Sequential hydroformylation/Diels-Alder processes: One-pot synthesis of polysubstituted cyclohexenes, cyclohexadienes, and phthalates from alkynes

Article abstract of DOI:10.1002/chem.201402981

A novel, one-pot hydroformylation/Diels-Alder sequence for the synthesis of multisubstituted cyclohexenes, cyclohexadienes, and phthalates has been developed. Various alkynes were efficiently converted into the corresponding products in good yields and with excellent diastereoselectivity through palladium-catalyzed hydroformylation followed by an AAD-type reaction (AAD: Amides-Aldehydes-Dienophiles). In view of the availability of the substrates, the atom-efficiency of the overall process, and the convenient introduction of substituents in the cyclohexene ring, this method complements current methods for the preparation of polysubstituted cyclohexane derivatives. Putting it together: A one-pot procedure for the diversity-oriented synthesis of multisubstituted cyclohexenes, cyclohexadienes, and phthalates through hydroformylation of alkynes followed by a Diels-Alder reaction has been developed (see scheme; EWG=electron-withdrawing group).

Full text of DOI:10.1002/chem.201402981

DOI: 10.1002/chem.201402981
Communication
&
Synthetic Methods
Sequential Hydroformylation/Diels–Alder Processes: One-Pot
Synthesis of Polysubstituted Cyclohexenes, Cyclohexadienes, and
Phthalates from Alkynes
Xianjie Fang, Ralf Jackstell, and Matthias Beller*[a]
Abstract: A novel, one-pot hydroformylation/Diels–Alder
sequence for the synthesis of multisubstituted cyclohex-
enes, cyclohexadienes, and phthalates has been devel-
oped. Various alkynes were efficiently converted into the
corresponding products in good yields and with excellent
diastereoselectivity through palladium-catalyzed hydrofor-
mylation followed by an AAD-type reaction (AAD:
Amides–Aldehydes–Dienophiles). In view of the availability
of the substrates, the atom-efficiency of the overall pro-
cess, and the convenient introduction of substituents in
the cyclohexene ring, this method complements current
methods for the preparation of polysubstituted cyclohex-
ane derivatives.
Scheme 1. Schematic representation of the AAD, ANAD, ALAD, and IAD re-
action protocols.
In recent years, research in academia and industry has increas-
ersonine.[9] Furthermore, we have demonstrated the synthetic
ingly emphasized the search for atom-efficient transformations
of easily available starting materials into complex organic mol-
ecules.[1] In this respect, reactions that provide maximum diver-
sity are especially desirable. Here, expeditious multicomponent
reactions (MCR)[2] as well as domino reaction sequences offer
significant advantages over stepwise procedures.[3] In this con-
text, our group has developed multicomponent reactions in
which amides (AAD-reaction: Amides–Aldehydes–Dienophiles),
anhydrides (ANAD-reaction: Anhydrides–Aldehydes–Dieno-
philes), orthoesters (OAD-reaction: Orthoesters–Aldehydes–Di-
enophiles) and even isocyanates (IAD-reaction: Isocyanates–Al-
dehydes–Dienophiles) react with aldehydes and dienophiles to
afford a variety of multisubstituted cyclohexene and cyclohexa-
diene derivatives.[4] As shown in Scheme 1, these transforma-
tions take advantage of an initial condensation reaction of
amides and aldehydes to give amido-substituted 1,3-buta-
dienes (A, Scheme 1) as key intermediates, which are subse-
quently converted with electron-deficient dienophiles into the
corresponding MCR products. The versatility of functionalized
1,3-butadienes for Diels–Alder chemistry[5] has also been dem-
onstrated in the preparation of important natural products
such as pumiliotoxin,[6] gephyrotoxin,[7] dendrobine,[8] and tab-
applicability of MCRs in the preparation of highly substituted
anilines,[10 ] bicyclo[2.2.2]oct-2-enes,[11] enantiomerically pure cy-
clohexenols,[12] and cyclohexenylamines,[13] phthalic acids,[14] lu-
minol,[15] phenanthridones[16] as well as lactam derivatives.[17]
Based on our long-standing interest in hydroformylation re-
actions,[18] we recently set out to study less common hydrofor-
mylation catalysts. Here, we have demonstrated that metals
besides rhodium and cobalt[19] can be successfully applied in
the hydroformylation of olefins. More specifically, we showed
that palladium complexes with heterocyclic phosphine ligands
are efficient catalysts for the hydroformylation of alkynes to se-
lectively give a,b-unsaturated aldehydes.[20] On the basis of the
latter work, we utilized this protocol for the synthesis of more
complex organic molecules. Advantageously, both the palladi-
[a] X. Fang, Dr. R. Jackstell, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock
Albert-Einstein-Str. 29a, 18059 Rostock (Germany)
E-mail: matthias.beller@catalysis.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402981.
Scheme 2. Sequential hydroformylation/AAD reactions.
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Herein, we report our recent efforts to develop
a two-step, one-pot synthesis of diverse multisubsti-
tuted cyclohexenes and cyclohexadienes by combin-
ing hydroformylation and Diels–Alder reactions. No-
tably, this methodology provides an interesting
option to synthesize new organic products because
the corresponding a,b-unsaturated aldehydes are
traditionally difficult to synthesize and only a few ex-
amples are commercially available.
Table 1. Synthesis of multisubstituted cyclohexenes and cyclohexadienes from alkynes by
a one-pot hydroformylation/Diels–Alder process.[a]
Entry
1
1
2
3
MCR product (yield)[b]
Initially, we investigated the formation of 4a by
using a one-pot hydroformylation/Diels–Alder pro-
cess starting from 3-hexyne (1a). This substrate was
treated under the standard hydroformylation reac-
tion conditions recently reported by our research
group, which allow the direct conversion of alkynes
into a,b-unsaturated aldehydes.[20a] The a,b-unsatu-
rated aldehyde was directly subjected to the multi-
component Diels–Alder reaction conditions (includ-
ing one equivalent of methanesulfonamide (2a), N-
methylmaleimide (3a), and 3 mol% p-TsOH). To our
delight, an excellent 87% isolated yield of the de-
sired product 4a was obtained [Eq. (1)]. This yield is
comparable to that observed for the individual AAD-
reaction.
2
3
We then extended this straightforward synthesis
of 4a to a wider range of alkynes, amides, and dien-
ophiles. As depicted in Table 1, the present one-pot
process was surprisingly versatile. In general, both
symmetrical and unsymmetrical alkynes underwent
efficient hydroformylation/Diels–Alder reactions to
afford the corresponding multisubstituted cyclohex-
enes in good yields. Notably, functionalized a,b-un-
saturated aldehydes are traditionally difficult to syn-
thesize and they are not usually commercially avail-
able. Gratifyingly, alkynes having different functional
groups such as phthalimide and ester were well tol-
erated, and were smoothly transformed into the cor-
responding functionalized cyclohexenes in good
yields (Table 1, entries 8 and 9). Furthermore, various
carboxamides were stable under the standard reac-
tion conditions. Employment of 2-oxazolidinone 2d
with a tertiary amide moiety, gave the correspond-
ing product 4k in 69% yield (Table 1, entry 11). Ben-
zyloxycarbonyl (Cbz) protection of the amino func-
tion was realized for 4g and 4m (Table 1, entries 7
and 13). In addition to amides, anhydrides (ANAD re-
action) and orthoesters (OAD reaction) also served
as coupling partners, which led to an increase in
structural diversity (Table 1, entries 10 and 12). To
4
5
6
7
8[c]
um-catalyzed hydroformylation and the AAD-type reactions re-
quire acid as co-catalyst. From this point of view, it should be
possible to combine them as postulated in Scheme 2.
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study the influence of other dienophiles, dimeth-
yl acetylenedicarboxylate (3b), trans-b-nitrostyr-
ene (3c), and acrylonitrile (3d), were employed
and the reaction gave yields of 65, 51, and 65%,
respectively (Table 1, entries 14–17). For all prod-
ucts, one- and two-dimensional NMR experi-
ments established the stereochemical structure.
In all cases, we observed selective endo-addition
of the dienophile during the Diels–Alder step.
To enhance product diversity of the present
reaction protocol further on, tri- and tetra-substi-
tuted dimethyl phthalates 5 were prepared in
good yields after 48 h at 1608C from alkynes,
acetamide (2 f) and dimethyl acetylenedicarboxy-
late (3b) (Scheme 3). Both short- and long-
chained symmetrical aliphatic alkynes provided
the corresponding substituted dimethyl phtha-
lates in good yields through acylamine elimina-
tion from the intermediate cyclohexadienes.
Table 1. (Continued)
Entry
1
2
3
MCR product (yield)[b]
9[c]
10
In conclusion, several one-pot procedures for
diversity-oriented syntheses of multisubstituted
cyclohexenes, cyclohexadienes, and phthalates
have been developed. Key to success is the com-
bination of hydroformylation of alkynes followed
by Diels–Alder reactions. This methodology
shows broad scope and starts from alkynes,
which are very versatile substrates. Compared
with related multicomponent reactions, the
scope for substituted cyclohexene derivatives is
improved. Considering the ready availability of
the substrates, the atom-efficiency, and the good
yield with excellent diastereoselectivity, we be-
lieve that the present sequential hydroformyla-
tion/AAD-reactions complement known method-
ologies for the synthesis of substituted cyclohex-
enes, cyclohexadienes, and phthalates.
11
12
13
14[d]
15[d]
Experimental Section
General procedure for the preparation of 4
A 100 mL steel autoclave was charged under argon
atmosphere with Pd(acac)2 (22.8 mg, 1 mol%),
ligand (160.7 mg, 4 mol%), and p-TsOH (57 mg,
4 mol%). Toluene (30 mL) and alkyne 1 (7.5 mmol)
were then added and the autoclave was pressurized
with 40 bar synthesis gas and heated to 1008C. The
reaction was carried out for 10 h. After the reaction
time, the autoclave was cooled to RT, the pressure
was released, and p-TsOH (42.7 mg, 3 mol%), 2
(7.5 mmol), and 3 (7.5 mmol) were consecutively
added into the autoclave under an argon atmos-
phere. The resulting mixture was stirred at 1108C
for 16 h. After the reaction time, the autoclave was
cooled to RT, the solvent was removed under
vacuum, and the residue was directly purified by
flash chromatography on silica gel (heptane/ethyl
acetate 2:1) to give the desired product 4.
16
17[e]
[a] Reaction conditions: 1) 1 (7.5 mmol), Pd(acac)2 (1 mol%), L (4 mol%), p-TsOH (4 mol%),
CO/H2 (40 bar), toluene (30 mL), 1008C, 10 h; 2) p-TsOH (3 mol%), (7.5 mmol),
(7.5 mmol), 1108C, 16 h. [b] Yield of isolated product after column chromatography. [c] Ex-
periments were carried out on a 1.5 mmol scale. [d] 3b (11.25 mmol). [e] 3d (37.5 mmol),
the reaction temperature and time of the second step were 1608C and 48 h, respectively.
2
3
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Scheme 3. Synthesis of multisubstituted phthalates from alkynes by a one-
pot hydroformylation/Diels–Alder process. Reaction conditions: 1) 1
(7.5 mmol), Pd(acac)2 (1 mol%), L (4 mol%), p-TsOH (4 mol%), CO/H2 (40 bar),
toluene (30 mL), 1008C, 10 h; 2) p-TsOH (3 mol%), 2 f (7.5 mmol), 3b
(11.25 mmol), 1608C, 48 h, yield of isolated product after column chroma-
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Acknowledgements
This work has been funded by the BMBF (Germany) and the
State of Mecklenburg-Vorpommern. We thank Dr. Christine
Fischer, Susann Buchholz, and Susanne Schareina for their
technical and analytical support. We are grateful to Dr. Abhish-
ek Dutta Chowdhury for helpful discussions.
Keywords: alkynes
·
a,b-unsaturated
aldehydes
·
·
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cycloaddition
palladium
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Received: April 7, 2014
Published online on May 30, 2014
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