An efficient route to 2-substituted N-(1-amino-3-methylpyrrol)amides by ring-opening cyclization of benzylidene- and alkylidenecyclopropylcarbaldehydes with hydrazides

Article abstract of DOI:10.1021/jo900730t

(Chemical Equation Presented) A convenient and efficient synthetic method for the construction of 2,3-disubstituted pyrrolamides in moderate to good yields is established. The in situ generated water significantly accelerates the reaction rate. A possible

Full text of DOI:10.1021/jo900730t

pubs.acs.org/joc
An Efficient Route to 2-Substituted N-(1-Amino-3-methylpyrrol)amides
by Ring-Opening Cyclization of Benzylidene- and
Alkylidenecyclopropylcarbaldehydes with Hydrazides
Xiang-Ying Tang and Min Shi*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
mshi@mail.sioc.ac.cn
Received April 6, 2009
A convenient and efficient synthetic method for the construction of 2,3-disubstituted pyrrolamides in
moderate to good yields is established. The in situ generated water significantly accelerates the
reaction rate. A possible mechanism involving the cascade ring-opening and thermal-induced
rearrangement to produce the five-membered ring is proposed.
Introduction
Methylenecyclopropanes (MCPs) are useful building
blocks in organic synthesis due to their high level of reactivity
derived from ring strain and easy availability.5,6 During the
last 10 years, Lewis acid and transition-metal-catalyzed
reactions involving ring-opening of MCPs to form a variety
of different carbocycles and heterocycles have been exten-
sively investigated.7 Recently, Lautens and co-workers have
studied MgCl2-catalyzed ring expansion of MCP hydrazones
to form a class of isomeric cyclic diazadienes (Scheme 1a).8
The pyrrole ring system is a useful structure in heterocyclic
synthesis and displays a variety of important biological
activities.1 Although the pyrrolamides have broad applica-
tions in medicinal chemistry, only a few synthetic methods
have been developed thus far.2 Most of these methods relied
on the Paal-Knorr condensation of 1,4-dicarbonyl com-
pounds with hydrazine derivatives but in low yields.3 Using
exocyclic azolium ylide or other materials could also afford
pyrrolamides but need multistep transformations.4
(5) For selected reviews on MCPs, see: (a) Lautens, M.; Klute, W.; Tam,
W. Chem. Rev. 1996, 96, 49. (b) de Meijere, A.; Kozhushkov, S. I.;
Khlebnikov, A. F. Top. Curr. Chem. 2000, 207, 89. (c) Nakamura, I.;
Yamamoto, Y. Adv. Synth. Catal. 2002, 344, 111. (d) Brandi, A.; Cicchi,
S.; Cordero, F. M.; Goti, A. Chem. Rev. 2003, 103, 1213. (e) Nakamura, E.;
Yamago, S. Acc. Chem. Res. 2002, 35, 867. (f ) Shao, L. -X.; Shi, M. Curr.
Org. Chem. 2007, 11, 1135–1137.
*To whom correspondence should be addressed. Fax: 86-21-64166128.
(1) (a) Gribble, G. W. In Comprehensive Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 2, p 207.
(b) Jones, R. A. Pyrroles, Part II, The Synthesis, Reactivity and Physical
Properties of Substituted Pyrroles; Wiley: New York, 1992. (c) Effland, R. C.;
Klein, J. T. U.S. Patent 4,546,105, 1985; Chem. Abstr. 1986, 104, 186307. (d)
Kulagowski, J.; Janusz, J.; Leeson, P. D. UK Patent 2,265,372, 1993; Chem.
Abstr. 1993, 120, 134504.
(2) For reviews, see: (a) Cirrincione, G.; Almerico, A. M.; Aiello, E. In
Pyrroles. The Chemistry of Heterocyclic Compounds; Jones, R. A., Ed.; Wiley:
New York, 1992; Vol. 48, Part 2, Chapter 3, pp 315-323. (b) Bean, G. P. In
Pyrroles. The Chemistry of Heterocyclic Compounds; Jones, R. A., Bean, G. P.,
Eds.; Wiley: New York, 1990; Vol. 48, Part 1, Chapter 2, pp 218-219. (c) Jones,
R. A.; Bean, G. P. The Chemistry of Pyrroles; Academic Press: New York, 1977;
pp 384-387.
(3) (a) Paal, C. Ber. Dtsch. Chem. Ges. 1984, 17, 2756. (b) Knorr, L. Ber.
Dtsch. Chem. Ges. 1984, 17, 2863. (c) Christoph, A. Appl. Organometal.
Chem. 1985, 18, 367. (d) Epton, R. Chem. Ind. 1965, 425.
€
(6) (a) Cordero, F. M.; Pisaneschi, F.; Goti, A.; Ollivier, J.; Salaun, J.;
Brandi, A. J. Am. Chem. Soc. 2000, 122, 8075. (b) Nakamura, I.; Oh, B. H.;
Saito, S.; Yamamoto, Y. Angew. Chem., Int. Ed. 2001, 40, 1298. (c) Camacho,
D. H.; Nakamura, I.; Saito, S.; Yamamoto, Y. J. Org. Chem. 2001, 66, 270.
€
(d) Notzel, M. W.; Rauch, K.; Labahn, T.; de Meijere, A. Org. Lett. 2002, 4,
€
839. (e) Kozhushkov, S.; Spath, T.; Fiebig, T.; Galland, B.; Ruasse, M. F.;
Xavier, P.; Apeloig, Y.; de Meijere, A. J. Org. Chem. 2002, 67, 4100. (f )
Huang, X.; Zhou, H. Org. Lett. 2002, 4, 4419. (g) Karoyan, P.; Chassaing, G.;
Quancard, J.; Vaissermann, J. J. Org. Chem. 2003, 68, 2256. (h) Krafft, M. E.;
€
Bonaga, L. V. R.; Felts, A. S.; Hirosawa, C.; Kerrigan, S. J. Org. Chem. 2003,
68, 6039. (i) Huang, X.; Chen, W.; Zhou, H. Synlett 2004, 329.
(7) For selected examples on MCPs, see: (a) Hu, B.; Xing, S. Y.; Wang,
Z. W. Org. Lett. 2008, 10, 5481. (b) Shi, M.; Liu, L. P.; Tang, J. Org. Lett.
2006, 8, 4043. (c) Shi, M.; Xu, B.; Huang, J.-W. Org. Lett. 2004, 6, 1175. (d)
Huang, X.; Yang, Y. Org. Lett. 2007, 9, 1667. (e) Lautens, M.; Han, W.; Liu,
J. H. J. Am. Chem. Soc. 2003, 125, 4028.
(4) (a) Butler, R. N.; Cloonan, M. O.; Smith, G. M. ARKIVOC, 2003, vii,
244-254. (b) Batanero, B.; Elinson, M. N.; Barba, E. F. Tetrahedron 2004, 60,
10787.
(8) Scott, M. E.;Bathuel, Y.;Lautens, M. J. Am. Chem. Soc. 2007, 129, 1482.
DOI: 10.1021/jo900730t
r
Published on Web 07/17/2009
J. Org. Chem. 2009, 74, 5983–5986 5983
2009 American Chemical Society

Tang and Shi
JOCArticle
SCHEME 1. Previous Studies on the Formation of Heterocyclic
Compounds from MCPs
thus, some drying agents were added to get rid of the in situ
generated water. To our surprise, a much longer reaction
time was required and the yield of 3a did not increase
significantly even when the employed amounts of 2a were
doubled, suggesting that the in situ generated water could
significantly accelerate the reaction rate (Table 1, entries
3-5). Without any additive, 3a could be produced in 83%
yield within 10 min using 1.0 equiv of 1a and 2.0 equiv of 2a
as substrates upon heating at 110 °C (Table 1, entry 6).
Lowering the temperature to 80 and 100 °C afforded 3a in
43% and 63% yield after a prolonged reaction time (60 and
30 min), respectively, indicating that the reaction tempera-
ture is also a crucial factor to this reaction (Table 1, entries 7
and 8). In the reaction of 1a with 0.9 equiv of 2a under
otherwise identical conditions, the yield of 3a was 76%
(Table 1, entry 9).
SCHEME 2. Reaction of MCP Aldehyde 1a with Some Nu-
cleophilic Reagents
Next, we continued to investigate the solvent effect of this
reaction. The results are listed in Table 2. From tetrahydro-
furan (THF) to dioxane, as the the reaction temperature
rose, the yield of 3a steadily increased from 18% to 52%
(Table 2, entries 2-5). However, when the reaction was
conducted at 130 °C in dimethyl sulfoxide (DMSO), 3a
was obtained only in 32% yield (Table 2, entry 6). Using
o-xylene and N,N-dimethylformamide (DMF) as the sol-
vents afforded 3a in 68% yield at 130 °C and 78% yield at
140 °C, respectively (Table 2, entries 7 and 8). Carrying out the
reactions in DMSO, o-xylene, and DMF at 110 °C produced 3a
in 22-63% yields, respectively (Table 2, entries 9-11). There-
fore, toluene was the best solvent among all these solvents
examined.
In addition, Ma reported the reactions of alkylidenecyclopro-
pyl ketones under the catalysis of Pd(II), Pd(0), or I- to afford
different furan or pyrrole derivatives9 as well as an efficient
synthesis of trisubstituted pyrroles via intermolecular cycliza-
tion of MCP ketones with amines (Scheme 1b).10 Inspired by
these previous research findings, we applied ourselves to
investigate the intermolecular reactions of methylenecyclo-
propyl aldehydes with other heteroatom-containing com-
pounds. Interestingly, though no reactions occurred upon
treatment of MCP aldehydes (1) with phenylhydrazine and
aniline, we found that benzhydrazide 2a reacted with MCP
aldehyde 1a to generate a pyrrole product 3a in good yield
under reflux (Scheme 2). Therefore, we herein report a novel
ring-opening and thermal-induced cyclization approach to a
class of 2,3-disubstituted pyrrolamides.
Having these optimized reaction conditions in hand, we
next aimed to determine its reaction generality. We mainly
chose benzhydrazide 2a and 4-methylbenzenesulfonohydra-
zide 2b as the substrates to react with various MCP alde-
hydes. The results of these experiments are summarized in
Table 3. When the R1 group was changed from aryl to alkyl
or H, the reactions proceeded smoothly to afford the corre-
sponding products 3 in moderate to good yields in most
reactions of 1 with 2a (Table 3, entries 1-10). When R1 was
aromatic group, the reactions of 1 with 2b also proceeded
smoothly to afford the corresponding products 4 in moder-
ate to good yields whether electron-donating or electron-
withdrawing substituent was introduced on the aromatic
ring of 1 (Table 3, entries 1-8). However, in the cases of
R1 was alkyl group or hydrogen atom, complex product
mixtures were formed (Table 3, entries 9 and 10). As for other
hydrazides 2c, 2d, and 2e, the corresponding products 3k, 3l,
and 3m were obtained in 93%, 69%, and 43% yields under the
standard conditions, respectively (Table 3, entries 11-13).
The yield of products 4 is lower than that of 3 under identical
conditions presumably because compounds 4 are not very
stable upon heating. Especially in the cases of 4i and 4j,
the reaction was carried out at a relatively high temperature
(110 °C), which may cause the decomposition of 4i and 4j
during the reaction.
Results and Discussion
We began our work by examining the reaction of 1a with
benzhydrazide 2a at 110 °C in toluene catalyzed by Pd(0)
(the Pd(0) species was in situ generated by Pd(OAc)2/Ph3P).
It was found that substrate 1a was consumed within 10 min
(monitored by TLC plates), and a new product 3a was
formed in 53% yield (Table 1, entry 1). Further investigation
revealed that the reaction proceeded smoothly upon heating
at 110 °C without any catalyst, and the yield of 3a increased
to 76% (Table 1, entry 2). On the basis of previous literature
and our primary understanding, we thought that one mole-
cule of H2O should be generated during the reaction process;
It should be noted that using (Z)-benzylidenecyclopropane-
carbaldehyde 1k as the substrate led to the same product 3b in
75% yield as that of (E)-benzylidenecyclopropanecarbalde-
hyde (1b) as depicted in Scheme 3. Moreover, it was found that
using hydrazine hydrate (2f) as the substrate to react with 1a
under the standard conditions produced the corresponding
pyrrolamine product (3n) in 65% yield (Scheme 3).
(9) (a) Ma, S.; Zhang, J. Angew. Chem., Int. Ed. 2003, 42, 183. (b) Ma, S.;
Lu, L.; Zhang, J. J. Am. Chem. Soc. 2004, 126, 9645.
(10) Lu, L.; Chen, G.; Ma, S. Org. Lett. 2006, 8, 835.
5984 J. Org. Chem. Vol. 74, No. 16, 2009

Tang and Shi
JOCArticle
TABLE 1. Reaction of (E)-2-Benzylidenecyclopropyl Carbaldehyde (1a) with Benzhydrazide (2a) under Various Conditionsa
entry
additive
T (°C)
time (min)
equiv
yield (%)b of 3a
1
2
3
4
5
6
7
8
9
Pd(OAc)2 (10 mol %)/PPh3 (20 mol %)
110
110
110
110
110
110
80
10
10
40
30
30
10
60
30
10
1
1
1
2
2
2
2
2
0.9
53
76
79
76
80
83
43
63
76c
4A MS
MgSO4
4A MS
100
110
aReaction scale: 0.2 mmol of 1. bIsolated yields. c0.22 mmol of 1a and 0.2 mmol of 2a were used.
TABLE 2. Solvent Effect of the Reaction of (E)-2-Benzylidenecyclo-
propane Carbaldehyde (1a) with Benzhydrazide (2a)a
TABLE 3. Reaction of Various Methylenecyclopropyl Carbaldehyde
(1) with Different Hydrazides (2)a
yield (%)b
R2
2a, PhCO
yield (%)b
R2
entry
solvent
toluene
THF
T (°C)
yield (%)b of 3a
entry
R1
3
4
1
2
3
4
5
6
7
8
9
110
66
78
80
100
130
130
140
110
110
110
83
18
31
36
52
32
68
78
22
56
63
1
2
3
4
5
6
7
8
9
10
11
12
13
1a,C6H5
1b,3,4,5-(MeO)3C6H2 2a, PhCO
3a, 83 2b, Ts 4a, 61
3b, 89 2b, Ts 4b, 53
3c, 83 2b, Ts 4c, 75
3d, 82 2b, Ts 4d, 62
3e, 64 2b, Ts 4e, 66
3f, 83 2b, Ts 4f, 58
3g, 72 2b, Ts 4g, 73
3h, 71 2b, Ts 4h, 56
DCE
1c, p-MeC6H4
1d, m-FC6H4
1e, p-BrC6H4
1f, m-MeC6H4
1g, o-BrC6H4
1h, p-ClC6H4
1i, C7H15
2a, PhCO
2a, PhCO
2a, PhCO
2a, PhCO
2a, PhCO
2a, PhCO
2a, PhCO
2a, PhCO
CH3CN
1,4-dioxane
DMSO
o-xylene
DMF
DMSO
o-xylene
DMF
3i, 79
3j, 32
2b, Ts 4i, -c
2b, Ts 4j, -c
10
11
1j, H
1a, C6H5
2c, MeOCO 3k, 93
2d, C6H5SO2 3l, 69
aReaction scale: 0.2 mmol of 1a. bIsolated yields.
1a, C6H5
1h, p-ClC6H4
2e, phthalic
3m, 43
aReaction scale: 0.2 mmol of 1. b Isolated yields. cComplex product
mixtures were obtained.
1
The product structures were determined by H and 13C
NMR spectroscopy and HRMS or microanalyses. The
crystal structure of 3m was determined by X-ray diffraction,
and its CIF data are presented in the Supporting Informa-
tion.11 A larger scale reaction using 0.5 mmol of 1a and
1.0 mmol of 2a as the substrates has been also carried out
under the standard conditions, and it was found that 3a was
also obtained in 78% yield, suggesting that this reaction is
also suitable on a larger scale.
SCHEME 3. Further Determination of the Reaction Generality
On the basis of these results, a plausible mechanism for the
formation of the pyrrole product is outlined in Scheme 4
using 1a as a model. First, intermediate A is afforded by the
intermolecular reaction of 1a and 2a along with the libera-
tion of one molecule of H2O. Then, a thermal-induced
cyclization takes place to generate the five-membered cyclic
intermediate B, which undergoes an isomerization to give the
final product 3a. At the present stage, we believe that the in
situ generated imine intermediate is quite stable if it has an
electron-withdrawing group (EWG), and it can undergo the
next cyclization and isomerization upon heating.
A control experiment was also performed to investigate
whether intermediate C undergoes the reaction pathway to
(11) The crystal data of 3m have been deposited with the CCDC (no.
713526).
J. Org. Chem. Vol. 74, No. 16, 2009 5985

Tang and Shi
JOCArticle
SCHEME 4. Plausible Reaction Mechanism for the Formation
of Product 3a
intermediate A (Scheme 4). The H-D1, H-D2, or H-D3
exchange suggests that the extra H2O can join the isomeriza-
tion to accelerate the reaction rate by providing proton source
to assist the transformation of intermediate Bto product 3or 4.
The results were consistent with our assumption.
In summary, a convenient and efficient synthetic method
of disubstituted pyrrolamides 3 and 4 was developed from
the reaction of 1 and 2 via a cascade ring-opening reaction
and thermal-induced cyclization. The products 3 and 4 are
important compounds in organic and medicinal chemistry.
The potential utilization and extension of the scope of this
synthetic methodology are currently under investigation.
Experimental Section
General Procedure for the Synthesis of 3a. MCP aldehyde 1a
(32.0 mg, 0.2 mmol), benzhydrazide 2a (54.4 mg, 0.4 mmol), and
toluene (2.0 mL) were added into a Schlenk tube. The reaction
mixture was stirred at 110 °C for 10 min. The solvent was
removed under reduced pressure, and then the residue was
purified by a flash column chromatography.
SCHEME 5. Controlled Experiment for the Formation of 4a
N-(3-Methyl-2-phenyl-1H-pyrrol-1-yl)benzamide (3a): white
solid; mp 193-195 °C; 1H NMR (CDCl3, 300 MHz, TMS)
δ 2.10 (s, 3H, CH3), 6.11 (d, J = 3.0 Hz, 1H, CH), 6.64 (d, J =
3.0 Hz, 1H, CH), 7.24-7.37 (m, 7H, Ar), 7.46-7.51 (m, 1H, Ar),
7.60 (d, J = 7.5 Hz, 2H, Ar), 8.76 (s, 1H, NH); 13C NMR
(CDCl3, 75 MHz, TMS) δ 12.2, 109.4, 116.0, 121.7, 127.1, 127.3,
128.2, 128.7, 129.6, 130.4, 130.9, 131.7, 132.3, 167.3; IR
(CH2Cl2) ν 3261, 3059, 2922, 2865, 1665, 1602, 1524, 1488,
1281, 1214, 909 cm-1; MS (EI) m/z 276 [Mþ] (32.3), 173 (5.7),
171 (13.5), 115 (6.7), 106 (7.5), 104 (7.0), 77 (48.2), 51 (12.6).
Anal. Calcd for C18H16N2O: C, 78.24; H, 5.84; N, 10.14. Found:
C, 78.23; H, 5.83; N, 10.20.
SCHEME 6. Deuterium-Labeling Experiment in the Reaction
and the Product
4-Methyl-N-(3-methyl-2-phenyl-1H-pyrrol-1-yl)benzenesulfo-
1
namide (4a): white solid; mp 170-172 °C; H NMR (CDCl3,
300 MHz, TMS) δ 1.95 (s, 3H, CH3), 2.37 (s, 3H, CH3), 6.01 (d,
J = 3.0 Hz, 1H, CH), 6.77 (d, J = 3.0 Hz, 1H, CH), 6.82-6.84
(m, 2H, Ar), 6.99 (d, J = 8.4 Hz, 2H, Ar), 7.16-7.18 (m, 3H,
Ar), 7.25 (d, J = 8.4 Hz, 2H, Ar), 7.64 (s, 1H, NH); 13C NMR
(CDCl3, 75 MHz, TMS) δ 12.0, 21.6, 109.1, 116.6, 122.0, 126.5,
127.9, 128.0, 129.3, 129.4, 129.8, 130.2, 133.3, 144.4; IR
(CH2Cl2): ν 3244, 3060, 2924, 2866, 1705, 1598, 1500, 1474,
1346, 1164, 1091 cm-1; MS (EI) m/z 326 [Mþ] (38.0), 171 (100),
156 (30.8), 144 (19.5), 115 (22.7), 91 (36.9), 77 (15.2), 65 (16.7);
HRMS (EI) calcd for C18H18N2O2S (Mþ) requires 326.1089,
found 326.1092.
give the product 4a (Scheme 5). We first prepared inter-
mediate C by the reaction of 1a with 2b and then examined
the transformation of C to product 4a under the standard
reaction conditions. It was found that the direct transforma-
tion of C to 4a was sluggish but could be accelerated with the
addition of 2.0 equiv of H2O (Scheme 5).
A deuterium-labeling experiment was also conducted to
validate our hypothesis using intermediate C as the substrate
(Scheme 6). When 3.0 equiv of D2O was added into the
reaction system, it was found that besides sulfonamide NH
moiety (D3 content >90%), deuterium incorporation also
occurred at methyl carbon (D1 content 85%) and pyrrole
skeleton (D2 content 50%) based on 1H NMR spectroscopic
data (Scheme 6). Product 4a can only undergo the H-D3
exchange on the sulfonamide moiety upon treatment with D2O
under identical conditions (Scheme 6). The H-D1 and H-D2
exchange can take place in the conjugate enamine moiety in
Acknowledgment. We thank the Shanghai Municipal
Committee of Science and Technology (08dj1400100-2),
National Basic Research Program of China (973)-
2009CB825300, and the National Natural Science Founda-
tion of China for financial support (20472096, 20872162,
20672127, 20821002, and 20732008).
Supporting Information Available: Spectroscopic data (1H,
13C spectroscopic data), HRMS of the compounds shown in
Tables 1 and 2, X-ray crystal structure of compound 3m, and a
detailed description of experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
5986 J. Org. Chem. Vol. 74, No. 16, 2009