Allylation of ketones with a ferrocene-based planar chiral lewis acid

Article abstract of DOI:10.1002/anie.200704687

Flat, like your hand: The heteronuclear bidentate Lewis acid 1,2-Fc(BMeCl)-(SnMe₂Cl) is readily resolved into its constituent enantiomers through highly stereoselective complexation with N-methylpseudoephedrine. The resulting planar chiral Lewis acids show optical purities greater than 97 % and, upon conversion to the respective allylborane derivatives (see scheme), rapidly add to ketones with enantiomeric excess of up to 80 %. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200704687

Communications
DOI: 10.1002/anie.200704687
Chiral Lewis Acids
Allylation of Ketones with a Ferrocene-Based Planar Chiral
Lewis Acid**
Ramez Boshra, Ami Doshi, and Frieder Jäkle*
Owing to its rigid three-dimensional framework, ferrocene
provides an excellent environment for chiral synthesis.
However, most of the planar chiral ferrocene derivatives
reported to date relate to the Lewis basic phosphine and
amine ligands, which have found widespread use as nucleo-
philic catalysts[1] and as ligands in transition-metal-catalyzed
chiral synthesis.[2] Surprisingly, the use of the charge-reverse
complementary Lewis acids,[3] the planar chiral ferrocenyl-
boranes, in asymmetric synthesis has not been demonstrated,
although chiral organoboranes are well known to serve as
highly versatile reagents and catalysts.[4] In fact, the
only prior example of a planar chiral organoborane
in stereoselective synthesis is the use of (h5-1,2-
azaborolyl)iron complexes in stereoselective aldol
reactions and imine additions by Fu and co-work-
ers.[5]
merically pure planar chiral bidentate Lewis acids in the
stereoselective allylation of ketones.
A convenient approach for the chiral resolution of
organoboranes relies on the selective chelation of methoxy
boranes with optically active amino alcohols.[8,9] We con-
verted 1-Cl to the methoxy derivative 1,2-Fc(BMe(OMe))-
(SnMe2Cl) (1-OMe) and treated the latter with 0.5 equiv-
alents of (1R,2R)-(À)-N-methylpseudoephedrine ((À)-MPE)
or
(1S,2S)-(+)-N-methylpseudoephedrine
((+)-MPE,
Scheme 1).[10,11] The crude product was extracted with hex-
We have demonstrated that the heteronuclear
bidentate Lewis acid 1,2-Fc(BMeCl)(SnMe2Cl) (1-
Cl, Fc = ferrocenediyl) is readily available through
highly regioselective ortho borylation of 1,1’-bis-
(trimethylstannyl)ferrocene and subsequent ther-
mal rearrangement.[6] Unusual binding phenom-
ena are observed for 1-Cl, including the diastereo-
selective coordination of pyridine from the exo
side of ferrocene, which is aided by a bridging
chlorine substituent between the neighboring
boron and tin centers.[7] However, since 1-Cl is
Scheme 1. a) Me3SiOMe, CH2Cl2, 408C, 48 h; b) (+)-N-methylpseudoephedrine,
toluene, RT, 2 h; c) (À)-N-methylpseudoephedrine, toluene, RT, 2 h.
obtained in racemic form, it has not been applied
to stereoselective synthesis. We report herein a
facile route for the chiral resolution of 1-Cl and
describe the application of the resulting enantio-
anes, and the chelate complexes (Rp)-2-(À)-MPE and (Sp)-2-
(+)-MPE were isolated from the corresponding solid frac-
tions; the characteristics of the (Sp)-2-(+)-MPE enantiomer
are described below, and similar considerations apply to the
Rp isomer.
[*] R. Boshra, A. Doshi, Prof. F. Jäkle
Department of Chemistry
Rutgers University Newark
73 Warren Street, Newark, NJ 07102 (USA)
Fax: (+1)973-353-1264
E-mail: fjaekle@rutgers.edu
Homepage: http://www.andromeda.rutgers.edu/~fjaekle/
1
Only one set of signals was observed in the H, 11B, and
119Sn NMR spectra of (Sp)-2-(+)-MPE, confirming the
selective conversion of only one of the enantiomers of 1-
OMe to form a single diastereomer of the chelate complex. To
determine the stereochemical configuration at boron, we
acquired 2D-NOESY 1H NMR spectroscopy data. Strong
cross-peaks between the BMe signal at d = 0.48 ppm and
those of the unsubstituted Cp ring at d = 4.23 ppm and the Cp
proton adjacent to the boryl group (Cp-H3) demonstrate that
the methyl group points downward in the direction of the iron
atom (Figure 1). One of the NMe signals at d = 2.44 ppm also
shows a strong cross-peak with Cp-H3 but no cross-peaks with
the unsubstituted Cp ring, confirming its position above the
ferrocene moiety and pointing away from the Sn substituent.
[**] We gratefully acknowledge support by the Petroleum Research
Fund, administered by the American Chemical Society, and the
National Science Foundation (NSF CRIF-0443538). F.J. thanks the
Alfred P. Sloan Foundation for a research fellowship and the NSF for
a CAREER award (CHE-0346828). We thank Prof. Lalancette for
advice with the X-ray structure determination, Prof. Malhotra for
providing access to a polarimeter, and are indebted to Prof.
Soderquistand his group for helpful discussions during the
BORAM X meeting in San Juan, Puerto Rico.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
2.467(3) Š leads to a distorted trigonal bipyramidal environ-
ment at tin and is consistent with the upfield shift of the signal
in the 119Sn NMR spectrum in solution. The B N bond length
À
of 1.676(6) Š and the tetrahedral character of 71.7% for
boron are similar to literature data for related chelate
complexes.[13]
The chiral methoxy derivatives (Sp)-1-OMe and (Rp)-1-
OMe were isolated from the hexanes extracts of the reactions
of racemic 1-OMe with 0.5 equivalents (À)-MPE and (+)-
MPE, respectively. They were readily converted back to the
corresponding chlorine-substituted, but now enantiomerically
pure, bidentate Lewis acids (Sp)-1-Cl and (Rp)-1-Cl by
treatment with PhBCl2 in hexanes (Scheme 2). The optical
Figure 1. Methyl/Cp region of the NOESY spectrum of (Sp)-2-(+)-MPE
(CDCl3, 258C). Cocrystallized toluene is indicated with an asterisk.
Thus, the remaining boron substituent, the oxygen atom, must
be pointing toward Sn, as also suggested by the upfield shift of
the resonance in the 119Sn NMR spectrum (d = 22.4 ppm vs.
d = 69.0 ppm for 1-OMe). We conclude that the SB isomer is
preferentially formed in the binding of (+)-MPE to (Sp)-1-
OMe.
Scheme 2. a) PhBCl2, hexanes, RT, 30 min; b) for conversion of (Sp)-1-
Cl into (Sp)-3: Me3SnAll, CH2Cl2, RT, 24 h; c) for conversion of (Sp)-1-
OMe or (Sp)-2-(À)-MPE into (Sp)-4: AllMgBr (1.95 equiv), Et2O, RT,
2 h. All=allyl.
X-ray quality crystals of (Sp)-2-(+)-MPE were obtained
from a concentrated toluene solution at À388C.[12] Two
independent molecules are found, which are very similar;
only one of them is further discussed and displayed in
Figure 2. The structure confirms the stereochemical assign-
ment to the Sp,SB isomer as predicted from the NOESY data.
purity of the Lewis acids was assessed by complexation with
the chiral donor (4S,5S)-(À)-4,5-dihydro-4-methoxymethyl-2-
methyl-5-phenyl-oxazole. The 119Sn NMR spectra show indi-
vidual, well-resolved signals at 58.9 ppm for (Sp)-1-Cl and at
d = 56.5 ppm for (Rp)-1-Cl. On the basis of 119Sn and 1H NMR
spectroscopic analysis, the optical purity of each enantiomer
was estimated to be greater than 97% (see the Supporting
Information).
To examine the novel planar chiral bidentate Lewis acids
in asymmetric synthesis, we chose the boron-induced asym-
metric allylation of aldehydes and ketones as a model
reaction.[9,14] The boron-allylated compounds (Rp)-3 and
(Sp)-3 are obtained selectively from (Rp)-1-Cl and (Sp)-1-Cl,
respectively, by metathesis with Me3SnAll (Scheme 2, All =
allyl). Alternatively, the bis-allyl compounds (Rp)-4 and (Sp)-4
can be generated by reaction of the methoxy derivatives (Rp)-
1-OMe/(Sp)-1-OMe or the ephedrine complexes (Rp)-2-(À)-
MPE/(Sp)-2-(+)-MPE with 1.95 equivalents AllMgBr, as
illustrated in Scheme 2 for the Sp enantiomer.[15]
À
The five-membered B N heterocycle occupies the less
crowded space above the plane of the substituted Cp ring
and is fused to another five-membered heterocycle that is
formed as a result of donation from the oxygen atom to the
Lewis acidic tin atom. The short Sn1···O1 contact of
The allylborane reagents were isolated as oily materials
and used without further purification in the allylation of the
chosen aldehyde or ketone in CH2Cl2. Enantioselectivities
were similar at À788C and RT; the data in Table 1 are
reported for RT reactions. The planar chiral allylboranes did
not give any significant asymmetric induction in the allylation
of typical aldehydes (e.g. 8% ee with benzaldehyde). How-
ever, when applied to ketones, the reaction resulted in chiral
homoallylic alcohols in up to 80% ee in less than 30 minutes
(Table 1). This result contrasts most other boron-based
allylating agents, for which asymmetric allylation of ketones
is generally more difficult to achieve than with aldehydes.[16]
Figure 2. Molecular structure of one of the independent molecules of
(Sp)-2-(+)-MPE (thermal ellipsoids are shown at 50% probability). A
cocrystallized toluene molecule is omitted, and only hydrogen atoms
attached to stereogenic carbon atoms are shown. Selected interatomic
distances [Š] and angles [8]: Sn1–Cl1 2.4903(12), Sn1–C1 2.104(5),
Sn1–C23 2.143(5), Sn1–C24 2.123(5), Sn1···O1 2.467(3), B1–C2
1.608(8), B1–C11 1.615(7), B1–O1 1.511(7), B1–N1 1.676(6);
O1···Sn1-Cl1 172.05(9).
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1135

Communications
Table 1: Allylboration of ketones R1R2CO.
Entry ReagentYield [%]
R1 R2
pentyl Me
[1]G. C. Fu, Acc. Chem. Res. 2006, 39, 853.
[2]T. J. Colacot, Chem. Rev. 2003, 103, 3101.
[3]F. P. Gabbaï, Angew. Chem. 2003, 115, 2318; Angew. Chem. Int.
Ed. 2003, 42, 2218.
[a]
S:R[b,c]
1
(Rp)-3
(Sp)-3
(Rp)-4
(Rp)-4
80
96
86
97
70:30
2
3
4
Ph
Ph
Ph
Me
Me
pentyl
20:80[d]
90:10[e]
90:10[e]
[4]a) K. Ishihara in Lewis Acids in Organic Synthesis, Vol. 1 (Ed.:
H. Yamamoto), Wiley-VCH, Weinheim, 2000, p. 135; recent
examples: b) H. C. Brown, P. V. Ramachandran, J. Organomet.
Chem. 1995, 500, 1; c) K. Ishihara, K. Inanaga, S. Kondo, M.
Funahashi, H. Yamamoto, Synlett 1998, 1053; d) D. H. Ryu,
T. W. Lee, E. J. Corey, J. Am. Chem. Soc. 2002, 124, 9992; e) J. M.
Hawkins, M. Nambu, S. Loren, Org. Lett. 2003, 5, 4293; f) D. J.
Morrison, W. E. Piers, M. Parvez, Synlett 2004, 2429.
[5]a) S.-Y. Liu, I. D. Hills, G. C. Fu, J. Am. Chem. Soc. 2005, 127,
15352; b) S.-Y. Liu, M. M.-C. Lo, G. C. Fu, Tetrahedron 2006, 62,
11343.
[a] Yields of corresponding homoallylic alcohol determined by GC.
[b] Determined by chiral GC analysis. [c] Absolute configuration deter-
mined by measurement of the optical rotation of the product with R1 =
Ph and R2 =Me; other compounds were assigned based on their relative
order in the GC trace. [d] Duplicate run with (Rp)-3. [e] Duplicate run with
(Sp)-4.
Finally, the enantioselectivity can be tuned by suitable
substitution at tin, as evident from an increase of the ee value
for the allylation of acetophenone from 60% for (Rp)/(Sp)-3
to 80% for (Rp)/(Sp)-4 (entries 2 and 3 in Table 1).[17] The
following considerations provide a possible rational for the
observed enantioselectivity enhancement. Compound (Rp)/
(Sp)-3, with a chlorine substituent attached to tin, can easily
extend its coordination sphere from tetrahedral to trigonal
bipyramidal through coordination of a nucleophile trans to
chlorine. This feature is found, for example, in the structure of
(Sp)-2-(+)-MPE (Figure 2), where the ephedrine oxygen
atom adopts a bridging position between boron and tin.[18]
Hence, the intermediate complex formed upon allylation of
acetophenone likely features the carbonyl oxygen atom in a
bridging position between the Sn and B centers with a
favorable Sn···O interaction similar to that in the structure of
(Sp)-2-(+)-MPE.[19] In such a trigonal-bipyramidal Sn com-
plex, the Me groups are placed in equatorial positions, and
thus the space between the tin and boron centers is opened
up. In contrast, with an allyl group in place of the chlorine
substituent on tin, a tetraorganotin species is present, for
which hyper-coordination to form a trigonal-bipyramidal tin
environment is unfavorable. Hence, the Sn-Me groups more
closely approach the adjacent boryl group, which should
effectively reduce the space available in the chiral pocket and
lead to increased stereoselectivity.
In conclusion, the novel planar chiral bidentate Lewis
acids (Sp)-1-Cl and (Rp)-1-Cl are readily accessible by chiral
resolution with N-methylpseudoephedrine and serve as
versatile precursors to other chiral organoboranes. The
corresponding allylboranes were successfully employed in
the allylation reaction of ketones, which occurs rapidly and
especially selectively with ketones that are typically difficult
to convert selectively. This is the first successful application of
organoborane-functionalized metallocenes as chiral reagents.
The results also indicate the potential of this class of
compounds as chiral Lewis acid catalysts in stereoselective
synthesis.
[6]a) J. A. Gamboa, A. Sundararaman, L. Kakalis, A. J. Lough, F.
Jäkle, Organometallics 2002, 21, 4169; b) K. Venkatasubbaiah,
L. N. Zakharov, W. S. Kassel, A. L. Rheingold, F. Jäkle, Angew.
Chem. 2005, 117, 5564; Angew. Chem. Int. Ed. 2005, 44, 5428.
[7]R. Boshra, A. Sundararaman, L. N. Zakharov, C. D. Incarvito,
A. L. Rheingold, F. Jäkle, Chem. Eur. J. 2005, 11, 2810.
[8]S. Masamune, B. M. Kim, J. S. Petersen, T. Sato, S. J. Veenstra, T.
Imai, J. Am. Chem. Soc. 1985, 107, 4549.
[9]a) C. H. Burgos, E. Canales, K. Matos, J. A. Soderquist, J. Am.
Chem. Soc. 2005, 127, 8044; b) E. Canales, K. G. Prasad, J. A.
Soderquist, J. Am. Chem. Soc. 2005, 127, 11572.
[10]Initial attempts to resolve 1-OMe by employing 0.5 equivalents
(1S,2S)-(+)-pseudoephedrine resulted in a 1:1 mixture of the
diastereomeric complexes together with unreacted racemic 1-
OMe.
[11]For large-scale preparations, we used a slight excess of (1 S,2S)-
(+)-N-methylpseudoephedrine (0.55 equiv) to ensure the opti-
cal purity of (Rp)-1-OMe, which was isolated in 75% yield. The
residual material can then be converted to (Sp)-2-(+)-MPE
(93% yield of isolated product) by simple addition of a slight
excess of racemic 1-OMe.
[12]X-ray
C31H41BClFeNOSn, Mr = 664.45, monoclinic, space group P21,
a = 10.5287(2), b = 13.8844(2), c = 21.2409(3) Š, b =
structure
analysis
for
( Sp)-2-(+)-MPE:
102.9250(10)8, V= 3026.42(8) Š3, Z = 4, 1calcd = 1.458 gcmÀ3, l-
(CuKa) = 1.54178 Š, T= 100(2) K, crystal dimensions 0.40 ”
0.38 ” 0.37 mm3, m(CuKa) = 11.389 mmÀ1, range from 2.13 to
67.98, 23803 measured reflections, 9844 independent reflections
(Rint = 0.0468), R1 [I > 2(I)] = 0.0444, wR2 [I > 2(I)] = 0.1058,
GOF = 1.043, 682 parameters, final difference map within 1.875
and À0.734 eŠÀ3. The structure was solved using direct methods,
completed by subsequent difference Fourier syntheses, and
refined by full-matrix least-squares procedures on F2. Numerical
absorption corrections were applied (G. M. Sheldrick
SHELXTL (6.14), Bruker ACS Inc.: Madison, WI, 2004). Non-
hydrogen atoms were refined with anisotropic displacement
coefficients, and hydrogen atoms were treated as idealized
contributions. CCDC-66331 contains the supplementary crystal-
lographic 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.
[13]For an overview of related X-ray structures and a definition used
to determine the degree of tetrahedral character %THCDA, see:
H. Hꢀpfl, J. Organomet. Chem. 1999, 581, 129.
Received: October 10, 2007
Published online: December 28, 2007
[14]S. E. Denmark, J. Fu, Chem. Rev. 2003, 103, 2763.
[15]In these reactions a small amount of another product is formed,
which is tentatively assigned to a cyclic species that results from
intramolecular 1,2-allylboration of the allyl moiety on tin. For
related literature reports, see: a) J. M. Blackwell, W. E. Piers, R.
McDonald, J. Am. Chem. Soc. 2002, 124, 1295; b) Y. N. Bubnov,
Keywords: allylation · boron · chirality · ferrocene ·
organoboranes
.
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Angewandte
Chemie
N. Y. Kuznetsov, F. V. Pastukhov, V. V. Kublitsky, Eur. J. Inorg.
Chem. 2005, 4633.
spectra consistent with formation of 1,2-Fc(BMe(OMe))-
(SnMe2All).
[18]A bridging oxygen atom between Sn and B has also been
reported by Schulte and Gabbaï for a naphthalene derivative
that is substituted in the 1,8-positions with BMe(OH) and
SnMeCl2 groups: M. Schulte, F. P. Gabbaï, Can. J. Chem. 2002,
80, 1308.
[19]We were unable to detect the complex of ( Rp)/(Sp)-3 and
acetophenone directly by NMR spectroscopy even at À808C,
where the reaction with acetophenone proceeds relatively
slowly. At this temperature only the unshifted signals for the
starting material and those of the allylated product were
observed. However, when 1-Cl (0.02m solution in CD2Cl2) was
treated with a fivefold excess of anisic aldehyde at À808C, a
clear shift of both the 11B (d = 15 ppm) and 119Sn (d = 71 ppm)
NMR spectroscopy signals relative to free 1-Cl (11B NMR d =
61.5 ppm; 119Sn NMR d = 95 ppm) was observed.
[16]a) K. M. Waltz, J. Gavenonis, P. J. Walsh, Angew. Chem. 2002,
114, 3849; Angew. Chem. Int. Ed. 2002, 41, 3697; b) T. R. Wu, L.
Shen, J. M. Chong, Org. Lett. 2004, 6, 2701; c) Soderquist and co-
workers reported a bicyclic borane system that can be sterically
tuned to allow for favorable conditions for the allylation of
either aldehydes or ketones; see reference [9].
[17]A reviewer suggested that in the case of the diallylated species
(Rp)/(Sp)-4, allyl transfer may occur from Sn rather than B. NMR
spectroscopic analysis of the intermediate obtained upon
reaction of (Rp)/(Sp)-4 with acetophenone shows an 11B NMR
spectroscopy signal shifted to 48.9 ppm ((Rp)/(Sp)-4, d = 71 ppm)
and a 119Sn NMR spectroscopy signal at d = À14.4 ppm, which is
similar to that of (Rp)/(Sp)-4 (d = À14.3 ppm). Moreover,
quenching of the reaction mixture with MeOH gave NMR
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