Investigation of cyclization reactions of dicyclohexyl-6-iodo- and -6-tosylhexenylborane. A facile radical cyclization diverted to a rearrangement-cyclization with base

Article abstract of DOI:10.1021/jo900243q

(Chemical Equation Presented) Dicyclohexyl-6-iodohexenylborane efficiently undergoes radical cyclization at room temperature using tri-n-butyltin hydride as a hydrogen donor and without the aide of a radical initiator. Efforts to develop environmentally f

Full text of DOI:10.1021/jo900243q

Investigation of Cyclization Reactions of Dicyclohexyl-6-iodo- and
-6-tosylhexenylborane. A Facile Radical Cyclization Diverted to a
Rearrangement-Cyclization with Base
Diane M. Hinkens and M. Mark Midland*
Department of Chemistry, UniVersity of California, RiVerside, California 92521
mark.midland@ucr.edu
ReceiVed February 9, 2009
Dicyclohexyl-6-iodohexenylborane efficiently undergoes radical cyclization at room temperature using
tri-n-butyltin hydride as a hydrogen donor and without the aide of a radical initiator. Efforts to develop
environmentally friendly reagents using hypophosphites as substitutes for tin hydrides in this reaction
provided a 60% yield of cyclopentanemethanol when tetrabutylammonium hypophosphite was used. Air
was necessary as an initiator when hypophosphites were used. During investigations of the radical
cyclization reactions, it was discovered that excess tetrabutylammonium hydroxide provided the
rearrangement-cyclization product in excellent yield. Since this product was chiral, efforts were focused
on achieving enantioselectivity. Oxazaborolidines made from chiral amino alcohols and 6-tosyl-1-
hexenylboronic acid were treated with methyllithium to give 1-cyclopentylethanol after oxidation in 60%
ee, demonstrating that oxazaborolidines were effective chiral directors for this reaction.
Introduction
for radical cyclization reactions.3 Matteson’s studies of the
R-boryl radical concluded that extra stability is gained from
electron delocalization of the radical into the empty p-orbital
on boron.4
Vinylboronates have also been used for radical cyclizations.
Batey used a radical cyclization mechanism in the synthesis of
1-3, 1-4, and 1-5 diols.5,6 Carboni used alkenylboronates,7
obtaining good yields of the cyclized pinacolborane as well as
cyclized vinyl 9-BBN. Lee also studied radical cyclizations of
alkenylboronates.8
Radical reactions offer mild conditions and functional
group tolerance and often give different products and have
different selectivity from ionic reactions. The use of vinyl-
organoboranes for radical cyclization processes would provide
an organoborane product useful for further manipulation.1
However, this possibility has not been widely exploited.
Cooke2 in his study of anionic cyclizations of 6-iodohex-
enylboranes considered the possibility of radical involvement.
Using AIBN and Bu3SnH with dimesityl-6-iodohexenylbo-
rane, he obtained 80% yield of the cyclized alkylborane,
demonstrating that R-boryl radicals were effective terminators
(3) Cooke, M. P., Jr.; Widener, R. K. J. Am. Chem. Soc. 1987, 109, 931–
933.
(4) Matteson, D. S. J. Am. Chem. Soc. 1960, 82, 4228–4233.
(5) Batey, R. A.; Smil, D. V. Tetrahedron Lett. 1999, 40, 9183–9187.
(6) Batey, R. A.; Smil, D. V. Angew Chem. Int. Ed. 1999, 38, 1798–1800.
(7) Guennouni, N.; Lhermitte, F.; Cochard, S.; Carboni, B. Tetrahedron 1995,
51, 6999–7018.
(1) Brown, H. C.; Kramer, G. W.; Levy, A. B.; Midland, M. M. Organic
Synthesis Via Boranes; John Wiley & Sons: New York, 1975.
(2) Cooke, M. P., Jr. J. Org. Chem. 1992, 57, 1495–1503.
10.1021/jo900243q CCC: $40.75
Published on Web 05/08/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 4143–4148 4143

Hinkens and Midland
SCHEME 1
FIGURE 1. Hypophosphites used for the radical cyclization reaction.
Results and Discussion
SCHEME 2
Efforts began with optimization of the radical cyclization
reaction shown in Scheme 1.9,10 Applying Cooke’s methodology
(n-Bu3SnH, AIBN, refluxing benzene) to the radical cyclization
of dicyclohexyl-6-iodohexenylborane 1 provided good yields
of cyclopentanemethanol 2 and cyclohexanol after oxidation.
In order to reduce the temperature of the reaction, the use of
oxygen to initiate the reaction was investigated.11 Repeating
the reaction at room temperature with n-Bu3SnH and air at 0.5
mL/min as initiator also gave good yields of alcohol product.
Lower flow rates of air provided similar results. Indeed, the
reaction proceeded smoothly even in the absence of added air
to give yields of 89% 2 and 99% cyclohexanol after 2 h (Scheme
1). Presumably, small traces of air are initiating the reaction as
is the case with the 1,4 addition of organoboranes to acrolein.12
The major drawback to this reaction is the use of the organotin
reagent that is toxic and difficult to remove. There exist several
alternatives to tin hydrogen donors, including silanes, cyclo-
hexadienes, and silylated cyclohexadienes, as well as phosphorus
compounds.13-15 The use of hypophosphites was chosen since
they are nontoxic, cheap, and generally easy to remove from
the reaction mixture (Figure 1).
Ethylpiperidine hypophosphite (EPHP) has been used with
Et3B as a mediator for carbon-carbon bond formation.16 Radical
cyclizations with EPHP include aryl radical cyclizations to
cyclohexenes that proceeded efficiently with 10 equiv of EPHP
to form the expected cis-fused hexahydrocarbazoles17 as well
as efficient cyclizations to a tricyclic compound18 and to
trisubstituted tetrahydrofurans.19 An advantage of EPHP is that
it may be completely removed by washing with 2 M HCl and
then saturated NaHCO3 during the workup procedure.
flow rates of air led to competitive oxidation of the organobo-
rane. The use of triethylborane as a sacrificial organoborane
was of no advantage.20
Other hypophosphites were investigated. Anilinium hypo-
phosphite21 and sodium hypophosphite22 (NaH2PO2) provided
low yields of the desired product. Besides being insoluble, the
anilinium salt protonated the vinylborane giving 6-iodohexene
as the major product.
Tetrabutylammonium hypophosphite 3 (from tetrabutylam-
monium hydroxide and hypophosphorous acid) is soluble in
THF. The reaction was run with and without air in THF, using
2.5 equiv of 3 per mole of the borane. After 2.5 h, the yield of
2 was 60% with 0.2 mL/min of air and 5% without air (2 mmol
reaction). Higher flow rates of air led to lower yields. This
reagent was promising since it was inexpensive, easy to prepare,
and had good solubility in THF and the byproduct precipitated
out during workup.
The effect of excess hypophosphorous acid or tetrabutylam-
monium hydroxide on the reaction was also explored. The acid
could provide the alkene product by protonation of the vinylbo-
rane. Excess base could coordinate with the borane and decrease
its ability to stabilize the R-radical. When excess acid was added,
a slight decrease in the yield of 2 was found, but when excess
base was added, a new product, cyclohexylcyclopentylmethanol
4, was obtained.9,23 Our hypothesis for the mechanism (Scheme
2) is that the hydroxide adds to the boron, forming an ate
complex. Subsequent migration of the cyclohexyl group and
cyclization provides the rearranged organoborane that is oxidized
to 4.
The reaction in Scheme 1 was further investigated, but instead
of tributyltin hydride, EPHP (5 equiv/mol borane) in THF was
used in both the presence and absence of air. For the reactions
with no air, the yields of 2 were low. With 0.5 mL/min of air,
a 2 mmol scale reaction was over in 2.5 h, giving 50% GC
yield. When higher flow rates of air were used, the reaction
was complete in less time but the yields were lower. The higher
A related reaction has been reported by Negishi24 (Scheme 3)
in which the reaction of tosylvinylborane 5 with 1 equiv of
n-butyllithium gave the alkene products 6 and 7. However, the
alcohol 4 was not reported. The reaction in Scheme 3 presumably
proceeds through an ate complex that rearranges with formation
of the cyclopentyl ring. Elimination of the alkene can occur by
loss of n-Bu-c-HexBH from the rearranged organoborane. Presum-
ably, elimination of the alkene from the highly hindered orga-
noborane occurs before oxidation. Other ring-forming or rear-
(8) Lee, E.; Zong, K.; Kang, H. Y.; Lim, J.; Kim, J. Y. Bull. Korean Chem.
Soc. 2000, 21, 765–766.
(9) Hinkens, D. M. Dissertation, University of California, 2006.
(10) Midland, M. M.; Hinkens, D. Abstracts of Papers, 227th ACS National
Meeting, Anaheim, CA, March 28-April 1, 2004; American Chemical Society:
Washington, DC, 2004; ORGN-059.
(11) Ollivier, C.; Renaud, P. Chem. ReV. 2001, 101, 3415–3434.
(12) Brown, H. C.; Rogic, M. M.; Rathke, M. W.; Kabalka, G. W. J. Am.
Chem. Soc. 1967, 89, 5709–5710.
(13) Murphy, J. A. Pure Appl. Chem. 2000, 72, 1327–1334.
(14) Gilbert, B. C.; Parsons, A. F. J. Chem. Soc., Perkin Trans. 2 2002, 367,
387.
(15) Baguley, P. A.; Walton, J. C. Angew. Chem., Int. Ed. 1998, 37, 3072–
3082.
(16) Jang, D. O.; Cho, D. H.; Chung, C.-M. Synlett 2001, 12, 1923–1924.
(17) Martin, C. G.; Murphy, J. A.; Smith, C. R. Tetrahedron Lett. 2000, 41,
1833–1836.
(18) Graham, S. R.; Murphy, J. A.; Coates, D. Tetrahedron Lett. 1999, 40,
2415–2416.
(20) Brown, H. C.; Kabalka, G. W. J. Am. Chem. Soc. 1970, 92, 714.
(21) Deprele, S.; Montchamp, J.-L. J. Organomet. Chem. 2002, 643-644,
154–163.
(22) Deprele, S.; Montchamp, J.-L. J. Org. Chem. 2001, 66, 6745–6755.
(23) Midland, M. M.; Hinkens, D. Abstracts of Papers, 231st ACS National
Meeting, Atlanta, GA, March 26-30, 2006; American Chemical Society:
Washington, DC, 2006; ORGN-328.
(19) Roy, S. C.; Guin, C.; Rana, K. K.; Maiti, G. Tetrahedron 2002, 58,
2435–2439.
(24) Negishi, E.; Nguyen, T.; Boardman, L. D.; Sawada, H.; Morrison, J. A.
Heteroatom Chem. 1992, 3, 293–302.
4144 J. Org. Chem. Vol. 74, No. 11, 2009

Reactions of Dicyclohexyl-6-iodo- and -6-tosylhexenylborane
SCHEME 3
SCHEME 5
SCHEME 4
Methyllithium or methylmagnesium bromide was added
to alkenyl boronic esters made from chiral diol directors to
form an ate complex that would rearrange with cyclization,
providing 1-cyclopentylethanol after oxidation. Vinylboronic
acids were prepared by heating neat catecholborane with
6-iodo- or 6-tosyl-1-hexyne for 1 h at 70 °C followed by
water hydrolysis.32,33 The esters were made by refluxing the
boronic acid with a diol and molecular sieves in ether as
shown for hydrobenzoin in Scheme 5. In addition to
hydrobenzoin, esters were made from diethyl tartrate, pi-
nanediol and pinacol. The esters were filtered thru Celite and
either purified by chromatography or used directly.
It was found that the ethyl ester groups of diethyltartrate
boronic ester preferentially reacted with methyllithium. Also,
methyllithium preferentially exchanged with the iodide on the
iodo boronic esters. For this reason, the tosylate was used for
all future studies.
The best yield was obtained with the hydrobenzoin ester
13, giving 85% GC yield of 1-cyclopentylethanol (14) with
3 equiv of methylmagnesium bromide. However, the product
was racemic as determined by NMR using the chiral shift
reagent, europium tris[3-(heptafluoropropylhydroxymeth-
ylene)-(+)-camphorate] (Eu(hfc)3). These results suggested
that the Grignard or lithium reagent was displacing an
alkoxide from boron, eventually forming the trimethylvi-
nylborate complex that would then undergo cyclization. Since
the chiral auxiliary was displaced, the product would be
racemic, and thus other chiral directors were sought.
Oxazaborolidines were shown by Itsuno in the 1980s to be
chiral catalysts for the borane-mediated enantioselective reduc-
tion of a wide variety of achiral ketones.34 Corey’s studies on
this discovery included defining the structure of Itsuno’s ligand
and the mechanism of the reaction pathway and led to a new
and powerful catalytic version of the original stoichiometric
Itsuno reduction.35,36
rangement reactions have been reported by Brown25 (Scheme 4,
eq 1), Pelter26 (Scheme 4, eq 2), and Corey.27
Further studies of the reaction in Scheme 2 showed that the
use of 2.5 equiv of tetrabutylammonium hydroxide (40 wt. %
solution in water) gave a 92% GC yield (86% isolated yield)
of 4 from 1 after 4 h at room temperature. The reaction was
repeated using the tosylhexenylborane 5. The reaction was much
slower but after 65 h the GC yield of 4 was 80%.
The reaction of sodium methoxide or sodium t-butoxide with
1 provided no 4 after 50 h. With sodium hydroxide, compound
4 slowly formed and after 65 h, the GC yield was 85%.
The rearrangement-cyclization reaction provided 4 in excel-
lent yields, but the product was racemic. In order to obtain
optically active product, a chiral auxiliary would be needed.
This could be a chiral organoborane but one would have to
worry about selective migration of the alkyl groups on boron.
Therefore nonmigrating groups such as found in boronic esters
were investigated.
Boronic esters of chiral diols have been used effectively to
induce high enantiomeric excesses. Matteson used boronic esters
of C2 chiral diols and other chiral diols extensively for
homologation of boronic esters with dichloromethyllithium to
give R-chloroboronic esters.28 The R-chloroboronic ester reac-
tions permit efficient sequential syntheses of two or more
adjacent chiral centers with absolute control of the configuration
of each center while allowing incorporation of a wide variety
of functional and hydrocarbon groups. The synthesis of L-(+)-
ribose via pinanediol is a classic example of this chemistry.29
Many other examples exist.30 Roush found that allylic boronic
esters of diisopropyl tartrate yielded high diasteroselectivity with
chiral aldehydes.31
In general, for the preparation of the B-alkyl- and B-aryl-
substituted oxazaborolidines, a solution of the aminoalcohol and
the corresponding boronic acid were refluxed in toluene for
12-24 h with azeotropic removal of water.37
Vinyl oxazaborolidines were prepared from (S)-2-amino-3-
phenyl-1-propanol or from (S)-prolinol and the vinyl boronic
acid using the Gamsey38 method of refluxing overnight in THF
(25) Brown, H. C.; Rhodes, S. P. J. Am. Chem. Soc. 1969, 91, 4306–4307.
(26) Pelter, A.; Subrahmanyam, C.; Laub, R. J.; Gould, K. J.; Harrison, C. R.
Tetrahedron Lett. 1975, 16, 1633–1636.
(27) Corey, E. J.; Seibel, W. L. Tetrahedron Lett. 1986, 27, 909–910.
(28) Matteson, D. S. Tetrahedron 1989, 45, 1859–1885.
(29) Matteson, D. S.; Peterson, M. L. J. Org. Chem. 1987, 52, 5116–5121.
(30) Matteson, D. S. In Boronic Acids: Preparation and Applications in
Organic Synthesis and Medicine; Hall, D. G., Ed.; Wiley-VCH Verlag GmbH:
Weinheim, 2005; pp 305-340.
(32) Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1975, 97, 5249–5255.
(33) Lane, C. F.; Kabalka, G. W. Tetrahedron 1976, 32, 981–990.
(34) Itsuno, S.; Nakano, M.; Miyazaki, K.; Masuda, H.; Ito, K.; Hirao, A.;
Nakahama, S. J. Chem. Soc., Perkin Trans. 1 1985, 2039, 2044.
(35) Corey, E. J.; Helal, C. J. Angew Chem. Int. Ed. 1998, 37, 1986–2012.
(36) Singh, V. K. Synthesis 1992, 605, 617.
(31) Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc. 1985,
107, 8186–8190.
J. Org. Chem. Vol. 74, No. 11, 2009 4145

Hinkens and Midland
SCHEME 6
as chiral directors were ineffective, giving racemic products.
Oxazaborolidines made from chiral amino alcohols with a
secondary alcohol and secondary amine did provide selectivity.
Using the pseudoephedrine oxazaborolidine 16 with methyl-
lithium, ee’s of 60% were obtained.
Experimental Section
Iodohexyne41 and anilinium hypophosphite21 were prepared from
standard procedures. The airflow apparatus was set up using a
peristaltic pump (Low Flow (II), Model 3385 from Fischer, made
by Control Company), and ambient air was pumped through a
bubbler and into the reaction mixture with a needle attached to
tubing filled with a drying agent. 5-Iodohexyne,41 dicyclohexyl-
6-iodohexenylborane 1,42 and hex-5-yne-1-yl p-toluene-4-sul-
fonate43 were prepared from standard procedures. GC yields were
determined using a Supelco Carbowax-10 column, with dodecane
and pentanol as internal standards.
Dicyclohexyl-1-hexenyl-6-iodoborane (1). The vinylborane was
made according to the standard method:42 Borane-methyl sulfide
complex (BMS) (0.2 mL, 2 mmol) in dry THF (4 mL) was cooled
in an ice/water bath. Cyclohexene (0.42 mL, 4.2 mmol) was added,
the mixture was stirred for 3 h at 0 °C, and a white solid formed.
Then, 1-iodo-5-hexyne (1.04 g, 2.0 mmol) in THF (2 mL) at 0 °C
was added. The ice bath was removed, and the mixture slowly came
to rt while stirring for 1 h. The clear solution was used immediately
“as is”: 1H NMR (300 MHz, CDCl3) δ 6.68 (t,d, J ) 6.2, 17.4 Hz,
dCHCH2), 6.21 (d,t, J ) 17.4, 1.3 Hz, BCHd), 3.21 (t, J ) 7.0
Hz, CH2I), 2.25 (q,d, J ) 7.0, 1.2 Hz, CH2CH), 1.86 (quint, J )
7.2 Hz, 2-H), 1.74 (br d, 6-H), 1.58 (m, 2-H), 1.49 (br d, 4-H,),
1.26 (m, 12-H); 13C NMR (300 MHz, CDCl3) δ 152.8, 133.3 (br),
35.4, 29.6, 26.1, 6.9, 34.5, 27.9, 27.8, 27.4.
over CaH2. However, the amine reacted with the tosylate, and
these oxazaborolidines were easily hydrolyzed.
When (1S,2R)-(+)-2-amino-1,2-diphenylethanol39 was used
to make the oxazaborolidine equivalent 15, and 2 equiv of
MeMgBr was added, a 60% GC yield of (S)-14 with 20% ee
was obtained. Attempts to purify the vinyl oxazaborolidine by
recrystallization or distillation were unsuccessful.
It appeared that a more hindered oxazaborolidine was needed.
Pseudoephedrine was chosen as a suitable and readily available
amino alcohol. The Gamsey38 method at room temperature was
used to make the pseudoephedrine oxazaborolidine 16, and this
greatly reduced the reaction of the amine with the tosylate. A
14% GC yield of 1-cyclopentylethanol was obtained after
addition of 1 equiv of MeMgBr. Since all of the water may not
be removed at room temperature (either by CaH2 or molecular
sieves) due to formation of a hydroxy/amine ate complex (17),40
more drastic methods for water removal were explored. The
standard conditions of distillation with a Dean-Stark trap and
further heating under vacuum were used.37,40 The preparation
of 16 from pseudoephedrine is shown in Scheme 6.
Standard Oxidation Procedure of the Organoborane.1 To 1
mmol of borane was added 3 M NaOH (0.3 mL, 1 mmol), followed
by 30% H2O2 (0.3 mL, 3 mmol) below 40 °C. The mixture was
heated at 50 °C for 1 h. After cooling, ether was added, and solid
K2CO3 was added to remove the aqueous components. The ether/
THF was poured off and washed with brine. The brine was back-
extracted with ether, and the combined organic layers were dried
with K2CO3.
Cyclopentanemethanol (2). To the vinylborane 1 (2 mmol) in
20 mL of THF was added n-Bu3SnH (0.6 mL, 2.2 mmol) and the
mixture stirred at rt for 1 h. Then 3 M NaOH (2.0 mL, 6.0 mmol)
and 30% H2O2 (1.0 mL, 8.9 mmol) were added to oxidize the borane
to obtain 89% of 2. Excess base was used to facilitate removal of
the organotin reagents:44 1H NMR (300 MHz, CDCl3) δ 3.48 (d, J
) 7.03 Hz, 2-H, CH2OH), 2.22 (br s, 1-H, OH), 2.06 (septet, J )
7.47, 1-H, CHCH2OH), 1.71 (m, 2-H), 1.55 (m, 4-H), 1.22 (m,
2-H); 13C NMR (300 MHz, CDCl3) δ 67.4, 42.2, 29.2, 25.6.
Tetrabutylammonium Hypophosphite (3).45 Aqueous tetrabu-
tylammonium hydroxide (40 wt %, 13.625 g, 21 mmol) was added
to a flask containing H3PO2 (50 wt %, 2.788 g, 21 mmol). The pH
was tested with pH paper, and additional drops of either solution
were added until pH 7 was obtained. The water was removed under
vacuum (0.3 mmHg) while warming to 70 °C to obtain white
crystals. The removal of water was completed by freezing with
acetone/CO2 and continued pumping (lyophilization) to afford 100%
This time, 3 equiv of MeLi was added and a 41% yield and
60% ee of (S)-14 was obtained. Thus, the oxazaborolidine from
pseudoephedrine showed promise toward obtaining good enan-
tioselectivities.
Conclusion
In conclusion, the radical cyclization of 1 proceeded smoothly
when n-Bu3SnH was used as a hydrogen donor, even in the
absence of an initiator. The use of hypophosphite alternatives
to the organotin reagent also provided the cyclization product,
although the yields were lower and a radical initiator (oxygen)
was needed. Higher flow rates of air led to competitive oxidation
of the organoborane. Presumably, the chain-carrying steps were
not as efficient for the alternative reagents. During these
investigations, a new reaction was discovered in which adding
excess base to 1 gave excellent yields of the rearrangement-
cyclization product 4. Further studies aimed at the enantiose-
lective synthesis of 14 showed that using chiral boronic esters
1
of a white solid (7.17 g, 21 mmol): H NMR (300 MHz, DMSO-
d6) δ 7.05 (d, J ) 450 Hz, 2-H, PH), 3.18 (t, J ) 8.23, 8-H, CH2N),
(41) Mancini, I.; Cavazza, M.; Guella, G.; Pietra, F. J. Chem. Soc., Perkin
Trans. 1 1994, 2181, 2185.
(37) Mathre, D. J.; Jones, T. K.; Xavier, L. C.; Blacklock, T. J.; Reamer,
R. A.; Mohan, J. J.; Turner Jones, E. T.; Hoogsteen, K.; Baum, M. W.;
Grabowski, E. J. J. J. Org. Chem. 1991, 56, 751–762.
(38) Gamsey, S.; DeLaTorre, K.; Singaram, B. Tetrahedron: Asymmetry 2005,
16, 711–715.
(39) Quallich, G. J.; Woodall, T. M. Tetrahedron Lett. 1993, 34, 4145–4148.
(40) Brown, H. C.; Racherla, U. S.; Pellechia, P. J. J. Org. Chem. 1990, 55,
1868–1874.
(42) Brown, H. C.; Mandal, A. K.; Kulkarni, S. U. J. Org. Chem. 1977, 42,
1392–1398.
(43) Davison, E. C.; Fox, M. E.; Holmes, A. B.; Roughley, S. D.; Smith,
C. J.; Williams, G. M.; Davies, J. E.; Raithby, P. R.; Adams, J. P.; Forbes, I. T.;
Press, N. J.; Thompson, M. J. J. Chem. Soc., Perkin Trans. 1 2002, 1494, 1514.
(44) Renaud, P.; Lacote, E.; Quaranta, L. Tetrahedron Lett. 1998, 39, 2123–
6.
(45) Brigas, A. F.; Johnstone, R. A. W. Tetrahedron 1992, 48, 7735–7746.
4146 J. Org. Chem. Vol. 74, No. 11, 2009

Reactions of Dicyclohexyl-6-iodo- and -6-tosylhexenylborane
1.57 (m, 8-H), 1.31 (sextet, J ) 7.35, 8-H), 0.93 (t, J ) 7.30, 12-
H); 13C NMR (300 MHz, DMSO-d6) δ 57.4, 23.0, 19.1, 13.4; 31P
NMR (300 MHz, DMSO-d6) δ 1.275 (t, JP-H ) 519 Hz).
General Procedure for the Radical Cyclization Using Hypo-
phosphite and Air. The reaction with EPHP is representative. To
a stirred solution of vinylborane 1 (2 mmol) in THF was added
EPHP (1.8 g, 10 mmol), followed by air at 0.5 mL/min for 2.5 h,
after which the mixture was oxidized by the standard procedure,
except after the solid K2CO3 was added, the THF/ether was poured
off and the remainder extracted with 2 M HCl (2 × 5 mL), NaHCO3
(5 mL), and then brine (5 mL). The aqueous layers were back-
extracted with ether (3 mL) at each step, and the combined extracts
were dried with K2CO3 and filtered to give 50% GC yield.
Radical Cyclization Using 3. Hypohosphite 3 (1.5 g, 5 mmol)
was dissolved in 5 mL of THF, and the stirred solution was added
via cannula to 2 mmol of the vinylborane in 5 mL of THF. Air
was added at 0.2 mL/min for 2.5 h, and the solution was oxidized,
providing 60% GC yield of 2.
gel chromatography (1:1 hexane/ethyl acetate) to give (75%) (1.5
g, 5 mmol) of a clear gel, existing as the trimer, (BOR)3, which
was converted to the acid by adding 0.1 mL of water to the flask
1
during storage: H NMR (300 MHz, acetone-d6) δ 7.73 (d, J )
8.30, 2-H, aryl H), 7.44 (d, J ) 8.06, 2-H, aryl H), 6.43 (d,t, J )
17.90, 6.48, 1-H, BCHCH), 5.34 (d,t, J ) 17.82, 1.26, 1-H,
BCHCH), 4.01 (t, J ) 6.32, 2-H, CH2OSO2), 2.39 (s, 3-H, aryl
methyl), 2.00 (q,d, J ) 7.08, 1.31, 2-H, CHCHCH2), 1.58 (m, 2-H),
1.35 (m, 2-H); 13C NMR (300 MHz, acetone-d6) δ 151.8, 146.9,
134.6, 131.7, 129.3, 126.2 (br), 72.5, 36.0, 29.6, 25.6, 22.3.
General Procedure for the Preparation of the 6-Iodohex-
enyl- and 6-Tosylhexenylboronic Esters.46 The preparation of
(4R,5R,E)-2-(6-iodohex-1-enyl)-4,5-diphenyl-1,3,2-dioxaborolane
12 is representative. (R,R)-(+)-Hydrobenzoin (0.39 g, 1.8 mmol),
10 (0.46 g, 1.8 mmol), and 240 mg of 4 Å molecular sieves were
refluxed in 8 mL of dry diethyl ether overnight, after which time
the reaction mixture was filtered through a pad of Celite, washed
1
with ether, and used immediately: H NMR (300 MHz, CDCl3) δ
General Procedure for the Rearrangement-Cyclization
Reaction Using 1 or 3. Tetrabutylammonium hydroxide (40 wt %
solution in water) (8.10 g, 12.5 mmol) was added to 5 mmol of the
vinylborane in 20 mL of THF. After 4 h, it was oxidized by adding
3 M NaOH (1.7 mL, 5 mmol) and then 30% H2O2, (1.7 mL, 15
mmol) at below 40 °C and then heated at 50 °C for 1 h. After
cooling, ether and solid K2CO3 were added to remove the aqueous
components. The ether/THF was poured off, the remainder was
washed with brine and back-extracted with ether, and the combined
organic layers were dried with K2CO3, filtered, and analyzed by
GC to give 92% of 4 (from 1) and 86% of 4 (0.78 g, 4.3 mmol)
after purification by silica gel chromatography (9:1 hexane/ethyl
7.43-7.24 (m, 10-H, aryl H), 6.85 (d,t, J ) 17.97, 6.46, 1-H,
BCHCH), 5.67 (d,t, J ) 18.00, 1.38 1-H, BCHCH), 5.19 (s, 2-H,
CHOB), 3.23 (t, J ) 6.98, 2-H, CH2I), 2.20 (q,d, J ) 6.82, 1.43,
2-H, CHCHCH2), 1.90 (m, 2-H), 1.61 (m, 2-H).
(E)-6-((4R,5R)-4,5-Diphenyl-1,3,2-dioxaborolan-2-yl)hex-5-
enyl 4-Methylbenzenesulfonate (13). Purification by silica gel
chromatography (3:1 hexane/ethyl acetate) gave 71% (3.3 g, 7.0
1
mmol) of a clear gel: H NMR (300 MHz, CDCl3) δ 7.81 (d, J )
8.20, 2-H, aryl H), 7.44-7.24 (m, 12-H, aryl H), 6.77 (d,t, J )
17.98, 6.43, 1-H, BCHCH), 5.60 (d,t, J ) 17.95, 1.37, 1-H,
BCHCH), 5.18 (s, 2-H, CHOB), 4.06 (t, J ) 6.35, 2-H, CH2OSO2),
2.45 (s, 3-H, aryl methyl), 2.20 (q,d, J ) 6.94, 1.32, 2-H,
CHCHCH2), 1.72 (m, 2-H), 1.51 (m, 2-H).
1
acetate): H NMR (300 MHz, CDCl3) δ 3.20 (d,d, J ) 7.21, 4.20
Hz, 1-H, CHOH), 2.02 (sextet, 1-H, CHCHOH), 1.78 (m, 4-H)
1.40-1.65 (m, 8-H), 1.30-1.40 (m, 2-H), 1.05-1.30 (m, 6-H);
13C NMR (300 MHz, CDCl3) δ 80.1, 43.1, 42.1, 30.5, 29.3, 28.7,
26.7, 26.7, 26.4, 25.7, 25.7.
General Procedure for the Hydroboration of the Alkyne
with Catecholborane. Procedures by Brown32 and Lane33 were
modified, and the conversion of 1-iodo-5-hexyne into (E)-2-(6-iodo-
1-hexenyl)-1,3,2-benzodioxaborole 8 is representative. A mixture
of 1-iodo-5-hexyne (5.62 g, 27 mmol) and neat catecholborane (3.2
g, 27 mmol) was stirred under nitrogen at 70 °C for 1 h, after which
a 20% excess of catecholborane (0.64 g, 5.3 mmol) was added.
After an additional 0.5 h of stirring, the NMR revealed the reaction
to be complete by the absence of the R-alkynyl protons, and the
product was used without further purification.
General Reaction of the Boronic Esters and Oxazaboro-
lidines with Methyllithium or Methylmagnesium Bromide.
Modified from the procedure by Negishi,24 the reaction of (E)-6-
((4S,5S)-3,4-dimethyl-5-phenyl-1,3,2-oxazaborolidin-2-yl)hex-5-
enyl 4-methylbenzenesulfonate 16 with methyllithium is represen-
tative: To a stirred solution of the oxazaborolidine (0.34 g, 0.80
mmol) in 5 mL of THF at -78 °C, 3 equiv of methyllithium (1.5
mL, 1.6 M) was added dropwise. After 0.5 h, it was slowly brought
to rt and stirred for a total of 3 h. It was oxidized by adding 3 M
NaOH (0.4 mL, 1.2 mmol) followed by 30% H2O2 (0.50 mL, 4.4
mmol) and heated at 50 °C for 1 h. Ten milliliters of 1 M HCl was
added after cooling, and the mixture was extracted three times with
10 mL ether, washed with brine, and back-extracted with ether.
The organic phase was dried with K2CO4 and then filtered. After
GC analysis (41%), the solvent was removed under reduced
pressure, and after silica gel chromatography (3:1 hexane/ethyl
acetate), 38% (34 mg, 0.30 mmol) of 12 was obtained. The product
was evaluated by NMR (300 MHz, CDCl3) using the chiral shift
reagent Eu(hfc)3 to determine that it was 60% ee. The configuration
of the major isomer was determined to be (S)-1-cyclopentylethanol
by analogy47 to an NMR shift study of an authentic sample of (R)-
1-cyclohexylethanol.48
(E)-6-((4R,5R)-4,5-Diphenyl-1,3,2-dioxaborolan-2-yl)hex-5-
enyl 4-Methylbenzenesulfonate (13). With 3 equiv of methyl-
magnesium bromide: 85% GC yield of 14.
(E)-6-((4R,5S)-4,5-Diphenyl-1,3,2-oxazaborolidin-2-yl)hex-5-
enyl 4-Methylbenzenesulfonate (15). With 2 equiv of MeMgBr:
60% GC yield of (S)-14, 20% ee.
General Procedure for the Synthesis of Hexenyloxazaboro-
lidines. The combined procedures of Mathre,37 Gamsey,38 and
Brown40 were modified as follows, and the preparation of pseu-
doephedrine oxazaborolidine 16 is representative. A flame-dried
(E)-2-(6-Iodo-1-hexenyl)-1,3,2-benzodioxaborole (8): 1H NMR
(300 MHz, CDCl3) δ 7.24 (m, 2-H, aryl H), 7.10 (m, 2-H, aryl H),
7.04 (d,t, J ) 18.08, 6.49, 1-H, BCHCH), 5.84 (d,t, J ) 18.03,
1.32, 1-H, BCHCH), 3.24 (t, J ) 6.93, 2-H, CH2I), 2.35 (q,d, J )
7.07, 1.41, 2-H, CHCHCH2), 1.91 (m, 2-H), 1.66 (m, 2-H).
(E)-6-(Benzo[d][1,3,2]dioxaborol-2-yl)hex-5-enyl 4-Methyl-
benzenesulfonate (9): 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J )
8.31, 2-H, aryl H), 7.34 (d, J ) 8.20, 2-H, aryl H), 7.21 (m, 2-H,
aryl H), 7.07 (m, 2-H, aryl H), 6.93 (d,t, J ) 18.04, 6.49, 1-H,
BCHCH), 5.74 (d,t, J ) 18.03, 1.37, 1-H, BCHCH), 4.06 (t, J )
6.26, 2-H, CH2OSO2), 2.44 (s, 3-H, aryl methyl), 2.24 (q,d, J )
7.04, 1.44, 2-H, CHCHCH2), 1.69 (m, 2-H), 1.54 (m, 2-H).
General Procedure for the Preparation of the Alkenylbo-
ronic Acids.32 Illustrated for (E)-6-iodo-1-hexenylboronic acid 10.
Water (20 mL) was added to 8 (2.3 g, 7.0 mmol) and stirred at 25
°C overnight. The white crystalline product that formed was filtered
and recrystallized from hexane/THF, giving 84% (1.5 g, 5.9 mmol)
1
of 10: H NMR (300 MHz, CDCl3) δ 6.50 (d,t, J ) 17.94, 6.42,
1-H, BCHCH), 5.44 (d, J ) 17.92, 1-H, BCHCH), 3.20 (t, J )
6.91, 2-H, CH2I), 2.21 (q,d, J ) 6.85, 1.37, 2-H, CHCHCH2), 1.85
(m, 2-H), 1.59 (s, 2-H, OH), 1.57 (m, 2-H).
(46) Pietruszka, J.; Widenmeyer, M. Synlett 1997, 8, 977–979.
(47) Janssen, A. J. M.; Klunder, A. J. H.; Zwanenburg, B. Tetrahedron 1991,
47, 7645–7662.
(48) Eagon, S.; Kim, J.; Yan, K.; Haddenham, D.; Singaram, B. Tetrahedron
Lett. 2007, 48, 9025–9029.
(E)-6-(Tosyloxy)hex-1-enylboronic Acid (11) Trimer. The
hydrolysis of 7 was similarly carried out, and the foamy crude
mixture became completely hydrolyzed during purification by silica
J. Org. Chem. Vol. 74, No. 11, 2009 4147

Hinkens and Midland
50-mL flask equipped with a condenser and stir bar was charged
with vinylboronic acid (0.79 g, 2.7 mmol) and (+)-pseudoephedrine
(0.44 g, 2.7 mmol) and dissolved in THF (10 mL). Calcium hydride
(0.25 g, 6 mmol) was added, and the solution was stirred overnight
at room temperature. The solution was filtered through Celite under
argon and transferred to a dry flask via cannula. The THF was
concentrated at 1 atm to ∼5 mL, and 20 mL of toluene was added.
The solution was stirred at 135 °C for 2 h and then concentrated to
∼5 mL. Toluene (20 mL) was added, and the solution was
concentrated again. This process was repeated once more, and the
remaining solvent was removed under reduced pressure. The residue
was heated at 110 °C under vacuum (0.03 mmHg) for 2 h and
used “as is”.
(E)-6-((4S,5S)-3,4-Dimethyl-5-phenyl-1,3,2-oxazaborolidin-2-
yl)hex-5-enyl 4-Methylbenzenesulfonate (16): 1H NMR (300
MHz, CDCl3) δ 7.73 (d, J ) 8.23, 2-H, aryl H), 7.29-7.18 (m,
7-H, aryl H), 6.40 (t,d, J ) 6.47, 17.80, 1-H, BCHCH), 5.53 (d,t,
J ) 17.81, 1.20, 1-H, BCHCH), 4.72 (d, J ) 6.89, 1-H, CHOB),
3.97 (t, J ) 6.38, 2-H, CH2OSO2), 3.22 (quintet, J ) 6.33, 1-H,
CHNB), 2.62 (s, 3-H, NCH3), 2.37 (s, aryl methyl), 2.08 (q,t, J )
6.86, 1.22, 2-H, CHCHCH2), 1.62 (m, 2-H), 1.40 (m, 2-H), 1.18
(d, J ) 6.16, 3-H); 13C NMR (300 MHz, CDCl3) δ 149.7, 144.8,
143.3, 133.3, 130.0, 128.0, 127.8, 127.7, 125.8, 120.0 (br), 86.2,
70.6, 65.4, 35.3, 29.9, 28.4, 24.4, 21.5, 19.1.
Acknowledgment. We are grateful to Scott Eagon and
Bakthan Singaram for an authentic sample of (R)-1-cyclohexy-
lethanol.48 This work was supported by a GAANN Fellowship
and by the University of California, Riverside.
(E)-6-((4R,5S)-4,5-Diphenyl-1,3,2-oxazaborolidin-2-yl)hex-5-
enyl 4-Methylbenzenesulfonate (15). The following peaks are
1
representative of product formation: H NMR (300 MHz, CDCl3)
δ 7.75 (d, J ) 8.27, 2-H, aryl H), 7.36-6.87 (m, 12-H, aryl H),
6.57 (d,t, J ) 17.93, 6.43, 1-H, BCHCH), 5.77 (d, J ) 8.36, 1-H,
CHOB), 5.67 (d,t, J ) 17.99, 1.32, 1-H, BCHCH), 5.01 (d, J )
8.33, 1-H, CHNB), 4.07 (t, J ) 6.36, 2-H, CH2OSO2), 2.45 (s,
3-H, aryl methyl), 2.20 (q, J ) 7.08, 1.42, 2-H, CHCHCH2), 1.71
(m, 2-H), 1.52 (m, 2-H).
Supporting Information Available: Experimental details and
characterization data for known compounds. NMR spectra (1H
and 13C NMR) for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO900243Q
4148 J. Org. Chem. Vol. 74, No. 11, 2009