RhIII-catalyzed oxidative olefination of vinylic C-H bonds: Efficient and selective access to Di-unsaturated α-amino acid derivatives and other linear 1,3-butadienes

Article abstract of DOI:10.1002/chem.201101340

Olefin(s) get-together! A Rh^III-catalyzed oxidative cross-coupling of different olefins was developed, resulting in the formation of valuable linear butadiene products and especially di-unsaturated α-amino acid derivatives. 1,1-Di-, 1,2-di-, and 1,1,2-trisubstituted olefins could be coupled with styrenes and acrylates. In these reactions, remarkably high levels of chemo-, regio-, and stereoselectivity were obtained, rendering this a valuable synthetic tool. Copyright

Full text of DOI:10.1002/chem.201101340

COMMUNICATION
DOI: 10.1002/chem.201101340
III
À
Rh -Catalyzed Oxidative Olefination of Vinylic C H Bonds: Efficient and
Selective Access to Di-unsaturated a-Amino Acid Derivatives and Other
Linear 1,3-Butadienes
[
a]
[b]
[b]
[b]
Tatiana Besset, Nadine Kuhl, Frederic W. Patureau, and Frank Glorius*
Dedicated to Professor Gerhard Erker on the occasion of his 65th birthday
The directed oxidative olefination of aromatic CÀH
desirable [Eq. (2)], as it would obviate the need for tedious
and costly preactivation steps.
[1]
bonds, as pioneered by Fujiwara and Moritani, mostly cat-
[2–4]
alyzed by Pd
(e.g. work by
the groups of de Vries and van
[3]
[4]
Leeuwen, and Yu ) or Rh
(
e.g. work by Miura and Satoh
[5]
[6]
and co-workers,
us,
and
[7]
others ), has considerably im-
proved the field of cross-cou-
pling chemistry as it minimizes
waste formation and prefunc-
tionalization steps. However,
applying these directed arene
CÀH functionalization methods
to alkenes is challenging, be-
cause of the increased reactivity
and lability of olefins. Conse-
quently, the oxidative olefina-
[
8]
tion of vinylic CÀH bonds,
leading to valuable diene prod-
ucts, has remained underdevel-
[5c,9]
[9a]
oped. Inspiring seminal work
by the groups of Ishii,
Herein we report the direct Rh-catalyzed oxidative CÀH
olefination of functionalized alkenes as well as its applica-
tion to the formation of a,b-g,d-unsaturated amino acids, an
important class of products [Eq. (3)]. These latter ones are
versatile building blocks in the life sciences, and also serve
as substrates for asymmetric hydrogenation leading to
[9b,c]
[9d]
Loh,
and Yu showed that certain classes of butadienes
can be prepared by Pd-catalyzed oxidative cross-coupling of
some terminal olefins, although the substrate scope is usual-
ly limited to specific structures. Alternative synthetic meth-
[10]
ods for functionalized butadienes
such as the Horner–
[11,12]
Wadsworth–Emmons olefination or the Suzuki–Miyaura
coupling rely on prefunctionalized building blocks
highly valuable chiral a-amino acids derivatives.
To develop a Rh-catalyzed CÀH oxidative olefination of
functionalized alkenes, several different directing groups
and olefin substitution patterns were evaluated. We com-
menced our investigation with the coupling of commercially
available methacrylate 1a, a 1,1-disubstituted olefin, and sty-
rene, which under our best conditions using [{RhCp*Cl } ]
[11]
[Eq. (1)].
Thus, a general, direct and selective oxidative
vinylic CÀH/CÀH cross-coupling method would be highly
[
a] Dr. T. Besset
2
2
Van’t Hoff Institute for Molecular Sciences
University of Amsterdam
and AgSbF together with Cu ACHTUNGRETNN(UNG OAc) as oxidant in 1,4-diox-
2
6
Science Park 904, 1098 XH Amsterdam (Netherlands)
ane gave the corresponding linear diene 2a as a mixture of
two isomers (2Z,4E:2E,4E=45/55) in 54% yield
[
b] N. Kuhl, Dr. F. W. Patureau, Prof. Dr. F. Glorius
Organisch-Chemisches Institut
[13]
(Scheme 1). Even though a high reaction temperature of
608C was required, this reactivity is remarkable consider-
ing that ester directing groups are known to perform poorly
der Westfꢀlischen Wilhelms-Universitꢀt Mꢁnster
Corrensstrasse 40, 48149 Mꢁnster (Germany)
Fax : (+49)251 83-33202
1
[6b]
in oxidative olefination reactions of arenes.
E-mail: glorius@uni-muenster.de
Furthermore, replacing styrene by n-butylacrylate led to
the formation of linear unsaturated diester (Z)-2b in excel-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101340.
Chem. Eur. J. 2011, 17, 7167 – 7171
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7167

sociated with steric congestion
near the CÀH activation site.
While butyl crotonate only af-
forded traces of the desired
cross-coupling product with sty-
rene (even at 1608C), primary
and tertiary amides were found
to be excellent directing groups
in these difficult reactions.
When crotonamide (3a) was
coupled with styrene, 4a was
obtained as a mixture of iso-
[16]
mers (78:22, Z,E:E,E). Like-
wise, linear diene 4b was ob-
tained as the major product
(
74:26) when n-butylacrylate
replaced styrene. The cycliza-
tion reactivity towards unsatu-
rated lactams, which we previ-
ously reported by using primary
benzamides and n-butylacrylate,
[17]
was almost not observed.
When changing the directing
group into the reactive tertiary
crotonamide, full conversion
was observed in all cases and a
simple purification afforded
products, such as 4c in 68%
yield. The method is also appli-
cable to styrenes bearing elec-
tron-withdrawing (4e) or elec-
tron-donating
groups
(4 f).
Even some cinnamic acid deriv-
atives (4g and 4h) were selec-
tively prepared, although with
ÀH oxidative Heck-type reaction of 1,1- and 1,2-disubstituted olefins, conditions and moderate conversions. Argua-
Scheme 1. Rh-catalyzed C
isolated yields. [a] Compound 2b was obtained as an inseparable mixture of three diastereomers in a ratio of bly, the lower reactivity (start-
9
6.8:3.0:0.2 (Z,E:E,E:E,Z); NMR yield is given. [b] The ratio of the two starting materials was inverted, addi-
tionally 12% of the E,E- and 6% of the E,Z-isomer were isolated. [c] Reaction was run at 1208C in tert-
AmylOH. [d] See reference [16]. [e] Reaction was run at 1408C.
ing materials are still present at
the end of the reaction) can be
explained by the electron-with-
drawing character of the phenyl
substituent close to the vinylic
CÀH bond.
lent selectivity. Considering that the two coupling partners
differ only by one methyl group this selective coupling is
noteworthy (no homo-coupling dimer of the limiting compo-
nent could be detected in any case). Interestingly, phenyl
vinyl sulfone was also found to be a competent coupling
partner for methacrylate, providing highly functionalized
product 2c. Methacrylamide proved to be even more effi-
cient than methacrylate in the reaction with styrene afford-
ing product 2d under milder conditions (1208C) and with
higher diastereoselectivity (Z:E=79:21, Scheme 1). Unex-
pectedly, engaging simple enamide-type olefins bearing
NHAc, a privileged directing group in aromatic CÀH activa-
Impressively, even when sterically congested trisubstituted
2,3-dimethylacrylic amide 5 was engaged with styrene or n-
butylacrylate, the corresponding tetrasubstituted diene cou-
pling products 6a,b were obtained in good yield [Eq. (4)].
This highlights potential applications of this method, espe-
[14]
[15]
tion, did not provide the desired products.
We continued our study with the oxidative CÀH olefina-
tion of b-substituted acrylamides and acrylesters, arguably a
substantial challenge because of the reactivity problems as-
7168
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Chem. Eur. J. 2011, 17, 7167 – 7171

III
Rh -Catalyzed Oxidative Olefination of Vinylic CÀH Bonds
COMMUNICATION
cially for the stereoselective preparation of highly substitut-
ed olefins, which would be difficult to access more efficient-
ly otherwise.
It is noteworthy that halides such as bromide (8g) or chlo-
ride (8h,j) are nicely tolerated, as no proto-dehalogenation
nor other Heck coupling products were observed. Surpris-
ingly, the coupling of 7a with n-butylacrylate led to 8l as a
mixture of isomers in 69% yield, which is below our expect-
ation, considering the high reactivity of acrylates in olefina-
Moreover, in the course of our endeavor towards the de-
velopment of efficient routes to highly valuable classes of
compounds such as di-unsaturated a-amino acid derivatives,
[18–20]
[6b]
methyl 2-acetamidoacrylate (7a)
was selected as start-
tion reactions. The versatility of both partners under our
ing material. While we found that simple enamide deriva-
conditions could be an explanation. Impressively, even
phenyl vinyl sulfone was used with success, substantially in-
creasing the substrate scope. Furthermore, challenging trans-
1-phenyl-1,3-butadiene could be engaged as coupling part-
ner, yielding the corresponding triene 8n (64%) as a mix-
ture of linear isomers (83:10:7), which is especially remarka-
bly selective considering that the two substrates contain
seven olefinic CÀH bonds.
[15]
tives were not suitable for this transformation, we were
pleased to observe that the electronic structure of 7a, an en-
amide with an additional carboxylic ester substituent, offers
just the right electronic disposition, due to the electron-with-
drawing ester unit. Gratifyingly, when 7a was engaged with
styrene, the reaction proceeded smoothly towards 8a in
87% yield (easily separable mixture of isomers with a good
Z-diastereoselectivity, Scheme 2). Styrenes with various sub-
stitution patterns in all cases gave the expected linear prod-
ucts in good yields. Interestingly, di-olefinated products
The standard reaction was also reproduced on a larger
scale (5 mmol, (Z)-8a 76%, (E)-8a 9%) with a similar Z:E
ratio. Notably, the reaction could be successfully performed
[
21]
were generally not observed.
Substituents at the meta-
under air with a catalytic amount of Cu ACHTUNGERTNNGNU( OAc) (20 mol%),
2
affording (Z)-8a in 55% isolated yield.
For obtaining mechanistic insight, we submitted 7a to a
3
and para-position as well as electron-donating (R =Me,
tBu) and electron-withdrawing groups (R =Br, Cl) are well
3
tolerated (8c–h). This method is also compatible with other
functional groups like carboxylic esters (8 f). Notably, the
electronic properties of the styrenes do not seem to have a
strong influence on the yield or the diastereoselectivity.
Even more challenging ortho-functionalized styrenes
catalytic amount of Rh precursor and Ag salt in deuterated
[22]
methanol. As most of the starting material was recovered
undeuterated, an irreversible cyclometallation and/or an
[23]
electrophilic substitution of the cationic Rh can be pro-
[24,25]
posed as the initial step.
Engaging 7b bearing an elec-
(
electron-rich 8i and electron-poor 8j) were also successful-
tron-withdrawing directing group (NCOCF ) still furnished
3
ly employed.
8b in good yield (60%). Furthermore, using a methylated
directing group (7o) also af-
forded 8o in 63% yield. How-
ever, the specific mode of
action of the two directing
groups in 7 still remains un-
clear. Finally, a competition ex-
periment between a N-(m-toly-
l)acetamide and 7a with styrene
as limiting reagent was per-
formed. Intriguingly, no product
resulting from the aromatic CÀ
H
olefination (11) was ob-
served, suggesting that 7a out-
competes the aromatic sub-
[26]
strate 11 for the Rh catalyst.
In conclusion, we have stud-
ied the Rh-catalyzed olefination
of vinylic CÀH bonds of al-
kenes involving different direct-
ing or activating groups. Grati-
fyingly, 1,1- and 1,2-disubstitut-
ed and remarkably also 1,1,2-
trisubstituted olefins were suc-
cessfully converted into the cor-
Scheme 2. Rh-catalyzed vinylic CÀH bond functionalization, conditions and isolated yields; 0.5 mmol scale, responding linear butadienes.
.2m for all entries; yields of separately isolated major Z and minor E isomer are given. [a] Run on a 5 mmol
scale reaction. An inseparable mixture of three diastereomers was obtained in ratio of 86:5:9
Z,E:E,E:(most likely)Z,Z). [b] An inseparable mixture of two diastereomers was obtained in a ratio of 74:26
Z,E:E,E). [c] A mixture of three inseparable isomers was obtained (83:10:7), the major one is the 2Z,4E,6E
0
Especially
acetamidoacrylate
a
provided good yields and high
levels of selectivity (mono-olefi-
nation, cross-coupling, linear
(
(
isomer. [d] Only the major diastereoisomer was isolated.
Chem. Eur. J. 2011, 17, 7167 – 7171
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7169

F. Glorius et al.
product, Z-selective). Moreover, we have applied this pro-
cess as an efficient, atom-economical access to polyfunc-
tionalized a,b-g,d-unsaturated amino acids, valuable build-
ing blocks for further transformations.
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[
[
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General procedure for the a-amino acid derivative formation: In a
flame-dried sealed tube the olefin (0.5 mmol scale), acetamidoacrylate
(
(
0.75 mmol,
0.05 mmol), Cu
1.5 equiv),
[{RhCp*Cl
2
}
2
]
(0.0125 mmol),
AgSbF
6
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OAc) (1.05 mmol), and tert-amyl alcohol (2.5 mL) were
2
united under argon. The reactor was then closed and exposed to 1208C
for 16 h. Once the reactor cooled to room temperature and prior filtra-
tion of the crude mixture, 10 equivalents of NH
reaction mixture was stirred for 1 h (a dark blue color appeared). Then,
the reaction mixture was filtered through a short plug of SiO in EtOAc
and CH Cl . Subsequent solvent evaporation afforded the crude product
which was purified by SiO column chromatography.
4
OAc was added and the
1
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Acknowledgements
We thank Dr. Xavier Bugaut and Matthias Dahlkamp for substrates 7b
and 7o and Dr. Klaus Bergander for special NMR experiments. The
Fonds der Chemischen Industrie (N.K.), the Alexander von Humboldt
Foundation (F.P.), the Deutsche Forschungsgemeinschaft (SFB 858), and
the European Research Council (ERC starting grant) are gratefully ac-
knowledged for financial support. The research of F.G. was supported by
the Alfried Krupp Prize for Young University Teachers of the Alfried
Krupp von Bohlen und Halbach Foundation.
2
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Keywords: amino acids · butadienes · CÀH activation ·
oxidative Heck-coupling · rhodium
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ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 7167 – 7171

III
Rh -Catalyzed Oxidative Olefination of Vinylic CÀH Bonds
COMMUNICATION
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III
[20] We previously reported a first study towards Rh -catalyzed pyrrole
synthesis (see Ref. [6c]). Likewise, enamide 7a was engaged with
unactivated internal alkynes as coupling partners; reaction condi-
tions: 2.5 mol% [{RhCp*Cl } ], AgSbF , Cu AHCUTGNRENNGU( OAc) , DCE, 1208C,
2 2 6 2
16 h. Compound 10b was obtained starting from 8b, 10c from 8a
(Scheme 2). Compound 10 f is drawn as the main regioisomer, the
yield of the minor one (10g) is indicated in brackets; see the Sup-
porting Information.
2
005, 7, 2321.
11] a) M. J. Burk, J. G. Allen, W. F. Kiesman, J. Am. Chem. Soc. 1998,
20, 657, and references therein; b) M. J. Burk, J. G. Allen, W. F.
[
[
1
Kiesman, K. M. Stoffan, Tetrahedron Lett. 1997, 38, 1309.
12] J. Elaridi, J. Patel, W. R. Jackson, A. J. Robinson, J. Org. Chem.
2
006, 71, 7538. In this work, 8a was successfully selectively monohy-
I
drogenated under mild conditions (Rh -(S,S)-Et-DuPHOS, 75 psi
2
H ) leading to the corresponding amino acid derivative 9a in 97%
yield and 99% ee.
[
21] When ethylene was used as partner, only oligomers were detected.
Mono- and di-substituted aliphatic olefins, that is, 3,3-dimethyl-1-
butene or cyclohexene, yield only traces of product under the reac-
tion conditions.
[
[
13] A trace of a third diastereomer is barely detectable (<5%).
14] Examples of powerful CÀH activations utilizing acetanilides as sub-
[
[
22] See the Supporting Information.
23] In the absence of silver salt, 8a was isolated in a poor yield (25%)
indicating that the cationic character of the rhodium catalyst is im-
strates: a) V. G. Zaitsev, O. Daugulis, J. Am. Chem. Soc. 2005, 127,
4
156; b) X. Wan, Z. Ma, B. Li, K. Zhang, S. Cao, S. Zhang, Z. Shi, J.
Am. Chem. Soc. 2006, 128, 7416; c) Z. Shi, B. Li, X. Wan, J. Cheng,
Z. Fang, B. Cao, C. Qin, Y. Wang, Angew. Chem. 2007, 119, 5650;
Angew. Chem. Int. Ed. 2007, 46, 5554; d) D. R. Stuart, M. Bertrand-
Laperle, K. M. N. Burgess, K. Fagnou, J. Am. Chem. Soc. 2008, 130,
portant. Moreover, when [{Rh
2
ACHTUNGTNRENUNG( cod)Cl} ] was used as a precursor,
only starting material was recovered.
[
24] The two proposed pathways are illustrated by the following equa-
tions:
1
6474; e) R. J. Phipps, M. J. Gaunt, Science 2009, 323, 1593; f) T.
Nishikata, A. R. Abela, S. Huang, B. H. Lipshutz, J. Am. Chem. Soc.
2
1
6
010, 132, 4978; g) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110,
147; h) R. Giri, J. K. Lam, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132,
86.
[
[
[
15] In the cases of N-(1-phenyl-vinyl)-acetamide and N-vinylacetamide,
complete degradation of the starting materials was observed. (Z)-N-
Acetyl dehydrophenylalanine methyl ester, however, did not react.
16] Subjecting product 4a to the standard reaction conditions
(Scheme 1) did not alter the E/Z ratio, suggesting that isomerization
[
[
25] A Friedel–Crafts type mechanism involving the condensation of the
olefin onto 7a can be excluded as even electron-poor butylacrylate
reacts towards 8l in good yield. Furthermore, 4-methoxystyrene did
not lead to any product formation.
occurs during product formation. See reference [22].
17] The corresponding cyclic compound 4b’ with a Z-configuration ex-
clusively was obtained as a by-product in 12% isolated yield.
26]
[
[
18] For the use of 7a in asymmetric organocatalysis, see: T. Jousseaume,
N. E. Wurz, F. Glorius, Angew. Chem. 2011, 123, 1446; Angew.
Chem. Int. Ed. 2011, 50, 1410.
Received: March 3, 2011
19] During the preparation of this manuscript, two insightful reports on
III
the Rh -catalyzed CÀH bond functionalization of alkenes (espe-
cially enamide 7a) with internal alkynes, leading to pyrroles ap-
Published online: May 25, 2011
Chem. Eur. J. 2011, 17, 7167 – 7171
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7171