Facile synthesis of substituted 2,3,4,7-tetrahydro-1H-azepines via ring-closing metathesis

Article abstract of DOI:10.1016/j.tet.2005.11.049

A highly efficient synthesis based on inexpensive and readily available starting material towards the pharmacologically interesting class of substituted 2,3,4,7-tetrahydro-1H-azepines via a ring-closing metathesis (RCM) approach employing Grubbs catalysts

Full text of DOI:10.1016/j.tet.2005.11.049

Tetrahedron 62 (2006) 1777–1786
Facile synthesis of substituted 2,3,4,7-tetrahydro-1H-azepines
via ring-closing metathesis
*
¨
Sascha Brass, Hans-Dieter Gerber, Stefanie Dorr and Wibke E. Diederich
¨ ¨
Institut fur Pharmazeutische Chemie, Fachbereich Pharmazie, Philipps-Universitat Marburg, Marbacher Weg 6,
D-35037 Marburg, Germany
Received 10 October 2005; revised 17 November 2005; accepted 21 November 2005
Available online 19 December 2005
Abstract—A highly efficient synthesis based on inexpensive and readily available starting material towards the pharmacologically
interesting class of substituted 2,3,4,7-tetrahydro-1H-azepines via a ring-closing metathesis (RCM) approach employing Grubbs catalysts 1
and 2 is described. The influence of the substituents R1 and R2 on the outcome of the RCM reaction is discussed. The seemingly first example
of an RCM approach towards seven-membered azacycles bearing a substituent at the alkene moiety utilizing Grubbs catalyst 1 is presented.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
R1
N
R1
N
During the last decade, ring-closing metathesis (RCM) has
emerged as a powerful tool for the efficient synthesis of a
plethora of carbo- and heterocycles of different size and
substitution pattern.1 In the case of nitrogen-containing
heterocyles, the synthesis of five-, six-membered, and fused
ringsystems bearing various substituents via RCM is well
documented.2,3
X
X
RCM
alkylation
R3
R3
R2
R2
1
2
R1
R2
O
4 steps
N
However, the synthesis of medium-sized azacycles such as
azepines and unsaturated seven-membered lactames has not
been investigated in detail yet.4 Moreover, medium-sized
unsaturated azacycles bearing a substituent at the alkene
moiety are hardly known in literature.5
OMe
+
X
Br
R3
3
4
5
for X: CH2, C=O, R1: Boc, Bn, R2: H, CH2OH, CH2OTBS, R3: CO2Me
Rising interest in these classes of azacycles as putative
pharmaceuticals prompted us to develop a synthetic
sequence leading to 3-substituted as well as 3,5-disubsti-
tuted azepines and 3,5-disubstituted azepine-2-ones,
respectively, via an RCM approach.6
Scheme 1. Retrosynthetic analysis of the target structure.
For the key step of the synthetic approach only the
commercially available Grubbs catalysts 1 and 2 were
employed (Fig. 1).
As outlined in Scheme 1, our straightforward convergent
synthetic strategy towards these azacycles is mainly based
on inexpensive and readily available starting material such
as methyl acrylate, allylamine, allylbromide, and enables us
to introduce a variety of different substituents at a later stage
of the synthesis to optimize our preliminary synthesized
lead structure.
Mes
Ph
PCy3
Ru
N
Mes N
Cl
Cl
Cl
Ru
Ph
PCy3
Cl
PCy3
Keywords: Azacycles; Lactames; b-Amino ester.
*
6
7
Corresponding author. Tel.: C49 6421 2825810; fax: C49 6421
2828994; e-mail: diederic@staff.uni-marburg.de
Figure 1. Grubbs catalysts 1 (6) and 2 (7).
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.049

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S. Brass et al. / Tetrahedron 62 (2006) 1777–1786
2. Results and discussion
The syntheses of allylamines 13 and amide 15 being our
second building blocks were carried out according to
slightly modified literature procedures (Scheme 3).
Addition of allylamine to methyl acrylate led to the
corresponding b-amino ester 12.14 Subsequent reaction of
ester 12 with benzyl chloride and di-tert-butyl-dicarbonate,
respectively, furnished the N-protected-N-allyl-3-amino
methyl propanoates 13 in excellent overall yield. Analo-
gously, the corresponding 3-oxo-derivative of 13b, methyl
3-[allyl(benzyl)amino]-3-oxopropanoate 15, was prepared
starting from allylbenzylamine and methyl malonyl
chloride, which proceeded in high overall yield.15
2.1. Synthesis of the RCM precursors
As depicted in Scheme 1, we sought to synthesize our RCM
precursors of type 2 via an alkylation of an appropriately
functionalized allylamine derivative of type 3 with
bromoallyl derivative 4, each of them readily accessible
from methyl acrylate. Starting with a Baylis–Hillmann
reaction of methyl acrylate with formaldehyde, the
a-hydroxymethylated ester 8 could easily be obtained in
large quantities.7,8 Conversion of 8 into its TBS–ether 9,
followed by subsequent reduction with DIBAL-H gave rise
to the TBS-protected allylic alcohol 10 (Scheme 2).9
R1
H
N
N
a or b
MeO
MeO
O
O
O
OMe
OR
O
DIBAL-H
H2CO
OMe
13 a: R1 = BOC
73%
DABCO
68%
12
b: R1 = Bn
over two steps
5
8 R = H
9 R = TBS
Bn
O
O
N
c
N
H
MeO
Br2/TPP
Br
OH
imidazole
84%
OTBS
OTBS
14
15
10
11
Scheme 3. Synthesis of the allylamines 13 and 15. Reagents and conditions:
(a) (Boc)2O, TEA, cat. DMAP, DCM, rt, 14 h, 93%; (b) BnCl, K2CO3,
CH3CN, reflux, 3 h, 89%; (c) ClCOCH2CO2Me, TEA, cat. DMAP, DCM,
K30 8C to rt, 16 h, 86%.
Scheme 2. Synthesis of the substituted allylic fragment 11.
Following standard procedures for the required activation of
the unprotected allylic alcohol functionality in the next step
of our synthetic sequence, the corresponding mesylate as
well as the trifluoroacetate were obtained in good yields. As
we encountered difficulties in the following substitution
reaction with these activated precursors, we switched to an
alternative activation method such as the commonly used
transformation of the alcohol into its halogenated derivative
by means of a variety of reagents. For allylic alcohols,
triphenylphosphine (TPP) and CCl4 or TPP/CBr4 are
usually employed as they convert them into the correspond-
ing halides in general without allylic rearrangement.10
The next step of our synthetic approach (Table 1) was the
formation of the a-substituted b-amino esters 16 and 17 as
precursors for the subsequent RCM. The required substitution
Table 1. Synthesis of the RCM precursors 16 and 17a
R1
N
R1
N
Br
X
X
a or b
THF
+
MeO
R2
MeO
R2
O
O
13, 15
4
16a-f
for 16b, 16d, 16f
R2 = CH2OTBS
However, in our case the usage of TPP/CBr4 employing
various reaction conditions surprisingly gave rise to a
mixture of isomers and di-brominated derivatives as
c
17a-c
R2 = CH2OH
1
indicated by H NMR. Moreover, the reaction proceeded
Entry
Substrate R1
R2
H
X
Product
(yield, %)
only in moderate and varying yields and we were not able to
isolate the desired product in appropriate purity. Never-
theless, conversion of the allylic alcohol to the correspond-
ing bromide was successfully accomplished employing
TPP/Br2 as alternative brominating agent, even though it is
known that trialkylsilyl ethers can directly be converted to
alkyl bromides under these reaction conditions.11,12 In order
to prevent the cleavage of our protecting group we therefore
added a slight excess of imidazole as a mild proton
scavenger and were thus able to obtain our first building
block, the desired bromide 11, not only with excellent yield
but also in high purity.13
1
2
3
4
5
6
7
8
9
13b
13b
15
Bn
Bn
Bn
Bn
CH2
16a (96)
16b (70)
16c (70)
16d (65)
16e (62)
16f (82)
17a (65)
17b (79)
17c (79)
CH2OTBS CH2
H C]O
CH2OTBS C]O
H CH2
CH2OTBS CH2
15
13a
13a
16b
16d
16f
Boc
Boc
Bn
Bn
Boc
CH2OH
CH2OH
CH2OH
CH2
C]O
CH2
a Reagents and conditions: (a) for 13: LDA, HMPT, THF, K40 8C, 5 h;
(b) for 15: LiHMDS, THF, K50 8C to rt, 14 h; (c) HCl in THF, rt, 25 min.

S. Brass et al. / Tetrahedron 62 (2006) 1777–1786
1779
atthe a-carbon of esters13and 15withbromoallylprecursor 4
turned out to be a crucial step in our reaction sequence.
Deprotonation of 15 employing LiHMDS, followed by the
addition of the appropriate electrophile 4 easily rendered the
corresponding substitution products 16c and 16d in good
yields. In case of 13, however, generation of the intermediate
carbanion utilizing a variety of commercially available bases
such as LiHMDS or KHMDS, NaH, and LDA followed by the
subsequent addition of allylbromide did not give rise to any of
the desired product. Nevertheless, the use of HMPA as
carbanion-stabilizing additive and freshly prepared LDA
easily rendered the substituted b-amino esters 16 in high
yields.16,17
groups (amide vs carbamate), both catalysts rendered the
desired azepines 18b and 18e in comparably high yields,
indicating that the precursors bearing either an amide
functionality (16c) or a Boc-protecting group at the nitrogen
(16e) were suitable as starting material for the RCM
reaction.
To investigate the dependency of the outcome of the RCM
reaction on the presence of a substituent attached to one of
the terminal alkene moieties, we exposed gem-disubstituted
olefins (16d, 16f, 17b, and 17c) to ruthenium catalysts 6
and 7. It is remarkable that in all cases using catalyst 6, the
substituted azepines 18c, d, f, and 18g could be obtained in
moderate yields. To the best of our knowledge, seven-
membered azacycles bearing a substituent at the alkene
moiety have not yet been successfully synthesized utilizing
6. Moreover, yields even improved surprisingly applying 6
with increasing steric demand of the substituent at the
alkene moiety (OH vs OTBS, Table 2, entries 3, 4, 6, and 7).
Selective cleavage of the TBS group in 16b, d, and 16f
proceeded smoothly and resulted in formation of the
hydroxymethylated compounds 17a–c.
2.2. Synthesis of the azepine core structure via RCM
As expected, 7 overall performed significantly better giving
rise to the desired azepines 18c, d, f, and 18g with yields
ranging from 74–95%. However, yields dropped slightly
for substrates bearing the bulkier TBS protecting group.
Furthermore, we noticed that the N-Boc-protected sub-
strates 16f and 17c in general gave higher yields in
comparison to the analogous amide derivatives 16d and
17b employing either catalyst 6 or 7.
With the acyclic diolefins 16 and 17 in hand, we then
studied the outcome of the RCM reaction employing Grubbs
catalysts 1 (6) and 2 (7) as outlined in Table 2. All RCM
reactions were run with 1 mmol of the appropriate diolefinic
precursor and 5 mol% of the corresponding catalyst in DCM
at 40 8C for 8 h. Due to the rather sluggish reaction
employing Grubbs catalyst 1, the reaction mixtures were
stirred for an additional 12 h at room temperature.
These results clearly show that the outcome of the RCM
reaction in case of these seven-membered azacycles is not
only dependent on the substitution pattern of the alkene
moieties, but also strongly depends upon the nature of the
electron withdrawing group implemented in the RCM
precursors (16 and 17) and thus on the concomitantly
resulting geometry of the nitrogen atom (amide vs
carbamate).
In general, substrates bearing basic amine moieties are
believed to be incompatible with ruthenium catalysts.1 In
contrast to that, the six-membered alkaloid coniine has
recently been obtained in high yield via an RCM reaction
employing a tertiary amine as precursor and Grubbs
catalyst 6.18 Hence, we subjected diene 16a to our
standardized reaction conditions. However, the correspond-
ing azepine 18a was only formed in low yield applying 6
(Table 2, entry 1), whereas we observed decomposition of
the second generation catalyst during this reaction.
3. Conclusion
In case of substrates 16c and 16e, in which the electronic
environment of the nitrogen had been changed through
implementation of neighboring electron withdrawing
In summary we have developed a short and highly efficient
synthetic strategy towards the hitherto hardly known
Table 2. Synthesis of substituted 2,3,4,7-tetrahydro-1H-azepines 18
R1
R1
N
N
6 or 7
DCM, 40 °C
X
X
MeO
MeO
O
O
R2
R2
16, 17
18
Entry
Substrate
R1
R2
X
Compound
Catalyst 6 yield (%)a Catalyst 7 yield (%)a
1
2
3
4
5
6
7
16a
16c
17b
16d
16e
17c
16f
Bn
Bn
Bn
Bn
Boc
Boc
Boc
H
H
CH2
18a
18b
18c
18d
18e
18f
8b
0c
90
81
74
86
95
87
C]O
C]O
C]O
CH2
CH2
CH2
88
CH2OH
CH2OTBS
H
CH2OH
CH2OTBS
16b
23b
87
37b
44b
18g
a Reported yields refer to the analytically pure product obtained after column chromatography.
b Remaining starting material could be re-isolated.
c Decomposition of Grubbs 2 catalyst observed; starting material nearly quantitatively re-isolated.

1780
S. Brass et al. / Tetrahedron 62 (2006) 1777–1786
substituted azepines of type 18 based on inexpensive and
commercially available starting material. Derivative 18g for
example is accessible via a six-step sequence in 30% overall
yield. This core structure can easily be modified by means
of standard synthetic chemistry giving rise to a variety of
putative pharmacologically active derivatives and thus
enables us to probe structure–activity relationships in detail.
To our knowledge, utilizing 6 in our reaction pathway
represents the first synthesis of seven-membered azacycles
bearing a substituent at the alkene moiety. Furthermore, we
have presented a reliable large scale synthetic sequence
towards bromide 11, which serves as an interesting building
block.
a solution of TBSCl (27.36 g, 181.5 mmol, 1.1 equiv) in
DCM at 0 8C. The reaction mixture was allowed to reach
room temperature and was stirred for 15 h at ambient
temperature. After addition of t-BuOMe, the reaction mixture
was filtered and the solvent removed under reduced pressure.
The resulting slurry was re-dissolved in t-BuOMe and
washed with a saturated NH4Cl-solution. The aqueous layer
was extracted twice with t-BuOMe. The combined organic
layers were washed with saturated NaHCO3-solution, brine,
dried over MgSO4, filtered, and concentrated under reduced
pressure. Bulb to bulb distillation (1008C/1.5 mbar) afforded
34.71 g (91%) of 9 as a colorless liquid: 1H NMR d 6.24 (dt,
1H, JZ2.0, 2.0 Hz), 5.89 (dt, 1H, JZ2.0, 2.0 Hz), 4.35 (t,
2H, JZ2.0 Hz), 3.72 (s, 3H), 0.90 (s, 9H), 0.06 (s, 6H); 13C
NMR d 166.2, 139.6, 123.7, 61.4, 51.5, 25.8, 18.2, K5.5; MS
(ESC) m/z 231 (21 [MCH]C), 253 (100, [MCNa]C);
HRMS (ESC) m/z calcd for C11H22O3SiNa (MCNa)C:
253.123593 found 253.124812. Anal. Calcd for C11H22O3Si:
C, 57.35; H, 9.63. Found: C, 57.15; H, 9.28.
4. Experimental
4.1. General
Reported yields refer to the analytically pure product
obtained by distillation or column chromatography. All
proton and carbon nuclear magnetic resonance spectra were
recorded on a 500 MHz spectrometer (1H NMR: 500 MHz,
13C NMR: 125 MHz). Chemical shifts are stated in parts per
million (ppm) and were referenced to TMS at 0.00 ppm (1H)
except for compounds containing a silyl protecting group,
which were referenced to the residual CHCl3 in CDCl3 at
7.24 ppm and to CDCl3 at 77.0 ppm (13C), respectively.
NMR spectra were recorded in CDCl3 unless otherwise
indicated. Abbreviations: br ddZbroad doublet of doublets,
br mZbroad multiplet, br sZbroad singlet, dZdoublet,
mZmultiplet, smZsymmetric multiplet, qZquartet, sZ
singlet, tZtriplet, psZpseudo, APTZattached proton test,
COMZsingle pulse complete decoupling experiment. Mass
spectra were obtained from a double-focussing sectorfield
spectrometer. Combustion analyses were determined on a
CH analyzer or a CHN autoanalyzer (only nitrogen). Flash
column chromatography was performed using silica gel 60
(50–100 ASTM mesh) or silica gel 60 (40–63 ASTM mesh).
TLC was carried out using 0.2 mm aluminium plates coated
with silica gel 60 F254 and the products were visualized by
UV detection, iodine or by utilization of phosphormolybdic
acid (‘blue stain’). Solvents and reagents that are
commercially available were used without further purifi-
cation unless otherwise noted. Tetrahydrofuran was dried by
distillation from sodium/benzophenone. All moisture-
sensitive reactions were carried out using oven-dried
glassware under a positive pressure of argon. If necessary,
solvents were deoxygenated by standard procedures.
Grubbs catalysts 1 and 2 were purchased from Sigma-
Aldrich.
4.1.3. 2-(tert-Butyl-dimethyl-silanyloxymethyl)-prop-2-
en-1-ol (10).9 DIBAL-H (115 mL of a 1.5 M solution in
toluene, 172.5 mmol, 2.16 equiv) was added dropwise over
a period of 45 min to a stirred solution of 9 (18.43 g,
80.0 mmol, 1.0 equiv) in THF (200 mL) at K78 8C. After
90 min the reaction mixture was slowly warmed to 0 8C,
stirred for 30 min and then carefully quenched by addition
of 4.5 mL H2O in 10 mL of THF. Subsequent addition of
300 mL Et2O and 200 mL of saturated Rochelle’s solution
produced a gelatin-like solid, which, after addition of
100 mL of a saturated NH4Cl-solution, was stirred at room
temperature until the slurry re-dissolved and a separation of
the layers was observed (30 min). The aqueous layer was
extracted three times with Et2O and the combined organic
layers were washed twice with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. Bulb to
bulb distillation (100 8C/0.3 mbar) yielded 12.99 g (80%) of
10 as a colorless liquid: 1H NMR d 5.08 (s, 1H), 5.06 (s, 1H),
4.22 (s, 2H), 4.15 (d, 2H, JZ5.7 Hz), 2.00 (t, 1H, JZ
5.9 Hz), 0.89 (s, 9H), 0.07 (s, 6H); 13C NMR d 147.5, 110.8,
64.9, 64.3, 25.8, 18.2, K5.5; MS (ESC) m/z 203 (18, [MC
H]C), 225 (100, [MCNa]C). Anal. Calcd for C10H22O2Si:
C, 59.35; H, 10.96. Found: C, 59.48; H, 10.72.
4.1.4. (2-Bromomethyl-allyloxy)-tert-butyl-dimethyl-
silane (11).13 To a solution of triphenylphosphine (TPP,
7.68 g, 29.3 mmol, 1.1 equiv) in DCM (70 mL), a solution
of bromine (4.68 g, 29.3 mmol, 1.1 equiv) in 10 mL of
DCM was added dropwise at 0 8C. The reaction mixture was
stirred until a colorless precipitate indicated the formation
of the desired phosphonium salt, which was then added
slowly to a solution of imidazole (2.18 g, 31.9 mmol,
1.2 equiv) and 10 (5.39 g, 26.6 mmol, 1.0 equiv) in 140 mL
DCM at 0 8C. After stirring for 30 min maintaining the
temperature at 0 8C, the reaction mixture was poured into an
ice–water mixture and extracted twice with t-BuOMe. The
combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure.
The residual slurry was re-dissolved in a small amount of
DCM and added dropwise into hexane giving rise to a
suspension, which was filtered and the remaining residue
was washed several times with hexane. After concentration
under vacuum, hexane was added to the residual suspension,
4.1.1. 2-Hydroxymethyl-acrylic acid methyl ester (8).
The title compound was prepared according to literature
procedures.8 Anal. Calcd for C5H8O3: C, 51.72; H, 6.94.
Found: C, 51.58; H, 6.86. Other spectral data were identical
to those reported previously.
4.1.2. 2-(tert-Butyl-dimethyl-silanyloxymethyl)-acrylic
acid methyl ester (9). To a stirred solution of 8 (19.14 g,
165.0 mmol, 1.0 equiv) in DCM (420 mL) were added TEA
(27.83 mL, 198.0 mmol, 1.2 equiv) and DMAP (2.02 g,
16.5 mmol, 0.1 equiv) followed by the dropwise addition of

S. Brass et al. / Tetrahedron 62 (2006) 1777–1786
1781
which was filtered again and concentrated under reduced
pressure. Column chromatography (hexane/t-BuOMe: 22:1)
afforded 5.90 g (84%) of 11 as a colorless liquid: 1H NMR
d 5.218 (d, 1H, JZ1.4 Hz), 5.215 (d, 1H, JZ1.4 Hz), 4.25
(s, 2H), 3.99 (s, 2H), 0.90 (s, 9H), 0.08 (s, 6H); 13C NMR
d 144.8, 114.7, 63.5, 32.7, 25.9, 18.3, K5.4; MS (ESC) m/z
265 (100, [M(79Br)CH]C), 267 (85, [M(81Br)CH]C), 289
(22, [M(81Br)CNa]C). Anal. Calcd for C10H21BrOSi: C,
45.28; H, 7.98; Br, 30.12. Found: C, 45.50; H, 7.80; Br,
30.38.
(150 8C/0.4 mbar) of the remaining oily residue afforded
10.38 g (89%) of 13b as a colorless oil: H NMR d 7.32–
1
7.21 (m, 5H), 5.85 (ddt, 1H, JZ17.2, 10.3, 6.5 Hz), 5.18
(psdd, 1H, JZ17.2, 1.6 Hz), 5.14 (psd, 1H, JZ10.1 Hz),
3.65 (s, 3H), 3.60 (s, 2H), 3.08 (d, 2H, JZ6.5 Hz), 2.81 (t,
2H, JZ7.0 Hz), 2.49 (t, 2H, JZ7.0 Hz); 13C NMR d 172.6,
139.1, 135.4, 128.5, 127.9, 126.7, 117.1, 57.8, 56.4, 51.1,
48.8, 32.4; MS (EI) m/z 233 (5, MC), 192 (10), 160 (70),
142 (58), 91 (100). Anal. Calcd for C14H19NO2: C, 72.07;
H, 8.21; N, 6.00. Found: C, 72.08; H, 7.99; N, 6.25.
4.1.5. 3-(Allylamino)-propionic acid methyl ester (12).
The title compound was prepared according to a modified
literature procedure.14 A solution of methyl acrylate (17.2 g,
200 mmol, 1.0 equiv) and allylamine (11.7 g, 205 mmol,
1.03 equiv) in 250 mL of MeOH was stirred at 40 8C for 4 h.
Removal of the solvent under reduced pressure followed by
bulb to bulb distillation (105 8C/5 mbar) of the resulting
residue gave rise to 21.40 g (75%) of 12 as a colorless oil:
1H NMR d 5.86 (ddt, 1H, JZ17.2, 10.0, 6.0 Hz), 5.18 (ddt,
1H, JZ17.2, 1.6, 1.6 Hz), 5.10 (ddt, 1H, JZ10.2, 1.4,
1.4 Hz), 3.69 (s, 3H), 3.26 (dt, 2H, JZ6.0, 1.4 Hz), 2.87
(t, 2H, JZ6.5 Hz), 2.51 (t, 2H, JZ6.5 Hz), 1.4 (br s, 1H);
13C NMR d 172.7, 136.4, 115.5, 51.8, 51.1, 44.2, 34.3; MS
(EI) m/z 143 (13, MC), 102 (11), 84 (14), 70 (100), 68 (18),
55 (43); HRMS (EI) m/z calcd for C7H13NO2 143.094629
found 143.096734. Anal. Calcd for C7H13NO2: C, 58.72;
H, 9.15; N, 9.78. Found: C, 58.55; H, 8.64; N, 9.99.
4.1.8. Allylbenzylamine (14). The title compound was
prepared according to a literature procedure.15 1H NMR
d 7.35–7.23 (m, 5H), 5.94 (ddt, 1H, JZ17.2, 10.3, 6.0 Hz),
5.20 (ddt, 1H, JZ17.2, 1.6, 1.6 Hz), 5.12 (ddt, 1H, JZ10.1,
1.7, 1.4 Hz), 3.80 (s, 2H), 3.28 (psdt, 2H, JZ6.0, 1.4 Hz);
13C NMR d 140.2, 136.7, 128.2, 128.0, 126.8, 115.8, 53.1,
51.6; MS (EI) m/z 147 (38, MC), 146 (61), 106 (28), 91
(100), 56 (12); HRMS (EI) calcd for C10H13N 147.1048
found 147.1043.
4.1.9. N-Allyl-N-benzyl-malonamic acid methyl ester
(15). To a solution of 14 (2.95 g, 20.0 mmol, 1.0 equiv),
TEA (3.37 mL, 24.0 mmol, 1.2 equiv), and a catalytic
amount of DMAP in DCM at K30 8C, a solution of methyl
malonyl chloride (2.57 mL, 24.0 mmol, 1.2 equiv) in 70 mL
of DCM was added dropwise maintaining the temperature.
After additional stirring for 16 h at room temperature, the
reaction mixture was diluted with Et2O and consecutively
washed once with 1% HCl, a saturated NaHCO3-solution,
three times with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. Column chromato-
graphy (hexane/ethyl acetate: 2.5:1) of the oily residue gave
4.1.6. 3-(Allyl-tert-butoxycarbonyl-amino)-propionic
acid methyl ester (13a). To a solution of 12 (4.29 g,
30.0 mmol), TEA (5.06 mL, 36.0 mmol, 1.2 equiv) and a
catalytic amount of DMAP in DCM at 0 8C, a solution of
(Boc)2O (7.86 g, 36.0 mmol, 1.2 equiv) in DCM was added
dropwise over a period of 30 min. The reaction mixture was
allowed to reach room temperature and stirred for an
additional 14 h. After addition of t-BuOMe, the organic
layer was washed consecutively with 1% aqueous HCl,
a saturated NaHCO3-solution, brine, and finally dried
over MgSO4. Removal of the solvents under reduced
pressure followed by column chromatography (hexane/ethyl
acetate:9:1) gave rise to 6.75 g (93%) of 13a as a colorless
oil. For a large scale preparation, distillation (105 8C/
0.6 mbar) of the resulting residue after extractive work up is
preferable: 1H NMR (CD3OD, rotamers, ratio: w1:1) d 5.77
(br s, 1H), 5.14 (br s, 1H), 5.12 (br s, 1H), 3.84 (d, 2H, JZ
5.5 Hz), 3.65 (s, 3H), 3.46 (t, 2H, JZ7.0 Hz), 2.56 (t, 2H,
JZ7.0 Hz), 1.45 (s, 9H); 13C NMR (CD3OD, rotamers) d
173.9, 157.1, 135.6, 135.4, 117.4, 116.9, 81.4, 52.3, 51.7,
50.9, 44.4, 34.7, 34.3, 29.0; MS (EI) m/z 243 (2, MC), 187
(100), 170 (90), 156 (96), 142 (96). Anal. Calcd for
C12H21NO4: C, 59.24; H, 8.70; N, 5.76. Found: C, 59.30; H,
8.52; N, 5.48.
1
rise to 4.25 g (86%) of 15 as a colorless oil: H NMR
(rotamers, ratio: 1.6:1) d 7.39–7.17 (m, 5H), 5.83–5.69 (sm,
1H), 5.27–5.14 (m, 2H), 4.63 (s, 1.29H), 4.52 (s, 0.78H),
4.03 (psd, 0.79H, JZ6.0 Hz), 3.82 (psd, 1.31H, JZ5.5 Hz),
3.77 (s, 1.88H), 3.73 (s, 1.15H), 3.52 (s, 1.22H), 3.49
(s, 0.76H); 13C NMR (rotamers) d 167.9, 167.8, 166.3,
166.1, 136.7, 135.9, 132.1, 132.0, 128.8, 128.4, 128.14,
128.07, 127.9, 127.6, 127.3, 126.2, 117.6, 117.1, 52.2, 50.6,
49.5, 48.2, 48.0, 41.0, 40.7; MS (EI) m/z 248 (20, MCCH),
247 (85, MC), 216 (37), 207 (59), 206 (100), 174 (28), 156
(37), 146 (53), 91 (49); HRMS (EI) m/z calcd for
C14H17NO3 247.1208 found 247.1211.
4.2. General procedure for the synthesis of the RCM
precursors 16a, 16b, 16e, and 16f
To a solution of n-BuLi (1.6 mol in hexane, 1.5 equiv) in
THF, neat diisopropyl amine (1.5 equiv) was added at
K78 8C. The reaction mixture was allowed to reach 0 8C,
stirred for additional 15 min, and cooled again to K78 8C. A
solution of the respective ester (13a, b, 1.5 equiv) dissolved
in THF was added slowly. After stirring for 30 min, a
solution of the respective allylbromide derivative
(1.0 equiv) in HMPT (1.0 equiv) was then added slowly.
The reaction mixture was warmed to K40 8C and kept at
this temperature until TLC indicated the completion of the
reaction (approx. 5 h). After subsequent addition of Et2O
and a saturated NH4Cl-solution, the organic layer was
separated and the aqueous layer was extracted twice with
ether. The combined organic layers were washed with brine,
4.1.7. 3-(Allyl-benzyl-amino)-propionic acid methyl
ester (13b).19 A suspension of 12 (7.16 g, 50.0 mmol,
1.0 equiv), benzyl chloride (6.65 g, 52.5 mmol, 1.05 equiv),
and K2CO3 (8.295 g, 60.0 mmol, 1.2 equiv) in CH3CN was
refluxed for 3 h, diluted with n-hexane (200 mL), and
washed with water and brine. The aqueous layer was
extracted twice with hexane, and the combined organic
layers were dried over MgSO4, filtered, and concentrated
under reduced pressure. Bulb to bulb distillation

1782
S. Brass et al. / Tetrahedron 62 (2006) 1777–1786
dried over MgSO4, filtered, and concentrated under reduced
pressure. The remaining product was purified by flash
chromatography.
306.166972. Anal. Calcd for C15H25NO4: C, 63.58; H, 8.89;
N, 4.94. Found: C, 63.10; H, 8.54; N, 4.84.
4.2.4. 2-[(Allyl-tert-butoxycarbonyl-amino)-methyl]-4-
(tert-butyl-dimethyl-silanyloxymethyl)-pent-4-enoic
acid methyl ester (16f). The title compound was prepared
according to the general procedure employing 13a (1.82 g,
7.5 mmol, 1.5 equiv), and 1.33 g of bromide 11 (5.0 mmol,
1.0 equiv). Column chromatography (hexane/ethyl acet-
ate: 14:1) afforded 1.76 g (82%) of 16f as colorless oil: 1H
NMR (DMSO-d6) d 5.72 (br s, 1H), 5.09 (dd, 1H, JZ10.0,
1.5 Hz), 5.05 (d, 1H, JZ17.0 Hz), 4.99 (s, 1H), 4.78 (s,
1H), 4.03 (s, 2H), 3.84–3.73 (br s, 1H), 3.64 (dd, 1H, JZ
16.0, 5.0 Hz), 3.55 (s, 3H), 3.30–3.24 (br m, 2H), 2.88 (sm,
1H), 2.20 (dd, 1H, JZ14.3, 9.0 Hz), 2.09 (dd, 1H, JZ14.3,
6.0 Hz), 1.37 (s, 9H), 0.89 (s, 9H), 0.03 (s, 6H); 13C NMR
(DMSO-d6, rotamers) d 174.8, 155.3, 145.3, 133.9, 133.7,
116.5, 116.0, 110.8, 110.7, 79.9, 79.5, 65.5, 51.6, 50.7,
49.9, 49.1, 48.9, 43.6, 43.2, 33.2, 28.3, 25.8, 18.3, K5.5;
MS (ESC) m/z 428 (43, [MCH]C), 450 (100, [MC
Na]C), 877 (70, [2MCNa]C); HRMS (ESC) m/z calcd for
C22H41NO5NaSi 450.265172 found 450.265767. Anal.
Calcd for C22H41NO5Si: C, 61.79; H, 9.66; N, 3.28.
Found: C, 61.71; H, 9.51; N, 3.13.
4.2.1. 2-[(Allyl-benzyl-amino)-methyl]-pent-4-enoic acid
methyl ester (16a).19 The title compound was prepared
according to the general procedure utilizing 13b (2.80 g,
12.0 mmol, 1.5 equiv), and 0.968 g of allylbromide
(8 mmol, 1.0 equiv). Column chromatography (hexane/
ethyl acetate: 14:1) gave rise to 2.10 g (96%) of 16a as
colorless oil: 1H NMR d 7.31–7.20 (m, 5H), 5.81 (ddt, 1H,
JZ17.0, 10.6, 6.2 Hz), 5.70 (ddt, 1H, JZ17.2, 10.3,
6.9 Hz), 5.17–5.11 (m, 2H), 5.03 (psdd, 1H, JZ17.0,
1.6 Hz), 4.99 (psd, 1H, JZ10.1 Hz), 3.67 (d, 1H, JZ
13.8 Hz), 3.66 (s, 3H), 3.47 (d, 1H, JZ13.8 Hz), 3.10 (dd,
1H, JZ14.2, 6.0 Hz), 2.98 (dd, 1H, JZ14.2, 6.9 Hz), 2.80–
2.71 (m, 2H), 2.55–2.46 (m, 1H), 2.32–2.21 (m, 2H);
13C NMR d 174.9, 139.2, 135.4, 135.1, 128.7, 128.0, 126.7,
117.2, 116.5, 58.3, 56.7, 55.4, 51.1, 44.5, 34.4; MS (EI) m/z
273 (25, MC), 272 (33, MCKH), 258 (44), 232 (32), 182
(68), 160 (100), 91 (66); HRMS (EI) m/z calcd for
C17H23NO2 273.1729 found 273.1741. Anal. Calcd for
C17H23NO2: C, 74.69; H, 8.48; N, 5.12. Found: C, 74.77; H,
8.38; N, 4.95.
4.3. General procedure for the synthesis of the RCM
precursors 16c and 16d
4.2.2. 2-[(Allyl-benzyl-amino)-methyl]-4-(tert-butyl-
dimethyl-silanyloxymethyl)-pent-4-enoic acid methyl
ester (16b). The title compound was prepared according
to the general procedure utilizing 13b (2.1 g, 9.0 mmol,
1.5 equiv) and 1.59 g (6.0 mmol, 1.0 equiv) of bromide 11.
Column chromatography (hexane/ethyl acetate: 10:1) gave
rise to 1.75 g (70%) of 16b as colorless oil: 1H NMR d 7.27–
7.24 (m, 5H), 5.83–5.75 (sm, 1H), 5.15–5.10 (m, 2H), 5.01
(d, 1H, JZ1.3 Hz), 4.80 (s, 1H), 4.03 (d, 1H, JZ15.5 Hz),
4.00 (d, 1H, JZ14.9 Hz), 3.69 (d, 1H, JZ13.8 Hz), 3.62 (s,
3H), 3.43 (d, 1H, JZ13.8 Hz), 3.09 (dd, 1H, JZ14.0,
5.8 Hz), 2.95 (dd, 1H, JZ14.2, 7.1 Hz), 2.88 (br dd, 1H, JZ
15.4, 7.1 Hz), 2.77 (dd, 1H, JZ12.6, 9.7 Hz), 2.46 (dd, 1H,
JZ12.6, 5.7 Hz), 2.20 (d, 2H, JZ7.6 Hz), 0.89 (s, 9H), 0.04
(s, 6H); 13C NMR d 175.2, 145.7, 139.2, 135.5, 128.7,
128.0, 126.8, 117.3, 110.4, 65.6, 58.4, 56.7, 56.1, 51.2, 43.5,
33.5, 25.8, 18.3, K5.4; MS (EI) m/z 417 (17, MC), 402 (12),
376 (17), 326 (40), 284 (41), 160 (100), 91 (37); HRMS (EI)
m/z calcd for C24H39NO3Si 417.2699 found 417.2703. Anal.
Calcd for C24H39NO3Si: C, 69.02; H, 9.41; N, 3.35. Found:
C, 69.07; H, 9.38; N, 3.25.
To a solution of LiHMDS (1.0 mol in THF, 1.1 equiv) in
THF, N-allyl-N-benzyl-malonamic acid methyl ester 15 in
THF (1.0 equiv) was added at K50 8C, and gently warmed
to K10 8C. After stirring for additional 30 min, the reaction
mixture was cooled again to K50 8C and a solution of the
respective allylbromide derivative (1.0 equiv) in THF was
added slowly. The reaction mixture was warmed to room
temperature and stirred for an additional 14 h at ambient
temperature, diluted with Et2O and washed with NH4Cl-
solution. The aqueous layer was extracted twice with Et2O
and the combined organic layers were washed with water,
twice with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The remaining
product was purified by flash chromatography.
4.3.1. 2-(Allyl-benzyl-carbamoyl)-pent-4-enoic acid
methyl ester (16c). The title compound was prepared
according to the general procedure employing 15 (1.38 g,
5.6 mmol), and 0.71 g of allylbromide (5.9 mmol,
1.06 equiv). Column chromatography (hexane/ethyl
acetate: 3:1) furnished 1.11 g (70%) of 16c as colorless
4.2.3. 2-[(Allyl-tert-butoxycarbonyl-amino)-methyl]-
pent-4-enoic acid methyl ester (16e). The title compound
was prepared according to the general procedure utilizing
13a (2.55 g, 10.5 mmol, 1.5 equiv), and 0.85 g (7.0 mmol,
1.0 equiv) allylbromide. Column chromatography (hexane/
ethyl acetate: 14:1) yielded 1.20 g (62%) of 16e as colorless
oil: 1H NMR (CD3OD, rotamers, ratio: 1:1) d 5.75 (sm, 2H),
5.17–4.98 (m, 4H), 3.94–3.80 (br t, 1H), 3.79–3.69 (br s,
1H), 3.65 (s, 3H), 3.36 (d, 1H, JZ6.2 Hz), 3.35 (d, 1H, JZ
8.5 Hz), 2.34–2.27 (m, 1H), 2.23–2.15 (m, 2H), 1.46 (s,
4.5H), 1.44 (s, 4.5H); 13C NMR (rotamers) d 174.3, 155.1,
155.0, 134.4, 133.7, 116.8, 116.2, 115.7, 79.5, 79.4, 51.3,
50.5, 49.7, 48.5, 48.0, 44.5, 44.1, 34.1, 28.0; MS (ESC) m/z
306 (100, [MCNa]C), 589 (18, [2MCNa]C); HRMS
(ESC) m/z calcd for C15H25NO4Na 306.168128 found
1
oil: H NMR (rotamers, ratio: 1.6:1) d 7.38–7.18 (m, 5H),
5.83–5.67 (m, 4ddt overlapping, 2H), 5.26–5.05 (m, 4ddt
overlapping, 4H), 4.79 (d, 0.66H, JZ14.7 Hz), 4.68
(d, 0.40H, JZ17.2 Hz), 4.51 (d, 0.41H, JZ17.2 Hz), 4.47
(d, 0.64H, JZ14.7 Hz), 4.13 (psdd, 0.41H, JZ15.4,
5.5 Hz), 3.99 (psdd, 0.68H, JZ17.9, 4.1 Hz), 3.91 (psdd,
0.44H, JZ15.4, 5.8 Hz), 3.81 (psdd, 0.77H, JZ17.7,
4.6 Hz), 3.73 (s, 1.9H), 3.69 (s, 1.2H), 3.67 (t, 1H, JZ
7.2 Hz), 2.79–2.63 (sm, 2H); 13C NMR (rotamers) d 169.6,
169.5, 168.4, 168.2, 136.9, 136.1, 134.5, 134.4, 132.3,
132.2, 128.6, 128.3, 127.8, 127.4, 127.1, 126.2, 117.3,
117.21, 117.19, 116.97, 52.1, 50.1, 49.0, 48.5, 48.4, 48.3,
48.1, 33.3; MS (EI) m/z 288 (75, MCCH), 287 (100, MC),
256 (62), 246 (74), 228 (70), 196 (48), 174 (37), 146 (55),

S. Brass et al. / Tetrahedron 62 (2006) 1777–1786
1783
91 (42); HRMS (EI) m/z calcd for C17H21NO3 287.1521
found 287.1525. Anal. Calcd for C17H21NO3: C, 71.06; H,
7.37; N, 4.87. Found: C, 70.86; H, 7.37; N, 4.73.
4.4.2. 2-(Allyl-benzyl-carbamoyl)-4-hydroxymethyl-
pent-4-enoic acid methyl ester (17b). According to the
general procedure employing 1.530 g (3.5 mmol) of 16d,
0.871 g (79%) of 2-(allyl-benzyl-carbamoyl)-4-hydroxy-
methyl-pent-4-enoic acid methyl ester (17b) was obtained
as colorless oil after column chromatography (hexane/ethyl
4.3.2. 2-(Allyl-benzyl-carbamoyl)-4-(tert-butyl-dimethyl-
silanyloxymethyl)-pent-4-enoic acid methyl ester (16d).
The title compound was prepared according to the general
procedure utilizing 1.484 g (6.0 mmol, 1.0 equiv) of 15 and
1.687 g (6.36 mmol, 1.06 equiv) of bromide 11 to furnish
1.69 g (65%) of 16d as colorless oil after column
chromatography (hexane/ethyl acetate: 4:1): 1H NMR
(rotamers, ratio: 1.6:1) d 7.35–7.15 (m, 5H), 5.72
(sm, 1H), 5.23–5.08 (m, 2H, 4ddt, overlapping), 5.06 (br
d, 0.66H, JZ1.2 Hz), 5.03 (br d, 0.42H, JZ1.4 Hz), 4.85
(br d, 0.64H, JZ1.2 Hz), 4.78 (br d, 0.39H, JZ1.0 Hz),
4.67 (d, 0.63H, JZ14.9 Hz), 4.62 (d, 0.41H, JZ17.0 Hz),
4.54 (d, 0.40H, JZ17.2 Hz), 4.50 (d, 0.66H, JZ14.9 Hz),
4.10–3.91 (m, 3.4H), 3.91–3.80 (m, 1.7H), 3.69 (s, 1.9H),
3.65 (s, 1.2H), 2.76–2.57 (sm, 2H), 0.87 (s, 5.68H), 0.84
(s, 3.77H), 0.03 (s, 3.64H), K0.02 (s, 2.44H); 13C NMR
(rotamers) d 169.7, 169.6, 168.5, 168.4, 145.0, 144.8, 137.0,
136.1, 132.5, 132.3, 128.6, 128.3, 127.8, 127.4, 127.1,
126.3, 117.2, 117.1, 111.2, 111.0, 65.9, 65.7, 52.0, 50.1,
49.0, 48.3, 48.1, 47.8, 47.6, 32.0, 25.6, 18.04, 18.01, K5.69,
K5.72; MS (EI) m/z 431 (10, MC), 375 (60), 374 (100), 91
(17); HRMS (EI) m/z calcd for C24H37NO4Si 431.2492
found 431.2503. Anal. Calcd for C24H37NO4Si: C, 66.78;
H, 8.64; N, 3.24. Found: C, 66.64; H, 8.84; N, 3.17.
1
acetate: 1:1): H NMR (rotamers, ratio: w1.6:1) d 7.38–
7.17 (m, 5H), 5.80–5.70 (m, 1H), 5.24 (dd, 0.66H, JZ10.3,
1.2 Hz), 5.20 (psdd, 0.53H, JZ5.4, 0.9 Hz), 5.17 (pst,
0.47H, JZ1.4 Hz), 5.12 (psdd, 0.45H, JZ17.2, 1.4 Hz),
5.08 (d, 0.60H, JZ0.9 Hz), 5.03 (d, 0.40H, JZ0.9 Hz), 4.91
(s, 0.63H), 4.81 (s, 0.36H), 4.80 (d, 0.64H, JZ14.7 Hz),
4.69 (d, 0.38H, JZ17.2 Hz), 4.53 (d, 0.39H, JZ17.0 Hz),
4.44 (d, 0.64H, JZ14.9 Hz), 4.19 (dd, 0.42H, JZ15.4,
4.8 Hz), 4.07 (s, 1.2H), 4.01 (sm, 0.76H), 3.96 (s, 0.70H),
3.93–3.80 (sm, 2.20H), 3.73 (s, 1.89H), 3.68 (s, 1.16H),
2.83–2.68 (m, 2H), 2.20 (br s, 1H); 13C NMR (rotamers) d
170.0, 169.8, 168.8, 168.7, 145.6, 145.4, 136.8, 136.1,
132.2, 132.1, 128.7, 128.4, 127.9, 127.6, 127.3, 126.4,
117.5, 117.3, 112.5, 112.3, 65.8, 65.7, 52.3, 50.2, 49.2, 48.6,
48.5, 48.2, 48.0, 31.9; MS (EI) m/z 317 (15, MC), 286 (19),
285 (55), 245 (33), 244 (100), 194 (60), 147 (36), 146 (75),
106 (54), 91 (44); HRMS (EI) m/z calcd for C18H23NO4
317.1627 found 317.1589. Anal. Calcd for C18H23NO4: C,
68.12; H, 7.30; N, 4.41. Found: C, 67.88; H, 7.63; N, 4.43.
4.4.3. 2-[(Allyl-tert-butoxycarbonyl-amino)-methyl]-4-
hydroxymethyl-pent-4-enoic acid methyl ester (17c).
The title compound was prepared according to the general
procedure employing 4.786 g (11.19 mmol) of 16f. After
column chromatography (hexane/ethyl acetate: 2:1) 2.77 g
(79%) of 17c were obtained as colorless oil: 1H NMR
(rotamers, ratio: w1:1) d 5.80–5.67 (br s, 1H), 5.09 (psddd,
2H, JZ17.7, 10.3, 1.6 Hz), 4.97 (d, 1H, JZ1.6 Hz), 4.82 (t,
1H, JZ5.5 Hz), 4.75 (s, 1H), 3.84 (d, 2H, JZ5.5 Hz), 3.83–
3.75 (br s, 1H), 3.69–3.61 (br s, 1H), 3.57 (s, 3H), 3.31–3.21
(sm, 2H), 2.90 (br s, 1H), 2.21 (dd, 1H, JZ14.7, 9.3 Hz),
2.08 (dd, 1H, JZ14.7, 5.7 Hz), 1.38 (s, 9H); 13C NMR
(rotamers) d 175.0, 174.9, 155.5, 155.2, 145.6, 133.7, 116.5,
116.0, 112.2, 111.7, 79.9, 65.4, 51.7, 50.9, 49.9, 48.9, 43.7,
43.3, 33.6, 28.2; MS (ESC) m/z 336 (100, [MCNa]C), 649
(28, [2MCNa]C); HRMS (ESC) m/z calcd for
C16H27NO5Na 336.178693 found 336.178391. Anal.
Calcd for C16H27NO5: C, 61.32; H, 8.68; N, 4.47. Found:
C, 61.38; H, 8.44; N, 4.98. Anal. Calcd for C16H27NO5: C,
61.32; H, 8.68; N, 4.47. Found: C, 61.01; H, 8.68; N, 4.48.
4.4. General procedure for the synthesis of hydroxy-
methylated compounds 17a–c
The respective TBS-protected derivative (16b, 16d, or 16f)
was dissolved in a 30:1 mixture of THF and aqueous HCl
32% and stirred at room temperature for 25 min. After
addition of a saturated NaHCO3-solution, the reaction
mixture was extracted three times with Et2O. The combined
organic layers were washed with brine, dried over MgSO4,
filtered, and concentrated under vacuum. Column chroma-
tography of the oily residue afforded the corresponding
hydroxymethyl derivative 17a–c.
4.4.1. 2-[(Allyl-benzyl-amino)-methyl]4-hydroxymethyl-
pent-4-enoic acid methyl ester (17a). According to the
general procedure utilizing 1.286 g (3.1 mmol) of 16b,
0.610 g (65%) of 2-[(allyl-benzyl-amino)-methyl]-4-hydro-
xymethyl-pent-4-enoic acid methyl ester (17a) was obtained
after column chromatography (hexane/ethyl acetate: 3:1) as
colorless oil: 1H NMR d 7.32–7.22 (m, 5H), 5.87–5.78 (sm,
1H), 5.16 (d, 1H, JZ17.4 Hz), 5.15 (d, 1H, JZ9.6 Hz), 5.02
(s, 1H), 4.86 (s, 1H), 4.04 (s, 2H), 3.69–3.62 (sm, 1H), 3.66
(s, 3H), 3.51 (br d, 1H, JZ13.5 Hz), 3.10 (dd, 1H, JZ14.2,
6.0 Hz), 3.02 (dd, 1H, JZ14.0, 6.4 Hz), 2.97–2.89 (sm, 1H),
2.77 (dd, 1H, JZ12.6, 12.4 Hz), 2.53 (dd, 1H, JZ12.4,
6.0 Hz), 2.36–2.25 (m, 2H), 2.07 (br s, 1H); 13C NMR d
175.3, 146.0, 138.8, 135.1, 128.8, 128.0, 126.8, 117.5,
111.5, 65.4, 58.2, 56.6, 55.8, 51.3, 43.4, 33.7; MS (EI) m/z
303 (3, MC), 230 (64), 212 (13), 180 (95), 161 (61), 160
(100), 91 (61); HRMS (EI) m/z calcd for C18H25NO3
303.1834 found 303.1800. Anal. Calcd for C18H25NO3: C,
71.26; H, 8.31; N, 4.62. Found: C, 71.05; H, 8.78; N, 4.57.
4.5. General procedure for the synthesis of 18a–g
Method A. A solution of the corresponding precursor (16a,
16c–f, and 17b, c) in 90 mL of thoroughly degassed DCM
was heated to 40 8C and bis(tricyclohexylphosphine)benzy-
lidene ruthenium(IV) dichloride 6 (Grubbs 1 catalyst,
5 mol%), dissolved in 5 mL of degassed DCM, was added
to the reaction mixture. After stirring for 8 h at 40 8C, the
reaction mixture was allowed to reach room temperature
and stirred for an additional 12 h. After quenching the
reaction through addition of 20 mL of DMSO and
subsequent stirring for 12 h, the reaction mixture was
extracted three times with diluted NaCl-solution, twice with
brine, dried over MgSO4, and filtered.20 Removal of the
solvent under reduced pressure followed by column

1784
S. Brass et al. / Tetrahedron 62 (2006) 1777–1786
chromatography of the oily residue gave rise to the
corresponding azepines 18.
0.331 g (1.04 mmol) of 17b and 44 mg (0.052 mmol,
5 mol%) of 7, 0.243 g (81%) of 18c was obtained after
column chromatography (hexane/ethyl acetate: 3:1) as
colorless oil: 1H NMR d 7.35–7.21 (m, 5H), 5.69–5.65
(sm, 1H), 4.62 (s, 2H), 4.16 (br d, 1H, JZ17.9 Hz), 4.12 (dd,
1H, JZ12.1, 3.7 Hz), 3.98 (s, 2H), 3.81 (s, 3H), 3.48 (dd,
1H, JZ17.9, 7.3 Hz), 2.77–2.69 (sm, 1H), 2.58 (d, 1H, JZ
18.3 Hz), 1.70 (s, 1H); 13C NMR d 170.8, 170.0, 140.6,
136.6, 128.4, 127.7, 127.3, 118.8, 66.5, 52.2, 51.1, 48.0,
44.7, 27.5; MS (ESC) m/z 290 (11, [MCH]C), 312 (100,
[MCNa]C), 601 (85, [2MCNa]C), 890 (17, [3MCNa]C);
HRMS (ESC) m/z calcd for C16H19NO4Na 312.121178
found 312.120229. According to the general procedure
(Method A) employing 0.331 g (1.04 mmol) of 17b and
43 mg (0.052 mmol, 5 mol%) of 6, 0.048 g (16%) of 18c
was obtained as a colorless oil, which exhibited identical
spectroscopic data to those obtained using Method B.
Method B. A solution of the corresponding precursor (16a,
16c–f, and 17b, c) in 90 mL of thoroughly degassed DCM
was heated to 40 8C and benzyliden-[1,3-bis-(2,4,6-
trimethylphenyl)-2-imidazolidinylidene]-dichloro-(tricy-
clohexylphosphine)-ruthenium 7 (Grubbs 2 catalyst,
5 mol%), dissolved in 5 mL of degassed DCM, was added
to the reaction mixture. After stirring for 8 h at 40 8C, the
reaction mixture was allowed to reach room temperature.
After quenching the reaction through addition of 20 mL of
DMSO and subsequent stirring for 12 h, the reaction
mixture was washed three times with diluted NaCl-solution,
twice with brine, dried over MgSO4, and filtered.20 Removal
of the solvent under reduced pressure followed by column
chromatography of the oily residue gave rise to the
corresponding azepines 18.
4.5.4. 1-Benzyl-5-(tert-butyl-dimethyl-silanyloxymethyl)-
2-oxo-2,3,4,7-tetrahydro-1H-azepine-3-carboxylic acid
methyl ester (18d). The title compound was prepared
according to the general procedure (Method B) employing
0.432 g (1.00 mmol) of 16d and 42 mg (0.05 mmol,
5 mol%) of 7. Column chromatography (hexane/ethyl
acetate: 3:1) gave rise to 0.29 g (74%) of 18d as colorless
oil: 1H NMR d 7.31–7.19 (m, 5H), 5.66–5.62 (sm, 1H), 4.61
(s, 2H), 4.18–4.11 (sm, 1H), 4.08 (dd, 1H, JZ12.4, 3.7 Hz),
3.94 (s, 2H), 3.78 (s, 3H), 3.46 (dd, 1H, JZ17.7, 7.6 Hz),
2.68–2.59 (br m, 1H), 2.47 (br d, 1H, JZ18.3 Hz), 0.86 (s,
9H), 0.01 (s, 6H); 13C NMR d 170.8, 170.0, 140.3, 136.8,
128.5, 127.8, 127.4, 117.8, 66.8, 52.3, 51.3, 48.2, 44.8, 27.5,
25.8, 18.2, K5.5; MS (EI) m/z 403 (23, MC), 388 (19), 346
(100), 271 (69), 258 (23), 213 (51), 91 (33); HRMS (EI) m/z
calcd for C22H33NO4Si 403.2179 found 403.2181.
Following the general procedure (Method A) employing
0.432 g (1.00 mmol) of 16d and 41 mg (0.05 mmol,
5 mol%) of 6, 0.093 g (23%) of 18d was obtained after
column chromatography (hexane/ethyl acetate: 2:1) as
colorless oil. The isolated product exhibited identical
spectroscopic data to those obtained using Method B.
4.5.1.
1-Benzyl-2,3,4,7-tetrahydro-1H-azepine-3-
carboxylic acid methyl ester (18a). The title compound
was prepared according to the general procedure (Method
A) employing 0.311 g (1.14 mmol) of 16a and 47 mg
(0.057 mmol, 5 mol%) of 6. Column chromatography
(hexane/ethyl acetate: 14:1) gave rise to 0.235 g (76%) of
the recovered starting material and to 0.023 g (8%) of 18a as
1
colorless oil: H NMR d 7.35–7.21 (m, 5H), 5.86 (psquint,
1H, JZ11.0, 5.5 Hz), 5.66 (sm, 1H), 3.68 (s, 2H), 3.63 (s,
3H), 3.28–3.20 (m, 3H), 3.07 (dd, 1H, JZ13.1, 9.1 Hz),
2.88–2.81 (sm, 1H), 2.62–2.53 (m, 1H), 2.53–2.46 (m, 1H);
13C NMR d 174.8, 138.7, 130.0, 129.7, 128.9, 128.3, 127.1,
60.2, 58.9, 53.6, 51.7, 41.8, 29.5; MS (EI) m/z 246 (15,
MCCH), 245 (71, MC), 244 (18), 214 (30), 186 (30), 158
(25), 155 (31), 154 (100), 121 (31), 120 (27), 119 (35), 94
(27), 91 (54), 88 (57), 84 (88); HRMS (EI) m/z calcd for
C15H19NO2 245.1416 found 245.1413.
4.5.2. 1-Benzyl-2-oxo-2,3,4,7-tetrahydro-1H-azepine-3-
carboxylic acid methyl ester (18b). According to the
general procedure (Method A) utilizing 0.339 g
(1.18 mmol) of 16c and 49 mg (0.059 mmol, 5 mol%) of
6, 0.268 g (88%) of 18b was obtained after column
chromatography (hexane/ethyl acetate: 2:1) as colorless
4.5.5. 2,3,4,7-Tetrahydro-1H-azepine-1,3-dicarboxylic
acid-1-tert-butyl ester 3-methyl ester (18e). According
to the general procedure (Method A) utilizing 0.340 g
(1.20 mmol) of 16e and 49 mg (0.06 mmol, 5 mol%) of 6,
0.265 g (87%) of 18e was obtained after column chromato-
graphy (hexane/ethyl acetate: 14:1) as colorless oil: 1H
NMR (rotamers, ratio: w1.2:1) d 5.76–5.61 (m, 2H), 4.20
(br d, 0.56H, JZ17.4 Hz), 4.10 (br d, 0.47H, JZ15.8 Hz),
4.00 (br dd, 0.43H, JZ14.0, 6.2 Hz), 3.84 (br dd, 1.12H, JZ
14.4, 6.7 Hz), 3.75 (br d, 0.56H, JZ17.4 Hz), 3.70 (s,
1.63H), 3.69 (s, 1.36H), 3.58–3.49 (m, 1H), 2.99–2.91 (m,
1H), 2.50–2.40 (m, 2H) 1.46 (s, 5H), 1.45 (s, 4H); 13C NMR
(rotamers) d 173.9, 155.1, 155.0, 129.2, 128.8, 128.1, 126.9,
51.6, 48.0, 47.8, 47.3, 47.1, 43.5, 42.9, 28.2, 28.1, 27.2,
26.5; MS (ESC) m/z 278 (100, [MCNa]C), 533 (13, [2MC
Na]C); HRMS (ESC) m/z calcd for C13H21NO4Na
278.136828 found 278.135883. According to the general
procedure (Method B) employing 0.340 g (1.20 mmol)
of 16e and 51 mg (0.06 mmol, 5 mol%) of 7, 0.263 g
(86%) of 18e was obtained as a colorless oil, which
exhibited identical spectroscopic data to those obtained
using Method A.
1
oil: H NMR d 7.34–7.21 (m, 5H), 5.77–5.72 (sm, 1H),
5.63–5.58 (sm, 1H), 4.75 (d, 1H, JZ14.9 Hz), 4.54 (d, 1H,
JZ14.9 Hz), 4.18 (sm, 1H), 4.14 (dd, 1H, JZ12.2, 3.7 Hz),
3.80 (s, 3H), 3.42 (dd, 1H, JZ17.7, 7.1 Hz), 2.83–2.72 (sm,
1H), 2.62–2.53 (sm, 1H); 13C NMR d 170.7, 169.8, 136.7,
129.4, 128.3, 127.6, 127.2, 124.1, 51.9, 51.1, 48.4, 44.9,
27.2; MS (EI) m/z 260 (36, MCCH), 259 (100, MC), 228
(42), 200 (14), 168 (66), 146 (63), 136 (31), 108 (28), 101
(32), 91 (41); HRMS (EI) m/z calcd for C15H17NO3
259.1208 found 259.1213. Following the general procedure
(Method B) employing 0.287 g (1.00 mmol) of 16c and
42 mg (0.05 mmol, 5 mol%) of 7, 0.233 g (90%) of 18b was
obtained after column chromatography (hexane/ethyl
acetate: 2:1) as colorless oil. The isolated product
exhibited identical spectroscopic data to those obtained
using Method A.
4.5.3. 1-Benzyl-5-hydroxymethyl-2-oxo-2,3,4,7-tetra-
hydro-1H-azepine-3-carboxylic acid methyl ester (18c).
According to the general procedure (Method B) utilizing

S. Brass et al. / Tetrahedron 62 (2006) 1777–1786
1785
¨
to thank Prof. Dr. G. Klebe, Philipps Universitat Marburg,
for his generous support of their research.
4.5.6. 5-Hydroxymethyl-2,3,4,7-tetrahydro-1H-azepine-
1,3-dicarboxylic acid-1-tert-butyl ester 3-methyl ester
(18f). The title compound was prepared according to the
general procedure (Method B) employing 0.313 g
(1.00 mmol) of 17c and 42 mg (0.05 mmol, 5 mol%) of 7.
Column chromatography (hexane/ethyl acetate: 3:2) gave
rise to 0.271 g (95%) of 18f as colorless oil: 1H NMR
(rotamers, ratio: w1.5:1) d 5.67 (s, 0.4H), 5.64 (s, 0.6H),
4.28 (d, 0.6H, JZ17.6 Hz), 4.17 (d, 0.4H, JZ17.2 Hz),
4.06–3.95 (m, 2.46H), 3.88–3.74 (m, 1.59H), 3.70 (s,
1.79H), 3.69 (s, 1.31H), 3.52 (sm, 1H), 3.09–2.98 (m, 1H),
2.52–2.41 (sm, 2H), 2.13 (br s, 1H), 1.47 (s, 5.40H), 1.45 (s,
4.18H); 13C NMR (rotamers) d 174.4, 174.3, 155.0, 139.5,
138.3, 123.0, 122.8, 79.9, 79.7, 67.8, 67.6, 51.8, 47.9, 47.6,
46.9, 46.7, 42.8, 42.1, 28.2, 27.9, 27.4; MS (ESC) m/z 286
(56, [MCH]C), 308 (67, [MCNa]C), 593 (100, [2MC
Na]C); HRMS (ESC) m/z calcd for C14H23NO5Na
308.147393 found 308.150227. Anal. Calcd for
C14H23NO5: C, 58.93; H, 8.12; N, 4.91. Found: C, 58.60;
H, 7.90; N, 5.16. Following the general procedure (Method
A) employing 0.313 g (1.00 mmol) of 17c and 41 mg
(0.05 mmol, 5 mol%) of 6, 0.105 g (37%) of 18f was
obtained after column chromatography (hexane/ethyl
acetate: 2:1) as colorless oil. The isolated product
exhibited identical spectroscopic data to those obtained
using Method B.
References and notes
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tetrahydro-1H-azepine-1,3-dicarboxylic acid-1-tert-
butyl ester 3-methyl ester (18g). According to the general
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and 63 mg (0.077 mmol, 5 mol%) of 6, 0.267 g (44%) of
18g was obtained after column chromatography (hexane/
´
´ ´
Gonzalez-Perez, P.; Perez-Serrano, L.; Casarrubios, L.;
´
Domınguez, G.; Perez-Castells, J. Tetrahedron Lett. 2002,
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43, 4765–4767. (f) Declerck, V.; Ribiere, P.; Martinez, J.;
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1
ethyl acetate: 10:1) as colorless oil: H NMR (rotamers,
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1738–1742. (b) Vo-Thanh, G.; Boucard, V.; Sauriat-Dorizon, H.;
´ ´
Guibe, F. Synlett 2001, 37–40. (c) Li, H.; Bleriot, Y.;
ratio: w1.1:1) d 5.68 (s, 0.5H), 5.61 (s, 0.5H), 4.16 (d, 0.5H,
JZ17.9 Hz), 4.10 (d, 0.5H, JZ16.7 Hz), 4.04–3.93 (m,
2.6H), 3.86 (d, 0.5H, JZ17.1 Hz), 3.79 (dd, 0.5H, JZ14.5,
6.8 Hz), 3.71 (br d, 0.5H, JZ19.5 Hz), 3.67 (s, 1.50H), 3.65
(s, 1.50H), 3.52 (dd, 0.50H, JZ14.3, 8.3 Hz), 3.44 (dd,
0.5H, JZ14.0, 8.8 Hz), 2.91–2.83 (m, 1H), 2.32 (s, 1H),
2.31 (s, 1H), 1.43 (s, 4.6H), 1.42 (s, 4.4H), 0.88 (s, 4.9H),
0.87 (s, 4.5H), 0.04 (s, 6H); 13C NMR (rotamers) d 174.0,
155.2, 155.0, 139.6, 138.0, 121.7, 121.3, 79.8, 79.6, 67.3,
67.1, 51.7, 48.4, 47.8, 46.7, 46.6, 42.7, 42.3, 28.3, 28.2,
27.4, 25.8, 18.2, K5.4, K5.5; MS (ESC) m/z 422 (100,
[MCNa]C); HRMS (ESC) m/z calcd for C20H37NO5SiNa
422.233872 found 4222.229903. According to the general
procedure (Method B) employing 0.460 g (1.08 mmol) of
16f and 46 mg (0.054 mmol, 5 mol%) of 7, 0.375 g (87%) of
18g was obtained as a colorless oil, which exhibited
identical spectroscopic data to those obtained using
Method A.
Chantereau, C.; Mallet, J.-M.; Sollogoub, M.; Zhang, Y.;
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Rodrıguez-Garcıa, E.; Vogel, P.; Jimenez-Barbero, J.;
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Acknowledgements
We gratefully acknowledge the financial support of our
research by the Deutsche Pharmazeutische Gesellschaft
(DPhG) within the fellowship ‘DPhG Stiftung zur
Forderung des wissenschaftlichen Nachwuchses’ for
W.E.D. We also thank Wacker-Chemie GmbH for
supplying the TBSCl. The authors in particular would like
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¨

1786
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´
sequence: (a) Nave, J.-F.; Casara, P. J.; Taylor, D. L.;
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however, no spectral data were given.
Denes, F.;
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13. Compound 11 has already been prepared via two different
procedures: (a) Ref. 6b; reported yield (39%) was significantly