Air-Stable CpCoI–Phosphite–Fumarate Precatalyst in Cyclization Reactions: Comparing Different Methods of Energy Supply

Article abstract of DOI:10.1002/ejoc.201800196

The robust Co^I precatalyst [CpCo(P{OEt}₃)(trans-MeO₂CHC=CHCO₂Me)] was investigated in cyclotrimerizations, furnishing benzenes and pyridines from triynes, diynes and nitriles, comparing the influence of differen

Full text of DOI:10.1002/ejoc.201800196

A Journal of
Accepted Article
Title: Air-Stable CpCo(I)-phosphite-fumarate precatalyst in cyclization
reactions: comparing different methods of energy supply
Authors: Marko Hapke and Fabian Fischer
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800196
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10.1002/ejoc.201800196
European Journal of Organic Chemistry
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Air-Stable CpCo(I)-phosphite-fumarate precatalyst in cyclization
reactions: comparing different methods of energy supply
Fabian Fischer[a] and Marko Hapke*[a,b]
Abstract: The robust Co(I)-precatalyst [CpCo(P{OEt}3)(trans-
MeO2CHC=CHCO2Me)] was investigated in cyclotrimerizations
furnishing benzenes and pyridines from triynes, diynes and nitriles,
comparing the influence of different ways of energy supply, e.g.
irradiation and conventional (thermal) or microwave heating. The
precatalyst was found suitable to work under all conditions, including
the possibility to catalyze cyclotrimerizations at room temperature
under photochemical conditions at longer reaction times.
Performance of the reactions in a microwave reactor proved to be
the most time-efficient way to rapidly assemble the expected
reaction products, however, careful selection of reaction conditions
can be required. The synthesis of pyridines and isoquinolines
successfully comprised the utilization of versatile functionalized
nitriles, affording structurally interesting reaction products.
Exemplary comparison with the known and often applied precatalyst
CpCo(CO)2 demonstrated the significantly higher reactivity of the
CpCo(I)-phosphite-olefin precatalyst.
The recent developments in the area of cyclotrimerization
reactions of alkynes, diynes, oligoynes and heterocumules were
2
, 3 ]
nursed by both approaches of catalyst employment.[
Numerous studies by the groups of Okamoto, Hilt and others
promoted the application of catalysts generated from simple
cobalt(II) salts, appropriate ligands and reductants for the
4
]
application in cyclotrimerizations.[2c,
catalyst source for cobalt-mediated and -catalyzed [2+2+2]
cycloadditions is cyclopentadienyl cobalt(I) dicarbonyl
However, the prime
(CpCo(CO)2, 1), introduced by Vollhardt et at. in their classical
synthetic studies applying the cobalt-catalyzed cyclizations for
the synthesis of annelated benzenes and finally in estrone total
synthesis.[5,6] Even today this commercially available complex is
still the catalyst of choice for many cobalt-catalyzed
cyclotrimerizations, although it usually requires significant
amounts of energy for activation. Applications comprise the
synthesis of natural products, especially also those containing
heterocyclic cores; examples for both include angucyclinones,[7]
(dehydro)tylophorine,[8] (+)-complanadine A,[9] xylarinol A,[10] and
recently cyclopropylallocolchicinoid[11] and (±)-allocolchicine.[12]
Earlier reports on the photochemistry of CpCo(CO)2 (1)
discussing the possibility of the formation of clusters being
regularly responsible of catalyzing the cyclotrimerizations have
not been corroborated yet.[ 13 ] Recent studies only discuss
mononuclear CpCo(I)-species as responsible catalytic species.
When comparing the reaction conditions in the different
synthetic routes, in most cases rather high temperatures up to
150 °C (conventional heating) or 200 °C (microwave) are
required, in some cases together with additional irradiation.[14]
Such reaction conditions are necessitated by the tight bonding of
the CO groups to the Co(I)-center in 1 (Scheme 1). Highly
reactive CpCo(olefin)2-complexes like 2 were introduced by
Jonas et al. in the beginning of the 1980’s and were utilized in a
number of cases for cyclotrimerizations under very mild
conditions.[15] Butenschön et al. found that phosphoryl-tethered
Cp’Co(C2H4)-complexes are still active catalysts at 25 °C.[16 ]
Aubert and Gandon et al. presented the first “upgraded” and air-
stable CpCo(I)-carbonyl complex 3, containing an electron-
deficient dialkyl fumarate ligand instead of the second CO ligand,
obtained by heating in toluene under reflux and irradiation.[17]
Introduction
The development of isolable transition metal catalysts for
organic transformations is today often outrun by the invention of
in situ generated transition metal catalyst system. The most
significant advantage of the latter approach is the flexibility in
terms of the broad choice of metal sources and ligands that can
be screened together, including different metal-to-ligand ratios
and also the additional use of different beneficial additives. An
area which is currently intensively investigated and includes both
approaches, isolated precatalysts as well as in situ catalyst
generation, lies the field of C-H activation by base metal
1
]
complexes like cobalt.[
Inherent to the application of
molecularly defined transition metal precatalysts is that they
usually yield only a single defined reactive species upon
activation. This way usually cleaner catalytic reactions are
observed as well as mechanistic studies of a certain reaction
becomes possible without the interference of additional
substances from an alternative in situ generation procedure.
While precatalysts like
3 are easy to handle, still high
[a]
[b]
F. Fischer, Prof. Dr. Marko Hapke
Leibniz-Institut für Katalyse e.V. an der Universität Rostock (LIKAT)
Albert-Einstein-Strasse 29a
temperatures are required for application in cyclotrimerizations
(typically refluxing toluene (110 °C) or microwave conditions
(DMF, 200 °C)) due to strong bonding to the carbonyl ligand.
Recently the direct thermolysis of several examples of
substituted enediynes and eneynenitriles applying microwave
heating (200 °C) without a catalyst was reported to yield highly
substituted benzenes and pyridines.[18]
18059 Rostock (Germany)
E-mail: marko.hapke@catalysis.de or marko.hapke@jku.at
Johannes Kepler Universität Linz
Institut für Katalyse (INCA)
Altenberger Strasse 69
4040 Linz (Austria)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800196
European Journal of Organic Chemistry
FULL PAPER
pure heating to 100 °C in toluene, furnishing product 6 in better
yield even after only 4 h irradiation time versus the 17 h for
heating and also better than the microwave-assisted reaction
after 4h. Dipropargylmalonates like 7 have rarely been used for
co-cyclotrimerizations under such conditions for the synthesis of
pyridines. Reaction with benzonitrile (2 equiv.) furnished biaryl 8
with 36% on conventional heating to 100 °C oil-bath temperature
for 17 h. Performance under microwave conditions yielded
already 53% product after only 0.5 h reaction time. Irradiation for
5.5 h, however, yielded 8 with quantitative yield. In the final
example, using only 2 equiv. heterocyclic nitrile 9 in the reaction
with diyne 7 gave excellent yields of 10 with each way of energy
supply, again with the shortest reaction time for the microwave-
assisted reaction. Conducting the microwave-assisted reaction
completely under air led to a lower yield of product 10, resulting
in a inseparable mixture of substrate and product.
Scheme 1. CpCo(I)-catalysts: often utilized and novel precatalysts.
During our studies on novel derivatives of the Jonas complex 2,
we found that trimethylvinylsilane was a particular alkene ligand,
as the Jonas complex congener with this alkene was extremely
reactive in co-cyclotrimerizations with diynes and nitriles.[ 19 ]
Taming the reactivity by selectively exchanging one alkene with
a phosphite ligand led to CpCo(I)-complexes with mixed ligand
sets, which could be used for cyclizations already at 50 °C.[20]
With the obviously attractive olefin/phosphite combination we’ve
set out for further exploration and found that a phosphite ligand
together with dimethylfumarate furnished air-stable and
recyclable CpCo(I)-complexes like 4, which can easily be
applied to cyclotrimerization reactions[ 21 ] and has become
22
]
commercially available since.[
This particular ligand
combination also allows the efficient stabilization of
functionalized Cp’Co-fragments.[23]
Showcase applications of 4 in several synthetic projects already
proved to be beneficial,[24] leaving us with the idea, to explore
different reaction conditions in terms of the energy supply to
determine more precisely the requirements and circumstances,
under which complex 4 can be successfully applied. Especially
the
application
of
irradiation
versus
conventional
heating/microwave to activate the catalyst appears to be
attractive, as there not many precatalysts, which can be
efficiently activated under both activation methods. Microwave
irradiation of Co-mediated cyclotrimerizations in glass reactions
vessels is reported to be additionally favored by reduced
induction periods and increased triplet life time of organometallic
reaction intermediates.[25] Accordingly we report here the study
of the cyclization of different triyne and diyne/nitrile substrates
utilizing precatalyst 4 under thermal as well as photochemical
conditions.
Results and Discussion
Since we have found that catalysts of the type CpCoL1L2 (L1, L2
= olefin, olefin/phosphite or phosphite) can be applied using
conventional heating as well as microwave heating or irradiation
for successful cyclization reactions, the generality of a single
catalyst for such reactions for all ways of energy supply and
under generally mild conditions and even “wet” solvents would
be highly practical. We therefore started our investigation with
selected substrates and evaluated catalyst 1 under all conditions
mentioned above. In Scheme 2 the results for the diynes 5 and 7
for the reaction with benzonitrile and N-cyanopiperidine (9) are
displayed. Biaryl 6 has been prepared stereoselectively before
by the photochemical approach.[27b] The results (Scheme 2, top)
show here that the photochemical approach is superior to the
Scheme 2. Comparison of thermal and photochemical energy supply for co-
cyclotrimerization reactions of selected diynes and nitriles.
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The results clearly show that photochemically assisted reactions
be used. Examples 11 and 12 nicely illustrate the higher
often give excellent results at convenient temperatures, however, reactivity of terminal alkynes compared to internal diynes like
long reaction times are frequently required. The latter is also true
for thermal reactions, taking up to 22 h for maximum conversion
at 100 °C.
trideca-4,9-diyne in compound 13 with significantly higher yields
for 11 under identical conditions. Even para-chlorinated
benzonitrile can be reacted with 1,7-octadiyne to give good yield
of pyridine 11. The reaction with a dichlorinated phenyl-
derivative to compound 14 is possible with significantly lower
yield when using trideca-4,9-diyne as coupling partner.
Reactions of benzonitril-4-pinacolylboronat and 1-cyano-
naphthalene with trideca-4,9-diyne yielded products 15 and 16 in
yields not exceeding 25%, which again could be attributed to the
lower reactivity of this internal diyne. Extended reaction time did
not improve the yield significantly. The reaction of
carboxynaphthly-substituted 1,7-octadiynes delivered compound
17 with very good yield. Synthesis of biaryl products 18 and 19
corroborated the ability of complex 4 to mediate reactions with
unusual nitriles even containing heteroatoms, leading to
products, which could act as ligands inhibiting the catalyst by
coordination and preventing further catalysis.[27] Interestingly for
the conversion of 2-(benzo[d]thiazol-2-yl)acetonitrile to biaryl 19
a maximum in the yield was reached at 140 °C reaction
temperatures, while a higher temperature gave significantly
lower yield. We extended the scope of the investigation and
included the malonyl-substituted diyne 7 as substrate in our
investigations (Scheme 4).
Microwave heating often gives superior results at higher reaction
temperatures within short reaction times and therefore we
applied catalyst 4 in exemplary syntheses to rapidly assemble
different functionalized pyridines.[26] We were focusing on the
broadness of application and screening of different nitrile
substrates rather than general optimization of the reaction
conditions towards yield to display instructive examples. In
Scheme 3 cyclization results for internal, terminal as well as
monosubstituted diynes with different nitriles are presented.
Scheme 3. Synthesis of pyridines from different diynes and nitriles (2 equiv.)
using precatalyst 4 under microwave conditions.
The results proof that the co-cyclotrimerization using complex 4
allows a very broad array of differently functionalized nitriles to
Scheme 4. Preparation of different substituted pyridines from diyne 7 and
nitriles (2 equiv.) under microwave conditions.
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The yields obtained with diyne 7 and the different nitriles are in
general acceptable to very good, even under unoptimized
conditions. They were also higher than in comparable cases with
compound 5 as the diyne component (compare to structurally
related products 19 and 23), which possibly could be traced
back to the easier formation of the five-membered annulated
pyridine ring.[ 28 ] For compounds 20 and 21 higher yields at
yield after 19 h and leaving half of the starting material
unchanged. Irradiation for the same time worked even less well
and gave just 35% product. However, in both cases at least
unreacted substrate 27 could be retained and obviously no side
reaction has occurred. Applying microwave conditions, the
cyclization ran smooth and gave a very good yield of 28 after
just 30 minutes reaction time. This yield is superior to the
140 °C compared to 160 °C reaction temperature were observed. experiment conducted under microwave conditions in DMF for
Curiously, attempts to prepare an analogue of compound 21
using diyne 5 instead 7 did not work at all. The cyclization of 7
with a borylated benzonitrile led to triaryl 22 in excellent 90%
yield. Finally, using a azetidine-based nitrile could be cyclized
within an hour at 160 °C furnishing pyridine 24, albeit in
mediocre yield. In summary, an interesting array of structurally
more sophisticated nitriles was successfully reacted allowing
access to novel bi- and triaryl motifs.
After investigating the synthesis of pyridine derivatives under the
different conditions we also evaluated such conditions in the
cyclization of triynes. For the study we focused on methyl- or
phenyl-terminated triynes 25 and 27 and the results are shown
in Scheme 5. Cyclization of 25 under conventional thermal
conditions with precatalyst 4 yielded product 26 and unreacted
25 in nearly equal amounts (Scheme 5, top). Use of microwave
conditions improved the yield of 26 to 52%,[29] while irradiation
gave only 20% yield and most of the substrate must have
reacted to different other products, which were not identified.
10 min reaction time, giving only 52% yield of 28 with catalyst
4.[21]
The results presented above clearly provided evidence for the
differences in the reaction outcome under the chosen conditions.
However, which would be the conditions to choose for initial
screening of reaction parameters? While photochemical
conditions have the advantage to proceed under very mild
conditions, the reaction times are usually relatively long and
yields compared to pyridine synthesis rather low, as the
examples showed. Conventional heating in toluene solution
requires at least 100 °C to proceed over mostly long reaction
times to drive the reaction towards completion. Therefore,
microwave heating appears to be most compelling especially
due to the short reaction times, although reaction temperatures
of at least 120 °C for triynes are frequently required.
We investigated the cyclization of other triyne derivatives with 4
under microwave conditions and the results are given in Table 1.
Entry 1 und 2 are interesting as they show that even 20 °C
difference in reaction temperature for the transformation of 29 to
30 can make the difference between complete conversion and
no reaction at all. The reaction time is very short (10 min) and
the comparable cyclization using CoCl(PPh3)3 as catalyst gave
identical yield (92%), but required 36 h at 25 °C.[30] The reaction
temperature is in general lower compared to the pyridine
synthesis discussed before. Also here the structure of the triyne
appears to play a role for the reaction outcome, demonstrated
by the lower yields for the malonyl-substituted triynes 37, 39 and
41, even at prolonged reaction times.
Scheme 5. Comparison of thermal and photochemical energy supply for
[2+2+2] cycloaddition reactions of triynes 25 and 27.
The results for triyne 27 were partially different compared to
those achieved for 25. Conventional heating led to rather
sluggish conversion of 27, delivering product 28 only with 44%
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Table 1. [2+2+2] Cycloadditions of triynes under microwave conditions.
#
Triyne/
X
R1, R2
T
t
Yield[a]
Product
[°C]
1
2
3
4
29/30
29/30
29/30
31/32
O
O
O
O
1-napthyl
1-napthyl
1-napthyl
100
120
120
120
10 min
10 min
10 min
10 min
0%
98%
78%[b]
34%
2-MeO-1-
naphthyl
5
6
33/34
35/36
O
O
R1=2-MeO-1-
naphthyl;
R2=Ph
120
120
20 min
20 min
62%
83%
R1=1-
naphthyl;
R2=Ph
7
8
37/38
39/40
(EtO2C)2C
(EtO2C)2C
1-napthyl
120
120
30 min
30 min
15%
40%
R1=1-
naphthyl;
R2=Ph
Scheme 6. Comparison of precatalysts CpCo(CO)2 (1) and 4 in [2+2+2]
cycloaddition reactions.
9
41/42
(EtO2C)2C
R1=2-MeO-1-
naphthyl;
R2=Me
120
30 min
15%
We showed in Scheme
2 that photochemically assisted
reactions using precatalyst 4 were performing very smooth,
when using a high power medium pressure mercury lamp in
thermostated reaction vessels.[24] While the outcome of
photochemical reactions is often quite depending on the
experimental setup, we decided to exemplarily showcase
reactions using a convenient setup involving LED lamps for
irradiation without the requirement of extensive cooling for
temperature control required for powerful mercury pressure or
metal halide lamps (Scheme 7, see Supporting Informations for
details).[31]
Initial experiments using diyne 5 and PhCN as substrates gave
biaryl 6 with good yield (68%) after 4 h reaction time using
precatalyst 4. The reaction of diyne 40 with PhCN in the
presence of 4 proceeded with excellent 86% yield after 17.5 h
(Scheme 7, top), which excellently matches the results applying
[a] Isolated yield. [b] 2.5 mol% catalyst 4.
As discussed in the introduction, complex 1 has a longstanding
history as catalyst for [2+2+2] cycloaddition reactions. We were
keen to benchmark this precatalyst vs. complex 4 in selected
reactions to see their performance compared (Scheme 6). In the
first investigated reaction yielding pyridine 10 (Scheme 6, top)
the yields were high in both cases under identical reaction
conditions, however, complex 4 gave an even higher conversion.
The outcome with the preparation of 19 as the second example
(Scheme 6, middle) was even more impressive, as complex 1
failed to catalyze this transformation at all. The cyclization of
triyne 27 emphasizes the versatility of complex 4 even further
(Scheme 6, below), as the product 28 was obtained with 82%
while complex 1 again failed to give any product at all again.
CpCo(COD) (COD
= 1,5-cyclooctadiene) as often used
precatalyst for photo-assisted [2+2+2] cycloadditions (90%).
Comparable results were obtained for the cyclotrimerization of
triyne 29 with a yield of 56% for triaryl 30 applying CpCo(COD)
as catalyst and slightly higher 66% for precatalyst 4 (Scheme 7,
below). These investigations further corroborate the usefulness
of complex 4 under a variety of different reaction conditions and
also different setups for cyclizations performed under
photochemical conditions.
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General Procedure 1 (GP1) for [2+2+2] Cycloaddition Reactions
under Photochemically Assisted Conditions:
A
thermostated
photochemical reactor[24a] was loaded with precatalyst 4 (5 mol%) under
inert conditions and a solution of diyne (0.125 mml) and the appropriate
nitrile (2-5 equiv.) THF or toluene was added. The reaction mixture was
irradiated for the indicated time at 25 °C using medium-pressure metal
halide lamps (2*450 W). For stopping the reaction the lamps were turned
off and the reaction vessel opened to air. The reaction solution was
evaporated to dryness and loaded to a small amount of silica gel, yielding
a fine powder. The crude product was purified by flash chromatography,
furnishing the pure product. Exemplified synthesis for compound 10: For
the preparation of biaryl 10 the diyne 7 (49 mg, 0.125 mmol) and
piperidine-1-carbonitrile (28 mg, 0.25 mmol, 2 equiv.) as well as catalyst
4 (2.7 mg, 5 mol%) dissolved in 2 mL dry THF were irradiated according
to above General Procedure for the indicated time at 25 °C. After the end
of the reaction the solvent was removed in vacuum and the crude
product charged to a small amount of silica gel in Et2O and dried, to give
a dark free flowing powder. Column chromatography on silica gel using
cyclohexane (c-hex)-ethyl acetate (3:1, v/v) as eluent furnished one main
fraction of product 10 (63 mg, quantitive yield) of a yellowish syrup. 1H
NMR (CDCl3, 300 MHz):  = 1.12 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.0 Hz,
3H), 1.58-1.65 (m, 4H), 2.98 (d, J = 16.3 Hz, 1H), 3.36 (d, J = 16.3 Hz,
1H), 3.47-3.54 (m, 4H), 3.58-3.61 (m, 2h), 3.88 (s, 3H), 4.08 (q, J = 7.0
Hz, 1H), 4.10 (q, J = 7.0 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 6.61 (s, 1H),
7.29-7.35 (m, 2H), 7.35 (d, J = 9.2 Hz, 1H), 7.47-7.53 (m, 1H), 7.77-7.83
(m, 1H), 7.87 (d, J = 9.2 Hz, 1H) ppm; 13C NMR (CDCl3, 75 MHz):  =
14.0, 14.1, 24.9, 25.7, 27.0, 38.0, 40.8, 47.1 (2x), 56.9, 60.2, 61.7 (2x),
101.8, 114.0, 123.6, 125.4, 126.1, 126.3, 127.8, 129.3, 129.8, 133.2,
149.3, 151.6, 154.1, 159.7, 171.6, 171.7 ppm; HRMS (EI), C30H34O5N2:
calc.: 502.2462; found: 502.2459.
Scheme 7. Comparison of precatalysts CpCo(COD) and
cycloaddition reactions using LED irradiation.
4 in [2+2+2]
Conclusions
The presented investigation concentrated on the influence
different kinds of energy supply can exert on the application of
CpCo(I)-precatalysts in [2+2+2] cycloaddition reactions.
Investigation of the air-stable and commercially available
General Procedure 2 (GP2) for [2+2+2] Cycloaddition Reactions
under Standard Thermal Conditions: In a Schlenk flask precatalyst 4
was weighted under inert conditions, followed by addition of a solution of
diyne (0.125 mmol) and the appropriate nitrile (2-5 equiv.) in THF or
toluene. The reaction mixture was heated to 100 °C for the indicated time.
After cooling the reaction solution, the solvent was removed in vacuum.
The crude product was purified by flash chromatography. Exemplified
synthesis for compound 10 from (diyne 7 (49 mg, 0.125 mmol) and
piperidine-1-carbonitrile (28 mg, 0.25 mmol, 2 equiv.) as well as catalyst
4 (2.7 mg, 5 mol%) dissolved in 2 mL dry toluene were reacted according
to GP2 (22 h, 100 °C oil-bath temperature). Isolation of 10 according to
the aforementioned procedure gave the product with quantitive yield (63
mg) yield. The analytical data were in agreement to the data determined
before.
complex
CpCo[P(OEt)3](dimethyl
fumarate)
(4)
under
conventional thermal, microwave and photochemical conditions
verified the possibility to successfully perform cyclization
reactions under all three types of reaction conditions. Applying
microwave heating takes advantage of providing consistent high
temperatures in a confined reaction chamber and allowing short
reaction times, while other methods can be equally successful,
however, requiring significantly longer reaction times. We
applied complex 4 under microwave conditions for the synthesis
of pyridines from terminal and internal alkynes and substituted
alkyl and aryl nitriles, which allowed rapid access on more
complex structures. This is also possible for the cyclization of
triynes, even at temperatures as low as 120 °C, which can
otherwise require explicitly higher temperatures. Benchmarking
the reactivity of 4 against the routinely applied complex
CpCo(CO)2 (1) in pyridine and triaryl synthesis impressively
demonstrated that application of 4 as catalyst can led to
excellent yields even when complex 1 shows no reactivity at all.
Successful utilizing of 4 in photo-catalyzed cyclizations using a
convenient photo reactor with irradiation by a LED device further
substantiated the broadness of application of this particular
precatalyst.
General Procedure 3 (GP3) for [2+2+2] Cycloaddition Reactions
under Microwave Conditions: In a Schlenk flask precatalyst 4 was
weighted under inert conditions, followed by addition either of a solution
of diyne (0.125 mmol) and the appropriate nitrile (2-5 equiv.) in toluene or
the substrate triyne (0.125 mmol) in 2 mL toluene. The solution was filled
under inert conditions into the microwave reaction vial equipped with a
stir bar mixture. The reaction in the microwave was executed according
to the specified temperature and time. After cooling the reaction solution,
the solvent was removed in vacuum. The crude product was purified by
automated flash chromatography. Exemplified synthesis for compound
10 from (diyne 7 (49 mg, 0.125 mmol) and piperidine-1-carbonitrile (28
mg, 0.25 mmol, 2 equiv.) as well as catalyst 4 (2.7 mg, 5 mol%)
dissolved in 2 mL dry toluene were reacted according to above General
Procedure (0.5 h, 160 °C). Isolation of 10 according to the
aforementioned procedure gave the product with 96% yield (60 mg). The
analytical data were in agreement to the above data.
Experimental Section
General information:
Heterocyclic cyclization products:
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3-(4-Chlorophenyl)-5,6,7,8-tetrahydroisoquinoline (11): Compound 11
was synthesized from 1,7-octadiyne (26.5 mg, 0.25 mmol) and 4-chloro
benzonitrile (69 mg, 0.5 mmol, 2 equiv.) and catalyst 4 (5.4 mg, 5 mol%)
as orange syrup. 1H NMR (CDCl3, 400 MHz):  = 0.94 (t, J = 7.4 Hz, 3H),
1.03 (t, J = 7.4 Hz, 3H), 1.58-1.71 (m, 4H), 2.06-2.15 (m, 2H), 2.62-2.67
(m, 2H), 2.82-2.87 (m, 2H), 2.91 (ddd, J = 8.0, 7.6, 2.7 Hz, 4H), 5.21 (s,
2H), 6.90 (dd, J = 8.3, 7.8 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H) ppm;
13C NMR (CDCl3, 100 MHz):  = 14.3, 14.7, 22.3, 23.9, 24.7, 30.9, 31.6,
31.7, 37.8, 75.6, 125.0, 129.0 (2C), 130.1 (2C), 131.9, 138.1, 150.5,
151.8, 153.3, 154.5 ppm; HRMS (EI), C21H25Cl2NO: calc.: 377.1308;
found: 377.1301.
in
4 mL dry toluene according to GP3 (1 h, 160 °C). Column
chromatography on silica gel using c-hex-ethyl acetate (1:1, v/v) as
eluent gave pure product 11 (41 mg, 67% yield) as solid. M.p.: 96-99 °C;
1H NMR (CDCl3, 300 MHz):  = 1.81-1.88 (m, 4H), 2.75-2.84 (m, 4H),
7.38 (s, 1H), 7.41 (d, J = 8.7 Hz, 2H), 7.89 (ddd, J = 8.7 Hz, 2H), 8.36 (s,
1H) ppm; 13C NMR (CDCl3, 75 MHz):  = 22.6, 22.8, 26.2, 29.1, 120.6,
128.1, 128.9, 132.2, 134.5, 138.3, 147.2, 150.5, 153.3 ppm; HRMS (EI),
C15H14ClN: calc.: 243.0809; found: 243.0810.
1,4-Dipropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridine
(15):
For
the
preparation of triaryl 15 the 4,9-tridecadiyne (44 mg, 0.25 mmol) and 4-
(cyanophenyl)boronic acid pinacol ester (114.5 mg, 0.5 mmol, 2 equiv.)
and catalyst 4 (5.4 mg, 5 mol%) in 4 mL dry toluene according to GP3 (1
h, 160 °C). After performing the microwave-assisted reaction the reaction
solvent was removed in vacuum and the crude product charged to a
small amount of silica gel in ethyl acetate and dried. Column
chromatography on silica gel using c-hex/ethyl acetate (3:1, v/v) as
eluent furnished and product 15 (23 mg, 24% yield) of yellowish syrup. 1H
NMR (CDCl3, 300 MHz):  = 0.80 (t, J = 7.3 Hz, 3H), 0.98 (t, J = 7.3 Hz,
3H), 1.36 (s, 12H), 1.38-1.46 (m, 2H), 1.67-1.78 (m, 2H), 2.08-2.18 (m,
2H), 2.45-2.52 (m, 2H), 2.68-2.75 (m, 2H), 2.90-2.98 (m, 4H), 7.42 (d, J =
8.2 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H) ppm; 13C NMR (CDCl3, 75 MHz):  =
14.36, 14.44, 22.6, 23.4, 24.8, 25.0 (4x), 30.9, 32.0, 32.2, 38.2, 83.9 (2C),
128.5 (2C), 129.4, 134.6 (2C), 144.7, 153.2, 154.6, 156.3 (1 C could not
be detected due to C-B coupling) ppm; 11B NMR (CDCl3, 96 MHz):  =
30.9 ppm; HRMS (EI), C26H36BO2N: calc.: 405.2834; found: 405.2830.
3-(2-Fluoro-6-methoxyphenyl)-5,6,7,8-tetrahydroisoquinoline
(12):
Compound 12 was synthesized from 1,7-octadiyne (106 mg, 0.13 mL,
1.0 mmol) and 2-fluoro-6-methoxy benzonitrile (302.3 mmg, 2.0 mmol, 2
equiv.) and catalyst 4 (21.7 mg, 5 mol%) in 6 mL dry toluene according to
GP3 (1h, 160 °C). Reaction control via TLC with c-hex/ethyl acetate (1:1,
v/v) showed complete conversion of the diyne starting material. The
solvent was removed, and the crude product charged to a small amount
of silica gel to give a dark free flowing solid. Column chromatography on
silica gel using using c-hex-ethyl acetate (2:1, v/v) as eluent gave two
main fractions, which were identified as pure recovered benzonitrile
starting material (196 mg, according to 70% conversion) and product 12
1
(162 mg, 60% yield) of transparent syrupy consistency. H NMR (CDCl3,
300 MHz):  = 1.80-1.87 (m, 4H), 2.76-2.82 (m, 4H), 3.78 (s, 3H), 6.74-
6.81 (m, 2H), 7.09 (s, 1H), 7.28 (ddd, J = 8.7, 8.3, 6.6 Hz, 1H), 8.42 (s,
1H) ppm; 13C NMR (CDCl3, 75 MHz):  = 22.5, 22.7, 26.2, 28.9, 56.3,
106.8 (d, JC,F = 3.0 Hz); 108.4 (d, JC,F = 23.1 Hz), 126.2, 129.7 (d, JC,F
=
11.1 Hz), 132.0, 146.3, 148.2, 150.2, 158.5 (d, JC,F = 7.1 Hz), 159.4,
162.4 ppm; 19F NMR (CDCl3, 282 MHz): 115.8 ppm; HRMS (EI),
C16H15ONF: calc.: 256.1132; found: 256.1132.
3-(Naphthalen-1-yl)-1,4-dipropyl-6,7-dihydro-5H-cyclopenta[c]-
pyridine (16): Pyridine 16 was synthesized from 4,9-tridecadiyne (176.3
mg, 1.0 mmol) and 1-naphthonitrile (308 mg, 2.0 mmol, 2 equiv.) and
catalyst 4 (21.7 mg, 5 mol%) in 6 mL toluene according to GP3 (2 h,
160 °C). After completion of the reaction cycle the solvent was removed
in vacuo and the crude product charged to a small amount of silica gel in
ethylacetat and dried. Column chromatography on silica gel using c-
hex/ethyl acetate (3:1, v/v) as eluent furnished two main fractions, which
were identified as pure recovered 1-naphthonitrile starting material (238
mg, according to 78% recovery) and product 16 (80 mg, 25% yield) as
orange syrup. 1H NMR (CDCl3, 300 MHz):  = 0.64 (t, J = 7.4 Hz, 3H),
0.98 (t, J = 7.4 Hz, 3H), 1.27 (q, J = 7.4 Hz, 2H), 1.72 (q, J = 7.4 Hz, 2H),
2.11-2.25 (m, 3H), 2.32-2.45 (m, 1H), 2.71-2.79 (m, 2H), 2.95-3.05 (m,
4H), 7.30-7.47 (m, 4H), 7.51 (dd, J = 8.2, 7.0 Hz, 1H), 7.86 (dd, J = 8.2,
3.4 Hz, 2H) ppm; 13C NMR (CDCl3, 75 MHz):  = 14.3, 14.4, 22.9, 23.3,
24.8, 31.0, 32.0, 32.4, 38.2, 125.3, 125.7, 125.9, 126.2, 126.8, 127.7,
128.2, 130.9, 132.6, 133.9, 136.7, 139.1, 153.1, 154.7, 155.4 ppm;
HRMS (EI), C24H27N: calc.: 329.2138; found: 329.2126.
3-(2-Fluoro-6-methoxyphenyl)-1,4-di-n-propyl-6,7-dihydro-5H-
cyclopenta[c]pyridine (13): Pyridine 13 was synthesized from 4,9-
tridecadiyne (176.3 mg, 1.0 mmol) and 2-fluoro-6-methoxy benzonitrile
(302.3 mmg, 2.0 mmol, 2 equiv.) and catalyst 4 (21.7 mg, 5 mol%) in 6
mL dry toluene according to GP3 (1h, 160 °C). After completion of the
reaction cycle the solvent was removed in vacuo and the crude product
charged to a small amount of silica gel in Et2O and dried, to give a dark
free flowing powder. Column chromatography on silica gel using c-
hex/ethyl acetate (2:1, v/v) as eluent furnished two main fractions, which
were identified as pure recovered benzonitrile starting material (216 mg,
according to 57% conversion) and product 13 (122 mg, 37% yield) of a
transparent syrup. 1H NMR (CDCl3, 300 MHz):  = 0.76 (t, 3H), 0.97 (t,
3H), 1.28-1.42 (m, 2H), 1.63-1.76 (m, 2H), 2.07-2.19 (m, 2H), 2.28-2.36
(m, 2H), 2.68-2.77 (m, 2H), 2.91-2.99 (m, 4H), 3.73 (s, 3H), 6.72-6.79 (m,
2H), 7.27 (ddd, J = 8.7, 8.3, 6.6 Hz, 1H) ppm; 13C NMR (CDCl3, 75 MHz):
 = 14.2, 14.4, 22.5, 22.8, 24.5, 30.9, 31.9, 32.5, 38.3, 56.1, 106.9 (d, JC,F
= 2.7 Hz); 108.4 (d, JC,F = 22.8 Hz), 129.4 (d, JC,F = 9.8 Hz), 131.4, 137.1,
148.0, 152.8, 155.0, 158.6 (d, JC,F = 7.4 Hz), 159.4, 162.7 ppm; 19F NMR
(CDCl3, 282 MHz):  = 114.3 ppm; HRMS (EI), C21H26ONF: calc.:
327.1986; found: 327.1993.
Methyl 1-(3-phenyl-5,6,7,8-tetrahydroisoquinolin-1-yl)-2-naphthoate
(17): Pyridine 17 was synthesized from methyl 1-(octa-1,7-diyn-1-yl)-2-
naphthoate (37 mg, 0.125 mol) and benzonitrile (26 mg, 0.25 mmol, 2
equiv.) and catalyst 4 (2.7 mg, 5 mol%) in 2 mL dry toluene according to
GP3 (0.5 h, 160 °C). After completion of the reaction cycle the solvent
was removed in vacuum and the crude product charged to a small
amount of silica gel in ethylacetat and dried. Column chromatography on
silica gel using c-hex/ethyl acetate (3:1, v/v) as eluent furnished one main
fraction, which were product 17 (40 mg, 81% yield) of a yellowish solid.
The identification was accomplished by comparison with published NMR
data.[27b]
3-((2,6-Dichlorophenoxy)methyl)-1,4-dipropyl-6,7-dihydro-5H-
cyclopenta[c]pyridine (14): For the preparation of compound 14 the
4,9-tridecadiyne
(88
mg,
0.5
mmol)
and
2-(2,6-
dichlorophenoxy)acetonitrile (202 mg, 1 mmol, 2 equiv.) and catalyst 4
(10.8 mg, 5 mol%) in 4 mL dry toluene according to GP3 (1 h, 160 °C).
After performing the microwave-assisted reaction the reaction solvent
was removed in vacuo and the crude product charged to a small amount
of silica gel in ethyl acetate and dried. Column chromatography on silica
gel using c-hex/ethyl acetate (3:1, v/v) as eluent furnished two main
fractions, which were identified as pure recovered nitrile starting material
(70 mg, according to 62% conversion) and product 14 (45 mg, 24% yield)
3-(1-Benzhydrylazetidin-3-yl)-1-(2-methoxynaphthalen-1-yl)-5,6,7,8-
tetrahydroisoquino-line (18): Compound 18 was synthesized from
diyne 5 (33 mg, 0.125 mmol) and 1-benzhydrylazetidine-3-carbonitrile
(62 mg, 0.25 mmol, 2 equiv.) and catalyst 4 (2.7 mg, 5 mol%) in 2 mL
toluene according to GP3 (0.5 h, 160 °C). After completion of the reaction
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800196
European Journal of Organic Chemistry
FULL PAPER
cycle the solvent was removed in vacuo and the crude product charged
to a small amount of silica gel in ethylacetat and dried. Column
chromatography on silica gel using c-hex/ethyl acetate (3:1, v/v) as
eluent furnished two main fractions, which were identified as pure
recovered 1-benzhydrylazetidine-3-carbonitrile starting material (40 mg,
according to 65% recovery) and product 18 (19 mg, 30% yield) as syrup.
1H NMR (CDCl3, 300 MHz):  = 1.56-1.82 (m, 4H), 2.05-2.17 (m, 1H),
2.33-2.46 (m, 1H), 2.89 (dd, J = 7.1, 6.2 Hz, 2H), 3.34 (ddd, J = 7.2, 7.1,
2.4 Hz, 2H), 3.60-3.69 (m, 2H), 3.81-3.91 (m, 1H), 3.83 (s, 3H), 4.46 (s,
1H), 7.09-7.21 (m, 4H), 7.23-7.33 (m, 6H), 7.35 (d, J = 9.1 Hz, 1H), 7.41-
7.46 (m, 1H), 7.79-7.84 (m, 1H), 7.89 (d, J = 9.1 Hz, 1H) ppm; 13C NMR
(CDCl3, 75 MHz):  = 22.5, 23.1, 25.5, 29.8, 36.7, 56.9, 59.6, 59.7, 78.1,
114.0, 120.5, 123.6, 123.8, 124.7, 126.6, 127.1 (2C), 127.71 (4x), 127.74
(4x), 128.0, 128.5 (2C), 129.4, 129.7, 131.0, 133.3, 142.5, 146.8, 154.0,
158.6 ppm; HRMS (EI), C36H34ON2: calc.: 510.2666; found: 510.2669.
(benzyloxy)benzonitrile (52 mg, 0.25 mmol, 2 equiv.) and catalyst 4 (2.7
mg, 5 mol%) in 2 mL dry toluene according to GP3 (0.5 h, 140 °C). After
completion of the reaction cycle the solvent was removed in vacuo and
the crude product charged to a small amount of silica gel in ethylacetat
and dried. Column chromatography on silica gel using c-hex/ethyl
acetate (3:1, v/v) as eluent furnished one main fraction, which were
identified as product 21 (33 mg, 44% yield) of a transparent syrup. 1H
NMR (CDCl3, 300 MHz):  = 1.14 (t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz,
3H), 3.18 (d, J = 17 Hz, 1H), 3.54 (t, J = 17 Hz, 1H), 3.71 (bs, 2H), 3.88
(s, 3H), 4.06-4.18 (m, 2H), 4.22 (q, J = 7.1 Hz, 2H), 5.18 (t, J = 1.6 Hz,
2H), 6.97-7.05 (m, 2H), 7.27-7.49 (m, 10H), 7.79-7.85 (m, 3H), 7.92 (d, J
= 9.1 Hz, 1H) ppm; 13C NMR (CDCl3, 75 MHz):  = 14.0, 14.1, 38.8, 40.8,
56.7, 59.9, 61.9, 70.8, 113.4, 113.6, 120.1, 121.2, 121.6, 123.7, 125.0,
126.7, 127.1, 127.2 (2C), 127.8, 128.0, 128.3, 128.6 (2C), 128.8, 129.3,
129.6, 130.3, 131.9, 133.2, 135.7, 137.4, 151.6, 154.4, 154.7, 156.3,
171.4, 171.5 ppm; HRMS (EI), C38H35NO6: calc.: 601.2459; found:
601.2448.
2-((1-(2-Methoxynaphthalen-1-yl)-5,6,7,8-tetrahydroisoquinolin-3-
yl)methyl)benzo[d]-thiazole (19): Biaryl 19 was synthesized from diyne
5 (33 mg, 0.125 mmol) and 2-(benzo[d]thiazol-2-yl) acetonitrile (44 mg,
0.25 mmol, 2 equiv.) and catalyst 4 (2.7 mg, 5 mol%) in 2 mL toluene
according to GP3 (0.5 h, 140 °C). After completion of the reaction cycle
the solvent was removed in vacuo and the crude product charged to a
small amount of silica gel in ethylacetat and dried. Column
chromatography on silica gel using c-hex/ethyl acetate (1:1, v/v) as
eluent furnished two main fractions, which were identified as pure
recovered 2-(benzo[d]thiazol-2-yl)acetonitrile starting material (27 mg,
according to 61% recovery) and product 19 (22 mg, 40% yield) as yellow-
orange solid. M.p.: 129-131 °C; 1H NMR (CDCl3, 300 MHz):  = 1.55-1.81
(m, 4H), 2.09-2.21 (m, 1H), 2.36-2.48 (m, 1H), 2.81 (t, J = 6.2 Hz, 2H),
3.88 (s, 3H), 4.67 (s, 2H), 7.13 (s, 1H), 7.17-7.21 (m, 1H), 7.30-7.37 (m,
3H), 7.38 (d, J = 9.0 Hz, 1H), 7.46 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.79-
7.86 (m, 2H), 7.92 (d, J = 9.0 Hz, 1H), 8.04-8.0 (m, 1H) ppm; 13C NMR
(CDCl3, 75 MHz):  = 22.3, 22.9, 25.5, 27.0, 29.6, 43.2, 56.8, 113.8,
121.6, 122.8, 123.1, 123.7, 124.7, 124.8, 125.9, 126.7, 128.1, 129.4,
130.0, 136.2, 153.2 (2C), 154.2, 170.3 ppm (two carbon resonances are
missing presumably due to signal overlay); HRMS (EI), C28H23ON2S:
calc.: 435.1526; found: 435.1525.
Diethyl 1-(2-methoxynaphthalen-1-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)phenyl)-5,7-dihydro-6H-cyclopenta[c]pyridine-6,6-
dicarboxylate (22): For the preparation of triaryl 22, diyne 7 (49 mg,
0.125 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile
(57 mmg, 0,25 mmol, 2 equiv.) and catalyst 4 (2.7 mg, 5 mol%) dissolved
in 2 mL dry toluene according to GP3 (0.5 h, 160 °C). After performing
the microwave-assisted reaction the reaction solvent was removed in
vacuo and the crude product charged to a small amount of silica gel in
ethyl acetate and dried. Column chromatography on silica gel using c-
hex/ethyl acetate (5:1, v/v) as eluent furnished one main fraction, which
were identified as pure product 22 (70 mg, 90% yield) of yellowish syrupy
consistency. 1H NMR (CDCl3, 300 MHz):  = 1.14 (t, J = 7.1 Hz, 3H), 1.25
(t, J = 7.1 Hz, 3H), 1.35 (s, 12H), 3.15 (d, J = 17.1 Hz, 1H), 3.54 (d, J =
17.1 Hz, 1H), 3.76 (bs, 2H), 3.89 (s, 3H), 4.07-4.16 (m, 2H), 4.22 (qd, J =
7.1, 0.8 Hz, 2H), 7.32-7.37 (m, 2H), 7.38 (d, J = 9.2 Hz, 1H), 7.42-7.46
(m, 1H), 7.70 (s, 1H), 7.82-7.87 (m, 3H), 7.94 (d, J = 9.0 Hz, 1H), 8.00-
8.04 (m, 2H) ppm; 13C NMR (CDCl3, 75 MHz):  = 14.0, 14.2, 25.0 (2C),
38.8, 40.8, 56.7, 59.9, 62.0, 83.9, 113.7, 115.8, 122.5, 123.8, 125.0,
126.5, 126.8, 128.0, 129.4, 130.4, 133.2, 135.2, 136.4, 142.4, 150.9,
152.1, 154.3, 156.3, 171.3, 171.4 ppm; HRMS (EI), C37H40BNO7: calc.:
621.2892; found: 621.2892.
Diethyl
1-(2-methoxynaphthalen-1-yl)-3-(2-(3-methyl-1H-indol-1-
yl)ethyl)-5,7-dihydro-6H-cyclopenta[c]pyridine-6,6-dicarboxylate
(20): Compound 20 was synthesized from diyne 7 (49 mg, 0.125 mmol)
and 3-(3-methyl-1H-indol-1-yl)propanenitrile (46 mg, 0.25 mmol, 2 equiv.)
and catalyst 4 (2.7 mg, 5 mol%) in 2 mL dry toluene according to GP3
(0.5 h, 140 °C). After completion of the reaction cycle the solvent was
removed in vacuo and the crude product charged to a small amount of
silica gel in ethylacetat and dried. Column chromatography on silica gel
using c-hex/ethyl acetate (3:1, v/v) as eluent furnished one main fraction,
which were identified as product 20 (61 mg, 85% yield) of off-white
Diethyl 3-(benzo[d]thiazol-2-ylmethyl)-1-(2-methoxynaphthalen-1-yl)-
5,7-dihydro-6H-cyclopenta[c]pyridine-6,6-dicarboxylate (23): Pyridine
23 was synthesized from diyne
(benzo[d]thiazol-2-yl)acetonitrile (44 mg, 0.25 mmol,
7
(49 mg, 0.125 mmol) and 2-
equiv.) and
2
catalyst 4 (2.7 mg, 5 mol%) dissolved in 2 mL dry toluene according to
GP3 (0.5 h, 160 °C). After completion of the reaction cycle the solvent
was removed in vacuo and the crude product charged to a small amount
of silica gel in ethyl acetate and dried. Column chromatography on silica
gel using c-hex/ethyl acetate (1:1, v/v) as eluent furnished product 23 (42
1
syrupy consistency. H NMR (CDCl3, 400 MHz):  = 1.13 (t, J = 7.2 Hz,
1
3H), 1.22 (t, J = 7.2 Hz, 3H), 2.29 (d, J = 0.8 Hz, 3H), 3.08 (d, J = 16.8 Hz,
1H), 3.30 (t, J = 6.8 Hz, 2H), 3.34 (d, J = 16.8 Hz, 1H), 3.48-3.60 (m, 2H),
3.91 (s, 3H), 4.04-4.15 (m, 2H), 4.18 (q, J = 7.2 Hz, 2H), 4.50 (t, J = 6.8
Hz, 2H), 6.80 (d, J = 9.1 Hz, 2H), 7.06-7.11 (m, 1H), 7.14-7.19 (m, 1H),
7.23-7.29 (m, 2H), 7.34-7.37 (m, 2H), 7.40 (d, J = 9.1 Hz, 1H), 7.55 (d, J
= 7.7 Hz, 1H), 7.82-7.87 (m, 1H), 7.95 (d, J = 9.1 Hz, 1H) ppm; 13C NMR
(CDCl3, 100 MHz):  = 9.7, 14.0, 14.1, 38.5, 39.2, 40.6, 46.4, 56.7, 59.8,
61.9 (2C), 109.4, 110.2, 113.6, 118.5, 118.8, 119.0, 121.3, 123.8, 124.6,
125.8, 126.9, 128.1, 128.8, 129.3, 130.4, 133.0, 135.4, 136.4, 150.7,
151.9, 154.3, 157.3, 171.2, 171.3 ppm; HRMS (EI), C36H36O5N2: calc.:
576.2619; found: 576.2619.
mg, 59% yield, orange-brown solid). M.p.: 155-158 °C; H NMR (CDCl3,
300 MHz):  = 1.20 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H), 3.12 (d, J
= 17 Hz, 1H), 3.46 (d, J = 17 Hz, 1H), 3.67 (bs, 2H), 3.88 (s, 3H), 4.03-
4.14 (m, 2H), 4.18 (qd, J = 7.2, 0.7 Hz, 2H), 4.72 (d, J = 1.5 Hz, 2H), 7.29
(bs, 1H), 7.30-7.34 (m, 3H), 7.34-7.39 (m, 2H), 7.46 (ddd, J = 8.5, 7.2,
1.3 Hz, 1H), 7.80-7.85 (m, 2H), 7.93 (d, J = 9.1 Hz, 1H), 8.01-8.05 (m,
1H) ppm; 13C NMR (CDCl3, 75 MHz):  = 14.0, 14.1, 38.6, 40.7, 43.3,
56.6, 59.8, 61.9, 113.5, 118.5, 121.6, 122.9, 123.8, 124.9 (2x), 126.0,
126.8, 128.0, 129.3, 130.5, 132.9, 136.1, 136.2, 151.4, 152.1, 153.2,
154.3, 155.5, 171.2 (2x), ppm (two carbon resonances are missing
presumably due to signal overlay); HRMS (EI), C33H30N2O5S: calc.:
566.1870; found: 566.1861.
Diethyl
dihydro-6H-cyclopenta[c]pyridine-6,6-dicarboxylate (21): Triaryl 21
was synthesized from diyne (49 mg, 0.125 mmol) and 2-
3-(2-(benzyloxy)phenyl)-1-(2-methoxynaphthalen-1-yl)-5,7-
Diethyl 3-(1-benzhydrylazetidin-3-yl)-1-(2-methoxynaphthalen-1-yl)-
5,7-dihydro-6H-cyclopenta[c]pyridine-6,6-dicarboxylate (24): The
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800196
European Journal of Organic Chemistry
FULL PAPER
cyclization of diyne 7 (98 mg, 0.25 mmol) and 1-benzhydrylazetidine-3-
carbonitrile (124 mg, 0.5 mmol, 2 equiv.) and catalyst 4 (5.4 mg, 5 mol%)
dissolved in 4 mL dry toluene was conducted according to GP3 (1 h,
160 °C). For workup the solvent was removed and the crude product
charged to a small amount of silica gel in ethyl acetate and dried.
Purification by column chromatography on silica gel eluting with c-
hex/ethyl acetate (3:1, v/v) furnished product 24 (61 mg, 38% yield,
yellowish syrup). 1H NMR (CDCl3, 300 MHz):  = 1.15 (t, J = 7.1 Hz, 3H),
1.25 (t, J = 7.1 Hz, 3H), 3.10 (d, J = 16.9 Hz, 1H), 3.39 (q, J = 7.4 Hz, 2H),
3.48 (d, J = 16.9 Hz, 1H), 3.61-3.69 (m, 2H), 3.71-3.75 (m, 2H), 3.86 (s,
3H), 3.87-3.96 (m, 1H), 4.06-4.17 (m, 2H), 4.21 (qd, J = 7.2, 0.5 Hz, 2H),
4.47 (bs, 1H), 7.15-7.22 (m, 2H), 7.24-7.38 (m, 8H), 7.38 (s, 1H), 7.42-
7.47 (m, 4H), 7.79-7.85 (m, 1H), 7.92 (d, J = 9.1 Hz, 1H) ppm; 13C NMR
(CDCl3, 75 MHz):  = 14.0, 14.1, 37.0, 38.7, 40.8, 56.7, 59.6, 59.7, 59.8,
61.9, 78.0, 113.7, 116.0, 123.8, 124.9, 126.7, 127.1, 127.67 (2x), 127.72
(2x), 128.0, 128.5 (4C), 129.3, 130.3, 133.1, 135.1, 142.4, 150.6, 151.3,
154.2, 161.2, 171.4, 171.5 ppm.
[7]
C. Kesenheimer, A. Kalogerakis, A. Meißner, U. Groth, Chem. Eur. J.
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A. McIver, D. D. Young, A. Deiters, Chem. Commun. 2008, 4750-4752.
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Supporting Information (see footnote on the first page of this article):
Synthesis of substrates (compounds 7 and 43), experimental procedures
for cyclizations and data (products 6, 8, 26-44), benchmark experiments
with CpCo(CO)2 (1) and the photochemical cyclizations; copies of NMR
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Acknowledgements
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87-8 (http://www.tcichemicals.com/).
We thank Prof. Uwe Rosenthal for his support as well as the
LIKAT for providing resources for this investigation. Our special
thanks go to the analytical department of LIKAT (NMR: Susanne
Schareina and Susanne Buchholz; HRMS: Dr. Christine Fischer)
for their swift performance.
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Keywords: Cobalt • [2+2+2] Cycloaddition • Catalyst activation •
Microwave • Pyridines
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10.1002/ejoc.201800196
European Journal of Organic Chemistry
FULL PAPER
However, the result obtained under thermal conditions (4h, refluxing
toluene) was basically identical to ours.
[31] We used a commercially available photoreactor system of HepatoChem
(EvoluChem™ PhotoRedOx Box) for these experiments.
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9793.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800196
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
[2+2+2] Cycloadditions
Fabian Fischer, Marko Hapke*
Page No. – Page No.
Air-stable CpCo(I)-phosphite-
fumarate precatalyst in cyclization
reactions: comparing different
methods of energy supply
Fire, light and microwave: An air-stable CpCo(I)-precatalyst was able to catalyze
the synthesis of highly substituted benzenes and pyridines exploiting all kinds of
energy supply, proving to be more reactive than, e.g. CpCo(CO)2 as standard
catalyst.
This article is protected by copyright. All rights reserved.