Highly selective intramolecular carbene insertion into primary C-H bond of α-diazoacetamides mediated by a (p-cymene)ruthenium(II) carboxylate complex

Article abstract of DOI:10.1021/ja3006989

Complex [(p-cymene)Ru(η¹-O₂CCF₃) ₂(OH₂)] mediated transformation of α-diazoacetamides ArCH₂N(C(CH₃)₃)C(O)CHN₂ to result in carbene insertion into the primary C-H bond exclusively, with the γ-lactam products being isolated in up to 98% yield. This unexpected reaction is striking in view of the presence of usually more reactive sites such as secondary C-H bonds in the substrates. DFT calculations based on proposed Ru-carbene species provide insight into this unique selectivity.

Full text of DOI:10.1021/ja3006989

Communication
pubs.acs.org/JACS
Highly Selective Intramolecular Carbene Insertion into Primary C−H
Bond of α-Diazoacetamides Mediated by a (p-Cymene)ruthenium(II)
Carboxylate Complex
Vanessa Kar-Yan Lo, Zhen Guo, Matthew Kwok-Wai Choi, Wing-Yiu Yu,† Jie-Sheng Huang,
and Chi-Ming Che*
Department of Chemistry, State Key Laboratory of Synthetic Chemistry, and Open Laboratory of Chemical Biology of the Institute of
Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Pokfulam Road, Hong Kong (China)
S
* Supporting Information
Scheme 1
A B S T R A C T : C o m p l e x [ ( p - c y m e n e ) R u ( η 1 -
O2CCF3)2(OH2)] mediated transformation of α-diazo-
acetamides ArCH2N(C(CH3)3)C(O)CHN2 to result in
carbene insertion into the primary C−H bond exclusively,
with the γ-lactam products being isolated in up to 98%
yield. This unexpected reaction is striking in view of the
presence of usually more reactive sites such as secondary
C−H bonds in the substrates. DFT calculations based on
proposed Ru-carbene species provide insight into this
unique selectivity.
irect functionalization of sp3 C−H bonds by metal-
D
catalyzed carbene insertion1,2 is an attractive and
powerful strategy for C−C bond formation. One of the
challenges in this area is the functionalization of inert primary
(1°) C−H bonds, particularly the selective functionalization of
1° C−H bonds in the presence of more reactive secondary
(2°)/tertiary (3°) C−H bonds and/or other functional groups.
Intramolecular C−H bond functionalization by metal-
catalyzed carbene insertion has received tremendous attention,
predominantly using dirhodium catalysts, with diazo carbonyl
compound substrates including diazoesters, diazoketones, and
diazoamides (see, for example, reaction 1 in Scheme 1).2a−c,e,f,h
These reactions usually feature a selectivity order 3° > 2° > 1°
C−H bonds. The 1° C−H bonds, when coexisting with reactive
2° or 3° C−H bond(s),3 remain not efficiently functionalized
or in sparse cases4 are functionalized as major product(s) (up
to 80% isolated yield4e) along with considerable amounts of 2°
or 3° C−H bond functionalization products or other products.
For example, the dirhodium-catalyzed reaction of α-diazoace-
tamides 1 (reaction 2 in Scheme 1)5 selectively afforded the β-
lactams 2 through benzylic 2° C−H bond functionalization
and/or the cycloheptatriene 3 through aromatic cycloaddition
(Buchner reaction), without producing 1° C−H bond insertion
products such as γ-lactams 4 (reaction 3 in Scheme 1).
carbonyl complexes can catalyze intramolecular carbene
insertion of N,N-diethyl-2-diazoacetoacetamide to give a
mixture of 1° and 2° C−H bond functionalization products
in up to 87% combined yield, with 1° C−H bond
functionalization accounting for up to 70% yield.4g
Herein we report a (p-cymene)ruthenium(II) carboxylate
complex that mediated the transformation of 1 (R = H) to 4
(reaction 3 in Scheme 1) in up to 98% isolated yield with
neither 3 nor 2 being detected, together with DFT calculation
studies on the origin of such selectivity. To the best of our
knowledge, this work provides the first example of metal-
mediated intramolecular carbene insertion into 1° C−H bonds
in virtually quantitative yield in the presence of usually more
reactive sites such as 2° C−H bonds.
Ruthenium carboxylate complexes such as [CpRu(η2-
O2CR′)(PPh3)] (Cp = cyclopentadienyl) were previously
reported to react with diazo compounds (such as Ph2CN2
and EtO2CCHN2) to give five-membered cyclometalated
complexes7 (inset in Scheme 2), a reaction that can be
considered as carbene insertion into the M−O bond via attack
of carboxylate oxygen by a coordinated carbene group.8 In this
Previously we demonstrated the use of ruthenium complexes
as efficient catalysts for intramolecular carbene insertion into 2°
or 3° C−H bonds,6 including the transformation of 1 to 2 in up
to 98% yield using catalyst [(p-cymene)RuCl2]2 or polymer-
supported ruthenium nanoparticles.6c,d Similar formation of 2
from 1 was also observed by Maas and co-workers using di- or
tetraruthenium carbonyl catalysts, although these ruthenium
Received: January 21, 2012
Published: April 24, 2012
© 2012 American Chemical Society
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Communication
Scheme 2
Table 1. Intramolecular Carbene C−H Insertion of α-
a
Diazoacetamides 1 Mediated by 7
b
product ratio (%)
c
entry substrate 1
4
3
2
total yield (%)
d
d
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
4a, 100
4b, 100
4c, 100
4d, 100
4e, 100
4f, 82
−
−
−
−
−
−
98
98
98
97
96
−
−
−
−
−
3g, 43
work, we prepared [(p-cymene)Ru(η2-O2CR′)(η1-O2CR′)] (R′
= Me 5a, Ph 5b, CHPh2 5c) according to reported procedures9
and determined the crystal structure of 5b by X-ray analysis
(Figure S1, Supporting Information). Treatment of 5b,c with 1
equiv of 1 gave the five-membered cyclometalated complexes
6a−f (reaction 4 in Scheme 2) in 97−99% isolated yields; 2−4
were not detected by 1H NMR analysis of the reaction mixture.
Complex 6e has been structurally characterized by X-ray
crystallography (Figure S2).
b
2f, 18
95
b
1g
4g, 39
2g, 18
95
a
Reaction conditions: 1 (1.0 mmol), 7 (25 mol %), CH2Cl2 (4 mL),
b
40 °C, 1 h. Determined by 1H NMR analysis of crude reaction
c
mixture using 1,1-diphenylethene as internal standard. Isolated yield.
d
Not detected.
and 2a in up to 87% combined yield (reaction time: 24 h) with
poor selectivity of 4a. Other ruthenium complexes, including
[(p-cymene)RuCl2]2, Ru3(CO)12, [Ru(CO)3Cl2], and [Ru-
(TPP)(CO)], were also inferior to 7 in terms of 4a selectivity
(Table S1). Under optimized conditions (25 mol % of catalyst,
in CH2Cl2 at 40 °C for 1 h), using 7 as a catalyst resulted in the
transformation of 1a to 4a exclusively, with 4a isolated in 98%
yield (entry 1, Table 1).
Exclusive formation of 1° C−H bond insertion product 4
from α-diazoacetamides 1 catalyzed by 7 was also found using
substrates 1b,c,e bearing p-Y (Y = F, Cl, Br) substituents or 1d
bearing o-Cl substituent; the isolated yields of 4b−e were 96−
98% (entries 2−5, Table 1). For α-diazoacetamides 1f,g bearing
p-Me and p-OMe substituents, respectively, the selectivity for
the formation of 4 decreased, with a 4f/2f ratio of 82:18 and a
4g/3g/2g ratio of 39:43:18 (entries 6 and 7, Table 1), though
the combined yield still reached 95%.
We have undertaken hybrid DFT studies, at the B3LYP/6-
31G(d) (LANL2DZ for Ru) level of theory, to gain insight into
the origin of the unique selectivity in the 7-mediated carbene
insertion reaction. On the basis of previous DFT studies of
dirhodium-catalyzed inter-11a and intramolecular11b carbene
insertion into C−H bonds via Rh-carbene intermediates, we
propose the generation of Ru-carbene intermediate A (Figure
1) from reaction of complex 7 with 1a. Given the isolation of
6a−f for complexes 5b,c (Scheme 2), the possible trans-
formation of A to 6 in Scheme 2 with R′ = CF3 and Y = H
(species B) was considered in initial calculations. This
transformation is exothermic by 16.3 kcal/mol (Scheme S1),
and attempts to locate its transition state were unsuccessful; the
In efforts to prepare [(p-cymene)Ru(η2-O2CCF3)(η1-
O2CCF3)] according to the literature procedure,9 we obtained
[(p-cymene)Ru(η1-O2CCF3)2(OH2)] (7, Scheme 2), as
1
revealed by its X-ray crystal structure (Figure S3) and H
1
NMR analysis at −50 to 50 °C (Figure S4). The H NMR
analysis also revealed a nonfluxional behavior of 7 in solution,
unlike the fluxional behavior of 5b (Figure S5) attributable to
interconversion of η2- and η1-coordination modes of its
benzoate ligand.10 Upon treating 7 with 1 (Y = H, Cl, Me;
Scheme 2), the corresponding five-membered cyclometalated
complexes (6 in Scheme 2 with R′ = CF3 and Y = H, Cl, Me)
were not obtained.
The catalytic behavior of 7 toward intramolecular carbene
insertion was initially examined using substrate 1a (Table 1)
under various conditions (Table S1). Previously reported
reaction of 1a catalyzed by dirhodium complexes5a,b afforded a
mixture of cycloheptatriene 3a and the benzylic 2° C−H bond
insertion product 2a in 96−99% combined yields (3a/2a ratio
= 98:2 to 30:70) or in the case of catalyst [Rh2(O2CMe)4] gave
3a exclusively.
To our surprise, complex 7 (5 mol %) catalyzed the reaction
of 1a in CH2Cl2 at 40 °C for 1 h to predominantly give the 1°
C−H bond insertion product 4a in a 4a/3a/2a ratio of 84:7:9
with a 96% combined yield based on consumed substrate (65%
conversion, entry 1 in Table S1). At a higher loading of 7 (15
mol %), the selectivity of 4a increased to a 4a/3a ratio of 96:4
(95% combined yield with 100% substrate conversion; no 2a
1
was detected by H NMR). Complexes 5a−c at 5 mol %
loading catalyzed transformation of 1a to a mixture of 4a, 3a,
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Figure 1. Calculated potential energy surfaces for the formation of (pathway I, black) γ-lactam 4a by carbene insertion into the 1° C−H bond of tBu
group, route A to E, (pathway II, red) cycloheptatriene 3a by aromatic cycloaddition, route A to I, and (pathway III, blue) β-lactam 2a by carbene
insertion into benzylic 2° C−H bond, route A to F, from complex A at the B3LYP/6-31G(d):LANL2DZ level.
process might be barrierless (as further supported by the
potential energy surface of relaxed scan calculation on C−O
bond distance of B). However, formation of product 4a from B
is less favored, as its transition state TSD‑E (Scheme S1) is
higher in energy by 2.6 kcal/mol than that (TSC‑E, Figure 2)
from A (pathway I in Figure 1). Therefore, only species A was
considered in subsequent calculations.
insertion into 1° C−H bond is kinetically and thermodynami-
cally favorable, in agreement with selective formation of 4a in
the reaction of 1a catalyzed by 7. This preferential 1° C−H
insertion selectivity is likely to be attributed to the combined
−
steric effect of auxiliary CF3CO2 ligand and conformation of
coordinated carbene ligand generated in situ from the diazo
compound, directing the 1° C−H bond to the proximity of the
reactive Ru-carbene unit.
A closer approach of the N-tBu 1° C−H bond to the carbene
ligand for cyclization is suggested by Thorpe−Ingold effect, or
in more general terms the gem-dialkyl effect and gem-
disubstituent effect;12 such effects also include the reactive
rotamer effect (i.e., higher population of the rotamers properly
oriented for the cyclization). We examined the selectivity of 7
i
for substrates PhCH2N(iPr)C(O)CHN2 (1′) and PrN(iPr)C-
(O)CHN2 (1″) bearing N-iPr group(s), which would benefit
from gem-dialkyl effect in the 3° instead of 1° C−H bond
insertion. In these reactions, 1′ was converted into aromatic
cycloaddition product in ∼80% yield, with the 1° and 3° C−H
insertion products each in ∼5% yield for 1′ and ∼21% yield for
1″ (Scheme S2). Note that changing the N-tBu group in 1a to
N-iPr somewhat reduces the nucleophilicity of the 1° C−H
bonds, thus decreasing their reactivity toward electrophilic
Figure 2. Computed structures of transition states TSC‑E, TSA‑G, and
TSA‑F. Key C···H and C···C distances (Å) are shown.
t
carbene ligand. Superior reactivity of the Bu group has been
Starting from species A, products 3a and 2a were formed
through pathways II and III, via transition states TSA‑G and
TSA‑F (Figure 2), respectively, as depicted in Figure 1.
Compared with pathways II and III, pathway I has the
following features: (i) lower potential energy surface of the
reported in selective intermolecular 1° C−H functionalization
reactions catalyzed by palladium complexes13,14 via, for
example, five-membered palladacycle intermediates.13a,b How-
ever, the absence of product 4a in the dirhodium-catalyzed
reaction of 1a,5a,b and the low selectivity of 4a,g in the reaction
of 1a,g catalyzed by 5 and 7, respectively, indicate insignificant
or minor impact of the N-tBu group in these cases, possibly due
to steric hindrance and/or unfavorable electronic factors (such
as decreased electrophilicity of the carbene group due to lack of
strongly electron-withdrawing CF3 groups in 5, or increased
nucleophilicity of the phenyl group or benzylic 2° C−H bonds
transition state (11.0 (TSC‑E) vs 14.8 (TSA‑G) and 14.7 (TSA‑F
)
kcal/mol); (ii) more exothermic (−53.5 vs −8.0 and −41.8
kcal/mol); (iii) significantly less elongated C−H bond in the
transition state (C···H distance 1.276 (TSC‑E) vs 1.552 (TSA‑F
)
Å, Figure 2). Evidently, pathway I features an early transition
state with a lower energy barrier than pathways II and III.
Therefore, the transformation of species A to 4a via carbene
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Journal of the American Chemical Society
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545. (f) Davies, H. M. L.; Denton, J. R. Chem. Soc. Rev. 2009, 38, 3061.
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stituent). Thus, the selective formation of 4a−e from the 7-
catalyzed reaction of 1a−e should stem from both electronic
effects and steric effects or kinetic factors, including favorable
distance and shape of the transition state for the 1° C−H
insertion. Manipulation of steric and electronic effects is among
the strategies employed for selective functionalization of the
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catalyzed intermolecular reactions.15
(3) For diazoester (CH3)3COC(O)CHN2 containing neither 3° nor
2° sp3 C−H bond, a copper-catalyzed intramolecular carbene insertion
into the 1° C−H bond in up to 99% isolated yield has been reported.
See: Martín, C.; Belderraín, T. R.; Per
7, 4777.
́
ez, P. J. Org. Biomol. Chem. 2009,
In summary, the (p-cymene)ruthenium(II) carboxylate
complex 7 unexpectedly exhibited a strikingly high selectivity
toward intramolecular carbene insertion into 1° C−H bonds in
the presence of usually more reactive benzylic 2° C−H bonds.
Using 7 as catalyst, a number of α-diazoacetamides 1 (R = H)
were converted to γ-lactams 4 exclusively, with isolated yields of
96−98% (entries 1−5, Table 1). To the best of our knowledge, an
effective transformation of 1 to 4 has not been documented
previously. The present work provides a unique example of sp3
C−H bond functionalization and points to the feasibility of
developing ruthenium catalysts for selective functionalization of
1° C−H bonds via carbene insertion by judicious choice of
ligands and substrates. Studies are under way to extend the
reaction to other types of substrates; for example, reaction of
PhCH2CH2N(C(CH3)3)C(O)CHN2 mediated by 7 also
exclusively afforded the 1° C−H bond insertion product
(Scheme S3).
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, characterization of compounds (including
NMR spectra and CIF files), Table S1, Figures S1−S5,
Schemes S1−S3, and coordinates of computed structures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(8) (a) Daniel, T.; Mahr, N.; Braun, T.; Werner, H. Organometallics
1993, 12, 1475. (b) Rodríguez-García, C.; Oliva, A.; Ortuno, R. M.;
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Branchadell, V. J. Am. Chem. Soc. 2001, 123, 6157.
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AUTHOR INFORMATION
Corresponding Author
cmche@hku.hk
■
(10) Kavanagh, B.; Steed, J. W.; Tocher, D. A. J. Chem. Soc., Dalton
Trans. 1993, 327.
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Adv. Synth. Catal. 2003, 345, 1159.
Present Address
†State Key Laboratory of Chiralsciences and Department of
Applied Biology and Chemical Technology, The Hong Kong
Polytechnic University, Hung Hom, Kowloon, Hong Kong,
China
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(14) Selected recent reviews involving palladium-catalyzed 1° C−H
functionalization: (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by The University of Hong Kong and
Hong Kong Research Grants Council (HKU 1/CRF/08 and
HKU 7007/08). We thank Dr. Nianyong Zhu and Dr. Lap
Szeto for assistance in determining the crystal structures of
complexes 5b, 6e, and 7.
(15) (a) Chen, H.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science
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