Catalytic enantioselective pyrrole alkylations of α,β- unsaturated 2-acyl imidazoles

Article abstract of DOI:10.1021/ol060576e

Enantioselective additions of pyrroles to α,β-unsaturated 2-acyl imidazoles catalyzed by the bis(oxazolinyl)pyridine-scandium(III) triflate complex (1) have been accomplished. The α,β-unsaturated 2-acyl imidazoles were synthesized in high yields through W

Full text of DOI:10.1021/ol060576e

ORGANIC
LETTERS
2006
Vol. 8, No. 11
2249-2252
Catalytic Enantioselective Pyrrole
Alkylations of
Imidazoles
r,â-Unsaturated 2-Acyl
David A. Evans* and Keith R. Fandrick
Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
eVans@chemistry.harVard.edu
Received March 8, 2006
ABSTRACT
Enantioselective additions of pyrroles to
(1) have been accomplished. The
enantioselective synthesis of the alkaloid (
and cyclization. This methodology was then extended to the one-pot asymmetric synthesis of 2-substituted indoles.
r
,
â
-unsaturated 2-acyl imidazoles catalyzed by the bis(oxazolinyl)pyridine
−
scandium(III) triflate complex
r
,
â
-unsaturated 2-acyl imidazoles were synthesized in high yields through Wittig olefination. A short,
+
)-heliotridane has been accomplished utilizing this methodology and a 2-acyl imidazole cleavage
The Friedel-Crafts reaction has been employed as a power-
ful carbon-carbon bond forming process in modern organic
chemistry.1 Even though considerable effort has been ex-
pended in the development of asymmetric Michael-type
reactions between indoles and R,â-unsaturated carbonyl
compounds,2 the corresponding reaction with pyrroles has
received less attention. MacMillan was the first to report
catalytic asymmetric conjugate additions between pyrroles
and R,â-unsaturated carbonyl compounds.3 Palomo later
showed that R′-hydroxy enones are competent electrophiles
for the conjugate addition of pyrroles utilizing our previously
reported Cu(II) bis(oxazoline) catalyst.4 However, both of
these examples focused on the use of N-alkyl-substituted
pyrroles at subzero reaction temperatures. We previously
reported that R,â-unsaturated 2-acyl imidazoles exhibit
excellent enantioselectivity and yields for alkylations among
indoles, pyrrole, and 2-methoxyfuran catalyzed by Sc
complex 1 (Scheme 1).5 Considering the value of pyrroles
as useful synthons and as pyrrolidine surrogates,6 we have
expanded the reaction scope to include a range of pyrrole
nucleophiles. In this letter, we report our studies in the
enantioselective pyrrole Friedel-Crafts alkylation and the
synthesis of the requisite R,â-unsaturated 2-acyl imidazoles.
The synthesis of â-substituted R,â-unsaturated 2-acyl
imidazoles may be accomplished in a number of ways,5 and
(1) For a review on the Friedel-Crafts reaction, see: Olah, G. A.;
Krishnamurti, R.; Prakash, G. K. S. Friedel-Crafts Alkylations. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 3, pp 293-339.
(4) (a) Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garcia, J. M.; Linden,
A. J. Am. Chem. Soc. 2005, 127, 4154-4155. (b) Johnson, J. S.; Evans, D.
A. Acc. Chem. Res. 2000, 33, 325-335.
(5) Evans, D. A.; Fandrick, K. R.; Song, H.-J. J. Am. Chem. Soc. 2005,
127, 8942-8943.
(6) For the hydrogenation of pyrroles to pyrrolidines, see: (a) Kaiser,
H.-P.; Muchowski, J. M. J. Org. Chem. 1984, 49, 4203-4209. (b) Gilchrist,
T. L.; Lemos, A.; Ottaway, C. J. J. Chem. Soc., Perkin Trans. 1 1997,
3005-3012.
(2) (a) For a review on the previous work on the Friedel-Crafts reaction
between indoles and R,â-unsaturated carbonyl compounds, see: Bandini,
M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43, 550-
556. (b) For Sc(III)-catalyzed additions of indoles to R,â-unsaturated keto
phosphonates, see: Evans, D. A.; Sheidt, K. A.; Fandrick, K. R.; Lam, H.
W.; Wu, J. J. Am. Chem. Soc. 2003, 125, 10780-10781.
(3) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123,
4370-4371.
10.1021/ol060576e CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/06/2006

afforded the corresponding R,â-unsaturated 2-acyl imidazoles
4 in high yields and excellent E:Z selectivities.
As summarized in Table 1, more sterically demanding
Scheme 1. Asymmetric Catalytic Friedel-Crafts Alkylations
with R,â-Unsaturated 2-Acyl Imidazoles
Table 1. Effects of N-Substitution on the Friedel-Crafts
Reaction between 2-Acyl Imidazole 4 and Pyrrole (eq 4)a
entry
R1
R2
mol % of 1
ee (%)b
yield (%)
1
2
3
4
5c
6
Me
iso-Pr
Ph
Bn
Me
H
H
H
H
Me
Me
5
5
5
5
5
5
87
94
94
91
77
89
69 (6a)
91 (6b)
98 (6c)
84 (6d)
69 (6e)
78 (6f)
the preferred method for the preparation of a given substrate
will depend on the â-substituent. Direct acylation of the
corresponding R,â-unsaturated carboxylic acids is the most
direct route to substrates 4a and 4b. However, a more general
method is needed to prepare more complex substrates,
substrates with sensitive functional groups, or substrates
where the corresponding carboxylic acid is not readily
available. Shibasaki has shown that R,â-unsaturated N-acyl
pyrroles may be effectively synthesized via Wittig olefina-
tion.7 We chose to apply this methodology to the synthesis
of R,â-unsaturated 2-acyl imidazoles. Preparation of Wittig
reagent 2 proceeded cleanly starting from tert-butyl chloro-
iso-Pr
a All reactions were carried out at 0.13 M in substrate. b Enantiomeric
excess determined by chiral HPLC. c Reaction carried out at 0.26 M in
substrate.
N-substituents on the imidazole moiety afford an increase in
enantioselectivity. Even though the phenyl substituent was
optimal with regard to overall yield (98%) and enantioselectiv-
ity (94% ee), we decided to employ the more readily prepared
N-iso-propylimidazoles with a small sacrifice in yield.
After a determination of the optimal N-substituent on the
imidazole moiety 4, the effects of temperature and catalyst
loading on the illustrated reaction were evaluated (Table 2).
Table 2. Scandium-Catalyzed Alkylations of R,â-Unsaturated
2-Acyl Imidazoles 4 with Pyrrole 5a (eq 5)a
temp time ee
mol % of 1 (°C)
(h) (%)b
yield
(%)
entry
R
1
2
3
4
5
6
7
8
9
Me (4a)
Me (4a)
Me (4a)
Me (4a)
Me (4a)
Me (4a)
Me (4a)
Me (4a)
Me (4a)
5
5
5
20
0
5
5
85 99 (6b)
90 95 (6b)
94 96 (6b)
95 99 (6b)c
93 99 (6b)c
86 99 (6b)c
78 99 (6b)c
62 99 (6b)c
93 90 (6b)
86 91 (6g)
91 90 (6h)
84 99 (6i)
96 99 (6j)
92 98 (6k)
96 99 (6l)
91 95 (6m)
-40
-40
-40
-40
-40
-40
0
15
15
15
15
15
15
18
18
18
18
18
18
18
18
2
10
20
30
50
2
2
2
2
2
10
11
12
13
14
15
16
Et (4b)
i-Pr (4c)
0
0
0
0
0
0
0
CO2Et (4d)
Ph (4e)
p-MeOPh (4f)
p-CO2MePh (4g)
2-furyl (4k)
Figure 1. Synthesis of R,â-unsaturated 2-acyl imidazoles.a
2
2
2
a All reactions performed at 0.13 M in substrate. b Enantiomeric excess
acetate (Figure 1). Wittig reagent 2 was prepared on a
multigram scale and was used without further purification.
Wittig olefination between 2 and a variety of aldehydes 3
determined by chiral HPLC. c Reported as conversion based on H NMR
1
spectroscopy.
2250
Org. Lett., Vol. 8, No. 11, 2006

As summarized, the reaction may be conveniently run at 0
°C with good enantioselectivities (90% ee) and yields (95%,
entry 2). An increase in catalyst loading leads to lower
enantioselectivities (entries 3-7). This inverse relationship
between catalyst loading and ee was previously observed
by us.5 Finally, an increase in catalyst loading above 20 mol
% leads to deleterious effects on facial selectivities (Table
2, entries 6-8).
Table 4. Asymmetric Synthesis of 2-Substituted Indoles,
4,7-Dihydroindole Alkylations of R,â-Unsaturated 2-Acyl
Imidazoles,a and Subsequent One-Pot Aromatization
The effect of the â-substituent on reaction enantioselection
is also summarized in Table 2. Alkyl and aryl substitution
are well tolerated in the illustrated reaction (entries 9-16).
Next, the effects of pyrrole substitution were evaluated
(Table 3). N-substitution on the pyrrole heterocycle leads to
imidazole
R
ee (%)b
yield (%)
4a
4b
4c
4e
4f
4g
4h
4i
Me
Et
i-Pr
95
77
72
96
90
97
96
93
95
80
99 (9a)
97 (9b)
62 (9c)
98 (9e)
97 (9f)
85 (9g)
98 (9h)
90 (9i)
85 (9j)
92 (9k)
Ph
p-MeOPh
p-CO2MePh
p-ClPh
o-ClPh
p-BrPh
2-furyl
Table 3. Scandium-Catalyzed Alkylations of R,â-Unsaturated
2-Acyl Imidazole 4a and Substituted Pyrroles (eq 6)a
4j
4k
a All reactions performed at 0.13 M in substrate. b Enantiomeric excess
determined by chiral HPLC.
R1
R2
R3
temp (°C)
ee (%)b
yield (%)
significantly (Table 4). We found that if the addition of 2
equiv of p-benzoquinone to the reaction occurs at the end
of the conjugate addition a one-pot preparation of 2-substi-
tuted indoles from the enones 4 and 4,7-dihydroindole may
be realized. This two-step sequence is well tolerant of
â-substitution on the enone providing the 2-substituted
indoles in good to excellent enantioselectivities and yields.
Initial attempts to cleave the 2-acyl imidazole 6a directly
without pyrrole protection afforded the desired methyl ester
in low yields ((a) MeOTf, CH2Cl2, rt; (b) MeOH, DBU).
By utilizing acetonitrile as solvent and a Boc protection9 of
the pyrrole nitrogen (96% yield), a greatly increased yield
of the cleavage process to the derived methyl ester was
realized (92%, 11, Figure 2). Cleavage of the 2-substituted
H
Me
Bn
H
H
H
H
H
H
Et
Et
Me
Me
H
H
H
H
H
-40
-40
-40
-40
0
94
78
11
93
89
69
78
96 (6b)
89 (6f)
67 (7a)
99 (7b)
99 (7b)
99 (7c)
99 (7c)
Me
Me
-40
0
H
a All reactions performed at 0.13 M in substrate. b Enantiomeric excess
determined by chiral HPLC.
a decrease in enantioselectivity. For example, N-benzylpyr-
role is only poorly enantioselective (11% ee, Table 3), a result
that is in sharp contrast to the Friedel-Crafts reactions with
N-substituted indoles which afford the highest enantioselec-
tivities.5 The reaction is also not tolerant of substitution at
the 3-position of the pyrrole nucleus; however, 2-ethylpyrrole
was a competent nucleophile for the illustrated conjugate
addition reaction (93% ee, 99% yield).
One may also access the 2-position of the indole nucleus
if the dihydroindole is employed as the nucleophilic reaction
component.8 Sarac¸oglu has utilized this ploy in the racemic
conjugate addition of 4,7-dihydroindole to enones followed
by a p-benzoquinone oxidation to provide the 2-substituted
indoles in moderate yields (30-49%).8
Initial attempts at the conjugate addition of 4,7-dihydroin-
dole to enone 4a were quite successful (90% ee, 99% yield);
however, the subsequent aromatization to the indole nucleus
with p-benzoquinone was sluggish when the oxidation was
performed in dichloromethane as reported by Sarac¸oglu.9 If
this reaction is performed in acetonitrile, the yields improve
Figure 2. Cleavage of 2-acyl imidazoles 10 and 9e.
indole product 9e to the methyl ester (12, 99% yield) and
the carboxylic acid (13, 71% yield, Figure 2) was effective
using the modified methylation conditions described above.
For the dihydroindole substrates, N-protection was not
necessary.
(7) Matsunaga, S.; Kinosita, T.; Harada, S.; Shibasaki, M. J. Am. Chem.
Soc. 2004, 126, 7559-7570.
(8) C¸ avdar, H.; Sarac¸oglu, N. Tetrahedron 2005, 61, 2401-2405.
(9) Davies, H. W.; Matasi, J. J.; Ahmed, G. J. Org. Chem. 1996, 61,
2305-2313.
Org. Lett., Vol. 8, No. 11, 2006
2251

If the imidazole cleavage in the pyrrole series was
performed in the absence of an external nucleophile, the
pyrrole nitrogen was internally acylated to give a 2,3-
dihydro-1H-pyrrolizine (Scheme 2). We felt that this chem-
trace amounts of product. We found that with acetonitrile
as solvent we could use a slight excess (1.1 equiv) of methyl
triflate to completely methylate the 2-acyl imidazole (Scheme
2). The use of DMAP or Hu¨nig’s base to promote acyl
transfer provided the 2,3-dihydro-1H-pyrrolizine 14 in
quantitative yield in a one-pot operation.
With the 2,3-dihydro-1H-pyrrolizine 14 in hand, the
completion of the synthesis of (+)-heliotridane was straight-
forward. The hydrogenation6 of 14 afforded the hexahydro-
pyrrolizin-3-one 15 in quantitative yield (90:10 dr), and the
subsequent LAH reduction8 (97% yield) provided (+)-
heliotridane (Scheme 2). The material was purified and
Scheme 2. One-Pot Methylation and Cyclization of 6b to
2,3-Dihydro-1H-pyrrolizine 14 and the Synthesis of
(+)-Heliotridane
characterized as the picrate salt (optical rotation: [R]20
+20.4° (c ) 0.77, CHCl3) lit.11d (-)-heliotridane, [R]20
-22.4° (c ) 0.25, CHCl3)).
)
)
D
D
In summary, we have shown that a wide range of
â-substituted R,â-unsaturated 2-acyl imidazoles are compe-
tent electrophiles for the Friedel-Crafts reaction with free
pyrroles at noncryogenic temperatures. The use of 4,7-
dihydroindole allowed for the one-pot asymmetric synthesis
of a wide range of 2-substituted indoles. The R,â-unsaturated
2-acyl imidazoles are easily produced from the corresponding
aldehydes and the Wittig reagent 2 in high yields and E:Z
selectivity. With the synthesis of (+)-heliotridane, we
discovered a more facile and efficient cleavage protocol for
the 2-acyl imidazoles.
istry would be amenable to the synthesis of the hexahydro-
1H-pyrrolizinealkaloidssuchas(+)-heliotridane.10 Examination
of the one-pot methylation and cyclization utilizing the
known methods of 2-acyl imidazole cleavage11 proved to
be disappointing (excess MeOTf in CH2Cl2, <10% yield).
The use of excess MeI in DMF, which effectively cleaved
the 2-acyl imidazole in our previous work,5 only provided
Acknowledgment. Financial support was provided by the
NIH (GM-33328-20), the NSF (CHE-9907094), and Merck
Research Laboratories.
(10) For a partial list of syntheses of heliotridane, see: (a) Kim, S.-H.;
Kim, S.-I.; Cha, J. K. J. Org. Chem. 1999, 64, 6771-6775. (b) Pandey,
G.; Reddy, G. D.; Chakrabarti, D. J. Chem. Soc., Perkin Trans. 1 1994,
219-224. (c) Keusenkothen, P. F.; Smith, M. B. J. Chem. Soc., Perkin
Trans. 1 1994, 2485-2492. (d) Doyle, M. P.; Kalinin, A. V. Tetrahedron
Lett. 1996, 37, 1371-1374.
(11) (a) Miyashita, A.; Suzuki, Y.; Nagasaki, I.; Ishiguro, C.; Iwamoto,
K.-I.; Higashino, T. Chem. Pharm. Bull. 1997, 45, 1254-1258. (b) Ohta,
S.; Hayakawa, S.; Nishimura, K.; Okamoto, M. Chem. Pharm. Bull. 1987,
35, 1058-1069. (c) Davies, D. H.; Hall, J.; Smith, E. H. J. Chem. Soc.,
Perkin Trans. 1 1991, 2691-2698.
Supporting Information Available: Complete experi-
mental details, proton and carbon NMR spectra for all new
compounds, and stereochemical determination are available
in the Supporting Information document (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
OL060576E
2252
Org. Lett., Vol. 8, No. 11, 2006