Bromo-boronolactonization of olefins

Article abstract of DOI:10.1021/jo015838z

Exposure of a variety of mono- and disubstituted ortho-alkenylarylboronic acids to NBS in THF/H₂O under neutral conditions affords bromo-boronolactones, in some instances, with exceptional regiocontrol. The adducts, analogous to those formed by carboxylic acids, are shown to be useful synthetic intermediates.

Full text of DOI:10.1021/jo015838z

7148
J . Org. Chem. 2001, 66, 7148-7150
Br om o-Bor on ola cton iza tion of Olefin s1
J . R. Falck,* Muralidhar Bondlela, Sylesh K. Venkataraman, and Dale Srinivas
Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center,
Dallas, Texas 75390-9038
j.falck@utsouthwestern.edu
Received J une 14, 2001
Exposure of a variety of mono- and disubstituted ortho-alkenylarylboronic acids to NBS in THF/
H2O under neutral conditions affords bromo-boronolactones, in some instances, with exceptional
regiocontrol. The adducts, analogous to those formed by carboxylic acids, are shown to be useful
synthetic intermediates.
Sch em e 1
In tr od u ction
Boronic acids are widely known for their facile trans-
esterification, even with comparatively hindered alco-
hols.2 In particular, their proclivity for binding and
discrimination among polyols has found numerous ap-
plications in carbohydrate and analytical chemistry.3
They have also emerged as versatile intermediates for a
variety of cross-couplings4 with organic electrophiles
largely as a consequence of their low toxicity, ease of
preparation, and stability. More recently, considerable
attention has been focused on alternative modes of
reactivity for boronic acids and on extending their
synthetic utility.5 Herein, we report the facile formation
of bromo-boronolactones via exposure of ortho-alkenyl-
arylboronic acids to N-bromosuccinimide (NBS) in THF/
H2O (eq 1). The overall process provides opportunities
conditions at 0 °C, however, bromo-boronolactonization
predominates. The best yields are obtained in THF/H2O
rather than in THF or MeOH alone; NBS is preferable
to Br2. As anticipated for a styrenyl olefin,9 annulation
of boronic acid 1 proceeds in a Markovnikov sense to give
lactone 2 (entry 1) as the exclusive isomer in good yield.
This structure assignment was confirmed by transesteri-
fication of 2 with pinanediol and acetylation to give 20,
whose 1H NMR revealed a one proton doublet of doublets
at 6.67 ppm, consistent with a benzylic acetate. Likewise,
the 1,2- and 1,1-disubstituted styrenes 3 and 5 gave rise
to γ-lactones 4 (entry 2) and 6 (entry 3), respectively. The
presence of an electron-donating group on the aryl ring
improves the closure to lactone, as in the transformation
of 7 to 8 (entry 4), compared with unactivated examples
(cf. 1). Markovnikov addition again predominates for the
terminal olefin 9, which affords bromo-boronolactone 10
(entry 5) as the sole product. Adducts 12 and 14, obtained
from boronic acids 1110 (entry 6) and 13 (entry 7),
for regio- and stereochemical control at centers distal to
the boronic acid and introduces a template from which
new synthetic initiatives can be launched. Even though
the first arylboronolactone was prepared in 1957 by
Torssell,6 its structure has only recently been confirmed
spectroscopically,7 and relatively little is known about the
reactivity of this intriguing class of heterocycles.8
(4) (a) Harwood, L. M.; Currie, G. S.; Drew, M. G. B.; Luke, R. W.
A. Chem. Commun. 1996, 1953. (b) Nagata, W.; Okada, K.; Aoki, T.
Synthesis 1979, 365-368. (c) Sakai, M.; Ueda, M.; Miyaura, N. Angew.
Chem., Int. Ed. 1998, 37, 3279-3281. (d) Miyaura, N.; Suzuki, A.
Chem. Rev. 1995, 95, 2457-2483.
(5) Advances in Boron Chemistry; Siebert, W., Ed.; The Royal Society
of Chemistry: Cambridge, 1997.
Resu lts a n d Discu ssion
(6) Torssell, K. Ark. Kemi 1957, 10, 507-511.
Results from the cyclization of some representative
ortho-alkenylarylboronic acids are summarized in Table
1. In contrast to the halolactonization9 of their cognates,
i.e., carboxylic acids, boronic acids undergo preferential
boron-bromine exchange at basic pHs. Under neutral
(7) Zhdankin, V. V.; Persichini, P. J ., III; Zhang, L.; Fix, S.; Kiprof,
P. Tetrahedron Lett. 1999, 40, 6705-6708.
(8) Cummings, W. M.; Cox, C. H.; Snyder, H. R. J . Org. Chem. 1969,
34, 1669-1674. Haynes, R. R.; Snyder, H. R. J . Org. Chem. 1964, 29,
3239-3233.
(9) Reviews: (a) Dowle, M. D.; Davies, D. I. Chem. Soc. Rev. 1979,
171-197. (b) Cardillo, G.; Orena, M. In Stereoselective Synthesis;
Helmchem, G., Hoffmann, R. W., Mulzer, J ., Schaumann, E., Eds.;
Georg Thieme Verlag: New York, 1996; Vol. 8, Chapter 4.6.
(10) Bromohydrin formation using the pinanediol ester of 11 favors
the opposite regioisomer by a 5:1 ratio, presumably as a consequence
of the steric influence of the bulky bicyclic ester.
* Tel: 214-648-2406. Fax: 214-648-6455.
(1) Presented in part at the 219th American Chemical Society
National Meeting, San Francisco, CA, March 26-30, 2000; ORGN
abstract 577.
(2) Boronic acid review: Torssell, K. In Progress in Boron Chemistry;
Steinberg, H., McCloskey, A. L., Eds.: MacMillan Co.: New York, 1964;
Vol. 1, Chapter 9.
(3) (a) Sugihara, J . M.; Bowman, C. M. J . Am. Chem. Soc. 1958, 80,
2443-2446. (b) Yurkevich, A. M.; Kolodkina, I. I.; Varshavskaya, L.
S.; Borodulina-Shvetz, V. I.; Rudakova, I. P.; Preobrazhenski, N. A.
Tetrahedron 1969, 25, 477-484.
10.1021/jo015838z CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/05/2001

Bromo-Boronolactonization of Olefins
Ta ble 1. Br om o-Bor on ola cton iza tion s
J . Org. Chem., Vol. 66, No. 21, 2001 7149
transformed 2 into methyl ether 23 in excellent yield.
Under typical Suzuki conditions, 2 underwent facile
cross-coupling and concomitant ring closure to give epoxy-
biphenyl 24. On the basis of these initial results, we
anticipate halo-boronolactones and related intermediates
will find wide utility in synthesis.
Exp er im en ta l Section
Gen er a l. All experiments were conducted under an argon
atmosphere. Chromatography and routine laboratory proce-
dures were as reported unless otherwise stated.12 NBS was
freshly recrystallized from water. As a consequence of spon-
taneous aggregation and/or anhydride formation by boronic
acids, and to a lesser extent by boronolactones, melting points
and elemental analyses are difficult to reproduce.13 For the
same reason, it was generally necessary to record NMR spectra
in D2O-saturated CDCl3 at concentrations <2 mg/0.6 mL to
obtain first-order spectra. Further structural confirmation was
achieved by (1) conversion of the boronic acids/boronolactones
to the corresponding cyclic esters with pinacol or pinanediol
and/or (2) oxidation to the corresponding phenol with peracid
and peracetylation (vide infra). Pinacolboronate esters were
prepared from arylbromides14 or aryltriflates15 as described.
P r ep a r a tion of Bor on ic Acid s fr om P in a colbor on a te
Ester s. Sodium periodate (1.8 mmol) was added to a room-
temperature solution of pinacolboronate ester (0.6 mmol) in
THF/H2O (4:1, 5 mL). The mixture was stirred until homoge-
neous, and then 2 N HCl (0.2 mL) was added. After 12 h, the
reaction mixture was extracted with ethyl acetate (3 × 10 mL),
and the combined organic extracts were washed with water
and brine, dried (Na2SO4), and concentrated in vacuo. Further
purification was achieved as noted below for the individual
boronic acids.
Gen er a l P r oced u r e for Br om o-Bor on ola cton iza tion .
N-Bromosuccinimide (0.6 mmol) was added portionwise to a
stirring, 0 °C solution of boronic acid (0.5 mmol) in THF/H2O
(4:1, 5 mL). After 6 h, the reaction was diluted with ethyl
acetate (10 mL), washed with water and brine, dried (Na2SO4),
and concentrated in vacuo. The residue was suspended in ether
(5 mL), filtered, and concentrated in vacuo. Chromatographic
purification of the residue [SiO2 PTLC, EtOAc/hexane (1:3)]
afforded the corresponding bromo-boronolactone (see Table 1).
Ch em ica l Ch a r a cter iza tion of Br om o-Bor on ola cton es.
To further confirm their structures, the bromo-boronolactones
in Table 1 were subjected to peracid oxidation and peracety-
lation as follows: m-CPBA (0.24 mmol) was added portionwise
to a 0 °C solution of bromo-boronolactone (0.2 mmol) in
anhydrous CH2Cl2 (5 mL). After 1.5 h, the mixture was di-
luted with an equal volume of water, washed with 10% aque-
ous sodium bicarbonate solution and brine, dried, and con-
centrated in vacuo. Chromatographic purification of the resi-
due [SiO2, EtOAc/hexane (1:3)] afforded the corresponding
phenol (70-80%).
respectively, are more revealing. Their respective threo
and erythro stereochemistries are consistent with the well
established9 halonium ion mechanism of carboxylate
halolactonizations. More significantly, the regiochemical
outcomes are most consistent with the direct interception
of the bromonium intermediate by a nucleophilic boronic
acid. The alternative mechanism of prior bromohydrin
formation followed by lactonization seems highly un-
likely, as evident from the treatment of 21 with NBS
under the same reaction conditions. The latter reaction
is nonselective and yields an almost equal mixture of
bromohydrin regioisomers 22a and b. A somewhat di-
minished but still useful yield of δ-lactone 16 is obtained
from 15, despite the deactivating effect of a para-fluoro
group (entry 8). Even in the case of 17, creation of a
tertiary lactone proceeds smoothly, furnishing an excel-
lent yield of 18 (entry 9). On the other hand, trans-
cinnamate 19 (entry 10) is recovered unchanged even
after extended exposure to NBS. This is in agreement
with the generally sluggish participation of electron-poor
olefins in halolactonizations under similar conditions.11
The synthetic potential of the boronolactones was
briefly auditioned using oxaborol 2 (Scheme 1). Exposure
to excess Me3SiCHN2, followed by removal of all volatiles
Excess acetic anhydride (0.1 mmol) was added dropwise to
a 0 °C solution of the above phenol (0.05 mmol) and anhydrous
(11) For example see, Dalton, D. R.; Dutta, V. P. J . Chem. Soc. B
1971, 85-89. Smietana, M.; Gouverneur, V.; Mioskowski, C. Tetrahe-
dron Lett. 2000, 41, 193-195. However, bromohydrin formation with
R,â-unsaturated carbonyls is highly dependent upon the reaction
parameters and reagents: Guss, C. O.; Rosenthal, R. J . Am. Chem.
Soc. 1955, 77, 2549.
(12) Bhatt, R. K.; Chauhan, K.; Wheelan, P.; Murphy, R. C.; Falck,
J . R. J . Am. Chem. Soc. 1994, 116, 5050-5056.
(13) Torssell, K. Ark. Kemi. 1957, 10, 473-482.
(14) Ishiyama, T.; Murata, T.; Miyaura, N. J . Org. Chem. 1995, 60,
7508-7510.
(15) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett.
1997, 38, 3447-3450.

7150 J . Org. Chem., Vol. 66, No. 21, 2001
Falck et al.
pyridine (0.2 mmol) in dry CH2Cl2 (2 mL). After 3 h, the
mixture was diluted with CH2Cl2 (5 mL), washed with water
and brine, dried, and concentrated in vacuo. Chromatographic
purification of the residue [SiO2, EtOAc/hexane (1:4)] led to
the corresponding peracetylated phenol (80-85%).
Ltd. Elemental analyses were kindly provided by Mr.
Alan Humason, Southern Methodist University. The
authors thank Dr. E. R. Fogel for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and analytical data. This material is available free of
charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. Financial support provided by
the Robert A. Welch Foundation, NIH (GM 31278), and
an unrestricted grant from Taisho Pharmaceutical Co.,
J O015838Z