First regio- and enantioselective chromium-catalyzed homoallenylation of aldehydes

Article abstract of DOI:10.1002/anie.200903647

Game, set, and match: The first regio- and enantioselective version of the title reaction is described. The chiral catalyst prepared in situ from CrCl ₃ and a non-C₂-symmetric bis(oxazoline) ligand 1 affords the valuable chiral ss-al

Full text of DOI:10.1002/anie.200903647

Communications
DOI: 10.1002/anie.200903647
Asymmetric Catalysis
First Regio- and Enantioselective Chromium-Catalyzed
Homoallenylation of Aldehydes**
Vincent Coeffard, Miriam Aylward, and Patrick J. Guiry*
In memory of Jean-Pierre Finet
Metal-mediated allylation and allenylation are powerful
transformations in organic synthesis.[1,2] In particular, the
generation of enantiomerically enriched homoallylic and
allenic alcohols is a thriving area because of the importance
of these building blocks in the synthesis of biologically active
natural products and pharmaceutical drugs.[3,4] Whereas many
successful methods have been described for carbonyl allyla-
tion and allenylation, metal-catalyzed homoallenylation of
carbonyl compounds has been scarcely reported despite the
widespread utility of b-allenols as structural units.[5] Most of
the non-asymmetric homoallenylations of carbonyl com-
pounds reported to date require tedious preparation of the
starting materials and suffer from drawbacks such as the lack
of chemoselectivity or regioselectivity, which lowers the
synthetic appeal of this reaction.[6] In addition, to the best of
our knowledge, the regio- and enantioselective metal-cata-
lyzed homoallenylation of aldehydes has not been reported.
As part of our ongoing research into the development[7] and
application[8] of chiral ligands to the enantioselective Nozaki–
Hiyama–Kishi (NHK) reaction, we report herein the first
regio- and enantioselective NHK homoallenylation of alde-
hydes.
allowing non-asymmetric homoallenylation of aldehydes, we
first investigated the synthesis of racemic b-allenols through
the addition of homoallenyl bromide 1 to aldehydes 2 using
the CrCl3 (10 mol%)/Mn (3 equiv) in the presence of TMSCl
(Table 1). After screening of solvents, temperatures, and
Table 1: Chromium-catalyzed homoallenylation of various aldehydes.
Entry
R
3/4[a]
Product
Yield [%][b]
1
2
3
4
5
6
7
C6H5
77:23
75:25
85:15
86:14
69:31
70:30
74:26
3a
3b
3c
3d
3e
3 f
45
48
50
55
25
32
20
1-naphthyl
p-ClC6H4
m-ClC6H4
(E)-PhCH CH
PhCH2CH2
c-C6H11
=
3g
The NHK reaction,[9] first reported in the late 1970s, has
become an important and versatile carbon–carbon bond-
forming process which has been widely applied in total
synthesis.[10] Its unique and important features prompted us to
consider the NHK reaction as a method to develop an
efficient and regioselective homoallenylation of aldehydes.
Hence, we surmised that the readily available homoallenyl
bromide 1 would generate b-allenol 3 using chromium-
mediated catalysis.[11] Because of the lack of a method
[a] Ratio 3/4 was determined by 1H NMR spectroscopy of the crude
product after workup. [b] Yield of isolated b-allenol 3 after careful
purification. TMS=trimethylsilyl.
ligands, the best reaction conditions included THF as
the solvent and N,N,N’,N’-tetramethylethylenediamine
(TMEDA) as the ligand (20 mol%), leading to a mixture of
alcohols 3/4 wherein 3 was the major product.[12] Under these
optimized conditions, a range of aromatic and aliphatic
aldehydes were successfully homoallenylated to give pure b-
allenols 3 after careful purification by column chromatogra-
phy (Table 1).
Similar levels of regioselectivity were obtained regardless
of the aldehyde (Table 1). b-Allenols 3 were obtained in
moderate to good yields with aromatic aldehydes (Table 1,
entries 1–4), and the use of trans-cinnamaldehyde or aliphatic
aldehydes led to a decrease in product yields (Table 1,
entries 5–7). The best result was obtained with meta-chlor-
obenzaldehyde leading to pure b-allenol 3d in 55% yield with
an 86:14 ratio of 3/4 (Table 1, entry 4). With a racemic method
in hand, we decided to explore the asymmetric variant using a
chiral ligand to access enantioenriched b-allenols.[13] For this
purpose, the ligand has to fulfill certain criteria to allow an
efficient asymmetric homoallenylation: the chromium(III)–
ligand intermediate has to be reactive with a wide range of
[*] Dr. V. Coeffard, M. Aylward, Prof. P. J. Guiry
Centre for Synthesis and Chemical Biology (CSCB)
School of Chemistry and Chemical Biology
Conway Institute of Biomolecular Research
University College Dublin
Belfield, Dublin 4 (Ireland)
Fax: (+353)1-716-2501
E-mail: patrick.guiry@ucd.ie
[**] We thank Science Foundation Ireland for the award of a postdoc-
toral scholarship (054/RFP4/CHE/0075) for V.C. and the Irish
Research Council for Science Engineering and Technology (RS/
2006/6) for a grant to M.A. We also acknowledge financial support
from the Centre for Synthesis and Chemical Biology, which was
funded by the Higher Education Authority’s Programme for
Research in Third-Level Institutions (PRTLI).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903647.
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aldehydes (aromatic and aliphatic), and regioselectively and
enantioselectively deliver the desired b-allenols 3.
good to excellent enantioselectivities (Table 2, entries 4–6).
The best result was obtained with the tert-butyl/isopropyl
ligand 5 f, which afforded only the desired b-allenol 3a in a
51% yield in favor of the R enantiomer in 96% ee (Table 2,
entry 6). This is the same sense of induction as previously
observed for the allylation, methallylation, and crotylation of
benzaldehyde using 5 f as the ligand.[8] These results also
represent one of the few examples in the literature where
non-symmetric bis(oxazoline) ligands are used to induce high
enantioselectivity in an asymmetric process.[8,14] Furthermore,
the importance of the oxazoline substitution pattern is
underlined by the homoallenylation of benzaldehyde using
the unsubstituted ligand 5g (Table 2, entry 7) which led to a
mixture of alcohols 3a and 4a (3a/4a 69:31).
We recently reported the straightforward synthesis of
tridentate C2- and non-C2-symmetric bis(oxazoline) ligands
5a–f and their successful application to the enantioselective
NHK allylation, crotylation, and methallylation of aldehydes
(Figure 1).[7,8] Because of the high diastereo- and enantiose-
lectivities induced by these tridentate ligands, we envisioned
that 5a–f could satisfy the above criteria.
The chromium-catalyzed addition of homoallenyl bro-
mide 1 using the optimal ligand 5 f was then used with other
aldehydic substrates (Table 3). The yields (40–73%) and
Figure 1. Tridentate bis(oxazoline) ligands 5.
Table 3: Asymmetric chromium-catalyzed homoallenylation of various
aldehydes using ligand 5 f.
By using the reaction conditions described previously with
THF as the solvent,[8a] ligands 5 were investigated in the
chromium-mediated homoallenylation of benzaldehyde with
homoallenyl bromide 1 (Table 2). The results show a dramatic
Table 2: Chromium-catalyzed homoallenylation of benzaldehyde using
ligands 5.
Entry
R
3/4[a]
Product Yield [%][b]
ee [%]
(Config.)[c]
1
2
3
4
5
6
7
8
9
C6H5
100:0
97:3
3a
3b
3c
3d
3h
3i
51
50[d]
53
63
40
50
49
58
50
73
96 (R)
92 (R)
91 (R)
98 (R)
95 (R)
93 (R)
87 (R)
96 (R)
95 (S)[e]
60 (S)[e]
1-naphthyl
p-ClC6H4
m-ClC6H4
p-MeOC6H4
p-MeSC6H4
3-furyl
(E)-PhCH CH
PhCH2CH2
c-C6H11
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
Entry Ligand 3a/4a[a] Conv. [%][b] Yield 3a [%][c] ee [%]
3j
=
(Config.)[d]
3e
3 f
3g
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5 f
71:29
74:26
84:16
100:0
100:0
100:0
69:31
80
93
85
35
45
87
83
39
33
40
16
23
51
43
8 (S)
11 (R)
49 (R)
84 (R)
91 (R)
96 (R)
–
10
1
[a] The ratio 3/4 was determined by H NMR spectroscopy of the crude
product after workup. [b] Yield of isolated product after purification.
[c] The ee value was determined by chiral HPLC methods and the
absolute configuration of the alcohol was assigned by a modified
Mosher’s method or by comparison of the specific rotation to literature
values (see the Supporting Information). [d] Obtained as a 97:3 mixture
of 3/4. [e] Same sense of induction as entries 1–8.
5g
1
[a] Ratio 3a/4a was determined by H NMR spectroscopy of the crude
product after workup. [b] Conversion of substrates into alcohols 3a and
4a was determined by 1H NMR spectroscopy on the crude reaction
mixture. [c] Yield of isolated product after careful purification. [d] The
ee value was determined by chiral HPLC methods and the absolute
configuration of the alcohol was assigned by a modified Mosher’s
method (see the Supporting Information).
regioselectivities obtained for both aromatic and aliphatic
aldehydes were similar to those with benzaldehyde. In terms
of enantiodiscrimination, the reaction of 1 with aromatic and
heteroaromatic aldehydes gave rise to (R)-b-allenols 3 with
excellent enantiomeric excesses regardless of the substitution
on the aromatic ring in 2 (Table 3, entries 1–7).[15] As in the
case of aromatic aldehydes, the homoallenylation of trans-
cinnamaldehyde and 3-phenylpropanal furnished the desired
b-allenols 3e and 3 f, respectively, with excellent enantiose-
lectivities (Table 3, entries 8 and 9), and the chiral b-allenol
3g derived from cyclohexanecarboxaldehyde was obtained
with good enantiocontrol (Table 3, entry 10).
influence of the oxazoline substitution pattern upon the
reactivity, regioselectivity, as well as the extent of asymmetric
induction of this reaction. Homoallenylation using ligands
5a–c proceeded in high conversions but with moderate
regioselectivities and low ee values (Table 2, entries 1–3). At
this point, we were pleased to observe that ligands 5d–f
allowed the formation of b-allenol 3a as the only product with
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On the basis of the above results, a plausible mechanism
[1] For reviews of carbonyl allylation, see: a) Y. Yamamoto, N.
Asao, Chem. Rev. 1993, 93, 2207 – 2293; b) Stereoselective Syn-
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Weinheim, 2000, chapt. 10 and 11, pp. 299 – 490.
for the catalytic asymmetric homoallenylation of aldehydes
using ligand 5 f (L) is shown in Scheme 1. We propose that the
homoallenyl bromide 1 reacts with two equivalents of the
[2] For recent reviews about allenylation, see: a) C. H. Heathcock
In Comprehensive Organic Synthesis, Vol. 2 (Eds.: B. M. Trost, I.
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H. Yamamoto, J. Am. Chem. Soc. 2007, 129, 496 – 497.
Scheme 1. Possible mechanism for the chromium-mediated homoalle-
nylation (R1 =iPr, R2 =tBu).
ligand–chromium complex (L–CrX) to form the
organochromium(III) reagents A and B and one equivalent
of L–CrX2 complex, similar to the catalytic cycle outlined by
Fꢀrstner and Shi.[16] The regioselectivity of this addition may
be explained by a rapid equilibration of the homoallenyl and
1,3-butadien-2-yl chromium(III) intermediates A and B. The
1,3-butadien-2-yl chromium(III) species B is more favored
and is proposed to add to the aldehyde via transition state C.
In this transition state, the 1,3-butadien-2-yl moiety would be
bonded to chromium in the equatorial position while the
aldehyde would coordinate at the apical position through an
anti geometry to minimize the steric interactions between the
R group and the oxazoline ring.[17] Therefore, Re-face attack
should be favored through this transition state. Notably, a
mechanism involving a dinuclear complex or proceeding
through an intermolecular pathway cannot be ruled out at this
stage.[18]
[5] For recent applications of b-allenols, see : a) V. K. Brel, V. K.
Belsky, A. I. Stash, V. E. Zavodnik, P. J. Stang, Eur. J. Org.
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In summary, we have disclosed the first regio- and
enantioselective homoallenylation of aldehydes using the
chiral ligand 5 f. A noteworthy feature of this reaction is the
excellent level of regioselectivity for the addition of the
chromium(III) intermediate to give only the desired b-allenol
in most cases. In the future, this novel reaction should allow
access to a wide range of chiral b-allenols of considerable
synthetic interest. Applications as well as a detailed study of
the mechanism are underway and will be reported in due
course.
[7] H. A. McManus, P. J. Guiry, J. Org. Chem. 2002, 67, 8566 – 8573.
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[11] During our studies on chromium-mediated homoallenylation,
asymmetric addition of 1 to aldehydes in the presence of a chiral
tethered bis(8-quinolinato) (TBOx) chromium complex was
reported to lead exclusively to the formation of 1,3-butanedien-
2-ylcarbinols 4; see: M. Naodovic, G. Xia, H. Yamamoto, Org.
Lett. 2008, 10, 4053 – 4055.
Received: July 3, 2009
Revised: September 7, 2009
Published online: October 1, 2009
Keywords: asymmetric catalysis · chromium · enantioselectivity ·
homoallenylation · regioselectivity
[12] See the Supporting Information for a detailed description of
solvent, temperature, and ligand screening.
.
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Chemie
[13] For the preparation of chiral b-allenols, see: a) M. Santelli, M.
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Iwabuchi, K. Ogasawara, J. Chem. Soc. Chem. Commun. 1989,
1371 – 1372; c) D. Xu, Z. Lu, Z. Li, S. Ma, Tetrahedron 2004, 60,
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[15] Notably, homoallenylation of 4-methoxybenzaldehyde, 4-meth-
ylthiobenzaldehyde, and 3-furaldehyde (Table 3, entries 5–7)
using ligand 5 f gave rise to (R)-b-allenols 3 in 40–50% yields
while the use of TMEDA as a ligand led to low conversions
(<10%) of the same substrates into alcohols 3 and 4.
[16] A. Fꢀrstner, N. Shi, J. Am. Chem. Soc. 1996, 118, 12349 – 12357.
[17] A similar model has been proposed by Nakada and co-workers
for the chromium-mediated propargylation of aldehydes using
carbazole tridentate ligands, see: a) M. Inoue, M. Nakada, Org.
Lett. 2004, 6, 2977 – 2980; b) M. Inoue, T. Suzuki, A. Kinoshita,
M. Nakada, Chem. Rec. 2008, 8, 169 – 181.
[18] For an example of a dinuclear complex, see: T. R. Ruck, E. N.
Jacobsen, J. Am. Chem. Soc. 2002, 124, 2882 – 2883.
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