Directed ortho metalation and Suzuki-Miyaura cross-coupling connections: Regiospecific synthesis of all isomeric chlorodihydroxybiphenyls for microbial degradation studies of PCBs

Article abstract of DOI:10.1039/a907279i

Monochloro DHBs 1a-d and 2a-c have been regioselectively synthesised in good overall yields by a combination of directed ortho metalation and Suzuki- Miyaura cross-coupling.

Full text of DOI:10.1039/a907279i

Directed ortho Metalation and Suzuki–Miyaura cross-coupling connections:
regiospecific synthesis of all isomeric chlorodihydroxybiphenyls for microbial
degradation studies of PCBs
a
b
a
a
b
b
c
S. Nerdinger, C. Kendall, R. Marchhart, P. Riebel, M. R. Johnson, C.-F. Yin, L. D. Eltis † and
V. Snieckus*
b
a
Guelph-Waterloo Centre for Graduate Work in Chemistry, University of Waterloo, Waterloo, ON, Canada
N2L 3G1
b
Department of Chemistry, Queen’s University, Kingston, ON, Canada K7L 3N6.
E-mail: snieckus@chem.queensu.ca
Department of Biochemistry, Université Laval, Québec City, Québec, Canada G1K 7P4
c
Received (in Corvallis, OR, USA) 7th September 1999, Accepted 28th September 1999
Monochloro DHBs 1a–d and 2a–c have been regioselectively
synthesised in good overall yields by a combination of
directed ortho metalation and Suzuki–Miyaura cross-cou-
pling.
metalation group (DMG) use in walk-around-the-ring function-
alization (2a, 2c).
7
Metalation and a trimethyl borate quench of 6 (Scheme 3)
afforded the boronic acid 7 which, in crude form, was subjected
to Suzuki–Miyaura cross-coupling with bromobenzene or
commercially available isomeric chloroiodobenzenes followed
The aerobic microbial degradation of aromatic compounds such
as toluene, naphthalene and biphenyl is an essential link in the
global carbon cycle and generally proceeds via catechol
intermediates involving cleavage by either intradiol or extradiol
3
by standard BBr deprotection to furnish biaryls 1a–d in modest
overall yields on a gram scale. A comparable yielding (58%)
alternate synthesis (Scheme 4) of parent compound 1a from
2-MOM biphenyl 8, prepared (NaH, MOMCl, THF, room
temperature) from inexpensive 2-hydroxybiphenyl, proceeded
by metalation–boronation–oxidation10 to introduce an OH+
synthon to afford 9 followed by hydrolysis.
1
dioxygenases. For biphenyl, fundamental interest in under-
standing the respective proposed mechanisms of the extradiol
cleavage of catechol by 2,3-dihydroxybiphenyl-1,2-dioxygen-
ases (DHBDs)2 and the subsequent hydrolysis of the ring
,3
cleaved product catalysed by 2-hydroxy-6-oxo-6-phenylhexa-
Intermediate 9 also served for a concise synthesis of
4-chloro-DHB 2a (Scheme 4). Thus, conversion to the MOM
derivative 10 as before followed by a second DoM reaction,
3
2
,4-dienoate hydrolase (BphD) (Scheme 1) is intensified by the
prospect of exploiting these enzymes in the degradation of
environmental pollutants such as polychlorinated biphenyls
(
PCBs).4 In connection with ongoing studies in this area, we
,5
6
describe the regiospecific synthesis of all six isomeric mono-
chloro-2,3-dihydroxybiphenyls (DHBs) 1b–d and 2a–c. The
synthetic route takes advantage of combined Directed ortho
7
Metalation (DoM) and Pd-catalyzed Suzuki–Miyaura cross-
8
coupling reactions, a methodological theme currently evolving
9
in our laboratories. The key conceptual features, depicted for
3–5 (Scheme 2), include new strategies of oxygen-directed
Scheme 2
Scheme 1 Enzymes involved in the aerobic microbial degradation of
biphenyl and PCBs: BPDO = biphenyl dioxygenase; BphB = 2,3-dihydro-
2,3-dihydroxybiphenyl dehydrogenase; DHBD = 2,3-dihyroxybiphenyl
dioxygenase; BphD
hydrolase.
=
2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoate
†
Current address: Department of Microbiology and Immunology, Uni-
versity of British Columbia, Vancouver, B.C., Canada V6T 1Z3.
Scheme 3
Chem. Commun., 1999, 2259–2260
This journal is © The Royal Society of Chemistry 1999
2259

achieved in a similar fashion, again exploiting the walk-around-
the ring sequence. Thus, metalation of 13 followed by
boronation–oxidation afforded the intermediate phenol which
was converted to the MOM derivative 14. Subsequent metala-
tion–trimethyl borate quench afforded the 2-boronic acid,
which, in crude form, was subjected to Suzuki–Miyaura cross-
coupling with bromobenzene to give 15, followed by hydrolysis
3
and BBr deprotection to afford 2c (15%). The regiospecificity
of all DoM reactions was established by 1D- and 2D-NMR.
Final products were obtained in purities > 99% as required for
the substrate specificity and inhibition studies of DHBD and
BphD.6
This work demonstrates the expedient synthesis of all
monochloro 2,3-DHBs by the directed ortho metalation–
7
Suzuki–Miyaura cross-coupling sequence. The key attribute of
DoM, its regioselectivity, is imparted singularly and in an
iterative manner (3), and leads to single isomer chloro-DHBs in
high purity and in gram quantities. The method is being used for
the provision of other diverse chloro-DHBs as well as
Scheme 4
catechols12 to gain further understanding of the respective
catalytic mechanisms of DHBD and BphD.2
,3
‡
We are grateful to NSERC (Strategic grant STP0193182) for
generous support of this interdisciplinary study.
Notes and references
All new compounds show analytical and spectral ( H, 13C NMR, HRMS)
1
‡
data fully consistent with their structures.
1
S. Dagley, in The Bacteria, ed. J. R. Sokatch and L. N. Ornston,
Academic Press, New York, 1986, pp. 527–555.
2
3
4
L. Que and R. Y. N. Ho, Chem. Rev., 1996, 96, 2607.
T. D. H. Bugg and C. J. Winfield, Nat. Prod. Rep., 1998, 513.
K. N. Timmis, R. J. Steffan and R. Unterman, Annu. Rev. Microbiol.,
Scheme 5
1
994, 48, 525.
5
6
D. D. Focht, Curr. Opin. Biotechnol., 1995, 6, 341.
(a) S. Y. K. Seah, G. Terracina, J. T. Bolin, P. Riebel, V. Snieckus and
L. D. Eltis, J. Biol. Chem., 1998, 273, 22943; (b) F. H. Vaillancourt, S.
Han, P. D. Fortin, J. T. Bolin and L. D. Eltis, J. Biol. Chem., 1998, 273,
3
4887; (c) S. Y. K. Seah, G. Labbe, S. Nerdinger, M. R. Johnson, V.
Snieckus and L. D. Eltis, submitted for publication.
7
8
V. Snieckus, Chem. Rev., 1990, 90, 879.
N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457; (b) A. Suzuki,
in Metal Catalyzed Cross-Coupling Reactions, ed. F. Diedrich and P. J.
Stang, Wiley-VCH, Weinheim, 1998.
9
C. A. Quesnelle, O. B. Familoni and V. Snieckus, Synlett, 1994, 349 and
references cited therein; V. Snieckus, in Chemical Synthesis: Gnosis to
Prognosis, ed. C. Chatgilialoglu and V. Snieckus, NATO ASI Series E,
1
996, vol. 320, Kluwer, Dordrecht, The Netherlands, p. 191; G.
Queguiner, F. Marsais, V. Snieckus and J. Epsztajn, Adv. Heterocycl.
Chem., 1991, 52, 187.
1
1
0 A. D. Ainley and F. Challenger, J. Chem. Soc., 1930, 2171.
1 6-Cl-DHB (2c) was also prepared as follows: iodination (I
Scheme 6
2
, AgO-
COCF
isomer which, upon metal–halogen exchange and chlorination (Bu
THF, 278 °C then C Cl ) followed by deprotection (BBr , CH Cl
278 °C) furnished 2c in an overall yield of 29%.
3
, CHCl
3
) of 2,3-dimethoxybiphenyl gave exclusively the 6-iodo
chlorination with C
2
Cl
6
, and HCl-mediated deprotection com-
t
Li,
pleted the walk-around-the-ring sequence to afford 2a in good
overall yield (49%). The regiospecific construction of 5-chloro-
DHB 2b (Scheme 5) began from the 4-chlorophenol-derived 11
which, upon metalation–boronation-cross-coupling, gave the
2
6
3
2
2
,
i
t
1
2 3-Et (23% overall), 3-Pr (11% overall), 3-Bu (28% overall), and 3-Cl
species (77% overall) have been prepared by this method (P. Riebel and
V. Snieckus, unpublished results and utilized as described elsewhere).
+
biphenyl 12. Adapting the OH synthon introduction as for 8,
[ref. 6(a), (b)].
followed by hydrolysis, led to 2b in an acceptable overall yield
(
43%). The synthesis of 6-chloro-DHB11 2c (Scheme 6) was
Communication 9/07279I
2260
Chem. Commun., 1999, 2259–2260