Conformational analysis and stereochemical assignments of products derived from C-H activation at secondary sites

Article abstract of DOI:10.1016/S0040-4039(01)00385-9

The products derived from C-H activation of secondary sites by rhodium-carbenoids exist in a well-defined conformation. Consequently, their stereochemical assignment can be readily determined on the basis of chemical shift arguments.

Full text of DOI:10.1016/S0040-4039(01)00385-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3149–3151
Conformational analysis and stereochemical assignments of
products derived from CꢀH activation at secondary sites
Huw M. L. Davies* and Pingda Ren
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260-3000, USA
Received 31 January 2001; revised 27 February 2001; accepted 6 March 2001
Abstract—The products derived from CꢀH activation of secondary sites by rhodium–carbenoids exist in a well-defined
conformation. Consequently, their stereochemical assignment can be readily determined on the basis of chemical shift arguments.
© 2001 Elsevier Science Ltd. All rights reserved.
CꢀH activation by means of metal carbenoid induced
CꢀH insertion has great synthetic potential.1 It has
recently been established that Rh2(S-DOSP)4 catalysed
decomposition of aryldiazoacetates 1 results in highly
enantioselective intermolecular CꢀH activation on a
range of substrates as illustrated in Eq. (1).2,3 One of
the major challenges associated with this work has been
the assignment of relative stereochemistry of the CꢀH
activation products, 2 and 3. In this paper, we describe
these CꢀH activation products preferentially exist in a
well-defined conformation, and their relative configura-
tion is readily determined from their distinctive proton
NMR chemical shift data.
In our initial studies on the intermolecular CꢀH activa-
tion, the relative configuration of the products was
determined by X-ray crystallography or by conversion
to compounds of known relative configuration.2a–h
Having now prepared a variety of different compounds,
we find that all the compounds exist in a well-defined
conformation, and that the stereochemistry can be
assigned from the distinctive proton NMR chemical
shift differences between the two diastereomers. Our
recent study on the reaction of p-bromophenyldiazo-
acetate 4 with dihydronaphthalene 5 illustrates this
point (Eq. (2)).2h Two diastereomers, 6 and 7, were
formed in this reaction and the configuration of the
O
Rh
Rh
N
O
R1
SO2Ar
R1
R1
N2
4
+
CO2Me
CO2Me
R2
R2
+
R2
Ar
CO2Me
p-C12H25C6H4
Ar =
Rh2(S-DOSP)4
(1)
Ar
Ar
1
2
3
R1 = alkyl, alkenyl, Osilyl, NBOC
R2 = alkyl, alkenyl
N2
OTIPS
OTIPS
OTIPS
5.17 δ
5.25 δ
4.57 δ
H
H
H
p-BrC6H4
CO2Me
4
(shielded)
2
+
2'
CO2Me
CO2Me
Rh2(S-DOSP)4
CH2
2.75 δ
CH2
CH2
(2)
H
H
H
H
C6H4(p-Br)
C H (p-Br)
6 4
2.72, 2.22 δ
(shielded)
3.01, 2.64 δ
J = 11.0 Hz
J = 11.3 Hz
5
6
7
* Corresponding author. E-mail: hdavies@acsu.buffalo.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00385-9

3150
H. M. L. Da6ies, P. Ren / Tetrahedron Letters 42 (2001) 3149–3151
major diastereomer 6 was unambiguously determined
by X-ray crystallography. Both diastereomers, however,
have a large JH2%–H2 (ꢀ11 Hz), which indicates that for
both compounds the H2%–H2 protons preferentially
exist in an antiperiplanar conformation. Furthermore,
the proton NMR signals for the vinyl hydrogen in 6
and the methylene group in 7 are significantly shielded.
This shielding effect can be rationalised as illustrated in
Fig. 1. If the compounds preferentially exist in the
antiperiplanar arrangement then the phenyl ring lies
over the vinyl proton in 6 and the methylene site in 7.
the case of 10,2f 12,2d 15,2d and 18,2f the relative
configuration has been unambiguously assigned on the
basis of X-ray crystallography or by correlation to
compounds of known stereochemistry. The same shield-
ing effect extends to saturated and unsaturated cyclic
systems. Even acyclic systems, 18 and 19, exhibit the
same shielding behaviour. In all cases, the coupling
constant between the two hydrogens at the newly
formed stereogenic centres is large (8–11 Hz), indicative
of a strong preference for these hydrogens to exist in an
antiperiplanar arrangement. Early conformational analy-
sis on tetrasubstituted ethanes has shown that steric
effects cause the antiperiplanar arrangement to be the
favoured conformation.4 The conformational analysis
A similar shielding effect is apparent in a wide variety
of CꢀH activation products as illustrated in Table 1. In
shielded
region
shielded
region
H
H
H2C
H
CH2
H
MeO2C
MeO2C
H
H
Br
Br
antiperiplanar conformation of 6
antiperiplanar conformation of 7
Figure 1. Newman projections of 6 and 7.
Table 1. Proton NMR data (CDCl3, rt) of selected CꢀH activation substrates and products
C-H Activation products
Substrate
∆ δ
2.14, 1.69 δ
1.69, 1.47 δ
+0.45, +0.22
1.85 δ
CO2Me
CO2Me
O
O
O
H
H
H
2-naphthyl
2-naphthyl
H
10
8
9
J = 10.1 Hz
J = 8.3 Hz
+0.55, +0.28
1.80, 1.24 δ
CO2Me
1.25, 0.96 δ
CO2Me
Ph
J = 10.2 Hz
1.53 δ
N
H
N
N
H
H
H
H
H
H
Ph
13
12
11
J = 10.3 Hz
5.70 δ
H
5.20 δ
CO2Me
Ph
H
+0.50
H
5.78 δ
CO2Me
N
H
N
H
N
H
H
H
H
H
Ph
16
15
14
J = 10.5 Hz
J = 10.5 Hz
1.15 δ
0.82 δ
1.11 δ
+0.29
-0.33
CH2
CH2
CH2
H
CO2Me
C6H4(p-Br)
J = 10.7 Hz
H3C
H3C
0.87 δ
CO2Me
H3C
H
0.96 δ
H
0.63 δ
H
C6H4(p-Br)
18
19
17
J = 10.7 Hz

H. M. L. Da6ies, P. Ren / Tetrahedron Letters 42 (2001) 3149–3151
3151
H
5.27 δ
5.03 δ
H
1
1
2' CO2Me
2' CO2Me
H
H
5.40 δ
H
H
5.67 δ
H
H
Ph
Ph
20
21
J = 10.3Hz
N2
J = 10.3Hz
OTIPS
Me
OTIPS
Me
OTIPS
1.67 δ
1.07 δ
1.62 δ
Me
p-BrC6H4
CO2Me
4
+
CO2Me
CO2Me
CH2
CH2
Rh2(S-DOSP)4
CH2
22
H
H
H
H
C6H4(p-Br)
C6H4(p-Br)
1.79, 1.58 δ
1.36, 1.10 δ
J = 10.0 Hz
23
J = 9.8 Hz
24
Acknowledgements
of certain compounds in this group such as ritalin (12)
has been extensively studied, and this work has shown
that 12 exists in an antiperiplanar conformation in
solution.5 The effect of this alignment, however, on the
chemical shift has not been discussed previously.
This work was supported by grants from the National
Science Foundation (CHE 0092490) and the National
Institutes of Health (GM57425).
The CꢀH activation products 202b and 212e derived
from reaction with 1,4-cyclohexadiene and 1,3,5-cyclo-
heptatriene, respectively, display a similar shielding
effect. The proton NMR signals for the two adjacent
vinyl protons have a considerable difference in chemical
shift. The large JH1–H2% (10–12 Hz) is again indicative of
the antiperiplanar conformation and this would cause
the observed shielding.
References
1. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Cata-
lytic Methods for Organic Synthesis with Diazo Com-
pounds; Wiley-Interscience: New York, 1998; pp.
112–162.
2. (a) Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc.
1997, 119, 9075; (b) Davies, H. M. L.; Stafford, D. G.;
Hansen, T. Org. Lett. 1999, 1, 233; (c) Davies, H. M.
L.; Antoulinakis, E. G.; Hansen, T. Org. Lett. 1999, 1,
383; (d) Davies, H. M. L.; Hansen, T.; Hopper, D.;
Panaro, S. A. J. Am. Chem. Soc. 1999, 121, 6509; (e)
Davies, H. M. L.; Stafford, D. G.; Hansen, T.;
Churchill, M. R.; Keil, K. M. Tetrahedron Lett. 2000,
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An example of how this distinctive shielding effect can
be used to determine the relative stereochemistry of new
compounds from the CꢀH activation reaction is illus-
trated in Eq. (3).2h The CꢀH activation product 23 is
formed with moderate diastereocontrol. The JH1–H2%
(ꢀ10 Hz) is large for both diastereomers, and in the
proton NMR of the major diastereomer 23, the methyl
group is shielded while the methylene group is not. The
opposite is seen for the minor diastereomer 24. On the
basis of this information, the relative stereochemistry
can be assigned as drawn for 23 and 24 with reasonable
confidence.
In conclusion, the stereochemical assignment of the
products derived from CꢀH activation at secondary
sites can be readily determined on the basis of chemical
shift arguments. All such compounds preferentially
exist in an antiperiplanar conformation leading to pre-
dictable effects on proton NMR chemical shifts. The
general trends in chemical shifts described herein will be
extremely useful for the assignment of relative configu-
ration for CꢀH activation products and related systems.
3. For a general review, see: Davies, H. M. L.; Antouli-
nakis, E. G. J. Organomet. Chem. 2001, 517, 45.
4. Ru¨chardt, C.; Beckhaus, H.-D. Angew. Chem., Int. Ed.
Engl. 1980, 19, 429.
5. (a) Glaser, R.; Adin, I.; Shiftan, D.; Shi, Q.; Deutsch,
H. M.; George, C.; Wu, K.-M.; Froimowitz, M. J. Org.
Chem. 1998, 63, 1785; (b) Deutsch, H. M.; Shi, Q.;
Kowalik, E. G.; Schweri, M. M. J. Med. Chem. 1996,
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