Chiral phosphoric acid-catalyzed enantioselective aza-Friedel-Crafts reaction of indoles

Article abstract of DOI:10.1002/adsc.200700151

A highly enantioselective 1,2-aza-Friedel-Crafts reaction of N-tert-butyldimethylsilylindole with N-tert-butoxycarbonyl aromatic imines is demonstrated using a BINOL-derived monophosphoric acid catalyst. The present approach provides efficient access to 3-indolylmethaneamines with aryl substituents in excellent enantioselectivities (up to 98% ee). An inversion in the sense of enantioselection was found between monophosphoric acid catalysts bearing different substituents introduced at the 3,3′-position of binaphthyl backbone. We also calculated the three-dimensional structure of the monophosphoric acid catalysts to speculate on the inversion of the stereochemical outcome.

Full text of DOI:10.1002/adsc.200700151

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DOI: 10.1002/adsc.200700151
Chiral Phosphoric Acid-Catalyzed Enantioselective Aza-Friedel–
Crafts Reaction of Indoles
Masahiro Terada,a,* Shigeko Yokoyama,a Keiichi Sorimachi,a
and Daisuke Uraguchib
a
Department of Chemistry, Graduate School of Science, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578, Japan
Fax : (+81)-22-795-6602; e-mail: mterada@mail.tains.tohoku.ac.jp
Department of Applied Chemistry, Graduate School of Engineering, Nagoya University, Chikusa-ku, Nagoya 464-8603,
b
Japan
Received: March 22, 2007; Revised: June 14, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A highly enantioselective 1,2-aza-Friedel–
Crafts reaction of N-tert-butyldimethylsilylindole
with N-tert-butoxycarbonyl aromatic imines is dem-
onstrated using a BINOL-derived monophosphoric
acid catalyst. The present approach provides effi-
cient access to 3-indolylmethaneamines with aryl
substituents in excellent enantioselectivities (up to
98% ee). An inversion in the sense of enantioselec-
tion was found between monophosphoric acid cata-
lysts bearing different substituents introduced at the
3,3’-position of binaphthyl backbone. We also calcu-
lated the three-dimensional structure of the mono-
phosphoric acid catalysts to speculate on the inver-
sion of the stereochemical outcome.
as the chiral Brønsted acid catalyst.[4–7] Further appli-
cations of the chiral monophosphoric acid-catalyzed
1,2-aza-F–C reaction are desirable as it has the poten-
tial for high catalytic efficiency and enantioselectivity
and should provide a diverse array of optically active
arylmethaneamine derivatives. In particular, the 1,2-
aza-F–C reaction of indoles is an attractive transfor-
mation towards enantioenriched 3-indolylmethane-
amine derivatives.[3g,4c] These indolyl derivatives are
widely identified as “privileged” structures among
pharmacophores and are represented in thousands of
natural isolates and many medicinal agents of versa-
tile therapeutic action.[8] Herein we describe a highly
enantioselective Friedel–Crafts reaction of indoles (2)
with N-acyl aromatic imines (3) catalyzed by chiral
monophosphoric acids (1) [Eq. (1)].[9] The present ap-
proach, which gives optically active 3-indolylmethane-
amines substituted with an aromatic group, is a good
complement to our previous method for preparing 3-
Keywords: asymmetric catalysis; Brønsted acid;
enantioselectivity; Friedel–Crafts reaction; organic
catalysis; phosphoric acid
The enantioselective Friedel–Crafts (F–C) reaction
via activation of electron-deficient multiple bonds is
undoubtedly the most straightforward, atom-economi-
cal, and practical approach for the introduction of a
chiral side chain to aromatic compounds.[1] Since the
1,4-F–C reaction of a,b-unsaturated carbonyl com-
pounds with pyrrole derivatives catalyzed by small or-
ganic molecules, so-called organocatalysts,[2] was ac-
complished by MacMillan and co-workers,[3a] the de-
velopment of organocatalytic F–C reactions has been
a challenging topic of continued interest in synthetic
organic chemistry. To date several efficient organoca-
talysts have been reported.[3,4] Our group has also
demonstrated a highly enantioselective 1,2-aza-F–C
reaction of N-protected imines with 2-methoxyfuran
using the BINOL-derived monophosphoric acid 1a[4a]
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Masahiro Terada et al.
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indolylmethaneamines with a variety of aliphatic sub- (67% ee) (entry 2). It is noteworthy that, for enantio-
stituents where a highly enantioselective F–C reaction selective catalysis by (R)-1b, the stereochemical out-
of indoles with enecarbamates as electron-rich olefins come of (S)-4aa was opposite to that observed for the
catalyzed by chiral monophosphoric acid (1) was suc- catalysis by (R)-1a, where the methyl groups were re-
cessfully developed.[4c] We also conducted computa- moved from the HMT substituent without any change
tional analysis of the three-dimensional structure of to the terphenyl skeleton. To our delight, further opti-
the monophosphoric acid catalyst (1) to speculate mization of the catalysis by (R)-1b (entries 3–6) mark-
about the activation mode of imines.
edly improved the enantioselectivity from 67% ee to
The initial reaction of the N-tert-butyldimethylsilyl 96% ee; in the optimum reaction conditions the tem-
(TBS)-protected indole (2a: X=H)[10] with N-Boc perature was set to À408C and the solvent was
imne (3a: Ar=C6H5) was performed using the steri- 1,1,2,2,-tetrachloroethane (entry 6). The reaction can
cally hindered hexamethylterphenyl (HMT)-substitut- be performed using a low loading of the catalyst (2
ed catalyst [(R)-1a] as it was the most enantioselective mol%) and the use of only a slight excess of imines
and efficient catalyst for the 1,2-aza-F–C reaction of (3) to N-TBS indoles (2) is possible to afford the cor-
2-methoxyfuran with N-Boc imines (3).[4a] The 1,2- responding products (4) in good chemical yield[11]
aza-F–C reaction was carried out using 2 mol% of without formation of the bisindolyl by-product[12]
(R)-1a, and an enantioenriched F–C product (4aa: under the optimized conditions.
X=H, Ar=C6H5) was obtained in 68% yield [55%
With the optimized reaction conditions in hand, the
ee (R)] as shown in Table 1 (entry 1). However, catal- scope of the enantioselective 1,2-aza-F–C reaction was
ysis of the reaction by (R)-1a was sluggish and the investigated. Representative results of (R)-1b-catalyzed
enantioselectivity was not sufficient despite thorough reactions are summarized in Table 2. The electronic
optimization of the reaction conditions. In order to nature of the indole ring did not compromise the cata-
enhance the catalytic activity and enantioselectivity, lytic activity and the corresponding F–C products (4)
we derivatized the catalyst (1) by changing the sub- were obtained in good yield while maintaining a high
stituent (G) attached at the 3,3’-position of the bi- enantioselectivity (entries 1 and 2). High enantioselec-
naphthyl backbone. Screening of the substituents re- tivities were also observed for a series of aromatic
vealed that terphenyl (TPH) groups (1b) were effec- imines examined (entries 3–17), but the position of the
tive for the present enantioselective F–C reaction, substituent on the aromatic ring exhibited a strong
albeit affording only moderate enantioselectivity impact on the catalytic activity. For example, the ortho
substituents retarded the reaction markedly (entries 3
and 7) and an increase in catalyst loading was required
to obtain the desired product (4ab) in an acceptable
yield (entries 4 and 8). Although meta substitution re-
chiral monophosphoric acid (R)-(1) [Eq. (1): X=H, Ar=
Table 1. Enantioselective 1,2-aza-Friedel–Crafts reaction of
N-TBS indole (2a) with N-Boc imine (3a) catalyzed by
C6H5].[a]
sulted in slightly lower enantioselectivities (entries 5, 9,
11), 1b exhibited excellent performance in reaction
with para-substituted aromatic imines (3) bearing a
broad range of substituents irrespective of their stereo-
electronic properties (entries 6, 10, 12–17).
Entry 1 Solvent Temperature Time Yield
ee
[h]
[%][b]
68
[%][c]
1
2
3
4
5
6
1a CHCl3
1b CHCl3
r.t.
r.t.
12
55
(R)
67
(S)
60
(S)
47
(S)
93
(S)
96
To understand the inversion in the sense of stereo-
chemical outcome observed in the catalysis between
(R)-1a and (R)-1b, we conducted a computational
study[6d] of the 3D-structures of the catalysts (1) at the
B3LYP/6-31G** level of theory. The optimized 3D-
structures of (R)-1b and (R)-1a are shown in
Figure 1.[13] We speculate that the observed inversion
of the enantioselectivity would be attributed to the
accessibility of the reactants to acidic site of the cata-
lyst (1). As depicted in Figures 1a and 1b, the TPH
substituents of (R)-1b were arranged somewhat paral-
lel on the top and bottom sides of the phosphoric acid
moiety making a reaction pocket, in what we termed
the “front” of the acid moiety. It is likely that the cat-
alyst (R)-1b provides just enough space to construct a
transient structure of the F–C reaction in front of the
acidic moiety (Figure 1a). In contrast, for the sterical-
ly demanding HMT substituents of (R)-1a (Figures 1c
and 1d), the ortho methyl substituents force the mesi-
12
12
24
24
24
79
84
37
74
85
1b CH3C6H5 r.t.
1b Et2O
r.t.
1b CHCl3
À408C
1b
A
(S)
[a]
All reactions were carried out with 0.002 mmol of (R)-1
(2 mol%), 0.1 mmol of N-TBS indole (2a), and
0.11 mmol of N-Boc imine (3a: Ar=C6H5) in 1 mL of
the indicated solvent.
[b]
[c]
Isolated yield.
Enantiomeric excess was determined by chiral HPLC
analysis. See Supporting Information for details. The ab-
solute stereochemistry was estimated from X-ray single
crystal analysis of 4aj.
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Enantioselective Aza-Friedel–Crafts Reaction of Indoles
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Table 2. Enantioselective aza-Friedel–Crafts reaction of N-TBS indole (2) with a series of N-Boc imine derivatives (3) cata-
lyzed by (R)-1b.[a]
Entry
1b [mol%]
2
3 (Ar)
4
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
2
2
2
10
3
3
2
10
2
2
2
2
2
2
2
3
3
2b
2c
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
3a: C6H5
3a
4ba
4ca
4ab
4ab
4ac
4ad
4ae
4ae
4af
4ag
4ah
4ai
4aj
4ak
4al
83
79
16
65
76
91
20
81
77
82
73
89
80
80
85
81
76
94
91
90
91
94
96
82
83
89
97
87
98
3b: 2-CH3C6H4
3b
3c: 3-CH3C6H4
3d: 4-CH3C6H4
3e: 2-FC6H4
3e
3f: 3-FC6H4
3g: 4-FC6H4
3h: 3-ClC6H4
3i: 4-ClC6H4
3j: 4-BrC6H4
3k: 4-CF3C6H4
3l: 4-MeOC6H4
3m: 4-i-PrC6H4
3n: 4-PhC6H4
9
10
11
12
13
14
15
16
17
98 (S)[d]
93
89
97
97
4am
4an
[a]
All reactions were carried out with (R)-1b, 0.1 mmol of N-TBS indole (2), and 0.11 mmol of N-Boc imine (3) in 1 mL of
1,1,2,2-tetrachloroethane at À408C for 24 h.
[b]
[c]
[d]
Isolated yield.
Enantiomeric excess was determined by chiral HPLC analysis. See Supporting Information for details.
The absolute stereochemistry of 4aj was determined to be S by X-ray single crystal analysis.
sient structure of the F–C reaction would be prevent-
ed on the “front” side of the acidic moiety (Fig-
ure 1c). As a result, we speculate that the catalytic re-
action would proceed avoiding the sterically congest-
ed front side of the acidic moiety.[13]
In conclusion, a highly enantioselective 1,2-aza-F–C
reaction of indole with aromatic imines is demonstrat-
ed using a BINOL-derived monophosphoric acid cata-
lyst [(R)-1b]. The present approach provides efficient
access to enantioenriched 3-indolylmethaneamines with
aryl substituents (up to 98% ee) and effectively com-
plements our previous method that afforded aliphatic
group-substituted 3-indolylmethaneamines via activa-
tion of enecarbamates. Furthermore, a large excess of
reactants was not necessary to avoid the formation of
the undesirable bisindolyl by-product. Further studies
to elucidate the inversion in the sense of the enantiose-
lectivities are in progress in our laboratory.
Figure 1. 3D-structures for the optimized geometries (at the
B3LYP/6-31G** level of theory) of (R)-1. P tan, O red, C
gray, H white. (a, top left) Front view of (R)-1b (G=TPH).
(b, top right) Side view of (R)-1b. (c, bottom left) Front view
of (R)-1a (G=HMT). (d, bottom right) Side view of (R)-1a.
Experimental Section
Typical Procedure for Aza-Friedel–Crafts Reaction of
N-TBS-Protected Indole (2) with N-Boc Protected
Aldimines (3)
To a dried test tube was weighed the binaphthol monophos-
phoric acid [(R)-1a; 1.95 mg, 2 mol%, 0.002 mmol] and the
atmosphere was replaced with nitrogen. The catalyst was
tyl ring to be perpendicular to the basal phenyl
moiety and thus causing the “front” side of the acidic
moiety to be congested. Hence, formation of the tran- dissolved in 1,1,2,2-tetrachloroethane (1 mL). N-Boc pro-
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Masahiro Terada et al.
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tected imine (3a: Ar=C6H5, 22.6 mg, 1.1 equivs., 0.11 mmol)
and N-TBS protected indole (2a: X=H, 23.1 mg,
0.10 mmol) were introduced at À408C in this order. The re-
sulting solution was stirred for 24 h under these conditions,
then the reaction was quenched by addition of saturated
aqueous NaHCO3 (1 drop). The reaction mixture was
poured on silica gel column and purified by column chroma-
tography (hexane/EtOAc=12/1–8/1 as eluent). The F–C
product (4aa) was obtained in 85% yield as a white solid.
The enantiomeric excess was determined by HPLC analysis.
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Acknowledgements
This work was partially supported by JSPS for a Grant-in-
Aid for Scientific Research (B) (Grant No. 17350042) and
The Sumitomo Foundation. We gratefully acknowledge fund-
ing from the JSPS Research Fellowship for Young Scientists
(K.S.). We also thank Dr. Chizuko Kabuto for X-ray analy-
sis.
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Enantioselective Aza-Friedel–Crafts Reaction of Indoles
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lysts even at room temperature for 24 h; see Support-
ing Information for details.
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at the B3LYP/6–31G** level of theory. See Supporting
Information for details.
[11] In previous reports of the enantioselective organocata-
lytic approach for 1,2-aza-F–C reaction of N-sulfonyl-
imines, at least 10 mol% of catalyst loading and an
excess of indoles (more than 2 equivalents) were re-
quired for the reaction to proceed effectively; see
refs.[3g,9]
[12] The initial F–C products are prone to undergo further
substitution reaction to give bisindolyl by-products
owing to the intrinsic instability of the initial products,
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