Constructing multiply substituted arenes using sequential palladium(II)-catalyzed C-H olefination

Article abstract of DOI:10.1002/anie.201002077

A balancing act: Complementary catalytic systems are described, in which the reactivity/selectivity balance in PdII-catalyzed ortho-C=H olefination can be modulated to enable sequential C=H functionalization for the rapid preparation of 1,2,3- trisubstituted arenes 1. Additionally, a rare example of iterative C=H activation, in which a newly installed functional group directs subsequent C=H activation has been demonstrated (2).

Full text of DOI:10.1002/anie.201002077

Angewandte
Chemie
DOI: 10.1002/anie.201002077
À
C H Activation
Constructing Multiply Substituted Arenes Using Sequential
À
Palladium(II)-Catalyzed C H Olefination**
Keary M. Engle, Dong-Hui Wang, and Jin-Quan Yu*
Divinylbenzene derivatives represent an important class of
molecular building blocks in organic chemistry and materials
science.[1,2] Therefore, their synthesis has been an active area
of research.[2] Indeed, shortly after the initial reports describ-
ing Pd0-catalyzed haloarene/olefin coupling (the Mizoroki–
Heck reaction),[3] Plevyak and Heck disclosed an example of
divinylation of ortho-dibromobenzene.[4] Since that time,
Heck and co-workers, as well as others, have studied differ-
ential olefination of arenes containing two different halides
(or pseudohalides) to synthesize unsymmetrical divinylben-
zenes.[5,6]
À
Scheme 2. The challenges of sequential directed C H functionaliza-
tion. a) Poor selectivity. b) Poor reactivity.
II
À
In light of the recent advances in Pd -catalyzed C(aryl) H
functionalization reactions,[7] including those that directly
[8–17]
À
couple C(aryl) H bonds and olefins,
an exciting method
for divinylbenzene synthesis would be to use an arene
substrate containing a synthetically versatile directing group
give the difunctionalized by-product. Strategies to avoid this
problem include substituting the ortho or meta positions to
block the second C H insertion, lowering the reaction
(DG)[7c] and perform sequential olefination of both ortho-C
À
À
H bonds (Scheme 1). In this way, two different alkenes could
be expediently introduced in a position-selective fashion to
form valuable 1,2,3-trisubstituted products,[18] thereby obviat-
ing the complications associated with preparing dihaloarene
starting materials.
temperature or time to suboptimal levels, or using reduced
equivalents of one of the reactants. However, these maneu-
vers often lead to limited substrate scope or compromised
yields. Similarly, achieving suitable reactivity can also be
problematic. For instance, if the first new group is sterically
bulky, the substrateꢀs binding affinity for PdII can be
attenuated. Alternatively, if the first new group is electron-
withdrawing (e.g., halogen, olefin, or carboxylate), it can
À
deactivate the aromatic ring for the second C H activation
step. Lastly, the original directing group and the newly
installed functional group can coordinate to PdII in a
bidentate fashion, preventing the catalyst from accessing the
À
Scheme 1. Sequential directed C H functionalization. DG=directing
group
À
second C H bond.
Reflecting on these interrelated challenges, we became
aware of a need for complementary catalytic systems in which
the selectivity/reactivity balance of PdII could be modulated
through coordination of an external ligand. We report herein
the realization of this goal in the case of sequential PdII-
However, generally speaking, methods for sequential,
II
À
directed ortho-C H activation with Pd remain underdevel-
oped[19,20] owing to problems rooted in both selectivity and
reactivity (Scheme 2). In terms of selectivity, a major chal-
lenge lies in forming the monofunctionalized product in high
À
catalyzed C(aryl) H olefination. Furthermore, as part of our
À
À
yield without functionalizing the second ortho-C H bond to
research program to develop expedient and versatile C(aryl)
H functionalization techniques, we describe an example of
À
À
iterative C H functionalization, wherein one C H activation
[*] K. M. Engle, D.-H. Wang, Prof. J.-Q. Yu
Department of Chemistry, The Scripps Research Institute (TSRI)
10550 N. Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-2409
À
reaction installs a directing group for a subsequent C H
functionalization reaction (Scheme 3).
To this end, we began by revisiting our recently disclosed
ortho-C H olefination reaction for phenylacetic acids.[14] The
E-mail: yu200@scripps.edu
Homepage: http://www.scripps.edu/chem/yu/index/html
À
original conditions gave good yields and high levels of
monoselectivity with electron-rich and electron-neutral sub-
strates. However, when we took a product from this reaction
and resubmitted it to the reaction conditions in the presence
of a different olefin, we observed a less than 10% conversion
of the desired unsymmetrical diolefinated product. Further-
more, we noted that during our original screening studies to
[**] We gratefully acknowledge TSRI, the NIH (NIGMS, 1 R01
GM084019-02), Amgen, and Eli Lilly for financial support. We thank
the A. P. Sloan Foundation for a fellowship (J.-Q.Y.) and the NSF, the
DOD, TSRI, and the Skaggs Oxford Scholarship program for
predoctoral fellowships (K.M.E.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002077.
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6169

Communications
ligands. We found that Boc-Val-OH, Ac-Ile-OH,
and Ac-Val-OH (Table 1, entries 5, 11, and 12) gave
the highest conversion of diolefinated product 4a.
Ac-Ile-OH was found to be the highly active;
however, with this ligand the results varied sub-
stantially from trial to trial. Ac-Val-OH was found
to be the best in terms of activity and reproduci-
bility. Importantly, 1,4-benzoquinone (BQ), which
we previously used in our monoselective olefina-
tion procedure,[14] was found to decrease the
reaction rate. With Ac-Val-OH, increasing the
reaction time from 2 hours to 6 hours improved
the conversion from 63% to greater than 99%
(86% yield of isolated product; entry 18). Impor-
tantly, with the reaction time extended to 24 hours,
2 mol% catalyst could also be used to give an 82%
yield of 4a upon isolation.
By using these optimized conditions, a wide
range of phenylacetic acids (1) were converted into
the corresponding products (4) (Scheme 4). The
reaction worked well with electron-rich substrates
containing ether and alkyl groups (4b, 4d, 4j–4m,
Scheme 3. Outline of this work. a) Improved reactivity: direct diolefination of ortho-
À
À
C H bonds. b) Combining high selectivity and reactivity: sequential C H olefina-
À
tion. c) Sequential and iterative C H olefination to build multiply substituted
arenes.
Table 1: Ligand optimization.[a]
develop the monoselective reaction,
we never observed more than 30%
of the diolefinated by-product, even
as we extensively surveyed different
reaction conditions. In light of these
findings, we concluded that we
Entry
Ligand
%
1a
Entry
Ligand
%
1a
faced a problem of low reactivity
and needed a more reactive catalyst
for the installation of a second
olefin.
Encouraged by our recent suc-
cess in using amino acid ligands[21]
to enhance the reactivity of PdII
3a
4a
3a
4a
1
–
BQ
BQ +
Boc-Ile-OH
Boc-Ile-OH
Boc-Val-OH
Boc-Leu-OH
Boc-tLeu-OH
Boc-Ala-OH
Boc-Phe-OH
93
98
72
7
2
27
0
0
1
10
Boc-Ser-OH
Ac-Val-OH
Ac-Ile-OH
77
4
3
23
33
43
0
63
54
2[b]
3[b]
11[c]
12[c]
4
24
3
11
81
25
47
62
62
70
19
65
49
14
35
19
0
10
4
13
14
15
16
17
18[e]
Ac-Leu-OH
54
77
68
57
64
0
43
23
31
41
35
0
3
0
1
2
1
>99
(86)
5[c]
6
formyl-Ile-OH
formyl-Leu-OH
Men-Leu-OH[d]
Men-Val-OH[d]
Ac-Val-OH
with
electron-deficient
sub-
strates,[14] we hypothesized that we
could develop a generally applica-
ble diolefination protocol using an
optimized amino acid ligand and
apply it as the second step in a two-
step, sequential olefination proce-
dure. Gratifyingly, we found in our
initial screening studies that an
array of mono-N-protected amino
7
8
9
1
[a] The conversion was determined by H NMR analysis of the crude reaction mixture. [b] 5 mol% BQ
used. [c] Average of three trials. [d] Men=(À)-Menthyl(O2C). [e] Run for 6 h.
acid ligands (10 mol%) were highly efficient in promoting
diolefination with both electron-poor and electron-rich sub-
strates, such as 4-(trifluoromethyl)phenylacetic acid (1a) and
4-methoxyphenylacetic acid (1b), fashioning the desired
products in quantitative conversion after 48 hours in the
presence of ethyl acrylate (2a), Pd(OAc)2 (5 mol%), KHCO3
(2 equiv), and tAmylOH under O2 (1 atm) at 908C.
To determine the optimal ligand, we selected substrate 1a
for screening. Notably, in the absence of amino acid ligands,
1a was found to give only 13% yield of the mono-olefinated
product 3a after 48 hours. We chose an abridged reaction time
of 2 hours to see the comparative kinetic behavior of the
and 4p) and with electron-poor substrates containing halogen
atoms (4a, 4e–4h, 4n, and 4q). Substrates that contained
bulky substitutents at the a position (4o–4q) or at the
position meta to the carboxylic acid directing group (4j–4n)
required extended reaction times (48 h), but still generally
gave good to excellent yields. 1-Naphthylacetic acid was also
found to be a reactive substrate for this reaction (4r);
although the yield was somewhat low (35%), the second
olefination proceeds via an unusual seven-membered cyclo-
palladated intermediate and represents a unique example of
À
remote C H activation at the 8-position of a naphthalene ring
with a directing group at the 1-position. The reaction was also
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4x led to substantial product decompo-
sition. Other olefins, such as vinyl sul-
fones, vinyl phosphonates, and internal
alkenes were unreactive.
With this robust PdII-catalyzed diole-
fination protocol in hand, we returned to
À
our goal of effecting two sequential C H
olefination reactions to install two differ-
ent alkenes (Scheme 6). We began by
À
using our monoselective C H olefina-
tion reaction,[14] which is compatible with
electron-rich and electron-neutral sub-
strates, to couple 1b and benzyl acrylate
(2b), giving 3b in 70% yield (over 2 g
prepared). Using this intermediate, we
attempted to perform a second olefina-
tion reaction with representative alkene
coupling partners in the presence of our
more active system [PdII/Ac-Val-OH]
catalyst. Gratifyingly, we found that
orthogonally protected acrylates could
be smoothly coupled to give differen-
tially protected aromatic triacids 5a and
5b and that styrene (2d) could also be
installed in good yield (5c). Interestingly,
in accordance with our earlier observa-
tion,[14] when 1-hexene (2 f) was used, the
unique nonconjugated product 5d was
obtained, thereby representing a formal
À
C H allylation. The yield of the isolated
product was low as a result of the
decomposition of the product during
the course of the reaction. In principle,
virtually all of the substrates used in
Scheme 4 could be used for a similar two-
step sequence. meta-Substituted acids
offer another unique element of spatial
control because the first olefin selec-
tively reacts away from the substituent.
Scheme 4. Substrate scope for PdII-catalyzed diolefination. The reported yields are of the
isolated products. [a] 48 h. [b] 15 mol% Pd(OAc)2, 30 mol% Boc-Val-OH, 96 h. [c] 10 mol%
Pd(OAc)2, 20 mol% Boc-Val-OH, 96 h.
optimized for hydrocinnamic acids (4s and 4t) (see the
Supporting Information). In these cases, Boc-Val-OH was
found to be the best ligand. Higher catalyst loadings (10–
15 mol%) and extended reaction times (48–96 h) were
needed to improve the yield of the products 4s and 4t. In
nearly all of the cases in Scheme 4 where the yield is below
80%, the remaining starting material had been completely
converted into the mono-olefinated product (as evidenced by
1H NMR analysis of the crude reaction mixture).
Subsequently, different olefin coupling partners were
examined (Scheme 5). Several acrylates (2a–2c) were found
to be highly reactive. Styrene (2d) was also found to be a
competent coupling partner to give 4w in 61% yield;
however, the reaction required extended time (48 h) and
higher Pd loading (10 mol%). Ethyl vinyl ketone (2e) was
found to be effective, giving 50% yield of 4x after 6 hours.
Attempts to extend the reaction time to improve the yield of
Scheme 5. Olefin scope for PdII-catalyzed diolefination. Reaction con-
ditions: olefin (2 equiv), Pd(OAc)2 (5 mol%), Ac-Val-OH (10 mol%),
KHCO3 (2 equiv), tAmylOH, 908C, 1 atm O2, 6 h. Reported yields are
for the isolated products. [a] 10 mol% Pd(OAc)2, 20 mol% Ac-Val-OH,
48 h.
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Communications
quantities of 7 remained in solution
after 24 h. Though this yield is low,
given the possibility of nonproductive
multidentate coordination of the sub-
strate with PdII, a slow reaction rate can
be expected. Moreover, this case repre-
sents the most complex setting in which
À
C H olefination of a hydrocinnamic acid
has been attempted. In the absence of
Boc-Val-OH, the reaction did not pro-
ceed.
In summary, through the discovery
and development of complementary cat-
alytic systems that exhibit tunable reac-
tivity and selectivity, we have demon-
Scheme 6. Sequential olefination. Reaction conditions (1st step): 2b (2 equiv), Pd(OAc)2
(5 mol%), BQ (5 mol%), KHCO3 (2 equiv), tAmylOH, 908C, 1 atm O2, 48 h. Reaction
conditions (2nd step): olefin (2 equiv), Pd(OAc)2 (5 mol%), Ac-Val-OH (10 mol%), KHCO3
(2 equiv), tAmylOH, 908C, 1 atm O2, 6 h. Reported yields are for the isolated products.
[a] Used 1-hexene (2 f; 1 equiv).
À
strated a sequential C H olefination
protocol for synthesizing complex
divinylbenzene derivatives from simple
starting materials. We first established
The two-step preparation of these advanced unsymmetrical
1,2,3,5-tetrasubstituted arenes demonstrates the power of
robust reaction conditions to effect diolefination with a range
of different phenylacetic and hydrocinnamic acids. We then
applied these conditions as the second step in a two-step
À
sequential C(aryl) H functionalization reactions.
À
Finally, we sought to explore the possibility of performing
sequential C H olefination to prepare 1,2,3-trisubstitued
À
À
iterative C H functionalization, wherein a newly installed
arenes. Lastly, we used sequential C H olefination to set the
À
functional group would serve as the directing group for an
stage for a rare example of iterative C H functionalization,
wherein C H activation installs a directing group for a
À
À
additional C H activation (Scheme 7). In particular, we
À
envisioned using sequential olefination to install two different
subsequent C H functionalization reaction.
Experimental Section
General procedure for PdII-catalyzed diolefination of phe-
nylacetic acids: A 50 mL Schlenk-type sealed tube (with a
Teflon high-pressure valve and side arm) equipped with a
magnetic stir bar was charged with the phenylacetic acid
substrate (0.5 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol),
KHCO3 (100.1 mg, 1.0 mmol), Ac-Val-OH (8.0 mg,
0.05 mmol), the olefin coupling partner (1.0 mmol), and
tAmylOH (2.5 mL). The reaction tube was capped, then
evacuated briefly under high vacuum and charged with O2
(1 atm, balloon; repeated three times). The reaction mixture
was stirred at room temperature for 5 min, then at 908C for
6 h (or 48 h in the case of less-reactive substrates, see
Schemes 4 and 5). Subsequently, the reaction vessel was
cooled to 08C in an ice bath. A 2.0n HCl solution (5 mL)
was added, and the mixture was extracted with EtOAc (3 ꢁ
20 mL). The organic layers were combined, dried over
Na2SO4, filtered, and then concentrated in vacuo. The
resulting residue was purified by silica gel flash column
chromatography using hexanes/EtOAc (1:1; with 2–5%
HOAc) as the eluent.
À
Scheme 7. Sequential and iterative C H olefination to synthesize multiply
substituted arenes. See the Supporting Information for experimental details.
olefins and then, after functional group manipulations, to use
one of the new moieties to direct an additional remote ortho-
Received: April 8, 2010
Published online: July 14, 2010
À
C H functionalization reaction. To test this idea, we prepared
5e in good yield using our sequential olefination method
(Scheme 7). After methylation and hydrogenation, we
À
Keywords: arenes · aromatic substitution · C H activation ·
olefination · palladium
.
obtained highly decorated hydrocinnamic acid 6. Gratifyingly,
we found that treatment of 6 with benzyl acrylate (2b;
2 equiv) in the presence of Pd(OAc)2 (10 mol%), Boc-Val-
OH (20 mol%), and tAmylOH for 12 hours under O2 (1 atm)
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Angew. Chem. Int. Ed. 2010, 49, 6169 –6173
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