A novel and highly regioselective Cr-mediated route to functionalised quinone boronic ester derivatives

Article abstract of DOI:10.1039/a906643h

A novel and highly regioselective route to quinone boronic ester derivatives has been developed using a Fischer carbene mediated benzannulation process.

Full text of DOI:10.1039/a906643h

A novel and highly regioselective Cr-mediated route to functionalised quinone
boronic ester derivatives
Mark W. Davies,a Christopher N. Johnsonb and Joseph P. A. Harrity*a
a Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, UK S3 7HF.
E-mail: j.harrity@sheffield.ac.uk
b Discovery Chemistry Europe, SmithKline Beecham, New Frontiers Science Park, Harlow, Essex, UK CM19 5AW
Received (in Liverpool, UK) 10th August 1999, Accepted 13th September 1999
A novel and highly regioselective route to quinone boronic
ester derivatives has been developed using a Fischer carbene
mediated benzannulation process.
Arylboronic acids and esters represent one of the most heavily
utilised classes of synthetic intermediates of recent times.1
These compounds are typically prepared using alkyllithium or
Grignard reagents and a suitable boronic ester or halide. More
recently, palladium catalysed coupling of aryl halides with
alkoxydiboron2 or alkoxyborane3 reagents has provided a mild
alternative for conducting this transformation. In an effort to
develop an efficient method for the preparation of complex aryl
boronic esters, we envisaged a conceptually novel approach to
these compounds by the employment of a Dötz annulation
reaction4 of Fischer carbene complexes5 with alkynylbor-
onates.6 As illustrated in Scheme 1, this approach would
provide a direct technique for the assembly of highly function-
alised boronic ester derivatives from simple starting materials.
We were mindful that disubstituted alkynes generally undergo
insertion with low levels of regioselectivity7 and therefore our
initial goal was to investigate whether arylboronic esters could
be prepared in this manner with useful levels of regiocontrol.
Scheme 3
scope of the cyclisation process with respect to sterically
hindered alkynylboronates (Scheme 3). The employment of
tert-butyl substituted boronate 5 led only to the formation of
cyclobutenone 6. This result is in accord with Yamashita’s
observations that bulky electron deficient alkynes provide
cyclobutenone products at the expense of benzannulated
compounds.10 Nonetheless, again a single regioisomer was
observed and the product displayed an analogous insertion
pattern to that outlined in Scheme 2.9
Having developed the technique to access hydroquinone
boronic esters we turned our attention to conversion of these
compounds to the corresponding quinones. As outlined in
Scheme 4, hydroquinone 3 was oxidised smoothly to 7 in good
yield with cerium ammonium nitrate in only 30 min at room
temperature. Significantly, these quinones represent a novel
class of boronic esters and are a potentially valuable source of
a range of quinone containing medicinally important agents.11
Whilst a thorough investigation of the functionalisation of the
carbon–boron bond must await future studies, we have found
that 7 is readily further oxidised to hydroxyquinone 8 through
treatment with basic H2O2 for 20–30 min.
Scheme 1
As shown in Scheme 2, we were pleased to find that complex
1 reacted smoothly with pinacol ester 2 to provide arylboronate
3 in excellent yield, and remarkably, as a single regioisomer.
Notably, a minor quantity of deboronated cyclisation product 4
was also produced but was easily separated from 3 by
chromatography. The origin of the generation of 4 has not been
unambiguously established although it likely arises from
protodeboronation of 2 followed by annulation of the terminal
alkyne.8 The regiochemistry of boronate ester 3 was elucidated
by X-ray crystallography and shows that the boronate unit is
inserted adjacent to the methoxy unit.9 We also examined the
Scheme 4
In general, direct oxidation of the crude reaction mixture after
benzannulation provided a simple and routine method for the
isolation of quinone boronic ester compounds (Scheme 5). We
briefly investigated the scope of this technique with respect to
alkynylboronates and Fischer carbene complexes, as shown in
Table 1.
Initial screening showed the reaction to be efficient in both
polar and non-polar solvents. However, THF gave consistently
higher yields of boronate esters. We attempted to promote the
reaction by the employment of dry state conditions (Table 1,
entry 3).12 Unfortunately, adsorption onto silica gel served only
Scheme 2
Scheme 5
Chem. Commun., 1999, 2107–2108
This journal is © The Royal Society of Chemistry 1999
2107

Table 1 Benzannulation reaction of alkynylboronates and Fischer carbene complexes (see Scheme 5)
Product Yield
Product Yield
Entry
X
R1
Conditionsa
A
(%)
B
(%)
1
2
3
4
5
6
CHNCH 1
CHNCH 1
CHNCH 1
O 10
CHNCH 1
O 10
Bu 2
Bu 2
Bu 2
Bu 2
Ph 13
Ph 13
THF, 45 °C
Hexane, 45 °C
SiO2, 45 °C
THF, 65 °C
THF, 45 °C
THF, 65 °C
7
7
7
11
14
16
66
62
0
47
57
35
9
9
9
12
15
17
6
35
84
30
12
42
a Reaction conditions: (1) 0.05 M solution of complex and 3 equiv. of alkyne heated for 14–16 h under inert atmosphere. (2) Crude reaction mixture dissolved
in Et2O and stirred for 0.5 h with 0.5 M CeIV in 0.1 M aq. HNO3.
6 For the synthesis of alkynylboronates, see: H. C. Brown, N. G. Bhat and
M. Srebnik, Tetrahedron Lett., 1988, 29, 2631.
7 W. D. Wulff, P. C. Tang and J. S. McCallum, J. Am. Chem. Soc., 1981,
103, 7677; K .H. Dötz, J. Muhlemeier, U. Schubert and O. Orama,
J. Organomet. Chem., 1983, 247, 187; W. D. Wulff, K. S. Chan and
P. C. Tang, J. Org. Chem., 1984, 49, 2293.
8 Alkynylboronates are readily hydrolysed to the parent alkyne in the
presence of protic reagents, (ref. 6), it is therefore plausible that the
phenolic benzannulated product mediates alkyne protodeboronation.
Indeed, hex-1-yne was recovered in the volatile material isolated from
the reaction mixture in Table1, entry 1.
Scheme 6
9 Crystal data for 3: C21H29BO4, M = 356.25, triclinic, a = 9.4916(6),
11.1685(8), c 18.9638(13) Å, a 90.1890(10), b =
b
=
=
=
to provide quinone 9, albeit in high yield. The reaction was
found to be readily extended to furan complex 10, although
higher temperatures and longer reaction times were generally
required for complete conversion and resulted in the recovery of
larger quantities of deboronated products (entries 4 and 6, Table
1). Nonetheless, these quinones were again isolated as single
regioisomers.13
91.2770(10), g = 92.5080(10)°, U = 2007.9(2) Å3, Z = 4, Dc = 1.179
¯
g cm23, space group P1 (no. 2), T = 150 K, Mo-Ka radiation (l =
0.71073 Å), m(Mo-Ka) = 0.079 mm21, F(000) = 768. Data were
collected in the range 1.83 < q < 28.36°, 5420 independent reflections
(Rint = 0.0549), final R = 0.0778, with allowance for the thermal
anisotropy of all non-hydrogen atoms. For 6: C21H29BO4, M = 356.25,
monoclinic, a = 8.845(2), b = 19.493(5), c = 12.055(3) Å, b =
103.804(6)°, U = 2018.5(10) Å3, Z = 4, Dc = 1.172 g cm23, space
group P 21/n (a non-standard setting of P21/c, no. 14), T = 150 K, Mo-
Ka radiation (l = 0.71073 Å), m(Mo-Ka) = 0.079 mm21, F(000) =
768. Data were collected in the range 2.03 < q < 28.31°, 1895
The origin of the high preference of insertion of the boronate
group in the more hindered position adjacent to the MeO group
is not clear at this time, however we are currently investigating
three possible rationales. The insertion may simply be sterically
controlled and therefore follows traditional insertion patterns
where the boronate unit acts as the sterically less demanding
independent reflections (Rin
= 0.0932), final R = 0.0618, with
allowance for the thermal anisotropy of all non-hydrogen atoms. CCDC
182/1418.
group.14 Alternatively, Hofmann has proposed that h -vinyl-
3
10 A. Yamashita and A. Toy, Tetrahedron Lett., 1986, 27, 3471.
11 For example see: Anthracycline and Anthracenedione - Based Anti-
cancer Agents, in Bioactive Molecules, ed. J. W. Lown, Elsevier,
Oxford, 1988, vol. 6.
12 J. P. A. Harrity, W. J. Kerr and D. Middlemiss, Tetrahedron Lett., 1993,
34, 2995.
13 The rigorous establishment of compounds 11 and 16 is ongoing but at
present is assumed to follow the same insertion patterns as outlined in
Scheme 4.
14 The A value of the alkynyl substituent can often serve as a useful guide
to predicting regioselectivity (ref. 10). In this context, studies are
underway to determine the A value of a range of boronic ester moieties
and will be the subject of a future disclosure.
carbene complex intermediates are responsible for controlling
regiochemical insertion patterns.15 Therefore, 19 may be
energetically disfavoured due to the positioning of the electron
withdrawing boronate unit adjacent to the electrophilic carbene
carbon atom (Scheme 6). Finally, a model proposed by Wulff to
explain the contrasteric insertion of alkynylstannanes in the
benzannulation process may be invoked whereby the re-
giochemistry is controlled by a Lewis acid/base interaction
[CO?B(OR)2] in the metallohexatriene intermediate 18, thus
directing regiochemical insertion.16
In conclusion, this study provides a rapid and efficient
approach to a novel class of hydroquinone and quinone
boronate esters.17 Additionally, the boron unit is incorporated
into these structures in a reliable and predictable fashion, and
with excellent selectivity. Studies on the origin of regioselectiv-
ity are currently underway as are the employment of these
intermediates in transition metal catalysed C–C coupling
reactions.
The authors are grateful to the EPSRC for a studentship (M.
W. D.) and to SmithKline Beecham for generous financial
support. We also wish to thank Dr S.L. Heath and Mr H. Adams
for assistance with X-ray data.
15 P. Hofmann, M. Hämmerle and G. Unfried, New J. Chem., 1991, 15,
769.
16 S. Chamberlin, M. L. Waters and W. D. Wulff, J. Am. Chem. Soc., 1994,
116, 3113.
17 Typical experimental procedure as exemplified by benzannulation of
complex 1 and alkyne 2 (Scheme 2): to a solution of 1 (102 mg, 0.327
mmol) in THF (6.4 ml) was added alkyne 2 (204 mg, 0.980 mmol) via
syringe under nitrogen. The reaction mixture was stirred at 45 °C for 14
h and concentrated by rotary evaporation. Purification of the resulting
residue by silica gel chromatography provided hydroquinone 4 (ref. 18)
(11 mg, 15%) and boronate ester 3 (85 mg, 73%) which could be
crystallised from hexanes to provide an amber solid, mp 116–116.5 °C.;
dH (250 MHz, CDCl3)0.96 (3H, t, J 7.3, CH3CH2), 1.42 (12H, s, CH3),
1.47–1.72 (4H, m, CH2CH2CH3), 2.73 (2H, app t, J 7.9, CNCCH2), 3.91
(3H, s, CH3O), 4.93 (1H, br s, OH), 7.39–7.53 (2H, m, Ar-H) 7.95–8.03
(1H, m, Ar-H), 8.05–8.13 (1H, m, Ar-H); dC (62.9 MHz, CDCl3) 14.1,
24.7, 24.9, 30.2, 33.0, 63.5, 84.0, 121.6, 122.0, 124.3, 125.2, 125.9,
126.6, 144.4, 153.9; nmax/cm21 3445 (br), 2991 (m), 2977 (m), 1662
(m), 1142 (s) (calc. for C21H29BO4: C, 70.80; H, 8.20. Found: C, 70.67;
H, 8.36%).
Notes and references
1 For a review see: A. Suzuki, Pure Appl. Chem., 1994, 66, 213.
2 T. Ishiyama, M. Murata and N. Miyaura, J. Org. Chem., 1995, 60,
7508.
3 M. Murata, S. Watanabe and Y. Masuda, J. Org. Chem., 1997, 62,
6458.
4 For a recent review see: K. H. Dötz and P. Tomuschat, Chem. Soc. Rev.,
1999, 28, 187.
5 For an overview on the synthesis of Fischer carbene complexes see: E.
O. Fischer, C. G. Kreiter, H. J. Kollmeier, J. Muller and R. D. Fischer,
J. Organomet. Chem., 1971, 28, 237.
18 13C and 1H spectra of 4 were identical to an authentic sample prepared
from hex-1-yne: A. Yamashita, S. Ayako, R. G. Schaub, M. K. Bach,
G. J. White and A. Toy, J. Med. Chem., 1990, 33, 775.
Communication 9/06643H
2108
Chem. Commun., 1999, 2107–2108