Asymmetric propargylation of ketones using allenylboronates catalyzed by chiral biphenols

Article abstract of DOI:10.1021/ol201535b

Chiral biphenols catalyze the enantioselective asymmetric propargylation of ketones using allenylboronates. The reaction uses 10 mol % of 3,3′-Br₂-BINOL as the catalyst and allenyldioxoborolane as the nucleophile, in the absence of solvent, and

Full text of DOI:10.1021/ol201535b

ORGANIC
LETTERS
2011
Vol. 13, No. 15
4020–4023
Asymmetric Propargylation of Ketones
Using Allenylboronates Catalyzed by
Chiral Biphenols
David S. Barnett and Scott E. Schaus*
Department of Chemistry, Life Science and Engineering Building, Boston University,
24 Cummington Street, Boston, Massachusetts 02215, United States
seschaus@bu.edu
Received June 8, 2011
ABSTRACT
Chiral biphenols catalyze the enantioselective asymmetric propargylation of ketones using allenylboronates. The reaction uses 10 mol % of 3,
30-Br2-BINOL as the catalyst and allenyldioxoborolane as the nucleophile, in the absence of solvent, and under microwave irradiation to afford the
homopropargylic alcohol. The reaction products are obtained in good yields (60ꢀ98%) and high enantiomeric ratios (3:1ꢀ99:1). Diastereoselective
propargylations using chiral racemic allenylboronates result in good diastereoselectivities (dr >86:14) and enantioselectivities (er >92:8) under the
catalytic conditions.
Homopropargyl alcohols are versatile building blocks
for use in synthesis1 possessing divergent options for
synthetic transformations in comparison to the analogous
homoallylic alcohol reagents.2 However, few methodsexist
to prepare them in enantioenriched form. Chiral allenyl
metal reagents have proven effective,3,4 and recently de-
scribedcatalytic approaches5ꢀ7 are notable alternatives for
accessing these chiral synthetic intermediates. As a reagent
for propargylation reactions, allenylboronates are attractive
starting materials due to the ease of preparation and
predictable reactivity patterns.4a,b,8 Chiral diols are cap-
able of activating boronates as chiral nucleophiles under
catalytic conditions,9 and we postulated that chiral biphe-
nols could function as effective promoters of the asym-
metric propargylation of ketones. Herein we describe the
development of an operationally simple addition of allenyl
boronates to ketones catalyzed by chiral biphenols under
microwave irradiation.
Insight we garnered during our investigations of the
asymmetric allylboration of ketones employing cyclic
boronate reagents and chiral biphenols as catalysts9g
proved valuable in expanding the scope of diol acti-
vated reagents to include allenyl boronates. We envi-
saged conditions that activate more stable, easier to
handle, cyclic boronates could be ascertained for pro-
pargylation reactions. We began by investigating the
reaction of allenyldioxaborinane 1 with acetophenone
3 using 5a as the catalyst (Table 1). At room tempera-
ture, in the absence of solvent (Table 1, entry 1), no
reaction was observed after three days. However, under
gentle heating at 65 °C, homopropargyl alcohol 4 was
isolated in 80% yield after 15 h in an enantiomeric ratio
(er) of 93:7 (Table 1, entry 3). Temperature had little
effect on the reaction, and the reaction time could be
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r
10.1021/ol201535b
Published on Web 07/06/2011
2011 American Chemical Society

Table 1. Progargylation of Ketonesa
Table 2. Catalyst Dependence on Enantioselective Propargyla-
tiona
temp
time
(h)
yield
(%)b
entry
boronate
methoda
(°C)
erc
1
2
3
4
5
6
7
8
9
1
1
1
1
1
2
2
2
2
a
b
b
b
c
20
65
72
1
0
5
ꢀ
4:1
65
15
1
80
60
77
75
80
64
85
93:7
93:7
93:7
3:1
105
105
20
1
entry
catalyst
yield (%)b
erc
a
b
b
c
72
15
1
1
2
3
4
5
6
7
8
9
5b
5c
5d
5e
5f
5g
6
81
82
79
65
70
55
58
80
84
52:48
92.5:7.5
93:7
65
97:3
97:3
97:3
65
60
1
92.5:7.5
94:6
a Catalyst (0.05 mmol) was dissolved in boronate (0.75 mmol) and
then added ketone (0.5 mmol) using the following methods: (a) stirred at
room temp. (b) conventional heating (c) microwave reactor held at 10 W.
b Isolated yield. c Determined by chiral HPLC analysis.
97:3
92:8
7
96:4
8
89:11
lowered substantially by the use of microwave irradia-
tion (entries 4ꢀ7).
a Reactions run with 10 mol % catalyst (0.05 mmol) that was
dissolved in boronate (0.75 mmol) and then added ketone (0.5 mmol)
and submitted directly to the microwave at 10 W for 60 min. b Isolated
yield. c Determined by chiral HPLC analysis.
We proposed the use of allenyldioxaborolane 2 as the
nucleophilewith the expectationthatthe greater ringstrain
in the cyclic boronate would result in a better exchange
partner for the biphenol catalyst leading to a faster reac-
tion. Indeed, the use of boronate 2 resulted in an increase in
the rate of reaction, 64% yield after 1 h at 65 °C
(Table 1, entry 8) compared to a 5% yield with boronate
1 (Table 1, entry 2), with an increase in enantioselec-
tivity. Boronate 2 also demonstrated greater reactivity
at room temperature (Table 1, entry 6) over boronate 1.
While a higher rate of the racemic background reaction
is expected for boronate 2, upon heating, the rate of the
BINOL/boronate exchange reaction and entry into the
catalytic pathway appears to exceed the uncatalyzed
pathway (entries 7 and 8). Ultimately, the microwave-
promoted reaction at a powermax setting of 10 W for
1 h afforded the product in excellent yield and enantios-
electivity (Table 1, entry 9).
We next investigated the dependence of catalyst struc-
ture on enantioselectivity in the propargylation reaction
(Table 2). Although 3,30-Br2-BINOL 5a afforded the
product in excellent yield and selectivity, other related
structures may be equally effective and that insight could
prove useful when investigating the reaction substrate
scope. The 3,30-substitution on the BINOL appeared
crucial (entry 1 vs entries 2ꢀ6) for enantioselectivity, and
the aryl substituted BINOLs 5f10 and 5g11 gave compar-
able results to 5a. Biphenols 612 and 713 were also suitable
catalysts (entries 7 and 8) while the use of VAPOL 813
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Org. Lett., Vol. 13, No. 15, 2011
4021

resulted in lower enantioselectivity (entry 9). Based on the
accessibility and ease of synthesis, biphenol 5a was chosen
for use in the assessment of the substrate scope.
The scope of the propargylation reaction using boronate
2 was determined using a selection of ketones that varied in
both electronic and steric properties (Table 3). Aromatic
substrates were generally good substrates with notably
better selectivities when R1 = aromatic and R2 = alkyl
chain (entries 3ꢀ4). Conversely, lower enantioselectivities
are observed when the steric bias is reduced as is the case
for ketones 9g, 9h, and 9i. However, the use of 3,30-Mes2-
BINOL 5g in the reaction of 9g with 2 resulted in an
improvement of the selectivity to 95:5 er (from 85:15 with 5a)
in good yield. In addition, 3,30-9-anthracyl-BINOL
enhanced selectivities of ketone 9h to 90:10 er (from
60:40 er with 5a). In general, the reaction catalyzed by
5a possessed good substrate scope affording the pro-
ducts in high enantioselectivities and good yields
(Table 3, entries 10ꢀ21).
Table 3. Propargylation of Ketones Catalyzed by Chiral Bi-
phenolsa
Diastereoselective propargylation reactions using race-
mic boronates offered intriguing possibilities for reaction
development. The successful addition reaction in high
enantioselectivities would be the result of a chiral boronate
kinetic resolution process.14
Table 4. Diastereoselective Propargylationsa
entry boronate cat.
prod
yieldb
93
erc
drc
1
11a
11a
5a
5a
12a
92:8 (major)
98:2 (minor)
86:14
2d
12a
76
76:24 (major) 3:1
98:2 (minor)
3
4
5
11a
11b
11c
13
5a
5a
(12a
12b
70
82
98
1:1
91:9
94:6 (major)
93:7 (major)
96:4 (minor)
>25:1
87:13
12c
a Catalyst (0.05 mmol) was dissolved in boronate (1.25 mmol) and
then added ketone (0.5 mmol) and submitted directly to the microwave.
b Combined isolated yield. c Determined by chiral HPLC analysis.
d Acetophenone was used in excess (0.55 mmol) with respect to boronate
11a (0.5 mmol), and microwave time was extended to 5 h.
A mixture of enantiomers would, upon exchange with
the chiral biphenol, form a set of diastereomers that would
disproportionately react with the electrophile to give one
diastereomer preferentially. Under the optimized condi-
tions, (()-methyl-allenylboronate 11a afforded the syn-
methylpropargyl product 12a in 93% yield and in a 86:14
diasteromeric ratio (dr) (Table 4, entry 1). Preference for
the syn diastereomer has been reported using aluminum
reagents generated from 3-substituted propargylic bro-
mides and PbCl2 as a catalyst resulting in the formation
of (12a in 85% yield and 89:11 dr.15
a Catalyst (0.05 mmol) was dissolved in boronate (0.75 mmol) and
then added ketone (0.5 mmol) and submitted directly to the microwave.
b Isolated yield. c Determined by chiral HPLC analysis. d Reaction run
with 10 mol % 5g. e Reaction run with 10 mol % 5h. f Ketone was added
to mixture of 2 and 5a previously heated to 70 °C and stirred for 30 min.
g Reaction run in 0.5 mL of toluene and heated to 65 °C overnight.
(8) (a) Blais, J.; L’Honore, A.; Soulie, J.; Cadiot, P. J. Organomet.
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1995, 60, 4686.
4022
Org. Lett., Vol. 13, No. 15, 2011

We reasoned that a greater degree of diastereoselectivity
could be achieved using allenes possessing larger substituents
at the γ-position.15 This was indeed the case, as a signifi-
cantly greater degree of selectivity was observed upon using
the isopropyl-allenylboronate 11c as a nucleophile, yield-
ing 12c as essentially one diastereomer in 94:6 er (Table 4,
entry 4). Finally, phenyl-allenylboronate 11b also afforded
the addition product 12b in good yields and selectivities
(Table 4, entry 5).
In summary, we have developed a ketone propargyla-
tion reaction using allenylboronate reagents and biphenol
catalysts, expanding the scope of enantioselective diol-
catalyzed boronate reactions. The reaction is run in the
absence of solvent, and the use of microwave irradiation
enhances the reaction yields without loss of selectivity. The
catalytic reaction conditions are also effective at promot-
ing the diastereoselective addition of chiral racemic allenyl
boronates to ketones. Continued investigations will seek to
expand the type of reaction partners promoted by this
mode of catalysis.
Figure 1. Methylpropargylation diastereoselectivity.
Preference for the syn diastereomer can be rationalized
via a model with the methyl groups on acetophenone and
boronate 11a aligned antiperiplanar to each other (Figure 1)
giving rise to the syn product.15 Conversely, the alter-
native reacting diastereomer possesses a disfavored
gauche interaction with both the methyl and phenyl
groups of acetophenone. Both diastereomers were ob-
tained in good enantioselectivities with major syn dia-
stereomer 92:8 er and the minor anti diastereomer in
98:2 er. For comparison, the reaction using achiral
biphenol 13 as the catalyst resulted in a greater pre-
ference for the formation of 12a-syn, providing evidence
that the catalyst structure influences the diastereomeric
preference (Table 4, entry 3).
Acknowledgment. This research was supported by the
NIH (R01 GM078240). The authors acknowledge Artus-
Labs, a PerkinElmer company, for laboratory information
management software support.
Supporting Information Available. Synthetic proce-
dures, chiral HPLC analysis, together with characteriza-
tion and spectral data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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