Asymmetric allylboration of aldehydes and ketones using 3,3′-disubstitutedbinaphthol-modified boronates

Article abstract of DOI:10.1021/ol0490882

Allylboronates derived from 3,3′-disubstituted 2,2′-binaphthols react with aldehydes and ketones to give the expected allylated products with up to >99:1 er. Highest selectivities were observed for aromatic ketones. The bis(trifluoromethyl) derivative is particularly outstanding in terms of reactivity, selectivity, and robustness.

Full text of DOI:10.1021/ol0490882

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2701-2704
Asymmetric Allylboration of Aldehydes
and Ketones Using
3,3′-Disubstitutedbinaphthol-Modified
Boronates
T. Robert Wu, Lixin Shen, and J. Michael Chong*
Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry,
(GWC)2, Department of Chemistry, UniVersity of Waterloo, Waterloo,
Ontario, Canada N2L 3G1
jmchong@uwaterloo.ca
Received May 18, 2004
ABSTRACT
Allylboronates derived from 3,3′-disubstituted 2,2′-binaphthols react with aldehydes and ketones to give the expected allylated products with
up to >99:1 er. Highest selectivities were observed for aromatic ketones. The bis(trifluoromethyl) derivative is particularly outstanding in terms
of reactivity, selectivity, and robustness.
1,1′-Bi-2-naphthol (BINOL, 1) has been used extensively
in asymmetric synthesis for the past 2 decades.1 Since the
seminal work reported by Noyori in 1981 on asymmetric
reductions using BINOL-modified aluminum hydrides,2 this
ligand has been used very successfully for a wide variety of
asymmetric processes.3
Derivatives of BINOL, particularly 3,3′-disubstituted de-
rivatives, have also been used in asymmetric synthesis.4 The
pioneering contributions of Kelly5 and Yamamoto6 showed
that dramatic increases in enantioselectivities could be
achieved with 3,3′-disubstituted BINOLs compared to BINOL
itself. More recently 3,3′-disubstituted BINOLs have been
used to obtain increased enantioselectivities in 1,2-additions
of dialkylzincs to aldehydes,7 conjugate additions of dieth-
ylzinc to enones,8 aldol reactions,9 cyanosilylations,10 olefin
metathesis reactions,11 and hetero-Diels-Alder reactions.12
There is also a report that substitution at the 3,3′-positions
of BINOL gave decreased enantioselectivities in hydrophos-
phonylation of aldehydes.13
We have previously shown that 3,3′-disubstitution can
have a dramatic effect on the asymmetric conjugate alky-
nylations of enones using alkynylboronates.14 Thus, with
(1) See, for example: (a) Seyden-Penne, J. Chiral Auxiliaries and
Ligands in Asymmetric Synthesis; Wiley: New York, 1995. (b) Pu, L. Chem.
ReV. 1998, 98, 2405-2494.
(7) (a) Kitajima, H.; Ito, K.; Katsuki, T. Chem. Lett. 1996, 343-344.
(b) Kitajima, H.; Aoki, Y.; Katsuki, T. Bull. Chem. Soc. Jpn. 1997, 70,
207-217.
(2) Nishizawa, M.; Yamada, M.; Noyori, R. Tetrahedron Lett. 1981, 22,
247-250.
(8) Kang, J.; Lee, J. H.; Lim, D. S. Tetrahedron: Asymmetry 2003, 14,
305-315.
(3) Balsells, J.; Davis, T. J.; Carroll, P.; Walsh, P. J. J. Am. Chem. Soc.
2002, 124, 10336-10348 and references therein.
(4) Chen, Y.; Yekta, S.; Yudin, A. K. Chem. ReV. 2003, 103, 3155-
3211.
(5) Kelly, T. R.; Whiting, A.; Chandrakumar, N. S. J. Am. Chem. Soc.
1986, 108, 3510-3512.
(6) Maruoka, K.; Itoh, T.; Shirasaka, T.; Yamamoto, H. J. Am. Chem.
Soc. 1988, 110, 310-312.
(9) Yoshikawa, N.; Shibasaki, M. Tetrahedron 2001, 57, 2569-2579.
(10) Hamashima, Y.; Sawada, D.; Nogami, H.; Kanai, M.; Shibasaki,
M. Tetrahedron 2001, 57, 805-814.
(11) Tsang, W. C. P.; Schrock, R. R.; Hoveyda, A. H. Organometallics
2001, 20, 5658-5669.
(12) (a) Long, J.; Hu, J.; Shen, X.; Ji, B.; Ding, K. J. Am. Chem. Soc.
2002, 124, 10-11. (b) Du, H.; Long, J.; Hu, J.; Li, X.; Ding, K. Org. Lett.
2002, 4, 4349-4352. (c) Du, H.; Ding, K. Org. Lett. 2003, 5, 1091-1093.
10.1021/ol0490882 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/16/2004

BINOL as ligand, selectivities were never better than ∼60:
40 er, whereas reagents prepared with 3,3′-Ph2BINOL gave
selectivities up to >99:1 er. We now report that 3,3′-Ph2-
BINOL and other 3,3′-disubstituted binaphthols can also be
used to prepare other boronates that can be used in reactions
such as allylborations with excellent results.
been used to prepare allylboronates that can effect allylation
of aldehydes with variable selectivities.19 Tartrate derivatives,
developed extensively by Roush and used in many natural
product syntheses, are the most popular diols.20 There is one
report of an allylboronate derived from BINOL being used
for allylations, but benzaldehyde was the only substrate
examined.21 Thus it seemed worthwhile to investigate this
reaction further and particularly to examine the effect of the
3,3′-substituent.
3,3′-Disubstituted BINOLs could be easily prepared from
MOM derivative 2 (Scheme 1).15 Thus lithiation of 2
Allylboronates 5 could be easily prepared by treating
binaphthols 4 with triallylborane.22 In general, the resulting
reagents reacted rapidly with PhCHO in THF23 at -78 °C
to afford the expected homoallylic alcohol in high yield
(Table 1).
Scheme 1
Table 1. Reactions of Allylboronates 5 with PhCHOa
reagenta
yield of 6a b
er of 6a c
(R:S)
entry
Y
compd no.
(%)
1
2
3
4
5
6
7
8
H
I
CH3
Ph
4-CH3OC6H4
3,5-(CH3)2C6H3
3,5-(t-Bu)2C6H3
3,5-(CF3)2C6H3
2-naphthyl
5a
5b
5c
5d
5e
5f
5g
5h
5i
50
91
91
90
89
94
92
92
90
90
71:29
87:13
88:12
73:27
81:19
80:20
83:17
85:15
75:25
98:2
followed by trapping with the appropriate electrophiles gave
3a-c. Dibromide 3a underwent Suzuki cross-coupling with
arylboronic acids to afford the expected diaryl derivatives
3d-i. The trifluoromethyl derivative 3j proved to be
problematic but was eventually obtained by treating iodide
3b with methyl fluorosulfonyldifluoroacetate and CuI.16
Finally, each of the MOM derivatives could be deprotected
using Amberlyst 15 in THF/MeOH to give the desired
substituted BINOLs 4 in excellent yields.
9
10
CF3
5j
a Reactions were run in THF at -78 °C, 1 h. b Isolated yields of
chromatographed products. c Determined by HPLC analysis with a Chiralcel
OD column.
Ligand 4j, bearing trifluoromethyl groups at the 3,3′-
positions,17 was of particular interest. The intent was that
the strongly electron-withdrawing CF3 groups should make
any derived boronates more electrophilic and hence more
reactive toward carbonyl compounds. The CF3 groups should
also be sufficiently large such that good selectivities should
be possible.
An intriguing application of ligands 4 is the allylboration
of carbonyl compounds. Asymmetric allylborations have
become very important in synthesis.18 Other chiral diols have
Somewhat surprisingly, the allylboronate derived from
BINOL (1) and 3,3′-Ph2-BINOL (4d) gave comparable
selectivities, and these were the lowest selectivities observed
(entries 1 and 4). We were unable to reproduce the 94:6
selectivity previously reported for allylation of PhCHO using
reagent 5a (prepared from 1).21 Other aryl-substituted bi-
naphthols (entries 5-9) gave slightly higher but unspectacu-
(18) Reviews: (a) Chemler, S. R.; Roush, W. R. Modern Carbonyl
Chemistry; Otera, J.; Ed.; Wiley-VCH: Weinheim, 2000; Chapter 11. (b)
Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763-2793.
(19) Mears, R. J.; De Silva, H.; Whiting, A. Tetrahedron 1997, 53,
17395-17406.
(13) Qian, C.; Huang, T.; Zhu, C.; Sun, J. J. Chem. Soc., Perkin Trans.
1 1998, 2097-2103.
(14) Chong, J. M.; Shen, L.; Taylor, N. J. J. Am. Chem. Soc. 2000, 122,
1822-1823.
(15) Cox, P. J.; Wang, W.; Snieckus, V. Tetrahedron Lett. 1992, 33,
2253-2256.
(20) Roush, W. R.; Grover, P. T. J. Org. Chem. 1995, 60, 3806-3813.
(21) Thormeier, S.; Carboni, B.; Kaufmann, D. E. J. Organomet. Chem.
2002, 657, 136-145.
(16) Chen, Q.; Wu, S. J. Chem. Soc., Chem. Commun. 1989, 705-706.
(17) When this work was conceived, binaphthol 4j was an unknown
compound. It has since appeared in the Japanese patent literature: JP
2002356454 as quoted in CAN 138:39104 and JP 2001139508 as quoted
in CAN 134:366697. It was used to make a chiral Zr catalyst for hetero-
Diels-Alder reactions.
(22) Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc. 1985,
107, 8186-8190.
(23) Other solvents surveyed (PhCH3, CH2Cl2, CH3CN, ether) using
reagent 5j and PhCHO gave respectable (91:9-95:5) but lower enantiose-
lectivities.
2702
Org. Lett., Vol. 6, No. 16, 2004

lar selectivities. The iodo and methyl analogues (entries 2
and 3) showed small improvements in selectivity.
Table 3. Allylation of Ketones with Boronate 5ja
Much to our delight, reagent 5j, derived from 3,3′-(CF3)2-
BINOL (4j), gave by far the best selectivity (Table 1, entry
10). It also showed the highest reactivity, with allylation of
PhCHO complete within 5 min at -78 °C. Allylation of other
aldehydes using 5j proceeded smoothly at -78 °C to give
products in high yields (Table 2). High selectivities were
ketone
7
Table 2. Allylation of Aldehydes with Boronate 5ja
entry
R
R′
compd no. yieldb (%) erc (R:S)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
CH3
CH3
CH2Br
7a
7a
7b
7c
7d
7e
7f
60d
88
87e
95
94
91
75
98
98:2
96:4
97:3
4-CH3OC6H4 CH3
99:1
4-ClC6H4
PhCHdCH
t-Bu
CH3
CH3
CH3
CH3
>99:1f
88:12
95:5g
75:25
PhCH2CH2
7g
6
a Reactions were run in toluene at -78 to -40 °C, 48 h. b Isolated yields
of chromatographed products. c Determined by HPLC analysis with a
Chiralcel OD column. d Reaction was run in toluene at -78 °C, 6 h.
e Isolated yield of 1-phenyl-1-(2-propenyl)oxirane after workup with 1 M
NaOH. f The minor enantiomer was not detected by HPLC analysis.
entry
aldehyde R
Ph
4-CH3OC6H4
4-ClC6H4
4-O2NC6H4
4-CF3C6H4
PhCHdCH
c-C6H11
compd no.
yieldb (%)
erc (R:S)
1
2
3
4
5
6
7
6a
6b
6c
6d
6e
6f
90
93
93
96
94
98
90
98:2
97:3
97:3
96:4
97:3
88:12
88:12
1
g Determined by H NMR analysis in the presence of Eu(hfc)3.
to be no previous reports of enantioselective allylborations
of ketones using allylboronates. This is likely due to the low
reactivity of most allylboronates toward ketones or to low
selectivities observed that were therefore not reported.
Ketones bearing adjacent coordinating groups show higher
reactivities toward allylboronates, and diastereoselective
reactions have been reported.25 In the case of 5j, higher
reactivity is undoubtedly due to the electron-withdrawing CF3
groups.26 Roush has previously shown that addition of
fluorinated groups to a tartramide leads to higher reactivity
(in aldehyde allylations) in the derived allylboronate.20
6g
a Reactions were run in THF at -78 °C, 1 h. b Isolated yields of
chromatographed products. c Determined by HPLC analysis with a Chiralcel
OD column.
observed for all of the aromatic aldehydes examined (Table
2, entries 1-5). High yields but slightly lower selectivities
were found with an enal (cinnamaldehyde) and an aliphatic
aldehyde (Table 2, entries 6 and 7).
Allylboronate 5j also reacted with ketones, albeit much
more slowly than with aldehydes (Table 3). Thus, whereas
aldehydes usually showed complete reaction with 5j within
5 min at -78 °C, acetophenone was only partially consumed
and the expected 3° alcohol 7a was isolated in a modest
60% yield even after 6 h at -78 °C. However, the
enantioselectivity observed (er ) 98:2) was excellent (Table
3, entry 1). The yield of 7a could be improved by allowing
the reaction to warm to -40 °C with only a small drop in
enantioselectivity (entry 2). Other alkyl aryl ketones were
allylated with uniformly high selectivities (entries 3-5). An
R,â-unsaturated ketone, benzalacetone, gave lower but still
respectable selectivity. Pinacolone (t-Bu vs Me) was also
allylated with good selectivity (entry 7), but poor enantio-
facial discrimination was observed for a ketone with sterically
similar alkyl groups (entry 8). In all cases, reactions were
very clean with near quantitative conversion to the desired
3° alcohol. High isolated yields were typically observed with
the lower yield of 7f attributable to its volatility.
The high selectivities obtained with 5j compare very
favorably with other methods for the asymmetric allylation
of ketones.27 In fact, boronate 5j is one of the most selective
reagents for the allylation of alkyl aryl ketones thus far
developed. The yields and selectivities observed with sub-
stituted acetophenones (Table 3, entries 4 and 5) are par-
ticularly impressive.
The absolute configurations of the major products in the
allylation of both aldehydes and ketones were determined
by comparison of optical rotations with known materials.28
(24) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org.
Chem. 1986, 51, 432-439.
(25) (a) Wang, Z.; Meng, X. J.; Kabalka, G. W. Tetrahedron Lett. 1991,
32, 1945-1948. (b) Wang, Z.; Meng, X. J.; Kalbalka, G. W. Tetrahedron
Lett. 1991, 32, 5677-5680.
(26) Brown, H. C.; Racherla, U. S.; Pellechia, P. J. J. Org. Chem. 1990,
55, 1868-1874.
(27) (a) Kii, S.; Maruoka, K. Chirality 2003, 15, 68-70. (b) Walsh, K.
M.; Gavenonis, J.; Walsh, P. J. Angew. Chem., Int. Ed. 2002, 41, 3697-
3699. (c) Casolari, S.; D’Addario, D.; Tagliavini, E. Org. Lett. 1999, 1,
1061-1063. (d) Yamasaki, S.; Fujii, K.; Wada, R.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2002, 124, 6536-6537.
Asymmetric allylboration of ketones is typically a very
poor reaction. For example, allylboration of acetophenone
with Ipc2BCH2CHdCH2 gives 7a with 5% ee.24 There appear
(28) See Supporting Information for details.
Org. Lett., Vol. 6, No. 16, 2004
2703

In each case, allylations using R-BINOLs all gave R alcohols
as major products. The sense of asymmetric induction using
allylboronates 5j may be explained using a six-membered
chair transition-state model (Scheme 2). In this model, the
binaphthol is easily recovered from the reaction in near-
quantitative yields and with no detectable racemization by
simple extraction with aqueous base. In fact, 4j seems to be
extremely resistant to racemization. Even under strongly
acidic conditions (10% HCl, H2O-THF, reflux, 24 h) or
basic (0.1 M KOH, n-BuOH, 60 °C, 48 h) that cause
complete racemization of BINOL, 4j shows no detectable
racemization. This remarkable configurational stability is
likely due, at least in part, to the strongly electron-with-
drawing character of the CF3 group. Yudin introduced an
octafluoro-BINOL that showed much higher configurational
stability compared to that of BINOL.31 Although this in-
creased stability is very desirable, synthetic challenges in
preparing enantiomerically pure F8-BINOL have limited its
applications. In contrast, 3,3′-(CF3)2-BINOL 4j is easily
prepared from BINOL 1, which is commercially available
in either enantiomeric form, in four steps with 80% overall
yield.
Scheme 2
In summary, we have shown that 3,3′-disubstituted-
BINOLs can be used to prepare allylboronates that will
allylate carbonyl compounds. 3,3′-(CF3)2-BINOL 4j is an
especially effective auxiliary that allows for allylborations
of both aldehydes and ketones in high enantioselectivities.
We anticipate that many other applications of 4j in asym-
metric synthesis will be found.
larger or aryl group occupies an equatorial position in either
of two possible transition states. The 3- and 3′-substituents
on the binaphthol play an important role in destabilizing one
of the possible transition states. In the case of aldehydes,
this destabilizing interaction is between a CF3 group and the
aldehydic H, whereas with ketones it would be between a
CF3 group and the smaller group of the ketone, usually a
methyl group.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada for financial
support, and Mr. D. Gehle for racemization studies on
binaphthol 4j.
Supporting Information Available: Experimental details
for the preparation of and spectral data for compounds 2-4,
procedures for allylations, and details for determinations of
enantiomer ratios and absolute configurations. This material
is available free of charge via the Internet at http://pubs.acs.org.
It should be noted that although stoichiometric amounts
of ligand 4j are used in these reactions (as opposed to the
metal-catalyzed allylborations recently developed29,30), the
OL0490882
(30) Ishiyama, T.; Ahiko, T.-a.; Miyaura, N. J. Am. Chem. Soc. 2002,
124, 12414-12415.
(31) Yudin, A. K.; Martyn, L. J. P.; Pandiaraju, S.; Zheng, J.; Lough,
A. Org. Lett. 2000, 2, 41-44.
(29) (a) Kennedy, J. W. J.; Hall, D. G. J. Am. Chem. Soc. 2002, 124,
11586-11587. (b) Lachance, H.; Lu, X.; Gravel, M.; Hall, D. G. J. Am.
Chem. Soc. 2003, 125, 10160-10161.
2704
Org. Lett., Vol. 6, No. 16, 2004