Pd0-catalyzed three-component tandem double-addition-cyclization reaction: Stereoselective synthesis of cis-pyrrolidine derivatives

Article abstract of DOI:10.1002/anie.200290033

Cis-2,5-Disubstituted pyrrolidine skeletons have been constructed by the Pd^0- catalyzed three-component tandem double-addition-cyclization reaction of 2-(2,3-butadienyl)malonates, organohalides, and imines (see scheme, yields: 81-100%; cis/tran

Full text of DOI:10.1002/anie.200290033

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[15] To help with further reading, we note briefly that resonant Raman
spectroscopy is defined as a Raman experiment in which the exciting
wavelength coincides with, or is near to, the wavelength of an
electronic absorption of the sample. This condition guarantees a high
transfer of energy to the sample. Moreover, the use of a UV exciting
source also guarantees a significant reduction of the fluorescence
background signal. If the electronic absorption involves a localized
center, such as a transition-metal atom and its ligands in the nearest
coordination shells, excitation is also partially localized and the
vibrational features of the grouping of atoms constituted by the
central ions and the surrounding ligands can be enhanced by several
orders of magnitude, if they meet the appropriate enhancement
selection rules. Two kinds of vibrations are enhanced: a) the vibrations
which are totally symmetric with respect to the absorbing center, and
b) the vibrational modes directly involving atoms that undergo the
same molecular deformation induced by the electronic excitation.
a) Y. Nishimura, A. Y. Hirakawa, M. Tsuboi in Advances in Infrared
and Raman Spectroscopy (Eds.: R. J. H. Clark, R. E. Hester), Heyden
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64 71.
Pd0-Catalyzed Three-Component Tandem
Double-Addition Cyclization Reaction:
Stereoselective Synthesis of cis-Pyrrolidine
Derivatives**
Shengming Ma* and Ning Jiao
Pd0-catalyzed cyclization reactions of functionalized al-
lenes[1] leading to carbo- and heterocyclic compounds[2 has
4]
been studied extensively. In some of these reactions, the p-
allyl palladium intermediate formed in situ[5] was trapped by
an intramolecular nucleophile (path A, Scheme 1). Recently,
development of multicomponent reactions to preserve atom
economy[6] and stereoselectively construct an array of several
stereogenic centers in one pot is attracting the attention of
many chemists.[7] Therefore, if there is another potential
electrophilic receptor such as an imine group in the reaction
system, the Pd0-catalyzed reaction of organohalides and
allenes with a nucleophilic center would allow the formation
of pyrrolidine derivatives (path B, Nu ¼ C, Scheme 1). To
make this concept synthetically attractive, we must address
the issues of matched relay, regioselectivity (by excluding the
formation of seven-membered product 6), and diastereose-
lectivity (Scheme 1).
The construction of pyrrolidine skeletons, a frequently
observed structural unit in various natural products, ligands,
etc., is of current interest.[8,9] Although the transition-metal-
catalyzed cyclization of g-allenic amides to yield 2-substituted
[*] Prof. S. Ma, N. Jiao
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences
354 Fenglin Lu, Shanghai 200032 (P.R. China)
Fax : (þ 86)21-6416-6128
E-mail: masm@pub.sioc.ac.cn
[**] Financial support from the Major State Basic Research Development
Program (Grant No. G2000077500), the National Natural Science
Foundation of China, and the Shanghai Municipal Committee of
Science and Technology are greatly appreciated.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2002, 41, No. 24
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Scheme 1. Protocol for the selective synthesis of pyrrolidine derivatives
through a three-component reaction.
pyrrolidine has been well-documented,[10,11] the transition-
metal-catalyzed multicomponent reaction of functionalized
allenes to form polysubstituted heterocyclic compounds with
high stereoselectivity has not been reported. Herein we
disclose our recent results on the three-component tandem
double-addition cyclization of 2-(2,3-allenyl)malonates, or-
ganohalides, and imines. By tuning the reaction conditions, we
have addressed the issues of smooth relay, regio-, and
diastereoselectivity.
We recently developed four sets of reaction conditions
under which the coupling cyclization of 2-(2,3-allenyl)malo-
nates with organohalides afforded cyclopropane derivative 2
or cyclopentene derivatives 3 with high regioselectivity (Nu ¼
C, Scheme 1).[12 14] Fortunately, under the same conditions for
path A[14d] ([Pd(PPh3)4] (5 mol%), K2CO3 (4 equiv), nBu4NBr
(10 mol%), CH3CN, reflux), the reaction of 2-(2,3-allenyl)-
malonates with PhI and N-benzylidene p-toluenesulfonamide
(4a) afforded pyrrolidine derivative 5a in 89% yield (cis/trans
9:1; Scheme 2). Premature products 2a and 3a and seven-
membered product 6a (n ¼ 1; Nu ¼ C; R1, R2, R3, R4 ¼ H; R,
R5 ¼ Ph; R6 ¼ Ts) were not observed. The structure of cis-5a
was determined by X-ray diffraction studies (Figure 1).[15] On
the other hand, the corresponding reaction of 1a and 4a with
Figure 1. ORTEP representation of cis-5a.
o-methylphenyl iodide afforded pyrrolidine derivative 5c in
36% yield (cis/trans 94:6; Scheme 2). The use of Na2CO3 as
base gives higher yield and stereoselectivity. Based on the
results shown in Scheme 2, it can be concluded that the base
and the steric hindrance of the aryl iodide are two of the major
factors that control the stereoselectivity of this tandem
coupling cyclization reaction. Thus, control of the stereo-
selectivity of the two carbon centers in a general manner
would be a new challenge.
The effects of different bases, solvents, and additives for the
reaction of Pd0-catalyzed reaction of 1a, iodobenzene, and
imine 4a are shown in Table 1. Of several bases tested, K2CO3
and Na2CO3 gave higher yields of 5a, but the cis/trans ratio is
still not excellent (Table 1, entries 2and 4). The use of a
stronger base (e.g. Cs2CO3, nBu4NBr (10 mol%), or NaH) in
the reaction favors the formation of the premature three-
membered cycle 2a or cyclopentene derivative 3a (Table 1,
entries 3 and 5), indicating a lower relay ability. The use of a
phase-transfer catalyst (nBu4NBr, 10 mol%) has no dramatic
effect on the stereoselectivity (compare Table 1, entries 1 with
2). Fortunately, the use of THF as the solvent led to the
isolation of 5a in 72% yield with excellent stereoselectivity
(cis/trans > 99:1), albeit that 2a was also formed in 26% yield
(Table 1, entry 8). Even with 3.0 equivalents of imine, the
relay is still not satisfactorily smooth (Table 1, entries 10 and
11). The addition of a Lewis acid did not produce better
relaying results; on the contrary, the cis/trans ratio decreased
(Table 1, entries 12). Furthermore, the effect of the temper-
ature on the reaction is clear: in THF as solvent, the reaction
in a sealed screw tube at 858C overnight afforded pyrrolidine
derivative 5a in 90% yield exclusively, and the ratio is still
excellent (Table 1, entry 13; compare entries 10, 11, and 13).
A decrease in the amount of imine 4a from 3.0 to 1.2equiv-
alents also gave a similar result (Table 1, entry 14). The
reaction at 1008C afforded 5a with a slightly lower stereo-
selectivity (98:2; Table 1, entry 15). Similar results are also
observed in 1,4-dioxane (Table 1, entries 16 and 17). Thus, the
solvent (THF or 1,4-dioxane) and reaction temperature
Scheme 2. Control of stereoselectivity by the steric effect and base.
4738
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Table 1. [Pd(PPh3)4]-catalyzed tandem double-addition cyclization of 1a with PhI and imine 4a under
entries 7 9) the cis-pyrrolidine deriv-
atives 5 are formed exclusively with
high stereoselectivities by a subtle
adjustment of the solvent or the
amount of the corresponding imine.
From Tables 2and 3, it is clear that
the current reaction can be success-
fully extended to a variety of organo-
iodides (Table 2, entries 1 14), phen-
yl bromide (Table 2, entry 15), phenyl
triflate (Table 2, entry 16) and imines
(Table 3) leading to the formation of
the corresponding cis-pyrrolidine de-
rivatives in 81 100% yield with ex-
cellent stereoselectivities. The elec-
tron-withdrawing tosyl group of
imine 4 is important for this reaction
since the corresponding reaction of
1a with PhI and N-(4-chlorobenzyli-
dene)aniline afforded 2a as the only
product in 92% yield, probably as a
result of the lower reactivity of this
imine.
different reaction conditions.[a]
Entry Base
Additive[b] Imine
[equiv]
Solvent T [8C] Time [h]
5a
Yield
Yield [%] cis/trans 2a [%]
1
2
3
4
5
6
7
8
K2CO3
1.2CH
1.2CH
1.2CH
1.2CH
1.2DMF
1.2DMF
1.2toluene 85
1.2THF
1.2THF
3.0
3.0
3.0
3.0
1.2THF
1.2THF
1.2C
3CN reflux 11
3CN reflux 10
3CN reflux 11
3CN reflux 11
71
86:14
0
K2CO3
Cs2CO3
Na2CO3
NaH
K2CO3
K2CO3
K2CO3
Na2CO3
K2CO3
K2CO3
2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
A
A
A
8290:10
trace
89
0
-
43[c]
0
95:5
0
[d]
85
85
11
12 73
12 63
31
86:14
[e]
5
0
750:2
808:2
A
B
reflux 11
reflux 36
72
65
> 99:1
> 99:1
> 99:1
> 99:1
96:4
> 99:1
> 99:1
98:20
26
11
10
8
5
0
9
10
11
12K
13
14
15
16
17
THF
THF
THF
THF
40
58
82
reflux 1288
reflux 11
85[f]
89
90
86
87
86
75
11
10
10
7
[f]
85
100
0
[f]
[g]
[g]
85
> 99:1
> 99:1
0
0
1.2C
reflux
6
The corresponding reaction of di-
methyl 2-(2,3-decadienyl)malonate
with PhI and 4a afforded cis-5l in
85% yield (Scheme 3). The configu-
[a] PhI (1.2equiv), base (4.0 equiv), and NaH (1.1 equiv) were used. [b] A ¼ nBu4NBr (10 mol%), B ¼
Cu(OTf)2 (10 mol%); [c] 4% of 3a was produced. [d] 57% of 3a was produced. [e] 5% of 3a was
produced. [f] The reaction was carried out in a tube with a screw cap. [g] C ¼ 1,4-Dioxane.
¼
(858C) are key to a smooth relay and high stereoselectivity of
5a.
ration of the C C bond in 5 l was determined from the
1H,1H NOESY spectra.
The results of the [Pd(PPh3)4]-catalyzed tandem coupling
cyclization reaction of 1a with different organohalides and
imines in THF or 1,4-dioxane are summarized in Tables 2
and 3. In all other cases, except in the reactions of aryl halides
with strongly electron-withdrawing substituents (Table 2,
In conclusion, we have developed a three-component
tandem double-addition cyclization reaction that provides
an efficient route to polysubstituted cis-pyrrolidine deriva-
tives with matched relay and excellent regio- and stereo-
selectivity. As all three building blocks are readily available,
this study will open a new area for the
transition-metal-catalyzed chemistry
Table 2. [Pd(PPh3)4]-catalyzed tandem double-addition cyclization of 1a with imine 4a and different
organohalides and triflates in THF or 1,4-dioxane.[a]
of allenes. Further studies on the
scope and synthetic applications of
this reaction are being pursued in our
laboratory.
Experimental Section
Typical procedure: Malonate 1a (46 mg,
0.25 mmol) and iodobenzene (61 mg,
0.3 mmol, 1.2equiv) were added consecutive-
ly to a sealed tube charged with a mixture of
potassium carbonate (138 mg, 1.0 mmol,
Entry
R1X
Imine
[equiv]
Solvent[b]
T [8C]
5
Yield of 2 [%]
Yield
cis/trans
1
2
3
4
5
6
7
8
p-CH3C6H5I
p-CH3C6H5I
p-MeOC6H5I
p-MeOC6H5I
p-MeOC6H5I
p-MeOC6H5I
p-MeO2CC6H5I
p-MeO2CC6H5I
p-MeO2CC6H5I
thienyl-I
(E)-PhC C I
E)-PhC C I
(E)-nBuC C I
(E)-nBuC C I
C5H5Br
C5H5OTf
3.0
1.2A
1.2
3.0
1.2
1.2B
3.0
3.0
1.2B
3.0
3.0
1.2
A
reflux
92
85
85
85
92( 5b)
5b)
85 ( 5d)
84 (5d)
90 ( 5d)
5d)
92( 5e)
92( 5e)
5e)
100 (5 f)
96 (5g)
83 ( 5g)
> 99:1
97:3
95:5
6 (2b)
0
3 (2d)
0
85
(
A
B
4.0 equiv),
[Pd(PPh3)4]
(14.5 mg,
A
95:5
0.0125 mmol, 5 mol%), and 4a (78 mg,
0.3 mmol, 1.2equiv) in THF (3 mL) under
nitrogen. The resulting mixture was heated at
858C overnight and monitored by TLC. After
evaporation, the residue was purified by flash
column chromatography on silica gel (eluent:
petroleum ether/ether 3:1) to afford pure 5a
(111 mg, 86%; cis/trans > 99:1). cis-5a: white
solid, m.p. 146 1478C (ethyl acetate/hexane);
1H NMR (300 MHz, CDCl3): d ¼ 7.53 (d, J ¼
8.29 Hz, 2H), 7.41 7.30 (m, 5H), 7.28 7.11 (m,
7H), 5.86 (s, 1H), 5.36 (s, 1H), 5.25 (s, 1H),
4.50 (dd, J ¼ 11.68, 5.98 Hz, 1H), 3.65 (s, 3H),
3.15 (s, 3H), 2.84 (dd, J ¼ 13.70, 11.68 Hz,
> 98:20
> 98:20
> 99:1
> 99:1
> 99:1
> 99:1
97:3
95:5
96:4
97:3
> 98:20
96:4
reflux
81 (
A
B
85
reflux
64 (
85
85
6 (2e)
7 (2e)
35 (2e)
0
0
0
0
0
9
reflux
10
11
12(
13
14
15
16
A
A
¼ À
¼ À
B
A
B
85
85
85
¼ À
1.2
1.2
3.0
3.0
84 (
84 (
5h)
5h)
¼ À
A
A
85
85
82( 5a)
86 (5a)
0
[a] R1I (1.2equiv) was used. [b] A ¼ THF, B ¼ 1,4-dioxane.
Angew. Chem. Int. Ed. 2002, 41, No. 24
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COMMUNICATIONS
Table 3. [Pd(PPh3)4]-catalyzed tandem double-addition cyclization of 1a
with PhI and different imines 4 in THF or 1,4-dioxane.[a]
Pinder, Nat. Prod. Rep. 1992, 9, 17; d) G. Massiot, C. Ddelaude in
Alkaloids (Ed.: A. Brossi), Academic Press, New York, 1996, 27, 269.
[9] a) J.-E. B‰ckvall, H. E. Schink, Z. D. Renko, J. Org. Chem. 1990, 55,
826; b) E. Lee, E. J. Jeong, S. J. Min, S. Hong, J. Lim, S. K. Kim, H. J.
Kim, B. G. Chio, K. C. Koo, Org. Lett. 2000, 2, 2169; c) A. Boto, R.
Hernµndez, Y. de LeÛn, E. Suµrez, J. Org. Chem. 2001, 66, 7796; d) B.
Schlummer, J. F. Hartwig, Org. Lett. 2002, 4, 1471.
[10] For the Pd(0)-catalyzed coupling cyclization reaction of g-allenic
amides with aryl or vinyl halides, see: a) S.-K. Kang, K.-J. Kim, Org.
Lett. 2001, 3, 511; b) I. W. Davies, D. I. C. Scopes, T. Gallagher, Synlett
1993, 85.
Entry
R
Solvent[b]
5
Yield of 2a [%]
Yield[%] cis/trans
[11] For the Agþ-catalyzed cycloisomerization of g-allenic amides, see:
a) I. W. Davies, T. Gallagher, R. B. Lamont, D. I. C. Scopes, J. Chem.
Soc. Chem. Commun. 1992, 335; b) D. N. A. Fox, D. Lathbury, M. F.
Mahon, K. C. Molloy, T. Gallagher, J. Chem. Soc. Chem. Commun.
1989, 1073; c) R. Kinsman, D. Lathbury, P. Vernon, T. Gallagher, J.
Chem. Soc. Chem. Commun. 1987, 243; for lanthanide-catalyzed
cycloisomerization of g-allenic amides, see: V. M. Arredondo, S. Tian,
F. E. McDonald, T. J. Marks, J. Am. Chem. Soc. 1999, 121, 3633.
[12] For the Pd-catalyzed two-component reaction of 2-(2,3-allenyl)mal-
onates with electron-deficient alkenes leading to five-membered
carbocycles, see: M. Meguro, Y. Yamamoto, J. Org. Chem. 1999, 64,
694.
1
2
3
4[c]
5
p-O2NC6H4 (4b) THF
p-O2NC6H4 (4b)
p-MeOC6H4 (4c) THF
p-MeOC6H4 (4c) THF
89 (5i)
95 (5i)
52( 5j)
99 (5j)
52( 5j)
95 (5k)
95:5
97:3
> 99:1 42
> 99:1
97:3
> 98:20
0
0
A
0
p-MeOC6H4 (4c)
p-ClC6H4 (4d)
A
THF
2
9
6
[a] PhI (1.2equiv) was used. [b] A ¼ 1,4-dioxane; [c] Imine 4c (3.0 equiv)
was used.
[13] For the Pd-catalyzed cycloisomerization of allenes with a nucleophilic
center, see: a) S. Kamijo, Y. Yamamoto, Tetrahedron Lett. 1999, 40,
1747; b) M. Meguro, S. Kamijo, Y. Yamamoto, Tetrahedron Lett. 1996,
37, 7453; c) B. M. Trost, P.-Y. Michellys, V. J. Gerusz, Angew. Chem.
1997, 109, 1837; Angew. Chem. Int. Ed. 1997, 36, 1750.
[14] For the Pd-catalyzed coupling cyclization of 2-(2,3-allenyl)malonates
with organohalides, see: a) L. Besson, J. Bazin, J. Gore, B. Cazes,
Tetrahedron Lett. 1994, 35, 2881; b) M. Ahmar, B. Cazes, J. Gore,
Tetrahedron Lett. 1985, 26, 3795; c) S. Ma, S. Zhao, Org. Lett. 2000, 2,
2495; d) S. Ma, N. Jiao, S. Zhao, H. Hou, J. Org. Chem. 2002, 67, 2837.
[15] X-ray data for compound 5a: C29H29NSO6, Mr ¼ 519.61, triclinic, space
group P1 (#2), a ¼ 10.228(2), b ¼ 13.310(4), c ¼ 9.980(2) ä, V¼
1328.9(5) ä3, a ¼ 97.57(2)8, b ¼ 96.13(2)8, g ¼ 96.17(2)8, T¼ 20.08C,
Z ¼ 2, m(MoKa) 1.65 cmÀ1, reflections collected 4926 (unique 4642),
number of data with I > 3.00s(I) 3978, parameters 335, R1 ¼ 0.043,
Rw ¼ 0.057, Rint ¼ 0.022. CCDC-189277 contains the supplementary
crystallographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB21EZ, UK; fax: (þ 44)1223-336-033; or deposit@ccdc.cam.
ac.uk).
Scheme 3. Synthesis of 5l from 1b and imine 4a.
1H), 2.60 (dd, J ¼ 13.70, 5.98 Hz, 1H), 2.39 ppm (s, 3H); 13C NMR
(75.4 MHz, CDCl3): d ¼ 170.04, 167.18, 147.84, 143.71, 139.88, 139.05,
139.04, 135.69, 129.34, 128.55, 128.51, 128.46, 128.38, 128.25, 128.08,
116.63, 68.14, 64.03, 63.83, 53.73, 52.62, 39.28, 21.79 ppm; MS (70 eV): m/
z (%): 520 (14.32) [MþH]þ, 364 (100); IR (KBr): n˜ ¼ 1749, 1729, 1635, 1597,
1493, 1350, 1165 cmÀ1; elemental analysis: calcd for C29H29NO6S (%):
C 67.03, H 5.63, N 2.70; found C 67.04, H 5.48, N 2.63.
Received: July 9, 2002
Revised: September 10, 2002 [Z19689]
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Catalytic Electronic Activation: Indirect
™Wittig∫ Reaction of Alcohols**
Michael G. Edwards and Jonathan M. J. Williams*
Tandem, domino, and cascade reactions have become
increasingly popular in recent years, driven by the opportunity
to simplify linear sequences and achieve otherwise unfeasible
reactions.[1] Contributions from this group have involved the
idea of ™catalytic electronic activation∫, which temporarily
enhances the electronic nature of a functional group to a given
reaction. We have recently reported the indirect addition of
[*] Prof. Dr. J. M. J. Williams, M. G. Edwards
Department of Chemistry
University of Bath
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1995, 107, 285; Angew. Chem. Int. Ed. Engl. 1995, 34, 259.
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A. J. Shell, Chem. Rev. 1996, 96, 195; c) R. A. Bunce, Tetrahedron
1995, 51, 13103.
Claverton Down, Bath BA27AY (UK)
Fax : (þ 44)1225-826-231
E-mail: j.m.j.williams@bath.ac.uk
[**] This work was supported by the EPSRC (M.G.E.).
[8] For some reviews, see: a) D. Enders, C. Thiebes, Pure. Appl. Chem.
2001, 73, 573; b) D. O’hagan, Nat. Prod. Rep. 2000, 17, 435; c) A. R.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
4740
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0044-8249/02/4124-4740 $ 20.00+.50/0
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