Directed ring-closing metathesis of trienes by silyl substitution

Article abstract of DOI:10.1016/j.tet.2004.05.115

A synthetic strategy for 'disarming' a terminal alkene by substitution with a bulky silyl blocking group has been developed. In a series of model studies, sequential selective ring-closing metathesis of trienes followed by selective mono-hydrogenation of the resulting diene is described. The bulky silylated alkene is activated for a subsequent cross-metathesis reaction with a range of diverse alkenes by protodesilylation.

Full text of DOI:10.1016/j.tet.2004.05.115

Tetrahedron 60 (2004) 7515–7524
Directed ring-closing metathesis of trienes by silyl substitution
Carsten Schultz-Fademrecht,a Prashant H. Deshmukh,a Karine Malagu,a Panayiotis A. Procopioub
and Anthony G. M. Barretta
,
*
aDepartment of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK
bDepartment of Medicinal Chemistry, GlaxoSmithKline Research and Development Ltd, Gunnels Wood Road, Stevenage,
Hertfordshire SG1 2NY, UK
Received 6 January 2004; revised 12 May 2004; accepted 14 May 2004
Available online 25 June 2004
Abstract—A synthetic strategy for ‘disarming’ a terminal alkene by substitution with a bulky silyl blocking group has been developed. In a
series of model studies, sequential selective ring-closing metathesis of trienes followed by selective mono-hydrogenation of the resulting
diene is described. The bulky silylated alkene is activated for a subsequent cross-metathesis reaction with a range of diverse alkenes by
protodesilylation.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
[Me2(R1O)Si]CR2vCH2, with either R1 or R2 bearing a
terminal alkene, has been recently described.7 To the best of
our knowledge, there are no examples of any metathesis of
b-substituted vinylsilanes (R3Si)HCvCH2R or even of the
analogous alkoxysilanes. Additionally, there are a few
examples of the use of Me3Si as a blocking group for
metathesis.8 Tam has reported the selective ring opening-
crossed metathesis of 2,3-bis-(trimethylsilyl)norbornadiene
in which the two trimethylsilyl substituents completely
block reaction at the more hindered alkene.9 Additionally,
Nelson and co-workers, in a total synthesis of (2)-
laulimalide, have utilized a selective RCM of a trienyl-
stannane to provide a dihydropyran derivative.10 In this
case, the selectivity was the result of the ‘disarming’ of an
alkene by substitution with a tributylstannyl residue
(Scheme 1). Finally, Hodgson has directed selectivity in
the RCM of trienes with alkene disarming using an iodo-
substituent.11
During the past decade, the synthetic potential of ring-
closing metathesis (RCM) as a mild and catalytic C–C bond
forming method has been well recognized, and as a result
RCM has been widely used in the synthesis of various small,
medium and large rings.1 Recently, we have been pursuing
the synthesis of macrocyclic compounds using selective
RCM of dienes 1 to afford, after ring alkene hydrogenation,
the macrocyclic core 2. Selectivity in both the RCM step
and hydrogenation are clearly prerequisites for this process.
In this respect we envisaged the use of a sterically
demanding, readily cleaved vinyl silane substituent, to
‘disarm’2 one of the alkene units by blocking both
metathesis and hydrogenation at this position. Desilylation
of 2 should afford the ‘armed’2 alkene 3. Finally, cross-
metathesis3 and hydrogenation would provide the target
analogues 4, bearing a variety of functionalized ‘R’ groups.
This method would therefore facilitate, by a synthetically
convergent late stage diversification strategy, the synthesis
of a range of macrocyclic analogues. The strategy has
indirect precedent. Early studies by Schrock showed that
metathesis of trialkylvinylsilanes were slow and inefficient.4
It was later found that vinylsiloxanes are better metathesis
substrates.5 More recently, cross-metathesis of alkoxy- or
silyloxy-vinylsilanes with alkenes in the presence of
Grubbs I catalyst, ((Cy3P)2Ru(vCHPh)Cl2), has also
been reported.6 Successful RCM reactions of
2. Results and discussion
2.1. Selective cross-metathesis of dienyl monosilanes
In a preliminary experiment, we studied the cross-meta-
thesis of diene 5 with 3-methyl-2-butene, using the saturated
imidazolylidene catalyst 712 (Scheme 2). According to the
Stoltz procedure, 3-methyl-2-butene acts as both solvent
and alkene partner in the cross-metathesis reaction.13 We
successfully applied these conditions to the alkene 5 and
obtained the desired product 6 in 82% yield. No metathetic
desilylation of the ‘disarmed’ double bond was observed.
This result demonstrated that the disarming of a terminal
Keywords: Ring-closing metathesis; Crossed metathesis; Ruthenium
catalysts; Macrocyclization.
*
Corresponding author. Tel.: þ44-207-594-5766; fax: þ44-207-594-5805;
e-mail address: agmb@ic.ac.uk
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.115

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Scheme 1.
Scheme 2. Reagents and conditions: (a) excess 3-methyl-2-butene, 7 (10 mol%), 35 8C.
alkene could effectively be achieved via protection by
terminal methyldiphenylsilylation.
Stereospecific reduction using Red-Alw in toluene, followed
by oxidation of the resulting allylic alcohol with manganese
dioxide gave the key unsaturated aldehyde 10. The
stereochemistry of the alkene was determined to be
exclusively trans by 1H NMR spectroscopy. Reductive
amination of 10 gave the secondary amines 11a and 11b in
high yields, which were further derivatized by acylation to
provide the amides 12a-d (Scheme 3).
2.2. Selective ring-closing-metathesis of trienyl
monosilanes
The encouraging result in Scheme 2 prompted us to prepare
the series of amides 12a-d as substrates to explore directed
RCM. Thus, double deprotonation of propargyl alcohol (8)
using methylmagnesium bromide, followed by reaction
with methyl(diphenyl)chlorosilane (2 equiv.), and sulfuric
acid-mediated monodeprotection afforded acetylene 9 in
95% overall yield, following the procedure by Denmark.14
Our first application of the strategy involved the triene 12a
(Scheme 4). Reaction with catalyst 7 (5 mol%) in
dichloromethane gave, after 12 h, selective conversion to
the desired lactam 13 in 80% yield. No products of
Scheme 3. Synthesis of ring-closing metathesis precursors 12a-d. Reagents and conditions: (a) (i) MeMgBr (2.6 equiv.), THF, Et2O, 0 8C; (ii) Ph2MeSiCl
(2.6 equiv.), 40 8C; (iii) 1.4 M H2SO4, 0 8C; (b) 50% Red-Alw, PhMe, Et2O, 0–25 8C; (c) MnO2 (10 equiv.), CH2Cl2, 45 8C; (d) CH2vCH(CH2)nNH2, NaBH4,
MeOH, 25 8C; (e) ClCOCH(R)(CH2)mCHvCH2, NEt3, CH2Cl2, 25 8C.

C. Schultz-Fademrecht et al. / Tetrahedron 60 (2004) 7515–7524
7517
Scheme 4. Arming–disarming strategy for the substituted 2-piperidinone series. Reagents and conditions: (a) 7 (5 mol%), CH2Cl2, 12 h; (b) H2 (1 atm),
(Ph3P)3RhCl (10 mol%), THF, EtOH, 4 h; (c) Bu4NF, DMSO, 80 8C, 1.5 h; (d) 3-methyl-2-butene, 7 (10 mol%), 45 8C, 20 h; (e) allyl acetate (2.0 equiv.), 7
(10 mol%), CH2Cl2, 25 8C, 16 h; (f) methyl vinyl ketone (3.0 equiv.), 7 (20 mol%), CHCl3, 60 8C, 18 h.
desilylation were observed. Significantly reduced yields
(23–33%) were obtained using the less reactive Grubbs I
catalyst.15 The endocyclic double bond in 13 was selectively
hydrogenated using Wilkinson’s catalyst ((Ph3P)3RhCl), in
THF and ethanol at atmospheric pressure to afford the
saturated lactam 14 (82%). The choice of solvent was
critical, since other solvents resulted in competitive alkene
migration or over-reduction of the silylalkene unit. When
palladium on charcoal was used for the hydrogenation
reaction at atmospheric pressure, no selectivity was
observed. Both alkenes were hydrogenated giving the
fully saturated product. Alternatively, ROMPgel supported
Wilkinson’s catalyst16 was used for the selective hydrogen-
ation, allowing a facile isolation of the product 14.
Hydrogenation over platinum oxide in benzene was
irreproducible, whereas reaction using (Ph3P)3RhCl in
toluene resulted in double bond migration. The methyl(di-
phenyl)silyl blocking group in 14 was readily cleaved using
tetrabutylammonium fluoride in DMSO, giving lactam 1517
(98%). Cross-metathesis of 15 following the Stolz pro-
cedure13 yielded the desired product 16a in 95% yield.
Cross-metathesis was also successfully accomplished with
allyl acetate and methyl vinyl ketone to afford the
functionalized alkenes 16b (67%) and 16c (54%),
respectively.
Further improvements were obtained using microwave
irradiation. After 15 min at 100 8C, the desired product 17
was isolated in 52% yield. RCM of triene 12c using
microwave heating at 100 8C for 15 min gave the lactam 18
in 59% yield. The lower yields observed in the seven-
membered rings are not surprising, however, since studies
by Grubbs et al. have shown that the synthesis of several
seven- and eight-membered rings by RCM typically give
only modest yields.18 However, it is noteworthy to point out
that the RCM in Scheme 5 selectively provided the
1-lactams 17 and 18 rather than the corresponding
desilylated 1-lactams or N-acyl-pyrrolines. Selective hydro-
genation of dienes 17 and 18 were accomplished in high
yields (86 and 80%, respectively) using (Ph3P)3RhCl in
THF and ethanol.
The promising results obtained for the 2-piperidinone series
were extended to larger ring systems. Thus, we investigated
various RCM conditions for the substituted 2-azepanone
series precursors 12b and 12c (Scheme 5). Reaction of 12b
with catalyst 7 (5 mol%) at 25 8C gave the product 17 in
very low yield, together with recovered starting material.
Higher reaction temperatures increased the yield. Thus at
90 8C after 24 h, lactam 17 was obtained in 35% yield. In all
reactions at higher temperature a minor unidentified side
product(s) was also isolated. The silyl functionality was
absent and the product appeared to be oligomeric with broad
signals in the 1H NMR spectrum. Trace amounts of
methyl(diphenyl)vinylsilane were also detected (GCMS).
These observations suggest that metathetic desilylation may
have been a minor side reaction at elevated temperatures.
Scheme 5. Application of the strategy to the substituted 2-azepanone series.
Reagents and conditions: (a) 7 (5 mol%), CH2Cl2, microwave, 100 8C,
15 min; (b) H2 (1 atm), (Ph3P)3RhCl (10 mol%), THF, EtOH, 4 h.

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C. Schultz-Fademrecht et al. / Tetrahedron 60 (2004) 7515–7524
2.3. Macrocyclization via selective ring-closing-
metathesis of trienyl monosilanes
allyl acetate or 5-hexene-2-one gave the modified alkenes
25a-c, respectively.
The use of the methyl(diphenyl)silyl blocking group to
direct selective RCM to provide a macrocyclic alkene was
next investigated (Scheme 6). When the metathesis
precursor 12d was allowed to react with catalyst 7
(10 mol%) under reflux for 24 h, the lactam 21 was obtained
in 65% yield as a cis/trans-mixture. The mixture was
carefully hydrogenated using (Ph3P)3RhCl over 4 h, when
21 was converted into 22 and 23 (3.1:1; 89%). It is possible
that the loss in selectivity here, in comparison with the
2-piperidinone series (Scheme 4) and the 2-azepanone
series (Scheme 5) could stem from increased steric
hindrance of the endocyclic alkene by the ring carbon
skeleton. Additionally, the formation of trans as well as cis
alkenes in the previous metathesis could lead to a loss of
differentiation in reactivity between the macrocyclic alkene
and the alkenylsilane. Nevertheless, it is important to note
that the hydrogenation of 21 proceeds selectively with more
rapid reduction of the macrocyclic alkene rather than the
alkenylsilane. In any case, the mixture of lactams 22 and 23
were allowed to react with tetrabutylammonium fluoride in
THF selectively to give the terminal alkene 24 in good yield
(87%), based upon the quantity of 22 present in the reaction
mixture. Cross-metathesis of 24 with 3-methyl-2-butene,
3. Conclusions
In conclusion, we have demonstrated the application of the
methyl(diphenyl)silyl moiety to direct selectivity in both
crossed and RCM. We have shown that RCM of a triene
monosilane takes place selectively between the non-silylated
alkenes and may be used to prepare six-, seven- and 16-
membered lactams. Furthermore, selective hydrogenation
of the diene products over (Ph3P)3RhCl proceeded with
good selectivity in the reduction of the ring alkene, whereas
the alkenylsilane was not reduced. Application of this
strategy to the synthesis of further macrocyclic systems will
be reported in due course.
4. Experimental
4.1. General
All reactions were carried out in an atmosphere of dry
nitrogen. Where solvents have been described as dry or
anhydrous, they have been vigorously dried over CaH2
Scheme 6. Metathesis and selective hydrogenation of the 2-azacyclohexadecanone series. Reagents and conditions: (a) 7 (10 mol%), CH2Cl2, 45 8C; (b) H2
(1 atm), (Ph3P)3RhCl (10 mol%), THF, EtOH, 25 8C; (c) Bu4NF, THF, DMSO, 80 8C; (d) 7 (10 mol%), 3-methyl-2-butene, 35 8C, 20 h; (e) allyl acetate
(2.0 equiv.), 7 (10 mol%), CH2Cl2, 25 8C, 16 h; (f) 5-hexene-2-one (8.4 equiv.), 7 (20 mol%), CHCl3; 60 8C, 18 h.

C. Schultz-Fademrecht et al. / Tetrahedron 60 (2004) 7515–7524
7519
(CH2Cl2, PhMe), Na/K alloy (THF), and Na (Et2O). All
reagents were obtained from commercial suppliers and used
without further purification unless otherwise stated. Column
chromatography was carried out on BDH silica gel, particle
size 40–63 mm, using flash techniques (eluants are given in
parenthesis). Analytical thin layer chromatography was
performed on Merck pre-coated silica gel F254 plates.
mixture was allowed to cool to room temperature and was
filtered through silica, eluting with CH2Cl2. Rotary
evaporation and chromatography (hexanes/EtOAc, 9:1)
gave 10 (2.1 g, 85%) as a colorless oil: TLC Rf 0.31
(hexanes/EtOAc, 9:1; KMnO4); IR (thin film) 1692, 1428,
1
1115 cm21; H NMR (300 MHz, CDCl3) d 9.63 (d, 1H,
J¼7.6 Hz), 7.56–7.42 (m, 11H), 6.63 (dd, 1H, J¼18.6,
7.6 Hz), 0.77 (s, 3H); 13C NMR (75 MHz, CDCl3) d 194.3,
154.2, 146.6, 134.8, 133.9, 130.1, 128.3, 24.4; MS (EI) m/z
252 (Mþz, 22), 237 (100), 197 (47), 183 (30), 174 (100);
HRMS (EI) m/z calcd for C16H16OSi: (Mþz), 252.0970,
found: (Mþz), 252.0964. Anal. calcd for C16H16OSi: C,
76.14; H, 6.39. Found: C, 75.99; H, 6.38.
4.1.1. Preparation of 3-(methyldiphenylsilyl)-2-propyn-
1-ol (9). Propargyl alcohol (8) (2.5 mL, 43 mmol,
1.0 equiv.) was added dropwise to MeMgBr in dry Et2O
(3.0 M, 37 mL, 112 mmol, 2.6 equiv.) and dry THF (20 mL)
at 0 8C under argon. The mixture was left overnight under
argon at 0–4 8C, recooled to 0 8C and Ph2MeSiCl (23.5 mL,
112 mmol, 2.6 equiv.) was added dropwise. The mixture
was heated under reflux at 40 8C for 2 h, cooled to 0 8C and
dilute H2SO4 (1.4 M; 46 mL) was added slowly with
stirring. After 5 min at 0 8C, Et2O (35 mL) was added, the
layers were separated and the aqueous phase was extracted
with Et2O (2£20 mL). The combined Et2O extracts were
washed with H2O (30 mL) and saturated aqueous NaCl
(30 mL), dried (MgSO4) and concentrated. Chromatography
(hexanes/EtOAc, 9:1) gave 9 (10.2 g, 95%) as a colorless
oil: TLC Rf 0.50 (hexanes/EtOAc, 1:1; KMnO4); IR (thin
film) 3338, 2176, 1428, 1253, 1114, 1040, 793, 729,
4.1.4. Preparation of propenyl-(3E-(methyldiphenylsi-
lyl)propenyl)amine (11a). Allylamine (620 mL, 8.3 mmol,
1.1 equiv.) was added to aldehyde 10 (1.9 g, 7.5 mmol,
1.0 equiv.) in dry MeOH (30 mL) and the mixture was
stirred at room temperature for 2 h. NaBH4 (0.31 g,
8.3 mmol) was added and the mixture was stirred at room
temperature for 18 h. H2O (20 mL) was added and the
combined solvents rotary evaporated. The residue was
partitioned between Et2O (30 mL) and H2O (30 mL). The
separated aqueous layer was further extracted with Et2O
(2£20 mL) and the combined ethereal phases were dried
(MgSO4) and rotary evaporated to give 11a (1.5 g, 70%) as
a colorless oil, which was used without purification: TLC Rf
0.09 (hexanes/EtOAc, 1:1; KMnO4); IR (thin film) 3068,
1
698 cm21; H NMR (300 MHz, CDCl3) d 7.63–7.69 (m,
4H), 7.38–7.47 (m, 6H), 4.38 (s, 2H), 1.79 (br s, 1H), 0.72
(s, 3H); 13C NMR (75 MHz, CDCl3) d 134.9, 134.6, 129.9,
128.1, 107.3, 87.1, 51.7, 22.1; MS (EI) m/z 252 (Mþz, 4),
237 (38), 137 (100), 115 (43), 105 (14), 91 (21), 45 (22);
HRMS (EI) m/z calcd for C16H15OSi: (Mþz), 252.09704,
found: (Mþz), 252.09791. Anal. calcd for C16H16OSi: C,
76.14; H. 6.39. Found: C, 76.18; H, 6.43.
1
3048, 1676, 1615, 1429, 794 cm21; H NMR (300 MHz,
CDCl3) d 7.63–7.56 (m, 4H), 7.45–7.39 (m, 6H), 6.27–
6.22 (m, 2H), 5.95 (ddt, 1H, J¼17.2, 10.3, 6.0 Hz), 5.22 (dd,
1H, J¼17.2, 1.2 Hz), 5.14 (d, 1H, J¼10.3 Hz), 3.42 (d, 2H,
J¼4.1 Hz), 3.31 (d, 2H, J¼6.0 Hz), 0.68 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 148.6, 136.7, 136.6, 134.9, 129.3,
127.9, 126.6, 116.1, 54.0, 52.0, 23.7; MS (FAB, þve) m/z
294 ((MþH)þ, 50), 197 (29), 159 (21), 121 (20), 109 (20),
55 (100); HRMS (FAB, þve) m/z calcd for C19H24NSi:
(MþH)þ, 294.1678, found: (MþH)þ, 294.1671. Anal. calcd
for C19H23NSi: C, 77.76; H, 7.90; N, 4.77. Found: C, 77.69;
H, 7.80; N, 4.70.
4.1.2. Preparation of 3E-(methyldiphenylsilyl)-2-pro-
pen-1-ol (26). Acetylene 9 (3.9 g, 15 mmol) in dry Et2O
(20 mL) was added dropwise over 1 h to Red-Al in PhMe
(65% w/v, 7.5 mL, 24 mmol, 1.6 equiv.) in Et2O (10 mL) at
0 8C. After 2 h at room temperature, the mixture was
recooled to 0 8C when dilute H2SO4 (1.4 M, 50 mL) was
added cautiously. The separated aqueous layer was further
extracted with Et2O (2£20 mL) and the combined phases
were washed with H2O (30 mL) and saturated aqueous NaCl
(30 mL) and dried (MgSO4). Rotary evaporation and
chromatography (hexanes/EtOAc, 5:1) gave (E)-3-methyl(di-
phenyl)silyl-2-propen-1-ol (26) (3.9 g, 99%) as a colorless
oil: TLC Rf 0.47 (hexanes/EtOAc, 1:1; KMnO4); IR (thin
4.1.5. Preparation of (E)-hex-5-enyl-(3-(methyldiphenyl-
silyl)propenyl)-amine (11b). 5-Hexenyl-1-amine (300 mg,
3.02 mmol, 1.1 equiv.) was added to aldehyde 10 (699 mg,
2.75 mmol, 1.0 equiv.) in dry MeOH (6 mL) and the
mixture was stirred at room temperature for 2 h, prior to
the addition of NaBH4 (114 mg, 3.02 mmol, 1.1 equiv.).
The mixture was stirred at room temperature for 18 h, after
which H2O (20 mL) was added and the combined solvents
evaporated. The residue was partitioned between Et2O
(30 mL) and H2O (30 mL) and the separated aqueous layer
was extracted further with Et2O (2£20 mL). The combined
ethereal phases were dried (MgSO4) and rotary evaporated
to give 11b (846 mg, 92%) as a colorless oil, which was
used without further purification: TLC Rf 0.47 (EtOAc;
1
film) 3338, 3069, 1620, 1427 cm21; H NMR (300 MHz,
CDCl3) d 7.60–7.63 (m, 4H), 7.42–7.48 (m, 6H), 6.34 (m,
2H), 4.27 (m, 2H), 2.11 (br s, 1H), 0.73 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 149.0, 136.5, 134.9, 129.4, 128.0,
124.7, 65.3, 23.7; MS (CI, NH3) m/z 272 ((MþNH4)þ,
100), 256 (4), 232 (24), 216 (7), 214 (9), 194 (45), 179 (4),
154 (42), 173 (6); HRMS (CI, NH3) m/z calcd for
C16H22NOSi: (MþNH4)þ, 272.1471, found: (MþNH4)þ,
272.1478. Anal. calcd for C16H18OSi: C, 75.54; H, 7.13%.
Found: C, 75.58; H, 7.24.
1
KMnO4); IR (thin film) 1670, 1428, 791, 734 cm21; H
NMR (300 MHz, CDCl3) d 7.65–7.53 (m, 4H), 7.49–7.33
(m, 6H), 6.24 (m, 2H), 5.86 (m, 1H), 5.07 (d, 1H, J¼18 Hz),
5.01 (d, 1H, J¼11 Hz), 3.42 (d, 2H, J¼4 Hz), 2.68 (t, 2H,
J¼7 Hz), 2.12 (m, 2H), 1.53 (m, 4H), 0.69 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 148.9, 138.8, 136.7, 134.9, 129.3,
127.9, 126.3, 114.6, 54.8, 49.5, 33.7, 30.2, 26.7, 23.7; MS
(CI, NH3) m/z 336 ((MþH)þ, 100), 257 (12); HRMS (CI,
4.1.3. Preparation of 3E-(methyldiphenylsilyl)propenal
(10). Powdered MnO2 (8.8 g, 101 mmol, 10 equiv.) was
added to (E)-3-methyl(diphenyl)silyl-2-propen-1-ol (26)
(2.5 g, 9.8 mmol, 1.0 equiv.) in dry CH2Cl2 (15 mL) and
the resulting suspension stirred under reflux for 3 h. The

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C. Schultz-Fademrecht et al. / Tetrahedron 60 (2004) 7515–7524
NH3) m/z calcd for C22H30NSi: (MþH)þ, 336.2148, found:
(MþH)þ, 336.2144. Anal. calcd for C22H29NSi: C, 78.75;
H, 8.71; N, 4.17. Found: C, 78.91; H, 8.86, N, 3.96.
residue in EtOAc (30 mL) was washed with saturated
aqueous NaHCO3 (20 mL) H2O (30 mL), saturated aqueous
NH4Cl (20 mL) and H2O (30 mL). The solution was dried
(MgSO4), rotary evaporated and chromatographed (hex-
anes/EtOAc, 9:1) to give 12a (1.82 g, 64%) as an oily
mixture of rotamers: TLC Rf 0.73 (EtOAc; KMnO4); IR
(thin film) 1624, 1461, 1428, 1199, 1112, 995, 917, 791,
4.1.6. Preparation of N-(5-hexen-1-yl)-N-methyl-N-(3E-
(methyldiphenylsilyl)-propenyl)amine (5). Amine 11b
(0.7 g, 2.1 mmol, 1.0 equiv.) was added to HCO2H (98%
w/v; 0.2 mL, 5.2 mmol, 2.5 equiv.) at 0 8C and the resulting
clear solution was stirred for 5 min prior to the addition of
aqueous formaldehyde (37% w/v; 0.5 mL, 6.3 mmol,
3.0 equiv.). The cloudy solution was heated to 90 8C
under reflux for 3 h, prior to the addition of 10% NaOH
(10 mL) and extraction with CH2Cl2 (3£10 mL). The
combined extracts were dried (MgSO4), rotary evaporated
and chromatographed (CH2Cl2/MeOH, 19:1) to give 5
(0.6 g, 83%) as a clear colorless oil: TLC Rf 0.25 (CH2Cl2/
MeOH, 19:1; UV, KMnO4); IR (thin film) 1428, 1250,
1112, 791, 699 cm21; 1H NMR (300 MHz, CDCl3) d 7.70–
7.36 (m, 10H), 6.29 (dt, 1H, J¼18.5, 5.0 Hz), 6.22 (d, 1H,
J¼18.5 Hz), 5.87 (ddt, 1H, J¼17.0, 10.0, 7.0 Hz), 5.07 (d,
1H, J¼17.0 Hz), 5.02 (d, 1H, J¼10.0 Hz), 3.19 (d, 2H,
J¼5.0 Hz), 2.42 (t, 2H, J¼7.0 Hz), 2.29 (s, 3H), 2.13 (q, 2H,
J¼7.0 Hz), 1.62–1.41 (m, 4H), 0.70 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 148.1, 138.8, 136.7, 134.9, 129.3,
128.7, 127.9, 114.6, 63.7, 57.4, 42.5, 33.7, 26.9, 23.7; MS
(CI, NH3) m/z 350 ((MþH)þ, 100), 288 (15), 280 (17);
HRMS (CI, NH3) m/z calcd for C23H32NSi: (MþH)þ,
350.2304, found: (MþH)þ, 350.2315. Anal. calcd for
C23H31NSi: C, 79.02; H, 8.94; N, 4.01. Found: C, 79.13;
H, 8.96; N, 4.13.
1
734 cm21; H NMR (300 MHz, CDCl3) d 7.53–7.51 (m,
4H), 7.41–7.39 (m, 6H), 6.20–5.93 (m, 3H), 5.85–5.72
(m, 1H), 5.25–5.07 (m, 2H), 4.14–3.90 (m, 4H), 3.18–3.12
(m, 2H), 0.66 and 0.64 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 171.2 and 171.0, 144.8 and 143.8, 136.3 and 135.0, 134.8
and 134.7, 133.2 and 132.8, 131.8 (2C), 129.6 and 129.4,
128.3 and 127.8, 128.0 and 127.9, 117.8 (2C), 117.5 and
116.8, 51.4 and 50.1, 49.5 and 48.4, 38.5 and 38.4, 23.7 and
23.8; MS (FAB, þve) m/z 362 ((MþH)þ, 100), 284 (12),
197 (48), 159 (17), 121 (18), 55 (16); HRMS (FAB, þve)
m/z calcd for C23H28NOSi: (MþH)þ, 362.1940, found:
(MþH)þ, 362.1951.
4.1.9. Preparation of 1-[(E)-3-(methyldiphenylsilyl)pro-
penyl]-3,6-dihydro-1H-pyridin-2-one (13). Diene 12a
(273 mg, 0.75 mmol, 1.0 equiv.) and catalyst 7 (51 mg,
0.075 mmol, 0.1 equiv.) in CH2Cl2 (3.0 mL) were stirred for
18 h at room temperature under N2. Rotary evaporation and
chromatography (PhMe/EtOAc, 19:1) afforded 13 (200 mg,
80%) as an oil: TLC Rf 0.42 (hexanes/EtOAc, 1:1; KMnO4);
IR (thin film) 1649, 1490, 1427, 1118 cm21 1H NMR
;
(300 MHz, CDCl3) d 7.57–7.54 (m, 4H), 7.46–7.38 (m,
6H), 6.20–6.11 (m, 2H), 5.83–5.74 (m, 2H), 4.24 (d, 2H,
J¼3.6 Hz), 4.24 (d, 2H, J¼3.6 Hz), 3.91 (m, 2H), 3.04 (m,
2H), 0.68 (s, 3H); 13C NMR (75 MHz, CDCl3) d 166.9,
143.9, 136.2, 134.8, 129.5, 128.5, 128.0, 122.7, 120.9, 51.1,
48.6, 32.2, 23.7; MS (EI) m/z 333 (37), 332 (Mþz), 318 (19),
256 (100), 216 (35), 197 (95), 136 (54), 105 (38); HRMS
(EI) m/z calcd for C21H22NOSi: (Mþz), 332.1471, found
(Mþz), 332.1464. Anal. calcd for C21H23NOSi: C, 75.63; H,
6.95; N, 4.20. Found: C, 75.42; H, 7.06; N, 4.12.
4.1.7. Preparation of N-(6-methylhept-5-en-1-yl)-N-(3E-
(methyldiphenylsilyl)-propenyl)amine (6). Diene
7
5
(100 mg, 0.29 mmol, 1.0 equiv.), catalyst (25 mg,
0.03 mmol, 0.1 equiv.) and 2-methyl-2-butene (3.0 mL) in
CH2Cl2 (0.1 mL) were heated at reflux under N2 for 18 h.
Rotary evaporation and chromatography (CH2Cl2/MeOH,
39:1) gave 6 (88 mg, 82%) as a brown oil: TLC Rf 0.20
(CH2Cl2/MeOH, 39:1; UV, KMnO4); IR (thin film) 1680,
1
1618, 1449, 1429, 1378, 792, 733, 700 cm21; H NMR
4.1.10. Preparation of 2-(3E-(methyldiphenylsilyl)pro-
penyl)-2-piperidinone (14). Platinum oxide (6.8 mg,
0.03 mmol, 0.1 equiv.) and alkene 13 (100 mg, 0.3 mmol)
in dry PhH (3.0 mL) were purged with H2, cooled to
278 8C, evacuated, purged again with H2, and the process
repeated twice. The mixture was stirred under H2 at room
temperature for 18 h. Silica gel (200 mg) was added and the
mixture was filtered. Rotary evaporation gave 14 (99 mg,
98%) as a clear colorless oil: TLC Rf 0.16 (hexanes/EtOAc,
1:1; KMnO4); IR (thin film) 3067, 3047, 1642, 1492, 1427,
(300 MHz, CDCl3) d 7.57–7.55 (m, 4H), 7.40–7.38 (m,
6H), 6.26 (dd, 1H, J¼19.0, 4.5 Hz), 6.18 (d, 1H,
J¼19.0 Hz), 5.15 (t, 1H, J¼6.0 Hz), 3.16 (d, 2H,
J¼4.5 Hz), 2.41–2.40 (m, 2H), 2.26 (s, 3H), 2.20–2.01
(m, 2H), 1.73 (s, 3H), 1.64 (s, 3H), 1.52–1.47 (m, 2H),
1.41–1.31 (m, 2H), 0.67 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 148.1, 136.7, 134.8, 131.5, 129.3, 128.7, 127.8,
124.6, 63.7, 57.6, 42.4, 28.0, 27.8, 27.1, 25.8, 17.8, 23.7;
MS (CI, NH3) m/z 350 ((MþH)þ, 100), 288 (15), 280 (17);
HRMS (CI, NH3) m/z calcd for C25H36NSi: (MþH)þ,
378.2617, found: (MþH)þ, 378.2614. Anal. calcd for
C25H35NSi: C, 79.51; H, 9.34; N, 3.71. Found: C, 79.35;
H, 9.09; N, 3.61.
1
1351 cm21; H NMR (300 MHz, CDCl3) d 7.55–7.52 (m,
4H), 7.44–7.39 (m, 6H), 6.09 (m, 2H), 4.16 (d, 2H,
J¼2.5 Hz), 3.26 (m, 2H), 2.44 (m, 2H), 1.83 (m, 4H), 0.66
(s, 3H); 13C NMR (75 MHz, CDCl3) d 169.6, 144.5, 136.4,
134.8, 129.4, 128.4, 127.9, 51.5, 47.6, 32.3, 23.2, 21.5,
23.7; MS (EI) m/z 335 (Mþz, 38), 320 (26), 258 (85), 218
(52), 197 (100), 181 (18), 138 (79), 121 (32), 105 (40), 55
(23); HRMS (EI) m/z calcd for C21H25NOSi: (Mþz),
335.1705, found: (Mþz), 335.1711. Anal. calcd for
C21H2NOSi: C, 75.18; H, 7.51; N, 4.17. Found: C, 75.24;
H, 7.63; N, 4.26.
4.1.8. Preparation of N-propenyl-N-(3E-(methyldiphe-
nylsilyl)propenyl)-3-butenamide (12a). Dicyclohexyl-car-
bodiimide (774 mg, 3.75 mmol, 1.1 equiv.) in DMF (5 mL)
was added with stirring to amine 11a (1.0 g, 3.4 mmol,
1.0 equiv.), 3-butenoic acid (320 mL, 3.75 mmol,
1.1 equiv.) and N,N-dimethylaminopyridine (458 mg,
3.75 mmol, 1.1 equiv.) in DMF (15 mL) at 0 8C. After
18 h at 30 8C, the mixture was filtered to remove
dicyclohexylurea and the filtrate was evaporated. The
4.1.11. Preparation of 1-propenyl-2-piperidinone (15).
Bu4NF in THF (1.0 M; 5.2 mL, 5.2 mmol, 5.2 equiv.) was

C. Schultz-Fademrecht et al. / Tetrahedron 60 (2004) 7515–7524
7521
added to silylalkene 14 (350 mg, 1.0 mmol, 1.0 equiv.) in
DMSO (5.0 mL) at room temperature. The reaction mixture
was heated to 80 8C for 1.5 h, and was then partitioned
between Et2O (10 mL) and H2O (10 mL). The separated
aqueous layer was extracted further with Et2O (2£10 mL)
and the combined extracts were dried (MgSO4) and rotary
evaporated. Chromatography (hexanes/EtOAc, 4:1) gave
1517 (143 mg, 99%) as a clear colorless oil: TLC Rf 0.10
(hexanes/EtOAc, 1:1; KMnO4); IR (thin film) 1639, 1495,
1466, 1416 cm21; 1H NMR (300 MHz, CDCl3) d 5.76 (ddt,
1H, J¼18.0, 9.0, 5.8 Hz), 5.16 (dd, 1H, J¼9.0, 1.4 Hz), 5.14
(dd, 1H, J¼18.0, 1.4 Hz), 4.99 (d, 2H, J¼5.8 Hz), 3.24 (m,
2H), 2.39 (m, 2H), 1.80 (m, 4H); 13C NMR (75 MHz,
CDCl3) d 169.6, 132.9, 117.1, 49.3, 47.3, 32.3, 23.2, 21.4;
MS (CI, NH3) m/z 140 ((MþH)þ 100), HRMS (CI, NH3)
m/z calcd for C8H14NO: (MþH)þ, 140.10754, found:
(MþH)þ, 140.10731.
J¼16.2, 5.3 Hz), 6.05 (d, 1H, J¼16.2 Hz), 4.15 (d, 2H,
J¼5.3 Hz), 3.29–3.20 (m, 2H), 2.44–2.37 (m, 2H), 2.26–
2.23 (m, 2H), 1.85–1.79 (m, 4H); 13C NMR (75 MHz,
CDCl3) d 198.1, 169.9, 141.7, 131.6, 48.2, 48.0, 32.2, 29.7,
27.0, 23.2, 21.3; MS (CI, NH3) m/z 212 (3), 196 (13), 182
((MþH)þ, 100), 138 (5); HRMS (CI, NH3) m/z calcd for
C10H16NO2: (MþH)þ, 182.1182, found (MþH)þ,
182.1185.
4.1.15. Preparation of N-(3E-(methyldiphenylsilyl)pro-
penyl)-N-propenyl-pent-4-enamide (12b). 4-Pentenoyl
chloride (1.1 mL, 10 mmol, 1.4 equiv.) in dry CH2Cl2
(40 mL) was slowly added with stirring to amine 11a
(2.1 g, 7.2 mmol, 1.0 equiv.) and Et3N (1.6 mL, 11 mmol,
1.5 equiv.) in CH2Cl2 (40 mL) at 0 8C. After standing at
0 8C for 30 min and at room temperature for 4 h, H2O
(50 mL) was added and the organic phase washed with H2O
(2£30 mL) and saturated aqueous NaCl (40 mL) and dried
(MgSO4). Rotary evaporation and chromatography (hex-
anes/EtOAc, 4:1) gave 12b (2.1 g, 81%) as a clear yellow oil
containing a mixture of rotamers: TLC Rf 0.66 (EtOAc;
KMnO4); IR (thin film) 1650, 1428, 1251, 1191, 1112,
4.1.12. Preparation of 1-(3-methylbut-2-enyl)piperidin-
2-one (16a). Alkene 15 (5.0 mg, 0.036 mmol, 1.0 equiv.)
and catalyst 7 (3.0 mg, 0.0036 mmol, 0.1 equiv.) in 3-
methyl-2-butene (9.0 mL) were heated at reflux at 35 8C for
2 h, rotary evaporated and chromatographed (hexanes/
EtOAc, 1:1) to give 16a (6.0 mg, 95%) as a colorless oil:
TLC Rf 0.27 (EtOAc; KMnO4); IR (thin film) 1641, 1494,
1
791 cm21; H NMR (300 MHz, CDCl3) d 7.53–7.51 (m,
4H), 7.45–7.40 (m, 6H), 6.18–6.00 (m, 2H), 5.91–5.72 (m,
2H), 5.24–4.98 (m, 4H), 4.19–3.88 (m, 4H), 2.42 (m, 4H),
0.67 and 0.65 (s, 3H); 13C NMR (75 MHz, CDCl3) d 172.5
and 172.3, 145.0 and 144.0, 137.6, 136.3 and 136.0, 134.8
and 134.7, 134.0, 133.4 and 132.9, 128.1 and 128.0, 127.9
and 127.6, 117.3 and 116.7, 115.2, 51.3 and 50.2, 49.4 and
48.5, 32.4 and 32.3, 29.4 and 29.3, 23.7 and 23.8; MS (CI,
NH3) m/z 375 (Mþz, 37), 360 (20), 334 (24), 298 (74), 258
(15), 214 (24), 199 (100), 137 (17), 77 (10), 55 (10); HRMS
(CI, NH3) m/z calcd for C24H29NOSi: (Mþz), 375.2018,
found: (Mþz), 375.2006. Anal. calcd for C24H29NOSi: C,
76.75; H, 7.78; N, 3.73. Found: C, 76.26; H, 7.74; N, 3.65.
1
1448, 1352 cm21; H NMR (300 MHz, CDCl3) d 5.15 (t,
1H, J¼6.0 Hz), 4.02 (d, 2H, J¼6.0 Hz), 3.23 (m, 2H), 2.40
(m, 2H), 1.75 (s, 3H), 1.70 (s, 3H), 1.63 (m, 4H); 13C NMR
(75 MHz, CDCl3) d 169.3, 136.1, 119.7, 46.9, 44.2, 32.4,
25.7, 23.2, 21.4, 17.8; MS (CI, NH3) m/z 168 ((MþH)þ,
100), 124 (6), 100 (10); HRMS (CI, NH3) m/z calcd for
C10H17NO: (MþH)þ, 168.13884, found: (MþH)þ,
168.13856. Anal. calcd for C10H17NO: C, 71.81; H, 10.25;
N, 8.37. Found: C, 71.81; H, 10.14; N, 8.27.
4.1.13. Preparation of 1-(4-acetoxy-2E-buten-1-yl)-2-
piperidinone (16b). Catalyst
7
(62 mg, 0.07 mmol,
4.1.16. Preparation of N-(3E-(methyldiphenylsilyl)pro-
penyl)-2-((t-butyloxy-carbonyl)-amino)-N-propenyl-pent-
4-enamide (12c). N,N-Dimethylaminopyridine (114 mg,
0.93 mmol, 1.2 equiv.), 2-((t-butyloxycarbonyl)amino)-4-
pentenoic acid (225 mg, 0.85 mmol, 1.1 equiv.) and dicyclo-
hexylcarbodiimide (192 mg, 0.93 mmol, 1.2 equiv.) in
CH2Cl2 (1.5 mL) were added sequentially to amine 11a
(227 mg, 0.775 mmol) in CH2Cl2 (2 mL) at room tempera-
ture. The mixture was stirred at room temperature for 3 h
when the precipitate of N,N-dicyclohexylurea was removed
by filtration. The filtrate was washed with saturated aqueous
NaHCO3 (2 mL) H2O (2 mL), saturated aqueous NH4Cl
(1 mL) and H2O (2£2 mL). The organic layer was dried
(MgSO4), rotary evaporated and chromatographed (gradient
elution; hexanes/EtOAc, 99:1 to 95:5) to give 12c (354 mg,
93%) as a pale yellow oil: TLC Rf 0.18 (hexanes/EtOAc,
4:1); IR (thin film) 1713, 1651, 1484, 1428 cm21; 1H NMR
(300 MHz, CDCl3) d 7.52–7.49 (m, 4H), 7.39–7.37 (m,
6H), 6.13–6.02 (m, 2H), 5.77–5.69 (m, 2H), 5.30–5.03
(m, 4H), 4.65–4.52 (m, 1H), 4.27–4.21 (m, 1H), 4.01–3.99
(m, 2H), 2.53–2.30 (m, 2H), 1.43 (s, 9H), 0.65 and 0.63 (s,
3H); 13C NMR (75 MHz, CDCl3) d 171.9 and 171.8, 155.2,
144.1 and 143.8, 136.2 and 135.8, 134.8, 132.8 and 132.6,
129.5 and 129.4, 128.7 and 128.5, 128.0 and 127.9, 118.6,
117.6, 79.6, 51.4 and 49.8, 49.5 and 48.4, 37.9, 28.3, 23.8;
MS (EI) m/z 490 (Mþz, 6), 339 (10), 197 (27), 170 (24), 159
(22), 114 (67), 70 (100), 57 (91); HRMS (EI) m/z calcd for
0.1 equiv.) was added to alkene 15 (0.1 mL, 0.7 mmol,
1.0 equiv.) and allyl acetate (155 mL, 1.4 mmol, 2.0 equiv.)
in degassed CH2Cl2 at room temperature, under N2. After
18 h, rotary evaporation and chromatography (EtOAc) gave
16b (68 mg, 67%) as a colorless oil: TLC Rf 0.23 (EtOAc;
KMnO4); IR (thin film) 1739, 1640, 1448, 1355,
1
1235 cm21; H NMR (300 MHz, CDCl3) d 5.79–5.64 (m,
2H), 4.59–4.54 (m, 2H), 4.04–3.98 (m, 2H), 3.29–3.21 (m,
2H), 2.45–2.38 (m, 2H), 2.08 (s, 3H), 1.87–1.75 (m, 4H);
13C NMR (75 MHz, CDCl3) d 170.7, 169.6, 129.2, 126.8,
48.1, 47.4, 32.3, 23.1, 21.3, 20.9; MS (CI, NH3) m/z
((MþH)þ, 212), 152 (38), 100 (10), 45 (9); HRMS (CI,
NH3) m/z calcd for C11H18NO3 212.1287, found 212.1289.
Anal. calcd for C11H17NO3: C, 62.54; H, 8.11; N, 6.63.
Found: 62.47; H, 7.99; N, 6.61.
4.1.14. Preparation of 1-(4-oxo-2E-penten-1-yl)-2-piper-
idinone (16c). Methyl vinyl ketone (180 mL, 2.1 mmol) and
catalyst 7 (125 mg, 0.14 mmol) were added to alkene 15
(100 mg, 0.7 mmol) in degassed dry CHCl3 and the mixture
was heated at reflux for 20 h and allowed to cool to room
temperature. Rotary evaporation and chromatography
(gradient elution, EtOAc/MeOH, 1:0 to 97:3) gave 16c
(70 mg, 54%) as a brown oil: TLC Rf 0.22 (EtOAc/MeOH,
97:3; KMnO4); IR (thin film) 1677, 1641, 1418, 1355, 1257,
1
1157 cm21; H NMR (300 MHz, CDCl3) d 6.66 (dt, 1H,

7522
C. Schultz-Fademrecht et al. / Tetrahedron 60 (2004) 7515–7524
C29H38N2O3Si: (Mþz), 490.2652, found: (Mþz), 490.2661.
Anal. calcd for C29H38N2O3Si: C, 70.98; H, 7.81; N, 5.71.
Found: C, 71.06; H, 7.62; N, 5.86.
d 172.1, 155.1, 144.2, 136.1, 134.8, 130.4, 129.4, 129.0,
127.9, 127.3, 79.6, 53.5, 50.0, 45.2, 33.5, 28.4, 23.7; MS
(EI) m/z 462 (Mþz, 43), 406 (38), 385 (63), 373 (35), 329
(60), 311 (46), 197 (64), 159 (21), 121 (20), 114 (21), 105
(22), 82 (18), 70 (29), 57 (100); HRMS (EI) m/z calcd for
C27H34N2O3Si: (Mþz), 462.2338, found: (Mþz), 462.2357.
4.1.17. Preparation of 1-(3E-(methyldiphenylsilyl)pro-
penyl)-1,3,4,7-tetrahydro-2-azepinone (17). Diene 12b
(100 mg, 0.26 mmol) and catalyst 7 (15 mg, 0.06 mmol)
in CH2Cl2 (3 mL) were heated for 15 min in the microwave
at 100 8C. Rotary evaporation and chromatography (gra-
dient elution; hexanes/EtOAc, 3:1 to 1:1) gave 17 (48 mg,
52%) as a pale yellow oil: TLC Rf 0.25 (hexanes/EtOAc,
1:1; KMnO4); IR (thin film) 1650, 1481, 1427, 1112, 734,
4.1.20. Preparation of 3-((t-butyloxycarbonyl)amino)-1-
(3E-(methyldiphenyl-silyl)propenyl)-2-azepanone (20).
Degassed dry THF (0.5 mL) and EtOH (0.5 mL) were
added to (Ph3P)3RhCl (5 mg, 0.005 mmol, 0.1 equiv.) and
18 (25 mg, 0.05 mmol, 1.0 equiv.) under N2. The mixture
was purged once with H2 and stirred under H2 for 3 h,
monitoring reaction progress by 1H NMR spectroscopy.
Rotary evaporation and chromatography gave 20 (20 mg,
80%) as a clear, colorless oil: TLC Rf 0.73 (hexanes/EtOAc,
1
700 cm21; H NMR (300 MHz, CDCl3) d 7.55–7.52 (m,
4H), 7.44–7.36 (m, 6H), 6.15 (d, 1H, J¼18.0 Hz), 6.06 (dt,
1H, J¼18.0, 4.0 Hz), 5.81–5.70 (m, 2H), 4.20 (d, 2H,
J¼4.0 Hz), 3.85 (d, 2H, J¼4.0 Hz), 2.79 (t, 2H, J¼6.5 Hz),
2.44 (m, 2H), 0.65 (s, 3H); 13C NMR (75 MHz, CDCl3) d
174.5, 145.1, 136.3, 134.8, 131.6, 129.4, 128.0, 127.9,
124.5, 52.5, 45.5, 33.6, 25.2, 23.7; MS (EI) m/z 347 (Mþz,
34), 332 (16), 270 (68), 230 (17), 197 (100), 150 (44), 137
(24), 121 (16), 105 (27), 91 (15), 84 (43), 67 (59), 55 (56);
HRMS (EI) m/z calcd for C22H25NOSi: (Mþz), 347.1705,
found: (Mþz), 347.1699. Anal. calcd for C22H25NOSi: C,
76.03; H, 7.25; N, 4.03. Found: C, 75.93; H, 7.27; N, 3.94.
2:1; KMnO4); IR (thin film) 1710, 1648, 1479, 1442 cm21
;
1H NMR (300 MHz, CDCl3) d 7.57–7.47 (m, 4H), 7.43–
7.32 (m, 6H), 6.17 and 6.14 (m, 1H), 6.10 (m, 2H), 4.39 (m,
2H), 3.97 (dd, 1H, J¼15.0, 4.0 Hz), 3.47 (m, 1H), 3.22 (dd,
1H, J¼15.0, 4.0 Hz), 2.12–0.80 (m, 6H), 1.46 (s, 9H), 0.63
(s, 3H); 13C NMR (75 MHz, CDCl3) d 172.9, 155.2, 144.4,
136.1, 134.9, 134.8, 134.0, 129.7, 129.4, 128.4, 79.4, 53.3,
52.9, 47.9, 32.7, 29.7, 27.9, 27.6, 23.7; MS (EI) m/z 464
(Mþz, 7), 408 (7), 387 (8), 331 (9), 313 (18), 277 (12), 225
(11), 197 (33), 172 (20), 149 (19), 116 (63), 83 (30), 72 (63),
57 (100); HRMS (EI) m/z calcd for C27H36N2O3Si: (Mþz),
464.2495, found: (Mþz), 464.2515.
4.1.18. Preparation of 1-(3E-(methyldiphenylsilyl)pro-
penyl)-2-azepanone (19). Degassed dry THF (2.5 mL) and
EtOH (2.5 mL) were added to (Ph3P)3RhCl (21 mg,
0.23 mmol, 0.1 equiv.) and alkene 17 (80 mg, 0.23 mmol,
1.0 equiv.) under N2. The mixture was purged once with H2
and subsequently stirred under H2 for 3 h, monitoring the
progress of reaction by 1H NMR spectroscopy. Rotary
evaporation and chromatography (hexanes/EtOAc, 1:1)
gave 19 (69 mg, 86%) as a clear colorless oil: TLC Rf
0.25 (hexanes/EtOAc, 1:1; KMnO4); IR (thin film) 1644,
4.1.21. Preparation of N-5-hexenyl-N-(3E-(methyldiphe-
nylsilyl)propenyl)-10-undecenamide (12d). 10-Undece-
noyl chloride (264 mg, 1.3 mmol, 1.3 equiv.) in dry
CH2Cl2 (1 mL) was added slowly to amine 11b (335 mg,
1.0 mmol, 1.0 equiv.) and Et3N (0.21 mL, 1.5 mmol,
1.5 equiv.) in CH2Cl2 (10 mL) at 0 8C. After 18 h at room
temperature, the mixture was diluted with CH2Cl2 (5 mL)
and H2O (10 mL) and the layers were separated. The
aqueous layer was extracted further with Et2O (2£20 mL).
The combined ethereal phases were dried (MgSO4) and
rotary evaporated. Chromatography (hexanes/EtOAc, 20:1
to 5:1) gave 12d (429 mg, 86%) as an oil: TLC Rf 0.63
(hexanes/EtOAc, 3:1; KMnO4); IR (thin film) 1648, 1463,
1428, 1251 cm21; 1H NMR (300 MHz, CDCl3) d 7.57–7.48
(m, 4H), 7.44–7.35 (m, 6H), 6.09 (m, 2H), 5.82 (m, 2H),
5.00 (m, 4H), 4.15 (d, 1H, J¼3.0 Hz), 4.01 (d, 1H, J¼
3.0 Hz), 3.38 (t, 1H, J¼7.0 Hz), 3.26 (t, 1H, J¼7.0 Hz), 2.36
(t, 1H, J¼7.0 Hz), 2.27 (t, 1H, J¼7.0 Hz), 2.08 (m, 4H),
1.66 (m, 2H), 1.55 (m, 2H), 1.43–1.23 (m, 12H), 0.66 and
0.65 (s, 3H); 13C NMR (75 MHz, CDCl3) d 173.4, 172.7,
145.5, 144.5, 139.2, 138.6, 138.0, 136.4, 136.0, 134.8,
134.7, 129.5, 129.3, 128.0, 127.9, 127.5, 127.3, 115.1,
114.6, 114.2, 52.3, 50.2, 47.5, 46.3, 33.9, 33.6, 33.4, 33.2,
33.1, 29.6, 29.5, 29.4, 29.2, 29.0, 28.4, 27.4, 26.3, 26.1,
25.6, 25.4, 23.8; MS (EI) 501 (Mþz, 40), 460 (16), 424 (32),
390 (33), 362 (28), 304 (50), 266 (14), 197 (100), 159 (36),
138 (19), 121 (26), 112 (18), 83 (18), 69 (22), 55 (74);
HRMS (EI) calcd for C33H47NOSi: (Mþz), 501.3426, found:
(Mþz), 501.3449. Anal. calcd for C33H47NOSi: C, 78.98; H,
9.44; N, 2.79. Found: C, 78.74; H, 9.58; N, 2.82.
1482, 1444, 1428, 1354, 1195, 1112 cm21 1H NMR
;
(300 MHz, CDCl3) d 7.57–7.51 (m, 4H), 7.46–7.35 (m,
6H), 6.14–6.05 (m, 2H), 4.15 (d, 2H, J¼3.8 Hz), 4.32 (m,
2H), 3.32 (m, 2H), 2.57 (m, 2H), 1.72 (m, 4H), 1.61 (m, 2H),
0.64 (s, 3H); 13C NMR (75 MHz, CDCl3) d 175.7, 145.4,
136.3, 134.8, 129.4, 128.3, 127.9, 52.6, 48.9, 37.1, 30.0,
28.4, 23.5, 23.7; MS (EI) m/z 349 (Mþz, 40), 334 (20), 274
(55), 272 (50), 232 (35), 197 (100), 174 (22), 152 (45), 105
(31); HRMS (EI) m/z calcd for C22H27NOSi: (Mþz),
349.1862, found: (Mþz), 349.1877. Anal. calcd for
C22H25NOSi: C, 75.59; H, 7.79; N, 4.01. Found: C, 75.49;
H, 7.84; N, 3.87.
4.1.19. Preparation of 3-((t-butyloxycarbonyl)amino)-1-
(3E-(methyldiphenyl-silyl)propenyl)-1,3,4,7-tetrahydro-
2-azepinone (18). Diene 12b (50 mg, 0.1 mmol) and
catalyst 7 (9 mg, 0.01 mmol) in CH2Cl2 (3 mL) were heated
for 15 min in the microwave at 100 8C. Rotary evaporation
and chromatography (hexanes/EtOAc, 10:1 to 4:1) gave 18
(28 mg, 59%) as a pale yellow oil containing a mixture of
rotamers: TLC Rf 0.47 (hexanes/EtOAc, 2:1; KMnO4); IR
1
(thin film) 1712, 1658, 1480 cm21; H NMR (300 MHz,
CDCl3) d 7.56–7.48 (m, 4H), 7.41–7.31 (m, 6H), 6.17 and
6.12 (m, 1H), 6.03 and 5.98 (m, 1H), 5.87 (d, 1H,
J¼7.0 Hz), 5.75 (m, 2H), 4.96 (m, 1H), 4.38 and 4.34 (m,
2H), 4.29 and 4.12 (dd, 2H, J¼16.0, 5.0 Hz), 3.36 (dd, 1H,
J¼17.0, 7.0 Hz), 2.67 (dd, 1H, J¼18.0, 4.0 Hz), 2.23 (m,
1H), 1.47 (s, 9H), 0.57 (s, 3H); 13C NMR (75 MHz, CDCl3)
4.1.22. Preparation of 1-(3E-(methyldiphenylsilyl)pro-
penyl)-1-azacyclohexadec-11-en-2-one (21). Diene 12d
(251 mg, 0.5 mmol, 1.0 equiv.) and catalyst 7 (44 mg,

C. Schultz-Fademrecht et al. / Tetrahedron 60 (2004) 7515–7524
7523
0.05 mmol, 0.1 equiv.) in CH2Cl2 (25.0 mL) were stirred at
reflux for 24 h under N2. Rotary evaporation and chroma-
tography (hexanes/EtOAc, 20:1 to 3:1) gave 21 (cis/trans,
1:1) (153 mg, 65%) as a pale yellow oil: TLC Rf 0.33
(hexanes/EtOAc, 3:1; KMnO4); IR (thin film) 1642, 1461,
1428, 1112, 790, 732 cm21; 1H NMR (300 MHz, CDCl3) d
7.56–7.47 (m, 4H), 7.42–7.33 (m, 6H), 6.10 (m, 2H), 5.31
(m, 2H), 4.16 (m, 1H), 4.04 (m, 1H), 3.43 (t, 1H, J¼7.0 Hz),
3.28 (t, 1H, J¼7.0 Hz), 2.32 (m, 2H), 2.03 (m, 4H), 1.67 (m,
2H), 1.56 (m, 1H), 1.47 (m, 1H) 1.41–1.14 (m, 12H), 0.64
and 0.63 (s, 3H); 13C NMR (75 MHz, CDCl3) d 173.6,
173.2, 145.6, 144.8, 136.4, 135.9, 134.8, 134.7, 131.4,
131.3, 130.9, 130.4, 130.2, 129.7, 129.5, 129.3, 127.9,
127.9, 127.5, 52.8, 50.9, 48.7, 46.1, 32.8, 32.3, 32.1, 31.0,
28.6, 28.5, 28.4, 28.0, 27.8, 27.6, 27.1, 26.9, 26.6, 26.2,
25.9, 25.1, 23.8; MS (CI, NH3) m/z 474 ((MþH)þ, 100),
460 (10), 278 (19), 264 (22), 238 (21), 207 (14), 154 (10),
120 (11); HRMS (CI, NH3) m/z calcd for C31H44NOSi:
(MþH)þ, 474.3192, found: (MþH)þ, 474.3183. Anal. calcd
for C31H43NOSi: C, 78.59; H, 9.15; N, 2.96. Found: C,
78.68; H, 9.29; N, 2.89.
J¼5.3 Hz), 3.26 (t, 1.4H, J¼7.6 Hz); 2.38–2.32 (m, 2H),
1.76–1.49 (m, 4H), 1.45–1.23 (m, 20H); 13C NMR
(75 MHz, CDCl3) d 173.8, 173.1, 133.8, 133.5, 116.7,
116.4, 50.1, 47.9, 47.4, 44.7, 32.7, 32.4, 27.9, 27.8, 27.7,
27.6, 27.4, 27.2, 26.8, 26.7, 26.5, 26.4, 26.2, 26.1, 26.0,
25.9, 25.7, 25.6, 25.0, 24.6; MS (CI, NH3) m/z 560
((2MþH)þ, 50), 280 ((MþH)þ, 100), 266 (10); HRMS
(CI, NH3) m/z calcd for C18H34NO: (MþH)þ, 280.2640,
found: (MþH)þ, 280.2634. Anal. calcd for C18H33NO: C,
77.36; H, 11.90; N, 5.01. Found: C, 77.48; H, 11.82; N, 4.94.
4.1.25. Preparation of 1-(3-methylbut-2-enyl)azacyclo-
hexadecan-2-one (25a). 3-Methyl-2-butene (4.5 mL) and
catalyst 7 (31 mg, 0.036 mmol, 0.1 equiv.) were added
sequentially to lactam 24 (100 mg, 0.36 mmol, 1.0 equiv.)
under N2. The mixture was stirred at 35 8C for 18 h, and the
solvent rotary evaporated. Chromatography (hexanes/
EtOAc, 9:1) gave alkene 25a (89 mg, 81%) as a light
brown oily mixture of rotamers: TLC Rf 0.27 (hexanes/
EtOAc, 9:1; KMnO4); IR (thin film) 1643, 1446, 1421,
1
1375 cm21; H NMR (300 MHz, CDCl3) d 5.14–5.05 (m,
1H), 3.95 (d, 1.4H, J¼6.3 Hz), 3.85 (d, 0.7H, J¼5.9 Hz),
3.43 (t, 0.7H, J¼5.0 Hz), 3.20 (t, 1.4H, J¼7.6 Hz), 2.34–
2.27 (m, 2H), 1.69 (s, 2.1H), 1.71–1.61 (m, 8H), 1.58–1.45
(m, 2H), 1.38–1.24 (m, 20H); 13C NMR (75 MHz, CDCl3)
d 173.3, 172.9, 135.2, 134.8, 121.0, 120.6, 47.2, 45.8, 44.4,
42.6, 32.7, 32.5, 28.0, 27.8, 27.6, 27.5, 27.1, 26.8, 26.5,
26.4, 26.2, 26.0, 25.9, 25.8, 25.7, 25.5, 25.2, 24.5; MS (CI,
NH3) m/z 616 ((2MþH)þ, 100), 308 ((MþH)þ, 95), 264
(13); HRMS (CI, NH3) m/z calcd for C20H38NO: (MþH)þ,
308.2953, found: 308.2952. Anal calcd for C20H37NO: C,
78.11; H, 12.13; N, 4.55. Found: C, 78.29; H, 12.38, N, 4.64.
4.1.23. Preparation of 1-(3E-(methyldiphenylsilyl)pro-
penyl)-1-azacyclohexa-decan-2-one (22). Degassed dry
THF (2.0 mL) and EtOH (2.0 mL) were added to (Ph3P)3-
RhCl (8 mg, 8 mmol, 0.1 equiv.) and diene 21 (40 mg,
0.08 mmol, 1.0 equiv.) under N2. The mixture was purged
once with H2, and stirred in a H2 atmosphere for 4 h, whilst
monitoring reaction progress by 1H NMR spectroscopy.
Rotary evaporation and chromatography gave 22 (35 mg,
89%) as a pale yellow oil. Analysis by 1H NMR
spectroscopy showed the product to be contaminated by
23 (22/23 3.1:1): TLC Rf¼0.33 (hexanes/EtOAc, 3:1;
1
KMnO4); IR (thin film) 1642, 1458, 1427, 1111 cm21; H
4.1.26. Preparation of 4-(2-oxo-azacyclohexadec-1-yl)-
but-2-enyl acetate (25b). Allyl acetate (77 mL, 0.72 mmol,
2.0 equiv.) was added to lactam 24 (100 mg, 0.36 mmol,
1.0 equiv.) in CH2Cl2 (2 mL). The mixture was degassed
with N2 for 10 min and catalyst 7 (31 mg, 0.036 mmol,
0.1 equiv.) was added. The mixture was stirred under N2 at
25 8C for 24 h before rotary evaporation. Chromatography
(gradient elution; hexanes/EtOAc, 9:1 to hexanes/EtOAc,
4:1) gave alkene 25b (77 mg, 61%) as a pale brown oil: TLC
Rf 0.24 (hexanes/EtOAc, 1:1; KMnO4); IR (thin film) 1743,
NMR (300 MHz, CDCl3) d 7.57–7.48 (m, 4H), 7.43–7.33
(m, 6H), 6.11 (m, 2H), 4.17 (m, 1H), 4.05 (m, 1H), 3.54 and
3.45 (m, 1H), 3.30 and 3.19 (m, 1H), 2.38 (m, 2H), 1.78–
1.27 (m, 24H), 0.67 and 0.66 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 173.7, 172.8, 145.4, 144.5, 136.2, 135.7, 134.6,
134.5, 134.2, 129.3, 129.1, 129.0, 128.4, 127.8, 127.7,
127.3, 127.1, 52.2, 49.9, 47.8, 47.6, 45.0, 32.5, 32.3, 27.9,
27.8, 27.4, 27.3, 26.6, 26.5, 26.2, 26.0, 25.9, 25.7, 25.5,
25.4, 24.8, 24.4, 21.8, 23.9; MS (CI, NH3) m/z 476
((MþH)þ, 100), 462 (25), 414 (8), 400 (8), 387 (6), 282
(50), 279 (30), 249 (12), 240 (19), 214 (8), 52 (15); HRMS
(CI, NH3) m/z calcd for C31H46NOSi: (MþH)þ, 476.3349,
found: (MþH)þ, 476.3350. Anal. calcd for C31H45NOSi: C,
78.26; H, 9.53; N, 2.94. Found: C, 78.12; H, 9.62; N, 2.99.
1
1643, 1459, 1230 cm21; H NMR (300 MHz, CDCl3) d
5.76–5.60 (m, 2H), 4.53 (d, 2H, J¼5.0 Hz), 3.97 (d, 1.5H,
J¼4.3 Hz), 3.92 (bd m, 0.5H), 3.46 (bd m, 0.5H), 3.23 (t,
1.5H, J¼7.6 Hz), 2.35–2.29 (m, 2H), 2.05 (s, 3H), 1.72–
1.61 (m, 2H), 1.59–1.47 (m, 2H), 1.41–1.23 (m, 20H); 13C
NMR (75 MHz, CDCl3) d 173.6, 173.1, 170.7, 170.6, 130.4,
129.7, 126.3, 126.1, 64.3, 63.9, 48.9, 47.5, 46.5, 44.7, 32.6,
32.4, 29.7, 27.9, 27.8, 27.6, 27.4, 27.1, 26.7, 26.4, 26.2,
26.0, 25.9, 25.8, 25.6, 25.0, 24.5, 20.9; MS (CI, NH3) m/z
369 ((MþNH4)þ, 8), 352 ((MþH)þ, 100), 292 (28), 240
(15); HRMS (CI, NH3) m/z calcd for C21H38NO3: (MþH)þ,
352.2852, found: (MþH)þ, 352.2850. Anal. calcd for
C21H37NO3: C, 71.75; H, 10.61; N, 3.98. Found: C, 71.87;
H, 10.52; N, 3.89.
4.1.24. Preparation of 1-propenyl-azacyclohexadecan-2-
one (24). Bu4NF in THF (1.0 M; 0.6 mL, 0.6 mmol,
5 equiv.) was added to the mixture of silylalkenes 22 and
23 (61 mg, 0.13 mmol, 1.0 equiv.) in DMSO (2.6 mL) at
room temperature. The reaction mixture was heated to 80 8C
for 2 h, cooled and partitioned between Et2O (10 mL) and
H2O (10 mL). The separated organic layer was washed
further with H2O (4£10 mL), dried (MgSO4) and rotary
evaporated. Chromatography (hexanes/EtOAc, 17:3) gave
24 (31 mg, 87%) as a clear, colorless, oily mixture of
rotamers: TLC Rf 0.27 (hexanes/EtOAc, 15:1; KMnO4); IR
4.1.27. Preparation of 1-(5-oxohex-2E-en-1-yl)azacyclo-
hexadecan-2-one
(25c).
5-Hexen-2-one
(350 mL,
1
(thin film) 1646, 1460, 1415 cm21; H NMR (300 MHz,
1.1 mmol, 3.0 equiv.) and catalyst 7 (62 mg, 0.07 mmol,
0.2 equiv.) were added sequentially under N2 to lactam 24
(100 mg, 0.36 mmol, 1.0 equiv.) and the mixture refluxed
CDCl3) d 5.85–5.72 (m, 1H), 5.21–5.10 (m, 2H), 4.00 (d,
1.4H, J¼5.6 Hz), 3.93 (d, 0.7H, J¼2.3 Hz), 3.49 (t, 0.7H,

7524
C. Schultz-Fademrecht et al. / Tetrahedron 60 (2004) 7515–7524
3. For a recent review, see: Connon, S. J.; Blechert, S. Angew.
Chem., Int. Ed. 2003, 42, 1900.
for 18 h. Rotary evaporation and chromatography (hexanes/
EtOAc, 4:1) gave ketone 25c (101 mg, 81%) as a brown oily
mixture of rotamers: TLC Rf 0.15 (hexanes/EtOAc, 4:1;
4. (a) Schrock, R. R.; DePue, R. T.; Feldman, J.; Schaverien,
C. J.; Dewan, J. C.; Liu, A. H. J. Am. Chem. Soc. 1988, 110,
1423. (b) Schrock, R. R.; DePue, R. T.; Feldman, J.; Yap,
K. B.; Yang, D. C.; Davis, W. M.; Park, L.; DiMare, M.;
Schofield, M.; Anhaus, J.; Walborsky, E.; Evitt, E.; Kru¨ger, C.;
Betz, P. Organometallics 1990, 9, 2262.
1
KMnO4); IR (thin film) 1717, 1459, 1360 cm21; H NMR
(300 MHz, CDCl3) d 5.57–5.47 (m, 1H), 5.43–5.34 (m,
1H), 4.02–3.80 (m, 2H), 3.43–3.38 (m, 0.5H), 3.18 (t, 1.5H,
J¼7.6 Hz), 2.48 (t, 2H, J¼6.9 Hz), 2.35–2.20 (m, 4H),
1.68–1.44 (m, 4H), 1.41–1.17 (m, 20H); 13C NMR
(75 MHz, CDCl3) d 208.1, 207.7, 173.6, 173.0, 131.5,
131.2, 130.7, 126.9, 126.4, 126.1, 49.3, 47.2, 46.9, 44.4,
42.9, 42.8, 32.7, 32.5, 29.9, 29.7, 27.9, 27.7, 27.6, 27.4,
27.1, 26.7, 26.4, 26.3, 26.2, 26.0, 25.9, 25.8, 25.6, 25.0,
24.5; MS (CI, NH3) m/z 367 ((MþNH4)þ, 4), 350
((MþH)þ, 100), 292 (11), 240 (10), 153 (5), 52 (2);
HRMS (CI, NH3) m/z calcd for C22H40N1O2: (MþH)þ,
350.3059, found: (MþH)þ, 350.3063. Anal. calcd for
C22H39NO2: C, 75.59; H, 11.25; N, 4.01. Found: C, 75.74;
H, 11.18; N, 3.95.
5. (a) Marciniec, B.; Maciejewski, H.; Gulin˜ski, J.; Rzejak, L.
J. Organomet. Chem. 1989, 362, 273. (b) Marciniec, B.;
Pietraszuk, C. J. Organomet. Chem. 1991, 412, C1. (c)
Marciniec, B.; Foltynowics, Z.; Lewandowski, M. J. Mol.
Catal. 1994, 90, 125. (d) Foltynowics, Z.; Marciniec, B. Appl.
Organomet. Chem. 1997, 11, 667. (e) Silyl alkyne metathesis:
Baba, T.; Kato, A.; Takahashi, H.; Toriyama, F.; Handa, H.;
Ono, Y.; Sugisawa, H. J. Catal. 1998, 176, 488. (f) Pietraszuk,
C.; Fischer, H.; Kujawa, M.; Marciniec, B. Tetrahedron Lett.
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6. Pietraszuk, C.; Marciniec, B.; Fischer, H. Organometallics
2000, 19, 913.
Acknowledgements
7. (a) Denmark, S. E.; Yang, S.-M. Org. Lett. 2001, 3, 1749. (b)
Schuman, M.; Gouverneur, V. Tetrahedron Lett. 2002, 43,
3513.
We thank GlaxoSmithKline Research and Development Ltd
for support of our research and for the generous endowment
(to A. G. M. B.), the EPSRC for grant support, the
postdoctoral program of the German Academic Exchange
Service (DAAD) (to C. S. F.), the Royal Society and the
Wolfson Foundation for a Royal Society-Wolfson Research
Merit Award (to A. G. M. B.) and for establishing the
Wolfson Centre for Organic Chemistry in Medical Sciences
at Imperial College London.
8. Ono, K.; Nagata, T.; Nishida, A. Synlett 2003, 8, 1207.
9. Mayo, P.; Tam, W. Tetrahedron 2002, 58, 9513.
10. Nelson, S. G.; Cheung, W. S.; Kassick, A. J.; Hilfiker, M. A.
J. Am. Chem. Soc. 2002, 124, 13654.
11. Hodgson, D. M.; Foley, A. M.; Boulton, L. T.; Lovell, P. J.;
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˚
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