Diastereoselective synthesis of homoallylic alcohols with adjacent tertiary and quaternary centers by using functionalized allylic aluminum reagents

Article abstract of DOI:10.1002/anie.201003813

Al be there for you: Sensitive functional groups, including ester and cyano groups, can be present in allylic aluminum reagents prepared by aluminum insertion in the presence of InCl₃. These aluminum organometallic compounds undergo addition re

Full text of DOI:10.1002/anie.201003813

Communications
DOI: 10.1002/anie.201003813
Aluminum Reagents
Diastereoselective Synthesis of Homoallylic Alcohols with Adjacent
Tertiary and Quaternary Centers by Using Functionalized Allylic
Aluminum Reagents**
Zhihua Peng, Tobias D. Blꢀmke, Peter Mayer, and Paul Knochel*
Addition reactions of nucleophiles to carbonyl compounds
are excellent ways of generating quaternary centers in a
diastereoselective manner.[1] Especially the addition of allylic
organometallic compounds to aldehydes or ketones proceeds
with high diastereoselectivity in several cases.[2] Recently, we
have shown that functionalized allylic zinc reagents can be
prepared from allylic chlorides by the reaction of zinc powder
in the presence of LiCl. Their addition to aldehydes and
ketones proceeds with high diastereoselectivity.[3] Neverthe-
less, the preparation of allylic zinc reagents bearing sensitive
functional groups (such as a cyano or an ester function) is
limited by the high reactivity of such allylic organometallic
compounds.[4] Besides zinc, aluminum is a metal which has
many attractive features: it is of low toxicity, inexpensive, and
because of the low ionic character of the carbon–aluminum
bond, it may tolerate a number of important functional
groups.[5] The preparation of unsaturated aluminum organo-
metallic compounds from commercial aluminum powder is in
general difficult, but a proper activation of the aluminum
surface allows an effective insertion of aluminum into aryl
halides.[6] Previously, allylic aluminum reagents were pre-
pared from allylic bromides by the methods of Gaudemar
et al.[7] and Miginiac et al.[8] using diethyl ether as the solvent
and in the presence of a catalytic amount of HgCl2. Herein, we
wish to report a practical synthesis of functionalized allylic
aluminum reagents bearing an aryl, an ester, or a cyanide
substituent by the insertion of commercial aluminum powder
into various allylic chlorides or bromides in the presence of a
catalytic amount of InCl3. In addition we report the diaste-
reoselective addition of the resulting aluminum reagents to
aldehydes and ketones.
2a in 82% yield.[12] Its reaction with 4’-bromoacetophenone
(3a) leads to the syn-homoallylic alcohol (4a) in 97% yield as
only diastereoisomer. This selectivity is best rationalized by a
chair-like transition state A (Scheme 1).[13] Functional groups,
such as an ester, are readily compatible with this procedure.
Scheme 1. Preparation of the allylic aluminum reagents 2a and 2b,
and their addition to 4’-bromoacetophenone (3a).
Thus, starting from ethyl 6-chlorocyclohex-1-enecarboxy-
late[14] (1b), the functionalized allylic aluminum reagent
(2b) is obtained in 77% yield. Reagent 2b also reacted well
with 4’-bromoacetophenone (3a) affording the homoallylic
lactone (4e) with excellent diastereoselectivity (Scheme 1).
The relative stereoselectivity has been established by NOE
NMR spectroscopic analysis (see Supporting Information).
The reaction scope of such additions has been studied and
we have found that the allylic aluminum reagent 2a reacts
well with variously substituted aromatic ketones. Thus, the
addition to methyl 4-acetylbenzoate (3b) furnishes the
homoallylic alcohol 4b (Table 1, entry 1). Remarkably,
despite the seemingly high nucleophilicity of the allylic
aluminum reagent, the reagent 2a adds perfectly to 1-(4-
nitrophenyl)ethanone (3c) without reacting with the nitro
group and the homoallylic alcohol 4c is isolated in 95% yield
(Table 1; entry 2). An unprotected amino group is also
compatible with the aluminum reagent under these reaction
conditions and the addition of 2a to 2-amino-5-chlorobenzal-
Preliminary studies have shown that an appropriate
activation of aluminum is essential for achieving a smooth
insertion into organic halides.[9,10] Thus, 3-bromocyclohexene
(1a) reacts with Al powder and InCl3[11] in THF at 08C within
2 h and provides the corresponding allylic aluminum reagent
[*] Z. Peng, T. D. Blꢀmke, Dr. P. Mayer, Prof. Dr. P. Knochel
Department Chemie, Ludwig Maximilians-Universitꢁt Mꢀnchen
Butenandtstrasse 5–13, Haus F, 81377 Mꢀnchen (Germany)
Fax: (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie and the European
Research Council (ERC) for financial support. We also thank Evonik
Industries AG (Hanau) and BASF AG (Ludwigshafen) for generous
donations of chemicals.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003813.
8516
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 8516 –8519

Angewandte
Chemie
Table 1: Diastereoselective preparation of homoallylic alcohols and
lactones of type 4 using allylic aluminum reagents of type 2.
dehyde (3d) affords the aminoalcohol 4d in 95% yield
Entry Aluminum
reagent[a]
Carbonyl elec- Product[c,d]
trophile[b]
(Table 1, entry 3). Various aromatic aldehydes and ketones
(3e–g) react with the functionalized allylic aluminum
reagent 2b, leading to the corresponding lactones (4 f–h) in
77–87% yield (Table 1, entries 4–6). The structure of the
bicyclic lactone 4 f has been confirmed by X-ray analysis.[18]
Also, ethyl 5-chlorocyclopent-1-enecarboxylate (1c)
reacted with Al powder (3 equiv) and InCl3 (5 mol%) in
THF affording the aluminum reagent 2c within 16 h at 258C
(60% yield). However, in contrast to the six-membered
analogue (2b), a lactone formation is disfavored and the
reaction with 4-acetylbenzoate (3b) or 4’-bromoacetophe-
none (3a) yields the ester-substituted uncyclized homoallylic
alcohols (4i–j) in 70–71% (Table 1, entries 7–8). Again, X-
ray analysis of 4j has been used to establish its structure.[18]
Similarly, the reaction of Al powder (1.5 equiv) and InCl3
(1 mol%) with cinnamyl chloride (1d) provides the alumi-
num reagent 2d (73% yield) within 2 h at 258C. Addition to
methyl ketones, such as 4’-bromoacetophenone (3a),
methyl-4-acetylbenzoate (3b), or 4-acetylbenzonitrile (3g),
affords the corresponding alcohols 4k–m in almost quanti-
tative yields, with high diastereoselectivities (Table 1,
entries 9–11). Remarkably, in contrast to the preparation
of the corresponding cinnamylzinc reagent,[15] little homo-
coupling of the allylic reagent is observed. Even a more
electron-rich cinnamyl chloride (1e) bearing a methoxy
group provides the corresponding aluminum reagent 2e
under the same conditions (258C, 11 h, 71% yield). It adds
smoothly to 4-cyanobenzaldehyde (3 f) or 4’-bromoaceto-
phenone (3a) affording the polyfunctional anti-homoallyllic
alcohols 4n and 4o in 95 and 74% yield, respectively
(Table 1, entries 12, 13). Interestingly, a cinnamylaluminum
phosphate (2 f) could be readily prepared by reacting the
phosphoric cinnamyl ester (1 f) with Al powder (1.5 equiv)
and InCl3 (1 mol%) in THF (258C, 12 h, 70% yield).
Trapping this new organometallic reagent with aliphatic
methyl ketones, such as 1-cyclohexylethanone (3h) or 3-
methylbutan-2-one (3i) furnishes the corresponding homo-
allylic alcohols bearing two adjacent stereocontrolled ter-
tiary and quaternary centers 4p,q in 62–90% yield (Table 1,
entries 14, 15). The structures of all homoallylic alcohols
resulting from the addition to ketones and aldehydes could
be established either by literature comparison[3a,13] or X-ray
analysis in the case of 4 f, 4j, and 4n.[18]
1
2
2a
2a
3b: R=CO2Me 4b: 98%; 99:1
3c: R=NO2
4c: 95%; 99:1
3
2a
3d
4d: 95%; 99:1
4
5
2b
2b
3e: R=CO2Me 4 f: 78%; 99:1[e]
3 f: R=CN
4g: 87%; 99:1
6
2b
3g
4h: 79%; 98:2
7
8
2c
2c
3b: R=CO2Me 4i: 70%; 98:2
3a: R=Br
4j: 71%; 98:2[e]
9
10
11
2d
2d
2d
3a: R=Br
4k: 99%; 98:2
3b: R=CO2Me 4l: 99%; 96:4
3g: R=CN
4m: 98%; 94:6
12
13
2e
2e
3 f
4n: 95%; 97:3[e]
Usually, cyano groups react rapidly with allylic organo-
metallic compounds, such as zinc reagents (Blaise reac-
tion).[16] Remarkably, a cyano function is well tolerated
during the Al insertion reaction. Thus, the preparation of a
cyano-substituted cyclopentylaluminum reagent (2g) is
possible starting from 5-chlorocyclopent-1-enecarboni-
trile[17] (1g) using Al powder and InCl3 (Scheme 2). The
addition of this aluminum reagent to a ketone or an aldehyde
affords the homoallylic alcohols 4r and 4s in 89 and 70%
yield, respectively. An X-ray analysis for 4s has been
performed.[18]
3a
4o: 74%; 92:8
14
15
2 f
2 f
3h
3i
4p: 62%; 97:3
4q: 90%; 98:2
In the case of a b-silyl-substituted crotylaluminum
reagent (2h), which was prepared starting from the b-silyl-
substituted crotyl chloride 1h (Scheme 3), the addition to
benzaldehyde (3j) and 4ꢀ-bromoacetophenone (3a) was also
[a] All reactions were carried out on a 1–4 mmol scale. [b] 0.6–0.7 equiv-
alents were used. [c] Yield of isolated analytically pure products. [d] The
1
diastereoselectivities were determined by H NMR spectroscopy. [e] The
structures were established by X-ray analysis.[18]
Angew. Chem. Int. Ed. 2010, 49, 8516 –8519
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8517

Communications
[1] a) E. J. Corey, A. Guzman-Perez, Angew. Chem. 1998, 110, 402;
Angew. Chem. Int. Ed. 1998, 37, 388; b) J. Christoffers, A. Mann,
Angew. Chem. 2001, 113, 4725; Angew. Chem. Int. Ed. 2001, 40,
4591; c) M. dꢀAugustin, L. Palais, A. Alexakis, Angew. Chem.
2005, 117, 1400; Angew. Chem. Int. Ed. 2005, 44, 1376; d) G.
Sklute, D. Amsallem, A. Shabli, J. P. Varghese, I. Marek, J. Am.
Chem. Soc. 2003, 125, 11776; e) G. Sklute, I. Marek, J. Am.
Chem. Soc. 2006, 128, 4642; f) B. Breit, P. Demel, C. Studte,
Angew. Chem. 2004, 116, 3874; Angew. Chem. Int. Ed. 2004, 43,
3786; g) H. Li, P. J. Walsh, J. Am. Chem. Soc. 2004, 126, 6538;
h) J. W. J. Kennedy, D. G. Hall, J. Am. Chem. Soc. 2002, 124, 898;
i) S. E. Denmark, J. Fu, J. Am. Chem. Soc. 2001, 123, 9488;
j) S. E. Denmark, J. Fu, Org. Lett. 2002, 4, 1951; k) J.-N. Heo,
G. C. Micalizio, W. R. Roush, Org. Lett. 2003, 5, 1693; l) J. P. Das,
H. Chechik, I. Marek, Nat. Chem. 2009, 1, 128.
Scheme 2. Preparation of a cyano-substituted allylic aluminum reagent
(2g) and its addition reactions.
[2] For additions of allylic organometallic compounds to carbonyl
compounds, see: a) S. R. Chemler, W. R. Roush in Modern
Carbonyl Chemistry (Ed.: J. Otera), Wiley-VCH, Weinheim,
2000, chap. 10; b) S. E. Denmark, N. G. Almstead in Modern
Carbonyl Chemistry (Ed.: J. Otera), Wiley-VCH, Weinheim,
2000, chap. 11; c) Stereoselective Synthesis Methods of Organic
Chemistry (Houben-Weyl), Vol. 3 (Eds.: G. Helmchen, R.
Hoffmann, J. Mulzer, E. Schaumann), Thieme, Stuttgart, 1996;
d) S.-W. Li, R. A. Batey, Chem. Commun. 2004, 1382; e) C. T.
Buse, C. H. Heathcock, Tetrahedron Lett. 1978, 19, 1685; f) Y.
Yamamoto, H. Yatagai, Y. Naruta, K. Maruyama, J. Am. Chem.
Soc. 1980, 102, 7107; g) Y. Yatsumonji, T. Nishimura, A.
Tsubouchi, K. Noguchi, T. Takeda, Chem. Eur. J. 2009, 15, 2680.
[3] a) H. Ren, G. Dunet, P. Mayer, P. Knochel, J. Am. Chem. Soc.
2007, 129, 5376; b) M. D. Helm, P. Mayer, P. Knochel, Chem.
Commun. 2008, 1916.
Scheme 3. Preparation of a trimethylsilyl-substituted allylaluminum
reagent (2h) and its addition reactions.
selective, and the syn-homoallylic alcohols 4t and 4u were
obtained.
[4] a) N. El Alami, C. Belaud, J. Villieras, J. Organomet. Chem.
1988, 348, 1; b) N. El Alami, C. Belaud, J. Villieras, J. Organo-
met. Chem. 1988, 353, 157; c) M. Gaudemar, Bull. Soc. Chim. Fr.
1963, 7, 1475.
[5] Organoaluminum reagents: a) E.-i. Negishi, T. Takahashi, S.
Baba, D. E. Van Horn, N. Okukado, J. Am. Chem. Soc. 1987, 109,
2393; b) E.-i. Negishi, Acc. Chem. Res. 1982, 15, 340; c) S.-L. Ku,
X.-P. Hui, C.-A. Chen, Y.-Y. Kuo, H.-M. Gau, Chem. Commun.
2007, 3847; d) G. Zweifel, J. A. Miller in Organic Reactions (Ed.:
W. G. Dauben), Wiley, New York, 1984.
In summary, we have demonstrated that allylic aluminum
reagents can be conveniently prepared using aluminum
powder in the presence of catalytic amounts of InCl3 from
allylic chlorides or bromides under mild conditions. The
addition to various functionalized aldehydes or ketones
affords polyfunctionalized homoallylic alcohols, bearing
adjacent tertiary and quaternary centers in good diastereose-
lectivity. Further extensions of this method as well as
mechanistic studies are currently being investigated.
[6] T. D. Blꢁmke, Y.-H. Chen, Z. Peng, P. Knochel, Nat. Chem. 2010,
2, 313.
[7] a) M. Gaudemar, Bull. Soc. Chim. Fr. 1958, 1475; b) A. Stefani,
P. Pino, Helv. Chim. Acta 1972, 55, 1110.
[8] a) G. Picotin, P. Miginiac, J. Org. Chem. 1985, 50, 1299; b) L.
Miginiac-Groizeleau, Bull. Soc. Chim. Fr. 1963, 1449.
[9] Aluminum powder has been previously activated by PbCl2,
SnCl2, TiCl4. For insertion into allyl bromides and chlorides, see:
a) K. Uneyama, N. Kamaki, A. Moriya, S. Torii, J. Org. Chem.
1985, 50, 5396; b) H. Tanaka, T. Nakahara, H. Dhimane, S. Torii,
Tetrahedron Lett. 1989, 30, 4161; c) H. Tanaka, K. Inoue, Ulrike
Pokorski, M. Taniguchi, S. Torii, Tetrahedron Lett. 1990, 31, 3023.
[10] For general activation of aluminum powder, see: S. Saito, Sci.
Synth. 2004, 7, 5.
Experimental Section
Typical procedure: Preparation of 4a: Al powder (81 mg, 3 mmol)
and InCl3 (4.4 mg, 0.02 mmol) were placed in an argon-flushed dry
flask. After THF (5 mL) was added, a solution of 3-bromocyclohex-
ene (1a, 322 mg, 2 mmol) in THF (5 mL) was added with a syringe
pump over 1 h at 08C and the resulting solution was stirred at 08C for
1 h. The insertion reaction was monitored by GC analysis of
hydrolyzed reaction aliquots. The resulting allylic aluminum reagent
(2a) was added to a solution of 4’-bromoacetophenone (3a, 279 mg,
1.4 mmol) in THF (1.5 mL) at À788C and the resulting mixture was
stirred at À788C for 2 h. Standard work-up and purification by flash
chromatography over silica (eluting with pentane:diethyl ether 1:10)
yielded compound 4a as colorless liquid (384 mg, 97% yield).
[11] We assume that InCl3 activates the Al surface; see also Ref. [6];
see also: a) K. Takai, Y. Ikawa, Org. Lett. 2002, 4, 1727; b) S.
Araki, S.-J. Jin, Y. Idou, Y. Butsugan, Bull. Chem. Soc. Jpn. 1992,
65, 1736.
[12] Yields were determined by iodometric titration after trans-
metallation with ZnCl2: A. Krasovskiy, P. Knochel, Synthesis
2006, 890.
Received: June 22, 2010
Published online: September 6, 2010
[13] The stereochemistry has been established by a comparison with
the literature (1H NMR and 13C NMR spectra): M. Yasuda, K.
Hirata, M. Nishino, A. Yamamoto, A. Baba, J. Am. Chem. Soc.
2002, 124, 13442.
Keywords: aluminum · diastereoselectivity ·
nucleophilic additions · organometallic compounds
.
8518
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 8516 –8519

Angewandte
Chemie
[14] B. List, A. Dochring, M. T. H. Fonseca, A. Job, R. R. Torres,
Tetrahedron 2006, 62, 476.
[18] CCDC 775024 (4 f), CCDC 775025 (4j), CCDC 775023 (4n),
and CCDC 775026 (4s) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[15] M. Gaudemar, Bull. Soc. Chim. Fr. 1962, 974.
[16] a) P. Knochel, J. F. Normant, J. Organomet. Chem. 1986, 309, 1;
b) E. E. Blaise, Compt. Rend. 1901, 132, 478.
[17] J. Villieras, M. Rambaud, M. Graff, Synth. Commun. 1986, 16,
149.
Angew. Chem. Int. Ed. 2010, 49, 8516 –8519
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8519