Rhodium(I)-catalyzed [2 + 2 + 2] cycloaddition reactions of triacetylenic 15-membered aza macrocycles: A comparative structural study

Article abstract of DOI:10.1021/om200927f

A variety of new nitrogen-containing 15-membered triacetylenic macrocycles with one or two alkyl substituents in a propargylic position have been efficiently synthesized and completely characterized. These macrocyclic systems undergo [2 + 2 + 2] cycloaddition reactions, leading to the corresponding fused tetracycles with a benzene core on treatment with Wilkinson's catalyst, [RhCl(PPh₃)₃]. The effects of alkyl chains have been evaluated on both the efficiency of the reaction and the conformational and structural analysis of the reactants.

Full text of DOI:10.1021/om200927f

Article
pubs.acs.org/Organometallics
Rhodium(I)-Catalyzed [2 + 2 + 2] Cycloaddition Reactions of
Triacetylenic 15-Membered Aza Macrocycles: A Comparative
Structural Study
Sandra Brun,† Anna Torrent,† Anna Pla-Quintana,*,† Anna Roglans,*,† Xavier Fontrodona,‡
Jordi Benet-Buchholz,§ and Teodor Parella∥
‡
†Department of Chemistry and Technical Research Unit, Universitat de Girona, E-17071 Girona, Spain
§X-ray Diffraction Unit, Institute of Chemical Research of Catalonia, E-43007 Tarragona, Spain
∥NMR Unit, Universitat Auton
̀
oma de Barcelona, E-08193 Cerdanyola, Barcelona, Spain
S
* Supporting Information
ABSTRACT: A variety of new nitrogen-containing 15-membered
triacetylenic macrocycles with one or two alkyl substituents in
a propargylic position have been efficiently synthesized and
completely characterized. These macrocyclic systems undergo
[2 + 2 + 2] cycloaddition reactions, leading to the corre-
sponding fused tetracycles with a benzene core on treatment
with Wilkinson’s catalyst, [RhCl(PPh3)3]. The effects of alkyl
chains have been evaluated on both the efficiency of the
reaction and the conformational and structural analysis of the
reactants.
this fascinating transformation have been evaluated: the efficiency
of the catalyst used,6 the reaction media,7 the effect of the size of
the different cycles on the fused structures formed during the
cycloisomerization,8,9 and the detailed mechanistic outcome.9,10
As part of this ongoing project, here we study the effect of
introducing one or two substituents in propargylic positions of
the 15-membered aza macrocycles and their effect on their
cycloisomerization reactions (Scheme 1). By means of NMR
INTRODUCTION
■
A highly reliable and atom-economical method for the synthesis
of polysubstituted benzene derivatives is the transition-metal-
catalyzed [2 + 2 + 2] cycloaddition of alkynes.1 Intramolecular
reactions are especially interesting, as they provide multicyclic
compounds in one synthetic operation. This attractive strategy
has been widely applied in open-chain systems, but its
application in macrocycles is an area that is relatively un-
explored. A reason for this neglect can be found in the low
reactivity shown by most macrocyclic triynes. 1,5,9-Cyclo-
dodecatriyne, prepared by Vollhardt in 1976, proved to be inert
in the presence of light, high pressure and temperature, acidic
conditions, and the CpCo(CO)2 catalyst.2 Similarly, tribenzo-
cyclotriynes, which are known to interact with transition-metal
complexes,3 have never been found to undergo [2 + 2 + 2]
cycloaddition reactions, and only a lithium-induced cyclization
to a fulvalene dianion has been reported.4 It should be noted
that both macrocycles would have led to three 4-membered
rings fused to the central benzene core after cyclization. Only
with a larger macrocycle, such as the 15-membered silicon-
tethered macrocycles reported by Sakurai et al., does the
cycloisomerization reaction afford 5-membered rings fused to
the benzene, as has been reported, although with low yields and
in the presence of other π-electron systems.5
Scheme 1. [2 + 2 + 2] Cycloisomerization Reaction of
Mono- and Disubstituted Macrocycles Catalyzed by Rh(I)
and X-ray diffraction, the structural characteristics induced by
these substituents will also be evaluated in the macrocycles and
thus in their reactivity.
RESULTS AND DISCUSSION
Synthesis of Macrocycles. With the aim of obtaining a
■
The incorporation of a nitrogen tether in 15-membered
triacetylenic macrocycles has been shown by our group to give
macrocycles which participate in the [2 + 2 + 2] cyclo-
isomerization reaction, leading to tetrafused cyclic structures in
a highly efficient reaction with good yields. Various aspects of
series of triyne macrocycles with various substituents at the
Received: October 4, 2011
Published: December 23, 2011
© 2011 American Chemical Society
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Article
1
1
propargylic positions, the synthetic routes described by our
group for unsubstituted triyne macrocycles6b,8 were fine tuned
to achieve the precise incorporation of the substituents at the
appropriate positions. The substituents were introduced in all
cases in the 2-alkyne-1,4-diols of type 5 (Scheme 2) used as
the H and 13C NMR spectra. The H NMR spectrum for
macrocycle 1d shows two signals of equal intensity for the CH3 in
the propargylic position, as well as the terminal CH3 of the propyl
chain, indicating an equimolar mixture of diastereoisomers. The
hydrogens in geminal positions of the substituents could also be
differentiated. Also, clear evidence of the diastereomeric mixture is
found in the 13C NMR spectrum, where two sets of six signals are
observed for the acetylenic carbons and two sets of signals for the
geminal carbons. Macrocycle 1e shows a similar trend, although
some signals are superimposed mainly due to the increased number
of signals in the aliphatic region.
Scheme 2. Synthesis of Diols 5
Crystals suitable for X-ray diffraction could be obtained
for macrocycles 1a,c,e (described below when discussing the
reactivity).
[2 + 2 + 2] Cycloaddition Reactions. On the basis of the
optimized conditions described by our group before,8 the newly
synthesized triacetylenic macrocycles 1b−e were submitted to
the [2 + 2 + 2] cycloaddition reaction using Wilkinson’s
complex as the catalyst. Toluene was used as the solvent in all
the reactions, and the temperature and reaction time were
adjusted for each experiment. Macrocycle 1a,8 featuring a CH3
substituent in one of the propargylic positions, and the parent
unsubstituted macrocycle 1f6a were cycloisomerized under
analogous conditions in order to have comparable data. The
results obtained are summarized in Table 1.
Remarkably, the temperature and time needed to perform
the cycloaddition is quite variable depending on the sub-
stituents. Whereas all macrocycles could be cycloisomerized at
room temperature, monosubstituted macrocycle 1c, which is
the only one with a tertiary alkyl substituent and which had the
greatest steric hindrance (t-Bu), needed 1 day at reflux to afford
a 70% yield.12 At first sight, this might be ascribed to the steric
hindrance of the bulky t-Bu group. However, steric hindrance
was not able to explain all the results obtained, since surprisingly
the disubstituted macrocycles afforded the benzenic products
much more quickly than did the monosubstituted macrocycles
(compare entries 4 and 5 with entries 1 and 2).
starting materials for these macrocyclic syntheses. These diols
were synthesized according to Scheme 2: i.e., treatment of the
commercially available propargylic alcohol with 2 equiv of
n-butyllithium, followed by the addition of the appropriate
aldehyde to afford the corresponding diols with moderate to
good yields.11
A monosubstituted macrocycle featuring the CH3 substituent
1a (Scheme 1) has already been described by our group,8 and
its synthesis was used as a model for the preparation of
monosubstituted macrocycles with bulkier substituents such as
iBu and tBu. The synthesis started with the Mitsunobu reaction
of the corresponding 1,4-diol with 2 equiv of the N-BOC
protected p-methylphenylsulfonamide 6 to give the bis-
sulfonamidic intermediates 7. After deprotection with trifluoro-
acetic acid, compounds of type 8 were obtained which could be
macrocyclized with the dialkylated sulfonamide 98 to the
corresponding macrocycles 1, as outlined in Scheme 3.
The macrocycles with two substituents were synthesized
through an alternative synthetic pathway starting also with the
1,4-diols 5, which were converted to the corresponding
tosylates 10 and were directly used in the alkylation reaction
of the trisulfonamide intermediate 11,6a leading to the
corresponding macrocycles (Scheme 4). It should be noted
that both disubstituted diols and their corresponding ditosylates
and macrocycles were obtained as an inseparable mixture of
diastereoisomers.
The crystal structures of macrocycles 1a,c,e were determined
by performing single-crystal X-ray diffraction analysis (see
Figure 1 for perspective views of the molecules and Table 2 for
crystal data). Macrocycle 1e was obtained as an inseparable
mixture of diastereoisomers, and only one of these, namely the
SS/RR pair of enantiomers (with the two substituents in a
relative trans position, which we will now refer to as 1e-trans)
was crystallized. The molecules show a folded structure with
All new products were fully characterized with NMR experiments
and mass spectrometry. For the disubstituted macrocycles 1d,e, the
two possible diastereoisomers could be clearly differentiated in both
Scheme 3. Synthesis of Monosubstituted Macrocycles 1b,c
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Scheme 4. Synthesis of Disubstituted Macrocycles 1d,e
Table 1. Cycloisomerization Reactions of Mono- and Disubstituted Triyne Macrocycles 1a−f
entry
macrocycle (R1/R2)
temp
reacn time (h)
product (R1/R2)
yield (%)
a
1
1a (H/Me)
1b (H/iBu)
1c (H/tBu)
1d (Pr/Me)
1e (Pr/iBu)
1f (H/H)
room temp
room temp
reflux
26
15.5
24
2
2a (H/Me)
2b (H/iBu)
2c (H/tBu)
2d (Pr/Me)
2e (Pr/iBu)
2f (H/H)
91
75
70
99
83
84
2
3
4
5
room temp
room temp
room temp
2
a
6
1.5
a
Cycloisomerizations of compounds 1a,f were already described in refs 4 and 2, respectively, although under slightly different conditions.
the arylsulfonamide groups ordered in different planes and
wrapping the macrocyclic cavity.
an oxidative addition that generates a rhodacyclopentadiene. This
step is considered to be the rate-determining step of the overall
catalytic cycle. The third alkyne is then coordinated, generat-
ing a complex which may evolve either by alkyne insertion or a
cycloaddition, and finally reductive elimination furnishes the
benzene product and the catalyst is recovered. For the oxidative
addition step to occur, the two triple bonds have to be close in
space and, as far as possible, on the same plane. The pair of triple
bonds in each structure located in almost a perpendicular relative
conformation can be excluded as the ones reacting in the first step
in the catalytic cycle (distances and angles in black in Figure 2 and
in boldface in Table 3). Therefore, the differences should be
analyzed between the other two pairs, that between the triple
bonds linked by unsubstituted propargylic positions (in red in
Figure 2 and in italics in Table 3) and that with one alkyl radical in
one of the propargylic positions of the linker (in blue in Figure 2
and in boldface italics in Table 3).14
Macrocycles 1e-trans and 1f, featuring two alkyl substituents
and no substituents, respectively, are those which reacted
fastest in the series (2 h and 1.5 h at room temperature for 1e-
trans and 1f, respectively; see Table 1). For unsubstituted
macrocycle 1f, if we dismiss the pair of triple bonds folded in an
almost perpendicular position (in black in Figure 2), the other
two possible pairs of triple bonds are quite close spatially and
A more detailed analysis of the molecular structures obtained
for macrocycles 1a,c and 1e-trans and that already published
for macrocycle 1f6a help to explain the different reactivities of
the macrocycles. The C−C distances in each of the triple bonds
in the X-ray structures of macrocycles 1a,c, 1e-trans, and 1f
(see the Supporting Information) were collected and analyzed.
No significant differences were found between them, and so
inductive effects played by the substituents on the electronics of
the triple bond were discarded. A more interesting aspect to be
analyzed was the geometry adopted by the macrocycles depending
on the substituents: although these data are extracted from the
solid-state structure, it must follow the same trend in average in
solution. Accurate analysis of the relative orientation of the linear
triple bonds in each folded structure shows that two triple bonds
are nearly on the same plane, whereas the third is almost
perpendicular (Figure 1). The distances between consecutive triple
bonds were measured (Figure 2) as well as the dihedral angle
between the planes defined by each pair of consecutive triple
bonds13 (Table 3). Analysis of these data together with the generally
accepted mechanism reveals certain interesting trends. The
rhodium-catalyzed [2 + 2 + 2] cycloaddition is proposed to occur
through a sequential coordination of two alkynes followed by
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Figure 1. Ortep plots (30%) obtained from the X-ray crystallographic structural analyses of 1a,c and 1e-trans with two different views of each
molecule.
Table 2. Crystallographic Data for Structures 1a,c and
1e-trans
1a
1c
1e-trans
empirical formula
formula wt
temp, K
wavelength, Å
cryst syst
space group
a, Å
C34H35N3O6S3
677.83
C37H41N3O6S3
719.91
C40H47N3O6S3
761.99
300(2)
300(2)
300(2)
0.710 73
monoclinic
P21/c
0.710 73
monoclinic
P21/c
0.710 73
monoclinic
P21/n
17.728(9)
13.503(7)
15.199(8)
108.275(7)
3455(3)
4
28.676(14)
14.915(7)
18.614(9)
93.087(10)
7950(7)
8
19.242(12)
10.721(7)
0.441(13)
95.836(11)
4195(5)
4
b, Å
c, Å
β, deg
V, Å3
Z
ρ (g/cm3)
1.303
1.203
1.207
a
R1 (I > 2σ(I))
0.0867
0.0879
0.0579
b
wR2
0.2052
0.1873
0.1574
a
b
2
2
R1 = ∑||Fo| − |Fc||/∑|Fo|. wR2 = [∑{w(Fo − Fc )2}/
∑{w(Fo )2}]1/2, where w = 1/[σ2(Fo ) + (0.0042P)2] and P =
2
2
(Fo + 2Fc2)/3.
2
have relatively small dihedral angles, making them well-positioned
for the oxidative addition to occur. In the case of the trans di-
astereoisomer of macrocycle 1e, the two triple bonds linked by
the unsubstituted N linker have values that are comparable to
those observed for 1f. Thus it seems that the substituents exert
an influence on the folding of the macrocyclic structure,
resulting in two of the triple bonds becoming closer and thus
facilitating the oxidative addition step of the [2 + 2 + 2]
cycloaddition (generally accepted to be the rate-determining
step and supported as such in the 15-membered macrocycles by
DFT calculations9). This suitable positioning of two of the
triple bonds may speed up the whole cycloaddition reaction in
the disubstituted macrocycles.15 Next in the series in terms of
Figure 2. Distances (in Å) between triple bonds extracted from the X-
ray structures.
ease of reaction is macrocycle 1a, which has a methyl sub-
stituent (26 h at room temperature). The oxidative addition of
macrocycle 1a is presumably less favored, since neither of the
pairs of triple bonds is particularly well positioned for the
reaction to take place. On the one hand, the pair of triple bonds
that is closest to being on the same plane (those in blue) are
quite far apart and, furthermore, the methyl substituent in the
linker may exert steric hindrance. On the other hand, the
remaining pair of triple bonds (in red in Figure 2) is generally
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4.60 ppm corresponding to the 10H of the CH2 units of the
five-membered rings and the CH appears at a lower field. In
addition, two of the three methyl groups in the p-toluensulfonyl
units resonate at the same δ value, while that attached to the N
next to the substituent appears at a different δ value. This is in
good agreement with the structural differences found in the X-
ray structures (see below). The NMR spectra of the disub-
stituted cycloisomerized compounds 2d,e show two sets of
signals with a high degree of signal overlapping, confirming the
presence of two diastereoisomers as a 1:1 mixture.
Single-crystal X-ray structures have been obtained for the
cycloisomerized compounds 2c,d,f (see Figure 3 for perspective
views of the molecules and Table 4 for crystal data). Cyclo-
adduct 2d is obtained as an inseparable mixture of diastereo-
isomers, and only one of these, namely the SR/RS pair of
enantiomers, has been crystallized. If we compare the X-ray
structure for the unsubstituted cycloisomerized structure 2f
(Figure 3) with the compounds having substituents (com-
pound 2c with one tBu substituent and compound 2d having a
methyl and propyl substituents), clear differences can be
observed in the orientation of the arylsulfonamide groups. The
unsubstituted structure has the three arylsulfonamide units
located almost perpendicular to the plane defined by the central
tetracyclic fused core, in a structure that resembles a three-
legged table. In contrast, in the other two compounds having
substituents, one of the arylsulfonamide units is folded toward
the center of the structure in an almost parallel position above
the central benzene ring formed in the [2 + 2 + 2] cyclo-
addition reaction. The folded arylsulfonamide rest is always
located next to the bulkiest alkane substituent, indicating that
steric effects are forcing the folding.
Table 3. Dihedral Angles between Acetylenes Extracted from
the X-ray Structures
a
entry
1
macrocycle (R1/R2)
atoms
Dihedral angle (°)
1a (H/Me)
C2−C3−C6−C7
C6−C7−C10−C11
C10−C11−C2−C3
C2−C3−C6−C7
C6−C7−C10−C11
C10−C11−C2−C3
C2−C3−C6−C7
C6−C7−C10−C11
C10−C11−C2−C3
C2−C3−C6−C7
C6−C7−C10−C11
C10−C11−C2−C3
−27.4
−77.8
−15.4
81.5
2
3
4
1c (H/tBu)
−33.0
25.1
1e-trans (Pr/iBu)
1f (H/H)
25.8
−71.5
22.6
25.8
22.1
−79.0
a
Angles given in boldface correspond to those in black in Figure 2, those
in italics to those in red, and those in boldface italics to those in blue.
not sufficiently well positioned as to be optimal for the cyclo-
addition to take place. Finally, there is the case of macrocycle
1c, featuring a tert-butyl substituent, which has the two acetylenes
in closer proximity of the series (in blue, 3.17/3.70 Å) but reacts in
a much slower way. We explain this by the fact that two triple
bonds which are better suited geometrically for the oxidative
addition step are hindered by the tert-butyl group and thus might
not be reactive, forcing the system to react by another pair of triple
bonds (in red, 3.39/4.31 Å and 33.0°) which are less well-
positioned for the oxidative addition to take place.
To sum up, the reactivity of the substituted macrocycles is
conditioned by (a) the geometry adopted by the macrocycle,
which determines the relative position of the acetylenes, and
(b) the steric hindrance introduced by the substituents.
All new cycloisomerized products have been characterized by
NMR experiments. The unique substituent of the tetrafused
benzene derivatives 2b,c breaks the symmetry of these com-
pounds, which could be observed as a single set of resonances
As a singular feature of the structure for cycloisomerized
compound 2f, it can be seen that a dichloromethane molecule16 is
trapped inside the cavity formed by the triazatriindane structure
and the three p-tolyl units (“below the three-legged table”). The
molecule was found disordered in three orientations (1/3:1/3:1/3),
1
was also observed in the H NMR spectra, and could not be
1
1
in the H and 13C NMR spectra. The H NMR spectra of the
removed by heating the sample at 40 °C for 1 h, proving the quite
two compounds show overlapping multiplets between 4.20 and
strong interactions which exist in this supramolecular structure.
Figure 3. Ortep plots (2f, 50% ellipsoids; 2c,d, 30% ellipsoids) of the structure of 2f,c,d with two different views of the molecule (side and front
views). For 2f the delocalized dichloromethane molecule is included in the first side view.
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Crystals of 2d were twinned and of low quality. After several
attempts a suitable data set could be collected using a crystal fragment
of small dimensions (0.04 × 0.03 × 0.01 mm3). The measured crystal
was prepared under inert conditions immersed in perfluoropolyether
as protecting oil for manipulation. Measurements were made on a
Bruker-Nonius diffractometer equipped with a APEX 2 4K CCD area
detector, a FR591 rotating anode with Mo Kα radiation, Montel
mirrors as a monochromator, and a Kryoflex low-temperature device
(T = −100(2) °C). Full-sphere data collection was used with ω and φ
scans. For data collection Apex2 V2009.1-0 (Bruker-Nonius 2004) and
for data reduction19 and absorption correction SADABS20 programs
were used. For structure solution and refinement SHELXTL21 was
used. A structure solution could be obtained in the space groups C2/c
and Cc. Using the centrosymmetrical space group C2/c the best R1
value refined to 10.5%. Using the space group Cc and refining the
structure as a racemic twin, the R1 value could be lowered to 7.13%. In
the asymmetric unit two independent molecules were refined, which
were both disordered in two shifted positions. The ratio of the shifted
positions is 50:50 for the first molecule and 61:39 for the second
molecule. The disordered shifted positions of the independent
molecules are respectively equivalent to a mixture of the RS and SR
enantiomers. In addition to the main molecule, also dichloromethane
could be localized in the unit cell. The dichloromethane is localized in
Table 4. Crystallographic Data for Structures 2f,c,d
2f
2c
2d
empirical
formula
C34H35Cl2N3O6S3 C41H49N3 O7S3 C37.25H41.50Cll0.50N3O6S3
formula wt
temp, K
wavelength, Å
cryst syst
space group
a, Å
748.73
153(2)
792.01
300(2)
741.14
100(2)
0.710 73
rhombohedral
R3m
0.710 73
monoclinic
C2/c
0.710 73
monoclinic
Cc
17.866(3)
17.866(3)
9.887(3)
29.726(8)
11.085(3)
24.760(7)
96.319(5)
8109(4)
8
23.107(2)
10.9792(7)
29.489(2)
96.160(6)
7438.1(10)
8
b, Å
c, Å
β, deg
V, Å3
2733.1(10)
3
Z
ρ(g/cm3)
1.365
1.297
1.324
Flack param
(std)
0.1(2)
0.55(14)
a
R1 (I > 2σ(I))
0.0655
0.0703
0.1710
0.0713
b
wR2
0.1386
0.1710
a
b
R1 = ∑||Fo| − |Fc||/∑|Fo|. wR2 = [∑{w(Fo2 − Fc2)2}/∑{w(Fo )2}]1/2
,
2
1
two disordered positions with a total occupation ratio of /4 molecule
of dichloromethane for each organic molecule. The basf parameter
where w = 1/[σ2(Fo ) + (0.0042P)2] and P = (Fo + 2Fc2)/3.
2
2
related to the twinning of the crystal gave a ratio of 55:45.
CONCLUSIONS
A small crystal needle of 2f was prepared under inert conditions
immersed in perfluoropolyether as protecting oil for manipulation
(dimensions 0.28 × 0.14 × 0.04 mm3). Measurements were made on a
Bruker SMART 1000 CCD diffractometer equipped with a
MACScience M18X-HF rotating anode with Mo Kα radiation, a
graphite monochromator, and a Kryoflex low-temperature device (T =
−120(2) °C). Full-sphere data collection was used with ω and φ scans.
For data collection SMART (Bruker 2002), for data reduction
SAINT,19 and for absorption correction SADABS20 programs were
used. For structure solution and refinement SHELXTL21 was used.
The measured compound crystallized in the trigonal chiral space group
R3m with 1/6 of the molecule in the asymmetric unit (C3v symmetry).
Additionally to the main molecule the unit cell contains a
dichloromethane molecule which is disordered in three positions
around the C3 axes. The structure was refined and solved in the space
groups R3 and R3m. Although in the space group R3 the disordered
dichloromethane molecule can be better refined and a lower R1 value
was obtained (R1 = 6.24%), the space group R3m was selected, due to
the higher symmetry (R1 = 6.55%).
■
In conclusion, we have synthesized an array of differently
substituted triaza macrocycles and demonstrated that their
rhodium-catalyzed [2 + 2 + 2] cycloaddition can be effectively
accomplished. A complete structural analysis by means of NMR
and X-ray analysis of the macrocycles has allowed us to discuss
the effects of the substituents on the conformation of the
reactants and thus their reactivity.
EXPERIMENTAL SECTION
■
General Considerations. Unless otherwise noted, materials were
obtained from commercial suppliers and used without further
purification. Compounds 98 and 116a were prepared as described by
us. 5,5-Dimethyl-2-hexyne-1,4-diol (5c)17 and 3-octyne-2,5-diol (5d)18
were prepared by following the method described previously in the
literature.
NMR spectra were recorded on 500, 400, and 200 MHz NMR
spectrometers. Chemical shift assignments were performed by a
concerted use of 2D COSY, NOESY, HSQC, and HMBC experiments
All the structures were solved by direct methods and refined by full-
matrix least-squares methods on F2. The non-hydrogen atoms were
refined anisotropically. The H atoms were placed in geometrically
optimized positions and forced to ride on the atom to which they are
attached.
recorded under routine conditions. Chemical shifts (δ) for 1H and 13
C
NMR were referenced to internal solvent resonances and reported
relative to SiMe4. ESI-MS analyses were recorded on an Esquire 6000
Ion Trap Mass Spectrometer (Bruker) equipped with an electrospray
ion source.
1,4-Alkynediol Synthesis. 6-Methyl-2-heptyne-1,4-diol
(5b): prepared according to the method reported in the literature
for similar compounds18 (1.51 g, 60% yield) as a colorless oil; IR
(ATR) νmax 3321, 2922, 1466, 1019 cm−1; 1H NMR (200 MHz,
X-ray Diffraction Studies. Crystals of compounds 1a,c, 1e-trans,
and 2c were used for room-temperature (300(2) K) X-ray structure
determinations. The measurements were carried out on a Bruker
SMART APEX CCD diffractometer using graphite-monochromated
Mo Kα radiation from an X-ray tube. Full-sphere data collection was
carried out with ω and φ scans. Programs used: data collection, Smart
version 5.631 (Bruker AXS 1997-02); data reduction, SAINT;19
absorption correction, SADABS.20 Structure solution and refinement
was done using SHELXTL.21 For compounds 1a,c only extremely
weakly diffracting crystals were available and a long exposure time was
needed to collect suitable data sets. Due to the small size of the
crystals, high Rint values and low ratios of observed to unique
reflections were obtained. In spite of these bad values, it was
considered that these structures were of enough quality to be reported.
Since for compound 1c solvent molecules could not be properly
modeled, the program SQUEEZE (Platon) was used.22 The
disordered solvent molecules were treated as a diffuse contribution
to the overall scattering without specific atom positions.
3
3
CDCl3) δ 0.93 (d, JH,H = 6.4 Hz, 3H), 0.94 (d, JH,H = 6.4 Hz, 3H),
1.46−1.73 (m, 2H), 1.85 (m, 1H), 2.40 (br abs, 2H), 4.31 (br abs,
2H), 4.46 (t, 3JH,H = 7.2 Hz, 1H) ppm; 13C NMR (50 MHz, CDCl3) δ
22.6, 22.7, 24.8, 46.8, 51.1, 61.1, 83.1, 87.2 ppm; ESI-HRMS calcd m/z
for [C8H14O2 + Na]+ 165.0886, found 165.0894.
2-Methyl-5-decyne-4,7-diol (5e): prepared according to the
method reported in the literature for similar compounds18 (0.86 g,
53% yield) as a mixture of diastereoisomers as a yellowish oil; IR
(ATR) νmax 3298, 2933, 1468, 1369 cm−1; 1H NMR (400 MHz,
CDCl3) (diastereoisomeric mixture) δ 0.90−0.98 (m, 9H + 9H),
1.40−1.60 (m, 3H + 3H), 1.59−1.76 (m, 3H + 3H), 1.83 (sept, 3JH,H
=
6.8 Hz, 1H + 1H), 2.79 (br abs, 2H + 2H), 4.36−4.48 (m, 2H + 2H)
ppm; 13C NMR (100 MHz, CDCl3) (diastereoisomeric mixture) δ
13.8, 18.5, 18.6, 22.5, 22.6, 24.8, 39.8, 39.9, 46.8, 46.9, 60.9, 62.2, 85.9,
86.0, 86.2, 86.3 ppm; ESI-MS (m/z) 207.0 [M + Na]+. Anal. Calcd. for
C11H20O2: C, 71.70; H, 10.94. Found: C, 71.00; H, 11.17.
323
dx.doi.org/10.1021/om200927f | Organometallics 2012, 31, 318−326

Organometallics
Article
Synthesis of Monosubstituted Macrocycles. N,N′-Bis(tert-
butyloxycarbonyl)-N,N′-bis[(4-methylphenyl)sulfonyl]-1-isobutyl-2-
butyne-1,4-diamine (7b). A mixture of N-tert-butyloxycarbonyl-4-meth-
ylphenylsulfonamide (6; 3.82 g, 14.07 mmol), 6-methyl-2-heptyn-1,4-diol
(5b; 1.00 g, 7.04 mmol), and triphenylphosphane (4.80 g, 18.31 mmol)
in anhydrous and degassed tetrahydrofuran (70 mL) was stirred and
cooled to 0 °C in an ice−water bath. Diisopropyl azodicarboxylate (DIAD;
3.5 mL, 18.05 mmol) was added dropwise to this solution, and the resulting
mixture was stirred at room temperature for 5 h 30 min (TLC monitoring).
The solvent was removed, and the oily residue was purified by column
chromatography on silica gel using hexane/ethyl acetate/dichloromethane
mixtures (11/0.5/2) as the eluent to afford 7b (3.94 g, 86% yield) as a
colorless solid: mp 137−139 °C; IR (ATR) νmax 2954, 1728, 1348, 1165,
1087 cm−1; 1H NMR (200 MHz, CDCl3) δ 0.97 (d, 3JH,H = 6.4 Hz, 6H),
1.31 (s, 18H), 1.76 (m, 1H), 1.86−2.12 (m, 2H), 2.39 (s, 6H), 4.70 (s,
2-Isobutyl-1,6,11-tris[(4-methylphenyl)sulfonyl]-1,6,11-triazacy-
clopentadeca-3,8,13-triyne (1b). A mixture of 8b (0.90 g, 2.01
mmol) and potassium carbonate (1.39 g, 10.07 mmol) in acetonitrile
(100 mL) was stirred at reflux. The dichloro derivative 9 (0.80 g,
2.32 mmol) in acetonitrile (100 mL) was added dropwise to this solution
through a compensating pressure addition funnel, and the resulting
mixture was stirred at reflux for 25 h (TLC monitoring). The mixture
was cooled to room temperature, the salts were filtered off, and the
solvent was removed by vacuum evaporation. The residue was purified
by column chromatography on silica gel using hexane/dichloro-
methane/ethyl acetate mixtures (7/2/1) as the eluent to afford 8b
(1.07 g, 74% yield) as a colorless solid: mp 106−108 °C; IR (ATR)
1
νmax 2922, 1347, 1156, 1091 cm−1; H NMR (500 MHz, CDCl3) δ
3
3
0.86 (d, JH,H = 6.4 Hz, 3H), 0.90 (d, JH,H = 6.4 Hz, 3H), 1.34−1.45
(m, 2H), 1.55 (m, 1H), 2.41 (s, 3H), 2.43 (s, 3H), 2.44 (s, 3H), 3.55−
3.96 (m, 9H), 4.25 (d, JH,H = 18.4 Hz, 1H), 4.47 (t, JH,H = 8.0 Hz,
1H), 7.23 (AA′ part of an AA′BB′ system, JH,H = 8.0 Hz, 2H), 7.28
(AA′ part of an AA′BB′ system, JH,H = 8.0 Hz, 2H), 7.30 (AA′ part of
3
2
3
2H), 5.43 (t, JH,H = 7.6 Hz, 1H), 7.29 (AA′ part of an AA′BB′ system,
3
3JH,H = 8.2 Hz, 4H), 7.87 (BB′ part of an AA′BB′ system, JH,H
=
3
3
3
8.2 Hz, 2H), 7.94 (BB′ part of an AA′BB′ system, JH,H = 8.2 Hz, 2H)
ppm; 13C NMR (50 MHz, CDCl3) δ 21.7, 22.2, 22.6, 25.5, 27.9, 28.0,
36.0, 43.9, 48.5, 79.3, 82.0, 84.8, 84.9, 128.0, 128.3, 129.5, 136.9, 137.5,
144.1, 144.4, 150.2, 150.3 ppm; ESI-HRMS calcd m/z for
[C32H44N2O8S2 + Na]+ 671.2431, found 671.2418. Anal. Calcd for
C32H44N2O8S2: C, 59.24; H, 6.84; N, 4.32; S, 9.88. Found: C, 58.91;
H, 6.93; N, 4.19; S, 9.58.
3
an AA′BB′ system, JH,H = 8.0 Hz, 2H), 7.60 (BB′ part of an AA′BB′
system, 3JH,H = 8.0 Hz, 2H), 7.62 (BB′ part of an AA′BB′ system, 3JH,H
=
8.0 Hz, 4H) ppm; 13C NMR (125 MHz, CDCl3) δ 21.5, 21.6, 22.1,
22.2, 24.4, 33.1, 36.7, 36.8, 37.7, 37.8, 43.4, 47.1, 77.7, 78.0, 78.2, 79.1,
80.0, 83.1, 127.6, 127.7, 127.8, 129.2, 129.5, 129.6, 134.4, 135.1, 137.2,
143.5, 144.1, 144.3 ppm; ESI-HRMS calcd m/z for [C37H41N3O6S3 +
H]+ 720.2230, found 720.2209. Anal. Calcd for C37H41N3O6S3: C,
61.73; H, 5.74; N, 5.84. Found: C, 62.06; H, 6.15; N, 5.43.
N,N′-Bis(tert-butyloxycarbonyl)-N,N′-bis[(4-methylphenyl)-
sulfonyl]-1-tert-butyl-2-butyne-1,4-diamine (7c). 7c was prepared
according to the method described above for 7b (50% yield): colorless
solid; mp 107−109 °C; IR (ATR) νmax 2984, 1734, 1351, 1148,
2-tert-Butyl-1,6,11-tris[(4-methylphenyl)sulfonyl]-1,6,11-triazacy-
clopentadeca-3,8,13-triyne (1c). 1c was prepared according to the
method described above for 1b (30% yield): colorless solid; mp 115−
1
1088 cm−1; H NMR (200 MHz, CDCl3) δ 1.14 (s, 9H), 1.26 (s, 9H),
1
117 °C; IR (ATR) νmax 2922, 1346, 1157, 1091 cm−1; H NMR (400
1.31 (s, 9H), 2.39 (s, 6H), 4.74 (br s, 2H), 5.30 (br s, 1H), 7.25−7.31 (m,
3
MHz, CDCl3) δ 0.95 (s, 9H), 2.39 (s, 3H), 2.43 (s, 3H), 2.44 (s, 3H),
3.40−4.10 (m, 10H), 4.28 (s, 1H), 7.20 (AA′ part of an AA′BB′ system,
4H), 7.81 (m, 2H), 7.95 (BB′ part of an AA′BB′ system, JH,H = 8.2 Hz,
2H) ppm; 13C NMR (50 MHz, CDCl3) δ 21.7, 27.8, 27.9, 28.2, 36.2, 37.5,
59.0, 80.1, 81.1, 84.8, 128.3, 129.5, 137.0, 138.0, 143.9, 144.4, 150.3 ppm;
ESI-HRMS. calcd m/z for [C32H44N2O8S2 + Na]+ 671.2431, found
671.2433. Anal. Calcd for C32H44N2O8S2: C, 59.24; H, 6.84; N, 4.32.
Found: C, 58.81; H, 6.87; N, 4.27.
3
3JH,H = 8.4 Hz, 2H), 7.25 (AA′ part of an AA′BB′ system, JH,H = 8.4
Hz, 2H), 7.31 (AA′ part of an AA′BB′ system, 3JH,H = 8.4 Hz, 2H), 7.55
3
(BB′ part of an AA′BB′ system, JH,H = 8.4 Hz, 2H), 7.62 (BB′ part of
3
an AA′BB′ system, JH,H = 8.4 Hz, 4H) ppm; 13C NMR (50 MHz,
N,N′-Bis[(4-methylphenyl)sulfonyl]-1-isobutyl-2-butyne-1,4-di-
amine (8b). A mixture of 7b (1.80 g, 2.78 mmol), dichloromethane
(8 mL), and trifluoroacetic acid (7.9 mL, 102.54 mmol) was stirred at
room temperature for 9 h 30 min (TLC monitoring). The solvent was
removed, and the oily residue was redissolved in ethyl acetate (75 mL)
and washed with sodium bicarbonate (3 × 75 mL) and brine (75 mL).
The organic layer was dried with anhydrous sodium sulfate and the
solvent removed by vacuum distillation to afford 8b (1.14 g, 92%
yield) as a colorless solid;mp 109−111 °C; IR (ATR) νmax 3268, 2958,
CDCl3) δ 21.6, 21.7, 27.6, 29.8, 36.2, 37.4, 38.3, 38.4, 59.0, 78.4, 79.0,
79.5, 79.7, 79.8, 81.5, 127.8, 127.9, 128.1, 129.1, 129.6, 129.9, 134.7,
135.9, 138.1, 143.5, 143.9, 144.1, 144.5 ppm; ESI-HRMS calcd m/z for
[C37H41N3O6S3 + H]+ 720.2230, found 720.2248. Suitable crystals of
1c (colorless needles) were grown by slow diffusion of diethyl ether
into a CH2Cl2 solution.
Synthesis of Disubstituted Macrocycles. 2,5-Bis(p-toluenesul-
fonyloxy)-3-octyne (10d). 3-Octyn-2,5-diol (5d; 0.30 g, 2.11 mmol)
was dissolved in a dichloromethane/tetrahydrofuran (6/1, v/v)
mixture (6 mL) and cooled to −20 °C. p-Toluenesulfonyl chloride
(1.00 g, 5.25 mmol) and triethylamine (0.7 mL, 5.02 mmol) were
slowly added, and the mixture was stirred at −20 °C for 3 h. Then the
mixture was warmed to room temperature while the reaction was
monitored by TLC (24 h). The mixture was washed with water (3 ×
15 mL) and dried with anhydrous magnesium sulfate and the solvent
removed by vacuum evaporation. The residue was purified by column
chromatography on silica gel using hexanes/ethyl acetate mixtures of
increasing polarity (9/1 to 8/2) as the eluent to afford 10d (0.64 g,
68% yield, mixture of diastereoisomers) as a colorless solid: IR (ATR)
1327, 1151, 1090 cm−1; 1H NMR (200 MHz, CDCl3) δ 0.81 (d, 3JH,H
=
3
6.6 Hz, 3H), 0.83 (d, JH,H = 6.6 Hz, 3H), 1.11−1.42 (m, 2H), 1.62
3
(m, 1H), 2.45 (s, 6H), 3.50 (m, 2H), 3.87 (m, 1H), 4.26 (t, JH,H
=
6.0 Hz, 1H), 4.38 (d, 3JH,H = 9.4 Hz, 1H), 7.32 (AA′ part of an AA′BB′
system, 3JH,H = 8.0 Hz, 4H), 7.69 (BB′ part of an AA′BB′ system, 3JH,H
=
3
8.0 Hz, 2H), 7.73 (BB′ part of an AA′BB′ system, JH,H = 8.0 Hz, 2H)
ppm; 13C NMR (50 MHz, CDCl3) δ 21.7, 22.1, 24.6, 32.9, 44.1, 45.2,
78.6, 83.3, 127.6, 127.8, 129.6, 129.8, 136.9, 137.6, 144.0, 144.1 ppm;
ESI-HRMS calcd m/z for [C22H28N2O4S2 + Na]+ 471.1383, found
471.1363. Anal. Calcd for C22H28N2O4S2: C, 58.90; H, 6.29; N, 6.24.
Found: C, 58.26; H, 6.38; N, 5.88.
1
νmax 2920, 1361, 1170, 1096 cm−1; H NMR (400 MHz, DMSO-d6)
3
(mixture of diastereoisomers) δ 0.79 (t, JH,H = 7.2 Hz, 3H), 0.80 (t,
N,N′-Bis[(4-methylphenyl)sulfonyl]-1-tert-butyl-2-butyne-1,4-dia-
mine (8c). 8c was prepared according to the method described above
for 8b (82% yield): colorless solid; mp 105−107 °C; IR (ATR) νmax
3JH,H = 7.2 Hz, 3H), 1.09−1.21 (m, 2H + 2H), 1.22 (d, 3JH,H = 6.4 Hz,
3
3H), 1.24 (d, JH,H = 6.8 Hz, 3H), 1.38−1.59 (m, 2H + 2H), 2.41 (s,
1
3272, 2961, 1325, 1157, 1093 cm−1; H NMR (200 MHz, CDCl3) δ
3
5
6H), 2.42 (s, 6H), 4.96 (dt, JH,H = 6.8 Hz and JH,H = 0.8 Hz, 1H),
5.03 (dt, 3JH,H = 7.2 Hz and 5JH,H = 1.6 Hz, 1H), 5.10 (dq, 3JH,H = 6.4
0.83 (s, 9H), 2.45 (s, 3H), 2.46 (s, 3H), 3.47−3.60 (m, 3H), 4.17 (t,
3JH,H = 5.4 Hz, 1H), 4.33 (d, 3JH,H = 10.0 Hz, 1H), 7.31 (AA′ part of an
5
3
5
Hz and JH,H = 0.8 Hz, 1H), 5.16 (dq, JH,H = 6.8 Hz and JH,H = 1.6
Hz, 1H), 7.47 (AA′ part of a AA′BB′ system, 3JH,H = 7.6 Hz, 4H + 4H),
7.71−7.79 (m, 4H + 4H) ppm; 13C NMR (100 MHz, DMSO-d6)
(mixture of diastereoisomers) δ 13.0, 13.1, 17.2, 17.3, 21.0, 21.1, 21.7,
21.8, 36.5, 36.6, 67.4, 67.5, 70.6, 70.7, 82.4, 82.5, 84.0, 84.1, 127.5,
127.6, 127.7, 127.8, 129.9, 130.0, 130.1, 132.9, 133.0, 133.1, 145.0,
145.05, 145.1, 145.15 ppm; ESI-HRMS calcd m/z for [C22H26O6S2 +
Na]+ 473.1063, found 473.1069. Anal. Calcd for C22H26O6S2: C,
58.64; H, 5.82; S, 14.23. Found: C, 58.92; H, 5.90; S, 14.46.
3
AA′BB′ system, JH,H = 8.2 Hz, 2H), 7.35 (AA′ part of an AA′BB′
system, 3JH,H = 8.2 Hz, 2H), 7.67 (BB′ part of an AA′BB′ system, 3JH,H
=
3
8.2 Hz, 2H), 7.72 (BB′ part of an AA′BB′ system, JH,H = 8.2 Hz, 2H)
ppm; 13C NMR (50 MHz, CDCl3) δ 21.7, 25.9, 32.8, 35.4, 55.5, 79.7,
82.0, 127.5, 127.8, 129.6, 129.9, 136.8, 137.4, 144.0, 144.1 ppm; ESI-
HRMS calcd m/z for [C22H28N2O4S2 + Na]+ 471.1383, found
471.1381. Anal. Calcd for C22H28N2O4S2 + H2O: C, 56.63; H, 6.48; N,
6.00. Found: C, 56.61; H, 6.06; N, 5.63.
324
dx.doi.org/10.1021/om200927f | Organometallics 2012, 31, 318−326

Organometallics
Article
2-Methyl-4,7-bis(p-toluenesulfonyloxy)-5-decyne (10e). 10e was
prepared according to the method described above for 10d (73%
yield): colorless solid; IR (ATR) νmax 2956, 1367, 1175, 1096 cm−1;
1H NMR (400 MHz, CDCl3) (diastereoisomeric mixture) δ 0.82−0.88
(m, 9H + 9H), 1.23−1.37 (m, 3H + 3H), 1.44−1.70 (m, 4H + 4H),
2.44 (s, 3H + 3H), 2.45 (s, 3H + 3H), 4.82−4.95 (m, 2H + 2H),
7.30−7.35 (m, 4H + 4H), 7.71−7.77 (m, 4H + 4H) ppm; 13C NMR
(100 MHz, CDCl3) (diastereoisomeric mixture) δ 13.4, 17.9, 18.0,
21.6, 21.7, 21.8, 21.9, 22.4, 22.5, 24.2, 24.3, 37.3, 37.5, 44.2, 44.3, 69.7,
69.8, 70.8, 83.3, 83.5, 83.6, 83.8, 127.9, 128.0, 128.1, 128.15, 128.2,
129.7, 129.8, 129.9, 130.0, 134.0, 134.1, 144.8, 144.9, 145.0, 145.1
ppm; ESI-HRMS calcd m/z for [C25H32O6S2 + Na]+ 515.1533, found
515.1517. Anal. Calcd for C25H32O6S2: C, 60.95; H, 6.55; S, 13.02.
Found: C, 61.26; H, 6.69; S, 13.29.
acetate mixtures of increasing polarity (1/0 to 40/1) as the eluent to
afford 2b (0.046 g, 75% yield) as a colorless solid.
1-Isobutyl-2,5,8-tris[(4-methylphenyl)sulfonyl]-1H-2,5,8-triaza-
trindane (2b): colorless solid (75% yield); mp 162−165 °C; IR
(ATR) νmax 2921, 1342, 1162, 1094 cm−1; 1H NMR (500 MHz,
3
3
CDCl3) δ 0.63 (d, JH,H = 6.4 Hz, 3H), 0.88 (d, JH,H = 6.4 Hz, 3H),
1.46 (m, 1H), 1.54−1.63 (m, 2H), 2.24 (s, 3H), 2.35 (s, 6H), 4.24−
4.42 (m, 10H), 4.88 (m, 1H), 7.05 (AA′ part of an AA′BB′ system,
3JH,H = 8.0 Hz, 2H), 7.26 (AA′ part of an AA′BB′ system, JH,H
=
3
8.0 Hz, 2H), 7.27 (AA′ part of an AA′BB′ system, 3JH,H = 8.0 Hz, 2H),
7.52 (BB′ part of an AA′BB′ system, 3JH,H = 8.4 Hz, 2H), 7.66 (BB′ part
of an AA′BB′ system, 3JH,H = 8.4 Hz, 2H), 7.67 (BB′ part of an AA′BB′
system, JH,H = 8.4 Hz, 2H) ppm; 13C NMR (125 MHz, CDCl3) δ
3
21.4, 21.5, 22.5, 23.8, 24.3, 43.1, 51.7, 51.8, 51.9, 52.0, 63.9, 127.2,
127.5, 127.6, 129.7, 129.9, 130.1, 130.2, 130.5, 130.6, 130.7, 130.8,
133.4, 133.5, 134.5, 136.1, 143.8, 144.1, 144.2 ppm; ESI-HRMS calcd
m/z for [C37H41N3O6S3 + H]+ 720.2230, found 720.2191.
5-Methyl-2-propyl-1,6,11-tris[(4-methylphenyl)sulfonyl]-1,6,11-
triazacyclopentadeca-3,8,13-triyne (1d). A mixture of 1,6,11-tris[(4-
methylphenyl)sulfonyl]-1,6,11-triazaundeca-3,8-diyne (11; 0.20 g, 0.33
mmol) and potassium carbonate (0.24 g, 1.75 mmol) in acetonitrile
(12 mL) was stirred and heated to reflux. 2,5-Bis(p-toluenesulfony-
loxy)-3-octyne (10d; 0.17 g, 0.38 mmol) in acetonitrile (20 mL) was
added dropwise to this solution, and the resulting mixture was stirred
at reflux for 19 h (TLC monitoring). The mixture was cooled to room
temperature, the salts were filtered off, and the solvent was removed
by vacuum evaporation. The residue was purified by column chroma-
tography on silica gel using hexanes/ethyl acetate mixtures (7/3) as
the eluent to afford 1d (0.12 g, 50% yield, mixture of diastereisomers)
1-tert-Butyl-2,5,8-tris[(4-methylphenyl)sulfonyl]-1H-2,5,8-triaza-
trindane (2c): colorless solid (70% yield); mp 143−145 °C; IR
(ATR) νmax 2923, 1344, 1161, 1095 cm−1; 1H NMR (400 MHz,
CDCl3) δ 0.93 (s, 9H), 2.07 (s, 3H), 2.43 (s, 6H), 4.19−4.69 (m,
10H), 4.49 (s, 1H), 6.65 (AA′ part of an AA′BB′ system, 3JH,H = 8.0 Hz,
3
2H), 7.31 (BB′ part of an AA′BB′ system, JH,H = 8.4 Hz, 2H), 7.37
3
(AA′ part of an AA′BB′ system, JH,H = 8.0 Hz, 4H), 7.76 (BB′ part of
3
an AA′BB′ system, JH,H = 8.4 Hz, 2H), 7.77 (BB′ part of an AA′BB′
3
system, JH,H = 8.4 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ
21.2, 21.7, 27.2, 39.4, 51.8, 52.0, 52.1, 53.2, 53.6, 74.7, 126.9, 127.8,
128.9, 130.2, 130.4, 130.5, 130.6, 132.1, 133.3, 133.5, 133.7, 134.4,
135.4, 143.7, 144.3, 144.4 ppm; ESI-HRMS calcd m/z for
[C37H41N3O6S3 + H]+ 720.2230, found 720.2191. Suitable crystals
of 2c (colorless needles) were grown by slow diffusion of pentane into
a THF solution.
1
as a colorless solid: IR (ATR) νmax 2922, 1332, 1156, 1090 cm−1; H
NMR (400 MHz, CDCl3) (mixture of diastereoisomers) δ 0.86
(t, 3JH,H = 7.2 Hz, 3H), 0.91 (t, 3JH,H = 7.2 Hz, 3H), 1.18 (d, 3JH,H = 7.2
3
Hz, 3H), 1.26−1.33 (m, 2H + 2H), 1.36 (d, JH,H = 7.2 Hz, 3H),
1.45−1.68 (m, 2H + 2H), 2.41 (s, 3H), 2.42 (s, 3H), 2.43 (s, 9H),
2.44 (s, 3H), 3.61−3.89 (m, 6H + 6H), 3.97−4.09 (m, 2H + 2H), 4.51
2-Methyl-1-propyl-3,6,9-tris[(4-methylphenyl)sulfonyl]-1H,2H-
3
3
5
(t, JH,H = 7.6 Hz, 1H), 4.57 (dt, JH,H = 7.6 Hz and JH,H = 2.8 Hz,
3,6,9-triazatrindane (2d): colorless solid (99% yield); IR (ATR) νmax
1H), 4.67 (q, 3JH,H = 7.2 Hz, 1H), 4.72 (dq, 3JH,H = 7.2 Hz and 5JH,H
=
2922, 1342, 1160, 1093 cm−1
;
1H NMR (400 MHz, CDCl3)
2.8 Hz, 1H), 7.23−7.32 (m, 6H + 6H), 7.50−7.71 (m, 6H + 6H) ppm;
3
(diastereoisomeric mixture) δ 0.55 (m, 1H), 0.76 (t, JH,H = 7.2 Hz,
13C NMR (100 MHz, CDCl3) (mixture of diastereoisomers) δ 13.5,
3H), 0.85 (t, 3JH,H = 7.2 Hz, 3H), 1.15 (m, 2H), 1.37 (m, 1H), 1.45 (d,
3
3JH,H = 6.4 Hz, 3H), 1.51 (d, JH,H = 6.4 Hz, 3H), 1.62 (m, 1H), 1.69
19.3, 19.5, 21.5, 21.6, 21.7, 33.8, 33.9, 34.0, 36.8, 36.9, 37.4, 37.5, 37.6,
44.8, 44.9, 49.0, 49.2, 77.5, 77.7, 77.8, 77.9, 80.5, 80.6, 80.7, 80.8, 82.1,
82.3, 83.3, 83.6, 127.4, 127.6, 127.7, 127.8, 127.9, 129.4, 129.5, 129.6,
129.7, 129.8, 134.6, 134.8, 136.7, 136.8, 137.0, 137.1, 143.7, 143.8,
143.9, 144.2, 144.3 ppm; ESI-HRMS calcd m/z for [C37H41N3O6S3 +
Na]+ 742.2050, found 742.2061.
(m, 1H), 1.94 (m, 1H), 2.03 (m, 1H), 2.22 (s, 3H), 2.33 (s, 3H), 2.36
(s, 6H), 2.42 (s, 3H), 2.43 (s, 3H), 4.21−4.48 (m, 8H + 8H), 4.89−
5.01 (m, 3H), 5.09 (m, 1H), 6.92 (AA′ part of an AA′BB′ system, 3JH,H
=
8.0 Hz, 2H), 7.14 (AA′ part of an AA′BB′ system, 3JH,H = 8.0 Hz, 2H),
3
7.23 (AA′ part of an AA′BB′ system, JH,H = 8.0 Hz, 2H), 7.25 (AA′
3
2-Isobutyl-5-propyl-1,6,11-tris[(4-methylphenyl)sulfonyl]-1,6,11-
triazacyclopentadeca-3,8,13-triyne (1e). 1e was prepared according
to the method described above for 1d (40% yield): colorless solid; IR
(ATR) νmax 2957, 1333, 1156, 1090 cm−1; 1H NMR (400 MHz,
CDCl3) (mixture of diastereoisomers) δ 0.86−0.94 (m, 9H + 9H),
1.15−1.68 (m, 7H + 7H), 2.42 (s, 12H), 2.44 (s, 6H), 3.67−4.05
part of an AA′BB′ system, JH,H = 8.0 Hz, 2H), 7.33 (AA′ part of an
3
AA′BB′ system, JH,H = 8.4 Hz, 2H), 7.36 (AA′ part of an AA′BB′
3
system, JH,H = 8.4 Hz, 2H), 7.50 (BB′ part of an AA′BB′ system,
3
3JH,H = 8.4 Hz, 2H), 7.64 (BB′ part of an AA′BB′ system, JH,H
=
8.0 Hz, 2H), 7.65 (BB′ part of an AA′BB′ system, 3JH,H = 8.4 Hz, 2H),
7.67 (BB′ part of an AA′BB′ system, 3JH,H = 8.4 Hz, 2H), 7.73 (BB′ part
of an AA′BB′ system, 3JH,H = 8.4 Hz, 2H), 7.75 (BB′ part of an AA′BB′
3
3
(m, 8H + 8H), 4.51 (t, JH,H = 7.6 Hz, 1H), 4.57 (dt, JH,H = 7.6 Hz
and 5JH,H = 2.4 Hz, 1H), 4.64 (t, 3JH,H = 7.6 Hz, 1H), 4.66 (dt, 3JH,H
=
3
system, JH,H = 8.4 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3)
7.6 Hz and 5JH,H = 2.4 Hz, 1H), 7.23−7.33 (m, 6H + 6H), 7.58−7.69
(m, 6H + 6H) ppm; 13C NMR (100 MHz, CDCl3) (mixture of
diastereoisomers) δ 13.5, 13.6, 19.3, 19.5, 21.6, 21.7, 22.0, 22.2, 22.3,
22.5, 24.6, 24.9, 33.9, 34.0, 34.1, 37.1, 37.2, 37.6, 37.7, 37.8, 43.5, 43.8,
47.7, 47.8, 49.2, 49.3, 77.3, 77.6, 77.7, 77.8, 77.9, 80.6, 80.7, 80.8, 82.6,
82.7, 82.8, 83.1, 127.4, 127.5, 127.6, 127.7, 127.8, 127.9, 129.5, 129.6,
129.61, 129.62, 129.64, 129.8, 134.6, 134.9, 136.8, 136.9, 137.0, 137.1,
143.6, 143.7, 143.8, 144.2, 144.3 ppm; ESI-HRMS calcd m/z for
[C40H47N3O6S3 + Na]+ 784.2519, found 784.2513. Suitable crystals of
1e-trans (colorless plates) were grown by slow diffusion of pentane
into a CH2Cl2 solution.
(diastereoisomeric mixture) δ 13.7, 14.0, 16.6, 17.9, 21.4, 21.5, 21.6,
21.7, 22.1, 23.1, 36.0, 37.6, 50.7, 51.3 51.7, 52.0, 52.3, 60.6, 60.9, 64.4,
65.3, 127.1 127.25, 127.27, 127.3, 127.6, 127.7, 129.5, 129.8, 129.9,
130.0, 130.07, 130.1, 130.3, 130.4, 130.5, 130.7, 130.75, 130.77, 131.3,
131.8, 133.5, 133.7, 134.3, 134.7, 134.8, 135.2, 135.7, 135.9, 136.7,
143.7, 143.8, 143.9, 144.0, 144.1, 144.2 ppm; ESI-HRMS calcd m/z for
[C37H41N3O6S3 + Na]+ 742.2050, found 742.2014. Suitable crystals of
2d (colorless needles) were grown by slow diffusion of diethyl ether
into a CH2Cl2 solution.
1-Isobutyl-2-propyl-3,6,9-tris[(4-methylphenyl)sulfonyl]-1H,2H-3,6,9-
triazatrindane (2e): colorless solid (83% yield); IR (ATR) νmax 2956,
1
1343, 1159, 1092 cm−1; H NMR (400 MHz, CDCl3) (diastereoiso-
General Procedure for the [2 + 2 + 2] Cycloaddition Reaction. A
degassed mixture of triynic macrocycle 1b (0.062 g, 0.087 mmol) and
chlorotris(triphenylphosphane)rhodium(I) (Wilkinson’s catalyst;
0.008 g, 0.008 mmol) in anhydrous and degassed toluene (10 mL)
was stirred under a nitrogen atmosphere until completion (TLC
monitoring; for temperatures and reaction times for all macrocycles
see Table 1). The solvent was removed, and the residue was purified
by column chromatography on silica gel using dichloromethane/ethyl
3
meric mixture) δ 0.46 (m, 1H), 0.65 (d, JH,H = 6.8 Hz, 3H), 0.74−
3
0.88 (m, 3H + 3H), 0.91 (m, 1H), 0.90 (d, JH,H = 6.8 Hz, 3H), 0.97
3
3
(d, JH,H = 6.4 Hz, 3H), 1.04 (m, 1H), 1.09 (d, JH,H = 6.4 Hz, 3H),
1.15 (m, 1H), 1.31−1.55 (m, 2H + 2H), 1.61−1.75 (m, 3H), 1.94−
2.05 (m, 2H), 2.06 (s, 3H), 2.18 (m, 1H), 2.32 (s, 3H), 2.35 (s, 3H),
2.37 (s, 3H), 2.43 (s, 6H), 3.68−4.55 (m, 8H + 8H), 4.91−5.03 (m,
3
2H + 2H), 6.56 (AA′ part of an AA′BB′ system, JH,H = 8.0 Hz, 2H),
325
dx.doi.org/10.1021/om200927f | Organometallics 2012, 31, 318−326

Organometallics
Article
3
7.17 (AA′ part of an AA′BB′ system, JH,H = 8.0 Hz, 2H), 7.23 (AA′
(3) Youngs, W. J.; Tessier, C. A.; Bradshaw, J. D. Chem. Rev. 1999,
99, 3153−3180.
3
part of an AA′BB′ system, JH,H = 8.0 Hz, 2H), 7.26 (AA′ part of an
3
AA′BB′ system, JH,H = 8.0 Hz, 2H), 7.31 (BB′ part of an AA′BB′
(4) Youngs, W. J.; Djebli, A.; Tessier, C. A. Organometallics 1991, 10,
2089−2090.
system 3JH,H = 8.4 Hz, 2H), 7.34 (AA′ part of an AA′BB′ system, 3JH,H
=
8.0 Hz, 2H), 7.38 (AA′ part of an AA′BB′ system, 3JH,H = 8.0 Hz, 2H),
7.58 (BB′ part of an AA′BB′ system, 3JH,H = 8.0 Hz, 2H), 7.65 (BB′ part
of an AA′BB′ system, 3JH,H = 8.0 Hz, 2H), 7.72 (BB′ part of an AA′BB′
(5) (a) Sakurai, H.; Nakadaira, Y.; Hosomi, A.; Eriyama, Y.; Hirama,
K.; Kabuto, C. J. Am. Chem. Soc. 1984, 106, 8315−8316. (b) Sakurai,
H. Pure Appl. Chem. 1996, 68, 327−333. (c) Ebata, K.; Matsuo, T.;
Inoue, T.; Otsuka, Y.; Kabuto, C.; Sekiguchi, A.; Sakurai, H. Chem.
Lett. 1996, 1053−1054.
system, 3JH,H = 8.4 Hz, 2H), 7.75 (BB′ part of an AA′BB′ system, 3JH,H
=
3
8.0 Hz, 2H), 7.76 (BB′ part of an AA′BB′ system, JH,H = 8.4 Hz, 2H)
ppm; 13C NMR (100 MHz, CDCl3) (diastereoisomeric mixture) δ
13.5, 14.0, 16.3, 16.4, 21.1, 21.3, 21.5, 21.6, 22.4, 22.7, 23.7, 23.8, 24.1,
25.3, 36.2, 37.1, 43.1, 43.6, 50.1, 51.8, 51.9, 52.1, 52.4, 63.4, 63.7, 64.5,
65.2, 126.8, 127.1, 127.2, 127.3, 127.6, 127.7, 128.9, 129.8, 129.9,
130.0, 130.1, 130.4, 130.5, 130.6, 131.0, 131.1, 132.3, 133.4, 133.7,
134.0, 134.6, 134.8, 135.2, 135.6, 137.6, 143.5, 143.83, 143.87, 143.9,
144.1, 144.2 ppm; ESI-HRMS calcd m/z for [C40H47N3O6S3 + Na]+
784.2519, found 784.2481.
(6) (a) Pla-Quintana, A.; Roglans, A.; Torrent, A.; Moreno-Manas,
̃
M.; Benet-Buchholz, J. Organometallics 2004, 23, 2762−2767.
́
(b) Torrent, A.; Gonzalez, I.; Pla-Quintana, A.; Roglans, A.;
Moreno-Manas, M.; Parella, T.; Benet-Buchholz, J. J. Org. Chem.
̃
2005, 70, 2033−2041. (c) Gonzal
Synlett 2009, 2844−2848. (d) Brun, S.; Parera, M.; Pla-Quintana, A.;
Roglans, A.; Leon, T.; Achard, T.; Sola, J.; Verdaguer, X.; Riera, A.
Tetrahedron 2010, 66, 9032−9040.
(7) Gonzalez, I.; Bouquillon, S.; Roglans, A.; Muzart, J. Tetrahedron
Lett. 2007, 48, 6425−6428.
(8) Brun, S.; Garcia, L.; Gonzal
́
ez, I.; Pla-Quintana, A.; Roglans, A.
́
̀
́
ASSOCIATED CONTENT
* Supporting Information
■
́
ez, I.; Torrent, A.; Dachs, A.; Pla-
S
Quintana, A.; Parella, T.; Roglans, A. Chem. Commun. 2008, 4339−
Text, tables, figures, and CIF files giving experimental details,
NMR spectra for all new compounds and X-ray crystal
structure data for compounds 1a,c, 1e-trans, and 2c,d,f. This
material is available free of charge via the Internet at http://
pubs.acs.org. The crystallographic data as well as details of the
structure solution and refinement procedures are reported in
Tables 2 and 4. CCDC 836317 (1a), 836318 (1c), 836319
(1e-trans), 836320 (2c), 836321 (2f), and 836322 (2d) also
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge
CB2 1EZ, U.K.: fax, +44 1223 336033; e-mail, deposit@ccdc.
cam.ac.uk.
4341.
(9) (a) Dachs, A.; Torrent, A.; Roglans, A.; Parella, T.; Osuna, S.;
Sola,
Roglans, A.; Sola,
̀
M. Chem. Eur. J. 2009, 15, 5289−5300. (b) Dachs, A.; Osuna, S.;
̀
M. Organometallics 2010, 29, 562−569.
(10) For a review on [2 + 2 + 2] cycloadditions inside macrocyclic
scaffolds, see: Pla-Quintana, A.; Roglans, A. Molecules 2010, 15,
9230−9251.
(11) Yields were not optimized.
(12) The reaction did not proceed at all when carried out at room
temperature.
(13) As an example of how the dihedral angles have been calculated,
for structure 1a (Figure 2), the C2−C3−C6−C7 dihedral angle (entry
1, Table 3) has been calculated as the angle between the planes
defined by the C2−C3−C6 atoms and C3−C6−C7 atoms. We call
this a dihedral angle and not a torsion angle because of the
nonconsecutive nature of the atoms involved.
AUTHOR INFORMATION
Corresponding Author
*anna.plaq@udg.edu.
■
(14) Except for macrocycle 1f, having all triple bonds linked by
unsubstituted positions.
(15) Although the folding of the 1e-cis diastereoisomer is not known
(it has not been possible to obtain suitable crystals for its X-ray
analysis), this might be quite favorable for the cycloaddition reaction
to occur (the reaction time for the mixture of both diastereoisomers is
comparable to that for the unsubstituted macrocycle 1f).
(16) The compound was crystallized from a hexane/dichloromethane
solution.
(17) Hong, S.; Yoon, S.; Yu, B. Tetrahedron Lett. 2005, 46, 779−782.
(18) Pridmore, S. J.; Slatford, P. A.; Williams, J. M. J. Tetrahedron
Lett. 2007, 48, 5111−5114.
ACKNOWLEDGMENTS
■
We would like to thank the Spanish MICINN (projects CTQ2008-
05409 and CTQ2011-23121), and the Generalitat de Catalunya
(project 2009SGR637) for their financial support. S.B. thanks the
University of Girona (UdG) for a predoctoral fellowship.
Spectroscopic data have been partially funded by the University
of Girona under the project with reference STR-CT00059.
(19) Data reduction with SAINT versions 5.0, 6.36A, and 7.60A;
Bruker AXS Inc., Madison, WI, 2000, 2001, and 2007.
(20) SADABS versions 2.10, V2008, and V2008/1; Bruker AXS Inc.,
Madison, WI, 2003 and 2001
(21) SHELXTL versions V6.12 and 6.14: Sheldrick, G. M. Acta
Crystallogr. 2008, A64, 112−122.
(22) SQUEEZE/Platon: Spek, A. L. J. Appl. Crystallogr. 2003, 36,
7−13.
REFERENCES
■
(1) For recent reviews, see: (a) Saito, S.; Yamamoto, Y. Chem. Rev.
2000, 100, 2901−2915. (b) Varela, J. A.; Saa,
́
C. Chem. Rev. 2003, 103,
3787−3801. (c) Yamamoto, Y. Curr. Org. Chem. 2005, 9, 503−519.
(d) Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005,
4741−4767. (e) Chopade, P. R.; Louie, J. Adv. Synth. Catal. 2006, 348,
2307−2327. (f) Gandon, V.; Aubert, C.; Malacria, M. Chem. Commun.
2006, 2209−2217. (g) Heller, B.; Hapke, M. Chem. Soc. Rev. 2007, 36,
1085−1094. (h) Tanaka, K. Synlett 2007, 1977−1993. (i) Agenet, N.;
Buisine, O.; Slowinski, F.; Gandon, V.; Aubert, C.; Malacria, M. Org.
́
React. 2007, 68, 1−302. (j) Varela, J. A.; Saa, C. Synlett 2008, 2571−
2578. (k) Shibata, T.; Tsuchikama, K. Org. Biomol. Chem. 2008, 6,
1317−1323. (l) Galan, B. R.; Rovis, T. Angew. Chem., Int. Ed. 2009, 48,
2830−2834. (m) Tanaka, K. Chem. Asian J. 2009, 4, 508−518.
(n) Inglesby, P. A.; Evans, P. A. Chem. Soc. Rev. 2010, 39, 2791−2805.
(o) Shaaban, M. R.; El-Sayed, R.; Elwahy, A. H. M. Tetrahedron 2011,
67, 6095−6130. (p) Domínguez, G.; Per
́
ez-Castells, J. Chem. Rev.
2011, 40, 3430−3444.
(2) Barkovic, A. J.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1976, 98,
2667−2668.
326
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