Copper-Catalyzed Enantioselective 1,6-Boration of para-Quinone Methides and Efficient Transformation of gem-Diarylmethine Boronates to Triarylmethanes

Article abstract of DOI:10.1002/anie.201505926

Presented is the first enantioselective copper-catalyzed 1,6-conjugate addition of bis(pinacolato)diboron to para-quinone methides. The reaction proceeds with excellent yields and good to excellent enantioselectivities, and provides an attractive approach to the construction of optically active gem-diarylmehtine boronic esters. Additionally, the subsequent conversion of the derived potassium trifluoroborates into triarylmethanes with highly enantiospecificity was realized.

Full text of DOI:10.1002/anie.201505926

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International Edition: DOI: 10.1002/anie.201505926
German Edition: DOI: 10.1002/ange.201505926
Asymmetric Catalysis
Copper-Catalyzed Enantioselective 1,6-Boration of para-Quinone
Methides and Efficient Transformation of gem-Diarylmethine
Boronates to Triarylmethanes
Yazhou Lou, Peng Cao, Tao Jia, Yongling Zhang, Min Wang, and Jian Liao*
Abstract: Presented is the first enantioselective copper-cata-
lyzed 1,6-conjugate addition of bis(pinacolato)diboron to
para-quinone methides. The reaction proceeds with excellent
yields and good to excellent enantioselectivities, and provides
an attractive approach to the construction of optically active
gem-diarylmehtine boronic esters. Additionally, the subsequent
conversion of the derived potassium trifluoroborates into
triarylmethanes with highly enantiospecificity was realized.
E
nantiomerically pure organoboranes are interesting phar-
maceutical molecules[1] in medical chemistry and powerful
building blocks[2] in asymmetric synthesis. Chiral dibenzylic
(gem-diarylmethine) boronates, as a class of potential pre-
cursors for important triarylmethanes[3] and gem-diaryl
hydrocarbons,[4] has been employed by Aggarwal and co-
workers[5] in the synthesis of gem-diaryl-containing pharma-
ceuticals.[5d–e] However, despite the importance of these
compounds, the approaches to access nonracemic gem-diary-
lmethine boronates are still very scarce. Lithiation/borylation
of benzylic carbamates[6] is an exclusive route which relies on
either a substrate- or reagent-controlled strategy. (Sche-
me 1a). For instance, Crudden and co-workers recently
reported an elegant chiral bis(iPr-oxazoline)-controlled pro-
tocol to obtain chiral nonracemic gem-diarylmethine boronic
esters, albeit with substantial substrate restrictions.[7] To our
knowledge, to date, catalytic asymmetric approaches to access
gem-diarylmethine boronic esters, bearing a chiral benzylic
Scheme 1. Approaches to chiral gem-diarylmethine boronates.
para-Quinone methides (p-QMs),[12] which are classified as
electron-deficient alkenes with a unique assembly of carbonyl
and olefinic moieties, are versatile intermediates in many
chemical, medicinal, and biological processes.[13] We envi-
sioned that copper-catalyzed enantioselective 1,6-conjugate
boration of p-QMs could deliver nonracemic gem-diarylme-
thine boronates. (Scheme 1b). However, p-QMs have been
less-well studied in enantioselective catalysis, and to date,
only three organocatalysis cases, including anionic polymer-
izations,[14] phase-transfer catalysis,[15] and 1,6-conjugate addi-
tion of enamines,[16] have been reported. Herein, we report
the first copper-catalyzed asymmetric 1,6-conjugate addition
of B2(pin)2 to p-QMs, and stereoselective conversion of the
chiral gem-diarylmethine boronates into enantionenriched
triarylmethanes.
To test the feasibility of the 1,6-addition, we examined the
reaction of the p-QM 1a with B2(pin)2 using a P-diisopropyl
sulfoxide phosphine[17] (SOP; L1), and systematically
screened reaction conditions, such as copper salts, solvents,
additives, and bases (Table 1; see the Supporting Information
for details). With 10 mol% of CuCl, L1, and NaOtBu, the
reaction proceeded smoothly at À208C in the presence of
2 equivalents of MeOH and toluene as the solvent. 1a was
consumed within 15 hours and the 1,6-conjugate adduct, the
dibenzylic boronic ester 2a, was afforded in excellent yield
with a 93.5:6.5 e.r. (entry 1). By employing MeOK as the base,
the reaction proceeded within 30 min and gave 2a with 95:5
e.r. (entry 2). Ligand screening revealed that P-substituents of
SOPs have dramatic effects on the enantioselectivity. For
instance, P-diethyl and P-dicyclohexyl SOPs (L2 and L3)
show much worse enantiocontrol than L1, and L4 gave nearly
racemic dibenzylic boronic ester (entries 3–5). The commer-
cially available ligand (R)-BINAP was chosen to evaluate this
transformation, and modest enantioselectivity was afforded
(entry 6). Furthermore, the modified P-diisopropyl L6 was
À
C B bond, remain unexplored.
Transition-metal catalyzed[8] or organocatalyzed[9] asym-
metric conjugate borations of electron-deficient olefins with
diboron reagents, such as bis(pinacolato)diboron [B2(pin)2],
represent a powerful and site-selective route to access chiral
alkylboranes.[10] In particular, the use of chiral copper
catalysts has been highly successful in transforming a variety
of b-aryl-substituted a,b-unsaturated compounds into ben-
zylic boronic esters with excellent levels of enantiopurity.[11]
[*] Y. Z. Lou, Prof. Dr. P. Cao, T. Jia, Y. Zhang, Dr. M. Wang,
Prof. Dr. J. Liao
Chengdu Institute of Biology, Chinese Academy of Sciences
Chengdu 610041 (China)
and
University of Chinese Academy of Sciences
Beijing 100049 (China)
E-mail: jliao@cib.ac.cn
Prof. Dr. J. Liao
College of Chemical Engineering, Sichuan University
Chengdu 610065 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505926.
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Table 1: Screening of reaction conditions.[a]
Table 2: Scope with respect to the p-QMs.[a]
Entry
Ligand
Base
t [h]
15
Yield [%][b]
e.r.[c]
1
2
3
4
5
6
7
8
L1
L1
L2
L3
NaOtBu
MeOK
MeOK
MeOK
MeOK
MeOK
MeOK
MeOK
MeOK
MeOK
MeOK
98
96
86
74
85
89
85
94
91
86
97
(65)
93.5:6.5
95:5
70:30
89:11
55:45
75.5:24.5
95:5
95.5:4.5
96:4
95:5
94:6
0.5
0.5
0.5
0.5
0.5
0.5
0.5
4.5
L4
(R)-BINAP
L5
L6
L6
L6
L6
9[d]
10[e]
11[f]
15
48
(>99.5:0.5)
[a] Conducted with 1a (0.2 mmol), B2(pin)2 (0.3 mmol), CuCl
(10 mol%), ligand (11 mol%), MeOK (12 mol%), MeOH (0.4 mmol) in
toluene (1.0 mL) at À208C. [b] Yield of isolated product. [c] Determined
by HPLC. [d] Conducted with 5.0 mol% of CuCl at À408C. [e] Conducted
with 2.5 mol% of CuCl at À408C. [f] The reaction was performed in the
presence of 1.60 g (8.1 mmol) of 1a and 0.1 mol% of CuCl at 08C. Data
within parentheses is that obtained after one crystallization.
[a] Conducted with 1 (0.2 mmol), B2(pin)2 (0.3 mmol), CuCl (5 mol%),
ligand (5.5 mol%), MeOK (6 mol%), MeOH (0.4 mmol) in toluene
(1.0 mL) at À408C. [b] Yield of isolated product. [c] Determined by chiral
HPLC. Thermal ellipsoids shown at 50% probability.
used and it led to a slight enantiomeric excess increase
(entry 8). Reaction temperature and catalyst loading were
also optimized (entries 9 and 10). At À408C and with 5 mol%
of catalyst, 1a reacted completely with B2(pin)2 within
4.5 hours to furnish 2a in 91% yield and 96:4 e.r. The
reaction can also be run on a gram scale (1.60 g) with
0.1 mol% catalyst at 08C, thus delivering 2a in excellent yield
(2.23 g, 97%) and good enantioselectivity (94:6 e.r.). After
one recrystallization from n-hexane, enantiopure 2a
(> 99.5:0.5 e.r.) can be obtained in 65% yield (1.50 g;
entry 11).
Under the optimized reaction conditions, we examined
the scope of the reaction. As shown in Table 2, a series of
stable p-QMs with electron-neutral, electron-deficient, and
electron-rich aryls reacted with B2(pin)2 to provide chiral
gem-diarylmethine boronates (2a–m) in good yields with
generally high levels of enantiopurities. Multisubstituted (2n
and 2o), polycyclic (2p), and heterocyclic (2s) aryls were
tolerated in this reaction and resulted in excellent yields with
high enantioselectivities. o-Methoxy- and o-methyl-substitu-
tedp-QMs provided 2q and 2r, respectively, with decreased
e.r. values (83:17 and 75:25), probably because of the steric
effects. In addition, replacement of the bulky tert-butyl group
by methyl (2t), isopropyl (2u), and phenyl (2v) groups did not
lead to better enantioselectivities. The stereocenter of the
generated dibenzylic boronic esters was assigned to be S by X-
ray crystallographic analysis of 2a.[18] Accordingly, a model
was proposed to rationalize this stereochemical outcome. As
shown in Figure 1, the planar 1a approaches the (SOP)Cu/
Bpin species from Si-face (A) to avoid steric interactions
between the phenyl ring of 1a and tert-butyl sulfinyl group of
L6 (the steric hindrance is shown in B), thus (S)-2a was
obtained in a large excess. For o-methoxy- or o-methyl-
Figure 1. Stereochemical models of 1,6-boration.
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Table 3: Palladium-catalyzed cross-coupling of gem-diarylmethine tri-
readily transfer boronic esters to potassium trifluoroborates
and then protect the phenols with a methyl group in a one-pot
procedure in satisfactory yields (Table 3). The new dibenzylic
trifuoroborates can be readily coupled with aryltrifluorome-
thanesulfonates (ArOTf) in the presence of catalytic amounts
of Pd(OAc)2 and PCy3 under milder reaction conditions. By
using this method, a series of enantioenriched triarylme-
thanes were successfully constructed with high enantiospeci-
ficity.[20] Electronic properties of ArOTf have a slight influ-
ence on yield as well as specificity, and the cross-coupling
procedure was tolerated for a wide range of functional groups,
such as carbonyl(3ab), formyl (3ac), nitro (3ad), and alkoxy
(3ae and 3af). This method also enables efficient synthesis of
four different functionalized triarylmethanes (3bb, 3be, 3eb,
3ee). The current method, using ArOTf as electrophiles,
represents a practical cross-coupling technique owing to the
availability of phenols and their lack of toxicity compared to
aryl halides.[7,19b,21,22]
fluoroborates with ArOTf.[a]
By exposing 3aa to a mixture of Tf2O and TfOH, the
enantioenriched triarylmethane was readily converted into
the de-tert-butylated triarylmethane 4a in 67% yield with
a slight loss of stereopurity (Scheme 2). The absolute config-
uration of 4a was determined to be R by comparison of the
optical rotation with the literature value.[20c] It is noteworthy
that both enantiomers (R and S) of the triarylmethanes can be
obtained from the 1,6- adducts 2. Thus whilst coupling of the
trifluoroborate 5 with ArOTf occurred with inversion,[23] the
opposite stereochemistry (retention) was observed when
coupling the dibenzylic neopentyl glycol boronic ester 6
with aryliodide.[7] (Scheme 3).
[a] Reaction condition of the cross-coupling reaction: 2 (0.07 mmol,
e.r.>99.5:0.5 for 2a), ArOTf (0.07 mmol), Pd(OAc)2 (10 mol%), PCy3
(20 mol%), K2CO3 (0.2 mol) in toluene/H2O(1.1 mL, v/v=10:1) at 608C
for 15 h. [b] Yield of isolated product. [c] Determined by chiral HPLC.
[d] es=eeProduct/eeS.M.”100%. Tf =trifluoromethanesulfonyl, THF=te-
trahydrofuran.
Scheme 2. De-tert-butylation of triarylmethane.
substituted p-QMs, an assumed orthogonal orientation
of cyclohexadiene ring with the sterically bulky aryl ring
might render the enantioface discrimination elusive,
thus resulting in moderate e.r. values of 1,6-borylative
adducts.
To demonstrate the utility of this enantioselective
1,6-boration in asymmetric synthesis, we sought to
transform the 1,6-adducts into enantionenriched triaryls
by stereospecific Suzuki–Miyaura cross-coupling reac-
tions.[19] Firstly, all attempts at the palladium-catalyzed
cross-coupling of 2a with aryl halides or pseudohalides
failed, and is probably a result of the facile decom-
position of the dibenzylic palladium intermediate when
bearing a phenolic hydroxy group. Fortunately, we can
Scheme 3. Stereospecific cross-coupling experiments. TMS=trimethylsilyl.
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[6] For seminal examples, see: a) E. Beckmann, V. Desai, D. Hoppe,
In summary, we have demonstrated that copper-catalyzed
asymmetric 1,6-addition of B2(pin)2 to the p-QMs proceeds
with excellent yield and good to excellent enantioselectivities.
For the first time, enantioenriched gem-diarylmethine bor-
ontaes were prepared by a catalytic asymmetric method.
Subsequently, the derived chiral potassium trifluoroborates
were converted into enantioenriched triarylmethanes in good
yield and with high enantiospecificity. Additional asymmetric
transformations of gem-diarylmethine boronates are under-
way in our laboratory.
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Acknowledgements
We thank the NSFC (No. 21472184, 21272226, 21202160, and
21402186) for financial support.
Keywords: asymmetric catalysis · boron · copper ·
cross-coupling · synthetic methods
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Angew. Chem. 2015, 127, 12302–12306
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Received: June 28, 2015
Revised: July 27, 2015
Published online: August 28, 2015
12138 www.angewandte.org
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Angew. Chem. Int. Ed. 2015, 54, 12134 –12138