Palladium-catalyzed three-component tandem cyclization reaction of 2-(2,3-allenyl)acylacetates, organic halides, and amines: An effective protocol for the synthesis of 4,5-dihydro-1H-pyrrole derivatives

Article abstract of DOI:10.1002/adsc.201100002

A domino three-component reaction of 2-(2′,3′-allenyl) acylacetates with aryl or alkenyl halides and aryl- or benzylamines afforded 4,5-dihydro-1H-pyrrole derivatives highly chemo- and regioselectively in one pot through imine formation/imine-enamine taut

Full text of DOI:10.1002/adsc.201100002

COMMUNICATIONS
DOI: 10.1002/adsc.201100002
Palladium-Catalyzed Three-Component Tandem Cyclization
Reaction of 2-(2,3-Allenyl)acylacetates, Organic Halides, and
Amines: An Effective Protocol for the Synthesis of
4,5-Dihydro-1H-pyrrole Derivatives
Jiajia Cheng,a Xuefeng Jiang,a Can Zhu,a and Shengming Maa,b,*
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-6260-9305; e-mail: masm@sioc.ac.cn
Shanghai Key Laboratory of Green Chemistry and Chemical Process Department of Chemistry, East China Normal
b
University, 3663 North Zhongshan Road, Shanghai 200062, Peopleꢀs Republic of China
Received: January 2, 2011; Revised: April 22, 2011; Published online: July 7, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100002.
Abstract: A domino three-component reaction of 2-
(2’,3’-allenyl)acylacetates with aryl or alkenyl hal-
ides and aryl- or benzylamines afforded 4,5-dihy-
dro-1H-pyrrole derivatives highly chemo- and re-
gioselectively in one pot through imine formation/
imine-enamine tautomerization under the catalysis
of palladium(0) and toluenesulfonic acid monohy-
drate. A high diastereoselectivity was observed.
sioned that the reaction of b-keto esters 1 with
amines would provide imines 7a, which would isomer-
ize to enamines 7b. Under the catalysis of Pd(0), or-
ganic halides would react with this class of enamines
7b to provide 4,5-dihydro-1H-pyrroles. Due to the in-
troduction of the three-component reaction concept
here, the reaction would provide the azacyclic com-
pounds with diversity. In this paper, we wish report
such a concept for the efficient synthesis of 4,5-dihy-
Keywords: allenes; cyclization; 4,5-dihydro-1H-pyr-
roles; three-component reactions
Multi-component reactions (MCRs) involving domino
processes have emerged as powerful tools to synthe-
size molecules with efficiency and diversity from
simple substrates and with atom-economy.[1,2] In this
area, the development of new chemical processes pro-
ducing elaborate and important hetereocyclic struc-
tures in an efficient manner has been catching the at-
tention of synthetic organic chemists and medicinal
chemists due to the importance of heterocyclic com-
pounds.[3] As we know, pyrroles,[4] especially 4,5-dihy-
dro-1H-pyrroles,[5] are common structural units in var-
ious biologically active natural compounds. On the
other hand, functionalized allenes have been proven
to be efficient starting materials for the synthesis of
potentially useful carbo- and heterocycles.[6–8] Recent-
ly, we reported the highly selective synthesis of 4,5-di-
hydrofuran derivatives by Pd-catalyzed coupling-cycli-
zation of 2-(2’,3’-allenyl)acetylacetates with organic
halides.[7a,b] Based on these observations, we envi- Scheme 1.
1676
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1676 – 1682

Palladium-Catalyzed Three-Component Tandem Cyclization Reaction of 2-(2,3-Allenyl)acylacetates
Table 1. The effect of the amount of amine 2a and Brønsted acid on the Pd(0)-catalyzed three-component tandem cyclization
reaction of 1a, 2a, and phenyl iodide.
Entry
2a (equiv.)
Brønsted acid
Time t [h]
Yield of 4aa [%][a]
1
2
3
1
0.6
2
3
3
4
5
3
3
p-TsOH·H2O
p-TsOH·H2O
p-TsOH·H2O
p-TsOH·H2O
p-TsOH·H2O
p-TsOH·H2O
p-TsOH·H2O
–
16
9
16
10
8
10
5
10
10
6
27
22
52
72
56
60
63
50
56
54
53
4
5[b]
6
7
8
9
10
11
TfOH
TFA
AcOH
3
3
8
[a]
Yield of isolated product.
1.0 equiv. of MgSO4 was added.
[b]
Table 2. Solvent effect on the Pd(0)-catalyzed three-component tandem cyclization reaction of 1a, 2a, and phenyl iodide in
the presence of p-TsOH·H2O (20 mol%).
Entry
Solvent
Temperature [oC]
Time t [h]
Yield of 4aa [%][a]
1
2
3
4
5
6
MeNO2
DMF
DCE
DME
toluene
PhCl
reflux
90
reflux
reflux
90
7
8
7
8
10
8
complicated
57
64
65
72
73
90
[a]
Yield of isolated product.
dropyrrole derivatives via imine-formation/imine-en- anhydrous MgSO4 for removal of the in-situ formed
amine tautomerization (Scheme 1). water seems useless (entry 5). Furthermore, the effect
As a first try, we were happy to notice that the re- of Brønsted acids on this Pd(0)-catalyzed three-com-
action of ethyl 2-(2’,3’-allenyl)acetylacetate 1a ponent tandem reaction was also studied. The yield of
(1 equiv.), p-methoxyphenylamine 2a (1 equiv.), 4aa was much lower when no p-TsOH·H2O was
PdACHTUNGTRENNUNG(PPh3)4 (5 mol%), PhI (2 equiv.), and p-TsOH·H2O added (entry 8). Other Brønsted acids such as TfOH
(20 mol%) in toluene with stirring at 908C for 16 h af- (entry 9), TFA (entry 10), or AcOH (entry 11) are not
forded 4,5-dihydropyrrole 4aa in 27% yield (Table 1, as efficient as TsOH·H2O.
entry 1). Surprisingly, when 0.6 equiv. of 2a were ap-
Studies on the solvent effect revealed that toluene
plied, the yield of 4aa dropped to 22% (entry 2). (Table 2, entry 5) and PhCl (Table 2, entry 6) are the
When we increased the amount of the amine 2a, the best solvents for this reaction, thus, toluene was
reaction became cleaner and higher-yielding with chosen for further study.
3 equiv. of 2a being the best (entries 3–7). Addition of
Adv. Synth. Catal. 2011, 353, 1676 – 1682
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1677

Jiajia Cheng et al.
COMMUNICATIONS
Table 3. The Pd(0)-catalyzed three-component tandem cyclization reaction of 1a and PhI with different amines.
Entry
R3NH2
Time t [h]
Yield of 4 [%][a]
1
2
3
4
5
6
7
p-MeOC6H4 (2a)
p-MeC6H4 (2b)
Ph (2c)
p-MeOC6H4CH2 (2d)
PhCH2 (2e)
n-Bu (2f)
allyl (2g)
10
10
8
6
8
72 (4aa)
60 (4ab)
64 (4ac)
69 (4ad)
67 (4ae)
38 (4af)
42 (4ag)[b]
9
10
[a]
Yield of isolated product.
34% of 5a was also discovered.
[b]
Scheme 2. The Pd(0)-catalyzed diastereoselective cyclization of 1b, 1c or 1d with p-methoxyphenylamine 2a and phenyl
iodide.
Thus, the reaction of 1a with different amines was decomposed after being purified via silica-gel chroma-
studied under the optimized reaction conditions tography. The yield for the reaction with aniline
(Table 3). Aromatic amines with electron-donating (entry 3) is somewhat lower. Benzylamines (entries 4
groups (Table 3, entries 1 and 2) afforded good yields and 5) could also afford the corresponding products
of 4aa and 4ab. However, we found that 4ab easily in reasonable yields. However, the reaction with ali-
1678
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1676 – 1682

Palladium-Catalyzed Three-Component Tandem Cyclization Reaction of 2-(2,3-Allenyl)acylacetates
pyrrole derivatives trans-6b or trans-6c highly diaste-
reoselectively (Scheme 2). The relative configuration
here was established by its NOE study of 6b
(Figure 1).
Then the scope of organic iodides has also been
demonstrated (Table 4): The phenyl ring in the aryl
iodide could be substituted by p/m-Me (Table 4, en-
tries 2 and 3), OMe (entry 4), CO2Me (entry 5), Br
(entry 6), F (entry 7), or an extra aryl group (entries 8
and 9). Furthermore, the reaction may be extended to
Figure 1. NOE study of 6b.
phatic amines, such as n-butylamine (entry 6) and al- 1-alkenyl iodides (entries 10 and 11). The reaction of
lylamine (entry 7), is low-yielding. For ethyl-substitut- 1-naphthyl iodide (entry 12) is also smooth.
ed substrate 1b, the desired product 6a can also be
obtained in moderate yield (Scheme 2).
The reaction of 1a with (S)-(À)-a-phenylethylamine
2h afforded a mixture of diastereoisomers with 69%
The cyclization of polysubstituted 2-(1’-alkyl-2’,3’- yield in a ratio of 1.3:1. The starting allene without an
allenyl)-b-keto esters 1c or 1d with p-methoxyphenyl- ethoxycarbonyl moiety 1e afforded an unidentified
amine 2a and phenyl iodide afforded 4,5-dihydro-1H-
Scheme 3. Further study of the scope of substrates.
Table 4. The Pd(0)-catalyzed three-component tandem cyclization reaction of 1a, p-methoxyphenylamine, and different or-
ganic iodides.
Entry
R4
Time t [h]
Yield of 4 [%][a]
1
2
3
4
5
6
7
8
Ph (3a)
10
10
10
9
10
10
10
10
10
10
10
10
72 (4aa)
57 (4ba)
59 (4ca)
46 (4da)
67 (4ea)
74 (4fa)
58 (4ga)
78 (4ha)
64 (4ia)
66 (4ja)
48 (4ka)
54 (4la)
p-MeC6H4 (3b)
m-MeC6H4 (3c)
p-MeOC6H4 (3d)
p-MeO2CC6H4 (3e)
p-BrC6H4 (3f)
p-FC6H4 (3g)
p-PhC6H4 (3h)
p-(p-BrC6H4)C6H4 (3i)
hex-1(E)-enyl (3j)
(E)-2-phenylvinyl (3k)
1-naphthyl (3l)
9
10
11
12
[a]
Yield of isolated product.
Adv. Synth. Catal. 2011, 353, 1676 – 1682
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1679

Jiajia Cheng et al.
COMMUNICATIONS
Scheme 4. Synthetic application of 4,5-dihydro-1H-pyrrole 4ae.
Scheme 5. Control experiments for the mechanistic study.
mixture, suggesting that the ethoxycarbonyl moiety is
necessary for this reaction (Scheme 3).
Based on these results, a mechanism was proposed
to explain the regio- and stereoselectivity of this
In order to show the utility of our method, 4,5-dihy- transformation (Scheme 6). Condensation of allene 1
dro-1H-pyrrole 4ae was transformed to the N-Bn-pyr- with an amine in the presence of Brønsted acid would
role 8 with DDQ in toluene at room temperature form imine intermediate 7a, which could isomerize to
(Scheme 4). The subsequent deprotection of the Bn enmine 7b. Oxidative addition of the organic halide
group was also achieved with Na/liquid NH3/t-BuOH with Pd(0), followed by carbopallation with 7b would
at À788C to afford the NH pyrrole derivative 9.
afford the h3-allyl complex B. Finally, a nucleophilic
Three control experiments were conducted to attack by the nitrogen atom would provide 4 or 6
reveal the mechanism of this reaction (Scheme 5): highly regioselectively. The stereoselectivity may be
when the reaction was stopped right after the disap- explained by the 1,2-chiral induction. On the other
pearance of the allene substrate 1a, besides 4,5-dihy- hand, allene 1 may also afford A in the presence of
dro-1H-pyrrole 4aa, the enamine intermediate 7aa Pd(0) and the organic halide first. The intermediate
was isolated in 25% yield, which indicates the enam- A would react with amine to afford the intermediate
ine 7aa is the intermediate for the reaction; further- B in the presence of acid, finally providing the 4,5-di-
more, it was observed that the reaction of 4,5-dihy- hydro-1H-pyrrole 4 or 6.
drofuran derivative 5a under the same conditions also
In conclusion, we have developed a highly efficient
afforded 4aa smoothly; finally, it should be noted that Pd(0)-catalyzed one-pot protocol for the synthesis of
1f with an extra methyl group at the 2-position failed 4,5-dihydro-1H-pyrroles from 2-(2’,3’-allenyl)acetyl-
to afford any product.
ACHTUNGTRENaNUGN cetates, organic halides, and amines. The utilization
1680
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1676 – 1682

Palladium-Catalyzed Three-Component Tandem Cyclization Reaction of 2-(2,3-Allenyl)acylacetates
Scheme 6. Proposed catalytic cycle.
References
of 20 mol% of TsOH·H2O is required for the forma-
tion of the imine and enamine intermediate between
[1] For recent monographs and reviews on multi-component
the carbonyl of the ketone moiety and the amine. Be-
cause of the introduction of the three-component re-
action concept, this cyclization could provide multiple
points for the diversity and affords only single diaste-
reoisomers with a-(1’-alkyl-2’,3’-allenyl)-b-keto esters
1c and 1d. Further studies in this area including the
enatioselective cyclization are currently being carried
out in our laboratory.
reactions: a) R. V. A. Orru, M. de Greef, Synthesis 2003,
1471; b) J. Zhu, Eur. J. Org. Chem. 2003, 1133; c) D. J.
Ramꢂn, M. Yus, Angew. Chem. 2005, 117, 1628; Angew.
Chem. Int. Ed. 2005, 44, 1602; d) Multicomponent Reac-
tions, (Eds.: J. Zhu, H. Bienaymꢃ), Wiley-VCH, Wein-
heim, 2005; e) A. Dçmling, Chem. Rev. 2006, 106, 17;
f) D. M. D’Souza, T. J. J. Mꢄller, Chem. Soc. Rev. 2007,
36, 1095; g) Domino Reactions in Organic Synthesis,
(Eds.: L. F. Tietze, D. G. Brasche; K. M. Gericke),
Wiley-VCH, Weinheim, 2007; h) A. Alba, X. Companyo,
M. Viciano, R. Rios, Curr. Org. Chem. 2009, 13, 1432;
i) A. Basso, L. Banfi, R. Riva, Eur. J. Org. Chem. 2010,
1831.
Experimental Section
Typical Procedure
[2] For the most recent examples of multicomponent cyclo-
additions involving imine-enamine intermediates, see:
a) J. Jiang, J. Yu, X.-X. Sun, Q.-Q. Rao, L.-Z. Gong,
Angew. Chem. 2008, 120, 2492; Angew. Chem. Int. Ed.
2008, 47, 2458; b) B. O. Okandeji, J. R. Gordon, J. K.
Sello, J. Org. Chem. 2008, 73, 5595; c) P. Jakubec, M.
Helliwell, D. J. Dixon, Org. Lett. 2008, 10, 4267; d) W.
Lu, W. Song, D. Hong, P. Lu, Y. Wang, Adv. Synth.
Catal. 2009, 351, 1768; e) B.-L. Yang, Z.-T. Weng, S.-J.
Yang, S.-K. Tian, Chem. Eur. J. 2010, 16, 718; f) H.
Yang, R. G. Carter, Org. Lett. 2010, 12, 3108; g) L.-R.
Wen, C. Liu, M. Li, L.-J. Wang, J. Org. Chem. 2010, 75,
7605.
[3] For recent reviews on transition metal-catalyzed reac-
tions for the synthesis heterocyclic compounds, see:
a) G. Zeni, R. C. Larock, Chem. Rev. 2004, 104, 2285;
b) I. Nakamura, Y. Yamamoto, Chem. Rev. 2004, 104,
2127; c) P. R. Chopade, J. Louie, Adv. Synth. Catal. 2006,
348, 2307; d) V. Cadierno, P. Crochet, Curr. Org. Synth.
2008, 5, 343.
[4] a) E. Baltazzi, L. I. Krimen, Chem. Rev. 1963, 63, 511;
b) Heterocyclic Chemistry, 4th edn., (Eds.: J. A. Joule, K.
Mills), Blackwell, Oxford, 2000; c) B. A. Trofimov, L. N.
Sobenina, A. P. Demenev, A. I. Mikhaleva, Chem. Rev.
2004, 104, 2481; d) H. Fan, J. Peng, M. T. Hamann, J.-F.
Hu, Chem. Rev. 2008, 108, 264.
[5] a) J. Davoll, J. Chem. Soc. 1953, 3802; b) R. J. S. Beer,
W. T. Gradwell, W. J. Oates, J. Chem. Soc. 1958, 4693;
c) A. Hassner, A. S. Miller, M. J. Haddadin, J. Org.
Chem. 1972, 37, 2682; d) T. Eicher, J. L. Weber, Tetrahe-
In a flame-dried Schlenk tube, a mixture of ethyl 2-(2’,3’-al-
lenyl)acetylacetate 1a (42 mg, 0.23 mmol), 4-methoxyaniline
2a (94 mg, 0.76 mmol), PdACHTNUGTRENUNG(PPh3)4 (14 mg, 0.0125 mmol),
phenyl iodide 3a (107 mg, 0.52 mmol), and p-TsOH·H2O
(11 mg, 0.06 mmol) in 2 mL of toluene was stirred under
argon at 908C for 10 h. After the reaction was complete as
monitored by TLC (petroleum ether:ethyl acetate=15:1),
the reaction mixture was evaporated and purified via flash
chromatography on silica gel (eluent: petroleum ether:ethyl
acetate=20:1) to afford 4aa as a liquid; yield: 60 mg (72%).
1H NMR (300 MHz, CDCl3): d=7.42–7.20 (m, 5H), 6.98 (d,
J=8.7 Hz, 2H), 6.82 (d, J=9.0 Hz, 2H), 5.40 (s, 1H), 5.19
(s, 1H), 4.89 (dd, J=11.4, 9.0 Hz, 1H), 4.22–4.08 (m, 2H),
3.77 (s , 3H), 3.24 (t, J=13.8 Hz, 1H), 2.73 (dd, J=14.7,
8.7 Hz, 1H), 2.16 (s, 3H), 1.25 (d, J=7.5 Hz, 3H); 13C NMR
(75.4 MHz, CDCl3): d=167.2, 159.6, 157.5, 147.8, 139.1,
134.6, 128.3, 127.7, 127.4, 126.7, 115.0, 114.2, 98.5, 69.6, 58.7,
55.3, 35.8, 14.6, 14.0; MS (EI): m/z (%)=363 (M+, 22.95),
290 (100); IR (neat): n=3055, 2978, 2933, 1677, 1598, 1511,
1391, 1290, 1232, 1085, 1033 cmÀ1; HR-MS (EI): m/z=
363.1827, calcd. for C23H25NO3 (M+) 363.1834.
Acknowledgements
Financial support from National Natural Science Foundation
of China (20732005) and State Key Basic Research & Devel-
opment Program (2011CB808700) is greatly appreciated.
Adv. Synth. Catal. 2011, 353, 1676 – 1682
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1681

Jiajia Cheng et al.
COMMUNICATIONS
dron Lett. 1974, 15, 1381; e) C. Deshayes, S. Gelin, Syn-
thesis 1981, 6, 466; f) S. Gelin, C. Deshayes, Synthesis
1982, 8, 657.
4657; Angew. Chem. Int. Ed. 2008, 47, 4581; d) X. Jiang,
Q. Yang, Y. Yu, C. Fu, S. Ma, Chem. Eur. J. 2009, 15,
7283; e) X. Cheng, S. Ma, Chem. Commun. 2009, 28,
4263; f) W. Shu, Q. Yu, S. Ma, Adv. Synth. Catal. 2009,
351, 2807.
[6] For reviews see: a) R. Zimmer, C. U. Dinesh, E. Nan-
danan, F. A. Khan, Chem. Rev. 2000, 100, 3067; b) J. A.
Marshall, Chem. Rev. 2000, 100, 3163; c) X. Lu, C.
Zhang, Z. Xu, Acc. Chem. Res. 2001, 34, 535; d) S. Ma,
in: Handbook of Organopalladium Chemistry for Organ-
ic Synthesis, (Ed: Negishi, E.), Wiley, New York, 2002,
pp 1491–1523; e) R. W. Bates, V. Satcharoen, Chem.
Soc. Rev. 2002, 31, 12; f) S. Ma, Acc. Chem. Res. 2003,
36, 701; g) L.-L. Wei, H. Xiong, R. P. Hsung, Acc. Chem.
Res. 2003, 36, 773; h) S. Ma, Chem. Rev. 2005, 105, 2829;
i) S. Ma, in : Topics in Organometallic Chemistry, (Ed.: J.
Tsuji), Springer-Verlag, Heidelberg, 2005, pp 183–210;
j) S. Ma, Aldrichimica Acta 2007, 40, 91; k) M. Jeganmo-
han, C.-H. Cheng, Chem. Commun. 2008, 27, 3101; l) S.
Ma, Acc. Chem. Res. 2009, 42, 1679; m) B. Alcaide, P.
Almendros, C. Aragoncillo, Chem. Soc. Rev. 2010, 39,
783.
[8] For some of the most recent reports on cyclization of al-
lenes from other groups, see: a) S. Inuki, S. Oishi, N.
Fujii, H. Ohno, Org. Lett. 2008, 10, 5239; b) B. M. Trost,
J. Xie, J. Am. Chem. Soc. 2008, 130, 6231; c) H. Tsuka-
moto, T. Matsumoto, Y. Kondo, Org. Lett. 2008, 10,
1047; d) E. M. Beccalli, G. Broggini, F. Clerici, S. Galli,
C. Kammerer, M. Rigamonti, S. Sottocornola, Org. Lett.
2009, 11, 1563; e) L. Rout, A. M. Harned, Chem. Eur. J.
2009, 15, 12926; f) M. Li, D. J. Dixon, Org. Lett. 2010,
12, 3784; g) M. Kalek, T. Johansson, M. Jezowska, J. Sta-
winski, Org. Lett. 2010, 12, 4702; h) M. P. MuÇoz, M. C.
de La Torre, Adv. Synth. Catal. 2010, 352, 2189; i) D. N.
Tran, N. Cramer, Angew. Chem. 2010, 122, 8357; Angew.
Chem. Int. Ed. 2010, 49, 8181; j) B. Alcaide, P. Almen-
dros, R. Carrascosa, T. Martꢅnez del Campo, Chem. Eur.
J. 2010, 16, 13243; k) E. M. Beccalli, A. Bernasconi, E.
Borsini, G. Broggini, M. Rigamonti, G. Zecchi, J. Org.
Chem. 2010, 75, 6923.
[7] For some of the recent reports from this group, see: a) S.
Ma, Z. Zheng, X. Jiang, Org. Lett. 2007, 9, 529; b) X.
Jiang, X. Ma, Z. Zheng, S. Ma, Chem. Eur. J. 2008, 14,
8572; c) X. Cheng, S. Ma, Angew. Chem. 2008, 120,
1682
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1676 – 1682