Pd-catalyzed asymmetric aza-Wacker-type cyclization reaction of olefinic tosylamides

Article abstract of DOI:10.1016/j.tetlet.2010.07.084

The Pd-catalyzed asymmetric aza-Wacker-type cyclization reaction of the olefinic tosylamides with molecular oxygen as the green oxidant was developed. Under the optimized conditions, excellent catalytic activity and good enantioselectivity with up to 74%

Full text of DOI:10.1016/j.tetlet.2010.07.084

Tetrahedron Letters 51 (2010) 5124–5126
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Tetrahedron Letters
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Pd-catalyzed asymmetric aza-Wacker-type cyclization reaction of olefinic
tosylamides
*
Feng Jiang , Zhengxing Wu, Wanbin Zhang
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 June 2010
Revised 7 July 2010
Accepted 16 July 2010
Available online 11 August 2010
The Pd-catalyzed asymmetric aza-Wacker-type cyclization reaction of the olefinic tosylamides with
molecular oxygen as the green oxidant was developed. Under the optimized conditions, excellent cata-
lytic activity and good enantioselectivity with up to 74% ee were obtained with quinolineoxazoline
ligands. This reaction provides direct and easy access to chiral nitrogen-containing heterocycles which
retain the olefin functionality.
Ó 2010 Elsevier Ltd. All rights reserved.
In recent years, considerable efforts have been prompted to-
ward the synthesis of the nitrogen-containing heterocycles be-
cause many of them are core structures of potent drugs and
bioactive natural products.1 Pd-catalyzed aza-Wacker-type cycli-
zation reactions are versatile and powerful tools to construct nitro-
gen-containing heterocycles under mild conditions, and the
reactions become more and more attractive because their products
retain the olefin functionality.2
A landmark in the field of aza-Wacker-type cyclization reaction
was laid by Hegedus and co-workers, who initially used stoichiom-
etric amounts of Pd(II) and later turned to the use of catalytic
amounts.3 Starting from 2-allylaniline derivatives, they obtained
indoles using catalytic amounts of PdCl2(MeCN)2 or PdCl2 and a stoi-
chiometric amount of p-benzoquinone as reoxidant.3b The approach
was afterward adopted by other authors for the preparation of
dihydroindoles and dihydroquinolines.4 Recently catalyst stability
and product yields were improved by the use of compounds in
which Pd(II) was coordinated to NHC ligands such as IMes, IPr, or
the seven-membered heterocyclic carbene.5 Asymmetric aza-Wac-
ker-type cyclization reaction of the olefinic tosylamides was
attempted by Stahl and co-workers, who used axially-chiral
seven-membered N-heterocyclic carbene (NHC) ligands, however,
the substrates underwent cyclization to afford essentially racemic
products.6
tosylamides. Here we report our initial results about this reaction
for the preparation of chiral nitrogen-containing heterocycle prod-
ucts with olefin functionality.
It was reported that substrate 1b was easily prepared,5 and
compound 3 was the most efficient ligand for the asymmetric
Wacker-type cyclization of allylphenols (Table 1, Fig. 1).7c,7d So
substrate 1b and ligand 3 were first used in the aza-Wacker-type
cyclization reaction under similar conditions as Stahl’s report.5
However, only a trace product was obtained in toluene at 60 °C
after 2 d (Table 1, entry 1). Since pyridine was a very efficient
ligand in the preparation of rac-product, we anticipated that the
chiral ligands containing the pyridine structure may be effective
also in asymmetric aza-Wacker-type cyclization reaction. There-
fore, a tridentate pyridine-bisoxazoline ligand 4 was employed.
As expected, the reaction proceeded smoothly under the same
conditions as above and afforded a very high yield of 91%, albeit
with a lower enantioselectivity of 16% ee (entry 2). Another biden-
tate pyridine-oxazoline ligand 5 was also used here. As a result, the
high yield was also obtained and the enantioselectivity was
increased to 25% ee. It was interesting that the absolute configura-
tion of the major enantiomeric product was reversed in compari-
son with that using ligand 4 (entry 3).
In order to further improve the enantioselectivities of the
Pd-catalyzed aza-Wacker-type cyclization reaction, several quino-
lineoxazoline ligands 6 were prepared with our modified method
as follows (Scheme 2): A mixture of methyl 2-quinolinecarboxylate
We recently reported an efficient enantioselective Wacker-type
cyclization of allylphenols catalyzed by axially chiral Pd complexes
of biphenyl oxazoline ligands, which have shown the best catalytic
activity and enantioselectivity so far (Scheme 1).7 Encouraged by
the results, we turned our interest toward the Pd-catalyzed
asymmetric aza-Wacker-type cyclization reaction of olefinic
L, Pd(CF3COO)2
R
R
p-benzoquinone
methanol
O
OH
* Corresponding author. Tel./fax: +86 21 5474 3265.
E-mail address: wanbin@sjtu.edu.cn (W. Zhang).
On leave from Ningbo University.
ee up to 99%
Scheme 1. Wacker-type cyclization of allylphenols.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.084

F. Jiang et al. / Tetrahedron Letters 51 (2010) 5124–5126
5125
Table 1
Table 2
Aza-Wacker-type cyclization reaction of 1b with different ligandsa
Condition optimization of the aza-Wacker-type cyclization reaction of 1b with ligand
6ba
Pd(II)/L, O2
Pd(II)/6b
toluene, 60 ºC
N
Ts
2b
O2
N
Ts
2b
NHTs
NHTs
1b
1b
Entry
Yieldb (%)
eec (%)
Entry
Solvent
Time (d)
Temp (°C)
Yieldb (%)
eec (%)
Ligand
Time (d)
1
2
3
4
5
6
7
3
4
5
6a
6b
6c
6d
2
1
2
1
1
1
1
Trace
91
89
94
93
—
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
1
1
1
1
1
5
5
5
5
5
5
5
5
5
5
5
5
100
80
60
40
20
0
ꢀ10
ꢀ20
0
0
0
0
0
89
95
93
94
94
94
46
Trace
36
55
66
56
93
93
6
28
39
43
51
58
69
70
—
57
56
54
46
69
66
14
20
74
16
ꢀ25
27
43
42
14
91
94
a
All reactions were catalyzed by 10 mol % of Pd(II)–ligand complex generated
in situ by mixing Pd(OCOCH3)2 with ligand (Pd/ligand 1:2) in the presence of
oxygen in toluene at 60 °C.
9
THF
10
11
12
13
14d
15e
16f
17g
Methanol
Dichloromethane
Acetone
Benzotrifluoride
Toluene
Toluene
Toluene
Toluene
b
NMR yield (internal standard = ethyl acetate).
Determined by the HPLC using chiral AD-H column.
c
0
0
0
0
45
73
O
O
a
All reactions were catalyzed by 10 mol % of Pd(II)–ligand complex generated
in situ by mixing Pd(OCOCH3)2 with ligand 6b (Pd/ligand 1:2) in the presence of
oxygen.
Ph
Ph
Ph
Ph
O
O
N
N
N
N
N
O
N
N
N
N
b
NMR yield (internal standard = ethyl acetate).
Determined by the HPLC using chiral AD-H column.
3 Å molecular sieves was added (200 mg/mmol substrates).
20 mol % HNTf2 and 3 Å molecular sieves were added (200 mg/mmol substrates).
1 equiv. of K2CO3 was added.
2 equiv. of KOAc was added.
O
O
Ph
Ph
Ph
c
d
4
5
3
e
f
Figure 1. The ligands used for the aza-Wacker-type cyclization reaction.
g
7 and aminoalcohol was heated to give the crude hydroxylethyla-
mide 8. Direct treatment of 8 with SOCl2 gave the crude chloroeth-
ylamide 9, which was subjected to the oxazoline ring formation by
treatment with sodium hydroxide to give the ligands 6a–d with
the overall yields from 32% to 42%.8
Next ligands 6a–d were applied to the Pd-catalyzed aza-Wac-
ker-type cyclization reaction of 1b and the results were shown in
Table 1. All of the four ligands showed excellent catalytic activities
with 91–94% yields and moderate enantioselectivities (Table 1, en-
tries 4–7). It was found that the substituent R on the oxazoline ring
had some effect on enantioselectivity, and ligand 6b with an iso-
propyl group on the oxazoline ring afforded the best enantioselec-
tivity (entry 5).
The effect of reaction conditions on the aza-Wacker-type cycli-
zation reaction was taken into account. It was shown that when
the temperature was decreased from 100 to 0 °C, the yield did
not change obviously, however, the enantioselectivity increased
dramatically from 28% to 69% ee (Table 2, entries 1–6). Further
decreasing the temperature did not show any improvement of
enantioselectivity, but reduced the yield greatly (entry 7). When
the temperature was decreased to ꢀ20 °C, only trace product was
afforded (entry 8). It was also found that solvents had some effect
on this reaction (entries 6 and 9–13) and toluene was tested to be
the most efficient one based on the catalytic activity and enanti-
oselectivity (entry 6).
It was reported that 3 Å MS was used in the related Pd-cata-
lyzed enantioselective oxidative cyclizations.2d However, 3 Å MS
had no obvious effect in our reaction (Table 2, entry 14). It was also
reported that acid and base had some effect on the aza-Wacker-
type cyclization reaction catalyzed by NHC-coordinated Pd com-
plexes.5 Therefore, some acids and bases were selected to examine
our reaction. It was shown that the enantioselectivity as well as
catalytic activity of the reaction was dramatically reduced when
using HNTf2 or K2CO3 (entries 15 and 16). When using KOAc, the
enantioselectivity was increased, but the catalytic activity was
reduced (entry 17).
In order to explore the scope of the Pd(II)-catalyzed aza-Wac-
ker-type cyclization reaction, substrates 1 with different substi-
tuted group were prepared with Stahl’s method (Scheme 3).5,9
Then we used these olefinic tosylamides in the Pd(II)-catalyzed
a
OH
NH2
OH
b
a
R
R
R
H
N
NHTs
N
OH
N
COOCH3
11
10
12
O
R
7
8
Cl
c
R
c
b
H
N
NHTs
NHTs
O
N
1a~f
N
Cl
N
O
R
6a~d
9
R
1a: R=H; 1b: R=4-CH3; 1c: R=6-CH3;
1d: R=4-Cl; 1e: R=6-Cl; 1f: R=4-OCH3.
6a; R=Ph; 6b; R=i-Pr;
6c
; R=Bn;
6d
; R=t-Bu; .
Scheme 3. Reagents and conditions: (a) TsCl, pyridine, CH2Cl2, reflux (75–91%); (b)
SOCl2, CH2Cl2, reflux; (c) 1-propenyl Grignard reagent, THF, rt (45–72%, one-pot
yield from 11).
Scheme 2. Reagents and conditions: (a) aminoalcohol, 120 °C; (b) SOCl2, CH2Cl2,
reflux; (c) NaOH, EtOH, reflux (32–42%, overall yield).

5126
F. Jiang et al. / Tetrahedron Letters 51 (2010) 5124–5126
Table 3
Co., Ltd. We thank Professor Tsuneo Imamoto for the helpful dis-
cussion and Instrumental Analysis Center of Shanghai Jiao Tong
University for HRMS analysis.
Aza-Wacker-type cyclization reaction of different substrates with ligand 6ba
6b
Pd(II)/ , O2
R
R
N
Ts
2a~f
References and notes
toluene, 0 ºC
NHTs
1a~f
1. O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435–446.
2. For a review see: (a) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S.
Chem. Rev. 2007, 107, 5318–5365; For papers see: (b) Fix, S. R.; Brice, J. L.; Stahl,
S. S. Angew. Chem., Int. Ed. 2002, 41, 164–166; (c) Yip, K.; Yang, M.; Law, K.; Zhu,
N.; Yang, D. J. Am. Chem. Soc. 2006, 128, 3130–3131; (d) He, W.; Yip, K.; Zhu, N.;
Yang, D. Org. Lett. 2009, 11, 1911–1913.
3. (a) Hegedus, L. S.; Allen, G. F.; Waterman, E. L. J. Am. Chem. Soc. 1976, 98, 2674–
2676; (b) Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Waterman, E. L. J. Am. Chem.
Soc. 1978, 100, 5800–5807; (c) Hegedus, L. S.; Allen, G. F.; Olsen, D. J. J. Am.
Chem. Soc. 1980, 102, 3583–3587; (d) Hegedus, L. S.; McKearin, J. M. J. Am.
Chem. Soc. 1982, 104, 2444–2451; (e) Weider, P. R.; Hegedus, L. S.; Asada, H. J.
Org. Chem. 1985, 50, 4276–4281.
4. Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996,
61, 3584–3585.
5. Rogers, M. M.; Wendlandt, J. E.; Guzei, I. A.; Stahl, S. S. Org. Lett. 2006, 8, 2257–
2260.
6. Scarborough, C. C.; Bergant, A.; Sazama, G. T.; Guzei, I. A.; Spencer, L. C.; Stahl, S.
S. Tetrahedron 2009, 65, 5084–5092.
Entry
Substrate
Yieldb (%)
eec (%)
1
2
3
4
5
6
1a (R = H)
90
94
37
90
4
69d
69
1b (R = 4-CH3)
1c (R = 6-CH3)
1d (R = 4-Cl)
1e (R = 6-Cl)
ꢀ8
68
ꢀ35
74
1f (R = 4-OCH3)
75
a
All reactions were catalyzed by 10 mol % of Pd(II)–ligand complex generated
in situ by mixing Pd(OCOCH3)2 with ligand 6b (Pd/ligand 1:2) in the presence of
oxygen in toluene at 0 °C for 5 d.
NMR yield (internal standard = ethyl acetate).
Determined by the HPLC using chiral AD-H column. The relative configuration
of the 2b–f was assigned by similarity to 2a in the order of retention time in the
b
c
HPLC analysis.
The specific rotation of the product: ½a D26:6
ꢁ
= +120.2.
d
7. (a) Wang, F.; Zhang, Y. J.; Wei, H.; Zhang, J.; Zhang, W. Tetrahedron Lett. 2007,
48, 4083–4086; (b) Wang, F.; Zhang, Y. J.; Yang, G.; Zhang, W. Tetrahedron Lett.
2007, 48, 4179–4182; (c) Zhang, Y. J.; Wang, F.; Zhang, W. J. Org. Chem. 2007, 72,
9208–9213; (d) Wang, F.; Yang, G.; Zhang, Y. J.; Zhang, W. Tetrahedron 2008, 64,
9413–9416.
aza-Wacker-type cyclization reaction, and the corresponding
nitrogen-containing heterocycles 2 were afforded as expected
(Table 3).10 Excellent catalytic activity and good enantioselectivity
were achieved for p-substituted substrates, regardless of electron-
rich or electron-poor group on the substrates (entries 1, 2, 4 and 6),
and 1f with a methoxy group at p-position afforded the best
enantioselectivity with 74% ee (entry 6). However, the catalytic
activity and enantioselectivity were dramatically reduced for
o-substituted substrates, and the absolute configuration of the
major enantiomeric products was inversed (entries 3 and 5).
In summary, we have demonstrated the first Pd-catalyzed asym-
metric aza-Wacker-type cyclization reaction of olefinic tosylamides.
The reaction result is dependent on the solvent, reaction tempera-
ture, especially ligand and substituent group. Under the optimized
conditions, excellent catalytic activity and good enantioselectivity
were obtained and the substrate with a methoxy group at p-position
afforded the best enantioselectivity up to 74% ee. This method pro-
vides direct access to chiral nitrogen-containing heterocycles with
olefin functionality. Further study toward more efficient ligand for
this reaction is in progress in our laboratory.
8. Characterization data of the ligand 6a, 6b and 6d agree with reference: (a)
Chelucci, G.; Medici, S.; Saba, A. Tetrahedron: Asymmetry 1999, 10, 543–550;
Characterization data of the ligand 6c agree with reference: (b) Zhang, Y.;
Sigman, M. S. J. Am. Chem. Soc. 2007, 129, 3076–3077.
9. Characterization data of substrates 1a–d agree with Ref. 5. Characterization
data of substrate 1e: 1H NMR (400 MHz, CDCl3) d 7.55 (d, J = 8 Hz, 2H), 7.24–
7.19 (m, 3H), 7.16–7.08 (m, 2H), 6.22 (s, 1H), 5.68–5.59 (m, 1H), 5.54–5.45 (m,
1H), 3.72 (d, J = 8.0 Hz, 2H), 2.42 (s, 3H), 1.75–1.71 (m, 3H). 13C NMR (100 MHz,
CDCl3) d 144.2, 143.7, 136.9, 133.0, 131.3, 129.7, 129.2, 128.8, 128.3, 127.8,
127.4, 126.2, 30.2, 21.9, 13.2. HRMS calcd for
C
17H18ClNNaO2S (M+Na+),
358.0644; found, 358.0630. Characterization data of substrate 1f: 1H NMR
(400 MHz, CDCl3) d 7.54 (d, J = 8 Hz, 2H), 7.24–7.17 (m, 3H), 6.71–6.66 (m, 1H),
6.65–6.62 (m, 1H), 6.38 (s, 1H), 5.65–5.55 (m, 1H), 5.26–5.18 (m, 1H), 3.76 (s,
3H), 2.96 (d, J = 8.0 Hz, 2H), 2.39 (s, 3H), 1.65–1.61 (m, 3H). 13C NMR (100 MHz,
CDCl3) d 144.3, 139.5, 138.3, 135.9, 135.8, 129.8, 129.7, 127.9, 127.8, 127.7,
123.6, 116.3, 65.5, 35.7, 21.9. HRMS calcd for C18H21NO3S, 331.1242; found,
331.1240.
10. Characterization data of products 2a–d agree with Ref. 5. Characterization data
of product 2e: 1H NMR (400 MHz CDCl3) d 7.60 (d, J = 8.0 Hz 2H), 7.28–7.20 (m,
3H), 7.09–6.97 (m, 2H), 5.73–5.64 (m, 1H), 5.35–5.29 (m, 1H), 5.08–5.03 (m,
1H), 4.99–4.94 (m, 1H), 2.77–2.69 (m, 1H), 2.44–2.36 (m, 4H). 13C NMR
(100 MHz, CDCl3) d 144.3, 139.5, 138.3, 135.9, 135.8, 129.8, 129.7, 127.8, 127.7,
127.6, 123.6, 116.3, 65.5, 35.7, 21.9. HRMS calcd for C17H16ClNO2S, 333.0590;
found, 333.0595. Characterization data of product 2f: 1H NMR (400 MHz
CDCl3) d 7.58 (d, J = 8.0 Hz 1H), 7.52 (d, J = 8.0 Hz 2H), 7.17 (d, J = 8.0 Hz 2H),
6.78–7.73 (m, 1H), 6.59–6.56 (m, 1H), 5.93–5.83 (m, 1H), 5.42–5.36 (m, 1H),
5.17–5.12 (m, 1H), 4.73–4.67 (m, 1H), 3.74 (s, 3H), 2.81–2.74 (m, 1H), 2.56–
2.50 (m, 1H), 2.36 (s, 3H). 13C NMR (100 MHz, CDCl3) d 157.6, 144.0, 137.6,
135.2, 134.9, 133.6, 129.8, 127.4, 118.7, 115.9, 113.0, 111.1, 64.2, 55.8, 35.3,
21.8. HRMS calcd for C18H19NO3S, 329.1086; found, 329.1084.
Acknowledgments
This work was supported by the National Nature Science Foun-
dation of China (No. 20772081) and Nippon Chemical Industrial