A mild benzannulation through directed cycloaddition reactions

Article abstract of DOI:10.1002/anie.201200917

Simple as ABC: Alkynyl borane cycloadditions can be substrate-directed to assemble aromatic difluoroboranes within an extremely mild and efficient reaction manifold compared to that of traditional methods (see scheme). The aromatic boranes are readily transformed into a range of useful products. Copyright

Full text of DOI:10.1002/anie.201200917

.
Angewandte
Communications
DOI: 10.1002/anie.201200917
Cycloaddition
A Mild Benzannulation through Directed Cycloaddition Reactions**
James D. Kirkham, Roger J. Butlin, and Joseph P. A. Harrity*
The synthesis and study of aromatic compounds is a funda-
mental endeavor in organic chemistry. With regard to
benzene, classical synthesis methods have been dominated
by electrophilic and nucleophilic aromatic substitution pro-
Scheme 2. Concept of directed cycloaddition.
cesses, whereas ring synthesis has largely been the domain of
heteroaromatic chemistry. However, ring synthesis has the
advantage that it is not limited to specific substitution
patterns dictated by pre-existing directing groups. For this
reason, the use of cycloaddition strategies for the assembly of
aromatic rings is of significance.[1] Studies conducted in our
group in this area have placed a particular emphasis on
incorporating boronic ester functionality.[2] Whilst some
catalytic variants have emerged recently,[3] a significant draw-
back of this chemistry to date has been the requirement of
high temperatures and long reaction times. For example, as
outlined in Scheme 1, the cycloaddition of 2-pyrones and
alkynylboronates requires harsh reaction conditions, is
restricted to electron-deficient substrates, and provides prod-
ucts with variable levels of regiocontrol.[4]
although this chemistry was limited with respect to the
scope of products that could be prepared. 2-Pyrones repre-
sented a more challenging class of substrates as their cyclo-
additions with alkynes generally require very high reaction
temperatures (typically > 1408C) and long reaction times.[7]
Moreover, such processes are often poorly regioselective and
are relatively low yielding.[8] We report herein the successful
implementation of this concept for the mild and regiospecific
formation of 1,2,3-trisubstituted benzenes.[9,10]
We began our studies by investigating the cycloaddition of
2-pyrone 1a with in situ generated phenylethynyldifluorobor-
ane,[11] and our initial results were very encouraging. Signifi-
cant conversion of 1a was observed within 10 minutes at room
temperature when reacted with the difluoroborane derived
from the combination of trifluoroborate 2a and TMSCl
(Table 1, entry 1). Analysis of the reaction mixture confirmed
Table 1: Preliminary cycloaddition studies.
Scheme 1. Alkynylboronate cycloadditions of 2-pyrones. Pin=pinacol.
In an effort to uncover milder methods of benzannulation,
we have recently become interested in the use of directed
cycloadditions for the mild and regiocontrolled synthesis of
aromatic compounds. Central to our design was the use of an
alkyne bearing a Lewis acid acceptor which would promote
pre-association with a diene bearing a complementary Lewis
base (Scheme 2). The resulting complex would provide
a platform for rate enhancements in the ensuing cycloaddi-
tion.[5] Our preliminary studies indicated that this could be
successful for highly activated dienes such as tetrazines,[6]
Entry[a]
Lewis
acid
T [8C]
3a
3b
3c
Yield [%][b]
Yield [%][b]
Yield [%][b]
1
2
3
TMSCl
25
25
0
40
40
12
75
40
82
62
8
50
10
20
5
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
10
21
5
4
5[c]
–
–
[a] Used 3 equiv of alkyne and Lewis acid. [b] Yield of isolated product.
[c] Used 1 equiv of alkyne and Lewis acid. TMS=trimethylsilyl.
[*] J. D. Kirkham, Prof. J. P. A. Harrity
Department of Chemistry, University of Sheffield
Sheffield, S3 7HF (UK)
that cycloaddition had indeed taken place under these
remarkably mild reaction conditions, however, disappoint-
ingly a mixture of alkynylated and fluorinated borane
products, 3a–c, was observed. Interestingly, switching the
Lewis acid provided a better selectivity for the difluorobor-
ane, and provided an excellent overall conversion (entry 2).
Reducing the reaction temperature again provided a mixture,
but warming the reaction to 408C provided good selectivity
for the difluoroborane (entries 3 and 4). Finally, we found that
the reaction could be conducted under similarly mild reaction
E-mail: j.harrity@sheffield.ac.uk
Dr. R. J. Butlin
Research and Development, AstraZeneca
Alderley Park, Macclesfield, SK10 4TG (UK)
[**] The authors are grateful to the EPSRC and AstraZeneca for financial
support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200917.
6402
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 6402 –6405

Angewandte
Chemie
Table 2: Directing group scope.
conditions with stoichiometric quantities of alkyne, but
a lower conversion was obtained (entry 5).
The formation of alkynylated by-products 3b,c was
unexpected and intriguing, and our preliminary rationale
was envisaged on the basis of disproportionation of 3a with
the alkynyldifluoroborane present in solution. However,
exposing a pure sample of 3a to in situ generated alkynyldi-
fluoroborane resulted in less than 5% conversion (as judged
by 400 MHz 1H NMR spectroscopy), thus suggesting that 3b,c
do not originate from the aryl difluoroborane 3a itself
(Scheme 3). Alternatively, disproportionation of alkynyldi-
Scheme 3. Probing alkynylborane formation.
fluoroboranes to trialkynylboranes may be promoted by
pyridine.[12,13] We therefore postulate that alkynylated prod-
ucts 3b,c are formed from cycloaddition of intermediates such
as A. This process would be competitive when cycloaddition is
slow, and may well explain the reaction temperature/product
distribution trends highlighted in Table 1.
Having optimized the cycloaddition for the formation of
difluoroborane complexes,[14] we turned our attention to
exploring the scope of the reaction with regard to alternative
directing groups; our results are shown in Table 2. We were
pleased to discover that the chemistry could be extended to
other pyridine-substituted pyrones (entries 1 and 2) as well as
azole heterocycles (entries 3 and 4). In an effort to employ
more synthetically versatile functionality, we employed the
ester-substituted pyrone 1 f, but were disappointed to find
that the cycloaddition failed in this case (entry 5). The low
reactivity of 1 f provides additional evidence for a directing
group promoted reaction, as this very electron-deficient
pyrone would be expected to be more reactive than the
dienes 1a–e in inverse electron demand cycloadditions. In
contrast to 1 f, the corresponding amide in 1g was found to be
a very effective directing group, thus providing the aromatic
borane 9 in high yield (entry 6). The amide directing group is
generally very effective and we highlighted the scope of this
specific substrate in the rapid cycloaddition of a small series of
alkynes (entries 7–9). Moreover, the amide-directed reaction
can be extended to include pyrone substrates bearing
electron-donating substituents which would be expected to
retard the cycloaddition process (entry 10).
[a] The reactions were conducted using 3 equiv of alkyne and 3 equiv of
BF3.OEt2 at 408C over a period of 10 min. [b] Yield of isolated product.
proceeded smoothly under standard reaction conditions to
give the appropriate products in good yield.
The products highlighted in Table 2 that are generated by
this methodology can be considered to be stable Lewis acid
activated electrophiles. This classification suggests the intri-
guing possibility that different reactivity profiles might be
uncovered at these positions. In the context of the present
study, we were particularly interested in the amides present in
compounds 9–12. Specifically, amides are typically unreactive
towards reduction by mild hydride sources unless activated by
external Lewis acids,[15] so this transformation appeared to be
ideal for establishing the activating effects of the ArBF2
moiety. Indeed, treatment of 9 with sodium borohydride did
result in reduction of the carbonyl group (17; Scheme 5). To
The potential of these complexes to undergo additional
organic synthesis was next explored and we subjected
compound 9 to a selection of representative organoboron
transformations. Specifically, as highlighted in Scheme 4,
oxidation to the corresponding phenol 14, cross-coupling to
biaryl product 15, and conversion into the azido product 16 all
Angew. Chem. Int. Ed. 2012, 51, 6402 –6405
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 6403

.
Angewandte
Communications
Experimental Section
Typical cycloaddition procedure, as exemplified by the formation of
3a: BF3.OEt2 (0.22 mL, 1.71 mmol) was added dropwise to pyran-2-
one 1a (98 mg, 0.57 mmol), and potassium alkynyltrifluoroborate 2a
(356 mg, 1.71 mmol) in dichloromethane (5 mL) at 408C over
a period of 5 min under nitrogen. The resulting solution was stirred
at 408C for 10 min. The reaction mixture was cooled to room
temperature, diluted with CH2Cl2 (10 mL), and washed with saturated
aqueous sodium bicarbonate (20 mL). The organic layer was dried
over MgSO4, filtered, and evaporated, and the crude product was
purified by flash silica chromatography (elution gradient 10 to 100%
ethyl acetate in petrol) to provide 3a as a colorless solid: (128 mg,
82%). Mp 196–1988C; 1H NMR (250 MHz, CDCl3): d = 7.33–7.57
(5H, m), 7.63 (1H, dd, J = 1.0, 7.5 Hz), 7.74 (1H, dd, J = 0.5, 7.0 Hz),
7.85 (2H, m), 7.95 (1H, d, J = 8.0 Hz), 8.14 (1H, dt, J = 1.5, 8.0 Hz),
8.54 ppm (1H, d, J = 5.5 Hz); 13C NMR (100 MHz, CDCl3): d = 118.0,
120.5, 123.5, 127.5, 128.5 (ꢀ 2), 129.5, 132.5, 137.0, 141.5, 142.0, 143.5,
146.0, 156.0 ppm; 19F NMR (235 MHz, CDCl3): d = À155.7 ppm;
FTIR: n˜ = 2922 (w), 1623 (m), 1076 (s), 766 cmÀ1 (s). HRMS
calculated for C17H12BF2N (ES +): m/z 280.1109, found: 280.1097.
Scheme 4. Representative reactions of compound 9. DME=1,2-dime-
thoxyethane.
our delight, this transformation provided direct formation of
the corresponding benzoxaboroles. Benzoxaboroles are an
exciting class of organoboron compounds which have recently
emerged as potential therapeutic targets because of their
Received: February 2, 2012
Published online: May 16, 2012
Keywords: boron · cross-coupling · cycloaddition · heterocycles ·
.
synthetic methods
[1] For recent reviews, see: a) S. Saito, Y. Yao, Chem. Rev. 2000, 100,
2901; b) M. Rubin, A. W. Sromek, V. Gevorgyan, Synlett 2003,
2265; c) D. M. D’Souza, T. J. J. Mꢁller, Chem. Soc. Rev. 2007, 36,
1095.
[2] a) J. E. Moore, M. W. Davies, K. M. Goodenough, R. A. J.
Wybrow, M. York, C. N. Johnson, J. P. A. Harrity, Tetrahedron
2005, 61, 6707; b) M. D. Helm, J. E. Moore, A. Plant, J. P. A.
Harrity, Angew. Chem. 2005, 117, 3957; Angew. Chem. Int. Ed.
2005, 44, 3889; c) J. E. Moore, M. York, J. P. A. Harrity, Synlett
2005, 860; d) P. M. Delaney, J. E. Moore, J. P. A. Harrity, Chem.
Commun. 2006, 3323; e) D. L. Browne, J. F. Vivat, A. Plant, E.
Gomez-Bengoa, J. P. A. Harrity, J. Am. Chem. Soc. 2009, 131,
7762; f) J. Huang, S. J. F. Macdonald, J. P. A. Harrity, Chem.
Commun. 2009, 436.
[3] a) V. Gandon, D. Leboeuf, S. Amslinger, K. P. C. Vollhardt, M.
Malacria, C. Aubert, Angew. Chem. 2005, 117, 7276; Angew.
Chem. Int. Ed. 2005, 44, 7114; b) G. Hilt, K. I. Smolko, Angew.
Chem. 2003, 115, 2901; Angew. Chem. Int. Ed. 2003, 42, 2795;
c) Y. Yamamoto, J.-i. Ishii, H. Nishiyama, K. Itoh, J. Am. Chem.
Soc. 2004, 126, 3712; d) A.-L. Auvinet, J. P. A. Harrity, G. Hilt, J.
Org. Chem. 2010, 75, 3893; e) A.-L. Auvinet, J. P. A. Harrity,
Angew. Chem. 2011, 123, 2821; Angew. Chem. Int. Ed. 2011, 50,
2769.
[4] P. M. Delaney, D. L. Browne, H. Adams, A. Plant, J. P. A.
Harrity, Tetrahedron 2008, 64, 866.
[5] For a review of substrate directed reactions, see: A. H. Hoveyda,
D. A. Evans, G. C. Fu, Chem. Rev. 1993, 93, 1307.
Scheme 5. Synthesis of benzoxaboroles.
excellent physiochemical and biological properties.[16] As
shown in Scheme 5, this present method represents a new
approach to these compounds that facilitates the introduction
of substituents adjacent to boron on the benzene ring (17–19).
In conclusion, we report a substrate-directed alkyne/2-
pyrone [4+2] process that exhibits significant rate enhance-
ments over traditional thermal techniques (typically > 1408C,
> 16 h to 408C, 10 min). Moreover, the directing groups can
be synthetically useful motifs such as pyridines, azoles, or
amides. As well as providing a mild method for benzene ring
synthesis, the products have been shown to be amenable to
[6] J. F. Vivat, H. Adams, J. P. A. Harrity, Org. Lett. 2010, 12, 160.
[7] K. Afarinkia, T. D. Nelson, M. V. Vinader, G. H. Posner,
Tetrahedron 1992, 48, 9111.
À
À
À
[8] A. Reed, C. Schilling, R. Tarvin, T. Rettig, J. Stille, J. Org. Chem.
1969, 34, 2188.
[9] For early studies on boron-tethered intramolecular Diels – Alder
cycloadditions of 2-pyrones, see: K. Narasaka, S. Shimada, K.
Osoda, N. Iwasawa, Synthesis 1991, 1171.
additional functionalization through C O, C C, and C N
bond-forming reactions, and represent new precursors to
benzoxaboroles, a class of organic boron compounds receiv-
ing significant attention as new small-molecule therapeutics.
[10] For Lewis base directed arene borylation, see: a) S. Kawamorita,
H. Ohmiya, K. Hara, A. Fukuoka, M. Sawamura, J. Am. Chem.
Soc. 2009, 131, 5058; b) K. Yamazaki, S. Kawamorita, H.
6404 www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 6402 –6405

Angewandte
Chemie
Ohmiya, M. Sawamura, Org. Lett. 2010, 12, 3978; c) S. Kawa-
morita, T. Miyazaki, H. Ohmiya, T. Iwai, M. Sawamura, J. Am.
Chem. Soc. 2011, 133, 19310; d) A. Ros, B. Estepa, R. Lꢂpez-
Rodrꢃguez, E. ꢄlvarez, R. Fernꢅndez, J. M. Lassaletta, Angew.
Chem. 2011, 123, 11928; Angew. Chem. Int. Ed. 2011, 50, 11724.
[11] For the Lewis acid assisted formation of difluoroboranes from
trifluoroborate salts, see: E. Vedejs, R. W. Chapman, S. C. Fields,
S. Lin, M. R. Schrimpf, J. Org. Chem. 1995, 60, 3020.
[12] E. C. Ashby, W. E. Foster, J. Org. Chem. 1964, 29, 3225; M. J.
Bayer, H. Pritzkow, W. Siebert, Eur. J. Inorg. Chem. 2002, 2069.
[13] Addition of pyridine to in situ generated alkynyldifluoroborane
followed by 1a provides an approximately 1:1:1 ratio of 3a,b,c,
together with an additional product which is consistent with
a pyridine triphenylethynyl/borane complex. See the Supporting
Information for details.
[14] For recent reports of amine-complexed difluoroboranes, see:
a) R. L. Giles, J. A. K. Howard, L. G. F. Patrick, M. R. Probert,
G. E. Smith, A. Whiting, J. Organomet. Chem. 2003, 680, 257;
b) S. W. Coghlan, R. L. Giles, J. A. K. Howard, L. G. F. Patrick,
M. R. Probert, G. E. Smith, A. Whiting, J. Organomet. Chem.
2005, 690, 4784; c) R. Luisi, A. Giovine, S. Florio, Chem. Eur. J.
2010, 16, 2683.
[15] For recent studies and leading reference, see: a) S. H. Xiang, J.
Xu, H.-Q. Yuan, P.-Q. Huang, Synlett 2010, 1829; b) G. Barbe,
A. B. Charette, J. Am. Chem. Soc. 2008, 130, 18.
[16] F. L. Rock, W. Mao, A. Yaremchuk, M. Tukalo, T. Crepin, H.
Zhou, Y.-K. Zhang, V. Hernandez, T. Akame, S. J. Baker, J. J.
Plattner, L. Shapiro, S. A. Martinis, S. J. Benkovic, S. Cusack,
M. R. K. Alley, Science 2007, 316, 1759.
Angew. Chem. Int. Ed. 2012, 51, 6402 –6405
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 6405