Intramolecular C-H insertion using NHC-di-rhodium(II) complexes: the influence of axial coordination

Article abstract of DOI:10.1016/j.tetlet.2008.10.054

In this work we show that the intramolecular C-H insertion of diazo-acetamides catalysed by di-rhodium(II) complexes can be highly influenced by the axial ligand on the di-rhodium(II) complex. Axially monocoordinated NHC-Rh₂(OAc)₄ complexes have a distinct reactivity from the parent Rh₂(OAc)₄ complex affording the cyclisation products in different rates and selectivities. Surprisingly, a new reaction mode emerged when using these complexes which led to a decarbonylation pathway.

Full text of DOI:10.1016/j.tetlet.2008.10.054

Tetrahedron Letters 49 (2008) 7372–7375
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Intramolecular C–H insertion using NHC–di-rhodium(II) complexes:
the influence of axial coordination
a,
Luis F. R. Gomes a, Alexandre F. Trindade a, Nuno R. Candeias a, Pedro M. P. Gois b, , Carlos A. M. Afonso
*
*
a CQFM, Centro de Química-Física Molecular, IN—Institute of Nanosciences and Nanotechnology, Instituto Superior Técnico,1049-001 Lisboa, Portugal
b iMed.UL, Faculdadade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
In this work we show that the intramolecular C–H insertion of diazo-acetamides catalysed by di-rho-
dium(II) complexes can be highly influenced by the axial ligand on the di-rhodium(II) complex. Axially
monocoordinated NHC–Rh2(OAc)4 complexes have a distinct reactivity from the parent Rh2(OAc)4 com-
plex affording the cyclisation products in different rates and selectivities. Surprisingly, a new reaction
mode emerged when using these complexes which led to a decarbonylation pathway.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 11 August 2008
Revised 3 October 2008
Accepted 10 October 2008
Available online 17 October 2008
Keywords:
C–H insertion
Di-rhodium(II) complexes
N-heterocyclic carbenes (NHC)
Axial coordination
Decarbonylation
Di-rhodium(II) complexes are a well-known class of catalysts
among the organic chemistry community due to a broad catalytic
activity.1 They have been used in a variety of synthetically useful
transformations involving the arylation of aldehydes, intramolecu-
lar and intermolecular C–H bond activation,2 C–H bond amination,
oxidations, cycloadditions and a variety of ylide-based transforma-
tions. Among these, they are mostly recognised for their ability to
react with diazo substrates generating metallo-carbenes which are
pivotal intermediates in the activation of unfunctionalised C–H
bonds.3
using this family of complexes.4,5 In line with these results, we be-
came interested in understanding the influence of the NHC axial
coordination when these complexes are used to generate metal-
lo-carbenes from diazo substrates, and when these reactive inter-
mediates are involved in intramolecular C–H bond insertions.
In 2001, Arduengo, Snyder et al., reported the first NHC–di-
Rh(II) complex which was evaluated in a series of reactions with
diazo substrates.6 The observed results were identical to those ob-
tained when the parent di-rhodium(II) complex was used, which
The recognized catalytic activity of this class of complexes relies
on their Rh(II) bi-metallic structure. They have a Rh–Rh bond and
four bridging ligands, responsible for controlling the catalyst elec-
trophilicity and asymmetry.1,2 The two axial ligands (normally sol-
vent molecules) are generally considered to have a less important
role in catalysis as they form a much weaker bond with the electro-
philic centre and, for that reason, are easily displaced from the rho-
dium active centers.1,2 Recently, we reported that the axial ligands
can have a more profound impact on the complex overall reactiv-
ity. In particular, we showed that the axial coordination of N-het-
erocyclic carbenes (NHCs) allowed the arylation of aldehydes
using boronic acids to take place in considerably high yields and
selectivities, later Jang et al. also reported the allylic oxidation
* Corresponding authors. Fax: +351 21 7946470 (P.M.P.G.); fax; +351 21 846
4455/7 (C.A.M.A).
E-mail addresses: pedrogois@ff.ul.pt (P. M. P. Gois), carlosafonso@ist.utl.pt (C. A.
M. Afonso).
Figure 1. The iPr-NHC ligand confers a high stereoprotection to the Rh centre due
to a almost perfect structural match between the NHC and Rh2(OAc)4 as shown in
the optimised geometry (B3PW91) for the Rh2(OAc)4(NHC) complex 8 (left, NHC is
darkened) and its LUMO (right).4
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.054

L. F. R. Gomes et al. / Tetrahedron Letters 49 (2008) 7372–7375
7373
O
tBu
(EtO)2OP
O
O
(EtO)2OP
tBu
(EtO)2OP
tBu
Ph
N
(EtO)2OP
N
cat.,1 mol %
+
+
N
N
Ph
Ph
tBu
C2H4Cl2, reflux
N2
Ph
1
2
3
4
O
O
CF3
O
O
Rh
O
Rh
Rh
O
O
N
N
O
Rh
O
N
Rh
Rh
Rh
N
N
Rh
Rh
Rh
5
6
7
8
9
Scheme 1. Cyclisation of diazo-acetamide 1 using complexes 5–9.
Table 2
and accordingly with the authors, was a clear indication of com-
plex NHC–Rh(II) fragmentation in the reaction conditions. Follow-
ing this precedent, we anticipated that our complex, in which the
isopropyl groups fit in between the AcO bridges and the carbene
ring remains in an eclipsed conformation confering a high stereo-
protection to the Rh centre (Fig. 1),4 would endure the reaction
conditions, enabling a more clear view over the NHC influence on
the metallo-carbene formation and subsequent intramolecular C–
H insertion.
Cyclisation of diazo-acetamides 10 and 11 using complexes 8 and 9
Entry
Catalyst
Substrate
Conditionsa
12b
14b
16b
1
2
3
5
8
9
10
10
10
6 h, Reflux C2H4Cl2
6 h, Reflux C2H4Cl2
6 h, Reflux C2H4Cl2
65 (47)
18 (17)
32 (18)
13b
34 (25)
46 (35)
39 (14)
15b
—
36
29
4
5
6
5
9
9
11
11
11
12 h, Reflux CH2Cl2
53 h, Reflux CH2Cl2
4 h, Reflux C2H4Cl2
(95)10
89 (67)
64 (54)
—
—
—
—
8 (5)
30 (21)
We initiated our study with the cyclisation of substrate 1 in the
presence of complexes 5–9 (Scheme 1, Table 1). Not surprisingly
the reaction proceeded at a much slower rate when 8 and 9 were
used and comparing with catalysts 5–7. This fact is understandable
considering that the first step of the metallo-carbene formation is a
nucleophilic attack by the diazo compound onto the di-rhodium(II)
complex which, in the case of complexes 8 and 9, is less favourable
due to an electron-richer terminal Rh resulting from the NHC coor-
dination. The atomic charge of the Rh centres in complex 8 is 0.74
in terminal Rh centre and 0.89 in the RhNHC centre, while in the
parent complex 5, the Rh charge is 0.92.4a
a
Substrate 1 (0.3 mmol), solvent (0.03 M for 10 and 0.1 M for 11) and catalyst
(1 mol % for 10 and 2.5 mol % for 11).
b
The conversions were determined on the basis of the reaction crude mixture 1
H
NMR, in parenthesis are given the isolated yields.
plexes 8 and 9 derived from the parent complex 5, not only affor-
ded the -lactam (in considerably lower yields) and the b-lactam
c
isomer but also, and more importantly, a new product formed with
CO extrusion (Table 1, entries 4 and 5). Traces (less than 2%) of this
product could also be found in the crude reaction mixture when
using complex 7 but no decarbonylation product was formed with
any of the other catalysts, nor was it observed in our recent studies
regarding the UV-promoted cyclisation of diazo-acetamides (Table
1, entry 6).11 Product 4 corresponds to a new reactivity mode, and
as far as our knowledge goes, previously unreported for Rh(II)
intramolecular C–H insertions.
More surprising was the effect over the intramolecular C–H
insertion selectivity when using the NHC–Rh(II) complex. Typi-
cally, these reactions are known to proceed with high preference
for the c
-lactam formation.7–10 In line with this general consider-
ation, the cyclisation of substrate 1 with complex 5 afforded the
lactam 2 in high yield. Likewise, catalysts 6 and 7 bearing elec-
tron-withdrawing and electron-donating bridging ligands afforded
Intrigued by this result, we extended this cyclisation to other
families of diazo-acetamides with different
a-substituents to
the c-lactam in 82% and 80% yield, respectively. Differently, com-
determine if the formation of product 4 was an isolated event or
if truly corresponds to a new reaction mode for these transforma-
tions. We were quite pleased to discover that the same event oc-
curs with different substrates as shown in Table 2. The CO
liberation is even more pronounced in substrate 10 possessing a
more electron-withdrawing a-substituent. In this case, the decarb-
onylation product 16 was obtained in 36% using catalyst 8 (Scheme
2).
Apart from a distinct selectivity profile, no decarbonylation
product was detected in the cyclisation of substrate 11 with
complex 9 not even when the reaction was performed at higher
temperatures (Table 2, entries 4–6) (Scheme 2).
The acetamide N-substituents normally play a crucial role in
determining the metallo-carbene intermediate conformation.2c
Therefore, to probe the influence of the diazo-acetamide structure
in the decarbonylation process, we performed the reaction with
the symmetrical diazo-acetamide 17 (Scheme 3). Differently from
what happens with substrate 1 bearing a bulky N-substituent, no
Table 1
Cyclisation of diazo-acetamide 1 using complexes 5–9
Entry
Catalyst
Conditions
2c
cis/
3c
cis/
4c
transd
transd
1a
2e
3e
4a
5a
6b
5
6
7
8
9
4 h
12 h
7 h
46 h
24 h
8 h 30 min
(Hexanes)
91 (81)
82 (66)
80 (76)
60 (56)
79 (66)
66 (64)
0.06/1
0.02/1
0.09/1
0.07/1
0.06/1
1/1
5
2.1/1
3.9/1
2.3/1
2.7/1
2.6/1
—
—
—
11 (10)
3 (3)
9 (7)
8 (7)
—
<2 (0)
25 (23)
9 (9)
—
h
m
a
Substrate 1 (0.3 mmol), 1,2-dichloroethane (0.1 M) and catalyst (1 mol %).
Substrate 1 (0.103 mmol), n-hexane (1 mL), UV lamp (mercury lamp Model
b
Hanau TQ150).
c
Observed conversion by 31P NMR, in parenthesis are given the isolated yields.
The cis/trans ratios were determined on the basis of the reaction crude mixture
d
31P NMR.
e
Substrate 1 (0.157 mmol), 1,2-dichoroethane (0.1 M) and catalyst (1 mol %).

7374
L. F. R. Gomes et al. / Tetrahedron Letters 49 (2008) 7372–7375
O
O
tBu
X
O
X
tBu
Ph
X
tBu
cat., 1 mol %
N
N
X
N
+
+
N
Ph
solvent, reflux
N2
Ph
tBu
Ph
14 X = CH3CO
15 X = PhSO2
10 X = CH3CO
11 X = PhSO2
12 X = CH3CO
13 X = PhSO2
16 X = CH3CO
Scheme 2. Cyclisation of diazo-acetamides 10 and 11 using complexes 8 and 9.
O
decarbonylation product was formed, and the c-lactam 18 was ob-
tained in a 93% yield, similarly to what occurs when using
(EtO)2OP
Rh2(OAc)4.7
N
Ph
In line with these results, the reaction was performed with
asymmetrical diazo-acetamides which typically afford b-lactams.
Substrate 19 afforded the lactam in 87% yield with high preference
for the cis stereoisomer (Scheme 4). The selectivity was slightly im-
proved when using complex 9 (comparing with the selectivity ob-
25
O
90% (80%)
(EtO)2OP
Ph
Ph
cat. 8, 1 mol %
N
C2H4Cl2
53 h reflux
+
N2
(EtO)2OP
Ph
O
tained with
5 (cis/trans 1/0.40)). The cyclisation of diazo-
26
7% (6%)
24
acetamide 21, which differs from 19 due to an extra methyl group
in the insertion centre, afforded the decarbonylation product in
51% yield. This surprising result clearly highlighted the influence
of the diazo-acetamide structure in the formation of this product.
The insertion centre nature was also evaluated using substrate
24 (Scheme 5). This diazo-acetamide may afford two regioisomers
via two different reaction mechanisms: the b-lactam via C–H inser-
N
Ph
Scheme 5. Cyclisation of diazo-acetamide 24 using complexes 8.
using catalyst 5 (the reaction performed in refluxing C2H4Cl2 affor-
ded a 83:12 ratio of 25:26).
tion and the
c-lactam via aromatic substitution. Interestingly, a
Differently from the NHC–Rh(II) catalysts prepared by Ardu-
engo, Snyder et al., complexes 8 and 9 appear to be stable under
our reaction conditions, and they were isolated from the crude
reaction mixtures of different reactions presented in this study. De-
spite this fact, it was impossible to determine the exact mass of
recovered catalyst due to product contamination, a problem we
were unable to overcome.
A likely explanation for the effect observed when using the
NHC–Rh(II) complex stems from the possibility of this complexes
to engage in an axial push–pull mechanism via the Rh–Rh bond,
this may influence the cyclisation process reducing the tendency
to suffer the diazo nucleophilic attack, though once established,
the diazo liberation may be favoured due to the NHC effect. At this
moment, the effect of the NHC over the metallo-carbene, is still un-
clear though it must be substantial because in our view the decarb-
onylation pathway must be a direct consequence of this axial
coordination. DFT calculation is currently being carried out in order
to understand this process.
slight increase in the selectivity was obtained with complex 8 com-
paring with the same reaction performed in chlorinated solvents
O
O
(EtO)2OP
(EtO)2OP
nBu
N
N
cat. 9, 1 mol %
N2
C2H4Cl2
Et
16 h reflux
17
18
0.07/1 (cis/trans) 93% (89%)
Scheme 3. Cyclisation of substrates 17 using complex 9.
(EtO)2OP
O
O
(EtO)2OP
tBu
Ph
cat. 9
, 1 mol %
C2H4Cl2
47 h, reflux
N
N
Ph
tBu
In summary, this study shows for the first time that axial-coor-
dination of NHC ligands onto dirhodium(II) complexes can have an
impact on the intramolecular reaction rate and selectivity. Most
importantly, a new reaction mode was discovered which leads to
a decarbonylation pathway. The formation of this product strongly
depends on the three most important aspects of the diazo-acetam-
N2
20
19
87 % (84 %)
cis/trans 1/0.22
(EtO)2OP
Me
O
ide structure: the
insertion centre.
a-substituent nature, the N-substituent and the
N
tBu
Ph
O
22
tBu
Ph
Acknowledgements
(EtO)2OP
23 % (17 %)
cat. 9
, 1 mol %
C2H4Cl2
25 h, reflux
N
cis/trans 0.63/1
N2
We thank Fundação para a Ciência e Tecnologia (POCI 2010) and
FEDER (POCI/QUI/60175/2004, POCI/QUI/58791/2004, PTDC/QUI/
66695/2006 and SFRH/BD/30619/2006) for the financial support.
+
21
tBu
(EtO)2OP
N
Ph
Supplementary data
Me
51 % (44 %)
23
Supplementary data (products full characterization and crude
mixture analysis using 31P NMR) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2008.10.054.
Scheme 4. Cyclisation of substrates 19 and 21.

L. F. R. Gomes et al. / Tetrahedron Letters 49 (2008) 7372–7375
7375
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