Hg(OTf)2-BINAPHANE-catalyzed enantioselective anilino sulfonamide allyl alcohol cyclization

Article abstract of DOI:10.1002/chem.201001656

Chiral ligands: Hg(OTf)₂-catalyzed cyclization of anilino sulfonamide allyl alcohol is described; this reaction gives 2-vinyl indoline derivatives in good yields and excellent enantioselectivity by using a chiral BINAPHANE ligand (see scheme).

Full text of DOI:10.1002/chem.201001656

COMMUNICATION
DOI: 10.1002/chem.201001656
HgACHTUNGTRENNUNG
Hirofumi Yamamoto,*[a] Elisabeth Ho,[a] Kosuke Namba,[b] Hiroshi Imagawa,[a] and
[a]
Mugio Nishizawa†
Direct allylic amination of allylic alcohols with amine nu-
cleophiles to produce water as the only byproduct is one of
the most attractive reactions in modern organic synthesis.[1]
Therefore, significant resources have been devoted to devel-
oping the latent ability of transition-metal reagents with the
aim of achieving allylic amination from allylic alcohols in
high catalytic turnover.[2,3] Recently, Shibasaki, Matsunaga,
and co-workers reported the direct allylic amination with
doline 2 in 99% yield [Eq. (1), Scheme 1]. Because a new
chiral center is generated, we decided to perform the reac-
tion in the presence of chiral auxiliaries. We found that BI-
NAPHANE[10] provides effective chiral induction (up to
99% ee) during the conversion of 4 to 5 [Eq. (2)]. Although
asymmetric oxymercuration of alkene has already been re-
ported,[11] mercuric salt catalyzed asymmetric reactions are
seldom described in the literature.[12]
sulfonamides by using a catalytic amount of BiACTHUNRGTNEUNG(OTf)3 and
KPF6 under mild reaction conditions.[2b] Although intermo-
lecular allylic aminations are well-established reactions,
[PdCl2ACHTUNGTRENNUNG(MeCN)2] has been used exclusively as the catalyst
for intramolecular N-cyclization of amino allylic alcohols.[4]
Moreover, no catalytic enantioselective cyclization of amino
allylic alcohol has been reported thus far.[5]
We have developed mercuric triflate [HgACTHNURTGNENG(U OTf)2] as a key
catalyst for organic synthesis[6] by achieving the hydration of
terminal alkynes to methyl ketones in high catalytic turn-
over.[7] Indeed, enyne cyclization, arylyne cyclization, and
indole synthesis have been developed based on the signifi-
cant affinity of HgACHTUNGTRENNUNG
(OTf)2 for the alkyne group.[8] Recently
the procedure has expanded to include alkene cyclization by
the introduction of an allylic hydroxyl moiety as the leaving
group, thereby triggering the smooth demercuration step
that regenerates the catalyst.[9] The reaction of anilino sul-
Scheme 1. Catalytic cyclization of anilino sulfonamide allylic alcohol to 2-
vinyl indoline derivative. Tf=trifluoromethanesulfonyl; Ts=para-tolu-
ACHTUNGTRENNUNGfonACHTUNGTRENNUNGamide allyl alcohol 1 with 1 mol% of HgACHTNUGTREN(NUNG OTf)2 was com-
AHCTUNGTREGeNNUN nesulfonyl. R’=alkyl, phenyl; R’’=alkyl, methoxy, bromo.
pleted within 30 min at room temperature to give 2-vinyl in-
Our initial studies focused on the asymmetric cyclization
of 1 in the presence of 5 mol% of Hg(OTf)2 and a variety
of chiral auxiliaries (5 mol%). As shown in Table 1, reac-
tions with BINAP[13a] gave enantioenriched
in only
34% ee at room temperature using CH2Cl2 for 60 min in
90% yield (entry 1). PHANEPHOS,[13d] SDP,[13e] tol-SDP,[13e]
and NORPHOS[13f] also afforded some chiral inductions (en-
tries 5–7 and 9). However, BINAPHANE afforded the best
result (40% ee) under the same conditions (entry 10). It is
[a] Dr. H. Yamamoto, E. Ho, Dr. H. Imagawa, Prof. Dr. M. Nishizawa
Faculty of Pharmaceutical Sciences, Tokushima Bunri University
Yamashiro-cho, Tokushima 770-8514 (Japan)
Fax : (+81)88-655-3051
AHCTUNGTRENNUNG
2
E-mail: hirofumi@ph.bunri-u.ac.jp
[b] Dr. K. Namba
Division of Chemistry, Hokkaido University
Kita-ku, Sapporo 060-0810 (Japan)
Fax : (+81) 11-706-2703
[†] Deceased May 1, 2010
particularly noteworthy that the BINAPHANE–HgACHTUNGTRENNUNG(OTf)2
complex was highly reactive and 1 mol% was enough to
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001656.
Chem. Eur. J. 2010, 16, 11271 – 11274
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11271

Table 1. Hg
ACHTUNGTRENNUNG(OTf)2-catalyzed enantioselective cyclization of 1 to 2.
(Table 2, entry 1). 3,5-Di- as well as 2,4,6-trimethylarylsul-
fonyl groups were also less effective (entries 2 and 3).
4-Phenyl and 4-tert-butyl substituted arylsulfonamide
group afforded 7d and 7e in 70 and 74% ee, respectively
(entries 4 and 5). Alkylsulfonamide derivatives were found
to show higher enantioselectivity, with the bulkiness of the
alkyl group contributing to ee (entries 6–8). tert-Butyl-substi-
tuted sulfonamide derivative 6i induced the highest ee of
78%, when the reaction was conducted at À308C for 12 h
(entry 9), and 80% ee when the reaction was performed at a
lower temperature of À458C for 30 h (entry 10). The struc-
tures and absolute configurations of the products 2 and 7a–j
were confirmed by preparation of authentic samples from
(S)-indoline-2-carboxylic acid via 7k (R=H) according to
the reported procedure.[15]
Entry Auxiliary
Solvent
T [8C] t [h] Yield [%][a] ee [%][b]
1{c]
BINAP
CHIRAPHOS CH2Cl2
Et-DUPHOS CH2Cl2
Me-DUPHOS CH2Cl2
PHANEPHOS CH2Cl2
SDP
tol-SDP
xyl-SDP
NORPHOS
CH2Cl2
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
1
1
1
1
1
1
1
1
1
90
>95
>95
>95
>95
>95
>95
95
34
9
2{c]
3{c]
2
4
4{c]
5{c]
18
22
19
11
23
40
32
47
55
59
62
74
6{c]
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
7{c]
8{c]
9{c]
92
10{c]
11[d]
12[d]
13[d]
14[d]
15[d]
16[d]
BINAPHANE CH2Cl2
BINAPHANE CH2Cl2
BINAPHANE toluene
BINAPHANE p-xylene
BINAPHANE mesitylene RT
BINAPHANE mesitylene
BINAPHANE mesitylene À30
0.25 >95
0.3
0.3
0.3
0.3
0.6
40
>95
>95
>95
>95
0
>95
>95/99[e]
[a] Yield was determined by comparison of the integration in 1H NMR
spectrum of the crude mixture with CH2Br2, which was used as an inter-
nal standard. [b] Determined by HPLC analysis using a CHIRALCEL
OJ-H column. [c] Reaction carried out using 5 mol% of Hg
5 mol% of chiral auxiliary. [d] Reaction carried out using 1 mol% of Hg-
(OTf)2 and 1 mol% of chiral auxiliary. [e] Yield of isolated product.
ACHTUNGRTEN(NUNG OTf)2 and
Table 3. Catalytic enantioselective cyclization of sulfonamide allyl alco-
hols.
ACHTUNGTRENNUNG
Entry[a] Substrate
Product
Yield [%][b] ee [%][c]
1
91
98
95
72
79
84
Table 2. Optimization of anilino sulfonamide 6 in the enantioselective
cyclization.
2
3
Entry
6, R
t [h]
7
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
6a, SO2Ph
48
48
48
48
24
30
30
30
7a
7b
7c
7d
7e
7 f
7g
7h
7i
98
97
97
92
95
60
78
99
60
54
67
70
74
71
76
78
6b, SO2C6H3-3,5-Me
6c, SO2C6H2-2,4,6-Me
6d, SO2C6H4-4-Ph
6e, SO2C6H4-4-tBu
6 f, SO2Me
6g, SO2Et
6h, SO2iPr
6i, SO2tBu
6i, SO2tBu
4
5
6
96
93
99
99
83
93
9
12
30
99
97
78
80
10[c]
11[d]
12
7i
7i
7j
6i, SO2tBu
6j, Boc
48
trace
n.d.
48/6[e]
trace/72[e]
41[e]
[a] Yield of isolated product. [b] Determined by HPLC using CHIRAL-
CEL AD-H and OJ-H columns. [c] Reaction carried out at À458C.
[d] Reaction carried out using 1 mol% of HgACTHNURTGNENG(U OTf)2 and 2 mol% of
chiral auxiliary at À308C. [e] Reaction carried out at RT. Boc=tert-bu-
toxycarbonyl.
7
8
92
91
76
92
complete the reaction within 20 min (entry 11).[14] Mesity-
lene was the solvent of choice to give 2 in 59% ee
(entry 14). Moreover, an improved ee (i.e., 74% ee) was
achieved when the reaction was carried out at lower temper-
ature (À308C), although the reaction time had to be extend-
ed (entry 16).
9
97
88
Next, we investigated the effect of the protecting group
on the nitrogen. The phenylsulfonamide group gave a lower
enantioselectivity than the tosyl group when the reaction
[a] All reactions were carried out with (R)-BINAPHANE (1 mol%) and
Hg
ed product. [c] Determined by HPLC using CHIRALCEL AD-H and
OJ-H columns.
(OTf)2 (1 mol%) in mesitylene for 30 h at À308C. [b] Yield of isolat-
was carried out using 1 mol% of Hg
ACHTUNGRTEN(NNUG OTf)2 in the presence
of (R)-BINAPHANE (1 mol%) in mesitylene at À308C
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Chem. Eur. J. 2010, 16, 11271 – 11274

Enantioselective Cyclization
COMMUNICATION
Table 3 shows the generality of the present asymmetric
catalysis using a variety of tert-butyl sulfonamide derivatives.
The substituted methyl group at the aromatic ring of aniline
had a dramatic effect on the enantioselectivity. Reaction of
the 6-methylaniline derivative 8 afforded the corresponding
indoline 9 in 72% ee (entry 1). 5-Methyl-substituted 10 and
4-methyl-substituted 12 provided indolines 11 and 13, in 79
and 84% ee, respectively. The 3-methyl derivative 14 gave
15 in the highest (99%) ee (entry 4). The ee obtained using
4,5-dimethyl substituted 16 and 3,5-dimethyl derivative 18
was 83 and 93%, respectively. Although 3-methoxy-substi-
tuted 20 resulted in moderate enantioselectivity (i.e., only
up to 76% ee), the 3-bromoaniline derivative 22 gave 2-
vinyl indoline in 92% ee. Naphthalene derivative 24 also be-
haved as a suitable precursor to afford 25 in excellent enan-
tioselectivity.
Scheme 3. Deprotection of tert-butyl sulfonamide group. TFA=trifluoro-
acetic acid.
Experimental Section
General procedure for the catalyzed enantioselective cyclization of (E)-
N-[2-(4-hydroxybut-2-enyl)phenyl]-4-methylbenzenesulfonamide (1) (in
Table 1, entry 16):
A 0.1m CH3CN solution of HgCAHTUNTGRNUE(GN OTf)2 (30 mL,
3.0 mmol) was added to a dried two-neck flask under an atmosphere of
argon, and the CH3CN was evacuated under vacuum. To this was added
mesitylene (3.0 mL) and (R)-BINAPHANE (2.0 mg, 3.0 mmol). After
stirring for 5 min at room temperature,
a solution of 1 (100 mg,
315 mmol) was added to the mixture, which was then stirred for 40 h at
À308C. The reaction mixture was immediately subjected to column chro-
matography on silica gel (hexane/ethyl acetate 5:1) to give compound 2
(93 mg, 99%, 74% ee) as a white solid. Enantiomeric purity was deter-
mined by HPLC analysis using a DAICEL CHIRALCEL OJ-H column
(f 0.46ꢁ25 cm), n-hexane/iPrOH 9:1, flow rate: 3.0 mLminÀ1, detection
at 245 nm: tR =3.7 min (S, major) and 4.7 min (R, minor).
A conceivable mechanism for inducing the enantioselec-
tive formation of 2-vinyl indoline derivative is depicted in
Scheme 2. Generation of two plausible transition-state
models TS1 and TS2 are estimated from the interaction of
(R)-BINAPHANE–HgACTHNUTRGNEUNG
(OTf)2 complex[16] with regard to the
stable conformation 26b.[17] The effect of steric repulsion be-
tween the substituted aromatic ring of 26b and the naph-
thylmethyl moiety of (R)-BINAPHANE is clear in TS2. In
comparison to sterically strained transition-state TS2, the re-
action proceeds through the well-matched overlapping tran-
sition-state TS1, thereby predominantly affording (S)-27.
Cleavage of tert-butyl sulfonamide group in cyclic prod-
ucts was easily achieved under acidic conditions
(Scheme 3).[18] Treatment of 7i with anisole in the presence
of TFA under reflux conditions gave (S)-2-vinylindoline 7k
in 95% yield without isomerization of the chiral center.
In summary, we found that the novel combination of
Acknowledgements
We are grateful to Dr. Kenichi Harada of Tokushima bunri University
for his kind advice on calculating the minimum-energy structure of Hg
complex. This study was financially supported by a Grant-in-Aid from
the Ministry of Education, Culture, Sports, Science, and Technology of
the Japanese Government, and MEXT-HITEC.
Keywords: alcohols
· allylic compounds · cyclization ·
enantioselectivity · mercury
chiral ligand BINAPHANE with HgACTHNUTRGNENUG(OTf)2 acts as a highly
efficient chiral inducing agent for the dehydrative N-cycliza-
tion of anilino allyl alcohol derivatives giving rise to 2-vinyl
indoline with excellent selectivity. The present method is
useful for syntheses of various indoline derivatives, which
are important structural units for drug development.
À
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Chem. Eur. J. 2010, 16, 11271 – 11274
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11273

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Received: May 11, 2010
Published online: August 20, 2010
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Chem. Eur. J. 2010, 16, 11271 – 11274