Regioselective Heck reaction of aliphatic olefins and aryl halides

Article abstract of DOI:10.1039/c3cc45911j

A regioselective Heck reaction of aliphatic olefins and aryl bromides is realized at internal carbons of olefins. Methanol solvent promoted halide ionization from neutral arylpalladium halide complexes via hydrogen bonding, so as to create cationic aryl-Pd species for regioselective olefin insertion.

Full text of DOI:10.1039/c3cc45911j

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Regioselective Heck Reaction of Aliphatic Olefins and Aryl Halides
Liena Qin, Hajime Hirao and Jianrong (Steve) Zhou*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
previous Heck reaction using ArOTf. The rigid dnpf ligand helps
5
A regioselective Heck reaction of aliphatic olefins and aryl
bromides is realized at internal carbons of olefins. Methanol
solvent promoted halide ionization from neutral
arylpalladium halide complexes via hydrogen bonding, so as
to create cationic aryl-Pd species for regioselective olefin
to prevent competing internal insertion via steric effect.3 In
45 comparison, dppf gave only very low yield and 6:1 selectivity;
dippf was almost inactive. Other chelating bisphosphines such as
dppe, dppp, dppb, Xantphos and BINAP were inactive, too.
When 2 % Pd/dnpf catalyst was used, the conversion decreased.
The desired Heck process only proceeded efficiently in
50 methanol (Table 1). In other less polar alcohols, the catalytic
activity dropped dramatically. For instance, in tꢀBuOH, no
desired product was detected. In water and all other organic
solvents, no Heck reaction was seen.
10 insertion.
Heck reaction of acrylates and styrenes introduced aryl groups
very selectively at terminal positions. It has since been widely
used in synthesis.1 Aliphatic olefins that lack directing groups and
electronic bias gave a mixture of Heck isomers.2 Last year, we
15 reported internally selective arylation between aliphatic olefins
and aryl triflates using a bulky bisphosphine dnpf.3 The method
was a significant improvement of Carbri conditions that has been
largely limited to electronꢀrich vinyl ethers through cationic
pathways.4 In Heck reaction of common aliphatic olefins, aryl
20 halides are difficult to provide good regioselectivity, take Heck’s
example in Fig. 1a.2a Herein, we provide a solution to this
longstanding problem with about 10:1 internal selectivity (Fig.
1b).
Table 1. Effect of solvents on the model reaction (PhBr conversion, yield and
55 selectivity determined by GC).
Ar
R
5 mol% Pd(OAc)2
Ph
Ar
10 mol% dnpf
PhBr
nBu
+
nBu
desired isomer
Me
Me
R
R
2 eq. nBu3N
2 equiv
1 eq. nBu3NHCl
MeOH, 50 oC, 24 h
Ar
+
other isomers
Entry
Solvent
Conv (%)
Yield (%)
Selectivity
cat. Pd/PPh3
(a)
Ph
1
2
3
4
5
6
MeOH
EtOH
99
55
46
20
15
39
83
38
32
7
11
10
11
11
ꢀꢀ
PhBr
Et
+ isomers
(1 : 1)
Et
(Heck 1974)
nBuOH
iPrOH
tBuOH
Ar
P(1-Naph)2
P(1-Naph)2
cat. Pd/dnpf
ArBr
(b)
Fe
R
R
(this work)
selectivity: ~10:1
0
ligand: dnpf
25
Ethylene glycol
13
4
Fig. 1 Heck reactions of aliphatic olefins.
Initially, we attempted a model Heck reaction between PhBr
and 1ꢀoctene, using silver salts as halide abstractors. Contrary to
common belief, it led to very little Heck product and very poor
When nBu3N⋅HCl additive was not included, only about 40%
yield and 5:1 selectivity resulted (Table 2). nBu3N⋅HOTf had
60 little effect. With nBu4NCl or nBu4NBr was added, the yield was
only 60%. A combination of nEt3N⋅HCl and nEt3N only afforded
poor conversion and low selectivity.
30 selectivity under many conditions. We suspected that the AgI
salts may oxidize the Pd0 catalysts.
Previously in Heck reaction of vinyl ethers and styrene, Xiao
et al reported that ethylene glycol solvent or iPr2NH⋅HCl additive
can help chloride ionization from neutral ArꢀPdꢀX complexes via
35 hydrogen bonding.4b,5 Borrowing this idea, we found that the use
of both methanol solvent and nBu3N⋅HCl additive gave the
desired Heck isomer in 83% yield and 11:1 selectivity (Table 1).
The "s" ratio refers to the amount of the desired isomer versus all
other isomers. After catalytic hydrogenation, the intrinsic
40 regioselectivity was determined to be 16:1.
Table 2. Effect of additives on model Heck reaction (PhBr conversion, yield of the
desired isomer and internal selectivity determined by GC).
Entry
Additive
Conv (%)
Yield (%)
Selectivity
1
2
3
4
5
None
64
99
60
80
71
41
83
45
65
57
5
11
6
nBu3N⋅HCl
nBu3N⋅HOTf
nBu4NCl
nBu4NBr
7
The bisphosphine dnpf formed the most active and selective
catalyst. The high internal selectivity is consistent with our
11
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chlorides. Electronꢀneutral and electron–rich aryl chlorides did
30 not react due to slow oxidative addition. Aryl iodides gave poor
selectivity (3:1). The new method can be used to make olefin A
directly from homoallylic alcohol (Fig. 4b). A was previously
prepared via Suzuki coupling of arylꢀB(pin) and vinyl iodide in
Padwa's synthesis of minfiensine.9
6
16
13
5
Et3N⋅HCl; Et3N
Next, we examined various terminal olefins in reactions with
p-t-butylphenyl bromide (Fig. 2). Polar groups such as nitriles,
esters, phthalimides and free alcohols can be present on
oleins..4aꢀc Allylbenzene, which is prone to undergo palladium
hydrideꢀcatalyzed olefin isomerization, coupled well.6 Selective
insertion into internal positions was also seen with
vinylcyclohexane, but with t-butylethylene, insertion occurred
predominantly at terminal positions.
5
35
5 mol% Pd(OAc)2
Ar
10 mol% dnpf
(a)
ArX
nHex
nHex
DABCO
MeOH, 80 o
C
10
Br
Br
Cl
Cl
Br
5-10 mol% Pd(OAc)2
Ar
tBu
10-12 mol% dnpf
R
MeO2C
F3C
63% y, s 12:1
S
Me
R
nBu3N, nBu3NHCl
Br
80% y, s 9:1
10% Pd
MeOH, 50 o
C
79% y, s 12:1
10% dppf
85% y, s 10:1
10% dppf
86% y, s 9:1
Ph
CO2Me
96% y, s 10:1
tBu
10 mol% Pd(OAc)2
Ar
Br
NHAc
12 mol% dppf
76% y, s 11:1
86% y, s 10:1
86% y, s 10:1
91% y, s 11:1
OH
OH
(b)
DABCO
MeOH, 80 o
A
C
76% y, s >100:1
OH
CN
75% y, s 15:1
N(Phth)
OH
Fig. 4 Examples of aryl bromides and chlorides without using acidic additives.
78% y, s 14:1
80 o
72% y, s 11:1
92% y, s 33:1
80 o
C
C
Our Heck procedure can be applied to substituted styrens to
give 1,1'ꢀdiarylethenes (Fig. 5). 1,1–Diarylethylenes are core
Fig. 2 Examples of aliphatic olefins.
40 structures
in
anticancer
agents
bexarotene10
and
Various aryl bromides and some heteroaryl bormides can
couple selectively (Fig. 3). One example of alkenyl bromide was
15 also included. For oꢀtolyl and oꢀanisyl bromides, <10:1 selectivity
was seen and in some cases moderate yield resulted, due to
reduction of aryl bromides to arenes. Some alkylamines can
donate hydrides to arylpalladium species and lead to reduction.7
isocombretastatins A.11 Under most Heck conditions, selective
internal arylation of styrene was difficult to achieve.12
tBu
10 mol% Pd(OAc)2
tBu
12 mol% dnpf
nBu3N, nBu3NHCl
Br
R
MeOH, 50 o
C
5 mol% Pd(OAc)2
R
10 mol% dnpf
Ar
R = H
OMe 81% y, s 11:1
Cl
67% y, s 11:1, 80 o
76% y, s 13:1
ArBr
nHex
nHex
nBu3N, nBu3NHCl
MeOH, 50 o
C
C
MeO
Br
Br
Br
Br
Br
Fig.5 Examples of aromatic olefins.
MeO
MeOC
78% y, s 9:1
80 o
tBu
92% y, s 17:1
45
We then performed DFT calculations on the step of halide
ionization from (dnpf)Pd(phenyl)(Br) (Fig. 6). No significant
effect of hydrogen bonding was seen during oxidative addition of
PhBr. In a dissociative pathway (a), no energetic minimum could
be located for the cationic arylꢀPd species with a vacant site. In
OMe
85% y, s 10:1
87% y, s 13:1
91% y, s 16:1
C
Br
Br
Br
Br
N
S
Me
MeO
50 associative pathway (b), no stabilized pentacoordinate Pd species
can be located.13 Instead, a new pathway (c), hydrogen-bonding-
assisted concerted substitution is energetically more favorable.
The displacement of the bromide by one methanol on the Pd
center was concerted and stabilized by internal hydrogen bonding
55 between the two. Thus, the barrier was reduced to +13 kcal/mol
and the whole process became endergonic by +4 kcal/mol. The
barrier and energy of the ionized products can be further reduced
by incorporation of a second hydrogen bond donor, e.g., a second
MeOH or one Me3NH cation (d and e).
N
67% y, s 10:1
10% Pd, 80 o
81% y, s 11:1
80 o
85% y, s 9:1
72% y, s 16:1
C
C
Br
Br
Br
Br
N
Boc
Me
OMe
72% y, s 6:1
91% y, s 20:1
80 o
54% y, s 8:1
80 o
46% y, s 8:1
80 o
C
C
C
20
Fig. 3 Examples of aryl and vinyl bromides.
When we replaced nꢀtributylamine with DABCO, the
reduction was minimized to <5% (Fig. 4s). In DABCO,
hydrogens α to nitrogens are slow to eliminate to give a
60
Experimentally, we tested the validity that methanol promotes
halide dissociation from a neutral complex (dnpf)Pd(phenyl)(Br).
When it was treated with 1ꢀoctene in methanol, Heck products
were produced in excellent internal selectivity (Fig. 7). The high
internal selectivity is characteristic of insertion into cationic arylꢀ
25 bridgehead iminium species, according to Bredt’s rule.8 Also in
the modified procedure, the nBu3N⋅HCl was unnecessary. We
found in some cases the less hindered dppf performed better than
dnpf. The new procedure can also be applied to electronꢀpoor aryl
65 Pd(dnpf) species, as we reported previously.3 Notably, the
2
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DOI: 10.1039/C3CC45911J
Nanyang Technological University, 21 Nanyang Link, Singapore 637371
Fax: (+65) 67911961; E-mail: jrzhou@ntu.edu.sg
† Electronic Supplementary Information (ESI) available: Experimental
25 procedures and characterization of isolated compounds. See
DOI: 10.1039/b000000x/
selectivity decreased progressively over time, due to in situ
product isomerization. In 1,4ꢀdioxane or DMA, no such Heck
reaction occurred. The neutral complex is barely soluble in
methanol. When (dnpf)Pd(phenyl)(Br) was dissolved in 1:1
5
MeOH/CH2Cl2, no cationic complex can be detected at RT by 31
P
NMR spectroscopy. Thus, we gained indirect evidence
suggesting that methanol solvent promoted ionization of the
neutral bromide complex.
(a) Dissociative substitution
1
Reviews: (a) R. F. Heck, Acc. Chem. Res., 1979, 12, 146; (b) I. P.
Beletskaya and A. V. Cheprakov, Chem. Rev. , 2000, 100, 3009; (c)
K. C. Nicolaou, P. G. Bulger and D. Sarlah, Angew. Chem., Int. Ed.,
2005, 44, 4442; (d) Bräse, S.; de Meijere A. In MetalꢀCatalyzed
Crossꢀcoupling Reactions; de Meijere, A., Diederich, F., Eds.; Wileyꢀ
VCH: Weinheim, 2004; pp 217ꢀ316; (e) G. Zeni and R. C. Larock,
Chem. Rev., 2006, 106, 4644.
30
35
40
45
50
55
- Br_
L
L
L
L
L
L
MeOH
ꢀE = ꢀE = >17 kcal/mol
Pd
Pd
Pd
Ph
Br
Ph
Ph
OMe
H
(for the first step)
cationic intermediate
(b) Associative substitution
2
Examples: (a) H. A. Dieck and R. F. Heck, J. Am. Chem. Soc., 1974,
96, 1133; (b) A. C. Albéniz, P. Espinet, B. MartínꢀRuiz and D.
Milstein, J. Am. Chem. Soc., 2001, 123, 11504; (c) V. Calò, A. Nacci,
A. Monopoli and P. Cotugno, Angew. Chem., Int. Ed., 2009, 48,
6101; (d) E. W. Werner and M. S. Sigman, J. Am. Chem. Soc., 2011,
133, 9692.
Me
L
HO
Pd
- Br_
L
L
L
L
L
MeOH
Pd
Pd
Me
O
H
Ph
Br
Ph
Ph
Br
no stable intermediate
(c) Hydrogen-bonding-assisted substitution (one MeOH)
3
4
L. Qin, X. Ren, Y. Lu, Y. Li and J. Zhou, Angew. Chem. Int. Ed.,
2012, 51, 5915.
Me
L
L
L
L
Me
L
L
O
ꢀE = +4.1 kcal/mol
O
Pd
Pd
Pd
(a) Heck reaction of vinyl ethers with good internal selectivity: W.
Cabri, I. Candiani, A. Bedeschi and R. Santi, J. Org. Chem., 1992,
57, 3558; (b) Heck reaction of pꢀMeOꢀstyrene with 9:1 internal
selectivity (one example): J. Ruan, J. A. Iggo, N. G. Berry and J.
Xiao, J. Am. Chem. Soc., 2010, 132, 16689; (c) Heck reaction of ωꢀ
hydroxyolefins with ~4:1 internal selectivity in ionic liquids: J. Mo,
L. Xu, J. Ruan, S. Liu and J. Xiao, Chem. Comm., 2006, 3591; (d)
Oxidative Heck reaction of vinylboronic acids and terminal olefins:
C. Zheng, D. Wang and S. S. Stahl, J. Am. Chem. Soc., 2012, 134,
16496.
H
.
.
Br.
. H
ꢀE = +13.3 kcal/mol
Me
O
Ph
Ph
Ph
Br. .
H
Br_
transition state
(d) Hydrogen-bonding-assisted substitution (two MeOHs)
Me
L
L
L
L
Me
O
L
L
ꢀE = +3.0 kcal/mol
O
Pd
Pd
Pd
H
.
.
Br.
. . . . . .
. . . . . .
Me
Ph
. H
Ph
ꢀE = +12.5 kcal/mol
Br. .
Ph
O
H
.
.
.
.
.
.
H
.
.
.
.
.
.
Br_
H
MeO
MeO
.
.
.
.
.
.
.
.
.
.
.
.
H
transition state
MeO
5
6
J. Mo and J. Xiao, Angew. Chem. Int. Ed., 2006, 45, 4152.
D. Gauthier, A. T. Lindhardt, E. P. K. Olsen, J. Overgaard and T.
Skrydstrup, J. Am. Chem. Soc., 2010, 132, 7998.
(e) Hydrogen-bonding-assisted substitution (MeOH and Me3NH cationi)
Me
L
L
L
L
Me
L
L
O
7
J. M. Saa, M. Dopico, G. Martorell and A. GarciaꢀRaso, J. Org.
Chem., 1990, 55, 991.
O
Pd
Pd
ꢀE = +0.0 kcal/mol
Pd
H
.
.
Br.
. . . . . .
. . . . . .
Me
Ph
. H
Ph
Ph
O
Br. .
ꢀE = +10.6 kcal/mol
8
9
G. Köbrich, Angew. Chem., Int. Ed. Engl., 1973, 12, 464.
G. Li and A. Padwa, Org. Lett., 2011, 13, 3767.
H
.
.
.
.
.
.
.
.
.
.
.
.
H
Br_
H
Me3N
Me3N
.
.
.
.
.
.
.
.
.
.
.
.
H
60 10 (a) M. F. Boehm, L. Zhang, B. A. Badea, S. K. White, D. E. Mais, E.
Berger, C. M. Suto, M. E. Goldman and R. A. Heyman, J. Med.
Chem., 1994, 37, 2930; (b) M. M. Faul, A. M. Ratz, K. A. Sullivan,
W. G. Trankle and L. L. Winneroski, J. Org. Chem., 2001, 66, 5772.
11 S. Messaoudi, B. Treguier, A. Hamze, O. Provot, J.ꢀF. Peyrat, J. R. De
transition state
Me3N
10 Figure 6. Pathways for halide ionization in methanol solventThe B3LYP DFT
functional was used in conjunction with the Lanl2dz ECP basis set for Fe and Pd.
The solvent effect in methanol was taken into account by IEFPCM.
Ph
nBu3N (5 equv)
(dnpf)Pd(Ph)Br
+
1-octene
65
Losada, J.ꢀM. Liu, J. Bignon, J. WdzieczakꢀBakala, S. Thoret, J.
Dubois, J.ꢀD. Brion and M. Alami, J. Med. Chem., 2009, 52, 4538.
12 Y. Zou, L. Qin, X. Ren, Y. Lu, Y. Li and J. Zhou, Chem.-Eur. J.,
2013, 19, 3504
+ isomers
nHex
MeOH, RT
5 equiv
1 h, 28% y, s 52:1
5 h, 58% y, s 25:1
24 h, 69% y, s 15:1
13 J. F. Hartwig, in Organotransition metal chemistry: from bonding to
catalysis, University Science Books, Sausalito, 2009, p. 217.
14 When PhBr was replaced by PhOTf in the model reaction described in
Table 1 (50 oC, 24 h), the desired Heck isomer was produced in 84%
yield and 11:1 selectivity.
Figure 7. Stoichiometric reaction of olefin insertion in methanol.
70
15
In conclusion, Heck reaction of aliphatic alkenes and aryl
bromides can now be performed selectively at internal sites.14
Methanol solvent promoted efficient halide ionization to produce
cationic arylꢀPd species, critical for olefin insertion.
75
Notes and references
20 Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
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Heck reaction of aryl bromides and aliphatic olefins gives
selective arylation at internal positions of olefins. Methanol
solvent promotes halide dissociation from neutral arylpalladium
halides.
5
Ar
cat. Pd/dnpf
ArBr
+
isomers
Alkyl
Alkyl
selectivity ~10:1
methanol
P(1-naph)2
Fe
P(1-naph)2
ligand: dnpf
4
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