A Nickel-catalyzed benzannulation approach to aromatic boronic esters

Article abstract of DOI:10.1002/anie.201007598

Off and on: A nickel-catalyzed benzannulation of alkynylboronates provides functionalized phenols with high levels of chemo- and regioselectively. While transmetalation of organoboron intermediate to organonickel does not occur during cycloaddition, it is "switched on" by addition of base, thus allowing a one-pot benzannulation and cross-coupling to be realized (see scheme; Pin=pinacolato, Ms=mesyl). Copyright

Full text of DOI:10.1002/anie.201007598

DOI: 10.1002/anie.201007598
Catalysis
A Nickel-Catalyzed Benzannulation Approach to Aromatic Boronic
Esters**
Anne-Laure Auvinet and Joseph P. A. Harrity*
Benzannulation reactions are one of the most efficient and
direct methods for assembling highly substituted aromatic
compounds.[1] Nonetheless, this strategy provides a number of
considerable challenges that relate to chemoselectivity and
regioselectivity. With regard to exploiting such reactions for
the production of synthetically useful organic compounds,
aromatic boronic acids represent an important target as they
are widely acknowledged as being amongst the most useful
and versatile intermediates in synthetic chemistry.[2] Indeed,
such compounds have been accessed by benzannulation
techniques involving transition metal catalysis[3] and pericy-
clic[4] processes.
Our preliminary work in this area showed that the Dꢀtz
benzannulation reaction could be exploited to access quinone
boronic esters in good yield and with excellent levels of
regiocontrol.[5] As quinone boronic acids can serve as
precursors to bioactive quinones,[6] and have recently
emerged as useful substrates for regio- and stereocontrolled
Diels–Alder reactions,[7] this technique held some significant
synthetic potential. However, drawbacks associated with the
requirement for a stoichiometric organochromium reagent in
the Dꢀtz benzannulation reaction prompted us to search for a
transition metal catalyzed approach.
processes are known and exploit readily available cyclo-
butenones as the vinylketene precursors. Specifically, Liebe-
skind et al. have carried out detailed studies into metal-
mediated vinylketene formation and reactivity.[8] Moreover,
the same group showed that Ni catalysis can mediate the
reaction of cyclobutenones with alkynes to provide phenols.[9]
In addition, Kondo, Mitsudo et al. have employed Rh and Ru
catalysts to promote the cycloaddition of cyclobutenones with
strained alkenes.[10] Danheiser has employed a tandem [2+2]
cycloaddition–electrocyclic ring closure as a transition metal-
free approach to highly substituted phenols.[11] Given that
alkynylboronates are known to undergo transmetalation
reactions with group 7 and 8 transition metal complexes,[12]
we began our studies by investigating the potential for
chemoselective cycloaddition of these substrates using Rh
and Ni catalysts. As outlined in Scheme 2, while the Rh-
As outlined in Scheme 1, the Cr-mediated benzannulation
reaction can be envisaged to be a Cr-templated ketene
electrocyclization. We considered a metal-templated vinyl-
ketene [4+2] cycloaddition to be an alternative strategy to
oxygenated aromatic boronic ester systems. Indeed, such
Scheme 2. Preliminary catalyst screening.
mediated reaction of 1a and 2a delivered only the 2-pyrone 3
derived from cyclobutenone dimerization, [Ni(cod)2] (cod =
cyclooctadiene) promoted a smooth benzannulation reaction
at room temperature to provide the phenol 4 in high yield,
and with excellent regioselectivity. This remarkable selectiv-
ity was unexpected as unsymmetrical alkynes typically
undergo cycloaddition with only modest levels of regiocontrol
(< 3:1).[9] With this exciting preliminary observation in hand,
we decided to explore the scope of this Ni-catalyzed process
and our results are depicted in Table 1.
Scheme 1. Metal-templated benzannulation. Pin=pinacol.
We carried out the cycloaddition of cyclobutenone 1a
with alkynes bearing a selection of substituents. Specifically,
we found that the trimethylsilyl alkynylboronate 2b under-
went cycloaddition to give the corresponding phenol 5a in
excellent yield, and once again as a single regioisomer
(Table 1, entry 1). Surprisingly, the corresponding phenyl-
alkyne 2c showed a drastic reduction in regioselectivity,
moreover, the isomer bearing the boronate in the ortho-
position to the phenol 6b was now favored (entry 2).
[*] A.-L. Auvinet, Prof. J. P. A. Harrity
Department of Chemistry, University of Sheffield
Sheffield, S3 7HF (UK)
Fax: (+44)114-222-9346
E-mail: j.harrity@sheffield.ac.uk
[**] We are grateful to the EPSRC for financial support, and to Prof. R. L.
Danheiser for helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007598.
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Table 1: Nickel-catalyzed aromatic boronic ester synthesis.
Propargyl ether 2d underwent insertion to favor 7a, albeit in
modest yield (entry 3) whereas the 1-cyclohexenyl-substi-
tuted alkyne 2e exhibited a similar regiochemical preference
as the Ph-substituted alkyne 2c (entry 4). Extending the study
to include other 3-substituted cyclobutenones provided a
more complete picture of the regiochemical trends; alkynyl-
boronates bearing sp3-based substituents showed high selec-
tivities (5:1 to > 98:2) for regioisomer a, whereas those
bearing sp2-based substituents generally showed more modest
levels of regiocontrol, largely favoring isomer b.[13]
We next explored the cycloaddition of more heavily
substituted cyclobutenones in an effort to access more heavily
substituted aromatic products. In addition, we were interested
in how incorporating susbtituents adjacent to the carbonyl
would modulate the selectivities in comparison with the 3-
substituted cyclobutentones depicted in Table 1. In the event,
incorporating a methyl group at C4 resulted in the formation
of highly substituted phenols 17 and 18 in good yield, with
improved regioselectivities (in comparison to the reaction of
1b) being observed in both cases (Scheme 3).
No. R1
R2
Phenol[a]
Yield
(a/b)
81%
(>98:2)
1
2
3
nBu, 1a
Me3Si, 2b
Ph, 2c
5
6
7
76%
(33:67)
nBu, 1a
nBu, 1a
48%
(93:7)
CH2OBn, 2d
79%
(15:85)
4
nBu, 1a
8
54%
(85:15)
5
6
7
Ph, 1b
Ph, 1b
Ph, 1b
nBu, 2a
Me3Si, 2b
Ph, 2c
9
75%
(>98:2)
10
11
67%
(44:56)
Scheme 3. Cycloaddition of C4-substituted cyclobutenone 1d.
With regard to functionalization of the aromatic boronic
ester cycloadducts, we were cognizant of the fact that we
began this study to address some limitations in our Cr-
mediated approach to quinone boronic esters, where a
stoichiometric quantity of Fischer carbene complex is
required. Moreover, employing the Dꢀtz reaction for the
synthesis of monocyclic quinones is challenging because of
the relative instabilities of substrate vinylcarbene complexes.
We therefore set out to explore whether the Ni-catalyzed
cycloaddition could be appropriate for the synthesis of
quinone boronic acids and our results are summarized in
Scheme 4. To our delight, phenol 4 was smoothly oxidized by
PIFA[14] within 2 h to provide the corresponding quinone 19 in
quantitative yield. The chemistry was further employed on
regioisomers 6a and 6b; the former compound also under-
went oxidation in high yield whereas the latter phenol gave a
lower yielding reaction due to the surprising instability of
quinone 20b.[15]
67%
(33:67)
8
Ph, 1b
12
13
14
15
16
92%
(>98:2)
9
nBu, 2a
Me3Si, 2b
Ph, 2c
59%
(>98:2)
10
11
12
63%
(44:56)
The Ni-catalyzed alkyne cycloaddition outlined above
critically depends on obviating organoboron to organonickel
transmetalation during the benzannulation process (either at
the alkyne or phenol stage). We speculated, however, that
upon addition of base to this reaction mixture, the products
would be activated towards Ni-catalyzed cross-coupling
61%
(31:69)
[a] Major isomer shown. Bn=benzyl.
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and catalytic route to quinone boronic esters, as well as the
opportunity to carry out benzannulations and cross-coupling
reactions in one-pot with a single Ni pre-catalyst.
Experimental Section
Typical cycloaddition procedure, as exemplified by the formation of
4: A flame-dried Schlenk tube was charged with 3-n-butylcyclobute-
none 1a (50.0 mg, 0.40 mmol) and n-butylalkynylboronate 2a
(167.6 mg, 0.80 mmol) in anhydrous diethyl ether (1 mL) under an
argon atmosphere. The mixture was cooled to 08C before addition of
[Ni(cod)2] (5 mg, 0.02 mmol, 5 mol%). The mixture was stirred at 08C
for 1.5 h and another portion of [Ni(cod)2] (5 mg, 0.02 mmol, 5
mol%) was added before being allowed to reach room temperature
and stirred overnight. The reaction mixture was filtered through a pad
of silica gel and the volatiles were removed in vacuo. The crude
mixture was purified by flash chromatography over silica gel, eluting
with pentane/EtOAc (95:5) to provide the desired compound as an
oil. Recrystallization from petrol provided the product as a colorless
crystalline solid (113.7 mg, 85%, 95:5). M.p. 81–838C; 1H NMR
(400 MHz, CDCl3): d = 0.91–0.98 (6H, m), 1.34–1.64 (20H, m), 2.52–
2.56 (2H, m), 2.87–2.91 (2H, m), 4.68 (1H, br), 6.73 (1H, d, J =
1.5 Hz), 7.19 ppm (1H, d, J = 1.5 Hz); 13C NMR (100 MHz, CDCl3):
d = 14.0, 14.0, 22.5, 23.1, 24.8, 27.9, 33.6, 33.7, 35.1, 83.4, 118.0, 128.5,
132.0, 141.1, 153.1 ppm; FTIR: 3412 (br), 2957 (s), 2930 (s), 2859 (m),
1608 (w), 1580 (w), 1424 (m), 1369 (s), 1144 cmÀ1 (s); HRMS calcd for
C20H34BO3: m/z 333.2601, found 333.2595.
Scheme 4. PIFA: phenyliodine bis(trifluoroacetate).
thereby offering an intriguing opportunity to develop a one-
pot cycloaddition–coupling protocol, whereby a single tran-
sition metal catalyst would perform two different C C bond-
forming transformations. Our studies towards this end are
summarized in Scheme 5. Optimization of the Ni-catalyzed
cross-coupling of boronic ester 4 using the detailed studies of
À
Received: December 3, 2010
Published online: February 21, 2011
Keywords: alkynylboronates · boronic esters · cycloadditions ·
.
cyclobutenones · quinones
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presence of a Ni catalyst. This chemistry offers a versatile
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Communications
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