High performance of a palladium phosphinooxazoline catalyst in the asymmetric arylation of cyclic N-sulfonyl ketimines

Article abstract of DOI:10.1002/anie.201406147

A cationic palladium complex with a chiral phosphine-oxazoline ligand (iPr-phox) showed high catalytic activity and enantioselectivity in the asymmetric addition of arylboronic acids to six-membered cyclic N-sulfonyl ketimines to give high yields of the corresponding chiral cyclic sulfamidates with 96-99.9 % ee. The products have tetrasubstituted stereogenic centers with an amino group and a triaryl or alkyldiaryl group as substituents.

Full text of DOI:10.1002/anie.201406147

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Angewandte
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DOI: 10.1002/anie.201406147
Asymmetric Catalysis
High Performance of a Palladium Phosphinooxazoline Catalyst in the
Asymmetric Arylation of Cyclic N-Sulfonyl Ketimines**
Chunhui Jiang, Yixin Lu,* and Tamio Hayashi*
Abstract: A cationic palladium complex with a chiral phos-
phine-oxazoline ligand (iPr-phox) showed high catalytic
activity and enantioselectivity in the asymmetric addition of
arylboronic acids to six-membered cyclic N-sulfonyl ketimines
to give high yields of the corresponding chiral cyclic sulfami-
dates with 96–99.9% ee. The products have tetrasubstituted
stereogenic centers with an amino group and a triaryl or
alkyldiaryl group as substituents.
T
he rhodium- or palladium-catalyzed asymmetric addition
of arylboron reagents to imines is one of the most efficient
methods of producing chiral disubstituted and trisubstituted
methylamines.[1,2] Among the imines used for the asymmetric
arylation, cyclic N-sulfonyl imines have recently attracted
considerable attention owing to their advantages over others;
they have generally higher reactivity towards the catalytic
arylation and their cyclic structure makes the enantioface
differentiation of imines easier and simpler because no syn–
anti equilibration takes place.[3–6] A summary of the catalytic
asymmetric arylation reactions of cyclic N-sulfonyl imines
reported to date with rhodium (Hayashi,[3] Lam,[4] Xu[5]) and
palladium (Zhang)[6] complexes as catalysts is illustrated in
Scheme 1. The cyclic N-sulfonyl imines used as the arylation
substrates are classified into aldimines and ketimines, of
which the former are in general more reactive than the latter
and some of the ketimines substituted with electron-with-
drawing groups such as ester and CF3 are as reactive as
aldimines. The cyclic N-sulfonyl imines used so far are either
five-membered ring imines leading to benzosultams or six-
membered ring imines 1 leading to benzosulfamidates.
Although the five-membered ring imines are highly reactive,
giving the corresponding sultams upon arylation even for
ketimines, the ring cleavage giving the corresponding chiral
methylamines without loss of enantiomeric purity is not
trivial.[3a] On the other hand, the six-membered imines 1 are
less reactive toward the arylation, whereas the resulting
Scheme 1. Reactivity and utility of cyclic N-sulfonyl imines.
sulfamidates are known to undergo ring opening without loss
of enantiomeric purity.[3a,4a,5b,7] To date there have been very
few reports on the catalytic asymmetric addition to six-
membered ketimines 1 (R = alkyl, aryl) in high yields.[3–6]
During our studies on the catalytic asymmetric addition of
organoboron reagents to carbon–carbon and carbon–hetero-
atom double bonds,[8,9] we found that a cationic palladium
complex containing a chiral phosphine-oxazoline ligand
showed high catalytic activity and high enantioselectivity in
the asymmetric addition of arylboronic acids to cyclic N-
sulfonyl ketimines 1 (R = alkyl, aryl), giving high yields of the
corresponding chiral cyclic sulfonamides, which bear a tetra-
substituted stereogenic center.[10]
The results obtained for the addition of phenylboronic
acid (2m) to N-sulfonyl aldimine 1a (R = H) and ketimine 1b
(R = Me) in the presence of a cationic palladium complex
coordinated with (S)-iPr-phox[11] are summarized in Table 1.
For comparison, this Table also contains the results of
reactions in the presence of other palladium and rhodium
complexes, which have been previously reported as effective
catalysts for the asymmetric arylation of N-sulfonyl imines.
The best result was obtained with the catalyst generated
in situ from PdCl2[(S)-iPr-phox][12] and AgBF4 in dichloro-
ethane. Thus, aldimine 1a was reacted with 2m (2 equiv
relative to 1a) in the presence of 5 mol% of the cationic
palladium catalyst in dichloroethane at 65–708C for 12 h to
give a quantitative yield of the R isomer[5a] of the phenylation
product 3am with 99.6% ee (entry 1). The same conditions
[*] C. Jiang, Prof. Dr. Y. Lu, Prof. Dr. T. Hayashi
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
E-mail: chmlyx@nus.edu.sg
chmtamh@nus.edu.sg
Prof. Dr. T. Hayashi
Institute of Materials Research and Engineering
A*STAR, 3 Research Link, Singapore 117602 (Singapore)
E-mail: tamioh@imre.a-star.edu.sg
[**] We thank the National University of Singapore and the Ministry of
Education (MOE) of Singapore (R-143-000-362-112 and R-143-000-
539-133) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201406147.
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Table 1: Catalytic asymmetric addition of phenylboronic acid (2m) to
cyclic N-sulfonyl aldimine 1a and ketimine 1b.[a]
(OCOCF3)2 and (S)-iPr-phox efficiently catalyzed the phenyl-
ation of aldimine 1a in CF3CH2OH at 808C, but its catalytic
activity was lower for ketimine 1b, giving a modest yield
(58%) of (R)-3bm although the enantioselectivity was high
(99.8% ee) (entry 4). Cationic palladium bisphosphine com-
plexes[13] generated by mixing PdCl2[(S,S)-chiraphos] and
PdCl2[(S)-binap] with AgBF4 were less catalytically active
than that with the phosphine-oxazoline, (S)-iPr-phox, as
a ligand. They catalyzed the phenylation of aldimine 1a to
some extent, but did not convert ketimine 1b (entries 5 and
6). Palladium complexes with the chiral oxazoline-pyridine
ligand (S)-iPr-pyrox and its derivatives, have been reported by
Zhang and co-workers to be catalytically active for the
addition to five-membered-ring ketimines.[6] In our hands, the
palladium catalyst system described by Zhang and co-work-
ers, Pd(OCOCF3)2 and (S)-iPr-pyrox in CF3CH2OH, did not
catalyze the phenylation of ketimine 1b well,[14,15] whereas it
was highly active in the phenylation of aldimine 1a (entry 7).
A cationic palladium complex generated by the addition of
AgBF4 to PdCl2[(S)-iPr-pyrox] also catalyzed the addition to
aldimine 1a very efficiently, but was not active for ketimine
1b in either CF3CH2OH or dichloroethane (entries 8 and 9).
Chiral diene/rhodium catalysts, which we previously reported
to be the most active in the asymmetric arylation of ketimines
including the five-membered-ring ketimines, catalyzed the
phenylation of aldimine 1a to give 3am with high ee and
a quantitative yield (entries 10 and 11). They also catalyzed
the asymmetric phenylation of ketimine 1b with high
enantioselectivity, but the yields of 3bm are not as high as
those obtained with the present cationic palladium/(S)-iPr-
phox catalyst. The binap–rhodium catalyst was less active
than the diene–rhodium as was reported previously[3a]
(entry 12).
By monitoring the reaction progress of the palladium-
catalyzed addition of boron reagents to ketimine 1b to
compare the Pd/phox catalyst with the Pd/pyrox catalyst
(entry 1 versus 7), we found that the low yield with the Pd/
pyrox catalyst is mainly due to the short lifetime of the
catalyst system. Thus, the reaction with Pd/pyrox catalyst gave
7% yield of the product 3bm within 10 min, but the yield did
not increase after a reaction time of 10 min. In contrast, the
Pd/phox catalyst was found to keep its high catalytic activity
for at least one hour to give a high yield of 3bm.
The cationic palladium catalyst generated from PdCl2[(S)-
iPr-phox] and AgBF4 was widely applicable in the asymmetric
addition of arylboronic acids to the methyl-substituted
ketimine 1b (Table 2). The addition of phenylboronic acids
with a substituent (methyl, phenyl, phenoxy, and halides) at
the para position gave the corresponding arylation products in
high enantioselectivities (> 98% ee) and yields (entries 3, 5–
8). For those arylboronic acids which are not reactive enough
to give high yields of the arylation products under the
standard conditions (conditions A), the use of AgSbF6 and
K3PO4 as additives (conditions B) increased the chemical
yields and maintained the high enantioselectivity. The effects
of the additives are summarized in entries 12–15 for the
addition of 3-MeOC6H4B(OH)2 (2w) to ketimine 1b. The
reaction under the reaction conditions A (AgBF4) gave only
a modest yield (56%) of the arylation product 3bw, though
Catalyst [5 mol%]
additives
Solvent
3am
3bm
T [8C], t [h] Yield[b] (ee[c]) Yield[b] (ee[c])
1
2
3
4
5
6
7
8
9
PdCl2[(S)-iPr-phox]
AgBF4
PdCl2[(S)-iPr-phox]
ClCH2CH2Cl 99%
99%
65–70, 12 (99.6% ee, R) (99.5% ee, R)
ClCH2CH2Cl 0%
65–70, 12 (–)
ClCH2CH2Cl 10%
65–70, 12 (–)
CF3CH2OH 99%
80, 20 (92% ee, R)
0%
(–)
0%
(–)
58%
(99.8% ee, R)
0%
(–)
0%
(–)
7%
(–)
0%
(–)
0%
(–)
76%
PdCl2[(S)-iPr-phox]
AgOTf
Pd(OCOCF3)2
(S)-iPr-phox
PdCl2[(S,S)-chiraphos] ClCH2CH2Cl 50%
AgBF4
PdCl2[(S)-binap]
AgBF4
Pd(OCOCF3)2
(S)-iPr-pyrox
PdCl2[(S)-iPr-pyrox]
AgBF4
65–70, 12
(84% ee, S)
ClCH2CH2Cl 42%
65–70, 12
(94% ee, S)
CF3CH2OH 90%
80, 20
(68% ee, R)
CF3CH2OH 99%
80, 20
(77% ee, R)
PdCl2[(S)-iPr-pyrox]
AgBF4
ClCH2CH2Cl 99%
65–70, 12
(80% ee, R)
99%
10 [RhCl((R,R)-Ph-bod)]2 dioxane
K3PO4, t-amyl alcohol 60, 12
11 [RhCl((R)-diene*)]2
K3PO4, t-amyl alcohol 60, 12
12 [RhCl((S)-binap)]2 dioxane
K3PO4, t-amyl alcohol 60, 12
(98.0% ee, R) (97.0% ee, R)
99% 30%
(99.6% ee, R) (99.3% ee, R)
dioxane
26%
(89% ee, S)
<3%
(–)
[a] Reaction conditions: 1a (0.10 mmol), 2m (0.20 mmol), catalyst
(5 mol%), additive, solvent (1.0 mL) at a given temperature for 12 h.
[b] Yield of isolated 3am or 3bm. [c] Determined by HPLC analysis with
a chiral stationary phase. The absolute configurations of 3am and 3bm
were determined by comparison of their optical rotations with those
reported.[5a,6]
were successfully applied to the reaction of ketimine 1b,
which gave the corresponding phenylation product (R)-3bm[6]
in 99.5% ee and a quantitative yield (entry 1). The generation
of the cationic palladium species is essential for the high
catalytic activity. In the absence of AgBF4, no phenylation
was observed for either aldimine 1a or ketimine 1b (entry 2).
Using AgOTf as the silver salt is not a good choice and
resulted in a low yield (10%) of 3am and no reaction to 3bm
(entry 3).
A palladium complex generated from Pd-
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the enantioselectivity was high (99.5% ee). With AgSbF6
(conditions C) the yield was increased to 90%, but the
product was racemic. This is probably due to acid-contami-
nated AgSbF6, which causes the racemization of the product
via a benzylic cation intermediate. Addition of K3PO4 as
a weak base together with AgSbF6 inhibited the racemization
and resulted in a high yield and ee of 3bw. The combination of
K3PO4 and AgBF4 did not improve the yield of the product.
Under the reaction conditions B, meta- and ortho-substituted
phenylboronic acids gave the corresponding arylation prod-
ucts with high ee (entries 16–18). The high catalytic activity
and high enantioselectivity were also observed in the addition
of boronic acids to cyclic ketimines 1c and 1d, which are ethyl
and pentyl imines, respectively (entries 19–21).
Table 2: Palladium-catalyzed asymmetric addition of arylboronic acids
2m–z to cyclic N-sulfonyl ketimines 1b–d.[a]
The asymmetric addition of boron reagents to cyclic
ketimines with aryl groups on the imine carbon is more
challenging, because these ketimines are less reactive than
those with alkyl groups, and the arylation products (triaryl-
methylamines) are more likely to undergo racemization
under the reaction conditions (Table 3). The reaction of
1, conditions[b] ArB(OH)2 2
3, yield [%][c] ee [%][d]
Table 3: Palladium-catalyzed asymmetric addition of arylboronic acids 2
to cyclic N-sulfonyl aryl ketimines 1e–g.[a]
1
2
1b, A
1b, B
3bm, 99
3bm, 99
99.5 (R)
99.6 (R)
3
4
5
6
7
8
9
1b, A
1b, A
1b, B
1b, A
1b, A
1b, A
1b, A
3bn, 99
3bo, 99
3 bp, 99
3bq, 99
3br, 87
3bs, 88
3bt, 95
3bu, 51
98.1 (R)
98.8 (R)
99.9 (R)
98.6 (R)
98.4 (R)
99.4 (R)
99.9 (R)
99.4 (R)
10 1b, B
11 1b, A
1, additive
Ar2B(OH)2 2
3, yield [%][b] ee [%][c]
3bv, 99
99.4 (R)
1
2
3
4
5
1e, –
3ep, 75
3ep, 73
3ep, 70
3ep, 63
3ep, 80
0
0
0
81
99.2
1e, K3PO4
1e, K2CO3
1e, NEt3
12 1b, A
13 1b, B
14 1b, C[e]
15 1b, D[e]
3bw, 56
3bw, 88
3bw, 90
3bw, 48
99.5 (R)
99.9 (R)
0
1e, proton sponge
99.7 (R)
6
7
8
1 f, proton sponge
1g, proton sponge
1g, proton sponge
3 fp, 65
3gp, 75
3gn, 68
99.6
96
16 1b, B
17 1b, B
18 1b, B
3bx, 95
3by, 98
3bz, 51
99.7 (R)
99.9 (R)
99.9 (R)
97
[a] Reaction conditions: 1 (0.10 mmol), 2 (0.20 mmol), PdCl2[(S)-iPr-
phox] (10 mol%), AgSbF6 (30 mol%), additive (30 mol%), dichloro-
ethane (1.0 mL) at 65–708C for 12 h. [b] Yield of isolated product.
[c] Determined by HPLC analysis with a chiral stationary phase.
19 1c, B
20 1c, A
21 1d, A
3cm, 99
3cn, 99
3dm, 99
99.5 (R)
99.5 (R)
99.4 (R)
ketimine 1e with 4-methoxyphenylboronic acid (2p) in the
presence of PdCl2[(S)-iPr-phox] (10 mol%) and AgSbF6
(30 mol%) proceeded well to give the corresponding aryla-
tion product 3ep in 75% yield as a racemate (entry 1). The
formation of racemic product was also observed in the
presence of the inorganic base K3PO4 (30 mol%), which
corresponds to conditions B in Table 2, or K2CO3 (entries 2
and 3).[16] Finally, it was found that the addition of proton
sponge prevents the product from racemization under the
reaction conditions (entry 5). In the presence of proton
[a] Reaction conditions: 1 (0.10 mmol), 2 (0.20 mmol), PdCl2[(S)-iPr-
phox] (5 mol%), additive, dichloroethane (1.0 mL) at 65–708C for 12 h.
[b] Conditions A: AgBF4 (15 mol%). Conditions B: AgSbF6 (15 mol%)
and K3PO4 (15 mol%). [c] Yield of the isolated product. [d] Determined
by HPLC analysis with a chiral stationary phase. The absolute config-
urations are proposed to be R by similarity of the stereochemical pathway
to that giving (R)-3bm. [e] Conditions C: AgSbF6 (15 mol%). Condi-
tions D: AgBF4 (15 mol%) and K3PO4 (15 mol%).
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sponge, several triarylmethylamine products were obtained
with high enantioselectivity (entries 6–8).
Treatment of the asymmetric arylation products 3cn and
3gn with LiAlH4 gave the corresponding 2-hydroxyphenyl-
methylamines 4cn and 4gn, respectively, without loss of their
enantiomeric purity (Scheme 2).[7b]
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Scheme 2. Ring opening of the asymmetric arylation products 3.
[9] For a review on the palladium-catalyzed asymmetric addition of
arylboron reagents, see: Y.-W. Sun, P.-L. Zhu, Q. Xu, M. Shi,
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In summary, a cationic palladium complex with a chiral
phosphine-oxazoline ligand (iPr-phox) showed high catalytic
activity and enantioselectivity in the asymmetric addition of
arylboronic acids to six-membered cyclic N-sulfonyl keti-
mines to give the chiral cyclic sulfamidates in high yields and
with 96–99.9% ee. The products bear a tetrasubstituted
stereogenic center.
[10] A chiral phosphinooxazoline-palladium complex has been used
as a catalyst for the asymmetric addition of arylboronic acids to
isatins: Q. Li, P. Wan, S. Wang, Y. Zhuang, L. Lia, Y. Zhou, Y.
He, R. Cao, L. Qiu, Z. Zhou, Appl. Catal. A 2013, 458, 201.
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Mahon, M. E. Humphries, J. M. J. Williams, Chem. Eur. J. 2000,
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[13] Cationic bisphosphine-palladium catalysts have been used for
the conjugate addition of boron reagents to a,b-unsaturated
carbonyl compounds; for reviews, see: a) A. Gutnov, Eur. J. Org.
Chem. 2008, 4547; b) Y. Yamamoto, T. Nishikata, N. Miyaura, J.
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Hayashi, Boronic Acids, Vol. 1, 2nd ed. (Ed.: D. G. Hall), Wiley-
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Received: June 12, 2014
Published online: July 18, 2014
Keywords: arylboronic acids · asymmetric arylation ·
.
chiral amines · palladium · cyclic sulfonyl ketimines
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a chiral pyridyloxazoline-palladium
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complex in a sealed tube charged with oxygen at 808C for 48 h
gave 58% yield of the corresponding benzosulfamidate
(95% ee).
[15] A palladium complex coordinated with chiral pyridinooxazoline
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[16] The racemization of arylation product 3ep under the reaction
conditions was confirmed experimentally by exposing enantio-
merically enriched 3ep (99.2% ee) to the reaction conditions of
entry 3 in Table 3, which resulted in the complete racemization
of 3ep.
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