Versatile synthesis of pyrrole-2-acetic esters and (pyridine-2-one)-3- acetic amides by palladium-catalyzed, carbon dioxide-promoted oxidative carbonylation of (Z)-(2-en-4-ynyl)amines

Article abstract of DOI:10.1002/adsc.200606085

The oxidative carbonylation of readily available (Z)-(2-en-4-ynyl)amines, catalyzed by the PdI₂-KI system, selectively afforded in satisfactory yields (40-95%) either pyrrole-2-acetic ester or (pyridine-2-one)-3-acetic amide derivatives, depend

Full text of DOI:10.1002/adsc.200606085

FULL PAPERS
DOI: 10.1002/adsc.200606085
Versatile Synthesis of Pyrrole-2-acetic Esters and (Pyridine-2-
one)-3-acetic Amides by Palladium-Catalyzed, Carbon Dioxide-
Promoted Oxidative Carbonylation of (Z)-(2-En-4-ynyl)amines
Bartolo Gabriele,a,* Giuseppe Salerno,b Alessia Fazio,a and Lucia Veltrib
a
Dipartimento di Scienze Farmaceutiche, Università della Calabria, 87036 Arcavacata di Rende (Cosenza), Italy
Fax : (+39) 0984-492-044; e-mail: b.gabriele@unical.it
Dipartimento di Chimica, Università della Calabria, 87036 Arcavacata di Rende (Cosenza), Italy
b
Received: March 8, 2006; Accepted: July 7, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The oxidative carbonylation of readily reaction conditions. The presence of an excess of
available (Z)-(2-en-4-ynyl)amines, catalyzed by the carbon dioxide proved in most cases to be beneficial
PdI2-KI system, selectively afforded in satisfactory to both the reaction rate and product selectivity.
yields (40–95%) either pyrrole-2-acetic ester or (pyr-
idine-2-one)-3-acetic amide derivatives, depending Keywords: carbon dioxide; carbonylations; palladi-
on the susbtitution pattern of the substrate and the um; pyridinones; pyrroles
Introduction
thesis of furanacetic esters starting from (Z)-2-en-4-
yn-1-ols (Scheme 2).[5]
Palladium-catalyzed heterocyclization-carbonylation
of suitably functionalized alkynes has become a pow-
erful methodology for the direct, one-step synthesis of
carbonylated heterocycles.[1] In this respect, we have
recently reported several new syntheses of heterocy-
cles by PdI2-catalyzed 5-exo-dig cyclization-alkoxycar-
bonylation, as shown in Scheme 1 (in this and in the
following schemes unreactive ligands on palladium
are omitted for clarity).[2–4]
In some cases, the initially formed product may un-
dergo spontaneous or acid-promoted isomerization to
give an aromatic derivative, as exemplified by the syn-
Scheme 2.
Recently, we have also communicated that some
(Z)-(2-en-4-ynyl)amines can undergo PdI2-catalyzed,
CO2-promoted oxidative heteroannulation-alkoxycar-
bonylation-aromatization to give pyrrole-2-acetic
esters, according to Eq. (1).[6]
Scheme 1.
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Synthesis of Pyrrole-2-acetic Esters and (Pyridine-2-one)-3-acetic Amides
FULL PAPERS
In this work, we present a full account of the PdI2-
catalyzed oxidative carbonylation of (Z)-(2-en-4-
ynyl)amines. We have found that, depending on the
substitution pattern of the substrate and on the reac-
tion conditions, the process can selectively lead to
pyrrole-2-acetic ester or (pyridine-2-one)-3-acetic
amide derivatives, in satisfactory yields.[7] In most
cases, working in the presence of an excess of CO2
had a beneficial effect on both the reaction rate and
product selectivity.
Results and Discussion
substrate conversion and product distribution
The oxidative carbonylation reaction was initially car- (Table 1, entries 2–8). From these data, it is clear that
ried out using butyl-(2-ethylnon-2-en-4-ynyl)amine 1a selectivity toward 2a could be improved: a) by work-
as the substrate, under conditions analogous to those ing with a lower substrate-to-catalyst ratio; b) by de-
already successfully employed for the synthesis of creasing the substrate concentration; c) by increasing
furan-2-acetic esters starting from (Z)-2-en-4-yn-1- the KI/PdI2 molar ratio and d) by working in the pres-
ols,[5] that is, under 90 atm of a 9:1 mixture of CO-air ence of added CO2. Under the optimized conditions
at 708C for 15 h, in the presence of PdI2-KI as the cat- shown in Table 2, entry 9 (708C for 5 h in MeOH as
alytic system (1a/KI/PdI2 molar ratio=1000:50:1, sub- the solvent, substrate concentration=0.05 mmolmLÀ1
strate concentration=0.22 mmolmLÀ1 of MeOH). of MeOH, 1e:KI:PdI2 molar ratio=100:200:1, under
Under these conditions, however, the expected 2-(1- 90 atm of a 3:1:5 mixture of CO:air:CO2), the desired
butyl-4-ethyl-1H-pyrrol-2-yl)hexanoic acid methyl pyrrole-2-acetic derivative 2a was selectively obtained
ester 2a was obtained in only 18% GLC yield, togeth-
er with small amount of 1-butyl-4-ethyl-2-pentyl-1H-
pyrrole 3a (2% GLC yield, deriving from a competi-
tive cycloisomerization process)[8] and its oxidation
products, 1-butyl-3-ethyl-5-methoxy-5-pentyl-1,5-dihy-
dropyrrol-2-one 4a (5% GLC yield) and 1-butyl-3-
ethyl-5-hydroxy-5-pentyl-1,5-dihydropyrrol-2-one 5a
[7% GLC yield, Eq. (2) and Table 1, entry 1].[9,10]
In order to improve the reaction selectivity towards
the formation of 2a, we have carried out a systematic
study on the influence of the reaction conditions on
in 71% GLC yield [63% isolated, Eq. (3)].[11]
Table 1. Reactions of butyl-(2-ethylnon-2-en-4-ynyl)amine 1a with CO and O2 in MeOH at 708C in the presence of the PdI2-
KI catalytic system.
Entry PdI2:KI:1a Molar
PCO
[atm]
Pair
[atm]
Concentration of
t
Conversion of 1a
Yield of 2a
Yield of 3a
Ratio
1a[a]
[h] [%][b]
[%][c]
[%][c]
1[d]
2[e]
3
4
5
1:50:1000
1:50:1000
1:50:1000
1:50:1000
1:50:100
1:50:100
1:200:100
1:50:100
90
90
60
30
30
30
30
30
10
10
10
10
10
10
10
10
0.22
0.22
0.22
0.22
0.22
0.05
0.05
0.05
15 100
182
817
10
5
27
26
50 (40)
56
5
5
5
5
5
5
5
54
50
40
77
63
100
100
23
30
27
22
9
6
7
8[f]
[a]
[b]
[c]
[d]
Mmol of 1a/mL of MeOH.
Based on starting 1a, by GLC.
GLC yield (isolated yield) based on 1a.
The reaction also led to the formation of 1-butyl-3-ethyl-5-methoxy-5-pentyl-1,5-dihydropyrrol-2-one 4a (5%) and 1-
butyl-3-ethyl-5-hydroxy-5-pentyl-1,5-dihydropyrrol-2-one 5a (7%).
The reaction also led to the formation of 4a (1%) and 5a (1%).
The reaction was carried out under 30 atm of CO, 10 atm of air and 50 atm of CO2.
[e]
[f]
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Table 2. Synthesis of pyrrole-2-acetic esters 2a–c by Pd-cata-
lyzed, CO2-promoted oxidative methoxycarbonylation of
secondary (Z)-(2-en-4-ynyl)amines substituted at C-2 and at
C-5.[a]
in solution. On the other hand, CO2 may act by “buf-
fering” the basicity of the substrate, with formation of
a carbamate species, thus “freeing” the HI necessary
for Pd(0) reoxidation. The nitrogen of the carbamate,
while less basic than in the starting amine, may still
act as a nucleophile since CO2 can be eliminated
during the cyclization step leading to the 5-membered
product (Scheme 4).
Entry 1
R
R1 R2
1a Bu Et Bu
Yield of 2 [%][b] Yield of 3 [%][c]
9
10
11
71 (63)
1b Bu Et TMS 75 (65)[d]
1c Bu Ph Bu
70 (61)
8
12[e] 1b Bu Et TMS 36[d]
3[d]
28
13[e] 1c Bu Ph Bu
46
[a]
Unless otherwise noted, all reactions were carried out in
MeOH at 708C using 1 mol% of PdI2 in conjunction
with 200 equivs. of KI under 90 atm (at 258C) of a 3:1:5
mixture of CO:air:CO2 for 5 h (1–2 mmol scale based on
1, 0.05 mmol of 1 mL of MeOH). Substrate conversion
was quantitative in all cases. Formation of unidentified
heavy products accounted for substrate conversion in all
cases.
[b]
[c]
[d]
[e]
GLC yield (isolated yield) based on starting 1.
GLC yield based on starting 1.
R2 =H in the final product 2b.
The reaction was carried out under 30 atm of CO and 10
atm of air.
The beneficial effect exerted by the excess of
iodide anions and by CO2 on the carbonylation pro-
cess can be related to the easier reoxidation of Pd(0)
occurring under these conditions. In fact, according to
the mechanism we demonstrated several years ago in
the case of oxidative dicarbonylation of alkynes,[12]
Pd(0) reoxidation under our conditions occurs
Scheme 4.
In order to verify this mechanistic hypothesis we
through oxidation of HI by oxygen, followed by oxi- have synthesized butyl-(2-ethylnon-2-en-4-ynyl)carba-
dative addition of iodine to Pd(0) (Scheme 3). Clearly, mic acid allyl ester 6a by the reaction between 1a and
commercially available allyl chloroformate. Indeed,
working under the same conditions as optimized for
1a, but in the absence of CO2, Pd-mediated cleavage
of the allyl moiety of 6a was expected to afford the
Scheme 3.
same carbamate species as obtained from 1a in the
presence of CO2, eventually leading to 2a and methyl
but-3-enoate (Scheme 5). The cleavage of the allyl
in the presence of a basic substrate such as an amine, moiety could occur by oxidative addition to a Pd(0)
an acid-base equilibrium takes place [Eq. (4)], which species (formed in situ from PdI2, for example by de-
À
À
lowers the concentration of free HI in solution thus carboxylation of an I Pd CO2H species formed in
making the Pd(0) reoxidation less easy and therefore the presence of traces of water), as shown in
hampering the overall carbonylation process.
Scheme 5, or directly to PdI2, to give a Pd(II) or
Pd(IV) allylic intermediate, respectively. According to
our hypotheses, when 6a was allowed to react under
the same conditions of entry 7, 2a and methyl but-3-
enoate were obtained in a ca. 1:1 ratio, with no for-
mation of pyrrole 3a. The substrate conversion rate
was however rather slow, probably due to the kinetics
of cleavage of the allyl moiety (after 48h, the conver-
sion of 6a was 35% with a 22% GLC yield of 2a).
The reaction was then extended to other secondary
However, in the presence of a large excess of
iodide anions, the acid-base equilibrium can be shifted (Z)-(2-en-4-ynyl)amines 1b and c substituted at C-2
to the left, thus allowing a higher concentration of HI and at C-5. Under the optimized conditions found for
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Synthesis of Pyrrole-2-acetic Esters and (Pyridine-2-one)-3-acetic Amides
FULL PAPERS
ed yield) and a heavier product, whose mass spectrum
was compatible with the (pyridine-2-one)-3-acetic
amide structure 8d [Eq.(5), n.d.=not determined].[13]
Scheme 5.
Formation of product 7d follows a cyclocarbonyla-
tion-alkoxycarbonylation pathway, similar to that al-
1a (Table 2, entry 9), these substrates led to the corre- ready observed in the case of other functionalized al-
sponding pyrrole-2-acetic esters 2b and c in satisfacto- kynes (Scheme 6).[1–4] The key intermediate is a carb-
ry yields [75–70% by GLC, 65–61% isolated, Eq. (3)
and Table 2, entries 10 and 11]. In the case of (Z)-
butyl-[2-ethyl-5-(trimethylsilanyl)pent-2-en-4-ynyl]am-
ine 1b, the trimethylsilanyl group was lost in the
course of the process, as we already observed in the
oxidative carbonylation of (Z)-(5-trimethylsilanyl)-2-
en-4-yn-1-ols.[5] This reactivity allows the preparation
of a-unsubstituted pyrrole-2-acetic esters, which
cannot be obtained starting from (Z)-(2-en-4-ynyl)-
amines bearing a terminal triple bond due to their in-
stability and their spontaneous tendency to cycloiso-
merize to give the corresponding pyrroles.[8] The pro-
moting effect by CO2 was confirmed by the results
obtained by carrying out the reaction in the absence
of CO2: the yields of carbonylated products were
lower with respect to those obtained under the stan-
dard conditions, and cycloisomerization products 3b
and c were obtained in higher yields (entries 12 and
13).
Scheme 6.
amoylpalladium species,[14] stabilized by triple bond co-
ordination. Intramolecular triple bond insertion then
occurs, followed by CO insertion and nucleophilic dis-
placement by MeOH, with elimination of Pd(0) and
HI and formation of a 3,6-dihydro-1H-pyridin-2-one
intermediate. This compound eventually isomerizes to
give the final product, probably via MeOH addition
Very interestingly, the reaction of a secondary (Z)- to the double bond followed by MeOH elimination
(2-en-4-ynyl)amine bearing no substituents at C-2 and (Scheme 6). Palladium(0) is then reoxidized according
C-3, such as butyl(non-2-en-4-ynyl)amine 1d, carried to the usual mechanism (Scheme 3). Formation of
out under the same conditions of entries 9–11 for 4 h, (pyridine-2-one)-3-acetic amide 8d occurs through a
led to a mixture of products, including the expected mechanism similar to that showed in Scheme 6, with
pyrrole-2-acetic ester 2d (12% isolated yield) togeth- the substrate replacing MeOH in the nucleophilic dis-
er with (pyridine-2-one)-3-acetic ester 7d (25% isolat- placement step.
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Thus, two competitive oxidative carbonylation
mechanisms are in principle possible with enyna-
mines, that is, the cyclization-alkoxycarbonylation
mechanism (Scheme 1) and the cyclocarbonylation-al-
koxycarbonylation mechanism (Scheme 6). As we
have seen, both these mechanisms are followed in the
case of a 2,3-unsusbtituted enynamine, such as 1d,
while only the first mechanism was followed by 2-sub-
stituted enynamines 1a–c. The selectivity observed
with these latter substrates can be ascribed to a
“steric assistance” effect,[15] ensuing from the decrease
of steric repulsion between the substituent at C-2 and
À
the CH2NHR or CH2NRCO2 moiety going through
the transition state leading to the 5-membered inter-
mediate. Such a steric assistance effect clearly favors
an initial 5-exo-dig cyclization, as shown in Scheme 4.
The results obtained so far prompted us to test the
reactivity of enynamines unsubstituted at C-2 and
substituted at C-3, such as benzyl-(3-methylnon-2-en-
4-ynyl)amine 1e or butyl-(3-methylnon-2-en-4-ynyl)-
amine 1f. In fact, with these substrates, the above-
mentioned steric assistance effect could not be at
Scheme 7.
work, while the steric effect exerted by the substituent showed the formation of (pyridine-2-one)-3-acetic
at C-3 was actually expected to hinder the cyclization- ester 7e (32% GLC yield, 22% isolated), together
alkoxycarbonylation mechanism. In fact, as we have with a larger amount of a heavier product, whose
seen (Scheme 1), this mechanism involves an anti exo- mass spectrum was compatible with the (pyridine-2-
dig attack of the amino group to the triple bond coor- one)-3-acetic amide structure 8e [Eq. (6) and Table 3,
dinated to Pd(II), with the metal center on the oppo- entry 14].[16]
site site with respect to the nucleophilic group and
A slightly lower selectivity was obtained by de-
therefore close to the substituent at C-3. On the other creasing the amount of KI (entry 15) or by increasing
hand, the cyclocarbonylation-alkoxycarbonylation the substrate concentration (entry 16), while the same
mechanism could still be at work, since in this case reaction carried out in the absence of CO2 led to a
the triple bond coordination to Pd(II) occurs on the significant reduction of both the substrate conversion
opposite site with respect to the C-3 substituent (58%) and product yield (7%, entry 17). This clearly
(Scheme 7).
means that CO2 acts as a promoter even in the oxida-
Indeed, when the reaction of 1e was carried out tive carbonylation of 3-susbtituted enynamines lead-
under the conditions optimized for 2-susbtituted ing to (pyridine-2-one)-3-acetic derivatives. This is
enynamines 1a–c (entries 9-11), GLC-MS analysis conceivable, since also in this case CO2 may act by
Table 3. Reactions of butyl-(3-methylnon-2-en-4-ynyl)amine 1e with CO and O2 in MeOH at 708C in the presence of PdI2-
KI catalytic system.[a]
Entry
PdI2:KI:1e Molar Ratio
Concentration of 1e[b]
Conversion of 1e [%][c]
Yield of 7e [%][d]
14
15
1:200:100
1:100:100
1:200:100
1:200:100
1:50:100
0.05
0.05
0.22
0.05
0.22
100
100
100
587
55
32 (22)
28
15
16
17[e]
18[f,g]
[a]
Unless otherwise noted, all reactions were carried out in MeOH at 708C under 90 atm (at 258C) of a 3:1:5 mixture of
CO:air:CO2 for 5 h (1–2 mmol scale based on 1e).
Mmol of 1e/mL of MeOH.
Based on starting 1e, by GLC.
GLC yield (isolated yield) based on 1e.
The reaction was carried out under 40 atm (at 258C) of a 3:1 mixture of CO:air.
The reaction was carried out under 100 atm (at 258C) of a 9:1 mixture of CO:air for 15 h.
The reaction led to the formation of 1-butyl-3-methyl-2-pentyl-1H-pyrrole 3e (10% GLC yield, 8% isolated) and 2-(1-
butyl-4-methyl-2-oxo-1,6-dihydro-2H-pyridin-3-ylidene)hexanoic acid methyl ester 9e (30% GLC yield, 21% isolated).
[b]
[c]
[d]
[e]
[f]
[g]
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Table 4. Reactions of butyl-(3-methylnon-2-en-4-ynyl)amine
1e with CO, O2 and morpholine in the presence of PdI2-KI
catalytic system.[a]
“buffering” the substrate basicity, thus allowing a
higher concentration of HI, necessary for Pd(0) reoxi-
dation.
Entry Solvent T
Conversion of 1e
Yield of 10e
Interestingly, when 1e was allowed to react under
conditions similar to those employed in the analogous
carbonylation of the corresponding 3-methylnon-2-en-
4-yn-1-ol (708C for 15 h in MeOH as the solvent, sub-
strate concentration=0.22 mmolmLÀ1 of MeOH,
under 100 atm of a 9:1 mixture of CO-air, 1 mol% of
PdI2 along with 50 equivs. of KI), it was possible to
obtain and isolate the 3,6-dihydro-1H-pyridin-2-one
intermediate 9e as a ca. 1:1 E:Z mixture [total GLC
yield: 30%, isolated 21%, at 55% substrate conver-
sion, entry 18and Eq. (7)].
[8C] [%][b]
[%][c]
19
20
21
22
23
MeOH 70
MeOH 80
MeOH 100
DMA 80
DMA 100
27
45
100
50
100
22
38
92 (77)
38
81 (73)
[a]
All
reactions
were
carried
out
using
a
PdI2:KI:1e:morpholine molar ratio of 1:200:100:300
under 90 atm (at 258C) of a 3:1:5 mixture of CO:air:CO2
for 5 h (1–2 mmol scale based on 1e, 0.05 mmol of 1e/mL
of solvent).
Based on starting 1e, by GLC.
GLC yield (isolated yield) based on 1e.
[b]
[c]
strate conversion reached 100% at 1008C, giving 10e
in 92% GLC yield [77% isolated, Eq. (9) and
entry 21].
Similar results were obtained using enynamine 1f,
which, under the same conditions of entry 18, afford-
ed a mixture of 3,6-dihydro-1H-pyridin-2-one deriva-
tives 9f-E and 9f-Z in 27% GLC yield (20% isolated)
at 55% substrate conversion [Eq. (8)].[17]
The formation of (pyridine-2-one)-3-acetic amide
8e suggested the possibility to selectively synthesize
other amide derivatives by carrying out the reaction
In these reactions, morpholine was partially con-
in the presence of a suitable excess of a nucleophilic verted into morpholin-4-yl-oxoacetic acid methyl
amine. Indeed, when the same reaction of entry 14 ester, whose formation somewhat complicated the pu-
was carried out in the presence of morpholine rification procedure of 10e (see Experimental Section
(3 equivs. with respect to 1e), 1-butyl-4-methyl-3-[1- for details). We therefore also carried out the reaction
(morpholine-4-carbonyl)pentyl]-1H-pyridin-2-one 10e in a non-nucleophilic solvent such as N,N-dimethyl-
was obtained as the sole product in 22% GLC yield acetamide (DMA, entries 22 and 23). Working at
at 27% substrate conversion (Table 4, entry 19). Sub- 808C for 5 h, substrate conversion and GLC yield of
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Bartolo Gabriele et al.
FULL PAPERS
10e were 50% and 38%, respectively (entry 22),
while at 1008C the conversion of 1e was quantitative
and the GLC yield of 10e reached 81% (73% isolat-
ed, entry 23).
Enynamine 1f could also be selectively converted
into the corresponding amide 10f working in the pres-
ence of a nucleophilic amine such as morpholine. In
DMA as the solvent under the same conditions of
entry 23, the yield of 10f was moderate (46%, by
GLC, Table 5, entry 24), while in MeOH, under the
decreased, but the yield of 2g did not improve signifi-
cantly.
Table 5. Reactions benzyl-(3-methylnon-2-en-4-ynyl)amine
1f with CO, O2 and morpholine in the presence of PdI2-KI
catalytic system.[a]
Enynamine 1h turned out to be more reactive than
1g. Under the same conditions as above, substrate
conversion was quantitative after 2 h, with selective
formation of the corresponding pyrrole-2-acetic ester
2h in good yield [66% by GLC, 58% isolated,
Eq. (11)].
Entry Solvent T
Conversion of 1f
Yield of 10f
[8C] [%][b]
[%][c]
24
25
DMA 100
MeOH 100
94
100
100
46
95 (86)
52
26[d] MeOH 100
As expected in view of the reactivity of a primary
[a]
Unless otherwise noted, all reactions were carried out at
1008C using a PdI2:KI:1f:morpholine molar ratio of
1:200:100:300 under 90 atm (at 258C) of a 3:1:5 mixture
of CO:air:CO2 for 5 h (1–2 mmol scale based on 1f,
0.05 mmol of 1f/mL of solvent).
Based on starting 1f, by GLC.
GLC yield (isolated yield) based on 1f.
[b]
[c]
[d]
The reaction was carried out under 40 atm (at 258C) of a
3:1 mixture of CO:air.
same conditions of entry 21, the GLC yield of 10f was
as high as 95% [86% isolated, Eq. (9) and entry 25].
It is worth noting that the GLC yield of 10f dropped amino group under oxidative carbonylation conditions
to 52% working in MeOH in the absence of CO2 in the presence of the PdI2-KI catalytic system,[18] an
(entry 26).
enynamine bearing a primary amino group afforded
Very interestingly, we have found that it is also pos- urea derivatives rather than cyclization products. In
sible to direct the oxidative carbonylation of 3-sub- fact, under our conditions, primary amines are easily
stitued enynamines towards the formation of pyrrole- converted into ureas through the formation of an iso-
2-acetic derivatives, by placing a bulky alkyl group or cyanate as intermediate (Scheme 8).[18]
a phenyl group on the nitrogen atom, as in the case of
Thus, the reaction of (Z)-3-methylnon-2-en-4-ynyl-
(Z)-tert-butyl-(3-methylnon-2-en-4-ynyl)amine 1g and amine 1i, carried out in MeOH for 5 h under the
(Z)-(3-methylnon-2-en-4-ynyl)phenylamine 1h, re- same conditions of entry 14, afforded the methyl car-
spectively. In these cases, in fact, formation of the carb- bamate 11i in 15% isolated yield together with the
amoylpalladium species (which, as we have seen, is symmetrical urea 12i as the main reaction product
the key intermediate in the cyclocarbonylation-car-
bonylation mechanism, Scheme 7), is hindered for
steric reasons, so the cyclization-carbonylation mecha-
nism (Scheme 1) becomes the favored reaction path-
way. Under the same conditions of entry 14, but at
1008C rather than 708C, conversion of 1g was 48%
after 5 h, with a 40% GLC yield of 2-(1-tert-butyl-3-
methyl-1H-pyrrol-2-yl)hexanoic acid methyl ester 2g
[32% isolated, Eq. (10)]. The substrate conversion
was slightly higher when the reaction was carried out
for longer times or when the 1g:PdI2 molar ratio was Scheme 8.
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Synthesis of Pyrrole-2-acetic Esters and (Pyridine-2-one)-3-acetic Amides
FULL PAPERS
[40% isolated yield, Eq. (12)] at total substrate con- Experimental Section
version.
General Remarks
Melting points were determined with a Reichert Thermovar
apparatus and are uncorrected. 1H NMR and 13C NMR
spectra were recorded on a Bruker DPX Avance 300 spec-
trometer at 300 MHz and 75 MHz, respectively, with Me4Si
as internal standard. Chemical shifts (d) and coupling con-
stants (J) are given in ppm and in Hz, respectively. IR spec-
tra were taken with a Perkin–Elmer Paragon 1000 PC FT-
IR spectrometer. Mass spectra were obtained using a Shi-
madzu QP-2010 GC-MS apparatus at 70 eV ionization volt-
age. Microanalyses were carried out with a Carlo Erba Ele-
mental Analyzer Mod. 1106. All reactions were analyzed by
TLC on silica gel 60 F254 and by GLC using a Shimadzu GC-
2010 gas chromatograph and capillary columns with polyme-
thylsilicone + 5% phenylsilicone as the stationary phase
(HP-5). Column chromatography was performed on silica
gel 60 (Merck, 70–230 mesh) or neutral alumina. Evapora-
tion refers to the removal of solvent under reduced pres-
sure.
When the same reaction was carried out in the
presence of an excess of morpholine (morpholine:1i=
3:1), the mixed urea 13i was selectively formed in
89% GLC yield [81% isolated, Eq. (13)]. The CO2
Substrates were prepared, purified and characterized as
described in the Supporting Information. The procedures
for the oxidation of 3a with molecular oxygen to give 1,5-di-
hydropyrrol-2-ones 4a or 5a,[10] and the characterization data
for all products can also be found in the Supporting Infor-
mation.
Typical Procedure for Oxidative Methoxycarbonyla-
tion of 2-Substituted Enynamimes 1a–c and
Separation of Products [Eq. (3) and Table 2,
entries 9–11]
A 250-mL stainless steel autoclave was charged in the pres-
ence of air with PdI2 (3.7 mg, 1.03”10À2 mmol), KI
(341.9 mg, 2.06 mmol) and a solution of 1a–c (1.03 mmol) in
MeOH (20.5 mL). The autoclave was pressurized at room
temperature with stirring with CO2 (50 atm), CO (up to 80
atm) and air (up to 90 atm of total pressure), and then
heated at 708C with stirring for 5 h. After cooling, the auto-
clave was degassed, the solvent evaporated under reduced
pressure, and the products purified by column chromatogra-
phy (SiO2): 2a (hexane-AcOEt from 98:2 to 95:5, pale
yellow oil, 182.5 mg, 63% based on 1a); 2b (hexane-AcOEt,
95:5, pale yellow oil, yield: 150.2 mg, 65% based on 1b); 2c
(hexane-AcOEt, 99:1, yellow oil, yield: 205.3 mg, 61%
effect was at work even in this case: indeed, in the ab-
sence of CO2, the substrate conversion was 53% with
a yield of 13i of 29%.
Conclusions
In conclusion, we have shown that the PdI2/KI-cata-
lyzed oxidative carbonylation of readily available (Z)-
(2-en-4-ynyl)amines 1 is a powerful methodology for based on 1c).
the one-step synthesis of important carbonyl deriva-
tives such as pyrrole-2-acetic esters, (pyridine-2-one)-
Oxidative Methoxycarbonylation of Butyl(non-2-en-4-
ynyl)amine 1d and Separation of Products [Eq. (5)]
3-acetic amides, or urea derivatives under relatively
mild conditions. We have found that several mecha-
nistic pathways may be at work, and that it is possible
to direct the catalytic process towards a particular
route by suitably changing the substitution pattern of
the substrate and the nature of the external nucleo-
phile. We have also demonstrated that CO2 may act
as an effective and peculiar promoter in these reac-
tions, owing to its capability to “buffer” the basicity
of the amino group of the substrate without hamper-
ing its nucleophilicity.
A 250-mL stainless steel autoclave was charged in the pres-
ence of air with PdI2 (3.0 mg, 8.33”10À3 mmol), KI
(277.8mg, 1.67 mmol) and a solution of 1d (159.9 mg,
0.83 mmol) in MeOH (16.6 mL). The autoclave was pressur-
ized at room temperature with stirring with CO2 (50 atm),
CO (up to 80 atm) and air (up to 90 atm of total pressure),
and then heated at 708C with stirring for 4 h. After cooling,
the autoclave was degassed, the solvent evaporated under
reduced pressure, and the products purified by column chro-
matography (SiO2), using hexane-AcOEt, from 7:3 to 6:4, as
Adv. Synth. Catal. 2006, 348, 2212 – 2222
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
2219

Bartolo Gabriele et al.
FULL PAPERS
the eluent, to afford 2d (yellow oil, yield: 25.0 mg, 12%) fol-
lowed by 7d (yellow oil, yield: 58.0 mg, 25%) and unidenti-
fied decomposition products.
(277.8mg, 1.67 mmol) and a solution of 1e (173.0 mg,
0.83 mmol) and morpholine (220.0 mg, 2.53 mmol) in
MeOH (16.6 mL). The autoclave was pressurized at room
temperature with stirring with CO2 (50 atm), CO (up to 80
atm) and air (up to 90 atm of total pressure), and then
heated at 1008C with stirring for 5 h. After cooling, the au-
toclave was degassed, the solvent evaporated under reduced
pressure, and the product purified by column chromatogra-
phy (SiO2), using hexane-acetone, from 9:1 to 8:2, as the
eluent, to afford 10e as a pale yellow solid, which was some-
what impure with morpholin-4-yl-oxoacetic acid methyl
ester. Further purification by preparative TLC (hexane-ace-
tone, 9:1) afforded pure 10e as a pale yellow solid, mp 81–
838C (yield: 223.0 mg, 77%).
Oxidative Methoxycarbonylation of Butyl-(3-
methylnon-2-en-4-ynyl)amine 1e at 30 atm of CO and
Separation of Products [Eq. (6) and Table 3, entry 14]
A 250-mL stainless steel autoclave was charged in the pres-
ence of air with PdI2 (3.0 mg, 8.33”10À3 mmol), KI
(277.8mg, 1.67 mmol) and a solution of 1e (173.0 mg,
0.83 mmol) in MeOH (16.6 mL). The autoclave was pressur-
ized at room temperature with stirring with CO2 (50 atm),
CO (up to 80 atm) and air (up to 90 atm of total pressure),
and then heated at 708C with stirring for 5 h. After cooling,
the autoclave was degassed, the solvent evaporated under
reduced pressure, and the products purified by column chro-
matography (SiO2), using hexane-AcOEt, 8:2, as the eluent,
to afford 7e (colorless oil, yield: 54.0 mg, 22%) followed by
unidentified decomposition products.
Oxidative Aminocarbonylation of Butyl-(3-
methylnon-2-en-4-ynyl)amine 1e in DMA and
Separation of Products (Table 4, entry 23).
A 250-mL stainless steel autoclave was charged in the pres-
ence of air with PdI2 (3.0 mg, 8.33”10À3 mmol), KI
(277.8mg, 1.67 mmol) and a solution of 1e (173.0 mg,
0.83 mmol) and morpholine (220.0 mg, 2.53 mmol) in DMA
(16.6 mL). The autoclave was pressurized at room tempera-
ture with stirring with CO2 (50 atm), CO (up to 80 atm) and
air (up to 90 atm of total pressure), and then heated at
1008C with stirring for 5 h. After cooling, the autoclave was
degassed, the solvent evaporated under reduced pressure,
and the product purified by column chromatography (SiO2),
using hexane-acetone, from 9:1 to 8:2, as the eluent, to
afford pure 10e as a pale yellow solid, mp 81–838C (yield:
212.0 mg, 73%).
Oxidative Methoxycarbonylation of Butyl-(3-
methylnon-2-en-4-ynyl)amine 1e at 90 atm of CO and
Separation of Products [Eq. (7) and Table 3, entry 18]
A 250-mL stainless steel autoclave was charged in the pres-
ence of air with PdI2 (10.5 mg, 2.92”10À2 mmol), KI
(242.0 mg, 1.46 mmol) and a solution of 1e (644.7 mg,
3.11 mmol) in MeOH (14.0 mL). The autoclave was pressur-
ized at room temperature with stirring with CO (90 atm)
and air (up to 100 atm of total pressure), and then heated at
708C with stirring for 15 h. After cooling, the autoclave was
degassed, the solvent evaporated under reduced pressure,
and the products purified by column chromatography
(SiO2), using hexane-AcOEt, 9:1, as the eluent, to afford 3e
(colorless oil, yield: 51.2 mg, 8%) followed by a mixture of
9e-E and 9e-Z (yellow oil; total yield: 192.0 mg, 21%).
Oxidative Aminocarbonylation of Benzyl-(3-
methylnon-2-en-4-ynyl)amine 1f in MeOH and
Separation of Products [Eq. (9) and Table 5, entry 25]
A 250-mL stainless steel autoclave was charged in the pres-
ence of air with PdI2 (3.0 mg, 8.33”10À3 mmol), KI
(277.8mg, 1.67 mmol) and a solution of 1f (200.0 mg,
0.83 mmol) and morpholine (220.0 mg, 2.53 mmol) in
MeOH (16.6 mL). The autoclave was pressurized at room
temperature with stirring with CO2 (50 atm), CO (up to 80
atm) and air (up to 90 atm of total pressure), and then
heated at 1008C with stirring for 5 h. After cooling, the au-
toclave was degassed, the solvent evaporated under reduced
pressure, and the product purified by column chromatogra-
phy (SiO2), using hexane-AcOEt, 8:2, to give pure 10f as a
colorless solid, mp 77–788C (yield: 272.7 mg, 86%).
Oxidative Methoxycarbonylation of Benzyl-(3-
methylnon-2-en-4-ynyl)amine 1f at 90 atm of CO and
Separation of Products [Eq. (8)]
A 250-mL stainless steel autoclave was charged in the pres-
ence of air with PdI2 (10.0 mg, 2.78”10À2 mmol), KI
(230.0 mg, 1.39 mmol) and a solution of 1f (674.0 mg,
2.79 mmol) in MeOH (12.7 mL). The autoclave was pressur-
ized at room temperature with stirring with CO (90 atm)
and air (up to 100 atm of total pressure), and then heated at
708C with stirring for 15 h. After cooling, the autoclave was
degassed, the solvent evaporated under reduced pressure,
and the products purified by column chromatography
(SiO2), using hexane-AcOEt, from 9:1 to 8:2, as the eluent,
to afford 3f (colorless oil, yield: 71.5 mg, 10%) followed by
a mixture of 9f-E and 9f-Z (yellow oil; total yield: 183.0 mg,
20%).
Oxidative Methoxycarbonylation of tert-Butyl-(3-
methylnon-2-en-4-ynyl)amine 1g and Separation of
Products [Eq. (10)]
A 250-mL stainless steel autoclave was charged in the pres-
ence of air with PdI2 (3.0 mg, 8.33”10À3 mmol), KI
(277.8mg, 1.67 mmol) and a solution of 1g (177.2 mg,
0.85 mmol) in MeOH (17.0 mL). The autoclave was pressur-
ized at room temperature with stirring with CO2 (50 atm),
CO (up to 80 atm) and air (up to 90 atm of total pressure),
and then heated at 1008C with stirring for 5 h. After cooling,
the autoclave was degassed, the solvent evaporated under
Oxidative Aminocarbonylation of Butyl-(3-
methylnon-2-en-4-ynyl)amine 1e in MeOH and
Separation of Products [Eq. (9) and Table 4, entry 21]
A 250-mL stainless steel autoclave was charged in the pres-
ence of air with PdI2 (3.0 mg, 8.33”10À3 mmol), KI
2220
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 2212 – 2222

Synthesis of Pyrrole-2-acetic Esters and (Pyridine-2-one)-3-acetic Amides
FULL PAPERS
reduced pressure, and the product purified by column chro- References
matography (SiO2), using hexane-AcOEt, from 95:5 to 9:1,
as the eluent, to afford 2g as a yellow oil (yield: 73.1 mg,
32%).
[1] For excellent recent reviews, see: a) S. A. Vizer, K. B.
Yerzhanov, A. A. A. Al Quntar, V. M. Dembitsky, Tet-
rahedron 2004, 60, 5499–5538; b) G. Zeni, R. C.
Larock, Chem. Rev. 2004, 104, 2285–2309; c) I. Naka-
mura, Y. Yamamoto, Chem. Rev. 2004, 104, 2127–2198.
[2] B. Gabriele, G. Salerno, M. Costa, Synlett 2004, 2468–
2483.
Oxidative Methoxycarbonylation of Phenyl-(3-
methylnon-2-en-4-ynyl)amine 1 h and Separation of
Products [Eq. (11)]
A 250-mL stainless steel autoclave was charged in the pres-
ence of air with PdI2 (3.0 mg, 8.33”10À3 mmol), KI
(277.8mg, 1.67 mmol) and a solution of 1h (191.0 mg,
0.84 mmol) in MeOH (16.8 mL). The autoclave was pressur-
ized at room temperature with stirring with CO2 (50 atm),
CO (up to 80 atm) and air (up to 90 atm of total pressure),
and then heated at 1008C with stirring for 2 h. After cooling,
the autoclave was degassed, the solvent evaporated under
reduced pressure, and the product purified by column chro-
matography (SiO2), using hexane-AcOEt, from 100:0 to
95:5, as the eluent, to afford 2h as a yellow oil (yield:
140.0 mg, 58%).
[3] B. Gabriele, G. Salerno, M. Costa, G. P. Chiusoli, Curr.
Org. Chem. 2004, 8, 919–946.
[4] B. Gabriele, G. Salerno, M. Costa, G. P. Chiusoli, J. Or-
ganomet. Chem. 2003, 687, 219–228.
[5] B. Gabriele, G. Salerno, F. De Pascali, M. Costa, G. P.
Chiusoli, J. Org. Chem. 1999, 64, 7693–7699.
[6] B. Gabriele, G. Salerno, A. Fazio, F. B. Campana,
Chem. Commun. 2002, 1408–1409.
[7] Several derivatives of these classes of carbonyl com-
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Carson, (McNeil Laboratories, Inc.), Ger. Offen.
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c) J. R. Carson, (McNeil Laboratories, Inc.), US Patent
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d) M. W. Whitehouse, K. D. Rainsford, J. Pharm. Phar-
macol. 1980, 32, 795–796; e) L. J. Powers, S. W. Fogt,
Z. S. Ariyan, D. J. Rippin, R. D. Heilman, R. J. Mat-
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g) R. Zurita, (Laboratorios Rubio S. A.), Spanish
Patent 502650, 1982; Chem. Abstr. 1982, 97, P162811v;
h) J. B. Doherty, M. N. Chang, C. P. Dorn, Jr., (Merck
and Co., Inc.), European Patent 72013, 1983; Chem.
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Chang, C. P. Dorn, US Patent 4,434,175, 1984; Chem.
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Oglia, J. Med. Chem. 1985, 28, 1790–1796; k) J. M. Mu-
chowski, E. Galeazzi, R. Greenhouse, A. Guzmꢁn, V.
Perꢂz, N. Ackerman, S. A. Ballaron, J. R. Rovito, A. J.
Tomolosis, J. M. Young, W. H. Rooks, II, J. Med.
Chem. 1989, 32, 1202–1207; l) M. Lehr, Eur. J. Med.
Chem. Chim. Ther. 1997, 32, 805–814; m) M. Lehr, J.
Med. Chem. 1997, 40, 3381–3392; n) C. Dendrinou-
Samara, G. Tsotsou, L. V. Ekateriniadou, A. H. Kortsa-
ris, C. P. Reptopoulou, A. Terzis, D. A. Kyriakidis, D. P.
Kessissoglou, J. Inorg. Biochem. 1998, 71, 171–179;
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tochem. Photobiol. 1999, 70, 549–556; p) O. A. Attana-
si, S. M. Colombani, L. De Crescentini, R. Giorgi, S.
Monti, A. Perrone, F. R. Perrulli, A. R. Renzetti, S.
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M. A. Connell, M. M. Cudahy, B. R. Evans, P. D. May,
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Sih, F. C. Stevens, S. P. Tanis, C. M. Tegley, J. A. Tucker,
V. A. Vaillancourt, T. J. Vidmar, W. Watt, J. H. Yu, J.
Med. Chem. 2001, 44, 1217–1230; r) C. Anagnostou, I.
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Oxidative Carbonylation of (3-methylnon-2-en-4-
ynyl)amine 1i in the Absence of Morpholine and
Separation of Products [Eq. (12)]
A 250-mL stainless steel autoclave was charged in the pres-
ence of air with PdI2 (5.0 mg, 1.39”10À2 mmol), KI
(462.0 mg, 2.78mmol) and a solution of 1i (210.0 mg,
1.39 mmol) in MeOH (27.8mL). The autoclave was pressur-
ized at room temperature with stirring with CO2 (50 atm),
CO (up to 80 atm) and air (up to 90 atm of total pressure),
and then heated at 708C with stirring for 5 h. After cooling,
the autoclave was degassed, the solvent evaporated under
reduced pressure, and the products purified by column chro-
matography (SiO2), using hexane-AcOEt, from 9:1 to 8:2, as
the eluent, to afford 11i (yellow oil, yield: 44.1 mg, 15%)
followed by 12i (colorless solid, mp 83–848C, yield: 92.1 mg,
40%).
Oxidative Carbonylation of (3-methylnon-2-en-4-
ynyl)amine 1i in the Presence of Morpholine and
Separation of Products [Eq. (13)]
A 250-mL stainless steel autoclave was charged in the pres-
ence of air with PdI2 (5.0 mg, 1.39”10À2 mmol), KI
(462.0 mg, 2.78mmol) and a solution of 1i (210.0 mg,
1.39 mmol) and morpholine (365.0 mg, 4.19 mmol) in
MeOH (27.8mL). The autoclave was pressurized at room
temperature with stirring with CO2 (50 atm), CO (up to 80
atm) and air (up to 90 atm of total pressure), and then
heated at 708C with stirring for 5 h. After cooling, the auto-
clave was degassed, the solvent evaporated under reduced
pressure, and the product purified by column chromatogra-
phy (SiO2), using hexane-AcOEt, from 8:2 to 6:4, as the
eluent, to afford 13i as a pale yellow solid, mp 59–608C
(yield: 298.5 mg, 81%).
[8] The spontaneous or metal-catalyzed cycloisomerization
of (Z)-(2-en-4-ynyl)amines was reported to be a gener-
al methodology for the synthesis of substituted pyr-
Adv. Synth. Catal. 2006, 348, 2212 – 2222
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
2221

Bartolo Gabriele et al.
FULL PAPERS
roles: B. Gabriele, G. Salerno, A. Fazio J. Org. Chem.
2003, 68, 7853–7861.
ample: M. Aresta, P. Giannoccaro, I. Tommasi, A. Di-
benedetto, A. M. M. Lanfredi, F. Ugozzoli, Organome-
tallics 2000, 19, 3879–3889 and references cited therein.
[15] E. L. Eliel, S. H. Wilen, L. N. Mander, Stereochemistry
of Organic Compounds, John Wiley & Sons, New York,
1994, pp. 720–721.
[9] The oxidation of the pyrrole ring is a well-known reac-
tion. For general references, see: a) R. A. Jones, in:
Comprehensive Heterocyclic Chemistry, Vol. 4, (Eds.:
A. R. Katritzky, C. W. Rees, C. W. Bird, G. W. H.
Cheeseman), Pergamon, Oxford, 1984, pp. 246–254;
b) A. R. Katritzky, A. F. Pozharskii, Handbook of Het-
erocyclic Chemistry, 2nd edn., Pergamon, Oxford, 2000,
p. 318.
[10] That compounds 4a and 5a could derive from a subse-
quent oxidation of 3a was confirmed by reacting pure
3a under the same conditions as above, but in the ab-
sence of CO and with a 3a/KI/PdI2 molar ratio of
500:50:1, either in anhydrous MeOH or in aqueous di-
oxane as the solvent, to give 4a or 5a in 45% or 27%
isolated yield, respectively. See Supporting Information
for details.
[16] In particular, the mass spectrum showed the molecular
ion (M+ =468) with a relative intensity of 7% with re-
spect to the base peak (m/z=262), corresponding to
the ion ensuing from the cleavage of the amide bond.
Unfortunately, all the attempts to separate 8e at the
pure state were unsuccessful, since this compound in-
variably underwent decomposition during the purifica-
tion procedure (see Experimental Section for details).
[17] The analysis of the NOESY spectrum of the mixture of
9f-E and 9f-Z allowed the assignments of the signals to
each single diastereoisomer. In particular, the NOESY
spectrum (in CDCl3 at 258C) for the more abundant
isomer showed a distinct interaction between the pro-
tons of the CO2Me group and the protons of the
methyl group at C-4, thus indicating E stereochemistry
for this isomer. From the 1H NMR integration data
(either in CDCl3 or in DMSO-d6), it was therefore pos-
sible to calculate the E:Z ratio, which turned out to be
ca. 3:2. The interconversion between the two diastereo-
isomers at 1208C turned out to be fast with respect to
[11] The formation of unidentified heavy products account-
ed for substrate conversion (100%).
[12] B. Gabriele, M. Costa, G. Salerno, G. P. Chiusoli, J.
Chem. Soc., Perkin Trans. 1 1994, 8 3–8 7.
[13] In particular, the mass spectrum of 8d showed the mo-
lecular ion (M+ =440) with a relative intensity of 8%
with respect to the base peak (m/z=248), correspond-
ing to the ion ensuing from the cleavage of the amide
bond. Unfortunately, all the attempts to separate 8d in
the pure state were unsuccessful, since this compound
invariably underwent decomposition during the purifi-
cation procedure (see Experimental Section for de-
tails).
1
the NMR timescale, since a single H NMR spectrum
(in DMSO-d6), corresponding to an averaged situation,
was observed at that temperature (see Supporting In-
formation for details).
[18] B. Gabriele, G. Salerno, R. Mancuso, M. Costa, J. Org.
Chem. 2004, 69, 4741–4750.
[14] Carbamoylpalladium complexes, stabilized by appropri-
ate ligands, were reported in the literature. See, for ex-
2222
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 2212 – 2222