γ-Selective directed catalytic asymmetric hydroboration of 1,1-disubstituted alkenes

Article abstract of DOI:10.1039/c2cc36199j

Directed catalytic asymmetric hydroborations of 1,1-disubstituted alkenes afford γ-dioxaborato amides and esters in high enantiomeric purity (90-95% ee). The Royal Society of Chemistry 2012..

Full text of DOI:10.1039/c2cc36199j

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 12180–12182
www.rsc.org/chemcomm
COMMUNICATION
c-Selective directed catalytic asymmetric hydroboration of
1,1-disubstituted alkenesw
Sean M. Smith,a Gia L. Hoang,a Rhitankar Pal,a Mohammad O. Bani Khaled,a
Liberty S. W. Pelter,b Xiao Cheng Zenga and James M. Takacs*a
Received 26th August 2012, Accepted 31st October 2012
DOI: 10.1039/c2cc36199j
Directed catalytic asymmetric hydroborations of 1,1-disubstituted
alkenes afford c-dioxaborato amides and esters in high enantiomeric
purity (90–95% ee).
Chiral organoboronates are useful synthetic intermediates for
a growing number of stereospecific transformations.1 As such,
there is renewed interest in enantioselective methods for their
preparation.2–9 We reported advances in the carbonyl-directed
catalytic asymmetric hydroboration (CAHB) of (E)- and (Z)-
disubstituted and trisubstituted alkenes contained within a
b,g-unsaturated amide framework.10,11 Their rhodium-catalysed
reactions employ simple chiral monophosphite ligands to produce
b-borylated products regio- and enantioselectively. For example,
directed-CAHB of 1 by pinacolborane (pinBH) or 4,4,6-tri-
methyl-1,3,2-dioxaborinane (tmdBH, 5)12 using Rh(nbd)2BF4
in conjunction with TADDOL-derived phosphite (R,R)-6 gives
b-dioxaborato amide (S)-2 in high enantiomeric purity (tmdBH:
79% (96% ee); pinBH: 77% (95% ee), Fig. 1). Only trace amounts
of the regioisomeric g-substituted product are formed (o3%).
Fig. 1 Regio- and enantioselective carbonyl-directed CAHB of 1,2-
As highlighted in several recent reports,13 1,1-disubstituted
alkenes (i.e., methylidene substrates) are particularly challenging
substrates for asymmetric hydroboration.14 Directed-CAHB
of the methylidene substrate, b,g-unsaturated amide 3, affords
predominantly (R)-4 (tmdBH: 72% (95% ee); pinBH: 68%
(60% ee); Fig. 1). In contrast to unsaturated amide 1, the
isomeric substrate 3 affords the g-borylated, rather than
b-borylated, product predominantly. Equally unexpected,
using the same chiral ligand and catalyst, tmdBH adds to
opposite faces of the alkene in the isomeric substrates.
and 1,1-disubstituted alkenes (ee determined after oxidation).
Table 1 Enantioselective CAHB of 1,1-disubstituted alkenes 7a–7ia
7
X
R
g-Isomer % Yield (% ee)a % Yield 9b
a
b
NHPh Me
NHPh Et
(S)-8a
(R)-8b
53 (94)
60 (92)
73 (94)
70 (92)
72 (90)
71 (93)
62 (94)
65 (91)
78 (91)
11
10
3
3
2
4
6
5
4
The results obtained for a series of methylidene substrates
are summarized in Table 1. Amides 7a–e bearing a primary or
secondary alkyl substituent and the phenyl-substituted amide
7f give their respective g-borylated product predominantly
(i.e., 8a–f, 90–94% ee). Our previous reports of carbonyl-
directed CAHB used amide directing groups exclusively (i.e.,
–C(O)N(H)Ph and –C(O)N(Me)OMe). Here, we find that the
cc NHPh (CH2)2Ph (R)-8c
dc NHPh (CH2)3Ph (R)-8d
ec NHPh c-C6H11
fc NHPh C6H5
g
h
i
(S)-8e
(S)-8f
(S)-8g
(R)-8h
(R)-8i
O-tBu Me
O-tBu Et
O-tBu i-Bu
a
Isolated yield and (% ee) of 8; enantiomeric purity determined
by chiral HPLC analysis after oxidation and for 7g–i subsequent
a Department of Chemistry, University of Nebraska-Lincoln, Lincoln,
Nebraska, USA. E-mail: jtakacs1@unl.edu; Fax: +1 402 472-9402;
Tel: +1 402 472-6232
b
c
amidation. Isolated yield of b-isomer 9. Reaction run at 40 1C.
b Department of Chemistry and Physics, Purdue University Calumet,
Hammond, Indiana, USA
b,g-unsaturated tert-butyl esters serve equally well; 7g–i afford
g-borylated esters 8g–i (91–94% ee). Competing alkene
reduction and formation of the b-borylated regioisomer 9
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc36199j
c
12180 Chem. Commun., 2012, 48, 12180–12182
This journal is The Royal Society of Chemistry 2012

View Article Online
Table 2 Efficient cross-coupling of g-borylated esters and amides
Entry
Trifluoroboratea
Aryl halide
% Yield
1
(S)-10a
(S)-10a
(S)-10a
(S)-10g
(S)-10g
(S)-10g
(R)-10i
(R)-10i
(R)-10i
(R)-10i
(R)-10i
(R)-10i
(R)-10h
Chlorobenzene
3-Bromoanisole
Methyl-4-bromobenzoate
Chlorobenzene
3-Bromoanisole
Methyl-4-bromobenzoate
Chlorobenzene
3-Bromoanisole
Methyl-4-bromobenzoate
3-Chlorothiophene
5-Chloro-2-furaldehyde
5-Chloro-2-fluoropyridine
3-Chlorothiophene
81
71
70
82
82
88
80
92
94
98
84
51
80
2b
3
4
5
6
7
8
9
10
11
12
13
Scheme 1 (a) 2% Rh(nbd)2BF4, 4.1% (R,R)-6, 2 equiv. tmdBH,
THF, 40 1C (74%, 90% ee). (b) KHF2, MeCN/H2O (76%). (c) 5%
Pd(OAc)2, 10% RuPhos, K2CO3, PhMe/H2O, 85 1C, 24 h (91%).
(d) NaBO3, THF/H2O (98%). (e) 5% Pd(OAc)2, 10% RuPhos,
K3PO4, PhMe, 85 1C, 24 h (75%).
a
b
Enantiomeric purity of 8 is given in Table 1. Reaction was run with
SPhos in place of RuPhos.
account for the remainder of products formed; regiocontrol is
most problematic for amide substrates bearing relatively small
substituents (i.e., 7a–b, R = Me or Et).
Trifluoroborate salts are excellent reagents for Suzuki–
Miyaura cross-coupling reactions.15 Using Molander’s conditions,8
the g-borylated amide (S)-8a is cleanly converted to g-trifluoro-
borato amide (S)-10a (65%). The latter readily undergoes
palladium-catalyzed cross-coupling with several representative
aryl halides (70–81%, Table 2 entries 1–3) complementing the
cross-couplings of b-borylated carbonyl derivatives.16 The tert-
butyl ester derivatives (S)-10g and (R)-10i react similarly
(80–94%, entries 4–9). Heteroaromatic cross-couplings are
also promising (entries 10–12). For example, trifluoroborate
(R)-10h couples to 3-chlorothiophene (80%, entry 13) giving the
precursor to a chiral antispasmodic compound previously
reported only as the racemate.17
Directed CAHB can also be used to set the stage for intra-
molecular cross-couplings. CAHB of tert-butyl ester 12 produces
(R)-13 (74%, 90% ee, Scheme 1). Subsequent conversion to the
corresponding trifluoroborate (76%) followed by palladium-
catalyzed intramolecular cross-coupling affords (S)-14 in
excellent yield (91%). Alternatively, hydroboration followed
by mild oxidation with NaBO3 produces g-hydroxyester (R)-15
(73%, 90% ee). The latter undergoes palladium-catalyzed C–O
cross-coupling18 to afford the novel seven-membered ring ether
(R)-16 (75%).
Fig. 2 Preparation of chiral g-hydroxy amides and esters and b-substituted
g-lactones via CAHB-oxidation.
pregabalin.19 Similarly, tert-butyl ester 21a gives (R)-22a (80%,
95% ee) and 21b gives (R)-22b (79%, 95% ee) using the catalyst
with (R,R)-6. With the enantiomeric ligand (i.e., (S,S)-6), CAHB-
oxidation of 21c affords (S)-22c (75%, 92% ee). b-Substituted
butyrolactones undergo diastereoselective alkylation and have
been used in syntheses of the lignan natural products (À)-entero-
lactone and (+)-arctigenin.20
Directed CAHB of amides 3 and 7c using (R,R)-6 followed
by oxidative work-up with basic H2O2 gives the respective
g-hydroxyamides (R)-17 and (R)-18 (71% yield for each, 95
and 94% ee, respectively) (Fig. 2). Similarly, CAHB of tert-
butyl ester 7i followed by mild oxidation with NaBO3 affords
the labile g-hydroxyester (R)-19 (77%, 91% ee). However,
under basic H2O2 work-up conditions, the intermediate
g-hydroxyester spontaneously lactonizes to afford a chiral
b-substituted g-lactone. For example, CAHB of tert-butyl ester
7i using ligand (S,S)-6 affords lactone (S)-20 (78%, 91% ee); the
latter has been used as a precursor to the anticonvulsant drug
The relative energies of a series of octahedral intermediates
formed upon two-point binding of amide substrates followed
by oxidative addition of borane were evaluated by DFT
(Fig. 3, 23A/C and 24B/D).21 The modelled structures employ the
symmetric borane pinBH and the caged phosphite P(OCH2)3CH to
simplify the calculations. In line with experiment, the overall lowest
energy structure for the model methylidene substrate is consistent
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 12180–12182 12181

View Article Online
Chem., 2011, 76, 9102; H. E. Burks and J. P. Morken, Chem. Commun.,
2007, 4717; and references cited therein.
3 Catalytic asymmetric hydroboration of dienes and vinyl arenes:
R. J. Ely and J. P. Morken, J. Am. Chem. Soc., 2010, 132, 2534;
Y. Sasaki, C. Zhong, M. Sawamura and H. Ito, J. Am. Chem. Soc.,
2010, 132, 1226; D. Noh, J. Chea, J. Ju and J. Yun, Angew. Chem.,
Int. Ed., 2009, 48, 6062; S. A. Moteki, K. Toyama, Z. Liu, J. Ma,
A. E. Holmes and J. M. Takacs, Chem. Commun., 2012, 48, 263;
S. A. Moteki and J. M. Takacs, Angew. Chem., Int. Ed., 2008,
47, 894; S. A. Moteki, D. Wu, K. L. Chandra, D. S. Reddy and
J. M. Takacs, Org. Lett., 2006, 8, 3097.
4 Catalytic asymmetric conjugate boration of a,b-unsaturated
´ ´ ´
systems: J. Cid, H. Gulyas, J. J. Carbo and E. Fernandez, Chem.
Soc. Rev., 2012, 41, 3558.
5 Catalytic asymmetric conjugate additions to vinyl boronates:
H.-Y. Jung, X. Feng, H. Kin and J. Yun, Tetrahedron, 2012,
68, 3444; J. C. H. Lee and D. G. Hall, J. Am. Chem. Soc., 2010,
132, 5544; K. Sasaki and T. Hayashi, Angew. Chem., Int. Ed., 2010,
49, 8145.
6 Catalytic asymmetric hydrogenation of vinyl boronates:
I. G. Smilovic, E. Casas-Arce, S. J. Roseblade, U. Nettekoven,
´ ´
A. Zanotti-Gerosa, M. Kovacevic and Z. Casar, Angew. Chem.,
Int. Ed., 2012, 51, 1014; A. Paptchikkine, P. Cheruku, M. Engman
and P. G. Andersson, Chem. Commun., 2009, 5996; W. J. Moran
and J. P. Morken, Org. Lett., 2006, 8, 2413.
7 Stoichiometric asymmetric hydroboration: J. R. Gonza
A. Z. Gonzalez and J. A. Soderquist, J. Am. Chem. Soc., 2009,
131, 9924; L. Munoz-Hernandez and J. A. Soderquist, Org. Lett.,
2009, 11, 2571.
8 Asymmetric alkylation: G. A. Molander, I. Shin and L. Jean-
Gerard, Org. Lett., 2010, 12, 4384.
´
lez,
´
´
´
9 Enantioselective metalation: M. P. Webster and V. K. Aggarwal,
in Boronic Acids, ed. D. G. Hall, Wiley-VCH Verlag GmbH and
Co, Weinheim, 2011, vol. 2, p. 479.
10 S. M. Smith, M. Uteuliyev and J. M. Takacs, Chem. Commun.,
2011, 47, 7812; S. M. Smith and J. M. Takacs, J. Am. Chem. Soc.,
2010, 132, 1740; S. M. Smith and J. M. Takacs, Org. Lett., 2010,
12, 4612; S. M. Smith, N. C. Thacker and J. M. Takacs, J. Am.
Chem. Soc., 2008, 130, 3734.
11 See also: M. Rubina, M. Rubin and V. Gevorgyan, J. Am. Chem.
Soc., 2003, 125, 7198.
12 The chirality of tmdBH was shown to be inconsequential, see
ref. 10.
Fig. 3 Relative energies of model octahedral intermediates leading to
g- and b-borylation for 1,1- and (E) 1,2-disubstituted substrates (A/B
and C/D, respectively; only the vinyl C–H and Rh–H included for clarity.
with favored formation of the g-borylated product upon alkene
insertion into the Rh–H bond (i.e., A); the lowest energy structure
leading to b-borylation (i.e., B) is calculated to be about 1.9 kcal
higher in energy and arises from complexation to the opposite
face of the p-system. Structures C and D model a simple
1,2-disubstituted alkene with the (E)-geometry (i.e., a model
for amide 1). Consistent with the experimental observations,
the b-leading isomer D is favored for this substitution pattern.
In contrast to tri- and other disubstitution patterns, CAHBs
of b,g-unsaturated methylidene amides and esters afford the
g-borylated product and proceed in the opposite sense of asym-
metric induction. Chiral g-borylated derivatives are intermediates
for inter- and intramolecular cross-couplings, the formation of
chiral g-hydroxy carbonyl derivatives, and b-substituted-g-lactones.
Preliminary computational studies suggest that the preferred
conformation of the chelated substrate relative to the Rh–H
bond may explain the observed regio- and p-facial selectivity.
Further studies are in progress.
13 R. Corbera
Ed., 2011, 50, 7079; C. Mazet and D. Ge
2011, 47, 298; A. Z. Gonzalez, J. G. Roma
´
n, N. W. Mszar and A. H. Hoveyda, Angew. Chem., Int.
rard, Chem. Commun.,
n, E. Gonzalez,
´
´
J. Martinez, J. R. Medina, K. Matos and J. A. Soderquist,
J. Am. Chem. Soc., 2008, 130, 9218.
14 S. P. Thomas and V. K. Aggarwal, Angew. Chem., Int. Ed., 2009,
48, 1896.
15 M. Tobisu and N. Chatani, Angew. Chem., Int. Ed., 2009, 48, 3565;
G. A. Molander and N. Ellis, Acc. Chem. Res., 2007, 40, 275;
S. Darses and J.-P. Genet, Eur. J. Org. Chem., 2003, 4313.
16 D. L. Sandrock, L. Jean-Gerard, C.-y. Chen, S. D. Dreher and
´
G. A. Molander, J. Am. Chem. Soc., 2010, 132, 17108; T. Awano,
T. Ohmura and M. Suginome, J. Am. Chem. Soc., 2011,
133, 20738; T. Ohmura, T. Awano and M. Suginome, J. Am.
Chem. Soc., 2010, 132, 13191.
17 F. F. Blicke and F. Leonard, J. Am. Chem. Soc., 1946, 68, 1934.
18 S.-i. Kuwabe, K. E. Torraca and S. L. Buchwald, J. Am. Chem.
Soc., 2001, 123, 12202.
19 T. Ok, A. Jeon, J. Lee, J. H. Lim, C. S. Hong and H.-S. Lee, J. Org.
Chem., 2007, 72, 7390–7393.
Financial support from the NSF (CHE-0809637) and NIH
(GM100101) is gratefully acknowledged. We thank D. Boadwine
for optimizing the reactions leading to 22.
20 J. W. Bode, M. P. Doyle, M. N. Protopopova and W.-L. Zhou,
J. Org. Chem., 1996, 61, 9146.
Notes and references
21 Computational studies were performed using density functional
theory (DFT) implemented in the ab initio package Gaussian09.
B3LYP functional along with 6-31+G(d,p) (all non-metal atoms)
and LANL2DZ (Rh) basis sets was employed. Frequency calcula-
tions were performed at the same level of theory for each of the
optimized structures to check for the absence of any imaginary
frequencies. See ESIw for more details.
1 (a) H. K. Scott and V. K. Aggarwal, Chem.–Eur. J., 2011,
17, 13124; (b) C. M. Crudden, B. W. Glasspoole and C. J. Lata,
Chem. Commun., 2009, 6704.
2 Catalytic asymmetric diboration of dienes and alkenes: L. T. Kliman,
S. N. Mlynarski, G. E. Ferris and J. P. Morken, Angew. Chem., Int.
Ed., 2012, 51, 521; C. H. Schuster, B. Li and J. P. Morken, Angew.
Chem., Int. Ed., 2011, 50, 7906; K. Hong and J. P. Morken, J. Org.
c
12182 Chem. Commun., 2012, 48, 12180–12182
This journal is The Royal Society of Chemistry 2012