Palladium-catalyzed carbonylation/acyl migratory insertion sequence

Article abstract of DOI:10.1002/anie.200906349

Chemical Equation Presented On the move: A palladium-catalyzed reaction of aryl iodides, diazo compounds or N-tosylhyd razones, and carbon monoxide affords β-oxo esters or ketones/ enones (see scheme; DCE = l,2-dichloroethane). The products are delivered with high efficiency through the title sequence.

Full text of DOI:10.1002/anie.200906349

Angewandte
Chemie
DOI: 10.1002/anie.200906349
Synthetic Methods
Palladium-Catalyzed Carbonylation/Acyl Migratory Insertion
Sequence**
Zhenhua Zhang, Yiyang Liu, Mingxing Gong, Xiaokun Zhao, Yan Zhang, and Jianbo Wang*
Migratory insertion is one of the fundamental processes in
organopalladium chemistry. In particular, migratory insertion
of a CO ligand and the formation of reactive acylpalladium
intermediate is a powerful method for introducing a carbonyl
functionality into organic molecules. The catalytic cycle
involving such a key step has been developed into one of
the most important tools to synthesize various carbonyl
compounds.[1] However, for a long time, the scope of
migratory insertion processes of organopalladium has been
limited to those involving carbon monoxide. In view of the
similarity between a carbene and carbon monoxide, one may
conceive palladium–carbene as another species which may
undergo migratory insertion (Scheme 1). Indeed, the migra-
We have previously reported the palladium-catalyzed
cross-coupling reaction of diazo compounds with organo-
boronic acids.[3e] We also studied the coupling of iodides with
ethyl diazoacetate (EDA) in the presence of CO.[7] As a
continuation of our studies, we investigated the palladium-
catalyzed reaction of iodobenzene (1a) with methyl a-
diazopropionate (2a) in the presence of an atmosphere of
CO. Methyl 2-methyl-3-oxo-3-phenylpropanoate (4a) was
isolated in moderate yield (40%; Scheme 1). The formation
of 4a can be rationalized by invoking an acyl group migratory
insertion of a palladium–carbene species (from complex a to
complex b; Scheme 2).[8]
Optimization of this reaction was attempted (Table 1).
Firstly, since the product has a newly incorporated hydrogen
Scheme 1. Migratory insertion of CO and carbene.
Scheme 2. Palladium-catalyzed reaction of 1a and 2a in the presence
of CO.
tory insertion process has been reported for stable palladium–
carbene species.[2] More recently, catalytic reactions which are
proposed to include the migratory insertion of a palladium–
carbene intermediate have been reported.[3–6] The migratory
group has so far included aryl,[3] benzyl,[3a,4] vinyl,[5] and allyl[6]
groups. Herein we report an unprecedented acyl group
migration in this type of reaction. This reaction proceeds
with a palladium-catalyzed carbonylation of an aryl iodide,
palladium–carbene formation, and acyl migratory insertion.
atom from an external source, we anticipated that the
introduction of a hydrogen source should promote the
reaction. To our delight, this was indeed the case; when the
reaction was carried out in the presence of triethylsilane (3),
the yield of 4a was improved to 88% (Table 1, entry 1).
Furthermore, inspection of the reaction conditions revealed
that this reaction proceeded more efficiently in polar solvents
such as 1,2-dichloroethane (DCE) and CHCl3 (Table 1,
entries 1 and 3–6), whereas the nonpolar solvent PhMe was
found to be unfavorable (Table 1, entry 2). Several other
palladium catalysts were then examined. Of the palladium(II)
catalysts, Pd(OAc)2 gave trace amounts of products and
[Pd(PPh3)2Cl2] afforded moderate yields (Table 1, entries 7
and 8). [Pd2(dba)3] afforded low to moderate product yields
under the reaction conditions, both in the presence and
absence of phosphine ligands (Table 1, entries 9–15). There-
fore it was concluded that [Pd(PPh3)4] was the best catalyst for
this reaction. Notably, the products resulting from a b-hydride
elimination were not observed in any case. Finally, a control
experiment showed that product 4a could not be detected in
the absence of a palladium catalyst (Table 1, entry 16).
[*] Z. Zhang, Y. Liu, M. Gong, X. Zhao, 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)
Fax: (+86)10-6275-1708
E-mail: wangjb@pku.edu.cn
Homepage: http://www.chem.pku.edu.cn/physicalorganic/
home.htm
[**] The project is supported by NSFC (Grant No. 20832002, 20772003,
20821062), 973 Program (No. 2009CB825300).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906349.
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Table 1: Conditions for the palladium-catalyzed reaction of CO with 1a
Table 2: [Pd(PPh3)4]-catalyzed reactions of CO with 1a–i and 2a–j.[a]
and 2a.[a]
Entry 1: Ar
2: R, R’
t [h] Yield of 4, [%][b]
Entry
Cat. (mol%)
Solvent
Yield [%][b]
1
2
3
4
5
1a: C6H5
2a: Me, Me
2a: Me, Me
2a: Me, Me
2a: Me, Me
2a: Me, Me
10
11
9
4a: 88
4b: 43[c]
4c: 80
4d: 85
4e: 61
4 f: 74
4g: 80
4h: 87
4i: 77
1b: o-MeC6H4
1c: p-MeC6H4
1d: p-MeOC6H4
1e: p-NO2C6H4
1
2
3
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(OAc)2 (5)
DCE
88
50
73
75
21
84
<5
70
40
46
65
54
31
25
33
0
toulene
dioxane
MeCN
DMF
CHCl3
DCE
9
17
14
10
7
12
9
6
1 f: p-MeO2CC6H4 2a: Me, Me
7
8
1g: p-ClC6H4
1a: C6H5
2a: Me, Me
2b: Me, iPr
2c: Ph(CH2)3, Me
2d: Ph, Me
2e: p-MeOC6H4, Me
2a: Me, Me
2a: Me, Me
2 f: Me, tBu
2g: Me, Bn
6
7
9
1a: C6H5
8
[Pd(PPh3)2Cl2] (5)
DCE
10
11
12
13
14
15
16
18
19
1a: C6H5
1a: C6H5
1h: m-CH3C6H4
1i: p-BrC6H4
1a: C6H5
1a: C6H5
1a: C6H5
1a: C6H5
1a: C6H5
4j: 57
9
[Pd2(dba)3] (2.5)
DCE
8
4k: 75
4l: 64
10
11
12
13
14
15
16
[Pd2(dba)3] (2.5)/PPh3 (5)
[Pd2(dba)3] (2.5)/PPh3 (10)
[Pd2(dba)3] (2.5)/dppb (5)
[Pd2(dba)3] (2.5)/[HPnBu3]BF4 (10)
[Pd2(dba)3] (2.5)/PtBu3 (10)
[Pd2(dba)3] (2.5)/[HPCy3]BF4 (10)
none
DCE
DCE
DCE
DCE
DCE
DCE
DCE
10
10
12
12
10
20
4m: 75
4n: 82
4o: 79
4p: 66
4q: 62
2h: nPr, Me
2i: Bn, Me
2j: p-O2NC6H4, Me 12
[d]
–
[a] Reaction conditions: 1a (1.0 equiv), 2a (2.0 equiv), and 3 (1.1 equiv).
[b] Yield of isolated product. dba=dibenzylideneacetone, DMF=N,N-
dimethylformamide, Cy=cyclohexyl.
[a] Reaction conditions: 1a–i (1.0 equiv), 2a–j (2.0 equiv), and
(1.1 equiv). [b] Yield of the isolated products. [c] The product was a
mixture of keto and enol. [d] No reaction.
3
A series of aryl iodides 1a–i were then subjected to the
optimal reaction conditions with a-diazocarbonyl compounds
2a–j. As shown in Table 2, the corresponding 1,3-dicarbonyl
products were obtained in moderate to good yields in all
cases. The reaction was found to be marginally affected by the
sterics of the substituents on the aryl iodides, as shown by the
reaction of diazoester 2a with o-iodotoluene (1b), which gave
lower yields (Table 2, entry 2). For the scope of diazo
substrates, both a-alkyl- and a-aryl-substituted substrates
worked well to afford the corre-
products were drastically affected by the type of palladium
catalyst (Table 3, entries 2–7). After extensive optimization,[9]
two sets of reaction conditions were identified, which could
afford either 6a or 7a selectively, both in good yields [Table 3,
entry 8 (conditions I) and entry 9 (conditions II)].
With the two sets of optimized conditions, the reaction
scope was examined (Table 4). Both reaction conditions I and
II worked well, affording the either the ketone (6b–e) or the
enone (7b–e), respectively; however, in the case of 5c the b-
sponding products in good yields,
Table 3: Selected conditions of palladium-catalyzed reaction of CO with 1a and 5a.[a]
except in the case when the a-aryl
a-diazoacetate contains strong
electron-withdrawing substituents.
Next, this palladium-catalyzed
reaction was extended to diazo
substrates not bearing a carbonyl
substituent. These nonstabilized
diazo substrates can be generated
Entry
Cat. (mol%)
t
Yield [%][b]
Ratio[b]
(6a:7a)
[h]
(6a+7a)
1
2
3
4
[Pd(PPh3)4] (5)
[Pd(PPh3)2Cl2] (5)
[Pd2(dba)3] (2.5)/dppb (5)
[Pd2(dba)3] (2.5)/
8
12
8
71 (67)[c]
63
30
11
93:7
89:11
97:3
in situ
from
N-tosylhydrazo-
nes.[3b,c,4c] Therefore, phenyl iodide
(1a) and N-tosylhydrazone 5a were
subjected to similar reaction con-
ditions in the presence of LiOtBu.
A mixture of the expected ketone
6a and enone 7a (93:7) was iso-
lated in 67% yield (Table 3,
entry 1). The product 7a results
from a b-hydride elimination in
the last step of catalytic cycle (see
below). Additional studies revealed
that both the yield and ratio of the
12
>99:1
[HPnBu3]BF4 (10)
5
6
7
[Pd2(dba)3] (2.5)/P(OPh)3 (10)
[Pd2(dba)3] (2.5)/PtBu3 (10)
[Pd2(dba)3] (2.5)/
12
12
12
16
28
45
38:62
<1:99
31:69
[HPCy3]BF4 (10)
[Pd(PPh3)4] (5)
[Pd2(dba)3] (2.5)/
8[d]
9[e]
15
13
84 (76)[c]
80 (71)[c]
97:3
<1:99
[HPCy3]BF4 (10)
[a] Reaction conditions: 1a (1.0 equiv), and 5a (2.0 equiv). [b] Determined by GC/MS methods. [c] Yield
of isolated products given within the parentheses. [d] With 2.0 equiv of iPrNH2 instead of NEt3. [e] In the
absence of Et3SiH in MeCN.
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hydride elimination predominated under both conditions
(Table 4, entries 7 and 8).
be influenced by the phosphine ligands.[11] b-Hydride elimi-
nation from D affords enone product.
The entire catalytic cycle of this reaction is proposed in
Scheme 3.[9] The reaction is initiated by oxidative addition of
Pd0 to the aryl iodide, affording the PdII intermediate A. Then
Since the possibility exists that the primary product of the
reaction is a silyl enolate rather than a ketoester, we prepared
silyl enolate from ketoester 4a for comparison.[9] The silyl
enolate was found to be stable to silica gel column chroma-
tography. Careful inspection of the crude mixture of the
palladium-catalyzed reaction of 1a and 2a under standard
reaction conditions could not detect any silyl enolate. This
experiment rules out the possibility of silyl enolate as primary
product, which is evidence supporting the palladium hydride
species G as the intermediate in the final step of the catalytic
cycle.
Table 4: Palladium-catalyzed reaction of CO with 1a,d,f and 5a–c.
Entry[a] 1: Ar
5: Ar’, R
t
Yield Ratio (6:7)[c]
[h] [%][b]
To substantiate the mechanistic rationale, we examined
palladium-catalyzed reactions of methyl a-diazopropionate
(2a) and benzoyl chloride (8; Scheme 4). The reaction gave
1
2
3
4
5
6
7
8
1d: p-MeOC6H4
1d: p-MeOC6H4
1 f: p-MeO2CC6H4 5a: C6H5, H
1 f: p-MeO2CC6H4 5a: C6H5, H
1a: C6H5
1a: C6H5
1a: C6H5
1a: C6H5
5a: C6H5, H
5a: C6H5, H
15 85
12 86
14 56
12 54
93:7
<1:99
98:2
<1:99
96:4
<1:99
33:67[d]
<1:99[d]
5b: 2-napth, H 15 72
5b: 2-napth, H 12 71
5c: C6H5, Me
5c: C6H5, Me
15 94
12 72
[a] For entries 1, 3, 5, and 7, the reaction was carried out under reaction
conditions I, for entries 2, 4, 6, and 8, the reaction was carried out under
reaction conditions II. [b] Yield of isolated 6 and 7 combined. [c] Deter-
mined by 1H NMR (400 MHz) methods. [d] For 7e, E/Z=2:3.
Scheme 4. Palladium-catalyzed reaction of an acyl chloride with 2a.
the acyl group migration product 4a in 21% yield. In the
presence of an atmosphere of CO, the yield was slightly
higher. A control experiment suggests that no reaction occurs
in the absence of the palladium catalyst. These results are
consistent with the mechanistic rationale which involves acyl
migratory insertion as the key step.
In summary, we have reported the first palladium-
catalyzed tandem migratory insertion with both CO and a
carbene. This reaction builds a connection between a
palladium–carbene process and palladium-catalyzed carbon-
ylation, which may open new possibilities for the exploration
of the potential of palladium-catalyzed carbene transforma-
tions.
carbon monoxide insertion affords the Pd–acyl intermediate
B. Interaction of the a-diazo compound with B produces
palladium–carbene intermediate C, and migratory insertion
of the acyl group into the carbenic carbon atom of the
palladium–carbene generates C-bound enolate D, which
equilibrates with the corresponding O-bound enolate E. In
the reaction with a-diazocarbonyl compound, h2-O, O-bound
intermediate E (R’ = COR’’) is predominant, from which
transmetallation with Et3SiH and subsequent reductive
elimination affords 1, 3-dicarbonyl compound as the only
product. For the reaction with a nonstabilized diazo com-
pound as a substrate, the equilibrium between D and E would
Experimental Section
Typical procedure for [Pd(PPh3)4]-catalyzed reactions of CO with a-
diazocarbonyl compounds and aryl iodides: Under
a nitrogen
atmosphere, [Pd(PPh3)4] (17.3 mg, 0.015 mmol) was added to a
flame-dried round-bottomed flask. The flask was then sealed and
evacuated to a vacuum of 15 mmHg, and fitted with a CO balloon. A
solution of iodobenzene (1a; 61 mg, 0.3 mmol), methyl a-diazopro-
pionate (2a; 68 mg, 0.6 mmol), triethylsilane (3; 38 mg, 0.33 mmol),
and triethylamine (61 mg, 0.6 mmol) in 4 mL of DCE was added using
a syringe. The mixture was stirred at 608C until 2a disappeared as
judged by TLC. The solution was removed in vacuo to yield a residue,
which was purified by flash chromatography (silica gel) to afford pure
4a as a pale yellow oil (51 mg, 88%).
Received: November 11, 2009
Keywords: carbenes · carbonylation · diazo compounds ·
.
Scheme 3. Mechanistic rationale.
migratory insertion · palladium
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