Highly enantioselective 3-furylation of ketones using (3-Furyl)titanium nucleophile

Article abstract of DOI:10.1021/ol902454n

Chemical Equation Presented A novel asymmetric 3-furyl addition of (3-furyl)Ti(0'Pr)₃ to ketones in the presence of 10 mol % (S)-BINOL is reported. The catalytic system works excellently for aromatic ketones, αβhalophenones, αβ-unsaturated ketones, and acetylfuran, affording products in high yields with excellent enantioselectivities of up to 97% ee.

Full text of DOI:10.1021/ol902454n

ORGANIC
LETTERS
2010
Vol. 12, No. 1
48-51
Highly Enantioselective 3-Furylation of
Ketones Using (3-Furyl)titanium
Nucleophile
Shuangliu Zhou,†,‡ Chi-Ren Chen,† and Han-Mou Gau*,†
Department of Chemistry, National Chung Hsing UniVersity, Taichung 402, Taiwan,
and Laboratory of Functional Molecular Solids, Ministry of Education, College of
Chemistry and Materials Science, Anhui Normal UniVersity, Wuhu, P.R. China
hmgau@dragon.nchu.edu.tw
Received October 24, 2009
ABSTRACT
A novel asymmetric 3-furyl addition of (3-furyl)Ti(OiPr)3 to ketones in the presence of 10 mol % (S)-BINOL is reported. The catalytic system
works excellently for aromatic ketones, r- or ꢀ-halophenones, r,ꢀ-unsaturated ketones, and acetylfuran, affording products in high yields
with excellent enantioselectivities of up to 97% ee.
The enantioselective addition of organozinc reagents to organic
carbonyls is the most important and straightforward strategy
for the synthesis of optically active alcohols.1Chiral zinc2,3 and
titanium2r,4 catalysts are the two major systems that have
been extensively studied in parallel in the past two decades.
For zinc catalytic systems, the active metallic species are
generated from reactions of organozinc reagents with chiral
ligands, and the mechanisms of alkylzinc addition reactions
have been well established experimentally5 and theoretically.6
In contrast, the titanium catalytic systems are more compli-
cated. Studies of asymmetric alkylation reactions catalyzed by
† National Chung Hsing University.
‡ Anhui Normal University.
(1) For reviews, see: (a) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757.
(b) Walsh, P. J. Acc. Chem. Res. 2003, 36, 739. (c) Ramu¨n, D. J.; Yus, M.
Angew. Chem., Int. Ed. 2004, 43, 284. (d) Schmidt, F.; Stemmler, R. T.;
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Miyamoto, T.; Ishihara, K. Curr. Org. Chem. 2007, 11, 127. (f) Hatano,
M.; Ishihara, K. Chem. Rec. 2008, 8, 143. (g) Hatano, M.; Ishihara, K.
Synthesis 2008, 1647.
(2) Selected references for alkyl-zinc reagents, see: (a) Soai, K.; Niwa,
S. Chem. ReV. 1992, 92, 833. (b) DiMauro, E. F.; Kozlowski, M. C. Org.
Lett. 2001, 3, 3053. (c) Costa, A. M.; Jimeno, C.; Gavenonis, J.; Carroll,
P. J.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 6929. (d) Wipf, P.; Wang,
X. D. Org. Lett. 2002, 4, 1197. (e) Nugent, W. A. Org. Lett. 2002, 4, 2133.
(f) Park, J. K.; Lee, H. G.; Bolm, C.; Kim, B. M. Chem.sEur. J. 2005, 11,
945. (g) Hatano, M.; Suzuki, S.; Ishihara, K. J. Am. Chem. Soc. 2006, 128,
9998. (h) Hatano, M.; Miyamoto, T.; Ishihara, K. J. Org. Chem. 2006, 71,
6474. (i) Hatano, M.; Miyamoto, T.; Ishihara, K. Synlett 2006, 6474. (j)
Milburn, R. R.; Hussain, S. M. S.; Prien, O.; Ahmed, Z.; Snieckus, V. Org.
Lett. 2007, 9, 4403. For alkynyl-zinc reagents, see: (k) Anand, N. K.;
Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687. (l) Cozzi, P. G. Angew.
Chem., Int. Ed. 2003, 42, 2895. (m) Pu, L. Tetrahedron 2003, 59, 9873.
(n) Dahmen, S. Org. Lett. 2004, 6, 2113. (o) Emmerson, D. P. G.; Hems,
W. P.; Davis, B. G. Org. Lett. 2006, 8, 207. (p) Wolf, C.; Liu, S. L. J. Am.
Chem. Soc. 2006, 128, 10996. (q) Trost, B.; Weiss, M. A. H.; Wangelin,
A. J. J. Am. Chem. Soc. 2006, 128, 8. (r) Trost, B. M.; Weiss, A. H. AdV.
Synth. Catal. 2009, 351, 963.
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J. C.; Fu, G. C. J. Org. Chem. 1997, 62, 444. (b) Dosa, P. I.; Fu, G. C.
J. Am. Chem. Soc. 1998, 120, 445. (c) Huang, W.-S.; Pu, L. J. Org. Chem.
1999, 64, 4222. (d) Huang, W.-S.; Hu, Q.-S.; Pu, L. J. Org. Chem. 1999,
64, 7940. (e) Bolm, C.; Hermanns, N.; Hildebrand, J. P.; Muliz, K. Angew.
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Soc. 2002, 124, 14850. (g) Liu, X. Y.; Wu, X. Y.; Chai, Z.; Wu, Y. Y.;
Zhao, G.; Zhu, S. Z. J. Org. Chem. 2005, 70, 7432. (h) Lu, G.; Kwong,
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10.1021/ol902454n  2010 American Chemical Society
Published on Web 12/03/2009

titanium catalysts of TADDOLs,7 BINOLs,8 or N-sulfonylated
amino alcohols9 have suggested that the catalytic reaction
initially proceeds via a transmetalation of the organic nucleo-
phile from the zinc to the titanium metal center, followed by
an addition of the nucleophile to aldehydes via the titanium
active species. Despite evidence supporting additions of orga-
notitanium reagents, direct asymmetric additions to organic
carbonyls have been demonstrated in only a few studies.
Seebach and Weber reported the first asymmetric organotita-
nium additions of RTi(OiPr)3 (R ) alkyl or aryl) to aldehydes
catalyzed by the titanium complexes of 20 mol % TADDOLs.10
The reactions had been carried out first at a low temperature of
-78 °C, suggesting a high reactivity of organotitanium com-
pounds. In a delicate mechanistic study of titanium-catalyzed
dialkylzinc addition reactions, Walsh et al. demonstrated the
direct asymmetric MeTi(OiPr)3 addition to aldehydes at 0 °C
catalyzed by 20 mol % Ti(BINOLate)(OiPr)2, affording second-
ary alcohols in ∼50% ee.8 Cozzi and Alesi reported a titanium
phenylacetylide addition reaction to ketones in the presence of
10 mol % (R)-BINOL conducted at temperatures e -15 °C to
give the chiral propargyl alcohols in moderate yields with
moderate to good enantioselectivities.11 Although aryltitanium
compounds of ArTi(OiPr)3 have been used in recent years as
nucleophilic reagents in a few cases of late-transition metal
catalyzed asymmetric reactions12 and coupling reactions,13 it
seems that the high reactivity of organotitanium reagents limits
their direct use in titanium-catalyzed asymmetric reactions.
Recently, we discovered that organoaluminum compounds were
effective reagents in asymmetric additions to organic carbonyls,
affording secondary and tertiary alcohols in excellent enanti-
oselectivities.14 The reactions of the organotitanium reagents
and aldehydes in the presence of a stoichiometric amount of
chiral titanium catalyst precursor gave addition products in
enantioselectivities similar to those of products obtained from
titanium-catalyzed organozinc or organoaluminum addition
reactions,9,14a further supporting the argument of organoti-
tanium compounds as the actual addition reagents. For
titanium-catalyzed reactions, general features of excess
Ti(OiPr)4 and high equivalent of addition reagents are in
general required in order to achieve high enantioselectivities
of desired products.14,15 The roles of excess Ti(OiPr)4 are
(1) the transmetalation of an organic nucelophile from the
organozinc or organoaluminum compounds to form the
organotitanium reagents and (2) the formation of the ditita-
nium active species.8,9,16 Both Seebach’s10 and Walsh’s8
works show that the use of organotitanium reagents does
not require the addition of Ti(OiPr)4 and that a slight excess
of organotitanium reagents is sufficient to induce the reac-
tions. However, key factors for the direct use of the highly
reactive organotitanium reagents for achieving excellent
stereocontrol are either to suppress the background reaction
or to use a highly efficient catalytic system. In this study,
we report a direct asymmetric catalytic addition of (3-
furyl)tris(2-propoxide)titanium to a wide variety of ketones,
affording chiral tertiary alcohols containing 3-furyl moiety
in excellent enantioselectivities.
tives are versatile intermediates in organic synthesis owing to
their facile conversions to a series of functional groups.17
However, functionalized furans at the C-3 position were less
reported as a result of difficulties in the metalation processes
in which 3-furyllithium converts to 2-furyllithium at low
temperatures.17a,f In this study, the (3-furyl)titanium reagent,
[(3-furyl)Ti(OiPr)3]2 (1), was synthesized from a reaction of
3-furyllithium with Ti(OiPr)3Cl in THF at -78 °C. An X-ray
diffraction study of complex 1 (Figure 1) confirmed that the
Figure 1. Molecular structure of 1.
(3-furyl)tris(2-propoxo)titanium complex has the dimeric
structure with a Ti2O2 core bridging through the oxygen atom
of two 2-propoxide ligands. Compound 1 is represented as
(3-furyl)Ti(OiPr)3 for simplification. Unlike 3-furyllithium,
1 is stable enough to be manipulated under a dry nitrogen
atmosphere at room temperature.
Asymmetric 3-furyl addition reactions were optimized on
acetophenone (2a) with (3-furyl)Ti(OiPr)3 in the presence of
10 mol % of (S)-BINOL. The results are summarized in Table
1. The optimal reaction conditions of 1.5 equiv of (3-furyl)-
Table 1. Optimization of Enantioselective 3-Furyl Addition to
Acetophenone Catalyzed by a Titanium Catalyst of (S)-BINOLa
entry solvent Ti(3-furyl)(OiPr)3 (equiv)b convn (%)c ee (%)d
1
2
3
4
5
6
THF
1.4
1.4
1.4
1.4
1.3
1.5
1.6
1.5
1.5
92
93
85
86
78
100
100
100
30
87
86
94
95
95
94
93
89
CH2Cl2
hexane
toluene
toluene
toluene
toluene
toluene
toluene
7
8e
9f
a 0.050 mmol of (S)-BINOL, 0.50 mmol of acetophenone, toluene (6
b
mL), 0 °C. Equivalent of (3-furyl)Ti(OiPr)3 is relative to acetophenone.
c Conversions were determined by 1H NMR. d Enantioselectivities were
determinedbyHPLC.e Atroomtemperature.f Insituprepared(3-furyl)Ti(OiPr)3.
Functionalized furans are found in a variety of natural
products and pharmaceutical agents. In addition, furan deriva-
Org. Lett., Vol. 12, No. 1, 2010
49

Ti(OiPr)3 in toluene at 0 °C were found to furnish product 3a
in a 100% conversion with an excellent 94% ee (entry 6). In
the reaction, the active catalytic species was generated in situ
from a reaction of (3-furyl)Ti(OiPr)3 and (S)-BINOL, and an
excess of only 0.3 equiv of (3-furyl)Ti(OiPr)3 was used relative
to the ketone substrate. The reaction at room temperature was
also examined to furnish 3a in a good enantioselectivity of 89%
ee (entry 8). However, the addition of in situ prepared
(3-furyl)Ti(OiPr)3 to 2a afforded 3a in a low conversion of only
30% (entry 9).
We then examined the catalytic reactions with function-
alized ketones under the optimized conditions, and the results
are presented in Table 2. For aromatic ketones with
either an electron-withdrawing or an electron-donating sub-
stituent at the 2′-, 3′-, or 4′-position and 1′- or 2′-acetonaph-
thone, 3-furyl additions afforded tertiary alcohols in excellent
yields with excellent enantioselectivities of 90% ee or greater
(entries 1-18), except for substrates of 2′-methoxyacetophe-
none (2e) and 3′-methoxyacetophenone (2f), which afforded
3e and 3f in 38% and 83% ee (entries 5 and 6). The low
Table 2. Enantioselective 3-Furyl Addition to Ketones Catalyzed by the Titanium Catalyst of (S)-BINOLa
a 0.050 mmol of (S)-BINOL, 0.75 mmol of (3-furyl)Ti(OiPr)3, 0.50 mmol ketone, toluene (6 mL), 0 °C. b Isolated yields. c Enantioselectivities were
determined by HPLC. d Absolute configuration was determined by an X-ray diffraction study.
50
Org. Lett., Vol. 12, No. 1, 2010

enantioselectivity of 3e is attributed to the chelate effect of
2e, which resulted in small differentiations of both directions
while coordinating to the active metal center.
In summary, a novel direct asymmetric 3-furyl addition
of (3-furyl)Ti(OiPr)3 to ketones employing 10 mol % titanium
catalyst of (S)-BINOL is reported. A wide variety of ketones
are examined to afford products in good to excellent yields
with excellent enantioselectivities of 90% ee or greater for
most aromatic ketones bearing either an electron-donating
or an electron-withdrawing substituent on the aromatic ring.
The catalytic system also applies to R- or ꢀ-halophenones
and R,ꢀ-unsaturated ketones, affording products in good
yields with high enantioselectivities. Importantly, the catalytic
system does not require the addition of any Ti(OiPr)4, and a
slight excess of 0.3 equiv of (3-furyl)Ti(OiPr)3 is sufficient
for the reactions. This study represents the most effective
titanium-catalyzed nucleophilic addition reactions to ketones
with a reaction time of 12 h at a mild temperature of 0 °C
even for additions to sterically hindered ketones. Further
investigations of organotitaninum reagents in catalysis are
currently underway.
The asymmetric additions to R-halophenones, such as
R-chloroacetophenone, R-bromoacetophenone, and R-bromo-
2′-acetonaphthone, afforded the tertiary alcohols 3s, 3t, and
3u in high yields of 85-93% with good enantioselectivities
of 83-86% ee (entries 19-21). It is worth noting that the
asymmetric addition to the ꢀ-halophenone of 3-bromo-1-
phenylpropan-1-one afforded 3v in an excellent 95% ee
(entry 22). To determine the absolute configuration of the
3-furylation products, the 3-furyl alcohol 3t (Figure 2)
Acknowledgment. Financial support under grant number
NSC 96-2113-M-005-007-MY3 from the National Science
Council of Taiwan is appreciated.
Supporting Information Available: Experimental and
characterization data for all compounds and CIF file of
compounds 1 and (S)-3t. This material is available free of
charge via the Internet at http://pubs.acs.org.
Figure 2. Molecular structure of (S)-3t.
OL902454N
containing a heavy bromine atom was characterized by an
X-ray diffraction study, and the crystal data confirmed an
S-configuration for 3t. The catalytic system also applied to
R,ꢀ-unsaturated ketones such as 1-phenyl-1-buten-3-one and
1-acetyl-1-cyclohexene and to 2-acetylfuran, furnishing 3w,
3x, and 3y in good to excellent enanatioselectivities of 74%,
90%, and 88% ee (entries 23-25), respectively.
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