Cyclic alkenyl boronic half acid synthesis and applications

Article abstract of DOI:10.1021/jo1003423

The synthesis of cyclic alkenyl boronic half acids from vinyl and propenyl boronic esters and homoallylic alcohols by ring-closing metathesis is reported. The method is compatible with both conventional and microwave heating and comparable yields are obta

Full text of DOI:10.1021/jo1003423

pubs.acs.org/joc
accessing disubstituted and trisubstituted alkenylboronates
Cyclic Alkenyl Boronic Half Acid Synthesis
and Applications
from simple monosubstituted and disubstituted alkenyl
boronates.8 Marciniec and co-workers reported a comple-
mentary process for the preparation of di- and trisubstituted
alkenyl boronates by the transfer of a boryl group [B(OR)2]
from one alkene to another (trans-borylation) using a ruthe-
nium hydride catalyst.9
LuAnne McNulty,* Kris Kohlbacher, Katie Borin,
Bryan Dodd, Jeni Bishop, Lindsey Fuller, and Zach Wright
Butler University, 4600 Sunset Avenue, Indianapolis,
Indiana 46208
Limited reports of di- and trisubstituted cyclic boronic half
acids exist.10 In previously reported cross-couplings of this
type of cyclic boronic ester, reactions occur at the carbon-
boron bond, which results in the liberation of a tethered
alcohol that could be used for further transformations.11
Due to the stereospecificity of the Suzuki-Miyaura reaction,
the double bond geometry is retained, which in the case
of simple cyclic alkenyl boronic acids leads to cis-olefins,
which are challenging to make by other methods.7 Thus far,
the Suzuki-Miyaura reaction of cyclic alkenyl boronic half
acids has been limited to the preparation of R,β-unsaturated
carbonyl compounds.10d
lmcnulty@butler.edu
Received February 23, 2010
In this communication, we report the synthesis of mono-
substituted cyclic alkenyl boronic half acids, or oxaborinenes,
through ring-closing metathesis of acyclic alkenyl boronic
esters with homoallylic alcohols. In addition, we expand the
utility of the cyclic alkenyl boronic half acids in Suzuki cross-
coupling reactions. This work represents a new way to access
disubstituted cis-alkenes through cross-metathesis, which is
known to provide predominately trans- or E-alkenes.12
An initial study was undertaken to establish the optimal
conditions for the transesterification of vinyl boronic acid
dibutyl ester with homoallylic alcohols followed by ring-
closing metathesis to yield cyclic alkenyl boronic half acids.
On the basis of previous work, an acyclic alkynyl boronic
ester or an acyclic allyl boronic ester was needed.10a,b Thus,
1-phenyl-1,5-hexadien-3-ol 1 and vinyl boronic acid dibutyl
ester were allowed to react with varied catalyst, solvent, and
heating methods (eq 1). The two commercially available
Grubbs catalysts were tested in dichloromethane (DCM)
and toluene under both conventional heating and microwave
heating conditions.
The synthesis of cyclic alkenyl boronic half acids from
vinyl and propenyl boronic esters and homoallylic alco-
hols by ring-closing metathesis is reported. The method
is compatible with both conventional and microwave
heating and comparable yields are obtained under both
conditions. The cyclic alkenyl boronic acids participate in
Suzuki-Miyaura coupling reactions in good yields.
The utility of alkenyl boronic acids and esters in organic
synthesis is well established. Alkenyl boronates are versatile
substrates, which are converted to aldehydes,1 ketones,1
amines,1 halides,2 and the corresponding alkenes.3 The
stereospecific Suzuki-Miyaura cross-coupling reaction of
the boronic acid or ester with aryl, vinyl, or alkyl halides
results in the conversion of the boronate to aryl, vinyl, or
alkyl groups.
A variety of well-established methods exist for the forma-
tion of alkenyl boronic acids and esters.5-7 Recently, cross-
metathesis of alkenes has emerged as a new method of
(1) Rangaishenvi, M. V.; Singaram, B.; Brown, H. C. J. Org. Chem. 1991,
56, 3286–3294.
(2) (a) Brown, H. C.; Hamaoka, T.; Ravindran, N. J. Am. Chem. Soc.
1973, 95, 6456–6457. (b) Brown, H. C.; Hamaoka, T.; Ravindran, N. J. Am.
Chem. Soc. 1973, 95, 5786–5788.
(3) Brown, H. C.; Campbell, J. B. Aldrichimica Acta 1981, 14, 3–11.
(4) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
(5) Matteson, D. S. In The Chemistry of the Metal-Carbon Bond;
Hartley, F., Patai, S., Eds.; J. Wiley: New York, 1987; Vol. 4, p 307.
(6) Srebnik, M.; Bhat, N. G.; Brown, H. C. Tetrahedron Lett. 1988, 29,
2635–2638.
(7) (a) Brown, H. C.; Bhat, N. G.; Somayaji, V. Organometallics 1983, 2,
1311–1316. (b) Beletskaya, I.; Pelter, A. Tetrahedron 1997, 53, 4957–5026. (c)
Brown, H. C.; Zweifel, G. J. Am. Chem. Soc. 1961, 83, 3834–3840. (d) Lane,
C. F.; Kabalka, G. W. Tetrahedron 1976, 32, 981–990.
(8) (a) Renaud, J.; Ouellet, S. G. J. Am. Chem. Soc. 1998, 120, 7995–7996.
(b) Morrill, C.; Grubbs, R. H. J. Org. Chem. 2003, 68, 6031–6034. (c) Morrill,
C.; Funk, T. W.; Grubbs, R. H. Tetrahedron Lett. 2004, 45, 7733–7736. (d)
Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900–1923.
The results shown in Table 1 indicate that the optimal
conditions involve ring closing under conventional heating
(9) Marciniec, B.; Jankowska, J.; Pietraszuk, C. Chem. Commun. 2005,
663–665.
(10) (a) Micalizio, G. C.; Schreiber, S. L. Angew. Chem., Int. Ed. 2002, 41,
152–154. (b) Micalizio, G. C.; Schreiber, S. L. Angew. Chem., Int. Ed. 2002,
41, 3272–3276. (c) Jernelius, J. A.; Schrock, R. R.; Hoveyda, A. H. Tetra-
hedron 2004, 60, 7345–7351. (d) Hansen, E. C.; Lee, D. J. Am. Chem. Soc.
2006, 128, 8142–8143.
(11) (a) Oh-e., T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201–
2207. (b) Falck, J. R.; Bondlela, M.; Venkataraman, S. K.; Srivnivas, D. J.
Org. Chem. 2001, 66, 7148–7150.
(12) Blackwell, H. E.; O’Leary, D. J.; Chatterjee, A. K.; Washenfelder,
R. A.; Bussmann, D. A.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 58–71.
DOI: 10.1021/jo1003423
r
Published on Web 08/11/2010
J. Org. Chem. 2010, 75, 6001–6004 6001
2010 American Chemical Society

McNulty et al.
JOCNote
TABLE 1. Optimization of Conditions for Cyclic Alkenyl Boronic
Acids
TABLE 2. Scope of the Alkenyl Boronic Half Acids
entry
catalyst
heat
solvent
yield, %
1
2
3
4
5
6
7
8
3
3
3
3
4
4
4
4
reflux
reflux
mw
toluene
CH2Cl2
toluenea
CH2Cl2
toluene
CH2Cl2
toluene
CH2Cl2
33
62
58
58
25
21
37
44
b
mw
reflux
reflux
mw
mw
aMicrowave conditions for reactions run in toluene: 150 W, 100 °C,
200 psi, 4 h. bMicrowave conditions for reactions run in methylene
chloride: 150 W, 90 °C, 200 psi, 4 h.
FIGURE 1. Metathesis catalysts.
in DCM with bis(tricyclohexylphosphine)benzylideneru-
thenium(IV) chloride (Grubbs first generation catalyst) 3
(Figure 1). In most cases, toluene is not as effective as DCM
as a solvent. Microwave conditions yield comparable results
in DCM with catalyst 3. Previous work reported by Schrei-
ber and Micalizio indicates that 1,3-bis(2,4,6-trimethyl-
phenyl)-2-imidazolidynylidene)(dichlorophenylmethylene)-
(tricyclohexylphosphine)ruthenium 4(Grubbs second generation
catalyst) was optimal for the ring-closing metathesis of both
allyl boronic esters and alkynyl boronic esters with unsatu-
rated alcohols.10a,b The reaction timefor conventional heating
is 24 h versus 4 h under the microwave conditions.
The proposed reaction sequence for the formation of the
cyclic half acids involves the transesterification of the boro-
nic acid dibutyl ester, followed by ring-closing metathesis.10a,b
Although cross metathesis of alkenes generally provides the
trans-alkene, in this reaction, the cyclic boronic half acid 7
with the cis-alkene is formed exclusively under the reaction
conditions. It is likely that transesterification of the alcohol
with the vinyl boronic acid to form mixed boronic ester 6
occurs prior to ring-closing metathesis, which delivers the
observed selectivity for the cis-alkene. Proton NMR analysis
of the product supports the structure of the boronic half acid
product 7. Coupling constants of the vinyl protons in trans-
alkenyl boronic esters are around 18 Hz, while the coupling
constants of the alkenyl protons in the half boronic acids are
close to 12 Hz.
aConditions: alcohol (1 equiv), vinyl boronic acid dibutyl ester
(2 equiv), catalyst 3 (10 mol %), CH2Cl2 (0.1 M). bConditions: alcohol
(1 equiv), propenyl boronic acid diisopropyl ester (3 equiv), catalyst 3
(10 mol %), CH2Cl2 (1 M). cPropenyl boronic acid isolated prior to
esterification.
boronates used the propenyl boronic acid pinacol ester,
which will not undergo transesterification. Thus, we pre-
pared 1-propene-1-boronic acid by a modified procedure,
and then esterified the acid with isopropyl alcohol in hex-
anes. The modified procedure eliminated the need for cryo-
genics, prevented the use of the carcinogenic benzene since
hexanes and water form an azeotrope with similar qualities
to benzene and water,13 and allowed the easy removal of
hexanes. The propenyl boronic acid diisopropyl ester was
generated and used without purification.
The scope of the method is demonstrated with a variety of
alkyl, aryl, and alkenyl homoallylic alcohols. As shown in
Table 2, the yields of the aryl-substituted alcohols are slightly
higher than those of the alkyl-substituted alcohols. The use
of propargylic homoallylic alcohol 18, entry 7, led to a
separable 1:1 mixture of two products, which accounts for
the low isolated yield of the desired boronic acid.
Due to the expense of vinyl boronic acid dibutyl ester
(>$100 per 5 g) and the challenge of preparing vinyl boronic
acid due to its ready polymerization, we explored the possi-
bility of using a propenyl boronic acid ester as a more cost-
effective alternative in the formation of the cyclic alkenyl
boronic half acids. The previously reported use of propenyl
The use of the propenyl boronic acid diisopropyl ester in
place of vinyl boronic acid dibutyl ester resulted in the for-
mation of the desired cyclic alkenyl boronic half acids with
yields of the desired acids comparable to those of previous
work. On the basis of the comparability of the conventional
heating and microwave heating in the initial study, the
application of the propenyl boronate was tested in a micro-
wave to determine the feasibility of using the microwave for
(13) At 62 °C, 94% hexane, 6% water and at 69 °C 91% benzene, 9%
water, respectively. Gordon, A. J.; Ford, R. A. The Chemist’s Companion. A
Handbook of Practical Data, Techniques, and References; Wiley-Inter-
science: New York, 1972; pp 25-29.
6002 J. Org. Chem. Vol. 75, No. 17, 2010

McNulty et al.
JOCNote
TABLE 3. Suzuki Coupling of Cinnamyl Oxaborinene or 6-(2-Phenyl-
ethenyl)-2-hydroxy-1,2-oxaborin-3-enea
trienoate 20 undergoes isomerization after extended periods of
time. The phenyl- and nitrophenyl-substituted Z-alkenes 22
and 24, respectively, are stable indefinitely (Table 3). However,
thiazole product 23 decomposes in air. The reactions of the
liberated alcohol are being explored currently.
In conclusion, the synthesis of cyclic alkenyl boronic half
acids has been reported. Conventional and microwave heat-
ing are effective for the formation of these boronic acids from
homoallylic alcohols and alkenyl or propenyl boronic esters
with Grubb’s first generation catalyst. These substrates
undergo Suzuki coupling reactions to create new carbon-
carbon bonds and release an alcohol functional group that
can be further functionalized. Additional results in terms of
the Suzuki coupling reactions are forthcoming.
Experimental Section
General Procedure for Cyclic Vinyl Boronic Half Acid Synthesis.
To a round-bottomed flask charged with dry dichloromethane
was added Grubbs catalyst 3 (10 mol %). The stirred solution was
degassed with N2 for 3 min, then the alcohol (1.0 equiv) and vinyl
boronic acid dibutyl ester (2.0-3.0 equiv) were added. The
solution was degassed for another 3 min, then the stirred solution
was heated to reflux for 24 h. After 24 h, the solution was allowed
to cool to room temperature and then concentrated by rotary
evaporation. The dark oil was purified by flash column chroma-
tography beginning with 10% ethyl acetate-90% hexanes and
ending with 20% ethyl acetate-80% hexanes.
6-(2-Phenylethenyl)-2-hydroxy-1,2-oxaborin-3-ene (2): IR (ν,
1
cm-1) 3406, 3025, 2926, 1604, 1494, 1408; H NMR (CDCl3,
ppm) δ 7.39-7.19 (m, 5H), 6.9 (br d, J = 12.75 Hz, 1H), 6.6 (d,
J = 16 Hz, 1H), 6.3 (dd, J = 16 Hz, 6 Hz, 1H), 5.7 (d, J = 12 Hz,
1H), 4.8-4.71 (m, 1H), 4.14 (br s, 1H), 2.49-2.27 (m, 2H); 13C
NMR δ (ppm) 151, 133, 132, 128, 127, 125, 74, 35; HRMS (EI)
[M]þ calcd for C12H13BO2 200.1003, found 200.1010.
6-Phenyl-2-hydroxy-1,2-oxaborin-3-ene (9): IR (ν, cm-1) 3215
1
(m), 3064, 3027, 2958, 2927, 2871, 1603, 1417, 1350, 1322; H
aConditions: 6-cinnamyloxaborole (1 equiv), halide (1 equiv), Pd-
(PPh3)4 (1 equiv), Cs2CO3 (1 equiv), THF, 90 °C, 30 min, 100 W.
bConditions: 6-cinnamyloxaborole, halide, Pd(OAc)2, BINAP, aqueous
NaOH, THF.
NMR (CDCl3, ppm) δ 7.32-7.19 (m, 5H), 6.94-6.89 (m, 1H),
5.8 (d, J = 11.25 Hz, 1H), 5.11-5.04 (m, 1H), 4.06 (s, 1H),
2.48-2.37 (m, 2H); 13C NMR (CDCl3, ppm) δ 151, 128, 127,
125, 76, 38; HRMS (EI) [M]þ calcd for C10H11BO2 174.0847,
found 174.0852.
6-Furyl-2-hydroxy-1,2-oxaborin-3-ene (11): IR (ν, cm-1
)
the cyclic boronic acid synthesis. The microwave also was
used for the convenience of the shorter reactions.
3218, 2957, 2925, 2855, 1732, 1606, 1463, 1416, 1378, 1317; 1H
NMR (CDCl3, ppm) δ 7.37 (d, 1H, J = 4.75 Hz), 6.93 (br d, 1H,
J = 12.25), 6.33 (d, 1H, J = 1.75 Hz), 6.28 (d, 1H, J = 3 Hz),
5.76 (dd, 1H, J = 2 Hz, 12.25 Hz), 5.14 (dd, 1H, J = 4.5 Hz, 11
Hz), 4.39 (s, 1H), 2.8-2.45 (m, 2H); 13C NMR (CDCl3, ppm) δ
151, 142, 110, 107, 68, 33; HRMS (EI) [M]þ calcd for C8H9BO3
164.0639, found 164.0636.
In certain cases, a small amount of an inseparable by-
product was formed, which required the isolation of prope-
nyl boronic acid prior to formation of the isopropyl boronic
ester. The slightly lower yields relative to the studies with the
commercially available vinyl boronic acid dibutyl ester can
be attributed to impure propenyl boronic acid. The use of the
propenyl boronate ester starting material allowed the for-
mation of a single cyclic boronic acid from the propargyl-
substituted starting material 18.
The cyclic boronic half acids are good substrates for Suzuki
coupling reactions. These boronic half acids offer advantages
in the Suzuki reaction allowing for the formation of a new
carbon-carbon bond, liberating a masked alcohol functional
group and maintaining the cis-double bond geometry.
The Suzuki-Miyaura reactions were conducted in the
microwave for 30 min at 90 °C and 100 W with Pd(PPh3)4 as
the catalyst and cesium carbonate as the base. Both alkenyl
and aryl halides were suitable electrophiles for the cross-
coupling reactions. The use of ethyl cis-3-iodoacrylate10d and
ethyl trans-3-iodoacrylate as electrophiles allowed the genera-
tion of conjugated Z,Z- and Z,E-dienoates. Conjugated
6-Cyclohexyl-2-hydroxy-1,2-oxaborin-3-ene (13): IR (ν, cm-1
)
1
3396, 3210, 3019, 2925, 2852, 1605, 1506, 1448, 1412, 1320; H
NMR (CDCl3, ppm) δ 6.9 (br d, 1H, J = 11.8 Hz), 5.66 (d, 1H,
J = 12 Hz), 3.89 (s, 1H), 3.79 (q, 1H, J = 7.3 Hz), 2.2-2.15 (m,
2H), 1.9-0.9 (m, 11H); 13C NMR (CDCl3, ppm) δ 152, 149, 78,
43, 32, 29, 26, 25; HRMS (EI) [M]þ calcd for C10H17BO2
180.1316, found 180.1321.
6-Hexyl-2-hydroxy-1,2-oxaborin-3-ene(15): IR (ν, cm-1) 3211,
3020, 2956, 2857, 1605, 1410, 1320; 1H NMR (CDCl3, ppm) δ 6.8
(d, 1H), 5.62 (d, 1H, J = 10 Hz), 3.98 (s, 1H), 2.18-2.06 (m, 2H),
1.6-1.3 (m, 10H), 0.83-0.79 (m, 3H); 13C NMR (CDCl3, ppm) δ
151, 74, 38, 36, 33, 30, 29, 26, 23, 14; HRMS (EI) [M]þ calcd for
C10H19BO2 182.1473, found 182.1470.
6-(1-Pentenyl)-2-hydroxy-1,2-oxaborin-3-ene (17): IR (ν, cm-1
)
3211, 2960, 2926, 1605, 1410, 1318, 1260; 1H NMR (CDCl3, ppm)
δ 6.84 (d, 1H, J = 12 Hz), 5.7-5.5 (m, 3H), 4.6-4.45 (m, 1H),
3.98 (s, 1H), 2.28-2.22 (m, 2H), 2.05-1.96 (m, 2H), 1.46-1.32
J. Org. Chem. Vol. 75, No. 17, 2010 6003

McNulty et al.
JOCNote
(m, 2H), 0.9 (t, 3H, J = 7.25 Hz); 13C NMR (CDCl3, ppm) δ 151,
134, 132, 75, 36, 35, 30, 23, 15; HRMS (EI) [M]þ calcd for
C9H15BO2 166.1160, found 166.1167.
borate (40 mmol) was added to 50 mL of anhydrous diethyl
ether in a 500 mL round-bottomed flask equipped with an
addition funnel and submerged in an ice/acetone bath. A 0.5
M solution of propenyl magnesium bromide in THF (50 mmol)
was added to the addition funnel, then added dropwise to the
trimethyl borate solution over 30 min. The solution was allowed
to stir for an hour, then 70 mL of 30% aqueous HCl was added.
The aqueous layer was extracted four times with diethyl ether,
then the combined organic extracts were dried over MgSO4,
filtered, and concentrated until a solid began to form. Hexanes
(50 mL) was added to the round-bottomed flask, then the solid
precipitate was collected by vacuum filtration. The filtrate was
concentrated under vacuum without heat, to provide addi-
tional solid product, which was collected by vacuum filtration.
The solid was rinsed with hexanes. This process was repeated
for a total of five times to provide 2-4 g of propenyl boronic
acid as a mixture of cis- and trans-isomers. The propenyl
boronic acid was esterified with isopropyl alcohol as described
previously.
6-(1-Heptynyl)-2-hydroxy-1,2-oxaborin-3-ene (19): IR (ν, cm-1
)
1
3426, 3023, 2930, 2859, 2239, 1607, 1414, 1352, 1317; H NMR
(CDCl3, ppm) δ 6.85 (br d, 1H, J = 12 Hz), 5.73 (d, 1H, J = 12.25
Hz), 4.84-4.78 (m, 1H), 4.30 (s, 1H), 2.51-2.42 (m, 2H),
2.22-2.16 (m, 2H), 1.52-1.44 (m, 2H), 1.31-1.24 (m, 4H), 0.88
(t, 3H, J = 6.5 Hz); 13C NMR (CDCl3, ppm) δ 150, 86, 65, 35, 32,
28, 23, 18, 14; HRMS (FAB) [M þ H]þ calcd for C11H18BO2
193.1390, found 193.1394 .
Modified Procedure for Propenyl Boronic Acid Diisopropyl
Ester. Trimethyl borate (40 mmol) was added to 50 mL of
anhydrous diethyl ether in a 500 mL round-bottomed flask
equipped with an addition funnel and submerged in an ice/
acetone bath. A 0.5 M solution of propenyl magnesium bromide
in THF (50 mmol) was added to the addition funnel, then added
dropwise to the trimethyl borate solution over 30 min. The
solution was allowed to stir for an hour, then 70 mL of 30%
aqueous HCl was added. The aqueous layer was extracted four
times with diethyl ether, then the combined organic extracts
were dried over MgSO4, filtered, and concentrated until a solid
began to form. Isopropanol (80 mmol) was added along with
100 mL of hexanes. The round-bottomed flask was equipped
with a Dean-Stark trap, then the solution was heated to reflux.
When no additional water was generated, the solution was
concentrated under reduced pressure to provide impure prope-
nyl boronic acid diisopropyl ester, which was used for cyclic
alkenyl boronic half acid preparation.
Acknowledgment. We would like to acknowledge the
NSF for their generous financial support (CHE 0704050).
The authors thank Jonathon Karty of the IU Mass Spectro-
metry Facility for the HRMS data and Stacy O’Reilly of
Butler University for help with the preparation of this
paper.
Supporting Information Available: General methods, gen-
eral procedure for Suzuki couplings, spectroscopic data for
20-24, and copies of NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
Modified Procedure for Propenyl Boronic Acid Diisopropyl
Ester with Isolation of Solid Propenyl Boronic Acid. Trimethyl
6004 J. Org. Chem. Vol. 75, No. 17, 2010