Palladium/chiral amine co-catalyzed enantioselective β-arylation of α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/anie.201208634

Palladium and a simple chiral amine are used as co-catalysts for the enantioselective conjugate addition of aryl boronic acids to α,β-unsaturated aldehydes (see scheme). The synthetic utility of this co-catalyzed reaction was demonstrated in the short tot

Full text of DOI:10.1002/anie.201208634

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Angewandte
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DOI: 10.1002/anie.201208634
Asymmetric Catalysis
Palladium/Chiral Amine Co-catalyzed Enantioselective b-Arylation of
a,b-Unsaturated Aldehydes
Ismail Ibrahem,* Guangning Ma, Samson Afewerki, and Armando Cꢀrdova*
Enantioenriched chiral 3,3-diaryl-substituted aldehydes are
valuable chiral building blocks for the preparation of
numerous natural products and pharmaceuticals (e.g. 4-
arylchroman-2-ones, sertraline, and tolterodine).[1] However,
asymmetric synthesis of these aldehydes is cumbersome and
challenging, because little distinguishes the two arenes steri-
cally or electronically, in particular, when the aryl moiety is
substituted at the para position. One catalytic way to
synthesize nonracemic 3,3-diarylpropanals and 3-alkyl-3-
arylpropanals is the amine-catalyzed addition of aromatic
nucleophiles to enals.[2] However, this approach is restricted
to electron-rich aromatic nucleophiles. In fact, the low
reactivity of electron-poor aromatic nucleophiles leads to no
conjugate addition products.
The enantioselective conjugate addition (ECA) of aryl
boronic acids to Michael acceptors has been employed as the
key step in the preparation of enantioenriched 3,3-disubsti-
tuted carbonyl compounds.[3–9] In this context, Carreira[7] and
Hayashi[8] recently reported the use of chiral dienes as ligands
Scheme 1. Co-catalyzed b-arylation of enals 1 with possible side-
reaction pathways (1,2 additions) and further synthesis.
for the rhodium-catalyzed ECA of aryl boronic acids to b-
aryl-substituted acrolein derivatives.[7–10] Miyaura et al. dem-
onstrated that chiraphos can be used as the auxiliary for Pd-
catalyzed b-arylations of 3-aryl-substituted enals.[11] Despite
these advances, there are very few examples of catalytic
asymmetric conjugate additions of aryl boronic acids to 3-
alkyl-substituted enals.[8,9a,11b] In fact, the state of the art with
respect to the use of Pd catalysis is one example, giving the
corresponding product in poor yield (30%) and moderate e.r.
(74.5:25.5).[11c]
would next be used in the total synthesis of natural products
and biologically active substances (e.g. 4-arylchroman-2-ones
or bisabolane sesquiterpenes, such as (R)-(ꢀ)-curcumene).
However, a,b-unsaturated aldehydes represent an espe-
cially challenging class of substrates in metal-catalyzed
conjugate additions of aryl boronic acids.[16] This is due to
the high reactivity of aldehydes, which can undergo compet-
itive 1,2 addition either to the starting enal (regioselectivity)
or to the product (enal vs. product, chemoselectivity). We
envisioned that the ability of a chiral amine to lower the
LUMO of an enal 2 by iminium activation[17] in combination
with transition-metal-catalyzed conjugate addition of aryl
boronic acids 1 to this intermediate may allow the enantio-
selective 1,4 addition over 1,2 addition to give the corre-
sponding chiral b-arylated products 3 (Scheme 2).[12]
Herein we report the co-catalyzed ECA of electron-rich
and electron-poor aryl boronic acids 1 to b-alkyl- and b-aryl-
substituted enals 2, by combining simple palladium and chiral
amine catalysts. Excellent 1,4 selectivity was achieved and the
corresponding chiral 3,3-disubstituted aldehydes 3 were
isolated in high yields with up to 95:5 e.r.
We began our studies by investigating the catalytic ECA
of phenyl boronic acid 1a to trans-2-hexenal 2a using
different metal complexes, chiral amines (4), and additives
(key results in Table 1). The reaction that was performed
without an amine catalyst was not successful (Table 1,
entry 1). The same reaction with the chiral amine catalyst
4a, but without Pd(OAc)2 as co-catalyst, did also not provide
the b-arylated product 3a (Table 1, entry 2). To our delight,
Based on our previous research on synergistic catalysis,[12]
we envisioned a general co-catalyzed ECA of aryl boronic
acids 1 to both b-aryl- and b-alkyl-substituted a,b-unsaturated
aldehydes 2 by combining transition-metal and chiral amine
catalysts (Scheme 1).[12–15] The corresponding products 3
[*] Prof. Dr. I. Ibrahem, Dr. G. Ma, S. Afewerki, Prof. Dr. A. Cꢀrdova
Department of Natural Sciences, Engineering and Mathematics
Mid Sweden University
85170 Sundsvall (Sweden)
E-mail: ismail.ibrahem@miun.se
armando.cordova@miun.se
Prof. Dr. A. Cꢀrdova
Department of Organic Chemistry, The Arrhenius Laboratory
Stockholm University
10691 Stockholm (Sweden)
E-mail: acordova@organ.su.se
Prof. Dr. A. Cꢀrdova
The Berzelii Center EXSELENT, Stockholm University
10691 Stockholm (Sweden)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208634.
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Angew. Chem. Int. Ed. 2013, 52, 878 –882

Angewandte
Chemie
(Table 1, entries 3–7 and 15). Of the investigated metal
catalysts, Pd(OAc)2 and Pd(O2CCF3)2 were the most efficient
in combination with chiral amine 4a[18] (Table 1, entries 3, 14,
and 16). The use of [Rh(nbd)Cl]2 as metal co-catalyst also
gave product 3a. However, the e.r. was low and some 1,2
addition product 3a’ was also formed (Table 1, entry 12). The
highest enantiomeric ratios of 3a were achieved by combining
catalysts 4a or 4b with the palladium co-catalyst Pd(OAc)2
(Table 1, entries 3 and 16, respectively).
With these results in hand, we decided to probe the scope
of the catalytic ECA of aryl boronic acids 1 to enals 2 using 4a
and Pd(OAc)2 as co-catalysts together with Cs2CO3 and
MeOH as additives in toluene (Table 2). The co-catalyzed
Scheme 2. Merging of iminium activation with transition-metal-cata-
lyzed nucleophilic activation.
Table 1: Screening of the catalytic ECA of 1a to b-alkyl-substituted enal
2a.[a]
Table 2: ECA of aryl boronic acids 1 to enals 2 co-catalyzed by PdII and
chiral amine 4a.[a]
Ent. 1, Ar
2, R
Product Yield[%][b]
e.r.[c]
1
2
3
4
5
6
7
1a, C6H5
2a, nPr
1b, 4-CH3C6H4 2a, nPr
1c, 4-CF3C6H4 2a, nPr
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
79
80
81
79
81
83
78
80
80
79
81
79
75
76
77
70
71
87:13
86:14
87:13
89:11
87:13
89:11
87:13
83:17
94:6
93:7
93:7
93:7
92:8
1d, 4-ClC6H4
1e, 4-BrC6H4
1d, 4-ClC6H4
1d, 4-ClC6H4
1d, 4-ClC6H4
2a, nPr
2a, nPr
2b, nBu
2c, Et
Ent. Cat. Metal salt
Base
Solvent
t
Conv. Ratio
e.r.[c]
[h] [%][b]
3a/
3a’[b]
8[d]
9[e]
2d, Me
1
2
3
4
5
6
7
8
9
–
4a
Pd(OAc)2
–
Cs2CO3 toluene
Cs2CO3 toluene
Cs2CO3 toluene
Cs2CO3 CH2Cl2
Cs2CO3 THF
8
8
2
8
6
6
8
8
8
8
8
8
6
2
8
3
8
<2
<2
98
<2
10
<2
10
30
<2
<2
<2
60
15
98
n.d.
n.d.
>99:1 87:13
n.d.
n.d.
1b, 4-CH3C6H4 2e, Ph
10[e] 1c, 4-CF3C6H4 2e, Ph
4a Pd(OAc)2
4a Pd(OAc)2
4a Pd(OAc)2
4a Pd(OAc)2
4a Pd(OAc)2
4a Pd(PPh3)4
4a Ni(PPh3)4
11[e] 1d, 4-ClC6H4
12[e] 1e, 4-BrC6H4
13[f] 1a, C6H5
2e, Ph
2e, Ph
n.d.
n.d.
n.d.
n.d.
0:100
n.d.
n.d.
n.d.
80:20 47:53
n.d. n.d.
>99:1 85:15
n.d. n.d.
>99:1 87:13
n.d. n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
2 f, 4-MeOC6H4
2g, 4-ClC6H4
2h, 4-BrC6H4
2i, 2-BnOC6H4
2i, 2-BnOC6H4
Cs2CO3 DMF
14[f] 1a, C6H5
95:5
–
toluene
15[f] 1a, C6H5
94.5:5.5
90:10
91:9
Cs2CO3 toluene
Cs2CO3 toluene
Cs2CO3 toluene
Cs2CO3 toluene
16[g] 1a, C6H5
17[g] 1d, 4-ClC6H4
10 4a Cu(OTf)2
11 4a CuCl
12 4a [Rh(nbd)Cl]2 Cs2CO3 toluene
13 4a PdCl2 Cs2CO3 toluene
[a] Under N2 atmosphere, 1 (1.5 equiv), Pd(OAc)4 (5 mol%), 4a
(20 mol%), Cs2CO3 (25 mol%), MeOH (5.0 equiv), and 2 (1 equiv) in
toluene at 228C. Final concentration 0.20m. See the Supporting
Information for details. [b] Yield of purified product 3 after column
chromatography on silica gel. [c] Determined by HPLC analysis on
a chiral stationary phase. [d] 1 (1.0 equiv), enal 2d (2 equiv). [e] Reaction
time was 3 h. [f] Reaction time was 6 h. [g] Reaction time was 3 h and
temperature 508C. No 1,2 addition products (3’ or 3’’) were observed
(entries 1–17).
14 4a Pd(CF3CO2)2 Cs2CO3 toluene
15[d] 4a Pd(OAc)2
16 4b Pd(OAc)2
17 4c Pd(OAc)2
Cs2CO3 toluene
Cs2CO3 toluene
Cs2CO3 toluene
20
98
<2
[a] Under N2 atmosphere. Final concentration 0.20m. See the Supporting
Information for details. [b] Determined by 1H NMR spectroscopy on the
crude reaction mixture. [c] Determined by chiral-phase HPLC analysis.
[d] No MeOH was added. Bn=benzyl, DMF=N,N-dimethylformamide,
nbd=2,5-norbornadiene, TES=triethylsilyl, Tf= trifluoromethanesul-
fonyl, TMS=trimethylsilyl.
additions of aryl boronic acids 1a–1e to b-alkyl-substituted
enals 2a–2d proceeded with excellent 1,4 selectivities and
good enantioselectivities to give the chiral aldehyde products
3a–3h in high yields with good e.r. (Table 2, entries 1–8). It is
noteworthy that aryl boronic acids 1 with both electron-
withdrawing and electron-donating substituents could be used
as donors.[19]
We next investigated the co-catalyzed ECA of aryl
boronic acids 1 to a wide range of b-aryl-substituted enals
(2e–2i, Table 2, entries 9–17). The reactions proceeded
smoothly and gave the corresponding 3,3-diaryl-substituted
aldehydes 3i-3q in high yields (77–81%) with up to 95:5 e.r.
when the chiral amine catalyst 4a (20 mol%) and Pd(OAc)2
(5 mol%) were used as co-catalysts together with Cs2CO3
(25 mol%) and MeOH (5 equiv) as additives in toluene, the
corresponding b-aryl-substituted aldehyde 3a was formed
with high conversion and 87:13 e.r. within 2 h (Table 1,
entry 3). No 1,2 addition products 3a’ or 3a’’ were observed.
The use of toluene as the solvent and Cs2CO3 and MeOH as
additives was essential in order to achieve high conversion
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The absolute configuration of chiral b,b-disubstituted alde-
hydes 3 was established by total syntheses (Schemes 3 and 4).
We began with the expeditious total synthesis of (R)-(ꢀ)-
curcumene (Scheme 3).[20] Thus, the initial co-catalyzed
Scheme 4. Asymmetric synthesis of (R)-4-phenylchroman-2-one 10.
a) 1d, cat. 4a (20 mol%), cat. Pd(OAc)2 (5 mol%), Cs2CO3
(25 mol%), MeOH (5 equiv), toluene, 508C, 3 h; b) NaClO2, CH2Cl2,
228C, 18 h; c) Pd/C, EtOAc, 228C, 18 h; d) p-toluenesulfonic acid,
benzene, 808C.
Scheme 3. Asymmetric synthesis of (R)-(ꢀ)-curcumene 7. a) Cat. 4a
(20 mol%), cat. Pd(OAc)2 (5 mol%), Cs2CO3 (25 mol%), MeOH
(5 equiv), toluene, RT; b) 1) NaBH4, CH2Cl2, MeOH, 08C; 2) TsCl,
pyridine, CH2Cl2, RT, 5 h; 3) NaI, acetone, reflux, 2 h; c) 6, CuI, THF,
08C, 9 h.
addition, the reaction was inhibited by the addition of
phosphine ligands. Based on these results, the above-cited
literature,[10,11,22] the absolute configuration of products 3, and
our previous DFT calculations,[12a] we propose a mechanism
involving stereoselective addition of monocationic [ArPdII-
(OMe)L2]+ A or neutral ArPdIIL A’ to chiral iminium
intermediates B (Scheme 5).[10,23c] Here, we show the co-
catalyzed mechanism in which the neutral aryl–palladium(II)
species A’ is generated by transmetalation of the aryl boronic
acid (Scheme 5).[10,23c] In parallel, iminium intermediate B is
generated in situ by reaction of enals 2 with chiral amine
catalyst 4. Next, the catalytic cycles are merged and stereo-
selective addition of A’ to iminium intermediate B leads to
the C-bound-PdII/iminium intermediate C. Here, efficient
shielding of the Re face (R = aryl) of B by the bulky chiral
group of 4 leads to Si-facial nucleophilic attack at the b-
carbon atom via transition state D.[12a] Subsequent protonol-
asymmetric synthesis of aldehyde 3r (80% yield with 83:17
e.r.) was followed by subsequent reduction, tosylation, and
nucleophilic displacement to give iodine 5 in 69% overall
yield (3 steps). Grignard addition of 6 to 5 gave (R)-
curcumene 7 in 61% yield with 84:16 e.r. Comparison with
the literature showed that the stereochemistry of 7 was (R)
20
20
(½aꢁD ¼ꢀ24.0 (c = 0.5, CHCl3); Ref. [20a]: ½aꢁD ¼ꢀ37.5 (c =
2.9, CHCl3); Scheme 3).
After accomplishing the above total synthesis, we
embarked on the total synthesis of 4-arylchroman-2-ones
such as 10.[6a,3q] Thus, the reaction of 4-chlorophenyl boronic
acid 1d with 2-OBn-substituted cinnamic aldehyde 2i co-
catalyzed by amine 4a and Pd(OAc)2 gave the corresponding
3,3-diaryl-substituted aldehyde 3q in 71% yield. Next,
oxidation gave the corresponding acid 8 (Scheme 4), and
subsequent catalytic hydrogenation (H2, Pd/C in EtOAc)
afforded hydroxy acid 9. Interestingly, HRMS analysis of 9
showed that dechlorination had occurred under these con-
ditions. If desired, this side reaction can be circumvented by
the employment of PtO2 as the catalyst for the hydrogenation
step.[21] Acid-mediated lactonization by treatment of 9 with p-
toluenesulfonic acid in benzene gave the desired (R)-4-
phenylchroman-2-one 10[3q] (75% overall yield, 3 steps).
Comparison with the literature showed that the stereochem-
ꢀ
ysis of the palladium carbon bond of C and hydrolysis of the
iminium intermediate E leads to release of the PdII species,
the chiral amine co-catalyst, and the corresponding product 3
(Scheme 5). The presence of iminium intermediates B and E
was confirmed by direct HRMS analysis of the crude reaction
mixture.[24] It is noteworthy that deuterium-labeling experi-
ments with CD3OD instead of MeOH confirmed the presence
of deuterated products [D]-3. Thus, a C-bound-PdII/iminium
intermediate C was most likely present in the catalytic cycle.
In addition, this experiment confirms that MeOH was
20
ꢀ
istry of 10 was also (R) (½aꢁD ¼ꢀ38.2 (c = 0.2, CHCl3);
a proton source for the C Pd bond cleavage of C.
20
Ref. [3q]: ½aꢁD ¼ꢀ45.1 (c = 0.98, CHCl3); Scheme 4).
In summary, we have disclosed a co-catalyzed b-arylation
of a,b-unsaturated aldehydes with aryl boronic acids by
combining simple Pd and chiral amine catalysts. The reactions
are highly 1,4-selective and the corresponding aldehyde
products were obtained in high yields with good enantiomeric
ratios (up to 95:5 e.r.). The co-catalyzed asymmetric b-
arylation reaction allowed the use of both b-alkyl- and b-aryl-
substituted aldehydes as acceptors. The reaction was
employed for the short total syntheses of (R)-(ꢀ)-curcumene
and (R)-4-phenylchroman-2-one. It should also serve as an
With respect to the catalytic cycles of the palladium-co-
catalyzed conjugate addition, Miyaura and co-workers have
previously proposed a mechanism for the cationic PdII-
complex-catalyzed conjugate addition of aryl boronic
acids.[10,11a] However, these types of reactions can also be
catalyzed by neutral PdII complexes.[10a,22,23] The addition of
MeOH significantly accelerated our co-catalyzed reaction,
and the experimental results show clearly that the reaction is
not catalyzed by a Pd0 intermediate (Table 1, entry 8). In
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Scheme 5. Proposed catalytic cycle.
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efficient entry for diversity-oriented synthesis. Results in this
area and other total synthesis will be disclosed in due course.
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Received: October 26, 2012
Published online: November 23, 2012
Keywords: aldehydes · asymmetric catalysis · boronic acids ·
.
co-catalysts · total synthesis
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Angew. Chem. Int. Ed. 2013, 52, 878 –882
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