Asymmetric methallylation of ketones catalyzed by a highly active organocatalyst 3,3′-F2-BINOL

Article abstract of DOI:10.1021/ol400498a

(S)-3,3′-F₂-BINOL has been synthesized for the first time and demonstrated as a highly active organocatalyst for asymmetric methallylation of ketones. Up to 98:2 enantioselectivity and 99% yield were obtained with 5 mol % catalyst loading. The

Full text of DOI:10.1021/ol400498a

ORGANIC
LETTERS
2013
Vol. 15, No. 7
1710–1713
Asymmetric Methallylation of Ketones
Catalyzed by a Highly Active
Organocatalyst 3,30‑F2‑BINOL
Yongda Zhang,* Ning Li, Bo Qu, Shengli Ma, Heewon Lee, Nina C. Gonnella, Joe Gao,
Wenjie Li, Zhulin Tan, Jonathan T. Reeves, Jun Wang, Jon C. Lorenz, Guisheng Li,
Diana C. Reeves, Ajith Premasiri, Nelu Grinberg, Nizar Haddad, Bruce Z. Lu,
Jinhua J. Song, and Chris H. Senanayake
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc.,
900 Ridgebury Road/P.O. Box 368, Ridgefield, Connecticut 06877-0368, United States
yongda.zhang@boehringer-ingelheim.com
Received February 22, 2013
ABSTRACT
(S)-3,30-F2-BINOL has been synthesized for the first time and demonstrated as a highly active organocatalyst for asymmetric methallylation of
ketones. Up to 98:2 enantioselectivity and 99% yield were obtained with 5 mol % catalyst loading. The catalyst (S)-3,30-F2-BINOL could be easily
recovered and reused.
Chiral tertiary alcohols are commonly found motifs in
biologically active compounds. Recently, we needed to
develop a practical process for constructing a key chiral
building block 1 (Scheme 1) for a pharmaceutical agent.
The most direct synthetic strategy to install the chiral
tertiary alcohol subunit would involve an asymmetric
methallylation of ketone 3. A literature survey revealed
that although much effort has been dedicated to the area of
asymmetric allylation of ketones,1 there is a lack of effi-
cient, practical, and environmentally benign methods for
the corresponding asymmetric methallylation of ketones.2
The first catalytic asymmetric methallylation of ketones
with tetramethylallylstannane was reported by Walsh and
co-workers in 2006.2a Shortly after, a chromium-catalyzed
enantioselective addition of allyl bromide to ketones was
describedby the Sigmangroup2c and onlyoneexamplewas
reported for asymmetric methallylation. In both cases,
toxic metals such as tin and chromium were employed in
the transformation. Moreover, the optimized and well-
developed conditions for allylation of ketones were not
always directly applicable to the methallylation process
due to the unclear and elusive mechanistic differences
between the two processes.2a Given the importance of the
asymmetric methallylation reaction of ketones, it was
highly desirable to develop new catalytic conditions for
this transformation. Our efforts in this area focused on
organocatalysis considering its mild conditions, opera-
tional simplicity, and environmental benefits. Herein we
would like to report a highly practical and efficient process
for asymmetric methallylation of ketones using 3,30-F2-
BINOL as the organocatalyst.
Recent literature has suggested that Brønsted acids are
capable of activating allylboronates for nucleophilic addi-
tion reactions to carbonyl compounds.3 In particular,
Schaus et al. described an asymmetric allylboration of
ketones catalyzed by 3,30-Br2-BINOL.4 Intrigued by their
work, we prepared the corresponding methallyl boro-
nate 4 and applied these allylation conditions to the
(1) For asymmetric allylation of ketones, see reviews: (a) Hatano,
ꢀ
M.; Ishihara, K. Synthesis 2008, 11, 1647. (b) Yus, M.; Gonzalez-
ꢀ
Gomez, J. C.; Foubelo, F. Chem. Rev. 2011, 111, 7774. (c) Tietze,
L. F.; Kinzel, T.; Brazel, C. C. Acc. Chem. Res. 2009, 42, 367.
(2) (a) Kim, J. G.; Camp, E. H.; Walsh, P. J. Org. Lett. 2006, 8, 4413.
ꢀ
(b) Roman, J. G.; Soderquist, J. A. J. Org. Chem. 2007, 72, 9772.
(c) Miller, J. J.; Sigman, M. S. J. Am. Chem. Soc. 2007, 129, 2752.
(d) Hanhan, N. V.; Tang, Y. C.; Tran, N. T.; Franz, A. K. Org. Lett.
2012, 14, 2218.
r
10.1021/ol400498a
Published on Web 03/25/2013
2013 American Chemical Society

Table 1. Asymmetric Methallylation of Ketone 3
Scheme 1
methallylationreaction usingour substrate 3 (Table 1). Our
initial studies showed that the use of 3,30-Br2-BINOL 5 for
the methallylation of ketone 3 with cyclic boronate 4 gave
reasonable enantioselectivities. However, the reaction
proved to be sluggish, giving poor conversions (61% after
10 h with 5 mol % catalyst 5, entry 1). The observed low
catalytic activity of 3,30-Br2-BINOL for methallylation
prompted us to further investigate this reaction, aiming
at identifying a more reactive catalyst for the asymmetric
methallylation of ketones.
entrya
X
t (h)
conv (%)
erb
1
2
3
4
5
6
Br
10
16
20
16
10
10
61
84
88
82
70
98
89:11
51:49
50:50
52:48
91:9
CO2Me
SO2CF3
CF3
Cl
F
87:13
a All reactions were performed with ketone 3 (1.0 equiv) and bor-
onate 4 (1.2 equiv) under nitrogen. b The er was determined by chiral
HPLC of the reaction mixture.
Our approach is based on the hypothesis that catalytic
activities of substituted BINOLs can be modulated by the
substituents at the 3,30-positions of the biaryl skeleton. We
envisioned that by increasing the acidity of the substituted
BINOLs, we might be able to improve the catalyst reactiv-
ity for the challenging ketone methallylation. To test this
hypothesis, we prepared a range of chiral BINOL deriva-
tives with electron-withdrawing groups and tested them in
the asymmetric methallylation of ketone 3 (Table 1).5 Our
results indicated that the use of chiral BINOLs containing
extensive research on BINOL derivatives,9 3,30-F2-BINOL
7 has never been synthesized before, presumably due to the
difficulties associated with its synthesis. To examine its
catalytic activity, we first developed an efficient synthetic
route to 3,30-F2-BINOL 7 as shown in Scheme 2. Directed-
ortho-metalation of compound 9 generated the lithium
dianion, which was trapped with NFSI (N-fluorobenzene-
sulfonimide) to give intermediate 10.10 Subsequent acidic
deprotection furnished the desired product 7 in 85% over-
all yield from BINOL 8. The structure of 7 was confirmed
by NMR as well as the single crystal X-ray analysis.
Multikilograms of 3,30-F2-BINOL were readily prepared
using this procedure.
CF3,6 CO2Me, or SO2CF3 at the 3,30-positions gave
7
essentially no enantioselectivity (entries 2ꢀ4). Yet, when
we introduced Cl substituents at the 3,30-positions of
BINOL,8 the methallylation with ketone 3 proved to be
faster than the reaction with 3,30-Br2-BINOL 5, giving
70% conversion and good enantioselectivity (91:9 er,
entry 5). Encouraged by these results, we decided to install
an even more electron-withdrawing halogen, i.e. fluorine, at
the 3,30-positions of BINOL. After an extensive literature
search, we were surprised to find that, despite decades of
Scheme 2
(3) (a) Yu, S. H.; Ferguson, M. J.; McDonald, R.; Hall, D. G. J. Am.
Chem. Soc. 2005, 127, 12808. (b) Rauniyar, V.; Hall, D. G. Angew.
Chem., Int. Ed. 2006, 45, 2426. (c) Nowrouzi, F.; Thadani, A. N.; Batey,
R. A. Org. Lett. 2009, 11, 2631. (d) Matsuoka, H.; Kondo, K. Tetra-
dedron Lett. 2009, 50, 2320. (e) Meilly, M. K.; Ryschnovsky, S. D. Org.
Lett. 2010, 12, 4895.
(4) (a) Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2006,
128, 12660. (b) Barnett, D. S.; Moquist, P. N.; Schaus, S. E. Angew.
Chem., Int. Ed. 2009, 48, 8679.
(5) See Supporting Information for a full list of screening results of
various substituted BINOLs.
(6) Cook, G. R.; Kargbo, R.; Maity, B. Org. Lett. 2005, 7, 2767.
(7) Kargbo, R.; Takahashi, Y.; Bhor, S.; Cook, G. R.; LIoyd-Jones,
G. C.; Shepperson, I. R. J. Am. Chem. Soc. 2007, 129, 3846.
(8) Examples of application 3,30-Cl2-BINOL: (a) Orito, Y.; Hashimoto,
S.; Ishizuka, T.; Nakajima, M. Tetrahedron 2006, 62, 390. (b) Turner,
H. M.; Patel, J.; Niljianskul, N.; Chong, J. M. Org. Lett. 2011, 13, 5796.
(c) Ichibakase, T.; Kaneko, T.; Orito, Y.; Kotani, S.; Nakajima, M.
Tetrahedron 2012, 68, 4210. (d) Ito, K.; Takahashi, M.; Hoshino, T.;
Nishiki, M.; Ohba, Y. Letters in Org. Chem. 2006, 3, 735. (e) Ichibakase,
T.; Orito, Y.; Nakajima, M. Tetrahedron Lett. 2008, 49, 4427.
(9) (a) Shibasaki, M.; Matsunaga, S. Chem. Soc. Rev. 2006, 35, 269.
(b) Brunel, J. M. Chem. Rev. 2007, 107, PR1–PR45. (c) Brunel, J. M.
Chem. Rev. 2005, 105, 857. (d) Chen, Y.; Yekta, S.; Yudin, A. K. Chem.
Rev. 2003, 103, 3155. (e) Pu, L. Chem. Rev. 1998, 98, 2405. (f) Yoon,
T. P.; Jacobsen, E. N. Science 2003, 299, 1691.
To our delight, the methallylation reaction with 3,30-F2-
BINOL 7 as the catalyst proved to be much more facile
(10) (a) Snieckus, V.; Beaulieu, F.; Morhri, K.; Han, W.; Murphy,
C. K.; Davis, F. A. Tetrahedron Lett. 1994, 35, 3465. (b) Cox, P. J.;
Wang, W.; Snieckus, V. Tetrahedron Lett. 1992, 33, 2253. (c) Dofferding,
E.; Ofner, H. Synlett 1991, 187.
Org. Lett., Vol. 15, No. 7, 2013
1711

than reactions with 3,30-Br2-BINOL and 3,30-Cl2-BINOL.
With 5 mol % of 7, the reaction reached 98% conversion in
10 h with 87:13 er (Table 1, entry 6). To the best of our
knowledge, this is the first time that 3,30-F2-BINOL has
been synthesized and utilized to catalyze organic reactions.
Table 3. Asymmetric Methallylation of Ketones 11aꢀp with
3,30-F2-BINOL 7 as the Organocatalyst
Table 2. Asymmetric Methallylation of Ketone 3 with 3,30-F2-
BINOL 7 as the Organocatalyst
prod-
t
T yield
entrya ketone
uct (h)b (°C) (%)c erd
1
2
3
4
5
6
7
11a R1 = Ph, R2 = CH2Ph
12a
4
5
40 98 93:7e
40 95 96:4
11b R1 = Ph, R2 = CH2(3-MeOC6H4) 12b
11c R1 = 2-MeOC6H4, R2 = CH2Ph 12c 18 23 97 95:5
11d R1 = 4-FC6H4, R2 = CH2Ph
11e R1 = 4-CIC6H4, R2 = CH2Ph
11f R1 = 4-BrC6H4, R2 = CH2Ph
11g R1 = 2-MeOC6H4
12d
12e
12f
2
2
2
40 97 96:4
40 97 96:4
40 98 97:3
entrya
7 (mol %)
t (°C)
t (h)
erb
conv (%)c
12g 18 40 96 93:7
R2 = CH2(1-naphthyl)
11h R1 = 2-MeOC6H4
12h 40 99 98:2
5
1
2
3
4
5
6
5
5
5
5
5
2
23
23
0
10
10
41
8
86:14
86:14
87:13
86:14
85:15
84:16
98d
98
73
98
98
98
8
R2 = CH2(2-naphthyl)
9
11i R1 = 4-ClC6H4, R2 = (CH2)2Cl 12i 18 23 95 85:15
10
11
12
13
14
15
16
11j R1 = 3-thienyl, R2 = CH2Ph
11k R1 = 2-thienyl, R2 = CH2Ph
11l R1 = Ph,R2 = (CH2)2Ph
11m R1 = Ph,R2 = (CH2)3Ph
11n R1 = Ph,R2 = CH2OBn
11o R1 = Ph,R2=CH3
12j 18 23 98 96:4
12k 18 23 97 97:3
12l
12m 4 40 96 90:10
12n 18 23 93 85:15
12o 18 23 96 78:22
12p 18 23 95 78:22
40
60
23
3
4
40 97 91:9
41
a All reactions were performed with ketone 3 (1.0 equiv), boronate 4
(1.2 equiv), 3,30-F2-BINOL 7, and t-AmOH (2 equiv) under nitrogen at
the temperature indicated in the table unless noted otherwise. b The er
was determined by chiral HPLC of the reaction mixture. c HPLC
conversion of 3 to 2 at 220 nm. d t-BuOH was used.
11p R1 = Ph, R2 = CH2CO2tBu
a All reactions were performed with ketone 11aꢀq (1.0 equiv), 3,30-
F2-BINOL 7 (0.05 equiv), boronate 4 (1.5 equiv), and t-AmOH (2 equiv)
under nitrogen. b The reaction time was not optimized. c Isolated yields
after chromatography purification on silica gel. d The er was determined
on chiral HPLC. e 0.02 equiv of 7 was used.
Further optimization was focused on defining the reac-
tion temperatures as well as the loading of the catalyst and
the alcohol additive. The use of t-BuOH or t-AmOH gave
similar results in the asymmetric methallylation (Table 2,
entries 1ꢀ2). For convenience, t-AmOH was chosen for
further studies because of its lower melting point. To
improve the enantioselectivities, we attempted to perform
the reaction at lower temperatures. Interestingly, our
results indicated that the enantioselectivity, unlike the
reaction rate, is independent of the reaction temperature.
At 0 °C, in the presence of 5 mol % of catalyst 7, the
reaction gave the same enantioselectivity (87:13) (entry 3).
On the other hand, the reaction tolerated high tempera-
tures, allowing faster conversion without significant ero-
sion of enantioselectivity.11 With 5 mol % of 7, the reaction
reached 98% conversion after 3 h at 60 °C or 8 h at 40 °C,
still with good enantiomeric ratios (entries 4ꢀ5). The
catalyst loading can be decreased to 2 mol %, and excellent
conversion was still achieved after 41 h at 23 °C while
maintaining the similar level of enantioselectivity (entry 6).
It should be noted that 3,30-F2-BINOL can be easily
recycled via baseꢀacid extraction during the workup.
Considering the ready availability and recyclability of
3,30-F2-BINOL, the catalyst loading is not a critical issue
for this process and all the subsequent work was carried
out using 5 mol % of 7.
To delineate the scope of this asymmetric process using
3,30-F2-BINOL 7 as the organocatalyst, a variety of ke-
tones 11aꢀq were methallylated under the standard reac-
tion conditions (5 mol % catalyst 7, 1.5 equiv of boro-
nate 4, 2 equiv of t-AmOH, Table 3). In the case of
1,2-diphenylethanone11a, thereaction wenttocompletion
in 4 h at 40 °C to give product 12a in 98% yield and 93:7 er
(Table 3, entry 1). High enantioselectivities were obtained
on substrates with an electron-donating substituent on
either of the phenyl rings of 1,2-diphenylethanone
(entries 2ꢀ3). Due to low solubility under the reaction
conditions, no reaction was observed at 23 °C overnight
for halogenated 1,2-diphenylethanones 11d, 11e, and 11f.
Fortunately, the current protocol allowed the reaction to
be run at higher temperatures. At 40 °C, reactions with all
three ketones were successful and produced the corre-
sponding products 12d, 12e, and 12f in excellent enantios-
electivities (entries 4ꢀ6). Ketones 11g and 11h, containing
the naphthyl group at the 2-position of phenylethanone,
were examined, and both reactions were performed at
40 °C for completion and generated products 12g and
12h with high stereoselectivities (entries 7ꢀ8). In compar-
ison with ketone 3, the reaction with ketone 11i bearing
a fluorine substituent at the para-position of phenyl ring
was slower, indicating a negative effect of the electron-
withdrawing groups. With 5 mol % of 7, full conversion of
11i was achieved at 23 °C in 18 h (entry 9). Excellent results
(11) In the case of 3,30-Br2-BINOL 5 and 3,30-Cl2-BINOL 6, the
reactions at high temperature led to low conversion.
1712
Org. Lett., Vol. 15, No. 7, 2013

werealsoobtainedwithheteroaromatic ketones suchas11j
and 11k (entries 10ꢀ11). The reaction also worked well for
1,3-diphenylpropan-1-one 11l and 1,4-diphenylbutan-1-
one 11m, giving products 12l and 12m in 91:9 and 90:10 er,
respectively (entries 12ꢀ13). In the case of 2-(benzyloxy)-
1-phenylethanone 11n, good enantioselectivity (86:14) was
observed (entry 14). For acetophenone 11o, a simple
ketone, the reaction gave the product 12o in moderate
enantioselectivity (78:22 er) at 23 °C (Table 3, entry 15).
Catalyst 7 could also be applied to β-keto esters such as
11p, a type of difficult substrates due to the propensity to
enolize (entry 16). We were delighted to find that com-
pound 11p underwent smooth ketone methallylation un-
der standard conditions in excellent yield and with
moderate enantioselectivity (78:22 er).
catalyst, product 16 derived from 14 was isolated in 93%
yield and 95:5 er after 15 h. The reaction with 15 gave 17
with 93:7 er under similar conditions.
Scheme 4
In conclusion, we have synthesized 3,30-F2-BINOL for
the first time and employed it as a highly active organoca-
talyst for asymmetric methallylation of ketones with ex-
cellent yields and high enantioselectivities. It is noteworthy
that 3,30-F2-BINOL exhibited significantly higher catalytic
activity than 3,30-Br2-BINOL and 3,30-Cl2-BINOL for the
methallylation of ketones. We have also synthesized bo-
ronates 14 and 15 which proved to be effective alkylallylat-
ing agents. The new asymmetric methallylation method
represents an efficient, practical, and green process con-
sidering the ready availability and recyclability of 3,30-F2-
BINOL, as well as the solvent-free and near ambient
temperature reaction conditions. The process has been
demonstrated on kilogram scales for the preparation of
enantiomerically enriched synthon 1, a valuable building
block for medicinal chemistry. It is important to note that
rate acceleration by 3,30-F2-BINOL actually made this
process viable, and we believe in the future that the 3,
30-F2-BINOL derived catalytic systems can be utilized in
tuning the reaction rates in many other asymmetric trans-
formations. Further work using 3,30-F2-BINOL as an
organocatalyst or a chiral ligand for other catalytic asym-
metric CꢀC bond-forming reactions is ongoing.
Scheme 3
The newly developed asymmetric methallylation reac-
tion with 3,30-F2-BINOL allowed us to access our desired
chiral tertiary alcohol synthon 1 for the rapid construction
of a variety of pharmaceutically active molecules. The
process of asymmetric methallylation of 3 was successfully
carried out on kilogram scale to give product 2 in 95%
yield with 87:13 er after simple workup. A subsequent
reaction of alcohol 2 with isocyanate 13 provided cyclic
carbamate product 1 in 62% yield after crystallization. The
enantiomeric purity of1 was readily enriched from 87:13 to
99.4:0.6 during the crystallization process (Scheme 3).
To further demonstrate the synthetic utility of 7 as the
organocatalyst for the alkylallylation of ketones, more
sterically hindered boronates 14 and 15 were synthesized
and evaluated (Scheme 4). To our delight, both 14 and 15
were able to undergo complete reactions with ketone 11a
with 3,30-F2-BINOL as the catalyst. With 5 mol % of the
Supporting Information Available. Experimental pro-
cedures, characterization data, and copies of 1H and 13
C
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 7, 2013
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