Nickel(0)-promoted carboxylation of allenamides with carbon dioxide via a nickelalactone intermediate

Article abstract of DOI:10.1055/s-0033-1340628

Nickel(0)-promoted carboxylation of N-allenylamides (allenamides) with carbon dioxide proceeded via a nickelalactone intermediate to give β-amino acid derivatives. It was also found that the regioselectivity at the oxidative addition stage was strongly af

Full text of DOI:10.1055/s-0033-1340628

736▌
LETTER
lNettierckel(0)-Promoted Carboxylation of Allenamides with Carbon Dioxide via a
Nickelalactone Intermediate
Nickel-Promoted Carboxylation of Allenamides
Nozomi Saito,*a Yasuyuki Sugimura,a Yoshihiro Sato*a,b
a
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Fax +81(11)7064982; E-mail: biyo@pharm.hokudai.ac.jp
b
ACT-C, Japan Science and Technology Agency (JST), Sapporo 060-0812, Japan
Received: 21.11.2013; Accepted after revision: 18.12.2013
N-Allenylamides (allenamides, Scheme 2, 4) have been
Abstract: Nickel(0)-promoted carboxylation of N-allenylamides
recognized as versatile synthetic units in recent organic
(allenamides) with carbon dioxide proceeded via a nickelalactone
synthesis.9 Due to delocalization of lone-pair electrons of
intermediate to give β-amino acid derivatives. It was also found that
a nitrogen atom to a double bond of the allene moiety de-
picted as 4′, the sp carbon atom of allenamide has a partial
negative charge. Therefore, allenamide could act as a
polarized allene, and various organic transformations of
allenamide using its unique electronic property have been
reported in the past decade.
the regioselectivity at the oxidative addition stage was strongly af-
fected by the substituents on the allene part.
Key words: nickel, allenamide, carbon dioxide, fixation, β-amino
acid
Carbon dioxide (CO2) is an abundant, ubiquitous, cheap,
and relatively nontoxic one-carbon source in synthetic or-
ganic chemistry, and various methods for the incorpora-
tion of CO2 into organic compounds have been
demonstrated. Recently, transition-metal-promoted direct
carboxylation of organic compounds has attracted much
attention due to its high efficiency.1,2 In particular, the
zero-valent nickel complex has been widely used for car-
boxylation of carbon–carbon unsaturated compounds
(Scheme 1).3 The reaction proceeds via nickelalactone in-
termediate 2, which is generated by oxidative cycloaddi-
tion of unsaturated compound 1 and CO2 to a nickel(0)
complex, and hydrolysis of the nickelalactone affords the
corresponding carboxylic acid 3. Thus, the nickelalactone
can be regarded as a useful intermediate for the synthesis
of various carboxylic acids in synthetic organic chemistry.
From the viewpoint of development of a new synthetic
methodology using an atmospheric pressure of CO2, sev-
eral synthetic utilizations of carboxylation via nickelalac-
tone have recently been demonstrated using alkynes,4 1,3-
dienes,5 allenes,6 and diynes7 as well as enynes8 as plat-
forms.
EWG
EWG
R2
N
R1
R2
•
•
N
R1
4
4'
Scheme 2 Structure of allenamide 4
In this context, we planned the nickel-promoted carboxyl-
ation of allenamides (Scheme 3). Thus, if oxidative cyclo-
addition of the allenamide 4 and CO2 to a nickel(0)
complex proceeds in a manner similar to that of previous-
ly reported carboxylation of allene,6,10 carbon–carbon
bond formation would occur between the negatively po-
larized sp carbon atom of 4 and the positive sp carbon
atom of CO2 to give nickelalactone 5 or 7. Finally, hydro-
lysis of the nickelalactone could give β-amino acid deriv-
ative 6 or 8, the structure of which is often found in some
important biologically active compounds.
To examine the feasibility of the plan, we set out to con-
duct condition screening of the carboxylation of allen-
amide (Table 1). According to previous reports on
carboxylation of allene,6 tosylamide-derived terminal al-
lenamide 4a was reacted with an atmospheric pressure of
CO2 in the presence of a stoichiometric amount of
Ni(cod)2 and two equivalents of DBU as a ligand (Table
1, entry 1). After acidic workup with 10% aqueous HCl
solution followed by methylation by CH2N2, CO2-incor-
porated compound 6a was produced in 76% yield as a sin-
gle regio- and stereoisomer.11 When the amount of DBU
was increased to four equivalents, the yield of 6a in-
creased to 89% (Table 1, entry 2). The use of 1,10-phen-
anthroline and 1,2-bis(dicyclohexylphoshino)ethane
(DCPE) gave 6a in low yields (Table 1, entries 3 and 4).
Furthermore, TMEDA ligand was applicable to the car-
boxylation of 4a, giving 6a in 82% yield (Table 1, entry
5).
R1
R2
O
HO
LnNi
R1
H3O+
Ni(0)Ln
C
O
1
+
C
O
R2
R1
R2
O
C
O
2
3
nickelalactone
intermediate
Scheme 1 Synthesis of carboxylic acids from unsaturated com-
pounds and CO2 via a nickelalactone intermediate
SYNLETT 2014, 25, 0736–0740
Advanced online publication: 29.01.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340628; Art ID: ST-2013-U1076-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Nickel-Promoted Carboxylation of Allenamides
737
O
N
O
O
NiLn
H3O+
EWG
EWG
δ+
path A
path B
δ-
N
R1
OH
OH
EWG
R2
•
N
R1
R2
Ni(cod)2
ligand
R2
O
R1
5
EWG
EWG
6
4
O
+
LnNi
O
H3O+
δ- δ+ δ-
N
R1
O
C O
N
R1
R2
8
R2
7
Scheme 3 Plan for carboxylation of allenamide with CO2 via nickelalactone intermediate
Table 1 Nickel-Promoted Carboxylation of Allenamide 4aa
Next, we turned our attention to the carboxylation of
allenamide bearing a tert-butyl group on the allene moiety
(Scheme 5). Thus, the reaction of 4d and CO2 (1 atm) in
the presence of Ni(cod)2 and DBU followed by methyla-
tion gave 8d in 88% yield as a mixture of geometrical iso-
mers with respect to the alkene moiety.
O
1) Ni(cod)2 (1 equiv)
ligand (x equiv)
CO2 (1 atm)
Ts
Ts
·
N
OMe
N
Me
Me
4a
2) HCl (10%)
3) CH2N2
6a
Entry
Ligand (x equiv)
Time (h)
Yield (%)
O
1) Ni(cod)2 (1 equiv)
DBU (4 equiv)
CO2 (1 atm)
1
2
3
4
5
DBU (2)
2
1
1
1
1
76
89
4
MeO2C
MeO2C
N
OMe
•
N
t-Bu
DBU (4)
Bn
t-Bu
Bn
4d
2) HCl (10%)
3) CH2N2
1,10-phenanthroline (1)
DCPEb (1)
8d: 88% (E/Z = 91:9)
trace
82
Scheme 5 Carboxylation of tert-butyl group substituted allenamide 4d
TMEDA (1)
a The reaction was carried out in THF at 0 °C.
b DCPE = 1,2-bis(dicyclohexylphosphino)ethane.
Carboxylation of various substituted allenamides was in-
vestigated, and the results are shown in Table 2. The Boc
group protected allenamide 4e could react with CO2, and
the desired carboxylation product 8e was obtained in 91%
yield (Table 2, entry 1). Oxazolidinone-derived allen-
amide 4f was also applicable to the carboxylation, giving
the corresponding coupling product 8f in 88% yield (Ta-
ble 2, entry 2). Carboxylation of 2-pyridone derivative 4g
proceeded to give 8g in good yield as a single isomer (Ta-
ble 2, entry 3). Oxazolidinone-derived allenamide 4h hav-
ing a benzyloxy group was reacted with CO2 to give the
desired CO2-incorporated product 8h in 27% yield along
with diene 9, which would be formed from 8h by deben-
zyloxylation (Table 2, entry 4). A similar result was ob-
tained in the carboxylation of 4i, carboxylation
compounds 8i and 9 being produced in a total yield of
42% (Table 2, entry 5). On the other hand, the reaction of
siloxylethyl group substituted allenamide 4j with CO2 fol-
lowed by methylation afforded the corresponding product
8j in 68% yield as a single isomer (Table 2, entry 6). Car-
boxylation of allenamide having a methyl group 4k also
gave 8k in 44% yield in a similar regio- and stereoselec-
tive manner to that of the carboxylation of tert-alkyl group
substituted allenamides 4d–j (Table 2, entry 7). Trisubsti-
tuted allenamide 4l was applicable to the carboxylation,
giving the corresponding CO2-incorporated compound 8l
in 59% yield in a highly regioselective manner (Table 2,
entry 8).
With optimal conditions in hand, carboxylation of other
terminal allenamides was investigated (Scheme 4). Thus,
oxazolidione-derived allenamide 4b was reacted with
CO2 followed by methylation to give the corresponding
6b in 51% yield (Scheme 4, eq. 1). On the other hand, the
carboxylation of methylcarbamate-derived allenamide 4c
gave the desired 6c in 21% yield, and its regioisomer 8c
was also produced in 6% yield (Scheme 4, eq. 2).
1) Ni(cod)2 (1 equiv)
DBU (4 equiv)
CO2 (1 atm)
O
O
O
•
(1)
N
O
N
OMe
O
2) HCl (10%)
3) CH2N2
4b
6b: 51%
O
MeO2C
MeO2C
N
OMe
MeO2C
Bn
same as above
•
N
(2)
6c: 21%
Bn
4c
O
N
OMe
Bn
8c: 6%
Scheme 4 Nickel-mediated carboxylation of carbamate-derived ter-
minal allenamide
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 736–740

738
N. Saito et al.
LETTER
To gain insights into the reaction mechanism, a deuterium
incorporation experiment was carried out (Scheme 6).
Thus, after the reaction of terminal allenamide 4a and
CO2, acidic workup with 10% DCl–D2O followed by
methylation by CH2N2 was conducted (Scheme 6, eq. 1).
As a result, compound 6a-D, the allylic methyl group of
which was deuterated, was obtained in 90% yield as a sin-
gle regio- and stereoisomer. On the other hand, when alle-
namide 4d having a tert-butyl group was treated under
reaction conditions similar to those of 4a, the allylic meth-
ylene position of 8d-D was deuterated (Scheme 6, eq. 2).
1) Ni(cod)2 (1 equiv)
DBU (4 equiv)
CO2 (1 atm)
O
D
Ts
Ts
(1)
•
•
N
N
OMe
Me
2) DCl–D2O (10%)
3) CH2N2
Me
4a
6a-D: 90% (D content: >95%)
D
O
1) Ni(cod)2 (1 equiv)
MeO2C
DBU (4 equiv)
CO2 (1 atm)
MeO2C
N
t-Bu
N
OMe
Bn
(2)
Bn
2) DCl–D2O (10%)
3) CH2N2
4d
t-Bu
8d-D: 84% (E/Z = 87:13,
D content: >95%)
Based on the above results, possible reaction mechanisms
of the carboxylation of allenamides were considered
(Scheme 7). When terminal allenamides 4 (R2 = H) were
Scheme 6 Acidic workup with DCl–D2O
Table 2 Carboxylation of Various Substituted Allenamidesa
Entry
Allenamide 4
Time (h)
Product 8
Boc
CO2Me
Boc
N
N
•
t-Bu
Bn
t-Bu
1
15
Bn
4e
8e 91% (E/Z = 89:11)
O
O
CO2Me
N
O
N
N
•
t-Bu
t-Bu
O
2
3
16
17
t-Bu
4f
8f 88% (E/Z = >95:5)
O
O
CO2Me
N
•
t-Bu
4g
8g 60% (E/Z = >95:5)
O
O
O
CO2Me
CO2Me
N
O
N
OR
O
N
•
O
OR
4
5
4h R = Bn
4i R = TBS
15
18
8h R = Bn, 27% (E/Z = >95:5)
8i R = TBS, 29% (E/Z = >95:5)
9 41% (E/Z = 85:15)
9 13% (E/Z = >95:5)
O
O
CO2Me
N
O
N
O
•
6
16
TBDPSO
OTBDPS
4j
8j 68% (E/Z = >95:5)
O
O
CO2Me
R2
N
O
N
•
O
R2
R3
R3
7
8
4k R2 = Me, R3 = H
4l R2 = R3 = Me
1
1
8k R2 = Me, R3 = H, 44% (E/Z = >95:5)
8l R2 = R3 = Me, 59%
a The reaction of allenamide 4 was carried out in the presence of Ni(cod)2 (1 equiv) and DBU (4 equiv) in THF at 0 °C under CO2 (1 atm). After
acidic workup with 10% HCl, the crude product was treated with CH2N2.
Synlett 2014, 25, 736–740
© Georg Thieme Verlag Stuttgart · New York

LETTER
Nickel-Promoted Carboxylation of Allenamides
739
O
1) HCl
2) CH2N2
O
O
O
C
O
R2 = H
H
NiLn
NiLn
H
H
N
N
OMe
OMe
•
N
R2
•
N
H
6
N
10
11
O
H
1) HCl
2) CH2N2
O
4
LnNi
Ni(0)Ln
re face
si face
O
+
CO2
N
R2
(E)-8
O
R2
13
R2 = Me
or
EWG
C
O
major product
O
H
R2
N =
N
NiLn
re face
N
R
R1
1) HCl
2) CH2N2
•
O
LnNi
N
H
O
O
N
OMe
C
NiLn
si face
O
R2
(Z)-8
R2
12
14
minor product
Scheme 7 Possible reaction course including origin of regio- and stereoselectivity
used, the less-hindered distal double bond of the allene
part and CO2 would coordinate to the nickel center to give
10 first, from which oxidative cycloaddition would pro-
ceed to afford nickelalactone 11. Hydrolysis of 11 fol-
lowed by methylation would afford 6. On the other hand,
in the reaction of allenamides having an alkyl group (R2 =
Me or CMe2R), the less-hindered nitrogen-substituted
double bond of 4 would coordinate to the nickel center to
give 12. In this step, two types of coordinated complex
could be formed. That is, if oxidative cycloaddition of the
re face of the nitrogen-substituted double bond of allen-
amide and CO2 proceeded, nickelalactone 13 could be
formed. On the other hand, oxidative cycloaddition of the
si face of the double bond and CO2 would give nickelalac-
tone 14. Obviously, the formation of 14 from 12 seems to
be less favorable than the formation of 13 because of ste-
ric repulsion between the alkyl group in the allenamide
and CO2. Thus, nickelalactone 13 would be formed pref-
erably as compared with 14, resulting in (E)-8 being ob-
tained as a major product after hydrolysis followed by
methylation.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
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carbon dioxide. The reaction proceeds via a nickelalac-
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Acknowledgment
This work was partly supported by a Grant-in-Aid for Young Scien-
tists (B) (No. 24790002) and a Grant-in-Aid for Scientific Research
(B) (No. 23390001) from JSPS and by a Grant-in-Aid for Scientific
Research on Innovative Areas ‘Molecular Activation Directed to-
ward Straightforward Synthesis’ (Nos. 23105501 and 25105701)
from MEXT, Japan. N.S. acknowledges Takeda Science Foundati-
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 736–740

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N. Saito et al.
LETTER
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Synlett 2014, 25, 736–740
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