Rhodium(III)-catalyzed C-H olefination for the Synthesis of ortho-alkenyl phenols using an oxidizing directing group

Article abstract of DOI:10.1021/ol4014188

By using an oxidizing directing group, a mild, efficient Rh(III) catalyzed C-H olefination reaction between N-phenoxyacetamides and alkenes was developed. This reaction provided a straightforward way for the synthesis of ortho-alkenyl phenols, and the directing group is traceless in the product.

Full text of DOI:10.1021/ol4014188

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Rhodium(III)-Catalyzed CꢀH Olefination
for the Synthesis of ortho-Alkenyl Phenols
Using an Oxidizing Directing Group
Yangyang Shen, Guixia Liu,* Zhi Zhou, and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
guixia@sioc.ac.cn; xylu@sioc.ac.cn
Received May 19, 2013
ABSTRACT
By using an oxidizing directing group, a mild, efficient Rh(III) catalyzed CꢀH olefination reaction between N-phenoxyacetamides and alkenes was
developed. This reaction provided a straightforward way for the synthesis of ortho-alkenyl phenols, and the directing group is traceless in the
product.
Transition-metal-catalyzed CꢀH olefination of arenes
using alkenes has emerged as a powerful strategy to
directly functionalize arenes.1,2 This process has an advan-
tage over the traditional MizorokiꢀHeck reaction3 by
eliminating the need for preactivation of arenes. For
the sake of acquiring high regioselectivity and reactivity,
a directing group is usually assembled in the substrate.
A variety of directing groups have been developed for this
particular reaction, and important advances have been
made toward synthetically useful transformations. Despite
the tremendous progress, most CꢀH olefination reactions
required stoichiometric amounts of metal oxidants or
other additives along with high temperatures. Recently,
the use of an oxidizing directing group4 was introduced
in the field of CꢀH activation, and several external
oxidant-free CꢀH olefinations of arenes (Scheme 1)5 were
reported. In these reactions, an oxygen attached to the
nitrogen directing group acts as an internal oxidant to
maintain catalytic turnover. It is noteworthy that in all
these reactions, the O-linked part functioned as the leaving
group, and the nitrogen directing group remained in the
product.6 Our group recently discovered a novel oxidiz-
ing directing group for a rhodium(III)-catalyzed CꢀH
functionalization of N-phenoxyacetamides with alkynes,
(1) For reviews on CꢀH olefinations, see: (a) Jia, C.; Kitamura, T.;
Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633. (b) Yeung, C. S.; Dong,
V. M. Chem. Rev. 2011, 111, 1215. For recent reviews on CꢀH
activations, see: (c) Li, B.-J.; Shi, Z.-J. Chem. Soc. Rev. 2012, 41, 5588.
(d) Mei, T.-S.; Kou, L.; Ma, S.; Engle, K. M.; Yu, J.-Q. Synthesis 2012,
1778. (e) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012,
(4) For a review, see: Patureau, F. W.; Glorius, F. Angew. Chem., Int.
Ed. 2011, 50, 1977.
€
112, 5879. (f) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem.
Soc. Rev. 2011, 40, 4740. (g) Colby, D. A.; Tsai, A. S.; Bergman, R. G.;
Ellman, J. A. Acc. Chem. Res. 2012, 45, 814. (h) Hartwig, J. F. Chem.
Soc. Rev. 2011, 40, 1992. (i) Lyons, T. W.; Sanford, M. S. Chem. Rev.
2010, 110, 1147.
(5) (a) Wu, J.; Cui, X.; Chen, L.; Jiang, G.; Wu, Y. J. Am. Chem. Soc.
2009, 131, 13888. (b) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F.
J. Am. Chem. Soc. 2011, 133, 2350. (c) Li, B.; Ma, J.; Wang, N.; Feng, H.;
€
Xu, S.; Wang, B. Org. Lett. 2012, 14, 736. (d) Hyster, T. K.; Knorr, L.;
(2) For some examples, see: (a) Umeda, N.; Hirano, K.; Satoh, T.;
Miura, M. J. Org. Chem. 2009, 74, 7094. (b) Ackermann, L.; Wang, L.;
Wolfram, R.; Lygin, A. V. Org. Lett. 2012, 14, 728. (c) Patureau, F. W.;
Glorius, F. J. Am. Chem. Soc. 2010, 132, 9982. (d) Tsai, A. S.; Brasse, M.;
Bergman, R. G.; Ellman, J. A. Org. Lett. 2011, 13, 540. (e) Wang, D.-H.;
Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science 2010, 327, 315. (f) Patureau,
F. W.; Besset, T.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 1064.
(g) Wang, C.; Chen, H.; Wang, Z.; Chen, J.; Huang, Y. Angew. Chem.,
Int. Ed. 2012, 51, 7242.
Ward, T. R.; Rovis, T. Science 2012, 338, 500. (e) Ye, B.; Cramer, N.
Science 2012, 338, 504.
(6) For some examples, see: (a) Tan, Y.; Hartwig, J. F. J. Am. Chem.
Soc. 2010, 132, 3676. (b) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am.
Chem. Soc. 2010, 132, 6908. (c) Guimond, N.; Gorelsky, S. I.; Fagnou,
K. J. Am. Chem. Soc. 2011, 133, 6449. (d) Wang, H.; Glorius, F. Angew.
Chem., Int. Ed. 2012, 51, 7318. (e) Too, P. C.; Wang, Y.-F.; Chiba, S.
Org. Lett. 2010, 12, 5688. (f) Wang, H.; Grohmann, C.; Nimphius, C.;
Glorius, F. J. Am. Chem. Soc. 2012, 134, 19592. (g) Ackermann, L.;
Fenner, S. Org. Lett. 2011, 13, 6548. (h) Neely, J. M.; Rovis, T. J. Am.
Chem. Soc. 2013, 135, 66.
(3) The Mizoroki-Heck Reaction; Oestreich, M., Ed.; Wiley: Chichester,
2009.
r
10.1021/ol4014188
XXXX American Chemical Society

in which the acetamido group could act as the leaving
group.7 This prompted us to explore more transforma-
tions starting from N-phenoxyacetamides, and the CꢀH
olefination reactions between N-phenoxyacetamides and
alkenes are reported here.
In these approaches, an additional step is necessary to
remove the directing group for the synthesis of ortho-
alkenyl phenols. We herein disclose a Rh(III)-catalyzed
CꢀH olefination of N-phenoxyacetamides affording ortho-
alkenyl phenols in one step. The nitrogen directing group
was traceless in the product (Scheme 1). This reaction was
not sensitive to moisture and air and proceeded smoothly
under mild conditions without an external oxidant.
Scheme 1. Oxidizing Directing Group Directed CꢀH Olefination
of Arenes
Table 1. Reaction Conditions Screeninga
yield (%)b
entry
R
solvent
CH3CN
3aa
3aa0
1
Ac (1a)
64
61
49
53
90
89
84c
85
13
7
2
Ac (1a)
Ac (1a)
Ac (1a)
Ac (1a)
Ac (1a)
Ac (1a)
Ac (1a)
Piv (1j)
Ts (1k)
THF
3
ClCH2CH2Cl
DME
21
8
4
5
MeOH
EtOH
<5
<5
<5
6d
6
7
EtOH
8
EtOH
ortho-Alkenyl phenols are important building frame-
works in synthetic chemistry,8 which have attracted broad
interest from synthetic chemists. Directed by a silanol
9
EtOH
N. R.
<10
10
11
EtOH
62
<5
CONHBu (1l)
EtOH
a Reaction conditions: 1 (0.2 mmol), 2a (0.28 mmol), [RhCp*Cl2]2
(2.5 mol %), CsOAc (0.5 equiv), solvent (0.05 M), 50 °C, 3ꢀ8 h.
b 1H NMR yield. c Isolated yield. d 1.0 mol % of [RhCp*Cl2]2 was used
as the catalyst; 48 h.
Scheme 2. Substrates for the Synthesis of ortho-Alkenyl Phenols
via CꢀH Activation
We initiated our study with the coupling of N-phenoxy-
acetamide (1.0 equiv) and butyl acrylate (1.4 equiv). Among
the screened catalysts, to our delight, [Cp*RhCl2]2 gave the
desired ortho-alkenyl phenol 3aa (Table 1). The diolefinated
phenol 3aa0 was detected as the main side product (Table 1,
entries 1ꢀ4), and a 21% NMR yield of 3aa0 was observed
when dichloroethane was used as the solvent (Table 1,
entry 3). Fortunately, EtOH appeared to be the ideal solvent,
affording the desired product in 89% NMR yield, and the
side product 3aa0 could finally be suppressed to less than 5%
yield (Table 1, entry 6).10 The catalyst loading can be reduced
to 1.0 mol % without significant change in yield, albeit with
a prolonged reaction time (Table 1, entry 8). Compared with
N-phenoxyacetamide, other substrates with different sub-
stituents on the nitrogen atom were found to be ineffective or
less effective (Table 1, entries 9ꢀ11). The optimized condi-
tions were ultimately identified as 2.5 mol % of [Cp*RhCl2]2,
and 50 mol % of CsOAc in EtOH at 50 °C.
group,9a carbonyl group,9b,c or carboxylic acid,9d transi-
tion metal catalyzed ortho CꢀH olefination of phenol
derivatives provided straightforward and efficient ways
to produce diverse ortho-alkenyl phenols (Scheme 2).
(7) Liu, G.; Shen, Y.; Zhou, Z.; Lu, X. Angew. Chem., Int. Ed. 2013,
52, 6033.
(8) (a) Battistuzzi, G.; Cacchi, S.; De Salve, I.; Fabrizi, G.; Parisi,
L. M. Adv. Synth. Catal. 2005, 347, 308. (b) Koehler, K.; Gordon, S.;
€
Brandt, P.; Carlsson, B.; Backsbro-Saeidi, A.; Apelqvist, T.; Agback, P.;
Grover, G. J.; Nelson, W.; Grynfarb, M.; Farnegardh, M.; Rehnmark,
€
S.; Malm, J. J. Med. Chem. 2006, 49, 6635. (c) Aslam, S. N.; Stevenson,
P. C.; Phythian, S. J.; Veitch, N. C.; Hall, D. R. Tetrahedron 2006, 62,
4214. (d) Barancelli, D. A.; Salles, A. G., Jr.; Taylor, J. G.; Correia,
C. R. D. Org. Lett. 2012, 14, 6036. (e) Singh, F. V.; Wirth, T. Synthesis
2012, 44, 1171.
(9) (a) Huang, C.; Chattopadhyay, B.; Gevorgyan, V. J. Am. Chem.
Soc. 2011, 133, 12406. (b) Reddy, M. C.; Jeganmohan, M. Eur. J. Org.
Chem. 2013, 1150. (c) Li, B.; Ma, J.; Liang, Y.; Wang, N.; Xu, S.; Song,
H.; Wang, B. Eur. J. Org. Chem. 2013, 1950. (d) Dai, H.-X.; Li, G.;
Zhang, X.-G.; Stepan, A. F.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135,
7567.
(10) The reason for the formation of the diolefination product 3aa0 is
unclear. Control experiments demonstrated that 3aa cannot be trans-
formed to 3aa0 under reaction conditions. The addition of some external
oxidants such as Cu(OAc)2 or AgOAc could not increase the yield
of 3aa0.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Reaction Scope for Substituted N-Phenoxyacetamidesa
Scheme 3. Olefin Scope for CꢀH Olefination of
N-Phenoxyacetamidea
entry
substrate
1a: R = H
product
yield (%)
1
2
3
4
5
6
7
8
9
3aa
3ba
3ca
3da
3ea
3fa
84
81
77
85
77
69
61
45b
70
1b: R = 2-Me
1c: R = 3-Me
1d: R = 4-Me
1e: R = 4-Ph
1f: R = 3-CF3
1g: R = 4-F
3ga
3ha
3ia
1h: R = 4-NO2
1i: R = 3,5-difluoro
a Reaction conditions: 1 (0.2 mmol), 2a (0.28 mmol), [RhCp*Cl2]2
(2.5 mol %), CsOAc (0.5 equiv), EtOH (0.05 M), 50 °C, 3ꢀ8 h; Isolated
yield was reported. b 1H NMR yield.
Further experiments were carried out to obtain better
insight into the reaction mechanism. No reaction happened
in the absence of cesium acetate and the reaction proceeded
smoothly with Cp*Rh(OAc)2 as the catalyst, which sug-
gested that the acetate anion was crucial and Cp*Rh(OAc)2
may be the active catalyst. When 1a was treated with a
catalytic amount of [RhCp*Cl2]2 and CsOAc in deuterated
ethanol at 50 °C, the NꢀO bond remained intact, and
deuterium was incorporated exclusively at the ortho posi-
tion of the directing group (eq 1). In contrast, no deuterium
incorporation was found in the absence of CsOAc. A
competition olefination experiment between electronically
different N-phenoxyacetamide derivatives, 1g and 1d, in-
dicated that electron-deficient 1g was more reactive. Taken
together, these results implied that concerted metalationꢀ
deprotonation (CMD)11 might be responsible for the CꢀH
activation.
a Reaction conditions: 1a (0.2 mmol), 2 (0.28 mmol), [RhCp*Cl2]2
(2.5 mol %), CsOAc (0.5 equiv), EtOH (0.05 M), 50 °C, 3ꢀ16 h; isolated
yield was reported.
With the optimized conditions in hand, various olefins
were successfully employed for the novel transformation
(Scheme 3). All the cases were totally ortho-selective. Good
to excellent yields were observed with acrylic derivatives as
the substrates (3aaꢀ3ac). Acrylonitrile resulted in a mod-
erate conversion despite its high inclination to polymeriza-
tion (3ad). Noteworthily, vinylphosphonate was also a good
reactant for this transformation (3ae). Styrene and its
derivatives readily participated in this olefination reaction.
Moreover, the ferrocenyl group (3ao) and heterocycle (3ap)
were well tolerated to give good yields of the desired pro-
ducts. Delightfully, β,β-disubstituted alkenes also reacted
smoothly, affording a mixture of ortho-alkenyl phenol and
chromen-2-one (3aq and 3aq0). However, terminal alkyl
alkenes such as 1-octene gave poor results.
N-Alkyl-substituted phenoxyacetamides (1m and 1n)
did not give any desired product under standard condi-
tions, indicating the NꢀH bond in the substrate was
indispensable for the CꢀH bond olefination (eq 2).
The effect of the substituents on N-phenoxyacetamide was
then tested (Table 2). The CꢀH bond olefination proceeded
smoothly with different substituted N-phenoxyacetamides.
Notably, the substrate with a strong electron-withdrawing
nitro group also gave the desired product with a moderate
yield (Table 2, entry 8). When meta-substituted N-phenoxy-
acetamide was employed, olefination took place at the less
hindered CꢀH bond selectively (Table 2, entries 3 and 6).
When the reaction between 1a and styrene (2f) was
performed in deuterated ethanol, the desired product had
55% deuterium incorporation (eq 3), which illustrated the
(11) Ackermann, L. Chem. Rev. 2011, 111, 1315.
Org. Lett., Vol. XX, No. XX, XXXX
C

CꢀH activation is reversible in the presence of alkene.
Furthermore, the electron-deficient alkene was found to
insert into the CꢀRh bond more quickly than the electron-
abundant one. Also, a primary KIE value of 2.4 was
observed,12 so the CꢀH bond cleavage may be the rate-
determining step.
Scheme 4. Proposed Catalytic Cycle
Taking the above experiments and the mechanism stud-
ies of precedent literature13 into consideration, we put
forward the plausible catalytic cycle in Scheme 4. After
the generation of an active catalyst by anion exchange
with cesium acetate, a facile arene rhodation afforded
intermediate A, which was followed by alkene insertion,
giving seven-membered rhodacycle intermediate B. Subse-
quently, β-H elimination and reductive elimination took
place, giving intermediate D.14,15 Since the stoichiometric
experiments have demonstrated that the NꢀO bond could
be cleaved by Rh(I) complexes,7,16 it is reasonable to pro-
pose that Rh(I) in intermediate D could be oxidized by
the intramolecular NꢀO bond, forming the desired prod-
uct 3, acetamide,17 and Rh(III) to complete the catalytic
cycle.
In summary, by using an oxidizing directing group, a
mild, efficient Rh(III) catalyzed CꢀH olefination reaction
between N-phenoxyacetamides and alkenes was developed.
This reaction provided a straightforward method for the
synthesis of ortho-alkenyl phenols, and the directing group
was traceless in the product. More detailed mechanism
studies on the OꢀN bond cleavage and further properties
of the novel directing group are being explored in our
laboratory.
(12) The reported KIE value is the relative ratio of the initial rates
measured separately using 1a or 1a-d5 as the substrate under standard
reaction conditions.
(13) (a) Hyster, T. K.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 10565.
(b) Liu, B.; Fan, Y.; Gao, Y.; Sun, C.; Xu, C.; Zhu, J. J. Am. Chem. Soc.
2013, 135, 468. (c) Xu, L.; Zhu, Q.; Huang, G.; Cheng, B.; Xia, Y. J. Org.
Chem. 2012, 77, 3017.
Acknowledgment. We thank the National Basic Re-
search Program of China (2009CB825300), National Nat-
ural Science Foundation of China (21202184, 21232006),
and Chinese Academy of Sciences for financial support.
(14) Rh(I) can bind effectively with olefin ligands: Hahn, B. T.;
€
Tewes, F.; Frohlich, R.; Glorius, F. Angew. Chem., Int. Ed. 2010, 49,
1143.
(15) Intermediate B might undergo oxidative addition before β-H
elimination to form a rhodium(V) species, followed by reductive elim-
ination. This possibility cannot be ruled out at present.
(16) Das, A.; Basuli, F.; Peng, S.-M.; Bhattacharya, S. Inorg. Chem.
2001, 41, 440.
(17) For the reaction between 1a and 2a under standard conditions,
acetamide was distinguished in crude 1H NMR and isolated by flash
chromatogaraphy after the reaction completed.
Supporting Information Available. Experimental pro-
cedures, characterization data and copies of NMR spec-
tra for all new compounds. 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