Rh(III)-catalyzed halogenation of vinylic C-H bonds: Rapid and general access to Z-halo acrylamides

Article abstract of DOI:10.1021/ol4015915

Herein, the regio- and stereoselective iodination, along with some examples for the bromination, of readily available acrylamides to access a variety of differently substituted Z-haloacrylic acid derivatives is reported. The reaction proceeds under mild conditions via a Rh(III)-catalyzed C-H-activation/ halogenation mechanism and represents a rare example of a direct halogenation of electron-poor acrylic acid derivatives.

Full text of DOI:10.1021/ol4015915

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Rh(III)-Catalyzed Halogenation of Vinylic
CÀH Bonds: Rapid and General Access to
Z‑Halo Acrylamides
†
†
€
Nadine Kuhl, Nils Schroder, and Frank Glorius*
€
€
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster,
€
Corrensstrasse 40, 48149 Mu€nster, Germany
glorius@uni-muenster.de
Received June 5, 2013
ABSTRACT
Herein, the regio- and stereoselective iodination, along with some examples for the bromination, of readily available acrylamides to access a
variety of differently substituted Z-haloacrylic acid derivatives is reported. The reaction proceeds under mild conditions via a Rh(III)-catalyzed
CÀH-activation/halogenation mechanism and represents a rare example of a direct halogenation of electron-poor acrylic acid derivatives.
CÀH bond activation is arguably one of the most pro-
mising strategic tools in organic synthesis for simplifying
the preparation of functionalized building blocks and inter-
mediates.1 Its combination with other reliable and well
established transformations allows the synthesis of natural
products and biologically active compounds to be further
streamlined. In this regard, applying the CÀH bond
activation approach to the preparation of halogenated
compounds, which can be further utilized in well-established
cross-coupling reactions,2 would be valuable. Z-Haloacrylic
acid derivatives represent attractive building blocks for
the selective construction of the ubiquitous Z-configured
olefin motif.3 Known syntheses of Z-haloacrylic acid
derivatives, including carbohalogenations,4,5 hydrohalo-
genations,6 or MoritaÀBaylisÀHilman-type7 transformations,
utilize alkynes as starting materials and therefore are
(3) Examples for Z-halo compounds as intermediates in synthesis:
† The authors contributed equally.
ꢀ
~
(a) Franc-ais, A.; Leyva-Perez, A.; Etxebarria-Jardi, G.; Pena, J.; Ley,
S. V. Chem.;Eur. J. 2011, 17, 329. (b) Skepper, C. K.; Quach, T.;
Molinski, T. F. J. Am. Chem. Soc. 2010, 132, 10286. (c) Bian, M.; Yao,
W.; Ding, H.; Ma, C. J. Org. Chem. 2010, 75, 269. (d) Tang, S.; Erickson,
K. L. J. Nat. Prod. 2008, 71, 898. (e) Yao, T.; Larock, R. C. J. Org. Chem.
2003, 68, 5936. (f) Negishi, E.-i.; Kotora, M. Tetrahedron 1997, 53, 6707.
(g) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945.
(4) Examples on transition-metal catalyzed carbohalogenation: (a)
Huang, L.; Wang, Q.; Liu, X.; Jiang, H. Angew. Chem., Int. Ed. 2012, 51,
5696. (b) Wen, Y.; Huang, L.; Jiang, H.; Chen, H. J. Org. Chem. 2012,
77, 2029. (c) Friest, J. A.; Broussy, S.; Chung, W. J.; Berkowitz, D. B.
Angew. Chem., Int. Ed. 2011, 50, 8895. (d) Huang, J.-M.; Dong, Y.;
Wang, X.-X.; Luo, H.-C. Chem. Commun. 2010, 46, 1035. (e) Li, J.-H.;
Tang, S.; Xie, Y.-X. J. Org. Chem. 2005, 70, 477. (f) Hua, R.; Shimada,
S.; Tanaka, M. J. Am. Chem. Soc. 1998, 120, 12365.
(1) Recent reviews on CÀH bond activation: (a) Wencel-Delord, J.;
Glorius, F. Nat. Chem. 2013, 5, 369. (b) Yamaguchi, J.; Yamaguchi,
A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960. (c) Li, B.-J.; Shi,
Z.-J. Chem. Soc. Rev. 2012, 41, 5588. (d) Arockiam, P. B.; Bruneau, C.;
Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. (e) Kuhl, N.; Hopkinson,
M. N.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 10236. (f) McMurray,
L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40, 1885. (g)
Newhouse, T.; Baran, P. S. Angew. Chem., Int. Ed. 2011, 50, 3362. (h)
Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (i) Cho, S. H.;
Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (j)
€
Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011,
40, 4740. (k) Ackermann, L. Chem. Rev. 2011, 111, 1315. (l) Jazzar, R.;
Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O. Chem.;Eur.
J. 2010, 16, 2654. (m) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem.
Rev. 2010, 110, 624. (n) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010,
110, 1147. (o) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2009, 48, 5094. (p) Thansandote, P.; Lautens, M.
Chem.;Eur. J. 2009, 15, 5874.
(5) Examples for carbohalogenation using organometallic reagents:
^
(a) Abarbri, M.; Parrain, J.-L.; Duchene, A.; Thibonnet, J. Synthesis
2006, 17, 2951 and references therein. (b) Duboudin, J. G.; Jousseaume,
B. J. Organomet. Chem. 1979, 168, 1.
(2) (a) Handbook of Organopalladium Chemistry for Organic Synthe-
sis; Negishi, E.-i., Eds.; John Wiley & Sons: Hoboken, NJ, 2002. (b)
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
44, 4442.
(6) Examples on Hydrohalogenation: (a) Ma, S.; Lu, X.; Li, Z.
J. Org. Chem. 1992, 57, 709. (b) Ma, S.; Lu, X. J. Chem. Soc., Chem.
Commun. 1990, 1643. (c) Tanigushi, M.; Kobayashi, S.; Nakagawa, M.;
Hino, T.; Kishi, Y. Tetrahedron Lett. 1986, 27, 4763.
r
10.1021/ol4015915
XXXX American Chemical Society

unprecedented. Olefins are quite challenging substrates
to functionalize in CÀH bond activation reactions due to
their lability and increased reactivity relative to arenes.15,16
This challenge is predominant in the case of CÀH bond
halogenation of olefins using N-halosuccinimides, as com-
peting radical or cationic background reactions will have
to be circumvented in order to provide a chemo- and
regioselective outcome (Figure 1). Using the rather mild
Rh(III)-catalyzed halogenation methodologydeveloped in
our group,14 we anticipated that these challenges could be
met to provide a stereoselective synthesis of the Z-haloacrylic
acid motif.
Figure 1. Effect of the Rh(III)-catalyst on the direct halogena-
tion of acrylic acids.
Herein, we describe the first transition-metal catalyzed
iodination and bromination of vinylic CÀH bonds which
provides a simple and selective access to a variety of
Z-haloacrylic acid derivatives starting directly from the
alkene-oxidation state. Additionally, a broad overview on
the functional group tolerance and the application to
different amide directing groups are presented to facilitate
potential applications of the methodology described.
We began our study on vinylic CÀH bond halogena-
tions with the iodination of methacrylamide 2. When
applying similar reaction conditions as used for the halo-
genation of arenes14 (Scheme 1), 2 was smoothly converted
to the desired iodinated product 2-I in 76% yield as
determined by GC analysis. Control experiments demon-
strated that a cationic RhCp*-species and the pivalic acid
are essential to obtain satisfying conversion to 2-I. Nota-
bly, no conversion of the starting material was detected
when the reaction was conducted without [RhCp*Cl2]2
and AgSbF6, whereas if only the Rh(III)-catalyst was
omitted significant side reactions were observed, high-
lighting the efficiency of the Rh(III)-catalyzed pathway.17
With the optimized conditions in hand, we continued to
study the influence of different substituents on the effi-
ciency of the iodination and the corresponding bromina-
tion reaction (Scheme 1). In the case of the unsubstituted
vinylamide 1 the iodination reaction led to the desired
product 1-I. The bromination was dominated by a back-
ground reaction yielding a dibrominated amide as the
major product.17
often limited with regard to the accessible substitution
patterns.8 Consequently, the application of CÀH bond
activation in the direct halogenation of electron-deficient
olefins is desirable, as it would provide a more general
route to these halogenated motifs due to the ready avail-
ability of diversely substituted acrylic acid derivatives.
In the past decade, a variety of methods for the palladium-
catalyzed ortho-directed halogenation of aromatic sp2
CÀH bonds have been developed by Sanford,9 Yu,10
Shi,11 and others12 which allow the functionaliza-
tion of benzoic acid, aniline, or phenol derivatives. In
addition, our group recently demonstrated that also a
Rh(III)-catalystis competent for the ortho-halogenation of
different benzene derivatives.13,14 However, it seems that
the direct halogenation of vinylic CÀH bonds is still
(7) Examples on MoritaÀBaylisÀHilman-type reactions: (a) Senapati,
B. K.; Hwang, G.-S.; Lee, S.; Ryu, D. H. Angew. Chem., Int. Ed. 2009,
48, 4398. (b) Lee, S. I.; Hwang, G.-S.; Ryu, D. H. Synlett 2007, 1, 59. (c)
ꢀ
Wei, H.-X.; Hu, J.; Purkiss, D. W.; Pare, P. W. Tetrahedron Lett. 2003,
44, 949. (d) Taniguchi, M.; Hino, T.; Kishi, Y. Tetrahedron Lett. 1986,
27, 4767.
(8) For an aminohalogenation of R,β-unsaturated carbonyl com-
pounds, see: Sun, H.; Zhang, G.; Zhi, S.; Han, J.; Li, G.; Pan, Y. Org.
Biomol. Chem. 2010, 8, 4236.
(9) (a) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Org.
Lett. 2006, 8, 2523. (b) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am.
Chem. Soc. 2004, 126, 2300.
(10) (a) Mei, T. S.; Wang, D.-H.; Yu, J.-Q. Org. Lett. 2010, 12, 3140.
(b) Mei, T.-S.; Giri, R.; Maugel, N.; Yu, J.-Q. Angew. Chem., Int. Ed.
2008, 47, 5215. (c) Giri, R.; Chen, X.; Yu, Y.-Q. Angew. Chem., Int. Ed.
2005, 44, 2112.
(11) Wan, X.; Ma, Z.; Li, B.; Zhang, K.; Cao, S.; Zhang, S.; Shi, Z.
J. Am. Chem. Soc. 2006, 128, 7416.
In contrast, R-substituted vinylamides 2 and 3 were
successfully halogenated under these reaction con-
ditions in excellent yields. Nevertheless, conducting the
halogenations of vinylamide 3 in the absence of the
Rh(III)-catalyst gave the same yields and selectivities
for the Z-halogenated products.18 Interestingly, for the
β-substituted vinylamides 4 and 5, halogenation with NIS
(12) Selected examples on the halogenation of arenes via CÀH-bond
activation: (a) Sun, X.; Shan, G.; Sun, Y.; Rao, Y. Angew. Chem., Int.
Ed. 2013, 52, 4440. (b) Bedford, R. B.; Haddow, M. F.; Mitchell, C. J.;
Webster, R. L. Angew. Chem., Int. Ed. 2011, 50, 5524. (c) Zhao, X.;
ꢀ
Dimitrijevic, E.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 3466. (d)
Kakiuchi, F.; Kochi, T.; Mutsutani, H.; Kobayashi, N.; Urano, S.; Sato,
M.; Nishiyama, S.; Tanabe, T. J. Am. Chem. Soc. 2009, 131, 11310.
(13) Recent reviews on Rh(III)-catalyzed CÀH bond activation: (a)
Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. (b) Patureau,
F. W.; Wencel-Delord, J.; Glorius, F. Aldrichimica Acta 2012, 45, 31. (c)
Satoh, T.; Miura, T. Chem.;Eur. J. 2010, 16, 11212.
(16) Selected articles on Rh(III)-catalyzed vinylic CÀH bond activa-
tion: (a) Lian, Y.; Huber, T.; Hesp, K. D.; Bergman, R. G.; Ellman, J. A.
Angew. Chem., Int. Ed. 2013, 52, 629. (b) Neely, J. M.; Rovis, T. J. Am.
Chem. Soc. 2013, 135, 66. (c) Zhang, J.; Loh, T.-P. Chem. Commun. 2012,
48, 11232. (d) Wencel-Delord, J.; Nimphius, C.; Patureau, F. W.;
Glorius, F. Chem.;Asian J. 2012, 7, 1208. (e) Besset, T.; Kuhl, N.;
Patureau, F. W.; Glorius, F. Chem.;Eur. J. 2011, 17, 7167. (f) Hyster,
T. K.; Rovis, T. Chem. Sci. 2011, 2, 1606. (g) Mochida, S.; Hirano, K.;
Satoh, T.; Miura, M. J. Org. Chem. 2011, 76, 3024. (h) Morimoto, K.;
Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2011, 76, 9548. (i) Su, Y.;
Zhao, M.; Han, K.; Song, G.; Li, X. Org. Lett. 2010, 12, 5462. (j)
Mochida, S.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74,
6295.
€
(14) Schroder, N.; Wencel-Delord, J.; Glorius, F. J. Am. Chem. Soc.
2012, 134, 8298.
(15) Selected examples for transition-metal catalyzed vinylic CÀH
bond activation: (a) Wang, L.; Ackermann, L. Org. Lett. 2013, 15, 176.
(b) Duttwyler, S.; Chen, S.; Takase, M. K.; Wiberg, K. B.; Bergman,
R. G.; Ellman, J. A. Science 2013, 339, 678. (c) Yu, H.; Jin, W.; Sun, C.;
Chen, J.; Du, W.; He, S.; Yu, Z. Angew. Chem., Int. Ed. 2009, 49, 5792.
(d) Xu, Y.-H.; Lu, J.; Loh, T.-P. J. Am. Chem. Soc. 2009, 131, 1372. (e)
Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14082. (f) Hatamoto, Y.;
Sakaguchi, S.; Ishii, Y. Org. Lett. 2004, 6, 4623. (g) Sato, T.; Kakiuchi,
F.; Chatani, N.; Murai, S. Chem. Lett. 1998, 893. For a recent review on
this topic, see: (h) Shang, X.; Liu, Z.-Q. Chem. Soc. Rev. 2013, 42, 3253.
(17) For further details see SI.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 1. Halogenation of Differently Substituted Vinylamidesa
Figure 2. 0.4 mmol scale using 1.1 equiv of NIS; isolated yields.
a 1 mmol scale.
the desired Z-configured products 9-I and 10-I exclusively
in 64% and 84% isolated yield, respectively. Gratifyingly,
the synthetically versatile Weinreb amide 11 and the
secondary butyl amide 12 also gave the corresponding
iodinated products in moderate to good yields.
In order to study the influence of functionality directly
connected to the reactive center, the iodination of various
vinylamide derivatives leading to densely functionalized
Z-haloacrylic amides was investigated (Scheme 2). Grati-
fyingly, the R- and β-brominated substrates 13 and 17
smoothly reacted under standard reaction conditions.
The corresponding dihalogenated products 13-I and 17-I
were obtained in excellent yields and represent attractive
intermediates for further sequential functionalization.20 In-
terestingly, an ester functionality installed in close proximity
to the reactive center was well tolerated under the reaction
conditions. The corresponding product 16-I was obtained in
excellent yield. In comparison the reaction of alcohol 14 led
to decomposition of the starting material and benzyl protec-
tion was required to obtain the iodinated motif 15-I.
Investigation of cinnamic acid derivatives 18À20 further
disclosed a significant impact of the aryl substituent on the
efficacy of the iodination reaction. Whereas the p-methoxy
cinnamic amide 18 led to a complex reaction mixture, the
iodination of the less electron-rich substrate 20 yielded the
desired product 20-I in excellent 88% isolated yield.
To facilitate the application of this methodology, we
applied a robustness screen recently developed in our
group21 to access both the functional group tolerance of
the vinylic CÀH bond halogenation reaction and the
tolerance of specific motifs to the reaction conditions.
Therefore, the standard iodination reaction of 2 was
performed in the presence of a given functional group or
common motif (“additive”), and the conversion of the
starting material (sm), yield of 2-I, and stability of the
additive were determined by GC analysis. A selection of
the data obtained is summarized in Table 1 using simple
labeling to facilitate a quick assessment of the results (for
the full screening, see Supporting Information (SI)).17
To our delight, a variety of versatile and synthetically
useful functional groups such as an aromatic ester, aromatic
and aliphatic ketones, nitriles, aliphatic alcohols, aryl and
alkyl halides, and notably, the relatively sensitive aldehyde
functionality proved to be stable under the standard
halogenations conditions. In contrast, alkynes, alkenes,
a 0.4 mmol scale using 1.1 equiv of NXS; isolated yields are given.
Undesired E-isomers were not detected. 39% of a dibrominated
b
c
d
product were isolated, 2 Â 0.8 equiv of NXS, 24 h. Similar yields
e
were obtained without [RhCp*Cl2]2. 2 Â 0.7 equiv of NXS, 120 °C,
24 h. f Determined by GC-MS. g 5 mol % [RhCp*Cl2]2, 20 mol % AgSbF6
were used. h Determined by 1H NMR. Inseparable mixture of 8 and 8-I.
proved more facile. However, in the case of crotylamide 4 a
higher reaction temperature and two successive additions
of NIS were necessary to avoid noncatalyzed side reac-
tions. In contrast, R,β-disubstituted vinylamides 6À8
smoothly underwent bromination with NBS whereas the
iodination only proceeded in the case of the R-phenyl
cinnamic amide 6 with good efficacy. For the R,β-disub-
stituted vinylamides, in particular, it was noted that un-
selective bromination takes place when [RhCp*Cl2]2 is
omitted.17 Exemplary rate measurements based on the
conversion of 6 with and without the Rh(III)-catalyst
revealed markedly different reaction profiles in which the
catalyzed reaction exhibits a much higher initial rate.19
This further underlines the ability of the Rh(III)-cata-
lyzed process to suppress unwanted side reactions.
Noting that the iodination reaction was more robust
toward changes in the substitution pattern of the substrate,
further studieswere preferentiallyundertakenusing NIS as
the halogen source. A short screen of different amide
groups on the standard methacrylate framework revealed
that the iodination reaction is not dependent on the steric
character of the tertiary amide directing group (Figure 2).
Besides the bulky N,N-diisopropylamide, the smaller
amides 9 and 10 efficiently directed the iodination yielding
(18) For all substrate classes the bromination and iodination reac-
tions were also tested without the Rh(III)-catalyst and/or the silver salt.
For more details, see SI.
(19) For the bromination of 6 without the Rh(III)-catalyst full
conversion to a mixture of (E)-6-Br, (Z)-6-Br, and allylic-bromination
products was observed. For further details see SI.
(20) A method for the sequential functionalization of compounds
related to 16-I has already been described: Vu, V. A.; Marek, I.;
Knochel, P. Synthesis 2003, 1797.
(21) (a) Collins, K.; Glorius, F. Nat. Chem. 2013, 5, 597. (b) Collins,
K.; Glorius, F. Tetrahedron 2013, 69, 7817.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Exploring Functional Group Tolerancea
Scheme 3. Representative Applications
Finally, some additional experiments to further examine
characteristics of our methodology showed that our stan-
dard reaction still proceeds with similar efficacy when con-
ducted at rt or 60 °C with only 1 mol % Rh(III)-dimer (and
4 mol % of the silver salt) leading to a 73% and 68% isolated
yield of 2-I, respectively. Notably, the reaction can be easily
scaled up to a 6 mmol scale without loss in reactivity (80%
isolated yield of 2-I with 1 mol % [RhCp*Cl2]2, 4 mol %
AgSbF6, 0.5 equiv of PivOH, and otherwise identical
conditions).17 Initial rate measurements of 2-d0 and 2-d1
(easily prepared from 2-I, Scheme 3) revealed a KIE of 2.3
showing that the halogenation mechanism includes a CÀH
activation event which is rate determining.17
a 0.4 mmol scale using 1.1 equiv of NIS; isolated yields are given. If
not stated otherwise no E-isomers were detected. b Decomposition of 14.
c Reaction conducted on a 1 mmol scale. Z/E = 95:5 from the isolated
compound. d 80 °C reaction temperature.
Table 1. Selected Examples of the Robustness Screena
Additionally, a Sonogashira coupling of 2-I with 1-octyne
yielding enyne 21 in 77% isolated yield was performed to
demonstrate that such valuable motifs can be easily ac-
cessed in two steps by applying this CÀH halogenation
approach.
In summary, we have developed an efficient method to
selectively access Z-haloacrylic acid derivatives via a direct
route from readily available R,β-unsaturated carbonyl
compounds using Rh(III) CÀH bond activation.
The reaction offers a general approach to differently
substituted haloacrylic acid derivatives. Moreover, it pro-
ceeds under fairly mild conditions allowing the tolerance
of a variety of synthetically useful functional groups and
moieties. We expect this method to be complementary to
already existing methods for the synthesis of these highly
useful compounds.
Acknowledgment. This paper is dedicated to Professor
Teruaki Mukaiyama in celebration of the 40th anniversary
of the Mukaiyama aldol reaction. We thank C. Weitkamp
and C. Benndorf for experimental support and K. Collins
a 0.125 mmol scale. GC-yields using mesitylene as the internal
standard. [RhCp*(MeCN)3](SbF6)2 was used for simplification. b Com-
bined yield of recovered sm and additive. sm = starting material.
€
for helpful discussions (all WWU Munster). Generous
support by the DFG (IRTG Munster-Nagoya and Leibniz
award 2013), the Fonds der Chemischen Industrie (N.K.),
and the European Research Council under the European
Community’s Seventh Framework Program (FP7 2007-2013)/
ERC Grant Agreement No. 25936 is gratefully acknowledged.
as well as activated benzene derivatives, such as aniline,
were not well tolerated and also significantly hampered the
iodination reaction itself. In addition to functional groups,
the standard reaction of methacrylamide 2 was also per-
formed in the presence of different heterocycles. Unfortu-
nately, N-containing or electron-rich heterocycles typically
led to complete inhibition of the halogenation reaction.
However, satisfying results could be obtained in the pre-
sence of the more electron-deficient n-butyl thiophene,
benzofuran, and the 2-chloroquinoline heterocycles sug-
gesting that these motifs could be indeed applied in the
vinylic CÀH halogenation of more complex structures.
€
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX