Synthesis of alkyl-substituted six-membered lactones through ring-closing metathesis of homoallyl acrylates. An easy route to pyran-2-ones, constituents of tobacco flavor

Article abstract of DOI:10.1021/jo070600h

(Chemical Equation Presented) The ring-closing metathesis (RCM) reactions of homoallylic acrylates bearing alkyl substituents on various positions of their skeleton afford the corresponding pentenolides in the presence of carbene ruthenium catalysts. For R³ = R⁴ = H, or R³ = Me, R⁴ = H, the reactions are catalyzed by complex [RuCl ₂(PCy₃)₂(=CHPh)], while a second-generation Grubbs catalyst is required when R³ = H and R⁴ = Me, R³ = R⁴ = Me, or R³ = i-Pr and R⁴ = H. Alkyl substitution at the homoallylic carbon (R¹, R²) increases the yield of the reaction when both the acrylic and/or homoallylic double bonds are methyl-substituted. The interaction of the catalyst with the substrate in the initiation stage involves the homoallylic double bond rather than the acrylic moiety, and the resulting alkylidene species from the first-generation Grubbs catalyst can be observed by ¹H and ³¹P NMR. The racemic tobacco constituents 4-isopropyl-5,6- dihydropyran-2-one and 4-isopropyltetrahydropyran-2-one are prepared via a short reaction sequence, involving the RCM reaction as the key transformation.

Full text of DOI:10.1021/jo070600h

Synthesis of Alkyl-Substituted Six-Membered Lactones through
Ring-Closing Metathesis of Homoallyl Acrylates. An Easy Route to
Pyran-2-ones, Constituents of Tobacco Flavor
Andrea D’Annibale* and Laura Ciaralli
Dipartimento di Chimica, and Istituto CNR di Chimica Biomolecolare, Sezione di Roma, UniVersita` degli
Studi “La Sapienza”, P.le Aldo Moro 5, 00185 Roma, Italy
Mauro Bassetti* and Chiara Pasquini
Istituto CNR di Metodologie Chimiche, Sezione Meccanismi di Reazione, Dipartimento di Chimica,
UniVersita` degli Studi “La Sapienza”, P.le Aldo Moro 5, 00185 Roma, Italy
andrea.dannibale@uniroma1.it; mauro.bassetti@uniroma1.it
ReceiVed March 22, 2007
The ring-closing metathesis (RCM) reactions of homoallylic acrylates bearing alkyl substituents on various
positions of their skeleton afford the corresponding pentenolides in the presence of carbene ruthenium
catalysts. For R3 ) R4 ) H, or R3 ) Me, R4 ) H, the reactions are catalyzed by complex [RuCl2(PCy3)2-
(dCHPh)], while a second-generation Grubbs catalyst is required when R3 ) H and R4 ) Me, R3 ) R4
) Me, or R3 ) i-Pr and R4 ) H. Alkyl substitution at the homoallylic carbon (R1, R2) increases the yield
of the reaction when both the acrylic and/or homoallylic double bonds are methyl-substituted. The
interaction of the catalyst with the substrate in the initiation stage involves the homoallylic double bond
rather than the acrylic moiety, and the resulting alkylidene species from the first-generation Grubbs catalyst
1
can be observed by H and 31P NMR. The racemic tobacco constituents 4-isopropyl-5,6-dihydropyran-
2-one and 4-isopropyltetrahydropyran-2-one are prepared via a short reaction sequence, involving the
RCM reaction as the key transformation.
Introduction
and the catalysts are molybdenum or ruthenium carbene
complexes.2,4
Five- and six-membered lactones are widely present as
structural subunits in a large number of natural compounds
showing important biological activities.1 Since the olefin ring-
closing metathesis (RCM) reaction represents a powerful tool
to obtain cyclic alkenes,2 various syntheses of unsaturated
lactones by RCM of R,ω-diolefins have been reported in the
literature.3 Diene esters are suitable substrates for these reactions,
When the organic precursors are acrylates, Lewis acids can
be used as additives to promote the reactions catalyzed by first-
(2) Recent reviews on alkene metathesis: (a) Grubbs, R. H. Tetrahedron
2004, 60, 7117-7140. (b) Schrock, R. R.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2003, 115, 4740-4782. (c) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18-29. (d) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39,
3012-3043. (e) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998,
371-388.
(1) (a) Eidman, K. F.; MacDougall, B. S. J. Org. Chem. 2006, 71, 9513-
9516. (b) Schmidt, T. J. Curr. Org. Chem. 1999, 3, 577-608. (c) Marles,
R. J.; Pazos-Sanou, L.; Compadre, C. M.; Pezzuto, J. M.; Bloszyk, E.;
Arnason, J. T. Recent AdV. Phytochem. 1995, 29, 333-356. (d) Robles,
M.; Aregullin, M.; West, J.; Rodriguez, E. Planta Med. 1995, 61, 199-
203. (e) Fukusaki, E.; Senda, S.; Nakazono, Y.; Omata, T. Tetrahedron
1991, 47, 6223-6230. (f) Mori, K. Tetrahedron 1989, 45, 3233-3298. (g)
Bloch, R.; Gilbert, L. J. Org. Chem. 1987, 52, 4603-4605. (h) Sanemitsu,
Y.; Uematsu, T.; Inoue, S.; Tanaka, K. Agric. Biol. Chem. 1984, 48, 1927-
1929. (i) Rao, Y. S. Chem. ReV. 1976, 76, 625-694.
(3) (a) Fu¨rstner, A.; Langemann, K. Synthesis 1997, 792-803. (b) Ghosh,
A. K.; Cappiello, J.; Shin, D. Tetrahedron Lett. 1998, 39, 4651-4654. (c)
Dirat, O.; Kouklovsky, C.; Langlois, Y.; Lesot, P.; Courtieu, J. Tetrahe-
dron: Asymmetry 1999, 10, 3197-3207. (d) Gosh, A. K.; Liu, C. Chem.
Commun. 1999, 1743-1744. (e) Cossy, J.; Bauer, D.; Bellosta, V.
Tetrahedron Lett. 1999, 40, 4187-4188. (f) Ramachandran, P. V.; Reddy,
M. V. R.; Brown, H. C. Tetrahedron Lett. 2000, 41, 583-586. (g) Carda,
M.; Rodr´ıguez, S.; Gonza´lez, F.; Castillo, E.; Villanueva, A.; Marco, J. A.
Eur. J. Org. Chem. 2002, 2649-2655. (h) Deiters, A.; Martin, S. F. Chem.
ReV. 2004, 104, 2199-2238.
10.1021/jo070600h CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/13/2007
J. Org. Chem. 2007, 72, 6067-6074
6067

D’Annibale et al.
SCHEME 1. RCM of Allylic Acrylates Catalyzed by
Complex [RuCl2(PCy3)2(dCHPh)] (I)
sors. In particular, we have focused our attention on the effect
of alkyl substitution on the RCM reaction. In fact, while the
presence of alkyl groups on the double bonds poses increasing
limits to the reactivity of the diene precursors in the ring-closing
process, naturally occurring pentenolides of synthetic interest
are characterized by specific alkyl substitution patterns.1 There-
fore, the influence of this structural feature on reaction
parameters, such as catalyst loading, reaction times, and the
choice of the appropriate catalyst, is the subject of this work.
We then report on a straightforward synthetic route to isopropyl-
substituted six-membered lactones, as an application of the RCM
approach to the preparation of racemic pyran-2-one tobacco
constituents.
generation Grubbs catalysts. For instance, Ti(i-OPr)4 in sto-
ichiometric or catalytic amounts increases the reactivity of the
electron-poor acrylic double bond toward RCM, as an effect of
weak coordination of the ester group.5 The substrate reactivity
is further inhibited by an alkyl substituent on either the (homo)-
allylic or the acrylic double bond, as the result of steric
hindrance. With regards to the synthesis of lactones with tri- or
tetrasubstituted double bonds through RCM reaction, some
examples are reported in literature, employing second-gen-
eration6a,c,d or, exceptionally, first-generation Grubbs catalysts.6b
Although the use of either additives or the most efficient metal
catalysts renders the RCM reaction a useful procedure for the
preparation of lactones, the optimal reaction conditions with
respect to the structural features of the acrylic diene precursor
and/or the type of the required catalyst have not been specifically
discussed.
Results and Discussion
We have investigated the RCM reaction of homoallyl
acrylates 3-6 by catalysis of carbene ruthenium complexes
chosen among the commercially available compounds I-IV,
which are commonly used in olefin metathesis (Scheme 2).
Esters 3-6, bearing different alkyl substituents along the
carbon chain, were prepared by acylation of homoallylic alcohols
R1R2C(OH)CH2C(R3)dCH2 1 and 2 with acryloyl or meth-
acryloyl chloride (for experimental procedures and yields of
3-6, see Supporting Information).
The RCM reactions of acrylates 3a-d, which are function-
alized with two monosubstituted double bonds, were carried
out upon addition of catalyst I (Scheme 3), in order to test the
activity of the first-generation Grubbs catalyst on these sterically
unhindered diene systems.
In a typical experiment, complex I in 16 mL of dichlo-
romethane (0.17 mmol, 0.01 M) was added dropwise to a
refluxing solution of 3 in 160 mL of dichloromethane (1.7 mmol,
0.01 M). The consumption of the substrate was checked by TLC,
and the reaction was stopped after 6 h, when starting material
could no longer be detected. The expected lactones 7a-d were
isolated in good yields, as reported in Table 1.
The yields of the reaction are not affected by the presence of
an alkyl substituent (R1) on the homoallylic carbon (entries 1-3)
or by an increase in its substitution degree (entry 4, R1 ) R2 )
n-Pr). Substrates 3, functionalized with unhindered double
bonds, appear to be insensitive toward a potential gem-dialkylic
effect, which is otherwise known to produce a dramatic increase
on yields and rates of many ring-closing reactions, including
RCM.9 The reaction of the homoallylic acrylate 3c can be
performed with catalyst loads lower than 10 mol %, without
affecting the yield of the six-membered lactone 7c (entries 1,
5, and 6). We have previously observed in the RCM of methallyl
acrylate esters shown in Scheme 1 that comparable reaction
yields were obtained using either 5 or 10 mol % of complex I.7
Thus, these experiments confirm our previous findings; that is,
the acrylic double bond is not a crucial functionality for the
first-generation Grubbs catalyst.
We have previously reported on the RCM of acrylic esters
bearing a methyl group on the allylic double bond, for the
preparation of R,â-unsaturated 4,5-disubstituted γ-lactones
(Scheme 1).7
Although the combination of an electron-deficient acrylic
double bond and a methyl group on the allylic moiety was
expected to be incompatible with a first-generation Grubbs
catalyst,2,6a we obtained 4-methyl-5-alkyl-γ-lactones in good to
high yields, using complex [RuCl2(PCy3)2(dCHPh)] (I) as
catalyst and in the absence of other promoters. The proximity
of the two double bonds in the diene and the stability of the
resulting five-membered lactones may have counterbalanced the
unfavorable steric and electronic features of the acrylates. In
addition, we optimized the activity of the catalyst by using high
dilution conditions as well as by providing a constant supply
of fresh catalyst via dropwise addition of solutions of complex
I to the reaction mixture. While the slow addition of the catalyst
was adopted only occasionally in the lactone synthesis,3a,f,6b
this procedure or the related portion-wise addition for large
scale preparations has been widely employed in RCM
reactions.3a,8
We now report on the preparation of six-membered R,â-
unsaturated lactones, starting from homoallylic acrylate precur-
(4) (a) Castarlenas, R.; Fischmeister, C.; Bruneau, C.; Dixneuf, P. H. J.
Mol. Catal. A 2004, 213, 31-37. (b) Fu¨rstner, A.; Liebl, M.; Lehmann, C.
W.; Picquet, M.; Kunz, R.; Bruneau, C.; Touchard, D.; Dixneuf, P. H.
Chem.sEur. J. 2000, 6, 1847-1857. (c) Fu¨rstner, A.; Ackermann, L. Chem.
Commun. 1999, 95-96.
(5) (a) Fu¨rstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119, 9130-
9136. (b) Fu¨rstner, A.; Guth, O.; Du¨ffels, A.; Seidel, G.; Liebl, M.; Gabor,
B.; Mynott, R. Chem.sEur. J. 2001, 7, 4811-4820. (c) Wybrow, R. A. J.;
Johnson, L. A.; Auffray, B.; Moran, W. J.; Adams, H.; Harrity, J. P. A.
Tetrahedron Lett. 2002, 43, 7851-7854. (d) Fu¨rstner, A.; Schlede, M. AdV.
Synth. Catal. 2002, 344, 657-665. (e) Kangani, C. O.; Brukner, A. M.;
Curran, D. P. Org. Lett. 2005, 7, 379-382. (f) Yadav, J. S.; Prathap, I.;
Tadi, B. P. Tetrahedron Lett. 2006, 47, 3773-3776.
(6) (a) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan,
S. P. J. Org. Chem. 2000, 65, 2204-2207. (b) Fu¨rstner, A.; Dierkes, T.
Org. Lett. 2000, 2, 2463-2465. (c) Chatterjee, A. K.; Morgan, J. P.; Scholl,
M.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 3783-3784. (d) Grela,
K.; Kim, M. Eur. J. Org. Chem. 2003, 963-966.
(7) Bassetti, M.; D’ Annibale, A.; Fanfoni, A.; Minissi, F. Org. Lett.
2005, 7, 1805-1808.
The subsequent step was the evaluation of the reactivity of
dienic esters 4 bearing a methyl group on the homoallylic double
bond. Compound 4a, when reacted under similar conditions as
compounds 3, gave the expected lactone in a 20% yield (entry
7). For comparison, it is reported that compound 4a afforded
(8) (a) Camacho, D. H.; Salo, E. V.; Guan, Z.; Ziller, J. W. Organome-
tallics 2005, 24, 4933-4939. (b) Nicola, T.; Brenner, M.; Donsbach, K.;
Kreye, P. Org. Process Res. DeV. 2005, 9, 513-515. (c) Silver, S.; Leino,
R. Eur. J. Org. Chem. 2006, 1965-1977.
(9) Jung, M. E.; Piizzi, G. Chem. ReV. 2005, 105, 1735-1766.
6068 J. Org. Chem., Vol. 72, No. 16, 2007

Synthesis of Alkyl-Substituted Six-Membered Lactones
SCHEME 2. RCM of Homoallyl Acrylates 3-6, Catalyzed by Complexes I-IV, to Yield Alkyl-Substituted Six-Membered
r,â-Unsaturated Lactones
SCHEME 3. RCM of Homoallyl Acrylates 3 and 4 to
Pentenolides 7 and 8
SCHEME 4. Product Analysis for the RCM Reaction of the
Homoallylic Acrylate 3a
7e was identified as the product of a cross-metathesis (CM)
reaction of 3a involving presumably the homoallylic double
bond. So, the formation of 7e observed in the reaction of 3a
accounts for the yields of the desired lactones 7a-d in the range
of 60-70% (Table 1).
An analogous GC analysis performed on the reaction of the
homomethallylic acrylate 4a showed the presence of the
substrate and of the 3-methyl-substituted lactone 8a with relative
GC percentages of 81 and 16% (4 h), respectively, with other
significant peaks not being observed. The conversion into 8a
reached the 23% value at 20 h of reaction, and no further
changes were observed for longer reaction times.
TABLE 1. RCM of Homoallyl Acrylates 3 and 4 to Pentenolides 7
and 8
I
time
yielda
entry substrate
R1
R2
R3 (mol %) (h) product (%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3c
3c
4a
4b
4c
H
H
H
H
n-Pr
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
10
10
10
10
5
6
6
6
6
6
7a
7b
7c
7d
7c
7c
8a
8b
8c
65
62
67
68
58
61
20
55
74
n-C9H19
Bn
n-Pr
Bn
Bn
H
2
6
10
10
10
18
18
18
n-Bu
n-C9H19
The interaction of complex I with the homoallylic acrylate
3a and with the homomethallylic acrylate 4a in the initial stages
1
of the reaction was investigated by H and 31P NMR. Five
a Yields of isolated products.
minutes after addition of 3a (5 µL, 0.038 mmol) to a solution
of complex I in CD2Cl2 (0.0077 mmol, 0.015 M) at rt, the high-
frequency region of the spectrum showed the benzylidene proton
of I at 20.01 ppm, a triplet at 19.35 ppm (J ) 5 Hz), and a
singlet at 18.94 ppm. This was accompanied by the formation
of a triplet at 4.48 ppm (J ) 6 Hz). The peak of I and the
nearby triplet disappeared over 3 h at room temperature, or in
30 min when the NMR tube was heated to 38 °C; the only peak
left in the high-frequency region was the singlet at 18.97 ppm,
due to the methylidene group of the catalyst resting state [RuCl2-
(PCy3)2(dCH2)] (Ia).10 When the same NMR experiments were
carried out on a mixture of homomethallylic acrylate 4a and
complex I, this showed to be stable at rt, as indicated by the
presence of its benzylidene proton, while the transformation into
the active methylidene complex occurred upon heating the
sample to 38 °C, with the intermediate species not being
detected. The 1H NMR spectra for the reactions of I with either
3a or 4a, showing the corresponding carbenoid species, are
displayed in Figure 1. On the other hand, the species Ia was
not detected by NMR when complex I was treated with ethyl
acrylate either at rt or at 38 °C.
8a in 73% yield using the second-generation Grubbs catalyst
III (5 mol %) after 20 h in toluene at 80 °C.6a On the other
hand, we noticed that the presence of an alkyl group on the
homoallylic carbon atom raised significantly the yield of the
corresponding six-membered lactones 8b,c (entries 8 and 9),
suggesting that the chain conformation imposed by an alkyl
group could assist the reaction of these difficult substrates.
The reaction of the acrylate 3a was followed by GC, in order
to clarify if the moderate yield of lactone could be due to the
formation of side products during the RCM process. The
analysis after 4 h of reaction showed the presence of 3a (18%),
the expected lactone 7a (50%), and of a secondary product 7e
(32%) (Scheme 4). After an additional 2 h at reflux, the relative
GC percentages 3a:7a:7e changed into 4:71:24, indicating
further conversion of the mixture into 7a. When the reaction
was left at reflux overnight, the substrate totally disappeared,
but there was no increase in the GC percentage of 7a with
respect to 7e. However, upon addition of a second load of
complex I (10 mol %) to the mixture at 6 h reaction time,
compound 7e was converted overnight into the six-membered
lactone. On the basis of the molecular mass found at m/z )
247.18 (7e-Na+ adduct) in the ESI-MS spectrum, compound
(10) Schwab, P.; Grubbs, R. H.; Ziller, J. W. Am. Chem. Soc. 1996, 118,
100-110.
J. Org. Chem, Vol. 72, No. 16, 2007 6069

D’Annibale et al.
SCHEME 5. Initiation Stage of Complex I in the Reaction with Homoallyl Acrylate 3a, Yielding the Catalyst Resting State
[RuCl2(PCy3)2dCH2] (Ia)
SCHEME 6. Products of the RCM Reaction of Homoallyl
Methacrylate Esters 5, in the Presence of a Ruthenium
Catalyst I-IV
These experiments indicate that the attack of complex I to
the substrate occurs selectively at the homoallylic double bond
during the initiation stage of the catalytic process, yielding, in
the case of the monosubstituted homoallylic acrylate 3a, the
detectable intermediate [RuCl2(PCy3)2(dCH(CH2)2OCOCHd
CH2)] Ih. This species is characterized by the proton resonances
of the RudCH- (19.35 ppm) and -CH2O- (4.48 ppm) groups
and by a 31P NMR peak at 35.5 ppm, just next to the one of
complex I at 36.1 ppm. A GC analysis of the reaction mixture
of I and 3a from the NMR tube after 2 h at rt showed the
presence of 3a, 7a, and 7e with relative GC percentages of 72,
3, and 24%, respectively, indicating that, under the conditions
of the NMR experiment, the product from CM, in stereoisomeric
ratio 4:1, is formed abundantly in the early part of the reaction.
Therefore, the initiation stage of the process can be depicted as
in Scheme 5.
TABLE 2. RCM Reactions of Homoallyl Methacrylate Esters 5, in
Refluxing Dichloromethanea
catalyst
(10 mol %)
product 9
product 10
entry
substrate
R1
(% yield)b
(% yield)b
1
2
3
4
5
6
5a
5b
5a
5a
5b
5a
H
Bn
H
H
Bn
H
I
I
II
III
III
IV
9a (25)
9b (23)
9a (34)
9a (48)
c
We studied next the effect of a geminal methyl group on the
conjugated double bond on the RCM outcome. In this case, the
reactivity of the electron-poor acrylic moiety is further impaired
by steric hindrance. The reaction mixtures of the homoallyl
methacrylate esters 5 with the chosen catalyst were kept at reflux
10a (24)
10b (49)
10a (16)
9a (25)
a 20 h. b Yields of isolated products. c Not isolated.
for 20 h, according to standard metathesis conditions for gem-
dialkyl-substituted olefins, which generally require prolonged
reaction times.6a
The RCM reactions of the homoallylic methacrylate esters
5a,b were performed using complexes I-IV (Scheme 6), and
the results obtained under comparable conditions are reported
in Table 2. Both the first-generation Grubbs catalysts I or the
Hoveyda-Grubbs catalyst II11 afforded in modest yield only
the dimeric species 9, as the result of a cross-metathesis process
involving the monosubstituted alkene (Table 2, entries 1-3).
To increase the reactivity of the sterically hindered acrylic
double bond of esters 5 toward RCM, we employed complexes
with expected higher activity, namely, the second-generation
catalysts III or IV.12 The model compound 5a was reacted with
III, showing a modest conversion into the desired lactone 10a
and the prevalent formation of the dimer 9a. On the other hand,
treatment of 5a with complex IV afforded both compounds 9a
and 10a in poor yield.
The reaction of 5a with III was also monitored by GC-MS.
After 4 h, the analysis showed the substrate 5a, the lactone 10a,
and the dimeric species 9a in 18:26:55 relative percentage ratios.
Afterward, the conversion into 10a increased only modestly and
reached 30% after 22 h of reaction, and no further changes were
observed after this time. On the other hand, a second addition
in one portion of 10 mol % of complex III brought the relative
GC percentage ratio of the six-membered lactone to 69:21 versus
that of the dimer after an overnight reaction. This last result
FIGURE 1. High-frequency region of the 1H NMR spectra of complex
I in the presence of the homoallylic acrylate 3a (lower trace, rt, 25
min) and of the homomethallylic acrylate 4a (upper trace, 38 °C, 15
min). Chemical shift calibration was performed at each temperature.
6070 J. Org. Chem., Vol. 72, No. 16, 2007

Synthesis of Alkyl-Substituted Six-Membered Lactones
SCHEME 7. RCM of Compound 9a Catalyzed by the
Second-Generation Grubbs Catalyst III
SCHEME 9. RCM of Esters 6 Catalyzed by the
Second-Generation Grubbs Catalyst III
SCHEME 8. Initiation Stage of Complex III in the Reaction
with the Homoallyl Methacrylate Ester 5a
unsaturated intermediate. This process is rate determining for
the N-heterocyclic carbene complex III and faster by almost 2
orders of magnitude in the bisphosphine complex I.16
Since it is known that the activity of the second-generation
catalysts can overcome the difficulty of combining two gem-
disubstituted olefin moieties, even when one is electron-poor
by conjugation,6a we extended our study to the synthesis of 3,4-
disubstituted-5,6-dihydropyran-2-ones. The reactions of esters
6 catalyzed by complex III gave the expected products 11 under
the conditions and yields indicated in Scheme 9.
The conversion of 6a, followed by GC, required the addition
of a second load of catalyst III after 24 h to reach a 44% value
before the final work up (48 h), with the reaction mixture
containing unreacted substrate. A similar reaction yield (42%)
was reported for the preparation carried out in toluene at 80 °C
(III, 5 mol %, 40 h),6a which evidently benefits from the higher
temperature accessible in this solvent. It is worth noting that
the presence of an alkyl substituent R1 on the homoallylic carbon
atom of the methacrylate affects positively the formation of the
tetrasubstituted pentenolide 11b, with respect to both yields (64
vs 40%) and catalyst load. Similarly, appreciable yield incre-
ments are observed in the preparation of the trisubstituted R,â-
unsaturated lactones 10 (Table 2, entries 4 and 5) and 8 (Table
1, entries 7-9), rather than for compounds 7 formed from the
homoallyl acrylates 3a-d (Table 1, entries 1-4).
suggested that the side products 9a,b, even though undesired,
were good RCM substrates themselves. In fact, in the presence
of catalyst III, an isolated pure sample of 9a afforded 10a in
moderate yield, as the result of a RCM process between the
methacrylic alkene moiety and the internal double bond
(Scheme 7).
Thus, these results indicate the preference of the ruthenium
catalyst to attack the more electron-rich double bond of 5a and,
subsequently, to perform a cross-metathesis reaction, a process
fiercely competitive with the desired RCM process. It is evident
that only the more active catalysts III or IV can subsequently
convert the CM product into the desired lactone.
The use of internal olefins as starting materials or as
intermediates is common in cross-metathesis reactions promoted
by complexes of type III.13 Although the ruthenium catalysts
bearing N-heterocyclic carbene ligands are known to catalyze
the RCM process involving two methyl-substituted alkene
groups and affording tetrasubstituted olefins,6a,13,14 to the best
of our knowledge, there are no other examples describing the
RCM of a methacrylate double bond with an internal olefin.
On the other hand, the formation of an acyclic dimer and its
conversion via a retrometathesis process to form a macrolide,
catalyzed by various Grubbs catalysts, were previously described
in detail.15
The higher yield observed for 11b than for 10b was at first
surprising. It may reflect the fact that the gem-disubstitution
on the double bonds in 6b hinders substantially the dimerization
of the homomethallylic moiety,17 thus favoring the RCM
reaction of the alkylidene intermediate with the methacrylate
group.
On the basis of the results concerning the preparation of
4-methyl-5,6-dihydropyran-2-ones from homomethallyl acrylates
(Scheme 3),6a we wished to extend the use of RCM as the key
step in the synthesis of two naturally occurring δ-lactones,
components of tobacco flavor and widely used as aromatizers
in the cigarette manufacturing, that is, (()-4-isopropyl-5,6-
The initial interaction of the second-generation Grubbs
catalyst III with 5a was followed by NMR in CD2Cl2. Complex
III, characterized by the benzylidene proton resonance at 19.1
ppm and by a 31P NMR peak at 29.4 ppm, is stable at rt in the
presence of the homoallyl methacrylate ester. While the situation
does not change upon mild heating to 32 °C, complete
conversion of III into the corresponding methylidene complex
IIIa (17.7 ppm, RudCH2) is observed after 20 min at 40 °C,
other carbenoid species are not detected in the 1H NMR
spectrum. At this stage, the GC analysis of the reaction mixture
under the conditions of the NMR experiment ([III] ) 5.9 ×
10-3 M; [5a] ) 6 × 10-2 M) shows 45% of substrate, 4% of
the lactone 10a, and 50% of the CM product 9a in stereoiso-
meric ratio of 6:1. When compared to the behavior of the first-
generation Grubbs catalyst in the presence of the homoallyl
acrylate 3a, it is obvious that complex III, in contrast to complex
I, requires a thermal activation for the conversion into the
catalyst resting state IIIa (Scheme 8). This observation is
consistent with the intrinsic reactivity of complexes I and III.
In both cases, the first step of the reaction involves dissociation
of one PCy3 ligand to afford a 14-electron coordinatively
(11) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.; Hoveyda,
A. H. J. Am. Chem. Soc. 1999, 121, 791-799.
(12) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168-8179.
(13) (a) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360-11370. (b) Connon, S. J.; Blechert, S.
Angew. Chem., Int. Ed. 2003, 42, 1900-1923.
(14) (a) Briot, A.; Bujard, M.; Gouverneur, V.; Nolan, S. P.; Mioskowski,
C. Org. Lett. 2000, 2, 1517-1519. (b) Michrowska, A.; Bujok, R.;
Harutyunyan, S.; Sashuk, V.; Dolgonos, G.; Grela, K. J. Am. Chem. Soc.
2004, 126, 9318-9325.
(15) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L. Org. Lett. 2001, 3, 449-
451.
(16) Sanford, M. S.; Ulman, M.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 749-750.
(17) (a) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751-
1753. (b) Chatterjee, A. K.; Sanders, D. P.; Grubbs, R. H. Org. Lett. 2002,
4, 1939-1942.
J. Org. Chem, Vol. 72, No. 16, 2007 6071

D’Annibale et al.
SCHEME 10. RCM-Based Synthetic Pathway to Tobacco
Lactones 14 and 15
Grubbs catalysts is the ability of the latter to promote more
efficiently the RCM between the acrylic moiety and an in-
ternal olefin. 1H NMR spectroscopy and reaction products
show that the interaction of the catalyst with the substrate
in the initiation stage involves the homoallylic double
bond.
Experimental Section
4-Propyl hept-1-en-4-ol (1d): Colorless oil (52% yield); IR
(CHCl3) 3420, 2970, 1471, 1130 cm-1; 1H NMR (CDCl3, 200 MHz)
δ ) 0.91 (6H, t, J ) 6.6 Hz), 1.37 (9H, m), 2.19 (2H, d, J ) 7.3
Hz), 5.09 (2H, m), 5.83 (1H, ddt, J1 ) 16.8 Hz, J2 ) 11.0 Hz, J3
) 7.3 Hz) ppm; 13C NMR (CDCl3, 200 MHz) δ ) 14.6, 16.7, 41.6,
44.0, 73.9, 118.3, 134.0 ppm; MS (EI) m/z ) 114 (21%), 71 (100).
Anal. Calcd for C10H20O: C, 76.86; H, 12.90. Found: C, 76.74;
H, 12.66.
But-3-enyl acrylate (3a): Colorless oil (56% yield); IR (CHCl3)
1
1717, 1419, 1306 cm-1; H NMR (CDCl3, 200 MHz) δ ) 2.39
dihydropyran-2-one 14 and (()-4-isopropyltetrahydropyran-2-
one 15.18 A RCM-based retrosynthetic approach led us to choose
the ester 13, attainable from alcohol 12, as the suitable precursor
of the target molecules. The synthetic pathway to the tobacco
lactones is shown in Scheme 10.
The alcohol 12 was prepared according to a literature
procedure through an ene reaction between formaldehyde and
2,3-dimethylbut-1-ene19 and then acylated with acryloyl chloride.
The resulting ester 13 cyclized satisfactorily (53% yield) to 14
in the presence of the second-generation Grubbs catalyst III.
The catalytic hydrogenation of 14 on Pd/C afforded the racemic
tobacco lactone 15.20 Ester 13 gave no evidence of either
cyclization or cross-metathesis in the presence of complex I.
Evidently, the increased steric bulk of the gem-dialkylic group
on going from methyl to isopropyl inhibits the efficiency of
the first-generation catalyst.
(2H, qt, J1 ) 6.6 Hz, J2 ) 1.4 Hz), 4.18 (2H, t, J ) 6.6 Hz), 5.10
(2H, m), 5.78 (1H, dd, J1 ) 10.2 Hz, J2 ) 1.4 Hz), 5.78 (1H, ddt,
J1 ) 16.8 Hz, J2 ) 10.2 Hz, J3 ) 6.6 Hz, overlapped), 6.08 (1H,
dd, J1 ) 16.8 Hz, J2 ) 10.2 Hz), 6.37 (1H, dd, J1 ) 16.8 Hz, J2 )
1.4 Hz) ppm; 13C NMR (CDCl3, 200 MHz) δ ) 33.0, 63.5, 117.1,
128.5, 130.4, 133.9, 166.0 ppm. Anal. Calcd for C7H10O2: C, 66.65;
H, 7.99. Found: C, 66.52; H, 8.08.
1-Nonylbut-3-enyl acrylate (3b): Colorless oil (60% yield); IR
(CHCl3) 2970, 1712, 1416, 1307 cm-1; 1H NMR (CDCl3, 200 MHz)
δ ) 0.87 (3H, t, J ) 7.3 Hz), 1.24 (14H, m), 1.55 (2H, m), 2.33
(2H, t, J ) 6.6 Hz), 5.02 (3H, m), 5.75 (1H, ddt, J1 ) 17.5 Hz, J2
) 10.2 Hz, J3 ) 6.6 Hz, overlapped), 5.78 (1H, dd, J1 ) 10.2 Hz,
J2 ) 2.1 Hz), 6.09 (1H, dd, J1 ) 16.8 Hz, J2 ) 10.2 Hz), 6.37
(1H, dd, J1 ) 16.8 Hz, J2 ) 2.1 Hz) ppm; 13C NMR (50 MHz,
CDCl3) δ ) 14.0, 22.6, 25.2, 29.3, 29.4, 29.5, 31.8, 33.6, 38.6,
73.6, 117.6, 128.9, 130.1, 133.7, 165.8 ppm; MS (EI) m/z )
211 (8%), 139 (16), 97 (14), 83 (37), 67 (24), 55 (100). Anal.
Calcd for C16H28O2: C, 76.14; H, 11.18. Found: C, 76.26; H,
11.41.
Conclusions
1-Benzylbut-3-enyl acrylate (3c): Colorless oil (43% yield); IR
(CHCl3) 2960, 1717, 1417, 1306, 1048, 984 cm-1; 1H NMR (CDCl3,
200 MHz) δ ) 2.38 (2H, m), 2.89 (1H, dd, J1 ) 13.9 Hz, J2 ) 5.8
Hz), 2.97 (1H, dd, J1 ) 13.9 Hz, J2 ) 6.6 Hz), 5.10 (2H, m), 5.23
(1H, qd, J1 ) 6.6 Hz, J2 ) 5.8 Hz), 5.80 (1H, dd, J1 ) 10.2 Hz,
J2 ) 1.4 Hz, overlapped), 5.81 (1H, ddt, J1 ) 17.6 Hz, J2 ) 9.5
Hz, J3 ) 7.3 Hz, overlapped), 6.09 (1H, dd, J1 ) 17.6 Hz, J2 )
10.2 Hz), 6.38 (1H, dd, J1 ) 16.8 Hz, J2 ) 1.4 Hz), 7.24
(5H, m) ppm; 13C NMR (CDCl3, 50 MHz) δ ) 37.7, 39.8, 74.0,
117.9, 126.4, 128.3, 129.4, 130.3, 133.4, 137.3, 165.5 ppm;
MS (EI) m/z ) 144 (41%), 129 (47), 91 (53), 65 (18), 55(100).
Anal. Calcd for C14H16O2: C, 77.75; H, 7.46. Found: C, 77.68;
H, 7.56.
The reactivity of alkyl-substituted homoallyl acrylates toward
RCM is dependent on the catalyst used for the purpose. A
methyl group on the homoallylic double bond is still com-
patible with the use of catalyst I, while a bulkier group, such
as isopropyl, requires the use of the second-generation
Grubbs catalyst III. When the acrylic double bond is methyl-
substituted, the homoallylic moiety undergoes preferentially a
cross-metathesis reaction yielding a dimeric product, which
turns into the desired R,â-unsaturated lactone only in the
presence of a second-generation Grubbs catalyst. The key feature
which distinguishes the activity of first- and second-generation
1,1-Di-n-propylbut-3-enyl acrylate (3d): Colorless oil (24%
1
yield); IR (CHCl3) 2970, 1710, 1473, 1431, 1311, 1130 cm-1; H
(18) (a) Schumacher, J. N.; Rohde, W. A.; Roberts, D. L. U.S. Patent
US3380457, 1968. (b) Kaneko, H.; Harada, M. Agric. Biol. Chem. 1972,
36, 658-662. (c) Demole, E.; Berthet, D. HelV. Chim. Acta 1972, 55, 1866-
1882. (d) Lloyd, R. A.; Miller, C. W.; Roberts, D. L.; Giles, J. A.; Dickerson,
J. P.; Nelson, N. H.; Rix, C. E.; Ayers, P. H. Tobacco Sci. 1976, 20, 125-
133. (e) Fujimori, T.; Kasuga, R.; Matsushita, H.; Kaneko, H.; Noguchi,
M. Agric. Biol. Chem. 1976, 40, 303-315. (f) Wahlberg, I.; Karlsson, K.;
Austin, D. J.; Junker, N.; Roeraade, J.; Enzell, C. R.; Johnson, W. H.
Phytochemistry 1977, 16, 1217-1231. (g) Schumacher, J. N.; Green, C.
R.; Best, F. W.; Newell, M. P. J. Agric. Food. Chem. 1977, 25, 310-320.
(h) Petterson, T.; Eklund, A. M.; Wahlberg, I. J. Agric. Food Chem. 1993,
41, 2097-2103.
NMR (CDCl3, 200 MHz) δ ) 0.89 (6H, t, J ) 7.3 Hz), 1.27 (4H,
m), 1.80 (4H, m), 2.61 (2H, d, J ) 7.3 Hz), 5.08 (2H, m), 5.70
(1H, ddt, J1 ) 16.8 Hz, J2 ) 9.5 Hz, J3 ) 7.3 Hz, overlapped),
5.71 (1H, dd, J1 ) 10.2 Hz, J2 ) 1.4 Hz), 6.02 (1H, dd, J1 ) 16.8
Hz, J2 ) 10.2 Hz), 6.28 (1H, dd, J1 ) 16.8 Hz, J2 ) 1.4 Hz) ppm;
13C NMR (CDCl3, 50 MHz) δ ) 14.4, 16.5, 37.7, 40.0, 86.9, 118.0,
129.2, 130.1, 133.2, 165.2 ppm; MS (EI) m/z ) 169 (11%), 95 (9)
71 (6), 55 (100). Anal. Calcd for C13H22O2: C, 74.24; H, 10.54.
Found: C, 74.16; H, 10.62.
(19) (a) Snider, B. B.; Rodini, D. J.; Kirk, T. C.; Cordova, R. J. Am.
Chem. Soc. 1982, 104, 555-563. (b) Maruoka, K.; Concepcion, A. B.;
Murase, N.; Oishi, M.; Hirayama, N.; Yamamoto, H. J. Am. Chem. Soc.
1993, 115, 3943-3949.
(20) (a) Ohta, H.; Tetsukawa, H.; Noto, N. J. Org. Chem. 1982, 47,
2400-2404. (b) Tokoroyama, T.; Kusaka, H. Can. J. Chem. 1996, 12,
2487-2502.
1-Nonyl-3-methylbut-3-enyl acrylate (4b): Colorless oil (74%
1
yield); IR (CHCl3) 3035, 2970, 1711, 1432, 1307, 1045 cm-1; H
NMR (CDCl3, 200 MHz) δ ) 0.86 (3H, t, J ) 6.6 Hz), 1.24 (14H,
m), 1.56 (2H, m), 1.74 (3H, s), 2.21 (1H, dd, J1 ) 13.9 Hz, J2 )
5.8 Hz), 2.32 (1H, dd, J1 ) 13.9 Hz, J2 ) 7.3 Hz), 4.73 (2H, m),
5.11 (1H, dq, J1 ) 7.3 Hz, J2 ) 5.8 Hz), 5.77 (1H, dd, J1 ) 10.2
6072 J. Org. Chem., Vol. 72, No. 16, 2007

Synthesis of Alkyl-Substituted Six-Membered Lactones
Hz, J2 ) 2.2 Hz), 6.08 (1H, dd, J1 ) 16.8 Hz, J2 ) 10.2 Hz), 6.37
(1H, dd, J1 ) 16.8 Hz, J2 ) 2.2 Hz) ppm; 13C NMR (CDCl3, 50
MHz) δ ) 14.0, 22.5, 22.6, 22.6, 25.3, 29.3, 29.5 (overlapped
peaks), 31.8, 34.1, 42.9, 72.5, 113.2, 128.9, 130.0, 141.7, 165.8
ppm; MS (EI) m/z ) 194 (14%), 138 (9), 110 (8), 95 (18), 82
(24), 67 (9), 55 (100). Anal. Calcd for C17H30O2: C, 76.64; H,
11.35. Found: C, 76.47; H, 11.48.
6-Nonyl-5,6-dihydro-2H-pyran-2-one (7b): Colorless oil (6 h,
1
62% yield); IR (CHCl3) 3025, 1714, 1400, 1248, 1039 cm-1; H
NMR (CDCl3, 200 MHz) δ ) 0.84 (3H, t, J ) 6.6 Hz), 1.23 (14H,
m), 1.44 (4H, m), 2.30 (2H, m), 4.38 (1H, m), 5.97 (1H, dt, J1 )
9.5 Hz, J2 ) 1.4 Hz), 6.85 (1H, ddd, J1 ) 9.5 Hz, J2 ) 4.4 Hz, J3
) 3.6 Hz) ppm; 13C NMR (CDCl3, 50 MHz) δ ) 14.0, 22.5, 24.7,
29.2, 29.3, 29.4, 31.8, 34.8, 77.9, 121.3, 144.9, 165.4 ppm; MS
(EI) m/z ) 164 (12%), 97 (100), 81 (16), 68 (80), 55 (31).
Anal. Calcd for C14H24O2: C, 74.95; H, 10.78. Found: C, 74.78;
H, 10.98.
1-Butyl-3-methylbut-3-enyl acrylate (4c): Colorless oil (63%
1
yield); IR (CHCl3) 3165, 1751, 1455, 1347, 1069, 1004 cm-1; H
NMR (CDCl3, 200 MHz) δ ) 0.86 (3H, t, J ) 6.6 Hz), 1.29 (4H,
m), 1.55 (2H, m), 1.72 (3H, s), 2.19 (1H, dd, J1 ) 13.9 Hz, J2 )
5.8 Hz), 2.31 (1H, dd, J1 ) 13.9 Hz, J2 ) 7.3 Hz), 4.72 (2H, m),
5.09 (1H, dq, J1 ) 7.3 Hz, J2 ) 5.8 Hz), 5.75 (1H, dd, J1 ) 10.2
Hz, J2 ) 1.4 Hz), 6.07 (1H, dd, J1 ) 17.5 Hz, J2 ) 10.2 Hz), 6.34
(1H, dd, J1 ) 17.5 Hz, J2 ) 2.2 Hz) ppm; 13C NMR (CDCl3, 50
MHz) δ ) 13.9, 22.5, 27.4, 33.7, 42.8, 72.4, 113.2, 128.9, 130.0,
141.6, 165.8 ppm. Anal. Calcd for C12H20O2: C, 73.43; H, 10.27.
Found: C, 73.35; H, 10.37.
But-3-enyl methacrylate (5a): Colorless oil (46% yield); IR
(CHCl3) 3050, 2895, 1712, 1640, 1526, 1433, 1044 cm-1; 1H NMR
(CDCl3, 200 MHz) δ ) 1.89 (3H, s), 2.38 (2H, q, J ) 6.6 Hz),
4.15 (2H, t, J ) 6.6 Hz), 5.08 (2H, m), 5.49 (1H, br s), 5.76 (1H,
ddt, J1 ) 16.8 Hz, J2 ) 10.2 Hz, J3 ) 6.6 Hz), 6.05 (1H, br s)
ppm; 13C NMR (CDCl3, 50 MHz) δ ) 18.0, 33.0, 63.5, 117.0,
125.0, 133.9, 136.4, 167.2 ppm; MS (EI) m/z ) 99 (9%), 69 (100),
54 (47). Anal. Calcd for C8H12O2: C, 68.54; H, 8.63. Found: C,
68.42; H, 8.74.
6-Benzyl-5,6-dihydro-2H-pyran-2-one (7c): Colorless oil (6 h,
1
67% yield); IR (CHCl3) 2950, 1720, 1396, 1265, 1042 cm-1; H
NMR (CDCl3, 200 MHz) δ ) 2.30 (2H, m), 2.95 (1H, dd, J1 )
13.9 Hz, J2 ) 6.6 Hz), 3.16 (1H, dd, J1 ) 13.9 Hz, J2 ) 5.8 Hz),
4.65 (1H, dddd, J1 ) 8.8 Hz, J2 ) 7.3 Hz, J3 ) 6.6 Hz, J4 ) 5.8
Hz), 6.00 (1H, m), 6.84 (1H, ddd, J1 ) 9.5 Hz, J2 ) 4.4 Hz, J3 )
3.6 Hz), 7.25 (5H, m) ppm; 13C NMR (CDCl3, 50 MHz) δ ) 28.6,
41.1, 78.3, 121.4, 126.9, 128.6, 129.5, 136.0, 144.8, 164.1 ppm;
MS (EI) m/z ) 188 (4%), 97 (100), 91 (45), 69 (52). Anal.
Calcd for C12H12O2: C, 76.57; H, 6.43. Found: C, 76.43; H,
6.52.
6-Nonyl-4-methyl-5,6-dihydro-2H-pyran-2-one (8c): Colorless
oil (18 h, 74% yield); IR (CHCl3) 3055, 1748, 1436, 1232, 1064
1
cm-1; H NMR (CDCl3, 200 MHz) δ ) 0.86 (3H, t, J ) 6.6 Hz),
1.24 (14H, m), 1.60 (2H, m), 1.96 (3H, s), 2.16 (1H, dd, J1 ) 17.6
Hz, J2 ) 4.4 Hz), 2.32 (2H, dd, J1 ) 17.5 Hz, J2 ) 10.9 Hz), 5.35
(1H, m), 5.78 (1H, s) ppm; 13C NMR (CDCl3, 50 MHz) δ ) 14.0,
22.6, 22.9, 24.8, 29.2, 29.3, 29.4, 31.8, 34.7, 34.8, 77.2, 116.5,
156.9, 165.3 ppm. Anal. Calcd for C15H26O2: C, 75.58; H, 10.99.
Found: C, 75.49; H, 11.19.
1-Benzylbut-3-enyl methacrylate (5b): Colorless oil (73%
1
yield); IR (CHCl3) 3030, 2900, 1709, 1525, 1430, 1044 cm-1; H
NMR (CDCl3, 200 MHz) δ ) 1.91 (3H, s), 2.38 (2H, m), 2.88
(1H, dd, J1 ) 13.9 Hz, J2 ) 6.6 Hz), 2.98 (1H, dd, J1 ) 13.9 Hz,
J2 ) 6.6 Hz), 5.10 (2H, m), 5.19 (1H, dq, J1 ) 6.6 Hz, J2 ) 5.8
Hz), 5.52 (1H, m), 5.80 (2H, dddd, J1 ) 16.8 Hz, J2 ) 9.5 Hz, J3
) 7.3 Hz, J4 ) 6.6 Hz), 6.08 (1H, m), 7.24 (5H, m) ppm; 13C
NMR (CDCl3, 50 MHz) δ ) 18.2, 37.7, 39.8, 74.2, 117.9, 125.0,
126.4, 128.3, 129.5, 133.5, 136.6, 137.4, 166.8 ppm; MS (EI) m/z
) 144 (72%), 129 (66), 91 (40), 69 (100). Anal. Calcd for
C15H18O2: C, 78.23; H, 7.88. Found: C, 78.04; H, 8.01.
6-Benzyl-3-methyl-5,6-dihydropyran-2-one (10b): Colorless oil
1
(20 h, 49% yield); IR (CHCl3) 3050, 1720, 1327 cm-1; H NMR
(CDCl3, 200 MHz) δ ) 1.91 (3H, s), 2.25 (2H, m), 2.94 (1H, dd,
J1 ) 13.9 Hz, J2 ) 7.3 Hz), 3.16 (1H, dd, J1 ) 13.9 Hz, J2 ) 5.8
Hz), 4.61 (1H, m), 6.52 (1H, m), 7.26 (5H, m) ppm; 13C NMR
(CDCl3, 50 MHz) δ ) 18.5, 32.4, 38.9, 77.9, 120.4, 125.5, 128.4,
129.8, 134.2, 137.4, 163.8 ppm. Anal. Calcd for C13H14O2: C,
77.20; H, 6.98. Found: C, 77.13; H, 7.04.
6-Nonyl-3,4-dimethyl-5,6-dihydropyran-2-one (11b): Colorless
oil (24 h, 64% yield); IR (CHCl3) 2970, 1716, 1411, 1321, 1279,
1147, 1085 cm-1; 1H NMR (CDCl3, 200 MHz) δ ) 0.87 (3H, t, J
) 6.6 Hz), 1.26 (14H, m), 1.56 (2H, m), 1.88 (3H, s), 1.91 (3H, s),
2.14 (1H, dd, J1 ) 17.5 Hz, J2 ) 3.7 Hz), 2.36 (1H, m), 4.28 (1H,
m) ppm; 13C NMR (CDCl3, 50 MHz) δ ) 14.0, 20.2, 20.4, 22.56,
22.62, 24.8, 29.2, 29.4, 29.5, 31.8, 34.8, 36.0, 76.2, 122.2, 148.4,
166.6 ppm. Anal. Calcd for C16H28O2: C, 76.14; H, 11.18. Found:
C, 76.09; H, 11.36.
3-Methyl-1-nonylbut-3-enyl methacrylate (6b): Colorless oil
1
(49% yield); IR (CHCl3) 2935, 1705, 1468, 1332, 1171 cm-1; H
NMR (CDCl3, 200 MHz) δ ) 0.85 (3H, t, J ) 5.8 Hz), 1.23 (14H,
m), 1.56 (2H, m), 1.72 (3H, s), 1.90 (3H, s), 2.19 (1H, dd, J1 )
13.9 Hz, J2 ) 5.1 Hz), 2.32 (2H, dd, J1 ) 13.9 Hz, J2 ) 7.3 Hz),
4.70 (2H, m), 5.05 (1H, dq, J1 ) 7.3 Hz, J2 ) 6.6 Hz), 5.48 (1H,
m), 6.05 (1H, m) ppm; 13C NMR (CDCl3, 50 MHz) δ ) 14.0, 22.4,
22.5, 22.6, 25.3, 29.3, 29.5, 31.9, 34.0, 41.3, 42.8, 72.6, 113.2,
124.7, 136.8, 141.8, 167.0 ppm; MS (EI) m/z ) 194 (16%), 138
(7), 95 (12), 81 (14), 69 (100), 55 (10). Anal. Calcd for C18H32O2:
C, 77.09; H, 11.50. Found: C, 77.03; H, 11.64.
3-Isopropyl but-3-enyl acrylate (13): Colorless oil (84% yield);
IR (CHCl3) 3097, 2956, 1710, 1467, 1312, cm-1; 1H NMR (CDCl3,
200 MHz) δ ) 1.03 (6H, d, J ) 6.6 Hz), 2.26 (1H, septuplet, J )
6.6 Hz), 2.40 (2H, t, J ) 7.3 Hz), 4.27 (2H, t, J ) 7.3 Hz), 4.78
(2H, m), 5.81 (1H, dd, J1 ) 10.2 Hz, J2 ) 1.4 Hz), 6.11 (1H, dd,
J1 ) 17.5 Hz, J2 ) 10.2 Hz), 6.50 (1H, dd, J1 ) 16.8 Hz, J2 ) 1.4
Hz) ppm; 13C NMR (CDCl3, 50 MHz) δ ) 21.6, 33.1, 34.1, 63.5,
108.7, 128.6, 130.4, 151.5, 166.1 ppm. Anal. Calcd for C10H16O2:
C, 71.39; H, 9.59. Found: C, 71.31; H, 9.75.
General Procedure for the Preparation of Pentenolides 7, 8,
10, 11, and 14. First, 1.6 mmol of esters 3-6 or 13 was dissolved
in dry CH2Cl2 (160 mL) under argon atmosphere; a 0.01 M solution
of the suitable catalyst I-IV (0.16 mmol in 16 mL of CH2Cl2)
was added dropwise and the refluxing mixture stirred overnight.
When the starting material could no longer be detected by TLC,
the solvent was removed under reduced pressure, and the residue
was separated on a silica gel column eluted with light petroleum
ether/Et2O to afford the desired products 7, 8, 10, 11, or 14 as oils,
and in some cases (see Results and Discussion) also the more polar
homodimers 9.
1,6-Dimethacryloyloxyhex-3-ene (9a): E/Z mixture, colorless
oil (20 h, 25-48% yield range); IR (CHCl3) 3025, 1711, 1526,
1
1433, 1224, 1044 cm-1; H NMR (CDCl3, 200 MHz) δ ) 1.91
(6H, s), 2.40 (4H, m), 4.13 (4H, td, J1 ) 6.6 Hz, J2 ) 1.5 Hz),
5.52 (4H, m), 6.07 (2H, m) ppm; 13C NMR (CDCl3, 50 MHz) δ )
18.2, 26.9, 32.0, 63.9, 125.2, 127.4, 128.4, 136.4, 167.3 ppm.
Anal. Calcd for C14H20O4: C, 66.65; H, 7.99. Found: C, 66.58;
H, 7.90.
1,6-Diphenyl-2,5-dimethacryloyloxyoct-4-ene (9b): E/Z mix-
ture, colorless oil (20 h, 23% yield); IR (CHCl3) 3095, 1705, 1638,
1
1459, 1309, 1082 cm-1; H NMR (CDCl3, 200 MHz) δ ) 1.90
(6H, s), 2.33 (4H, m), 2.88 (4H, m), 5.14 (2H, m), 5.52 (4H, m),
6.05 (2H, m), 7.26 (10H, m) ppm; 13C NMR (CDCl3, 50 MHz,
E/Z mixture) δ ) 18.2, 31.4, 36.5, 40.0, 39.7, 74.4, 125.1, 126.4,
128.3, 129.4, 136.5, 137.4, 166.7 ppm; MS (EI) m/z ) 198 (39%),
107 (32), 91 (42), 69 (100). Anal. Calcd for C28H32O4: C, 77.75;
H, 7.46. Found: C, 77.70; H, 7.50.
Acknowledgment. Financial support from the Italian Min-
istry of University and Research (COFIN MIUR 2004, Project
J. Org. Chem, Vol. 72, No. 16, 2007 6073

D’Annibale et al.
1
data, charts of H and 13C NMR spectra, and references of the
compounds described in the text. This material is available
free of charge via the Internet at http://pubs.acs.org.
“Flavors and Fragrances”) is acknowledged. Thanks are also
due to the University of Rome “La Sapienza” (funds for selected
research topics).
Supporting Information Available: Preparation of esters
3-6, general procedure for RCM reactions, characterization
JO070600H
6074 J. Org. Chem., Vol. 72, No. 16, 2007