Enantioselective Copper(II)-Catalyzed Conjugate Addition of Indoles to β-Substituted Unsaturated Acyl Phosphonates

Article abstract of DOI:10.1002/adsc.201500923

The first copper-catalyzed enantioselective conjugate addition of indoles to β-substituted unsaturated acyl phosphonates was successfully realized by using a heteroarylidene-tethered bis(oxazoline) ligand. The reaction features high efficiency, cheap catalyst and broad generality. In the case of either β-alkyl- or β-aryl-substituted unsaturated acyl phosphonates, the 3-indolyl adducts were achieved in high yields with good to excellent enantioselectivities (up to 97% ee). The 3-indolyl adducts can serve as important intermediates in the synthesis of indole alkaloids.

Full text of DOI:10.1002/adsc.201500923

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DOI: 10.1002/adsc.201500923
Enantioselective Copper(II)-Catalyzed Conjugate Addition of
Indoles to b-Substituted Unsaturated Acyl Phosphonates
Hong-Li Ma,a Lei Xie,a ZhenHua Zhang,a Jia-Qi Li,a Zhao-Hai Qin,a and Bin Fua,*
a
Department of Applied Chemistry, China Agricultural University, Beijing 100193, Peopleꢀs Republic of China
Fax: (+86)-10-6273-2948; e-mail: fubinchem@cau.edu.cn
Received: September 30, 2015; Revised: December 20, 2015; Published online: March 17, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500923.
Abstract: The first copper-catalyzed enantioselec-
tive conjugate addition of indoles to b-substituted
unsaturated acyl phosphonates was successfully re-
alized by using a heteroarylidene-tethered bis(oxa-
zoline) ligand. The reaction features high efficiency,
cheap catalyst and broad generality. In the case of
either b-alkyl- or b-aryl-substituted unsaturated
acyl phosphonates, the 3-indolyl adducts were ach-
ieved in high yields with good to excellent enantio-
selectivities (up to 97% ee). The 3-indolyl adducts
can serve as important intermediates in the synthe-
sis of indole alkaloids.
Keywords: bis(oxazoline)s; conjugate addition;
copper; enantioselectivity; indoles; unsaturated acyl
phosphonates
Figure 1. Selected examples of indole derivatives.
nitroolefins,[11] alkylidenemalonates,[12] unsaturated a-
keto esters,[13] aldehyde or ketones,[14] have been suc-
Indole derivatives represent one of the most privi- cessfully employed for the purpose. Besides, b-substi-
leged alkaloids and are ubiquitous in natural products tuted unsaturated acyl phosphonate have also been
and pharmaceutical compounds.[1] Among them, po- introduced as a very useful synthon for enantioselec-
tential chiral 3-crotonyl or cinnamoyl group side tive indole functionalization. For instance, in 2003,
chain-substituted indoles constitute an important Evans et al. pioneered the first example of asymmet-
structural motif in various biological molecules. For ric conjugate addition of indoles to unsaturated acyl
example, indolmycin (1) exhibits inhibition of pro- phosphonates using an Sc(III)-pybox complex, afford-
karyotic tryotophanyl-tRNA synthetase (TrpRS),[2] ing the N-protected indole products in high yields
and b-phenyltryptophan (2) has analgesic activities as- with excellent enantioselectivities.[15] Subsequently,
sociated with anti-inflammatory properties.[3] Besides, Yamamoto et al. reported the same reaction catalyzed
synthetic compounds (3) and (4) are typical COX-2 by an Al-bis(8-quinolinolato) complex. Excellent
inhibitor[4] and 11-b-HSD-2 inhibitors,[5] respectively enantioselectivities (up to 98% ee) were achieved for
(Figure 1).
the N-benzyl- and N-methylindole products, but only
Over the past two decades, extensive efforts have moderate enantioselectivity (58% ee) was obtained
been devoted to the development of efficient methods for the N-unprotected indoles.[16] In 2010, Jørgensen
for the preparation of chiral functionalized indole de- et al. employed a chiral thiourea to realize the orga-
rivatives.[6] Among them, the asymmetric conjugate nocatalytic addition reaction of unprotected indole to
addition of indoles to unsaturated olefins (also called unsaturated acyl phosphonates, providing the indole
Friedel–Crafts reaction) represents a very powerful adducts in 72–90% ee.[17] Akiyama et al.[18] and Kim
strategy.[7] By now, various electrophiles such as keto et al.[19] reported, respectively, that chiral phosphoric
esters,[8] imines or enamines,[9] a’-hydroxy enones,[10] acid and the complexes of Pd-BINAP could efficient-
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Table 1. Optimization of the reaction conditions.[a]
ly catalyze this reaction, however, the substrate scope
is mainly limited to either b-aryl- or b-alkyl-substitut-
ed acyl phosphonates. Despite these impressive ad-
vances, the generality of the reaction is restricted by
substrate scope. To the best of our knowledge, no suc-
cessful example of a catalytic asymmetric reaction of
both b-alkyl- and b-aryl-substituted unsaturated acyl
phosphonates with unprotected indoles has been re-
ported. Therefore, the exploration of a facile, highly
enantioselective method with broad generality is very
valuable and still in great demand.
Our previous works have proved that heteroaryli-
dene-tethered bisoxazolines (BOX L1 and L2,
Figure 2) are effective chiral ligands in some asym-
metric reactions of indoles with electron-deficient ole-
fins.[20] As a continuation of our ongoing research to
explore new catalytic asymmetric methods using the
simple and cheap catalytic system, we herein report
the first copper-catalyzed conjugate addition of un-
protected indoles to b-alkyl- and b-aryl-unsaturated
acyl phosphonates, which afforded a broad range of
optically active indole adducts in high yields with
good to excellent enantioselectivities (up to 97% ee).
Entry Ligand Solvent Temp.
[oC]
Time Yield
[h]
ee
[%][b]
[%][c]
1
2
3
4
5
6
7
8
L1a
L1a
L1a
L1a
L1a
L1a
L1b
L1c
L2a
L2b
L2c
L3
DCM[d]
CHCl3
DCE[e]
THF
Et2O
toluene 0
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3 À30
CHCl3 À60
CHCl3 À60
0
0
0
0
0
1
1
1
4
4
4
1
1
1
1
1
1
1
4
12
24
96
94
96
89
88
92
94
94
95
94
95
92
86
94
89
76
80
84
77
78
80
78
17
-10
81
24
-6
76
48
87
94
94
0
0
0
0
0
0
0
9
10
11
12
13
14
15
16[f]
L4
L1a
L1a
L1a
[a]
All reactions were carried out using 10% mol of ligand-
Cu(OTf)2 in solvent (2 mL) under nitrogen, then treated
with MeOH (0.5 mL) and DBU (0.1 mL) for 1 h at room
temperature.
Isolated yield.
Determined by HPLC.
CH2Cl2.
ClCH2CH2Cl.
[b]
[c]
[d]
[e]
[f]
5 mol% L1a-Cu(OTf)2.
optimal solvent in terms of yield and ee value
(entry 2, 94% yield and 84% ee). Subsequently, the
effect of the ligand was also examined. The reaction
proceeded smoothly within 1 h at 08C to give the de-
sired adducts in quantitative conversions for all tested
ligands (entries 7–11), whereas the enantioselectivities
Figure 2. Screened bis(oxazoline) ligands.
Our initial investigation began with the conjugate were very poor except for furyl-tethered BOX L2a
addition of N-unprotected indole (1a) to b-methyl un- bearing a phenyl group (entry 9, 81% ee). For com-
saturated acyl phosphonate (2a) as the model reaction parison, Evansꢀ ligand L3 and cyclopropane-tethered
(Scheme 1).[15] First, the reaction was carried out at BOX ligand L4 were also tested, and furnished rela-
08C in the presence of 10 mol% L1a-Cu(OTf)2 com- tively lower ee values (entries 12 and 13). These pre-
plex, followed by addition of MeOH and DBU. The liminary results indicated L1a was the most effective
results are listed in Table 1. Of all the six typical sol- ligand. The reaction temperature and the catalyst
vents screened, generally good yields of indole adduct loading were next examined. When lowering the tem-
3a were afforded, albeit with different enantioselectiv- perature to À30 and À608C, the enantioselectivities
ities (entries 1–6). It turned out that CHCl3 was the were improved obviously to 87% ee and 94% ee, re-
spectively, albeit a longer reaction time was necessary
(entries 14 and 15). When the reaction was carried
out at a catalyst loading of 5 mol%, the enantioselec-
tivity remained completely but the reactivity dropped
slightly (entry 16). The absolute configuration of
product 3a was assigned to be R by comparison with
the reported results in the literature.[17]
With the optimal conditions in hand [10 mol%
L1a-Cu(OTf)2, CHCl3 as solvent, À608C], we next in-
vestigated the scope of indoles in this reaction. The
results are summarized in Table 2. First, the nucleo-
Scheme 1. The model reaction for optimization.
philic reagents EtOH, BnOH or BnNH2 were em-
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Enantioselective Copper(II)-Catalyzed Conjugate Addition of Indoles
Table 2. The addition of various indoles to b-alkyl unsaturat-
Table 3. The addition of various indoles to b-aryl unsaturat-
ed acyl phosphonates.[a]
ed acyl phosphonates.[a]
Entry R1
Alkyl
NucH Yield [%][b] ee [%][c]
Entry R1
Ar
Time Yield
[h]
ee
[%][b]
[%][c]
1
H
Me (2a) EtOH 90 (3b)
94
94
93
93
91
90
93
94
94
95
95
94
94
95
95
96
93
95
2
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
BnOH 85 (3c)
BnNH2 94 (3d)
EtOH 86 (3e)
EtOH 88 (3f)
EtOH 87 (3g)
EtOH 89 (3h)
EtOH 78 (3i)
EtOH 81 (3j)
EtOH 80 (3k)
EtOH 82 (3l)
EtOH 85 (3m)
EtOH 77 (3n)
EtOH 73 (3o)
EtOH 79 (3p)
EtOH 81 (3q)
1
H
Ph (2d)
Ph (2d)
8
8
95 (4a) 92
92 (4b) 88
3
H
2
5-Me
4
5
6
7
4-Me
5-Me
7-Me
5-MeO
5-F
3
5-MeO Ph (2d)
8
85 (4c)
95
4
5
6
7
7-Me
5-Cl
6-Br
H
Ph (2d)
Ph (2d)
Ph (2d)
8
87 (4d) 90
93 (4e) 80
90 (4f)
24
24
8
83
8
p-MeC6H4 (2e)
p-MeOC6H4 (2f)
o-MeC6H4 (2g)
p-ClC6H4 (2h)
p-BrC6H4 (2i)
p-CF3C6H4 (2j)
2-naphthyl (2k)
2-furyl (2l)
91 (4g) 87
9
5-Cl
5-Br
5-CN
5-CO2Me Me
5-NO2
6-F
6-Cl
6-Br
H
8
H
8
84 (4h) 80
10
11
12
13
14
15
16
17
18
9
H
8
8
85 (4i)
88 (4j)
96
94
10
11
12
13
14
H
H
H
H
8
8
92 (4k) 94
95 (4l) 97
Me
Me
Me
Me
8
8
98 (4m) 91
96 (4n) 78
H
[a]
All reactions were conducted in CHCl3 (2 mL) under ni-
trogen using 10 mol% of L1a-Cu(OTf)2 at À608C for 8-
24 h, then treatment by addition of EtOH (0.5 mL) and
DBU (0.1 mL) for 1 h.
Isolated yield.
Determined by chiral HPLC.
i-Pr (2b) EtOH 85 (3r)
Cy (2c) EtOH 90 (3s)
H
[a]
All reactions were conducted in CHCl3 (2 mL) under ni-
trogen using 10 mol% of L1a-Cu(OTf)2 at À608C for
12 h, then treatment by addition of EtOH, BnOH or
BnNH2 (0.5 mL) and DBU (0.1 mL) for 1 h.
Isolated yield.
[b]
[c]
[b]
[c]
Determined by chiral HPLC.
tween b-phenyl acyl phosphonate 2d and indole at
À608C, giving the desired product 4a in 95% yield
with 92% ee, which indicated the higher reactivity of
ployed instead of MeOH, both the high yields and ee 2d comparing with that of 2a–c (entry 1). In the case
values were almost maintained (entries 1–3). Second, of indoles with an electron-donating group, the prod-
for a series of indoles bearing electron-donating or ucts 4b–4d were all achieved in good results (en-
electron-withdrawing substituents at different posi- tries 2–4, 88–95% ee); while in the case of indoles
tions, they all worked well to furnish the correspond- with an electron-withdrawing group, the reaction
ing products 3e–3q in high yields and excellent enan- became sluggishly and a prolonged reaction time was
tioselectivities (entries 4–16, 73–89% yield and 90– needed for full conversion, the indole products were
96% ee), indicating that the substituents of indole had obtained in high yields with somewhat decreased ee
negligible influence on the reactivity and selectivity. values (entries 5, 6, 80–83% ee). The results showed
To our delight, the reaction was also compatible with the electron-withdrawing substituent on the indole
other b-alkyl group-substituted substrates and excel- ring had a negative effect on the reactivity and enan-
lent enantioselectivities were observed in the reac- tioselectivity of the reaction. Moreover, different sub-
tions of b-isopropyl- or b-cyclohexyl-substituted acyl stituted phenyl groups of the unsaturated acyl phos-
phosphonates 2b and 2c (entries 17 and 18, 93% and phonates were examined. All reactions could be com-
95% ee, respectively).
pleted within 8 h at À608C, exhibiting both high reac-
The substrate scope was further extended to b-aryl- tivities and good to excellent enantioselectivities (en-
substituted unsaturated acyl phosphonates, as sum- tries 7–12, 80–97% ee). In addition, 2-naphthyl-
marized in Table 3. Under the same conditions, it substituted acyl phosphonate 2k was also a suitable
took only 8 h for the completion of the reaction be- substrate in this reaction, giving the indole adduct 4m
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Hong-Li Ma et al.
in 98% yield with 91% ee (entry 13), whereas 2-furyl- a cooperative effect on the enantioselectivity and re-
substituted substrate 2l furnished a relatively low activity of the reaction. The enantioselectivity of the
enantioselectivity but excellent reactivity (entry 14, direct addition product-indole acyl phosphonate
96% yield and 78% ee). In most cases the catalyst should be identical with the resulting ester or amide,
L1a-Cu(OTf)2 provided more higher ee values and because this transformation is not related to the chiral
yields than the previously reported methods in this re- center under mild reaction conditions. To confirm this
action.[17,18] It was noteworthy that both b-alkyl- and deduction, we also separated the direct addition prod-
b-aryl-substituted unsaturated acyl phosphonates gave uct 3a’ under the same catalytic reaction conditions.
good to excellent results, indicating a much broader The enantioselectivity was determined to be 94% ee,
substrate scope.
which is the same as the level of 3a (For details, see
The absolute configuration of product 4k was deter- the Supporting information).
mined to be S on the basis of its single-crystal X-ray
structure (Figure 3),[21] which could also be confirmed
by comparison with previous reports.[17,18]
The stereochemistry outcome can be explained by
Figure 3. In general, a four-coordinated Cu(II) com-
plex prefers a square-planar geometry. When b-aryl
unsaturated acyl phosphonate coordinates with the
copper complex of thienyl-tethered bisoxazoline, a tet-
rahedral transition state is formed, subsequently
indole attacks preferably from the Si face of unsatu-
In summary, we have demonstrated the copper(II)
rated acyl phosphonate, leading to the formation of complexes of heteroarylidene-tethered BOX ligand
the predominant S-configured indole adduct. If using can efficiently catalyze the asymmetric conjugate ad-
b-methyl unsaturated acyl phosphonate instead of the dition of unprotected indoles to various b-substituted
b-aryl substituted one, the same reaction mode would unsaturated acyl phosphonates. The reaction proceed-
generate the major R-configured product. Given the ed to completion within 24 h at À608C, affording the
higher enantioselectivity afforded by L1a in contrast indole products in high yields and with good to excel-
to L3 or L4 (Table 1, entries 12 and 13), we believe lent enantioselectivities. In comparison to the previ-
that both the oxazoline ring and the heteroarylidene ously reported catalytic methods, the present method
skeleton can provide a well-defined chiral environ- displays some significant advantages: (i) the simple
ment in this catalytic transformation, which then has and cheap catalyst (chiral copper complexes); (ii)
broader substrate scope (almost the same high level
of asymmetric induction for both b-alkyl- and b-aryl-
substituted unsaturated acyl phosphonates); (iii) gen-
erally better enantioselectivities. The products of the
reaction can be transformed into biologically active
indole derivatives according to the previously report-
ed methods.[22] Further studies to expand the scope of
this methodology are underway in our laboratory.
Experimental Section
Typical Procedure for Asymmetric Conjugate
Addition of Indoles to b-Substituted Unsaturated
Acyl Phosphonates
To a Schlenk tube were successively added Cu(OTf)2
(0.030 mmol), ligand L1a (0.033 mmol) and CHCl3 (1.5 mL)
under nitrogen. The solution was stirred for 2 h at room
temperature, and then unsaturated acyl phosphonate 2a
(0.36 mmol) was added. The resulting mixture was cooled to
À608C and stirred for 20 min, a solution of indole 1a
(0.30 mmol) in CHCl3 (0.5 mL) was finally added by a sy-
ringe. After stirring for 12 h at À608C, MeOH (0.5 mL) and
DBU (100 mL) were directly added to the reaction mixture
Figure 3. Plausible transition state model and X-ray struc-
ture of 4k.
and stirred for another 1 hour at room temperature. Saturat-
ed NH4Cl solution (10 mL) was added and the mixture ex-
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Enantioselective Copper(II)-Catalyzed Conjugate Addition of Indoles
tracted with ethyl acetate (10 mL”3). The organic layer was
combined, and washed with brine (10 mL), dried over anhy-
drous Na2SO4, and then concentrated to give the crude
product, which was purified by flash column chromatogra-
phy on silica gel (eluted with ethyl acetate/petroleum ether
(1/10, v/v) to afford the desired indole product 3a, (R)-
methyl 3-(1H-indol-3-yl)butanoate, as a colorless oil; yield:
89%; [a]2D5: À3.5 (c 1.10, CH2Cl2); 1H NMR (300 MHz,
CDCl3): d=8.17 (br s, 1H), 7.75 (d, J=7.7 Hz, 1H), 7.35 (d,
J=7.8 Hz, 1H), 7.31–7.12 (m, 2H), 6.95 (d, J=2.1 Hz, 1H),
3.85–3.55 (m, 4H), 2.93 (dd, J=15.0, 6.2 Hz, 1H), 2.68 (dd,
J=15.0, 8.6 Hz, 1H), 1.51 (d, J=6.9 Hz, 3H); HPLC analy-
sis (Daicel Chiralcel OD-H column, n-hexane/i-PrOH=
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90:10,
1.0 mLminÀ1,
254 nm):
t(major)=15.95 min,
t(minor)=28.63 min, 94% ee.
Acknowledgements
We are grateful to the National Natural Sciences Foundation
of China (No. 21172255) and the Ministry of Science and
Technology of China (No.2015BAK45B01) for financial sup-
port.
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