The synthesis of highly functionalized 2-(2-methylenecycloalkyl)pyrroles by palladium-catalyzed cycloreduction

Article abstract of DOI:10.1055/s-2007-980350

By utilizing the facile formation of an imine from an aldehyde and an amine, we have discovered a new and highly efficient Pd-catalyzed cycloreduction of enediynals leading to the corresponding 2-(2-methylenecycloalkyl)pyrroles in good to excellent yields

Full text of DOI:10.1055/s-2007-980350

LETTER
1411
The Synthesis of Highly Functionalized 2-(2-Methylenecycloalkyl)pyrroles by
Palladium-Catalyzed Cycloreduction
S
ynthese
s
of Highly Function
a
alized 2-(2-
n
Methylenecy
g
cloalkyl)pyrroles Ho Oh,* Wooram Park, Mira Kim
Department of Chemistry, Hanyang University, Sungdong-Gu, Seoul 133-791, South Korea
Fax +82(2)22990762; E-mail: changho@hanyang.ac.kr
Received 15 March 2007
catalyzed cyclization. This idea came from the fact that
Abstract: By utilizing the facile formation of an imine from an
aldehyde and an amine, we have discovered a new and highly
efficient Pd-catalyzed cycloreduction of enediynals leading to the
corresponding 2-(2-methylenecycloalkyl)pyrroles in good to excel-
lent yields.
the imine formation between aldehydes and primary
amines occurs readily, even at room temperature, and Pd-
catalyzed cycloreduction requires a higher temperature.
Combining two reactions in a one-step process is im-
portant in terms of synthetic feasibility as well as atom
economy.
Key words: palladium, endiynal, pyrrole, catalyst, cycloreduction
Herein we report the highly efficient atom-economic syn-
thesis of 2-(2-methylenecycloalkyl)pyrrole derivatives by
a Pd-catalyzed cycloreduction of imines prepared in situ
from the corresponding aldehydes (Scheme 1). Initially,
we attempted Pd-catalyzed cycloreduction of 1a in the
presence of benzylamine and formic acid. When the alde-
hyde 1a was mixed with benzylamine in dioxane at room
temperature, the corresponding imine was formed almost
exclusively based on the NMR of the reaction mixture. In
a separate experiment, we know that the corresponding
imine was cycloreduced under Pd catalysis. In fact, the
pyrrole derivative 2aa was isolated in good yield (85%)
when Pd(PPh3)4 was employed as a catalyst in dioxane.
The reaction could be carried out on gram-scale without
loss of yield.
Multicomponent and multistep one-pot methods to form
complex molecules from structurally simple starting
molecules is an important strategy in organic synthesis.
Imines are versatile intermediates affording N-containing
organic compounds and are easily formed from the corre-
sponding aldehydes and primary amines. The Pd-cata-
lyzed cycloreduction of enynes and enediynes gives
various polycyclic compounds in a very convenient single
step.1 A major advantage of diyne cycloreduction is in the
formation of stable alkenylpalladium intermediates while
enyne cycloisomerization forms the labile alkylpalladium
intermediates for b-elimination. Such an increase in
stability of the intermediates has prompted us to further
explore new reactions.2 Recently we reported the highly
functionalized and stereocontrolled synthesis of 2-(2-
methylenecyclopentyl)furan derivatives by Pd-catalyzed
cycloreduction. This strategy has been extended to imines
to give the corresponding pyrroles.
With this successful result, we have attempted to explore
the scope of this method to synthesize a variety of
structurally diverse pyrrole derivatives using a one-pot
method. First, we selected six enediynals 1a–f and four
representative amines, benzylamine, ethylamine, aniline,
and n-dodecylamine (Figure 1). The substrates 1a, 1b,
and 1c vary in the ring size of the tethers. The substrate 1d
has a gem-diester group which could help in the cycliza-
tion. The substrate 1e has a TBSO-group and a stereo-
genic center and 1f has a heteroatom, nitrogen, in the
diyne group. The four amines include both aromatic and
N-Heterocyclic compounds have served as interesting
building blocks in pharmaceutical and synthetic chemis-
try.3 Among them, substituted pyrroles have been attract-
ing increasing attention as synthetic target compounds
due to their widespread occurrence in nature and due to
the wide range of biological activities.4 Our approach is a
simple combination of classical imine formation and Pd-
Bn
N
O
BnNH2 (1.1 equiv)
Bn
H
N
Pd(PPh3)4 (3 mol%)
HCOOH (1.5 equiv)
dioxane, 80 °C
1a
2aa
A
Scheme 1 Pd-catalyzed cycloreduction of endiynal 1a with benzylamine
SYNLETT 2007, No. 9, pp 1411–1415
0
1.
0
6.
2
0
0
7
Advanced online publication: 23.05.2007
DOI: 10.1055/s-2007-980350; Art ID: U01907ST
© Georg Thieme Verlag Stuttgart · New York

1412
C. H. Oh et al.
LETTER
monitoring imine formation by looking at 1H NMR spec-
tra of the reaction solutions. Benzylamine rapidly reacted
and aqueous ethylamine also reacted well with these ene-
diynals. However, aniline required heating to complete
the imine formation. We found that imine formations
worked by mixing aldehydes 1a–f and amines even in the
presence of water. We attempted the one-pot multicompo-
nent assembly by mixing enediynal, amine, Pd catalyst
and formic acid in 1,4-dioxane. Our results are summa-
rized in Table 1.5
E
E
O
O
O
O
1b
1a
1c
1d
Ts
N
BnNH2
TBSO
O
O
EtNH2
PhNH2
1e
1f
n-C12H25NH2
All reactions were carried out under similar conditions ex-
cept a few factors such as reaction temperatures and times.
Overall, all attempted reactions were successful affording
the corresponding pyrrole derivatives (Figure 2).
Figure 1 Representative endiynals 1a–f and amines
aliphatic amines, which have different reactivities toward
aldehydes. The enediynals 1a–f were easily prepared by
Sonogashira couplings of 2-bromocycloalkenecarboxal-
dehydes with diynes.
Cyclohexane-fused pyrroles 2aa–2ad were synthesized in
70% to 85% yields (Table 1, entries 1–4). Cyclopentane-
fused pyrroles were also synthesized in good yields
(Table 1, entries 5–7).
Since cycloreduction of these enediynals to the corre-
sponding furan derivatives was successful, we postulated
that complete imine formation prior to Pd-catalyzed
cycloduction must be accomplished for the success of our
multicomponent reactions. Thus, we initially focused on
To our surprise, aniline was also incorporated into the cor-
responding pyrroles, implying that imine formation with
aniline was faster than cycloreduction of the enediynals.
This strongly supports the fact that these cycloreductions
can be achieved in a three-component reaction consisting
Table 1 Pd-Catalyzed Tandem Cycloreductions of Enediynals in the Presence of Aminesa
Entry
1
Enynal
1a
1a
1a
1a
1b
1b
1b
1c
Amine
BnNH2
PhNH2
EtNH2
Temp (°C)
60
Time (h)
Product
2aa
2ab
2ac
Yield (%)
85
1
1
1
1
3
3
3
1
1
1
3
3
3
1
1
1
1
2
60
83
3
60
70
4
n-C12H25NH2
BnNH2
PhNH2
EtNH2
60
2ad
2ba
2bb
2bc
2ca
74
5
80
80
6
80
68b
56
7
80
8
BnNH2
PhNH2
EtNH2
80
71
9
1c
80
2cb
2cc
62
10
11
12
13
14
15
16
17
1c
80
41
1d
1d
1d
1e
BnNH2
PhNH2
EtNH2
80
2da
2db
2dc
2ea
61
80
71
80
68
BnNH2
PhNH2
EtNH2
80
81
1e
80
2eb
2ec
76
1e
80
69
1f
BnNH2
80
2fa
66
a All reactions were carried out in one pot by mixing enediynal 1, amine, Pd catalyst and formic acid in 1,4-dioxane. The reaction mixtures were
stirred for 30 min at room temperature and then for the indicated time at the indicated temperatures.
b 10% of the corresponding furan was formed as a byproduct.
Synlett 2007, No. 9, 1411–1415 © Thieme Stuttgart · New York

LETTER
Syntheses of Highly Functionalized 2-(2-Methylenecycloalkyl)pyrroles
1413
NR
H
H
O
R = Bn
R = Ph
R = Et
2ba
2bb
2bc
R
R
2aa
2ab
2ac
2ad
R = Bn
H
Z
N
N
R = Ph
RNH2
NR
(CH2)n
Z
(CH2)n
Z
R = Et
R = C12H25
1
A
2
(CH2)n
E
E
HCOOH
H
HCOO-PdLn-H
H
R
R
2da
2db
2dc
2ca
2cb
2cc
R = Bn
R = Ph
R = Et
R = Bn
R = Ph
R = Et
PdLn
N
N
O
O
(E = COOEt)
Ln
H
Ln
Pd
H
H
Z
Z
Pd
Z
PdLn
NR
+NR
–
NR
H
H
R
Bn
TBSO
Ts
N
2ea
2eb
2ec
R = Bn
R = Ph
R = Et
B
C
D
(CH2)n
(CH2)n
(CH2)n
N
N
Scheme 3 Proposed mechanism for the formation of pyrroles
2fa
face.7 Electron delocalization to D followed by reductive
elimination results in the formation of the corresponding
pyrrole 2 and PdLn then reenters the next catalytic cycle.
Figure 2 Pyrrole derivatives prepared in this study
of enediynal, amine and formic acid. Cycloheptane-fused
pyrroles were synthesized in good yields (Table 1, entries
8 and 9). Enediynal 1d bearing a gem-diester group under-
went the reaction with benzylamine, ethylamine and
aniline to give the corresponding methylenecyclopentyl-
substituted pyrroles 2da–dc in good yields. However, the
pyrroles 2da–dc were unstable and over a week gradually
decomposed to the corresponding aldehydes, even at 0 °C
(Scheme 2). The isolated pure product 2da was subjected
to a methylene chloride slurry of silica gel and stirred
overnight at room temperature and the hydrolyzed
product 3da was isolated almost quantitatively.
In conclusion, we have discovered a new tandem multi-
component Pd-catalyzed cycloreduction of enediynals 1,
amines and formic acid leading to the corresponding 2-(2-
methylenecycloalkyl)pyrrole derivatives 2 in good to
excellent yields. Construction of complex molecules by
combining all atoms of the reactants except CO2 is both an
atom-economical and an environmentally benign process.
Due to the broad applications of pyrroles in the medicinal,
synthetic and material chemistry fields, a convenient and
atom-economical method for their synthesis is very useful
to synthetic and medicinal chemists.
Acknowledgment
H
H
H
H
silica gel,
H2O
Z
Z
Z
H2O
OH
O
We wish to acknowledge the financial support of Korea Research
Foundation (KRF, 2004-C00197), Korea and BK21.
NR
NR
CH2Cl2
O
References and Notes
Z = C(COOEt)2
2da
3da
(1) For reviews, see: (a) Trost, B. M.; Krische, M. J. Synlett
1998, 1. (b) Lu, X.; Zhu, G.; Wang, Z.; Ma, S.; Ji, J.; Zhang,
Z. Pure Appl. Chem. 1997, 69, 553.
Scheme 2 Silica gel mediated decomposition of 2da
(2) (a) Tsuji, J. Palladium Reagents and Catalysis: Innovations
in Organic Synthesis; John Wiley: Chichester, 1995.
(b) Heck, R. F. Palladium Reagents in Organic Synthesis;
Academic Press: New York, 1985. (c) Suzuki, A. Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F.; Stang,
P. J., Eds.; VCH: Weinheim, 1988.
The TBS-containing enediynal 2e afforded the pyrroles
2ea–ec in high stereoselectivity along with their stereo-
isomers (less than 5%). Nitrogen-containing enediynal 2f
underwent the reaction with benzylamine to afford 2fa in
66% yield. These reactions were understood to proceed
in a similar manner as shown in Scheme 3. Enediynals 1
react with the corresponding amine to form imine A. The
terminal triple bond of substrates 1 undergoes facile hy-
dropalladation with a HPdOCOH species, generated in
situ by mixing a Pd compound with HCOOH. This forms
the vinylpalladium species which undergoes carbopalla-
dation with the alkyne unit to form the intermediate B.6
The imine nitrogen could then attack the palladium nucle-
us to release CO2 and subsequently transfer hydride to the
indicated carbon in C from the sterically less hindered
(3) Hölscher, M. Green Chem. 2004, 6, G75.
(4) (a) Patil, N. T.; Wu, H.; Yamamoto, Y. J. Org. Chem. 2005,
70, 4531. (b) Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem.
Soc. 2004, 126, 11164. (c) Bach, T.; Krüger, L. Eur. J. Org.
Chem. 1999, 2045. (d) Marshall, J. A.; Liao, J. J. Org.
Chem. 1998, 63, 5962. (e) Batna, A.; Spiteller, G. Lipids
1994, 29, 397. For reviews, see: (f) Maier, M. In Organic
Synthesis Highlights II; Waldmann, H., Ed.; VCH:
Weinheim, 1995, 231–242. (g) Hou, X. L.; Yang, Z.; Wong,
H. N. C. In Progress in Heterocyclic Chemistry, Vol. 14;
Gribble, G. W.; Gilchrist, T. L., Eds.; Pergamon Press:
Oxford, 2002, 139–179.
Synlett 2007, No. 9, 1411–1415 © Thieme Stuttgart · New York

1414
C. H. Oh et al.
LETTER
(5) General Experimental Procedure: The substrates
(enediynals 1, 0.5mmol) in anhydrous dioxane (1.0 mL)
were placed in a dry test tube. Then amine (1.2 equiv) was
added to the reaction mixture using a microsyringe. The
resultant solutions were stirred at r.t. for 30 min. To these
solutions, Pd(PPh3)4 (3.0 mol%) and HCOOH (2 equiv)
were added successively under an argon atmosphere. The
reaction mixture was stirred for the time and temperature
indicated in Table 1. Upon completion of the reactions, as
monitored by TLC, the solvent was removed under reduced
pressure and the products 2 were isolated by flash column
chromatography as colorless oils in the indicated yields. Full
characterization using 1H NMR, 13C NMR, IR and HRMS
was performed.
2bb: IR (NaCl): 1644, 1598, 1498, 1444, 1393, 1364 cm–1;
1H NMR (400 MHz, CDCl3): d = 7.41–7.34 (m, 2 H), 7.31–
7.27 (m, 3 H), 6.45 (s, 1 H), 4.76 (d, J = 1.6 Hz, 1 H), 4.40
(q, J = 1.6 Hz, 1 H), 3.10 (d, J = 13.2 Hz, 1 H), 2.73–2.63
(m, 4 H), 2.42–2.30 (m, 3 H), 1.95–1.87 (m, 2 H), 1.84–1.75
(m, 3 H), 1.41–1.32 (m, 2 H); 13C NMR (100 MHz, CDCl3):
d = 151.54, 141.24, 130.53, 129.36, 129.01, 126.49, 126.42,
125.94, 112.34, 108.14, 42.32, 36.29, 34.02, 31.67, 28.74,
27.16, 26.45, 24.96; HRMS: m/z [M + K]+ calcd for
C20H23KN: 316.1468; found: 316.1462.
2bc: IR (NaCl): 1716, 1653, 1558, 1507, 1361 cm–1; 1H
NMR (400 MHz, CDCl3): d = 6.30 (s, 1 H), 4.65 (s, 1 H),
4.09 (s, 1 H), 3.70 (q, J = 7.2 Hz, 2 H), 3.14 (dd, J = 12.4, 2.0
Hz, 1 H), 2.56 (m, 4 H), 2.41 (br d, J = 13.2 Hz, 1 H), 2.31–
2.23 (m, 2 H), 2.12–2.02 (m, 2 H), 1.94–1.85 (m, 2 H), 1.77
(ddd, J = 12.8, 12.8, 3.2 Hz, 1 H), 1.57–1.36 (m, 2 H), 1.30
(t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d =
151.57, 128.91, 127.39, 125.11, 109.72, 107.37, 42.49,
41.38, 36.39, 33.64, 31.60, 28.95, 27.39, 26.71, 25.00,
17.43; HRMS: m/z [M + K]+ calcd for C16H23KN: 230.1909;
found: 230.1912.
2ca: IR (NaCl): 1670, 1644, 1600, 1520, 1494, 1447, 1390,
1349, 1332, 1169, 1119, 1075, 1030 cm–1; 1H NMR (400
MHz, CDCl3): d = 7.31–7.19 (m, 3 H), 7.03 (d, J = 7.6 Hz,
2 H), 6.30 (s, 1 H), 4.91 (ABq, Dd = 23.0 Hz, J = 16.0 Hz, 2
H), 4.68 (s, 1 H), 4.44 (s, 1 H), 3.21 (dd, J = 12.0, 4.0 Hz, 1
H), 2.53 (m, 4 H), 2.40 (d, J = 13.2 Hz, 1 H), 1.96 (td,
J = 12.0, 2.0 Hz, 1 H), 1.85–1.70 (m, 4 H), 1.68–1.53 (m, 5
H), 1.36–1.22 (m, 3 H); 13C NMR (100 MHz, CDCl3): d =
149.14, 139.58, 129.44, 128.67, 127.25, 126.79, 125.34,
122.98, 117.57, 108.51, 50.90, 41.75, 36.46, 33.70, 33.60,
30.66, 30.03, 28.54, 28.24, 27.98, 27.63; HRMS: m/z [M +
K]+ calcd for C23H29KN: 358.1937; found: 358.1943.
2cb: IR (NaCl): 1643, 1598, 1518, 1445, 1389, 1326, 1171,
1068 cm–1; 1H NMR (400 MHz, CDCl3): d = 7.39–7.33 (m,
2 H), 7.30–7.20 (m, 3 H), 6.48 (s, 1 H), 4.83 (s, 1 H), 4.70 (s,
1 H), 3.20 (dd, J = 12.0, 3.2 Hz, 1 H), 2.70–2.52 (m, 4 H),
2.45 (d, J = 14.2 Hz, 1 H), 2.01–1.56 (m, 11 H), 1.46–1.22
(m, 2 H); 13C NMR (100 MHz, CDCl3): d = 149.84, 140.93,
129.82, 129.07, 126.70, 126.44, 125.86, 124.08, 117.97,
108.88, 42.24, 36.38, 33.66, 33.53, 30.38, 29.62, 28.45,
28.32, 28.04, 27.41; HRMS: m/z [M + K]+ calcd for
C22H27KN: 344.1781; found: 344.1782.
2aa: IR (NaCl): 1709, 1675, 1646, 1499, 1445, 1391, 1318,
1167 cm–1; 1H NMR (400 MHz, CDCl3): d = 7.34–7.20 (m,
3 H), 7.06 (d, J = 7.34 Hz, 2 H), 6.27 (d, J = 0.4 Hz, 1 H),
4.89 (ABq, Dd = 10.6 Hz, J = 15.6 Hz, 2 H), 4.65 (s, 1 H),
4.24 (s, 1 H), 3.19 (t, J = 8.0 Hz, 1 H), 2.56 (m, 4 H), 2.37
(dd, J = 12.0, 2.0 Hz, 1 H), 1.98 (br t, J = 12.0 Hz, 1 H),
1.84–1.72 (m, 6 H), 1.69–1.60 (m, 2 H), 1.38–1.25 (m, 2 H);
13C NMR (100 MHz, CDCl3): d = 149.28, 139.10, 128.46,
127.83, 127.06, 126.80, 118.69, 116.95, 115.63, 107.57,
50.52, 42.44, 36.09, 32.72, 28.20, 27.38, 24.40, 24.03,
23.51, 22.35; HRMS: m/z [M + K]+ calcd for C22H27NK:
344.1775; found: 344.1781.
2ab: IR (NaCl): 1598, 1501, 1445, 1385 cm–1; 1H NMR (400
MHz, CDCl3): d = 7.47–7.33 (m, 2 H), 7.34–7.23 (m, 3 H),
6.49 (s, 1 H), 4.82 (d, J = 1.6 Hz, 1 H), 4.53 (q, J = 1.6 Hz,
1 H), 3.16 (dd, J = 12.0, 3.6 Hz, 1 H), 2.75–2.56 (m, 4 H),
2.43 (d, J = 12.8 Hz, 1 H), 2.00–1.77 (m, 7 H), 1.76–1.61
(m, 2 H), 1.44–1.24 (m, 2 H); 13C NMR (100 MHz, CDCl3):
d = 149.48, 140.83, 128.75, 128.50, 126.38, 125.75, 119.89,
118.03, 116.35, 108.08, 42.48, 36.00, 32.59, 28.15, 27.13,
24.28, 24.00, 23.65, 22.23; HRMS: m/z [M + H]+ calcd for
C21H26N: 292.2065; found: 292.2039.
2ac: IR (NaCl): 1707, 1647, 1445, 1376, 1316 cm–1; 1H
NMR (400 MHz, CDCl3): d = 6.34 (s, 1 H), 4.68 (s, 1 H),
4.21 (s, 1 H), 3.81–3.71 (m, 2 H), 3.30–3.21 (m, 1 H), 2.65–
2.52 (m, 4 H), 2.50–2.44 (m, 1 H), 2.15–2.05 (m, 1 H), 1.99–
1.84 (m, 4 H), 1.81–1.73 (m, 2 H), 1.70–1.62 (m, 2 H), 1.52–
1.36 (m, 2 H), 1.29 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz,
CDCl3): d = 149.61, 127.48, 118.52, 116.68, 114.15, 107.76,
42.53, 41.54, 36.42, 32.97, 28.49, 27.74, 24.65, 24.29,
23.67, 22.55, 17.37; HRMS: m/z [M + K]+ calcd for
C17H25NK: 282.1624; found: 282.1615.
2cc: IR (NaCl): 1700, 1645, 1520, 1446, 1389, 1321, 1170
cm–1; 1H NMR (400 MHz, CDCl3): d = 6.31 (s, 1 H), 4.71 (d,
J = 2.0 Hz, 1 H), 4.40 (q, J = 2.0 Hz, 1 H), 3.75 (m, 2 H),
3.27 (br d, J = 12.0 Hz, 1 H), 2.59–2.45 (m, 5 H), 2.15–2.05
(m, 1 H), 1.93–1.83 (m, 3 H), 1.82–1.73 (m, 3 H), 1.65–1.54
2ad: IR (NaCl): 1705, 1646, 1581, 1446, 1383, 1167 cm–1;
1H NMR (400 MHz, CDCl3): d = 6.31 (s, 1 H), 4.69 (d,
J = 2.0 Hz, 1 H), 4.22 (d, J = 2.0 Hz, 1 H), 3.67 (m, 2 H),
3.24 (dd, J = 12.0, 4.0 Hz, 1 H), 2.62–2.52 (m, 4 H), 2.47 (d,
J = 13.2 Hz, 1 H), 2.09 (td, J = 13.6, 3.2 Hz, 1 H), 1.98–1.84
(m, 4 H), 1.81–1.74 (m, 2 H), 1.71–1.59 (m, 4 H), 1.52–1.39
(m, 2 H), 1.34–1.23 (m, 21 H); 13C NMR (100 MHz, CDCl3):
d = 149.20, 127.27, 118.00, 116.37, 114.81, 107.56, 46.86,
42.33, 36.20, 32.75, 31.90, 31.85, 29.64, 29.62, 29.58,
29.48, 29.33, 29.24, 28.27, 27.52, 26.89, 24.41, 24.06,
23.51, 22.68, 22.29, 14.11; HRMS: m/z [M + K]+ calcd for
C27H45NK: 422.3189; found: 422.3195.
(m, 4 H), 1.48–1.37 (m, 2 H), 1.25 (t, J = 7.2 Hz, 3 H); 13
NMR (100 MHz, CDCl3): d = 149.31, 128.79, 124.82,
C
122.42, 115.77, 108.44, 41.73, 41.56, 36.52, 33.65, 33.56,
30.53, 29.95, 28.49, 28.14, 28.02, 27.73, 17.32; HRMS: m/z
[M + K]+ calcd for C18H27KN: 296.1781; found: 296.1777.
2da: IR (NaCl): 1730, 1496, 1445, 1388, 1366, 1298, 1262,
1247, 1186, 1155, 1056 cm–1; 1H NMR (400 MHz, CDCl3):
d = 7.33–7.20 (m, 3 H), 7.06 (d, J = 7.2 Hz, 2 H), 6.32 (s, 1
H), 4.97 (s, 2 H), 4.94 (d, J = 2.0 Hz, 1 H), 4.65 (q, J = 2.0
Hz, 1 H), 4.16 (m, 4 H), 3.82 (br t, J = 8.8 Hz, 1 H), 3.06 (m,
2 H), 2.55 (br s, 2 H), 2.48–2.34 (m, 3 H), 2.16 (t, J = 12.8
Hz, 1 H), 1.70 (m, 4 H), 1.23 (t, J = 7.2 Hz, 3 H), 1.21 (t,
J = 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d = 171.86,
171.60, 148.70, 139.08, 128.81, 127.42, 126.86, 126.28,
119.28, 117.57, 116.53, 108.22, 61.69, 58.52, 50.90, 40.55,
40.35, 39.87, 24.29, 24.20, 22.96, 22.40, 14.23, 14.21;
HRMS: m/z [M + Na]+ calcd for C27H33NaNO4: 458.2307;
found: 458.2314.
2ba: IR (NaCl): 1644, 1496, 1443, 1350, 1158 cm–1; 1H
NMR (400 MHz, CDCl3): d = 7.32–7.21 (m, 3 H), 7.08–7.04
(m, 2 H), 6.24 (s, 1 H), 4.86 (s, 2 H), 4.67 (s, 1 H), 4.18 (s, 1
H), 3.10–3.02 (m, 1 H), 2.71–2.58 (m, 4 H), 2.42–2.35 (m, 1
H), 2.34–2.26 (m, 2 H), 2.03–1.93 (m, 2 H), 1.87–1.79 (m, 2
H), 1.78–1.69 (m, 1 H), 1.41–1.32 (m, 2 H); 13C NMR (100
MHz, CDCl3): d = 151.58, 139.57, 129.19, 128.79, 128.75,
127.90, 127.28, 126.97, 111.58, 107.37, 50.76, 42.49, 36.30,
33.57, 31.55, 28.89, 27.22, 26.74, 25.02; HRMS (ES): m/z
[M + K]+ calcd for C21H25KN: 330.1624; found: 330.1629.
2db: IR (NaCl): 1731, 1598, 1500, 1386, 1348, 1187, 1071,
1022 cm–1; 1H NMR (400 MHz, CDCl3): d = 7.43–7.38 (m,
Synlett 2007, No. 9, 1411–1415 © Thieme Stuttgart · New York

LETTER
Syntheses of Highly Functionalized 2-(2-Methylenecycloalkyl)pyrroles
1415
2 H), 7.36–7.26 (m, 3 H), 6.48 (s, 1 H), 5.00 (d, J = 2.8 Hz,
(td, J = 12.4, 9.2 Hz, 1 H), 1.82–1.69 (m, 4 H), 0.86 (s, 9 H),
0.03 (s, 3 H), 0.02 (s, 3 H); 13C NMR (100 MHz, CDCl3):
d = 150.49, 140.71, 128.94, 127.75, 126.69, 126.25, 120.17,
117.67, 116.53, 107.17, 71.57, 42.28, 41.68, 39.51, 25.86,
23.99, 23.96, 22.84, 22.16, 18.12, –4.67, –4.70; HRMS:
m/z [M + K]+ calcd for C26H37NaNOSi: 430.2542; found:
430.2546.
1 H), 4.75 (q, J = 2.8 Hz, 1 H), 4.18 (q, J = 7.2 Hz, 2 H),
4.14–4.04 (m, 2 H), 3.78 (m, 1 H), 3.05 (m, 2 H), 2.66–2.60
(m, 2 H), 2.59 (dd, J = 12.8, 7.6 Hz, 1 H), 2.55–2.39 (m, 2
H), 2.32 (t, J = 12.8 Hz, 1 H), 1.74 (m, 4 H), 1.24 (t, J = 7.2
Hz, 3 H), 1.13 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz,
CDCl3): d = 171.75, 171.63, 149.21, 140.69, 129.18, 127.11,
127.03, 126.47, 120.45, 118.16, 117.20, 108.06, 61.75,
61.66, 58.58, 40.88, 40.32, 39.87, 24.20, 24.14, 23.01,
22.35, 14.26, 14.14; HRMS: m/z [M + K]+ calcd for
C26H31KNO4: 460.1890; found: 460.1898.
2ec: IR (NaCl): 1710, 1658, 1471, 1376, 1252, 1109 cm–1;
1H NMR (400 MHz, CDCl3): d = 6.33 (s, 1 H), 4.91 (s, 1 H),
4.64 (s, 1 H), 4.26 (m, 1 H), 3.81 (q, J = 7.2 Hz, 2 H), 3.67
(m, 1 H), 2.76 (dd, J = 16.0, 7.0 Hz, 1 H), 2.57 (br s, 2 H),
2.46 (br s, 2 H), 2.42 (m, 1 H), 2.21 (m, 1 H), 1.88 (td,
J = 12.4, 9.0 Hz, 1 H), 1.71 (m, 4 H), 1.33 (t, J = 7.2 Hz, 3
H), 0.90 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H); 13C NMR (100
MHz, CDCl3): d = 150.48, 126.47, 118.77, 116.80, 114.32,
107.45, 72.06, 42.73, 42.12, 41.57, 39.31, 26.12, 24.41,
24.32, 22.76, 22.41, 18.43, 17.24, –4.42, –4.46; HRMS: m/z
[M + H]+ calcd for C22H38NOSi: 360.2723; found: 360.2724.
2fa: IR (NaCl): 1705, 1597, 1495, 1453, 1387, 1346, 1163,
1094, 1041, 1008 cm–1; 1H NMR (400 MHz, CDCl3): d =
7.63 (d, J = 8.8 Hz, 2 H), 7.32–7.24 (m, 5 H), 6.95–6.92 (m,
2 H), 6.32 (s, 1 H), 4.90 (d, J = 2.4 Hz, 1 H), 4.86 (s, 2 H),
4.61 (q, J = 2.4 Hz, 1 H), 4.05 (br d, J = 14.0 Hz, 1 H), 3.82
(m, 1 H), 3.78–3.70 (m, 1 H), 3.49 (t, J = 9.0 Hz, 1 H), 2.95
(t, J = 9.0 Hz, 1 H), 2.51 (t, J = 6.0 Hz, 2 H), 2.42 (s, 3 H),
2.22–2.12 (m, 1 H), 1.95 (dt, J = 15.6, 6.4 Hz, 1 H), 1.71–
1.61 (m, 2 H), 1.61–1.54 (m, 2 H); 13C NMR (100 MHz,
CDCl3): d = 144.73, 143.62, 138.44, 132.34, 129.60, 128.65,
127.78, 127.43, 126.22, 122.58, 119.19, 118.20, 117.26,
108.08, 52.34, 52.14, 50.70, 40.22, 23.86, 23.78, 22.63,
21.96, 21.53; HRMS (ES+): m/z [M + K]+ calcd for
C27H30KN2: 421.2046; found: 421.2050.
2dc: IR (NaCl): 1730, 1446, 1377, 1298, 1186, 1071 cm–1;
1H NMR (400 MHz, CDCl3): d = 6.33 (s, 1 H), 5.00 (d,
J = 2.4 Hz, 1 H), 4.70 (d, J = 2.4 Hz, 1 H), 4.30–4.17 (m, 4
H), 3.92 (m, 1 H), 3.80 (q, J = 7.2 Hz, 2 H), 3.15 (m, 2 H),
2.67 (dd, J = 12.8, 7.6 Hz, 1 H), 2.55 (br s, 2 H), 2.47–2.32
(m, 2 H), 2.25 (t, J = 12.6 Hz, 1 H), 1.69 (m, 4 H), 1.34 (t,
J = 7.2 Hz, 3 H), 1.28 (t, J = 7.2 Hz, 3 H), 1.25 (t, J = 7.2
Hz, 3 H); 13C NMR (100 MHz, CDCl3): d = 171.84, 171.42,
148.75, 125.28, 118.69, 116.76, 114.52, 107.86, 61.55,
58.34, 41.48, 40.34, 40.10, 39.81, 24.09, 23.99, 22.65,
22.13, 21.37, 19.93, 17.18, 14.04; HRMS: m/z [M + Na]+
calcd for C22H31NaNO4: 396.2151; found: 396.2154.
2ea: IR (NaCl): 1705, 1472, 1389, 1252, 1109 cm–1; 1H
NMR (400 MHz, CDCl3): d = 7.34–7.21 (m, 3 H), 7.10–7.05
(m, 2 H), 6.28 (s, 1 H), 4.98 (s, 2 H), 4.87 (s, 1 H), 4.62 (s, 1
H), 4.10 (m, 1 H), 3.58 (m, 1 H), 2.68 (dd, J = 16.0, 7.2 Hz,
1 H), 2.56 (m, 2 H), 2.47 (m, 2 H), 2.42–2.34 (m, 1 H), 1.94
(m, 1 H), 1.77 (dd, J = 12.4, 6.8 Hz, 1 H), 1.73–1.68 (m, 4
H), 0.85 (s, 9 H), 0.02 (s, 3 H), 0.00 (s, 3 H); 13C NMR (100
MHz, CDCl3): d = 149.72, 139.00, 128.49, 127.16, 126.75,
118.87, 117.00, 115.88, 107.46, 71.71, 50.67, 42.50, 41.89,
39.14, 25.86, 24.12, 24.04, 22.67, 22.19, –4.71, –4.76;
HRMS: m/z [M + K]+ calcd for C27H39KNOSi: 460.2438;
found: 460.2434.
(6) For reviews, see: (a) Trost, B. M. Science 1991, 254, 1471.
(b) Trost, B. M. Acc. Chem. Res. 1990, 23, 34.
(7) H-Transfer of the b-carbon to the Pd intermediate has not
been reported. We thought that the imine nitrogen could
attack the Pd and then concomitant electron moving might
lead to H-transfer to the b-carbon, and further delocalization
to the palladacycle D in Scheme 3. For more discussion, see:
Oh, C. H.; Park, H. M.; Park, D. I. Org. Lett. 2007, 9, 1191.
2eb: IR (NaCl): 1598, 1500, 1386, 1251, 1110 cm–1; 1H
NMR (400 MHz, CDCl3): d = 7.44–7.37 (m, 2 H), 7.35–7.23
(m, 3 H), 6.45 (s, 1 H), 4.92 (d, J = 1.2 Hz, 1 H), 4.72 (q,
J = 1.2 Hz, 1 H), 4.08 (m, 1 H), 3.52 (m, 1 H), 2.72–2.60 (m,
4 H), 2.54 (s, 1 H), 2.42–2.31 (m, 1 H), 2.06 (m, 1 H), 1.91
Synlett 2007, No. 9, 1411–1415 © Thieme Stuttgart · New York