Remarkably stable (Me3Al)2·DABCO and stereoselective nickel-catalyzed AlR3 (R = Me, Et) additions to aldehydes

Article abstract of DOI:10.1002/anie.200462569

(Chemical Equation Presented) Weigh it out in air! The DABAL reagent (Me₃Al)₂·(DABCO) (DABCO = 1,4-diazabicyclo[2.2.2] octane) can be easily handled under normal laboratory conditions. Furthermore, chiral secondary alcohols can be efficiently prepared from prochiral aldehydes (see scheme; TOF = turnover frequency) by using either DABAL or AIR₃ reagents (R = Me, Et). Thus, DABAL can be used as an efficient, convenient alternative to the Schumann-Blum reagent.

Full text of DOI:10.1002/anie.200462569

Communications
Asymmetric Synthesis
Remarkably Stable (Me Al) ·DABCO and
3
2
Stereoselective Nickel-Catalyzed AlR (R = Me,
3
Et) Additions to Aldehydes**
Kallolmay Biswas, Oscar Prieto, Paul J. Goldsmith, and
Simon Woodward*
The attainment of a largely air-stable, low-molecular-weight
À
equivalent of “chiral Me ” for addition to prochiral aldehydes
is reported herein together with complementary additions of
AlR (R = Me, Et). Although there has been considerable
3
interest recently in air-stable boron, silicon, and tin reagents
2
[1,2]
for the catalytic delivery of C(sp ) nucleophiles,
the
3
equivalent alkyl (C(sp )) chemistry, including methyl transfer,
remains quite underdeveloped; however, a notable exception
is the stabilization of a methylaluminum species by formation
of a Lewis acid/base pair, whose use has been pioneered by
[
3]
Blum, Schumann, and co-workers. Despite this develop-
ment, asymmetric addition to carbonyl compounds using such
reagents has not been realized.
The reports of X-ray crystallographic studies of several
Me Al·NR3 species encouraged us to test their synthetic
3
utility. Although Me Al·pyridine and (Me Al) ·TMEDA
3
3
2
(TMEDA = tetramethylethylenediamine) proved far too
reactive to handle under normal laboratory conditions, we
were astonished to find that (Me Al) ·DABCO (DABCO =
3
[
2
5]
1
,4-diazabicyclo[2.2.2]octane; 1a), which we call DABAL-
Me , is surprisingly robust and can be readily used in the
3
[*] Dr. K. Biswas, Dr. O. Prieto, P. J. Goldsmith, Dr. S. Woodward
School of Chemistry
The University of Nottingham
Nottingham NG7 2RD (UK)
Fax: (+44)115-951-3564
E-mail: simon.woodward@nottingham.ac.uk
[**] This work was supported in part by the European Union Framework
6
Programme (project FP6-505267-1; LIGBANK). P.J.G. is also
grateful for the support of the Grundy Educational Trust.
DABCO=1,4-diazabicyclo[2.2.2]octane.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
2
232
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200462569
Angew. Chem. Int. Ed. 2005, 44, 2232 –2234

Angewandte
Chemie
laboratory. Compound 1a has a hydrolytic
stability comparable to LiBH4 as it is
moisture sensitive but can be weighed out
easily on the bench without the need for an
inert air atmosphere and stored in standard
glassware. DABAL-Me3 (1a), unlike the
Schumann–Blum reagent 2, is prepared in a
single step from commercially available
materials and is obtained directly from the
reaction mixture as a free-flowing, white
Table 1: Alkylation of aldehydes (RCHO) with A) DABAL-R
3
1 or B) AlR
3
reagents.
[a]
Entry
R in RCHO
Method (R)
t [h]
Yield [%]
Product ee
(antipode) [%]
[
b]
1
2
3
4
5
6
7
8
9
Ph (a)
Ph (a)
Ph (a)
Ph (a)
A (Me)
B (Me)
A (Et)
B (Et)
A (Me)
A (Et)
A (Me)
A (Me)
A (Me)
A (Me)
A (Me)
A (Me)
A (Et)
A (Me)
A (Me)
A (Me)
A (Me)
A (Me)
A (Et)
1
3
5
5
1
1
1
3
1
1
1
1
1
1
3
1
1
1
10
1.5
6
6
7
6
6
1
92
60
95
95
98
91
79
84
77
81
69
58
90
93
90
82
78
80
91 (R)-(+)-4a
85 (R)-(+)-4a
86 (R)-(+)-5a
83 (R)-(+)-5a
93 (R)-(+)-4b
89 (R)-(+)-5d
93 (R)-(+)-4c
94 (R)-(+)-4d
94 (R)-(+)-4e
87 (R)-(+)-4 f
94 (R)-(+)-4g
94 (R)-(+)-4h
95 (R)-(+)-5h
93 (R)-(+)-4i
81 (R)-(+)-4j
93 (R)-(+)-4k
90 (R)-(+)-4l
94 (R)-(À)-4m
91 (R)-(+)-5m
7 (R)-(+)-5m
95 (R)-(À)-4n
48 (R)-(À)-5n
67 (R)-(À)-4o
61 (R)-(À)-4p
77 (R)-(À)-4q
66 (R)-(+)-4r
4-BrC
4-BrC H (b)
H
(b)
6
4
6
4
4-ClC H (c)
6
4
4-FC H (d)
6
4
powder. The analogous DABAL-Et species
3
3-FC H (e)
6
4
(1b) proved too reactive to isolate (possibly
1
0
2-FC H (f)
6 4
4-(CN)C H (g)
6 4
4-(CF )C H (h)
3 6 4
because of weaker AlÀC bonds) but it can
11
12
be generated and used in situ.
13
14
15
16
17
4-(CF )C H (h)
We initially concentrated on the addi-
3
6
4
3-(CF
3
)C
6
H
4
(i)
tion DABAL-Me to prochiral aldehydes to
3
4-MeC H (j)
3-MeC H (k)
2-MeC H (l)
6
4
fashion secondary alcohols to demonstrate
the utility of this reaction. Approaches
6
4
6
[c]
4
based on [L*AlMe ] (L* = chiral ligand)
n
18
19
20
c-C H (m)
6
11
[
c]
[d]
Lewis acids seemed unlikely to be very
successful as the Lewis acidity of the
aluminum center in 1 is rather compromised
by the coordination of DABCO to it, and so
an alternative strategy based on transmeta-
lation was sought. In 1997, Fujisawa and co-
workers demonstrated that phosphanes
cause dramatic rate acceleration in the
c-C H (m)
60
6
11
[
c]
c-C
H11 (m)
B (Et)
B (Me)
B (Et)
B (Me)
B (Me)
B (Me)
A (Me)
55
60
72
95
91
94
94
6
21
22
23
24
25
26
iBu (n)
iBu (n)
tBuCH (o)
2
n-C H (p)
6
13
PhCH CH (q)
2
2
(E)-PhCH CH (r)
=
[a] Yield determined from isolated product or by GC analysis: GC versus the internal standard on
nickel-catalyzed additions of (neat) AlMe
3
0
1
.25 mmol (RCHO) scale reaction and yields of isolated product were within 2–5% of these obtained on
.0 mmol scale duplicate reactions. Compounds 4 and 5 were authenticated against genuine samples
[
6]
to aldehydes. To the best of our knowl-
edge, no asymmetric version of this reaction
has appeared despite the enormous recent
prepared either by reactions catalyzed with achiral Ph P (2 mol%)/[Ni(acac) ] (1 mol%) and 1 and/or
3
2
NaBH
cases except 4a and 5a (GC analysis on lipodex-A); 4q and 4r (GC analysis on 2,6-me-3-pe-g-CD ); and
m–p, 5m, and 5n (determined by GC analysis of the acetate of isolated secondary alcohol as described
reduction of the parent ketones. [b] Determined by GC analysis on a cyclodex-B column in all
4
[
9]
[
7]
interest in selective nickel catalysis. Pleas-
4
ingly, when DABAL-Me3 (1a; 1.0–
[8]
before). Stereochemical correlations were assigned on the basis of the sign of the optical rotation or by
comparison with the GC data of authentic samples of known configuration. [c] 1.0 equivalents of
DABAL-R3 1 were used. [d] Mass balance was accounted for from by-products derived from
a deprotonation.
1
.5 equiv) is added to PhCHO in THF in
the presence of [Ni(acac) ] (acac = acetyla-
2
cetone; 1 mol%) and (R ,S,S)-Feringa
ax
ligand 3 (2 mol%) at 58C, the resulting
alcohol 4 (R = Ph) is isolated in high yield
and enantiomeric excess (Scheme 1). We were further grati-
fied to find that the range of substrates for this reaction using
DABAL-Me 1 was rather wider than that of the original
3
Fujisawa reaction (Table 1), which had a rather narrow
substrate range as only electron-rich aldehydes reacted
quickly. Furthermore, the scope of the reaction could be
extended by the use of DABAL-Et (1b). Remarkably, by-
3
product formation arising from b elimination of any
[
L Ni(Et)] intermediate amounted to less than 1 mol%,
n
which is in accordance with the findings of Fujisawa and co-
[
6]
workers.
Electron-deficient aromatic aldehydes gave the highest
enantioselectivities in our reaction, while the electron-rich
substrate 4-MePh gave the poorest (compare entries 15 versus
5
, 7–12, and 14). Control reactions showed that electronic
effects do not contribute to any competing reactions (4-
XPhCHO (X = MeO, H, NO ) did not react with 1a alone
2
within 3 h at 58C). The enantioselectivity and reactivity of the
reaction is also influenced significantly by steric factors
(compare entries 1 and 2 versus 8–10; 1, 2 versus 18 and 21;
1
5 versus 17; and 21 versus 23). The activities displayed
Scheme 1. The asymmetric synthesis of chiral secondary alcohols from
benzaldehyde using either A) DABAL-R or B) AlR reagents (R=Me,
Et).
outperform other reported data given for addition reactions
of AlR3 to an aldehyde, which normally require catalyst
3
3
Angew. Chem. Int. Ed. 2005, 44, 2232 –2234
www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2233

Communications
[
8]
loadings of 10–15 mol%. Further lowering of the ligand
loading was possible: methylation of PhCHO with 1 mol% of
equivalent manner to that for 1a. Screening reactions using AlR
R = Me, Et) were carried out in 2.0m hexanes solutions.
3
(
3
proceeded in identical enantiomeric excess but in a slightly
Received: November 10, 2004
Published online: March 14, 2005
lower yield (78%). PhCHO was converted into 4a even when
undried THF was used as the solvent (89% ee, 96% yield).
An enal also participated in the reaction with 1a but at lower
selectivity (4r, entry 26). In two cases, the use of 1a and 1b
allowed the isolation of secondary alcohols that are not
available from classical Noyori-type transfer hydrogenations
Keywords: aluminum · asymmetric catalysis · Lewis bases ·
.
nickel · phosphoramidites
[
10]
(4m and 5m). However, reagents 1a and 1b can cause the
2
[
1] Selected uses of RBXn (R = C(sp ), n = 2 or 3) reagents in
selective catalysis: a) C. Bolm, J. Rudolph, J. Am. Chem. Soc.
2002, 124, 14850 – 14851 (activation with ZnEt2 is required);
b) A. Takezawa, K. Yamaguchi, T. Ohmura, Y. Yamamoto, N.
Miyaura, Synlett 2002, 1733 – 1735; c) M. Ueda, N. Miyaura, J.
Org. Chem. 2000, 65, 4450 – 4452; d) R. A. Batey, A. N. Thadani,
D. V. Smil, Org. Lett. 1999, 1, 1683 – 1686.
a deprotonation of some aliphatic aldehydes, thus resulting in
aldol/Knovenagel derived by-products. This problem can be
overcome by carrying out the reaction with these substrates at
À208C in the absence of DABCO.
The enantioselectivities attained in reactions using AlR3
reagents are low to excellent (entries 4 and 20–25), thus
indicating that the structure of 3 requires modification for
2
[
2] Selected uses of RSiX3 and RSnX3 (R = C(sp )) reagents in
selective catalysis: a) J. Ichikawa, H. Fukui, Y. Ishibashi, J. Org.
Chem. 2003, 68, 7800 – 7805; b) S. Oi, Shuichi, M. Moro, H.
Fukuhara, T. Kawanishi, Y. Inoue, Tetrahedron 2003, 59, 4351 –
[
11]
each substrate. Again b elimination by-products are only
present at trace levels in all addition reactions using the AlEt3
reagent under DABCO-free conditions. The use of DABCO
is critical with some substrates, for example, 5m is attained in
only 7% ee in its absence (entry 20).
discussion of the mechanism of the catalytic cycle is prema-
ture at this point, we strongly suspect that Lewis acid
4361; c) M. Murata, R Shimazaki, M. Ishikura, S. Watanabe, Y.
Masuda, Synthesis 2002, 717 – 719.
[
12]
[3] a) H. Schumann, B. C. Wassermann, S. Schutte, B. Heymer, S.
Nickel, T. D. Seuß, S. Wernik, J. Demtschuk, F. Girgsdies, R.
Weimann, Z. Anorg. Allg. Chem. 2000, 626, 2081 – 2095; b) W.
Baidossi, A. Rosenfeld, B. C. Wasswemann, S. Schutte, H.
Schumann, J. Blum, Synthesis 1996, 1127 – 1130. Alternative
Although detailed
2
activation of an nickel/h -aldehyde complex by the aluminum
reagent, in a manner related to the work of Ogoshi et al., is
reagents based on {[Me AlYCH CH NMe ] } (Y= O, NR) can
2 2 2 2 2
[
13]
be of superior reactivity in some cases: c) D. Gelman, S. Dechert,
H. Schumann, J. Blum, Inorg. Chim. Acta 2002, 334, 149 – 158;
d) H. Schumann, M. Frick, B. Heymer, F. Girgsdies, J. Organo-
met. Chem. 1996, 512, 117 – 126.
involved. Extensive work to further delineate the reactivity
of other DABAL-reagents and to explore their substrate
range, both in the present reaction and other metal-catalyzed
processes, is underway.
[
4] CSD structure reference codes: Me Al·NMe (DOCQOB),
3
3
(
(
Me Al) ·DABCO
JUBHAP), and Me Al·(quinuclidine) (TMQUAL). These
(JOMBOC),
(Me Al) ·TMEDA
3
2
3
2
3
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Experimental Section
1
a: Neat AlMe (4.5 g, 62.5 mmol) was added to a solution of freshly
3
sublimed DABCO (3.4 g, 34.7 mmol) in toluene (30 mL) at 08C. The
resulting white precipitate was allowed to settle, and the supernatant
toluene was removed by cannula. Dry diethyl ether (20 mL) was
added and swirled with the solid. The solid was again allowed to settle
and the supernatant liquid removed by cannula. Washing with diethyl
ether was repeated four times before the residual slurry was
evaporated to dryness under vacuum to obtain 1a directly (4.5–
[5] A. M. Bradford, D. C. Bradley, M. B. Hursthouse, M. Moteiralli,
Organometallics 1992, 11, 111 – 115.
[6] T. Ichiyanagi, S. Kuniyama, M. Shimizu, T. Fujisawa, Chem. Lett.
1998, 1033 – 1034.
[7] Key overview: a) J. Montgomery, Angew. Chem. 2004, 116,
3980 – 3998; Angew. Chem. Int. Ed. 2004, 43, 3890 – 3908; the
following articles, in particular, should also be highlighted:
b) K. M. Miller, W.-S. Huang, T. J. Jamison, J. Am. Chem. Soc.
2003, 125, 3442 – 3443; c) E. A. Colby, J. T. Jamison, J. Org.
Chem. 2003, 68, 156 – 166.
6
.1 g; 60–81%); its spectroscopic properties were as described
[
5]
previously. DABAL-Me (1a) that had been stored in screw-top
3
vials under an argon blanket was still active after at least 4 months.
(
Warning: while we have encountered no problems using this reagent
[8] a) B. L. Pagenkopf, E. M. Carreira, Tetrahedron Lett. 1998, 39,
9593 – 9596; b) J.-S. You, S.-H. Hsieh, H.-M. Gau, Chem.
Commun. 2001, 1546 – 1547.
on scales of up to 25 g, we recommend caution on its initial handling.
For example, if washing with diethyl ether, as outlined above, is not
carried out properly traces of free AlMe can lead to very reactive
[9] A. J. Blake, A. Cunningham, A. Ford, S. J. Teat, S. Woodward,
Chem. Eur. J. 2000, 6, 3586 – 3594; C. Bꢀrner, M. R. Denis, E.
Sinn, S. Woodward, Eur. J. Org. Chem. 2001, 2435 – 2446.
[10] T. Ohkuma, R. Noyori in Comprehensive Asymmetric Catalysis,
Vol. 1 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
Berlin, 1999, pp. 199 – 246.
3
samples of 1a. Deliberate addition of water to 1a causes a strong
exothermic reaction and methane liberation. Furthermore, 1a ignites
on tissue paper especially on “damp” days.)
Catalytic addition to aldehydes: [Ni(acac) ] (0.6 mg, 2.33 mmol,
2
1
mol%) and (R ,S,S)-3 (2.7 mg, 0.005 mmol, 2 mol%) were stirred
ax
in dry THF (2 mL) under an argon atmosphere at 58C for 10–30 min.
[11] Individual ligand optimization is underway in our laboratory for
both alkyl aldehyde and enal substrates (on the basis of PM3
studies of the selective step in the reaction).
Neat aldehyde (0.25 mmol) was then added and DABAL-Me (1a)
3
(84 mg, 0.325 mmol, 1.3 equiv) was added after a further 10 min. The
yellow reaction mixture was stirred (1–3 h) before being quenched
[12] The presence of c-C H
6
11C(=O)Et (c = cyclo) can be detected,
with aqueous NH Cl. The yields of the obtained secondary alcohols
were determined either by isolation or by GC analysis after addition
which indicates product racemization by Meerwin–Pondorf–
Varley–Oppenauer reactions. Related ketones were not
detected in the products 4.
4
of dodecane as the internal standard. DABAL-Et (1b) was prepared
3
by mixing 2:1 molar quantities of AlEt and DABCO in THF. The use
of 1b or an uncoordinated AlR3 species was carried out in an
[13] S. Ogoshi, M. Oka, H. Kurasawa, J. Am. Chem. Soc. 2004, 126,
11802 – 11803.
3
2
234
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Angew. Chem. Int. Ed. 2005, 44, 2232 –2234