Asymmetric alkyldifluoroboranes and their use in secondary amine synthesis

Article abstract of DOI:10.1021/ol025973d

(matrix presented) Asymmetric diol boronic esters with potassium bifluoride form the corresponding alkyltrifluoroborate and free diol under mild conditions. Defluoridation with tetrachlorosilane produces an alkyldifluoroborane intermediate. This conversio

Full text of DOI:10.1021/ol025973d

ORGANIC
LETTERS
2002
Vol. 4, No. 13
2153-2155
Asymmetric Alkyldifluoroboranes and
Their Use in Secondary Amine
Synthesis
Donald S. Matteson* and Gyung Youn Kim
Department of Chemistry, P.O. Box 644630, Washington State UniVersity,
Pullman, Washington 99164-4630
dmatteson@wsu.edu
Received April 4, 2002
ABSTRACT
Asymmetric diol boronic esters with potassium bifluoride form the corresponding alkyltrifluoroborate and free diol under mild conditions.
Defluoridation with tetrachlorosilane produces an alkyldifluoroborane intermediate. This conversion of relatively unreactive boronic esters to
derivatives that are strong Lewis acids opens new synthetic opportunities, as illustrated by the preparation of (R)-2-phenylpyrrolidine in 98%
ee from a pinanediol or 1,2-dicyclohexyl-1,2-ethanediol boronic ester via potassium (2-phenyl-4-azidobutyl)trifluoroborate.
We have found a mild, efficient route from asymmetric
boronic esters via alkyltrifluoroborates to reactive alkyldi-
fluoroborane intermediates, which are converted to asym-
metric secondary amines via reaction with organic azides.
Vedejs and co-workers reported that arylboronic acids react
with potassium bifluoride to form aryltrifluoroborates, which
are converted to aryldifluoroborane intermediates by trim-
ethylsilyl chloride.1,2 Organotrifluoroborates prepared by the
Vedejs route have been found useful by others,3 but
organodifluoroboranes remain relatively unexplored.4
Our method of asymmetric synthesis based on R-halo
boronic ester chemistry provides a wide variety of function-
alized boronic ester intermediates in very high enantiomeric
and diastereomeric purity,5 but the scope of displacements
of boron from carbon has been limited by the low reactivity
of boronic esters. Thermodynamics disfavors hydrolysis of
the pinanediol or 1,2-dicyclohexylethanediol (DICHED)
esters used in our synthetic method. Separation of the diol
group from boron requires an exothermic reaction6 or
separation of the diol and the organoboron units into separate
phases,7 which is not always practical. Glass-catalyzed
reaction of boronic esters with thionyl chloride and imidazole
has provided good recovery of the chiral diols, but efficient
hydrolysis of the chloroborane imidazole derivatives has
proved elusive.8
The direct reaction of pinanediol or DICHED boronic
esters with potassium bifluoride under the Vedejs conditions
(4) (a) Classical synthesis: McCusker, P. A.; Glunz, L. J. J. Am. Chem.
Soc. 1955, 77, 4253-4255. McCusker, P. A.; Makowski, H. S. J. Am. Chem.
Soc. 1957, 79, 5185-5188. (b) From R-amido boronic acids and aqueous
hydrofluoric acid: Kinder, D. H.; Katzenellenbogen, J. A. J. Med. Chem.
1985, 28, 1917-1925. (c) R-Amido group makes boron tetracoordinate in
boronic ester analogue: Matteson, D. S.; Michnick, T. J.; Willett, R. D.;
Patterson, C. D. Organometallics 1989, 8, 726-729.
(5) (a) Matteson, D. S. Tetrahedron 1998, 54, 10555-10607. (b)
Matteson, D. S. J. Organomet. Chem. 1999, 581, 51-65. (c) Stereodirected
Synthesis with Organoboranes; Matteson, D. S.; Springer-Verlag: Berlin,
1995. (d) Matteson, D. S. Chem. ReV. 1989, 89, 1535-1551.
(6) (a) Matteson, D. S.; Sadhu, K. M.; Lienhard, G. E. J. Am. Chem.
Soc., 1981, 103, 5241-5242. (b) Matteson, D. S.; Ray, R.; Rocks, R. R.;
Tsai, D. J. S. Organometallics 1983, 2, 1536-1543. (c) Matteson, D. S.;
Sadhu, K. M. Organometallics 1984, 3, 614-618 (d) Brown, H. C.;
Rangaishenvi, M. V. J. Organomet. Chem. 1988, 358, 15-30.
(1) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R.
J. Org. Chem. 1995, 60, 3020-3027.
(2) It has been reported that the ethanolamine ester of diphenylborinic
acid was converted to potassium (difluoro)(diphenyl)borinate by KHF2:
Thierig, D.; Umland, F. Naturwissenschaften 1967, 54, 563. Vedejs et al.
speculated that boronic esters might also react but did not test the possibility.
(3) (a) Batey, R. A.; Thadani, A. N.; Smil, D. V. Org. Lett. 1999, 1,
1683-1686. (b) Molander, G. A.; Ito, T. Org. Lett. 2001, 3, 393-396.
10.1021/ol025973d CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/04/2002

Scheme 1. Conversion of Boronic Esters to Secondary
Table 2. Conversion of Trifluoroborates (2) and Azides (4) to
Secondary Amines (5)a
Amines via Trifluoroborates
R1 of 2
R2 of 4
R3SiCl
mmol T, °C 5, %
Ph
Ph
Ph
PhCH2
n-C5H11 TMSCl
H
PhCH2
PhCH2
SiCl4
5
7
5
1.5
1.5
1.5
80
90
80
70
80
80
82
70
73
70
85
75
SiCl4
SiCl4
SiCl4
SiCl4
b
c-C6H11
CH3(CH2)5
(S)-C6H13CH(Me)c PhCH2
a Borate 2 (1 mmol), SiCl4, or Me3SiCl (mmol tabulated), and azide 4
(1.3 mmol) were heated and stirred in toluene (∼7.5 mL), and the product
was recovered by aqueous workup and finally chromatography. b CH3CN
added to solubilize 2. c [R]22 ) +12.4 (c 0.24, CH2Cl2).
546
The preparation of an asymmetric pyrrolidine (14) was
chosen as a demonstration of the potential utility of the
trifluoroborate salts for asymmetric synthesis (Scheme 2).
has proved to be generally facile (Scheme 1). DICHED esters
(1a) are usually >90% converted to the trifluoroborate salts
(2) and free DICHED (3a), and pinanediol esters (1b) can
usually be cleaved to 2 and free pinanediol (3b) to the extent
of ∼70%. Reactions usually reach equilibrium within 0.5-2
h at 22 °C.9 Treatment of 2 with azido compounds (4) and
tetrachlorosilane results in nitrogen evolution and, after
hydrolysis, yields secondary amines (5).
Scheme 2. Preparation of (R)-2-Phenylpyrrolidinea
The scope of the conversion of DICHED boronic esters
1a to trifluoroborates (2) has been explored briefly with
simple substrates, summarized in Table 1.
Table 1. Conversion of DICHED Boronic Esters 1a to
Trifluoroborates 2 and DICHED 3aa
trifluoroborate 2
δ
19Fb
2, %
3, %
Ph-BF3K
-141
-146
-139
-148
-145
-146
-145
91
90
70
77
87
85
75
86
86
96
88
94
90
95
c-C6H11-BF3Kc
CH3(CH2)5-BF3K
(S)-PhCH(Cl)-BF3K
(R)-PhCH(OBn)-BF3Kc
(R)-N3(CH2)3CH(Ph)-BF3Kd
(S)-C6H13CH(Me)-BF3K
a (a) 8 (0.11 mol), NaN3 (1.1 mol), Bu4N+Br- (0.05 mol), EtOAc
(250 mL), H2O (75 mL), 80 °C, 8 h. (b) (1) LiCHCl2, -100 °C;
ZnCl2, -100 to +22 °C, 15 h; (2) PhMgBr.5 (c) KHF2, MeOH/
H2O. (d) 11 (5 mmol), PhCH3 (40 mL),CH3CN (5 mL), SiCl4 (26
mmol), 22 °C, 10 h. (e) Concentrated (vac), H2O.
a Conditions: 1a (1 mmol) in MeOH (8.5 mL), KHF2 (7 mmol) in H2O
(∼1.5 mL), mixed at ∼22 °C, 0.5-2 h; concentrated (vac) until MeOH
removed; CH3CN (10 mL), KHF2 + KF filtered; 1a and 3a extracted with
pentane, 3a crystallized; concentration of CH3CN sol. yielded 2. Traces of
KHF2 (19F δ -151) remained in some samples. b 282 MHz; broadened by
11B quadrupole; KHF2 <1%. c Anal. C, H, B, F. d Anal. C (0.56% high),
H, B (0.45% low), K.
Formation of secondary amines (5) from alkylchlorobo-
ranes is well-known,11 but the use of fluoroboranes for this
purpose has not been investigated previously. Trialkylboranes
have also been used with azides for secondary amine
synthesis.12 Only one of three alkyl groups is utilized in the
synthesis, and for practical utility the trialkylborane has to
be an isomer accessible by hydroboration. If differing alkyl
groups are present, selectivity can become a problem, though
ring closures tend to supersede competing alkyl migrations.
A significant advantage of the new route includes the
recovery of DICHED or pinanediol intact after trifluoroborate
formation. The destruction of pinanediol by boron trichloride
was discovered previously,6b and in the present work we have
found that DICHED is recovered in low yield (∼10%) if
Intermolecular reactions of potassium trifluoroborates with
tetrachlorosilane and azides have been explored briefly (Table
2).
Although chlorotrimethylsilane as used by Vedejs and co-
workers1 is an effective defluoridating agent, tetrachlorosilane
was observed to result in faster nitrogen evolution from the
azide reactions and was adopted as the standard reagent for
this purpose. A known asymmetric secondary amine, R1 )
2-octyl, R2 ) PhCH2,10 was chosen as a test target to
demonstrate feasibility.
2154
Org. Lett., Vol. 4, No. 13, 2002

trichloroborane is used to generate a reactive chloroborane
from a boronic ester 1a. Furthermore, the acid-sensitive
benzyloxy substituent survives alkyltrifluoroborate formation.
It is also significant that the reaction with potassium
bifluoride is the most efficient and generally useful method
that has been found to date for converting sterically hindered
asymmetric boronic esters to more reactive classes of
organoboranes.
The synthesis of the required boronic ester intermediates
followed well-established procedures.5 Bromopropylboronic
esters 8 are derived from the hydroboration of allyl bro-
mide.13 Azide substitution to form 9 was done according to
a recently improved phase transfer procedure,14 and asym-
metric homologation to boronic ester 10 has ample prece-
dent.5,14 The azide group is unaffected by formation of
trifluoroborate 11 (19F δ -146), but generation of postulated
difluoroborane 12 with tetrachlorosilane results in ring
closure to 13 (perhaps dimeric with tetracoordinate boron,
19F δ -151), which is readily hydrolyzed to (R)-2-phe-
nylpyrrolidine (14).
(7) (a) Tripathy, P. B.; Matteson, D. S. Synthesis 1990, 200-206. (b)
Wityak, J.; Earl, R. A.; Abelman, M. M.; Bethel, Y. B.; Fisher, B. N.;
Kauffman, G. S.; Kettner, C. A.; Ma, P.; McMillan, J. L.; Mersinger, L. J.;
Pesti, J.; Pierce, M. E.; Rankin., F. W.; Chorvat, R. J.; Confalone, P. N. J.
Org. Chem. 1995, 60, 3717-3722. (c) Matteson, D. S.; Man, H.-W.; Ho,
O. C. J. Am. Chem. Soc. 1996, 118, 4560-4566. (d) Matteson, D. S.; Man,
H.-W. J. Org. Chem. 1996, 61, 6047-6051.
(8) Matteson, D. S.; Hiscox W. C.; Fabry-Asztalos, L.; Kim, G.-Y.;
Siems, W. F., III. Organometallics 2001, 20, 2920-2923.
(9) The reversibility of the reaction has been demonstrated by the
formation of 33% pinanediol phenylboronate from pinanediol and potassium
phenyltrifluoroborate in the presence of potassium bifluoride under the usual
preparative conditions.
Acknowledgment. We thank the National Science Foun-
dation for support (grant CHE-0072788). The WSU NMR
Center equipment was supported by NIH grants RR0631401
and RR12948, NSF grants CHE-9115282 and DBI-9604689,
and a grant from the Murdock Charitable Trust.
(10) Lopez, R. M.; Fu, G. C. Tetrahedron 1997, 53, 16349-16353.
(11) (a) Brown, H. C.; Midland, M. M.; Levy, A. B. J. Am. Chem. Soc.
1972, 94, 2114-2115. (b) Brown, H. C.; Midland, M. M.; Levy, A. B. J.
Am. Chem. Soc. 1973, 95, 2394-2396. (c) Brown, H. C.; Midland, M. M.;
Levy, A. B.; Suzuki, A.; Sono, S.; Itoh, M. Tetrahedron 1987, 43, 4079-
4088. (d) Carboni, B.; Vaultier, M.; Carrie, R. Tetrahedron 1987, 43, 1799-
1810. (e) Carboni, B.; Vaultier, M.; Courgeon, T.; Carrie, R. Bull. Soc.
Chim. Fr. 1989, 844-849. (f) Brown, H. C.; Salunkhe, A. M.; Singaram,
B. J. Org. Chem. 1991, 56, 1170-1175. (g) Jego, J. M.; Carboni, B.;
Youssofi, A.; Vaultier, M. Synlett 1993, 595-597. (h) Brown, H. C.,
Salunkhe, A. M. Tetrahedron Lett. 1993, 34, 1265-1268.
Supporting Information Available: Preparative details
for trifluoroborates, secondary amines, compounds 9-14;
1
enantiomeric analysis of 14; H, 13C, 19F NMR spectra of
11 and of potassium 1-benzyloxy-2-phenylethyltrifluorobo-
rate. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL025973D
(12) (a) Suzuki, A.; Sono, S.; Itoh, M.; Brown, H. C.; Midland, M. M.
J. Am. Chem. Soc. 1971, 93, 4329-4330. (b) Evans, D. A.; Weber, A. E.
J. Am. Chem. Soc. 1987, 109, 7151-7157. (c) Salmon, A.; Carboni, B. J.
Organomet. Chem. 1998, 567, 31-37.
(13) Matteson, D. S.; Soundararajan, R. Organometallics 1995, 14,
4157-4166.
(14) Matteson, D. S.; Singh, R. P. J. Org. Chem. 2000, 65, 6650-6653.
Org. Lett., Vol. 4, No. 13, 2002
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