Diversity through isosterism: The case of boron-substituted 1,2-dihydro-1,2-azaborines

Article abstract of DOI:10.1021/ol702383u

(Chemical Equation Presented) The first general synthesis of boron-substituted 1,2-dihydro-1,2-azaborines is described. The versatile 1,2-dihydro-1,2-azaborine precursor 4 is synthesized through a ring-closing metathesis-oxidation sequence. Treatment of 4

Full text of DOI:10.1021/ol702383u

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ORGANIC
LETTERS
2007
Vol. 9, No. 23
4905-4908
Diversity through Isosterism: The Case
of Boron-Substituted
1,2-Dihydro-1,2-azaborines
Adam J. V. Marwitz, Eric R. Abbey, Jesse T. Jenkins, Lev N. Zakharov,† and
Shih-Yuan Liu*
Department of Chemistry, UniVersity of Oregon, Eugene, Oregon 97403
lsy@uoregon.edu
Received October 3, 2007
ABSTRACT
The first general synthesis of boron-substituted 1,2-dihydro-1,2-azaborines is described. The versatile 1,2-dihydro-1,2-azaborine precursor 4 is
synthesized through a ring-closing metathesis oxidation sequence. Treatment of 4 with a wide range of anionic nucleophiles furnishes the
−
desired adducts 5 in good yields. The scope includes hydrogen- and a variety of carbon- and heteroatom-based nucleophiles. Furthermore,
the boron-containing isostere (7) of the potent hypolipidemic agent, methyl 2-ethylphenoxyacetate (8), is readily prepared through our method.
Although boron is not an element commonly found in living
systems, there has been burgeoning interest in incorporating
boron into biologically active molecules.1 Over the past
decades, boron-containing compounds have been utilized as
potent antimicrobial agents,2 protease inhibitors,3 and anti-
cancer agents as part of boron neutron capture therapy
(BNCT).4 We have initiated a program directed toward the
development of boron-containing aromatic heterocycles that
mimic ubiquitous natural structures. Specifically, we are
interested in the 1,2-dihydro-1,2-azaborine core5 (from now
on abbreviated as 1,2-azaborine) as it relates to the quint-
essential aromatic compound, benzene, by substitution of one
of benzene’s CdC bond units with an isoelectronic and
isostructural B-N bond. The application of the B-N vs
CdC isosterism6 to benzene, and its many useful derivatives
could open unexplored opportunities in the development of
new drugs as well as provide new directions in the area of
conjugated organic materials.7
† Correspondence concerning X-ray crystallography should be directed
to L.N.Z.
(1) For a review, see: Morin, C. Tetrahedron 1994, 50, 12521-12569.
(2) (a) Rock, F. L.; Mao, W.; Yaremchuk, A.; Tukalo, M.; Cre´pin, T.;
Zhou, H.; Zhang, Y.-K.; Hernandez, V.; Akama, T.; Baker, S. J.; Plattner,
J. J.; Shapiro, L.; Martinis, S. A.; Benkovic, S. J.; Cusack, S.; Alley, M. R.
K. Science 2007, 316, 1759-1761. (b) Baldock, C.; de Boer, G.-J.; Rafferty,
J. B.; Stuitje, A. R.; Rice, D. W. Biochem. Pharmacol. 1998, 55, 1541-
1549.
(3) Fevig, J. M.; Buriak, J., Jr.; Cacciola, J.; Alexander, R. S.; Kettner,
C. A.; Knabb, R. M.; Pruitt, J. R.; Webber, P. C.; Wexler, R. R. Bioorg.
Med. Chem. Lett. 1998, 8, 301-306.
(4) For a recent review on BNCT, see: Barth, R. F.; Coderre, J. A.;
Vicente, M. G. H. Blue, T. E. Clin. Cancer Res. 2005, 11, 3987-4002.
In contrast to polycyclic boron-nitrogen heterocycles (e.g.,
borazarophenanthrene,7b,8 borazaronaphthalene,9 borazaro-
(5) Fritsch, A. J. Chem. Heterocycl. Compd. 1977, 30, 381-440.
10.1021/ol702383u CCC: $37.00
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pyrene,7a borazaroindene,10 and borazarotriphenylene11), the
chemistry of the biologically more relevant monocyclic 1,2-
azaborines has not been extensively explored, presumably
due to limited synthetic access. Dewar and White pioneered
the first syntheses of 1,2-azaborines in the early 1960s and
demonstrated that these compounds have substantial aromatic
character.12 More recently, Ashe has developed two comple-
mentary synthetic strategies for 1,2-azaborines: (1) a ring
expansion of lithium azaborolides13 and (2) a ring-closing
metathesis (RCM)-oxidation sequence.14 Ashe’s elegant
preparative routes established a more general approach to
BN-containing aromatic ring structures.
core, we set out to address this synthetic limitation. In this
paper, we establish the first general synthesis of B-substituted
1,2-azaborines that includes not only a variety of carbon-
based substituents but also a number of unprecedented
examples of B-heteroatom substitutions (Figure 1).
We envisioned that an intermediate bearing a good leaving
group on boron, e.g., A in Scheme 1, could serve as a
Scheme 1. Synthetic Strategy
Despite the groundbreaking advances made to date,
significant synthetic challenges remain. For instance, the
simplest member in the family of 1,2-azaborines, compound
1, is still elusive. More generally, the scope with respect to
the boron substituent (R2 in Figure 1) provided by current
versatile precursor toward a wide range of B-substituted 1,2-
azaborines via nucleophilic substitution.16 Heterocycle A
could be approached from the ring-opened precursor C via
RCM followed by dehydrogenation. However, neither the
RCM nor the oxidation have been performed in the presence
of the reactive and labile B-Cl bond. Gratifyingly we
determined that RCM of precursor 2 proceeds smoothly in
the presence of 2% first-generation Grubbs catalyst to
generate heterocycle 3 (eq 1), which is a testimony to the
robustness and the versatility of modern RCM protocols.17
Figure 1. Scope of boron substituents in 1,2-azaborines.
The aromatization of 3 proved to be more challenging.18
Our initial attempts using DDQ14 met with failure (Table 1,
entry 1). However, optimization of conditions showed that
palladium can serve as a catalyst for this transformation
(entry 2).11,12b The presence of a hydrogen acceptor (i.e.,
cyclohexene) further improves the yield (entry 3). A survey
synthetic methods is fairly limited. To the best of our
knowledge, carbon-9a,13 and oxygen-based15 groups are the
only boron substituents in all of the monocyclic 1,2-
azaborines that have been isolated to date. In order to take
full advantage of the BN-isosterism of the ubiquitous benzene
(6) Zhou, H.-B.; Nettles, K. W.; Bruning, J. B.; Kim, Y.; Joachimiak,
A.; Sharma, S.; Carlson, K. E.; Stossi, F.; Katzenellenbogen, B. S.; Greene,
G. L.; Katzenellenbogen, J. A. Chem. Biol. 2007, 14, 659-669.
(7) For examples in materials science, see: (a) Bosdet, M. J. D.; Piers,
W. E.; Sorensen, T. S.; Parvez, M. Angew. Chem., Int. Ed. 2007, 46, 4940-
4943. (b) Bosdet, M. J. D.; Jaska, C. A.; Piers, W. E.; Sorensen, T. S.
Parvez, M. Org. Lett. 2007, 9, 1395-1398. (c) Lee, B. Y.; Bazan, G. C. J.
Am. Chem. Soc. 2000, 122, 8577-8578.
Table 1. Aromatization of Heterocycle 3: Optimization
Survey
(8) Dewar, M. J. S.; Kubba, V. P.; Pettit, R. J. Chem. Soc. 1958, 3073-
3076.
(9) (a) Fang, X.; Yang, H.; Kampf, J. W.; Holl, M. M. B.; Ashe, A. J.,
III. Organometallics 2006, 25, 513-518. (b) Paetzold, P.; Stanescu, C.;
Stubenrauch, J. R.; Bienmu¨ller, M.; Englert, U. Z. Anorg. Allg. Chem. 2004,
630, 2632-2640. (c) Dewar, M. J. S.; Gleicher, G. J.; Robinson, B. P. J.
Am. Chem. Soc. 1964, 86, 5698-5699. (d) Dewar, M. J. S.; Dietz, R. J.
Chem. Soc. 1959, 2728-2730.
entry
conditions
yielda (%)
1
2
3
4
5
6
1 equiv of DDQ, pentane, 35 °C, 24 h
Pd/C (20 mol %), pentane 80 °C, 16 h
Pd/C (20 mol %), cyclohexene, 80 °C, 16 h
Ru/C (20 mol %), cyclohexene, 80 °C, 16 h
Rh/Al2O3 (20 mol %), cyclohexene, 80 °C, 16 h 23
Pd black (20 mol %), cyclohexene,
80 °C, 16 h
14
31
43
1
(10) Ashe, A. J., III; Yang, H.; Fang, X.; Kampf, J. W. Organometallics
2002, 21, 4578-4580.
(11) Culling, G. C.; Dewar, M. J. S.; Marr, P. A. J. Am. Chem. Soc.
1964, 86, 1125-1127.
75 (57)b
(12) (a) Dewar, M. J. S.; Marr, P. A. J. Am. Chem. Soc. 1962, 84, 3782.
(b) White, D. G. J. Am. Chem. Soc. 1963, 85, 3634-3636.
(13) Ashe, A. J., III; Fang, X.; Fang, X.; Kampf, J. W. Organometallics
2001, 20, 5413-5418.
7
Pd(PPh3)4 (10 mol %), benzene, 80 °C, 16 h
0
a Determined by 11B NMR analysis versus a calibrated internal standard.
b Isolated yield in parentheses (see the Supporting Information for details).
(14) Ashe, A. J., III; Fang, X. Org. Lett. 2000, 2, 2089-2091.
(15) Davies, K. M.; Dewar, M. J. S. J. Am. Chem. Soc. 1967, 89, 6294-
6297.
4906
Org. Lett., Vol. 9, No. 23, 2007

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of transition metals reveals that Pd black catalyzes the
aromatization of 3 most efficiently (entries 3-6). Finally,
we determined that a homogeneous Pd source is ineffective
in mediating this transformation (entry 7).
studies.20 Treatment of 1,2-azaborine precursor 4 with methyl
glycolate 6 in the presence of triethylamine furnishes 7 in a
straightforward manner (eq 2).
Heterocycle 4 serves as a general precursor to B-substituted
1,2-azaborines (Table 2). Displacement of the chloride in 4
Table 2. Synthesis of B-Substituted 1,2-Azaborines through
Nucleophilic Substitution of 4
We have characterized compound 7 by single-crystal X-ray
crystallography (Figure 2). There are only two reported
crystal structures of metal-free 1,2-azaborines (i.e., not
π-bound to a transition metal),21 and to the best of our
knowledge, the structure illustrated in Figure 2 is the first
containing an exocyclic B-heteroatom bond.
a Isolated yield.
occurs readily in the presence of alkyl- (entry 1), vinyl- (entry
2), aryl- (entry 3), and alkynyl-based (entry 4) nucleophiles.
Moreover, heteroatom substitution also proceeded smoothly,
resulting in the isolation of unprecedented nitrogen- (entry
5) and sulfur-substituted (entry 6) 1,2-azaborines. Potassium
tert-butoxide reacts readily with 4 to provide the alkoxy
adduct (entry 7). Treatment of 4 with Superhydride furnishes
a 1,2-azaborine containing the unique B-H bond (5h, entry
8). Compound 5h is stable toward purification by silica gel
chromatography, which stands in stark contrast to prior failed
attempts to isolate 1,2-azaborines bearing the B-H substitu-
tion.15,19 The successful preparation of 5h opens new
opportunities for the synthesis of the ultimate parent aza-
borine 1.
Figure 2. ORTEP illustrations, with thermal ellipsoids drawn at
the 35% probability level, of compound 7.
The exocyclic oxygen atom O(1) of 7 is trigonal (i.e., sp2-
hybridized), with B(1)-O(1)-C(7) ) 118.6(1)°. The
C(7)-O(1)-B(1)-N(1) torsion angle of -172.9(1)° and the
B(1)-O(1) bond distance of 1.389(2) Å suggest significant
π-bonding between oxygen and boron (sum of covalent radii
) 1.55 Å).22 The 1,2-azaborine ring is completely planar
within 0.003 Å. The bond distances in the 1,2-azaborine ring
(in Å), B(1)-N(1) ) 1.436(2), N(1)-C(1) ) 1.370(2),
C(1)-C(2) ) 1.355(2), C(2)-C(3) ) 1.413(2), C(3)-C(4)
) 1.363(2), and C(4)-B(1) ) 1.518(2), are similar to the
reported ones with B-Ph substitution.21 Thus, the oxygen
heteroatom does not appear to significantly affect the
aromatic delocalization of the 1,2-azaborine heterocycle.
A number of the compounds in Table 2 resemble aromatic
structures of significance in chemistry. For instance, the
vinyl-substituted 1,2-azaborine 5b is a heteroaromatic deriva-
tive of styrene. The alkyne adduct 5d is isoelectronic with
tolan. Thus, our synthetic method can provide ready access
to boron-containing heteroaromatics relevant to materials
science.
To further demonstrate the utility of our synthetic method,
we have prepared 7, which is the elemental isomer of methyl
2-ethylphenoxyacetate 8. Compound 8 and its derivatives
have demonstrated potent hypolipidemic activity in animal
(20) Zu´n˜iga, C.; Gardun˜o, L.; Cruz, M. d. C.; Salazar, M.; Pe´rez-
Paste´n,R.; Chamorro, G.; Labarrios, F.; Tamariz, J. Drug. DeV. Res. 2005,
64, 28-40.
(16) Qiao, S.; Hoic, D. A.; Fu, G. C. J. Am. Chem. Soc. 1996, 118, 6329-
6330.
(21) (a) Pan, J.; Kampf, J. W.; Ashe, A. J., III. Org. Lett. 2007, 9, 679-
681. (b) Pan, J.; Kampf, J. W.; Ashe, A. J., III. Organometallics 2006, 25,
197-202.
(17) Brown, R. C. D.; Satcharoen, V. Heterocycles 2006, 70, 705-736.
(18) For a review, see: Donohoe, T. J.; Orr, A. J.; Bingham, M. Angew.
Chem., Int. Ed. 2006, 45, 2664-2670.
(22) For, a collection of B-O distances, see: Gillespie, R. J.; Bytheway,
I.; Robinson, E. A. Inorg. Chem. 1998, 37, 2811-2825.
(19) Wille, H.; Goubeau, J. Chem. Ber. 1974, 107, 110-116.
Org. Lett., Vol. 9, No. 23, 2007
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In summary, we have developed a general method for the
synthesis of a wide range of B-substituted 1,2-azaborines,
including the first examples containing B-heteroatoms.
Because 1,2-azaborines are isostructural and isoelectronic to
the ubiquitous benzene motif, our study provides new
opportunities in the areas of drug discovery and material
science by increasing the diversity of biologically active
molecules and conjugated materials through BN-isosterism.
Chemistry Research and Instrumentation Services has been
furnished in part by the National Science Foundation (CHE-
0234965).
Supporting Information Available: Experimental pro-
cedures and compound characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. Support has been provided by the
University of Oregon. Funding for the University of Oregon
OL702383U
4908
Org. Lett., Vol. 9, No. 23, 2007