Nickel-promoted carboxylation/cyclization cascade of allenyl aldehyde under an atmosphere of CO2

Article abstract of DOI:10.1055/s-0030-1260565

In the presence of a stoichiometric amount of Ni(0) complex, allenyl aldehydes smoothly reacted with carbon dioxide at an ambient temperature and pressure in a regioselective manner. The reaction involves an intramolecular cyclization of aldehyde and alle

Full text of DOI:10.1055/s-0030-1260565

LETTER
1423
Nickel-Promoted Carboxylation/Cyclization Cascade of Allenyl Aldehyde
under an Atmosphere of CO2
C
arboxylation/Cycliza
a
s
e
of Allen
a
yl
A
ldehyd
n
e
ori Takimoto,1 Mitsunobu Kawamura, Miwako Mori, Yoshihiro Sato*
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
E-mail: biyo@pharm.hokudai.ac.jp
Received 10 February 2011
ence of Ni(cod)2 (1 equiv) and 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU, 2 equiv) (Scheme 2). After hydrolysis of
the reaction mixture followed by diazomethane esterifica-
tion, the desired cyclic carboxylic acid ester 3a was isolat-
Abstract: In the presence of a stoichiometric amount of Ni(0) com-
plex, allenyl aldehydes smoothly reacted with carbon dioxide at an
ambient temperature and pressure in a regioselective manner. The
reaction involves an intramolecular cyclization of aldehyde and
allene moieties to afford cyclic carboxylic acid derivatives having a ed in 50% yield. Treatment of 3a with NaH afforded
hydroxyl group.
bicyclic a-methylene lactone 4a in 92% yield. The ob-
served coupling constant value between Ha and Hb in the
1H NMR spectrum of 4a showed that 4a had a trans-fused
bicyclic structure, and thus the configuration of the hy-
droxyl group and alkenyl moiety on 3a was determined to
be trans.
Key words: allenes, aldehydes, carboxylic acid, cyclization, nickel
Development of new methods to incorporate carbon diox-
ide (CO2) into organic molecules through carbon–carbon
bond formations is still an important subject in synthetic
organic chemistry. With the aim of developing novel CO2
incorporation reactions, transition-metal-promoted car-
boxylation reaction has attracted much attention.2,3 Nick-
el-mediated or -catalyzed coupling reactions of CO2 with
unsaturated hydrocarbons have been extensively investi-
gated recently.4 Such nickel-mediated processes are at-
tractive not only because they can be conducted under
mild conditions but also because they can produce reac-
tive intermediates that are usable for further carbon–
carbon bond formation. In this letter, we report a nickel-
promoted CO2 incorporation reaction into allenyl alde-
hydes that involves an intramolecular carbon–carbon
bond formation between the allene and aldehyde moi-
eties.5,6
OH
CO2
Ni(0)/L
CHO
O
CHO
CO2H
O
Ni
1
2
3
Scheme 1 Carboxylation/cyclization cascade
1) Ni(cod)2 (1 equiv)
MeO2C
MeO2C
DBU (2 equiv)
CO2 (1 atm)
THF, r.t., 4 h
MeO2C
MeO2C
OH
CHO
CO2Me
then 10% HCl (aq)
2) CH2N2
1a
trans-3a
(50%)
MeO2C
MeO2C
MeO2C
CO2Me
Hb
In the course of our previous studies on nickel-promoted
or -catalyzed CO2 incorporation reactions,5 we found that
various allenes reacted with CO2 and a zero-valent nickel
complex to form a nucleophilic oxa-nickelacycle that
could react with aldehydes.5e From these results, we envi-
sioned a carboxylation/cyclization cascade of allenyl al-
dehyde 1, which would proceed according to the
following reaction process: (i) oxidative cyclization of 1
and CO2 with low-valent nickel species would afford an
oxa-nickelacycle 27 and (ii) intramolecular nucleophilic
addition of the oxa-nickelacycle moiety of 2 to the teth-
ered aldehyde would give cyclized product 3 (Scheme 1).8
O
NaH
=
O
THF, r.t.
O
Ha
J = 7.2 Hz
4a
(92%)
Scheme 2
To improve the yield of 3a, various reaction conditions
were examined (Table 1).
Among the solvents examined (entries 1–3), 1,4-dioxane,
a relatively polar solvent gave the best result (entry 3).
The effects of ligands were also investigated when diox-
ane was used as the solvent (entries 5 and 6). The use of
DBN, 1,2-bipyridine (bpy) or 1,2-dimethylimidazole
(DMI) did not result in any significant improvement com-
We first examined nickel-promoted carboxylation of the
allenyl aldehyde 1a under standard conditions previously
developed by us for nickel-promoted CO2 incorporation
reactions. To our delight, the reaction of 1a with CO2 (1
atm) proceeded in THF at room temperature in the pres- pared with DBU. Interestingly, by using tetramethylethyl-
ene diamine (TMEDA) as the ligand, the total yield of the
cyclized products was improved to 87%, although cis-3a
SYNLETT 2011, No. 10, pp 1423–1426
Advanced online publication: 16.05.2011
x
x
.x
x
.2
0
1
1
was also formed in 28% yield along with trans-3a.9
DOI: 10.1055/s-0030-1260565; Art ID: U01611ST
© Georg Thieme Verlag Stuttgart · New York

1424
M. Takimoto et al.
LETTER
Table 1 Carboxylative Cyclization of 1a under Various Conditionsa
With this knowledge in hand, we tried to apply the present
carboxylation/cyclization cascade for the synthesis of het-
erocyclic and benzene-fused bicyclic compounds, and the
results are summarized in Table 2.
MeO2C
1) Ni(cod)2/ligand
solvent, r.t.
OH
1a
+
MeO2C
trans-3a
CO2Me
then 10% HCl (aq)
2) CH2N2
1) CO2 (1 atm)
cis-3a
Ni(cod)2 (1 equiv)
TMEDA (1 equiv)
E
E
E
E
CHO
dioxane, r.t., 1 h
Entry Solvent
Ligand
Time (h) Yield of 3a (%)
CHO
(1)
CO2Me
then 10% HCl (aq)
3) CH2N2
trans cis
Total
42
1
2
3
4
5
6
7
toluene
DMF
DBUb
DBUb
DBUb
DBNb
bpyc
3
3
4
1
2
2
3
42
52
57
45
17
27
59
–
1c
(E = CO2Me)
5c
(45%)
–
52
NOE
H
O
dioxane
dioxane
dioxane
dioxane
dioxane
–
57
1) same as above
ZnCl2 (3 equiv)
E
E
(2)
O
–
45
then 10% HCl (aq)
Ni(0), CO2
H
–
17
cis-4c (41%)
DMIb
–
27
E
E
E
TMEDAc
28
87
CHO
CHO
O
ZnCl2
CO2ZnCl
NiCl
a The reactions were carried out using 1 equiv of Ni(cod)2 under an
atmosphere of CO2 (1 atm).
E
O
2c
6c
b 2 equiv relative to Ni(cod)2.
Ni
c 1 equiv relative to Ni(cod)2.
Scheme 4
The reaction of 1b with CO2 proceeded smoothly in the
presence of Ni(cod)2 and TMEDA at room temperature to
give the desired cyclic product with a five-membered ring Entry Substrate
(Scheme 3). Because the formed carboxylic acid easily
Table 2 Carboxylative Cyclization of 1d–ha
Time (h) Products (trans/cis)b Yield (%)
OH
( )n
underwent dehydration during the purification process,
TsN
TsN
CHO
1c
1
2
1
74
33
85
the product was isolated and characterized as 4b (61%
yield from 1b) after lactonization in the presence of an
acid catalyst. From the results of NOE experiments, the
stereochemistry of 4b was determined to be cis, as shown
in Scheme 3.
CO2Me
1d (n = 1)
3d (65:9)
O
TsN
O
2d 1e (n = 2)
1) CO2 (1 atm)
Ni(cod)2 (1 equiv)
TMEDA (1 equiv)
dioxane, r.t., 1 h
NOE
4e (0:1)
H
MeO2C
MeO2C
MeO2C
O
OH CO2Me
CHO
CHO
O
then 10% HCl (aq)
2) cat. PPTS, benzene
reflux, 2 h
3c
4c
5c
MeO2C
( )2
H
R
1b
cis-4b (61%)
1f (R = H)
3f (61:24)
Scheme 3
OH CO2Me
1g (R = Ph)
1h (R = Me)
2
3
66
74
In contrast, seven-membered ring formation from 1c was
sluggish under similar conditions, and simply carboxylat-
ed product 5c was obtained in 45% yield (Scheme 4,
Equation 1). This result indicated that the reaction did not
proceed further from intermediate 2c. However, fortu-
nately, we found that the use of ZnCl2 (3 equiv to 1c) as
an additive promoted the desired cyclization process to af-
ford the lactone cis-4c in 41% yield (Scheme 4, Equation
2). The use of other Lewis acids, including BF3 and
TMSOTf, did not work well as promoters. These results
suggest that ZnCl2 did not simply act as a Lewis acid but
also as a transmetalating reagent to form a more nucleo-
philic p-allylnickel chloride such as 6c.10
Ph
3g (51:15)
OH CO2Me
Me
3h (63:11)
a The reactions were carried out using Ni(cod)2 (1 equiv) and TMEDA
(1 equiv) in dioxane under an atmosphere of CO2 (1 atm).
b The ratio was determined by 1H NMR. For determination of the
stereochemistry of the products, see Supporting Information.
c The crude products were treated with CH2N2 for esterification.
d The crude products were treated with PPTS in benzene for lactoniza-
tion.
Synlett 2011, No. 10, 1423–1426 © Thieme Stuttgart · New York

LETTER
Carboxylation/Cyclization Cascade of Allenyl Aldehyde
1425
Carboxylative cyclization of 1d with CO2 in the presence regioselective manner and provides a novel method for
of a stoichiometric amount of Ni(cod)2 and TMEDA pro- the synthesis of bicyclic a-methylene-g-lactones. Further
ceeded smoothly to afford the desired cyclized product 3d studies on expansion of the scope of this procedure are
in 74% yield as a mixture of two stereoisomers. Although now in progress.
ZnCl2 was necessary, carboxylation of 1e also gave the
desired product 4e in 33% yield. Furthermore, the present
system was applicable to the synthesis of benzene-fused
bicyclic compounds (Table 2, entries 3–5). Benzaldehyde
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
derivative 1f, having a terminal allene moiety at the ortho
position, smoothly reacted with CO2 under similar condi-
tions to afford 3f in 85% yield. Interestingly, in the reac-
tions of 1g and 1h having an internal allene moiety, the
cyclization process proceeded to give 3g and 3h in 66%
and 74% yields, respectively. In both cases, configuration
of the newly formed double bond was controlled to be in
the E-form. The results of carboxylation of 1c in the ab-
sence of ZnCl2 (Scheme 4, Equation 1) strongly supported
our initial hypothesis of the carboxylation/cyclization cas-
cade shown in Scheme 1. However, the high regio- and
E-selectivity observed in the reactions of 1g and 1h
(Table 2, entries 4 and 5) suggest another possible reac-
tion pathway. Montgomery and co-workers reported a
nickel-catalyzed cyclization of allenyl aldehydes that in-
volved an oxidative cyclization of the allene and aldehyde
moieties to low-valent nickel species as the first step of
the catalytic cycle.8a Allenyl aldehydes 1g or 1h would
also be able to react with low-valent nickel species in a
similar way before the reaction with CO2 (Scheme 5). To
undergo such reaction, low-valent nickel species would be
preferably placed at the opposite side of the ‘R’ group due
to steric repulsion (Scheme 5, intermediate 7). Thus, oxi-
dative cyclization from 7 would give oxa-nickelacycle in-
termediate 8. Then insertion of CO2 into the nickel–
carbon bond would proceed in a stereospecific manner to
form 9, which would afford 3g or 3h after hydrolysis and
esterification. This cyclization/carboxylation cascade
pathway cannot be excluded in the reactions of other
allenyl aldehydes. Thus, in the actual system, the reaction
course might involve one or both cascades depending on
the substrate used.
References and Notes
(1) Present address: Organometallic Chemistry Laboratory,
RIKEN Advanced Science Institute, Hirosawa 2-1, Wako,
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H
Ni
O
O
Ni
R
1g
or
1h
Ni(0)
R
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7
8
Ni
O
O
O
O
Ni
O
C
O
CO2
R
R
9
Scheme 5 Cyclization/carboxylation cascade
In summary, nickel-mediated cyclization of allenyl alde-
hydes that involved a CO2 incorporation process was de-
veloped. The reaction proceeds under mild conditions in a
Synlett 2011, No. 10, 1423–1426 © Thieme Stuttgart · New York

1426
M. Takimoto et al.
LETTER
(8) For related examples for nickel-catalyzed inter- or
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the reaction of allenes, CO2, and nickel(0) complex, see:
Hoberg, H.; Oster, B. W. J. Organomet. Chem. 1984, 266,
321.
intramolecular reactions between allene and aldehyde, see:
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(9) Oxidation of the mixture of trans- and cis-3a afforded the
corresponding ketone as the sole product in high yield.
(10) Semmelhack reported a similar transformation involving an
intramolecular nucleophilic addition of p-allylnickel
bromide intermediate to aldehyde that formed a seven-
membered ring fused with a-methylene-g-lactone. The cis-
stereoselectivity observed in Semmelhack’s example shows
good accordance with our results: Semmelhack, M. F.; Wu,
E. C. S. J. Am. Chem. Soc. 1976, 98, 3384.
Synlett 2011, No. 10, 1423–1426 © Thieme Stuttgart · New York