Synthesis of unsaturated macrocycles by ru-catalyzed ring-closing metathesis: A comparative study

Article abstract of DOI:10.1002/ejoc.201200960

The activity and stereoselectivity of phosphane- and N-heterocyclic carbene (NHC)-containing ruthenium benzylidene complexes have been evaluated in macrocyclic ring-closing olefin metathesis to produce unsaturated lactones and lactams. The success of the macrocyclization depends on the nature of the ligand (phosphane or N-heterocyclic carbene) on the ruthenium center and on the NHC properties. As for stereoselectivity, E/Z ratios seem to be influenced not only by the nature of the ruthenium catalyst but also by the thermodynamic stabilities of the resulting unsaturated macrocycles, as confirmed by theoretical results. The synthesis of 14-and 15-membered macrolactones and macrolactams by ruthenium-catalyzed ring-closing metathesis is investigated. The reaction outcome is influenced both by the nature of the catalyst and the diene substrate.

Full text of DOI:10.1002/ejoc.201200960

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FULL PAPER
DOI: 10.1002/ejoc.201200960
Synthesis of Unsaturated Macrocycles by Ru-Catalyzed Ring-Closing
Metathesis: A Comparative Study
Fabia Grisi,*[a] Chiara Costabile,[a] Anna Grimaldi,[b] Colomba Viscardi,[b]
Carmela Saturnino,[b] and Pasquale Longo[a]
Keywords: Density functional calculations / Macrocycles / Metathesis / Ruthenium
The activity and stereoselectivity of phosphane- and N-
heterocyclic carbene (NHC)-containing ruthenium benzyl-
idene complexes have been evaluated in macrocyclic ring-
closing olefin metathesis to produce unsaturated lactones
and lactams. The success of the macrocyclization depends on
the nature of the ligand (phosphane or N-heterocyclic carb-
ene) on the ruthenium center and on the NHC properties. As
for stereoselectivity, E/Z ratios seem to be influenced not only
by the nature of the ruthenium catalyst but also by the
thermodynamic stabilities of the resulting unsaturated
macrocycles, as confirmed by theoretical results.
Introduction
The discovery of well-defined catalysts for olefin meta-
thesis has had a tremendous impact on organic synthesis
and polymer chemistry.[1] Among them, Ru-based com-
plexes developed by Grubbs et al. are of special interest
because of their ease of handling and their remarkable tol-
erance towards a wide range of functional groups (e.g., 1–
3 in Scheme 1).[2] They show excellent application profiles
in a variety of metathesis reactions such as ring-closing
metathesis (RCM), cross metathesis (CM), ring-opening
metathesis polymerization (ROMP), ring-opening cross
metathesis (ROCM), acyclic diene metathesis polymeriza-
tion (ADMET), and enyne metathesis.[1,2]
Catalytic RCM of alkenes allows the synthesis of cyclic
compounds containing five- or six-membered and even
higher-membered rings. A ring architecture of 12 or more
atoms is frequent in a large number of natural and unnatu-
ral macrocyclic lactones, lactams, ethers, and ketones, some
of which exhibit important biological properties, such as
antitumor, antibiotic, and antifungal activities; these com-
pounds are also used as perfumery ingredients.[1j,3]
Various studies on macrocyclization reactions by RCM
have been conducted to find appropriate conditions for the
success of the reactions, but there is no clear rule to follow.
Indeed, numerous factors, such as catalyst, steric demand
of the substrate, presence of coordinating heteroatoms, ring
Scheme 1.
size to be formed, solvent, concentration, temperature, and
reaction time, have to be taken into account for synthetic
RCM approaches to macrocyclic compounds.[3k,4]
Our recent interest in the synthesis of Ru-based com-
plexes as active catalysts for olefin metathesis has led to
the identification of a class of Ru catalysts containing N-
heterocyclic carbene ligands with methyl groups on the
NHC backbone in a syn and anti orientation.[5,6] Among
them, complexes with aryl N-substituents of different bulki-
ness (o-tolyl or o-isopropylphenyl) revealed high efficiency
in RCM reactions. In particular, syn complex 4[6a] with o-
tolyl N-substituents (Scheme 1) emerges among the most
efficient catalysts in the formation of hindered olefins
through RCM.
[a] Dipartimento di Chimica e Biologia, Universita’ di Salerno,
Via Ponte Don Melillo, 84084 Fisciano, Salerno, Italy
Homepage: http://www.unisa.it/dipartimenti/dip_chimica_e_
biologia/index
[b] Dipartimento di Scienze Farmaceutiche e Biomediche,
Universita’ di Salerno,
Via Ponte Don Melillo, 84084 Fisciano, Salerno, Italy
E-mail: fgrisi@unisa.it
To further explore the catalytic potential of this latter
catalyst in RCM reactions, herein we describe a systematic
study on the macrocyclic RCM of unsaturated 14- and 15-
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200960.
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F. Grisi, C. Costabile, A. Grimaldi, C. Viscardi, C. Saturnino, P. Longo
FULL PAPER
membered lactones and 14-membered lactams. The cata-
lytic behavior of complex 4 in the formation of these macro-
cyclic frameworks is compared to that of commercial
Results and Discussion
Ring-closure substrates 5–10 are depicted in Table 1.
benchmark catalysts 1,[7] 2,[8] and 3[9] (Scheme 1), in an at- Compounds 5, 7, and 8 were easily prepared by acylation[10]
tempt to find a trend in the reactivity and stereoselectivity of the corresponding commercially available alcohol or
of the different precatalysts.
amine with 10-undecenoyl chloride. Diene ester 6 was ob-
Table 1. Synthesis of macrocyclic lactones and lactams by RCM of dienes 5–10 with catalysts 1–4.[a]
[a] Reactions in CH2Cl2 (4 mm) at reflux temperature. [b] Determined by GC and NMR spectroscopy. [c] E/Z ratios were determined by
GC. [d] E/Z ratios obtained from DFT calculated energies in CH2Cl2 (for computational details see the Experimental Section).
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Unsaturated Macrocycles by Ru-Catalyzed Ring Closing Metathesis
tained by esterification of 2-hydroxystyrene[11] with unde- both geometrical isomers. Although the effect of catalyst on
cen-10-enoic acid; diene amides 9 and 10 were prepared by the geometric ratios of products formed by RCM reactions
condensation[12] of undecen-10-enoic acid with 2-vinyl- must be examined on a case-by-case basis, 1st generation
aniline[13] and 4-metoxy-2-vinylaniline,[14] respectively. Sub- catalysts are, in general, prone to produce macrocyclic com-
strates 5–10 were subjected to the macrocyclic RCM reac- pounds with a relatively kinetic E/Z ratios, whereas 2nd
tion with the catalyst (5 mol-%) in refluxing CH2Cl2, under generation catalysts are likely to give products under
high-dilution conditions (0.004 m), as described in thermodynamic control.[1e,3h,3k,3l]
Scheme 2. The formation of corresponding unsaturated
To afford further information on catalyst behavior,
lactones and lactams 11–16 was monitored by GC analysis thermodynamic stabilities of the E and Z isomers of 11
over a period of 24 h, and the most relevant results are sum- were evaluated by DFT calculations. Minimum-energy
marized in Table 1. All reactions were performed at least in structures and energies of 11-E and 11-Z are reported in
duplicate to confirm reproducibility.
Figure 1, whereas the relative calculated populations of the
two isomers in equilibrium are shown in Table 1. Isomer
11-E is favored by 2.1 kcalmol–1 over 11-Z, not only due to
the intrinsic stability of the trans double bond, but also as
a consequence of the higher energy of 11-E, which results
from two instances of eclipsing C–C atoms arising from
nearly gauche(+)–gauche(–) conformations. The distances
Scheme 2.
of the eclipsed
C atoms, which are shorter than
van der Waals distances, are indicated in Figure 1. The cal-
The ring closure of diene ester 5 was successfully carried culated E/Z populations are very close to the experimental
out by using catalysts 1 and 2 (Table 1, entries 1 and 2); ratio found for products obtained in the presence of cata-
Grubbs 2nd generation catalyst 2 performed slightly better lysts 2–4, confirming the tendency of these catalysts to give
than Grubbs 1st generation catalyst 1. This is in line with thermodynamic control.
previously reported results that show enhanced activities in
the macrocyclic RCM of a 14-membered lactone with a Ru
complex bearing an NHC (1,3-dimesytil-4,5-dihydroimid-
azol-2-ylidene) ligand (i.e., 2) with respect to its parent di-
phosphane complex (i.e., 1).[15] Conversions were lower
with catalysts 3 and 4 (Table 1, entries 3–6), and the maxi-
mum value was reached within 4 h of reaction, suggesting
that the replacement of the mesityl groups with less bulky
o-tolyl groups on the nitrogen atoms of the NHC ligand
has a detrimental effect on the efficiency of the Ru com-
plexes. This can be explained by considering that Ru cata-
lysts bearing NHCs with reduced bulk at the ortho positions
of N-aromatic substituents are rather unstable and are sus-
ceptible to decomposition through C–H activation pro-
cesses of the N-aryl groups on the NHC ligand.[16] Very
likely, the different macro-RCM reactivities observed for 3
and 4 are related to the different substitution patterns of
the NHC backbone. As already reported, the presence of
methyl groups on the NHC backbone improves catalyst sta-
bility, because restriction of the rotation of the N-aryl
group hinders the necessary proximity of an aryl C–H bond
and the ruthenium center to promote degradation path-
ways.[6,17]
In this RCM reaction, catalysts 2–4 displayed identical
stereoselectivity, furnishing macrocyclic product 11 with
very high E/Z ratios (94:6) regardless of the structure of the
RCM initiator. When 1 was employed as the catalyst, a
lower E/Z ratio (83:17) was observed. The results obtained
for the formation of macrolactone 11 with 1 and 2 are con-
sistent with literature data, both in yield and E/Z selectiv-
ity.[12,18] It is worth to note that the stereochemical outcome
of the RCM reaction to produce macrocycles is not easy to
predict and control, and in principle, the E/Z selectivity of
the olefin product reflects the thermodynamic stabilities of distances are in Å.
Figure 1. Structures and internal energies of the E and Z isomers of
compounds 11–13 calculated in CH2Cl2. Energies are in kcalmol–1,
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F. Grisi, C. Costabile, A. Grimaldi, C. Viscardi, C. Saturnino, P. Longo
FULL PAPER
Initiators 1–4 were then investigated in the macrocyclic tally observed E/Z ratios, indicating a mainly thermody-
RCM of 6 to give 14-membered lactone 12. This substrate namically controlled RCM in the formation of 13, for all
is characterized by the same double bond position within catalysts. As reported in Figure 1, internal energies of the
the macrocyclic ring as 1 but differs from the latter for the minimum-energy structures of the E and Z isomers of 13
presence of an aromatic ring located between the ester and are very close; 13-E is less stable than 13-Z by
the olefinic functionalities. The aromatic ring was installed 0.3 kcalmol–1. In the case of 15-membered rings, the lower
on the macrocyclization precursor as conformational con- stability of the E isomer is due to the presence of two in-
straint to facilitate metathesis ring-closure reactions.[4]
stances of eclipsing C–C atoms arising from a gauche(+)–
From the analysis of the data reported in Table 1, macro- gauche(–) conformation. This unfavorable conformation is
cyclic RCM of 6 performed with diphosphane catalyst 1 only partially compensated by the intrinsic stability of the
gave very poor yields (Table 1, entries 7 and 8), and the E/ trans double bond.
Z ratio slightly changed during the course of the reaction
We next examined the efficiency of catalysts 1–4 in the
to approach the thermodynamic value, as a consequence of RCM of amide dienes 8–10 to form macrolactams 14–16.
secondary metathesis reactions that can cause isomeriza- These latter RCM products present the same ring size and
tion. The decreased efficiency of 1 in the formation of 12 is the same double bond position within the macrocyclic ring
not surprising. Indeed, it was found to be totally ineffective as macrolactones 5 and 6. As widely described in the litera-
in the synthesis of a very similar macrolactone, the macro- ture, the nature of the heteroatoms influences the cycliza-
lide (S)-zearalenone, for attempted cyclizations of the re- tion reaction leading to a variety of results.[20] The effect of
quired styrenyl precursor.[19] On the other hand, the pres- the heteroatom appears evident in the ring closure of 8 with
ence of a cyclic conformational constraint in substrate 6 has catalyst 1 (Table 1, entries 20 and 21), which proceeded in
proven to have a beneficial effect on the same macro-RCM lower yield (28% in 24 h) with respect to the analogous re-
reaction carried out with monophosphane catalysts 2 and 4 action (Table 1, entry 1) to form macrolactone 11 (97% in
(Table 1, entries 9 and 12), which gave the only E-config- 4 h). For catalysts 2–4 (Table 1, entries 22–27), the general
ured product in quantitative yield. As previously observed, trend in yield is in alignment with that of previous RCM
for 3, conversions were slightly lower than those for 4, indi- reactions (Table 1, entries 2–6), but also in this case the
cating also in this case an appreciable influence of the sub-
stitution pattern of the backbone of the NHC on the ac-
tivity of the catalyst, whereas no difference in the stereo-
chemical outcome of the reaction was detected. It is worth
underlining that E-alkene units are frequently found in
macrocyclic natural products, but the synthesis of large
rings containing E-alkenes still represents a challenge.[3l]
The stereoselective course of this reaction is probably due
to the presence of the phenyl ring as a conformational con-
straint in 6, which favorably predisposes the reacting sites
of dienes during the metathesis ring closure. The excellent
E/Z selectivity observed is consistent with the calculated E/
Z ratio (99.8:0.2 in Table 1). Indeed, as shown in Figure 1,
the stability of the E isomer with respect to the Z isomer
for macrocycle 12 is very significant (ΔE = 3.8 kcalmol–1).
As for 12-Z, the lack of conjugation of the double bond
with the close aromatic ring, as indicated by the 77° torsion
angle reported in Figure 1, plays the main role in decreasing
the stability of the Z isomer.
Treatment of diene 7 (Table 1, entries 13–15) with cata-
lysts 1 and 2 furnished the corresponding 15-membered
macrolactone 13 in good yields, whereas unsatisfactory re-
sults were obtained with catalysts 3 and 4 (Table 1, en-
tries 16–19). The presence of one more carbon atom than
that in substrate 5 renders the cyclization reaction more dif-
ficult for monophosphane catalysts 3 and 4. Indeed, they
lose activity within 2 h from the beginning of the reaction,
which means, once again, a major tendency of these com-
plexes to decompose. From analysis of the E/Z ratios, in
this RCM reaction, the Z isomer of 13 was preferentially
formed. A very similar Z-selectivity was observed for cata-
lysts 1–4 (Table 1, entries 13–19). Once again, the calculated
E/Z populations (38.3:61.7) well reproduced the experimen- distances are in Å.
Figure 2. Structures and internal energies of the E and Z isomers of
compounds 14–16 calculated in CH2Cl2. Energies are in kcalmol–1,
4
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Unsaturated Macrocycles by Ru-Catalyzed Ring Closing Metathesis
presence of nitrogen led to less satisfactory results.[21] Com- vored E selectivity in the presence of all tested catalysts and
parison of results for ring closures of 9 and 10 shows that improved cyclization promoted by catalysts 3 and 4. Molec-
the introduction of a methoxy substituent on the aromatic ular modeling studies, performed to compare the relative
ring does not affect the cyclization reactions (Table 1, en- stabilities of the E and Z isomers of compounds 11–16,
tries 28–35, 36–43). As for the E/Z selectivity, it appears to indicate that for all compounds except 13 the favored
be clear that the stereochemical outcome of the examined thermodynamic product is the E isomer. In fact, calculated
RCM reactions is not influenced by the nature of the het- E/Z ratios for 11, 12, 14, 15, and 16 are Ͼ95:5, which re-
eroatom.
flects well the thermodynamic control of macrocycle RCM
Calculated minimum-energy structures for the E and Z in the presence of catalysts 2–4. This observation is further-
isomers of compounds 14–16 are reported in Figure 2. The more confirmed by the calculated E/Z population for 15-
replacement of oxygen with –NH– in the macrocyclic ring membered ring 13, which shows a slight prevalence of the
produces only slight conformational differences between the Z isomer (about 40:60), reproducing experimental E/Z ratio
lactones and the corresponding lactams. Indeed, for macro- obtained with all catalysts.
cycles 14–16, the E isomer was found to be about
2 kcalmol–1 more stable than the corresponding Z isomer,
indicating that under thermodynamic control the E isomer
Experimental Section
would prevail Ͼ95% in solution.
Experimental Details: All reactions involving metal complexes were
conducted in oven-dried glassware under a nitrogen atmosphere
with anhydrous solvents by using standard Schlenk techniques and
glove box techniques. Toluene and THF were distilled from so-
dium/benzophenone. CH2Cl2 was dried with CaH2 and freshly dis-
tilled before use. All chemical products were purchased from
Sigma–Aldrich and were reagent quality. These products were used
without further purification. The syntheses of substrates 5, 7, and
8 were carried out according to published procedures.[10] Ru cata-
lyst 4 was prepared as previously reported.[6a] Macrocycles 11,[22]
13,[23] and 14[18] were already known. Flash column chromatog-
raphy of organic compounds was performed by using silica gel 60
Conclusions
In this report, we have carried out a comparative study
on the synthesis of 14- and 15-membered lactones and lact-
ams (i.e., 11–16) by RCM of the corresponding dienes (i.e.,
5–10) with phosphane (i.e., 1) and NHC-containing cata-
lysts (i.e., 2–4). Much attention was focused on the influ-
ence of the N-aryl group and the substitution of the back-
bone of the NHC ligands in controlling the macrocycliza- (230–400 mesh). Analytical thin-layer chromatography (TLC) was
performed by using silica gel 60 F254 precoated plates (0.25 mm
thickness) with a fluorescent indicator. Visualization of the TLC
plate was performed by UV light or by using KMnO4 or I2 stains.
NMR spectra were recorded with a Bruker AM300 and Bruker
Avance 400 instruments operating at 300 and 400 MHz for 1H,
respectively. The 1H and 13C chemical shifts are referenced to
SiMe4 (δ = 0 ppm) by using the residual protio impurities of the
deuterated solvents as internal standard. GC analysis were per-
formed by using a Thermo Finnigan gas chromatograph equipped
with a FAMEWAX (Crossbond polyethylene glycol) capillary col-
tion outcome. Catalyst 1 was found to be highly efficient in
the formation of macrolactones 11 and 13, whereas it was
poorly active in the macrocyclic RCM of 12 and 14. The
synthesis of macrolactams 15 and 16 could not be achieved
with this catalyst. Catalyst 2 afforded macrocyclic com-
pounds 11–16 in good to excellent yields, whereas catalysts
3 and 4 with different NHC bulkiness showed a marked
dependence on the nature of the substrate in terms of ac-
tivity. The higher macro-RCM reactivity displayed by cata-
lyst 4 compared to 3 can be related to the increased stability umn for compound 8 and an OPTIMA 5 (5% phenyl/95% dimeth-
ylpolysiloxane) capillary column for all the other substrates.
of catalyst 4, which is less susceptible to degradation as a
result of the presence of methyl groups on the NHC back-
bone. Interestingly, the general trend in yield with mono-
phosphane catalysts 2–4 highlights that small variations in
the NHC aryl N-substituents and/or substitution of the
backbone lead to different catalyst behavior in RCM reac-
tions. More in detail, catalyst 2 with N-mesityl groups is
more efficient than catalysts 3 and 4 bearing N-o-tolyl
groups, whereas backbone-substituted catalyst 4 is more
active than catalyst 3 without backbone substitution. These
results are consistent with the notion that metathesis cata-
lysts need to be screened to determine the best catalyst for
a reaction and that no single catalyst is the most efficient
for all substrates.
General Procedures for the Synthesis of Substrates 6, 9, and 10:[12]
To a solution of 10-undecenoic acid (1.0 equiv.) in dichloromethane
was added triethylamine (4.0 equiv.) and 1-propylphosphonic acid
cyclic anhydride (1.2 equiv.) whilst stirring. After 15 min at room
temperature, the appropriate alcohol or amine (1.2 equiv.) was
added, and the mixture was stirred at room temperature for 2 h.
The solvent was removed under reduced pressure, and the residue
was purified by column chromatography on silica gel (hexane/
EtOAc, 5:1 for 6; hexane/EtOAc, 7:1 for 9 and 10).
1
6: Colorless oil (50%). H NMR (400 MHz, CDCl3): δ = 7.58 (d,
J = 7.7 Hz, 1 H), 7.26 (dt, J = 7.7 Hz, 2 H), 7.04 (d, J = 7.9 Hz, 1
H), 6.76 (dd, J = 11.0, 17.7 Hz, 1 H), 5.83 (m, 1 H), 5.76 (d, J =
17.7 Hz, 1 H), 5.33 (d, J = 11.0 Hz, 1 H), 5.01 (d, J = 17.4 Hz, 1
H), 4.95 (d, J = 10.5 Hz, 1 H), 2.60 (t, J = 7.6 Hz, 2 H), 2.06 (q, J
= 7.4 Hz, 2 H), 1.79 (m, 2 H), 1.48–1.27 (br. m, 10 H) ppm. 13C
NMR (400 MHz, CDCl3): δ = 172.3, 148.2, 139.4, 130.6, 130.4,
128.9, 126.6, 126.3, 122.8, 116.5, 114.4, 34.5, 34.0, 29.9, 29.5, 29.4,
29.3, 29.2, 29.1, 26.6, 25.2 ppm.
As for stereoselectivity, the E/Z ratios seem to be in-
fluenced by the nature of the ligand (phosphane or N-
heterocyclic carbene) on the ruthenium center as well as by
the thermodynamic stabilities of the resulting unsaturated
macrocycles. The presence of an aromatic ring system as
9: White microcrystalline solid (70%). 1H NMR (400 MHz,
conformational control element (substrates 6, 9, and 10) fa- CD2Cl2): δ = 7.76 (d, J = 7.7 Hz, 1 H), 7.46 (d, J = 7.5 Hz, 1 H),
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7.27 (t, J = 7.7 Hz, 1 H), 7.15 (t, J = 7.5 Hz, 1 H), 7.09 (br. s, NH), basis set with polarization functions of Ahlirchs and co-worker
6.81 (dd, J = 10.9, 17.3 Hz, 1 H), 5.82 (m, 1 H), 5.69 (d, J =
17.3 Hz, 1 H), 5.41 (d, J = 10.9 Hz, 1 H), 4.98 (d, J = 17.1 Hz, 1
H), 4.92 (d, J = 10.2 Hz, 1 H), 2.35 (t, J = 7.3 Hz, 2 H), 2.04 (q, J
= 6.9 Hz, 2 H), 1.70 (m, 2 H), 1.43–1.24 (m, 10 H) ppm. 13C NMR
(250 MHz, CD2Cl2): δ = 171.9, 139.9, 135.3, 132.7, 131.2, 128.8,
127.2, 125.8, 124.5, 118.0, 114.4, 38.0, 34.4, 29.9, 29.6, 29.5,
26.2 ppm.
(standard SVP basis set in Gaussian09), for H, C, N, and O.[29]
Minimum free-energy structures were characterized by the presence
of zero imaginary frequency. Solvent effects were estimated in cal-
culations based on the polarizable continuous solvation model
PCM. CH2Cl2 was chosen as model solvent.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization of all new com-
pounds as well as Cartesian coordinates and internal energies of
calculated structures.
10: White microcrystalline solid (70%). 1H NMR (400 MHz,
CDCl3): δ = 7.56 (d, J = 8.8 Hz, 1 H), 6.97 (d, J = 2.9 Hz, 1 H),
6.95 (s, NH), 6.84 (dd, J = 2.9, 8.9 Hz, 1 H), 6.75 (dd, J = 10.9,
17.6 Hz, 1 H), 5.87–5.75 (m, 1 H), 5.67 (d, J = 17.5 Hz, 1 H), 5.38
(d, J = 10.9 Hz, 1 H), 4.98 (d, J = 17.3 Hz, 1 H), 4.92 (d, J =
10.2 Hz, 1 H), 3.81 (s, 3 H), 2.36 (t, J = 7.5 Hz, 2 H), 2.07–1.98
(m, 2 H), 1.77–1.68 (m, 2 H), 1.43–1.23 (m, 10 H) ppm. 13C NMR
(400 MHz, CDCl3): δ = 171.8, 157.5, 139.4, 132.9, 132.5, 127.7,
126.4, 117.9, 114.4, 114.2, 111.8, 55.7, 37.6, 34.0, 29.5, 29.3, 29.1,
26.0 ppm.
Acknowledgments
The authors wish to thank Patrizia Oliva for the technical assist-
ance. Computational support from CINECA - High Performance
Computing Portal in the framework of class C awarded proposal
to the ISCRA programme (code RCMMSCMO - HP10C8VOGT)
and financial support from the Ministero dellЈUniversità e della
Ricerca Scientifica e Tecnologica are gratefully acknowledged.
Representative Procedure for the Synthesis of Macrocyclic Com-
pounds 11–16:[24] A 100-mL three-necked round-bottomed flask
was fitted with a condenser and two additional funnels. Solutions
of the ruthenium carbene (6.0 μmol) and the diene (120 μmol), each
in CH2Cl2 (10 mL), were independently added dropwise to re-
fluxing CH2Cl2 (10 mL) over a period of 15 min under a nitrogen
atmosphere. Aliquots were removed periodically for GC analysis,
and GC retention times and integration were confirmed with sam-
ples of authentic material. After 24 h, the solvent was removed in
vacuo, and the residue was purified by flash chromatography (hex-
ane/ethyl acetate, 10:1 for 12; hexane/ethyl acetate, 6:4 for 15, hex-
ane/ethyl acetate, 5:2 for 16) to afford analytically pure compounds.
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12: E isomer was obtained as a colorless oil (89%). 1H NMR
(400 MHz, CDCl3): δ = 7.52 (d, J = 7.7 Hz, 1 H), 7.31–7.19 (m, 2
H), 7.08 (d, J = 7.7 Hz, 1 H), 6.59 (d, J = 15.9 Hz, 1 H), 6.11 (dt,
J = 6.7, 16.0 Hz, 1 H), 2.64 (m, 2 H), 2.31 (q, J = 6.17 Hz, 2 H),
1.84 (br. m, 2 H), 1.61–1.28 (m, 10 H) ppm. 13C NMR (400 MHz,
CDCl3): δ = 172.1, 147.5, 132.9, 131.0, 127.7, 126.7, 126.2, 124.1,
123.0, 35.1, 30.6, 27.4, 26.1, 25.9, 25.3, 25.0, 24.0 ppm. C17H22O2
(258.36): calcd. C 79.03, H 8.58; found C 79.02, H 8.56.
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15: E isomer was obtained as an off-white microcrystalline powder
(85%). 1H NMR (300 MHz, CDCl3): δ = 7.79 (d, J = 7.9 Hz, 1 H),
7.34 (d, J = 7.4 Hz, 1 H), 7.25 (t, J = 7.9 Hz, 1 H), 7.13 (t, J =
7.4 Hz, 1 H), 6.49 (d, J = 15.7 Hz, 1 H), 5.97 (dt, J = 6.9, 15.7 Hz,
1 H), 2.47 (m, 2 H), 2.20 (q, J = 6.23 Hz, 2 H), 1.80–1.26 (m, 12
H) ppm. 13C NMR (300 MHz, CDCl3): δ = 171.6, 135.5, 134.2,
131.6, 127.9, 127.3, 125.8, 125.7, 124.2, 37.7, 31.0, 27.5, 26.7, 26.1,
25.6, 25.0 ppm. C17H23NO (257.37): calcd. C 79.33, H 9.01, N 5.44;
found C 79.33, H 9.03, N 5.42.
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1
16: E isomer was obtained as an off-white solid (87%). H NMR
(400 MHz, CDCl3): δ = 7.50 (d, J = 8.7 Hz, 1 H), 7.08 (br. s, 1 H,
NH), 6.93 (d, J = 2.9 Hz, 1 H), 6.80 (dd, J = 2.9, 8.8 Hz, 1 H),
6.48 (d, J = 15.8 Hz, 1 H), 6.03 (dt, J = 6.6, 15.7 Hz, 1 H), 3.82 (s,
3 H), 2.48–2.40 (m, 2 H), 2.29 (q, J = 6.2 Hz, 2 H), 1.85–1.18 (m,
12 H) ppm. 13C NMR (400 MHz, CDCl3): δ = 172.0, 157.8, 134.6,
134.3, 127.1, 127.0, 125.7, 113.2, 111.9, 55.6, 37.5, 30.8, 27.4, 26.7,
25.9, 25.8, 25.7, 24.8 ppm. C18H25NO2 (287.40): calcd. C 75.22, H
8.77, N 4.87; found C 75.20, H 8.76, N 4.87.
Computational Details: Density functional calculations were per-
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BP86 was used as a functional and gradient corrections were taken
from the work of Becke and Perdew.[26–28] The electronic configura-
tion of the molecular systems was described by the split-valence
6
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Unsaturated Macrocycles by Ru-Catalyzed Ring Closing Metathesis
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Received: July 18, 2012
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20960
/KAP1
Date: 06-09-12 15:34:09
Pages: 8
F. Grisi, C. Costabile, A. Grimaldi, C. Viscardi, C. Saturnino, P. Longo
FULL PAPER
Macrocycles
The synthesis of 14-and 15-membered
macrolactones and macrolactams by ruth-
enium-catalyzed ring-closing metathesis is
investigated. The reaction outcome is in-
fluenced both by the nature of the catalyst
and the diene substrate.
F. Grisi,* C. Costabile, A. Grimaldi,
C. Viscardi, C. Saturnino,
P. Longo ............................................ 1–8
Synthesis of Unsaturated Macrocycles by
Ru-Catalyzed Ring-Closing Metathesis: A
Comparative Study
Keywords: Density functional calculations /
Macrocycles / Metathesis / Ruthenium
8
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