Synthesis of conjugated δ-lactams using ring-closing metathesis

Article abstract of DOI:10.1016/S0040-4020(01)01221-2

Addition of allyl magnesium or metallyl magnesium bromide to the N-benzyl imines of benzaldehyde and cyclohexanone, followed by acylation with acryloyl or metacryloyl chloride provided the corresponding α,β-unsaturated amides. Ring-closing metathesis of the latter with ruthenium catalyst PhCH=RuCl₂(PPh₃)₂ in the presence of Ti(OiPr)₄ provided excellent yields of the corresponding conjugated δ-lactams with both disubstituted and trisubstituted C=C bonds. Some specific trisubstitution patterns, however, as well as tetrasubstituted C=C bonds, were not obtained. In these cases, even the use of a second generation, imidazolylidene-substituted ruthenium catalyst at high temperature did not lead to success.

Full text of DOI:10.1016/S0040-4020(01)01221-2

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 1185±1192
Synthesis of conjugated d-lactams using ring-closing metathesis
a
S. Rodrõguez, E. Castillo, M. Carda and J. A. Marco
b
a,p
c,p
Â
a
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Depart. de Q. Inorganica y Organica, Univ. Jaume I, Castellon, E-12080 Castellon, Spain
bDep. de Farm. y Tecn. Farmac., Fac. de C. Exp. y de la Salud, Univ. Card. Herrera-CEU, E-46115 Moncada, Valencia, Spain
c
Â
Depart. de Q. Organica, Univ. de Valencia, Burjassot, c/D Moliner 50, E-46100 Valencia, Spain
Received 12 November 2001; accepted 13 December 2001
AbstractÐAddition of allyl magnesium or metallyl magnesium bromide to the N-benzyl imines of benzaldehyde and cyclohexanone,
followed by acylation with acryloyl or metacryloyl chloride provided the corresponding a,b-unsaturated amides. Ring-closing metathesis of
the latter with ruthenium catalyst PhCHvRuCl2(PPh3)2 in the presence of Ti(OiPr)4 provided excellent yields of the corresponding
conjugated d-lactams with both disubstituted and trisubstituted CvC bonds. Some speci®c trisubstitution patterns, however, as well as
tetrasubstituted CvC bonds, were not obtained. In these cases, even the use of a second generation, imidazolylidene-substituted ruthenium
catalyst at high temperature did not lead to success. q 2002 Elsevier Science Ltd. All rights reserved.
The transition-metal catalyzed ole®n metathesis reaction1
has received a high degree of attention in the last 10
years. At the nonindustrial level, the intramolecular ring-
forming version (the `ring-closing metathesis', RCM)2 is
the most used variant, which has permitted the synthesis
of both carbocyclic and heterocyclic ring systems with
sizes varying from ®ve to several dozens of atoms.3 Further-
more, the smooth reaction conditions of metathetic
processes are compatible with almost all functional groups,
even in sensitive molecules.4
acylation of the latter with acryloyl or metacryloyl chloride
(1!2) gave low yields in the case of tertiary alcohols;
furthermore, direct RCM of conjugated esters 2 to a,b-
unsaturated lactones 5 worked only for disubstituted CvC
bonds (R3ˆR4ˆH). We circumvented this problem
though O-allylation of alcohols 1 and submission of allyl
ethers 3 to sequential RCM and allylic oxidation (3!4!5)
(Scheme 1).
The RCM catalysts used were the commercially available
Grubbs' ruthenium1b complex 6 and Schrock's moly-
bdenum6 complex 7 (Arˆ2,6-diisopropylphenyl). With the
aid of these catalysts, the preparation of both disubstituted
and trisubstituted7 CvC bonds proved feasible. Lactones
having tetrasubstituted ole®nic bonds were not obtained,
however, under these conditions.
Two years ago, we reported on the preparation of conju-
gated g- and d-lactones via a reaction sequence including
a RCM.5 The starting substrates were aldehydes or ketones,
which were ®rst subjected to treatment with allyl or alkenyl
metal reagents to yield unsaturated alcohols 1. Attempts at
Scheme 1.
Keywords: ring-closing metathesis; ruthenium catalysts; lactams.
Corresponding authors. Tel.: 134-96-3864337; fax: 134-96-3864328; e-mail: alberto.marco@uv.es
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)0 1221-2

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S. Rodrõguez et al. / Tetrahedron 58 (2002) 1185±1192
1186
Ê
Scheme 2. Reaction conditions: (a) BnNH2, toluene, 4 A MS, rt; allylmagnesium bromide, THF, rt, 3 h. Overall yields: 8 (75%) and 9 (70%); (b) acryloyl or
metacryloyl chloride, NEt3, DMAP, CH2Cl2, rt, 12 h. Yields: 88±92%; (c) 4% catalyst 6, CH2Cl2, Ti(OiPr)4, re¯ux, 12±18 h. Yields: 90±92%.
On the basis of these results, we extended our investigation
to the preparation of a,b-unsaturated lactams by means of
the same methodology. Heterocyclic nitrogen-containing
ring systems have often been obtained via RCM.2c As
regards lactams,8 ring sizes from 5 to 14 atoms have been
synthesized. In the reported examples with ruthenium
catalysts such as 6, the generated double bond was almost
always disubstituted and, in most cases, not conjugated with
the amide carbonyl group. As in our previous work with
lactones,5 we wished to establish in the case of conjugated
lactams the limits in the degree of substitution at the double
bond attainable with the aid of RCM. The present non-
commercial availability6 and the rather uncomfortable use
of complex 7 led us to employ catalyst 6 in the initial phase
of the work.
The benzylimines of benzaldehyde and cyclohexanone were
chosen as the starting model compounds. Addition of allyl-
magnesium bromide gave the expected addition products 8
and 9, respectively, which were then acylated with acryloyl
Ê
Scheme 3. Reaction conditions: (a) BnNH2, toluene, 4 A MS, rt; metallylmagnesium bromide, THF, rt, 3 h. Overall yields: 18 (70%) and 19 (60%);
(b) acryloyl or metacryloyl chloride, NEt3, DMAP, rt, 12 h. Yields: 88±91%; (c) 4% catalyst 6, CH2Cl2, Ti(OiPr)4, 48 h, re¯., or 16% catalyst 24, toluene,
with or without Ti(OiPr)4, 48 h, 80±1108C.

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S. Rodrõguez et al. / Tetrahedron 58 (2002) 1185±1192
1187
Scheme 4. Chauvin's catalytic cycle in the case of amides 11, 13, 20 and 22.
and metacryloyl chloride to yield the conjugated amides
10±13. These were then subjected to RCM reaction condi-
tions in the presence of 4% of complex 6. In all four cases,
the conjugated amides 14±17 were obtained with good
yields, provided that Ti(OiPr)4 was added to the reaction
mixture.9 It is interesting to note here that, in contrast to
the case of lactones,5 trisubstituted, conjugated CvC bonds
were directly formed (Scheme 2).
presence of catalyst 6. In view of this failure, we took
recourse to the recently developed, second-generation
ruthenium complex 24 (Arˆmesityl) containing one imi-
dazolylidene ligand replacing one of the phosphines.
Metathesis catalysts of this general type have been shown
to perform extremely well, even for the creation of tetra-
substituted CvC bonds.10 Furthermore, they are much more
comfortable to use than 7, more tolerant to a range of func-
tional groups, and less stringent in their requirements as to
purity of solvents and exclusion of air and humidity. In our
case, however, this active catalyst failed to promote the
cyclization of amides 20±23, even at elevated temperatures
(Scheme 3).
In order to check whether other substitution patterns at the
double bond were achievable, the previous reaction
sequence was repeated using metallylmagnesium bromide
in the ®rst step. Acryloyl and metacryloyl chloride were
again the acylating reagents. Disappointingly, none of the
conjugated amides 20±23 underwent cyclization in the
RCM processes are reversible and usually characterized by
Ê
Scheme 5. Reaction conditions: (a) allyl amine, toluene, 4 A MS, rt; metallylmagnesium bromide, THF, rt, 3 h. Yields: 25 (70%) and 28 (67%); (b) (BOC)2O,
NEt3, DMAP, rt, 12 h. Yield: 85%. (c) 4% catalyst 6, CH2Cl2, Ti(OiPr)4, 18 h, re¯. Yields: 27 (70%), 30 (78%); (d) Ac2O, NEt3, rt, 7 h. Yield: 80%.

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1188
small changes in enthalpy (DH,0). Their advance is driven
mainly by the favorable entropic factor (DS.0) related to
the extrusion of a small volatile molecule (most often,
ethylene). RCM rates have been shown to depend on both
electronic and steric factors.1,2 For instance, polar functional
groups on the CvC bond may in some cases block the
catalytic cycle.11 Particularly marked is the retarding effect
of an increasing degree of substitution, not only on the CvC
bond itself, but also in its close proximity.12 Within
Chauvin's mechanistic view,13 it may be assumed that the
®rst intermolecular metal carbene±ole®n [212] cyclo-
addition step of the catalytic cycle (Scheme 4) is rate-
determining (r.d.) and takes place on the electronically
least deactivated and/or sterically least encumbered CvC
bond. The second, and faster, [212] cycloaddition is intra-
molecular and therefore less sensitive to steric hindrance. In
amides 10±13, the obvious target for the catalyst in the ®rst
cycloaddition is the monosubstituted, unconjugated double
bond of the allyl moiety. The second, intramolecular
cycloaddition does not ®nd apparently any electronic and/
or steric hurdles, even when the reacting CvC bond is both
conjugated and disubstituted (amides 11 and 13). In
contrast, the nonconjugated CvC bond in amides 20±23
is disubstituted, which makes it much less reactive for steric
reasons. Furthermore, initial cycloaddition to the conjugated
double bond may be also slow for electronic reasons or
perhaps lead to a blockage of the catalytic cycle. It is dif®-
cult to decide here, however, which of either pathway is
responsible to a major extent of the observed failure
(compare with the reactions of Scheme 5).
1. Experimental
NMR spectra (Varian 400 and 500 NMR spectrometers)
were measured in CDCl3 solution at 258C. The NMR spectra
of some amides showed very broad signals, due to the
presence of slowly interconverting rotamers. For this
reason, these NMR spectra were measured at 330K
(578C), where sharper signals were visible. Mass spectra
were run either by the electron impact (EIMS, 70eV) on a
VG AutoSpec mass spectrometer. IR spectra were recorded
as oily ®lms on NaCl plates (oils) or as KBr pellets (solids).
Reactions which required inert atmosphere were carried out
under argon with ¯ame-dried glassware. Commercial
reagents (Aldrich or Fluka) were used as received. THF
was freshly distilled from sodium benzophenone ketyl.
Dichloromethane was distilled from P2O5 and stored over
Ê
4 A molecular sieves. Toluene was freshly distilled from
sodium wire. Unless detailed otherwise, `work-up' means
pouring the reaction mixture into brine, extraction with the
indicated solvent, additional washing with 5% aq NaHCO3,
(if acids had been utilized in the reaction) or with 5% aq HCl
(if bases had been utilized), then again with brine, drying
over anhydrous Na2SO4 or MgSO4 and elimination of
the solvent in vacuo. The obtained material was then
chromatographed on a silica gel column (SuÈd-Chemie
AG, 60±200 m) with the indicated eluent.
1.1. General procedure for the preparation of secondary
amines 8, 9, 18, 19, 25 and 28 from benzaldehyde or
cyclohexanone
In an attempt to circumvent the problem of the failed
synthesis of b-methylsubstituted lactams, and in analogy
to our work with lactones,5 we performed the experiments
depicted in Scheme 5. The reaction sequences are in
principle the same as those depicted in Schemes 2 and 3
except that the N-allyl imines of benzaldehyde and cyclo-
hexanone were the starting materials. The N-allyl moiety
was intended to provide the necessary material to build up
the heterocyclic ring during the metathesis. Allylic oxida-
tion would then create the amide carbonyl group. In the
event, reaction of the N-allyl imines with metallyl
magnesium bromide gave the expected addition products
25 and 28, which were N-protected as their respective
BOC derivatives, and then subjected to RCM. The reaction
was successful in the case of 2614 but not with the corre-
sponding cyclohexanone-derived product (not indicated in
the scheme), where a dimer formed by cross metathesis was
the main reaction product. However, when acetyl was the
N-protecting group as in 29, RCM provided the N-acetyl
tetrahydropyridine 30.14 Unfortunately, tetrahydropyridines
27 and 30 proved useless for our purposes, as we were
unable to perform an oxidation in the allylic position
contiguous to the nitrogen atom.15
The appropriate carbonyl compound (10mmol) and the
primary amine (15 mmol) were dissolved under Ar in dry
Ê
toluene (20mL). After addition of activated 4 A molecular
sieves (3 g), the mixture was stirred overnight at room
temperature. The solution was then ®ltered through a pad
of anhydrous MgSO4, all volatiles were removed carefully
in vacuo and the oily imine was then directly used without
puri®cation in the next step.
The crude imine obtained above was dissolved under Ar in
dry THF (25 mL) and treated dropwise at 08 with the appro-
priate Grignard reagent (15 mmol, 1 M solution in THF).
The mixture was then stirred for 3 h at room temperature.
Work-up (extraction with Et2O), removal of all volatiles in
vacuo and column chromatography of the residue on silica
gel (hexane±EtOAc 9:1 and then 4:1) afforded the desired
amine. Overall chemical yields (two steps from the starting
carbonyl compound): 8 (75%), 9 (70%), 18 (70%), 19
(60%), 25 (70%), 28 (67%).
1.2. General procedure for the preparation of a,b-
unsaturated amides 10±13 and 20±23
The appropriate amine (6 mmol), triethyl amine (1.25 mL,
ca. 9 mmol) and DMAP (55 mg, 0.45 mmol) were dissolved
under Ar in dry CH2Cl2 (25 mL), treated with the appropri-
ate acyl chloride (8 mmol) and stirred overnight at room
temperature. Work-up (extraction with CH2Cl2), removal
of all volatiles in vacuo and column chromatography of
the residue on silica gel (hexane±EtOAc 7:3) yielded the
desired amides. Chemical yields: 10 (90%), 11 (92%), 12
(90%), 13 (89%); 20 (89%), 21 (90%), 22 (88%), 23 (91%).
In summary, we have reported an ef®cient method for the
preparation of conjugated monocyclic or spirocyclic
lactams via RCM. The conjugated CvC bond may be not
only disubstituted but also trisubstituted, provided that
the additional substituent is bound to the a carbon atom.
The present report further points to certain limitations in the
catalytic ef®ciency of the second-generation ruthenium
complex 24.

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S. Rodrõguez et al. / Tetrahedron 58 (2002) 1185±1192
1189
1.3. General procedure for the ring-closing metathesis
with ruthenium catalyst 6
173.7, 141.7, 139.1, 138.5, 134.9, 128.6, 128.4, 128.2,
127.8, 127.7, 127.0, 117.6, 115.2, 59.5p, 47.2p, 36.3, 20.7
(the starred signals are low and broad).
The appropriate a,b-unsaturated amide 10±13 (1 mmol)
and Ti(OiPr)4 (570mg, ca. 2 mmol) were dissolved under
Ar in dry CH2Cl2 (50mL) and heated at re¯ux for 1 h. After
this time, catalyst 6 (33 mg, 0.04 mmol) was added and the
mixture was stirred at re¯ux for 12±18 h (monitoring by
means of TLC). After removal of all volatiles in vacuo,
the residue was chromatographed on silica gel (hexane±
EtOAc 4:1) to furnish the desired a,b-unsaturated lactams.
For compounds 26 and 29, 10% of catalyst 6 was used and
the re¯ux was maintained for 48 h. Chemical yields: 14
(92%), 15 (90%), 16 (92%), 17 (90%); 27 (70%), 30
(78%). Under these conditions, amides 20±23 did not
react, even after 48 h.
1.4.5. N-(1-Allylcyclohexyl)-N-benzylacrylamide, 12. Oil,
IR nmax cm21: 3071, 3033, 2933, 2863, 1655 (amide CvO),
1611, 1495, 1451, 1411, 1301, 1226, 1200, 994, 913, 797,
725; EIMS, m/z 283.1932 (M1, 3), 242 (100), 188 (84), 91
(80). Calc. for C19H25NO, Mˆ283.1936; 1H NMR
(500 MHz): d 7.40±7.20 (5H, br m), 6.34 (1H, dd,
Jˆ16.5, 9.5 Hz), 6.28 (1H, dd, Jˆ16.5, 3 Hz), 5.77 (1H,
br m), 5.50(1H, dd, Jˆ9.5, 3 Hz), 5.15±5.00 (2H, m),
4.58 (2H, s), 2.93 (2H, br d, Jˆ7.5 Hz), 2.50(2H, m),
1.60±1.40 (8H, br m); 13C NMR (125 MHz): d 168.9,
139.8, 134.6, 132.0, 128.7, 127.1, 127.0, 125.7, 118.0,
63.6, 49.1, 35.7, 33.5, 25.4, 22.7.
1.4.6.
N-(1-Allylcyclohexyl)-N-benzyl-2-methylacryl-
1.4. Attempts at ring-closing metathesis using ruthenium
catalyst 24
amide, 13. Oil, IR nmax cm21: 3074, 3031, 2932, 2873,
1631 (amide CvO), 1451, 1386, 1296, 1183, 1049, 911,
729, 700; EIMS, m/z 297.2091 (M1, 4), 256 (100), 176
The appropriate precursor (1 mmol) and catalyst 24 (68 mg,
0.08 mmol) were dissolved under Ar in dry CH2Cl2 (50mL)
and heated at re¯ux for 24 h. After this time, an additional
amount of catalyst (68 mg) was added and the re¯ux was
continued for further 24 h. TLC monitoring revealed that no
RCM was taking place, a conclusion con®rmed later by
means of NMR. When CH2Cl2 was replaced by toluene
and the reaction was carried out at temperatures from 80
to 1108C for 48 h, the same lack of success was observed.
Addition of Ti(OiPr)4 was of no avail, either.
1
(22), 91 (93). Calc. for C20H27NO, Mˆ297.2092; H NMR
(400 MHz): d 7.35±7.20(5H, br m), 5.79 (1H, ddt, Jˆ16,
11, 7.5 Hz), 5.10±5.04 (2H, m), 5.00 (1H, quint, Jˆ1.5 Hz),
4.89 (1H, quint, Jˆ1.5 Hz), 4.62 (2H, s), 2.84 (2H, d,
Jˆ7.5 Hz), 2.30(2H, m), 1.85 (3H, t, Jˆ1.5 Hz), 1.70
(3H, m), 1.55±1.45 (4H, br m), 1.10(1H, m); 13C NMR
(100 MHz): d 175.2, 143.5, 140.7, 134.5, 128.5, 126.9,
126.5, 117.9, 113.6, 63.6, 50.7, 36.7, 33.7, 25.6, 22.7, 20.8.
1.4.7. 1-Benzyl-6-phenyl-5,6-dihydro-1H-pyridin-2-one,
14. Oil, physical data in agreement with published data.18
1.4.1. Benzyl-(1-phenylbut-3-enyl)-amine, 8. Oil, physical
data in agreement with published data.16
1.4.8. 1-Benzyl-3-methyl-6-phenyl-5,6-dihydro-1H-pyri-
din-2-one, 15. Oil, IR nmax cm21: 3070, 3030, 2924, 1672
(amide CvO), 1629, 1495, 1452, 1358, 1222, 1078, 1030,
835, 736, 700; EIMS, m/z 277.1471 (M1, 100), 200 (12),
186 (33), 173 (40), 91 (80). Calc. for C19H19NO,
1
1.4.2. (1-Allylcyclohexyl) benzyl amine, 9. Oil, H NMR
(500 MHz): d 7.45±7.25 (5H, m), 5.95 (1H, m), 5.15 (2H,
m), 3.69 (2H, s), 2.29 (2H, d, Jˆ7.5 Hz), 1.70±1.30(10H, br
m); 13C NMR (125 MHz): d 141.4, 134.4, 128.2, 128.1,
126.5, 117.2, 53.9, 45.4, 41.9, 35.5, 26.2, 21.8. Other data
in agreement with published data.17
1
Mˆ277.1466; H NMR (400 MHz): d 7.35±7.10(10H, br
m), 6.02 (1H, br d, Jˆ6.5 Hz), 5.62 (1H, d, Jˆ15 Hz), 4.54
(1H, dd, Jˆ8, 1.5 Hz), 3.50(1H, d, Jˆ15 Hz), 2.86 (1H, br
m), 2.36 (1H, br ddq, Jˆ15, 6, 1 Hz), 1.97 (3H, quint,
Jˆ1 Hz); 13C NMR (100 MHz): d 166.0, 140.4, 138.1,
131.5, 130.5, 128.6, 128.5, 128.0, 127.6, 127.3, 126.5,
57.6, 48.2, 31.9, 17.3.
1.4.3. N-Benzyl-N-(1-phenylbut-3-enyl)acrylamide, 10.
Oil, IR nmax cm21: 3064, 3031, 2979, 2874, 1651 (amide
CvO), 1614, 1423, 1222, 1163, 978, 919, 795, 752, 731,
700; EIMS, m/z 291.1616 (M1, 3), 250(34), 196 (70), 91
(100). Calc. for C20H21NO, Mˆ291.1623; 1H NMR
(400 MHz, 578C): d 7.40±7.00 (10H, br m), 6.40 (2H, m),
6.0(1H, very br m), 5.70(1H, m), 5.60(1H, br m),
5.05±5.00 (2H, m), 4.55 (1H, very br s), 4.30 (1H, very br
s), 2.70(2H, br m); 13C NMR (100 MHz, 578C): d 167.6,
139.2, 138.3, 134.7, 129.0, 128.5, 128.3, 128.2p, 127.8,
127.0, 117.6, 57.5p, 47.3, 35.7 (the starred signals are low
and broad).
1.4.9. 1-Benzyl-1-azaspiro[5.5]undec-3-en-2-one, 16. Oil,
IR nmax cm21: 3061, 2930, 2864, 1667 (amide CvO), 1614,
1494, 1453, 1415, 1340, 1268, 1253, 1124, 842, 731; EIMS,
m/z 255.1619 (M1, 67), 212 (49), 164 (22), 91 (100). Calc.
for C17H21NO, Mˆ255.1623; 1H NMR (400 MHz): d
7.30±7.15 (5H, br m), 6.46 (1H, dt, Jˆ9.7, 4.5 Hz), 6.06
(1H, dt, Jˆ9.7, 2 Hz), 4.73 (2H, br s), 2.50(2H, dd, Jˆ4.5,
2 Hz), 1.75±1.50(6H, br m), 1.30±1.10(4H, br m);
13C
NMR (100 MHz): d 165.5, 140.2, 136.9, 128.3, 126.8,
126.5, 125.2, 59.8, 43.2, 34.1, 31.8, 25.2, 22.6.
1.4.4. N-Benzyl-2-methyl-N-(1-phenylbut-3-enyl)acryl-
amide, 11. Oil, IR nmax cm21: 3064, 3031, 2975, 2925,
1640sh, 1625 (amide CvO), 1452, 1412, 1338, 1195,
1156, 1048, 915, 731, 700; EIMS, m/z 305.1776 (M1, 7),
1.4.10. 1-Benzyl-3-methyl-1-azaspiro[5.5]undec-3-en-2-
one, 17. Oil, IR nmax cm21: 3029, 2923, 1672 (amide
CvO), 1628, 1494, 1452, 1358, 1220, 1076, 1029, 736,
700; EIMS, m/z 269.1776 (M1, 48), 226 (42), 178 (31),
91 (100). Calc. for C18H23NO, Mˆ269.1779; 1H NMR
(400 MHz): d 7.30±7.15 (5H, br m), 6.22 (1H, tq, Jˆ4,
1
264 (100), 91 (72). Calc. for C21H23NO, Mˆ305.1779; H
NMR (400 MHz, 578C): d 7.40±7.00 (10H, br m), 5.70 (1H,
m), 5.55 (1H, br m), 5.16 (2H, br s), 5.05±5.00 (2H, m),
4.63, 4.19 (2H, broadened AB system, Jˆ15.5 Hz), 2.70
(2H, br m), 1.92 (3H, br s); 13C NMR (100 MHz, 578C): d

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S. Rodrõguez et al. / Tetrahedron 58 (2002) 1185±1192
1190
2 Hz), 4.73 (2H, br s), 2.45 (2H, sext, Jˆ2 Hz), 1.92 (3H, q,
Jˆ2 Hz), 1.75±1.50(6H, br m), 1.35±1.00(4H, br m); 13C
NMR (100 MHz): d 166.7, 140.5, 131.2, 131.1, 128.3,
126.8, 126.4, 59.7, 43.7, 34.2, 31.6, 25.3, 22.6, 17.4.
dd, Jˆ10.2, 2.3 Hz), 4.92 (1H, br s), 4.72 (1H, br s), 4.58
(2H, s), 2.90(2H, s), 2.60(2H, m), 1.79 (3H, s), 1.65±1.40
(7H, br m), 1.10(1H, m); 13C NMR (100 MHz, 578C): d
169.2, 143.1, 140.1, 132.5, 128.8, 127.0, 126.6, 125.9, 64.0,
49.5, 38.1, 34.3, 25.6, 24.8, 23.0.
1.4.11. Benzyl-(3-methyl-1-phenylbut-3-enyl)-amine, 18.
Oil, IR nmax cm21: 3450(br, NH), 3026, 2933, 1492, 1453,
1115, 1028, 894, 700; EIMS, m/z 196.1102 (M12C4H7,
1.4.16.
N-Benzyl-2-methyl-N-[1-(2-methylallyl)cyclo-
hexyl]acrylamide, 23. Oil, IR nmax cm21: 3070, 3030,
2925, 2863, 1650(amide C vO), 1455, 1182, 1155, 1030,
902, 729, 700; EIMS, m/z 311.2247 (M1, 3), 256 (100), 176
1
100), 91 (72). Calc. for C18H21N2C4H7, Mˆ196.1126; H
NMR (500 MHz): d 7.50±7.25 (10H, br m), 4.88 (1H, br s),
4.84 (1H, br s), 3.84 (1H, dd, Jˆ9.5, 4.7 Hz), 3.78 (1H, d,
Jˆ13.5 Hz), 3.56 (1H, d, Jˆ13.5), 2.45 (1H, dd, Jˆ14,
9.5 Hz), 2.37 (1H, dd, Jˆ14, 4.7 Hz), 1.85 (1H, br s), 1.72
(3H, s); 13C NMR (125 MHz): d 144.3, 142.7, 140.6, 128.4,
128.3, 128.1, 127.3, 127.0, 126.8, 113.4, 59.3, 51.5, 47.6,
22.1.
1
(14), 91 (89). Calc. for C21H29NO, Mˆ311.2249; H NMR
(400 MHz, 578C): d 7.35±7.20(5H, br m), 5.03 (1H, quint,
Jˆ1.5 Hz), 4.90(1H, quint, Jˆ1.5 Hz), 4.87 (1H, sext,
Jˆ1.5 Hz), 4.72 (1H, m), 4.65 (2H, s), 2.79 (2H, s), 2.30
(2H, m), 1.84 (3H, t, Jˆ1.5 Hz), 1.80(3H, t, Jˆ1.5 Hz),
1.60±1.40(7H, br m), 1.20(1H, m); 13C NMR (100 MHz,
578C): d 175.2, 143.4, 142.7, 140.6, 128.4, 126.8, 126.6,
64.1, 50.9, 39.9, 34.1, 25.6, 25.1, 22.9, 20.7.
1.4.12. Benzyl-[1-(2-methylallyl)cyclohexyl]amine, 19.
Oil, IR nmax cm21: 3400 (br, NH), 3070, 3048, 2940,
2853, 1494, 1451, 1373, 1262, 1184, 1143, 1091, 1068,
889, 742, 699; EIMS, m/z 242.1912 (M12H, 5), 188
1.4.17. Allyl-(3-methyl-1-phenylbut-3-enyl)amine, 25.
Oil, IR nmax cm21: 3330 (br, NH), 3074, 3027, 2934,
2878, 1492, 1455, 1375, 1113, 1029, 893, 756, 700;
EIMS, m/z 146.0964 (M12C4H7, 100), 91 (22). Calc. for
C14H19N±C4H7, Mˆ146.0969; 1H NMR (400 MHz): d
7.40±7.20 (5H, br m), 5.83 (1H, dddd, Jˆ17.3, 10.3, 7,
5.3 Hz), 5.08 (1H, dq, Jˆ17.3, 1.5 Hz), 5.06 (1H, dq,
Jˆ10.3, 1.5 Hz), 4.81 (1H, quint, Jˆ1.5 Hz), 4.76 (1H, br
s), 3.80(1H, dd, Jˆ9.2, 5 Hz), 3.12 (1H, ddt, Jˆ14, 5.3,
1.5 Hz), 2.98 (1H, ddt, Jˆ14, 7, 1.2 Hz), 2.39 (1H, dd,
Jˆ13.7, 9.2 Hz), 2.30(1H, dd, Jˆ13.7, 5 Hz), 1.73 (3H,
s); 13C NMR (100 MHz): d 144.0, 142.6, 136.7, 128.3,
127.3, 127.1, 116.0, 113.5, 59.6, 50.0, 47.3, 22.2.
1
(100), 91 (60). Calc. for C17H25N2H, Mˆ242.1908; H
NMR (500 MHz): d 7.50±7.25 (5H, br m), 4.93 (1H, br
s), 4.73 (1H, br s), 3.70(2H, s), 2.23 (2H, s), 1.88 (3H, s),
1.80±1.20 (10H, br m); 13C NMR (125 MHz): d 143.1,
141.6, 128.3, 128.2, 126.7, 114.1, 54.6, 45.4, 45.1, 35.9,
26.2, 25.6, 21.8.
1.4.13. N-Benzyl-N-(3-methyl-1-phenylbut-3-enyl)acryl-
amide, 20. Oil, IR nmax cm21: 3065, 3031, 2931, 1651
(amide CvO), 1611, 1451, 1420, 1212, 977, 893, 794,
731, 700; EIMS, m/z 305.1790 (M1, 10), 250 (60), 196
(77), 91 (100). Calc. for C21H23NO, Mˆ305.1779; 1H
NMR (400 MHz, 578C): d 7.40±6.90 (10H, br m),
6.40±6.20 (2H, br m), 5.56 (1H, br s), 4.77 (1H, br s),
4.72 (1H, br s), 4.52 (1H, br m), 4.37 (1H, br d,
Jˆ17 Hz), 2.66 (2H, d, Jˆ7.5 Hz), 1.69 (3H, s); 13C NMR
(100 MHz, 57deg;C): d 167.3, 141.7p, 139.4, 138.3p, 129.0,
128.4, 128.3, 128.1, 128.0, 127.7, 127.0, 126.6p, 113.2,
55.3p, 47.3, 39.2p, 22.4 (the starred signals are low and
broad).
1.4.18. N-Allyl-N-(tert-butyloxycarbonyl)-N-(3-methyl-
1-phenylbut-3-enyl)amine, 26. Amine 25 (503 mg,
2.5 mmol), (BOC)2O (590mg, 2.7 mmol) and NEt 3
(420 mL, ca. 3 mmol) were dissolved in dry CH2Cl2
(5 mL) and stirred under Ar at room temperature for 4 h.
Work-up (extraction with CH2Cl2) and column chromato-
graphy on silica gel (hexane±EtOAc 7:3) furnished 562 mg
(75%) of 26 as an oil, IR nmax cm21: 3076, 2979, 2932, 1683
(uretane CvO), 1453, 1400, 1367, 1251, 1168, 1120, 1075,
912, 734, 700; EIMS, m/z 301.2029 (M1, 1), 246 (29), 190
(100), 146 (88), 57 (55). Calc. for C19H27NO2,
Mˆ301.2042; 1H NMR (400 MHz, 578C): d 7.35±7.20
(5H, br m), 5.55 (2H, br m), 4.90(2H, m), 4.82 (1H, br s),
4.78 (1H, br s), 3.70±3.50 (2H, br m), 2.68 (2H, m), 1.79
(3H, s), 1.46 (9H, s); 13C NMR (100 MHz, 578C): d 155.7p,
142.3, 140.9, 136.0, 128.3, 128.0, 127.3, 115.4, 113.1, 79.7,
56.5p, 46.5, 39.5, 28.5, 22.5 (the starred signals are low and
broad).
1.4.14. N-Benzyl-2-methyl-N-(3-methyl-1-phenylbut-3-
enyl)acrylamide, 21. Oil, IR nmax cm21: 3065, 3031,
2979, 2929, 1625 (broad, amide CvO), 1451, 1420, 1181,
1048, 910, 731, 700; EIMS, m/z 319.1944 (M1, 8), 264
(100), 91 (68). Calc. for C22H25NO, Mˆ319.1936; 1H
NMR (400 MHz, 578C): d 7.40±6.90 (10H, br m), 5.80
(1H, br m), 5.12 (2H, br s), 4.79 (1H, br s), 4.70(1H, br
s), 4.59, 4.29 (2H, broadened AB system, Jˆ15.7 Hz), 2.70
(2H, br m), 1.84 (3H, br s), 1.70(3H, s); 13C NMR
(100 MHz, 578C): d 173.7, 141.9, 141.8, 139.3, 138.5,
128.6, 128.4, 128.2, 127.8, 127.6, 126.9, 115.1, 113.4,
57.3p, 47.6p, 40.1, 22.4, 20.5 (the starred signals are low
and broad).
1.4.19. 1-tert-Butyloxycarbonyl-4-methyl-2-phenyl-1,2,
3,6-tetrahydropyridine, 27. Oil, IR nmax cm21: 3030,
2977, 2885, 1695 (uretane CvO), 1455, 1368, 1253,
1168, 1027, 885, 858, 764, 700; EIMS, m/z 273.1724
(M1, 1), 217 (25), 57 (100). Calc. for C17H23NO2,
1.4.15. N-Benzyl-N-[1-(2-methylallyl)cyclohexyl]acryl-
amide, 22. Oil, IR nmax cm21: 3064, 3031, 2931, 2864,
1655 (amide CvO), 1611, 1451, 1412, 1353, 1192, 993,
729, 700; EIMS, m/z 297.2093 (M1, 4), 242 (100), 188
1
Mˆ273.1728; H NMR (500 MHz): d 7.35±7.25 (5H, br
m), 5.55 (1H, br m), 5.34 (2H, br s), 4.19 (1H, br d,
Jˆ18 Hz), 3.30(1H, br d, Jˆ18 Hz), 2.62 (1H, br d,
Jˆ17 Hz), 2.2.37 (1H, br d, Jˆ17 Hz), 1.78 (3H, br s),
1.49 (9H, s); 13C NMR (125 MHz): d 155.0, 141.3, 128.2,
126.8, 126.6, 118.3, 79.7, 40.2, 32.5, 28.4, 27.9, 23.2.
1
(76), 91 (81). Calc. for C20H27NO, Mˆ297.2092; H NMR
(400 MHz, 578C): d 7.40±7.20 (5H, br m), 6.35 (1H, dd,
Jˆ16.6, 10.2 Hz), 6.24 (1H, dd, Jˆ16.6, 2.3 Hz), 5.47 (1H,

Â
S. Rodrõguez et al. / Tetrahedron 58 (2002) 1185±1192
1191
M.; Kunz, R.; Bruneau, C.; Touchard, D.; Dixneuf, P. H.
Chem. Eur. J. 2000, 6, 1847±1857.
Â
3. For an extreme example of macrocyclic RCM, see: Espõnola,
1.4.20. Allyl-[1-(2-methylallyl)cyclohexyl]amine, 28. Oil,
IR nmax cm21: 3360(br, NH), 3074, 2929, 2854, 1642, 1449,
1373, 1147, 1092, 995, 916, 889; EIMS, m/z 192.1744
(M12H, 1), 178 (1), 150 (3), 138 (100). Calc. for
Â
Â
C. G.; Perez, R.; Martõn, J. D. Org. Lett. 2000, 2, 3161±3164.
4. For a representative example, see: Diver, S. T.; Schreiber, S. L.
J. Am. Chem. Soc. 1997, 119, 5106±5109.
1
C13H23N2H, Mˆ192.1752; H NMR (500 MHz): d 5.90
(1H, ddd, Jˆ17, 10, 6 Hz), 5.14 (1H, br d, Jˆ17 Hz), 5.00
(1H, br d, Jˆ10Hz), 4.86 (1H, br s), 4.60(1H, br s), 3.12
(2H, d, Jˆ6 Hz), 2.10(2H, s), 1.80(3H, s), 1.60±1.30(10H,
br m); 13C NMR (125 MHz): d 142.9, 137.7, 114.9, 114.1,
54.4, 44.0, 37.9, 35.8, 26.1, 25.5, 21.9.
Â
5. Carda, M.; Castillo, E.; Rodrõguez, S.; Uriel, S.; Marco, J. A.
Synlett 1999, 1639±1641.
6. Schrock, R. R. Tetrahedron 1999, 55, 8141±8153. Schrock's
catalyst has recently been eliminated from the Strem
catalogue. No other commercial source of this catalyst is
known to us.
1.4.21.
N-Allyl-N-[1-(2-methylallyl)cyclohexyl]aceta-
mide, 29. Amine 28 (387 mg, ca. 2 mmol) was dissolved
under Ar in dry CH2Cl2 (2 mL) and treated with acetic
anhydride (1 mL) and NEt3 (560 mL, ca. 4 mmol). The
reaction mixture was stirred overnight at room temperature.
Work-up (extraction with EtOAc) and column chromato-
graphy on silica gel (hexane±EtOAc 7:3) afforded 376 mg
(80%) of acetamide 29 as an oil, IR nmax cm21: 3073, 2929,
2861, 1642 (amide CvO), 1392, 1242, 1193, 891; EIMS,
m/z 235.1938 (M1, 1), 180 (64), 138 (100). Calc. for
C15H25NO, Mˆ235.1936; 1H NMR (400 MHz): d 5.82
(1H, ddt, Jˆ17, 10.5, 4.5 Hz), 5.21 (1H, dq, Jˆ17,
1.5 Hz), 5.18 (1H, dq, Jˆ10.5, 1.5 Hz), 4.84 (1H, sext,
Jˆ1.5 Hz), 4.64 (1H, m), 3.86 (2H, m), 2.80(2H, br s),
2.40(2H, br d, Jˆ12 Hz), 2.06 (3H, s), 1.71 (3H, t,
Jˆ1 Hz), 1.70±1.20 (8H, br m); 13C NMR (100 MHz): d
172.6, 143.1, 136.6, 115.8, 114.6, 63.4, 48.4, 38.3, 34.3,
25.7, 25.6, 24.6, 23.0.
7. The formation of trisubstituted CvC bonds, but not of tetra-
substituted ones, by means of RCM with catalyst 6 has
previously been reported. See: Kirkland, T. A.; Grubbs,
R. H. J. Org. Chem. 1997, 62, 7310±7318.
8. For examples where the lactam ring was speci®cally formed
via RCM, see Ref. 2c and (a) Ghosh, A. K.; Hussain, K. A.
Tetrahedron Lett. 1998, 1881±1884. (b) Goldring, W. P. D.;
Hodder, A. S.; Weller, L. Tetrahedron Lett. 1998, 4955±4958.
(c) Grossmith, C. E.; Senia, F.; Wagner, J. Synlett 1999, 1660±
1662. (d) Goldring, W. P. D.; Weller, L. Org. Lett. 1999, 1,
1471±1473. Failure of attempts at obtaining trisubstituted
CvC bonds is speci®cally reported in some of these papers
Â
(e) Vo-Thanh, G.; Boucard, V.; Sauriat-Dorizon, H.; Guibe, F.
Synlett 2001, 37±40.
9. FuÈrstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119,
9130±9136. Without Ti(OiPr)4, no RCM took place with our
substrates.
10. (a) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H.
Tetrahedron Lett. 1999, 2247±2250. (b) Scholl, M.; Ding, S.;
Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953±956.
(c) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1,
1751±1753. (d) Briot, A.; Bujard, M.; Gouverneur, V.;
Nolan, S. P.; Mioskowski, C. Org. Lett. 2000, 2, 1517±
1519. (e) Wright, D. L.; Schulte II, J. P.; Page, M. A. Org.
Lett. 2000, 2, 1847±1850. (f) Lee, C. W.; Grubbs, R. H. Org.
Lett. 2000, 2, 2145±2147. (g) Morgan, J. P.; Grubbs, R. H.
Org. Lett. 2000, 2, 3153±3155. (h) Ackermann, L.; El Tom,
D.; FuÈrstner, A. Tetrahedron 2000, 56, 2195±2202.
(i) FuÈrstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.;
Nolan, S. P. J. Org. Chem. 2000, 65, 2204±2207. (j) Heck,
M. P.; Baylon, C.; Nolan, S. P.; Mioskowski, C. Org. Lett.
2001, 3, 1989±1991. (k) Kinderman, S. S.; van Maarseveen,
J. H.; Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. Org.
Lett. 2001, 3, 2045±2048.
1.4.22. 1-Acetyl-4-methyl-1-azaspiro[5.5]undec-3-ene,
30. Oil, IR nmax cm21: 2928, 2850, 1655 (amide CvO),
1444, 1391, 1342, 1223, 1191, 1172, 700; EIMS, m/z
207.1624 (M1, 100), 164 (94), 150 (66), 122 (98), 105
(60). Calc. for C13H21NO, Mˆ207.1623; 1H NMR
(400 MHz): d 5.38 (1H, m), 3.75 (2H, m), 2.68 (2H, m),
2.07 (3H, s), 1.66 (5H, br s), 1.60±1.20 (8H, m); 13C NMR
(100 MHz): d 171.6, 134.5, 117.9, 58.6, 44.5, 40.6, 34.8,
26.1, 25.7, 23.1, 22.6.
Acknowledgements
The authors wish to acknowledge ®nancial support by the
Â
DGICYT (Project PB98-1438), by Fundacio Caixa
Castello-Univ. Jaume I (P1B99-18) and by the Conselleria
Á
de Cultura de la Generalitat Valenciana (project GV-99-77-
1-02). E. C. thanks the latter institution for a pre-doctoral
fellowship.
11. Wu, Z.; Nguyen, S. T.; Grubbs, R. H.; Ziller, J. W. J. Am.
Chem. Soc. 1995, 117, 5503±5511.
12. Allylic substitution has been shown to decrease the rate of
RCM processes: Ulman, M.; Grubbs, R. H. Organometallics
1998, 17, 2484±2489. It has been reported, however, that
allylic hydroxyl groups have an accelerating effect: Hoye,
T. R.; Zhao, H. Org. Lett. 1999, 1, 1123±1125.
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13. Herisson, J.-L.; Chauvin, Y. Makromol. Chem. 1970, 141,
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Synthesis, FuÈrstner, A., Ed.; Springer: Berlin, 1998.
(b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413±
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bond of the N-allyl group is most likely attacked in the ®rst
cycloaddition step.
15. The following oxidizing reagents were tried without success
(partial decomposition with recovery of some starting
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Barta, M. A.; Havens, J. L. J. Org. Chem. 1978, 43, 2057±
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Chindambaram, N.; Chandrasekaran, S. J. Org. Chem. 1987,
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