Palladium-Catalyzed C-H Functionalization of Acyldiazomethane and Tandem Cross-Coupling Reactions

Article abstract of DOI:10.1021/ja513275c

Palladium-catalyzed C-H functionalization of acyldiazomethanes with aryl iodides has been developed. This reaction is featured by the retention of the diazo functionality in the transformation, thus constituting a novel method for the introduction of diazo functionality to organic molecules. Consistent with the experimental results, the density functional theory (DFT) calculation indicates that the formation of Pd-carbene species in the catalytic cycle through dinitrogen extrusion from the palladium ethyl diazoacetate (Pd-EDA) complex is less favorable. The reaction instead proceeds through Ag₂CO₃ assisted deprotonation and subsequently reductive elimination to afford the products with diazo functionality remained. This C-H functionalization transformation can be further combined with the recently evolved palladium-catalyzed cross-coupling reaction of diazo compounds with aryl iodides to develop a tandem coupling process for the synthesis of α,α-diaryl esters. DFT calculation supports the involvement of Pd-carbene as reactive intermediate in the catalytic cycle, which goes through facile carbene migratory insertion with a low energy barrier (3.8 kcal/mol). (Chemical Equation Presented).

Full text of DOI:10.1021/ja513275c

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Article
Pd-Catalyzed C-H Functionalization of Acyldiazomethane
and Tandem Cross-Coupling Reactions
Fei Ye, Shuanglin Qu, Lei Zhou, Cheng Peng, Chengpeng Wang, Jiajia Cheng,
Mohammad Lokman Hossain, Yizhou Liu, Yan Zhang, Zhi-Xiang Wang, and Jianbo Wang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja513275c • Publication Date (Web): 20 Mar 2015
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Pd-Catalyzed C-H Functionalization of Acyldiazomethane and
Tandem Cross-Coupling Reactions
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Fei Ye,†,║ Shuanglin Qu,‡,║ Lei Zhou,§,║ Cheng Peng,† Chengpeng Wang,† Jiajia Cheng,† Mohammad
Lokman Hossain,† Yizhou Liu,† Yan Zhang,† Zhi-Xiang Wang,*,‡ and Jianbo Wang*,†
†Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry
and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing
100871, China
‡School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Beijing
100049, China
§School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China
ABSTRACT: Pd-Catalyzed C-H functionalization of acyldiazomethanes with aryl iodides has been developed. This re-
action is featured by the retention of the diazo functionality in the transformation, thus constituting a novel method for
the introduction of diazo functionality to organic molecules. Consistent with the experimental results, the DFT calcula-
tion indicates that the formation of Pd carbene species in the catalytic cycle through dinitrogen extrusion from the pal-
ladium-EDA complex is less favorable. The reaction instead proceeds through Ag2CO3-assisted deprotonation and sub-
sequently reductive elimination to afford the products with diazo functionality remained. This C-H functionalization
transformation can be further combined with the recently evolved Pd-catalyzed cross-coupling reaction of diazo com-
pounds with aryl iodides to develop a tandem coupling process for the synthesis of -diaryl esters. DFT calculation
supports the involvement of Pd carbene as reactive intermediate in the catalytic cycle, which goes through facile carbene
migratory insertion with a low energy barrier (ca 4.0 kcal/mol).
bearing electron-withdrawing groups (Scheme 1a, R = ester
or ketone), while the diazo substrate is only limited to EDA.
Therefore, it is essential to further optimize the reaction
conditions in order to make this transformation a practical
method for the synthesis of diazo compounds.
INTRODUCTION
Diazo compounds are commonly used as metal carbene
precursors in transition-metal-catalyzed reactions. In gen-
eral, diazo compounds are highly reactive substrates in
transition-metal catalysis. In most cases transition-metal-
catalyzed dediazoniation occurs readily to generate short-
lived metal carbene species, which undergoes a wide array
of metal carbene transformations, such as C-H insertions,
X-H insertions (X = O, N, S, Si, etc.), cyclopropanations and
ylide formations. These reactions have found wide applica-
tions in organic synthesis.1
Scheme 1. Pd-Catalyzed Cross-Coupling of EDA
In 2007, we developed a palladium-catalyzed reaction of
ethyl diazoacetate (EDA) with aryl or vinyl iodides (Scheme
1).2 Subsequently, the groups of Frantz and Reissig reported
similar coupling reactions.3 A surprising feature of this type
of coupling reactions is that the diazo moiety retains in the
products and thus the transformation can be viewed as a C-
H functionalization of EDA.4 Moreover, when the reaction is
carried out under an atmosphere of CO, carbonylation oc-
curs to afford -keto--diazoesters (Scheme 1c).2
This coupling reaction, which seems to be the first ex-
ample of transition-metal-catalyzed C-H functionalization
of EDA, provides a potentially useful approach to introduce
diazo functionality to organic compounds.5,6 However, the
reaction is not efficient with relatively low yields and limited
scope. In particular, the vinyl iodides are limited to these
Furthermore, diazo compounds have recently emerged
as a new type of partners in Pd-catalyzed cross-coupling
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reactions. Pd-carbene species are suggested to be the key
catalyst for cross-coupling of (Z)-ethyl 3-iodoacrylate 1a
intermediates undergoing migratory insertions to form C-C
bond.7 This type of coupling reaction has been shown to be
general, with the migratory group being aryl, benzyl, allyl,
allenyl, alkynyl, acyl, and vinyl group.7,8 Notably, for the Pd-
catalyzed C-H functionalization of EDA with aryl or vinyl
iodides (Scheme 2, Coupling I), the reaction temperature is
slightly lower as compared with the Pd-catalyzed cross-
coupling reactions involving carbene intermediates (Scheme
2, coupling II). We conceived that with the same Pd catalyst
a tandem coupling reactions may be possible, thus generat-
ing two different C-C bonds on the carbon that bears diazo
functionality of the diazo substrate. Herein we wish to re-
port an efficient three-component coupling reaction of ArI,
Ar'I and EDA via palladium-catalyzed coupling (C-H func-
tionalization)/migratory insertion sequence.
and EDA 2a, whereas other palladium catalysts were found
to decompose the diazo compound rapidly to give a complex
mixture. The introduction of 1 equiv of n-Bu4NBr as additive
could appreciably improve the yield of the coupling product
3a. It was also found that the reaction gave better results in
the polar solvent and with NEt3 as the base. We then con-
centrated our re-optimization efforts on the testing of a se-
ries of additives. After some experimentation, we obtained
the optimized reaction conditions as following: 0.5 equiv of
Ag2CO3 as additive and NEt3 as base in toluene at room
temperature. Under such conditions, the reaction could
afford the coupling product 3a in 95% isolated yield (eq 1).
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(1)
Scheme 2. Pd-Catalyzed Tandem Cross-Coupling
with EDA
Next we explored the scope of the new catalytic system
with various vinyl halides. As shown in Table 1, the cross-
coupling of vinyl iodides 1a-e with EDA, which only result-
ed in moderate yields in our previous report, now proceeds
efficiently to afford the corresponding diazo esters in excel-
lent yields (entries 1-5). For example, the yield of 3d was
improved from 48% to 72% by using the newly optimized
reaction conditions. Besides, a limitation of the previous
reaction is that the reaction only works for the substrates
with strong electron-withdrawing substituents at the double
bond.2 Gratifyingly, under the new reaction conditions, -
iodo styrene derivatives could also react with EDA smoothly
to give the corresponding products in moderate yields (en-
tries 6-9). Vinyl bromides, which are less reactive but more
readily available than the corresponding vinyl iodides, were
also suitable substrates for the cross-coupling with EDA,
leading to the corresponding coupling products in moderate
to good yields (entries 10-13). It is noteworthy that in all the
cases the cross-coupling reaction proceeded with retention
of configuration at the double bond.
The tandem coupling (Scheme 2) also raises intriguing
mechanistic issues. Of particular interest, in the Pd-
catalyzed C-H functionalization of EDA with aryl or vinyl
iodides (Coupling I), the Pd-carbene is obviously not gener-
ated from intermediate I, thus the products with diazo moi-
ety remaining intact could be produced. However, in the
subsequent Pd-catalyzed coupling of aryl diazoacetate with
aryl iodide (Coupling II), the Pd carbene III should be
formed, thus leading to the final products via migratory
insertion according to previous studies.7,8 To gain insights
into the details of these processes, DFT (Density Functional
Theory) mechanistic computations were carried out for both
coupling stages. The computations indicate that the dedia-
zoniation to form Pd carbene from the palladium-EDA
complex I is energetically less competitive with the C-H
activation generating II despite being feasible, and support
the involvement of Pd carbene III as reactive intermediate
in the Pd-catalyzed coupling of aryl diazoacetate with aryl
iodide, followed by a facile migratory insertion to form pal-
ladium species IV with an energy barrier as low as 4.3
kcal/mol.
In our previous report, the reaction conditions for the
coupling of vinyl iodides with EDA were not efficient when
vinyl iodides were extended to the aryl iodides. Although the
Pd-catalyzed cross-coupling of aryl iodides with EDA was
realized upon modified reaction conditions, the generality
and efficiency of the reaction were still limited.2 Encour-
aged by the improved yields for the coupling of vinyl halides
and EDA, we applied the new catalytic conditions to the
cross-coupling reaction of aryl iodides with EDA. We were
pleased to find that various aryl iodides reacted smoothly
with EDA in the presence of 5 mol% of Pd(PPh3)4 and 0.5
equiv of Ag2CO3. The reaction carried out in toluene at room
temperature for 4 h afforded the corresponding products in
good to excellent yields (Table 2). Compared with the previ-
ous results, the present reaction conditions afforded better
yields with lower catalyst loading, and the reaction complet-
ed within shorter time at room temperature and showed
much wider substrate scope. As shown in Table 2, aryl io-
dides bearing electron-donating (entries 2-4) or electron-
withdrawing (entries 5-11) groups all worked well under the
identical conditions. To our delight, free -OH and -NH2 also
tolerated this transformation (entries 12 and 13). Besides,
the diazo product bearing pyridine, thiophene and naphtha-
lene were obtained under the same conditions (entries 14-
16). The substrate scope was then expanded to diazoketones.
RESULTS AND DISCUSSION
Reaction optimization and scope. Our initial cata-
lysts screening revealed Pd(PPh3)4 to be the most active
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It was found that a series of functional groups were sur-
Table 1. Palladium-Catalyzed Cross-coupling of
Vinyl Halides with EDAa
vived under the optimized reaction conditions to afford the
corresponding products (entry 17-22). Similarly, phenyldi-
azoamides were obtained successfully via this transfor-
mation (entry 23 and 24).
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Table 2. Palladium-Catalyzed Cross-coupling of
Aryl Halides with Diazo Compounds 2a-ga
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entry 4, ArX
2, R=
5, yield (%)b
1
2
4a, C6H5I
2a, OEt
2a, OEt
2a, OEt
2a, OEt
2a, OEt
2a, OEt
2a, OEt
2a, OEt
2a, OEt
2a, OEt
2a, OEt
2a, OEt
2a, OEt
2a, OEt
5a, 86
5b, 82
5c, 84
5d, 86
5e, 83
5f, 91
4b, p-MeC6H4I
4c, m-MeC6H4I
4d, p-MeOC6H4I
4e, p-ClC6H4I
3
4
5
6
4f, p-MeO2CC6H4I
4g, p-NO2C6H4I
4h, p-BrC6H4I
7
5g, 96
5h, 86
5i, 92
5j, 81
8
9
4i, p-F3CC6H4I
4j, p-NCC6H4I
10
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12
13
14
15
16
17
18
19
20
21
22
4k, m-FC6H4I
5k, 84
5l, 89
5m, 55
5n, 95
5o, 38
5p, 22
5q, 90
5r, 99
5u, 80
5v, 47
5w, 78
4l, p-HOH2CC6H4I
4m, m-H2NC6H4I
4n, 4-iodopyridine
4o, 1-iodonaphthalene 2a, OEt
4p, 3-iodothiophene
4g, p-O2NC6H4I
4g, p-O2NC6H4I
4f, p-MeO2CC6H4I
4q, p-PhC6H4I
4a, C6H5I
2a, OEt
2b, Ph
2c, Me
2b, Ph
2b, Ph
2d, CH2Ph
4a, C6H5I
2e, 2,6-di-tBu-4-MeC6H3 5x, 97
23
24
4g, p-O2NC6H4I
4g, p-O2NC6H4I
2f, NPh2
2g, N(i-Pr)2
5s, 81
5t, 77
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27
28
29
4r, p-O2NC6H4Br
4s, p-NCC6H4Br
4t, p-F3CC6H4Br
2a, OEt
2a, OEt
2a, OEt
5g, 70
5j, 63
5i, 30
5y, 40
5z, 34
4u, 3,5-di-F3CC6H3Br 2a, OEt
4v, 3,5-di-BrC6H3Br 2a, OEt
aAll the reactions were carried out with aryl iodides 4a-v
(0.5 mmol), 2a-g (1.3 equiv), NEt3 (1.3 equiv), Ag2CO3 (0.5
equiv) in the presence of Pd(PPh3)4 (5 mol%) in toluene at
room temperature for 4 h. Isolated yield by column chro-
matography with silica gel.
b
aReaction conditions: aryl halides (0.5 mmol), EDA (1.3
equiv), NEt3 (1.3 equiv), Ag2CO3 (0.5 equiv), Pd(PPh3)4 (5
mol %), in 2 mL toluene at room temperature for 4 h. bI-
solated yield by column chromatography with silica gel.
Finally, the cross-coupling between aryl bromides with
ethyl diazoacetate 2a was examined. It was found that aryl
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bromides could also give the corresponding products under
the conditions, albeit in lower yields (entries 25-29).
Next, we proceeded to expand the reaction to the cou-
pling with two different aryl iodides. As shown by the results
summarized in Table 3, the coupling reactions all afforded
the desired products in comparable yields (entries 10-24).
The reaction was found not significantly affected by the
electronic properties of the substituents on the aromatic
rings. Aryl iodides substituted by electron-donating or elec-
tron-withdrawing groups in either first or second step
worked equally well, affording the three-component cross-
coupling products in moderately good yields (entries 10-19,
21-24). Notably, 1-iodonaphthalene is also a suitable sub-
strate for the coupling reaction (entry 20).
Since palladium catalysts also catalyze the cross-
coupling reaction of the aryldiazoacetates such as 5a-z with
aryl halides,7,8 we thus considered the possibility to carry
out further coupling reaction in the same reaction system
with the same palladium catalyst upon the completion of the
coupling of aryl iodides and acyldiazomethanes. Such a tan-
dem process, in which multiple chemical transformations
are performed with single catalyst sequentially in a single
reaction vessel without intermediary purification steps,
should significantly increase the efficiency of the catalyst
and reduce the time, costs, and waste generation.9
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With this in mind, we initially carried out the reaction in
one-pot manner with 1.3 equiv of EDA 2a and 2.0 equiv of
iodobenzene 4a in the presence of 5 mol% of Pd(PPh3)4, 2.3
equiv of NEt3 and 0.5 equiv of Ag2CO3 in toluene. The reac-
tion mixture was stirred at room temperature for 4 h and
Table 3. Pd-Catalyzed Tandem Cross-coupling of
Aryl Iodides, Aryl Iodides and EDAa
o
then it was heated up to 65 C for 12 h. The desired product
6a could be isolated in 53% yield (Scheme 3, A). However,
when two different aryl iodides were subjected to the same
one-pot reaction, complex mixture was observed due to the
competing homo-coupling reactions. To avoid such problem,
the same reaction was carried out by adding the aryl iodides
and NEt3 separately. Interestingly, even for the coupling
with the same iodobenzene 4a, the reaction gave better
yield with separate addition approach (Scheme 3, B).
entry ArI
Ar'I
6, yield (%)b
1
2
4a, C6H5I
4a, C6H5I
6a, 74
6b, 77
6c, 71
4b, p-MeC6H4I
4c, m-MeC6H4I
4w, o-MeOC6H4I
4d, p-MeOC6H4I
4x, m-MeOC6H4I
4e, p-ClC6H4I
4b, p-MeC6H4I
4c, m-MeC6H4I
3
4
4w, o-MeOC6H4I 6w, trace
4d, p-MeOC6H4I 6d, 73
4x, m-MeOC6H4I 6e, 79
Scheme 3. Tandem Cross-Coupling Reaction
5
6
7
4e, p-ClC6H4I
6f, 71
8
4f, p-MeO2CC6H4I 4f, p-MeO2CC6H4I 6g, 75
9
4q, p-PhC6H4I
4a, C6H5I
4q, p-PhC6H4I
6h, 66
10
11
12
13
14
15
16
17
18
19
20
21
22
4d, p-MeOC6H4I 6i, 66
4d, p-MeOC6H4I
4a, C6H5I
6i, 64
6j, 70
6k, 73
4f, p-MeO2CC6H4I 4a, C6H5I
4f, p-MeO2CC6H4I 4b, p-MeC6H4I
4f, p-MeO2CC6H4I 4y, m,p-Me2C6H3I 6l, 67
4f, p-MeO2CC6H4I 4d, p-MeOC6H4I 6m, 65
4q, p-PhC6H4I
4d, p-MeOC6H4I
4a, C6H5I
4a, C6H5I
6n, 71
6o, 63
6p, 64
6q, 54
4q, p-PhC6H4I
4g, p-O2NC6H4I
4j, p-NCC6H4I
4a, C6H5I
4a, C6H5I
4o, 1-iodonaphthalene 6r, 51
4x, m-MeOC6H4I
4x, m-MeOC6H4I
4y, p-FC6H4I
4i, p-F3CC6H4I
4z, o-ClC6H4I
6s, 56
6t, 60
6u, 56
23
24
4x, m-MeOC6H4I
4y, p-FC6H4I
Under the same reaction conditions as shown in Scheme
3 (B), we then examined the generality of this reaction by
employing a variety of aryl iodides to couple with EDA. First,
we studied the tandem coupling reactions with same aryl
iodides for both steps. As shown in Table 3, aryl iodides
with same para, or meta-substituents all worked well in the
present reaction system (entries 1-3). However, only trace of
the desired product was detected when ortho-substituted
aryl iodide was employed as the substrate (entry 4). Func-
tional groups, such as chloro, ester and phenyl, tolerate the
reaction conditions, giving the corresponding products in
moderate to good yields (entries 5-9).
4x, m-MeOC6H4I 6s, 69
aReaction conditions: a solution of ArI (0.48 mmol), EDA
2a (0.64 mmol), NEt3 (0.64 mmol), Ag2CO3 (0.24 mmol)
and Pd(PPh3)4 (0.024 mmol) in toluene (2 mL) was stirred
at room temperature for 4 h and then Ar'I (0.4 mmol) and
NEt3 (0.48 mmol) were added, the resulted mixture was
o
heated at 65 C for another 12 h. bIsolated yield with silica
gel column chromatography.
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Since diverse transformations are possible from the ar-
Scheme 5. Pd-Catalyzed C-H Functionalization of
EDA/Cu-Catalyzed N-H Insertion Cascadea
yldiazoacetate intermediates,1 it is thus possible to further
devise various tandem processes through different combi-
nations. Herein we demonstrate the combination of Pd-
catalyzed C-H functionalization of EDA with aryl iodides
and the Cu(I)-catalyzed C-H/N-H insertions of the aryldi-
azoacetate intermediates. Following the established reaction
conditions for the formal Cu(I) carbene C-H insertion,10,11
indole derivatives were chosen as the substrates for demon-
strating the tandem transformation. As shown in the
Scheme 4, indoles bearing different protecting group on
nitrogen worked well in the tandem reaction (7a-c). Besides,
N-methylindoles bearing OMe, Me and Br substituents were
also good substrates (7d-f). When pyrroles were introduced
into the tandem reaction, the corresponding products were
also obtained, but in low yields (7g-h).
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aReaction conditions are same as described in Scheme 4.
bIsolated yield with silica gel column chromatography.
On the basis of our computational study, Scheme 6 out-
lines our proposed mechanism for the whole tandem reac-
tion. It is composed of two sequential coupling stages to
form two new C-C bonds, namely, Coupling I and Coupling
II. Both stages start with an oxidative addition step of PhI to
the Pd(0) catalyst (A). In Coupling I, the diazo substrate 2a
is deprotonated by Ag2CO3 from E to F, followed by C-C
coupling via reductive elimination, giving 5a and regenerat-
ing the Pd(0) catalyst A. In Coupling II, the diazo interme-
diate 5a generated in Coupling I decomposes by extrusion
of N2 gas from I, resulting in a Pd(II)-carbene species J,
then the phenyl group migrates to the Pd(II)-carbene car-
bon, leading to K with another C-C bond formed. Finally,
NEt3 reduces the Pd(II) complex K back to the Pd(0) cata-
lyst (A) and simultaneously releases the final product 6a,
completing the tandem C-C couplings. In the following, we
discuss the details of the mechanism in terms of the two
stages.
Scheme 4. Pd-Catalyzed C-H Functionalization of
EDA/Cu-Catalyzed Formal R-H Insertion
Cascadea
Coupling I: The pathway for Coupling I is depicted in
Figure 1, together with energetic and key geometric results.
This stage can be characterized by three steps, including the
oxidative addition of PhI to the Pd(0) catalyst, deprotona-
tion of the diazo substrate 2a by Ag2CO3, and reductive
elimination to give 5a and regenerate the Pd(0) catalyst
simultaneously.
Like many palladium-catalyzed cross-coupling reac-
tions,15 the catalytic cycle starts from the oxidative addition
of PhI to PdL2 (A). Generally, the oxidative addition gives a
cis isomer first, but the cis isomer can easily isomerize to
the more stable trans isomer.16 The mechanism of oxidative
addition of aryl halides to Pd(0) species has been well stud-
ied,15-17 thus we did not pursue the details of the process and
chose the more stable trans isomer (B) to continue the cou-
pling stage. After oxidative addition, one phosphine ligand
in B is replaced by Ag2CO3, leading to complex C, in which
an O atom of Ag2CO3 coordinates to the Pd center and a
silver atom forms AgI moiety with the iodine atom. The lig-
and exchange lowers the energy of the system by 7.7
kcal/mol, mainly due to the driving force of forming a stable
AgI moiety. Upon forming C, two scenarios were considered
for proceeding the coupling. In the first scenario which
could be the case in which the concentration of AgI particles
is low, e.g. at the beginning of the reaction, the AgI moiety
retains. In the second scenario which could occur when the
concentration of AgI particles is relatively high, e.g. at the
ending of the reaction, the AgI moiety could be extracted by
AgI particles. We found that both scenarios are energetically
aReaction conditions: a solution of PhI (0.48 mmol), EDA
2a (0.64 mmol), NEt3 (0.64 mmol), Ag2CO3 (0.24 mmol)
and Pd(PPh3)4 (0.024 mmol) in toluene (2 mL) was stirred
at room temperature for 4 h and then RH (0.4 mmol), CuI
(0.04 mmol) was added. The resulted mixture was heated
at 80 oC for 2 h. bIsolated yield with silica gel column
chromatography.
Finally, Cu(I)-catalyzed N-H insertion10,12 was combined
with the Pd(0)-catalyzed C-H functionalization of EDA. The
cascade reaction proceeded smoothly, providing the ex-
pected products in good yields (Scheme 5).
Computational studies. To gain insights into the re-
action mechanism, we performed DFT mechanistic study
using Gaussian 09.13,14 We chose the reaction shown in
Scheme 3(A) as a representative for mechanistic investiga-
tion.
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Scheme 6. Proposed Catalytic Cycle for the Tandem Coupling Reaction
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Figure 1. (a) Energy profile of Coupling I. (b) Key optimized structures with selected bond lengths in angstroms, the values in
brackets are Wiberg bond indices. Trivial hydrogen atoms are omitted for clarity.
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Fiugure 2. (a) Energy profile for dediazoniation and migratory insertion in Coupling II. (b) Key optimized structures with
selected bond lengths in angstroms, the values in brackets are Wiberg bond indices. Trivial hydrogen atoms are omitted for
clarity. The values in parenthesis in Pd-carbene are bond lengths in X-ray structure.19e
feasible and follow the same mechanism except for some
energetic differences. Herein we continue the discussion
based on the results of the second scenario and give the re-
sults of the first scenario in Supporting Information (Figure
S1). Note that Coupling II also features an intermediate (i.e.
G in Figure 3) similar to C and we also took both scenarios
into account for G to proceed (vide infra).
certainty of the exergonicity of the extraction by different
sizes of AgI particles, we select D as energy reference to
discuss the process from D to 5a (the red section in Figure
1).
The extraction of AgI from C results in D in which two O
atoms of Ag2CO3 moiety coordinate to the Pd center. Be-
cause EDA features a carbon center bearing a formal lone
pair, EDA would attack the Pd center of D, which repels the
neighboring (Pd-)O atom, resulting in E in which the re-
pelled O atom forms a CH…O hydrogen bond with the EDA
moiety (see the structure of E in Figure 1b). This process is
slightly exergonic by 3.0 kcal/mol. Once E is formed, the O
atom in CH…O hydrogen bond grabs the proton of the EDA
moiety facilely with a barrier of only 0.2 kcal/mol, resulting
As a simplified model of AgI particles, we used AgI mon-
omer to examine the feasibility of the extraction (AgI + C 
(AgI)2 + D), which shows that the process is exergonic by
19.2 kcal/mol. Larger AgI particles should drive the extrac-
tion more favorably because AgI precipitates. Thus no mat-
ter which size of AgI particle participates in the extraction,
the intermediate D can be generated. Considering the un-
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in F with a AgHCO3 moiety formed. The facile deprotona-
tion can be attributed to the weakened CH bond and the
proximity of the basic O center. Relative to EDA, the C-H
bond in E is stretched by 0.06Ǻ and the Wiberg bond or-
der18 of the bond is decreased by 0.19. Finally, the reductive
elimination occurs by crossing a barrier of 13.8 kcal/mol
(TS3), followed by the recoordination of phosphine ligand
to the Pd center, releasing the product (5a) of Coupling I
and AgHCO3 and regenerating the catalyst PdL2 (A). In our
one-pot experiments, the base (NEt3) was available in the
system. We also considered whether NEt3 can perform the
deprotonation, but the results show that NEt3 is less effec-
tive than Ag2CO3 to perform the deprotonation (see Sup-
porting Information, Figure S3).
in Coupling I replaces one of phosphine ligands, giving
complex G. Similar to the exergonic process from B to C in
Figure 1, the formation of AgI moiety from B to G is also
exergonic by 9.8 kcal/mol. G is the counterpart of C. Simi-
larly, G could proceed with AgI either extracted or reserved.
The extraction of AgI by AgI monomer from G is exergonic
by 10.8 kcal/mol, compared to 19.2 kcal/mol of C. The red
section of the energy profile in Figure 2 is for the scenario
with AgI removed and that with AgI reserved is given in
Supporting Information (Figure S2).
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The extraction of AgI from G leads to H. Subsequently,
5a produced in situ in Coupling I attacks the Pd center of H,
leading to I. Intermediates H and I correspond to D and E
in Coupling I, respectively. As the process from D to E is
exergonic by 3.0 kcal/mol, the process from H to I is ender-
gonic by 6.3 kcal/mol, which reflects the contribution of C-
HO hydrogen bond in stabilizing E. In contrast to E, there
is no acidic proton in the diazo fragment of I, thus I can
only release N2, which needs to climb a barrier of 17.3
kcal/mol (TS4 relative to H+5a) and leads to a palladium
species J. The barrier is comparable to the 17.0 kcal/mol for
releasing N2 from E (Figure 1), which further confirms that
the preference of deprotonation over N2 extrusion in E is
due to the very facile deprotonation. The palladium species
J is a metal carbene, as validated by comparing to the X-ray
structures of well-recognized palladium carbenes,19,20 e.g.
the experimentally-captured cationic Pd-carbene shown in
Figure 2b.19e The computed length (1.987 Å) of the formal
Pd=C double bond in J is shorter than that in the X-ray
Previous studies have found that the diazo fragment of
diazo compounds could be readily released to form palladi-
um carbene in various palladium catalyzed coupling reac-
tions.7 Intriguingly, the diazo fragment in this coupling
stage maintains. Apparently, E is the possible intermediate
to release N2. Relative to E, the barrier (TS2) for N2 release
is 17.0 kcal/mol, which is not high and accessible but is sig-
nificantly higher than TS1 (by 16.8 kcal/mol). Therefore,
the retention of the diazo fragment in this coupling is be-
cause the deprotonation is too easy rather than that the N2
release is so difficult. Note that the EDA coordination in E
also weakens the C-N bond, as shown by the elongated bond
length by 0.037 Ǻ and decreased bond order by 0.141.
Coupling II: Figure 2 and 3 show the energy profiles of
the Coupling II stage, together with key structural results.
After the oxidative addition from A to B, AgHCO3 generated
Figure 3. (a) Energy profile for the reduction of the Pd(II) species K by NEt3. (b) Key optimized structures with selected bond
lengths in angstroms. Trivial hydrogen atoms are omitted for clarity.
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(2.005 Å) and the computed (2.023 Å) structures of Pd-
reaction conditions are milder than the original ones and
proved efficient over a wide range of substrates, thus
providing a practical approach to introduce diazo function-
ality to organic compounds. Furthermore, a one-pot tandem
coupling process for the synthesis of -diaryl esters was
developed via Pd-catalyzed cross-coupling of aryl iodides
with the resulted diazo compounds. The three-component
cross-coupling of EDA with two different aryl iodides could
also be realized through adding the aryl iodides in separate
manner.
carbene, and the Wiberg bond index of the bond (0.670) in
J is larger than that (0.567) in Pd-carbene. Moreover, Pd-
carbene and J have similar  and  orbitals involved in the
formal Pd=C bonds (see Supporting Information, Figure
S7). Similar to the palladium carbene species we reported
previously,20 J is also unstable and can easily undergo mi-
gratory insertion by crossing a barrier (TS5) of 3.8 kcal/mol.
The migratory insertion results in a much more stable com-
plex K (37.7 kcal/mol lower than J) with a new C-C bond
formed. Note that the phenyl group in K still coordinates to
the Pd center with one of its formal C=C double bonds. Be-
cause the transformation from J to K is very feasible in
terms of both kinetics and thermodynamics, it would be
difficult to detect the palladium carbene species J experi-
mentally. The energetic results indicate that 5a is able to
react with H to produce Pd-carbene species feasibly via N2
release. However, the overall barrier for the coupling of PhI
with 2a (13.8 kcal/mol from F to TS2 in Figure 1) is lower
than that for dediazoniation of 5a (17.3 kcal/mol from H to
TS4 in Figure 2). Therefore, in Coupling I stage under room
temperature, the catalyst (A) would prefer acting on the
coupling of PhI with 2a rather than 5a, as far as 2a is avail-
able in the system.
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Computational study provides interesting insights into
the reaction mechanism. For the Pd-catalyzed coupling of
EDA with phenyl iodide, the intriguing issue is the retention
of the diazo functionality in the transformation. Computa-
tional study indicates that the dinitrogen extrusion from the
palladium-EDA complex is energetically less favored as
compared with the Ag2CO3-assisted deprotonation process
by 16.8 and 11.5 kcal/mol (see Figure 1, and Figure S1 in
Supporting Information) under the two deprotonation sce-
narios, respectively, which is in good agreement with the
experimental observation. For the Pd-catalyzed coupling of
diazoacetate intermediate with phenyl iodide, computation-
al study supports the involvement of Pd carbene as reactive
intermediate, which undergoes rapid migratory insertion
process with a low energy barrier of ca 4.0 kcal/mol. The
calculation also indicates that the rate-limiting step for the
overall tandem transformation is the hydrogen transfer
from NEt3 to the palladium species generated from the mi-
gratory insertion of Pd carbene.
The generation of K from A is highly exergonic. To pro-
duce the final product 6a and complete the catalytic cycle,
the -C(Ph)2COOEt fragment needs to gain a hydrogen atom
and the Pd(II) species needs to be reduced to Pd(0) complex.
Previously, NEt3 was reported to reduce Pd(II) species,21 We
also used NEt3 as a reductant for the reduction of the Pd(II)
species K. As shown in Figure 3, NEt3 approaches the Pd(II)
center of K, leading to complex L. Subsequently, an Cα-H
atom of NEt3 transfers to the Pd(II) center through TS6 by
crossing a barrier of 29.1 kcal/mol (relative to K + NEt3),
leading to M which contains an ion-pair. After displacing
the ion-pair N by a phosphine ligand giving O, reductive
elimination via TS7 take place, resulting in the final prod-
uct 6a and regenerating the Pd(0) catalyst (A). The process
(K + NEt3 + PPh3  6a + N + A) spans a barrier of 29.1
kcal/mol and is exergonic by 20.3 kcal/mol. We realized
ASSOCIATED CONTENT
Supporting Information
1
Experimental procedure, characterization data, copies of H
and 13C NMR spectra and DFT calculation details. This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
wangjb@pku.edu.cn
zxwang@ucas.ac.cn
o
that, considering the reaction temperature (65 C), the bar-
rier is somewhat high, though the value lies in the accepta-
ble range, considering the accuracy that computational
methods can reach. To corroborate the mechanism, we fur-
－
║FY, SQ and LZ contributed equally to this work.
ther examined a possible alternative that the HCO3 moiety
in K offers a hydrogen atom to form 6a, but the hydrogen
-
transfer from HCO3 either to the -C(Ph)2COOEt fragment
ACKNOWLEDGMENT
or to the Pd(II) center was found to be unlikely (see Sup-
porting Information, Figure S5, S6).
The project is supported by the National Basic Research
Program of China (973 Program, No. 2015CB856600) and
the Natural Science Foundation of China (Grant 21472004,
21332002, and 21373216 (to ZXW)).
Comparing the two coupling stages, Coupling I is more
favorable than Coupling II. The rate-determining-step for
the whole transformation is the hydrogen transfer from
NEt3 to the Pd (II) species (TS6) in Coupling II. This is in
agreement with our experiments that the reaction can oper-
ate to produce 5a (via Coupling I) under room temperature
while we need to elevate the temperature (65 oC) for the
tandem transformation via Coupling I followed by Coupling
II.
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(14) All the structures were optimized and characterized to be
energy minima or transition states at M06/BSI level,
where BSI denotes a basis set of LANL2DZ for Pd, I, Ag
and 6-31G(d) for other atoms. The energies were then im-
proved by M06/BSII//M06/BSI single point calculations
with the solvent effects accounted by SMD solvent model,
using toluene as the solvent. BSII denotes a basis set of
SDD for Pd, I, Ag and 6-311++G(d,p) for other atoms. The
gas phase M06/BSI harmonic frequencies were used for
thermal corrections to free energies at 298.15K and 1 atm.
More details are given in Supporting Information.
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