Palladium-catalyzed cyclization of vinyl iodide-tethered allensulfonamide

Article abstract of DOI:10.1016/j.tetlet.2014.02.087

This Letter describes a palladium-catalyzed cyclization of vinyl iodide-tethered allensulfonamide in the presence of alkylol, which provides a facile access to 2-alkoxy-3-methylene-tetrahydropyridine. The asymmetric version of this reaction has also been preliminarily realized with up to 81% enantioselectivity when chiral bisphosphine ligands were used.

Full text of DOI:10.1016/j.tetlet.2014.02.087

Tetrahedron Letters 55 (2014) 2160–2162
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed cyclization of vinyl iodide-tethered
allensulfonamide
⇑
⇑
Zheng Xie, Pan Wu, Liangzhen Cai , Xiaofeng Tong
Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai 200237, 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 a palladium-catalyzed cyclization of vinyl iodide-tethered allensulfonamide in the
presence of alkylol, which provides a facile access to 2-alkoxy-3-methylene-tetrahydropyridine. The
asymmetric version of this reaction has also been preliminarily realized with up to 81% enantioselectivity
when chiral bisphosphine ligands were used.
Received 6 December 2013
Revised 14 February 2014
Accepted 24 February 2014
Available online 3 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Palladium catalysis
Allensulfonamide
Cyclization
N,O-acetal
Allenamides represent a class of stable allenamine which was
firstly reported by Viehe in 1968.1 In the past decades, along with
the substantive emergence of their synthetic methods, allenamides
have been identified to be powerful and versatile building blocks.2
In these contexts, palladium-catalyzed cyclization of allenamides
has been proven to be a useful method for the construction of di-
verse heterocycles.3 For example, Grigg reported a Pd(0)-catalyzed
cyclizative carbopalladation-anion capture cascade process using
aryl iodide-tethered allenamide (Scheme 1a).4 This reaction would
menced our research from establishing optimized reaction
conditions with the use of 1a as the model substrate (Table 1).
When 1a was subjected to the reaction systems combined by
Pd(OAc)2 (10 mol %), PPh3 (20 mol %), and K2CO3 (2 equiv) in
refluxing MeOH solvent, it was pleased to isolate the desired a-at-
tack product 2a albeit in the yield of 12% (Table 1, entry 1). It was
disappointed to find that some common bisphosphine ligands,
including DPPE, DPPP, DPPB as well as BINAP, only somewhat im-
proved the yield (Table 1, entries 2–5). To our delight, catalyst pre-
cursor Pd(PPh3)Cl2 was proven to be superior, resulting in the
isolation of 2a in 53% yield (Table 1, entry 6). On the base of these
results, we then investigated the effect of base additive. We found
that base additive imposed strong effect on the reaction with re-
spect to the isolated yield (Table 1, entries 7–12). Et3N gave the
best result, improving the yield to be 85% (Table 1, entry 9). More
involve Pd-
attacked at
p
c
-allyl intermediate A, which could be regioselectively
-position by amine.5
With the combination of Grigg’s report and our continuous ef-
forts on the palladium-catalyzed transformation of (Z)-vinyl
iodides,6 we envisioned that vinyl iodide-tethered allensulfona-
mide 1 would also be capable of interacting with Pd(0) catalyst
to form similar Pd-p-allyl intermediate B (Scheme 1b). Herein,
importantly, the corresponding c-attack isomer was not detected
we report a Pd(0)-catalyzed cyclization of 1 with the use of alkylol
as nucleophile to capture intermediate B. Furthermore, this reac-
tion is found to be different from the Grigg’s reports and highly
under these reaction conditions, demonstrating the high regiose-
lectivity of this transformation. It is worth noting that reduction
of the amount of MeOH to 1.5 equiv still gave acceptable yields
when the reaction was conducted in THF or MeCN solvent (Table 1,
entries 13 and 14).
regioselective
a-attack was observed, leading to cyclic N,O-acetal
2 as major product (Scheme 1b).
According to the base-induced isomerization of propargyl
amide,7 allenamide 1 can be readily obtained in two steps from
(Z)-N-(3-iodoallyl)-sulfonamide and 3-bromoprop-1-yne (see Sup-
porting Information). With the allenamide 1 in hand, we com-
With the optimized conditions (Table 1, entry 9) in hand, we
then turned our attention to investigate the reaction scope and
the results are summarized in Table 2. In general, this Pd(0)-cat-
alyzed cyclization of (Z)-vinyl iodide tethered allenamide 1 could
be easily achieved with high regioselectivity, delivering N,O-ace-
tal 2 in moderate to high yields. For the substrates with R1 = H,
the nature of R2 substituent strongly affects the regioselectivity
⇑
Corresponding authors. Tel./fax: +86 21 64253881.
E-mail address: tongxf@ecust.edu.cn (X. Tong).
http://dx.doi.org/10.1016/j.tetlet.2014.02.087
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

Z. Xie et al. / Tetrahedron Letters 55 (2014) 2160–2162
(a): previous work
2161
γ
NR2
NTs
Pd(II)
α
NTs
I
HNR2
base
Pd(0)
NTs
A
γ
mainly -attack
(b): present work
R1
γ
R1
R2
I
R2
Pd(0)
Pd(II)
α
NTs
R1
R2
HOR
base
NTs
N
OR
1
Ts
B
α
mainly -attack
Scheme 1. Design plan for Pd(0)-catalyzed cyclization of allenamides 1.
Table 2
Reaction scopea
Table 1
Reaction conditions optimizationa
R1
R1
1
Ph
Ph
R2
R2
I
10 mol% Pd(PPh3)2Cl2
10 mol% [Pd], 20 mol% L
I
2
Et3N (2 equiv)
MeOH, 80 oC, 10 h
base (2 equiv)
N
N
OMe
N
OMe
N
Ts
Ts
MeOH, 80 oC, 10 h
Ts
Ts
1a
2a
1
2
2a (R2 = Ph): 85% yield, only α-attack
Entry
[Pd]
L
Base
K2CO3
Yieldb (%)
R2
(R2 = Et): 74% yield, α : γ = 9.6:1b
2b
2c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
12
5
DPPEc
DPPPc
DPPBc
BINAPc
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
NaOAc
Et3N
2
b
α
γ
= 19:1
(R = Bu): 80% yield,
:
N
OMe
34
24
40
53
65
74
85
55
67
79
76e,f
69e,g
Ts
2d (R2 = H): 35% yield, α : γ = 10:1b
R1
Pd(OAc)2
d
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
—
—
—
—
—
—
—
—
2e (R2 = Et, R1= Ph): 91% yield, α : γ > 20:1b
R2
d
(R2 = Ph, R1= Ph): 60% yield, α : γ > 20:1b
(R2 = Et, R1 = Bu): NDc
2f
d
d
2g
N
OMe
OR
Ts
d
DBU
d
DABCO
DMAP
Et3N
Ph
d
2a-2d (R = Et): 73% yield, α : γ > 20:1b
d
i
2a-3e
d
(R1 = Pr): 50% yield, α : γ > 20:1b
N
—
Et3N
Ts
a
b
c
d
e
f
Reaction conditions see Supporting Information.
Isolated yield.
10 mol % ligand was used.
Without additional ligand.
1.5 equiv of MeOH was used.
THF was used as solvent.
a
Reaction conditions see Supporting Information. The isolated yields were
presented.
b
The ratio of
a-attack and c-attack products. The ratio was determined on the
basis of 1H NMR analysis. cND = not detection. dWith the use of EtOH as solvent.
eWith the use of PrOH as solvent.
i
g
MeCN was used as solvent.
might arise from steric hindrance of EtOH or iPrOH which is
believed to make the
mediate B less efficiently.
a
-attack of nucleophile to Pd-
p
-allyl inter-
and the yield. Not like the case of 1a, the reactions of 1b (R2 = Et)
and 1c (R2 = Bu) form both
-attack and -attack products with
a
c
9.6:1 and 19:1 regioselectivity, respectively. On the other hand,
H-atom substituent furnishes the corresponding product 2d in
somewhat lower combined yield and the ratio of a-attack to c-at-
10 mol% Pd(PPh3)2Cl2
I
(eq 1)
Et3N (2 equiv)
MeOH, 80 oC, 10 h
X
N
R
X
N
R
OMe
tack is 10:1. The substituents at C1-position impose stronger ef-
fect on the yield. For example, the substrates with phenyl group
at C1-position react well to provide products 2e and 2f in the iso-
lated yields of 91% and 60%, respectively, while the corresponding
product 2g with butyl group at C1-position cannot be detected at
all. The introduction of butyl group into C1-position might in-
crease the steric hindrance, leading to the failure of oxidative
addition between vinyl iodide and Pd(0). Furthermore, the
Pd(0)-catalyzed cyclization can be conducted in EtOH or iPrOH
solvent, enabling the isolation of N,O-acetals 2a–2 and 2a–3 in
the yields of 73% and 50%, respectively. The relative lower yields
1h
: R = Ts, X= H2
1i: R = NPh, X= O
2h
: 55% yield, α:γ > 20:1
2i: 53% yield, α:γ > 20:1
In the Grigg’s reports, amine was used as nucleophile and
tack products were mainly formed. Complementarily, -attack
products 2a–2g were obtained with high regioselectivity under
our reaction conditions. Furthermore, the catalytic systems can
be extended to aryl iodide tethered alleamides 1h and 1i. Again,
c-at-
a
a
-attack products 2h and 2i were isolated in moderate yields with
high regioselectivity (eq. 1).8

2162
Z. Xie et al. / Tetrahedron Letters 55 (2014) 2160–2162
Cl
Ph
Ph
I
10 mol% PdCl2, 20 mol% L1
MeO
MeO
PPh2
PPh2
DBU (2 equiv)
EtOH/CH3CN (1:1), 80 oC, 10 h
N
N
OEt
Ts
Ts
1a
2a-2
Cl
89 % yield, 81 % ee
L1
Scheme 2. Preliminary attempt at asymmetric catalysis.
O
Ph
Ph
Ph
Cs2CO3 (3 equiv)
DMF, 100 o
m-CPBA (1.2 equiv)
OiPr
N
OiPr
aq. NaHCO3, CH2Cl2
C
N
N
Ts
Ts
2a-3
Scheme 3. Synthetic applications.
3:
37% yield
4
: 43% yield
It should be noted that product 2a–2 was obtained with 53% ee
when (R)-BINAP was used as ligand under otherwise identical con-
ditions. The result inspired us to carry out a preliminary attempt at
the asymmetric catalysis. Finally, it was found that the highest 81%
enantioselectivity could be realized when ligand L19 was employed
under the modified reaction conditions (Scheme 2).
References and notes
1. (a) Hubert, A. J.; Viehe, H. G. J. Chem. Soc. C 1968, 228; (b) Saalfrank, R. W.; Lurz,
C. J. In Methoden Der Organischen Chemie (Houben-Weyl); Kropf, H., Schaumann,
E., Eds.; Georg Thieme: Stuttgart, 1993; pp 3093–3102.
2. For reviews, see: (a) Lu, T.; Lu, Z.; Ma, Z.-X.; Zhang, Y.; Hsung, R. P. Chem. Rev.
2013, 113, 4862; (b) Hsung, R. P.; Wei, L.-L.; Xiong, H. Acc. Chem. Res. 2003, 36,
773.
The products of the present Pd(0)-catalyzed cyclization can be
converted into other potentially useful compounds. Indeed, pyri-
dine 3 was formed when 2a–3 was treated with Cs2CO3 in DMF sol-
vent (Scheme 3). Furthermore, selective epoxidation of 2a–3 was
readily realized, leading to compound 4 in 43% yield (Scheme 3).
Compound 4 was isolated as a single diastereoisomer,10 which
demonstrates the potential of stereo-control element of cyclic
N,O-acetal.11
In summary, we have developed a Pd(0)-catalyzed cyclization of
vinyl iodide-tethered allenamides 1, which provides cyclic N,O-
acetals 2 in moderate to good yields. An asymmetric version has
also been attempted and the highest 81% enantioselectivity was
obtained although only one example was presented. Further inves-
tigations are aimed at the development of the asymmetric catalysis
and the synthetic applications of products with the use of cyclic
N,O-acetal as stereo-control element.
3. For selected reviews, see: (a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104,
2127; (b) Yamamoto, Y.; Radhakrishnan, U. Chem. Soc. Rev. 1999, 28, 199; (c)
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Husinec, S.; Petkovic, M.; Savic, V.; Simic, M. Synthesis 2012, 44, 399; (e) Fuwa,
H.; Sasaki, M. Org. Biomol. Chem. 2007, 5, 2214; (f) Parthasarathy, K.;
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Acknowledgments
10. It should be noted that decomposition of 4 was observed during the NMR-nOe
experiment, demonstrating that compound
cannot determine the stereochemistry of 4 at this stage.
11. (a) Kim, H.; Lim, W.; Im, D.; Kim, D.; Rhee, Y. H. Angew. Chem., Int. Ed. 2012, 51,
12055; (b) Kim, H.; Rhee, Y. H. J. Am. Chem. Soc. 2012, 134, 4011.
4 is quite unstable. Thus, we
We thank NSFC (No. 21002025 and 21272066), the Fundamen-
tal Research Funds for the Central Universities, Fok Ying-Tong Edu-
cation Foundation for Young Teachers in the Higher Education
Institutions of China (131011) and NCET (No. 12-0851) for funding
this research.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.02.
087.