Tandem catalytic asymmetric Friedel-Crafts/Henry reaction: Control of three contiguous acyclic stereocenters

Article abstract of DOI:10.1002/anie.200801373

(Chemical Equation Presented) Good things come in threes: Highly functionalized indole derivatives with three contiguous stereocenters were formed in the title reaction of an indole, a nitroalkene, and an aldehyde with the imidazoline-aminophenol catalyst 1-CuOTf in the presence of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP). The major isomers of the adducts were obtained with up to 99% ee. Tf = trifluoromethanesulfonyl, Ts = p-toluenesulfonyl; R = H, Me; R′,R″ = alkyl, aryl.

Full text of DOI:10.1002/anie.200801373

Angewandte
Chemie
DOI: 10.1002/anie.200801373
Multicomponent Reactions
Tandem Catalytic Asymmetric Friedel–Crafts/Henry Reaction:
Control of Three Contiguous Acyclic Stereocenters**
Takayoshi Arai* and Naota Yokoyama
Highly functionalized, optically pure compounds are in strong
demand in the pharmaceutical and agricultural industries.
Catalytic asymmetric tandem reactions[1] are powerful tools
for providing such complex molecules. They minimize the
number of steps required in target-oriented synthesis, and the
compounds obtained, which may have multiple stereogenic
centers, serve as a fascinating scaffold for diversity-oriented
synthesis.[2] The impressive work of Enders et al.[3a] on cascade
organocatalytic reactions demonstrated the fundamental
importance of the conformational stability of cyclic com-
pounds in the construction of multiple contiguous stereocen-
ters.[3] However, the control of multiple contiguous stereo-
centers in acyclic products is difficult even in modern
chemistry.
Herein, we report the catalytic asymmetric tandem
Friedel–Crafts/Henry (FCH) reaction of indoles, nitroal-
kenes, and aldehydes catalyzed by the imidazoline–amino-
phenol catalyst 1–CuOTf. To the best of our knowledge, this is
the first successful demonstration of the formation of chiral
acyclic products with three contiguous stereocenters in a
Scheme 1. Asymmetric reactions with the imidazoline–aminophenol–
Cu catalyst. Tf=trifluoromethanesulfonyl, Ts=p-toluenesulfonyl.
tandem FCH reaction.
In a recent study aimed towards the identification of a new
asymmetric catalyst, we developed the chiral imidazoline–
aminophenol ligand 1.[4] The 1–Cu(OAc)2 complex catalyzed
the enantioselective Henry reaction to give the adduct with
up to 95% ee.[5,6] Furthermore, 1–CuOTf was an effective
catalyst in the Friedel–Crafts (FC) reaction of indole with
nitroalkenes (Scheme 1).[7]
In contrast, the FC reaction of indole with aldehydes was
relatively slow. On the basis of these experimental results, we
envisioned that it would be possible to carry out a highly
stereocontrolled tandem FCH reaction with the 1–Cu cata-
lyst.
When benzaldehyde (1 equiv) was added to the conven-
tional FC reaction mixture of indole and nitrostyrene (1:1),
the desired three-component-coupling product
3 was
obtained in 37% yield (Table 1, entry 1). Although 3 was
formed with only moderate diastereoselectivity (2:4:1), the
major adduct of 3 was obtained with 99% ee. (In the current
Table 1: Optimization of the reaction conditions for the FCH reaction.
[*] Prof. Dr. T. Arai, N. Yokoyama
Department of Chemistry, Graduate School of Science
Chiba University
Inage, Chiba 263-8522 (Japan)
Fax: (+81)43-290-2889
E-mail: tarai@faculty.chiba-u.jp
Homepage: http://synthesis.chem.chiba-u.jp/
Entry
a/b/c/d
Yield [%]
3
2[a]
3[b]
d.r.[c]
ee [%][d,e]
1
2
3
4
5
1/1/1/0
2/1/2/0
2/1/2/1
2/1/2/2
2/1/2/3
28 (82)
8 (85)
7 (70)
17 (70)
13 (70)
37
38
73
79
73
2:4:1
1:2:1
1:5:0
1:19:0
1:5:0
99
99
99
99
99
[**] This research was supported by the Industrial Technology Research
Grant Program in 2006 from the New Energy and Industrial
Technology Development Organization (NEDO) of Japan and by a
Grant-in Aid for Scientific Research on Priority Areas (No. 19028007,
“Chemistry of Concerto Catalysis”) from the Ministry of Education,
Culture, Sports, Science and Technology (Japan). We thank Prof.
Akira Yanagisawa at Chiba University for helpful discussions.
[a] The value in parentheses is the ee value of 2. [b] Combined yield of the
diastereomers. [c] Determined by 1H NMR spectroscopic analysis.
[d] The ee value of the major diastereomer is given. [e] The ee value
was determined by HPLCby using a chiralcel OD-H column.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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study, only three of the four possible diastereomers were
catalytic system; in this case, the FCH adduct was produced in
72% yield, and the two diastereomers obtained exhibited
99% ee (Table 2, entry 11).
The relative configuration of the major product obtained
in entry 6 of Table 2 was determined by X-ray diffraction
analysis to be 1R*,2R*,3R*, and the absolute configuration at
the benzylic position was determined to be 1R after con-
version into the known FC product 2 by a retro-Henry
reaction (Figure 1).
detected.) The result was not improved when the amounts of
indole and aldehyde were increased (Table 1, entry 2).
Encouragingly, the addition of 1,1,1,3,3,3-hexafluoro-2-prop-
anol (HFIP; 2 equiv) was effective in enhancing the catalytic
reaction, with the adduct now formed in up to 79% yield.
Importantly, the use of HFIP promotes the reaction in a
highly diastereoselective manner to give the adducts 3 in the
ratio 1:19:0, with the major isomer formed with 99% ee.
By using these optimized conditions, we were able to
confirm the generality of the current FCH reaction (Table 2).
Electron-deficient aldehydes, such as 4-bromobenzaldehyde,
Table 2: FCH reaction with various substrates.
Entry
R
R’
R’’
t
Yield [%]
3
[h] 2[b] 3[c] d.r.[d]
ee [%][e]
1
2
H
H
H
H
H
H
H
H
H
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
n-C5H11 C6H5
n-C5H11 4-BrC6H4
PhC2H4 C6H5
C6H5
16 17 (70) 79 1:19:0 99
4-BrC6H4
4-BrC6H4
4-ClC6H4
3
2 (7) 29 1:9:0 87
3[a]
4[a]
5[a]
6
14 trace
17
84 1:16:0 90 (99)[f]
82 1:10:0 90 (99)[f]
2
4-NO2C6H4 15 10 (18) 90 1:10:0 89 (99)[f]
Figure 1. ORTEP structure and retro-Henry reaction of an FCH product
(major product in Table 2, entry 6). TMEDA=N,N,N’,N’-tetramethyl-
ethylenediamine.
n-C5H11
c-C6H11
14 14 (77) 82 1:3:0 99
21 21 (70) 79 1:7:0 99
7
8
15
17
15 12
13
4
–
76 1:2:0 98 (97)[g]
66 3:4:0 99 (99)[g]
83 2:3:0 90
9[a]
10
Scheme 2 shows a plausible reaction mechanism. In the
first step, the nitroalkene is activated by the Lewis acid
catalyst 1–Cu to start the enantioselective Friedel–Crafts
reaction. The diastereoselective Henry reaction is then
promoted by the Cu nitronate functionality of the intermedi-
ate that results from the FC addition.[8] The isolated FC
product 2 did not react with the aldehyde under the reaction
conditions. Moreover, the ee value of 3 was greatly improved
to 99% from the 70% ee observed for the FC adduct 2
(Table 2, entry 1). Thus, the Henry reaction appears to
proceed directly from the Cu nitronate intermediate and is
accompanied by kinetic resolution of the nitronate.
The 1–CuOTf-catalyzed FC reaction provided R-enriched
2; therefore, the major R Cu–nitronate intermediate reacts
with the aldehyde to give the Cu–alkoxide of the 1R FCH
product. The formation of the 1R,2R,3R product indicates
that the diastereoselective Henry reaction proceeds in a syn-
selective manner. This syn selectivity can be explained well by
considering an intermediate with a Cu-containing six-mem-
bered ring (see the structure below the catalytic cycle in
Scheme 2). The relatively strong Lewis acidity of the CuOTf
catalyst would favor the diastereoselective Henry reaction via
this cyclic transition state. Finally, protonation of the Cu–
alkoxide and aromatization furnishes the desired FCH
product and regenerates the 1–Cu catalyst. The additive
HFIP enhances the release of the FCH product from the
catalyst.
11[a] Me C6H5
C6H5
–
72 2:3:0 99 (99)[g]
[a] The reaction was performed at 08C. [b] The value in parentheses is the
ee value of 2. [c] Combined yield of the diastereomers. [d] Determined by
1H NMR spectroscopic analysis. [e] The ee value of the major diastereo-
mer was determined by HPLCby using a chiralcel OD-H or chiralpak AS-
H column. [f] The ee value of the major diastereomer after a single
recrystallization from iPrOH is given in parentheses. [g] The ee value of
the minor diastereomer is given in parentheses.
provided the adduct in poor yield at room temperature
because of the generation of bisindole as an undesired side
product (Table 2, entry 2). However, when the reaction was
performed at 08C, the corresponding FCH product was
obtained in 84% yield with 90% ee (Table 2, entry 3). Other
electron-deficient aldehydes were converted into the desired
products under similar conditions with high enantioselectiv-
ities (Table 2, entries 4 and 5). A single recrystallization from
iPrOH afforded the products with 99% ee (Table 2, entries 3–
5). The FCH reaction is also applicable to aliphatic aldehydes;
the corresponding adducts were obtained with excellent
enantioselectivities (Table 2, entries 6 and 7). When the
reaction was examined with aliphatic nitroalkenes, the FCH
products were obtained as a mixture of diastereomers.
However, the two diastereomers obtained were formed with
high enantioselectivities (Table 2, entries 8 and 9). N-Meth-
ylindole can also be used as a substrate with the current
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indicated temperature for the time indicated, then purified by column
chromatography on silica gel to afford the adduct. The ee values of the
products were determined by HPLC by using a Daicel chiralcel OD-
H or chiralpak AS-H column.
Received: March 21, 2008
Published online: June 2, 2008
Keywords: asymmetric catalysis · domino reactions · Friedel–
.
Crafts reaction · Henry reaction · multicomponent reactions
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Scheme 2. Plausible reaction mechanism. CuL* represents the 1–Cu
catalyst.
In conclusion, we have developed a three-component
tandem reaction of indole, nitroalkenes, and aldehydes to
construct acyclic products with three contiguous stereocen-
ters. We also tested other conventional Lewis acids (BEt3,
Ti(OiPr)4) and a base (KOtBu) in the FCH reaction; however,
the use of these catalysts resulted in the formation of only the
FC product or bisindole, or both (see the Supporting
Information). Our results clearly show the potential for the
application of the 1–Cu catalyst in the construction of
multiple contiguous acyclic stereocenters. The well-organized
1–Cu catalyst satisfies the requirement of the activation of the
reaction intermediates at the appropriate times in the
catalytic cycle. A variety of transformations of these highly
functionalized FCH products can be envisaged readily, such
as the synthesis of hydroxytryptamines by reduction of the
nitro group, and Pictet–Spengler cyclization reactions to give
polycyclic alkaloids. The novel FCH reaction developed
herein has significant potential in chemistry and chemical
biology.
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71, 75 – 80.
Experimental Section
General procedure: A solution of 1 (14.9 mg, 19 mmol) in toluene
(0.43 mL) was added to (CuOTf)2·C6H6 (4.4 mg, 8.7 mmol) under Ar,
and the mixture was stirred for 2 h at room temperature. HFIP
(35 mL, 0.34 mmol), the aldehyde (0.34 mmol), the nitroalkene
(0.17 mmol), and indole (0.34 mmol) were added sequentially to the
resulting clear green solution. The reaction mixture was stirred at the
[8] For examples of catalytic asymmetric Michael–aldol reactions,
see: a) T. Arai, H. Sasai, K. Aoe, K. Okamura, T. Date, M.
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