Pd/light-accelerated atom-transfer carbonylation of alkyl iodides: Applications in multicomponent coupling processes leading to functionalized carboxylic acid derivatives

Article abstract of DOI:10.1002/chem.201200752

The atom-transfer carbonylation reaction of various alkyl iodides thereby leading to carboxylic acid esters was effectively accelerated by the addition of transition-metal catalysts under photoirradiation conditions. By using a combined Pd/hv reaction system, vicinal C-functionalization of alkenes was attained in which α-substituted iodoalkanes, alkenes, carbon monoxide, and alcohols were coupled to give functionalized esters. When alkenyl alcohols were used as acceptor alkenes, three-component coupling reactions, which were accompanied by intramolecular esterification, proceeded to give lactones. Pd-dimer complex [Pd₂(CNMe)₆][PF₆]₂, which is known to undergo homolysis under photoirradiation conditions, worked quite well as a catalyst in these three- or four-component coupling reactions. In this metal/radical hybrid system, both Pd radicals and acyl radicals are key players and a stereochemical study confirmed the carbonylation step proceeded through a radical carbonylation mechanism. Light, camera, ATCion: Atom-transfer carbonylation of alkyl iodides to afford carboxylic acid esters was accelerated by the addition of transition-metal catalysts under photoirradiation. The carbonylation step proceeded through a radical mechanism. Copyright

Full text of DOI:10.1002/chem.201200752

FULL PAPER
DOI: 10.1002/chem.201200752
Pd/Light-Accelerated Atom-Transfer Carbonylation of Alkyl Iodides;
Applications in Multicomponent Coupling Processes Leading to
Functionalized Carboxylic Acid Derivatives
Akira Fusano, Shuhei Sumino, Satoshi Nishitani, Takaya Inouye, Keisuke Morimoto,
Takahide Fukuyama, and Ilhyong Ryu*[a]
Abstract: The atom-transfer carbonyla-
tion reaction of various alkyl iodides
thereby leading to carboxylic acid
esters was effectively accelerated by
the addition of transition-metal cata-
lysts under photoirradiation conditions.
By using a combined Pd/hn reaction
system, vicinal C-functionalization of
alkenes was attained in which a-substi-
tuted iodoalkanes, alkenes, carbon
monoxide, and alcohols were coupled
to give functionalized esters. When al-
kenyl alcohols were used as acceptor
alkenes, three-component coupling re-
actions, which were accompanied by in-
tramolecular esterification, proceeded
to give lactones. Pd-dimer complex
[Pd2ACHTUNGRTENNU(G CNMe)6]CATHUNGTREN[NUGN PF6]2, which is known to
undergo homolysis under photoirradia-
tion conditions, worked quite well as
a catalyst in these three- or four-com-
ponent coupling reactions. In this
metal/radical hybrid system, both Pd
radicals and acyl radicals are key play-
ers and a stereochemical study con-
firmed the carbonylation step proceed-
Keywords: carbon monoxide · car-
bonylation · multicomponent reac-
tions · palladium · radical reactions
ed through
mechanism.
a radical carbonylation
Introduction
To circumvent a longstanding problem surrounding the
carbonylation of alkyl halides thereby leading to aliphatic
carboxylic-acid derivatives, we have developed a conceptual-
ly different approach involving radical carbonylation and
iodine-atom transfer, which we call atom-transfer carbonyla-
tion (ATC). Either light initiation or thermal initiation by
using a radical initiator begins the ATC process, with which
aliphatic carboxylic acid esters, amides, and their related
Carbonylation reactions by using carbon monoxide have
found widespread applications in organic synthesis.[1] Where-
as the transition-metal-catalyzed carbonylation of vinyl,
allyl, and benzyl halides to give carboxylic acid derivatives
has been established as a reliable process, the corresponding
carbonylation of alkyl halides has remained a challenge[2–4]
because the relatively slow oxidative addition onto the
metal center and b-hydride elimination hamper the realiza-
tion of an efficient carbonylation process.[5] The synthesis of
acetic acid by transition-metal-catalyzed carbonylation from
MeOH and carbon monoxide represents one of the most
successful examples of an industrial carbonylation process
for which the transition-metal-catalyzed carbonylation of io-
domethane is key.[6,7] However, the extension of Monsanto
acetic acid synthesis to C3 and larger alcohols is known to
give isomeric mixtures of carboxylic acids owing to the iso-
merization of rhodium–alkyl intermediates through b-hy-
dride elimination.[7a]
compounds
were
prepared
without
isomerization
(Scheme 1).[8,9] Recent work by Istchenko, Lꢀngstrçm, and
co-workers demonstrated the successful application of the
ATC method in the synthesis of the positron emission to-
mography of active carboxylic acids[10] by incorporating
11CO as a carbonyl carbon moiety.[11]
[a] Dr. A. Fusano, S. Sumino, S. Nishitani, T. Inouye, K. Morimoto,
Dr. T. Fukuyama, Prof. I. Ryu
Department of Chemistry, Graduate School of Science
Osaka Prefecture University
Scheme 1. Atom-transfer carbonylation of alkyl iodides.
Sakai, Osaka 599-8531 (Japan)
Fax : (+81)72-254-9695
E-mail: ryu@c.s.osakafu-u.ac.jp
To increase the usefulness of the ATC reactions of alkyl
iodides, acceleration of the reaction, in particular the accel-
eration of the reactions of primary alkyl iodides, is crucial
because slow reactions that are inherent to the lower ability
Supporting information for this article, including experimental proce-
dures and characterization data, is available on the WWW under
http://dx.doi.org/10.1002/chem.201200752.
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Table 1. Acceleration of the atom-transfer carbonylation reactions of alkyl
iodides to afford esters and lactones by the addition of Pd catalysts.[a]
of an iodine-atom transfer compared with secondary and
tertiary iodides[12] allows undesirable side reactions, such as
the E2-type elimination of HI, to be avoided.[13] Accelera-
tion of the ATC is also desirable in performing effective
multicomponent reactions with the incorporation of CO.
In the 1980s, Watanabe and co-workers and Suzuki,
Miyaura, and co-workers independently reported that the
transition-metal-catalyzed carbonylation of iodoalkanes to
give esters[14a,b] and ketones[14c] is facilitated by photoirradia-
tion. In particular, the presence of radical intermediates is
proposed in both of these metal-catalyzed carbonylation re-
actions to lead to alkylmetal species. Stimulated by these
precedent-setting studies, we investigated a metal/radical
hybrid system by adding transition-metal catalysts to our
ATC system under photoirradiation and found that a Pd/hn
irradiation system significantly accelerated ATC cyclization
reactions to form cyclopentanones with ester and amide sub-
stituents.[15] This result highly motivated us to explore more
general multicomponent coupling processes by using Pd/hn-
induced ATC reactions. Consequently, we reported a series
of three- or four-component coupling reactions to afford
a wide range of carboxylic acid derivatives.[16]
Entry Alkyl iodides
t
Catalyst
Ester
Yield
[%][b]
[h]
1
2
3
50
16
14
none
54
87
87
[Pd
(CNMe)6]
none
(PPh3)4]
ACHTUNGTRENNUNG
[Pd
E
ACHTUNGTRENNUNG
4
5
16
16
40
83
[Pd
A
27
(cis/
trans=
36:64)[c]
91
6
7
16
16
none
[Pd
ACHTUNGTRNE(NUNG PPh3)4]
(cis/
trans=
36:64)[c]
40
83
96
8
9
10
6.5
6.5
6.5
none
(PPh3)4]
[PF6]2
[Pd
(CNMe)6]
G
E
G
N
11
12
13
6.5
6.5
6.5
none
[Pd(PPh3)4]
(CNMe)6][PF6]2
38
80
92
AHCTUNGTRENNUNG
[Pd
N
ACHTUNGTRENNUNG
73
14
15
16
16
[Pd
[Pd
ACHTUNGTRENNUNG
Herein, we report the full scope of the Pd/hn-induced
ATC reaction for primary, secondary, and tertiary alkyl io-
dides, which can provide useful synthetic methods to pre-
pare a variety of carboxylic acid derivatives. Interestingly,
more than two decades ago, Kubiak and co-workers report-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
[a] Conditions: compound 1 (0.5 mmol); [PdACTHUNGTRENNUNG
ed that [Pd2ACHTUNGTRENNUNG(CNMe)6]ACHUTNRTGENG[NUN PF6]2 is an isolable Pd dimer that,
ACHTNUGTNER(NUGN CNMe)6]
ACHTUNGTRENNUNG
under photoirradiation, is likely to produce a pair of Pd rad-
icals.[17] With great interest in this basic phenomena, we
tested this dimeric PdI complex in our three-component cou-
pling reactions and found that it also worked well. Some
mechanistic studies were undertaken to assess how radicals
and organopalladium species are associated with the acceler-
ated ATC reactions. The stereochemical outcome of these
reactions strongly suggested that radical formation and sub-
sequent carbonylation operated first, followed by the forma-
tion of acylpalladium complexes, which we suggested in-
volved a coupling reaction between acyl radicals and PdI
radicals. We extended our mechanistic probe based on the
diastereoselectivity of the above-mentioned studies on the
metal-catalyzed carbonylation of haloalkanes under photoir-
radiation and thermal conditions[14] and found that these car-
bonylation reactions were also subjected to the same radi-
cal-carbonylation mechanism.
(10 mol%), K2CO3 alone (entries 1 and 2; 1.2–2.0 equiv), or K2CO3 (1.2–
2.0 equiv) plus DMAP (entry 3; 10 mol%); solvent, EtOH (entries 1 and 2;
5 mL), toluene/EtOH (5 mL/40 equiv; entry 3), benzene (entries 6 and 7;
5 mL), benzene/BuOH (entries 4, 5, 8, 9, 11, 12, and 14; 5 mL/0.18 mL), or
toluene/BuOH (5 mL/0.18 mL; entries 10, 13, and 15); CO (45 atm); light
(500 W xenon lamp, Pyrex). [b] Yield of isolated product after column chro-
1
matography on silica gel. [c] Cis/trans ratio determined by H NMR spectros-
copy.
under photoirradiation conditions (500 W xenon lamp
through Pyrex) and 45 atm of CO pressure, the formation of
the corresponding ethyl nonanoate (2a) was dramatically ac-
celerated in the presence of a [PdACHTNUTRGNEUNG(PPh3)4] catalyst (Table 1,
entries 1 and 2). We also tested a dimeric Pd complex.
When the reaction of 1-iodooctane (1a), CO, and EtOH
was carried out in the presence of a catalytic amount of
[Pd2ACHTNUTRGENN(UG CNMe)6]ACHUTTGNERN[NUGN PF6]2 under photoirradiation conditions, the
corresponding carboxylic acid ester (2a) was obtained in
87% yield (Table 1, entry 3). Pd/light-induced acceleration
was also observed when cyclopropylcarbinyl iodide (1b) was
used as a substrate (Table 1, entries 4 and 5), which gave
butyl 4-butenoate (2b) through the ring-opening of a cyclo-
propylcarbinyl radical.[18] Whereas the ATC reaction of hy-
droxyalkyl iodide 1c suffered from a competitive ionic cycli-
zation reaction that led to an oxetane ring,[9c] the addition of
a Pd catalyst greatly improved the yield of the correspond-
ing lactone (2c, Table 1, entries 6 and 7). In the case of sec-
ondary and tertiary alkyl iodides, the ATC reactions pro-
Results and Discussion
To determine the scope of the acceleration of the photoirra-
diation-promoted atom-transfer carbonylation reaction by
Pd salts, various 1-iodoalkanes (1a–1e) were exposed to
both original and Pd-incorporated conditions (Table 1).
After optimization of the reaction conditions, we deter-
mined the optimal base, amount of alcohol, light source, and
CO pressure for each alkyl iodide substrate. When the reac-
tion of 1-iodooctane (1a), CO, and EtOH was carried out
ceeded more smoothly in the presence of either [PdACHTUNGTRENNUNG(PPh3)4]
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Pd/Light-Accelerated Carbonylation of Alkyl Iodides
FULL PAPER
or [Pd
(CNMe)6]
E
6a was not obtained without the addition of water.[21] Tolu-
ene was a good solvent for this reaction (Table 2, entry 6).
The use of a dimeric Pd catalyst under light irradiation also
worked well to give diester 6a in 86% yield (Table 2,
entry 7).
We also examined a cyclization/carbonylation sequence
(Table 1, entries 14 and 15). Thus, when alkyl iodide 1 f was
exposed to Pd/light-induced carbonylation conditions, the
anticipated pyrrolidine derivative (2 f), which contained
a carboxylic acid ester group, was obtained in 73% yield.
The reaction of alkyl bromide 1g also proceeded well to
afford the same product in 58% yield. Recently, Alexanian
and co-workers reported that, under thermal conditions (110
or 1308C), intramolecular Heck-type or carbonylative Heck
reactions of alkenyl iodides proceeded to afford five- or six-
By using a combination of light irradiation with either
a monomeric PdII catalyst plus water (conditions A) or a di-
meric PdI catalyst (conditions B), we examined a variety of
a-substituted iodoalkanes, alkenes, and alcohols in these
four-component coupling reactions (Table 3). In general, the
dimeric Pd catalyst worked equally as well as the monomer-
ic catalyst to give the anticipated four-component-coupled
products. The reaction of benzyl alcohol (5b) gave the an-
ticipated diester (6b) in 67% yield (conditions A) and 71%
yield (conditions B; Table 3, entry 2). The use of MeOH
(5c) caused transesterification of an ethyl ester and, as
a result, dimethyl ester 6c was obtained as the product in
70% yield (Table 3, entry 3). Cl- and Ph-substituted alkenes
4b and 4c were converted into their corresponding diesters
(6d and 6e, respectively) in good yields (Table 3, entries 4
and 5). The reaction of perfluorohexyl iodide (3b) with
compounds 4a and 4c also proceeded effectively to furnish
esters 6 f and 6g in good yields (Table 3, entries 6 and 7). Io-
doacetonitrile (3c) and iodomethyl phenyl sulfone (3d) also
worked well in these coupling reactions (Table 3, entries 8
and 9). We also examined a radical cascade sequence to ac-
company the intramolecular 5-exo-cyclization process
(Table 3, entry 10). When the reaction of compound 3a with
1,5-hexadiene (4d) was carried out in the presence of
membered rings in the presence of [PdACTHNUTRGNEUNG
(PPh3)4].[19]
Having confirmed the acceleration of the ATC reaction
by using a combined Pd/light system, we embarked on the
development of multicomponent coupling processes through
the vicinal carbon-functionalization of alkenes. In a related
study, we had previously reported the photoinduced addi-
tion of a-phenylseleno-substituted esters to alkenes and CO
to afford acyl selenides;[20] however, this system was not ap-
plicable to the synthesis of ordinary esters. We attempted
a four-component coupling reaction that comprised ethyl io-
doacetate (3a), 1-octene (4a), EtOH (5a), and CO
(Table 2). First, we used thermal conditions in the presence
of [PdCl2ACHTUNGTRENNUNG(PPh3)2], DMAP, base, and small amount of water
under CO pressure (45 atm; Table 2, entries 1 and 2). De-
spite the fact that the anticipated coupling reaction proceed-
ed, the yields of diester 6a were poor. The reaction under
photoirradiation without Pd catalyst was reluctant (Table 2,
entry 3) but the combination of the Pd catalyst and photoir-
radiation conditions was quite effective and compound 6a
was obtained in good yield (Table 2, entry 4). The use of
K2CO3 as a base in the place of triethylamine was also effec-
tive, thus giving compound 6a in 77% yield (Table 2,
entry 5). We assumed that the added water may contribute
to the smooth generation of Pd0 from PdII because diester
[PdCl2ACHTUGNRTENN(NUG PPh3)2] or [Pd2ACHTNUTREGGNN(UN CNMe)6]ACHTNUGRTNE[UNGN PF6]2, the anticipated five-
component coupling reaction through the incorporation of
two molecules of CO proceeded to give diester 6j with a cy-
clopentanone scaffold. In these cases, uncyclized product 6k
was formed as a by-product.
Ester-functionalized lactones 8a–8c were prepared from
three-component cyclization reactions of alkenyl alcohols
7a–7c (Scheme 2). The yield of seven-membered-ring lac-
tone 8c was rather modest, owing to the competitive ionic
cyclization reaction to give a tetrahydropyran ring. When
the three-component cyclization reaction was carried out
with alkenylamine 9, the anticipated lactam (10) was only
obtained in 14% yield.[22]
Table 2. Four-component coupling reaction of ethyl iodoacetate (3a)
with 1-octene (4a), EtOH (5a), and carbon monoxide.[a]
Mechanistic insight: To determine the precise role of the Pd
catalyst, we performed experiments by using Pd/photoirra-
diation and Et3B-initiated radical conditions (Scheme 3).
When the iodine-atom-transfer reaction of 6-iodo-1-octene
Entry Catalyst [mol%]
Base
Conditions
t
Yield
[h] [%][b]
1
N
N
Et3N
K2CO3
Et3N
808C
1208C
hn
hn
hn
16 21
16 23
14 25
2
N
U
3
(11) was carried out in the presence of [PdACTHNUTRGNE(UNG PPh3)4] under
4
5
N
G
Et3N
8
8
72
77
photoirradiation conditions, the anticipated cyclized product
(12) was obtained as a cis/trans mixture (73:27). Interesting-
ly, the reaction of compound 11 by using Et3B as a radical
initiator resulted in the formation of compound 12 in the
same 73:27 isomeric ratio. We also examined a Pd/hn-in-
duced carbonylation reaction, which also gave ethyl ester 13
in a nearly identical isomeric ratio (74:26). The calculated
cis/trans ratio of the 5-exo cyclization of a 1-methyl-5-hexen-
yl radical by known rate constants reported by Beckwith
K2CO3
K2CO3
K2CO3
6
hn
hn
14 82
12 86
7[c]
G
[a] Conditions: compound 3a (0.5 mmol), compound 4a (10 equiv),
EtOH (5a, 40 equiv), CO (45 atm), catalyst (5 or 2 mol%), base
(1.1 equiv), DMAP (10 mol%), benzene (entries 1 and 3–5; 5 mL) or tol-
uene (entries 2, 6 and 7; 5 mL), H2O (10 mL). [b] Yield of isolated com-
pound 6a after column chromatography on silica gel. [c] Compound 4a
(5.0 equiv) was used without the addition of H2O.
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Table 3. Four-component
coupling
ROH
reactions
leading
to
esters.[a]
initiator in the cyclization reaction of a-iodo
carbonyl compounds by atom-transfer meth-
ods.[24]
Next, our attention was directed to the car-
bonylation step; in principle, two mechanistic
pathways are conceivable: 1) radical addition of
an alkyl radical to CO to form an acyl radical
and 2) migratory insertion of CO into an alkyl–
palladium bond. We decided to compare the
stereochemical outcomes of the carbonylation
step by using 2-iodo-3-methylheptane (14) as
the substrate in both cases, with and without
a Pd catalyst (Scheme 4). The three-component
coupling reaction of 2-iodo-3-methylheptane
(14), CO, and MeOH under photoirradiation
conditions without a Pd catalyst for 6.5 h gave
the corresponding methyl ester (15) in 29%
yield with a diastereomeric ratio of 42:58 (anti/
syn).[25] A similar reaction in the presence of
Entry
R-I
Alkene
Product
Conditions Yield
[%][b]
EtOH
5a
A
B
82
86
1
3a
3a
3a
4a
4a
BnOH
5b
A
B
67
71
2[c]
MeOH
5c
A
70
3
5a
A
B
72
75
4
3a
5a
5a
5a
A
74
[PdACHTNURTGENUNG(PPh3)4] gave the same methyl ester (15) in
a quite similar diastereomeric ratio (43:57) in
61% yield. This similarity between the diaste-
5
6
7
C6F13I
3b
4a
4c
A
B
84
79
À
reoselectivities strongly suggests that the C C
bond-forming step proceeds through a radical
CO-addition mechanism in both cases.
3b
A
76
The [PtCl2ACTHUNTRGNE(UNG PPh3)2]-catalyzed carbonylation
reaction of alkyl iodides in the presence of alco-
hols under irradiation by a high-pressure Hg
lamp (200 W) was previously reported by Wata-
nabe and co-workers, which gave their corre-
sponding carboxylic acid esters.[14a,b] They pro-
posed a non-chain-radical mechanism in which
the migratory insertion of carbon monoxide into
an alkyl–metal bond, thereby leading to an
acyl–metal complex, was negated. We became
curious as to whether or not their carbonylation
4a
4a
5a
5a
A
B
64
69
8
9
A
B
56
53
47
(cis/
trans=
38:62)
40
3a
5a
A[d]
B[e]
10
À
step involved a radical C C bond-forming pro-
(cis/
cess and decided to re-examine the reaction by
using alkyl iodide 14 as a stereochemical probe.
Thus, the reaction of compound 14, CO, and
MeOH was carried out in the presence of
trans=
37:63)
27
A[d]
B[e]
30
[PtCl2ACHTNUGRTNEUNG(PPh3)2] under irradiation from a Xe lamp
(300 W, Scheme 5). The anticipated methyl ester
(15) was obtained in 42% yield with a 43:57
diastereomer ratio, which was the same ratio as
in our Pd/light reaction. Watanabe and co-work-
ers also reported the Pt-catalyzed carbonylation
of iodoalkanes under heat treatment (1208C).[26]
Again, we tested alkyl iodide 14 and found that
ester 15 was obtained in 47% yield with a diaste-
reomeric ratio of 42:58. Thus, we can conclude
[a] Conditions A: compound
(40 equiv), CO (45 atm), [PdCl
(10 mol%), toluene (5 mL), H2O (10 mL). Conditions B: compound 3 (0.5 mmol), com-
pound 4 (5 equiv), compound 5 (40 equiv), CO (45 atm), [Pd2A(CNMe)6][PF6]2 (2 mol%),
K2CO3 (1.2–1.3 equiv), DMAP (10 mol%), toluene (5 mL). [b] Yield of isolated product
after column chromatography on silica gel. [c] BnOH (5.0 equiv). [d] CO (95 atm). [e] CO
(85 atm).
3
(0.5 mmol), compound
CTHUNGTRENNUNG
4 (10 equiv), compound 5
C
ACHTUNGTRENNUNG
and Schiesser[23] was 73:27, which is identical to our ob-
served diastereomeric ratios. Thus, it seems reasonable to
say that our Pd/hn-induced cyclization ATC reactions pro-
ceeded through a mechanism that involved radical forma-
tion and subsequent radical cyclization steps. As a precedent,
that, even in the Pt/light- or Pt/thermal-carbonylation
system reported by Watanabe and co-workers, a radical-car-
bonylation mechanism operates, as well as in our case.
Taking these results into consideration, we proposed a re-
action mechanism for this Pd/hn-assisted three-component
coupling reaction (Scheme 6), by using the transformation
Curran and Chang previously reported that [Pd
ACHTUNGTNER(NUNG dppe)2]
(dppe=1,2-bis(diphenylphosphino)ethane) acted as radical
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Pd/Light-Accelerated Carbonylation of Alkyl Iodides
FULL PAPER
À
from compound 1a into compound 2a in the presence of
the cleavage of the I C bond of compound 1a, which may
be triggered by a single electron transfer from the photoex-
cited Pd0 species. The precedence for a single electron trans-
fer from low-valent palladium complexes to iodoalkanes is
well-established.[27] In addition, the intervention of a radical
mechanism has been strongly suggested by radical-cascade
experiments and electron spin resonance (ESR) spectrosco-
py in the iodine-atom-transfer reaction of perfluoroalkyl io-
dides and alkenes.[28] In the case of a dimeric PdI complex,
the Pd radical that was generated under photoinduced ho-
molysis of the dimeric Pd complex may undergo iodine-
atom abstraction from alkyl iodides. Then, the coupling of
the alkyl radical and PdI to give an alkylpalladium species
might take place, but this process scarcely contributes to this
reaction mechanism because we employed highly concen-
trated CO conditions. The resultant alkyl radical is quickly
a Pd0 catalyst as an example. Alkyl radicals are formed by
Scheme 2. Three-component coupling reactions to afford lactones and
lactams.
Scheme 5. Comparison of the isomeric ratios of the previously reported
Pt-catalyzed carbonylation reactions.[14a,b]
Scheme 3. Comparison of the isomeric ratios of the atom-transfer 5-exo
cyclization and carbonylation reactions.
Scheme 4. Comparison of the isomeric ratios of the atom-transfer carbon-
ylation reactions with and without a Pd catalyst.
Scheme 6. Possible reaction mechanism.
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I. Ryu et al.
consumed by adding to CO to afford an acyl radical that is
eventually trapped by PdII to form an acylpalladium com-
plex, which is a precursor for the ethyl ester (2a). When we
investigated the three-component reaction of an alkyl
iodide, CO, and amines, keto amide 17 was formed as the
principal product from the incorporation of two molecules
of CO (Scheme 7).[16a] In contrast, in the absence of a Pd
nation of the rather labile alkylpalladium intermediates.
However, these Pd/hn-mediated radical processes can avoid
these issues by proceeding through a free-radical pathway:
1) the formation of an alkyl-radical/Pd-radical pair, 2) subse-
À
quent C C bond-forming reaction by the radicals (carbony-
lation), and 3) radical/Pd-radical coupling to form an orga-
nopalladium intermediate (acylpalladium complexes). We
believe that, as seen in the mechanistic considerations in re-
lated work, a radical-carbonylation mechanism may operate
in other metal-catalyzed carbonylation reactions that involve
alkyl halides.
Experimental Section
General procedure for the synthesis of esters through a three-component
coupling reaction:
0.28 mmol), BuOH (0.095 g, 1.3 mmol), Et3N (0.048 g, 0.47 mmol), 4-di-
methylaminopyridine (0.002 g, 0.016 mmol), [Pd(PPh3)4] (0.018 g,
A magnetic stirrer bar, compound 1b (0.051 g,
AHCTUNGTRENNUNG
0.016 mmol), and benzene (3.0 mL) were placed in a stainless steel auto-
clave that was equipped with a Pyrex glass liner. The autoclave was
closed, purged three times with carbon monoxide, pressurized with CO
(45 atm), and then irradiated by a Xenon arc lamp (500 W) with stirring
for 16 h. Excess CO was discharged after the reaction at RT. The reaction
mixture was added to water (20 mL) and extracted with Et2O (3ꢂ
20 mL). The Et2O layer was washed with brine, dried over MgSO4, fil-
tered, and concentrated in vacuo to give a residue that was purified by
column chromatography on silica gel (n-hexane/EtOAc) to afford com-
pound 2b (0.036 g, 83%).
Scheme 7. Three-component coupling reaction to afford amide 16 and a-
keto amide 17.
catalyst, amide 16 was obtained as the sole carbonylated
product.[9b] Because the carbonylation of an acyl radical is
rarely observed in radical-carbonylation reactions,[29] the in-
tervention of an acylcarbamoylpalladium complex, which
has been well-established by Yamamoto and co-workers for
a Pd-catalyzed double-carbonylation reaction,[30] is strongly
suggested to account for the formation of compound 17. We
believe that the PdII species may be a persistent radical[31]
that may exist in equilibrium with a PdI dimer under the
photoirradiation conditions.[19] Interestingly, when we mea-
sured the MS (FAB) of the reaction mixture with [Pd-
General procedure for the synthesis of esters through a four-component
coupling reaction: A magnetic stirrer bar, ethyl iodoacetate (3a, 0.13 g,
0.61 mmol), 1-octene (4a, 0.69 g, 6.2 mmol), EtOH (5a, 1.2 g, 26 mmol),
K2CO3 (0.10 g, 0.72 mmol), [PdCl2ACTHNURTGENUNG(PPh3)2] (0.025 g, 0.036 mmol), 4-dime-
thylaminopyridine (DMAP, 0.0084 g, 0.069 mmol), toluene (5.0 mL), and
H2O (10 mL) were placed in a stainless steel autoclave that was equipped
with a Pyrex glass liner. The autoclave was closed, purged three times
with carbon monoxide, pressurized with CO (45 atm), and then irradiated
by a Xenon arc lamp (500 W) with stirring for 14 h. Excess CO was dis-
charged after the reaction at RT. The reaction mixture was added to
water (20 mL) and extracted with Et2O (3ꢂ20 mL). The combined Et2O
layer was washed with brine, dried over MgSO4, filtered, and concentrat-
ed in vacuo. The resulting residue was purified by column chromatogra-
phy on silica gel (n-hexane/Et2O) to afford compound 6a (0.14 g, 82%).
ACHTUNGTRENNUNG(PPh3)4] as the catalyst, the observed fragment-ion peaks of
General procedure for the synthesis of lactones: A magnetic stirrer bar,
ethyl iodoacetate (3a, 55 mg, 0.25 mmol), 4-penten-1-ol (7b, 105 mg,
1.3 mmol), Et3N (30 mg, 0.30 mmol), [PdCl2ACHTNUGTRNEGNU(PPh3)2] (9.1 mg,
the Pd species corresponded well with the simulated isotope
pattern for dinuclear Pd complexes.[32]
0.013 mmol), DMAP (4.1 mg, 0.033 mmol), toluene (5.0 mL), and H2O
(50 mL) were placed in a stainless steel autoclave that was equipped with
a Pyrex glass liner. The autoclave was closed, purged three times with
CO (10 atm), pressurized with CO (45 atm), and then irradiated by
a Xenon arc lamp (300 W) with stirring for 16 h. Excess CO was dis-
charged after the reaction at RT. The reaction mixture was added to
water (20 mL) and extracted with Et2O (3ꢂ20 mL). The combined Et2O
layer was washed with brine, dried over MgSO4, filtered, and concentrat-
ed in vacuo. The resulting residue was purified by column chromatogra-
phy on silica gel (n-hexane/Et2O) to afford compound 8b (39 mg, 77%).
Conclusion
In summary, we have demonstrated that the photoinduced
atom-transfer carbonylation reactions of a variety of alkyl
iodides can be effectively accelerated by the addition of Pd
complexes. This procedure provides a general synthetic ap-
proach for the synthesis of various carboxylic-acid deriva-
tives through useful cascade sequences that are tolerant of
a variety of alkyl iodides as starting materials. In many
Procedure for the synthesis of lactam: A magnetic stirrer bar, ethyl io-
doacetate (3a, 50 mg, 0.24 mmol), N-(pent-4-enyl)aniline (9, 205 mg,
1.3 mmol), Et3N (29 mg, 0.29 mmol), [PdCl2ACHTNUGTRNEGNU(PPh3)2] (9.3 mg,
0.013 mmol), DMAP (4.3 mg, 0.035 mmol), toluene (5.0 mL), and H2O
(50 mL) were placed in a stainless steel autoclave that was equipped with
a Pyrex glass liner. The autoclave was closed, purged three times with
CO (10 atm), pressurized with CO (45 atm), and then irradiated by
a Xenon arc lamp (300 W) with stirring for 16 h. Excess CO was dis-
charged after the reaction. The reaction mixture was added to water
cases, Pd dimer [Pd2ACHTNUGTRENNG(U CNMe)6]ACHTUNGTRENN[UNG PF6]2 worked equally as well
as Pd0 catalysts for these photoinduced carbonylation reac-
tions. To affect the somewhat-inefficient oxidative addition
of sp3-carbon–halogen bonds to Pd0 complexes, electron-rich
ligands are used[33,34] that can suppress the b-hydride elimi-
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Pd/Light-Accelerated Carbonylation of Alkyl Iodides
FULL PAPER
(20 mL) and extracted with Et2O (3ꢂ20 mL). The combined Et2O layer
was washed with brine, dried over MgSO4, filtered, and concentrated in
vacuo. The resulting residue was purified by column chromatography on
silica gel (n-hexane/Et2O) to afford compound 10 (9.0 mg. 14%).
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Palladium accelerated atom transfer carbonylation with diethylamine: A
magnetic stirrer bar, compound 1a (0.122 g, 0.51 mmol), Et2NH (0.187 g,
2.6 mmol), [Pd2ACHTUNGTRENNUNG(dba)3]·CHCl3 (dba=dibenzylideneacetone, 0.015 g,
0.014 mmol), (p-MeOC6H4)3P (0.019 g, 0.054 mmol), and benzene
(5.1 mL) were placed in a stainless steel autoclave that was equipped
with a Pyrex glass liner. The autoclave was closed, purged three times
with carbon monoxide, pressurized with CO (75 atm), and then irradiated
by a Xenon arc lamp (500 W) with stirring for 16 h. Excess CO was dis-
charged after the reaction at RT. The reaction mixture was added to
water (20 mL) and extracted with Et2O (3ꢂ20 mL). The Et2O layer was
washed with brine, dried over MgSO4, filtered, and concentrated in
vacuo to give a residue that was purified by column chromatography on
silica gel (n-hexane/EtOAc) to afford compounds 16 (0.013 g, 11%) and
17 (0.082 g, 64%).
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Acknowledgments
We thank the JSPS, MEXT Japan, and Scientific Research on Innovative
Areas (No. 2105) for their generous funding of this work. We thank Prof.
Armido Studer for helpful discussions on the mechanistic possibility of
persistent Pd radicals. We are grateful to Fumikazu Araki for initial ex-
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Received: March 6, 2012
Published online: && &&, 0000
[32] For details, see the Supporting Information.
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Pd/Light-Accelerated Carbonylation of Alkyl Iodides
FULL PAPER
Carbonylation
A. Fusano, S. Sumino, S. Nishitani,
T. Inouye, K. Morimoto, T. Fukuyama,
I. Ryu* ......................... &&&& — &&&&
Pd/Light-Accelerated Atom-Transfer
Carbonylation of Alkyl Iodides; Appli-
cations in Multicomponent Coupling
Processes Leading to Functionalized
Carboxylic Acid Derivatives
Light, camera, ATCion: Atom-transfer
carbonylation of alkyl iodides to afford
carboxylic acid esters was accelerated
by the addition of transition-metal cat-
alysts under photoirradiation. The car-
bonylation step proceeded through
a radical mechanism.
Chem. Eur. J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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