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International Edition: DOI: 10.1002/anie.201505926

Asymmetric Catalysis German Edition: DOI: 10.1002/ange.201505926

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.

Enantiomerically pure organoboranes are interesting phar-

maceutical molecules[1] in medical chemistry and powerful
building blocks[2] in asymmetric synthesis. Chiral dibenzylic Scheme 1. Approaches to chiral gem-diarylmethine boronates.
(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- para-Quinone methides (p-QMs),[12] which are classified as
workers[5] in the synthesis of gem-diaryl-containing pharma- electron-deficient alkenes with a unique assembly of carbonyl
ceuticals.[5d–e] However, despite the importance of these and olefinic moieties, are versatile intermediates in many
compounds, the approaches to access nonracemic gem-diary- chemical, medicinal, and biological processes.[13] We envi-
lmethine boronates are still very scarce. Lithiation/borylation sioned that copper-catalyzed enantioselective 1,6-conjugate
of benzylic carbamates[6] is an exclusive route which relies on boration of p-QMs could deliver nonracemic gem-diarylme-
either a substrate- or reagent-controlled strategy. (Sche- thine boronates. (Scheme 1 b). However, p-QMs have been
me 1 a). For instance, Crudden and co-workers recently less-well studied in enantioselective catalysis, and to date,
reported an elegant chiral bis(iPr-oxazoline)-controlled pro- only three organocatalysis cases, including anionic polymer-
tocol to obtain chiral nonracemic gem-diarylmethine boronic izations,[14] phase-transfer catalysis,[15] and 1,6-conjugate addi-
esters, albeit with substantial substrate restrictions.[7] To our tion of enamines,[16] have been reported. Herein, we report
knowledge, to date, catalytic asymmetric approaches to access the first copper-catalyzed asymmetric 1,6-conjugate addition
gem-diarylmethine boronic esters, bearing a chiral benzylic of B2(pin)2 to p-QMs, and stereoselective conversion of the
C¢B bond, remain unexplored. chiral gem-diarylmethine boronates into enantionenriched
Transition-metal catalyzed[8] or organocatalyzed[9] asym- triarylmethanes.
metric conjugate borations of electron-deficient olefins with To test the feasibility of the 1,6-addition, we examined the
diboron reagents, such as bis(pinacolato)diboron [B2(pin)2], reaction of the p-QM 1 a with B2(pin)2 using a P-diisopropyl
represent a powerful and site-selective route to access chiral sulfoxide phosphine[17] (SOP; L1), and systematically
alkylboranes.[10] In particular, the use of chiral copper screened reaction conditions, such as copper salts, solvents,
catalysts has been highly successful in transforming a variety additives, and bases (Table 1; see the Supporting Information
of b-aryl-substituted a,b-unsaturated compounds into ben- for details). With 10 mol % of CuCl, L1, and NaOtBu, the
zylic boronic esters with excellent levels of enantiopurity.[11] reaction proceeded smoothly at ¢20 8C in the presence of
2 equivalents of MeOH and toluene as the solvent. 1 a was
[*] Y. Z. Lou, Prof. Dr. P. Cao, T. Jia, Y. Zhang, Dr. M. Wang, consumed within 15 hours and the 1,6-conjugate adduct, the
Prof. Dr. J. Liao dibenzylic boronic ester 2 a, was afforded in excellent yield
Chengdu Institute of Biology, Chinese Academy of Sciences with a 93.5:6.5 e.r. (entry 1). By employing MeOK as the base,
Chengdu 610041 (China) the reaction proceeded within 30 min and gave 2 a with 95:5
and e.r. (entry 2). Ligand screening revealed that P-substituents of
University of Chinese Academy of Sciences
SOPs have dramatic effects on the enantioselectivity. For
Beijing 100049 (China)
E-mail: [email protected] instance, P-diethyl and P-dicyclohexyl SOPs (L2 and L3)
Prof. Dr. J. Liao show much worse enantiocontrol than L1, and L4 gave nearly
College of Chemical Engineering, Sichuan University racemic dibenzylic boronic ester (entries 3–5). The commer-
Chengdu 610065 (China) cially available ligand (R)-BINAP was chosen to evaluate this
Supporting information for this article is available on the WWW transformation, and modest enantioselectivity was afforded
under http://dx.doi.org/10.1002/anie.201505926. (entry 6). Furthermore, the modified P-diisopropyl L6 was

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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] Yield [%][b] e.r.[c]

1 L1 NaOtBu 15 98 93.5:6.5
2 L1 MeOK 0.5 96 95:5
3 L2 MeOK 0.5 86 70:30
4 L3 MeOK 0.5 74 89:11
5 L4 MeOK 0.5 85 55:45
6 (R)-BINAP MeOK 0.5 89 75.5:24.5
7 L5 MeOK 0.5 85 95:5
8 L6 MeOK 0.5 94 95.5:4.5
9[d] L6 MeOK 4.5 91 96:4
10[e] L6 MeOK 15 86 95:5
11[f ] L6 MeOK 48 97 94:6
(65) (> 99.5:0.5)
[a] Conducted with 1 a (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 ¢20 8C. [b] Yield of isolated product. [c] Determined
by HPLC. [d] Conducted with 5.0 mol % of CuCl at ¢40 8C. [e] Conducted
with 2.5 mol % of CuCl at ¢40 8C. [f] The reaction was performed in the
presence of 1.60 g (8.1 mmol) of 1 a and 0.1 mol % of CuCl at 0 8C. 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 %),
used and it led to a slight enantiomeric excess increase ligand (5.5 mol %), MeOK (6 mol %), MeOH (0.4 mmol) in toluene
(entry 8). Reaction temperature and catalyst loading were (1.0 mL) at ¢40 8C. [b] Yield of isolated product. [c] Determined by chiral
also optimized (entries 9 and 10). At ¢40 8C and with 5 mol % HPLC. Thermal ellipsoids shown at 50 % probability.
of catalyst, 1 a reacted completely with B2(pin)2 within
4.5 hours to furnish 2 a in 91 % yield and 96:4 e.r. The
reaction can also be run on a gram scale (1.60 g) with lead to better enantioselectivities. The stereocenter of the
0.1 mol % catalyst at 0 8C, thus delivering 2 a in excellent yield generated dibenzylic boronic esters was assigned to be S by X-
(2.23 g, 97 %) and good enantioselectivity (94:6 e.r.). After ray crystallographic analysis of 2 a.[18] Accordingly, a model
one recrystallization from n-hexane, enantiopure 2 a was proposed to rationalize this stereochemical outcome. As
(> 99.5:0.5 e.r.) can be obtained in 65 % yield (1.50 g; shown in Figure 1, the planar 1 a approaches the (SOP)Cu/
entry 11). Bpin species from Si-face (A) to avoid steric interactions
Under the optimized reaction conditions, we examined between the phenyl ring of 1 a and tert-butyl sulfinyl group of
the scope of the reaction. As shown in Table 2, a series of L6 (the steric hindrance is shown in B), thus (S)-2 a was
stable p-QMs with electron-neutral, electron-deficient, and obtained in a large excess. For o-methoxy- or o-methyl-
electron-rich aryls reacted with B2(pin)2 to provide chiral
gem-diarylmethine boronates (2 a–m) in good yields with
generally high levels of enantiopurities. Multisubstituted (2 n
and 2 o), polycyclic (2 p), and heterocyclic (2 s) aryls were
tolerated in this reaction and resulted in excellent yields with
high enantioselectivities. o-Methoxy- and o-methyl-substitu-
tedp-QMs provided 2 q and 2 r, 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 (2 t), isopropyl (2 u), and phenyl (2 v) groups did not 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
fluoroborates with ArOTf.[a] 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(3 ab), formyl (3 ac), nitro (3 ad), and alkoxy
(3 ae and 3 af). This method also enables efficient synthesis of
four different functionalized triarylmethanes (3 bb, 3 be, 3 eb,
3 ee). 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]
By exposing 3 aa to a mixture of Tf2O and TfOH, the
enantioenriched triarylmethane was readily converted into
the de-tert-butylated triarylmethane 4 a in 67 % yield with
a slight loss of stereopurity (Scheme 2). The absolute config-
uration of 4 a 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 2 a), 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 60 8C
for 15 h. [b] Yield of isolated product. [c] Determined by chiral HPLC.
[d] es = eeProduct/eeS.M. Ö 100 %. Tf = trifluoromethanesulfonyl, THF = te- Scheme 2. De-tert-butylation of triarylmethane.
trahydrofuran.

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 2 a 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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