Synthesis of 3-pyrroline via domino Heck-aza-Michael reaction

Article abstract of DOI:10.1016/j.tetlet.2012.06.075

This Letter describes the Pd(0)-catalyzed domino Heck-aza-Michael reaction between (Z)-N-(3-iodoallyl)-tosylamide and acrylic ester. The reaction provides a facile access to an important class of substituted 3-pyrroline.

Full text of DOI:10.1016/j.tetlet.2012.06.075

Tetrahedron Letters 53 (2012) 4673–4675
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Tetrahedron Letters
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Synthesis of 3-pyrroline via domino Heck–aza-Michael reaction
⇑
Pan Wu, Hui Liu, Xiaofeng Tong
Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai 200237, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes the Pd(0)-catalyzed domino Heck–aza-Michael reaction between (Z)-N-(3-iodoal-
lyl)-tosylamide and acrylic ester. The reaction provides a facile access to an important class of substituted
3-pyrroline.
Received 2 May 2012
Revised 11 June 2012
Accepted 15 June 2012
Available online 23 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Palladium catalysis
Domino
Heck–aza-Michael
3-Pyrroline
Domino reactions, where a series of reactions proceed in a
defined order in one sequence, have emerged as a powerful tool
for organic synthesis due to their well-known advantages, such
as economies of time, labor, and resource management, as well
as efficient construction of complex molecules.1 In recent years,
the strategy of couple metal-catalysis and classical reactions in
a single one-pot operation to achieve domino sequence has been
realized.2 In this context, the palladium-catalyzed Heck-reaction
of acrylic ester is an ideal platform because of the following
facts: (1) acrylic esters are commercial chemicals; (2) they are
able to undergo facile Heck-reaction; (3) most importantly, the
When a mixture of 3a (1 equiv) and tert-butyl acrylate 5a
(2.5 equiv) was treated with Pd(OAc)2 (10 mol %), PPh3
(20 mol %), and Na2CO3 (2 equiv) in refluxing THF for 14 h, it was
pleased to find that the desired product 4aa could be isolated albeit
only in 10% yield (Table 1, entry 1). Solvent screening disclosed
that dioxane is the optimal one, enabling 4aa being isolated in
48% yield (Table 1, entries 2–6). To our delight, Bu4NBr (2 equiv)
was found to be an efficient additive,6 increasing the yield to 65%
(Table 1, entry 7). However, we could not improve the yield of
4aa any more, although other reaction parameters, including li-
gand and base, were thoroughly investigated (Table 1, entries 8–
13). It should be noted that the use of 2.5 equiv 5a is mandatory
for higher yield. Indeed, the use of 2.0 equiv 5a led to 55% yield
newly formed
a,b-unsaturated esters are readily available for
Michael addition, especially intramolecular variant. Indeed, a
domino process combining Heck and aza-Michael reactions has
been developed with the use of 1 and acrylic ester as substrates
(Scheme 1a).3 This process provides a facile entry to various ben-
zo-azaheterocycles 2.
As our continuous efforts on the palladium-catalyzed trans-
formation of (Z)-vinyl iodide,4 we are interested in compounds
3 due to its similar reactivity with that of 1 with respect to
the domino Heck and aza-Michael process (Scheme 1b). Further-
more, compounds 3 can be readily synthesized in gram scale
with a simple two-step procedure.5 Herein, we report a domino
Heck and aza-Michael reaction between 3 and acrylic ester
(Scheme 1b). This new reaction complements the previous cases
of substrate 1, as far as it allows access to a range of 3-pyrro-
lines 4, whose olefin and ester groups are capable of further
transformations to synthesize complex molecule.
(a) previous reports:
Pd Cat. / base
acrylic ester
NPG
NHPG
X
CO2R
1
(X = Br, I)
2
(b) present work:
R1
R2
I
R1
R2
Pd Cat. / base
acrylic ester
CO2R
N
NHTs
Ts
3
4
⇑
Corresponding author. Tel./fax: +86 21 64253881.
E-mail address: tongxf@ecust.edu.cn (X. Tong).
Scheme 1. Domino Heck and aza–Michael reactions.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.075

4674
P. Wu et al. / Tetrahedron Letters 53 (2012) 4673–4675
Table 1
Reaction conditions optimizationa
10 mol% Pd(OAc)2
20 mol% Ligand
base, additive
solvent
Ph
Ph
O
CO2tBu
4aa
+
OtBu
5a (2.5 equiv)
I
N
NHTs
Ts
3a
Entry
Ligand
Base (2 equiv)
Solvent
Additive (2 equiv)
Isolated yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14d
15e
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
(4-FC6H4)3P
(2-Furan)3P
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
Ag2CO3
DBU
Et3N
Na2CO3
Na2CO3
THFb
—
—
—
—
—
—
10
42
11
13
<5
48
65
44
30
36
9
MeCNb
PhMec
DMFc
DMSOc
Dioxanec
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
<5
<5
55
63
a
b
c
Reaction conditions see Supplementary data.
Refluxing.
100 °C.
2.0 equiv of 5a was used.
3.0 equiv of 5a was used.
d
e
3
R1
R2
substrates 5d and 5e reacted well with 3a, delivering 4ad and
4ae in 43% and 40% yields, respectively (Table 2, entries 8–9).
On the basis of previous reports3 and the present results, we
proposed a possible mechanism of this transformation (Scheme
2). This would involve the oxidative addition of vinyl iodide 3 to
Pd(0) center to initiate Heck-type reaction with acrylic ester, which
leads to the formation of intermediate C. Subsequently, aza-Mi-
chael addition occurs to afford pyrroline product. It should be men-
tioned that intermediate C could not be detected in the course of
reaction, indicating that the subsequent aza-Michael addition
might be a fast step.
Pd(0)
COR3
R1
R2
N
4
Ts
PdH
Heck
Pd(II)
aza-Michael
NHTs
A
R1
R2
R1
R2
5
Pd(II)
COR3
NHTs
COR3
NHTs
The products of the present Heck–aza-Michael reaction can be
converted into other potentially useful compounds (Scheme 3).
For example, the ester group of 4aa can be readily hydrolyzed to
afford acid 6, which underwent iodolactonization7 to give com-
pound 8 as a single diastereomer in the presence of I2 and NaHCO3.
With the treatment of LiAlH4, 4aa can be reduced to afford alcohol
7. Similarly, after bromoetheration in the presence of NBS,8 7 can
be converted into bridged compound 9.9
In summary, we have developed a Pd(0)-catalyzed Heck–aza-
Michael domino reaction of (Z)-3-iodoprop-2-en-1-amine deriva-
tive with acrylic ester, which complements the related reactions
of 2-iodoaniline. It provides a convenient access to a variety of
substituted 3-pyrrolines in mediate to good yields. Further expan-
sion of the reaction scope and synthetic applications are underway.
C
B
Scheme 2. The proposed mechanism.
of 4aa (Table 1, entry 14) while 3.0 equiv 5a was found not to be
any positive effect (Table 1, entry 15).
With the optimized reaction conditions in hand, we then turned
our attention to investigate the reaction scope and the results are
summarized in Table 2. Firstly, various substrates 3 were tested.
Both alkyl and aryl substituents at C2-position of 3 are well toler-
ated (Table 2, entries 1 and 2). But the reaction of substrate 3c with
a butyl group at C1-position gave no corresponding product while
3c was recovered in 89% yield (Table 2, entry 3). This failure might
stem from less reactivity imposed by steric hindrance of butyl
group. However, substrates with phenyl substituted at C1-position,
such as 3d and 3e, show good reactivity, delivering the correspond-
ing products with good yields (Table 2, entries 4 and 5). Secondly, a
range of substrates 5 were also investigated. Likely due to its high
volatility, the reaction of methyl acrylate 5b affords 4ab in some-
what lower yield. The yield of 4ab can be improved to be 71% when
5.0 equiv 5b is used instead (Table 2, entry 6). Somewhat surpris-
Acknowledgments
The financial support from NSFC (No. 21002025), the Funda-
mental Research Funds for the Central Universities, Shanghai Ris-
ing-Star Program (11QA1401700), Specialized Research Fund for
the Doctoral Program of Higher Education (20100074120014)
and Fok Ying-Tong Education Foundation for Young Teachers in
the Higher Education Institutions of China (131011) are highly
appreciated.
ingly, the reaction of a,b-unsaturated ketone 5c with 3a gave 4ac
only in 43% yield (Table 2, entry 7). It was pleased to find that
the reaction protocol was also applicable to acrylamide. Indeed,

P. Wu et al. / Tetrahedron Letters 53 (2012) 4673–4675
4675
Table 2
Reaction scopea
R1
R2
10 mol% Pd(OAc)2
20 mol% PPh3
R1
2
R2
1
I
O
COR3
+
R3
5 (2.5 equiv)
2 equiv Na2CO3
2 equiv. Bu4NBr
N
NHTs
Ts
3
Entry
3 (R1, R2)
5 (R3)
4
Yieldb (%)
1
2
3
4
5
6
7
3a (Ph, H)
3b (Bu, H)
3c (Et, Bu)
3d (Ph, Ph)
3e (Et, Ph)
3a (Ph, H)
3a (Ph, H)
5a (OtBU)
5a (OtBU)
5a (OtBU)
5a (OtBU)
5a (OtBU)
5b (OMe)
5c (Ph)
4aa
4ba
4ca
4da
4ea
4ab
4ac
65
50
ND
51
70
54 (71)c
43
Ph
O
8
43
40
N(OMe)Me
N
4ad
Ts
Ph
O
9
N
O
N
4ae
Ts
a
Reaction conditions see Supplementary data.
Isolated yield.
The data in parentheses was obtained with the use of 5.0 equiv 5b.
b
c
Tandem Organic Reactions; Wiley: New York, 1992; (c) Tietze, L. F. Chem. Rev.
1996, 96, 115; (d) Nicolaou, K. C.; Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993.
2. For representative examples: (a) Fustero, S.; Jiménez, D.; Sánchez-Roselló, M.;
del Pozo, C. J. Am. Chem. Soc. 2007, 129, 6700; (b) Bi, H.-P.; Liu, X.-Y.; Gou, F.-R.;
Guo, L.-N.; Duan, X.-H.; Shu, X.-Z.; Liang, Y.-M. Angew. Chem., Int. Ed. 2007, 46,
7068; (c) Gai, X.; Grigg, R.; Khamnaen, T.; Rajviroongit, S.; Sridharan, V.; Zhang,
L.; Collard, S.; Keep, A. Tetrahedron Lett. 2003, 44, 7441; (d) Zeng, Y.; Reddy, D. S.;
Hirt, E.; Aubé, J. Org. Lett. 2004, 6, 4993; (e) Kirschbaum, S.; Waldmann, H.
Tetrahedron Lett. 1997, 38, 2829.
3. (a) Dyker, G.; Grundt, P. Tetrahedron Lett. 1996, 37, 619; (b) Rolfe, A.; Young, K.;
Hanson, P. R. Eur. J. Org. Chem. 2008, 5254; (c) Khan, M. W.; Masud Reza, A. F. G.
Tetrahedron 2005, 61, 11204; (d) Barr, N.; Bartley, J. P.; Clark, P. W.; Dyke, P.;
Dunstan, S. F. J. Organomet. Chem. 1986, 302, 117; (e) Rolfe, A.; Young, K.; Volp,
K.; Schoenen, F.; Neuenswander, B.; Lushington, G. H.; Hanson, P. R. J. Comb.
Chem. 2009, 11, 732.
Ha
Ph
1 equiv I2
Ph
I
3 equiv NaHCO3
HCO2H
rt
CO2H
HO
4aa
4aa
O
6 equiv NaI
H2O, rt, in dark
N
Ts
TsN
CO
6
8
80% overall yield
Hb
Ph
O
Ph
Br
1.4 equiv. NBS
acetone, 0oC
LiAlH4
THF, rt
N
Ts
TsN
9
7
4. (a) Liu, H.; Li, C.; Qiu, D.; Tong, X. J. Am. Chem. Soc. 2011, 133, 6187; (b) Liu, H.;
Wang, L.; Tong, X. Chem. Commun. 2011, 47, 12206.
70% overall yield
5. The detail for synthesis of compounds 3 please see the Supplementary data.
6. (a) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287; (b) Larock, R. C.; Leung,
W.-Y.; Stolz-Dunn, S. Tetrahedron Lett. 1989, 30, 6629; (c) Larock, R. C.; Yum, E.
K.; Yang, H. Tetrahedron 1994, 50, 305; (d) Basavaiah, D.; Muthukumaran, K.
Tetrahedron 1998, 54, 4943.
Scheme 3. Synthetic transformation.
Supplementary data
7. Martin, S. F.; Dappen, M. S.; Dupre, B.; Murphy, C. J.; Colapret, J. A. J. Org. Chem.
1989, 54, 2209.
8. Rico, R.; Zapico, J.; Bermejo, F.; Bamidele Sanni, S.; García-Granda, S.
Tetrahedron: Asymmetry 1998, 9, 293.
Supplementary data associated with this article can be found, in
theonline version, at http://dx.doi.org/10.1016/j.tetlet.2012.06.075.
9. The structural determination of compounds 8 and 9 is based on the following
considerations: in the 1H NMR spectra of 8 and 9, the corresponding peaks of Ha
and Hb are singlet. If they are [3,3,0]-bicyclic system, the peaks of Ha and Hb
should be doublet. For similar [3,3,0]bicyclic compound see: Ranieri, B.; Curti,
C.; Battistini, L.; Sartori, A.; Pinna, L.; Casiraghi, G. Zanardi, F. J. Org. Chem. 2011,
76, 10291.
References and notes
1. For selected reviews, see: (a) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino
Reactions in Organic Chemistry; Wiley-VCH: Weinheim, 2006; (b) Ho, T.-L.