Regioselective hydroboration-oxidation and -amination of fluoro-substituted styrenes

Article abstract of DOI:10.1016/j.jfluchem.2006.06.013

Hydroboration of fluorinated styrenes with common hydroborating agents results in polymerization. However, regioselective hydroboration has been achieved by utilizing iodoborane-dimethyl sulfide. A series of fluorinated β-phenethyl alcohols and amines were synthesized via this methodology.

Full text of DOI:10.1016/j.jfluchem.2006.06.013

Journal of Fluorine Chemistry 127 (2006) 1252–1255
www.elsevier.com/locate/fluor
Short communication
Regioselective hydroboration-oxidation and -amination
of fluoro-substituted styrenes
a
b
P. Veeraraghavan Ramachandran a, , Sateesh Madhi , Martin J. O’Donnell
*
a Herbert C. Brown Center for Borane Research, Department of Chemistry, Purdue University,
560 Oval Drive, West Lafayette, IN 47907-2084, United States
b Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis,
Indianapolis, IN 46202-3274, United States
Received 10 May 2006; received in revised form 7 June 2006; accepted 14 June 2006
Available online 18 June 2006
Abstract
Hydroboration of fluorinated styrenes with common hydroborating agents results in polymerization. However, regioselective hydroboration has
been achieved by utilizing iodoborane-dimethyl sulfide. A series of fluorinated b-phenethyl alcohols and amines were synthesized via this
methodology.
# 2006 Elsevier B.V. All rights reserved.
Keywords: Fluorinated styrenes; Hydroboration-oxidation; Amination; Iodoboranes; Regioselectivity
1. Introduction
2. Results and discussion
Due to the similarity in size, fluorine has been used as a
replacement for hydrogen in many biologically active organic
molecules, for use in PET (Positron Emission Tomography)
scanning as well as to examine its influence in the biochemistry
of such molecules [1]. Fluorine substitution on 2-substituted-1-
alkenes substantially modifies the regioselectivity in the
transition-metal catalyzed [2] and uncatalyzed [3–5] hydro-
boration reaction. While the hydroboration-oxidation of
2,3,4,5,6-pentafluorostyrene with BH3ÁTHF, BHCl2ÁSMe2,
BHBr2, ChxBClH, catecholborane (CBH), pinacolborane
(PBH) yields the Markovnikov product [2,3], CHx2BH, 9-
BBN and Sia2BH provide the anti-Markovnikov product [4].
Hydroboration with ThxBH2 provides equal amounts of
Markovnikov and anti-Markovnikov products [4].
The hydroboration-oxidation of 2-, 3-, and 4-fluorostyrenes
under transition-metal catalyzed conditions provide the
secondary alcohols (Scheme 2). In continuation of our research
on the utilization of organoboranes for the synthesis of various
fluorinated amino acids [6], we desired a simple, direct method
for the selective access to the hydroboration products, which
can be readily converted to the anti-Markovnikov alcohols as
oxidation products. The preparation of Markovnikov alcohols
from fluoro-substituted styrenes have been reported [7–13]. We
expected the anti-Markovnikov products via the non-catalyzed
(stoichiometric) hydroboration of fluoro-substituted styrenes
with common hydroborating agents [14]. Our assumption was
based on the fact that a lone fluorine atom on the benzene ring
will have minimal electronic effect.
Herein we report a simple and highly regioselective
hydroboration of fluoro-substituted styrenes (1) for the
synthesis of b-fluoroaryl organoboranes (2), which were
readily converted to the corresponding fluorinated primary
alcohols (3) and primary amines (4) (Scheme 1).
The initial hydroboration experiments were attempted on
2-fluorostyrene with BH3ÁSMe2 in ethyl ether at 0 8C. To our
surprise, the 11B NMR of an aliquot of the reaction mixture
showed a quartet (d À20.3) corresponding to unreacted
1
BH3ÁSMe2. However, a TLC and H NMR analysis revealed
consumption of the olefin. Upon careful analysis, we observed
that the attempted hydroboration had resulted in the
polymerization of the olefin in the presence of borane, with
the quantitative recovery of the borane reagent, as determined
by hydrolysis [15]. The fluorostyrene met with the same fate in
* Corresponding author. Tel.: +1 765 494 5303; fax: +1 765 494 0239.
E-mail address: chandran@purdue.edu (P.V. Ramachandran).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.06.013

P.V. Ramachandran et al. / Journal of Fluorine Chemistry 127 (2006) 1252–1255
1253
Scheme 1. Regioselective hydroboration, followed by oxidation/amination.
Table 1
Regioselective hydroboration-oxidation of fluoro-substituted styrenesa
Scheme 2. Hydroboration-oxidation of fluoro-substituted styrenes.
Entry
F
Yieldb (%)
Product alcoholc
18-ol
28-ol
5a (3)
5b (6)
5c (3)
5d (7)
5e (8)
5f (5)
5g (67)
1
2
3
4
5
6
7
2-F
96
92
95
82
80
92
72
3a (97)
3b (94)
3c (97)
3d (93)
3e (92)
3f (95)
3g (33)
3-F
4-F
2-CF3
3-CF3
4-CF3
2,3,4,5,6-F5
Scheme 3. Attempted hydroboration of fluoro-substituted styrenes with com-
mon boranes.
a
Reaction conditions: 1:1 ratio, BH2IÁSMe2/fluorostyrene, RT, methanol
(2 mL), 1.2 equiv. NaOH, 1.2 equiv. H2O2, 0 8C.
Isolated yields.
b
Isomer ratio determined by 1H NMR.
c
the presence of several other boranes, such as BHCl2ÁSMe2, 9-
BBN, BHCl2, BH2Cl and CHx2BH. Hydroboration of 3-, 4-
fluoro and 2-CF3-, 3-CF3- and 4-CF3-styrenes also led to
polymerization in the presence of BH3ÁSMe2, BH3ÁTHF, 9-
BBN, BHCl2, BH2Cl and CHx2BH (Scheme 3).
conditions to obtain a 95 % yield of essentially pure primary
alcohol product 3c (3c:5c = 97:3).
This protocol was then applied to a variety of fluoro-
substituted styrenes to provide the corresponding primary
alcohols with high selectivity (Table 1). Interestingly, hydro-
boration of 2,3,4,5,6-pentafluorostyrene with BH2IÁSMe2,
followed by oxidation with alkaline H2O2 provided a 72%
yield of a 33:67 mixture of primary and secondary alcohols
(3g and 5g) (Table 1, entry 7). This mighty be expected on the
basis of our earlier results on the hydroboration of 2,3,4,5,6-
pentafluorostyrene with ThxBH2 [4].
Our quest for a borane reagent that would not polymerize
fluorostyrenes, led to the examination of BH2IÁPy or BH2IÁSMe2.
Vedejs and co-workers have recently reported the possibility
of activating PyÁBH3 by replacing one of the hydrogens of
borane with iodine and carrying out the hydroboration of
alkenes and alkynes [16,17]. We applied the same technique
for the hydroboration-oxidation of fluoro-substituted styrenes
(Scheme 4). Thus, the hydroboration of 4-fluorostyrene with
BH2IÁSMe2,preparedviatheiodination[18]ofBH3ÁSMe2 inCS2,
was complete within 5 h at RT, as revealed by a doublet at d À6.5
in the 11B NMR spectrum. The reaction mixture was cooled to
0 8C, quenched with methanol and oxidized under alkaline
Having succeeded in achieving the synthesis of the
fluorinated b-phenethanols, we turned our attention to the pre-
paration of representatives of the corresponding b-phenethyl
amines [19–22]. Following hydroboration of 4-fluorostyrene
Scheme 4. Hydroboration-oxidation of fluoro-substituted styrenes with iodoborane.

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P.V. Ramachandran et al. / Journal of Fluorine Chemistry 127 (2006) 1252–1255
Scheme 5. Hydroboration-amination of fluoro-substituted styrenes with iodoborane.
with BH2IÁSMe2, the reaction mixture was cooled to 0 8C,
quenched with methanol and aminated using hydroxylamine-
O-sulfonic acid to obtain a 72% yield of essentially pure
primary amine (4a:6a = 97:3) (Scheme 5). Similarly, the
hydroboration-amination of 3-trifluoromethyl styrene gave a
65% yield of primarily the primary amine (4b:6b = 92:8).
evolution was completed (2 h), the solvent was evaporated
under reduced pressure. Fractional distillation yielded
iodoborane-dimethyl sulfide (24 g, 80% yield). 11B NMR:
d À20.1 (t).
5.2. Hydroboration-oxidation of fluoro-substituted styrenes
3. Conclusion
An oven-dried, 50 mL round-bottomed flask, equipped
with a side arm, was cooled to 0 8C under a stream of
nitrogen. In the flask was placed CS2 (10 mL) and BH3ÁSMe2
(1.485 mL, 10.0–10.2 M, 15 mmol). The flask was maintained
at 0 8C by immersion in ice-water bath. To this flask was
added a precooled I2 solution (1.903 g, 7.5 mmol) in CS2
(10 mL) slowly using a double-ended needle. After hydrogen
evolution was completed (2 h), the solution was warmed to
room temperature and 4-fluorostyrene (15 mmol) was added.
After the completion of the reaction (5 h, monitored
periodically by 11B NMR doublet at d À6.5), the reaction
mixture was cooled to 0 8C with an ice bath, and quenched
with methanol. NaOH (1.2 equiv., 3 M in H2O) and H2O2
(1.2 equiv., 30% aqueous) were added. This mixture was
allowed to stir at room temperature for an additional 2 h. The
solution was then poured into separatory funnel, diluted with
ethyl ether and H2O, and acidified with HCl (aq). The water
layer was washed with ether (2 Â 20 mL) and dried with
Na2SO4. Solvent was removed to afford 3c (95%,
3c:5c = 97:3). The regioselectivity was determined by 1H
NMR spectroscopic analysis of the final crude reaction
mixture after oxidative work-up.
In conclusion, we have developed a simple and highly
regioselective preparation of b-fluoroaryl organoboranes and
converted them to the corresponding fluorinated alcohols and
amines.
4. Experimental
Unless otherwise noted, all manipulations were carried out
under an inert atmosphere using flame-dried glassware. Iodine
was purchased from Fisher Scientific. Carbon disulfide (CS2),
and hydroxylamine-O-sulfonic acid were purchased from the
Aldrich Chemical Co. Fluorostyrenes were purchased from
Apollo Scientific Co. Other chemicals were used without
further purification, unless otherwise noted.
1
The H, 11B and 19F nuclear magnetic resonance (NMR)
spectra were plotted on a Varian Gemini-300 spectrometer
(300, 75 and 282 MHz, respectively) with a Nalorac-quad
1
probe. H NMR spectra were obtained using CDCl3 as the
solvent with either tetramethylsilane (TMS: 0 ppm) or
chloroform (CHCl3: 7.2 ppm) as the internal standard. 19F
NMR spectra were recorded in CDCl3 using CFCl3 or
1
trifluoroacetic acid (TFA) as the internal standard. H NMR
5.2.1. 2-Fluorophenethyl alcohol (3a)
1H NMR (300 MHz, CDCl3): d 7.30–6.95 (m, 4H), 3.86–
3.81 (t, J(H,H) = 6.6 Hz, 2H), 2.98–2.86 (t, 2H), 2.22 (brs, 1H).
data are reported as chemical shifts (d, ppm), multiplicity (s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling
constant (Hz), and integration. Flash chromatography was
performed on 40–60 mm silica gel (230–400 mesh).
5.2.2. 3-Fluorophenethyl alcohol (3b)
1H NMR (300 MHz, CDCl3): d 7.40–7.21 (dd, 2H), 7.02–
6.80 (dd, 2H), 3.83–3.79 (t, J(H,H) = 6.45 Hz, 2H), 2.90–2.79
(t, 2H), 2.22 (brs, 1H).
5. Representative experimental procedures
5.1. Iodoborane-dimethyl sulfide [18]
5.2.3. 4-Fluorophenethyl alcohol (3c)
1H NMR (300 MHz, CDCl3): d 7.22–7.14 (dd, 2H) 7.06–
6.94 (dd, 2H), 3.85–3.77 (t, 2H), 2.89–2.80 (t, 2H), 1.80 (brs,
1H).
An oven-dried, 250 mL round-bottomed flask, equipped
with a side arm, was cooled to 0 8C under a stream of
nitrogen. In the flask was placed CS2 (10 mL) and BH3ÁSMe2
(14.85 mL, 10.0–10.2 M, 0.15 mol). The flask was main-
tained at 0 8C by immersion in an ice-water bath. To this flask
was added a precooled I2 solution (19.03 g, 0.075 mol) in CS2
(75 mL) slowly using a double-ended needle. After hydrogen
5.2.4. 2-(Trifluoromethyl)phenethyl alcohol (3d)
1H NMR (300 MHz, CDCl3): d 7.71–7.22 (m, 4H), 3.98–
3.82 (t, 2H), 3.12–2.98 (t, 2H), 1.89 (brs, 1H).

P.V. Ramachandran et al. / Journal of Fluorine Chemistry 127 (2006) 1252–1255
1255
5.2.5. 3-(Trifluoromethyl)phenethyl alcohol (3e)
Acknowledgement
1H NMR (300 MHz, CDCl3): d 7.61–7.30 (m, 4H), 3.87–
3.83 (t, J(H,H) = 6.42 Hz, 2H), 2.98–2.82 (t, 2H), 2.22 (brs,
1H).
We gratefully acknowledge the National Institutes of Health
(R01 GM28193) for support of this research.
References
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5.3. Hydroboration-amination of fluoro-substituted
styrenes
An oven-dried, 50 mL round-bottomed flask, equipped
with a side arm, was cooled to 0 8C under a stream of
nitrogen. In the flask was placed CS2 (10 mL) and BH3ÁSMe2
(1.485 mL, 10.0–10.2 M, 15 mmol). The flask was main-
tained at 0 8C by immersion in an ice-water bath. To this
flask was added a precooled I2 solution (1.903 g, 7.5 mmol)
in CS2 (10 mL) slowly using a double-ended needle. After
hydrogen evolution was completed, the solution was warmed
to room temperature and 4-fluorostyrene (1.79 mL, 15 mmol)
was added. After the completion of the reaction (5 h),
monitored periodically by 11B NMR doublet at d À6.5, the
reaction mixture was cooled to 0 8C with an ice bath, and
quenched with methanol. To this boronic ester, solid
hydroxylamine-O-sulfonic acid (3.392 g, 30 mmol) was
added by using a solid addition tube. The reaction mixture
was stirred at RT for 12 h to ensure complete conversion.
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acidic aqueous layer was separated, cooled to 0 8C and
layered with ethyl ether. The solution was then made
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