Rhodium(II)-catalyzed cross-coupling of diazo compounds

Article abstract of DOI:10.1002/anie.201004923

Nothing left to chance: A convenient protocol for selective cross-coupling of diazo compounds for the convergent synthesis of alkenes was developed (see scheme; EDG=aryl, heteroaryl, vinyl; R=O-alkyl, aryl). The selectivity control elements were identifie

Full text of DOI:10.1002/anie.201004923

Communications
DOI: 10.1002/anie.201004923
Diazo Cross-Coupling
Rhodium(II)-Catalyzed Cross-Coupling of Diazo Compounds**
Jørn H. Hansen, Brendan T. Parr, Philip Pelphrey, Quihui Jin, Jochen Autschbach, and
Huw M. L. Davies*
The convergent synthesis of alkenes occupies a central
position as strategic reaction in organic synthesis
procedures for intermolecular reactions were available. The
cross-coupling of diazo carbonyl compounds with trimethyl-
silyldiazomethane has been demonstrated to be a viable
process.[4b,c] In contrast, a selective cross-coupling of two
diazocarbonyl compounds to form alkenes has, to our knowl-
edge, not been reported prior to this study. In recent years, we
have explored the broad synthetic potential of donor/
acceptor-substituted rhodium carbenoids.[8] These carbenoids
are more stabilized than conventional carbenoids lacking a
donor group and have a low tendency to undergo homodi-
merization, which has made them useful intermediates in a
range of synthetic transformations.[8d,e,9] Here, we describe
that these carbenoids can undergo selective cross-coupling
with diazocarbonyl compounds lacking a donor group.[5]
Mechanistic studies to determine the factors that control
selectivity in the dimerization chemistry will also be de-
scribed.
a
(Scheme 1). The Wittig reaction and its many variants are
often used as key transformations in retrosynthetic analysis.[1]
In recent years, olefin metathesis has become a dominant
synthetic approach for the convergent synthesis of alkenes.[2]
Here we describe an alternative convergent method for the
synthesis of unsymmetrical alkenes by a carbenoid-induced
cross-coupling of diazo compounds.
À
During studies on intermolecular C H functionalization,
using two diazo compounds in the reaction mixture, it was
discovered that the cross-coupling of methyl phenyldiazoa-
cetate (1a) and ethyl diazoacetate (2) is a favorable process.
This reaction was studied further in experiments that involved
adding an equimolar mixture of the diazo compounds rapidly
to a solution of a RhII catalyst (Table 1). The reaction affords
predominantly a mixture of cross-coupling product 3a and
ethyl diazoacetate homodimerization product 4. In order to
find reaction conditions that would minimize homodimeriza-
tion, and maximize the stereoselectivity of the heterodimer,
several conditions were screened. Under the optimal con-
ditions, synthetically useful selectivities could be achieved
Scheme 1. Olefin formation.
Since the pioneering work of Grundmann,[3] only a few
synthetically useful processes have been reported using
carbenoid-induced coupling of diazo compounds.[4,5] Typi-
cally, the process is considered to be an undesired side-
reaction, and the homocoupling of ethyl diazoacetate has
been an especially vexing problem.[4,6] In many instances, it
can only be avoided by very slow addition of the diazo
compound to the reaction mixture.[6] The most useful
synthetic applications to date have been intramolecular and
transannular reactions of bis-diazocarbonyl compounds.[7]
The diazo coupling would be of much greater synthetic
utility for the convergent synthesis of alkenes if practical
Table 1: Optimization of cross-coupling conditions.
[*] J. H. Hansen, B. T. Parr, Prof. H. M. L. Davies
Department of Chemistry, Emory University
1515 Dickey Drive, Atlanta GA 30322 (USA)
E-mail: hmdavie@emory.edu
Entry
Catalyst[a]
Solvent
T [8C]
Ratio[b]
3a:4
E:Z
3a[a]
1
2
3
4
5
6
7
8
9
[Rh2(OPiv)4]
[Rh2(OPiv)4]
[Rh2(OOct)4]
[Rh2(esp)2]
[Rh2(tpa)4]
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhCF3
Et2O
RT
63:37
91:9
9.5:1
Homepage: http://chemistry.emory.edu/faculty/davies/
Home.html
À63
À63
À63
À63
À63
À63
À63
À63
>20:1
6.9:1
12:1
79:22
77:16
64:36
75:25
87:13
72:28
75:26
Dr. P. Pelphrey, Dr. Q. Jin, Dr. J. Autschbach
Department of Chemistry, University at Buffalo
The State University of New York, Buffalo, NY 14260 (USA)
20:1
[Rh2(tfa)4]
7.3:1
>20:1
13:1
[Rh2(OPiv)4]
[Rh2(OPiv)4]
[Rh2(OPiv)4]
[**] Support by the NSF (CHE 0750273 for H.M.L.D., CHE 952253 for
J.A.) is gratefully acknowledged. P.P. was supported by a NIH Ruth
L. Kirchstein postdoctoral fellowship. We also wish to acknowledge
The University at Buffalo Center for Computational Research.
n-Hex
18:1
[a] Piv=pivaloyl;
esp=a,a,a’,a’-tetramethyl-1,3-benzenedipropionic
acid; tpa=triphenylacetate; tfa=trifluoroacetate. [b] From 1H NMR
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004923.
analysis of crude residue.
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Table 3: Cross-coupling between vinyldiazoacetates and ethyl diazoace-
tate.
(91:9 product selectivity, > 20:1 stereoselectvity favoring (E)-
3a) using dichloromethane as solvent at low temperatures
with dirhodium(II) tetrakispivaloate, [Rh2(OPiv)4], as cata-
lyst (Table 1, Entry 2).
The cross-coupling reaction between aryldiazoesters and 2
was then examined using the optimized reaction conditions
(Table 2). For a series of p-substituted aryldiazoacetates, good
yields (67–73%) and excellent stereoselection towards the E-
Entry
Compd.
Ar=
E:Z[a]
Yield
[%][b]
1
2
3
a
b
c
Ph
5.6:1
5.5:1
5.1:1
82
67
61
p-MeOC6H4
p-BrC6H4
Table 2: Cross-Coupling of aryldiazo compounds with ethyl diazoace-
tate.
4
d
5.1:1
61
[a] From 1H NMR analysis of crude residue. [b] Combined yields.
Entry
Compd.
Ar
EWG
E:Z[a]
Yield
[%][b]
The next series of experiments explored methods to
enhance the stereoselectivity of the cross-coupling process.
By increasing the bulkiness of the unsubstituted diazo
compound, significantly more selective reactions could be
achieved. The reaction between tert-butyl diazoacetate 7a
and 1a produced the E-alkene 8a in 87% yield (Table 4,
1
2
3
4
5
a
b
c
d
e
Ph
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
>20:1
>20:1
>20:1
5.1:1
71
73
p-MeOC6H4
p-BrC6H4
p-CF3C6H4
2-Naphthyl
67
40[c]
58
>20:1
6
f
CO2Me
>20:1
83
Table 4: Cross-coupling of 1a with 7a and diazoketones 7b–e.
7
8
9
g
h
i
Ph
Ph
Ph
CN
COMe
PO(OMe)2
3.3:1
2.0:1
N/A
86[d]
71[d]
N/R
[a] From 1H NMR analysis of crude residue. [b] Yields of isolated
products. [c] 20–30% of homocoupled products were also formed.
[d] Combined yield.
Entry
1
Compd.
R=
E:Z[a]
Yield
[%][b]
a
>20:1
87
2
3
4
5
b
c
d
e
Ph
>20:1
>20:1
>20:1
>20:1
87
80
79
87
p-MeOC6H4
p-BrC6H4
(3,4-Cl2)C6H3
isomer (E:Z ratio > 20:1) was observed, unless the aryl
substituent was very electron-withdrawing. In the case of p-
trifluoromethyl substitution (1d), the isolated yield of 3d was
only 40% and the E:Z-selectivity declined substantially (E:Z
ratio 5.1:1). The best result was obtained with benzofuranyl
diazoacetate 1 f, which afforded the E-alkene 3 f in 83% yield,
again with very good stereoselectivity. The influence of the
acceptor group on the aryldiazoacetate was also investigated
(Table 2, Entries 7–9), and although good overall reaction
yields were obtained (71–86%), the stereoselectivity was
significantly attenuated when this group was cyano or methyl
ketone. The dimethyl phosphonate-substituted compound
gave no cross-coupling product, presumably because the
diazo compound is too stable under the reaction conditions.[8c]
These studies demonstrate that aryldiazoacetates with elec-
tron-neutral or electron-releasing substituents are optimal for
achieving high chemo- and stereoselectivities.
The cross-coupling of vinyldiazoacetates with 2 would
form substituted dienes, a feature that would add significant
value to the products. Indeed, the reaction between methyl
styryldiazoacetate 5a and 2 gave diene 6a in 82% yield,
however with attenuated stereoselectivity (E:Z ratio 5.6:1).
Moderate to good overall yields (61–82%) can be obtained
with a variety of vinyldiazoacetates 5a–d, but with only
moderate stereoselectivity across the board (Table 3).
[a] From 1H NMR analysis of crude residue. [b] Yields of isolated
products.
Entry 1). Aryldiazoketones proved to give good coupling
reactions, and produced the E-alkenes 8b–e in > 20:1 and in
79–87% yields.
The cross-coupling of the diazo compounds is favored
over the homocoupling process. A possible explanation for
this would be that one of the diazo compounds is decomposed
faster than the other, and then preferentially reacts with the
other diazo compound.[4d,8e] In order to shed light on what
factors control the cross-coupling process, the reaction
progress was monitored using ReactIR. The first round of
experiments explored the conversion rates of decomposition
of the two diazo compounds in the presence of an external
trap, styrene (6 equiv). An aliquot of catalyst (0.1 mol%) was
added to a solution of diazo compound at À158C and trap,
generating cyclopropane products (Figure 1). The reactions
=
were monitored by the disappearance of the C N2 stretch
bands (2088 cmÀ1 for 1a and 2114 cmÀ1 for 2). These studies
showed that methyl phenyldiazoacetate 1a reacted faster
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2545

Communications
consistent with the formation of predominantly cross-dimer
and some homodimer of 2.
We next carried out density functional calculations to
obtain an understanding of the stereoselection in the dime-
rization events. As a model for this we used the reaction
between methyl phenyldiazoacetate (1a) and methyl diazo-
acetate (12) with dirhodium formate (9) as a catalyst. These
carbenoid systems have been studied previously in cyclo-
[12,13]
propanation[11] and C H insertion reactions.
The main
À
discussion here is based on free energies and enthalpies
calculated at the B3LYP/6-31G*[Rh-RSC+4f] level of
theory.[13]
Transition structures were sought for reaction between the
carbenoid complex 11, derived from 1a, and 12. The most
stable of these transition states, TS-IIb, is shown in Figure 3a.
Figure 1. Reactions of 1a (red data) and 2 (blue data) at À158C in the
presence of styrene.
than ethyl diazoacetate 2, which is consistent with related
studies.[8e]
The second series of experiments determined the relative
rates of decomposition of ethyl diazoacetate (2) alone
(Figure 2, gray data), and an equimolar mixture of ethyl
Figure 3. a) Most stable transition state TS-IIb. b) Dimerization stereo-
selectivity from three lowest-energy transition structures. Gas-phase
enthalpies and Gibbs free energies reported relative to 11+12.
Figure 2. Decomposition of a mixture of 1a (red data) and 2 (blue
data) at 08C, and decomposition of 2 only (grey data) at 08C.
The three most stable structures TS-IIa–c are shown in
Figure 3b (see Supporting Information for more details),
including enthalpies and Gibbs energies relative to free
reactants (carbenoid 11 + 12). The structures are represented
by Newman projections, analogous to models previously
presented by Nagai,[14] Wulfman,[15] and Shechter[16] in homo-
dimerization chemistry.
diazoacetate (2, blue data) and methyl phenyldiazoacetate
(1a, red data). In the absence of styrene, the reactions are
much faster, which may be an indication that the styrene has a
poisoning effect on the catalyst. The cross-coupling reaction is
especially fast. All of 2 is consumed within ca. 7 s, while about
30% of 1a is retained. The consumption of 2 is ca. 1.5-times
faster than that of 1a. Once 2 is consumed, the decomposition
of 1a is significantly slowed down (by a factor of ca. 300),
presumably because the homocoupling of the donor/acceptor
carbenoid is not a favorable process.[8d] The initial rate of
conversion of 2 in the mixture is about 7-times faster than the
homocoupling of 2 by itself. Furthermore, the latter reaction
does not go to completion as poisoning of the catalyst is a
problem with this diazo compound at 0.1 mol% catalyst
loading.[8e] An explanation for the observed trends would be
that 1a is converted to the carbenoid faster than 2, but both
carbenoids, if formed, react quickly with 2 to form dimers. In
the mixture, 2 decomposes faster than 1a because some of it is
consumed in a homodimerization process. These results are
Stereoselection is indirectly governed by the stereoelec-
tronic requirement that the elimination must occur with the
À
À
Rh C and C N bonds arranged in a periplanar conforma-
tion.[16] Whether this affords the E- or Z-product, depends on
the preferred transition state for addition to the carbenoid.
The preference for TS-IIb is related to the steric influence of
the carbenoid on the three substituents on 12. The largest
substituent of 12 (methyl ester), prefers to be oriented anti to
the catalyst “wall”, the diazonium moiety (medium bulk)
towards the lower right quadrant, and hydrogen (small)
oriented towards the most sterically crowded sector (between
the carbenoid ester group and catalyst). The forward intrinsic
reaction coordinate drive from TS-IIb leads to formation of
an ylide 13b, which is kinetically unstable. Clockwise rotation
of the front of this ylide gives a syn-elimination to form the
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observed major E-product. The counter-clockwise rotation to
give anti-elimination and Z-product is disfavored since the
system must pass through an eclipsed conformation for this to
happen. TS-IIIb for the conversion of 13b to (E)-15 could not
insights into factors controlling stereo- and chemoselectivity
in the dimerization events have been identified.
be located computationally, presumably due to the flat nature Experimental Section
General procedure for cross-coupling: To a flame-dried, 50 mL
of the potential energy surface in this region. However, a
coordinate scan towards the product side indicated that a
small barrier may exist (< 0.5 kcalmolÀ1). For comparison,
rotation of ylide 13b to give anti-elimination (Z-alkene
formation), has a barrier of DG° = 7.7 kcalmolÀ1. Transition
states TS-IIa–c were next optimized at the B3LYP/6-311 +
G(d,p)[Rh-RSC+4f] level of theory, with included solvent
effects from dichloromethane (IEFPCM model)[17] at À788C.
A simple Eyring analysis, based on the re-optimized struc-
tures TS-IIb and TS-IIc, gives a predicted diastereomer ratio
of 19:1. These results are in very good agreement with
experimental observations (Table 1 shows E:Z ratios in the
range 6.9–22:1), particularly considering potential errors in
DFT calculations.[18] The mechanistic model is consistent with
an increase in stereoselectivity with increasing steric bulk of
the unsubstituted diazo compound (tert-butyl ester group or
diazoketone) as it would favor the preferred trajectory even
more.
round-bottom flask, equipped with a magnetic stir bar, a rubber
septum, and an argon inlet adaptor was added dirhodium(II)
tetrakispivaloate (0.01 equiv). The flask was evacuated and purged
with argon three times before placing it under a positive Ar
atmosphere. Dry and degassed CH2Cl2 (5.0 mL) was added by
syringe and the reaction flask was cooled to À788C in an acetone/
CO2 bath.
A mixed, equimolar solution of diazo compounds
(1.0 mmol each, 1.0 equiv each) was prepared by combining the
appropriate diazo compounds in CH2Cl2 (5.0 mL). This solution was
then added to the cooled reaction mixture over 1 h through a syringe
pump. Following addition, the reaction flask was slowly allowed to
obtain ambient temperature. The solvent was removed in vacuo and
the crude material was purified by column chromatography.
Received: August 6, 2010
Revised: October 6, 2010
Published online: February 14, 2011
Keywords: alkenes · carbenoids · cross-coupling reactions ·
.
diazo compounds
We propose a catalytic cycle for the dimerization process
as shown in Scheme 2. The results of the calculations, in
conjunction with the ReactIR studies, suggest that productive
cross-coupling occurs through reaction between the donor/
acceptor-substituted carbenoid and the unsubstituted diazo
compound.
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Scheme 2. Proposed coupling mechanism.
In summary, we have described a convergent process for
the selective cross-coupling of diazo compounds to afford
trisubstituted alkenes in synthetically useful yields. Produc-
tive cross-dimerization appears to rely on: 1) a significant
decomposition rate difference between the two diazo com-
pounds and, 2) a preference for trapping of the initial
carbenoid with the other diazo compound. The study
represents significant progress towards synthetic utilization
of diazo coupling reactions in alkene synthesis, since valuable
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