Synthesis of carbamoylacetates from α-iodoacetate, CO, and amines under Pd/light combined conditions

Article abstract of DOI:10.1055/s-0031-1290690

We developed a novel synthetic method of carbamoylacetates from -iodoacetate, carbon monoxide, and amines under photoirradiation conditions in the presence of a Pd catalyst. This reaction likely proceeds via interplay of radical and organopalladium species. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290690

LETTER
▌1331
lSetyternthesis of Carbamoylacetates from α-Iodoacetate, CO, and Amines under
Pd/Light Combined Conditions
Carbamoylacetates from α-Iodoacetate
Shuhei Sumino, Akira Fusano, Takahide Fukuyama, Ilhyong Ryu*
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
E-mail: ryu@c.s.osakafu-u.ac.jp
Received: 19.02.2012; Accepted after revision: 14.03.2012
action was carried out under photoirradiation using two 15
Abstract: We developed a novel synthetic method of carbamoylac-
W black lights, the desired 3a was obtained in 74% yield
etates from α-iodoacetate, carbon monoxide, and amines under pho-
after chromatographic separation (entry 2). Even under 10
toirradiation conditions in the presence of a Pd catalyst. This
atm of CO, 3a was obtained without decrease in the yield
(entry 3), whereas the reaction with 1 atm of CO gave a
very low yield of 3a (entry 4). Without water, the reaction
gave poor results. We assume that the added water may
contribute to the effective conversion of Pd(II) to Pd(0).9
reaction likely proceeds via interplay of radical and organopalladi-
um species.
Key words: radical reaction, carbonylation, carbamoylacetates,
palladium, photo reaction
previous work (ref. 3)
Carbamoylacetates serve as key intermediates in the syn-
thesis of biologically active heterocyclic compounds.1 In
a recent example, Boros and co-workers reported the syn-
thesis of HIV integrase inhibitors, in which Claisen con-
densation reaction of carbamoylacetates was employed to
prepare the core structure.2 For the synthesis of carbamo-
ylacetates, amidation of malonates has been frequently
employed, whereas carbonylation methods using CO are
quite limited. To our knowledge, two examples by Pd-cat-
alyzed carbonylation of α-diazo esters as substrate have
been reported (Scheme 1, equation 1).3,4 Atom transfer
carbonylation (ATC) reactions provide useful methods to
prepare aliphatic carboxylic acid derivatives from readily
available alkyl iodides and CO,5 and we recently reported
that ATC reactions under photoirradiation conditions6
were dramatically accelerated by Pd catalysts.7 As such an
example, the reaction of α-substituted iodoalkanes, CO,
and alkenyl alcohols gave good yields of functionalized
lactones.8 Interestingly, however, in a similar reaction us-
ing an alkenylamine, we found that the envisioned lactam
was obtained only in a low yield, and the carbamoylace-
tate was formed as a principal product. This led us to in-
vestigate the carbonylation reaction, and herein we report
a novel synthesis of carbamoylacetates by the three-com-
ponent coupling reactions comprising α-iodoacetate, CO,
and amines (Scheme 1, equation 2).
O
O
O
Pd
(1)
CO
HNR1R2
N2
R3O
R3O
NR1R2
R3O
this work
O
O
O
Pd, hν
CO
HNR1R2
(2)
I
R3O
NR1R2
Scheme 1 Synthesis of carbamoyl acetates by carbonylation with
CO
Table 1 Optimizations of the Reaction Conditionsa
O
O
O
PdCl2(PPh3)2
H
Ph
Ph
N
CO
EtO
N
+
+
I
Et3N, DMAP
toluene, H2O
EtO
1
2a
3a
Entry
Conditionsb
CO (atm)
45
Time (h)
Yield (%)c
1d,e
2
80 °C
hν
16
16
8
(13)
74 (86)
77
45
10
1
3
hν
4
hν
16
(25)
a Conditions: 1 (0.25 mmol), 2a (3.0 equiv), CO (1–45 atm),
PdCl2(PPh3)2 (5.0 mol%), Et3N (1.2 equiv), DMAP (12 mol%), tolu-
ene (5 mL), H2O (50 μL).
We examined several reaction conditions using α-iodo
ethyl acetate (1) and ethylphenylamine (2a) as model sub-
strates in the hope of preparing carbamoyl acetate 3a (Ta-
ble 1). When a mixture of 1, 2a, a catalytic amount of
PdCl2(PPh3)2, Et3N, DMAP, and water8 was heated at 80 °C
for 16 hours under 45 atm of CO pressures, the desired 3a
was obtained but in only a 13% yield (Table 1, entry 1).
Under the heated conditions, the direct amination product
was formed. To our delight, however, when a similar re-
b hν: black light (2 × 15 W), Pyrex, peak wavelength at λ = 352 nm.
c Isolated (NMR) yield.
d Direct amination product was obtained in 5% yield.
e The reaction was performed under 80 °C without photoirradiation.
Having the optimized conditions in hand, we then exam-
ined a variety of amines for the present carbamoylation re-
action, the results of which are summarized in Table 2.10
The reactions of 1 with aniline derivatives 2a–e gave the
corresponding carbamoylacetates 3a–e in moderate to
good yields (entries 1–5). A sterically hindered aniline,
2,6-dimethylaniline (2f), also participated in the reaction
SYNLETT 2012, 23, 1331–1334
Advanced online publication: 14.05.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290690; Art ID: ST-2012-U0151-L
© Georg Thieme Verlag Stuttgart · New York

1332
S. Sumino et al.
LETTER
Table 2 Synthesis of Various Carbamoylacetates 3a (continued)
to give the expected carbamoylacetate 3f in 71% yield
(entry 6). The reaction of 2-aminopyridine (2g) gave the
carbamoylacetate 3g in moderate yield (entry 7). The re-
action of 1 with secondary and primary aliphatic amines
2h and 2i also proceeded to give the corresponding car-
bamoylacetates 3h and 3i in 64% and 44% yields, respec-
tively (entries 8 and 9). However, aliphatic amines, such
as morpholine and diethyl amine, gave direct amination
products as major products. When pyrrole (2j) was used
as a nucleophile, a half ester of malonic acid (4) was ob-
tained in 52% yield (entry 10). Since in the absence of
pyrrole but with water, the yield of 4 decreased to 33%,
pyrrole likely acts as a base to promote an attack of hy-
droxy anion to acylpalladium species. Using similar
Pd/light combined conditions, we also examined carbon-
ylation of α-iodo-γ-butyrolactone in the presence of 2a,
however, the desired amide lactone was formed in poor
yield (<20%).
hν [black light (15 W × 2), Pyrex]
O
PdCl2(PPh3)2
product
CO
+
amine
2
+
I
Et3N, DMAP
toluene, H2O
3
EtO
1
Entry Amine
Product
Yield
(%)b
O
O
O
H
EtO
N
N
7
41
64
N
H
N
Ph
2g
3g
O
H
N
EtO
N
8c
2h
3h
Table 2 Synthesis of Various Carbamoylacetates 3a
O
O
O
O
H
N
H
9c
44
52
hν [black light (15 W × 2), Pyrex]
EtO
N
H
O
PdCl2(PPh3)2
product
3
CO
+
amine
2
+
I
2i
Et3N, DMAP
toluene, H2O
3i
EtO
1
H
N
Entry Amine
Product
Yield
(%)b
10
EtO
OH
4
2j
O
O
a Conditions: 1 (0.25 mmol), 2 (3.0 equiv), CO (10 atm), PdCl2(PPh3)2
(5.0 mol%), Et3N (1.2 equiv), DMAP (12 mol%), toluene (5 mL), H2O
(50 μL).
H
Ph
N
Ph
N
EtO
1
77
b Isolated yield of 3 or 4 after silica gel chromatography.
c CO (45 atm) were used.
2a
3a
O
O
H
Ph
Ph
N
H
To get some insights into the reaction mechanism, we
conducted the experiments using a free radical trap and
electron transfer (ET) block. We observed that the addi-
tion of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)
completely suppressed the formation of 3a and gave the
TEMPO adduct 5 in 8% yield (Scheme 2). In the presence
of 1,4-dinitrobenzene, an electron transfer inhibitor, the
reaction did not give 3a at all. These results may suggest
the intermediacy of acetate radicals and the importance of
an ET step to cause the reaction. Since the carbonylation
of stable radicals like acetate radicals is a very difficult
process,5d,11 we think that Pd-catalyzed carbonylation
should be responsible for the present carbamoylation re-
action.12 Thus, we propose a radical–metal combined re-
action mechanism for this reaction (Scheme 2). Acetate
radicals A are formed via cleavage of the C–I bond of 1,
which might be triggered by single electron transfer from
photoexcited Pd complex.13,14 Coupling of acetate radicals
A and Pd(I)I radicals then takes place to give α-pallado es-
ters B, which then undergo aminocarbonyaltion12 to give
the carbamoyl esters 3 with liberation of Pd(0).
EtO
N
H
2
3
87
77
2b
3b
O
n-Bu
n-Bu
O
H
2c
H
N
H
EtO
N
H
3c
O
O
EtO
N
H
Cl
N
H
Cl
4
5
62
47
2d
3d
Me
N
Me
N
Me
O
O
Me
H
N
H
EtO
N
H
2e
3e
O
O
H
6c
71
EtO
N
H
N
H
In summary, we have demonstrated that the carbamoylac-
etates can be prepared by carbonylation of α-iodoacetate
under Pd/light combined conditions. We propose the reac-
tion mechanism in which radical reactions would lead to
2f
3f
Synlett 2012, 23, 1331–1334
© Georg Thieme Verlag Stuttgart · New York

LETTER
Carbamoylacetates from α-Iodoacetate
1333
177. (c) Ryu, I. Chem. Soc. Rev. 2001, 30, 16. (d) Also see a
review on acyl radicals: Chatgilialoglu, C.; Crich, D.;
Komatsu, M.; Ryu, I. Chem. Rev. 1999, 99, 1991.
O
O
O
I
EtO
NR1R2
EtO
(6) For the atom-transfer carbonylation reactions, see: (a) Ryu,
I.; Nagahara, K.; Kambe, N.; Sonoda, N.; Kreimerman, S.;
Komatsu, M. Chem. Commun. 1998, 1953. (b) Nagahara,
K.; Ryu, I.; Komatsu, M.; Sonoda, N. J. Am. Chem. Soc.
1997, 119, 5465. (c) Kreimerman, S.; Ryu, I.; Minakata, S.;
Komatsu, M. Org. Lett. 2000, 2, 389. (d) Also see a review:
Ryu, I. Chem. Soc. Rev. 2001, 30, 16.
(7) For radical–metal hybrid reactions, see: (a) Ryu, I.;
Kreimerman, S.; Araki, F.; Nishitani, S.; Oderaotoshi, S.;
Minakata, S.; Komatsu, M. J. Am. Chem. Soc. 2002, 124,
3812. (b) Fukuyama, T.; Nishitani, S.; Inouye, T.;
Morimoto, K.; Ryu, I. Org. Lett. 2006, 8, 1383.
3
1
Pd(0)
hν
Et3N⋅HI
NEt3
HNR1R2
2
O
O
O
Pd(I)I
EtO
A
EtO
Pd(II)I
(c) Fukuyama, T.; Inouye, T.; Ryu, I. J. Organomet. Chem.
2007, 692, 685. (d) Fusano, A.; Fukuyama, T.; Nishitani, S.;
Inouye, T.; Ryu, I. Org. Lett. 2010, 12, 2410. (e) Also see a
review: Ryu, I. Chem. Rec. 2002, 2, 249.
C
TEMPO
O
(8) Fusano, A.; Sumino, S.; Fukuyama, T.; Ryu, I. Org. Lett.
2011, 13, 2114.
O
N
O
EtO
Pd(II)I
(9) For water-promoted activation of Pd(II) to generate Pd(0),
see: (a) Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S.
L. Org. Lett. 2008, 10, 3505. (b) Grushin, V. V.; Alper, H.
Organometallics 1993, 12, 1890. (c) Amatore, C.; Jutand, A.
J. Organomet. Chem. 1999, 576, 254.
EtO
CO
B
5
Scheme 2 Proposed reaction mechanism
(10) General Procedure for the Synthesis of 3a
A magnetic stirring bar, 1 (54.1 mg, 0.25 mmol), 2a (92.9
mg, 0.77 mmol), Et3N (29.9 mg, 0.30 mmol), PdCl2(PPh3)2
(8.4 mg, 0.012 mmol), DMAP (3.7 mg, 0.031 mmol),
toluene (5.0 mL), and H2O (50 μL) were placed in a stainless
steel autoclave for photoreaction equipped with an inserted
Pyrex glass liner. The autoclave was closed, purged three
times with 10 atm of CO, pressurized with 10 atm of CO, and
then irradiated by two 15 W black lights with stirring for 8 h.
Excess CO was discharged after the reaction. The reaction
mixture was added to H2O (20 mL) and extracted with Et2O
(3 × 20 mL). The combined ether layer was washed with
brine, and dried over MgSO4, then filtered and concentrated
in vacuo. The resulting residue was subjected to silica gel
column chromatography using hexane–Et2O as eluent
affording 3a (45.8 mg, 77%).1H NMR (400 MHz, CDCl3):
δ = 7.45–7.35 (m, 3 H), 7.20 (d, J = 6.8 Hz, 2 H), 4.05 (q,
J = 7.2 Hz, 2 H), 3.78 (q, J = 7.2 Hz, 2 H), 1.23 (t, J = 7.2
Hz, 3 H), 1.14 (t, J = 7.2 Hz, 3 H). 13C NMR (100 MHz,
CDCl3): δ = 12.89, 14.06, 41.96, 44.25, 61.20, 128.38,
129.81, 141.77, 165.47, 167.83. IR (neat): 1740, 1667, 1404,
1368 cm–1. MS: m/z (%) = 235 (55) [M+], 190 (16), 148 (21),
121 (49), 120 (44), 105 (100), 104 (12), 77 (23). HRMS (EI):
m/z calcd for C13H17NO3 [M]+: m/z = 235.1208; found:
235.1213.
the effective formation of key organopalladium species
available for carbonylation.
Acknowledgment
We thank JSPS and MEXT Japan for generous funding of this work.
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Synlett 2012, 23, 1331–1334

1334
S. Sumino et al.
LETTER
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