Indium-mediated asymmetric allylation of acylhydrazones using a chiral urea catalyst

Article abstract of DOI:10.1002/anie.200603354

(Chemical Equation Presented) Urea-ka! A new role for urea-based chiral catalysts has been uncovered in the asymmetric allylation of acylhydrazones with allylindium reagents (see scheme; Bz: benzoyl). The best results were obtained using the bifunctional

Full text of DOI:10.1002/anie.200603354

Angewandte
Chemie
DOI: 10.1002/anie.200603354
Asymmetric Allylations
Indium-Mediated Asymmetric Allylation of Acylhydrazones Using a
Chiral Urea Catalyst**
Kian L. Tan and Eric N. Jacobsen*
Imine allylation represents a powerful strategy for the
synthesis of enantioenriched homoallylic amines, and consid-
erable effort has been devoted to devising enantioselective
versions of this transformation.[1–3] In situ generated allylin-
dium reagents are attractive candidates as nucleophilic
attained with such a simple bifunctional catalyst, so we
pursued further optimization of this scaffold. The presence of
an electron-donating group on the aromatic ring of the
catalyst (6) resulted in a decrease in enantioselectivity to 24%
ee. In contrast, improving the hydrogen-bond-donor ability of
the catalyst by introducing electron-withdrawing groups on
the aromatic ring, as in 7, led to significant improvements in
enantioselectivity. Replacing the phosphinic amide with a tert-
=
partners in C Nallylation reactions because of their mildness,
functional group tolerance, and low toxicity.[4] While several
chiral-auxiliary-based methods for stereoselective allylindium
addition to C Ndouble bonds have been developed, [5] only a
À
single catalytic asymmetric variant has been identified thus
far.[6] In that example, an organic catalyst derived from binol
was shown to catalyze hydrazone allylation in moderate yield
and enantioselectivitiy ( ꢀ 70–85% ee), with improved results
attainable when stoichiometric quantities of the binol deriv-
ative were employed (84–97% ee).
Chiral urea and thiourea derivatives have proven extra-
ordinarily useful as catalysts for the enantioselective activa-
tion of imine and carbonyl derivatives toward nucleophilic
addition.[7] However, despite the extensive application of
these organic catalysts in asymmetric synthesis, their use in
conjunction with organometallic reagents has yet to be
developed. We sought to take advantage of the modular
nature of these catalysts by incorporating a Lewis basic group
in proximity to the urea moiety in order to promote the
=
addition of organometallic reagents to C Nbonds through
dual activation.[8,9] We report here the successful evolution of
this strategy, with the discovery of a new sulfinamide-urea
catalyst that promotes the indium-mediated allylation of
acylhydrazones with high levels of enantioselectivity and
yield.
The first-generation thiourea catalyst 3 (Scheme 1) was
found to mediate the addition of allylindium reagent to N-
acylhydrazone 1 in 79% yield but with only 38% ee (Table 1).
Replacement of the imine portion of catalyst 3 with a
phosphinic amide (4) yielded almost racemic product; how-
ever, when the tert-leucine portion of the catalyst was
replaced by a phenyl group (5), moderate enantioselectivity
was restored. We were intrigued by the promising results
Scheme 1. Model allylation reaction and representative catalysts.
Bz: benzoyl;Piv: pivaloyl.
Table 1: Catalyst optimization studies for the enantioselective allylation
of 1.
[*] Dr. K. L. Tan, Prof. E. N. Jacobsen
Department of Chemistry and Chemical Biology
Harvard University
Catalyst
Yield [%][a]
ee [%]
Cambridge, MA 02138 (USA)
3
4
5
6
7
8a
8b
79
52
91
82
90
75
87
38
À2
30
24
52
26
91
Fax: (+1)617-496-1880
E-mail: jacobsen@chemistry.harvard.edu
[**] This work was supported by the NIH (GM-43214 and P50 GM-
69721). K.L.T. gratefully acknowledges the NIH for a postdoctoral
fellowship. Dr. Richard Staples is acknowledged for the determi-
nation of the X-ray crystal structure of 8b.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
[a] Determined by HPLC by integration against an internal standard.
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Communications
butyl sulfinamide functionality had a dramatic impact on
(generally less than 50% ee); however, measurable improve-
ments were attained with substrates bearing electron-defi-
cient N-acyl groups (Scheme 2).
catalyst performance.[10] The diastereomeric sulfinamides 8a
and 8b promoted the allylation of 1 with 26% and 91% ee,
respectively. Crystallographic analysis of 8b revealed an
intramolecular hydrogen bond between the NH group of the
=
sulfinamide and the C O function of the urea in the solid-
state structure (Figure 1). This hydrogen bond may serve to
increase the Lewis acidity of the urea functionality and/or to
rigidify the catalyst structure.
Scheme 2. Allylation of an aliphatic acylhydrazone catalyzed by 8b.
During the course of these studies, we observed that the
generation of the allylindium species was dependent on both
the batch of indium and the rate of stirring. When the stir rate
was high, the formation of the allylindium was rapid, resulting
in complete consumption of the indium metal. In these cases,
slightly lower enantioselectivities but increased yields were
obtained in acylhydrazone allylations (Table 2, entries 4 and
6–8; values in parentheses). To address whether this phenom-
enon might lead to problems upon reaction scale-up, the
allylation was performed on 10 mmol of 1. This reaction was
found to proceed with 89% ee and 94% yield, only a minor
deviation from the aforementioned results of 87% yield and
92% ee obtained on a 1-mmol scale (Scheme 3 vs entry 1,
Table 2).
Figure 1. ORTEP view (50% probability level) of the solid-state struc-
ture of catalyst 8b (O red, S yellow, F green, N blue, C gray).
The scope of the indium-mediated allylation was devel-
oped with optimized catalyst 8b (Table 2). Acylhydrazones
derived from aromatic or heteroaromatic aldehydes were
Table 2: Asymmetric allylation of acylhydrazones catalyzed by 8b.
Entry
R
Yield [%]
ee [%]
Scheme 3. Gram-scale allylation of hydrazone 1.
[a]
1
2
3
4
5
6
7
8
9
C6H5
87
83
90
92
92
87
[b]
p-ClC6H4
2-furyl[a]
Enantioselective crotylation reactions were also exam-
ined using catalyst 8b (Table 3). The syn and anti diastereo-
meric products were generated with high ee values but with
2-thienyl[a]
82 (93)[c]
92
93 (87)[c]
76
[a]
p-(CO2CH3)C6H4
o-BrC6H4
78 (89)[c]
89 (98)[c]
89 (99)[c]
79
93 (90)[c]
95 (94)[c]
95 (92)[c]
93
[a]
[a]
o-CH3C6H4
Table 3: Asymmetric crotylation of acylhydrazone catalyzed by 8b.
1-naphthyl[a]
[b]
p-(CH3O)C6H4
[a] Conditions: 8b (10 mol%), À208C, toluene, indium powder
(1.75 equiv), allyl bromide (2.63 equiv). [b] Conditions: 8b (10 mol%),
À208C, toluene, indium powder (1.35 equiv), allyl bromide (2.00 equiv).
[c] Yields and ee values in parentheses correspond to results obtained
using higher stir rates (see Supporting Information for experimental
details).
found to undergo the allylation with both high ee and yield.[11]
Substrates bearing ortho substituents on the aromatic ring
were particularly effective, with enantioselectivities between
93–95% ee observed (Table 2, entries 6–8). Aryl halides were
compatible with the reaction conditions (Table 2, entries 2
and 6). Acylhydrazones derived from aliphatic aldehydes
underwent allylation with substantially lower ee values
Substrate
Yield [%]
70
Product ratio
syn
anti
a
(E)-crotyl
bromide
1.10
(90% ee)
1.00
(85% ee)
0.40
(>90% ee)
(Z)-crotyl
bromide
71
1.57
(95% ee)
1.00
(86% ee)
0.38
(90% ee)
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Angewandte
Chemie
Chem. Soc. 2003, 125, 14133 – 14139; e) D. Ferraris, T. Dudding,
very poor diastereoselectivities. It is likely that the allylin-
dium reagent is not geometrically stable,[12] as the reactions of
both (Z)- and (E)-crotyl bromide afforded similar product
mixtures.
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The discovery of catalyst 8b, which bears both a urea and
sulfinamide functionality, has led to the first application of
urea catalysis for highly enantioselective additions of organ-
ometallic reagents. The bifunctional nature of the catalyst, in
which a hydrogen-bond donor and a Lewis base are posi-
tioned properly and in close proximity, was found to be crucial
for the attainment of high ee values. The utility of 8b and
related urea derivatives in other synthetically interesting
nucleophile–electrophile reactions is under current investi-
gation.
[2] For examples of hydrazone allylation with chiral reagents, see:
a) C. Ogawa, M. Sugiura, S. Kobayashi, Angew. Chem. 2004, 116,
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5686 – 5687.
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G. K. Friestad, Synthesis 2005, 2815 – 2829.
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1743.
[6] G. R. Cook, R. Kargbo, B. Maity, Org. Lett. 2005, 7, 2767 – 2770.
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5427; b) M. S. Taylor, E. N. Jacobsen, Angew. Chem. 2006, 118,
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Schreiner, Chem. Soc. Rev. 2003, 32, 289 – 296; d) Y. Takemoto,
Org. Biomol. Chem. 2005, 3, 4299 – 4306.
[8] For reviews on multifunctional catalysis, see: a) H. Groger,
Chem. Eur. J. 2001, 7, 5246 – 5251; b) M. Shibasaki, M. Kanai, K.
Funabashi, Chem. Commun. 2002, 1989 – 2183.
[9] For reports of bifunctional thiourea catalysts that promote
enantioselective reactions through dual activation, see ref. [7b]
and: a) S. B. Tsogoeva, S. Wei, Chem. Commun. 2006, 1451 –
1453; b) H. Huang, E. N. Jacobsen, J. Am. Chem. Soc. 2006, 128,
7170 – 7171; c) T. Inokuma, Y. Hoashi, Y. Takemoto, J. Am.
Chem. Soc. 2006, 128, 9413 – 9419; d) J. Song, Y. Wang, L. Deng,
J. Am. Chem. Soc. 2006, 128, 6048 – 6049.
Experimental Section
General procedure for the allylation of acylhydrazones catalyzed by
8b: Benzoic acid N’-[1-(2-bromo-phenyl)-but-3-enyl]-hydrazide
(Table 2, entry 6). 2-bromobenzoic acid benzylidene hydrazide
(303 mg, 1.00 mmol), indium powder (200 mg, 1.74 mmol), and 8b
(47 mg, 0.10 mmol) were added to a 20-mL scintillation vial. The vial
was purged with N2 for approximately 20 min, and then toluene
(10 mL) was added. The reaction mixture was cooled to À788C, and
then allyl bromide was added (228 mL, 2.63 mmol; purified through
an alumina plug immediately prior to use). The reaction mixture was
stirred vigorously at À208C for 19 h, then removed from the cold
bath, and immediately quenched with 1n HCl (4 mL) at room
temperature. The reaction mixture was diluted with ethyl acetate
(25 mL) and 0.67n NaOH (60 mL). The aqueous layer was extracted
with ethyl acetate (2 ” 25 mL), and the organic layer was dried with
Na2SO4, filtered, and concentrated. The resulting residue was purified
by chromatography on silica gel (20% ethyl acetate/hexanes) to
afford a white solid (270 mg, 0.78 mmol, 78% yield). The enantio-
meric excess was determined to be 93% by SFC using a commercial
chiral stationary phase (Chiralpak OD-H, 15% methanol/CO2,
4 mLminÀ1À1, 308C, 254 nm; tr(minor): 2.42 min, tr(major): 2.77 min;
[a] = À78 degcm3 gÀ1 dmÀ1 (c = 0.730 gcmÀ3
,
CHCl3); 1H N MR
(400 MHz, CDCl3): d = 7.67 (dd, J = 1.8, 7.7, 1H), 7.62–7.58 (m,
2H), 7.54 (dd, J = 1.1, 7.7, 1H), 7.50–7.40 (m, 2H), 7.39–7.31 (m, 3H),
7.13 (dt, 1H, J = 1.8, 8.1), 5.97–5.88 (m, 1H), 5.31 (dd, J = 2.6, 7.0,
1H), 5.21 (dd, J = 2.1, 17.2, 1H), 5.17 (d, J = 10.6, 1H), 5.8–5.6 (m,
1H), 2.6–2.5 (m, 1H), 2.40 ppm (app dt, J = 8.4, 14.3, 1H); 13C N MR
(100 MHz, CDCl3): d = 167.2, 140.7, 134.0, 133.0, 132.8, 131.8, 128.8,
128.6, 128.3, 127.7, 126.8, 124.5, 118.4, 62.1, 39.3 ppm. IR (NaCl): n˜ =
3282.7 (br), 3064.7, 1638.4 9 (s), 1467.7 cmÀ1. ESI m/z [M+1]: 345.1
and 347.1.
Received: August 17, 2006
Published online: January 9, 2007
Keywords: allylation · asymmetric catalysis · indium ·
.
[10] Catalyst 8b was synthesized using commercially available
racemic tert-butyl sulfinyl chloride (Aldrich). The thiourea
variant of 8b promoted the model reaction with decreased
enantioselectivity, presumably owing to competitive coordina-
tion of the thiourea functionality to the allylindium species.
[11] The absolute configuration was determined for entries 2 and 7
(Table 2) to be S by comparison to optical rotations reported in
the literature. See ref. [2b].
synthetic methods
[1] For examples of enantioselective metal-catalyzed allylations of
imines, see: a) K. Nakamura, H. Nakamura, Y. Yamamoto, J.
Org. Chem. 1999, 64, 2614 – 2615; b) R. A. Fernandes, Y.
Yamamoto, J. Org. Chem. 2004, 69, 735 – 738; c) H. Nakamura,
K. Nakamura, Y. Yamamoto, J. Am. Chem. Soc. 1998, 120, 4242 –
4243; d) R. A. Fernandes, A. Stimac, Y. Yamamoto, J. Am.
[12] M. B. Isaac, T. H. Chan, Tetrahedron Lett. 1995, 36, 8957 – 8960.
Angew. Chem. Int. Ed. 2007, 46, 1315 –1317
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