New regio and stereoselective intermolecular Pauson-Khand reactions of allenamides

Article abstract of DOI:10.1016/j.tetlet.2004.04.061

Intermolecular Pauson-Khand reactions are still quite limited in scope and yields. There are also few reports using allenes as the olefinic part in this version. We report herein new regio and stereoselective reactions of allenamides with several alkynes. These reactions give functionalized cyclopentenones bearing an exocyclic enamide, which can be useful synthetic intermediates.

Full text of DOI:10.1016/j.tetlet.2004.04.061

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4441–4444
New regio and stereoselective intermolecular Pauson–Khand
reactions of allenamides
*
~
Loreto Anorbe, Amalia Poblador, Gema Domınguez and Javier Perez-Castells
ꢀ
ꢀ
Departamento de Quꢀımica, Facultad de Ciencias Experimentales y de la Salud, Universidad san Pablo-CEU, Urb. Monteprꢀıncipe,
28668 Boadilla del Monte (Madrid), Spain
Received 29 March 2004; revised 13 April 2004; accepted 13 April 2004
Abstract—Intermolecular Pauson–Khand reactions are still quite limited in scope and yields. There are also few reports using allenes
as the olefinic part in this version. We report herein new regio and stereoselective reactions of allenamides with several alkynes.
These reactions give functionalized cyclopentenones bearing an exocyclic enamide, which can be useful synthetic intermediates.
Ó 2004 Elsevier Ltd. All rights reserved.
Allenamines and allenamides are an emerging group of
R2
O
O
R1
substrates that are becoming useful in organic synthe-
sis.1 Although there are still very few literature examples
using allenamines, this electron enriched allenes have
found use in some reactions with electrophiles and in
certain cyclizations. The parent allenamides are more
stable and thus are increasing their use in synthetic
methodologies.2
R1
R2
R2
Co2(CO)8
+
+
R1
Scheme 1.
There are a wide variety of catalytic protocols available
to effect this reaction, some of them under mild condi-
tions. Nevertheless the catalytic PKR is not a completely
solved problem specially in the intermolecular processes
where there are still few results.3b
On the other hand, the Pauson–Khand reaction (PKR)
is a powerful tool in the synthesis of cyclopentenones, a
structural feature present in a large variety of natural
products.3 The intermolecular version of this reaction is
still quite limited, as unstrained olefins scarcely react.4
Some vinylethers/esters5 and vinyl sulfoxides6 are also
useful in the intermolecular PKR. The use of traceless
tethers7 or directing groups like pyridisilyl8 are strategies
that circumvent partially this problem, also avoiding the
formation of regioisomeric mixtures. In the majority of
cases, the intermolecular PKR is regioselective from the
alkyne being the bulkier substituent situated adjacent to
the carbonyl in the final product. It has been demon-
strated recently that both steric and electronic effects
may be responsible for this regioselectivity.9 Unsym-
metrical olefins usually give mixtures of regioisomers
(Scheme 1).
Allenes are one of the most promising substrates for the
PKR introduced in the past years. Several groups have
used the intramolecular allenic PKR for the synthesis of
medium sized rings. However there is only one prece-
dent in the use of simple allenes in an intermolecular
PKR due to Cazes and co-workers.10 There is also a
precedent of an intramolecular PKR with an allenamide
equivalent.11
We herein report new intermolecular PKR of allen-
amides. These reactions show many possibilities in
selectivity, and as we will see have resulted to be very
regio and stereoselective.
To explore this chemistry we carried out the synthesis of
a series of allenamides bearing aromatic rings. This
synthesis was effected using a classical strategy depicted
Keywords: Intermolecular Pauson–Khand; Allenamides; Cobalt.
* Corresponding author. Tel.: +34913724798; fax: +34913510475;
e-mail: jpercas@ceu.es
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.061

4442
R1
L. A~norbe et al. / Tetrahedron Letters 45 (2004) 4441–4444
would accelerate the decomposition of our starting
R1
R2
R2
materials.14 Thus, we used trimethylamine N-oxide
(TMANO) and N-methylmorpholine N-oxide (NMO)
as promoters testing several solvents. Heat promotion
was also unsuccessful due to thermal decomposition of
the allenamide. The results are summarized in Table 1.
Entries 1–3 show that the presence of molecular sieves
and/or heat prevent the formation of the PK product
probably due to rapid decomposition of the allene into
the acetanilide 7a, which was isolated in high yield.
Br
N
Z
NH
Z
KOH, Bu4NI
THF,
1a, R1=OCH3, R2=H, Z=Ac
2a, 91%
2b, 81%
2c, 67%
1b, R1=F, R2=H, Z=Ac
1c, R1=OCH3, R2=H, Z=Ts
2d, R1=H, R2= CH=CH2, Z=Ac
R1
R2
3a, 70%
Among the conditions tested, those of entry 6, were
selected. Although yields were still not excellent in this
example, the reaction gave only one compound, jointly
with a small amount of a mixture of other compounds,
which could not be identified and with a 7% of 7a. The
structure of the major reaction product was assigned
based on NMR experiments as E-5a. The first important
data is the position of the signal of the CH2 of the
cyclopentenone. This carbon appears at 38 ppm, which
agrees with calculated values for compound 5a. The
CH2 in 6a is expected to appear at 22 ppm. Additionally,
NOE experiments showed that irradiation of Ha lead to
a 9.7% increment in the signal of Hb and a 6.4% incre-
ment in Hc. No effect was observed in the signal corres-
ponding to the CH2. These increments demonstrate an
E-stereochemistry for the reaction product. It is inter-
esting to note the great number of possibilities in the
formation of isomers that are possible in this reaction.
The regioselectivity from the alkyne part follows the
vast number of examples reported in the literature and
the bulky substituent is placed near the carbonyl. On the
other hand it is rare to find intermolecular PKR with
nonsymmetric olefins that do not give mixtures of
regioisomers. In our case we only detected the product
with the exocyclic double bond in the b-position. This
exocyclic double bond has two possible stereochemist-
ries, being the E-compound the only one isolated. When
purifying the crude mixture, small amounts of complex
mixtures were separated from E-5a, being the only other
tBuO-K+
3b, 69%
3c, 70%
N
Z
THF
3d, 82%
Scheme 2.
in Scheme 2. Starting from tosylanilides and acetanilides
1, propargylation under sonication using solid KOH as
the base gave the corresponding propargylamides 2 in
good yields. These compounds were converted totally
into the corresponding allenamides 3 by treatment with
tBuOK. In the synthesis of 3c some amount of allene is
formed in the propargylation reaction but we were
unable to have good direct conversions from 1 into 3
that would improve the two-step process.12 One of the
allenes formed, compound 3d, was designed to show the
competence in the PKR of the allene and the olefin. We
obtained this substrate from our previously described
product 2d.13
The Pauson–Khand reaction of compound 3a with
p-tolylacetylene, 4a, was selected as a model to test
several conditions. We used first two reaction conditions
developed in our group that use molecular sieves as
promoters. However, in this case, we found no results
probably due to decomposition of the allenamide.
Molecular sieves are known for being catalysts in the
formation of enamines and thus it is possible that they
Table 1. Reaction conditions for the PKR of compound 4a
H
6.4%
9.7%
Hc
H
MeO
N
O
O
PKR
Ha
Hb
O
+
+
+
0%
N
H
O
N
O
N
O
MeO
OMe
MeO
6a (not detected)
7a
3a
Conditions
1.5 equiv alkyne, 1.5 equiv Co2 (CO)8, 4 A mol. sieves, reflux
4a
E-5a
Entry
Solvent
Yield of 7a (%)a
Yield of E-5a (%)a
ꢁ
1
2
3
4
5
6
Toluene
Toluene
Toluene
Toluene
CH3CN
CH3CN
75
28
80
18
8
<5
10
<5
18
32
45
ꢁ
1.5 equiv alkyne, 1.5 equiv Co2(CO)8, 4 A mol. sieves, 9 equiv TMANO, rt
1.5 equiv alkyne, 1.5 equiv Co2(CO)8, reflux
1.5 equiv alkyne, 1.5 equiv Co2(CO)8, 9 equiv TMANO, rt
1.5 equiv alkyne, 1.5 equiv Co2(CO)8, 9 equiv TMANO, rt
1.5 equiv alkyne, 1.5 equiv Co2 (CO)8, 6 equiv NMO, rt
7
a In pure product with correct spectroscopical and analytical data.

L. A~norbe et al. / Tetrahedron Letters 45 (2004) 4441–4444
Table 2. Intermolecular PKR of alleneamides
4443
R3
R4
R3
R4
H
Z
R1
R2
N
Co2(CO)8
O
R2
+
R2
+
CH3CN
NMO
N
Z
N
Z
R1
R4
R1
7
4
R2
E-5
Entry Substrate
R1
Z
R3
Product
Yield of 7 (%)a Yield of E-5 (%)a
1
2
3a
3a
3a
3b
3c
3d
3c
3c
3c
3c
MeO
MeO
MeO
F
H
H
H
H
H
Ac
Ac
Ac
Ac
Ts
p-Tolyl
Bu
Et
H
E-5a
E-5b
E-5c
E-5d
E-5e
E-5f
E-5g
––
7
8
45
50
65
61
85
58
25
––
85b
78b
H
3
Et
Et
Et
Et
H
10
9
4
Et
Et
5
MeO
H
5
6
CH@CH2 Ac
Et
––
––
––
––
––
7
MeO
MeO
MeO
MeO
H
H
H
H
Ts
Ts
Ts
Ts
p-Tolyl
CH2OH
Pr
8
H
TMS
9
10
E-8h+E-5h (4:1)
E-8i+E-5i (4:1)
CH2OTBDMS TMS
a In pure product with correct analytical and spectroscopic data.
b In pure mixture of both isomers.
compound that could be identified in those mixtures,
one isomer of E-5a that we have assigned to Z-5a.
R
R
TMS
O
TMS
N
R
12-9.5%
Co2(CO)8
CH3CN
NMO
H
O
3c +
+
Substrate scope for this process was then addressed. The
results are summarized in Table 2.15 Yields are moderate
with terminal alkynes (entries 1,2) even when switching
the allenamide protecting group to tosyl (entry 7). We
also noted an unsuccessful result with propargyl alcohol
(entry 8). On the other hand, nonterminal alkynes gave
better results (entries 3–6) and we recorded some
excellent yields. Reaction of entry 6 was performed to
study the competence between the olefin and the allene.
We did not observe any reaction with the olefin, being
E-5f the only observed product (Scheme 3). The NOE
experiments effected in all the products showed they all
had the same E-stereochemistry. The reactions of entries
2 and 7 were sluggish and other isomers might have been
present in the crude mixtures.
N
TMS
Ar
Ar
Ts
Ts
R = Et,
E-8h +E-5h (4:1), 85%
E-8i + E-5i (4:1), 78%
OTBDMS
Scheme 4.
The NOE experiments showed the major compounds
corresponded with E-8h–i with the TMS group in the
a-position, being E-5h–i the minors.
In conclusion we have described a highly selective
intermolecular PKR of allenamides that give interesting
funtionalized cyclopentenones, which we will use as
synthetic intermediates in the synthesis of natural
products. We are currently completing the study on the
scope of this reactions and on the chemistry of these new
products.
In view of these results we carried out the reaction of 3c
with 1-trimethylsilyl-1-pentyne (entry 9). This reaction
led to a 4:1 mixture of isomers in 85% yield. The reac-
tion with protected propargyl alcohol (entry 10) led
smoothly and with good yield to 4:1 mixture of isomers.
These two isomers are the regioisomers derived from the
two possible orientations of the alkyne. A small amount
of the major isomer was separated for characterization
(Scheme 4).
Acknowledgements
This work was supported by MCYT-Spain, BQU2002-
00137) and the Universidad San Pablo-CEU (grant 07/
03). A.P. acknowledges fellowship from the FUSP-
CEU.
Co2(CO)8
O
+
CH3CN
NMO
N
N
References and notes
O
O
1. Wei, L.-L.; Xiong, H.; Hsung, R. P. Acc. Chem. Res. 2003,
36, 773–782.
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Sakamoto, T. J. Org. Chem. 2004, 69, 1126–1136; (b)
3d
E-5f
Scheme 3.

4444
L. A~norbe et al. / Tetrahedron Letters 45 (2004) 4441–4444
ꢀ
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15. Typical experimental procedure for the synthesis of E-5e:
To a solution of 3-hexine (135 lL, 1.19 mmol) in aceto-
nitrile (8 mL), Co2(CO)8 (407 mg, 1.19 mmol) was added
and the resulting mixture was stirred for 90 min at room
temperature. The solution was then cooled in an ice/water
bath and NMO (557 mg, 4.76 mmol) was added. A
solution of allene 3a (250 mg, 0.79 mmol) in acetonitrile
(8 mL) was then added to the reaction mixture and this
was stirred at room temperature overnight. The reaction
mixture was filtered off through a celite pad and washed
with acetonitrile (10 mL). The solvent was removed and
the residue was purified by column chromatography on
silica gel (hexane/ethyl acetate, 2/1) affording 288 mg
(85%) of the product E-5e as a white solid. Mp 122–
24 °C Et2O). 1H NMR (CDCl3): 0.91 (t, 3H, CH3,
J ¼ 7:7 Hz), 1.18 (t, 3H, CH3, J ¼ 7:7 Hz), 1.96 (s, 2H,
CH2), 2.14 (q, 2H, CH2, J ¼ 7:7 Hz), 2.38 (s, 3H, CH3),
2.53 (q, 2H, CH2, J ¼ 7:7 Hz), 3.75 (s, 3H, CH3), 6.75 (d,
2H, Ar, J ¼ 9:3 Hz), 6.85 (d, 2H, Ar, J ¼ 8:8 Hz), 7.16 (s,
1H, CH), 7.24 (d, 2H, Ar, J ¼ 8:2 Hz), 7.50 (d, 2H, Ar,
J ¼ 8:2 Hz). 13C NMR (CDCl3): 204.2, 169.0, 159.8, 144.3,
140.4, 134.7, 131.2, 129.6, 129.2, 127.4, 122.1, 119.1, 114.3,
55.2, 37.0, 21.4, 19.3, 16.3, 13.8, 13.2. IR (KBr): 1690
(C@O), 1350 (SO2), 1180 (SO2). Anal. Calcd for
C24H27NO4S: C, 67.74; H, 6.40; N, 3.29; S, 7.54. Found:
C, 67.87; H, 6.48; N, 3.41; S, 7.32.
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€
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