Rhodium(III) Catalyzed Carboamination of Alkenes Triggered by C-H Activation of N-Phenoxyacetamides under Redox-Neutral Conditions

Article abstract of DOI:10.1021/acs.orglett.6b00616

N-Alkoxyacrylamides are coupled with N-phenoxyacetamides by Rh^III catalysis through C-H functionalization and amido group transfer under external oxidant-free conditions, which affords acyclic alkene carboamination products in an atom-economica

Full text of DOI:10.1021/acs.orglett.6b00616

Letter
pubs.acs.org/OrgLett
Rhodium(III) Catalyzed Carboamination of Alkenes Triggered by C−H
Activation of N‑Phenoxyacetamides under Redox-Neutral Conditions
Zhiyong Hu,†,‡ Xiaofeng Tong,‡ and Guixia Liu*,†
†State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
‡Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Shanghai
200237, China
S
* Supporting Information
ABSTRACT: N-Alkoxyacrylamides are coupled with N-
phenoxyacetamides by RhIII catalysis through C−H function-
alization and amido group transfer under external oxidant-free
conditions, which affords acyclic alkene carboamination
products in an atom-economical way. Mechanistic insight
into this transformation indicates the amide group in N-
alkoxyacrylamide plays a critical role in this C−C/C−N bond formation reaction. This methodology provides a highly efficient
way to construct o-tyrosine derivatives under mild conditions.
Scheme 1. Diversified Reactions between N-
Phenoxyacetamides and Alkenes
ranisition metal catalyzed C−H functionalization con-
Tstitutes an economical and straightforward approach for
site-selective formation of carbon−carbon and carbon−
heteroatom bonds.1 Intensive research efforts in this field
have led to a variety of useful synthetic applications. One
example is carboamination of alkenes using an unactivated
arene or alkene as the carbon functionality source.2,3 The C−H
bond to be involved in carboamination usually presents
intramolecularly with the nitrogen functionality source.2 In
some rare cases, inexpensive unactivated arenes could react
intermolecuarly with alkenes bearing pendant amines to give a
carboamination product.3 Although these transformations are
synthetically useful for the construction of a broad array of
nitrogen heterocycles, stoichiometric amounts of oxidant,
mostly a metallic oxidant, are normally used to regenerate the
catalyst or produce high oxidant state metal species. To obviate
this limitation, an attractive redox-neutral strategy employing an
oxidizing N−O directing group4 has been applied in this field,
which furnishes nitrogen heterocycles as the carboamination
product and liberates a small molecule (ROH) as the result of
the N−O bond cleavage.5 Therefore, it is of great value to
develop new alkene carboaminations that can construct the
acyclic product in an atom-economical and efficient way.
During the preparation of this manuscript, Rovis and co-
workers reported a rhodium(III)-catalyzed intermolecular syn-
carboamination of alkenes from enoxyphthalimides, which
reaches this goal.6
challenge in making the reaction of C(sp3)−M species more
diversified and the coordinative saturation of metal center is a
frequently used strategy to overcome this difficulty.8,5a Thus,
we reasoned that introducing a coordinating functional group
in the substrates may enable the metal center in intermediate I
to be coordinatively saturated, which might divert the reaction
from the C−H olefination toward the alkene carboamination.
Here, we validate this design by the employment of N-
alkoxyacrylamide as the coupling partner in the RhIII-catalyzed
C−H functionalization of N-phenoxyacetamide to produce 2-
hydroxyphenylalanine (o-tyrosine) derivatives.9 In this reaction,
the amido group is formally transferred from the oxidizing
directing group to the alkene. While the synthesis of the o-
tyrosine backbone in literature was mainly achieved via
In our previous work, we disclosed a rhodium(III)-catalyzed
C−H olefination of N-phenoxyacetamide7 affording ortho-
alkenyl phenols as the product and acetamide as the waste
(Scheme 1a).7b One of the potential intermediates proposed in
that work is the seven-membered rhodacycle I, which
undergoes facile β-H elimination to give the olefination
product. In fact, the inhibition of β-hydride elimination is a
Received: March 9, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00616
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Letter
multistep processes,9d−f our protocol represents an efficient
way to construct this useful structure unit under very mild
conditions.
Scheme 2. Reaction Scope for the Synthesis of o-Tyrosine
Derivatives
a
To test the proposed strategy, a brief survey of alkenes was
conducted and N-methoxyacrylamide (2a) was found to give
encouraging results. Under the reaction conditions that were
developed for C−H olefination, the reaction between N-
phenoxyacetamide (1a) and 2a delivered the desired product
3aa in 33% yield along with C−H olefination product 4aa and
dihydrobenzofuran 5aa (Table 1, entry 1). This result
a
Table 1. Selected Optimization Studies
b
yield (%)
entry
solvent
base
time (h)
3aa
4aa
5aa
c
1
ethanol
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CsOAc
CsOAc
Cs2CO3
K2CO3
KOAc
24
14
90
92
22
48
20
36
69
50
52
57
78
93
26
10
3
26
2
3
4
5
6
23
ND
ND
15
2
5
K3PO4
K3PO4
ND
ND
ND
ND
d
7
a
Reaction conditions: 1a (0.12 mmol), 2a (0.1 mmol), [Cp*RhCl2]2
b
(2.5 mol %), and base (0.5 equiv) in solvent at rt. 1H NMR yield.
a
c
d
Reaction conditions: substrate 1 (0.24 mmol), 2 (0.2 mmol),
Run at 50 °C. 4 Å MS (50 mg) were added.
[Cp*RhCl2]2 (2.5 mol %), K3PO4 (0.1 mmol), and 4 Å MS (100 mg)
b
in CH3CN (0.5 mL) at rt under N2; isolated yields were given. After
prompted us to improve the yield of 3aa, and the selected
optimization studies were shown in Table 1. Solvent effects
were dramatic, and a significantly improved yield (69%) was
observed with CH3CN as the solvent (entry 2). Screening of
several bases revealed K3PO4 as the optimal choice giving 3aa
in 78% yield (entries 3−6). The addition of molecular sieves
was found to increase the reaction rate as well as the yield of
3aa (entry 7). Under the optimized conditions, the rhodium
catalyzed coupling of N-phenoxyactamide and N-methoxy-
acrylamide afforded 3aa in 87% isolated yield without any
olefination product or dihydrobenzofuran.
With the optimized reaction conditions in hand, the scope of
this system for the synthesis of o-tyrosine derivatives was
investigated (Scheme 2). We were pleased to find that this new
transformation was productive for a variety of substituted N-
phenoxyacetamides in the coupling with N-methoxyacrylamide
(2a). Several important functional groups such as halogens (F,
Br), trifluoromethyl, ester, methoxy, and nitro group were well
tolerated. Notably, the substrates with a strong electron-
withdrawing group (3fa and 3ga) or electron-donating group
(3la and 3la′) participated well under standard reaction
conditions furnishing the desired product with moderate to
good yields. It was noted that orth-CH3 substituted N-
phenoxyacetamide gave a relatively low yield (3ka, 32%)
compared with the para- and meta- substituted analogues (3ba
and 3ha, 69% and 87%, respectively). When substrates with a
meta-CF3 and meta-CH3 group were employed, C−H
functionalization took place at a less hindered position
selectively (3ha and 3ia). In contrast, the meta-OMe
substituted substrate produced two isomers in the ratio 3.1:1
(3la:3la′).
20 h, a second batch of [Cp*RhCl2]2 (2.5 mol %) was added, and the
reaction proceeded for another 20 h.
Various N-alkoxyacrylamides were then subjected to the
reaction with N-phenoxyacetamide (1a) under standard
conditions. With the N-alkoxyl substituent as the methoxy,
benzyloxy, and cyclopropylmethoxy group (2a−2c), the
reaction proceeded smoothly affording good yields of the
desired products (3aa−3ac, 85%−89%).10 Alkenes with a more
t
hindered alkoxy group (iPrO, BuO, and Ph3CO) resulted in
decreased yields (3ad−3af, 15%−75%). Especially, the reaction
of N-triphenylmethoxyacrylamide (2f) with 1a led to a low
yield of the desired product (3af, 15%). While no C−H
olefination product was detected in this reaction, the main side
product was dihydrobenzofuran 5af. These results indicated the
steric property of the alkoxy group in the alkenes influenced the
outcome of the C−C/C−N formation reaction.
To better understand the role of the N-alkoxy group in the
alkenes,11 different substituted acrylamides were applied to this
reaction. Under standard conditions, the reaction of 1a with
acrylamides 2g−i afforded the C−H olefinatin product
exclusively (Scheme 3a). While C−C/C−N formation was
influenced by the steric property of the alkoxy group in N-
alkoxyacrylamides, no steric effect was observed for C−H
olefination when different acrylamides 2g−i were employed.
The employment of aryl substituted acrylamides (2j and 2k)
could furnish a low yield of carboamination products along with
C−H olefination products (Scheme 3b). Modification of the
electronic properties of the aryl group in N-aryl acrylamides did
not alter the yield of the carboamination product significantly.
In addition, the C−H olefinatin product was produced
B
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Letter
to the literature,14 anionic RhIII complexes could undergo
reductive elimination generating RhI species. We suspect that
reductive elimination followed by protonolysis of the anionic
amido ligand might take place from the anionic Rh complex B
affording intermediate C and RhI (path a). Subsequently, RhIII
was regenerated by the cleavage of the N−O bond in the
oxidizing directing group to form intermediate D, which upon
protonolysis will produce the desired product 3.16 Alternately,
the RhIII center in species C might be oxidized by the N−O
internal oxidant giving the high oxidant state RhV species F
(path b),17 which undergoes reductive elimination to form a
C−N or C−O bond and subsequent protonolysis to furnish
carboamination product 3 or dihydrobenzofuran product 5,
respectively. The use of a sterically hindered N-alkoxy group
such as a triphenylmethoxy group (2f) may lead to a hindered
metal center in intermediate F, which might facilitate the
dissociation of the acetamido ligand and favor the reductive
elimination of the C−O bond to form the product 5.18 The
current experimental evidence remains insufficient, and further
studies to understand the reaction pathway are ongoing in our
laboratory.19
Scheme 3. Test of Different Substituted Acrylamides
exclusively with N-methoxy-N-methylacrylamide 2l as the
alkene substrate (Scheme 3c). Overall, these results demon-
strate that the N-substituent in acrylamide influences the
reaction outcome by modulating the character of the amide
group, and the N−H bond rather than the N-alkoxy group in
acrylamide is indispensible for the carboamination.
In conclusion, we have developed a RhIII-catalyzed coupling
of N-phenoxyacetamide with N-alkoxyacrylamide under redox-
neutral and mild conditions. This carboamination of alkenes
provides an efficient and highly atom-economical way to
construct 2-hydroxyphenyl-alanine (o-tyrosine) derivatives.
Further studies to explore new transformation properties of
the directing group based on −ONHAc are in progress in this
laboratory.
In light of our mechanistic studies12 and the known
literature, the mechanism hypotheses are shown in Scheme 4.
Scheme 4. Proposed Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00616.
Experimental procedures, compounds characterization
data, and copies of NMR spectra (PDF)
Crystallographic data for compound 3ab (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: guixia@sioc.ac.cn.
Notes
The reaction might be initiated by an irreversible C−H
activation to give a five-membered rhodacycle, followed by
alkene insertion to furnish the key intermediate A. Our
previous work7b,c had shown that the N−H bond in N-
phenoxyacetamide is crucial for C−H activation, which
indicates the deprotonation of N-phenoxyacetamide may
promote the C−H activation.13 Having a similar structure
with the directing group −ONHAc, the amide group in N-
alkoxy acrylamide might coordinate with Rh in a similar way.
Thus, the amide group in the alkene 2a−f might act as an anion
ligand after deprotonation leading to the anionic Rh complex
B,14 which might be in equilibrium with intermediate A and C.
In these C(sp3)−Rh species, the metal center is coordinatively
saturated. As a result, β-H elimination was suppressed and no
C−H olefination product was observed. In contrast, the amide
group in acrylamides (2g−i) might not be acidic enough15 to
act as the anionic ligand to the Rh center, thus leading to the
C−H olefination product exclusively (Scheme 3a). According
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Basic Research Program of China
(2015CB856600), the National Natural Science Foundation of
China (21202184, 21232006, 21572255), and the Chinese
Academy of Sciences for financial support.
REFERENCES
■
(1) For selected recent reviews, see: (a) Yamaguchi, J.; Yamaguchi, A.
D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960. (b) Rouquet, G.;
Chatani, N. Angew. Chem., Int. Ed. 2013, 52, 11726. (c) Li, B.; Dixneuf,
P. H. Chem. Soc. Rev. 2013, 42, 5744. (d) Wencel-Delord, J.; Glorius,
F. Nat. Chem. 2013, 5, 369. (e) Ackermann, L. Acc. Chem. Res. 2014,
47, 281. (f) Zhang, X.-S.; Chen, K.; Shi, Z.-J. Chem. Sci. 2014, 5, 2146.
(g) Ros, A.; Fernan
3229. (h) Shi, G.; Zhang, Y. Adv. Synth. Catal. 2014, 356, 1419.
́
dez, R.; Lassaletta, J. M. Chem. Soc. Rev. 2014, 43,
(i) Kuhl, N.; Schroder, N.; Glorius, F. Adv. Synth. Catal. 2014, 356,
̈
C
DOI: 10.1021/acs.orglett.6b00616
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1443. (j) Guo, X.-X.; Gu, D.-W.; Wu, Z.; Zhang, W. Chem. Rev. 2015,
115, 1622.
(2) (a) Fuller, P. H.; Chemler, S. R. Org. Lett. 2007, 9, 5477.
(b) Zeng, W.; Chemler, S. R. J. Am. Chem. Soc. 2007, 129, 12948.
́
(c) Houlden, C. E.; Bailey, C. D.; Ford, J. G.; Gagne, M. R.; Lloyd-
Jones, G. C.; Booker-Milburn, K. I. J. Am. Chem. Soc. 2008, 130, 10066.
(d) Miao, L.; Haque, I.; Manzoni, M. R.; Tham, W. S.; Chemler, S. R.
Org. Lett. 2010, 12, 4739. (e) Yip, K.-T.; Yang, D. Org. Lett. 2011, 13,
2134. (f) Kaneko, K.; Yoshino, T.; Matsunaga, S.; Kanai, M. Org. Lett.
(12) For deuterium-labeling experiments, see the Supporting
Information.
(13) (a) Wang, N.; Li, B.; Song, H.; Xu, S.; Wang, B. Chem. - Eur. J.
2013, 19, 358. (b) Lam, H.-W.; Man, K.-Y.; Chan, W.-W.; Zhou, Z.;
Yu, W.-Y. Org. Biomol. Chem. 2014, 12, 4112.
(14) (a) García, M. P.; Oro, L. A.; Lahoz, F. J. Angew. Chem., Int. Ed.
Engl. 1988, 27, 1700. (b) Haynes, A.; Mann, B. E.; Morris, G. E.;
Maitlis, P. M. J. Am. Chem. Soc. 1993, 115, 4093. (c) Maitlis, P. M.;
Haynes, A.; Sunley, G. J.; Howard, M. J. J. Chem. Soc., Dalton Trans.
1996, 2187.
(15) (a) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456. (b) Bordwell,
F. G.; Fried, H. E.; Hughes, D. L.; Lynch, T.-Y.; Satish, A. V.; Whang,
Y. E. J. Org. Chem. 1990, 55, 3330. (c) Decouzon, M.; Exner, O.; Gal,
J.-F.; Maria, P.-C. J. Org. Chem. 1990, 55, 3980.
2013, 15, 2502. (g) Zhao, D.; Vas
Chem., Int. Ed. 2015, 54, 1657.
́ ́
quez-Cespedes, S.; Glorius, F. Angew.
(3) (a) Sibbald, P. A.; Rosewall, C. F.; Swartz, R. D.; Michael, F. E. J.
Am. Chem. Soc. 2009, 131, 15945. (b) Rosewall, C. F.; Sibbald, P. A.;
Liskin, D. V.; Michael, F. E. J. Am. Chem. Soc. 2009, 131, 9488.
(4) For reviews, see: (a) Patureau, F. W.; Glorius, F. Angew. Chem.,
Int. Ed. 2011, 50, 1977. (b) Huang, H.; Ji, X.; Wu, W.; Jiang, H. Chem.
Soc. Rev. 2015, 44, 1155. (c) Mo, J.; Wang, L.; Liu, Y.; Cui, X. Synthesis
2015, 47, 439. (d) Hu, Z.; Tong, X.; Liu, G. Youji Huaxue 2015, 35,
539.
(5) (a) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J. Am.
Chem. Soc. 2011, 133, 2350. (b) Guimond, N.; Gorelsky, S. I.; Fagnou,
K. J. Am. Chem. Soc. 2011, 133, 6449. (c) Li, B.; Ma, J.; Wang, N.;
Feng, H.; Xu, S.; Wang, B. Org. Lett. 2012, 14, 736. (d) Davis, T. A.;
Hyster, T. K.; Rovis, T. Angew. Chem., Int. Ed. 2013, 52, 14181.
(e) Neely, J. M.; Rovis, T. J. Am. Chem. Soc. 2013, 135, 66. (f) Neely, J.
M.; Rovis, T. J. Am. Chem. Soc. 2014, 136, 2735. (g) Zhao, D.; Lied, F.;
Glorius, F. Chem. Sci. 2014, 5, 2869. (h) Shi, Z.; Boultadakis-Arapinis,
M.; Koester, D. C.; Glorius, F. Chem. Commun. 2014, 50, 2650.
(i) Romanov-Michailidis, F.; Sedillo, K. F.; Neely, J. M.; Rovis, T. J.
Am. Chem. Soc. 2015, 137, 8892.
(16) (a) Guimond, N.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc.
2011, 133, 6449. (b) Neufeldt, S. R.; Jimenez-Oses, G.; Huckins, J. R.;
́ ́
Thiel, O. R.; Houk, K. N. J. Am. Chem. Soc. 2015, 137, 9843.
(17) (a) Li, L.; Brennessel, W. W.; Jones, W. D. J. Am. Chem. Soc.
2008, 130, 12414. (b) Xu, L.; Zhu, Q.; Huang, G.; Cheng, B.; Xia, Y. J.
Org. Chem. 2012, 77, 3017. (c) McBee, J. L.; Escalada, J.; Tilley, T. D.
J. Am. Chem. Soc. 2009, 131, 12703. (d) Hartwig, J. F.; Cook, K. S.;
Hapke, M.; Incarvito, C. D.; Fan, Y.; Webster, C. E.; Hall, M. B. J. Am.
Chem. Soc. 2005, 127, 2538.
(18) (a) Hartwig, J. F. Organotransition Metal Chemistry. From
Bonding to Catalysis; University Science Books: Sausalito, CA, 2010; pp
321−348. (b) Feller, M.; Diskin-Posner, Y.; Leitus, G.; Shimon, L. J.
W.; Milstein, D. J. Am. Chem. Soc. 2013, 135, 11040.
(19) The nonoxidative cleavage of the O−N bond in N-
phenoxyamide, which usually proceeds under acidic conditions, was
not proposed here. For some examples, see: (a) Endo, Y.; Shudo, K.;
Okamoto, T. Synthesis 1980, 1980, 461. (b) Endo, Y.; Shudo, K.;
Okamoto, T. J. Am. Chem. Soc. 1982, 104, 6393. (c) Endo, Y.; Shudo,
K.; Okamoto, T. Synthesis 1983, 1983, 471.
(6) Piou, T.; Rovis, T. Nature 2015, 527, 86.
(7) (a) Liu, G.; Shen, Y.; Zhou, Z.; Lu, X. Angew. Chem., Int. Ed.
2013, 52, 6033. (b) Shen, Y.; Liu, G.; Zhou, Z.; Lu, X. Org. Lett. 2013,
15, 3366. (c) Zhou, Z.; Liu, G.; Shen, Y.; Lu, X. Org. Chem. Front.
2014, 1, 1161. (d) Hu, F.; Xia, Y.; Ye, F.; Liu, Z.; Ma, C.; Zhang, Y.;
Wang, J. Angew. Chem., Int. Ed. 2014, 53, 1364. (e) Zhang, H.; Wang,
K.; Wang, B.; Yi, H.; Hu, F.; Li, C.; Zhang, Y.; Wang, J. Angew. Chem.,
Int. Ed. 2014, 53, 13234. (f) Duan, P.; Lan, X.; Chen, Y.; Qian, S. S.;
Li, J. J.; Lu, L.; Lu, Y.; Chen, B.; Hong, M.; Zhao, J. Chem. Commun.
2014, 50, 12135. (g) Chen, Y.; Wang, D.; Duan, P.; Ben, R.; Dai, L.;
Shao, X.; Hong, M.; Zhao, J.; Huang, Y. Nat. Commun. 2014, 5, 4610.
(h) Zhou, J.; Shi, J.; Liu, X.; Jia, J.; Song, H.; Xu, H. E.; Yi, W. Chem.
Commun. 2015, 51, 5868. (i) Zhou, J.; Shi, J.; Qi, Z.; Li, X.; Xu, H. E.;
Yi, W. ACS Catal. 2015, 5, 6999. (j) Li, B.; Lan, J.; Wu, D.; You, J.
Angew. Chem., Int. Ed. 2015, 54, 14008. (k) Zhou, Z.; Liu, G.; Chen,
Y.; Lu, X. Org. Lett. 2015, 17, 5874.
(8) For a review, see: Lu, X. Top. Catal. 2005, 35, 73.
(9) (a) Uchida, I.; Ezaki, M.; Shigematsu, N.; Hashimoto, M. J. Org.
Chem. 1985, 50, 1341. (b) Sun, G.; Slavica, M.; Uretsky, N. J.; Wallace,
L. J.; Shams, G.; Weinstein, D. M.; Miller, J. C.; Miller, D. D. J. Med.
Chem. 1998, 41, 1034. (c) Marvin, L. F.; Delatour, T.; Tavazzi, I.; Fay,
L. B.; Cupp, C.; Guy, P. A. Anal. Chem. 2003, 75, 261. (d) Dugave, C.
J. Org. Chem. 1995, 60, 601. (e) Paintner, F. F.; Gorler, K.; Voelter, W.
̈
Synlett 2003, 522. (f) Batuwangala, M.; Camarda, V.; McDonald, J.;
Marzola, E.; Lambert, D. G.; Ng, L. L.; Calo’, G.; Regoli, D.; Trapella,
C.; Guerrini, R.; Salvadori, S. Peptides 2009, 30, 1130.
(10) For the crystallographic data for 3ab, refer to CCDC number
1418659 and the CIF Supporting Information.
(11) A series of alkenes which bear potentially coordinating groups
were attempted in the C−H functionalization of 1a under standard
conditions (see below), but no desired alkene carboamination product
was observed. While alkenes 6−10 were unreactive, alkenes 11 and 12
led to complicated results producing a small amount of C−H
olefination products along with other unidentified byproducts.
D
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