Ambient-temperature cobalt-catalyzed cycloaddition strategies to aromatic boronic esters

Article abstract of DOI:10.1021/jo1004907

Figure presented The room-temperature cobalt-catalyzed [4 + 2] cycloaddition of alkynylboronates and 1,3-dienes provides a convenient and general method for the synthesis of benzene-based aromatic boronic esters. Two complementary aromatization strategies involving in situ elimination and DDQ oxidation were explored, with the latter finding more generality. Finally, the potential of this technique to generate highly functionalized biaryls has been demonstrated via the synthesis of chiral (racemic) DMAP catalysts.

Full text of DOI:10.1021/jo1004907

pubs.acs.org/joc
of cyclopentadienones and 2-pyrones provides such com-
Ambient-Temperature Cobalt-Catalyzed
Cycloaddition Strategies to Aromatic Boronic Esters
pounds in good overall yield and with modest to high levels
of regiocontrol.5 The latter method has proved to be of more
general utility, although it requires activated 1,3-diene sub-
strates. Some typical examples are outlined in Scheme 1.
While this strategy permits the formation of highly functio-
nalized aromatic boronic acid derivatives in a single step,
the process requires elevated temperatures and long reaction
times.
Anne-Laure Auvinet,† Joseph P. A. Harrity,*,† and
Gerhard Hilt*,‡
†Department of Chemistry, University of Sheffield,
Sheffield, S3 7HF, U.K., and ‡Fachbereich Chemie,
€
Philipps-Universitat Marburg, Marburg, Germany
SCHEME 1
*j.harrity@sheffield.ac.uk; hilt@chemie.uni-marburg.de
Received March 16, 2010
In an effort to uncover more efficient and less demanding
conditions for benzannulation reactions, catalytic benzan-
nulation techniques have begun to find prominence. In the
context of alkynylboronate reactions, Yamamoto has de-
monstrated the use of the boronate moiety as a temporary
tether to control the regioselectivity of Ru-catalyzed [2 þ 2 þ 2]
cyclotrimerization reactions.6 An intriguing alternative to
this process is the cobalt-catalyzed [4 þ 2] cycloaddition of
nonactivated 1,3-dienes with alkynylboronates.7 This pro-
cess gives rise to 1,4-dienylboronic esters in high yield and
with excellent levels of regiocontrol. As outlined in Scheme 2,
we were interested in the potential of these 1,4-dienylboronic
esters to function as precursors to the aromatic analogues.
Specifically, we envisaged that chemoselective oxidation of
the hydrocarbon ring (instead of the oxidatively labile C-B
bond) would provide the desired compounds.8 Should this
approach prove to be unwieldy, we anticipated that 1,3-
dienes bearing a nucleofuge at C-1 would provide access to
the correct ring oxidation level after a simple elimination
reaction.9,10 We report herein our investigations toward this
end and the realization of a general and mild method for the
synthesis of aromatic boronic esters bearing substitution
patterns not readily accessible by traditional strategies.
The room-temperature cobalt-catalyzed [4 þ 2] cycloaddition
of alkynylboronates and 1,3-dienes provides a convenient
and general method for the synthesis of benzene-based
aromatic boronic esters. Two complementary aromatization
strategies involving in situ elimination and DDQ oxida-
tion were explored, with the latter finding more generality.
Finally, the potential of this technique to generate highly
functionalized biaryls has been demonstrated via the syn-
thesis of chiral (racemic) DMAP catalysts.
Aromatic boronic acid derivatives are among the most
widely used synthetic intermediates in organic chemistry.1
Their synthesis has traditionally involved the employment of
aryl halides and related species via the intermediacy of a
main group organometallic reagent2 or, more recently, by
the exploitation of Pd catalysis.3 Additionally, an alternative
approach whereby a C-H bond is transformed directly to a
C-B bond has emerged and has proved to be particularly
effective for the synthesis of heteroaromatic compounds.4
Benzannulation approaches to aromatic boronic acid
derivatives hold some significant potential as they provide
the opportunity to construct complex and heavily substitu-
ted systems from relatively simple starting materials. In this
context, the inverse-electron-demand [4 þ 2] cycloaddition
(5) (a) Moore, J. E.; York, M.; Harrity, J. P. A. Synlett 2005, 860.
(b) Delaney, P. M.; Moore, J. E.; Harrity, J. P. A. Chem. Commun. 2006,
3323. (c) Delaney, P. M.; Browne, D. L.; Adams, H.; Plant, A.; Harrity, J. P.
A. Tetrahedron 2008, 64, 866.
(6) (a) Yamamoto, Y.; Ishii, J.-i.; Nishiyama, H.; Itoh, K. J. Am. Chem.
Soc. 2004, 126, 3712. (b) Yamamoto, Y.; Ishii, J.-i.; Nishiyama, H.; Itoh, K.
Tetrahedron 2005, 61, 11501.
(1) Boronic Acids; Hall, D.G., Ed.; Wiley-VCH: Weinheim, 2005.
(2) Vaultier, M.; Carboni, B. In Comprehensive Organometallic Chemistry
II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford,
1995; Vol. 11, p 191.
(7) (a) Hilt, G.; Smolko, K. I. Angew. Chem., Int. Ed. 2003, 42, 2795.
(b) Hilt, G.; Hess, W.; Schmidt Eur. J. Org. Chem. 2005, 2526. (c) Hilt, G.;
€
Luers, S.; Smolko, K. I. Org. Lett. 2005, 7, 251.
(8) A single example of DDQ oxidation of 1,4-dienylboronic esters was
(3) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508. (b) Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem. 1997, 62,
6458. (c) Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J. Org. Chem.
2000, 65, 164.
(4) For recent examples, see: (a) Harrison, P.; Morris, J.; Marder, T. B.;
Steel, P. G. Org. Lett. 2009, 11, 3586. (b) Kawamorita, S.; Ohmiya, H.; Hara,
K.; Fukuoka, A.; Sawamura, M. J. Am. Chem. Soc. 2009, 131, 5058. (c) Jo,
T. S.; Kim, S. H.; Shin, J.; Bae, C. J. Am. Chem. Soc. 2009, 131, 1656.
reported by Hilt.7b
(9) For an early demonstration of this strategy for the synthesis of
aromatic compounds by Diels-Alder reactions, see: Dowd, P.; Weber, W.
J. Org. Chem. 1982, 47, 4774.
(10) For cobalt-catalyzed cycloaddition of 1-alkoxydienes toward aromatic
products, see: Hilt, G.; Smolko, K. I.; Lotsch, B. V. Synlett 2002, 1081.
DOI: 10.1021/jo1004907
r
Published on Web 05/06/2010
J. Org. Chem. 2010, 75, 3893–3896 3893
2010 American Chemical Society

Auvinet et al.
JOCNote
SCHEME 2
FIGURE 1. Unreactive thioenol ether substrates.
substrates. This latter point is noteworthy given the facile
hydrolysis of the alkyne carbon-boron bond by protic species.11
As depicted in Table 1, the phenyl-substituted alkynylboro-
nate 4 was converted into 8 in good to high yield with all three
dienes, although the thiophenol-based substrate 3 proved to be
the most efficient (entries 1-3). The same trend was noted when
the cyclohexenyl- and n-butyl-substituted alkynes 5 and 6 were
used (entries 4-9), and so the studies were completed by carry-
ing out the cycloaddition of trimethylsilyl-substituted alkyne 7
with 3 alone to provide 11 (entry 10). An important issue that
relates to the 1,3-diene substrates in all cases is that they are
prone to polymerization during storage and under the reaction
conditions. Indeed, we suspect that the consistently better yields
obtained in the case of 3 as compared to 1 and 2 may be due to
the relative stability of this particular substrate.
TABLE 1. Scope of the Cycloaddition-Elimination Strategy
With these preliminary observations in hand, we decided
to extend this chemistry to include more heavily substituted
dienes as a means to obtaining more functionalized aromatics
and as a vehicle for studying cycloaddition regioselectivity. To
our disappointment, 1,3-dienes 12-14 were found to be inert to
cycloaddition or produced complex reaction mixtures (Figure 1).
While the cycloaddition-elimination concept proved to
be quite effective for the synthesis of 1,2-disubstituted aro-
matic boronic esters, the limitations associated with more
heavily substituted congeners prompted us to explore the
cycloaddition-oxidation pathway in the hope that a more
general protocol could be uncovered. Accordingly, we ex-
plored the cobalt-catalyzed reaction of a range of commer-
cial or readily prepared 1,3-dienes and subjected the crude
cycloadducts to oxidation; our results are shown in Table 2.
Pleasingly, simple ortho-substituted benzene boronic esters
could be readily generated in good yield following a cobalt-
catalyzed cycloaddition-DDQ oxidation protocol (entries
1-3). More importantly, and in contrast to the cycloaddi-
tion-elimination approach, more heavily substituted pro-
ducts were also found to be accessible by this protocol.
Isoprene 16 provided 1,3,4-trisubstituted products 20-23
in excellent yield and with complete regiocontrol (entries
4-7), and the method was equally effective for the formation
of 1,2,3,4-tetrasubstituted products 24-27 (entries 8-11).
Finally, we employed 1-phenylbuta-1,3-diene 19 for the
synthesis of 1,2,3-trisubstituted aromatic systems. Previous
studies on internal alkynes had shown that the cobalt-catalyzed
cycloaddition of 1-substituted 1,3-dienes proceeded with
variable regioselectivity.12 In the event, the corresponding
1,2,3-trisubstituted product 28 was generated in good yield
and with useful levels of regiocontrol (entry 12).13
We began our studies by exploring the cycloaddition-
elimination strategy and prepared a selection of 1,3-dienes
bearing various potential leaving groups at C-1. Specific-
ally, we prepared a silyl enol ether, an aryl enol ether, and a
thiophenol-based enol ether. After some preliminary optimi-
zation studies, we found that a catalyst solution generated
from 10 mol % of CoBr2(dppe) and 20 mol % of Zn metal
and ZnI2 provided clean and consistent conversion of each
1,3-diene to the corresponding aromatic boronic ester at
room temperature. Moreover, we were pleased to find that
the corresponding leaving groups (silanol, phenol, and thio-
phenol) did not interfere with the active catalyst, nor did they
appear to promote significant deboronation of the alkyne
The present methodology makes hindered aromatic com-
pounds that are amenable to further elaboration (e.g., 24-28),
(12) Hilt, G.; Danz, M. Synthesis 2008, 2257.
(13) The regiochemistry of compounds 21, 22, 25, and 26 was assigned by
NOE spectroscopy; the regiochemistry of compound 28 was made by
chemical derivatization of the minor regioisomer (see the Supporting
Information). The regiochemistry of the remaining unsymmetrical com-
pounds was assigned by inference.
(11) Brown, H. C.; Bhat, N. G.; Srebnik Tetrahedron Lett. 1988, 29, 2631.
3894 J. Org. Chem. Vol. 75, No. 11, 2010

Auvinet et al.
JOCNote
TABLE 2. Scope of the Cycloaddition-oxidation Strategy
SCHEME 3
hindered aromatic compounds in recent times has been their
application as chiral organocatalysts. Specifically, a large
family of chiral 4-aminopyridines have emerged that have
shown significant potential in the kinetic resolution of chiral
secondary alcohols.14 Among this family of catalysts, Spivey
and co-workers have investigated an elegant class of DMAP
equivalents that incorporate an atropisomeric axis as the key
element of chirality.15 We envisaged that the methodology
developed in this program could represent a flexible and
modular strategy for the synthesis of such catalysts. Accord-
ingly, and as depicted in Scheme 3, cross-coupling of 3,5-
dibromo-4-chloropyridine 29 with boronic ester 26 provided
hindered biaryl 30. Subsequent reduction of the remaining
bromide and nucleophilic aromatic substitution of chloride
31 with LDA resulted in the synthesis of hindered DMAP
analogue 32. The concise synthesis of functionalized boronic
esters such as 26 outlined herein, together with the robust-
ness of the Spivey route for the synthesis of these atropiso-
meric biaryl pyridines, suggests that this approach could
provide a powerful method for the discovery of new asym-
metric kinetic resolution catalysts.
In conclusion, we have demonstrated that benzene boronic
acids bearing a range of substitution patterns can be accessed
by a Co-catalyzed [4 þ 2] cycloaddition of alkynylboronates
via cycloaddition-elimination and cycloaddition oxidation
strategies. This method provides a powerful means for the
generation of heavily substituted aromatic products under
ambient conditions, and the potential for this chemistry to
provide new chiral biaryl catalysts and ligands is underway
and will be reported in due course.
Experimental Section
Representative Procedure for the Cycloaddition-Elimination
Strategy. 2-(2-Cyclohexenylphenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (9). A flame-dried Schlenk tube was charged with
[CoBr2(dppe)] (62 mg, 0.1 mmol, 10 mol %), zinc iodide (63 mg,
0.2 mmol, 20 mol %), and powdered zinc (13 mg, 0.2 mmol,
20 mol %) in anhydrous dichloromethane (1 mL) under an
argon atmosphere. After addition of diene 3 (162 mg, 1 mmol)
and cyclohexynylalkynylboronate (232 mg, 1 mmol), the reaction
(14) For a review, see: Spivey, A. C.; Arseniyadis, S. Angew. Chem., Int.
Ed. 2004, 43, 5436.
aValues in parentheses are cycloaddition regioselectivities.13
(15) (a) Spivey, A. C.; Arseniyadis, S.; Fekner, T.; Maddaford, A.; Leese,
D. P. Tetrahedron 2006, 62, 295. (b) Spivey, A. C.; Leese, D. P.; Zhu, F.;
Davey, S. G.; Jarvest, R. L. Tetrahedron 2004, 60, 4513. (c) Spivey, A. C.;
Zhu, F.; Mitchell, M. B.; Davey, S. G.; Jarvest, R. L. J. Org. Chem. 2003, 68,
7379. (d) Spivey, A. C.; Fekner, T.; Spey, S. E. J. Org. Chem. 2000, 65, 3154.
and we anticipate that this method could constitute a valu-
able technique for the synthesis of axially chiral catalysts and
ligands. Indeed, one of the most exciting applications of
J. Org. Chem. Vol. 75, No. 11, 2010 3895

Auvinet et al.
JOCNote
mixture was stirred at ambient temperature for 16 h. The
mixture was filtered through a pad of silica gel and the solvent
removed in vacuo. Purification by flash chromatography over
silica gel, eluting with pentane/EtOAc (95/5), provided the desi-
red compound as a clear oil (222 mg, 78%): 1H NMR (250 MHz,
CDCl3) δ 1.35 (12H, s), 1.65-1.83 (4H, m), 2.15-2.19 (2H, m),
2.35-2.38 (2H, m), 5.55-5.58 (1H, m), 7.19-7-27 (2H, m),
7.33-7.40 (1H, m), 7.63-7.66 (1H, m); 13C NMR (62.9 MHz,
CDCl3) δ 22.1, 23.2, 24.8, 25.7, 30.6, 83.5, 125.2, 125.7, 127.1,
129.8, 134.3, 140.9, 150.7; FTIR (film) 2978 (s), 2926 (s), 1596
(w), 1392 (s), 1145 (s) cm-1; HRMS (EI) m/z [MH]þ calcd for
C18H26BO2 285.2021, found 285.2026.
Representative Procedure for the Cycloaddition-Oxidation
Strategy. 2-(2-n-Butylphenyl)4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolane (10). A flame-dried Schlenk tube was charged with
[CoBr2(dppe)] (62 mg, 0.1 mmol, 10 mol %), zinc iodide (63 mg,
0.2 mmol, 20 mol %), and powdered zinc (13 mg, 0.2 mmol,
20 mol %) in anhydrous dichloromethane (1 mL) under an argon
atmosphere. After addition of butadiene (54 mg, 1 mmol) and
n-butylalkynylboronate (208 mg, 1 mmol), the reaction mixture
was stirred at ambient temperature for 4 h. The mixture was
filtered through a pad of silica gel and the solvent removed in
vacuo. The crude mixture was dissolved in benzene (10 mL), and
DDQ (250 mg, 1.1 mmol) was added. The mixture was stirred
for 1 h. A basic solution (10% NaOH/10% Na2S2O3, 20 mL)
was introduced, and the aqueous layer was extracted with
diethyl ether (3ꢀ20 mL). The resulting organic layer was washed
with brine and dried over MgSO4. After evaporarion in vacuo,
the crude product was purified by flash chromatography over
silica gel eluting with pentane/EtOAc (95/5) to provide the desi-
red compound as a clear oil (174 mg, 67%): 1H NMR (250 MHz,
CDCl3) δ0.98 (3H, t, J=7.5Hz), 1.39(12H, s), 1.39-1.47 (2H, m),
1.56-1.60 (2H, m), 2.90-2.94 (2H, m), 7.20-7-23 (2H, m),
7.36-7.40 (1H, m), 7.80-7.83 (1H, m); 13C NMR (62.9 MHz,
CDCl3) δ 14.0, 22.8, 24.9, 35.6, 35.7, 83.3, 124.8, 129.2, 130.8,
136.0, 150.2; FTIR (film) 3051 (w), 2977 (s), 2871 (m), 1600 (s),
1442 (s), 1146 (s) cm-1; HRMS (EI) m/z [MH]þ calcd for
C16H26BO2 261.2037, found 261.2026.
20.7, 22.8, 33.3, 33.6, 122.1, 126.8, 130.8, 134.7, 134.8, 135.2,
138.2, 138.9, 144.2, 150.3, 151.7; FTIR (film) 2955 (s), 2929 (s),
2863 (m), 1558 (w), 1425 (m), 1389 (s), 749 (s) cm-1; HRMS (EI)
m/z [M]þ calcd for C17H1979Br35ClN 351.0401, found 351.0389.
3 (6-n-Butyl-2,3-dimethylphenyl)-4-chloropyridine (31). To a
solution of 30 (41 mg, 0.12 mmol) in THF (1 mL) was added
i
dropwise at room temperature a solution of PrMgCl (2 M,
90 μL, 0.17 mmol) in THF. After being stirred at room temper-
ature for 2 h, the reaction mixture was quenched with water and
extracted with dichloromethane, and the extracts were washed
with brine, dried over MgSO4, and evaporated in vacuo. The
crude product was purified by flash chromatography (petroleum
ether/EtOAc 5/1) to give 31 as a clear oil (26 mg, 82%): 1H NMR
(400 MHz, CDCl3) δ 0.77 (3H, t, J=7.5 Hz), 1.14-1.23 (2H, m),
1.32-1.42 (2H, m), 1.91 (3H, s), 2.13-2.21 (1H, m), 2.26-2.33
(1H, m), 2.33 (3H, s), 7.10 (1H, d, J=8.0 Hz), 7.21 (1H, d, J=
8.0 Hz), 7.48 (1H, d, J=5.5 Hz), 8.41 (1H, s), 8.54 (1H, d, J=5.5
Hz); 13C NMR (100.6 MHz, CDCl3) δ 13.8, 16.8, 20.3, 22.4,
32.9, 33.3, 124.3, 126.3, 130.1, 134.2, 134.4, 135.0, 136.2, 138.9,
144.0, 149.2, 151.8; FTIR (film) 2958 (s), 2928 (s), 2861 (m), 1581
(w), 1456 (m), 1260 (m), 1194 (w), 750 (s) cm-1; HRMS (EI) m/z
[MH]þ calcd for C17H2035ClN 273.1271, found 273.1284.
3(6-n-Butyl-2,3-dimethylphenyl)-N,N-diisopropylpyridin-4-amine
(32). To a solution of 31 (15 mg, 0.05 mmol) in THF (0.5 mL)
was added diisopropylamine (48 mg, 0.5 mmol). A freshly
prepared solution of LDA in THF (2.1 M, 55 μL, 0.11 mmol)
was then added at room temperature via syringe. The mixture
was heated to reflux for 16 h. The reaction mixture was cooled to
rt, and then the solvent was removed in vacuo. The residue was
extracted from water with dichloromethane, the organic layer
dried over MgSO4, and solvent removed in vacuo. The crude
mixture was purified by flash chromatography (petroleum ether/
1
EtOAc 2/1) to give 32 as a yellow oil (11 mg, 69%): H NMR
(400 MHz, CDCl3) δ 0.78 (3H, t, J=7.5 Hz), 1.15-1.30 (14H,
m), 1.36-1.44 (2H, m), 1.98 (3H, s), 2.32-2.35 (5H, m),
3.76-3.87 (2H, m), 6.98-6.99 (1H, m), 7.07 (1H, d, J =
8.0 Hz), 7.15 (1H, d, J=8.0 Hz), 7.83 (1H, d, J=1.5 Hz), 8.26
(1H, d, J=3.0 Hz); 13C NMR (100.6 MHz, CDCl3) δ 13.8, 17.4,
20.4, 21.1, 21.4, 22.6, 33.4, 33.7, 47.7, 126.2, 126.4, 129.2, 134.1,
135.0, 136.3, 138.3, 138.9, 139.3, 139.6, 143.7; FTIR (film) 2965
(s), 2930 (s), 2871 (m), 1582 (w), 1456 (s), 1368 (m), 1195(s), 817
(w) cm-1; HRMS (EI) m/z [M]þ calcd for C23H34N2 338.2711,
found 338.2722.
3 Bromo-5-(6-n-butyl-2,3-dimethylphenyl)-4-chloropyridine
(30). To a solution of 26 (196 mg, 0.68 mmol) and 3,5-dibromo-
4-chloropyridine (148 mg, 0.54 mmol) in benzene (7 mL) were
added silver(I) carbonate (375 mg, 1.36 mmol) and Pd(PPh3)4
(79 mg, 0.05 mmol, 10 mol %), and the resulting mixture was
heated at reflux for 60 h. The reaction mixture was filtered, the
organic layer washed with water and brine, dried over MgSO4,
and the solvent removed in vacuo. The crude mixture was
purified by flash chromatography (pentane/CH2Cl2 25/75) to
give 30 as a pale yellow oil (135 mg, 71%): 1H NMR (250 MHz,
CDCl3) δ 0.79 (3H, t, J=7.5 Hz), 1.15-1.25 (2H, m), 1.33-1.43
(2H, m), 1.91 (3H, s), 2.11-2.19 (1H, m), 2.25-2.31 (1H, m),
2.33 (3H, s), 7.11 (1H, d, J=8.0 Hz), 7.23 (1H, d, J=8.0 Hz), 8.31
(1H, s), 8.79 (1H, s); 13C NMR (62.9 MHz, CDCl3) δ 14.2, 17.2,
Acknowledgment. We are grateful to the EPSRC (EP/
F024118/1) and the University of Sheffield for financial
support.
Supporting Information Available: 1H and 13C NMR spec-
tra for selected compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
3896 J. Org. Chem. Vol. 75, No. 11, 2010