A metal-free cycloaddition approach to highly substituted aromatic boronic esters

Article abstract of DOI:10.1055/s-2005-863727

Alkynylboronates participate in [4+2] benzannulation reactions to furnish highly functionalised aromatic boronic esters, further manipulation of these boronic esters has been achieved via oxidation and Suzuki coupling reactions.

Full text of DOI:10.1055/s-2005-863727

860
LETTER
A Metal-Free Cycloaddition Approach to Highly Substituted Aromatic
Boronic Esters
M
etal-Fre
a
e
C
ycloadd
n
ition
A
pproa
e
ch to Highly Subs
E
tituted Aromat
.
E
s
M
ters oore,a Mark York,b Joseph P. A. Harrity*a
a
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S3 7HF, UK
E-mail: j.harrity@sheffield.ac.uk
b
Department of Medicinal Chemistry, Organon Laboratories Ltd., Newhouse, Lanarkshire, ML1 5SH, UK
Received 17 January 2005
R1
Abstract: Alkynylboronates participate in [4+2] benzannulation
reactions to furnish highly functionalised aromatic boronic esters,
further manipulation of these boronic esters has been achieved via
oxidation and Suzuki coupling reactions.
O
O
R2
R3
R5
R1
X
R5
B
R2
R3
O
B
Keywords: cycloaddition, alkynylboronates, regioselective, aro-
matic boronic esters
R4
O
–"X"
R4
Equation 2
We have recently embarked upon a programme designed
to explore new strategies for the preparation of aromatic
and heteroaromatic boronic esters through the employ-
ment of cycloaddition reactions.1 Our initial investiga-
tions showed that highly substituted functionalised
hydroquinone boronic ester derivatives could be obtained
in high yield by employment of alkynylboronates in a
chromium carbene-mediated benzannulation reaction (the
Dötz reaction, see Equation 1).1a,b Although this process is
enticing in that it allows highly functionalised arylboronic
esters to be assembled in a single step, the requirement for
stoichiometric quantities of an organochromium reagent
is unattractive from an economical and environmental
standpoint. In an effort to address this shortcoming, we
have been investigating the potential for metal free [4+2]
cycloaddition reactions2 to furnish similarly highly func-
tionalised aromatic systems (Equation 2), we wish to re-
port herein our initial results towards this goal.
Indeed, these compounds rapidly dimerise by a [4+2] cy-
cloaddition pathway unless they are sterically congested
and they undergo efficient annulation reactions with
alkynes.3 In the context of our proposed benzannulation
scheme, the initial cycloadducts readily extrude CO to
form an aromatic product, usually under the conditions of
the cycloaddition reaction. Accordingly, in an effort to
gauge the feasibility of this technique for aromatic boron-
ic ester synthesis we prepared a representative series of
cyclone substrates as outlined in Table 1. The established
method of aldol condensation provided ester substituted
substrate 1 as well as unsymmetrical cyclones 2–4. Unfor-
tunately, the a,a¢-bis-ether substrate 5 could not be ac-
cessed by this route and starting material was returned in
this case. The cyclones were isolated as orange/red crys-
talline solids except for 3, which was found to be a colour-
less solid. NMR spectroscopy suggests that this
compound exists as a dimer, however, we found that
HO
O
R3
R1
R2
R3
Cr(CO)5
OMe
Table 1 Preparation of a Representative Series of Cyclone Sub-
strates
B
R2
R1
O
O
B
MeO
O
Equation 1
R1
R2
Yield (%)
1 (96)
In our search for a process that would permit the direct
formation of a benzenoid nucleus, we became interested
in the Diels–Alder cycloaddition reactions of cyclopenta-
dienones (cyclones). Cyclones are readily prepared by
aldol condensation of ketones with 1,2-dicarbonyl com-
pounds and they are an extremely reactive class of dienes.
CO2Me
Me
CO2Me
Ph
2 (71)
Me
n-Pr
3 (65)
Me
CO2Me
OBn
4 (83)
OBn
5 ( 0)
SYNLETT 2005, No. 5, pp 0860–0862
2
1.
0
3.
2
0
0
5
Advanced online publication: 09.03.2005
DOI: 10.1055/s-2005-863727; Art ID: D01105ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Metal-Free Cycloaddition Approach to Highly Substituted Aromatic Boronic Esters
861
Table 2 [4+2] Cycloaddition Reactions of Cyclone 1
MeO2C
Ph
O
O
CO2Me
R
B
R
Ph
Ph
MeO2C
Ph
R
O
6a–d
O
O
Mesitylene
reflux, 16 h
Ph
MeO2C
B
–CO
B(OR)2
CO2Me
O
CO2Me
Ph
1
7a–d
Entry
R
Yield (%)
1
2
3
4
Me
6a
6b
6c
6d
7a (64)
7b (59)
7c (58)
7d (58)
n-Bu
Ph
Me3Si
warming a sample of this compound in mesitylene provid- particular, we were interested in the regiochemical out-
ed a deep red solution that suggested fragmentation back come of reactions employing unsymmetrical cyclopenta-
to the cyclone monomer 3 could occur at elevated temper- dienones. We firstly investigated the regioselectivity of
atures.
cycloadditions of alkyl-substituted cyclones 2–4 with
alkynes 6c and 6e, the results are shown in Table 3.
With a series of cyclones in hand, we decided to investi-
gate their participation in cycloaddition reactions with As outlined in entry 1 (Table 3), alkynylboronate 6c un-
alkynylboronates. We began our studies with symmetrical derwent a cycloaddition reaction with 2-methyl-3,4,5-
diene 1 and a representative series of alkynes as outlined triphenyl-cyclopenta-2,4-dienone 2 to give boronic ester 8
in Table 2. Upon heating the starting materials in reflux- in 68% yield with low levels of regiocontrol. We attempt-
ing mesitylene for 16 hours we were pleased to recover ed to improve the regioselectivity by employing a termi-
the desired aromatic boronic ester 7a in good yield (entry nal alkynylboronate 6e but were disappointed to find that
1). Further investigations revealed that this reaction was 9A was produced together with isomer 9B in a 2:1 ratio,
general for a series of alkyl/aryl-substituted alkyne sub- albeit in excellent yield (Table 3, entry 2). Changing the
strates (entries 2–4).
diene substrate to the a,a¢-dialkyl-substituted cyclone 3
did not result in improved regioselectivity in the cycload-
dition reactions with alkynes 6c and 6e (Table 3, entries 3
and 4).4 This is perhaps unsurprising given the small dif-
ference in steric and electronic properties of the substi-
Having validated the [4+2]cycloaddition reaction strategy
to functionalised aromatic boronic esters, we turned our
attention to investigating the scope of cyclopentadienone
substrates that would participate in benzannulations. In
Table 3 Regiochemical Studies
Me
O
O
R2
Me
R1
O
B
Ph
Ph
R2
B
Me
R1
Ph
Ph
O
O
6c,e
O
B
R2
Ph
Ph
Mesitylene
reflux, 16 h
R1
O
2–4
A
B
Entry
R1
R2
Yield (%, A:B)
8 (68, 1:2)
9 (100, 2:1)
10 (50, 2:1)
11 (90, 1:1)
12 (70)a
1
2
3
4
5
6
Ph 2
Ph 6c
H 6e
Ph 6c
H 6e
Ph 6c
H 6e
Ph 2
n-Pr 3
n-Pr 3
CO2Me 4
CO2Me 4
13 (75, 3:1)
a A 2:1 mixture of regioisomers was obtained, the identity of the major isomer was not determined.
Synlett 2005, No. 5, 860–862 © Thieme Stuttgart · New York

862
J. E. Moore et al.
LETTER
tutents in this case. Finally, we attempted to improve
cycloaddition regioselectivity by employing ester-substi-
tuted cyclone 4. Once again, Ph-substituted alkynylbor-
onate 6c provided low levels of regiocontrol whereas the
terminal alkyne 6e showed a marginal improvement
(Table 3, entries 5 and 6). Accordingly, whilst our studies
thus far indicate that the cyclopentadienone cycloaddition
reactions of alkynylboronates provide a novel and rapid
method for the synthesis of highly substituted aryl boronic
esters, they suggest that this method is particularly suited
to symmetrical cyclone substrates given that the regiose-
lectivity of unsymmetrical substrates is rather poor.
Acknowledgment
We gratefully acknowledge the support of this research by EPSRC,
The University of Sheffield and Organon Laboratories Ltd.
References
(1) (a) Davies, M. W.; Johnson, C. N.; Harrity, J. P. A. Chem.
Commun. 1999, 2107. (b) Davies, M. W.; Johnson, C. N.;
Harrity, J. P. A. J. Org. Chem. 2001, 66, 3525. (c) Davies,
M. W.; Wybrow, R. A. J.; Johnson, C. N.; Harrity, J. P. A.
Chem. Commun. 2001, 1558. (d)Moore, J. E.; Goodenough,
K. M.; Spinks, D.; Harrity, J. P. A. Synlett 2002, 2071.
(2) For previous [4+2] cycloaddition reactions of
alkynylboronates see: (a) Hilt, G.; Smolko, K. I. Angew.
Chem. Int. Ed. 2003, 42, 2795. (b) Matteson, D. S.;
Waldbillig, J. O. J. Org. Chem. 1963, 28, 366. (c) Woods,
W. G.; Strong, P. L. J. Organomet. Chem. 1967, 7, 371.
(3) (a) Ogliaruso, M. A.; Romanelli, M. G.; Becker, E. I. Chem.
Rev. 1965, 65, 261. (b) Allen, C. F.; Van Allan, J. A. J. Am.
Chem. Soc. 1950, 72, 5165. (c) Merlet, S.; Birau, M.; Wang,
Z. Y. Org. Lett. 2002, 4, 2157. (d) White, D. M. J. Org.
Chem. 1974, 39, 1951.
A final issue that remained to be resolved was to investi-
gate the capability of the hindered arylboronic ester prod-
ucts to participate in further functionalisation reactions.
Accordingly and as outlined in Scheme 1, we investigated
the oxidation of 7a to the corresponding phenol and the
Suzuki coupling reaction5 of 7a with aryl/allyl iodides.
We were pleased to find that these C–O and C–C bond
forming processes took place to produce the desired prod-
ucts in good to excellent yields.
(4) Regiochemical assignments in compounds 8, 9, 10, 13 were
carried out by NOE spectroscopy.
(5) (a) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96,
555. (b) Suzuki, A. Pure Appl. Chem. 1994, 66, 213.
(c) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(6) Representative Experimental Procedure for
Alkynylboronate Cycloaddition Reactions: Synthesis of
4¢-Butyl-5¢-{4,4,5,5-tetramethyl-[1,3,2,]dioxaborolan-2-
yl}-[1,1¢,2¢,1¢¢]terphenyl-3¢,6¢-dicarboxylicAcidDimethyl
Ester (7b).
MeO2C
Ph
MeO2C
Ph
Me
Me
OH
30% H2O2, EtOH
86%
O
Ph
MeO2C
B
Ph
MeO2C
O
7a
14
2-Oxo-4,5-diphenyl-cyclopenta-3,5-diene-1,3-dicarboxylic
acid dimethyl ester (1, 460 mg, 1.32 mmol) was weighed
into a round-bottomed flask together with 2-hex-1-ynyl-
4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (6b, 200 mg,
0.096 mmol). The flask was fitted with a reflux condenser
and mesitylene (1 mL) was added. The resulting orange
solution was stirred for 16 h at 160 °C under nitrogen. The
dark brown reaction mixture was cooled to r.t., and purified
by flash column chromatography (eluting solvent CH2Cl2–
MeOH, 50:1 ratio) to give the title compound as a pale
yellow solid (299 mg, 59% yield). Mp 123–125 °C. 1H NMR
(250 MHz, CDCl3): d = 0.85 (3 H, t, J = 7.0 Hz), 1.30 (12 H,
s), 1.11–1.42 (2 H, m), 1.48–1.66 (2 H, m), 2.70 (2 H, t,
J = 8.5 Hz), 3.30 (3 H, s), 3.33 (3 H, s), 6.52–6.79 (4 H, m),
6.93–7.05 (6 H, m). 13C NMR (62.9 MHz, CDCl3): d = 13.9,
23.3, 25.1, 33.8, 35.1, 51.6, 51.7, 84.3, 126.5, 126.8, 127.1,
127.2, 129.9, 130.2, 136.4, 136.7, 138.3, 138.6, 139.4,
140.4, 143.4, 169.6, 170.7. FT-IR (CHCl3): 2954 (w), 1731
(s), 1562 (w), 1436 (m), 1361 (s), 1322 (s) cm–1. HRMS:
m/z calcd for C32H37BO6: 528.2683; found: 528.2684. Anal.
Calcd for C32H37BO6: C, 72.73; H, 7.06. Found: C, 72.88; H,
7.01.
MeO2C
Ph
Me
Ph
10 mol% PdCl2(dppf)
K3PO4, PhI, dioxane
85 °C, 48 h; 67%
7a
Ph
MeO2C
15
MeO2C
Ph
10 mol% PdCl2(dppf)
Me
K3PO4, dioxane
I
7a
Ph
MeO2C
85 °C, 16 h; 61%
16
Scheme 1
In conclusion, we have reported the direct generation of
functionalised aryl boronic esters via [4+2] cycloaddition
reactions of alkynylboronates.6 Furthermore, the synthetic
utility of these intermediates has been demonstrated
through oxidation of the C-B bond and by Suzuki cou-
pling reactions.
Synlett 2005, No. 5, 860–862 © Thieme Stuttgart · New York