Rhodium-Catalyzed Intermolecular Carbonylative [2 + 2 + 1] Cycloaddition of Alkynes Using Alcohol as the Carbon Monoxide Source for the Formation of Cyclopentenones

Article abstract of DOI:10.1021/acs.orglett.7b00458

A highly regioselective rhodium-catalyzed intermolecular carbonylative [2 + 2 + 1] cycloaddition of alkynes using alcohol as a CO surrogate to access 4-methylene-2-cyclopenten-1-ones has been developed. In this transformation, the alcohol performs multiple roles, including generating the Rh-H intermediate, functioning as the CO source, and assisting in the isomerization of the alkyne. Alkynes can act as both the olefin and the alkyne partner in the cyclopentenone core.

Full text of DOI:10.1021/acs.orglett.7b00458

Letter
pubs.acs.org/OrgLett
Rhodium-Catalyzed Intermolecular Carbonylative [2 + 2 + 1]
Cycloaddition of Alkynes Using Alcohol as the Carbon Monoxide
Source for the Formation of Cyclopentenones
Ju Hyun Kim, Taemoon Song, and Young Keun Chung*
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea
S
* Supporting Information
ABSTRACT: A highly regioselective rhodium-catalyzed intermolecular carbonylative [2 +
2 + 1] cycloaddition of alkynes using alcohol as a CO surrogate to access 4-methylene-2-
cyclopenten-1-ones has been developed. In this transformation, the alcohol performs
multiple roles, including generating the Rh−H intermediate, functioning as the CO source,
and assisting in the isomerization of the alkyne. Alkynes can act as both the olefin and the alkyne partner in the cyclopentenone
core.
he cyclopentenone motif is a very powerful synthon for
the synthesis of various biologically active molecules.1
Rhodium-catalyzed carbonylative cycloaddition reactions of
unsaturated hydrocarbons have been studied extensively.11,12
Although considerable progress has been made in this area, the
intermolecular version may suffer from regioselectivity,
reactivity of substrates, or feasibility of the required catalyst.
Thus, development of an efficient synthetic method with
regiocontrolled, readily available substrates and a proper
catalyst is still required. Toward this end, we and other groups
reported13 the carbonylative cycloaddition of allenes with CO
in the presence of a catalyst (Scheme 1b). Although the
inclusion of allenes within the scope of useful substrates has
widened the utility of the rhodium-catalyzed carbonylative
cycloaddition, their use14 leads to regioselectivity problems and
undesirable side reactions, such as dimerization and hydro-
dimerization.15
T
Among the available synthetic methods,2−4 the Pauson−Khand
reaction (PKR) has been developed as a powerful tool in the
synthesis of cyclopentenone cores (Scheme 1a).5 In 1994, an
Scheme 1. Transition Metal-Catalyzed Formal [2 + 2 + 1]
Cycloaddition
In general, carbonylation reactions, including PK-type
reactions, are carried out in the presence of carbon monoxide
(Schemes 1a,b). However, the use of CO gas is not desirable
due to its toxicity and difficulty to control. Thus, in some
studies, CO was replaced by other organic and inorganic
carbonyl compounds.16 Several years ago, we reported the use
of alcohols as a CO and hydride in a rhodium-catalyzed
intramolecular Pauson−Khand reaction without the require-
ment for external CO gas and reductive cyclization.17,18
With this in mind, we designed a new, one-pot synthesis
including alkyne isomerization followed by intermolecular [2 +
2 + 1] carbonylative cycloaddition19 using an alcohol as a CO
surrogate. We hypothesized that the alkyne could act as an
allene replacement due to the feasibility of its isomerization
with a transition-metal hydride, such as rhodium or iridium.20
Thus, 1-aryl-1-propynes were expected to serve both as an
alkene and alkyne-like moiety in the construction of a
cyclopentenone skeleton (Scheme 1c). We envisioned that it
would be a straightforward and efficient process for assembling
cyclopentenones from readily available 1-aryl-1-propynes21,22
important catalytic conversion, using Co2(CO)8, P(OPh)3, and
3 bar of CO as reagents, was reported.6 Since then, other
metals, including ruthenium,7 rhodium,8 iridium,9 and
titanium,10 have been established as suitable catalysts of the
PKR. Moreover, synthetic utility has been significantly
expanded by the incorporation of more reactive allenes in
place of alkenes.11
Received: February 15, 2017
© XXXX American Chemical Society
A
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Letter
and alcohols. To the best of our knowledge, this is the first
report of rhodium-catalyzed intermolecular carbonylative
cycloaddition of alkynes with alcohols for constructing
cyclopentenones.
Scheme 2. Scope with Various Alkyne Substrate and 1-
Octanol
a,b
The Rh-catalyzed synthesis of 4-alkylidene-2-cyclopenten-1-
ones was discovered from the reaction of 1-phenyl-1-propyne
in the presence of 1-octanol, bis[2-(diphenylphosphino)-
phenyl]ether (DPEPhos), InCl3, and [Rh(COD)Cl]2 in
toluene at 120 °C. A yield of 76% was achieved (Table 1).23
a
Table 1. Screening the Reaction Conditions
b
entry
variation from standard conditions
yield (%)
1
2
none
76
Xantphos instead of DPEPhos
RhCl3 instead of [Rh(COD)Cl]2
benzyl alcohol instead of 1-octanol
4-chlorobenzaldehyde instead of 1-octanol
without InCl3
NR
NR
dec
NR
15
3
4
5
6
7
diphenylacetylene instead of 1-phenyl-1-propyne
with 2,6-dichlorobenzoquinone
without [Rh(COD)Cl]2
NR
trace
NR
NR
8
9
10
without alcohol
a
Reaction conditions: 0.3 mmol of 2, 3 equiv of 1a, 6 mol % of
Rh(COD)Cl]2, 12 mol % of DPEPhos, 15 mol % of InCl3, and 2 mL
b
of toluene. Isolated yield. NR: no reaction.
Next, we screened various reaction conditions (Table 1 and
Supporting Information, SI). Ligand exchange from DPEphos
to Xantphos19b and other bidentate phosphines was ineffective
(entry 2 and SI). Other rhodium compounds like RhCl3 were
also examined as catalysts (entry 3 and SI). When 1-octanol
was replaced with benzyl alcohol, the decomposed product was
formed due to the reactivity of benzyl alcohol (entry 4).
Interestingly, the use of a CO surrogate, 4-chlorobenzalde-
hyde,16 resulted in no desired product (entry 5). Using 1-
octanol as a CO surrogate, different additives, varying amounts
of catalyst, and different reaction temperatures were explored.
Among the additives used, the carbonylative [2 + 2 + 1]
cycloaddition was most favorable in the case of InCl3 (see the
SI). Without InCl3, the reaction was sluggish (entry 6),
suggesting that InCl3 was a key additive in this reaction.24
Other alkynes such as diphenylacetylene showed no activity
(entry 7), which implies that the [2 + 2 + 1] cycloaddition was
specific to 1-phenyl-1-propyne.22 Addition of hydride acceptors
gave no product (entry 8). As expected, no product was formed
in the absence of the alcohol, the ligand, or the rhodium
catalyst (entries 9 and 10 and SI).
a
Reaction conditions: 0.3 mmol of 2, 3 equiv of 1, 6 mol % of
Rh(COD)Cl]2, 12 mol % of DPEPhos, 15 mol % of InCl3, and 2 mL
of toluene. Isolated yield. Regioselectivity (E/Z isomer) of products
shown in parentheses.
b
c
With the optimum reaction conditions established, the
substrate scope was studied next (Scheme 2).
propynyl)thiophene (3q,r), reasonable yields (44% and 45%,
respectively) were observed. Substrates bearing an ester, a
ketone, or an acetal group gave poor yields (13%, 15%, and
22% yields for 3s, 3t, and 3u, respectively) with low selectivity
(2:1−10:1). Steric effects were observed in some cases; when a
methoxy group was located at the para or meta positions, the
corresponding cyclic enones were isolated in yields of 80% and
69%, respectively. However, in the cases of 1-methoxy-2-(prop-
1-yn-1-yl)benzene and 2,4-dimethoxy-1-prop-1-yn-1-yl)-
Arylmethylacetylenes with an electron-donating group (Me,
OMe, OEt, and t-Bu) on the aryl group were found to be good
substrates (3b−l). However, a poor yield (26%) was observed
for N,N-dimethyl-4-(1-propynyl)aniline (3m). Arylmethylace-
tylenes with an electron-accepting group (F, Cl, CF3) on the
aryl group were also studied (3n−p). For substrates bearing F,
Cl, or CF3 groups, reasonable yields (52%, 62%, and 53%,
respectively) were observed. In the cases of 2- and 3-(1-
B
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benzene, reasonable yields (57% and 60%, respectively) were
observed. The regioselectivity was highly dependent upon the
substrate. In some cases, a single isomer was isolated, and most
of the products except 3s, 3t, and 3u were isolated with high
regioselectivity (generally >14:1).
Scheme 5. Reaction of Allene and Allene/Alkyne
To gain some insight into the possible reaction mechanism,
the following reactions were studied (Scheme 3).
Scheme 3. Carbonylative Cycloaddition Reaction with
Ethanol-d1
enone derived from methyl-p-tolylethyne was isolated in 28%
yield. Thus, phenylallene did not participate in the carbon-
ylative cycloaddition reaction under our reaction condi-
tions.15c,21 Moreover, this observation suggested that isomer-
ization of methyl-p-tolylethyne to 1-methyl-4-(propa-1,2-dien-
1-yl)benzene occurred within the coordination sphere of
rhodium through the formation of a π-methyl-p-tolylethyne
rhodium hydride intermediate resulting from methyl-p-
tolylethyne and a rhodium hydride. The rhodium hydride
might come from a reaction between the rhodium catalyst and
1-octanol.
On the basis of these experimental results, together with
observations from previous studies,17,20−22 a plausible reaction
mechanism is proposed for the carbonylative [2 + 2 + 1]
cycloaddition of methylphenylethyne in the presence of a
rhodium catalyst with an alcohol as a CO surrogate (Scheme
6). The reaction begins with the formation of an Rh−H
Reactions of 1-phenyl-1-propyne (1a) with ethanol-d1 and
ethanol-d6 were studied under the optimized reaction
conditions, and the corresponding deuterated product was
isolated (Scheme 3 and SI). The degree and position(s) of
deuteration were highly dependent upon the ratio of 1a to
ethanol-d1. When the ratio was 1:1, the percentage of
deuterium incorporated at the benzylidene was 20%. When
the ratio was 1:10, 80% of the hydrogens at the benzylidene and
70% of the hydrogens at the C-5 position were replaced by
deuterium. These observations suggested the involvement of an
Rh−H intermediate and a facile scrambling of the three
hydrogens at the benzylic and C-5 positions. Moreover, as the
amount of ethanol-d1 increased, the concentration of metal−
deuteride species increased, resulting in high contents of
deuterium in various positions in the product.
Scheme 6. Proposed Reaction Mechanism
We also performed a competition experiment with various
substrates (Scheme 4 and SI). When a 1:1 mixture of
Scheme 4. Intercrossing Experiment of Different Alkyne
Systems
methylphenylethyne and 3-hexyne was used as the substrates,
two cyclic enones were isolated in a 4.6:1 ratio with overall 90%
yield. In the case of a 1:3 substrate mixture of methylpheny-
lethyne and hept-3-yne, two cyclic enones were isolated in a
2.6:1 ratio with an overall yield of 87%. These observations
suggested that an arylmethylethyne, in any combination with
other alkynes, could react as both an alkyne and an alkene
partner under our conditions, eventually generating cyclic
enones.
Phenylallene has often been suggested as a reaction
intermediate in Rh-catalyzed catalytic reactions with 1-phenyl-
1-alkyne.21,22a Thus, phenylallene was included as a substrate in
our reaction (Scheme 5).
intermediate via a sequential reaction of the rhodium
compound with an alkyne and alcohol in path I.25 The alkyne
is hydrogenated to 1-phenyl-1-propene during the formation of
the Rh−H intermediate B. Intermediate B then isomerizes to
form another intermediate π-allene rhodium complex C. The
intermediate C could form an equilibrium mixture with the π-
allyl rhodium intermediate C′ and Rh−alkene complexes (C″
and C‴). The π-allyl rhodium intermediate then reacts with an
aldehyde to form D. This intermediate D reacts with another
alkyne to form the π-allylalkyne rhodium intermediate E. The
allyl group acts as an olefin partner in the ring formation of the
metallacyclic intermediate F, which then generates products G
and A by a reductive elimination. The intermediate A can then
enter the catalytic cycle path II. In one example, the generation
of the alkene in path II, 1-phenyl-1-propene, was confirmed by
GC analysis. Thus, 3 equiv of alkyne was needed to accomplish
When phenylallene was reacted with 1-octanol, no cyclo-
pentenone was observed. Instead, a trimer of allene with several
regioisomers was detected in the GC analysis with 100%
conversion (see the SI). When a 1:1 mixture of phenylallene
and methyl-p-tolylethyne was reacted with 1-octanol, a cyclic
C
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both cycles: 2 equiv of alkyne was used to build a
cyclopentenone backbone and 1 equiv of alkyne was for the
reaction of regeneration of rhodium hydride A via path II.23
In conclusion, we have developed an intermolecular [2 + 2 +
1] carbonylative cycloaddition of simple alkynes in the presence
of an alcohol, InCl3, and an [Rh(COD)Cl]2/DPEPhos catalytic
system. The alcohol plays an important role in the formation of
cyclopentenones by acting as the source of CO and facilitating
the Rh−hydride intermediate. In these transformations, alkynes
act as both the olefin and the alkyne partner in the Pauson−
Khand-type reaction. It is likely that the reaction proceeds via a
π-allylalkyne rhodium intermediate. A deeper understanding of
these reactions and their application toward organic synthesis,
as well as a comprehensive theoretical study on the mechanistic
details, are underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00458.
Experimental procedure, characterization and NMR
spectral data (PDF)
Single-crystal X-ray diffraction data for compound 3g
(CIF)
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1973, 22, 2491−2497. (c) Park, B. Y.; Nguyen, K. D.; Chaulagain, M.
R.; Komanduri, V.; Krische, M. J. J. Am. Chem. Soc. 2014, 136, 11902−
11905.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ykchung@snu.ac.kr.
ORCID
(16) (a) Shibata, T.; Toshida, N.; Takagi, K. J. Org. Chem. 2002, 67,
7446−7450. (b) Morimoto, T.; Kakiuchi, K. Angew. Chem., Int. Ed.
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(17) Park, J. H.; Cho, Y.; Chung, Y. K. Angew. Chem., Int. Ed. 2010,
49, 5138−5141.
Young Keun Chung: 0000-0002-2837-5176
Notes
The authors declare no competing financial interest.
(18) Park, J. H.; Kim, S. M.; Chung, Y. K. Chem. - Eur. J. 2011, 17,
10852−10856.
ACKNOWLEDGMENTS
■
(19) (a) Hoshimoto, Y.; Ohata, T.; Sasaoka, Y.; Ohashi, M.; Ogoshi,
S. J. Am. Chem. Soc. 2014, 136, 15877−15880. (b) Miura, H.;
Takeuchi, K.; Shishido, T. Angew. Chem., Int. Ed. 2016, 55, 278−282.
(20) (a) Gellrich, U.; Meißner, A.; Steffani, A.; Kahny, M.; Drexler,
H.-J.; Heller, D.; Plattner, D. A.; Breit, B. J. Am. Chem. Soc. 2014, 136,
1097−1104. (b) Phadke, N.; Findlater, M. Molecules 2015, 20, 20195−
20205.
This work was supported by a National Research Foundation of
Korea (NRF) grant funded by the Korean government
(2014R1A5A1011165 and 2007-0093864). J.H.K. and T.S.
are recipients of a BK21 Plus fellowship.
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D
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