Synthesis of Aryldiazoacetates through Palladium(0)-Catalyzed Deacylative Cross-Coupling of Aryl Iodides with Acyldiazoacetates

Article abstract of DOI:10.1002/anie.201407653

Palladium(0)-catalyzed deacylative cross-coupling of aryl iodides and acyldiazocarbonyl compounds can be achieved at room temperature under mild reaction conditions. The coupling reaction represents a highly efficient and general method for the synthesis of aryldiazocarbonyl compounds, which have found wide and increasing applications as precursors for generating donor/acceptor-substituted metallocarbenes.

Full text of DOI:10.1002/anie.201407653

Angewandte
Chemie
DOI: 10.1002/anie.201407653
Synthetic Methods
Synthesis of Aryldiazoacetates through Palladium(0)-Catalyzed
Deacylative Cross-Coupling of Aryl Iodides with Acyldiazoacetates**
Fei Ye, Chengpeng Wang, Yan Zhang, and Jianbo Wang*
Abstract: Palladium(0)-catalyzed deacylative cross-coupling
of aryl iodides and acyldiazocarbonyl compounds can be
achieved at room temperature under mild reaction conditions.
The coupling reaction represents a highly efficient and general
method for the synthesis of aryldiazocarbonyl compounds,
which have found wide and increasing applications as
precursors for generating donor/acceptor-substituted metal-
locarbenes.
2) The yield of diazo transfer may be drastically affected by
the azide, the base, and the solvent depending on the
electronic nature of the aryl substituents.[6] In view of the
importance of aryldiazoacetates and the drawbacks of the
existing method, the development of alternative general
methods to synthesize aryldiazoacetates and related diazo
compounds is highly desirable.
We have previously reported palladium(0)-catalyzed
cross-coupling of aryl iodides with ethyl diazoacetate
(EDA).[7,8] The reaction represents a straightforward syn-
thesis of aryldiazoacetates. However, the protocol we
reported previously is less efficient in that a high loading of
the palladium(0) catalyst and excess amount of EDA are
required. Moreover, the substrate scope is limited. As a result,
the reaction is not practically useful as a synthetic method for
aryldiazoacetates. Herein we report a deacylative cross-
coupling of aryliodides with acyldiazoacetates for the syn-
thesis of aryldiazoacetates (Scheme 1). The deacylative
approach is highly efficient and can be carried out at room
temperature with low palladium(0) catalyst loading, and it
shows a much wider substrate scope. In addition, this reaction
uses relatively stable diazo compounds as the coupling
partners (acyldiazoacetates versus EDA). This deacylative
coupling approach can also be extended to the synthesis of
acyldiazophosphates and aryldiazoketones.
a-Diazo compounds have found wide applications
because of their diverse reactivities.[1] In particular, the
aryldiazoacetates have been extensively explored as the
precursors for generating donor/acceptor-substituted metal-
locarbenes, which show excellent reactivity and selectivity in
various transformations.[2,3] To access aryldiazoacetates,
diazo-group-transfer reactions from an azide to arylacetates
represents the classic method and has been extensively
practiced (Scheme 1).[4] However, this important method
At the outset of this study, phenyl iodide (1a) and
acyldiazoacetate (2a) were employed as the model substrates
to study the coupling reaction (Table 1). In the presence of
Scheme 1. Different strategies for the synthesis of aryldiazoacetates.
Table 1: Optimization of the reaction conditions.[a]
suffers two major drawbacks: 1) The arylacetates bearing
various substituents are not readily available. Both traditional
methods such as the reaction of benzyl Grignard reagents
with CO2, or modern transition-metal-catalyzed coupling
reactions requires rigorous or forced reaction conditions,[5]
and thus the functional-group tolerance is rather limited;
Entry
Cat. (mol%)
Base (equiv)
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
[Pd(PPh3)4] (5)
[Pd(PPh3)4] (5)
[Pd(PPh3)4] (5)
[Pd(PPh3)4] (5)
[Pd(PPh3)4] (5)
[Pd(PPh3)4] (5)
[Pd(PPh3)4] (5)
[Pd(PPh3)4] (5)
[Pd(PPh3)4] (1.5)
none
LiOtBu (1.2)
NaOMe (1.2)
NaOMe (1.2)
NaOMe (1.2)
NaOMe (1.2)
NaOMe (1.2)
NaOH (3.0)
KOH (3.0)
toluene
toluene
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
trace
6
17
31
45
[*] F. Ye, C. Wang, Dr. Y. Zhang, Prof. Dr. J. Wang
Beijing National Laboratory of Molecular Sciences (BNLMS) and
Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of Ministry of Education, College of Chemistry
Peking University, Beijing 100871 (China)
63
86
79
E-mail: wangjb@pku.edu.cn
Prof. Dr. J. Wang
The State Key Laboratory of Organometallic Chemistry
Chinese Academy of Sciences, Shanghai 200032 (China)
NaOH (3.0)
NaOH (3.0)
85(68)[c]
n.r.
[**] The project is supported by the 973 Program (No. 2012CB821600)
and NSFC (Grants No. 21272010 and 21332002).
[a] All the reactions were carried out with 1a (0.25 mmol), 2a (0.3 mmol)
in 1 mL solvent under room temperature for 5 h. [b] Yield of isolated
product. [c] The yield within the parentheses refers to a gram-scale
experiment. n.r.=no reaction.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407653.
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5 mol% [Pd(PPh3)4], 1.2 equivalents of LiOtBu, and toluene,
only a trace amount of the desired product 3a was detected
(Table 1, entry 1). The reaction was slightly improved when
NaOMe was used as the base instead of LiOtBu (entries 2–4).
Further improvement was observed by increasing the amount
of NaOMe and using EtOH as the solvent (entries 4–6).
Further experiments indicated that a significant increase of
the yield could be achieved with either KOH or NaOH as the
base (entries 7 and 8). Moreover, the palladium(0) catalyst
loading could be reduced to 1.5 mol% without compensation
of the yield (entry 9). A scale-up experiment under these
reaction conditions with 10 mmol of 1a afforded 1.3 grams of
3a (68%). Finally, a control experiment indicated that no
reaction occurred in the absence of the palladium(0) catalyst
(entry 10).
With the optimized reaction conditions (Table 1, entry 9),
we proceeded to survey the substrate scope with a series of
aryl iodides as shown in Scheme 2. First, we found that the
halogen substituents tolerate the reaction (3aa–ad). The aryl
iodides bearing electron-withdrawing groups (3ba–bd) and
electron-donating groups (3ca, 3 cd) are all suitable sub-
strates, thus affording the corresponding products in good
yields. It was noteworthy that aryl iodides with sensitive
substituents, such as TMS and Bpin groups, are also suitable
substrates for the reaction (3d, e). Unsaturated substituents,
such as allene, alkyne, and vinyl groups, also tolerate the
reaction conditions (3 f–h). In addition, the reactions of the
aryl iodides bearing azo and acetal substituents worked well
under the standard reaction conditions, thus affording the
corresponding products 3i and 3j in moderate yields.
Remarkably, unprotected hydroxy and amino groups tolerate
this transformation (3cc, 3k). For the aryl iodides bearing
ortho substituents, including NO2 and bulky CH3, increased
loading of the palladium(0) catalyst was required presumably
for facilitating the oxidative addition of the iodide substrate
to the palladium(0) catalyst.
In the case of polycyclic substrates, such as 1-iodonaph-
thalene, 5-iodo-2-methylbenzothiazole, and 2-iodoanthraqu-
nione, the desired products 3m–o (Scheme 2) could also be
formed in moderate yields. Substrates bearing a pyridine and
thiophene moiety also gave the corresponding products 3p
and 3q, albeit in slightly diminished yields. Next, we proceed
to explore the coupling reaction with multisubstituted aryl
iodides. As shown by the results, the coupling reaction all
proceeded well to give the corresponding products in good
yields (3ra, 3rb, 3s, 3t). When the ethyl group is displaced by
bulky tert-butyl group in the diazoester, the corresponding
product 3u is also obtained in excellent yield. Finally, aryl
iodides containing estrone and tocopherol moieties could also
smoothly undergo the reaction to give the corresponding
products in good yields (3v, w).
Next, we expanded this coupling reaction to aryl iodides
and the acyldiazophosphate 4. As shown in Scheme 3, the
cross-coupling reactions proceeded smoothly under slightly
modified reaction conditions. Thus, with K2CO3 as the base
and a 1:1 mixture of toluene and MeOH as the solvent, the
aryl iodides bearing both electron-withdrawing and electron-
donating groups all worked well to give the corresponding
products in moderate to good yields. A scale-up experiment
Scheme 2. Scope of the coupling reaction of acyldiazoacetate with aryl
iodide. If not otherwise noted, the reactions were carried out with the
aryl iodides 1a–u (0.25 mmol), acyldiazoacetate 2a,b (0.3 mmol),
[Pd(PPh3)4] (1.5 mol%), NaOH (3.0 equiv) in EtOH (1 mL) for 5 h at
room temperature. All the yields refer to products isolated after
column chromatography. [a] The substituent X in the substrate is
CO2Et. [b] Used [Pd(PPh3)4] (5 mol%). [c] To enhance the solubility,
petroleum ether (0.5 mL) was added. TMS=trimethylsilyl.
was also carried out with 6 mmol of 1a under the same
reaction conditions, thus affording 0.9 grams of 5a (66%).
Encouraged by the above results, we proceeded to further
apply this coupling reaction for the synthesis of aryldiazoke-
2
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Scheme 3. Scope of the coupling reaction of acyldiazophosphate with
aryl iodide. All the reactions were carried out with 1 (0.2 mmol), 4
(0.25 mmol), [Pd(PPh3)4] (5 mol%), K2CO3 (2.0 equiv) in a mixed
solvent of toluene (0.5 mL) and MeOH (0.5 mL) at room temperature
for 5 h. All the yields refer to products isolated after column chroma-
tography. [a] The yield within the parentheses refers to the scale-up
experiment.
Scheme 5. Proposed reaction mechanism.
a plausible reaction mechanism is proposed as shown in
Scheme 5. First, oxidative addition of phenyl iodide to the
palladium(0) catalyst affords the intermediate A, which
coordinates to diazo substrate to generate the intermediate
B. Nucleophilic attack by hydroxide anion then generates the
intermediate C (path a). Alternatively, the acyldiazoacetate
2a may be first activated through nucleophilic attack of
hydroxide anion to give E. Then A coordinates to E to give C
(path b). Subsequently, deacylation from C gives the inter-
mediate D,[11] from which reductive elimination affords the
deacylative coupling product and regenerates palladium(0)
catalyst.
Since ethyl diazoacetate (EDA) can be formed through
the base treatment of 2a,[1e] an alternative pathway involving
the in situ generation of EDA followed by the coupling of
EDA with 1a may be operative.[7] However, a control experi-
ment indicates that the palladium(0)-catalyzed reaction of 1a
with EDA under the standard reaction conditions resulted in
the formation of 3a in only trace amount, thus indicating that
EDA is not the intermediate for this reaction.
tones. The palladium(0)-catalyzed cross-coupling of 1a with
3-diazopentane-2,4-dione under the same reaction conditions
shown in Scheme 2 was found to not be efficient. Trifluor-
oacyldiazoketones were then proven to be good coupling
partners because of the activation effect of the trifluoro-
methyl group.[9] As summarized in Scheme 4, aryldiazoke-
tones (7a–e) could be prepared under slightly modified
reaction conditions with K2CO3 as the base and MeOH as the
solvent. Notably, the reaction with p-acylphenyl iodide gave
the corresponding coupling product 7d, while the corre-
sponding reaction with 2a in NaOH/EtOH system failed. It is
also noteworthy that vinyldiazoketone could also be
obtained, albeit in low yield (7h).
Based on our previous studies and our understanding of
palladium-catalyzed reaction of diazo compounds,[1n,7,10]
In summary, we have developed a highly efficient
deacylative cross-coupling, which can serve as
a new
method for the synthesis of acyldiazocarbonyl compounds
and aryldiazophosphates.[12] This coupling reaction use easily
available starting materials and proceeds at room temper-
ature and tolerates various functional groups. It is thus
expected that this reaction will find wide applications for the
synthesis of diazo compounds.
Experimental Section
General procedure for the reaction of ethyl 2-diazo-3-oxobutanoate
and aryl iodides. [Pd(PPh3)4] (4.3 mg, 1.5 mol%, or 14.4 mg,
5 mol%), NaOH (30.0 mg, 0.75 mmol), and the aryl iodide 1a–
u (0.25 mmol) were suspended in ethanol (1.0 mL) in a 10 mL
microwave tube under N2. Ethyl 2-diazo-3-oxobutanoate (2a;
46.8 mg, 0.30 mmol) was then added, and the resulting solution was
stirred at room temperature for 5 h. The mixture was filtered through
a short path of silica gel (eluting with ethyl acetate), and the filtrate
was evaporated in vacuo to remove the volatile compounds. The
Scheme 4. Scope of the coupling reaction of trifluoroacyldiazoketones
with aryl iodides. If not otherwise noted, the reactions were carried out
with 1 (0.3 mmol), 6 (0.25 mmol), [Pd(PPh3)4] (5 mol%), K2CO3
(3.0 equiv) in MeOH (1 mL) at room temperature for 5 h. All the yields
refer to the isolated products. [a] [Pd(PPh3)4] (1.5 mmol%) were used.
The reactions were carried out with 1 (0.25 mmol) and 6c (0.3 mmol).
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crude residue was further purified by silica gel column chromatog-
raphy to give the diazo products as shown in Scheme 2.
M. Chen, H.-H. Wu, L. Liu, J. Zhang, J. Am. Chem. Soc. 2014,
136, 6904; l) P.-S. Wang, H.-C. Lin, X.-L. Zhou, L.-Z. Gong, Org.
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McClain, Y. Lan, X. Shi, Angew. Chem. Int. Ed. 2014, DOI:
10.1002/anie.201404946; Angew. Chem. 2014, DOI: 10.1002/
ange.201404946.
Received: July 27, 2014
Published online: && &&, &&&&
Keywords: carbenes · cross-coupling · diazo compounds ·
.
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Synthetic Methods
F. Ye, C. Wang, Y. Zhang,
J. Wang*
&&&& — &&&&
Synthesis of Aryldiazoacetates through
Palladium(0)-Catalyzed Deacylative
Cross-Coupling of Aryl Iodides with
Acyldiazoacetates
New access: An alternative method for
the synthesis of aryldiazoacetates and
related diazo compounds based on pal-
ladium(0)-catalyzed deacylative cross-
coupling of aryl iodides and acyldiazo-
carbonyl compounds is presented. This
highly efficient coupling reaction can be
achieved at room temperature under mild
reaction conditions and shows wide
substrate scope.
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