Cobalt-catalyzed enantioselective hydroboration of 1,1-disubstituted aryl alkenes

Article abstract of DOI:10.1021/ja5093908

We report the synthesis of cobalt complexes of novel iminopyridine-oxazoline (IPO) ligands and their application to the asymmetric hydroboration of 1,1-disubstituted aryl alkenes. The new catalysts afforded α-alkyl-β-pinacolatoboranes with exclusive regioselectivity in high yields with up to 99.5% ee. Furthermore, we have applied this method to an efficient synthesis of naproxen.

Full text of DOI:10.1021/ja5093908

Communication
pubs.acs.org/JACS
Cobalt-Catalyzed Enantioselective Hydroboration of 1,1-
Disubstituted Aryl Alkenes
Lei Zhang,† Ziqing Zuo,† Xiaolong Wan, and Zheng Huang*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200032,
China
S
* Supporting Information
with pinacolborane (HBPin). While the reaction with α-
ABSTRACT: We report the synthesis of cobalt com-
plexes of novel iminopyridine−oxazoline (IPO) ligands
and their application to the asymmetric hydroboration of
1,1-disubstituted aryl alkenes. The new catalysts afforded
α-alkyl-β-pinacolatoboranes with exclusive regioselectivity
in high yields with up to 99.5% ee. Furthermore, we have
applied this method to an efficient synthesis of naproxen.
methylstyrene afforded 93% ee, most reactions occurred with
low to moderate enantioselectivity (<5 to 80% ee). Another
attractive protocol was reported by Hoveyda and co-workers,
where NHC−Cu complexes catalyze asymmetric hydroboration
of 1,1-disubstituted aryl alkenes with bis(pinacolato)diboron
(B2Pin2). The Cu-catalyzed processes afforded excellent site
selectivity and ≥90% ee in the case of four α-alkyl aryl olefins
(overall range of ee: 61−93%).13
Base-metal catalysts have received significant attention in the
past decade not only because of their low cost, high earth
abundance, and environmentally benign nature but also because
they may supplant the traditional precious-metal catalysts in
some catalytic processes.14,15 As one manifestation of this
phenomenon, Fe and Co complexes of tridentate bipyridyl
phosphine (PNN) pincer ligands developed in our group have
proven to be 2−4 orders of magnitude more active than the
classical Rh and Ir catalysts for hydroborations of α-olefins with
HBPin.16 The PNN−iron complex was also found to be active
for the anti-Markovnikov hydroboration of 1,1-disubstituted
alkenes. We envisioned that asymmetric hydroboration of 1,1-
disubstituted alkenes might be feasible through the use of base-
metal catalysts containing suitable chiral ligands. Herein we
report the preparation of Co complexes of new iminopyridine−
oxazoline (IPO) ligands and the first Co-catalyzed asymmetric
alkene hydroborations with HBpin. This system exhibits
unprecedented levels of enantioselectivity for hydroborations
of 1,1-disubstituted aryl alkenes (up to 99.5% ee). The reactions
occur at ambient temperature with low catalyst loadings.
The synthesis of the new IPO ligands and their corresponding
Co complexes is outlined in Scheme 2. Treatment of 2-acetyl-6-
cyanopyridine with an arylamine bearing iPr substituents at the
2,6-aryl positions formed iminopyridine compound 1. The
condensation of 1 with various amino alcohols in the presence of
Zn(OTf)2 produced the chiral IPO ligands (S)-2a−c and (R)-2a
in moderate yields. The neutral Co(II) dichloride complexes
[(R/S)-R-IPO]CoCl2 (R = iPr for (S)-3a or (R)-3a; R = tBu for
(S)-3b; and R = Bn for (S)-3c) were formed in high yields by the
addition of the corresponding ligands to the anhydrous Co salt.
These Co(II) complexes show broadened and paramagnetically
shifted resonances in the 1H NMR spectrum. Single-crystal X-ray
diffraction analysis of (S)-3c revealed a distorted square-
pyramidal geometry around the Co center (Figure 1).
nantioselective transformations of 1,1-disubstituted alkenes
Erepresent an ultimate challenge because of the difficulty in
discriminating the enantiotopic faces of such substrates.1 Until
recently, high enantioselectivity (>90% ee) has been achieved
only in asymmetric hydrogenation2 and dihydroxylation3
reactions. On the other hand, enantioselective hydroboration
of 1,1-disubstituted alkenes is of especial interest because it can
provide access to optically pure alkylboron compounds, which
are vital intermediates in organic synthesis (Scheme 1).4 Thus, an
efficient method for asymmetric hydroboration of 1,1-
disubstituted alkenes is highly desirable.
Scheme 1
There are two strategies for asymmetric alkene hydroboration:
one involves the use of chiral organoborane agents, and the other
involves asymmetric catalysis. Pioneered by Brown,5 numerous
chiral organoboranes have been developed for uncatalyzed
asymmetric anti-Markovnikov hydroborations of alkenes.6
Recently, Soderquist and co-workers developed chiral 9-
borabicyclo[3.3.2]decanes that gave the best enantioselectivity
of any chiral boron reagents investigated to date for hydro-
borations of 1,1-disubstituted alkenes. The reactions with α-
deuterium-labeled styrene and α-methylstyrene gave 98% and
78% ee, respectively.7
To avoid using the expensive and difficult-to-access chiral
organoborane reagents, several transition-metal catalysts have
been developed for asymmetric hydroborations with common
boron reagents.8−10 The Rh- and Ir-catalyzed hydroborations of
1,1-disubstituted alkenes with catecholborane exhibit low regio-
and enantioselectivity.8c,11 Recently, Mazet and Gerard12
reported an Ir complex of phosphinooxazoline for anti-
Markovnikov hydroboration of 1,1-disubstituted aryl alkenes
Received: September 11, 2014
Published: October 17, 2014
© 2014 American Chemical Society
15501
dx.doi.org/10.1021/ja5093908 | J. Am. Chem. Soc. 2014, 136, 15501−15504

Journal of the American Chemical Society
Communication
Scheme 2. Synthesis of the IPO Ligands and Their
Corresponding Co Complexes
Table 1. Cobalt-catalyzed Asymmetric Hydroboration of α-
Methylstyrene (5a) with HBPin
a
a
Reaction conditions: 5a (0.5 mmol), HBPin (0.5 mmol), (S)-3 or
(S)-4a (0.5 mol %), and NaBEt3H (1 mol %) in THF (2 mL) at 25
°C. Isolated yields and ee’s determined by HPLC analysis are shown.
b
c
Without the addtion of NaBEt3H. Reaction conditions: 5a (0.5
mmol), HBPin (0.5 mmol), (S)-iPr-Pybox (0.5 mol %), CoCl2 (0.5
mol %), and NaBEt31H (1 mol %) in THF (2 mL) at 25 °C. The yield
was determined by H NMR analysis with mesitylene as an internal
standard.
Upon activation with NaBEt3H, the Co dichloride complex (S)-
3a with an iPr substituent on the oxazoline moiety is active for
hydroboration of 5a with HBPin. The process with 1 mol % (S)-
3a in THF (3 h, 25 °C) formed the primary alkylboronate ester
6a in 85% yield. The reaction gave exclusive regioselectivity and
excellent enantioselectivity (97% ee). An increase in the steric
bulk in going from (S)-3a to (S)-3b by replacing the iPr
substituent with tBu led to a lower enantioselectivity (91% ee).
However, the precatalyst (S)-3c with a Bn substituent afforded
the product with 99% ee in 91% yield. When the Co methyl
complex (S)-4a derived from (S)-3a was employed, the best
results in terms of enantioselectivity and yield were obtained
(99% ee, 95% yield). The high activity of (S)-4a allowed the
reaction to occur with a lower catalyst loading (0.5 mol %) and a
shorter reaction time (0.5 h), furnishing 6a in 95% yield with 99%
ee (Table 2). It should be noted that the reactions with (S)-4a do
not need an activating reagent.
To probe whether the imino moiety of the IPO ligands is
required for the asymmetric hydroboration reaction, the IPO
ligand was replaced by (S)-iPr-Pybox. Under otherwise identical
reaction conditions, a combination of (S)-iPr-Pybox and CoCl2
led to a reduced yield of 6a (22% NMR yield; Table 1). The
preliminary results suggest that while the oxazoline unit of the
IPO ligands induces the enantioselectivity, the imino group is
essential for enhanced activity of the Co catalyst in alkene
hydroborations.
Figure 1. Crystal structure of complex (S)-3c. H atoms have been
omitted for clarity. Ellipsoids are drawn at the 30% probability level.
Selected bond distances (Å) and angles (deg): Co1−N1, 2.143(3);
Co1−N2, 2.065(4); Co1−N3 2.200(3); Co1−Cl1, 2.2614(14); Co1−
Cl2, 2.2998(12); N1−Co1−N2, 74.47(14); N2−Co1−N3, 73.61(14);
N1−Co1−N3, 139.63(13); N2−Co1−Cl1, 151.80(9); N2−Co1−Cl2,
91.04(9); Cl1−Co1−Cl2, 117.13(5).
The Co dichloride complexes can be readily converted to the
Co methyl species. The reaction of [(S)-iPr-IPO]CoCl2 (S)-3a
with 2 equiv of MeLi formed the Co methyl complex [(S)-iPr-
IPO]CoMe (S)-4a in 96% yield (eq 1). (S)-4a is diamagnetic,
To delineate the scope of the Co-catalyzed asymmetric
hydroboration, (S)-4a was applied to the reactions of various 1,1-
disubstituted aryl alkyl ethenes. The results are summarized in
Table 2. All of the reactions proceeded smoothly at ambient
temperature with low catalyst loadings (0.5−2 mol %). Most of
the reactions provided high isolated yields with excellent
enantioselectivity (95−99.5% ee) and complete regioselectivity.
The method works efficiently for α-methylstyrene derivatives
bearing both electron-donating and -withdrawing groups.
Halogen-substituted α-methylstyrenes, including the p-iodo-
which facilitates its characterization by NMR spectroscopy. The
characteristic Co−Me resonance appears at −2.34 ppm as a
1
singlet in the H NMR spectrum, which is consistent with that
observed for the related bis(imino)pyridine Co methyl complex-
es.2b
The enantiopure C1-symmetric (IPO)Co complexes were
evaluated as precatalysts for the asymmetric hydroboration of α-
methylstyrene (5a). The results are summarized in Table 1.
15502
dx.doi.org/10.1021/ja5093908 | J. Am. Chem. Soc. 2014, 136, 15501−15504

Journal of the American Chemical Society
Communication
excellent enatioselectivity. Earlier work showed that the
asymmetric hydroboration of ortho-substituted α-methylstyrene
is very difficult (e.g., the Ir-catalyzed hydroboration of o-methyl-
α-methylstyrene (5n) reported by Mazet gave <5% ee and 66%
yield.12) To our delight, the Co-catalyzed hydroboration of 5n
afforded 76% ee and 94% yield. The substrates bearing naphthyl
groups reacted smoothly to afford the desired products (6l, 93%
yield, 99% ee; 6m, 93% yield, 99% ee).
Table 2. Cobalt-catalyzed Asymmetric Hydroboration of 1,1-
Disubstituted Alkenes
a
Increasing the steric demand in the vicinity of the benzylic
position by using an Et, nPr, or Bn group did not affect the
enantioselectivity (6o−q). Ester and chloride functionalities in
the alkyl chains were also tolerated, as demonstrated by the
isolation of 6r and 6s with excellent enantioselectivity.
Furthermore, the hydroboration of exocyclic 1,1-disubstituted
alkene 5p provided the product in 78% yield with 92% ee.
Asymmetric hydroboration of 1,1-diarylethenes is a significant
challenge. Indeed, no catalyst systems for asymmetric hydro-
boration of this substrate type have previously been reported.
The Co-catalyzed hydroboration of 1,1-diarylethene 5u bearing a
p-methyl substituent gave the product in 84% yield with 8% ee.
Although the bulkier diarylethene 5v with an o-methyl
substituent was less reactive (24 h, 19% yield), the steric bias
at the ortho position led to the formation of 6v with 54% ee.
The hydroboration of the 1,1-dialkylethene 2-methyl-4-
phenyl-1-butene (5w) gave the product 6w with low
enantioselectivity (14% ee). However, the reaction of chiral
(L)-limonene (5x) with (S)-4a afforded the S,R diastereomer 6x
with 80:20 dr. The mismatched combination of 5x with (R)-3a
provided 68:32 dr in favor of the S,S diastereomer. It is
noteworthy that the trisubstituted olefin in 5x is unreactive under
the Co-catalyzed hydroboration conditions.
Our preliminary results show that the (IPO)Co catalyst is also
active for hydroboration of 1,2-disubstituted internal olefins. The
asymmetric hydroboration of norbornene gave the exo product
6y exclusively with an impressive 94% ee.17 The reaction of (E)-
1,2-diphenylethene formed 6z in 77% ee.
Finally, the asymmetric hydroboration provided an efficient
method for the synthesis of naproxen. Hydroboration of 5m with
(S)-4a as the catalyst precursor as shown above produced the S
enantiomer selectively (see Table 2). We were pleased to find
that a simple change of the precatalyst from (S)-4a to (R)-3a (0.5
mol %) resulted in the formation of the R enantiomer 7 in 95%
yield with 98% ee. A three-step oxidation sequence converted 7
to naproxen without epimerization of the stereogenic center
(98% ee, 66% overall yield) (Scheme 3).
Scheme 3. Synthesis of Naproxen
a
Reaction conditions: 5 (0.5 mmol), HBPin (0.5 mmol), and (S)-4a
(0.5 mol %) in THF (2 mL) at 25 °C. Isolated yields and ee’s
determined by HPLC analysis are shown. The absolute configurations
b
were assigned by comparison with reported optical rotations. With
c
d
2.0 mol % (S)-4a. With 3.0 mol % (S)-4a. Determined by oxidation
to the corresponding alcohol using 30% H2O2 and quantitative 13C
NMR analysis.
substituted one, were hydroborated in high yields with 95−99%
ee. Ester and dimethylamine functionalities are tolerated, as
shown by the isolation of 6j and 6k in high yields with high
enantioselectivity. Substituents at the para and meta positions of
the phenyl ring are tolerated under the reaction conditions,
furnishing the hydroboration products in high yields with
15503
dx.doi.org/10.1021/ja5093908 | J. Am. Chem. Soc. 2014, 136, 15501−15504

Journal of the American Chemical Society
Communication
A.; Marder, T. B.; Baker, R. T. Organometallics 1993, 12, 975. (f) Doucet,
H.; Fernandez, E.; Layzell, T. P.; Brown, J. M. Chem.Eur. J. 1999, 5,
1320. (g) Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert, H.;
Tijani, A. J. Am. Chem. Soc. 1994, 116, 4062. (h) Schnyder, A.;
Hintermann, L.; Togni, A. Angew. Chem., Int. Ed. Engl. 1995, 34, 931.
In summary, we have prepared and characterized cobalt
complexes ligated by chiral iminopyridine−oxazoline (IPO)
ligands. The new cobalt catalyst system is highly efficient for
asymmetric hydroboration of 1,1-disubstituted aryl alkenes, thus
affording optically pure primary alkylboronate esters with
unprecedented enantioselectivity. Additional studies of asym-
metric transformations with the IPO ligands are currently
underway in our laboratory.
(i) Kollner, C.; Togni, A. Can. J. Chem. 2001, 79, 1762. (j) Kwong, F. Y.;
̈
Yang, Q.; Mak, T. C. W.; Chan, A. S. C.; Chan, K. S. J. Org. Chem. 2002,
67, 2769. (k) Crudden, C. M.; Hleba, Y. B.; Chen, A. C. J. Am. Chem. Soc.
2004, 126, 9200. (l) Segarra, A. M.; Daura-Oller, E.; Claver, C.; Poblet, J.
M.; Bo, C.; Fernan
́
dez, E. Chem.Eur. J. 2004, 10, 6456. (m) Moteki, S.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data, and crystallo-
graphic data (CIF) for complex (S)-3c. This material is available
free of charge via the Internet at http://pubs.acs.org.
A.; Wu, D.; Chandra, K. L.; Reddy, D. S.; Takacs, J. M. Org. Lett. 2006, 8,
3097. (n) Noh, D.; Chea, H.; Ju, J.; Yun, J. Angew. Chem., Int. Ed. 2009,
48, 6062.
■
S
(9) Lee and Yun reported a Cu-catalyzed asymmetric hydroboration of
β-substituted vinyl arenes with HBPin. See: Noh, D.; Yoon, S. K.; Won,
J.; Lee, J. Y.; Yun, J. Chem.Asian J. 2011, 6, 1967.
(10) Takacs and co-workers described a carbonyl-directed Rh-
catalyzed asymmetric hydroboration of 1,1-disubstituted alkenes. The
anti-Markovnikov products were obtained as the major products with
90−94% ee. See: (a) Smith, S. M.; Hoang, G. L.; Pal, R.; Khaled, M. O.
B.; Pelter, L. S. W.; Zeng, X. C.; Takacs, J. M. Chem. Commun. 2012, 48,
12180. For examples of carbonyl-directed asymmetric hydroboration of
other types of alkenes, see: (b) Smith, S. M.; Thacker, N. C.; Takacs, J.
M. J. Am. Chem. Soc. 2008, 130, 3734. (c) Smith, S. M.; Takacs, J. M. J.
Am. Chem. Soc. 2010, 132, 1740.
AUTHOR INFORMATION
Corresponding Author
huangzh@sioc.ac.cn
■
Author Contributions
†L.Z. and Z.Z. contributed equally.
Notes
The authors declare no competing financial interest.
(11) (a) Sato, M.; Miyaura, N.; Suzuki, A. Tetrahedron Lett. 1990, 31,
231. (b) Burgess, K.; Ohlmeyer, M. J. J. Org. Chem. 1988, 53, 5178.
(12) Mazet, C.; Gerard, D. Chem. Commun. 2011, 47, 298.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (21272255,
21121062).
(13) Corberan
2011, 50, 7079.
́
, R.; Mszar, N. W.; Hoveyda, A. H. Angew. Chem., Int. Ed.
(14) For reviews, see: (a) Iron Catalysis in Organic Chemistry; Plietker,
B., Ed.; Wiley-VCH: Weinheim, Germany, 2008. (b) Bolm, C.; Legros,
J.; Le Paih, J.; Zani, L. Chem. Rev. 2004, 104, 6217. (c) Sherry, B. D.;
REFERENCES
■
Furstner, A. Acc. Chem. Res. 2008, 41, 1500. (d) Chirik, P. J. Catalysis
̈
(1) (a) Thomas, S. P.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2009, 48,
without Precious Metals; Bullock, R. M., Ed.; Wiley-VCH: Weinheim,
Germany, 2010; pp 83−110. (e) Junge, K.; Schroder, M.; Beller, M.
Chem. Commun. 2011, 47, 4849. (f) Morris, R. H. Chem. Soc. Rev. 2009,
38, 2282. (g) Nakazawa, H.; Itazaki, M. Top. Organomet. Chem. 2011, 33,
27.
1896. (b) Verendel, J. J.; Pam
Chem. Rev. 2014, 114, 2130. (c) Cui, X.; Burgess, K. Chem. Rev. 2005,
105, 3272. (d) Roseblade, S. J.; Pfaltz, A. Acc. Chem. Res. 2007, 40, 1402.
̀
ies, O.; Dieg
́
uez, M.; Andersson, P. G.
́ ̀
(2) (a) Dieguez, M.; Mazuela, J.; Pamies, O.; Verendel, J. J.; Andersson,
P. G. J. Am. Chem. Soc. 2008, 130, 7208. (b) Monfette, S.; Turner, Z. R.;
Semproni, S. P.; Chirik, P. J. J. Am. Chem. Soc. 2012, 134, 4561. (c) Bess,
E. N.; Sigman, M. S. Org. Lett. 2013, 15, 646. (d) McIntyre, S.;
(15) (a) Yu, R. P.; Darmon, J. M.; Milsmann, C.; Margulieux, G. W.;
Stieber, S. C. E.; DeBeer, S.; Chirik, P. J. J. Am. Chem. Soc. 2013, 135,
13168. (b) Tondreau, A. M.; Atienza, C. C. H.; Weller, K. J.; Nye, S. A.;
Lewis, K. M.; Delis, J. G. P.; Chirik, P. J. Science 2012, 335, 567.
(c) Zhang, G.; Scott, B. L.; Hanson, S. K. Angew. Chem., Int. Ed. 2012, 51,
12268.
(16) (a) Zhang, L.; Peng, D.; Leng, X.; Huang, Z. Angew. Chem., Int. Ed.
2013, 52, 3676. (b) Zhang, L.; Zuo, Z.; Leng, X.; Huang, Z. Angew.
Chem., Int. Ed. 2014, 53, 2696. (c) Obligacion, J. V.; Chirik, P. J. Org.
Lett. 2013, 15, 2680. (d) Greenhalgh, M. D.; Thomas, S. P. Chem.
Commun. 2013, 49, 11230. (e) Obligacion, J. V.; Chirik, P. J. J. Am.
Chem. Soc. 2013, 135, 19107. (f) Ruddy, A. J.; Sydora, O. L.; Small, B. L.;
Stradiotto, M.; Turculet, L. Chem.Eur. J. 2014, 20, 13918.
(17) As a comparison, the best enantioselectivity reported in early
studies was obtained by Rh-catalyzed hydroboration of norbornene with
catecholborane (64% ee). See ref 11b.
Hormann, E.; Menges, F.; Smidt, S. P.; Pfaltz, A. Adv. Synth. Catal. 2005,
347, 282. (e) Song, S.; Zhu, S.-F.; Yu, Y.-B.; Zhou, Q.-L. Angew. Chem.,
Int. Ed. 2013, 52, 1556.
̈
(3) (a) Wang, X.; Zak, M.; Maddess, M.; O’Shea, P.; Tillyer, R.;
Grabowski, E. J. J.; Reider, P. J. Tetrahedron Lett. 2000, 41, 4865.
(b) Becker, H.; King, S. B.; Taniguchi, M.; Vanhessche, K. P. M.;
Sharpless, K. B. J. Org. Chem. 1995, 60, 3940.
(4) (a) Brown, H. C. Organic Synthesis via Organoboranes; Wiley
Interscience: New York, 1975. (b) Mikhailov, B. M.; Bubnov, Y. N.
Organoboron Compounds in Organic Synthesis; Harwood Academic:
Amsterdam, 1983. (c) Crudden, C. M.; Edwards, D. Eur. J. Org. Chem.
2003, 4695. (d) Boronic Acids: Preparation and Applications in Organic
Synthesis and Medicine; Hall, D. G., Ed.; Wiley-VCH: Weinheim,
Germany, 2005. (e) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev.
2011, 111, 1417.
(5) (a) Brown, H. C.; Zweifel, G. J. Am. Chem. Soc. 1961, 83, 486.
(b) Brown, H. C.; Ayyangar, N. R.; Zweifel, G. J. Am. Chem. Soc. 1964,
86, 397.
(6) Masamune, S.; Kim, B. M.; Petersen, J. S.; Sato, T.; Veenstra, S. J.;
Imai, T. J. Am. Chem. Soc. 1985, 107, 4549.
́
(7) Gonzalez, A. Z.; Roman, J. G.; Gonzalez, E.; Martinez, J.; Medina, J.
R.; Matos, K.; Soderquist, J. A. J. Am. Chem. Soc. 2008, 130, 9218.
(8) For examples of asymmetric Markovnikov hydroboration of 1-
substituted styrene derivatives, see: (a) Hayashi, T.; Matsumoto, Y.; Ito,
Y. J. Am. Chem. Soc. 1989, 111, 3426. (b) Zhang, J.; Lou, B.; Guo, G.; Dai,
L. J. Org. Chem. 1991, 56, 1670. (c) Hayashi, T.; Matsumoto, Y.; Ito, Y.
Tetrahedron: Asymmetry 1991, 2, 601. (d) Brown, J. M.; Hulmes, D. I.;
Layzell, T. P. J. Chem. Soc., Chem. Commun. 1993, 1673. (e) Westcott, S.
15504
dx.doi.org/10.1021/ja5093908 | J. Am. Chem. Soc. 2014, 136, 15501−15504