Palladium-catalyzed allylic alkylation using chiral P,O-ligands synthesized via sulfonamide directed ortho-lithiation

Article abstract of DOI:10.1016/j.tetlet.2014.02.040

An efficient approach for the synthesis of chiral P,O-ligands containing sulfonamide and phosphine moieties is designed. The introduction of the chirality is achieved through different stereogenic groups attached to the sulfonamide nitrogen. The highly ef

Full text of DOI:10.1016/j.tetlet.2014.02.040

Tetrahedron Letters 55 (2014) 2093–2096
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Tetrahedron Letters
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Palladium-catalyzed allylic alkylation using chiral P,O-ligands
synthesized via sulfonamide directed ortho-lithiation
⇑
Zhanina Petkova, Malinka Stoyanova, Vladimir Dimitrov
Institute of Organic Chemistry with Center of Phytochemistry, Bulgarian Academy of Science, Acad. G. Bonchev 9, Sofia 1113, Bulgaria
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient approach for the synthesis of chiral P,O-ligands containing sulfonamide and phosphine moi-
eties is designed. The introduction of the chirality is achieved through different stereogenic groups
attached to the sulfonamide nitrogen. The highly effective sulfonamide directed ortho-lithiation and
the subsequent reaction with ClPPh2 is the key step in the synthesis of the ligands. The prepared P,O-com-
pounds are applied in Pd-catalyzed asymmetric allylic alkylation (AAA) under optimized conditions, to
obtain high degrees of enantioselectivity.
Received 20 December 2013
Revised 24 January 2014
Accepted 12 February 2014
Available online 21 February 2014
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Chiral sulfonamides
Directed ortho-lithiation
P,O-ligands
Allylic alkylation
Phosphine ligands have been used in numerous catalytic appli-
cations. In particular, phosphines possessing chirality are of great
importance in different types of transition metal catalyzed trans-
formations (e.g., hydrogenations, isomerizations, CAC coupling
reactions, etc.).1 A growing interest has been directed toward the
synthesis and application of phosphine ligands containing addi-
tional functionality, as in the case of the mixed amido-phosphine
compounds that combine the properties of hard and soft donor li-
gands. These types of ligands offer the opportunity of ‘fine-tuning’
of ligand-to-metal binding properties and thus have significant
influence on the catalytic activity of the corresponding complexes.
A comprehensive review analyzing the results in this area was
published in 2012.2 In previous studies, we were interested in
the synthesis of chiral amido-phosphine derivatives for two rea-
sons: firstly, to use them as chiral ligands for Pd-catalyzed CAC
bond-forming reactions, and secondly to study the ortho-directing
ability, and in some cases the diastereoselectivity induced by the
chiral amido group in lithiation reactions.3 Considering the litera-
ture data in respect of ortho-directing groups for lithiation reac-
tions the application of the sulfonamide group attracts
considerable interest as a powerful auxiliary for Directed ortho
Metalation (DoM) of aromatic compounds.4 This selective metala-
tion reaction using butyllithium reagents offers various synthetic
opportunities to obtain sulfonamide ligands in a subsequent
treatment of the lithiated intermediate with suitable phospho-
rus-containing electrophiles. The DoM by means of a sulfonamide
group has been utilized in different types of synthetic applica-
tions.5 It is interesting to note that the sulfonamide functionality
has not been used as a directing group for the synthesis of chiral
phosphine ligands. There is only one report on the synthesis of a
nonchiral sulfonamide-phosphine ligand through DoM, and its
subsequent application in Suzuki–Miyaura cross-couplings.6 On
the other hand, there are several reports on the application of sul-
fonamide–phosphine derivatives possessing chirality.7 However,
these ligands have been synthesized by other synthetic methods
and not using the DoM approach. Herein, we present a viable syn-
thesis of a series of chiral sulfonamide-phosphine ligands via
highly efficient DoM and their application in Pd-catalyzed asym-
metric allylic substitutions.
The chiral tertiary sulfonamides serving as precursors of the
chiral P,O-ligands were synthesized in two steps, starting from
benzenesulfonyl chloride (1). In the first step, the sulfonamides
3a–f were prepared using 1 and a series of chiral amines 2a–f
(Scheme 1).8 The reactions were carried out under standard
conditions (DIPEA/CH2Cl2) leading to almost quantitative
conversions.
The selected chiral amines were commercially available with
the exception of 2c and 2d. The synthesis of amines 2c and 2d
was realized utilizing known procedures.9,10 Amine 2c was formed
as a mixture of two diastereoisomers in 86:14 ratio. It was not
possible to separate them by column chromatography, therefore
the mixture was applied directly in the reaction with 1 forming
the desired sulfonamide in high yield (Scheme 2). The separation
of exo-3c and endo-3c was performed effectively by column
chromatography without mixed fractions. It is worth mentioning
⇑
Corresponding author. Tel.: +359 878940391.
E-mail address: vdim@orgchm.bas.bg (V. Dimitrov).
http://dx.doi.org/10.1016/j.tetlet.2014.02.040
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2094
Z. Petkova et al. / Tetrahedron Letters 55 (2014) 2093–2096
O
S
O
O
S
O
O O
R*
R*
S
DIPEA
CH2Cl2
NaH, EtI
Cl
N
N
+
R*NH2
H
THF or DMF
Et
1
2
3a-f
4a-f
NH2
OH
NH2
R*NH2 =
NH2
NH2
NH2
NH2
2c
Scheme 1. Synthesis of chiral tertiary sulfonamides 4a–f.
2a
2b
2d
2e
2f
Ph2P
O
S
O
O O
1
n-BuLi, -78 οC
R*
S
R*
H
N
H
N
N
N
+
+
THF
ClPPh2
S
S
2c
O
O
O O
4a-f
5a-f
exo-3c
endo -3c
95%
exo/endo = 90:10
Scheme 3. Synthesis of phosphine derivatives 5a–f by directed ortho-lithiation.
reactions proceeded in excellent yields (Table 1). No experimental
results have been obtained in respect of possible deprotonation at
the benzylic position in the case of 4e and 4f. However, this side
reaction could not be excluded, considering the observed decrease
of the yield in transforming 4e into 5e.
Scheme 2. Synthesis of secondary sulfonamides with camphene-based amine 2c.
that during the formation/separation process of 3c, the ratio of the
exo/endo diastereoisomers changed slightly in favor of exo-3c.
For the preparation of amine 2d an efficient procedure
providing the amino alcohol in two steps in high yield and ca.
90% diastereomeric purity of the di-exo-diastereoisomer was
utilized.10 We were able to synthesize the target compound in
90% diastereomeric purity (by NMR) in accordance with the pub-
lished data. It is necessary to mention that in the literature11 the
formation of all possible diastereoisomers of 2d has been de-
scribed. The crude amino alcohol 2d was used for the synthesis
of the sulfonamide 3d, which was isolated in 52% yield after col-
umn chromatography.
The subsequent alkylation of the secondary sulfonamides 3a–f
with EtI, using NaH as the deprotonating agent, afforded com-
pounds 4a–f in excellent yields (Scheme 1).8 All the reactions were
carried out under reflux conditions with a large excess of alkylating
reagent. The reactions performed at room temperature required
longer reaction times. The N-ethylation of sulfonamide 3c bearing
the camphane moiety proceeded very slowly in THF and the iso-
lated yield of 4c was relatively low (28%). However, performing
the reaction in dry DMF afforded the desired product in a consid-
erably higher yield (72%). The sulfonamide 3d was also alkylated
using DMF, but unexpectedly, in this case, the alkylation led to
the formation of two products: N-ethyl- and N,O-diethyl-deriva-
tives, and even a large excess of the alkylating reagent and a
prolonged reaction time (24 h) did not lead to a higher yield of
the dialkylated product. Both products, N-ethyl-4d (65%) and
N,O-diethyl-4d (35%), were isolated in pure form by column chro-
matography. The isolated N-alkylated product was applied in a
subsequent ethylation reaction to give an additional quantity of
N,O-diethyl-4d. Remarkably, the alkylation of N-ethyl-4d was
accomplished much faster, compared to its formation from 3d in
a mixture with the dialkylated product.
The next step in our work was to evaluate the synthesized chiral
diphenylphosphine sulfonamides as P,O-ligands in Pd-catalyzed
asymmetric allylic alkylation (AAA) of racemic (E)-1,3-diphenyl-
2-propenyl acetate. The active palladium(II) catalyst was generated
by the reaction of 6 mol % of the corresponding chiral ligand 5a–f
with 3 mol % of allylpalladium(II) chloride dimer. The reactions
were performed by varying the conditions with respect to the base,
solvent, and temperature (Table 2).13 Initially, following Trost’s
procedure,14 the nucleophile was generated in situ using
N,O-bis(trimethylsilyl)acetamide (BSA) and a catalytic amount of
potassium acetate in dichloromethane at room temperature. Under
these conditions, the reactions proceeded with excellent
conversions with all of the tested ligands 5a–f (Table 2). Ligand
exo-5c induced the highest enantioselectivity in favor of the
(S)-enantiomer (58% ee, Table 2, entry 5). Aiming toward the
achievement of higher enantioselectivity, exo-5c was used for
optimization of the reaction conditions. Catalytic reactions in two
different solvents (toluene and THF) were performed, however,
the resulting enantioselectivities were lower (15% and 31% ee,
respectively, Table 2, entries 6 and 7). Further, Cs2CO3 was
employed as a base15 instead of BSA/KOAc and the reaction was
conducted at room temperature in CH2Cl2. These reaction condi-
tions led to a promising result, that is, 77% ee (Table 2, entry 8).
This encouraged us to test the activity of exo-5c with the same base
at ꢀ5 °C which led to an increase of the enantioselectivity to 83%.
At this temperature, the reaction proceeded considerably slower,
0.5 h versus 24 h (Table 2, entries 8 and 9), while at ꢀ40 °C the
product was not formed at all. Following the Cs2CO3 protocol, fur-
ther catalytic reactions were performed at room temperature,
using ligands 5a, 5b, and 5d–f. In all cases, a slight increase in
the enantioselectivity was achieved (see Table 2).
In conclusion, we have described a very efficient and viable
approach for the synthesis of chiral P,O-ligands based on introduc-
tion of chirality within the sulfonamide group and Directed ortho
Metalation (DoM). The application of these ligands in Pd-catalyzed
allylic alkylation was high yielding leading, in some cases, to high
degrees of enantioselectivity (up to 83%). These promising results
should lead to further development in respect of chirality
modifications of the ligands and further catalytic processes.
The key stage of our synthetic strategy to produce chiral biden-
tate ligands was the introduction of a phosphine group. The prop-
erty of the sulfonamide moiety as an ortho-directing group in
aromatic systems4 was efficiently applied in the case of com-
pounds 4a–f. Thus, we successfully prepared chiral diphenylphos-
phine ligands 5a–f by reacting 4a–f with 1.2 equiv of n-BuLi and
subsequent treatment of the formed organolithium intermediate
with two equivalents of ClPPh2 (Scheme 3).12 In all cases, the

Z. Petkova et al. / Tetrahedron Letters 55 (2014) 2093–2096
2095
Table 1
Synthesis of chiral P,O-ligands via directed ortho-lithiation
Entry
Sulfonamide
Timea (h)
Product
Yieldb (%)
N
N
S
O O
S
1
1
70
93
O O
Ph2P
Ph2P
5a
4a
N
N
S
S
O
2
2
3
O
O
O
5b
4b
3'
6
5
4
3
2'
10"
1"
N
N
2"
S
3c
68
84
6"
9"
1
S
8"
2
O
O
Ph2P
Ph2P
7"
4"
O
O
3"
5"
5c
exo-
4c
exo-
3'
11"
6
12"
10"
O
5
4
3
2'
O
N
2"
N
3"
8"
S
1"
4c
2
1
S
2
7"
O
O
O
O
6"
9"
4"
5"
5d
2,3-exo-
2,3-exo-4d
N
S
N
S
5
6
0.7
4
69
98
O
O
O
O
O
Ph2P
Ph2P
4e
5e
N
N
S
S
O
O
O
4f
5f
a
b
c
Reaction time after addition of the electrophile, ClPPh2.
Isolated yield after purification by chromatography.
The arbitrary numbering given in entries 3 and 4 is used for NMR analysis.
Table 2
Palladium-catalyzed AAA of racemic (E)-1,3-diphenyl-2-propenyl acetate with dimethyl malonate
MeOOC
Ph
COOMe
Ph
OAc
Ph
CH2(COOMe)2
Ph
[Pd(η3-C3H5)Cl]2, L*
*
base, solvent
Entry
L⁄
Solvent
Base
Temp (°C)
Time (h)
Yieldc (%)
eed (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
5a
5a
5b
5b
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhCH3
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
BSA, KOAca
rt
rt
rt
rt
rt
rt
rt
rt
ꢀ5
ꢀ40
rt
rt
rt
rt
rt
rt
2
1
3
4
1
13
4
0.5
24
—
3
99
99
99
99
99
99
99
99
95
—
99
99
99
99
99
99
13 (R)
19 (R)
0
8 (S)
58 (S)
15 (S)
31 (S)
77 (S)
83 (S)
—
9 (R)
12 (R)
5 (S)
22 (S)
5 (R)
8 (R)
b
Cs2CO3
BSA, KOAca
b
Cs2CO3
exo-5c
exo-5c
exo-5c
exo-5c
exo-5c
exo-5c
2,3-exo-5d
2,3-exo-5d
4e
BSA, KOAca
BSA, KOAca
BSA, KOAca
b
Cs2CO3
b
Cs2CO3
b
Cs2CO3
BSA, KOAca
b
Cs2CO3
3
1
1
2
BSA, KOAca
b
4e
4f
4f
Cs2CO3
BSA, KOAca
b
Cs2CO3
2
a
b
c
Method A: 1 equiv substrate, 0.03 equiv [Pd(
Method B: 1 equiv substrate, 0.03 equiv [Pd(
Isolated yield of pure product after column chromatography.
g
g
3-C3H5)Cl]2, 0.06 equiv ligand, 3 equiv BSA, 3 equiv dimethylmalonate.
3-C3H5)Cl]2, 0.06 equiv ligand, 3 equiv Cs2CO3, 3 equiv dimethylmalonate.
d
Enantiomeric excess determined by HPLC analysis (Chiralpak IC chiral column). The absolute configuration was determined by comparison of the specific rotation with
the literature value.16

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Z. Petkova et al. / Tetrahedron Letters 55 (2014) 2093–2096
127.06 (C-2, C-20), 128.84 (C-3, C-30), 132.07 (C-4), 140.62 (C-1); MS (ESI) m/z
Acknowledgements
(rel.int): 366 (100, M+1); Anal. Calcd for C20H31NO3S: C, 65.72; H, 8.55; N, 3.83;
Found: C, 65.48; H, 8.18; N, 3.63.
Financial support from the National Science Fund of Bulgaria
(Projects ID09/0105 and DRNF02/13/2009) is greatly appreciated.
9. (a) Carman, R. M.; Greenfield, K. L. Aust. J. Chem. 1984, 37, 1785–1790; (b)
Ipaktschi, J. Chem. Ber. 1984, 117, 856–858.
10. Chen, Y. K.; Jeon, S.; Walsh, P. J.; Nugent, W. A. Org. Synth. 2005, 82, 87–92.
11. (a) Chittenden, R. A.; Cooper, G. H. J. Chem. Soc. C 1970, 49–54; (b) Gawley, R. E.;
Zhang, P. J. Org. Chem. 1996, 61, 8103–8112; (c) Cheng, G. I.; Shei, C. T.; Sung, K.
Chirality 2007, 19, 235–238.
References and notes
12. General procedure for the synthesis of ortho-diphenylphosphino-benzene
sulfonamides 5a–f: To a stirred solution of chiral sulfonamide 4a–f (1 equiv)
in THF at ꢀ78 °C, n-BuLi (1.1 equiv, 1.6 M solution in n-hexane) was added
dropwise. The solution was stirred at ꢀ78 °C for 1 h and quenched with ClPPh2
(2 equiv). The mixture was stirred at this temperature until completion of the
reaction, as monitored by the consumption of the starting sulfonamide (TLC).
The mixture was worked-up by filtration through Celite, which was then
washed with Et2O. The collected organic filtrates were concentrated and the
residue chromatographed. Data for exo-5c: Yield 68%; colorless crystals; mp
1. (a) Lu, Zh.; Ma, Sh. Angew. Chem., Int. Ed. 2008, 47, 258–297; (b) Alexakis, A.;
Bäckvall, J. E.; Krause, N.; Pàmies, O.; Diéguez, M. Chem. Rev. 2008, 108, 2796–
2823.
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2. Štepnicka, P. Chem. Soc. Rev. 2012, 41, 4273–4305.
3. (a) Stavrakov, G.; Philipova, I.; Ivanova, B.; Dimitrov, V. Tetrahedron: Asymmetry
2010, 21, 1845–1854; (b) Philipova, I.; Stavrakov, G.; Chimov, A.; Nikolova, R.;
Shivachev, B.; Dimitrov, V. Tetrahedron: Asymmetry 2011, 22, 970–979; (c)
Philipova, I.; Stavrakov, G.; Dimitrov, V. Tetrahedron: Asymmetry 2012, 23, 927–
930.
150–153 °C; ½a 2D0
ꢁ
= ꢀ31.50 (c 1, CHCl3); 1H NMR (600 MHz, CDCl3): d 0.84 (s,
4. Familoni, O. B. Synlett 2002, 1181–1210.
3H, 1000-H), 0.86 (s, 3H, 800-H), 0.97 (s, 3H, 900-H), 1.19 (t, 3H, 6-H, J = 7.0 Hz),
1.21–1.27 (m, 2H, 500-Hendo, 600-Hendo), 1.47–1.53 (m, 1H, 600-Hexo), 1.66–1.76 (m,
3H, 300-Hendo, 400-H, 500-Hexo), 1.94–1.99 (m, 1H, 300-Hexo), 3.30–3.37 (m, 1H, 5-H),
3.73–03.79 (m, 1H, 5-H), 4.41–4.47 (m, 1H, 200-H), 7.11 (ddd, 1H, 20-H, J = 7.7,
3.1, 1.3 Hz), 7.18–7.21 (m, 2H, PPh2) 7.22–7.26 (m, 2H, PPh2), 7.30–7.34 (m, 6H,
PPh2), 7.37 (ddd, 1H, 30-H, J = 8.8, 7.5, 1.4 Hz), 7.43 (ddd, 1H, 4-H, J = 8.8, 7.5,
1.3 Hz), 8.02 (ddd, 1H, 3-H, J = 7.8, 3.6, 1.3 Hz); 13C NMR (150 MHz, CDCl3): d
12.24 (C-1000), 17.31 (C-6), 21.42 (C-800), 21.65 (C-900), 26.30 (C-500), 35.14 (C-300),
38.82 (C-600), 39.78 (C-5), 44.72 (C-400), 46.57 (C-700), 50.08 (C-100), 65.76 (C-200),
128.44–128.59 (m, 6C, PPh2), 128.77 (d, C-4, JCP = 21.9 Hz), 130.01 (d, C-20,
JCP = 21.9 Hz), 131.71 (C-30), 133.65 (d, 2C, PPh2, JCP = 14.9 Hz), 133.79 (d, 2C,
PPh2, JCP = 14.7 Hz), 136.26 (C-3), 136.85 (d, C-2, JCP = 11.2 Hz), 137.38 (d, 1C,
PPh2, JCP = 28.96 Hz), 137.82 (d, 1C, PPh2, JCP = 14.01 Hz), 145.96 (d, C-1,
5. (a) Takahashi, H.; Tsubuki, T.; Higashiyama, K. Chem. Pharm. Bull. 1991, 39,
260–265; (b) Aliyenne, A. O.; Khiari, J. E.; Kraïem, J.; Kacem, Y.; Hassine, B. B.
Tetrahedron Lett. 2006, 47, 6405–6408; (c) Liu, Z. P. Heterocycles 2007, 71, 1843–
1849; (d) Liu, Z.; Takeuchi, Y. Heterocycles 2009, 78, 1387–1412; (e) Xie, F.; Gao,
B. L.; Wang, D. F.; Liu, Z. P. Lett. Org. Chem. 2010, 7, 332–334; (f) Schneider, C.;
Broda, E.; Snieckus, V. Org. Lett. 2011, 13, 3588–3591.
6. Chapman, C. J.; Frost, C. G.; Mahon, M. F. Dalton Trans. 2006, 2251–2262.
7. (a) Hiroi, K.; Hidaka, A.; Sezaki, R.; Imamura, Y. Chem. Pharm. Bull. 1997, 45,
769–777; (b) Ho, D. E.; Betancort, J. M.; Woodmansee, D. H.; Larter, M. L.;
Walsh, P. J. Tetrahedron Lett. 1997, 38, 3867–3870; (c) Ongeri, S.; Piarulli, U.;
Roux, M.; Monti, C.; Gennari, C. Helv. Chim. Acta 2002, 85, 3388–3399; (d) Yu, S.
L.; Li, Y. Y.; Dong, Z. R.; Zhang, J. N.; Li, Q.; Gao, J. X. Chin. Chem. Lett. 2011, 22,
1269–1272; (e) Wei, M. M.; García-Melchor, M.; Daran, J. C.; Audin, C.; Lledós,
A.; Poli, R.; Deydier, E.; Manoury, E. Organometallics 2012, 31, 6669–6680.
8. General procedure for the synthesis of chiral sulfonamides 3a–f and 4a–f: To a
stirred, cold (ice bath) solution of benzenesulfonyl chloride (1 equiv) in CH2Cl2
were added DIPEA (1 equiv) and the corresponding chiral amine 2a–f
(1.1 equiv). The ice bath was removed and the mixture was allowed to warm
to room temperature and stirred until the sulfonyl chloride had been
completely consumed (TLC). The mixture was washed with H2O (100 mL),
and the organic phase dried (Na2SO4), and concentrated. The residue was
purified by flash chromatography on silica gel to give the corresponding target
JCP = 24.93 Hz); 31P NMR (250 MHz, CDCl3):
d
ꢀ6.10 (s); MS (ESI) m/z
(rel.int): 506 (94, M+1), 370 (100). Data for 2,3-exo-5d: Yield 84%; colorless
crystals; mp 51–56 °C; ½a D20
ꢁ
= +20.30 (c 1, CHCl3); 1H NMR (600 MHz, CDCl3): d
0.70 (s, 3H, 900-H), 0.75 (t, 3H, 6-H, J = 6.36 Hz), 1.07 (s, 3H, 1000-H), 1.01–1.06
(m, 2H, 500-Hendo, 600-Hendo), 1.07 (s, 3H, 800-H), 1.23 (t, 3H, 1200-H, J = 6.9 Hz),
1.34–1.43 (m, 1H, 500-Hexo), 1.59–1.66 (m, 1H, 600-Hexo), 1.89 (d, 1H, 400-H,
J = 4.2 Hz), 3.17 (d, 1H, 300-H, J = 7.3 Hz), 3.22 (q, 1H, 5-Ha, J = 7.1 Hz), 3.30 (q,
1H, 1100-Ha, J = 7.0 Hz), 3.36–3.44 (m, 2H, 5-Hb, 1100-Hb), 4.11 (dd, 1H, 200-H,
J = 7.3, 1.7 Hz), 7.11 (ddd, 1H, 3-H, J = 7.5, 3.1, 1.3 Hz), 7.14–7.17 (m, 2H, PPh2)
7.20–7.25 (m, 8H, PPh2), 7.29 (ddd, 1H, 4-H, J = 8.9, 7.5, 1.4 Hz), 7.34 (ddd, 1H,
30-H, J = 8.8, 7.9, 1.4 Hz), 7.90 (ddd, 1H, 20-H, J = 7.8, 3.7, 1.3 Hz); 13C NMR
(150 MHz, CDCl3): d 11.76 (C-1000), 15.12 (C-6), 15.61 (C-1200), 21.68 (C-900),
21.80 (C-800), 28.95 (C-600), 32.33 (C-500), 42.31 (C-1100), 47.26 (C-700), 48.01 (C-
400), 49.77 (C-100), 66.22 (C-200), 68.27 (C-5), 90.61 (C-300), 128.42 (d, 6C, PPh2,
JCP = 6.9 Hz), 128.66, (d, C-30, JCP = 7.1 Hz), 128.88 (d, C-20, JCP = 4.5 Hz), 131.27
(C-4), 133.65 (d, 2C, PPh2, JCP = 20.1 Hz), 133.85 (d, 2C, PPh2, JCP = 20.5 Hz),
136.67 (C-3), 136.98 (d, 1C, PPh2, JCP = 13 Hz), 137.30 (d, 1C, PPh2, JCP = 13 Hz),
137.75 (C-2), 146.53 (C-1); 31P NMR (250 MHz, CDCl3): d ꢀ9.22 (s); MS (ESI) m/
z (rel.int): 550 (89, M+1), 325 (100).
products (sulfonamides 3a–f).
A solution of the corresponding secondary
sulfonamide 3a–f (1 equiv) in THF was cooled in an ice bath and then NaH
(2.2 equiv) was added, followed by EtI (20 equiv). After 5 min, the ice bath was
removed, and the mixture was allowed to warm to room temperature and
stirred until the starting material had been completely consumed (TLC). The
mixture was quenched with sat. aq NH4Cl, and extracted with CH2Cl2. The
organic phase was dried (Na2SO4) and concentrated. The crude product was
purified by flash chromatography. Data for exo-4c: Yield 72%; colourless oil;
1
½
a 2D0
ꢁ
= ꢀ28.26 (c 1, CHCl3); H NMR (600 MHz, CDCl3): d 0.80 (s, 3H, 1000-H),
0.84 (s, 3H, 8-H), 0.91 (s, 3H, 9-H), 1.12–1.17 (m, 1H, 500-Hendo), 1.20–1.22 (m,
1H, 600-Hendo), 1.28 (t, 3H, 6-H, J = 7.0 Hz), 1.40 (dd, 1H, 300-Hendo, J = 12.6,
9.5 Hz), 1.51–1.56 (m, 1H, 600-Hexo), 1.67–1.75 (m, 2H, 400-H, 500-Hexo), 1.78–1.83
(m, 1H, 300-Hexo), 3.19 (q, 1H, 5-H, J = 7.0 Hz), 3.40 (q, 1H, 5-H, J = 7.0 Hz), 3.95–
3.98 (m, 1H, 200-H), 7.47–7.50 (m, 2H, 2-H), 7.53–7.56 (m, 1H, 4-H) 7.80–7.82
(m, 2H, 2-H); 13C NMR (150 MHz, CDCl3): d 12.01 (C-1000), 17.54 (C-6), 21.15 (C-
800), 21.61 (C-900), 26.30 (C-500), 34.64 (C-300), 39.16 (C-600), 39.44 (C-5), 44.65
(C-400), 46.30 (C-700), 49.85 (C-100), 65.97 (C-200), 127.00 (C-2, C-20), 128.93 (C-3,
C-30), 132.13 (C-4), 141.15 (C-1); MS (ESI) m/z (rel. int.): 322 (20, M+1), 137
(100); Anal. Calcd for C18H27NO2S: C, 67.25; H, 8.47; N, 4.36; Found: C, 67.48;
13. General procedure for the palladium-catalyzed allylic alkylation; Method A: A
solution of [Pd(g
3-C3H5)Cl]2 (3 mol %), ligand 4a–f (6 mol %), and anhydrous
KOAc (5 mol %) in dry CH2Cl2 (2 mL) was stirred at room temperature in a
Schlenk tube for 1 h. Then rac-1,3-diphenylprop-2-en-1-yl acetate (1 equiv),
BSA (3 equiv), and dimethyl malonate (3 equiv) were added. Method B: A
solution of [Pd(g
3-C3H5)Cl]2 (3 mol %) and ligand 4a–f (6 mol %) in dry CH2Cl2
(2 mL) was stirred at room temperature in a Schlenk tube for 1 h. Then rac-1,3-
diphenylprop-2-en-1-yl acetate (1 equiv), dimethyl malonate (3 equiv), and
Cs2CO3 were added. The mixture was stirred at room temperature and
monitored by TLC. The mixture was diluted with Et2O (30 mL) and washed
with sat. aq. NH4Cl solution. The organic phase was dried (Na2SO4), filtered,
and concentrated. The residue was purified by flash chromatography (silica gel,
hexane/EtOAc = 4.6:0.4). The enantioselectivity was determined by HPLC
analysis on a chiral column Chiralpak IC; hexane/i-PrOH, 96:4; flow rate,
1 mL/ min; t(R) = 9.421 min; t(S) = 10.817 min.
H, 8.18; N, 4.33. Data for 2,3-exo-4d: Yield 35%; colourless oil; ½a D20
ꢁ
= +6.37 (c
0.80, CHCl3); 1H NMR (600 MHz, CDCl3): d 0.76 (s, 3H, 900-H), 0.92 (s, 3H, 1000-H),
0.94–0.98 (m, 1H, 600-Hendo), 1.05 (t, 3H, 6-H, J = 7.0 Hz), 1.09–1.14 (m, 1H, 500-
H
endo), 1.12 (s, 3H, 800-H), 1.29 (t, 3H, 1200-H, J = 6.9 Hz), 1.43–1.48 (m, 1H,
500-Hexo), 1.65–1.71 (m, 1H, 600-Hexo), 1.76 (d, 1H, 400-H, J = 4.2 Hz), 3.16 (q, 1H,
1100-Ha, J = 6.9 Hz), 3.26 (q, 1H, 1100-Hb, J = 6.9 Hz), 3.28 (d, 1H, 300-H, J = 7.2 Hz),
3.46 (q, 1H, 5-Ha, J = 7.0 Hz), 3.74 (q, 1H, 5-Hb, J = 7.0 Hz), 3.86 (d, 1H, 200-H,
J = 7.2 Hz), 7.47–7.50 (m, 2H, 3-H, 30-H), 7.52–7.55 (m, 1H, 4-H), 7.86–7.87 (m,
14. Trost, B. M.; Murphy, D. J. Organometallics 1985, 4, 1143–1145.
15. Lyle, M. P. A.; Narine, A. A.; Wilson, P. D. J. Org. Chem. 2004, 69, 5060–5064.
16. Hayashi, T.; Yamamoto, A.; Hagihara, T.; Ito, Y. Tetrahedron Lett. 1986, 27, 191–
194.
13
2H, 2-H, 20-H); C NMR (150 MHz, CDCl3): d 11.71 (C-1000), 15.25 (C-6), 16.11
(C-1200), 21.68 (C-900), 21.97 (C-800), 29.36 (C-600), 32.37 (C-500), 42.19 (C-5), 47.25
(C-700), 47.71 (C-400), 49.57 (C-100), 68.89 (C-200), 68.53 (C-1100), 90.80 (C-300),