Rhodium(III)-catalyzed C-H activation and amidation of arenes using N -arenesulfonated imides as amidating reagents

Article abstract of DOI:10.1021/ol401569u

Rhodium(III)-catalyzed C-H activation-amidation of arenes bearing chelating groups has been achieved using N-arenesulfonated imides as efficient amidating reagents without using any base additive. Pyridine, oxime, and pyrimidine proved to be viable direct

Full text of DOI:10.1021/ol401569u

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Rhodium(III)-Catalyzed CÀH Activation
and Amidation of Arenes Using
N‑Arenesulfonated Imides
as Amidating Reagents
Songjie Yu, Boshun Wan,* and Xingwei Li*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences,
Dalian 116023, China
xwli@dicp.ac.cn; bswan@dicp.ac.cn
Received June 4, 2013
ABSTRACT
Rhodium(III)-catalyzed CÀH activationÀamidation of arenes bearing chelating groups has been achieved using N-arenesulfonated imides as efficient
amidating reagents without using any base additive. Pyridine, oxime, and pyrimidine proved to be viable directing groups.
CÀN bonds are a key linkage in organics, pharmaceu-
ticals, and materials. Various methods for catalytic CÀN
couplings such as the BuchwaldÀHartwig coupling, the
Ullman coupling, and the ChanÀLam coupling have been
developed.1 These systems utilize aryl halides/tosylates or
boronic acids as a coupling partner. With increasing
interest in catalytic activation of CÀH bonds,2 it is im-
portant to take advantage of the ubiquity of CÀH bonds
for CÀN coupling. Hence considerable studies on the
amination of CÀH bonds have been performed using
Pd3 and Cu4 catalysts under oxidative conditions.
Alternatively, there have been increasing studies using
internaloxidizing NÀO and NÀhalogen groups for overall
redox-neutral amination reactions.5 Despite the progress,
because of the structural diversity and specificity of arene
substrates, it is necessary to develop amination reactions
catalyzed by other transitional metals. In this context,
Rh(III) complexes have been successfully employed as
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Liu, L. J. Am. Chem. Soc. 2011, 133, 1466. (g) Shrestha, R.; Mukherjee,
P.; Tan, Y.-C.; Litman, Z. C.; Hartwig, J. F. J. Am. Chem. Soc. 2013,
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10.1021/ol401569u
XXXX American Chemical Society

highly efficient and selective catalysts to entail amina-
tion via a CÀH activation pathway6 using isocyanates,7
amine chlorides (Scheme 1),8 sulfonylazides,9 and NFSI.10
While oxidizing NÀO groups consistently effected CÀH
amination,11 both amination and halogenation of CÀH
bonds have been achieved for NÀhalogen groups. For
example, NFSI is known as both an amidating and
a fluorinating reagent.12 In 2012, Glorius et al. reported
the highly efficient Rh(III)-catalyzed bromination of
a broad spectrum of arenes using NBS (Scheme 1).13
We reasoned that electrophilic N-OTs imides should be
suitable amidating reagents because, in comparison to the
NÀBr bond in NBS, the NÀO bond is more polarized
or even inversely polarized by a more electronegative
OTs group. Therefore, replacing the Br group in NBS with
an OTs group should switch the selectivity from CÀH
bromination to amidation.
phthalimide, a readily available source of NÀO bond
(Table 1). While no coupling occurred when [RhCp*Cl2]2
(5 mol %) alone was used as a catalyst (DCE, 100 °C),
addition of AgSbF6 (20 mol %) can effect a smooth CÀN
coupling, and product 3aa was isolated in 69% yield
(entry 2). Product 3aa was fully characterized, including
by X-ray crystallography. Screening of the solvent gave
DCE as an optimal one, while lower isolated yields were
obtained when this reaction was performed in other sol-
vents including DCM, PhCl, 1,4-dioxane, and acetic acid
(entries 2À6). The amount of AgSbF6 played an important
role. Thus an optimal isolated yield of 83% was obtained
when the amount of AgSbF6 was doubled (entry 7). Low-
ering the catalyst loading to 3 mol % resulted in a reduced
yield of 3aa (entry 8), and a comparably unfavorable yield
was obtained when the reaction temperature was lowered
to 80 °C (entry 9). In contrast to the smooth coupling of
this N-OTs phthalimide, essentially no reaction occurred
for N-OAc and N-OC(O)Ph phthalimides, likely due to
reduced electrophilicity. Given that a Ru(II) complex can
be an alternative catalyst for CÀN coupling reactions,14
[Ru(p-cymene)Cl2]2 was used under otherwise the same
conditions. Unfortunately, although the selectivity of this
reaction remains high, product 3aa was isolated in only
63% yield due to lower conversion (entry 10), indicating
the superiority of Rh(III) catalysis in this system.
Scheme 1. Rh(III)-Catalyzed Coupling of CÀH Bonds with
NÀHalogen Groups
Table 1. Optimization Studiesa
catalyst
(mol %)
AgSbF6
(mol %)
yieldb
(%)
We initiated our studies with the screening of the con-
ditions for the coupling of 2-phenylpyridine and N-OTs
entry
solvent
1
2
3
4
5
6
7
8
9
10
[Cp*RhCl2]2 (5)
[Cp*RhCl2]2 (5)
[Cp*RhCl2]2 (5)
[Cp*RhCl2]2 (5)
[Cp*RhCl2]2 (5)
[Cp*RhCl2]2 (5)
[Cp*RhCl2]2 (5)
[Cp*RhCl2]2 (3)
[Cp*RhCl2]2 (5)
[Ru(p-cymene)Cl2]2 (5)
0
DCE
0
20
20
20
20
20
40
40
40
40
DCE
69
61
<5
65
53
83
72
70c
63
(6) For reviews, see: (a) Satoh, T.; Miura, M. Chem.;Eur. J. 2010,
16, 11212. (b) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev.
2010, 110, 624. (c) Song, G.-Y.; Wang, F.; Li, X.-W. Chem. Soc. Rev.
2012, 41, 3651. (d) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman,
J. A. Acc. Chem. Res. 2012, 45, 814. (e) Patureau, F. W.; Wencel-Delord,
J.; Glorius, F. Aldrichimica Acta 2012, 45, 31.
(7) (a) Hesp, K. D.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2011, 133, 11430. (b) Zhou, B.; Hou, W.; Yang, Y.-X.; Li, Y.-C. Chem.;
Eur. J. 2013, 19, 4701. (c) Hou, W.; Zhou, B.; Yang, Y.-C.; Feng, H.-J.;
Li, Y.-C. Org. Lett. 2013, 15, 1814.
(8) (a) Ng, K.-H.; Zhou, Z.; Yu, W.-Y. Org. Lett. 2012, 14, 272.
(b) Grohmann, C.; Wang, H.; Glorius, F. Org. Lett. 2012, 14, 656. During
the preparation of this manuscript, Yu et al. reported Rh(III)-catalyzed
CÀH amination using primary chloroalkylamines. See: (c) Ng, K.-H.;
Zhou, Z. Yu, W. Y. Chem. Commun. DOI: 10.1039/C3CC42937G.
(9) (a) Kim, J. Y.; Park, S. H.; Ryu, J.; Cho, S. H.; Kim, S. H.; Chang,
S. J. Am. Chem. Soc. 2012, 134, 9110. (b) Yu, D. G.; Suri, M.; Glorius, F.
J. Am. Chem. Soc. 2013, 135, 8802.
DCM
AcOH
PhCl
dioxane
DCE
DCE
DCE
DCE
a Reaction conditions: 2-phenylpyridine (0.2 mmol), N-OTs phtha-
limide (0.3 mmol), solvent (2 mL), catalyst, AgSbF6 additive, 100 °C,
20 h, sealed tube under Ar. b Yields refer to isolation after chromato-
graphy. c 80 °C.
(10) Tang, R.-J.; Luo, C.-P.; Yang, L.; Li, C.-J. Adv. Synth. Catal.
2013, 355, 869.
With the optimized conditions in hand, we set out
to explore the scope and generality of this coupling system.
When a simple pyridine ring was used as a directing
group for the coupling with 2a, introduction of various
(11) During the preparation of this manuscript, Glorius et al. re-
ported Rh(III)-catalyzed CÀH amidation using aroyloxycarbamates.
See: Grohmann, C.; Wang, H.-G.; Glorius, F. Org. Lett. 2013, 15, 3014.
(12) (a) Sun, K.; Li, Y.; Xiong, T.; Zhang, J.-P.; Zhang, Q. J. Am.
Chem. Soc. 2011, 133, 1694. (b) Qiu, S.-F.; Xu, T.; Zhou, J.; Guo, Y.-L.;
Liu, G.-S. J. Am. Chem. Soc. 2010, 132, 2856. (c) Iglesias, A.; Alvarez,
R.; Muniz, K. Angew. Chem., Int. Ed. 2012, 51, 2225.
(14) (a) Kim, J. Y.; Kim, J. W.; Chang, S. Chem.;Eur. J. 2013, 19,
7328. (b) Zheng, Q.-Z.; Liang, Y.-F.; Qin, C.; Jiao, N. Chem. Commun.
2013, 49, 5654. (c) Yadav, M. R.; Rit, R. K.; Sahoo, A. K. Org. Lett.
2013, 15, 1638.
(13) Schroder, N.; Wencel-Delord, J.; Glorius, F. J. Am. Chem. Soc.
2012, 134, 8298.
B
Org. Lett., Vol. XX, No. XX, XXXX

pyrimidyl-functionalized thiophene, albeit with a rela-
tively lower conversion (3na, 3oa), and no amidation in
the pyridine ring was detected.
Scheme 2. Scope of Arene Substrates in Amidation Using
N-OTs Phthalimidea,b
To demonstrate the scope of the imide substrate, different
N-OTs imides were applied as coupling partners in the reac-
tion with 2-phenylpyridine. Thus N-OTs phthalimides with
different electron-donating and -withdrawing substituents
in the backbone reacted smoothly with comparably high
efficiency (3abÀ3af, Scheme 3). In contrast, N-OTs succini-
mide gave poor reactivity, which is likely ascribable to the
lower electrophilicity with this saturated imide backbone.
Indeed, switching to the more electrophilic N-OTf succini-
mide afforded a moderate yield of the amidation product 3ag.
Scheme 3. Scope of N-Arenesulfonated Imides in CÀH
Amidationa,b
a Reactions conditions: arene (0.2 mmol), N-OTs phthalimide
(0.3 mmol), [RhCp*Cl2]2 (5 mol %), AgSbF6 (40 mol %), DCE (2 mL),
100 °C, 20 h, sealed tube under argon. b Isolated yield after chromatography.
electron-donating (3ba, 3da, 3ea, 3ga), -withdrawing (3fa,
3ha), and halogen (3ca) groups into different positions of
the phenyl ring is well tolerated, and the amidation product
was isolated in 58À87% yield (Scheme2). Inparticular, the
isolation of product 3ga in good yield indicated the steric
tolerance of this system. The presence of a nitro group in
the coupled product 3fa can allow further functionaliza-
tion. Besides using the simple pyridine directing group, the
reaction tolerated pyridine rings functionalized with a
variety of electron-donating (3ia, 3la, 3ma), -withdrawing
(3ka), and halogen (3ja) groups at different positions, and
the CÀN coupled products were isolated in 48À81% yield.
In all such cases, only monoamidation was observed.
In contrast, introduction of a pyrimidine directing group
resulted in competitive mono- and diamidation as a result
of facile coordination and cyclometalation, although the
monoamidation product remained the major one isolated
in moderate yield. Exclusive monoamidation was achieved
when a meta blocking group was introduced (3sa, 3ta).
We next explored the replacement of these heterocyclic
directing groups with more readily available and more syn-
thetically useful directing groups. Thus the O-Me oxime
proved to be a viable directing group, and the amidation
product was isolated in moderate togood yield (3uaÀ3wa).
Besides CÀH activation in benzene rings, the CÀH activa-
tion can be smoothly extended to heterocyclic systems. Thus
the same coupling reaction was applicable to pyridyl- and
a Reactions conditions: 2-phenylpyridine(0.2mmol), imide(0.3 mmol),
[RhCp*Cl2]2 (5 mol %), AgSbF6 (40 mol %), DCE (2 mL), 100 C, 20 h,
3
sealed tube under argon. b Isolated yield after chromatography. c N-OTf
succinimide was used.
To demonstrate the synthetic usefulness of this coupling
reaction, facile and high-yielding derivatization of product
3aa has been performed (Scheme 4). Treatment of 3aa with
hydrazine led to the quantitative formation of primary
amine 4. Partial reduction using NaBH4 readily gave an
alcohol 5, while Zn/AcOH treatment afforded a further
reduced product 6.
Scheme 4. Derivatization of a Coupled Product
Several experiments have been performed to probe
the reaction mechanism. To explore the relevance of
Org. Lett., Vol. XX, No. XX, XXXX
C

provided.11,13,17 While no conclusion could be drawn at
this stage, it should be safe to rationalize that, with two
highly withdrawing groups attached to the nitrogen group,
the current imide substrate is much less coordinating
than those recently examined including chloroamines
and aroyloxycarbamates.8,11 Hence the lower coordinating
ability and high electrophilicity of the imide substrate should
argue for a higher tendency for the oxidative addition
(Rh(III)ÀRh(V)) pathway. Further mechanistic studies
are underway.
^
cyclometalation, a cyclometalated RhCp*(NC)Cl com-
plex was prepared and was applied as a catalyst precursor
(9 mol %), which catalyzedthisreactionwitha comparable
efficiency under the same catalytic conditions (eq 1). This
suggests the relevancy of CÀH activation. The kinetic
isotope effect was next studied in an intermolecular com-
petitive coupling of 2a with an equimolar mixture of 1a
and 1a-d5. 1H NMR analysis of the isolated product gave
KIE = 1.1 (see the SI). This small value suggests that the
CÀH bond cleavage is not likely involved in the rate-
limiting step, which is in contrast to those reported in other
Rh(III)-catalyzed amination reactions.8,11 Since the NÀO
bond in the imide might undergo hemolytic cleavage, we
next probed the possibility of radical species in this reaction.
Addition of TEMPO (1.0 equiv) to the coupling reaction of
1a and 2a only caused a slight decrease of the isolated yield
(eq 2), indicating that a radical species is likely irrelevant.
Scheme 5. Two Possible Reaction Pathways Following Cyclo-
metalation
Insummary, we have achieved a novel Rh(III)-catalyzed
CÀH amidation of arenes using readily available
N-arenesulfonated imides as amidating reagents. This
reaction proceeded in the absence of any base additive.
Arenes bearing pyridine, oxime, and pyrimidine directing
groups are all viable substrates, and a broad spectrum of
coupling partners have been established. The CÀN coupled
product can be further functionalized. This method may
find applications in the synthesis of related arylamine
compounds.
Despite these mechanistic data, it remains a question
whether this coupling proceeded via an all-Rh(III) path-
way oran alternative Rh(III)ÀRh(V) pathway (Scheme 5).
In an all-Rh(III) pathway, after the cyclometalation was
achieved, N-coordination of the imide is followed by
nucleophilic displacement of the OTs by the RhÀC(aryl)
bond (electrophilic amidation) with concerted ligation of
the OTs group.15 Alternatively, the N-bound imide might
undergo oxidative addition to give a Rh(V) intermediate,
followed by reductive elimination. A related scenario of
NÀO bond cleavage has been studied in Pd-catalyzed
NarasakaÀHeck coupling reactions.16 Of note, although
Rh(V)ÀRh(III) pathways have been postulated as a pos-
sibility in some systems, no experimental evidence has been
Acknowledgment. Financial support from the NSFC
(21272231 (X.L.) and 21172218 (B.W.) and the Dalian
Institute of Chemical Physics, Chinese Academy of Sciences
is gratefully acknowledged. X.L. conceived and designed the
experiments.
Supporting Information Available. Detailed experimen-
tal procedures, spectroscopic data of all new products,
and crystal data of 3aa (PDF and CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) (a) Xu, L.; Zhu, Q.; Huang, G.; Cheng, B.; Xia, Y.-Z. J. Org.
Chem. 2011, 77, 3017. For a report on metal-free electrophilic amina-
tion, see: (b) Zhu, C.; Li, G.-Q.; Ess, D. H.; Falck, J. R.; Kurti, L. J. Am.
Chem. Soc. 2012, 134, 18253.
(16) Faulkner, A.; Bower, J. F. Angew. Chem., Int. Ed. 2012, 51, 1675.
(17) Wencel-Delord, J.; Nimphius, C.; Patureau, F. W.; Glorius, F.
Angew. Chem., Int. Ed. 2012, 51, 2247.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX