Carbamate as an accelerating group in intermolecular Pauson-Khand reaction

Article abstract of DOI:10.1016/j.tetlet.2020.151974

The Pauson-Khand reaction (PKR) is a powerful means for the construction of cyclopentenones. However, its applications have been limited to the intramolecular version of this reaction because poor yield and regioselectivity are often the major problems in intermolecular PKR. Here we describe that a carbamate moiety in alkene substrate accelerates this intermolecular PKR. The reaction of N-4-dimethylaminophenyl O-allyl carbamate with alkyne-cobalt complex gave cyclopentenones in high yield (up to 90%) and regioselectivity (>9:1).

Full text of DOI:10.1016/j.tetlet.2020.151974

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Carbamate as an accelerating group in intermolecular Pauson-Khand reaction
Shota Asano, Kaori Itto-Nakama, Hirokazu Arimoto
PII:
S0040-4039(20)30417-2
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151974
TETL 151974
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Tetrahedron Letters
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Revised Date:
Accepted Date:
3 February 2020
20 April 2020
23 April 2020
Please cite this article as: Asano, S., Itto-Nakama, K., Arimoto, H., Carbamate as an accelerating group in
intermolecular Pauson-Khand reaction, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.
2020.151974
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Carbamate as an accelerating group in
intermolecular Pauson-Khand reaction
Leave this area blank for abstract info.
Shota Asanoa, Kaori Itto-Nakamaa and Hirokazu Arimotoa
O
O
NMe2
R
R
NMe2
NMO (6.0 eq)
R
O
O
O
toluene
16 h
0 °C to rt
+
Co2(CO)6
O
O
N
N
H
HN
NMe2
O
H
Yield: up to 90%
Regioselectivity: up to 96:4

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Carbamate as an accelerating group in intermolecular Pauson-Khand reaction
Shota Asanoa , Kaori Itto-Nakamaa, and Hirokazu Arimotoa*
aGraduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The Pauson-Khand reaction (PKR) is a powerful means for the construction of
cyclopentenones. However, its applications have been limited to the intramolecular version of
this reaction because poor yield and regioselectivity are often the major problems in
intermolecular PKR. Here we describe that a carbamate moiety in alkene substrate accelerates
this intermolecular PKR. The reaction of N-4-dimethylaminophenyl O-allyl carbamate with
alkyne-cobalt complex gave cyclopentenones in high yield (up to 90%) and regioselectivity
(>9:1).
Available online
Keywords:
Intermolecular
Pauson-Khand Reaction
carbamate
2020 Elsevier Ltd. All rights reserved.
accelerating group
cyclopentenone
Scheme 2. Krafft et al.9
Introduction
The Pauson-Khand reaction (PKR)1 is
a
[2+2+1]
cycloaddition of a set of an alkyne, alkene, and carbon monoxide
meditated by transition metal to provide five-membered
carbocycles (Scheme 1). The intermolecular PKR has been
frequently used in total synthesis of natural products,2 but
examples of intermolecular PKR have been limited to highly-
reactive alkene substrates,3 such as norbornene,4 cyclopropene,5
allene,6 and heterocycles.7
Scheme 3. Yoshida et al.10
O
CO
transition metal
Scheme 1. The Pauson-Khand Reaction
Scheme 4. Carretero et al.11
To address this limitation of intermolecular PKR, Krafft and
co-workers investigated neighboring effects of heteroatomes8 and
found that sulfur and nitrogen atoms in alkene substrates
improved both yield and regioselectivity of cyclopentenone
products9 (Scheme 2). In a ruthenium-catalyzed variant of
intermolecular PKR, Yoshida and co-workers10 used dimethyl (2-
pyridyl)-silyl group as a directing group (Scheme 3). The yields
were not always satisfactory. Carretero and co-workers reported11
that 2-(N,N-diethylamino)-phenyl vinyl sulfoxide afforded good
diasteroselectivities and yields (Scheme 4).
Scheme 5. This work
In this report, we explore new directing groups in
intermolecular PKR. We found that alkene substrates with a
carbamate moiety afforded cyclopentenones in good to excellent
yields and regioselectivities (Scheme 5).

2
Tetrahedron
Result and discussion
Table 1
Intermolecular PKRs with selected alkene substrates and examination of various
carbonyl functionalities.
We initiated our study by screening of a series of alkenes with
a potentially coordinating functionality for the intermolecular
PKR with 100 mM alkyne cobalt complex (1a) and several
groups of alkenes (Table S1) in the presence of NMO12 (Scheme
6). The Krafft’s alkene 29 with a sulfide moiety was used in each
experiment as a competitive substrate. Most of the alkenes (>30
compounds, Supplementary Table S.1) were less reactive than
the Krafft's alkene 2, and 3 and 4 were the predominant products.
However, alkenes (7a, 8 and 9) with a carbamate moiety were
able to complete with 2 to exhibit signals of their corresponding
cyclopenetenones in LC/MS.
Br
NMO (6.0 eq)
alkene
+
toluene
0 °C to RT
16 h
Co2(CO)6
1a (1.0 eq)a
(1.2 eq)
Br
Br
O
O
R
R
Scheme 6
5
6
Screening for alkene substrates with a potentially coordinating functionality.
entry
1
yield [%]b
18d
5:6c
alkene
R1~30
85:15
OH
(1.2 equiv)
Br
NMO (6.0 eq)
Me
substrates for screening
+
toluene
O
2
3
4
7a
8
46d
53e
62e
93:7
72:28
77:23
[9]
0°C to RT
Co2(CO)6
O
N
S
NMe2
16 h
H
1a (1.0 equiv)
2 (1.2 equiv)
(100 mM)
(competitor)
O
NEt2
O
N
H
Br
Br
O
O
O
R1~30
NEt2
O
N
9
H
R1~30
5
6
Br
Br
O
NMe2
O
O
NEt2
S
O
N
5
10
tracef
H
S
Me2N
3
4
O
NEt2
6
7
11
12
30e
46e
80:20
77:23
N
H
O
Me
O
O
O
NEt2
NEt2
O
N
O
N
O
N
H
O
H
H
7a
8
9
NEt2
NEt2
NEt2
N
H
selected alkene substrates
O
O
8
9
13
14
15
tracef
35e
N
H
To further examine the effect carbamates on intermolecular
PKR, alkene substrates, we performed the intermolecular PKRs
in the absence of alkene 2. Homoallyl alcohol without a
carbamate moiety gave the corresponding cyclopentenones in
18% yield (Table 1, entry 1). On the other hand, substrates 7a, 8
and 9 including a carbamate moiety gave PKR adducts in 46-
62% yields (entries 2-4). Then, we modified a homoallyl moiety
and a carbamate moiety of substrate 8. Vinyl carbamate 10
afforded only a trace amount of PKR adducts (entry 5).
Carbamate 11, a regioisomer of alkene 8, provided with a
decreased yield (entry 6). We also examined amides (12 and 13),
esters (14 and 15), carbonate 16, and urea 17. These substrates
afforded the corresponding cyclopentenones in low to modest
yields (entries 7-12), and O-allyl carbamate among various
carbonyl functionalities was concluded to be an excellent
75:25
75:25
76:24
O
O
O
O
10
11
32e
44e
NEt2
NEt2
O
O
16
17
O
NEt2
23e
78:22
N
H
N
H
12
a100 mM. bYields are the sum of 5 and 6. cRegioselectivity was determined by
1H NMR. dIsolated yield. eYields are estimated from 1H NMR of the mixture
of alkene and cyclopentenone 5 and 6. The corresponding cyclopentenone
substrate in intermolecular PKRs. The importance of
a
f
diethylamino group on the intermolecular PKR was then
investigated (Supplementary Table S.2) and these attempts
suggested the amine functionality was not crucial.
was detected in a LC/MS analysis..
We modified the N-aryl moiety of alkene substrates 7a (Table
2). The reaction with phenyl carbamate 7b afforded the
corresponding cyclopentenones in 51% yields (entry 1).

3
Compared with 7a and 7b, substrates with an electron-deficient
aryl ring (7c, 7d, 7e and 7f) gave decreased yields (entries 2-5).
Electron-donating substitutes such as tert-butyl, methoxy and i-
propoxy (7g, 7h and 7i) also decreased the yields of the
intermolecular PKR. These results may indicate that the electron
density of aryl ring is not the key determinant of this reaction.
Interestingly, however, the substrate with a p-dimethylamino
substituent (entry 9) significantly improved the yield of
cyclopentenones up to 81%. NMO was indispensable in the
reaction (entry 10). By increasing the amount of substrate 7j to
2.0 equiv, the yield and regioselectivity were improved further
(entry 11) and the PKR adducts were obtained in satisfactory
yield in a shorter reaction period (4 hours, entry 12). With a
substrate derived from homoallyl alcohol (entry 13), yield of the
cyclopentenones was 32% that was lower than that with related
substrate 7j (81%, Table 2, entry 9). These results suggest the
importance of the distance of two coordinating moieties,
urethane and alkene, in a substrate. We also examined additive-
and solvent-effects with the substrate 7j, but the efforts did not
improve the reaction (Supplementary Table S.3 and S.4).
Intermolecular PKRs with internal alkyne did not proceed with
internal alkynes (entries 6 and 7).
To support our hypothesis of a carbamate as a ligand of
cobalt in intermolecular PKR, we performed the reaction of
cobalt complex 1a and alkene 7j in the presence of carbamate 7j’
(Scheme 7). Because 7j’ lacks alkene, it cannot be the substrate
of PKR. The reaction conditions were otherwise the same with
those of entry 11 in Table 2. We found that the presence of 7j’
not only decreased the yield by ca. 40% but also altered the
selectivity between two cyclopentenone products. We believe
that both of the carbamate moieties of 7j and 7j’ competitively
coordinate to a cobalt intermediate of PKR and thus reduced the
efficiency of the reaction. Moreover, 7j’ may have affected the
regioselectivity of the PKR products by coordinating a reaction
intermediate.13
In summary, carbamate functionality is a good accelerating
group in the intermolecular PKR. Further efforts towards the use
of this finding to total synthesis of natural products are now in
progress and will be reported in due course.
Table 2
Intermolecular PKRs with various N-aryl carbamates.
Br
O
NMO (6.0 eq)
+
R
O
N
toluene
0 °C to RT
16 h
n
H
Co2(CO)6
1a (1.0 equiv)a
7 (1.2 equiv)
Br
Br
O
O
O
O
R
O
N
HN
R
O
H
5
6
5:6d
entry
yield [%]b,c
7
1
7b (n=1) (R = Ph)
51
0
92:8
2
7c (n=1) (R = 4-Pyridyl)
3e
7d (n=1)
0
(R = 4-NCC6H4)
(R = 4-FC6H4)
4
7e (n=1)
7f (n=1)
7g (n=1)
7h (n=1)
38
<38
37
21
89:11
88:12
90:10
72:28
(R = 4-NO2C6H4)
(R = 4-tBuC6H4)
(R = 4-MeOC6H4)
5
6
7
(R = 4-iPrOC6H4)
8
7i (n=1)
46
94:6
(R = 4-Me2NC6H4)
9
10f
11g 7j
7j (n=1)
7j
81
<2
87
92:8
85:15
96:4
12g,h 7j
78
32
92:8
(R = 4-Me2NC6H4)
13
7k (n=2)
76:24
a100 mM. bYields are the sum of 5 and 6. cIsolated yield. dRegioselectivity
was determined by 1H NMR. ep-Aminobenzonitlire was obtained in 74 %.
fThe reaction was performed for 48 h without NMO. galkene = 2.0 equiv.
hThe reaction was performed for 4 h.
Having optimized the alkene substrate 7j, we turned our attention
to the scope of alkyne-cobalt complex (Table 3). We had used
cobalt-complex 1a throughout this study, but phenyl (1b) and 4-
methoxyphenyl derivatives (1c) were also shown to be good
substrates for the reaction with alkene 7j (entries 1 and 2).
However, aliphatic and silyl substituents in alkyne-cobalt
complex 1d, 1e, and 1f with alkene 7j decreased the yield and
regioselectivity of intermolecular PKR (entries 3~5).

4
Tetrahedron
Table 3
Intermolecular PKRs with various alkyne and alkene 7j.
O
R
O
NMe2
R
O
NMe2
O
O
NMO (6.0 eq)
toluene
O
R'
R
R'
+
R'
N
H
HN
NMe2
O
N
O
H
Co2(CO)6
0 °C to RT
16 h
1 (1.0 equiv)a
7j (2.0 equiv)
5
6
entry
1
products
yield [%]b,c
5:6d
O
O
NMe2
Ph
Ph
O
O
HN
O
O
1
90
81
33
91:9
Co2(CO)6
N
NMe2
H
1b
5b
6b
O
O
MeO
NMe2
4-MeOC6H4
4-MeOC6H4
O
O
92:8
O
2
N
H
HN
NMe2
Co2(CO)6
O
1c
5c
6c
n-C6H13
O
O
n-C6H13
NMe2
NMe2
NMe2
n-C6H13
3
O
85:15
O
Co2(CO)6
O
N
HN
NMe2
O
H
1d
5d
6d
O
O
TMS
TMS
TMS
O
4
O
44
71:29
O
Co2(CO)6
N
HN
NMe2
O
H
1e
5e
6e
O
O
MeO
MeO
MeO
O
HN
5
O
52
87:13
O
Co2(CO)6
N
NMe2
O
H
1f
5f
5f
O
O
NMe2
Ph
Ph
Ph
O
O
O
6
Ph
0
N
HN
NMe2
O
H
Co2(CO)6
1g
5g
6g
O
O
NMe2
Me
Me
Me
Me
O
O
Me
Me
Co2(CO)6
1h
7
tracee
O
N
HN
NMe2
O
H
5h
6h
a100 mM. bYields are the sum of 5 and 6. cIsolated yield. dRegioselectivity was determined by 1H NMR. eCorresponding cycloppentenone was detected
in a LC/MS analysis..

5
Scheme 7
Competitive reaction
Ar
Ar
H
Co(CO)n
(CO)m
H
Co(CO)n
(CO)m
Co
Co
O
Ar
O
Br
O
O
NMe2
NMe2
O
O
O
N
NMe2
O
H
HN
NMe2
N
O
N
H
H
II
I
5a
7j (2.0 equiv)
Co2(CO)6
NMO (6.0 equiv)
Me2N
+
H
toluene
0 °C to RT
16 h
NMe2
1a (1.0 equiv)
O
O
NMe2
Ar
Ar
(100 mM)
O
O
N
HN
H
O
H
Co(CO)n
CO
O
7j' (2.0 equiv)
N
Co
NMe2
O
H
6a
O
NH
O
5a+6a = 46 %
5a:6a = 81:19
III
Derdau, S. Laschat, R. G. Jones, Eur. J. Chem. 2000,
681-689.
(a) M. E. Krafft, C. A. Juliano, I. L. Scott, C. Wright, M.
D. McEachin, J. Am. Chem. Soc., 1991 , 113, 5799-5810.
(b) M. E. Krafft, I. L. Scott, R. H. Romero, S.
Feibelmann, C. E. Van Pelt, J. Am. Chem. Soc., 1993,
115, 7199-7207.
Acknowledgement
We thank Prof. Makoto Sasaki (Tohoku University) for
LC/MS analyses.
8.
Appendix A. Supplementary data
9.
M. E. Krafft, C. A. Juliano, J. Org. Chem., 1992, 57,
5106-5115.
Supplementary data to this article can be found online.
10.
11.
12.
13.
K. Itami, K. Mitsudo, J. Yoshida, Angew. Chem. Int. Ed.,
2002, 41, 3481-3484.
M. R. Rivero, I. Alonso, J. C. Carretero, Chem. Eur. J,
2004, 10, 5443-5459.
M. Ahmar, F. Antras, B. Cazes, Tetrahedron Lett., 1999,
40, 5503-5506.
(a) M. E. Krafft, J. Am. Chem. Soc., 1988, 110, 968-970.
(b) M. E. Krafft, C. A. Juliano, I. L. Scott, C. Wright, M.
D. McEachin. J. Am. Chem. Soc., 1991, 113, 1693-1703.
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Declaration of interests

The authors declare that they have no
known competing financial interests or
personal relationships that could have
appeared to influence the work reported in
this paper.
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(a) S. E. Gibson and N. Mainolfi, Angew. Chem. Int. Ed.,
2005, 44, 3022-3037. (b) S. Laschat, A. Becheanu, T.
Bell, A. Baro, Synlett, 2005, 17, 2547-2570.
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☐The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:
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6
Tetrahedron
Graphical Abstract
Highlights

Examples of intermolecular Pauson-Khand
reaction (PKR) have been limited to reactive
alkene substrates.
Carbamate as an accelerating group in
intermolecular Pauson-Khand reaction
Leave this area blank for abstract info.
Shota Asanoa, Kaori Itto-Nakamaa and Hirokazu Arimotoa
O
O
NMe2
R
R
NMe2
NMO (6.0 eq)
R
O
O
O
toluene
16 h
0 °C to rt
+
Co2(CO)6
O
O
N
N
H
HN
NMe2
O
H
Yield: up to 90%
Regioselectivity: up to 96:4


Carbamate in alkene substrates was
demonstrated to facilitate intermolecular
PKRs.
Arylalkynes are the suitable substrates of
this reaction.