Formation of C(sp3)-C(sp3) Bonds by Palladium Catalyzed Cross-Coupling of α-Diazoketones and Allylboronic Acids

Article abstract of DOI:10.1021/acs.orglett.6b01132

Palladium catalyzed cross-coupling of allylboronic acids with α-diazoketones was studied. The reaction selectively affords the linear allylic product. The reaction proceeds with formation of a new C(sp³)-C(sp³) bond. The reaction was

Full text of DOI:10.1021/acs.orglett.6b01132

Letter
pubs.acs.org/OrgLett
Formation of C(sp3)−C(sp3) Bonds by Palladium Catalyzed Cross-
Coupling of α‑Diazoketones and Allylboronic Acids
Marie-Charlotte Belhomme, Dong Wang, and Kalman J. Szabo*
́
́
́
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-10691 Stockholm, Sweden
S
* Supporting Information
ABSTRACT: Palladium catalyzed cross-coupling of allylboronic
acids with α-diazoketones was studied. The reaction selectively
affords the linear allylic product. The reaction proceeds with
formation of a new C(sp3)−C(sp3) bond. The reaction was
performed without an external oxidant, likely without the Pd-catalyst
undergoing redox reactions.
llylboronates have found many important applications in
and Gong6 applied allylic chlorides (Scheme 1a) and terminal
A
selective carbon−carbon bond formation reactions.1 The
alkenes (Scheme 1b) as coupling components. These processes
required the use of an oxidant (benzoquinone) affording linear
butadiene products. Considering these5,6 (Scheme 1a−b) and
our recent results4d (Scheme 1c), it was appealing to study the
Pd-catalyzed reactions of α-diazocarbonyl compounds and
allylboronic acids (Scheme 1c). Indeed, we have found that α-
diazocarbonyl compounds and allylboronic acids underwent
Pd-catalyzed cross-coupling. Surprisingly, this cross-coupling
reaction did not require use of an oxidant and the reaction
occurred with formation of a new C(sp3)−C(sp3) bond (cf.
Scheme 1c with 1a−b). Furthermore, in contrast to the Cu-
catalyzed procedure4d the Pd-catalyzed process gave the linear
allylic product (Scheme 1c). Optimization of the reaction
conditions showed that Pd(0) catalysts are not efficient for
cross-coupling of α-diazoketone 1a and cinnamylboronic acid2i
2a (Table 1, entries 1−2). Pd(II) catalysts, such as Pd(TFA)2
and Pd(OAc)2, in CH2Cl2 gave promising yields (entries 3−5).
Variation of the solvent (entries 6−7) led to lower yields than
in the case of CH2Cl2. We have found that addition of catalytic
amounts (20 mol %) of CuI substantially improved the yield
(entry 8). However, other Cu-salts were not as efficient as CuI
(entries 9−12). Addition of tBuOH did not improve the yield
either (entry 13). Addition of PPh3, dppe, and 1,10-
phenanthroline (potential ligands to Pd) also led to lowering
of the yield. We have found that the yield can be slightly
improved (70%), when α-diazoketone 1a was added in two
portions (in 15 min) to the reaction mixture (entry 14).
When the reaction was conducted without a Pd-catalyst, we
did not observe formation of 3a (entry 15). Similarly to Cu-
catalyzed cross-coupling,4d product 3a did not form, when 2a
was replaced by its Bpin analog 4 (eq 1).
most important selective transformations involve allylboration
of carbonyl compounds2 and imines,3 but recently an increasing
number of metal-catalyzed cross-coupling reactions involving
allylboronates have also been appeared.4 A particularly
interesting feature is the regiochemistry of the cross-coupling.
The Pd-catalyzed cross-coupling of allyl boron compounds with
aryl halides inherently results in the branched allylic
product.4b,c,e,f However, the ligand effects and the applied
substrates can alter this regioselectivity affording a linear cross-
coupling product.4e,f Very recently, we reported4d a Cu-
catalyzed cross-coupling of allylboronic acids and α-diazoke-
tones, which also resulted in a branched allylic product
(Scheme 1c).
Scheme 1. Cross-Coupling of α-Diazocarbonyl Compounds
with Allyl Substrates by the Groups of Wang,5 Gong,6 and
Our Group4d
With the optimal conditions in hand, we studied the
synthetic scope of the reaction. All reactions are completed in
about 1 h under mild neutral conditions at rt selectively
affording the linear allylic product with a new C(sp3)−C(sp3)
Applications involving α-diazocarbonyl compounds with
organoboronates represent a very interesting concept for new
selective cross-coupling reactions. The typical organoboronate
components in previously reported examples of Pd-catalyzed
coupling reactions included aryl and vinyl boron species.7 Allyl
boron species have never been used in these types of
transformations. On the other hand, the groups of Wang5
Received: April 19, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01132
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Variation of the Reaction Conditions for Cross-
Coupling of Allylboronic Acid 2a with α-Diazoketone 1a
Table 2. Palladium Catalyzed Cross-Coupling of
Allylboronic Acids with α-Diazoketones
a
a
b
entry
Pd catalyst
solvent
additive
yield (%)
c
1
Pd(PPh3)4
Pd(dba)2
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
−
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
−
−
−
−
−
−
−
Cul
0
21
36
44
51
18
6
c
2
c
3
c
4
5
6
7
8
60
0
9
Cul·Me2S
CuOAc
CuBr
CuCl
tBuOH
Cul
10
11
12
0
50
41
47
70
0
d
13
e
l4
15
Cul
a
Unless otherwise stated a mixture of 1a (0.12 mmol), 2a (0.10
mmol), Pd catalyst (10 mol %), and the additive (20 mol %) in
b
c
CH2Cl2 (0.5 mL) was stirred for 1 h at rt. Isolated yield. 1a (0.10
mmol), 2a (0.12 mmol), and Pd catalyst (10 mol %) were used. The
reaction was performed with 10 equiv of tBuOH. 1a was added in two
d
e
portions.
bond. The aromatic substituents of the α-diazoketone
component had a relatively weak effect. α-Diazoketones with
electron-withdrawing substituents (such as 1c−e) reacted
readily (Table 2, entries 2−6). In some cases, as for example
for 1b with a methoxy substituent (entry 2) and 1f with a nitro
group, an excess of α-diazoketone substrate was employed to
improve the yield.
On the other hand 1g with a naphthyl group reacted similarly
to 1a affording 3g in 64% yield. The coupling of 2a with 1a−g
gave a single diastereomer. Not only cinnamylboronic acid 2a
but also alkyl substituted allyl boronic acids 2b−2d also proved
to be useful cross-coupling partners (entries 8−15). In the case
of monosubstituted allylboronic acid 2b, the E/Z ratio of the
product varied between 6.0 and 9.0 to 1.
When γ-disubstituted boronic acids, such as geranyl (2c) and
neryl (2d) boronic acids, were used the E/Z ratio was poor
(1.6−0.9 to 1) indicating that substantial isomerization of the
allylic E and Z double bond occurs (entries 13−14). We tried
to improve the E/Z ratio by conducting the reaction at low
temperature (0 °C and −20 °C) or by dilution of the reaction
mixture. However, these attempts remained fruitless. In these
reactions (entries 8−14) we observed a formation of traces
(<5%) of the branched allylic product as well. We were able to
perform cross-coupling of aliphatic α-diazoketone 1h with 2a
affording 3n (entry 15). Disubstituted α-diazoketone 1i was
also reacted readily giving a linear allylic product 3o (entry 16).
Probably the most interesting feature of the cross-coupling
reaction of α-diazoketones and allylboronic acids is the
opposite regioselectivity in Cu- and Pd-catalyzed reactions
(Scheme 1c). A decrease in the diastereoselectivity for the
a
Unless otherwise stated a mixture of 1 (0.12 mmol, added in two
portions), 2 (0.10 mmol), Pd(OAc)2 (10 mol %), and CuI (20 mol %)
b
c
in CH2Cl2 (0.5 mL) were stirred at rt for 1 h. Isolated yields. The
reaction was performed with 0.15 mmol of 1. The reaction was
performed with 0.20 mmol of 1. The product contains less than 5% of
the branched product. The reaction was performed without CuI, and
d
e
f
g
1 mL of CH2Cl2 was used. 2 mL of CH2Cl2 were used.
aliphatic (2b−d), especially using the disubstituted allyl boronic
acids 2c−d, suggests formation of η3-allylpalladium complexes,
which may undergo η3-η1-η3 isomerization.8 Thus, a conceiv-
able initial step of the reaction is transmetalation of the
allylboronic acid component with the Pd(II) catalyst to give η3-
allylpalladium complex 5. In order to test this hypothesis, we
prepared complex 5 and reacted it with α-diazoketone 1a in the
presence and in the absence of CuI. We could not observe
B
DOI: 10.1021/acs.orglett.6b01132
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
formation of 3a in any of these reactions (eq 2). This clearly
indicates that 5 is not a kinetically competent intermediate of
would also explain the regioselective formation of the linear
allylic product 3. Migratory insertion of vinyl and aryl groups to
Pd-carbene was previously suggested by the groups of Van
Vranken,12 Barluenga,13 and Wang.7c,d The last step of the
reaction is probably formation of Pd-enolate 10 via oxa-η3-
intermediate 9.14 By a rapid 8 → 10 tautomerization, the β-
hydride elimination in 8 can be avoided, and therefore
formation of a diene product, such as in the reaction of α-
diazocarbonyl compounds with allylic chlorides5 or alkenes6
(Scheme 1a−b), can be avoided. The Pd(II) catalyst is
recovered by formation of product 3 and boric acid from 10.
Water necessary for this process was probably formed by
dehydration of B(OH)n (n = 2, 3) species by formation of
boroxines.2i A very interesting feature of the above-mentioned
reaction is that palladium does not undergo redox reactions but
it is kept in oxidation state +2. Therefore, we did not need to
use oxidants (such as BQ), as in the analogous allylation
reactions of α-diazocarbonyl compounds (Schemes 1a−b).
In summary we have shown that Pd-catalyzed cross-coupling
of α-diazoketones and allylboronic acids can be performed. The
reaction selectively provides a linear allylic product. Thus, the
presented Pd-catalyzed coupling and the previously reported
Cu-catalyzed reaction have the opposite regiopreference. The
reaction was performed without using oxidants. The Pd-catalyst
probably preserves its oxidation state during the entire reaction.
The presented process widens the synthetic scope of the
transition metal catalyzed cross-coupling reactions,15 which are
suitable for formation of C(sp3)−C(sp3) bonds.
the Pd-catalyzed cross-coupling reaction of α-diazoketones
(such as 1a) and allylboronic acids (such 2a). This is a very
surprising finding in view of the fact that Wang5 and Gong6
have shown that the reaction of α-diazocarbonyl compounds
with allyl chlorides5 and alkenes6 do proceed via η3-allyl
palladium complexes, such as 5.
Considering the above-mentioned results (including eq 2),
we propose a catalytic cycle initiated by formation of Pd-
carbenoid 6 from 1 and Pd(OAc)2 (Figure 1). A similar type of
Pd-carbenoid formation has been reported in the literature9 and
was invoked7a,b in many Pd-catalyzed transformations of α-
diazocarbonyl compounds.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01132.
Detailed experimental procedures and compound char-
acterization data (PDF)
Figure 1. Proposed catalytic cycle for the cross-coupling of allyl-
boronic acids with α-diazoketones.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: kalman@organ.su.se.
Notes
Subsequently, Pd-carbenoid 6 may undergo transmetalation
with allylboronic acid 2 affording η3-allylpalladium carbenoid
complex 7. As mentioned above (Table 1, entries 8), addition
of CuI improved the yield of the reaction. A possible
explanation is that the Cu-salt facilitates the transmetalation10
of allylboronic acid 2 with the palladium atom of 6. In this
process CuI was more efficient than CuCl and CuBr (Table 1,
entries 11−12), possibly because of the better solubility in the
reaction media. Formation of η3-allylpalladium carbenoid
complexes, such as 7, has been suggested in the coupling of
α-diazocarbonyl compounds with allylic substrates.5,6 Complex
7 may undergo η3-η1-η3 isomerization. An indication of the η3-
η1-η3 isomerization is the formation of the E/Z isomers of 3m
using geranyl 2c and neryl boronic acids 2d in the cross-
coupling with 1a (Table 2, entries 13−14). The η3-η1-η3
isomerization involves formation of various syn−anti isomers
of the η3-allylpalladium complexes.8,11 The final E/Z ratio is
mainly determined by the steric effects of the substituents.8,11
The η1-form of 7 with the least substituted allylic terminus is
probably more stable than the other η1-allylic isomer. The η1-
allyl group may undergo migratory insertion into the Pd-
carbene to give 8. Formation of η1-alkylpalladium complex 8
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the financial support of the Swedish
Research Council (VR) and the Knut och Alice Wallenbergs
Foundation.
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