Regio- and stereoselective copper-catalyzed β-borylation of allenoates by a preactivated diboron

Article abstract of DOI:10.1039/c0cc02270e

A mild and efficient copper-catalyzed borylation of electron deficient allenoates using an sp²-sp³ mixed hybridized diboron regioselectively installs a boron moiety on the β-position with exclusive (Z)-double bond geometry.

Full text of DOI:10.1039/c0cc02270e

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Regio- and stereoselective copper-catalyzed b-borylation of allenoates by
a preactivated diboronwz
Steven B. Thorpe, Xi Guo and Webster L. Santos*
Received 30th June 2010, Accepted 3rd September 2010
DOI: 10.1039/c0cc02270e
A mild and efficient copper-catalyzed borylation of electron
deficient allenoates using an sp2–sp3 mixed hybridized diboron
regioselectively installs a boron moiety on the b-position with
exclusive (Z)-double bond geometry.
To date, however, direct borylation of electron-deficient
allenes has not been reported. We recently disclosed the
synthesis of an internally activated, sp2–sp3 hybridized
diboron compound, PDIPA diboron (pinacolato diisopropanol-
aminato diboron, 2), and demonstrated its utility in the
copper-catalyzed, b-borylation of a,b-unsaturated conjugated
compounds.13 In pursuit of expanding the scope of this
reaction to more intricate substrates, we investigated the
utility of 2 to the borylation of electrophilic allenoates.
These substrates are attractive because they give rise
to b,g-unsaturated carbonyl compounds, as opposed to
acetylenic esters which produce a,b-unsaturated carbonyl
compounds,14 allowing for further functionalization of the
resulting nonconjugated olefin. In addition, we were excited by
the possibility that a racemic mixture of the starting allenoate
forms a product containing a defined double bond geometry
and a vinyl boronic ester, which is potentially a Suzuki–
Miyaura cross-coupling partner.9
In recent years, allenes have emerged as an important
structural unit in the construction of complex molecules.1
For example, cycloaddition, radical, nucleophilic addition
and metalation reactions demonstrate the versatility and
unique reactivity of allenes.2 Because of their potential in
organic synthesis and other applications, their preparation is
subject to intense investigation. In particular, the reactivity of
electron-deficient allenes can be tuned to produce either
b,g-unsaturated carbonyl compounds or g-addition products
depending on the reaction conditions. For example, Shibasaki
and co-workers elegantly developed the construction of highly
functionalized d-lactones with tetrasubstituted chiral centers
using a three component assembly of dialkylzincs, allenic
esters and ketones.3 Jorgensen et al. demonstrated the organo-
catalytic asymmetric conjugate addition to electron-deficient
allenes to form tertiary and quaternary stereogenic centers.4
These reactions produce b,g-unsaturated carbonyl compounds,
and examples in the literature are limited. However, the regio-
selectivity of the reaction can be reversed. Indeed, Lewis bases
such as phosphines catalyze g-additions of carbon, nitrogen,
oxygen and sulfur nucleophiles to allenoates.5
To explore the feasibility of the borylation reaction, we
investigated reaction conditions to generate b-borylated
b,g-unsaturated ethyl ester 3b using ethyl 2,3-butadienoate
(1b) as the substrate. As shown in Table 1, agents with strong
sigma bond donor capacity to activate bis(pinacolato)diboron
such as N-heterocyclic carbenes (NHC),15 (IMe)CO2 and
16
(ICy)BF4,17 promoted the borylation reaction with good yields
(entries 1 and 2). However, the use of a strong base to generate
the carbene can be a disadvantage for sensitive substrates. In
addition, NHC ligands are expensive and difficult to handle.
With the effort to use milder reaction conditions, we investi-
gated whether a preactivated diboron13 also effects the desired
transformation. To our delight, treating allenoate 1b with a
catalytic amount of CuCl, trifluoroethanol (TFE) and 2 in
dichloromethane produced 3b in excellent yield (entry 3).18
Running the reaction in the absence of TFE successfully
provided the product (entries 4 and 12). Other additives such
as base and phosphine ligand were effective although a copper
stabilizing DPEphos dramatically decreased the product yield
(entries 5–7). As expected, when the reaction was attempted
without a copper catalyst, the reaction was sluggish (entry 8).
Evaluation of the effect of solvent revealed that the reaction
was tolerant of aprotic solvents used, although the reaction
performed in THF was most effective (entries 4, 9 and 10).
We also screened the effect of temperature on the reaction
and discovered that the borylation reaction is efficient
at room temperature in the presence of TFE (compare
entries 1–10 vs. 11). CuCl as the copper source appears to be
important since CuBr or other Cu(II) sources afforded
the product in moderate yields (entries 12–14). Finally, an
examination of other transition metals such as Rh, Pt, Ni and
Ag resulted in minor or undetectable product formation
Transition metal-catalyzed reactions of electrophilic allenoates
generate molecular scaffolds with functional and structural
diversity.1a,6 For example, 2,3-allenyl carboxylic acids cyclo-
isomerize in the presence of Cu(I) source7 or undergo
halolactonization with CuX2 (X = Br, Cl).8 These inter-
mediates are useful building blocks in the synthesis of more
elaborate chemical structures, especially with cross-coupling
reactions. As complementary reacting partners, organoboron
compounds increasingly provide access to the formation of
difficult carbon–carbon bonds. Indeed, the Suzuki–Miyaura
coupling reaction, which employs a boronic acid and organo-
halide, is a powerful method for the construction of complex
molecules partly because of its functional group tolerance.9
Thus far, silaboration,10 cyanoboration,11 and diboration12
have been achieved with allenes using transition metals.
Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24061,
USA. E-mail: santosw@vt.edu; Fax: +1 540 231 3255;
Tel: +1 540 231 5041
w This article is part of the ‘Emerging Investigators’ themed issue for
ChemComm.
z Electronic supplementary information (ESI) available: Detailed
experimental procedures, synthesis and characterization of unknown
allenoates, analytical data for b-borylated b,g-unsaturated esters. See
DOI: 10.1039/c0cc02270e
c
424 Chem. Commun., 2011, 47, 424–426
This journal is The Royal Society of Chemistry 2011

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Table 1 Optimization of reaction conditionsa
Table 2 b-Borylation of allenoatesa
Entry
Catalyst
Solvent
Additives (equiv.)
Conv%b
81.3
Entry R1 R2 R3
Product Z/Eb
%c Yield (%)d
1
2
CuClc
CuClc
ACN
THF
(IMe)CO2 (0.1)
(ICy)BF4 (.05)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Et
(CH2)3Ph
Me
Et
3a
3b
3c
3d
3e
3f
3g
3h
3i
—
—
—
59
60
41 (71)
NaOtBu (0.1)
TFE (4)
—
95.1
96.9
96.4
98.3
45.7
3
4
5
6
7
CuCld
CuCld
CuCld
CuCld
CuCld
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Ph
Ph
Ph
Me
Me
Me
Me
Me
100 : 0 41
100 : 0 46
100 : 0 14 (45)
100 : 0 72
100 : 0 58
NaOtBu (0.1)
DPEphos (0.1)
(CH2)3Ph
Me
Et
NaOtBu (0.1)
TFE (4)
9
iPr
100 : 0 78
100 : 0 71
97.5
4.9
d
—
10
11
12
tBu
3j
8
9
CH2Cl2
DMF
THF
THF
THF
THF
THF
THF
THF
THF
THF
—
—
—
TFE (4)
—
—
—
—
CuCld
CuCle
CuClf
CuBre
CuBr2e
CuCl2
78.0
98.3
96.7
87.8
76.6
86.7
ND
ND
ND
1.5
o-Nitrobenzyl 3k
3l
100 : 0 33 (75)
100 : 0 38e (81)
10
11
12
13
14
15
16
17
18
Me Me Et
a
b
For detailed synthetic procedure, see ESI.z The ratio of E/Z
e
isomers were determined by GC and the geometry of the product
c
was assigned based on NOESY experiments. Isolated yield.
e
d
e
Corrected yield with recovered starting material. Reaction was
[Rh(cod)Cl]2
Pt(cod)Cl2
e
—
—
—
stirred 24 hours before workup. Product contaminated with 22%
a,b-unsaturated isomer.
Ni(cod)e
Ag(NO3)e
a
PDIPA diboron (2, 1.2 equiv.), catalyst (0.1 equiv.), and additives
were suspended in solvent and stirred for 5 minutes. Ethyl 2,3-
butadienoate (1.1 equiv.) was then added and the reaction was stirred
also diastereoselectively. In contrast with phosphine-catalyzed
reactions to electrophilic allenoates that afford g-substituted
products,5 the copper-catalyzed reaction regioselectively
installed the boryl moiety on the b-position. In addition, under
the reaction conditions of our investigation, we did not
observe any cycloisomerization products seen in other
copper-catalyzed reactions with allenoates (vide infra).7 Inter-
estingly, the geometry of the double bond on the resulting
product was determined to be Z based on NOESY experi-
ments, and 1H NMR and GC-MS analysis of the crude
reaction mixture showed exclusive formation of this product.19
The stereoselectivity of the reaction can be rationalized by
analysis of the approach of the boryl–copper intermediate
(Fig. 1). Since the two double bonds are orthogonal to each
other, boryl addition to the b-carbon is expected to occur on
the opposite side of the g-substituent of the allenoate because
of a strong steric interaction. Furthermore, 1,3-allylic strain in
the (E)-isomer should favor the formation of the more stable
(Z)-isomer. Indeed, only the (Z)-product was observed.
b
for 2 hours at the indicated temperature. Conversion was determined
c
by GC analysis of the crude material. The reaction was performed at
d
rt and bis(pinacolato)diboron was used instead of 2. The reaction
e
f
was heated to 40 1C. The reaction was heated to 70 1C. The
reaction was performed at rt. Abbreviations: DPEphos
=
bis(2-diphenylphosphinophenyl)ether; (IMe)CO2 = 1,3-dimethylimid-
azolium carboxylate; (ICy)BF4 = 1,3-dicyclohexylimidazolium tetra-
fluoroborate; TFE = 2,2,2-trifluoroethanol; ND = none detected.
(entries 15–18). Thus, subsequent investigations used 10 mol%
CuCl, 4 equiv. TFE, allenoate substrate and 2 in THF at room
temperature.
With the optimized conditions in hand, we next investigated
the scope of the reaction using various allenoates. The results
of our study are summarized in Table 2. Increasing the size of
the ester moiety from methyl to ethyl on unsubstituted
allenoates provided the b-borylated b,g-unsaturated ethyl
esters 3a and b in good yields (entries 1 and 2). A change to
the bulkier 3-phenylpropyl ester 1c resulted in slight decrease
in yield with some unreacted starting material isolated
(entry 3). Gratifyingly, the presence of a bulky phenyl sub-
stituent on the g-position allowed the borylation to proceed in
moderate yields (entries 4–6). When the phenyl substituent was
replaced with a less sterically demanding methyl group, the
product was isolated in good yield (58–78%, entries 7–10). The
presence of a bulky o-nitrobenzyl moiety resulted in a much
lower yield in part because this group is sensitive to light
(entry 11). Finally, a,g-disubstituted ethyl allenoate 1l was
converted to the product in moderate yield presumably
because of the bulkiness of the substrate (entry 12).
It is important to highlight that the copper catalyzed
b-borylation reaction proceeded not only regioselectively but
Fig.
1 Steric interactions lead to exclusive formation of the
(Z)-isomer.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 424–426 425

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(Z)-double bond geometry. These borylated products are
useful intermediates for subsequent elaboration to more
complex structures.
We gratefully acknowledge financial support from Virginia
Tech Department of Chemistry and the Thomas F. Jeffress
and Kate Miller Jeffress Memorial Trust.
Notes and references
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M. Shibasaki, Tetrahedron Lett., 2006, 47, 1403; (c) D. Zhao,
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128, 14440.
4 P. Elsner, L. Bernardi, G. D. Salla, J. Overgaard and
K. A. Jorgensen, J. Am. Chem. Soc., 2008, 130, 4897.
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Fig. 2 Proposed reaction mechanism.
6 S. Ma, Acc. Chem. Res., 2009, 42, 1679.
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8 S. Ma and S. Wu, J. Org. Chem., 1999, 64, 9314.
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Fig. 3 Coupling of b-boronic ester with iodobenzene.
Finally, we were pleased to find that although the allenoate
substrates were used as racemic mixtures, the reaction
provides a single product.
A possible catalytic cycle for the b-borylation reaction is
shown in Fig. 2. Preactivated sp2–sp3 hybridized diboron 2 is
sufficiently activated to transmetalate with CuCl to generate
nucleophilic boryl species 4. DFT calculations on the copper-
catalyzed borylation of related a,b-unsaturated carbonyl
compounds20 suggest the formation of metalated inter-
mediates 6/7 that can be protonated to yield the desired
b-borylated b,g-unsaturated ester 8 with the simultaneous
regeneration of copper–alkoxide that continues the catalytic
cycle. The essential role of TFE is to accelerate the reaction by
protonation of 6/7 and formation of copper–alkoxide.18
To demonstrate the utility of the regio- and stereoselective
borylation reaction, Suzuki–Miyaura cross coupling reaction
between 3g and iodobenzene was attempted. In this case, the
coupled product 9 was isolated in quantitative yield (Fig. 3).
In contrast, 9 was previously synthesized as a mixture of
E/Z isomers at 52% yield from a cyclopropanone acetal
derivative.21
16 A. M. Voutchkova, M. Feliz, E. Clot, O. Eisenstein and
R. H. Crabtree, J. Am. Chem. Soc., 2007, 129, 12834.
17 K. S. Lee, A. R. Zhugralin and A. H. Hoveyda, J. Am. Chem. Soc.,
2009, 131, 7253.
18 Detailed kinetic studies of the borylation of a,b-unsaturated
carbonyls with 2 show that TFE is the best protic additive.
M. Gao, S. B. Thorpe, C. Kleeberg, T. B. Marder, W. L. Santos,
submitted.
In conclusion, an efficient and catalytic copper-catalyzed
regioselective borylation of allenoates was developed. To the
best of our knowledge, this reaction is the first example of a
boryl addition to electrophilic allenoates. The reaction
provided b-borylated b,g-unsaturated esters with exclusive
19 See ESIz for details.
20 L. Dang, H. T. Zhao, Z. Y. Lin and T. B. Marder, Organo-
metallics, 2008, 27, 1178.
21 A. Oku, M. Abe and M. Iwamoto, J. Org. Chem., 1994, 59, 7445.
c
426 Chem. Commun., 2011, 47, 424–426
This journal is The Royal Society of Chemistry 2011