Rhodium(iii)-catalyzed formal oxidative [4 + 1] cycloaddition of benzohydroxamic acids and α-diazoesters. A facile synthesis of functionalized benzolactams

Article abstract of DOI:10.1039/c4ob00512k

A Rh(iii)-catalyzed oxidative [4 + 1] cycloaddition of benzohydroxamic acids and α-diazoesters is achieved to afford benzolactams in up to 93% yields. With the N-OAc amido moiety as a directing group, the ortho-C-H is selectively functionalized and the catalytic reaction exhibits excellent tolerance to different functional substituents. A notable rhodacyclic complex is isolated and structurally characterized, suggesting that C-H/N-H cyclometallation is a key step in the catalytic cycle. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00512k

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Rhodium(III)-catalyzed formal oxidative [4 + 1]
cycloaddition of benzohydroxamic acids and
α-diazoesters. A facile synthesis of functionalized
benzolactams†
Cite this: Org. Biomol. Chem., 2014,
12, 4112
Hon-Wah Lam, Ka-Yi Man, Wai-Wing Chan, Zhongyuan Zhou and Wing-Yiu Yu*
A Rh(III)-catalyzed oxidative [4 + 1] cycloaddition of benzohydroxamic acids and α-diazoesters is achieved
to afford benzolactams in up to 93% yields. With the N-OAc amido moiety as a directing group, the
ortho-C–H is selectively functionalized and the catalytic reaction exhibits excellent tolerance to different
Received 7th March 2014,
Accepted 1st April 2014
DOI: 10.1039/c4ob00512k
functional substituents.
A notable rhodacyclic complex is isolated and structurally characterized,
www.rsc.org/obc
suggesting that C–H/N–H cyclometallation is a key step in the catalytic cycle.
Transition metal-catalyzed oxidative coupling of arene C–H
bonds is a powerful and atom-economical strategy for con-
struction of carbon–carbon and carbon–heteroatom bonds.1
Notably, extensive investigations revealed that [Cp*RhCl2]2 and
derivatives can effect regioselective arene C–H bond activation
under mild conditions to form reactive arylrhodium(III) com-
plexes, which would undergo heteroannulation with alkenes
and alkynes.2 Miura and Satoh pioneered the synthesis of iso-
coumarins by oxidative dehydrogenative coupling of benzoic
acids with alkynes (Scheme 1).3 Similarly, Fagnou and co-
workers also developed the analogous alkyne cycloaddition
with benzohydroxamic acids and anilides for the synthesis of
isoquinolones and indoles.4 Recently, Glorius and co-workers
achieved the cycloaddition of benzohydroxamic acids with
vinyl methyl ketones to afford seven-membered azepinones.5
Our approach to develop regioselective oxidative arene C–H
coupling reactions is to explore the cross-coupling reactions of
transition metal aryl complexes with carboradicals,6a–f
nitrenes6g,h and carbenes.6i Recently, we achieved the ortho-
selective arene C–H coupling reactions with diazomalonates;
acetophenone oximes, arylpyridines, benzoic acids and benzyl-
amines are effective substrates for this transformation.6i Perti-
nent to the coupling reaction of arylrhodium(III) complexes
with diazomalonates, an alkylrhodacyclic complex was structu-
rally characterized. It was believed that protonolysis of this
Scheme 1 Rh(III)-catalyzed heteroannulation to build heterocyclic
rings.
alkylrhodacyclic(III) complex should furnish the necessary C–H
bond for the product formation. Motivated by the characteriz-
ation of the alkylrhodacyclic complex, we anticipated that
reductive elimination rather than protonolysis should bring
about a formal (4 + 1) cycloaddition.
While the oxidative C–H coupling reactions with alkynes to
give six-membered heterocycles have been extensively investi-
gated, the analogous carbenoid cycloadditions to afford five-
membered heterocycles are sparse in the literature.7 Herein we
describe the Rh(III)-catalyzed formal (4 + 1) cycloaddition of
diazomalonates with O-acetyl benzohydroxamic acids to form
State Key Laboratory of Chirosciences and Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon,
Hong Kong. E-mail: wing-yiu.yu@polyu.edu.hk; Fax: (+852) 2364-9932
†Electronic supplementary information (ESI) available: Detailed experimental
procedure, 1H and 13C NMR data and spectra for all compounds, and X-ray crys-
tallographic data. CCDC 987993. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c4ob00512k
4112 | Org. Biomol. Chem., 2014, 12, 4112–4116
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oxisoindoles. During our investigation, Rovis and co-workers (e.g. R = C(O)tBu or C(O)Ph) were found to be effective sub-
reported a similar cycloaddition with methyl α-aryldiazo- strates for the Rh-catalyzed cycloaddition reaction with 3a
acetates as carbenoid coupling partners.8
being formed in ca. 90% yields. However, no reactivity was
First, O-acetyl benzohydroxamic acid 1a (1 equiv.) was observed with benzohydroxamic acids bearing the hydroxyl or
treated with diazomalonate 2a (1.2 equiv.) in the presence of the methoxy groups. This result indicated that the carboxylate
[Cp*Rh(OAc)2] (5 mol%) in THF (2 mL) at 60 °C for 4 h; the group is essential to the cycloaddition reaction. Fagnou and
desired lactam 3a was obtained in 93% yield (Table 1, entry 1). co-workers also reported the similar findings on the Rh-cata-
The molecular structure of 3a was confirmed by the single- lyzed heteroannulation with alkynes.2l Presumably, the N–O
crystal X-ray diffraction study. Lowering the Rh catalyst loading (carboxylate) linkage should function as an internal oxidant
to 1 mol% also gave 91% product yield, albeit with a longer that facilitates the reductive elimination step of the rhodacycle
reaction time (16 h) for complete substrate consumption intermediates (see later sections).
(entry 2). No product formation was observed in the reaction
Table 2 depicts the result of the substrate scope study.
without the Rh catalyst (entry 3). Employing other solvents O-Acetyl benzohydroxamic acids bearing electron-releasing
such as DMF, DCE, MeCN and toluene, the analogous C–H and withdrawing substituents (substituent = OMe, Me, NO2,
transformations ran smoothly to afford 3a in 64–95% yields CF3) smoothly reacted with 2a to give the corresponding
(entries 4–7). Notably, our previous work on the Rh-catalyzed lactams (3b–3e) in 76–93% yields. Chloro and bromo substitu-
carbenoid aryl C–H bond functionalizations showed that the ents were well tolerated; 3f and 3g were obtained in 82 and
MeOH solvent should favor protonolysis of the alkylrhodium 77% yields respectively. With the assistance of the amide
(III) intermediate.6i However, in this work, no protonolysis directing group, the ortho-C–H bond was chemoselectively
product was obtained with MeOH as the solvent (entry 8). functionalized. When the di-substituted benzohydroxamic acid
Other Rh catalysts such as [(COD)RhCl]2 and (Ph3P)3RhCl1j was treated with 2a, the less hindered ortho-C–H bond was
exhibited negligible catalytic activity for the carbenoid cyclo- functionalized to furnish lactam 3h exclusively in 73% yield.
addition reaction (entries 9 and 10).
Nevertheless, the reaction of the meta-substituted benzo-
The effect of the N-substituent was examined (Scheme 2); hydroxamic acid afforded a mixture of regioisomeric products
benzohydroxamic acids bearing the N–OR carboxylate linkage in 48% combined yield (3i : 3i′ = 4.3 : 1). It is well established
that rhodium-carbenoids would react with oxygen, nitrogen
and sulfur atoms to afford reactive ylides. In this work, facile
functionalization of the benzohydroxamic acids containing a
Table 1 Reaction optimizationa
heterocyclic moiety with 2a was achieved, and 3j was obtained
in 63% yield. No ylide-mediated reactions (e.g. the Stevens
rearrangement of sulfonium ylides) were observed.
The scope of the diazo reagents was also investigated
(Table 3). Apart from diazomalonate 2a, diazoesters bearing
functional groups such as phenylsulfone, cyano and diethyl
Entry
Rh catalyst
Solvent
Yieldb (%)
phosphonate would effectively couple with 1a under Rh cata-
1
Cp*Rh(OAc)2
Cp*Rh(OAc)2
—
THF
THF
THF
93
91
0
2c
3
Table 2 Rh-catalyzed cycloaddition of benzohydroxamic acids 1 with
diazomalonate 2aa
4
5
6
7
8
9
10
Cp*Rh(OAc)2
Cp*Rh(OAc)2
Cp*Rh(OAc)2
Cp*Rh(OAc)2
Cp*Rh(OAc)2
[(COD)RhCl]2
(Ph3P)3RhCl
DMF
DCE
MeCN
Toluene
MeOH
THF
95
84
82
64
0
0
0
THF
a Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol) and Rh catalyst
(5 mol%) in a solvent (2 mL) at 60 °C for 4 h. b Yields were determined
1
by H NMR analysis using 1,2-dibromoethane as an internal standard.
c Reaction was run with [Cp*Rh(OAc)2] (1 mol%) for 16 h.
a Reaction conditions: 1 (0.2 mmol), 2a (0.24 mmol) and [Cp*Rh-
(OAc)2] (5 mol%) in THF (2 mL) at 60 °C for 4 h. Isolated yield. b The
regioisomeric ratio was determined by 1H NMR analysis.
Scheme 2 N-leaving group effect on Rh(III)-catalyzed cycloaddition of
benzohydroxamic acids with 2a.
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Table 3 Scope of diazo compoundsa
hydroxamic acids (0.12 mmol) with [Cp*Rh(OAc)2] (0.1 mmol)
in THF at 60 °C for 2 h under a N2 atmosphere. 1H NMR analy-
sis of the crude mixture revealed a complicated mixture, which
was then purified by column chromatography over alumina
with dichloromethane as the eluent. Removal of the dichloro-
methane gave a dark orange solid, which was recrystallized
from dichloromethane and diethyl ether to afford 4 as a dark
red crystal (5% yield) after 3 days at room temperature. By
means of X-ray crystallography, the molecular structure of 4 was
established to be a dinuclear arylrhodium(III) complex (Fig. 1).
The complex exhibits a five-membered cyclic structure with the
measured Rh(1)–C(19) distance to be 2.024(3) Å.12 The four-
membered aza-rhodium cycle was characterized by the
measured Rh(1)–N(1) and Rh(1)–N(1A) distances of 2.111(3) Å
and 2.169(3) Å, respectively. As expected, the two Cp
rings adopt an anti-conformation. Notably, a methyl group on
the Cp rings was acetoxylated with the C(10)–O(2) distance
being 1.397 Å. In this work, treatment of 4 with diazo 2a
(1.2 equiv.) in THF at 60 °C failed to effect any cycloadduct for-
mation, and the complex was fully recovered. This poor reactiv-
ity of 4 is attributed to the strong azo-rhodium cycle, which
may be difficult to dissociate for diazo coordination. Further-
more, we performed a kinetic isotope effect (KIE) study based
on two parallel reactions with d5-1a and 1a as substrates.
While KIE values >2 was observed in many [Cp*RhIII]-catalyzed
C–H coupling reactions,6a,8 no KIE was observed for this case
with a kH/kd of 1.03, suggesting that the C–H activation is not
involved in the rate-limiting step.
a Reaction conditions: 1 (0.2 mmol), 2a (0.24 mmol) and [Cp*Rh-
(OAc)2] (5 mol%) in THF (2 mL) at 60 °C for 4 h. Isolated yield.
lysis to afford the cycloaddition products (3k–3m) in 30–77%
yields. It is worth mentioning that the internal CvC bond was
also tolerated in the analogous reaction, and 3n was obtained
in 86% yield. Indeed, alkene moieties are known to undergo
cyclopropanation with carbenoid species.9 In addition, donor–
acceptor substituted diazo reagents were reactive coupling
partners. Treating methyl phenyldiazoacetate and its bromo-
substituted derivative with substrate 1a under standard reac-
tion conditions afforded the corresponding 3p and 3q in 83%
and 90% yields, respectively. Note that spirocyclic oxindoles
are attractive molecules of remarkable biological importance;
the Rh-catalyzed reaction with diazooxindole smoothly gave
the bicyclic product 3r in 75% yield. Alkyl diazoacetates are
challenging reagents for the carbenoid C–H functionalization;
the competitive β-hydride elimination of the putative alkyl-
rhodium complex would terminate the catalytic cycle with
inactive Rh-hydride species.10 Yet, in this work, alkyl diazoace-
tates were found to be effective reagents with 3s and 3t being
obtained in 32% and 62% yields, respectively. Likewise, reac-
tion of diphenyldiazomethane with 1a gave the desired cyclo-
adduct 3a in 82% yield.
On the basis of our mechanistic studies and literature pre-
cedent, a plausible mechanism for this Rh-catalyzed cyclo-
addition reaction is proposed in Scheme 3. It is postulated
that the electrophilic [Cp*Rh(OAc)2] would initially undergo a
O-Acetyl benzohydroxamic acids are common substrates for
[Cp*Rh]-catalyzed direct arene C–H coupling reactions, includ-
ing alkyne cycloaddition and aminations. The coupling reac-
tions were believed to occur via some reactive rhodacyclic
complexes;11 however, reports on isolation and structural
characterization of the rhodacyclic complexes are sparse. To
ascertain the involvement of the rhodacyclic complex in the
carbenoid [4 + 1] cycloaddition, we reacted O-acetyl benzo-
Fig. 1 Molecular structure of
4 with 50% displacement ellipsoid.
H atoms are omitted for clarity. Selected bond distances [Å] and bond
angles [deg]: Rh(1)–N w(1), 2.111(3); Rh(1)–N(1A), 2.169(3); Rh(1)–C(19),
2.024(3) Å; C(10)–O(2), 1.397(8); C(19)–Rh(1)–N(1), 78.11(13); C(19)–
Rh(1)–N(1A), 85.48(13); N(1)–Rh(1)–N(1A), 81.24(13); Rh(1)–N(1)–Rh(1A),
98.76(13).
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Scheme 3 Proposed mechanism.
chelation-assisted C–H/N–H deprotonation of O-acetyl benzo-
hydroxamic acids to form a five-membered rhodacycle (A) with
elimination of acetic acid. We proposed that coordination of
the diazo compound with A may form the diazonium inter-
mediate B. Extrusion of N2 from B would afford the Rh-car-
bene C, which subsequently undergoes migratory insertion to
give D. Further C–N bond formation via reductive elimination
would furnish the desired product 3 and the N-OAc moiety
may act as an internal oxidant to regenerate the active Rh
catalyst.
Conclusion
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In conclusion, we have developed a Rh(III)-catalyzed C–H acti-
vation/cycloaddition of benzohydroxamic acids with diazo
compounds. The functionalized lactam derivatives were
obtained in good yields under mild reaction conditions. In
this case, an external oxidant was not required and diazo
bearing different substituents were well-tolerated.
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Acknowledgements
We thank The Hong Kong Research Grants Council
(PolyU503811P) for financial support.
Notes and references
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7 For examples of Rh(III)-catalyzed carbenoid cycloadditions
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12 Davies and co-workers reported the synthesis of a five-
membered rhodacycle [Cp*Rh(C6H4-2-C5H4N-κ-C,N)Cl] in
which the distance of Rh–C(aryl) was determined to be
2.305(3). (see ref. 11e).
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