Microwave-enhanced rhodium-catalyzed [2+2+2] cycloaddition reactions to afford highly functionalized pyridines and bipyridines

Article abstract of DOI:10.1002/ejoc.200901318

Rhodium(I)-catalyzed [2+2+2] cycloaddition reactions of Ntosyl-, carbon-, and oxygen-tethered cyanodiynes in a completely intramolecular fashion have been optimized to afford highly functionalized pyridines by conventional and/or microwave heating. Microwaves have been shown to enhance the process by allowing the reaction to be conducted effectively in short reaction times. The methodology has been extended for the synthesis of bipyridines, either by treating a cyanodiyne with an appended pyridine or by conducting a double [2+2+2] cycloaddition reaction on a dicyanotetrayne scaffold. The choice of the solvent in the microwave heating reaction has been shown to be crucial for the success of the process.

Full text of DOI:10.1002/ejoc.200901318

FULL PAPER
DOI: 10.1002/ejoc.200901318
Microwave-Enhanced Rhodium-Catalyzed [2+2+2] Cycloaddition Reactions To
Afford Highly Functionalized Pyridines and Bipyridines
Lídia Garcia,[a] Anna Pla-Quintana,*[a] Anna Roglans,*[a] and Teodor Parella[b]
Keywords: Cycloaddition / Microwave chemistry / Rhodium / Nitrogen heterocycles / Fused-ring systems
Rhodium(I)-catalyzed [2+2+2] cycloaddition reactions of N-
tosyl-, carbon-, and oxygen-tethered cyanodiynes in a com-
pletely intramolecular fashion have been optimized to afford
highly functionalized pyridines by conventional and/or mi-
crowave heating. Microwaves have been shown to enhance
the process by allowing the reaction to be conducted effec-
tively in short reaction times. The methodology has been ex-
tended for the synthesis of bipyridines, either by treating a
cyanodiyne with an appended pyridine or by conducting a
double [2+2+2] cycloaddition reaction on a dicyanotetrayne
scaffold. The choice of the solvent in the microwave heating
reaction has been shown to be crucial for the success of the
process.
the door to the one-step preparation of new polycyclic-
fused pyridines displaying frameworks that can be found in
compounds of biological interest. To the best of our knowl-
edge, there are only a few reported cases of completely in-
tramolecular reactions for the synthesis of pyridine deriva-
tives. The first cases, described in 2006 by Yamamoto et
al.,[4] were of three different cyanodiynes bearing a 1,6-di-
yne moiety and a pendant nitrile, which were efficiently
converted into tricyclic pyridines under ruthenium catalysis.
Later, Snyder et al.[5] described a Co-catalyzed [2+2+2] cy-
cloaddition of cyanodiynes to give tetrahydro-1,6-naphthyr-
idines promoted by microwave heating, and Cheng et al.[6]
reported the synthesis of tetra- and pentacyclic pyridine de-
rivatives by cycloaddition of cyanodiynes with a bulky sub-
stitution at the terminal carbon atom of the alkyne and
catalyzed by a CoI2(dppe)/Zn system. More recently, Aub-
ert, Malacria et al.[7] described an efficient preparation of
tricyclic-fused 3-aminopyridines through intramolecular
CoI-catalyzed [2+2+2] cycloaddition reactions. In the case
of rhodium complexes, there has only been one report by
Tanaka et al.[8] in which a cationic rhodium(I) complex and
chiral bidentate phosphanes promoted a double [2+2+2] cy-
cloaddition of bis-diynenitriles to afford spirobipyridine li-
gands in excellent yields and moderate enantiomeric ex-
cesses.
Introduction
Transition-metal-catalyzed [2+2+2] cycloadditions are
essential strategic reactions in increasing the complexity of
target molecules, as they enable bond connections to be
made in one single step.[1] This reaction is remarkable in
terms of its ability to generate carbocyclic systems by the
involvement of various unsaturated substrates such as alk-
ynes and alkenes and heterocyclic systems when involving
heterounsaturated derivatives such as nitriles, isocyanates,
isothiocyanates, CO2, SO2, and carbonyl groups.[1b,1e,1g,1h,1j]
Of these, cycloaddition between two alkynes and a nitrile is
one of the most powerful methods for creating large num-
bers of differentially substituted pyridines.[1b,1h,1j] The prep-
aration of complex polycyclic pyridine derivatives is a major
goal, because these compounds have taken on an important
role in various scientific branches such as the chemistry of
biological systems, the pharmaceutical and agrochemical
industries, preparative organic chemistry, as well as coordi-
nation chemistry and polymers.[2]
The synthesis of pyridines by this methodology has been
discussed in detail in recent reviews.[1b,1h,1j] The most com-
mon cases described are either intermolecular or partially
intramolecular reactions between two alkynes and a ni-
trile.[3] However, the completely intramolecular version,
namely, the [2+2+2] cycloaddition of cyanodiynes, opens
In this study, we present RhI-catalyzed [2+2+2] cycload-
dition reactions of N-tosyl-, carbon-, and oxygen-tethered
cyanodiynes to afford highly functionalized tricyclic-fused
pyridines by conventional and/or microwave heating. The
use of microwave heating was found to favor cycloaddition
and only short reaction times were required. Furthermore,
it was even successful in cases where conventional heating
failed. This methodology was also applied to the synthesis
of bipyridines.
[a] Departament de Química, Universitat de Girona,
Campus de Montilivi s/n, 17071 Girona, Spain
Fax: +34-972-41-81-50
E-mail: anna.roglans@udg.edu
[b] Servei de RMN, Universitat Autònoma de Barcelona,
08193 Bellaterra, Barcelona, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901318.
Eur. J. Org. Chem. 2010, 3407–3415
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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L. Garcia, A. Pla-Quintana, A. Roglans, T. Parella
FULL PAPER
Results and Discussion
In a first step we chose 1,6-diynes tethered to an N-tosyl
group and a pendant nitrile. Substituents with different
steric demand were introduced into the terminal alkyne
moiety. We have fine-tuned the synthetic pathways as shown
in Scheme 1 to achieve the preparation of cyanodiyne deriva-
tives 1–4. The synthesis started when N-(2-cyanoethyl)(4-
methylphenyl)sulfonamide 5[9] was treated with bromide
6[10] to give derivative 7 in 88% yield. The removal of the
Boc group was first attempted by employing trifluoroacetic
acid in dichloromethane but this resulted in the partial hy-
drolysis of the cyano group. In order to eliminate this sec-
ondary reaction, we avoided strongly acidic elimination
conditions. Trimethylsilyl triflate (TMSOTf) in the presence
of 2,6-lutidine and the later treatment with MeOH was used
by Ohfune[11] to remove the Boc group from compounds
that have other functional groups that are sensitive in acidic
conditions. Hence, unprotected derivative 8 was obtained in
81% yield under these conditions. Compound 8 was a com-
mon intermediate in the synthesis of the four cyanodiynes.
Treatment of 8 with bromide 6 (1 equiv.) using K2CO3 as a
base in refluxing CH3CN afforded 1 in 94% yield. The same
conditions as described previously were employed to elimin-
ate the Boc group of 1. Cyanodiyne 2 was obtained in 91%
yield. The reaction of 8 with 1-bromobut-2-yne (9) and pro-
pargyl bromide (10) also with the use of K2CO3 in CH3CN
gave derivatives 3 and 4 in 82 and 98% yield, respectively.
Once the corresponding unsaturated substrates were ob-
tained, we studied their [2+2+2] cycloaddition reactions.
Our aim was to use the Wilkinson complex, as it is simple,
relatively inexpensive, and commercially available
(Scheme 2 and Table 1).
Scheme 1. Synthesis of cyanodiynes 1–4.
The cycloaddition reactions of cyanodiynes 1–4 were car-
ried out with RhCl(PPh3)3 (10 mol-%) in toluene at 90 °C.
Derivative 1 gave an excellent yield of cycloaddition prod-
uct 11 in only 3 h (Table 1, Entry 1). However, cyanodiynes
Scheme 2. [2+2+2] Cycloaddition reactions of cyanodiynes 1–4.
2 and 3 gave only moderate yields whilst affording large not participate in the [2+2+2] cycloaddition reaction
quantities of decomposition products (Table 1, Entries 2 (Table 1, Entry 4). In order to minimize temperature-associ-
and 3). Derivative 4 with a terminal alkyne gave a benzene ated decomposition processes, we tested the reaction at
dimer[12] as a product (Figure 1), whereas the nitriles did 60 °C (Table 1, Entries 5–8). The reaction time was longer
Table 1. RhI-catalyzed [2+2+2] cycloadditions of cyanodiynes 1–4 with conventional heating.
Entry
Cyanodiyne
Catalyst (mol-%)
Solvent
T [°C]
Time [h]
Product, % Yield
1
2
3
4
5
6
7
8
1
2
3
4
1
2
3
4
1
3
4
1
3
4
RhCl(PPh3)3 (10)
RhCl(PPh3)3 (10)
RhCl(PPh3)3 (10)
RhCl(PPh3)3 (10)
RhCl(PPh3)3 (10)
RhCl(PPh3)3 (10)
RhCl(PPh3)3 (10)
RhCl(PPh3)3 (10)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CH2Cl2
CH2Cl2
DCE
90
90
90
90
60
60
60
60
reflux
reflux
reflux
reflux
reflux
reflux
3
3
5.5
24
5
6
8
11, 84
12, 39
13, 53
14, 0
11, 93
12, 67
13, 42
14, 0
11, 68
13, 37
14, 0
11, 72
13, 41
14, 0
7
9[a]
10[a]
11[a]
12[a]
13[a]
14[a]
[Rh(cod)2]BF4 / binap (5)
[Rh(cod)2]BF4 / binap (5)
[Rh(cod)2]BF4 / binap (5)
[Rh(cod)2]BF4 / binap (5)
[Rh(cod)2]BF4 / binap (5)
[Rh(cod)2]BF4 / binap (5)
24
24
24
5.5
8.5
7
DCE
DCE
[a] H2 was bubbled into the mixture of the rhodium complex and the ligand for 30 min prior to the addition of the cyanodiyne.
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Microwave-Enhanced Rhodium-Catalyzed [2+2+2] Cycloadditions
but yields were generally improved with the exception of cessfully given derivative 14 under conventional heating,
terminal cyanodiyne 4 (Table 1, Entry 8), which gave the could be cycloisomerized under microwave heating with a
same benzene derivative depicted in Figure 1. Other RhI 73% yield when reacted in a toluene/chlorobenzene (3:1)
catalytic systems were also tested. By changing to a mixture mixture (Table 2, Entry 3). The addition of the higher mi-
of the cationic complex [Rh(cod)2]BF4 and the bidentate crowave absorbing solvent chlorobenzene was selected, as
phosphane binap in CH2Cl2, conditions typically used with the reaction in toluene alone did not reach completion. For
excellent results by Tanaka et al.,[1g,8] our reaction times the cycloaddition of 4 we also tested the [Rh(cod)2]BF4/
were extended to 24 h and the yields of 11 and 13 were binap catalytic system in dichloromethane at 75 °C under
worse than those obtained when using the Wilkinson com- microwave heating for 30 min. Derivative 14 was obtained
plex (Table 1, Entries 9 and 10 vs. Entries 5 and 7). Cyano- in 67% yield (Table 2, Entry 4).[14]
diyne 4 behaved in the same way as before (Table 1, En-
After optimizing the microwave reaction conditions for
try 11). When the reaction temperature was increased to re- the synthesis of tricyclic pyridines 12–14, we investigated
flux in dichloroethane (DCE) with the cationic rhodium the scope of the cyanodiyne substrates. We extended the
catalyst, almost the same results were obtained as those in methodology to malonate-linked 1-cyano-6,11-diyne 18 and
Entries 9–11 (Table 1). Shorter reaction times were required 1-cyano-5,10-diyne 19 and ether-linked cyanodiyne 20[4]
for cyanodiynes 1 and 3 (Table 1, Entries 12 and 13) to ob- (Scheme 3). Compounds 18 and 19 were prepared by alk-
tain similar yields of 11 and 13. Again, pyridine derivative ylation of the corresponding cyanomalonates 16[15] and 17[7]
14 was not obtained under these reaction conditions with bromo derivative 15.[16] The cycloaddition of deriva-
(Table 1, Entry 14).
tives 18–20 furnished good yields of pyridine derivatives 21–
23 when they were treated with Wilkinson’s catalyst
(10 mol-%) in toluene at 90 °C under microwave irradiation.
Figure 1. Benzene derivative obtained in the conventional heating
cycloaddition of 4.
In order to avoid the decomposition products caused by
prolonged heating of the reactants and to attempt to in-
crease the yields of the desired reaction, especially the reac-
tion of cyanodiyne 4, which until then had always failed,
we decided to carry out the cycloaddition under microwave
irradiation. The synthetic utility of microwave irradiation in
organic synthesis has increased considerably in recent years.
Dramatic rate enhancements between reactions performed
at room temperature or heating under reflux and high-tem-
perature microwave-heated processes have frequently been
observed.[13] The results obtained by using microwave irra-
diation are shown in Table 2.
We began to test cyanodiynes 2–4, as 1 had already given
good results under conventional heating conditions. Ini-
tially, toluene was used as the solvent at 90 °C with
RhCl(PPh3)3 (10 mol-%) under microwave irradiation. We
were pleased to find that good yields of pyridine derivatives
12 and 13 were obtained with short reaction times (Table 2,
Scheme 3. [2+2+2] Cycloaddition reactions of cyanodiynes 18, 19,
Entries 1 and 2). Even cyanodiyne 4, which had not suc- and 20.
Table 2. RhI-catalyzed [2+2+2] cycloadditions of cyanodiynes 2–4 with microwave irradiation.[a]
Entry
Cyanodiyne
Solvent
T [°C]
Time [min]
Product, % Yield
1
2
2
3
4
4
toluene
toluene
toluene/chlorobenzene, 3:1
dichloroethane
90
90
90
75
30
10
30
30
12, 75
13, 81
14, 73
14, 67
3
4[b]
[a] Reactions were carried out in the presence of RhCl(PPh3)3 (10 mol-%) unless otherwise noted. [b] [Rh(cod)2]BF4/binap (5 mol-%) was
used as the catalytic system. H2 was bubbled into the mixture of the rhodium complex and the ligand for 30 min prior to the addition
of the cyanodiyne.
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L. Garcia, A. Pla-Quintana, A. Roglans, T. Parella
FULL PAPER
Interestingly the formation of 22 and 23 showed that this whereas in the case of derivative 28 only the starting prod-
protocol allowed us not only to obtain five–six–six-fused uct was recovered. We then decided to change to DMSO,
ring compounds but also five–six–five-fused derivatives. as this is a higher microwave absorbing solvent.[13] Deriva-
The results are shown in Scheme 3.
tive 26 was tested at 90 °C, and the reaction, which was
We then extended the methodology to bipyridines, which complete after 30 min, gave bipyridine 29 in 92% yield
are useful ligands for metal coordination.[17] We tested two (Table 3, Entry 1). Derivative 28 also underwent complete
different ways of constructing such compounds. The first cycloaddition in DMSO at 90 °C after a reaction time of
was to start with a cyanodiyne containing a pyridine ring just 10 min to afford bipyridine 31 in 88% yield (Table 3,
in its structure and perform the [2+2+2] cycloaddition, and Entry 4). Surprisingly, 2-pyridine derivative 27 did not react
the second was to start with a dicyanotetrayne and con- in DMSO at 90 °C nor at 150 °C when the temperature was
struct the two pyridine rings in one step by two simulta- increased (Table 3, Entry 2). Other solvents would be re-
neous [2+2+2] cycloaddition reactions.
quired. In a mixture of DMF/H2O (1:1), derivative 30 was
From cyanoyne intermediate 8, pyridine derivatives 26 obtained in 89% yield (Table 3, Entry 3).
and 27 were prepared by treating 8 with 3-(pyridin-3-yl)-
2-propyn-1-ol (24) and 3-(pyridin-2-yl)-2-propyn-1-ol (25),
respectively (Scheme 4).
Scheme 4. Synthesis of cyanodiynepyridine derivatives 26 and 27.
Propargylic alcohols 24 and 25 were prepared by palla-
dium-catalyzed coupling of propargyl alcohol with the ap-
propriate pyridine halide under Sonogashira conditions.[18]
These alcohols were then converted into the corresponding
bromides by treatment with PBr3. Without isolation, the
halo derivatives were coupled with derivative 8 in the pres-
ence of potassium carbonate as a base. Pyridine derivatives
26 and 27 were obtained in 49 and 46% yield, respectively,
in a two-step procedure.
In order to prepare dicyanotetrayne 28, a palladium-cat-
alyzed acetylenic oxidative homocoupling reaction between
the two sp-carbon terminal alkyne atoms of 4 (Glaser-type
Scheme 6. [2+2+2] Cycloaddition reactions of derivatives 26–28.
process)[19] was run (Scheme 5).
Table 3. RhI-catalyzed [2+2+2] cycloadditions of derivatives 26–28
under microwave irradiation.[a]
Entry Substrate
Solvent
T
[°C]
Time
[min]
Product,
% Yield
1
2
3
4
26
27
27
28
DMSO
DMSO
DMF/H2O (1:1)
DMSO
90
90 or 150
90
30
30
60
10
29, 92
30,
0
30, 89
31, 88
90
[a] Reactions were carried out in the presence of RhCl(PPh3)3
(10 mol-%).
Scheme 5. Synthesis of dicyanotetrayne derivative 28.
Substrates 26–28 were tested for a [2+2+2] cycloaddition
process by using Wilkinson’s catalyst under microwave heat-
ing. The results are shown in Scheme 6 and Table 3. In a
Conclusions
In summary, we have synthesized a series of highly func-
first step, we began by testing the optimized conditions of tionalized fused-tricyclic pyridines and bipyridines by
earlier cases. The use of toluene as a solvent led to decom- [2+2+2] cycloaddition reactions under rhodium(I) catalysis.
position products in the cases of derivatives 26 and 27, We have also demonstrated that microwave irradiation con-
3410
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Microwave-Enhanced Rhodium-Catalyzed [2+2+2] Cycloadditions
[M + K]+. HRMS (ESI+): calcd. for [C10H12N2SO2 + Na]+
247.0512; found 247.0523.
siderably improves the yields and reactions times achieved
with conventional heating and is even effective in cases
where conventional heating fails. This study has shown the
importance of fine-tuning the reaction conditions. This is
especially seen in the case of the solvent, as even when the
N,NЈ-Bis(4-methylphenyl)sulfonyl-N-(tert-butyloxycarbonyl)-NЈ-(2-
cyanoethyl)-2-butyn-1,4-diamine (7): A stirred mixture of 5 (0.81 g,
3.61 mmol), 6 (1.45 g, 3.59 mmol), potassium carbonate (2.00 g,
substrates are very similar, the choice of solvent dramati- 14.45 mmol), and acetonitrile (50 mL) was heated at reflux for 4 h
(TLC monitoring). The salts were filtered off, and the filtrate was
evaporated. The residue was purified by column chromatography
on silica gel (hexanes/ethyl acetate, 9:1 to 7:3) to afford 7 (1.73 g,
cally affects the outcome of the reaction.
88%) as a colorless oil. IR (ATR): ν = 2982, 1729, 1349, 1154 cm–1.
˜
Experimental Section
1H NMR (200 MHz, CDCl3, 25 °C): δ = 1.32 (s, 9 H, Boc), 2.43
3
General: Unless otherwise noted, materials were obtained from
commercial suppliers and used without further purification. N-(4-
Bromo-2-butynyl)-N-(tert-butyloxycarbonyl)(4-methylphenyl)sulf-
onamide (6) was prepared as described previously by our group.[10]
5,5-Bis(carbethoxy)-1-bromonona-2,7-diyne (15),[16] cyanomalon-
ates 16[15] and 17,[7] and 1-cyano-2,7-dioxaundeca-4,9-diyne (20)[4]
were prepared following the method described previously in the
literature. Spectroscopic data for pyridine derivative 23 are as de-
scribed in the literature for this compound.[4] Propargylic alcohols
24 and 25 were prepared with a modification of the reported
method[18] by using PdCl2(PPh3)2 as the palladium source. All reac-
tions requiring anhydrous conditions were conducted in oven-dried
glassware under a dry nitrogen atmosphere. Dichloromethane and
THF were degassed and dried under a nitrogen atmosphere by
passing through solvent purification columns (MBraun, SPS-800).
Toluene was distilled under a nitrogen atmosphere over sodium as
the drying agent. Solvents were removed under reduced pressure
with a rotary evaporator. When necessary, reaction mixtures were
chromatographed on a silica gel column (230–400 mesh) by using
(s, 3 H, CH3-Ar), 2.45 (s, 3 H, CH3-Ar), 2.71 (t, JH,H = 7.1 Hz, 2
3
H, CH2-CH2-CN), 3.45 (t, JH,H = 7.1 Hz, 2 H, CH2-CH2-CN),
3
4.21 (s, 2 H, N-CH2-C), 4.46 (s, 2 H, N-CH2-C), 7.33 (d, JH,H
=
3
3
8.4 Hz, 2 H, Ar), 7.34 (d, JH,H = 8.4 Hz, 2 H, Ar), 7.74 (d, JH,H
= 8.4 Hz, 2 H, Ar), 7.80 (d, JH,H = 8.4 Hz, 2 H, Ar) ppm. 13C
3
NMR (50 MHz, CDCl3, 25 °C): δ = 18.9, 22.2, 22.3, 28.4, 36.2,
39.1, 43.9, 77.1, 82.4, 85.8, 118.0, 128.2, 128.6, 130.0, 130.6, 135.6,
137.3, 145.0, 145.3, 150.8 ppm. HRMS (ESI+): calcd. for
[C26H31N3S2O6 + Na]+ 568.1546; found 568.1540.
N,NЈ-Bis(4-methylphenyl)sulfonyl-NЈ-(2-cyanoethyl)-2-butyn-1,4-di-
amine (8): A mixture of 7 (2.40 g, 4.39 mmol), trimethylsilyl triflate
(2.40 mL, 13.26 mmol), 2,6-lutidine (2.10 mL, 18.03 mmol), and
dichloromethane (50 mL) was stirred in a sealed tube at room tem-
perature for 7 h (TLC monitoring). The reaction mixture was sub-
sequently washed with saturated aqueous ammonium chloride
solution (2ϫ10 mL) and water (3ϫ10 mL). The organic phase was
dried (Na2SO4) and concentrated in vacuo to give an oil that was
dissolved in MeOH (20 mL) and evaporated under reduced pres-
sure. The residue was purified by column chromatography on silica
gel (dichloromethane/ethyl acetate, 9:1) to afford 8 (1.58 g, 81%)
1
a gradient solvent system as the eluent. H and 13C NMR spectra
were recorded with 600, 400, 250, and 200 MHz NMR spectrome-
ters. Chemical shifts (δ) for 1H and 13C NMR are referenced to
internal solvent resonances and reported relative to SiMe4. Electro-
spray mass spectrometry analyses were recorded with an Esquire
6000 Ion Trap Mass Spectrometer (Bruker) equipped with an elec-
trospray ion source. The instrument was operated in the positive
ESI(+) ion mode. Microwave heated reactions were performed in
septum-containing, screw-capped sealed vials in an Ethos SEL Lab
station (Milestone Inc.), a multimode microwave with a dual mag-
netron (1600 W). During the experiments, the time, temperature,
and the power were measured with an “EasyControl” software
package. The temperature was monitored and controlled through-
out the reaction by an ATC-400FO Automatic Fiber Optic Tem-
perature Control system. The wattage was automatically adjusted
to maintain the desired temperature for the desired period of time.
as a colorless solid. M.p. 83–85 °C. IR (KBr): ν = 3348, 2971, 2253,
˜
1
1364, 1162 cm–1. H NMR (200 MHz, CDCl3, 25 °C): δ = 2.44 (s,
3
6 H, CH3-Ar), 2.66 (t, JH,H = 6.8 Hz, 2 H, CH2-CH2-CN), 3.30
3
3
(t, JH,H = 6.8 Hz, 2 H, CH2-CH2CN), 3.61 (dt, JH,H = 6.0 Hz,
5JH,H = 2.0 Hz, 2 H, HN-CH2-C), 3.95 (t, 5JH,H = 2.0 Hz, 2 H, N-
CH2-C), 4.81 (t, 3JH,H = 6.0 Hz, 1 H, NH), 7.32 (d, 3JH,H = 8.2 Hz,
2 H, Ar), 7.33 (d, 3JH,H = 8.2 Hz, 2 H, Ar), 7.66 (AAЈ part, AAЈBBЈ
3
system, JH,H = 8.4 Hz, 2 H, Ar), 7.72 (BBЈ part, AAЈBBЈ system,
3JH,H = 8.4 Hz, 2 H, Ar) ppm. 13C NMR (50 MHz, CDCl3, 25 °C):
δ = 19.3, 22.2, 33.5, 39.2, 43.9, 78.1, 81.3, 118.3, 128.0, 128.4, 130.4,
130.5, 135.5, 137.2, 144.7, 145.3 ppm. MS (ESI+): m/z = 446 [M +
H]+, 468 [M + Na]+, 484 [M + K]+. HRMS (ESI+): calcd. for
[C21H23N3S2O4 + Na]+ 468.1022; found 468.1014.
1-(tert-Butyloxycarbonyl)-11-(2-cyanoethyl)-1,6,11-tris[(4-methyl-
phenyl)sulfonyl]-1,6,11-triazaundeca-3,8-diyne (1): A stirred mixture
of 8 (0.16 g, 0.36 mmol), 6 (0.12 g, 0.31 mmol), potassium carbon-
ate (0.19 g, 1.37 mmol), and acetonitrile (15 mL) was heated at re-
flux for 8 h (TLC monitoring). The salts were filtered off, and the
filtrate was evaporated. The residue was purified by column
chromatography on silica gel (dichloromethane/ethyl acetate/hex-
anes, 1:1:9 to 1:2:8) to afford 1 (0.22 g, 94%) as a colorless solid.
N-(2-Cyanoethyl)-(4-methylphenyl)sulfonamide (5): A mixture of (4-
methylphenyl)sulfonamide (2.07 g, 12.11 mmol), acrylonitrile
(1.6 mL, 24.30 mmol), cesium carbonate (7.89 g, 24.21 mmol), and
toluene (80 mL) was heated at 110 °C and stirred in a sealed tube
for 5.5 h (TLC monitoring). The liquid was distilled off under vac-
uum, and the residue was dissolved in dichloromethane (10 mL).
The organic layer was subsequently washed with water (3ϫ10 mL),
dried (Na2SO4), and filtered. The solvent was removed under re-
duced pressure to afford 5 (2.22 g, 82%) as a colorless solid. M.p.
M.p. 61–63 °C. IR (ATR): ν = 2980, 1729, 1347, 1154 cm–1. 1H
˜
NMR (200 MHz, CDCl3, 25 °C): δ = 1.32 (s, 9 H, Boc), 2.44 (s, 3
80–81 °C (ref.[9] 83–83.5 °C). IR (ATR): ν = 3257, 2250, 1303, H, CH3-Ar), 2.45 (s, 6 H, CH3-Ar), 2.66 (t, JH,H = 6.8 Hz, 2 H,
3
˜
1
3
1155 cm–1. H NMR (200 MHz, CDCl3, 25 °C): δ = 2.43 (s, 3 H,
CH2-CH2-CN), 3.37 (t, JH,H = 6.8 Hz, 2 H, CH2-CH2-CN), 3.93
3
5
5
CH3-Ts), 2.59 (t, JH,H = 6.6 Hz, 2 H, CH2-CH2-CN), 3.22 (q, (t, JH,H = 1.8 Hz, 2 H, N-CH2-C), 3.95 (t, JH,H = 1.8 Hz, 2 H,
3JH,H = 6.6 Hz, 2 H, CH2-CH2-CN), 5.60 (t, JH,H = 6.6 Hz, 1 H,
N-CH2-C), 4.05 (t, JH,H = 1.8 Hz, 2 H, N-CH2-C), 4.46 (t, JH,H
= 1.8 Hz, 2 H, N-CH2-C), 7.28–7.37 (m, 6 H, Ar), 7.66 (BBЈ part,
AAЈBBЈ system, 3JH,H = 8.4 Hz, 2 H, Ar), 7.67 (BBЈ part, AAЈBBЈ
3
5
5
3
NH), 7.33 (AAЈ part, AAЈBBЈ system, JH,H = 8.3 Hz, 2 H, Ar),
7.76 (BBЈ part, AAЈBBЈ system, 3JH,H = 8.3 Hz, 2 H, Ar) ppm. 13
C
3
NMR (50 MHz, CDCl3, 25 °C): δ = 19.8, 22.1, 39.5, 118.3, 127.6,
system, JH,H = 8.4 Hz, 2 H, Ar), 7.81 (BBЈ part, AAЈBBЈ system,
130.5, 137.0, 144.6 ppm. MS (ESI+): m/z = 247 [M + Na]+, 263
3JH,H = 8.4 Hz, 2 H, Ar) ppm. 13C NMR (50 MHz, CDCl3, 25 °C):
Eur. J. Org. Chem. 2010, 3407–3415
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3411

L. Garcia, A. Pla-Quintana, A. Roglans, T. Parella
FULL PAPER
δ = 19.0, 22.2, 22.3, 28.5, 36.3, 36.9, 37.2, 38.8, 43.6, 76.9, 78.9,
79.6, 82.1, 85.8, 118.1, 128.2, 128.4, 128.6, 130.0, 130.4, 130.6,
135.7, 135.8, 137.3, 144.9, 145.1, 145.3, 150.8 ppm. MS (ESI+): m/z
= 2.1 Hz, 1 H, H-Calkyne), 2.43 (s, 3 H, CH3-Ar), 2.45 (s, 3 H, CH3-
3
3
Ar), 2.67 (t, JH,H = 6.9 Hz, 2 H, CH2-CH2-CN), 3.36 (t, JH,H
=
6.9 Hz, 2 H, CH2-CH2-CN), 3.95 (d, 4JH,H = 2.1 Hz, 2 H, N-CH2-
= 789 [M + Na]+. HRMS (ESI+): calcd. for [C37H42N4S3O8
+
CalkyneH), 3.98 (s, 2 H, N-CH2-C), 4.08 (s, 2 H, N-CH2-C), 7.30
Na]+ 789.2057; found 789.2018. C37H42N4O8S3 (766.95): calcd. C (AAЈ part, AAЈBBЈ system, JH,H = 7.8 Hz, 2 H, Ar), 7.34 (AAЈ
3
3
57.94, H 5.52, N 7.31, S 12.54; found C 57.62, H 6.00, N 6.91, S
12.49.
part, AAЈBBЈ system, JH,H = 7.8 Hz, 2 H, Ar), 7.65 (BBЈ part,
AAЈBBЈ system, 3JH,H = 7.8 Hz, 2 H, Ar), 7.68 (BBЈ part, AAЈBBЈ
system, 3JH,H = 7.8 Hz, 2 H, Ar) ppm. 13C NMR (50 MHz, CDCl3,
25 °C): δ = 19.0, 22.1, 22.2, 36.8, 36.9, 38.8, 43.6, 74.8, 76.6, 78.8,
79.6, 118.0, 128.2, 128.4, 130.3, 130.5, 135.6, 135.7, 144.8,
145.1 ppm. MS (ESI+): m/z = 506 [M + Na]+. HRMS (ESI+):
calcd. for [C24H25N3O4S2 + Na]+ 506.1179; found 506.1166.
1-(2-Cyanoethyl)-1,6,11-tris[(4-methylphenyl)sulfonyl]-1,6,11-triaza-
undeca-3,8-diyne (2): A mixture of 1 (0.10 g, 0.13 mmol), trimethyl-
silyl triflate (0.21 mL, 1.16 mmol), 2,6-lutidine (0.18 mL,
1.54 mmol), and dichloromethane (2 mL) was stirred in a sealed
tube at room temperature for 48 h (TLC monitoring). The crude
was subsequently washed with saturated aqueous ammonium chlo-
ride solution (1ϫ10 mL) and water (1ϫ10 mL). The organic layer
was dried (Na2SO4) and concentrated in vacuo to give an oil that
was dissolved in MeOH (1 mL) and evaporated under reduced
pressure. The residue was purified by column chromatography on
silica gel (dichloromethane/ethyl acetate/hexanes, 10:1:6 to 10:1:4)
to afford 2 (0.08 g, 91%) as a colorless solid. M.p. 50–53 °C. IR
1-Cyano-3,3,8,8-tetra(carbethoxy)dodeca-5,10-diyne (18): Diethyl 2-
cyanoethylmalonate (16) (0.096 g, 0.45 mmol) in anhydrous THF
(2 mL) was added to a suspension of NaH (60% dispersion in min-
eral oil, 0.021 g, 0.52 mmol) in anhydrous THF (2 mL) at 0 °C un-
der an atmosphere of N2. A solution of 15 (0.17 g, 0.49 mmol) in
anhydrous THF (2 mL) was then added to the first solution, and
the resulting mixture was stirred at room temperature for 16 h
(TLC monitoring). Water was added to quench the reaction, and
the reaction mixture was extracted with EtOAc. The organic solu-
(ATR): ν = 3286, 2923, 1328, 1154 cm–1
.
1H NMR (200 MHz,
˜
3
CDCl3, 25 °C): δ = 2.44 (s, 9 H, CH3-Ar), 2.67 (t, JH,H = 6.8 Hz,
3
2 H, CH2-CH2-CN), 3.36 (t, JH,H = 6.8 Hz, 2 H, CH2-CH2-CN), tion was washed with water (2ϫ10 mL), dried (Na2SO4), filtered,
3.55–3.63 (m, 2 H, HN-CH2-C), 3.78–3.87 (m, 4 H, N-CH2-C), and concentrated. The residue was purified by column chromatog-
3
4.03 (br. s, 2 H, N-CH2-C), 4.80 (t, JH,H = 6.0 Hz, 1 H, NH), raphy on silica gel (hexanes/ethyl acetate, 20:1 to 10:1) to afford 18
3
7.27–7.37 (m, 6 H, Ar), 7.61 (BBЈ part, AAЈBBЈ system, JH,H
=
(0.170 g, 79%) as a pale-yellow oil. IR (ATR): ν = 2921, 1727,
˜
3
1
3
8.2 Hz, 2 H, Ar), 7.68 (BBЈ part, AAЈBBЈ system, JH,H = 8.4 Hz,
2 H, Ar), 7.70 (BBЈ part, AAЈBBЈ system, 3JH,H = 8.2 Hz, 2 H, Ar)
ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ = 18.9, 22.2, 33.4, 37.0,
37.1, 38.9, 43.8, 77.5, 79.1, 79.6, 81.1, 118.2, 127.8, 128.2, 128.5,
130.3, 130.4, 130.6, 135.5, 135.7, 137.1, 144.6, 145.0, 145.2 ppm.
MS (ESI+): m/z = 689 [M + Na]+. HRMS (ESI+): calcd. for
[C32H34N4S3O6 + Na]+ 689.1533; found 689.1566.
1187 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 1.24 (t, JH,H
= 7.2 Hz, 6 H, CH3-CH2-OCO), 1.27 (t, 3JH,H = 7.2 Hz, 6 H, CH3-
CH2-OCO), 1.74 (t, JH,H = 2.4 Hz, 3 H, CH3-Calkyne), 2.32–2.40
5
(m, 2 H, CH2-CH2-CN), 2.41–2.48 (m, 2 H, CH2-CH2-CN), 2.78
5
5
(t, JH,H = 2.2 Hz, 2 H, C-CH2-C), 2.84 (q, JH,H = 2.4 Hz, 2 H,
C-CH2-CalkyneCH3), 2.90 (t, 5JH,H = 2.2 Hz, 2 H, C-CH2-C), 4.18–
4.30 (m, 8 H, CH3-CH2-OCO) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 3.4, 12.8, 13.8, 13.9, 22.7, 22.8, 23.6, 28.4, 55.7, 56.5,
61.7, 62.1, 72.9, 78.7, 78.9, 118.8, 168.9, 169.1 ppm. HRMS (ESI+):
calcd. for [C25H33NO8 + Na]+ 498.2098; found 498.2121.
1-(2-Cyanoethyl)-1,6-bis[(4-methylphenyl)sulfonyl]-1,6-diazadeca-
3,8-diyne (3): A stirred mixture of 8 (0.28 g, 0.63 mmol), 9
(0.06 mL, 0.36 mmol), potassium carbonate (0.44 g, 3.16 mmol),
and acetonitrile (20 mL) was heated at reflux for 6 h (TLC moni-
toring). The salts were filtered off, and the filtrate was evaporated.
The residue was purified by column chromatography on silica gel
(dichloromethane/ethyl acetate/hexanes, 1:1.5:8.5 to 1:3:7) to afford
1-Cyano-2,2,7,7-tetra(carbethoxy)undeca-4,9-diyne (19): Diethyl cy-
anomethylmalonate (17) (0.090 g, 0.45 mmol) in anhydrous THF
(2 mL) was added to a suspension of NaH (60% dispersion in min-
eral oil, 0.021 g, 0.52 mmol) in anhydrous THF (2 mL) at 0 °C un-
der an atmosphere of N2. A solution of 15 (0.170 g, 0.49 mmol) in
3 (0.26 g, 82%) as a colorless solid. M.p. 114–115 °C. IR (KBr): ν =
˜
2927, 2254, 1345, 1163 cm–1. 1H NMR (200 MHz, CDCl3, 25 °C): δ anhydrous THF (2 mL) was then added to the reaction, and the
= 1.62 (s, 3 H, CH3-Calkyne), 2.42 (s, 3 H, CH3-Ar), 2.45 (s, 3 H,
resulting mixture was stirred at room temperature for 16 h (TLC
monitoring). Water was added to quench the reaction, and the reac-
3
CH3-Ar), 2.68 (t, JH,H = 7.0 Hz, 2 H, CH2-CH2-CN), 3.37 (t,
3JH,H = 7.0 Hz, 2 H, CH2-CH2-CN), 3.85 (br. s, 2 H, N-CH2-C), tion mixture was extracted with EtOAc. The organic solution was
3.92 (br. s, 2 H, N-CH2-C), 4.08 (br. s, 2 H, N-CH2-C), 7.32 (AAЈ
washed with water (2ϫ10 mL), dried (Na2SO4), filtered, and con-
centrated. The residue was purified by column chromatography on
silica gel (hexanes/ethyl acetate, 20:1 to 10:1) to afford 19 (0.169 g,
3
part, AAЈBBЈ system, JH,H = 8.1 Hz, 4 H, Ar), 7.67 (BBЈ part,
3
AAЈBBЈ system, JH,H = 8.1 Hz, 4 H, Ar) ppm. 13C NMR
(50 MHz, CDCl3, 25 °C): δ = 3.9, 18.9, 22.1, 22.2, 36.8, 37.4, 38.8,
43.6, 71.7, 78.5, 80.0, 82.8, 118.0, 128.2, 128.5, 130.1, 130.5, 135.6,
135.9, 144.5, 145.1 ppm. MS (ESI+): m/z = 520 [M + Na]+. HRMS
(ESI+): calcd. for [C25H27N3O4S2 + Na]+ 520.1335; found
520.1330. C25H27N3O4S2 (497.63): calcd. C 60.34, H 5.47, N 8.44, 2 H, C-CH2CalkyneCH3), 2.91 (t, JH,H = 2.2 Hz, 2 H, C-CH2-C),
S 12.89; found C 59.98, H 5.40, N 8.16, S 12.69.
81%) as a pale-yellow oil. IR (ATR): ν = 2982, 1732, 1192 cm–1.
˜
3
1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.25 (t, JH,H = 7.2 Hz, 6
H, CH3-CH2-OCO), 1.29 (t, 3JH,H = 7.2 Hz, 6 H, CH3-CH2-OCO),
1.74 (t, 5JH,H = 2.4 Hz, 3 H, CH3-Calkyne), 2.83 (q, JH,H = 2.4 Hz,
5
5
5
2.96 (t, JH,H = 2.2 Hz, 2 H, C-CH2-C), 3.12 (s, 2 H, CH2-CN),
3
3
4.21 (q, JH,H = 7.2 Hz, 4 H, CH3-CH2-OCO), 4.26 (q, JH,H
=
1-(2-Cyanoethyl)-1,6-bis[(4-methylphenyl)sulfonyl]-1,6-diazanona-
3,8-diyne (4): A stirred mixture of 8 (0.45 g, 1.02 mmol), 10
(0.12 mL, 1.08 mmol), potassium carbonate (0.70 g, 5.05 mmol),
and acetonitrile (40 mL) was heated at reflux for 1 h (TLC moni-
toring). The salts were filtered off, and the filtrate was evaporated.
The residue was purified by column chromatography on silica gel
(hexanes/ethyl acetate, 7:3 to 6:4) to afford 4 (0.48 g, 98%) as a
7.2 Hz, 4 H, CH3-CH2-OCO) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 3.4, 13.8, 13.9, 21.5, 22.7, 22.8, 23.6, 54.9, 56.5, 61.8,
62.7, 72.9, 76.1, 78.9, 79.4, 116.1, 167.3, 168.9 ppm. HRMS (ESI+):
calcd. for [C24H31NO8 + Na]+ 484.1972; found 484.1960.
1-(2-Cyanoethyl)-9-(3-pyridyl)-1,6-bis[(4-methylphenyl)sulfonyl]-1,6-
diazanona-3,8-diyne (26): PBr3 (1  in dichloromethane, 0.43 mL,
0.43 mmol) was added to a cold (–10 °C) stirred solution of 3-(pyr-
idin-3-yl)-2-propyn-1-ol (24) (0.05 g, 0.39 mmol) in anhydrous
colorless solid. M.p. 146–147 °C. IR (ATR): ν = 3277, 2925, 1346,
˜
1
4
1156 cm–1. H NMR (600 MHz, CDCl3, 25 °C): δ = 2.11 (t, JH,H
3412
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3407–3415

Microwave-Enhanced Rhodium-Catalyzed [2+2+2] Cycloadditions
dichloromethane (5 mL) under a N2 atmosphere. The reaction mix-
ture was stirred at –10 to 0 °C for 1.5 h and warmed to room tem-
perature over 2 h until completion (TLC monitoring). The dichlo-
romethane solution was washed with water (3ϫ10 mL), and the
organic layer was dried (Na2SO4) and added directly over a solu-
tion of 8 (0.19 g, 0.44 mmol), K2CO3 (0.28 g, 2.00 mmol), and ace-
tonitrile (20 mL). The reaction mixture was heated at reflux for 7 h
until completion (TLC monitoring). The salts were filtered off, and
the filtrate was evaporated. The residue was purified by column
chromatography on silica gel (dichloromethane/ethyl acetate, 20:1
HRMS (ESI+): calcd. for [C48H48N6S4O8 + Na]+ 987.2309; found
987.2270.
General Method for [2+2+2] Cycloaddition Reactions of 1–4 using
Conventional Heating:
(0.08 mmol) and
A
degassed solution of cyanodiyne
chlorotris(triphenylphosphane)rhodium(I)
(0.008 mmol, 10 mol-%) in anhydrous toluene (5 mL) was heated
(temperature and reaction time specified in Table 1) until comple-
tion (TLC monitoring). The solvent was then evaporated, and the
residue was purified by column chromatography on silica gel.
to 9:1) to afford 26 (0.11 g, 49%) as a pale-yellow oil. IR (ATR):
General Method for [2+2+2] Cycloaddition Reactions of 2–4, 18–20,
and 26–28 using Microwave Heating: In a sealed 20-mL, septum-
containing, screw-capped vial a degassed solution of chlorotris(tri-
phenylphosphane)rhodium(I) (0.008 mmol, 10 mol-%) and cyano-
diyne (0.08 mmol) in the stated solvent (5 mL) (Table 2, Scheme 3,
and Table 3) was heated for the time indicated (Table 2, Scheme 3,
and Table 3) at 90 °C under microwave irradiation (TLC monitor-
ing). Upon completion, the solvent was evaporated and the residue
was purified.
1
ν = 2923, 1347, 1157 cm–1. H NMR (400 MHz, CDCl , 25 °C): δ
˜
3
3
= 2.37 (s, 3 H, CH3-Ar), 2.44 (s, 3 H, CH3-Ar), 2.68 (t, JH,H
=
3
6.8 Hz, 2 H, CH2-CH2-CN), 3.39 (t, JH,H = 6.8 Hz, 2 H, CH2-
CH2-CN), 4.00 (br. s, 2 H, N-CH2-C), 4.13 (br. s, 2 H, N-CH2-C),
4.20 (s, 2 H, N-CH2-C), 7.19–7.25 (m, 1 H, pyr-H), 7.28 (AAЈ part,
AAЈBBЈ system, 3JH,H = 8.0 Hz, 2 H, Ar), 7.34 (AAЈ part, AAЈBBЈ
system, 3JH,H = 8.0 Hz, 2 H, Ar), 7.46 (dt, 3JH,H = 7.6 Hz, 4JH,H
=
1.6 Hz, 1 H, pyr-H), 7.67–7.72 (m, 4 H, Ar), 8.32 (br. abs, 1 H,
pyr-H), 8.53 (br. abs, 1 H, pyr-H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 18.4, 21.4, 21.6, 36.6, 37.0, 38.3, 43.0, 78.3,
79.0, 82.6, 84.6, 117.3, 119.3, 123.0, 127.6, 127.8, 129.7, 129.9,
134.9, 135.0, 138.5, 144.3, 144.5, 148.9, 152.1 ppm. MS (ESI+): m/z
= 561 [M + H]+. HRMS (ESI+): calcd. for [C29H28N4S2O4 + H]+
561.1626; found 561.1618.
Pyridine Derivative 11: Column chromatography: dichloromethane/
ethyl acetate/hexanes (10:1:10 to 10:1:7); colorless solid; m.p. 175–
177 °C (decomp.). IR (ATR): ν = 2982, 1728, 1361, 1341,
˜
1
1160 cm–1. H NMR (200 MHz, CDCl3, 25 °C): δ = 1.27 (s, 9 H,
Boc), 2.40 (s, 3 H, CH3-Ar), 2.42 (s, 3 H, CH3-Ar), 2.44 (s, 3 H,
3
CH3-Ar), 2.88 (t, JH,H = 5.7 Hz, 2 H, N-CH2-CH2-pyr), 3.36 (t,
3JH,H = 5.7 Hz, 2 H, N-CH2-CH2-pyr), 4.02 (br. s, 2 H, CH2-N),
4.45 (br. s, 2 H, CH2-N), 4.66 (br. s, 2 H, CH2-N), 4.95 (s, 2 H,
CH2-N), 7.22 (d, 3JH,H = 8.2 Hz, 2 H, Ar), 7.34 (d, 3JH,H = 8.2 Hz,
2 H, Ar), 7.36 (d, 3JH,H = 8.2 Hz, 2 H, Ar), 7.72 (d, 3JH,H = 8.2 Hz,
2 H, Ar), 7.78 (d, 3JH,H = 8.2 Hz, 2 H, Ar), 7.82 (d, 3JH,H = 8.2 Hz,
2 H, Ar) ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ = 22.1, 22.2,
22.3, 28.5, 32.4, 44.3, 45.3, 49.2, 52.1, 52.4, 85.3, 121.5, 128.2,
128.3, 128.4, 129.3, 129.5, 130.7, 130.8, 133.4, 134.0, 137.6, 144.1,
144.8, 144.9, 149.6, 151.6, 152.8 ppm. MS (ESI+): m/z = 767 [M +
H]+. HRMS (ESI+): calcd. for [C37H42N4S3O8 + H]+ 767.2238;
found 767.2232. C37H42N4O8S3·H2O: calcd. C 56.61, H 5.65, N
7.14, S 12.25; found C 56.85, H 5.78, N 6.93, S 11.78.
1-(2-Cyanoethyl)-9-(2-pyridyl)-1,6-bis[(4-methylphenyl)sulfonyl]-1,6-
diazanona-3,8-diyne (27): Prepared by following the general method
described above. Column chromatography: dichloromethane/ethyl
acetate (10:1); pale-yellow oil. IR (ATR): ν = 2922, 1346,
˜
1
1157 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 2.35 (s, 3 H,
CH3-Ar), 2.43 (s, 3 H, CH3-Ar), 2.68 (t, 3JH,H = 6.8 Hz, 2 H, CH2-
CH2-CN), 3.39 (t, JH,H = 6.8 Hz, 2 H, CH2-CH2-CN), 4.00 (br. s,
3
2 H, N-CH2-C), 4.10 (br. s, 2 H, N-CH2-C), 4.16 (s, 2 H, N-CH2-
C), 7.10–7.15 (m, 1 H, pyr-H), 7.22–7.26 (m, 1 H, pyr-H), 7.27
3
(part AAЈ, AAЈBBЈ system, JH,H = 8.0 Hz, 2 H, Ar), 7.34 (part
3
3
AAЈ, AAЈBBЈ system, JH,H = 8.0 Hz, 2 H, Ar), 7.62 (dt, JH,H
=
4
7.6 and JH,H = 1.6 Hz, 1 H, pyr-H), 7.65–7.73 (m, 4 H, Ar), 8.54
(br. abs, 1 H, pyr-H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ
= 18.4, 21.4, 21.5, 36.7, 37.0, 38.2, 43.0, 78.4, 79.0, 81.3, 85.2,
117.4, 123.3, 127.1, 127.6, 127.8, 129.6, 129.9, 134.9, 135.0, 136.1,
142.1, 144.1, 144.5, 150.0 ppm. MS (ESI+): m/z = 561 [M + H]+.
HRMS (ESI+): calcd. for [C29H28N4S2O4 + Na]+ 583.1444; found
583.1454.
Pyridine Derivative 12: Column chromatography: dichloromethane/
ethyl acetate (20:1); colorless solid; m.p. 228–230 °C (decomp.). IR
(ATR): ν = 2924, 1332, 1158 cm–1. 1H NMR (200 MHz, CDCl3,
˜
25 °C): δ = 2.35 (s, 3 H, CH3-Ar), 2.43 (s, 3 H, CH3-Ar), 2.44 (s, 3
3
H, CH3-Ar), 2.95 (t, JH,H = 5.7 Hz, 2 H, N-CH2-CH2-pyr), 3.36
(t, 3JH,H = 5.7 Hz, 2 H, N-CH2-CH2-pyr), 3.97–4.04 (m, 4 H, CH2-
N), 4.40 (br. s, 2 H, CH2-N), 4.47 (br. s, 2 H, CH2-N), 5.81 (t,
1,18-Bis(2-cyanoethyl)-1,6,13,18-tetrakis[(4-methylphenyl)sulfonyl]-
1,6,13,18-tetraazaoctadeca-3,8,10,15-tetrayne (28): A mixture of 4
(0.108 g, 0.22 mmol), PdCl2 (0.0004 g, 0.0022 mmol), CuI
(0.0022 g, 0.011 mmol), triethylamine (0.28 mL, 2.01 mmol), and
anhydrous THF (5 mL) was stirred at room temperature for 2 h
(TLC monitoring). The salts were filtered off, and the filtrate was
evaporated. The residue was purified by column chromatography
on silica gel (hexanes/ethyl acetate, 1:1) to afford 28 (0.402 g, 37%)
3
3JH,H = 5.2 Hz, 1 H, NH), 7.17 (d, JH,H = 8.2 Hz, 2 H, Ar), 7.34–
3
3
7.38 (m, 4 H, Ar), 7.64 (d, JH,H = 8.2 Hz, 2 H, Ar), 7.71 (d, JH,H
= 8.2 Hz, 2 H, Ar), 7.77 (d, JH,H = 8.2 Hz, 2 H, Ar) ppm. 13C
3
NMR (50 MHz, CDCl3, 25 °C): δ = 22.1, 22.2, 32.4, 44.2, 45.2,
45.6, 51.8, 52.5, 122.1, 127.8, 128.3, 128.4, 128.7, 130.2, 130.7,
130.9, 133.3, 133.9, 137.0, 144.3, 145.0, 145.1, 147.8, 152.9 ppm.
MS (ESI+): m/z = 667 [M + H]+. HRMS (ESI+): calcd. for
[C32H34N4S3O6+ H]+ 667.1713; found 667.1685.
as a colorless solid. M.p. 172–173 °C (decomp.). IR (ATR): ν =
˜
1353, 1334, 1159 cm–1. H NMR (400 MHz, [D6]DMSO, 25 °C): δ Pyridine Derivative 13: Column chromatography: dichloromethane/
1
3
= 2.38 (s, 6 H, CH3-Ar), 2.40 (s, 6 H, CH3-Ar), 2.76 (t, JH,H
=
ethyl acetate/hexanes (9:1:4); colorless solid; m.p. 217–218 °C. IR
6.4 Hz, 4 H, CH2-CH2-CN), 3.23 (t, JH,H = 6.4 Hz, 4 H, CH2- (ATR): ν = 2918, 1339, 1154 cm–1. 1H NMR (200 MHz, CDCl3,
3
˜
CH2-CN), 3.81 (br. s, 4 H, N-CH2-C), 3.98 (br. s, 4 H, N-CH2-C), 25 °C): δ = 2.35 (s, 3 H, CH3-pyr), 2.43 (s, 3 H, CH3-Ar), 2.44 (s,
4.10 (br. s, 4 H, N-CH2-C), 7.36–7.43 (m, 8 H, Ar), 7.63 (BBЈ part, 3 H, CH3-Ar), 3.02 (t, 3JH,H = 5.8 Hz, 2 H, N-CH2-CH2-pyr), 3.40
3
AAЈBBЈ system, 3JH,H = 8.0 Hz, 4 H, Ar), 7.68 (BBЈ part, AAЈBBЈ
(t, JH,H = 5.8 Hz, 2 H, N-CH2-CH2-pyr), 4.02 (s, 2 H, CH2-N),
system, JH,H = 8.0 Hz, 4 H, Ar) ppm. 13C NMR (100 MHz, [D6]- 4.47 (s, 2 H, CH2-N), 4.54 (s, 2 H, CH2-N), 7.36 (d, 3JH,H = 7.8 Hz,
DMSO, 25 °C): δ = 17.0, 21.0, 36.7, 36.8, 36.9, 42.6, 68.4, 72.6, 4 H, Ar), 7.72 (d, 3JH,H = 7.8 Hz, 2 H, Ar), 7.78 (d, 3JH,H = 7.8 Hz,
78.1, 78.8, 118.5, 127.4, 127.5, 129.8, 134.4, 134.9, 143.9, 2 H, Ar) ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ = 22.2, 22.4,
3
144.2 ppm. MS (ESI+): m/z = 965 [M + H]+, 987 [M + Na]+.
32.5, 44.4, 45.2, 52.8, 120.3, 128.2, 128.4, 129.4, 130.6, 130.7, 133.5,
Eur. J. Org. Chem. 2010, 3407–3415
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3413

L. Garcia, A. Pla-Quintana, A. Roglans, T. Parella
FULL PAPER
134.2, 143.2, 144.8, 151.6, 152.8 ppm. HRMS (ESI+): calcd. for
[C25H27N3S2O4 + H]+ 498.1516; found 498.1518.
3
7.79–7.88 (m, 1 H, pyr-H), 8.36 (d, JH,H = 7.8 Hz, 1 H, pyr-H),
8.66 (d, JH,H = 4.8 Hz, 1 H, pyr-H) ppm. 13C NMR (75 MHz,
CD2Cl2, 25 °C): δ = 21.5, 21.6, 32.3, 44.2, 45.2, 51.7, 55.3, 122.2,
123.9, 125.3, 127.8, 128.0, 130.3, 132.9, 133.8, 135.5, 137.1, 144.4,
144.7, 145.3, 149.1, 152.3 ppm. HRMS (ESI+): calcd. for
[C29H28N4S2O4 + H]+ 561.1625; found 561.1614.
Pyridine Derivative 14: Column chromatography: dichloromethane/
hexanes (8:2); colorless solid; m.p. 216–217 °C (decomp.). IR
(ATR): ν = 2920, 1334, 1157 cm–1. 1H NMR (400 MHz, CDCl3,
˜
25 °C): δ = 2.42 (s, 3 H, CH3-Ar), 2.44 (s, 3 H, CH3-Ar), 3.06 (t,
3JH,H = 5.8 Hz, 2 H, N-CH2-CH2-pyr), 3.41 (t, JH,H = 5.8 Hz, 2
3
Bipyridine Derivative 31: Filtered off and washed with diethyl ether;
H, N-CH2-CH2-pyr), 4.06 (s, 2 H, CH2-N), 4.47 (s, 2 H, CH2-N),
colorless solid; m.p. 293–294 °C (decomp.). IR (ATR): ν = 1346,
˜
3
1160 cm–1. H NMR (400 MHz, [D5]pyridine, 25 °C): δ = 2.10 (s,
1
4.61 (s, 2 H, CH2-N), 7.35 (d, JH,H = 8.4 Hz, 2 H, Ar), 7.36 (d,
3JH,H = 8.4 Hz, 2 H, Ar), 7.72 (d, JH,H = 8.4 Hz, 2 H, Ar), 7.77
3
6 H, CH3-Ar), 2.21 (s, 6 H, CH3-Ar), 2.98 (br. abs, 4 H, N-CH2-
CH2-pyr), 3.46 (br. abs, 4 H, N-CH2-CH2-pyr), 4.32 (s, 4 H, CH2-
N), 4.77 (s, 4 H, CH2-N), 5.35 (s, 4 H, CH2-N), 7.22–7.30 (m, 8 H,
Ar), 7.93 (BBЈ part, AAЈBBЈ system, 3JH,H = 8.0 Hz, 4 H, Ar), 8.09
3
(d, JH,H = 8.4 Hz, 2 H, Ar), 8.26 (s, 1 H, pyr-H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 21.5, 31.7, 43.6, 44.5, 51.7, 122.2,
127.5, 127.6, 129.9, 130.0, 130.5, 132.5, 133.2, 142.1, 142.7, 144.2,
152.3 ppm. HRMS (ESI+): calcd. for [C24H25N3S2O4 + H]+
484.1359; found 484.1364.
3
(BBЈ part, AAЈBBЈ system, JH,H = 7.6 Hz, 4 H, Ar) ppm. 13C
NMR (100 MHz, [D5]pyridine, 25 °C): δ = 21.9, 22.0, 32.1, 44.5,
45.4, 51.9, 55.3, 122.7, 128.4, 130.2, 130.3, 130.8, 133.6, 134.3,
144.4, 144.5, 145.1, 152.1 ppm. MS (ESI+): m/z = 987 [M + Na]+.
HRMS (ESI+): calcd. for [C48H48N6S4O8 + H]+ 965.2489; found
965.2434.
Pyridine Derivative 21: Column chromatography: dichloromethane/
ethyl acetate (10:1 to 9:1); pale-yellow oil. IR (ATR): ν = 2979,
˜
1727, 1243, 1183 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ =
3
3
1.24 (t, JH,H = 7.2 Hz, 6 H, CH3-CH2-OCO), 1.27 (t, JH,H
=
7.2 Hz, 6 H, CH3-CH2-OCO), 2.39 (s, 3 H, CH3-pyr), 2.40 (t, 3JH,H
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra of intermediates 5, 7, and 8; cyano-
diynes 1–4, 18–19, and 26–27; dicyanotetrayne 28; pyridine deriva-
tives 11–14 and 21–22; and bipyridines 29–31.
3
= 6.6 Hz, 2 H, C-CH2-CH2-pyr), 2.90 (t, JH,H = 6.6 Hz, 2 H, C-
CH2-CH2-pyr), 3.13 (s, 2 H, CH2-C), 3.53 (s, 4 H, CH2-C), 4.15–
4.30 (m, 8 H, CH3CH2-OCO) ppm. 13C NMR (100 MHz, CD2Cl2,
25 °C): δ = 13.9, 21.7, 27.9, 28.6, 31.3, 38.7, 38.9, 53.1, 59.5, 61.6,
61.9, 122.6, 132.9, 148.2, 150.8, 152.4, 170.9, 171.3 ppm. HRMS
(ESI+): calcd. for [C25H33NO8 + H]+ 476.2279; found 476.2277.
Acknowledgments
Pyridine Derivative 22: Column chromatography: dichloromethane/
ethyl acetate (10:1 to 8:2); pale-yellow oil. IR (ATR): ν = 2981,
˜
Financial support from the Ministerio de Ciencia e Innovación
(MICINN), Spain (CTQ2008-05409), “Generalitat de Catalunya”
(2009SGR-637), and the University of Girona (grant to L.G.) is
acknowledged. We also thank the Research Technical Services of
the University of Girona for analytical data and Johnson and
Matthey for a loan of RhCl3.
1
1727, 1248, 1182, 1064 cm–1. H NMR (400 MHz, CDCl3, 25 °C):
3
3
δ = 1.26 (t, JH,H = 7.2 Hz, 6 H, CH3-CH2-OCO), 1.27 (t, JH,H
=
7.2 Hz, 6 H, CH3-CH2-OCO), 2.43 (s, 3 H, CH3-pyr), 3.49 (s, 2 H,
3
CH2-C), 3.52 (s, 4 H, CH2-C), 3.62 (s, 2 H, CH2-C), 4.21 (q, JH,H
= 7.2 Hz, 4 H, CH3-CH2-OCO), 4.22 (q, 3JH,H = 7.2 Hz, 4 H, CH3-
CH2-OCO) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 13.9,
21.7, 36.6, 38.6, 38.9, 41.5, 58.0, 59.6, 61.8, 61.9, 126.6, 132.5,
145.2, 152.5, 159.0, 171.1, 171.3 ppm. HRMS (ESI+): calcd. for
[C24H31NO8 + Na]+ 484.1942; found 484.1931.
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Bipyridine Derivative 29: Column chromatography: dichlorometh-
ane/ethyl acetate (10:1 to 0:10); colorless solid; m.p. 247–248 °C
(decomp.). IR (ATR): ν = 2922, 1339, 1157 cm–1. 1H NMR
˜
(400 MHz, CD2Cl2, 25 °C): δ = 2.41 (s, 3 H, CH3-Ar), 2.44 (s, 3
3
H, CH3-Ar), 3.10 (t, JH,H = 5.8 Hz, 2 H, N-CH2-CH2-pyr), 3.43
3
(t, JH,H = 5.8 Hz, 2 H, N-CH2-CH2-pyr), 4.11 (s, 2 H, CH2-N),
4.52 (s, 2 H, CH2-N), 4.76 (s, 2 H, CH2-N), 7.32–7.42 (m, 4 H + 1
3
H, Ar + pyr-H), 7.73 (BBЈ part, AAЈBBЈ system, JH,H = 8.4 Hz,
3
2 H, Ar), 7.76 (BBЈ part, AAЈBBЈ system, JH,H = 8.4 Hz, 2 H,
3
4
Ar), 8.00 (dt, JH,H = 8.0 Hz, JH,H = 1.8 Hz, 1 H, pyr-H), 8.63
(br. abs, 1 H, pyr-H), 8.85 (br. abs, 1 H, pyr-H) ppm. 13C NMR
(100 MHz, CD2Cl2, 25 °C): δ = 21.6, 32.4, 44.2, 45.1, 52.1, 121.9,
123.9, 127.9, 128.1, 128.6, 129.9, 130.3, 130.4, 133.1, 133.4, 134.3,
134.4, 135.5, 144.7, 148.6, 149.1, 150.2, 153.5 ppm. HRMS (ESI+):
calcd. for [C29H28N4S2O4 + H]+ 561.1625; found 561.1617.
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Bipyridine Derivative 30: Column chromatography: dichlorometh-
ane/ethyl acetate (10:1); colorless oil. IR (ATR): ν = 2922, 1338,
˜
1
1156 cm–1. H NMR (300 MHz, CD2Cl2, 25 °C): δ = 2.37 (s, 3 H,
3
CH3-Ar), 2.41 (s, 3 H, CH3-Ar), 3.11 (t, JH,H = 5.7 Hz, 2 H, N-
CH2-CH2-pyr), 3.41 (t, 3JH,H = 5.7 Hz, 2 H, N-CH2-CH2-pyr), 4.07
(s, 2 H, CH2-N), 4.47 (s, 2 H, CH2-N), 5.09 (s, 2 H, CH2-N), 7.24–
3
7.32 (m, 1 H, pyr-H), 7.30 (AAЈ part, AAЈBBЈ system, JH,H
=
3
8.1 Hz, 2 H, Ar), 7.36 (AAЈ part, AAЈBBЈ system, JH,H = 8.1 Hz,
2 H, Ar), 7.71 (BBЈ part, AAЈBBЈ system, JH,H = 8.1 Hz, 2 H,
Ar), 7.80 (BBЈ part, AAЈBBЈ system, JH,H = 8.1 Hz, 2 H, Ar),
3
3
3414
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Eur. J. Org. Chem. 2010, 3407–3415

Microwave-Enhanced Rhodium-Catalyzed [2+2+2] Cycloadditions
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(s, 6 H), 2.56 (t, J = 7.2 Hz, 2 H), 3.21 (t, J = 7.2 Hz, 2 H),
3.25 (t, J = 7.2 Hz, 2 H), 3.79 (s, 2 H), 3.90 (s, 2 H) 4.15 (s, 2
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= 967 [M + H]+.
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Received: November 17, 2009
Published Online: May 11, 2010
Eur. J. Org. Chem. 2010, 3407–3415
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3415