Stereochemistry of transmetalation of alkylboranes in nickel-catalyzed alkyl-alkyl cross-coupling reactions

Article abstract of DOI:10.1021/jo201263r

Deuterium-labeled alkylborane reagents 2a and 2b were prepared and subjected to cross-coupling reactions in the presence of a nickel catalyst. NMR analysis of the products indicates that transmetalation from boron to nickel proceeds with retention of conf

Full text of DOI:10.1021/jo201263r

NOTE
pubs.acs.org/joc
Stereochemistry of Transmetalation of Alkylboranes in
Nickel-Catalyzed AlkylꢀAlkyl Cross-Coupling Reactions
Buck L. H. Taylor and Elizabeth R. Jarvo*
Natural Sciences I 4114, Depazrtment of Chemistry, University of California, Irvine, California 92697
S Supporting Information
b
ABSTRACT: Deuterium-labeled alkylborane reagents 2a and 2b were prepared and
subjected to cross-coupling reactions in the presence of a nickel catalyst. NMR analysis
of the products indicates that transmetalation from boron to nickel proceeds with
retention of configuration. These results demonstrate that alkylnickel intermediates are
configurationally stable under Suzuki cross-coupling conditions.
ransition-metal-catalyzed cross-coupling reactions have
revolutionized the synthesis of natural products and medic-
Scheme 1. Possible Mechanisms for Racemization of Alkyl
Halides in Nickel-Catalyzed Cross-Coupling Reactions
T
inal agents and provided rapid synthetic access to a diverse range
of molecules for biological testing.1 The development of cross-
coupling reactions of alkyl electrophiles and alkyl nucleophiles is
important because these reactions generate new CꢀC bonds
between sp3-hybridized carbons.2 Such transformations are less
well-developed than related reactions of aryl and vinyl reaction
partners,3 in part due to competing side reactions of the
alkylmetal intermediates. Many of the inherent challenges to
sp3ꢀsp3 cross-couplings have been overcome with the use of
nickel catalysts.4,5 In contrast to palladium-catalyzed cross-
couplings, in which detailed mechanistic studies have led to
major advances in cross-coupling methods,6,7 the mechanistic
details of nickel-catalyzed reactions are less well-understood.
Additional mechanistic data concerning the elementary steps of
nickel-catalyzed reactions are important for the continued devel-
opment of these reactions.
Scheme 2. Stereochemical Studies of Alkylmetal Reagents in
Nickel-Catalyzed Cross-Coupling Reactions
Our interest in the development of a stereospecific nickel-
catalyzed cross-coupling reaction required that all steps in-
volving alkylnickel intermediates proceed with stereochemical
fidelity.8 It has been shown that nickel-catalyzed cross-coupling
reactions of alkyl halides lead to loss of stereochemical information
from the alkyl halide.9,10 Stille proposed two possible rationales for
this observation: oxidative addition via a radical mechanism (path
a, Scheme 1) or reversible homolysis of NiꢀC bonds to provide
radical intermediates (path b, Scheme 1).11 Recent studies of
Negishi cross-coupling reactions by the groups of Vicic,12
Cꢀardenas,5d and Phillips13 have provided support for a radical
mechanism for oxidative addition. On the other hand, Halpern has
shown that benzylnickel(II) complexes undergo rapid and rever-
sible NiꢀC bond homolysis at room temperature.14 Since race-
mization of alkylnickel complexes would preclude a stereospecific
cross-coupling reaction, we set out to examine the stereochemical
integrity of nonbenzylic alkylnickel complexes using a chiral
organometallic cross-coupling partner.
(Scheme 2).15,16 Hoffmann found that cross-coupling of
Grignard reagents proceeds with retention of configuration.17
While, to the best of our knowledge, detailed studies of the
stereochemical outcome of transmetalation from alkylzinc reagents
and nickel catalysts have not been reported, Knochel has
reported diastereoselective cross-coupling of a norbornylzinc
reagent that procedes with retention of configuration.18,19 In
Nickel-catalyzed cross-coupling reactions of chiral alkylmag-
nesium and alkylzinc reagents have been studied at low tempera-
tures, where racemization of the alkylmetal reagent is suppressed
Received: June 15, 2011
Published: July 28, 2011
r
2011 American Chemical Society
7573
dx.doi.org/10.1021/jo201263r J. Org. Chem. 2011, 76, 7573–7576
|

The Journal of Organic Chemistry
NOTE
Table 1. Stereospecific BoronꢀNickel Transmetalation in Suzuki Cross-Coupling Reactions
entry
styrene
R1
R2
catalyst
ligand
product
yield (%)
1
2
3
1a
1b
1b
D
H
H
H
D
D
NiCl2 DME
4
4
5
3a
3b
3b
85
71
56
3
NiCl2 DME
3
Ni(cod)2
catalysts is important for the further development of asymmetric
alkylꢀalkyl cross-coupling reactions, particularly reactions that
will employ secondary organometallic reagents.
’ EXPERIMENTAL SECTION
General Methods. All reactions were carried out under an atmo-
sphere of N2. All glassware was oven- or flame-dried prior to use.
Tetrahydrofuran (THF), diethyl ether (Et2O), and toluene (PhMe)
were degassed with Ar and then passed through two columns of
anhydrous neutral A-2 alumina (activated under a flow of argon at
350 °C for 12 h) to remove H2O. Dioxane was freshly distilled from
sodium benzophenone ketyl prior to use. Isobutanol (i-BuOH) was distilled
from CaH2 prior to use. Proton chemical shifts are reported in parts per
million (δ) relative to internal tetramethylsilane (TMS, δ 0.00). Carbon
chemical shifts are reported in parts per million (δ) relative to TMS with
the solvent resonance as the internal standard (CDCl3, δ 77.23 ppm).
Deuterium chemical shifts are reported in parts per million (δ) relative to
TMS with the solvent resonance as the internal standard (CDCl3,
δ 7.24 ppm). NMR data were collected at 25 °C. Flash chromatography
was performed using EMD Geduran silica gel 60A (0.040ꢀ0.063 μm).
cis-1,2-Dideuteriostyene (1a) was prepared by treating phenylacetylene
with Cp2ZrDCl, followed by D2O, according to a procedure by Bercaw
et al.25 1H NMR spectroscopy indicated 93% deuterium incorporation,
in accord with reported spectral data.26 The product was stored at
ꢀ20 °C and used within 12 h of isolation.
Figure 1. Newman projections of predominant conformers of cross-
couping products.
this report, we examine the nickel-catalyzed cross-coupling of
alkylboranes, common reagents in sp3ꢀsp3 cross-coupling reactions
that show robust stereochemical integrity at room temperature.
We designed a stereochemical test using deuterium label-
ing, inspired by the work of Whitesides,20 Woerpel,6a and
Soderquist.6b Deuterium-labeled styrenes 1a and 1b were pre-
pared and subjected to hydroboration to provide boranes 2a and
2b, respectively (Table 1).21 Application of cross-coupling con-
ditions developed by Fu and co-workers furnished the products
2
1
3a and 3b, respectively.5a Analysis by H-decoupled H NMR
indicated that the products were formed as single diastereomers
(>95%) using two different nickel catalysts.22 The products 3a
and 3b can be distinguished based on their HaꢀHb coupling
constants because the predominant conformers in solution
should be anti-3a and anti-3b (Figure 1). The HaꢀHb coupling
constant in anti-3a (in which Ha and Hb are gauche) is expected
to be significantly smaller than in anti-3b (in which Ha and Hb are
anti).20 The HaꢀHb coupling constants for 3a and 3b were found
to be 6.3 and 9.1 Hz, respectively, supporting the relative
stereochemistry shown in Table 1.23 These results are consistent
with retention of configuration in the transmetalation step of the
cross-coupling reaction.24
trans-1,2-Dideuteriostyene (1b) was prepared by treating deuteriophe-
nylacetylene with Cp2ZrDCl, followed by H2O, according to a proce-
dure by Bercaw et al.25 Note: there is a typo in the reported procedure:
the metalated complex must be treated with H2O, rather than D2O. 1H
NMR spectroscopy indicated 95% deuterium incorporation, in accord
with reported spectral data.26 The product was stored at ꢀ20 °C and
used within 12 h of isolation.
syn-3,4-Dideuterio-4-phenylbutoxy(tert-butyl)dimethylsilane (3a).
The procedure reported by Saito and Fu was adapted.5a In a N2
atmosphere glovebox, styrene 1a (240 mg, 2.26 mmol) was added to a
suspension of 9-BBN dimer (275 mg, 1.13 mmol dimer) in dioxane
(0.6 mL). The flask was sealed with a septum and removed from the
glovebox. A N2 inlet was introduced, and the mixture was stirred at
60 °C for 1 h. The mixture was then cooled to rt and returned to the
glovebox. The clear solution was transferred to a vial, and dioxane was
added to produce a total volume of 4.5 mL (0.5 M). A portion of the
resulting solution of 2a (4.0 mL, 2.0 mmol, 0.5 M) was added to a
mixture of KOt-Bu (150 mg, 1.34 mmol) and i-BuOH (0.21 mL, 2.3
mmol) in a 6 mL vial. The solution was stirred vigorously for 30 min.27
In conclusion, we have demonstrated that nickel catalysts
obtained from diamine ligands 4 and 5 undergo transmetalation
with an alkylborane with retention of configuration during cross-
coupling reactions. The formation of 3a and 3b as single
diastereomers is consistent with slow racemization of alkylnickel
complexes at room temperature under Suzuki cross-coupling
conditions. This result precludes NiꢀC bond homolysis under
these conditions (path b, Scheme 1) and lends indirect support
for a radical mechanism for oxidative addition as the process in
which alkyl halides lose stereochemical information during nickel-
catalyzed reactions. The stereospecificityoftransmetalationtonickel
7574
dx.doi.org/10.1021/jo201263r |J. Org. Chem. 2011, 76, 7573–7576

The Journal of Organic Chemistry
NOTE
To the resulting white suspension was added a solution of NiCl2 DME
’ REFERENCES
3
(24mg, 0.11 mmol) and rac-trans-N,N0-dimethyl-1,2-cyclohexanediamine
(4, 19 mg, 0.13 mmol) in dioxane (1 mL), followed by 2-bromoethoxy-
(tert-butyl)dimethylsilane28 (263 mg, 1.10 mmol). The vial was capped,
and the mixture was stirred at rt for 24 h, after which it was passed
through a pad of silica gel eluting with Et2O/pentane (1:1, 20 mL) and
concentrated in vacuo. The product was purified by flash chromatogra-
phy (3% Et2O/pentane) to afford 3a as a colorless oil (250 mg, 85%):
TLC Rf = 0.3 (5% Et2O/pentane); 1H{2H} NMR (600 MHz, CDCl3) δ
7.27 (t, J = 7.5 Hz, 2H), 7.19ꢀ7.15 (m, 3H), 3.62 (t, J = 6.4 Hz, 2H), 2.60
(d, J = 6.3 Hz, 1H), 1.64 (q, J = 7.0 Hz, 1H), 1.55 (q, J = 6.8 Hz, 2H), 0.89
(1) (a) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2004. (b) Beller,
M.; Bolm, C. Transition Metals for Organic Synthesis, 2nd ed.; Wiley-
VCH: Weinheim, Germany, 2004. (c) Magano, J.; Dunetz, J. R. Chem.
Rev. 2011, 111, 2177–2250.
(2) For a recent example of alkylꢀalkyl cross-coupling reactions in
target-oriented synthesis, see: Griggs, N. D.; Phillips, A. J. Org. Lett.
2008, 10, 4955–4957.
(3) For a representative sample of recent advances in palladium-
catalyzed alkylꢀaryl cross-coupling reactions, see: Molander, G. A.;
Canturk, B. Angew. Chem., Int. Ed. 2009, 48, 9240–9261.
(4) Reviews of alkyl cross-coupling reactions: (a) Jana, R.; Pathak,
T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417–1492. (b) Rudolph, A.;
Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 2656–2670. (c) Frisch,
A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674–688.
(5) Representative examples of nickel-catalyzed alkyl cross-coupling
reactions: (a) Saito, B.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 9602–
9603. (b) Singh, S. P.; Terao, J.; Kambe, N. Tetrahedron Lett. 2009,
50, 5644–5646. (c) Ren, P; Vechorkin, O.; von Allmen, K.; Scopelliti, R.;
Hu, X. J. Am. Chem. Soc. 2011, 133, 7084–7095. (d) Phapale, V. B.;
Bu~nuel, E.; García-Iglesias, M.; Cꢀardenas, D. J. Angew. Chem., Int. Ed.
2007, 46, 8790–8795.
(6) Mechanistic studies of transmetalation of alkylboranes to
palladium: (a) Ridgway, B. H.; Woerpel, K. A. J. Org. Chem. 1998, 63,
458–460. (b) Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461–
470.
(7) For example, stereochemical studies of transmetalation of alkyl-
boranes to palladium catalysts have facilitated stereospecific cross-
coupling reactions of these reagents: (a) Imao, D.; Glasspoole, B. W.;
Laberge, V. S.; Crudden, C. M. J. Am. Chem. Soc. 2009, 131, 5024–5025.
(b) Ohmura, T.; Awano, T.; Suginome, M. J. Am. Chem. Soc. 2010, 132,
13191–13193.
(s, 9H), 0.04 (s, 6H); 2H{1H} NMR (92 MHz, CHCl3) δ 2.62, 1.67; 13
C
NMR (125 MHz, CDCl3) δ 142.8, 128.6, 128.5, 125.8, 63.2, 35.4 (t,
1JCD = 19.5 Hz), 32.5, 27.4 (t, 1JCD = 18.9 Hz), 26.2, 18.6, ꢀ5.1; IR (thin
film) 3025, 2954, 2858, 2150, 1105 cmꢀ1; HRMS (TOF MS ES+) m/z
calcd for C16H26D2OSi (M + H)+ 267.2113, found 267.2121.
anti-3,4-Dideuterio-4-phenylbutoxy(tert-butyl)dimethylsilane (3b).
In a N2 atmosphere glovebox, styrene 1b (160 mg, 1.51 mmol) was
added to a suspension of 9-BBN dimer (183 mg, 0.750 mmol dimer) in
dioxane (0.4 mL). The flask was sealed with a septum and removed from
the glovebox. A N2 inlet was introduced, and the mixture was stirred at
60 °C for 1 h. The mixture was then cooled to rt and returned to the
glovebox. The clear solution was transferred to a vial, and dioxane was
added to produce a total volume of 3.0 mL (0.5 M). A portion of the
resulting solution of 2b (0.80 mL, 0.40 mmol, 0.5 M) was added to a
mixture of KOt-Bu (30 mg, 0.27 mmol) and i-BuOH (0.041 mL, 0.44
mmol) in a 6 mL vial. The solution was stirred vigorously for 30 min. To
the resulting white suspension was added a solution of NiCl2 DME (4.8 mg,
3
0.022 mmol) and rac-trans-N,N0-dimethyl-1,2-cyclohexanediamine (4, 3.7 mg,
0.026 mmol) in dioxane (0.2 mL), followed by 2-bromoethoxy(tert-bu-
tyl)dimethylsilane (52 mg, 0.22 mmol). The vial was capped, and the mixture
was stirred at rt for 24 h, after which it was passed through a pad of silica gel
eluting with Et2O/pentane (1:1, 20 mL) and concentrated in vacuo. The
product was purified by flash chromatography (3% Et2O/pentane) to afford
3b as a colorless oil (42 mg, 71%): TLC Rf =0.3(5%Et2O/pentane); 1H{2H}
NMR (600 MHz, CDCl3) δ 7.27 (t, J = 7.6 Hz, 2H), 7.19ꢀ7.15 (m, 3H),
3.62(t, J= 6.5 Hz, 2H), 2.60 (d, J=9.1Hz, 1H), 1.64(q, J= 8.1 Hz, 1H), 1.55
(q, J = 6.8 Hz, 2H), 0.89 (s, 9H), 0.04 (s, 6H); 2H{1H} NMR (92 MHz,
CHCl3) δ 2.62, 1.67; 13C NMR (125 MHz, CDCl3) δ 142.8, 128.6, 128.5,
125.8, 63.2, 35.4 (t, 1JCD = 18.9 Hz), 32.5, 27.4 (t, 1JCD = 19.5 Hz), 26.2, 18.6,
ꢀ5.1; IR (thin film) 3026, 2922, 2910, 2150, 1110 cmꢀ1; HRMS (TOF MS
ES+) m/z calcd for C16H26D2OSi (M + H)+ 267.2113, found 267.2117.
(8) Taylor, B. L. H.; Swift, E. C.; Waetzig, J. D.; Jarvo, E. R. J. Am.
Chem. Soc. 2011, 133, 389–391.
(9) Loss of stereochemistry from the alkyl halide has enabled the
development of enantioselective, stereoconvergent cross-coupling
methodologies. For representative examples, see: (a) Lu, Z.; Wilsily,
A.; Fu, G. C. J. Am. Chem. Soc. 2011, 133, 8154–8157. (b) Owsten, N. A.;
Fu, G. C. J. Am. Chem. Soc. 2010, 132, 11908–11909. (c) Saito, B.; Fu,
G. C. J. Am. Chem. Soc. 2008, 130, 6694–6695.
(10) In contrast, oxidative addition of alkyl halides and tosylates to
palladium proceeds with inversion of configuration: (a) Becker, Y.; Stille,
J. K. J. Am. Chem. Soc. 1978, 100, 838–844. (b) Netherton, M. R.; Fu,
G. C. Angew. Chem., Int. Ed. 2002, 41, 3910–3912.
(11) Stille, J. K.; Cowell, A. B. J. Organomet. Chem. 1977, 124, 253–
261.
(12) (a) Jones, G. D.; McFarland, C.; Anderson, T. J.; Vicic, D. A.
J. Chem. Soc., Chem. Commun. 2005, 4211–4213. (b) Anderson, T. J.;
Jones, G. D.; Vicic, D. A. J. Am. Chem. Soc. 2004, 126, 8100–8101.
(13) Lin, X.; Phillips, D. L. J. Org. Chem. 2008, 73, 3680–3688.
(14) Schofield, M. H.; Halpern, J. Inorg. Chim. Acta 2003,
345, 353–358.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra for
S
b
all new compounds, Figure S1, and Table S1. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) Grignard reagents racemize above 0 °C: (a) Davies, A. G.;
Roberts, B. P. J. Chem. Soc. B. 1969, 317–321. (b) Whitesides, G. M.;
Roberts, J. M. J. Am. Chem. Soc. 1965, 87, 4878–4888.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: erjarvo@uci.edu.
(16) Alkylzinc halides racemize slowly at room temperature:Guijarro,
A.; Rieke, R. D. Angew. Chem., Int. Ed. 2000, 39, 1475–1479.
(17) H€olzer, B.; Hoffmann, R. W. Chem. Commun. 2003, 732–733.
(18) Jensen, A. E.; Knochel, P. J. Org. Chem. 2002, 67, 79–85.
(19) For recent development of highly diastereoselective palladium-
catalyzed Negishi couplings that proceed via equilibration of diastere-
omeric alkylzinc reagents, see: (a) Thaler, T.; Haag, B.; Gavryushin, A.;
Schober, K.; Hartmann, E.; Gschwind, R. M.; Zipse, H.; Mayer, P.;
Knochel, P. Nat. Chem. 2010, 2, 125–130. (b) Seel, S.; Thaler, T.;
Takatsu, K.; Zhang, C.; Zipse, H.; Straub, B. F.; Mayer, P.; Knochel, P.
J. Am. Chem. Soc. 2011, 133, 4774–4777.
’ ACKNOWLEDGMENT
This work was supported by the University of California,
Irvine, Academic Senate Council on Research, Computing, and
Library Resources. B.L.H.T. is grateful for a University of
California Chancellor’s Fellowship. Dr. Philip Dennison is
acknowledged for assistance with NMR experiments.
7575
dx.doi.org/10.1021/jo201263r |J. Org. Chem. 2011, 76, 7573–7576

The Journal of Organic Chemistry
NOTE
(20) Whitesides pioneered the use of deuterium labeling to study the
stereochemistry of reactions of alkylmetal intermediates: Bock, P. L.;
Boschetto, D. J.; Rasmussen, J. R.; Demers, J. P.; Whitesides, G. M. J. Am.
Chem. Soc. 1974, 96, 2814–2825.
(21) Hydroborationisasynadditionprocess:Kabalka, G. W.;Bowman,
N. S. J. Org. Chem. 1973, 38, 1607–1608.
(22) The cross-coupling of unlabeled borane 2 was investigated with
a variety of diamine ligands (see Supporting Information, Table S1).
Table 1 represents the only catalysts that provided a satisfactory yield of
cross-coupled product.
2
(23) 1H spectra without H decoupling gave comparable coupling
constants (5.6 Hz for 3a and 9.5 Hz for 3b). See Supporting Information
1
for details and a comparison of the H NMR signals for 3a and 3b
(Figure S1).
(24) Reductive elimination at nickel catalysts occurs with retention
of configuration: B€ackvall, J. E.; Andell, O. S. Organometallics 1986,
5, 2350–2355.
(25) Nelson, J. E.; Parkin, G.; Bercaw, J. E. Organometallics 1992,
11, 2181–2189.
(26) Smith, P. J.; Crowe, D. A. J.; Westaway, K. C. Can. J. Chem.
2001, 79, 1145–1152.
(27) The activated borane complex is poorly soluble in dioxane. It
can be solubilized by dilution to ca. 0.1 M; however, it is convenient to
add the catalyst as a solution to the activated borane complex.
(28) Prepared from 2-bromoethanol according to: Vader, J.; Sengers,
H.; de Groot, A. Tetrahedron 1989, 45, 2131–2142.
7576
dx.doi.org/10.1021/jo201263r |J. Org. Chem. 2011, 76, 7573–7576