Transmetalation of Alkylboranes to Palladium in the Suzuki Coupling Reaction Proceeds with Retention of Stereochemistry

Article abstract of DOI:10.1021/jo970803d

Deuterium-labeling experiments demonstrate that the transmetalation step of the Suzuki coupling reaction of alkylboranes and α-iodoenones proceeds with retention of stereochemistry.

Full text of DOI:10.1021/jo970803d

458
J . Org. Chem. 1998, 63, 458-460
Tr a n sm eta la tion of Alk ylbor a n es to P a lla d iu m in th e Su zu k i
Cou p lin g Rea ction P r oceed s w ith Reten tion of Ster eoch em istr y
Brian H. Ridgway and K. A. Woerpel*
Department of Chemistry, University of California, Irvine, California 92697-2025
Received May 5, 1997
Deuterium-labeling experiments demonstrate that the transmetalation step of the Suzuki coupling
reaction of alkylboranes and R-iodoenones proceeds with retention of stereochemistry.
The palladium-catalyzed cross-coupling of organo-
signals in their 1H NMR spectra at the stereocenter of
interest, permitting facile determination of coupling
constants between the protons of the CHD units.10 The
deuterated alkenes were prepared as shown in eqs 1 and
2. Because of the volatility of the tert-butyldimethylsilyl
boranes and alkenyl or aryl halides (the Suzuki reaction)
has achieved prominence as one of the most important
metal-catalyzed carbon-carbon bond-forming reactions
in organic synthesis.1 The mechanism of this transfor-
mation is believed to involve oxidative addition of the
electrophilic halide to a Pd(0) intermediate followed by
transmetalation of the carbon substituent from boron to
the resulting Pd(II) complex and finally reductive elimi-
nation to provide the coupled product.1 The Suzuki
reaction is a particularly powerful transformation be-
cause it permits the coupling of primary alkylboranes and
alkenyl or aryl halides, a process that can be used to great
synthetic advantage.2 In contrast to stereochemical
investigations of the related cross-couplings involving
silanes3 and stannanes,4-6 the stereochemistry of the
transmetalation of alkylboranes to palladium (either
retention or inversion of configuration) has received little
attention.7,8 We provide evidence that primary alkyl-
boranes undergo transmetalation to palladium with
retention of configuration.9
The stereochemistry of the coupling reaction was
determined by hydroboration of diastereomeric dideute-
rioalkenes cis-2 and trans-5 followed by coupling of the
diastereomeric boranes to R-iodocyclohexenone and ex-
amination of the spectral properties of the resulting
cyclohexenones (eqs 3 and 4). These particular deriva-
tives were chosen because they displayed well-resolved
(1) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
(2) See, for example: J ohnson, C. R.; Braun, M. P. J . Am. Chem.
Soc. 1993, 115, 11014-11015.
(3) Hatanaka, Y.; Hiyama, T. J . Am. Chem. Soc. 1990, 112, 7793-
7794.
(4) Labadie, J . W.; Stille, J . K. J . Am. Chem. Soc. 1983, 105, 6129-
6137.
(5) Ye, J .; Bhatt, R. K.; Falck, J . R. J . Am. Chem. Soc. 1994, 116,
1-5.
ethers 1 and cis-2, the tert-butyldiphenylsilyl ether was
chosen for the longer sequence leading to trans-5. The
enones syn-7 and anti-8 were obtained by hydroboration
of the respective alkenes with 9-BBN followed by addition
of 2-iodocyclohexenone,11 palladium catalyst, and aqueous
sodium hydroxide (eqs 3 and 4, the reaction conditions
were not optimized).1
(6) Falck, J . R.; Bhatt, R. K.; Ye, J . J . Am. Chem. Soc. 1995, 117,
5973-5982.
(7) Cyclopropylboranes with alkyl substituents trans to the boron
undergo coupling to provide trans products. This observation indicates
that transmetalation may occur with retention of configuration,
although coupling with cis-substituted cyclopropylboranes was not
investigated: (a) Wang, X.-Z.; Deng, M.-Z. J . Chem. Soc., Perkin Trans.
1 1996, 2663-2664. (b) Hildebrand, J . P.; Marsden, S. P. Synlett 1996,
893-894. (c) Charette, A. B.; De Freitas-Gil, R. P. Tetrahedron Lett.
1997, 38, 2809-2812.
(8) Knochel has recently demonstrated that transmetalation of a
secondary alkyl group from boron to zinc occurs with retention of
configuration: Micouin, L.; Oestreich, M.; Knochel, P. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 245-246.
(9) Soderquist has recently presented a similar strategy to the one
reported here and has arrived at the same conclusion: Soderquist, J .
A.; Rane, A.; Matos, K. Presented at the 213th National Meeting of
the American Chemical Society, San Francisco, CA, April 1997; paper
ORGN 582. Matos, K.; Soderquist, J . A. J . Org. Chem. 1997, 63, 461-
470.
The stereochemistries of the enones syn-7 and anti-8
were assigned by analysis of their 1H NMR spectra.
(10) Whitesides pioneered the use of similarly deuterated substrates
to evaluate the stereochemical course of reactions involving alkylmetal
compounds: Bock, P. L.; Boschetto, D. M.; Rasmussen, J . R.; Demers,
J . P.; Whitesides, G. M. J . Am. Chem. Soc. 1974, 96, 2814-2825.
(11) J ohnson, C. R.; Adams, J . P.; Braun, M. P.; Senanayake, C. B.
W.; Wovkulich, P. M.; Uskakovic, M. R. Tetrahedron Lett. 1992, 33,
917-918.
S0022-3263(97)00803-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/22/1998

Transmetalation of Alkylboranes to Palladium
J . Org. Chem., Vol. 63, No. 3, 1998 459
OSi (M+) 174.1409, found 174.1409. Anal. Calcd for C9H20
OSi: C, 62.00; H, 11.56. Found: C, 62.26; H, 11.48.17
-
1-(ter t-Bu tyld ip h en ylsiloxy)-3-d eu ter io-2-p r op yn e (4).
1-(tert-Butyldiphenylsiloxy)-2-propyne (3)16 (2.0 g, 6.8 mmol)
was dissolved in THF (14 mL). n-Butyllithium (9.3 mL, 1.1
M in hexane) was added dropwise at -78 °C. The mixture
was stirred at -78 °C for 1 h. D2O (20.4 mL, 10.2 mmol) was
added, and the mixture was stirred for 4 h. The reaction
mixture was partitioned between 50 mL of NH4Cl (saturated
aqueous) and 50 mL of Et2O and separated. The aqueous layer
was washed with 2 × 50 mL of Et2O, and the organic layers
were combined, dried over Na2SO4, and reduced in vacuo. The
product was purified by flash chromatography, yielding a white
Because the dominant conformational isomer in solution
should be the anti conformers depicted, the two stereo-
isomers should display significantly different coupling
constants between the protons Ha and Hb.10 The isomer
derived from cis-2 possesses a 5.8 Hz coupling constant,
whereas the isomer from trans-5 has a 9.1 Hz coupling
constant.12,13 Consequently, the palladium-catalyzed
coupling occurred to give the products syn-7 and anti-8
from eqs 3 and 4, respectively. Because hydroboration
is a syn addition process,14 and reductive elimination
from palladium proceeds with retention of configura-
tion,15 transmetalation from boron to palladium must
therefore occur with retention of configuration.
In conclusion, these experiments indicate that the
Suzuki coupling of primary alkylboranes to iodoalkenes
proceeds with retention of configuration at the carbon
atom. The results are in accord with a frontside SE2
(cyclic) mechanism for transmetalation, similar to what
has been suggested for alkylsilanes.3
solid (100% by NMR): IR (KBr) 3070, 2598, 1998, 1071 cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.92 (m, 4H), 7.56 (m, 6H), 4.49
(s, 2H), 1.27 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 135.5, 132.8,
2
1
129.8, 127.7, 81.4 (t, J CD ) 6.8), 72.9 (t, J CD ) 37.8), 52.4,
26.6, 19.1; HRMS (EI) m/z calcd for C19H21DOSi (M+) 295.1503,
found 295.1512. Anal. Calcd for C19H22OSi: C, 77.23; H, 7.50.
Found: C, 77.29; H, 7.52.17
1-(ter t-bu tyldiph en ylsiloxy)-2,3-tr a n s-dideu ter io-2-pr o-
p en e (tr a n s-5). Zirconocene chloride deuteride (130 mg, 0.5
mmol, prepared from lithium aluminum deuteride and zir-
conocene dichloride18,19 ) and benzene (3 mL) were mixed in a
round-bottom flask. 1-(tert-Butyldiphenylsiloxy)-3-deuterio-
2-propyne (4, 135 mg, 0.46 mmol in 1 mL of benzene) was
added. The heterogeneous mixture was stirred for 10 h in the
absence of light, becoming red and homogeneous. HCl was
added (2 mL, 1 M, aqueous), and after 20 min, NaHCO3 was
added (35 mL, saturated aqueous) followed by NH4Cl (15 mL,
saturated aqueous) and Et2O (50 mL). The aqueous layer was
separated and washed with 2 × 50 mL of Et2O. The combined
organic layers were dried over Na2SO4, filtered, and reduced
in vacuo. Flash chromatography (10:90 CH2Cl2:hexane) yielded
the product as a clear oil (87 mg, 64%): IR (thin film) 3071,
Exp er im en ta l Section
1
1590, 1112 cm-1; H NMR (500 MHz, CDCl3) δ 7.69 (m, 4H),
Gen er a l Meth od s. General experimental details are pro-
vided as Supporting Information. All coupling constants are
reported in Hz. Decoupling experiments were performed to
confirm structural assignments. Microanalyses were per-
formed by Atlantic Microlab, Atlanta, GA. All reactions were
carried out under an atmosphere of nitrogen in glassware that
had been flame-dried under a stream of nitrogen.
7.38 (m, 6H), 5.10 (d, J ) 1.6, 1H), 4.21 (d, J ) 1.6, 2H), 1.07
1
(s, 9H); 13C NMR (125 MHz, CDCl3) d 136.6 (t, J CD ) 24.2),
1
135.5, 135.3, 133.7, 127.6, 113.5 (t, J CD ) 23.4), 64.5, 26.8,
19.3; HRMS (EI) m/z calcd for C19H22D2OSi (M+) 298.1722,
found 298.1719. Anal. Calcd for C19H24OSi: C, 76.45; H, 8.10.
Found: C, 76.52; H, 8.16.17
2-[3-(ter t-Bu tyld im eth ylsiloxy)-1,2-syn -d id eu ter iop r o-
p yl]-2-cycloh exen -1-on e (syn -7). Propene cis-2 (150 mg,
0.86 mmol) was added to a solution of 9-BBN (126 mg, 1.03
mmol) in THF (15 mL) at 0 °C. The reaction mixture was
heated to reflux for 12 h. The mixture was cooled to 25 °C,
and 2-iodo-2-cyclohexene-1-one11 (229 mg, 1.03 mmol), Pd-
(dppf)Cl2 (14 mg, 0.017 mmol), and NaOH (0.6 mL, 3 M,
aqueous) were added sequentially. The mixture was again
brought to reflux where it remained for 2 h. The reaction
mixture was partitioned between NaCl (75 mL, saturated
aqueous) and Et2O (50 mL). The aqueous phase was separated
and washed with 2 × 25 mL of Et2O. The combined organic
layers were dried over Na2SO4, filtered, and reduced in vacuo.
Purification by flash chromatography (10:90 EtOAc:hexane)
yielded pure product as a colorless oil (119 mg, 51%): IR (thin
1-(ter t-Bu tyld im eth ylsiloxy)-2,3-cis-d id eu ter io-2-p r o-
p en e (cis-2). 1-(tert-Butyldimethylsiloxy)-2-propyne (1)16 (844
mg, 4.96 mmol) was dissolved in pentane (12 mL). Quinoline
(640 mg, 4.96 mmol) and Pd on CaCO3 (100 mg, 5% Pd) were
added, and the reaction flask was flushed with nitrogen. A
balloon containing D2 was affixed, and the reaction flask was
purged to ensure a D2 atmosphere. After being stirred for 45
min, the heterogeneous reaction mixture was filtered through
Celite and purified by flash chromatography (10:90 CH2Cl2:
pentane), yielding a volatile, clear oil (270 mg, 31%): IR (thin
film) 2957, 2351, 1472, 1071 cm-1; 1H NMR (500 MHz, CDCl3)
δ 5.24 (m, 1H), 4.17 (s, 2H), 0.92 (s, 9H), 0.07 (s, 6H); 13C NMR
1
1
(125 MHz, CDCl3) δ 137.1 (t, J CD ) 24.2), 113.5 (t, J CD
)
24.2), 64.0, 25.9, 18.4, -5.3; HRMS (EI) m/z calcd for C9H18D2-
1
film) 2953, 2168, 1677, 1471, 1097 cm-1; H NMR (500 MHz,
(12) The 1H{2H} NMR spectra showed coupling constants similar
to these values (6.1 and 9.2 Hz, for syn-7 and anti-8, respectively).
Variable-temperature NMR experiments also indicated only minor
changes in the spectral data. At -50 °C, the coupling constant for syn-7
decreased; this resonance became a broad singlet. At this temperature,
the coupling constant for anti-8 increased slightly to 9.3 Hz.
(13) A similar analysis has been used to determine the stereochem-
istry of polydeuterated alkanes: Gilchrist, J . H.; Bercaw, J . E. J . Am.
Chem. Soc. 1996, 118, 12021-12028.
CDCl3) δ 6.70 (t, J ) 4.2, 1H), 3.56 (d, J ) 6.5, 2H), 2.39 (t, J
) 6.8, 2H), 2.31 (m, 2H), 2.16 (d, J ) 5.8, 1H), 1.94 (quintet,
2
J ) 6.4, 2H), 1.56 (m, 1H), 0.86 (s, 9H), 0.01 (s, 6H); H{1H}
NMR (77 MHz, CDCl3) δ 1.58, 2.20; 13C NMR (125 MHz,
1
CDCl3) δ 199.4, 145.1, 139.3, 62.5, 38.5, 31.1 (t, J CD ) 19.4),
1
26.0, 25.9, 25.4 (t, J CD ) 19.4), 23.1, 18.2, -5.4; HRMS (EI)
m/z calcd for C14H23D2O2Si (M+ - CH3) 255.1749, found
255.1745. Anal. Calcd for C15H28O2Si: C, 66.61; H, 10.43.
Found: C, 66.76; H, 10.42.17
(14) Kabalka, G. W.; Bowman, N. S. J . Org. Chem. 1973, 38, 1607-
1608.
(15) Milstein, D.; Stille, J . K. J . Am. Chem. Soc. 1979, 101, 4981-
4991.
(16) The details of the preparation and characterization of this
compound are provided as Supporting Information.
2-[3-(ter t-Bu tyld ip h en ylsiloxy)-1,2-a n ti-d id eu ter iop r o-
p yl]-2-cycloh exen -1-on e (a n ti-8). The procedure is identical
(17) The combustion analysis data did not differentiate deuterium
and hydrogen in the evolved water. Therefore, the calculated hydrogen
analyses were determined by dividing the combined masses of the
hydrogen atoms (as if they were all protons) by the formula weight of
the deuterated compound.
(18) Kautzner, B.; Wailes, P. C.; Weigold, H. J . Chem. Soc., Chem.
Commun. 1969, 1105.
(19) For a recent example of reactions of Schwartz’s reagent with
alkynes, see: Lipshutz, B. H.; Keil, R.; Ellsworth, E. L. Tetrahedron
Lett. 1990, 31, 7257-7260.

460 J . Org. Chem., Vol. 63, No. 3, 1998
Ridgway and Woerpel
with that employed to prepare syn-7 (vide supra) to provide
the product in 43% yield: IR (thin film) 3071, 2168, 1673, 1110
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.66 (m, 4H), 7.39 (m, 6H),
6.65 (t, J ) 4.2, 1H), 3.64 (d, J ) 6.3, 2H), 2.39 (t, J ) 6.7,
2H), 2.29 (m, J ) 5.8, 2H), 2.24 (d, J ) 9.1, 1H), 1.93 (quintet,
J ) 6.4, 2H), 1.64 (m, 1H), 1.05 (s, 9H); 2H{1H} NMR (77 MHz,
thank the National Institutes of Health, the National
Science Foundation, and Pharmacia & Upjohn for
support of our research. K.A.W. thanks the American
Cancer Society (for a J unior Faculty Research Award)
and the Research Corporation (for a Cottrell Scholars
Award). We thank Dr. J ohn Greaves and Dr. J ohn Mudd
for mass spectrometric data.
CDCl3) δ 1.67, 2.28; 13C NMR (125 MHz, CDCl3) δ 199.4, 145.3,
1
139.2, 135.5, 134.0, 129.5, 127.6, 63.2, 38.5, 30.8 (t, J CD
)
1
19.4), 26.8, 26.0, 25.5 (t, J CD ) 19.4), 23.1, 19.2; HRMS (EI)
m/z calcd for C21H21D2O2Si (M+ - C(CH3)3) 337.1593, found
337.1601.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
1
tails for the preparation of 1 and 3 as well as H and 13C NMR
spectra for cis-2, 4, trans-5, syn-7, and anti-8 (13 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
Ack n ow led gm en t. We thank Professor J ohn A.
Soderquist (University of Puerto Rico, Rio Piedras) for
sharing the results of his experiments prior to publica-
tion. Acknowledgment is made to the donors of the
Petroleum Research Fund, administered by the Ameri-
can Chemical Society, for support of this research. We
J O970803D