀ aryl-CHc), 128.81 (aryl-CHt), 123.6
(styryl-C1), 116.8 (CN), 66.9 (C-2), 45.4 (C-3), 41.3 (C-4)ppm.
Data of isomeric mixture: IR (film) 2927, 2805, 2240, 1633,
1579, 1491, 1407, 1351, 1090, 1012, 970, 907, 811, 728 cm-1
;
FAB-MS m/z 339 (100) [M - H]þ, 313(12) [M - HCN]þ, 167
(54). Anal. Calcd for C19H14Cl2N2 (341.23): C, 62.68; H, 3.71;
N, 12.90. Found: C, 62.64; H, 3.45; N, 12.83.
3-(4-Chlorophenyl)-5-isopropyl-3,4-dihydro-2H-pyrrole-2-carbo-
nitrile (3k). The title compound was prepared according to the
general procedure from aminoacetonitrile hydrochloride (200
mg, 2.16 mmol), (E)-1-(4-chlorophenyl)-4-methylpent-1-en-3-
one37 (300 mg, 1.44 mmol), and pyridine (7.1 mL). After 4 h,
TLC indicated incomplete conversion, and another portion of
aminoacetonitrile hydrochloride (70 mg, 0.76 mmol) was added.
After a further 14 h, workup yielded a black oil (452 mg). Ratio
of isomers: trans/cis=1.2:1. Purification of the crude product by
flash chromatography (cyclohexane/ethyl acetate, 10:1) gave
trans-3k as a yellow oil (72 mg, 0.29 mmol, 21%), Rf (cyclo-
hexane/ethyl acetate 2:1)=0.36, and cis-3k as brown oil (42 mg,
0.17 mmol, 12%), Rf (cyclohexane/ethyl acetate 2:1) = 0.14.
Both products still contained impurities after chromatography.
trans-Isomer: 1H NMR (400 MHz, CDCl3) δ 7.28 (AA0-part
of AA0BB0-system, 2H, aryl), 7.10 (BB0-part of a AA0BB0-
system, 2H, aryl), 4.62 (d-pseudo-q, Jd=6.9, Jq ≈ 1.5 Hz, 1H,
H-2), 3.70 (d-pseudo-t, Jt ≈ 7 Hz, Jd=9.3 Hz, 1H, H-3), 3.18
(ddd, J=17.8, 9.4, 1.5 Hz, 1H, H-4a), 2.64-2.76 (m, 2H) this
multiplet contains: 2.73 (ddd, J=17.8, 7.5, 1.7 Hz, H-4b), 2.70
(d-sept, Jsept=7.0 Hz, Jd=1.4 Hz, 1H, CH(CH3)2), 1.18 (dd, J=
7.0, 1.0 Hz, 6H, CH(CH3)).
5-(4-Fluorophenyl)-3-(2-chlorophenyl)-3,4-dihydro-2H-pyr-
role-2-carbonitrile (3i). The title compound was prepared accord-
ing to the general procedure from aminoacetonitrile hydro-
chloride (150 mg, 1.62 mmol), 2-chloro-40-fluorochalcone (281
mg, 1.08 mmol), and pyridine (4.7 mL). After 2 h, TLC indicated
incomplete conversion, and another portion of aminoaceto-
nitrile hydrochloride (52 mg, 0.56 mmol) was added. After a
further 1.5 h, workup yielded a black oil (374 mg). Ratio of
isomers: trans/cis=1.3:1. Purification of the crude product by
flash chromatography (cyclohexane/ethyl acetate, 10:1) only
gave an isomeric mixture of 3i as a yellow oil (248 mg,
0.83 mmol, 77%, trans/cis: 1.25:1), Rf trans (cyclohexane/ethyl
acetate 2:1)=0.45, Rf cis (cyclohexane/ethyl acetate 2:1)=0.39.
Data of isomeric mixture: 1H NMR (400 MHz, CDCl3) δ=
c,t
c,t
7.87-7.94 (m, 2H, H-2c,t00, 200 ,600 ), 7.40-7.46 (m, 1H, H-30c,t),
7.22-7.30 (m, 2H, aryl-H), 7.11-7.17 (m, 3H, aryl-H), 5.48 (td,
0.45H, Jd=8.2 Hz, Jt=1.4 Hz, H-2c), 5.10 (d, 0.55H, Jd=6.0 Hz,
Jt=1,2 Hz, H-2t), 4.48 (q, 0.45H, J=8.1 Hz, 1H, H-3c), 4.38 (dt,
0.55H, Jt=9.7 Hz, Jd=6.0 Hz, H-3t), 3.67 (ddd, J=17.6, 9.7, 1.8
Hz, 0.55H, H-4at), 3.46 (dd, 0.9H, J=8.1 Hz, J=1.4 Hz, 2H, H-
cis-Isomer: 1H NMR (400 MHz, CDCl3) δ 7.29 (AA0-part of a
AA0BB0-system, 2H, aryl), 7.09 (BB0-part of a AA0BB0-system,
2H, aryl), 5.03 (d-pseudo-q, Jd=8.5 Hz, Jq ≈ 1 Hz, 1H, H-2),
3.71 (dt, Jt=8.5 Hz, Jd=6.4 Hz, 1H, H-3), 3.01 (ddd, J=17.5,
8.5, 1.2 Hz, 1H, H-4a), 2.86 (ddd, J=17.5, 6.4, 1.3 Hz, 1H H-4b),
2.73 (d-sept, Jsept=7.0 Hz, Jd=0.9 Hz, 1H), 1.20 (d, J=7.0 Hz,
6H CH(CH3)).
General Procedure for the Synthesis of Pyrroles (15a-m).
Synthesis of Precursors (12 or 14). R-Aminonitrile 11 (1.2 mmol)
and the R,β unsaturated carbonyl compound 1 (1.44 mmol, 1.2
equiv) were dissolved in dry dichloromethane (2.5 mL each)
under argon atmosphere. In case of the hydrochlorides, the
4a,bc), 3.27 (ddd, 0.55H, J=17.6, 6.2, 1.4 Hz, 1H, H-4bt); 13
NMR (101 MHz, CDCl3) δ=176.5 (C-5c), 175.7 (C-5t), 166.6
C
t
c
(1JC,F=253.1 Hz, C-4c,t00),137.7 (C-10 ), 135.7 (C-10 ), 134.5 (C-
20 ), 133.9 (C-20 ), 130.8 (Ct), 130.70 (1C), 130.68 (2C), 130.6
c
t
(Cc), 130.2 (Ct), 129.5 (Cc), 129.3(Ct) (C-30 , C-40 , C-50 , C-60 , C-
t
t
t
t
30 , C-40 , C-50 , C-60 ) 128.0 (Ct), 127.9 (Cc), 127.9 (Ct), 127.7
c
c
c
c
(Cc) (C-200, 600 , C-200, 600c), 119.0 (CNt), 116.7 (CNc), 116.2
t
(2JC,F =22.1 Hz, C-300,500 ), 116.2 (2JC,F =22.1 Hz, C-300,500c),
t
115.8, 115.6 (C-100c,t), 67.4 (C-2t), 66.0 (C-2c), 45.8 (C-3t), 43.1
(C-4t), 42.9 (C-3c), 41.0 (C-4c); EI-MS m/z 298 (25) [M]þ, 261
(20), 160 (100); FAB-HRMS calcd for [C17H12ClFN2 þ H]þ
299.0751, found 299.0750.
5-Methyl-3-phenyl-3,4-dihydro-2H-pyrrole-2-carbonitrile (3j).
The title compound was prepared according to the general proce-
dure from aminoacetonitrile hydrochloride (494 mg, 5.34 mmol),
(37) Marcas, G. B.; Municio, A. M.; Vega, S. An. R. Soc. Esp. Fis. Quim.,
Ser. B 1964, 60, 639–652.
J. Org. Chem. Vol. 74, No. 21, 2009 8249

Bergner et al.
JOCArticle
obtained suspension turned clear after addition of triethylamine
(232 μL). Dry dichloromethane (5 mL) was cooled to 0 °C in a
dried flask equipped with a septum under argon atmosphere.
Successively, TiCl4 (1 mol/L in dichloromethane, 1.2 mmol,
1 equiv) and triethylamine (732 μL, 5.282 mmol, 4.4 equiv) were
added. The amount of triethylamine was reduced to 500 μL
when R-aminonitrile hydrochlorides were used. Both dissolved
starting materials were added to the brown TiCl4/triethylamine
solution simultaneously within 1 min using syringes. Stirring
was continued at 0 °C. Depending on the conversion (TLC
monitoring), the reaction mixture was worked up directly or was
warmed to room temperature. Water was added and a slimy
precipitate appeared. After being stirred for 10-20 min at room
temperature, the reaction mixture was extracted with dichloro-
methane (4 ꢀ 15 mL). The combined organic layers were washed
with satd aq NaHCO3 (20 mL), water (20 mL), and brine
(20 mL). After drying over Na2SO4, the solvent was removed
in vacuo and the crude product was converted to pyrrole 6 or
was purified by flash chromatography.
(m/z)=322 (31) [M]þ, 218 (100), 115 (41); FAB-HRMS calcd for
[C23H18N2 þ H]þ 323.1548, found 323.1546.
2,3,5-Triphenyl-1H-pyrrole (15a)38. The title compound was
prepared according to the general method from chalcone
(150.8 mg, 0.724 mmol) and amino(phenyl)acetonitrile hydro-
chloride (11a HCl,28 148.8 mg, 0.882 mmol), 1 N TiCl4 in
3
dichloromethane (0.72 mL, 0.72 mmol), and triethylamine
(439 μL, 3.169 mmol, 4.4 equiv). The reaction mixture was
stirred for 30 min at 0 °C and for 3.5 h at room temperature. The
crude intermediate (228.8 mg) was converted to pyrrole 15a
without further purification. A portion (98.5 mg, 0.306 mmol) of
crude 14a was reacted with KO-t-Bu (37.7 mg, 0.336 mmol) in
DMF (0.99 mL) according to the general procedure. A portion
(83.4 mg) of the crude pyrrole (92.9 mg) was purified by column
chromatography (petroleum ether/ ethyl acetate 8:1) to yield 6a
(34.5 mg, 0.117 mmol, 41% overall) as a slightly yellow solid: mp
134-136 °C (lit.38 mp 135-137 °C); Rf 0.42 (petroleum ether/
ethyl acetate 8:1); IR (ATR) ν=3425, 3058, 1603, 1486, 1451,
1261, 1071, 955, 757, 695, 586, 593, 506 cm-1; H NMR (400
1
MHz, DMSO-d6) δ = 11.4 (bs, 1H, NH), 7.79 (AA0 part of
AA0BB0C system, 2H), 7.42-7.31 (m, 6H), 7.30-7.26 (m, 4H),
7.25-7.15 (m, 3H), 6.76 (d, J=2.7 Hz, 1H, H4); 13C NMR,
PENDANT (100.6 MHz, DMSO-d6) δ=136.5 (Cq), 132.8 (Cq),
132.2 (Cq), 131.9 (Cq), 129.3 (Cq), 128.5 (2C), 128.2 (4C), 128.0
(2C), 127.8 (2C), 126.6, 125.8, 125.5, 123.8 (2C), 122.6 (Cq),
107.9 (C4); EI-MS (m/z)=295 (100) [M]þ; ESI-HRMS calcd for
[C22H17N]þ 295.1361, found 295.1353.
Dehydrocyanation. The precursor (12 or 14) was dissolved in
DMF (100 μL for 10 mg of 12 or 14), and potassium tert-
butoxide (1.1 equiv) was added. The intensely colored mixture
was heated to 100 °C in an argon-filled closed vial by irradiation
with microwaves for 3 min (CEM Discover, air cooling, IR
temperature control, maximum power 150 W). After pressure
equilibration, satd aq NaHCO3 (5-10 mL) was added, and the
mixture was extracted with ethyl acetate (4 ꢀ 5-10 mL). The
combined organic layers were washed with water and brine
(10-20 mL each) and dried over Na2SO4, and the solvent was
removed in vacuo. The crude product was purified by flash
chromatography.
5-(4-Fluorophenyl)-3-(4-methoxyphenyl)-2-phenyl-1H-pyrrole
(15b). The title compound was prepared according to the general
method from 4-methoxy-40-fluorochalcone (307.8 mg, 1.20
mmol), amino(phenyl)acetonitrile (11a, 190.6 mg, 1.44 mmol,
1.2 equiv), 1 N TiCl4 solution in dichloromethane (1.2 mL,
1.2 mmol), and triethylamine (732 μL, 5.28 mmol, 4.4 equiv).
The reaction mixture was stirred for 140 min at 0 °C and for 3.5 h
at room temperature. Workup yielded a brown resin (424.9 mg,
96%) which was converted to 15b without further purification.
A portion of the crude precursor (68.5 mg, 0.185 mmol) was
reacted with KO-t-Bu (22.8 mg, 0.203 mmol) in DMF (0.69 mL).
A portion (50.5 mg) of the crude pyrrole (63.5 mg) was purified
by column chromatography (cyclohexane/ethyl acetate 10:1) to
yield 15b (26.5 mg, 0.077 mmol, 53%, 50% overall) as a yellow
resin: Rf 0.38 (cyclohexane/ ethyl acetate 5:1); IR (ATR) ν =
1511 (m), 1493, 1242, 1173, 833, 799, 764, 696, 519, 507 cm-1; 1H
NMR (400 MHz, DMSO-d6) δ=11.29 (bs, 1H, NH), 7.81 (mc,
2H, H20,60), 7.41-7.37 (m, 2H), 7.33 (pseudo-t, Japp ≈ 7.6 Hz,
2H), 7.26-7.17 (m, 5H), 6.85 (BB0 part of AA0BB0system, 2H,
H300,500), 6.66 (d, J=2.7 Hz, 1H, H4), 3.74 (s, 3H, OCH3); 13C
2,3,5-Triphenyl-3,4-dihydro-2H-pyrrole-2-carbonitrile (14a).
The title compound was prepared according to the general
procedure from chalcone (250.3 mg, 1.20 mmol), amino(phenyl)-
acetonitrile hydrochloride (11a HCl,28 190.3 mg, 1.13 mmol),
3
1 N TiCl4 solution in dichloromethane (1.20 mL, 1.20 mmol),
and triethylamine (732 μL, 5.28 mmol). The reaction mixture
was stirred for 1 h at 0 °C and for 1 h at room temperature.
Although TLC indicated incomplete conversion, the dark
brown reaction mixture was worked up. A portion (335.7 mg)
of the crude product (356.7 mg) was purified by flash chroma-
tography (petroleum ether/ethyl acetate 8:1) to yield 14a (159.6
mg, 0.496 mmol, 47%) as a diastereomeric mixture (1.45:1). The
relative configuration could not be assigned: brown resin; Rf
0.38 (petroleum ether/ethyl acetate 5:1); IR (ATR) ν=2240 (vw,
CN), 1605, 1573, 1494, 1448, 1343, 1025, 758, 732, 690 cm-1
;
major diastereomer 1H NMR, COSY, HMBC (400 MHz,
CDCl3) δ = 8.10-8.07 (m, 2H, H20,60), 7.62-7.49 (m, 3H,
H30,50, H40), 7.17-7.04 (m, 6H, H300,500, H400, H3000,5000, H4000),
7.00-6.94 (m, 2H, H200,600), 6.84-6.79 (m, 2H, H2000,6000), 4.38
(t, J=8.4 Hz, 1H, H3), 3.67-3.59 (m, 1H, Ha4), 3.39 (dd, J=
17.1, 8.4 Hz, 1H, Hb4); 13C NMR, HSQC, HMBC (100.6 MHz,
400 MHz, CDCl3) δ = 178.4 (C5), 136.3 (C1000), 134.3 (C100),
132.9 (C10), 132.5 (C40), 129.1 (2C, C30,50), 128.7 (2C, C20,60),
128.5 (C400), 128.4 (2C, C2000,6000), 128.4 (2C, C300,500/C3000,5000),
128.3 (2C, C300,500/C3000,5000), 127.8 (C4000), 126.7 (2C, C200,600),
121.8 (CN), 79.7 (C2), 56.2 (C3), 41.0 (C4). Characteristic
chemical shifts of minor diastereomer: 1H NMR, COSY,
HMBC (400 MHz, CDCl3) δ = 8.06-8.03 (m, 2H, H20,60),
3.72 (dd, J = 10.1, 7.9 Hz, H3), 3.67-3.59 (m, 2H, H4); 13C
NMR, HSQC, HMBC (100.6 MHz, 400 MHz, CDCl3) δ=178.4
(C5), 139.4 (C1000), 136.2 (C100), 133.2 (C10), 132.4 (C40), 129.0
(2C), 129.0 (2C), 128.9 (2C), 128.8, 128.6 (2C), 128.6 (2C), 128.5,
125.9 (2C), 118.3 (CN), 81.9 (C2), 58.9 (C3), 42.0 (C4); EI-MS
NMR, PENDANT (125.8 MHz, DMSO-d6) δ=160.6 (d, 1JC,F
=
242.8 Hz, 1C, C40), 157.4 (C400), 133.0 (Cq), 130.9 (Cq), 129.1
(Cq), 129.0 (2C), 128.9 (Cq), 128.7 (Cq), 128.3 (2C), 127.9 (2C),
3
126.4 (C4000), 125.7 (d, JC,F=8.2 Hz, 2C, C20,60), 122.4 (Cq),
115.4 (d, 2JC,F=22.0 Hz, 2C, C30,50), 113.8 (2C), 108.0 (C4), 55.0
(OCH3); EI-MS (m/z)=343 (100) [M]þ, 328 (30), 298 (10), 84
(69), 69 (26), 56 (92), 41 (59); FAB-HRMS calcd for
[C23H18FNO]þ 343.1372, found 343.1360.
3-(2-Chlorophenyl)-5-(4-fluorophenyl)-2-phenyl-1H-pyrrole
(15c). The title compound was prepared according to the
general method from 2-chloro-40-fluorochalcone (312.8 mg,
1.20 mmol), amino(phenyl)acetonitrile hydrochloride (11a
3
HCl,28 242.8 mg, 1.44 mmol, 1.2 equiv), 1 N TiCl4 solution in
dichloromethane (1.2 mL, 1.2 mmol), and triethylamine (732
μL, 5.28 mmol, 4.4 equiv). The reaction mixture was stirred
80 min at 0 °C. The crude intermediate (brown resin, 464.1 mg)
was converted to 15c without further purification. A portion
of the crude intermediate (112.9 mg, 0.301 mmol) was reac-
ted according to the general procedure with KO-t-Bu (37.2
mg, 0.331 mmol) in DMF (1.13 mL). A portion (105.0 mg)
of the crude pyrrole (111.2 mg) was purified by column
€
(38) Furstner, A.; Weintritt, H.; Hupperts, A. J. Org. Chem. 1995, 60,
6637–6641.
8250 J. Org. Chem. Vol. 74, No. 21, 2009

Bergner et al.
JOCArticle
chromatography (toluene) to yield 15c (44.6 mg, 0.128 mmol,
45%, 45% overall) as a slightly pink resin: Rf 0.70 (toluene),
0.48 (cyclohexane/ ethyl acetate 5:1); IR (ATR) ν=3414, 1489,
1226, 1158, 830, 793, 758, 729, 695, 544 cm-1; 1H NMR (500
MHz, DMSO-d6) δ = 11.41 (bs, 1H, NH), 7.83 (mc, 2H,
H200,600), 7.49 (mc, 1H), 7.33-7.15 (m, 10H), 6.62 (d, J=2.7
Hz, 1H, C4); 13C NMR, PENDANT (100.6 MHz, DMSO-d6)
δ=160.6 (d, 1JC,F=243.6 Hz, 1C, C400), 135.8 (Cq), 132.9 (Cq),
132.5 (Cq), 132.4, 130.7 (Cq), 130.1 (Cq), 129.5, 128.8 (d,
4JC,F=2.9 Hz, 1C, C100), 128.3, 128.1 (2C), 127.0, 126.4 (2C),
126.1, 125.8 (d, 3JC,F=8.1 Hz, 2C, C200,600), 120.1 (Cq), 115.3
(d, 2JC,F=21.3 Hz, 2C, C300,500), 109.3 (C4); EI-MS (m/z)=347
(100) [M]þ, 312 (34), 189 (12), 156 (22), 103 (20), 84 (37), 69
(14), 56 (53), 40 (46); FAB-HRMS calcd for [C22H15ClFN]þ
347.0877, found 347.0880.
H4), 2.80 (mc, 1H, cyclohexyl-H1), 1.77 (mc, 7H, cyclohexyl),
1.29 (bs, 3H, cyclohexyl); 13C NMR, PENDANT (100.6 MHz,
DMSO-d6) δ=137.1 (Cq), 135.6 (Cq), 132.7 (Cq), 129.7 (Cq),
128.3 (2C), 128.2 (2C), 127.6 (2C), 125.1 (Ph-C4), 124.9 (Ph-
C4), 123.4 (2C), 120.6 (Cq), 105.6 (C4), 35.3 (cyclohexyl-C1),
32.5 (2C, cyclohexyl-C2,6), 26.3 (2C, cyclohexyl-C3,5), 25.4
(cyclohexyl-C4); EI-MS (m/z) = 301 (64) [M]þ, 258 (49), 244
(15), 232 (13), 83 (20), 70 (15), 55 (50), 43 (100); FAB-HRMS
calcd for [C22H23N]þ 301.1831, found 301.1828.
5-(4-Chlorophenyl)-2-cyclohexyl-3-(3-nitrophenyl)-1H-pyr-
role (15f). The title compound was prepared according to the
general method from (E)-40-chloro-3-nitrochalcone (496.2 mg,
1.73 mmol), amino(cyclohexyl)acetonitrile (11c, 286.0 mg, 2.07
mmol, 1.2 equiv), 1 N TiCl4 solution in dichloromethane
(1.74 mL, 1.74 mmol), and triethylamine (1.06 mL, 7.65 mmol).
The reaction mixture was stirred for 2.5 h at 0 °C. A portion
(626.0 mg) of the crude intermediate (brown resin, 636.3 mg)
was filtered through a pad of silica with petroleum ether/ethyl
acetate 9:1 to yield a yellow waxy substance (500.2 mg,
1.23 mmol, 72%). A portion of purified intermediate (102.5
mg, 0.251 mmol) was reacted according to the general procedure
with KO-t-Bu (31.0 mg, 0.276 mmol) in DMF (1.03 mL). A
portion (92.9 mg) of the crude pyrrole (98.2 mg) was purified by
column chromatography (toluene) to yield 15f (42.3 mg, 0.111
mmol, 47%, 34% overall) as a yellow solid: mp 227-229 °C; Rf
0.75 (toluene); IR (ATR) ν=3394, 2922, 1530, 1515, 1347, 1087,
802, 741, 722, 588, 502 cm-1; 1H NMR (500 MHz, DMSO-d6)
δ=11.00 (bs, 1H, NH), 8.11 (bs, 1H, 3-NO2-C6H4-H2), 8.06 (d,
J=8.0 Hz, 1H, H400), 7.80-7.74 (m, 3H, H600, H20,60), 7.68 (t, J=
8.0 Hz, 1H, H500), 7.42 (XX0 part of AA0XX0 system, Japp ≈ 8.5
Hz, 2H, H30,50), 6.76 (d, J =2.5 Hz, 1H, H4), 2.80 (mc, 1H,
cyclohexyl-H1), 1.80 (mc, 6H, cyclohexyl), 1.72 (mc, 1H,
cyclohexyl), 1.31 (mc, 3H, cyclohexyl); 13C NMR, PENDANT
(100.6 MHz, DMSO-d6) δ=148.0 (C300), 138.5 (Cq), 137.1 (Cq),
133.8, 131.2 (Cq), 129.8, 129.7 (Cq), 129.3 (Cq), 128.4 (2C),
125.2 (2C), 121.4, 119.7, 118.6, 106.2 (C4), 35.4 (cyclohexyl-C1),
32.3 (2C, cyclohexyl-C2,6), 26.2 (2C, cyclohexyl-C3,5), 25.3
(cyclohexyl-C4); EI-MS (m/z)=380 (100) [M]þ, 350 (13), 337
(58), 331 (15), 290 (14), 40 (21); FAB-HRMS calcd for
[C22H21ClN2O2]þ 380.1292, found 380.1302.
2-(4-Fluorophenyl)-3,5-diphenyl-1H-pyrrole (15d)39. The title
compound was prepared according to the general method from
chalcone (250.4 mg, 1.20 mmol), amino(4-fluorophenyl)-
acetonitrile 11b (216.9 mg, 1.45 mmol, 1.2 equiv), 1 N TiCl4
solution in dichloromethane (1.2 mL, 1.2 mmol), and triethyla-
mine (732 μL, 5.28 mmol, 4.4 equiv). The reaction mixture was
stirred for 120 min at 0 °C. The crude brown resin (388.4 mg,
95%) was reacted to 15d without further purification. A portion
of the crude intermediate (119.2 mg, 0.350 mmol) was reacted
according to the general procedure with KO-t-Bu (43.2 mg,
0.385 mmol) in DMF (1.2 mL). A portion (170.7 mg) of the
crude pyrrole (190.8 mg) was purified by column chromato-
graphy (petroleum ether/ethyl acetate 8:1) to yield 15d (45.2 mg,
0.144 mmol, 46%, 44% overall) as a slightly yellow foam:
Rf 0.68 (petroleum ether/ ethyl acetate 5:1); IR (ATR)
ν =1691, 1508, 1488, 1220, 838, 812, 752, 691, 541, 518, 499
cm-1; 1H NMR (400 MHz, DMSO-d6) δ=11.40 (bs, 1H, NH),
7.78 (pseudo-d, Japp ≈ 7.8 Hz, 2H), 7.44-7.35 (m, 4H),
7.29-7.26 (m, 4H), 7.20 (pseudo-t, Japp ≈ 8.6 Hz, 4H), 6.75
(d, J=2.6 Hz, 1H, H4); 13C NMR, PENDANT, HMBC (100.6
MHz, DMSO-d6) δ=161.0 (d, 1JC,F=244.0 Hz, 1C, C40), 136.3
(Cq), 132.2 (Cq), 131.8 (Cq), 129.9 (d, 3JC,F=8.1 Hz, 2C, C20,60),
129.2 (d, 4JC,F=2.9 Hz, 1C, C10), 128.5 (3C, contains C2), 128.2
(2C), 127.8 (2C), 125.8, 125.5, 123.8 (2C), 122.5 (Cq), 115.1
(d, 2JC,F=21.3 Hz, 2C, C30,50), 107.8 (C4); EI-MS (m/z)=313
(100) [M]þ; FAB-HRMS calcd for [C22H16FN]þ 313.1267,
found 313.1272.
2-Cyclohexyl-3,5-diphenyl-1H-pyrrole (15e). The title com-
pound was prepared according to the general method from
chalcone (249.4 mg, 1.20 mmol), amino(cyclohexyl)acetonitrile
(11c, 199.1 mg, 1.44 mmol, 1.2 equiv), 1 N TiCl4 solution in
dichloromethane (1.2 mL, 1.2 mmol), and triethylamine
(732 μL, 5.28 mmol, 4.4 equiv). The reaction mixture was stirred
for 165 min at 0 °C. The crude material (reddish brown resin,
399.2 mg) was reacted to 15e without further purification. A
portion of crude intermediate (150.9 mg, 0.459 mmol) was
reacted according to the general procedure with KO-t-Bu
(56.7 mg, 0.505 mmol) in DMF (1.5 mL). A portion (145.3
mg) of the crude pyrrole (151.0 mg) was purified by column
chromatography (petroleum ether/ethyl acetate 8:1) to yield 15e
(51.2 mg, mmol, 0.170 mmol, 38%, 38% overall) as a slightly
yellow resin: Rf 0.60 (petroleum ether/ ethyl acetate 5:1); IR
(ATR) ν=2927, 2917, 2848, 1603, 1493, 1447, 978, 755, 695, 665,
514, 502 cm-1; 1H NMR (400 MHz, DMSO-d6) δ=10.77 (bs,
1H, NH), 7.69 (pseudo-d, Japp ≈ 7.4 Hz, 2H, Ph), 7.40-7.30 (m,
6H, Ph), 7.20 (pseudo-t, Japp ≈ 7.1 Hz, 1H, Ph-H4), 7.14
(pseudo-t, Japp ≈ 7.3 Hz, 1H, Ph-H4), 6.53 (d, J=2.7 Hz, 1H,
3,5-Diphenyl-2-methyl-1H-pyrrole (15g)40. A portion (90.0
mg, 0.346 mmol) of crude imine 12g was reacted with KO-
t-Bu (42.7 mg, 0.381 mmol) in DMF (0.9 mL) according to the
general procedure. A portion (61.9 mg) of the crude pyrrole
(77.6 mg) was purified by column chromatography (toluene)
to yield pure 15g (29.6 mg, 0.127 mmol, 46%, 43% overall) as
a slightly yellow resin: Rf 0.50 (toluene); IR (ATR) ν=3418,
3053, 1604, 1523, 1494, 1448, 1352, 1152, 804, 754, 691, 647, 523
cm-1; 1H NMR (500 MHz, DMSO-d6) δ=11.13 (bs, 1H, NH),
7.63 (pseudo-d, Japp ≈ 8.2 Hz, 2H, Ph), 7.46-7.42 (m, 2H, Ph),
7.35 (mc, 4H, Ph), 7.19-7.11 (m, 2H, Ph), 6.70 (d, J=2.6 Hz,
1H, H4), 2.41 (s, 3H, CH3); 13C NMR (100.6 MHz, DMSO-d6)
δ = 136.8 (Cq), 132.6 (Cq), 129.2 (Cq), 128.5 (2C), 128.3
(2C), 126.6 (2C), 125.8 (Cq), 125.1, 124.7, 123.0 (2C), 121.2
(Cq), 105.3 (C4), 12.6 (CH3); EI-MS (m/z)=233 (100) [M]þ, 40
(35); FAB-HRMS calcd for [C17H15N]þ 233.1205, found
233.1193.
5-(4-Chlorophenyl)-2-methyl-3-(3-nitrophenyl)-1H-pyrrole
(15h). The title compound was prepared according to the general
method from (E)-40-chloro-3-nitrochalcone (345.9 mg, 1.20
mmol), 2-aminopropanenitrile hydrochloride (11d HCl,28
3
154.3 mg, 1.45 mmol, 1.2 equiv), 1 N TiCl4 solution in dichloro-
methane (1.2 mL, 1.2 mmol), and triethylamine (732 μL, 5.28
mmol, 4.4 equiv). The reaction mixture was stirred for 85 min at
0 °C and for 85 min at room temperature. The crude brown resin
(415.9 mg) was reacted to 15h without further purification. A
(39) de Laszlo, S. E.; Visco, D.; Agarwal, L.; Chang, L.; Chin, J.; Croft,
G.; Forsyth, A.; Fletcher, D.; Frantz, B.; Hacker, C.; Hanlon, W.; Harper,
C.; Kostura, M.; Li, B.; Luell, S.; MacCoss, M.; Mantlo, N.; O0Neill, E. A.;
Orevillo, C.; Pang, M.; Parsons, J.; Rolando, A.; Sahly, Y.; Sidler, K.;
Widmer, W. R.; O’Keefe, S. J. Bioorg. Med. Chem. Lett. 1998, 8, 2689–2694.
(40) Chiu, P. K.; Sammes, M. P. Tetrahedron 1988, 44, 3531–3538.
J. Org. Chem. Vol. 74, No. 21, 2009 8251

Bergner et al.
JOCArticle
portion of the crude precursor (125.2 mg, 0.368 mmol) was
reacted according to the general procedure with KO-t-Bu (45.5
mg, 0.405 mmol) in DMF (1.25 mL). A portion (115.0 mg) of the
crude pyrrole (150.8 mg) was purified by column chromatogra-
phy (cyclohexane/ ethyl acetate 10:1 to 8:1) to yield 15h (35.1 mg,
0.112 mmol, 40%, 40% overall) as an orange solid: mp 179-
182 °C; Rf 0.34 (cyclohexane/ethyl acetate 3:1); IR (ATR)
2H, Ar-H200,600), 7.46 (d, J=7.5 Hz, 1H, H60), 7.36-7.32 (m,
2H, Ar), 7.30-7.25 (m, 1H, Ar), 7.18 (pseudo-t, Japp ≈ 8.9 Hz,
2H, H300,500), 6.51 (d, J=2.8 Hz, 1H, H4), 2.18 (s, 3H, CH3); 13C
NMR, PENDANT (125.8 MHz, DMSO-d6) δ=160.2 (d, 1JC,F
=
241.9 Hz, 1C, C400), 135.4 (C10), 132.4 (C20), 132.0, 129.6, 129.4
(d, 4JC,F=2.9 Hz, 1C, C100), 128.1 (Cq), 127.6, 126.9 (Cq), 126.9,
124.8 (d, 3JC,F=7.9 Hz, 2C, C200,600), 119.1 (C3), 115.5 (d, 2JC,F
=
ν=1526, 1509, 1488, 1341, 824, 782, 736, 721, 672, 499 cm-1
;
21.3 Hz, 2C, C300,500), 107.1 (C4), 55.0 (OCH3), 12.0 (CH3); EI-
MS (m/z)=285 (100) [M]þ, 249 (19), 69 (61), 55 (29), 41 (23);
FAB-HRMS calcd for [C17H13ClFN]þ 285.0721, found
285.0714.
1H NMR (500 MHz, DMSO-d6) δ=11.41 (bs, 1H, NH), 8.22 (s,
1H, H200), 8.01 (dd, J=8.1, 1.5 Hz, 1H, H400), 7.91 (d, J=7.8 Hz,
1H, H600), 7.70 (AA0 part of AA0BB0 system, 2H, H20,60), 7.66 (t,
J=7.8 Hz, 1H, H500), 7.42 (BB0 part of AA0BB0 system, 2H,
H30,50), 6.95 (d, J=2.7 Hz, 1H, H4), 2.47 (s, 3H, CH3); 13C
NMR, PENDANT (100.6 MHz, DMSO-d6) δ=148.2 (Cq, Ar-
C300), 138.4 (Cq, Ar-C100), 132.7 (Ar-C600), 131.2 (Cq), 129.9
(Ar-C500), 129.7 (Cq), 128.7 (Cq), 128.6 (2C, Ar-C20,60), 127.8
(Cq), 124.8 (2C, Ar-C30,50), 120.2 (Ar-C400), 119.3 (Ar-C200),
119.2 (C3), 106.0 (C4), 12.7 (CH3); EI-MS (m/z) = 312 (100)
[M]þ, 282 (11), 266 (21), 251 (11); FAB-HRMS calcd for
[C17H13ClN2O2]þ 312.0666, found 312.0656.
3-Methyl-2,5-diphenyl-1H-pyrrole (15k)21. The title com-
pound was prepared according to the general method from
(E)-1-phenylbut-2-en-1-one41 (175.4 mg, 1.20 mmol), amino-
(phenyl)acetonitrile hydrochloride (11a HCl,28 242.8 mg, 1.44
3
mmol, 1.2 equiv), 1 N TiCl4 solution in dichloromethane
(1.2 mL, 1.2 mmol), and triethylamine (732 μL, 5.28 mmol,
4.4 equiv). The reaction mixture was stirred for 120 min at 0 °C.
The crude intermediate (brown resin, 308.4 mg) was reacted to
15k without further purification. A portion of the crude pre-
cursor (124.9 mg, 0.480 mmol) was reacted with KO-t-Bu (59.2
mg, 0.528 mmol) in DMF (1.25 mL) according to the general
procedure. A portion (137.1 mg) of the crude pyrrole (155.5 mg)
was purified by column chromatography (toluene) to yield 15k
(30.4 mg, 0.130 mmol, 31%, 31% overall) as a slightly yellow
solid: mp 100-101 °C (lit.21 mp 100-101 °C); Rf 0.62 (toluene);
IR (ATR) ν=3451, 1602, 1491, 1467, 1439, 1263, 807, 755, 702,
5-(4-Fluorophenyl)-3-(4-methoxyphenyl)-2-methyl-1H-pyr-
role (15i). The title compound was prepared according to the
general method from 4-methoxy-40-fluorochalcone (307.5 mg,
1.20 mmol), 2-aminopropanenitrile hydrochloride (11d HCl,28
3
153.4 mg, 1.44 mmol, 1.2 equiv), 1 N TiCl4 solution in dichloro-
methane (1.2 mL, 1.2 mmol), and triethylamine (732 μL, 5.28
mmol, 4.4 equiv). The reaction mixture was stirred for 3.5 h at
0 °C. The crude intermediate (brown foam, 354.5 mg) was
reacted to 15i without further purification. A portion of the
crude precursor (126.5 mg, 0.410 mmol) was reacted according
to the general procedure with KO-t-Bu (50.6 mg, 0.451 mmol) in
DMF (1.27 mL). A portion (89.1 mg) of the crude pyrrole (105.8
mg) was purified by column chromatography (cyclohexane/
ethyl acetate 10:1 to 8:1) to yield 15i (40.3 mg, 0.143 mmol,
42%, 40% overall) as a yellow resin which crystallized at
-18 °C: mp 106-109 °C dec; Rf = 0.36 (cyclohexane/ethyl
acetate 5:1); IR (ATR) ν=1506, 1223, 1175, 1152, 1024, 831,
811, 793, 604, 533, 522 cm-1; 1H NMR (500 MHz, DMSO-d6)
δ=11.03 (bs, 1H, NH), 7.64 (mc, 2H, H20,60), 7.33 (AA0 part of
AA0BB0 system, 2H, H200,600), 7.18 (pseudo-t, Japp ≈ 8.9 Hz, 2H,
H30,50), 6.93 (BB0 part of AA0BB0 system, 2H, H300,500), 6.58 (d,
1
692, 660, 506, 494 cm-1; H NMR (400 MHz, DMSO-d6) δ=
11.00 (bs, 1H, NH), 7.73-7.70 (m, 2H, Ph), 7.58-7.55 (m, 2H,
Ph), 7.45-7.40 (m, 2H, Ph), 7.37-7.32 (m, 2H, Ph), 7.26-7.21
(m, 1H, Ph), 7.17-7.13 (m, 1H, Ph), 6.46 (d, J=2.6 Hz, 1H, H4),
2.21 (s, 3H, CH3); 13C NMR, PENDANT (100.6 MHz, DMSO-
d6) δ=133.2 (Cq), 132.5 (Cq), 131.0 (Cq), 129.2 (Cq), 128.5 (2C),
128.3 (2C), 126.5 (2C), 125.5, 125.4, 123.7 (2C), 116.8 (Cq),
109.7 (C4), 12.8 (CH3); FAB-MS (m/z) 234.2 (42) [M þ H]þ,
233.2 (100) [M]þ; FAB-HRMS calcd for [C17H15N]þ 233.1205,
found 233.1204.
2,3-Diphenyl-1H-pyrrole (15l)12,31. The title compound was
prepared according to the general method from cinnamalde-
hyde (151 μL, 158.6 mg, 1.20 mmol), amino(phenyl)acetonitrile
hydrochloride (11a HCl,28 242.9 mg, 1.44 mmol, 1.2 equiv), 1 N
3
J=2.8 Hz, 1H, H4), 3.76 (s, 3H, OCH3), 2.36 (s, 3H, CH3); 13
C
=
TiCl4 solution in dichloromethane (1.2 mL, 1.2 mmol), and
triethylamine (732 μL, 5.28 mmol, 4.4 equiv). The reaction
mixture was stirred for 120 min at -50 °C. The crude inter-
mediate (slightly brown resin, 323.0 mg) was reacted to 15l
without further purification. A portion of the crude precursor
(133.4 mg, 0.542 mmol) was reacted with KO-t-Bu (66.9 mg,
0.596 mmol) in DMF (1.33 mL) according to the general
procedure. A portion (126.0 mg) of the crude pyrrole (153.4
mg) was purified by column chromatography (cyclohexane/
ethyl acetate 10:1) to yield 15l (20.0 mg, 0.091 mmol, 21%,
21% overall) as a slightly brown solid: mp 125-126 °C dec (lit.31
mp 127 °C); Rf 0.43 (cyclohexane/ ethyl acetate 5:1); IR (ATR) ν
=3331, 1504, 1492, 1101, 893, 772, 757, 740, 687, 669, 605, 580,
NMR, PENDANT (100.6 MHz, DMSO-d6) δ=160.1 (d, 1JC,F
4
241.6 Hz, 1C, C40), 156.8 (C400), 129.5 (d, JC,F =3.1 Hz, 1C,
C10), 129.3 (Cq), 128.1 (Cq), 127.7 (2C, C200,600), 124.9 (Cq),
124.7 (d, 3JC,F=7.6 Hz, 2C, C20,60), 121.0 (C3), 115.4 (d, 2JC,F
=
21.3 Hz, 2C, C30,50), 113.8 (2C, Ar-C300,500), 105.2 (C4), 55.0
(OCH3), 12.4 (CH3); EI-MS (m/z) 281 (100) [M]þ, 266 (43), 55
(20), 41 (13); FAB-HRMS calcd for [C18H16FNO]þ 281.1216,
found 281.1222.
3-(2-Chlorophenyl)-5-(4-fluorophenyl)-2-methyl-1H-pyrrole
(15j). The title compound was prepared according to the general
method from 2-chloro-40-fluorochalcone (313.4 mg, 1.20 mmol),
2-aminopropanenitrile hydrochloride (11d HCl,28 154.9 mg,
3
1
551 cm-1; H NMR (400 MHz, DMSO-d6) δ=11.19 (bs, 1H,
1.45 mmol, 1.2 equiv), 1 N TiCl4 solution in dichloromethane
(1.2 mL, 1.2 mmol), and triethylamine (732 μL, 5.28 mmol,
4.4 equiv). The reaction mixture was stirred for 135 min at 0 °C
and for 60 min at room temperature. The crude intermediate
(reddish resin, 355.2 mg) was reacted to 15j without further
purification. A portion of the crude precursor (125.7 mg, 0.402
mmol) was reacted with KO-t-Bu (49.6 mg, 0.442 mmol) in
DMF (1.25 mL) according to the general procedure. A portion
(139.5 mg) of the crude pyrrole (161.8 mg) was purified by
column chromatography (cyclohexane/ethyl acetate 15:1) to
yield 15j (30.9 mg, 0.108 mmol, 31%, 30% overall) as a yellow
resin: Rf 0.26 (cyclohexane/ethyl acetate 10:1); IR (ATR) ν=
NH), 7.32-7.28 (m, 4H, Ph), 7.26-7.23 (m, 4H, Ph), 7.23-7.18
(m, 1H, Ph), 7.17-7.12 (m, 1H, Ph), 6.88 (t, J=2.6 Hz, 1H, H5),
6.25 (t, J=2.6 Hz, 1H, H4); 13C NMR, PENDANT (100.6 MHz,
DMSO-d6) δ=137.1 (C100), 133.3 (C10), 128.3 (2C), 128.2 (2C),
127.9 (2C), 127.3 (Cq), 127.3 (2C), 126.2, 125.3 (C40, C400), 121.0
(Cq), 118.6 (C5), 110.0 (C4); EI-MS (m/z) 219 (100) [M]þ, 129
(22), 117 (68), 103 (51), 90 (36), 83 (18), 77 (30), 55 (43), 40 (28);
FAB-HRMS calcd for [C16H13N]þ 219.1048, found 219.1058.
2,3-Diphenyl-4,5,6,7-tetrahydro-1H-indole (15m). The title
compound was prepared according to the general method from
1
1527, 1491, 1226, 1155, 832, 808, 757, 744, 590, 524 cm-1; H
(41) Pitts, M. R.; Harrison, J. R.; Moody, C. J. J. Chem. Soc., Perkin
Trans. 1 2001, 955–977.
NMR (400 MHz, DMSO-d6) δ=11.20 (bs, 1H, NH), 7.64 (mc,
8252 J. Org. Chem. Vol. 74, No. 21, 2009

Bergner et al.
JOCArticle
(E)-2-bezylidenecyclohexanone42 (224.1 mg, 1.20 mmol), amino-
(100.6 MHz, DMSO-d6) δ=136.9, 133.6 (C10, C100), 130.2 (C3),
129.4 (2C, C200,600), 128.1 (4C, C30,60, C300,600), 127.6 (C3a), 126.3
(2C, C20,60), 125.3 (C400), 125.2 (C40), 119.8 (C2), 116.6 (C7a),
23.5 (C6), 22.9 (C5), 22.5 (C4), 22.1 (C7); the NMR spectra
showed the presence of impurities; EI-MS (m/z) 273 (100) [M]þ,
244 (52), 40 (36); FAB-HRMS calcd for [C20H19N]þ 273.1518,
found 273.1516.
(phenyl)acetonitrile hydrochloride (11a HCl,28 243.1 mg, 1.44
3
mmol, 1.2 equiv), 1 N TiCl4 solution in dichloromethane (1.2 mL,
1.2 mmol), and triethylamine (732 μL, 5.28 mmol, 4.4 equiv). The
reaction mixture was stirred for 90 min at 0 °C. The crude
intermediate (green resin, 356.2 mg) was reacted to 15m without
further purification. A portion of the crude precursor (140.1 mg,
0.466 mmol) was reacted with KO-t-Bu (57.6 mg, 0.513 mmol) in
DMF (1.40 mL) according to the general procedure. A portion
(132.5mg) of the crudepyrrole(160.1mg) was purified bycolumn
chromatography (cyclohexane/ethyl acetate 10:1) to yield 15m
(19.7 mg, 0.072 mmol, 19%, 19% overall) as a yellow film: Rf =
0.62 (cyclohexane/ ethyl acetate 5:1); IR (ATR) ν=2925, 1599,
Acknowledgment. This work was supported by the Deutsche
Forschungsgemeinschaft. We thank Dr. D. Schollmeyer
(University of Mainz) for the crystallographic analysis of com-
pounds 3f and 3g.
1527, 1503, 1491, 1442, 1070, 785, 755, 695, 593, 510 cm-1; H
1
NMR, COSY (400 MHz, DMSO-d6) δ=10.71 (bs, 1H, NH),
7.39-7.13 (m, 9H, Ph), 7.07 (mc, 1H, H-40), 2.60 (t, J=5.9 Hz,
2H, H2-4), 2.34 (t, J=5.7 Hz, 2H, H2-7), 1.77 (mc, 2H, H2-5),
1.67 (mc, 2H, H2-6); 13C NMR, PENDANT, HSQC, HMBC
Supporting Information Available: General methods; pro-
cedures for the preparation of 40-chloro-3-nitrochalcone and
compounds 9, 10, 11b, and 12g including physical data, copies of
1H and 13C spectra, ORTEP plots, as well as crystallographic
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
(42) Poggi, R.; Saltini, P. Gazz. Chim. Ital. 1932, 62, 678–686.
J. Org. Chem. Vol. 74, No. 21, 2009 8253