Nitrous Oxide Promoted Pauson-Khand Cycloadditions

Article abstract of DOI:10.1021/acs.organomet.8b00810

A Pauson-Khand cycloaddition of alkynes, alkenes, and carbon monoxide promoted by cobalt carbonyl and nitrous oxide to furnish cyclopentenones is described. Preliminary mechanistic experiments suggest that nitrous oxide functions in a manner similar to th

Full text of DOI:10.1021/acs.organomet.8b00810

Communication
pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
Nitrous Oxide Promoted Pauson−Khand Cycloadditions
J. David Ricker, Vahid Mohammadrezaei, Thomas J. Crippen, Austin M. Zell, and Laina M. Geary*,a
Department of Chemistry, University of Nevada, Reno, Reno, Nevada, 89557, United States
S
* Supporting Information
ABSTRACT: A Pauson−Khand cycloaddition of alkynes, alkenes, and
carbon monoxide promoted by cobalt carbonyl and nitrous oxide to
furnish cyclopentenones is described. Preliminary mechanistic experi-
ments suggest that nitrous oxide functions in a manner similar to that of
the N-oxide promoters typically employed in Pauson−Khand reactions.
Only dinitrogen and carbon dioxide are produced as a consequence of
the activation mechanism, thus avoiding high-molecular-weight reagents
and the buildup of basic byproducts. The chemistry is done using equimolar amounts of alkyne, alkene, and dicobalt
octacarbonyl and is performed directly from the acetylenic component without the need to presynthesize a cobalt-alkyne
complex. Terminal acetylenes were suitable substrates, as was solid calcium carbide, and the corresponding adducts were
isolated in good yields. Furthermore, two sequential [4 + 3] and [2 + 2+1] cycloadditions were performed, generating
functionalized cyclopentenones in only two steps from readily available starting materials.
he Pauson−Khand reaction (PKR) is a [2 + 2 + 1]
the cyclopentenone adducts,7 generating a substantial amount
of waste. Thus, it is somewhat surprising that the simplest N-
oxide, nitrous oxide (N2O), has never been used as a promoter
in this reaction. Replacing the commonly employed trimethyl-
amine N-oxide (TMAO) with N2O reduces the amount of
waste generated. Moreover, nitrous oxide is inexpensive and
widely available, yet there are few applications of the gas as a
reagent in chemical synthesis.8 Most transition-metal-catalyzed
or -mediated processes that currently utilize N2O involve direct
transfer of the oxygen atom of N2O to the transition-metal
center.9 However, we hypothesized that, if N2O could oxidize
the CO ligand rather than cobalt,10 we could promote the PKR
and avoid the need for large excesses of solid oxide promoters
(Scheme 1B).
T
cycloaddition among an alkyne, an alkene, and carbon
monoxide to yield cyclopentenones.1 It was first discovered in
the early 1970s as a stoichiometric reaction between
acetylenedicobalt hexacarbonyl (1a; R = H) and norbornene
(2a) at elevated temperatures to yield the cycloadduct in
moderate yield.2
The accepted mechanism (Scheme 1A)3 was proposed on
the basis of the observed regiochemistry of 3a and has been
Scheme 1. Summary of Cobalt-Mediated Pauson−Khand
Cycloadditions
We began the study by comparing the isolated yields of
cyclopentenone 3b when the cycloaddition was performed in
the presence of 1 equiv of Co2(CO)8 either with 1 equiv of a
solid N-oxide promotor or in the presence of N2O at 40 °C in
acetonitrile (Table 1). We found that at that loading TMAO
was an effective promoter of the PKR (entry 1), but N-
methylmorpholine N-oxide (NMO) required higher loading in
accordance with previously reported studies7 (entry 2 vs entry
3) to be effective. Nicotinamide N-oxide (NNO) was
ineffective, and 3b was produced in low yields among other
unidentifiable materials (entry 4). We were pleased to note
that performing the PKR in an N2O-saturated acetonitrile
solution gave cyclopentenone 3b in 80% yield after 20 h (entry
5). Extending the reaction time to 24 h improved the isolated
yield of 3b to 86% (entry 6). Performing the reaction at room
temperature led to a slight reduction in the isolated yield of 3b
(entry 7); performing the reaction in the total absence of
promoter led to only a trace amount of 3b (entry 8). We
largely supported by DFT calculations4 and mass spectrom-
etry.5 After formation of the dicobalt acetylene complex 1,
dissociation of a molecule of CO from 1 to form 4 must occur
so that an alkene can coordinate to generate 5, which goes on
to form the cyclopentenone product 3. The most common
method for the formation of 4 is the application of a promoter,
typically amine N-oxides.6 The amine N-oxide is required to be
used in 5−10-fold excess to get synthetically useful yields of
Received: November 4, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.8b00810
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
Table 1. Selected Optimization Experiments in the N2O-
a
Mediated PKR
a
entry
R3NO
solvent (0.1 M) T (°C) t (h)
yield of 3a (%)
69
29
75
1
2
3
4
5
6
7
8
TMAO
NMO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
DME
40
40
40
40
40
40
20
40
40
40
40
40
40
20
20
20
24
20
24
24
24
24
24
24
24
24
b
NMO
NNO
N2O
N2O
N2O
intractable mixture
80
86
64
trace
74
10
77
40
52
9
N2O
N2O
N2O
N2O
N2O
10
11
12
13
THF
DCM
CHCl3
a
b
Yields are of material isolated by silica gel chromatography. 6 equiv
of NMO. See the Supporting Information for further details.
Figure 1. In situ FTIR data comparing the activation of the cobalt
phenylacetylene complex 1b (top) as promoted by TMAO (middle)
and N2O (bottom). The x-axis shows the region of CO2 absorbance,
and the z-axis begins at the addition of the N-oxide.
attempted to further improve the yield of the cycloadduct by
varying the solvent (entries 8−12), but the reaction performed
best in MeCN.
To determine whether N2O was in fact acting in a manner
analogous to that of other N-oxides, we compared in situ FTIR
data for the reaction between the cobalt phenylacetylene
hexacarbonyl complex 1b and both TMAO and N2O. The
generation of CO2 was observed at 2338 cm−1 upon addition
of each promoter, though rapid outgassing of the solution
prevented kinetic analysis of the two processes (Figure 1).
While production of CO2 is consistent with the oxidative
extrusion of a CO ligand from the hexacarbonyl intermediate
1b and formation of the putative pentacarbonyl species 4b, we
cannot rule out a more complex role for N2O at this time.
We then turned to examining the scope of the alkyne
component in the reaction (Table 2, top). To synthesize the
parent cyclopentenone, we opted to use the solid reagent
calcium carbide (6a) rather than gaseous acetylene to avoid
concurrent introduction of two gaseous reagents. Calcium
carbide, though exceedingly inexpensive, is not often employed
as an acetylene surrogate.11 We were pleased to note that CaC2
was an effective substrate when it was used with 2 equiv of
water, and the cyclopentenone 3a was isolated in good yield.12
Phenylacetylene 6b was an excellent substrate, giving cyclo-
pentenone 3b in high yield. Electronically different species,
whether electron rich (6c) or electron poor (6d,e) were
somewhat less effective, and products 3c−e were isolated in
somewhat lower yields. The internal alkyne dimethyl
acetylenedicarboxylate 6f was an excellent substrate, and the
product 3f was isolated in good yield. Other functional groups
were well tolerated, and cyclopentenones containing coor-
dinative alcohol and nitrile functional groups, 3h,i, were
isolated in good yields. Norbornadiene was also an effective
partner in the PKR,13 and adducts 3j−l were isolated in
generally good yield.
little functionality.7,14 We were interested in applying more
functionalized alkenes to the PKR. The [3.2.1] and [3.2.2]
bicyclic olefins 8a−c were particularly interesting, as they are
easily constructed from cyclic butadienes and ureas via [4 + 3]
cycloadditions15 and contain many synthetic handles for
downstream transformations. We thus subjected bridged
bicyclic alkenes 8a−c to our standard conditions. Though
not as strained as the [2.2.1] bicyclic alkenes,16 these olefins
were ready participants in the PKR, and densely functionalized
cyclopentenones 3m−o were produced in good yields (Table
2, bottom). All cyclopentenones were isolated as single
isomers, and exo selectivity was determined by comparing
acquired spectral data to those of the known compounds
3a,b,f−h,j−l and extrapolating them to those of the unknown
compounds 3c−e,i,m−o.
Finally, we demonstrated the applicability of these reaction
conditions to the cyclization of a 1,6-enyne (eq 1). The
malonate derivative 9 smoothly reacted with Co2(CO)8 in the
presence of N2O to give the [5.5] bicyclic compound 10 in
high yield (89%).
In conclusion, N2O has been used for the first time as a
promoter in the Pauson−Khand reaction. Its use avoids the
buildup of basic waste in situ that other often used promoters
(NMO, TMAO) leave behind. We have preliminary evidence
that N2O oxidatively removes a CO ligand from the cobalt
complex, but more detailed mechanistic explorations are
The intermolecular PKR is typically limited to either olefins
with a low LUMO or those that possess a pendant Lewis base
for secondary coordination to cobalt but otherwise contain
B
DOI: 10.1021/acs.organomet.8b00810
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
Table 2. Scope of the Intermolecular PKR between Alkynes
1a−i and Norbornene 2a As Promoted by Nitrous Oxide
AUTHOR INFORMATION
■
a
Corresponding Author
*E-mail for L.M.G.: lgeary@unr.edu.
ORCID
Laina M. Geary: 0000-0001-7511-4983
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Research reported in this publication was partially supported
by the National Institute of General Medical Sciences of the
National Institutes of Health under award number
R15GM120738 and by the University of Nevada, Reno, via
start-up funds. T.J.C. acknowledges the University of Nevada,
Reno, for an undergraduate research scholarship.
REFERENCES
■
(1) (a) The Pauson−Khand reaction. Scope, variations and
applications; Wiley: 2012. (b) Ricker, J. D.; Geary, L. M. Recent
advances in the Pauson−Khand reaction. Top. Catal. 2017, 60, 609−
619.
(2) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman,
M. I. Organocobalt complexes. Part II. Reaction of acetylenehex-
acarbonyldicobalt complexes, (R1C2R2)Co2(CO)6, with norbornene
and its derivatives. J. Chem. Soc., Perkin Trans. 1 1973, 1, 977−981.
(3) Magnus, P.; Principe, L. M. Origins of 1,2- and 1,3-
stereoselectivity in dicobaltcarbonyl alkene-alkyne cyclizations for
the synthesis of substituted bicyclo[3.3.0]octenones. Tetrahedron Lett.
1985, 26, 4851−4854.
(4) (a) Yamanaka, M.; Nakamura, E. Density functional studies on
the Pauson−Khand reaction. J. Am. Chem. Soc. 2001, 123, 1703−
1708. (b) de Bruin, T. J. M.; Michel, C.; Vekey, K.; Greene, A. E.;
Gimbert, Y.; Milet, A. First C-C bond formation in the Pauson−
Khand reaction: Influence of carbon-carbon triple bond polarization
on regiochemistry. A density functional theory study. J. Organomet.
Chem. 2006, 691, 4281−4288.
(5) (a) Gimbert, Y.; Lesage, D.; Milet, A.; Fournier, F.; Greene, A.
E.; Tabet, J.-C. On early events in the Pauson−Khand reaction. Org.
Lett. 2003, 5, 4073−4075. (b) Henderson, M. A.; Luo, J.; Oliver, A.;
McIndoe, J. S. The Pauson−Khand reaction: A gas-phase and
solution-phase examination using electrospray ionization mass
spectrometry. Organometallics 2011, 30, 5471−5479. (c) Lesage, D.;
Milet, A.; Memboeuf, A.; Blu, J.; Greene, A. E.; Tabet, J.-C.; Gimbert,
Y. The Pauson−Khand mechanism revisited: Origin of CO in the
final product. Angew. Chem., Int. Ed. 2014, 53, 1939−1942.
(6) CO dissociation can also occur thermally or photochemically,
though these methods are less commonly used.
a
b
Yields are of material isolated by silica gel chromatography. 2 equiv
of H2O was added. See Supporting Information for further details
(7) Gibson, S. E.; Mainolfi, N. The intermolecular Pauson−Khand
warranted. We found that N2O promoted the cycloaddition
between alkynes and bridged bicyclic olefins in moderate to
good yields and that the reaction could be executed directly
from the alkyne with no need to presynthesize the cobalt
alkyne complex. Our application of sequential [4 + 3] and [2 +
2 + 1] cycloadditions combines inexpensive and readily
available starting materials to give complex, densely function-
alized tricyclic ring systems in only two steps.
reaction. Angew. Chem., Int. Ed. 2005, 44, 3022−3037.
(8) Severin, K. Synthetic chemistry with nitrous oxide. Chem. Soc.
Rev. 2015, 44, 6375−6386.
(9) (a) Tskhovrebov, A. G.; Solari, E.; Scopelliti, R.; Severin, K.
Activation of nitrous oxide by dinuclear ruthenium complexes.
Organometallics 2012, 31, 7235−7240. (b) Tskhovrebov, A. G.;
Solari, E.; Wodrich, M. D.; Scopelliti, R.; Severin, K. Sequential N-O
and N-N bond cleavage of N-heterocyclic carbene-activated nitrous
oxide with a vanadium complex. J. Am. Chem. Soc. 2012, 134, 1471−
1473. (c) Gianetti, T. L.; Rodríguez-Lugo, R. E.; Harmer, J. R.;
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00810.
■
Trincado, M.; Vogt, M.; Santiso-Quinones, G.; Grutzmacher, H.
̈
S
Zero-valent amino-olefin cobalt complexes as catalysts for oxygen
atom transfer reactions from nitrous oxide. Angew. Chem., Int. Ed.
2016, 55, 15323−15328.
(10) There are limited examples of CO oxidation by N2O; for an
example, see: Bottomley, F.; Lin, I. J. B.; Mukaida, M. Reactions of
dinitrogen oxide (nitrous oxide) with dicyclopentadienyltitanium
Experimental details and 1H and 13C NMR, HRMS, and
elemental analyses of new compounds (PDF)
C
DOI: 10.1021/acs.organomet.8b00810
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
complexes including a reaction in which carbon monoxide is oxidized.
J. Am. Chem. Soc. 1980, 102, 5238−5242.
(11) Rodygin, K. S.; Werner, G.; Kucherov, F. A.; Ananikov, V. P.
Calcium carbide: a unique reagent for chemical synthesis. Chem. -
Asian J. 2016, 11, 965−976.
(12) When gaseous acetylene was used in conjunction with N2O, a
more complex reaction outcome was observed by TLC.
(13) Aiguabella, N.; Pesquer, A.; Verdaguer, X.; Riera, A. Pauson−
Khand Adducts of N-Boc-propargylamine: A New Approach to 4,5-
Disubstituted Cyclopentenones. Org. Lett. 2013, 15, 2696−2699.
(14) Though there have been a few examples of simple endocyclic
olefins used in PKR, these olefins are typically used in large excess,
and the conditions are generally harsh.
(15) Anumandla, D.; Littlefield, R.; Jeffrey, C. S. Oxidative 1,4-
diamination of dienes using simple urea derivatives. Org. Lett. 2014,
16, 5112−5115.
(16) Fishman, J. M.; Kiessling, L. L. Synthesis of functionalizable and
degradable polymers by ring-opening metathesis polymerization.
Angew. Chem., Int. Ed. 2013, 52, 5061−5064.
D
DOI: 10.1021/acs.organomet.8b00810
Organometallics XXXX, XXX, XXX−XXX