New 1,3-dihydroazepin-2-one derivatives by [3,3]-sigmatropic rearrangement of suitably substituted 2-alkenylcyclopropyl isocyanates

Article abstract of DOI:10.1139/v03-186

The 2-siloxysubstituted 2-alkenylcyclopropanecarboxylic acids 10-14 were converted into the corresponding carbonyl azides by treatment with DPPA (diphenyl phosphorazidate) and triethylamine. On heating to 80°C these intermediates smoothly furnished azepinone derivatives 19-25 in moderate to good overall yields, which are the result of a sequence of Curtius reaction to cyclopropylisocyanates, [3,3]-sigmatropic rearrangement, and a final proton shift. The primary products may undergo desilylation (to afford azepin-2,5-diones such as 23) or double bond migration (to compound 25). Cyclopropanecarboxylic acids cis-32, cis-34, and cis-35, which bear no 2-siloxy group, similarly provided azepinone derivatives 36-38 in good yields. No influence of the 2-siloxy substituent on the reaction course and rates could be observed in these qualitative studies, which was confirmed by DFT calculations with model compounds 39-42 showing similar reaction barriers for rearrangements of cyclopropylisocyanates with or without a 2-hydroxy group.

Full text of DOI:10.1139/v03-186

166
New 1,3-dihydroazepin-2-one derivatives by [3,3]-
sigmatropic rearrangement of suitably substituted
2-alkenylcyclopropyl isocyanates1
Hans-Ulrich Reissig, Gesine Böttcher, and Reinhold Zimmer
Abstract: The 2-siloxysubstituted 2-alkenylcyclopropanecarboxylic acids 10–14 were converted into the corresponding
carbonyl azides by treatment with DPPA (diphenyl phosphorazidate) and triethylamine. On heating to 80 °C these inter-
mediates smoothly furnished azepinone derivatives 19–25 in moderate to good overall yields, which are the result of a
sequence of Curtius reaction to cyclopropylisocyanates, [3,3]-sigmatropic rearrangement, and a final proton shift. The
primary products may undergo desilylation (to afford azepin-2,5-diones such as 23) or double bond migration (to com-
pound 25). Cyclopropanecarboxylic acids cis-32, cis-34, and cis-35, which bear no 2-siloxy group, similarly provided
azepinone derivatives 36–38 in good yields. No influence of the 2-siloxy substituent on the reaction course and rates
could be observed in these qualitative studies, which was confirmed by DFT calculations with model compounds 39–42
showing similar reaction barriers for rearrangements of cyclopropylisocyanates with or without a 2-hydroxy group.
Key words: vinyl cyclopropanes, carbonylazides, [3.3]-sigmatropic rearrangements, azepinones.
Résumé : Les acides carboxyliques 2-alcénylcyclopropanecarboxyliques portant un substituant 2-siloxy (10–14) peuvent
être transformés en azotures de carbonyle correspondants par traitement avec du phosphorazidate de diphényle (« DPPA »)
et de la triéthylamine. Par chauffage à 80 °C, ces intermédiaires peuvent facilement se transformer en dérivés de
l’azépinone (19–25) avec des rendements allant de moyens à bons; cette transformation est le résultat d’une séquence
impliquant une réaction de Curtius conduisant aux isocyanates de cyclopropyle, d’un réarrangement sigmatropique [3,3]
et d’un déplacement final de proton. Les produits primaires peuvent aussi subir une désilylation (qui conduisent à des
azépine-2,5-diones, tel le produit 23) ou une migration de double liaison (conduisant au composé 25). Les acides cy-
clopropanecarboxyliques cis-32, cis-34 et cis-35 qui ne portent pas de groupe siloxy en position 2 conduisent aussi à
des dérivés de l’azépinone (36–38) avec de bons rendements. Dans ces études qualitatives, on n’a pas observé
d’influence du substituant siloxy en position 2 sur l’orientation ou la vitesse des réactions; cette observation a été
confirmée par des calculs DFT sur les composés modèles 39–42 qui ont montré que les barrières aux réactions de réar-
rangement sont semblables pour les isocyanates de cyclopropyle avec ou sans groupe hydroxy en position 2.
Mots clés : vinylcyclopropanes, azoture de carbonyle, réarrangements sigmatropiques [3,3], azépinones.
[Traduit par la Rédaction]
Reissig et al. 176
Introduction
corresponding silyl enol ethers B. Their thermolysis fur-
nished cycloheptadiene derivatives C, and desilylation gave
a series of 4-cyclohepten-1-ones D (3). Inspired by these
results we anticipated that 2-siloxycyclopropanecarboxalde-
hydes E should be convertible into divinylcyclopropane de-
rivatives F with an alternative substitution pattern that
would finally provide 3-cyclohepten-1-ones via cyclohepta-
diene derivatives G. However, we had to learn that donor–
acceptor substituted cyclopropanes (4) such as E can not be
isolated since they immediately undergo the related [3,3]-
The Cope rearrangement of divinylcyclopropanes to
cycloheptadienes establishes a valuable and stereoselective
pathway to seven-membered ring systems often applied in
natural product synthesis (1). Seminal contributions are due
to the efforts of the Piers group (2). One method to generate
functionalized divinylcyclopropane derivatives able to un-
dergo the crucial 3,3-sigmatropic rearrangement employed
vinylcyclopropyl ketones A that by O-silylation provided the
Received 2 July 2003. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 15 January 2004.
Dedicated with warm affection to Ed Piers, a great synthetic chemist, whom we owe our interest in cyclopropane and
organometallic chemistry.
H.-U. Reissig2,3 and R. Zimmer. Institut für Chemie – Organische Chemie, Freie Universität Berlin, Takustr. 3, D-14195 Berlin,
Germany.
G. Böttcher. Institut für Organische Chemie, Technische Universität Dresden, D-01061 Dresden, Germany.
1This article is part of a Special Issue dedicated to Professor Ed Piers.
2Also at: Institut für Organische Chemie, Technische Universität Dresden, D-01061 Dresden, Germany.
3Corresponding author (e-mail: hans-reissig@chemie.fu-berlin.de).
Can. J. Chem. 82: 166–176 (2004)
doi: 10.1139/V03-186
© 2004 NRC Canada

Reissig et al.
167
Scheme 1.
sigmatropic rearrangement involving the CO double bond,
smoothly affording functionalized 2,5-dihydrooxepines H
(5, 6) (Scheme 1).
This surprising entry to seven-membered heterocycles
prompted us to investigate the rearrangements of other com-
pounds derived from easily available methyl 2-alkenyl-2-
siloxycyclopropanecarboxylates. Among several systems ex-
amined (7) cyclopropyl isocyanates turned out to be the most
interesting compounds. Although early examples of their re-
arrangement have been known since the pioneer study of
Vogel et al. (8) in 1965, this pathway to azepinone deriva-
tives was an almost forgotten reaction. Vogel found that
heating of cis-substituted carbonyl azide I to 80 °C smoothly
provided the 1,3-dihydroazepin-2-one L. Logical intermedi-
ates are isocyanate J, formed by Curtius reaction, which re-
arranged to 3,6-dihydroazepin-2-one K and a hydrogen shift
finally furnished lactam L. Only heating to 350 °C caused
rearrangement of the corresponding trans-substituted car-
bonyl azide. Meanwhile, just a few additional examples have
been reported (9), although this approach to seven-
membered heterocycles seems to be fairly flexible. In this
report we want to disclose full details of our experiments,
which involved siloxysubstituted cyclopropyl isocyanates
and provided the corresponding functionalized 1,3-dihydro-
azepin-2-ones. For comparison, a few examples without
siloxy group were included in this study (Scheme 2).
Results
Although donor–acceptor substituted cyclopropanes are
extremely versatile building blocks in organic synthesis (4),
those with an additional 2-alkenyl group are even more use-
ful. They open further pathways such as (formal) pericyclic
processes involving the double bond or — after ring cleav-
age — Michael-type additions or Diels–Alder reactions of
the intermediately generated enones. For the purpose of this
study methyl 2-alkenyl-2-siloxycyclopropanecarboxylates 1–
4 (10) with the less base labile tert-butyldimethylsilyl group
were employed as starting materials. Compounds 1–4 are
mixtures of cis/trans isomers, however, treatment with lith-
ium diisopropylamide (LDA) followed by addition of an ap-
propriate electrophile afforded C-1 substituted derivatives 5–9
in good yields and — most importantly — with the required
cis arrangement of the alkenyl groups and the methoxy-
carbonyl group (11). We found many years ago that enolates
derived from methyl siloxycyclopropanecarboxylates accept
electrophiles with a surprising diastereoselectivity, which
was interpreted as a stereoelectronic effect of the siloxy
group (12) (Scheme 3).
Scheme 2.
Methyl esters 5–9 were easily converted into carboxylic
acids 10–14 by treatment with potassium trimethylsilanolate —
a mild method that has considerable advantages over stan-
dard saponification procedures (13). With carboxylic acid 13
we examined known literature methods for the conversion to
the carbonyl azide. The Weinstock procedure (method A)
(14), which employs ethyl chloroformate, triethylamine, and
finally sodium azide in water, provided the desired cyclo-
propylcarbonyl azide 15 in 54% yield, whereas application
of the commercially available diphenyl phosphorazidate
(DPPA) in toluene at 0 °C (method B) (15) afforded 15 in
22% yield. Despite the lower yield in this example we gen-
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Can. J. Chem. Vol. 82, 2004
Scheme 3.
Scheme 4.
azepin-2,5-dione 23. The rearrangement product obtained
from carboxylic acid 14 seems to be even more labile. Here
only 1H-azepin-2,5-dione derivatives 24 and 25 were iso-
lated, primarily as a mixture with 7-(2-propenyl) and 7-(1-
propenyl) substituents, but after treatment with triethylamine,
compound 25 with conjugated double bonds was obtained
exclusively in moderate yield. All reactions collected in
Scheme 5 were not optimized, which should leave room for
improvement of yields.
With carboxylic acid 13 we tried to trap the intermediate
cyclopropyl isocyanate by performing the reaction sequence
in tert-butanol instead of toluene. Surprisingly, only 1H-
azepin-2,5-dione 23 was isolated in low yield (7). The ex-
pected urethane 26 could not be detected indicating that the
rearrangement of the cyclopropyl isocycanate is consider-
ably faster than the intermolecular reaction with tert-butanol.
To gain additional insight into the reactivity of siloxy-
substituted cyclopropyl azides we also studied phenyl-
substituted derivative 28, which was efficiently prepared
from carboxylic acid 27 by the DPPA method. Curtius rear-
rangement of azide 28 occurred at 80 °C affording isocyan-
ate 29 in excellent yield. Product 29 is the first siloxy-
substituted cyclopropyl isocyanate that could be isolated.
Unfortunately, this compound could not successfully be rear-
ranged into a benzannulated azepine derivate. Finally, after a
BF3 etherate treatment of 29, we isolated a little amount of a
crystalline compound to which we assign structure 30 (16)
(Scheme 6).
erally employed the latter method because it is easy to per-
form in organic solvents and the generated carbonyl azide
can therefore be directly converted into the 1,3-dihydroaze-
pin-2-ones by heating to 80 °C. To demonstrate this option
carboxylic acid 10 was treated with DPPA at room tempera-
ture to furnish carbonyl azide 16 in 76% yield. Heating of
this product to 80 °C for 3 h induced the Curtius rearrange-
ment to cyclopropyl isocyanate 17, which directly suffered
the 3,3-sigmatropic ring-enlargement process, thus affording
the expected bicyclic azepin-2-one derivative 19 in 68%
yield via intermediate 18. This sequence may be performed
as a one-pot procedure without isolation of azide 16; com-
pound 19 was isolated in 48% yield, which is comparable to
the two step procedure, but more convenient to perform
(Scheme 4).
Having established the proper reaction conditions, we em-
ployed carboxylic acids 11–14 as starting materials. As ex-
pected, compounds 11 and 12 furnished seven-membered
heterocycles 20 and 21 in good overall yield. The less-
substituted carboxylic acid 13 led to rearranged product 22,
which is apparently more sensitive with respect to desilyl-
ation. Hydrolysis of the silyl enol ether unit of azepin-2-one
22 occurred probably during purification and produced 1H-
For comparison, we included cis-alkenylcyclopropanecar-
boxylic acids without a siloxy group into this study. The
sequence to obtain the required cis-compounds is demon-
strated for diphenyl-substituted compound 32. Standard
© 2004 NRC Canada

Reissig et al.
169
Scheme 5.
Scheme 6.
Scheme 7.
cyclopropanation of 2,3-diphenyl-1,3-butadiene with methyl
diazoacetate provided the expected vinylcyclopropane deriv-
ative 31 in good yield and as a 57:43 mixture of
diastereomers. The ester was saponified and the cis/trans-
carboxylic acids 32 were subjected to iodolactonization (17),
which provided a mixture of the iodolactone 33 (two
diastereomers) derived from the cis-isomer and of uncon-
sumed trans-32. Since the latter could easily be separated by
extraction, the remaining iodolactone 33 was finally con-
verted back to diastereomerically pure carboxylic acid cis-32
by reduction with a zinc–silver couple in acetic acid (18).
This chemical separation of diastereomers is fairly conve-
nient and allowed the use of diastereomerically pure cis-
cyclopropanecarboxylic acid 32. Analogously, cis-
compounds 34 and 35 were prepared from the corresponding
alkenylcyclopropanes (Scheme 7).
Conversions of these three cis-alkenylcyclopropanecar-
boxylic acids 32, 34, and 35 into the corresponding azides
by the DPPA method proceeded in good yields and subse-
quent thermal rearrangement of the purified azides smoothly
afforded the expected 1,3-dihydroazepin-2-ones 36, 37, and
38, respectively, in moderate to good overall yields. No ap-
parent difference in the reaction rates of the carbonyl azide
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170
Can. J. Chem. Vol. 82, 2004
Scheme 8.
Scheme 9.
Cope rearrangements are located early at the reaction coor-
dinate, thus strongly resembling the starting materials and
not the seven-membered products (Scheme 9).
Finally, we want to stress that the almost unexplored route
to azepin-2-one derivatives via cyclopropyl isocyanates of-
fers an interesting possibility for generating this type of
heterocycle (20). The functionalized compounds presented
in this report should be of interest for further synthetic use
and can probably be employed in combinatorial chemistry.
Experimental section
All reactions were carried out under an argon atmosphere
in flame-dried flasks, and the components were added by us-
ing syringes. All solvents were dried by standard methods.
IR spectra were measured with a PerkinElmer FT-IR spec-
conversion or the rearrangement steps compared with
siloxy-substituted
(Scheme 8).
compounds
could
be
observed
1
trometer Nicolet 5 SXC. H and 13C NMR spectra were re-
corded on Bruker instruments (AC 300, AC 500) in CDCl3
solution. The chemical shifts are given relative to the TMS
or to the CDCl3 signal (δH = 7.27, δC = 77.0). The splitting
patterns are designated as singulet (s), doublet (d), triplet (t),
and multiplet (m). Higher order NMR spectra were approxi-
mately interpreted as first-order spectra if possible. CO2H
protons could not be identified for all carboxylic acids. Neu-
tral alumina (activity III, Fa. Merck) was used for column
chromatography. Melting points (uncorrected) were mea-
sured with an apparatus from Rapido.
Starting materials 1–4 and compounds 7–9 were prepared
by literature procedures (21). Detailed procedures for syn-
thesis of cis-34 and cis-35 are given in ref. 7. All other
chemicals were commercially available and were used as re-
ceived.
Discussion
We found efficient methods to generate cis-alkenylcyclo-
propanecarboxylic acids (with or without a 2-siloxy group)
and to convert these intermediates into the corresponding
carbonyl azides. Individual examples of these azides were
isolated. Their thermolysis at 80 °C afforded the desired 1,3-
dihydroazepin-2-ones via alkenylcyclopropyl isocyanates.
The Curtius rearrangement seems to be the rate-determining
step of the sequence, since the isocyanate could only be iso-
lated when a cis-located alkenyl group was absent (see com-
pound 29). For suitably cis-substituted compounds the
subsequent [3,3]-sigmatropic ring-enlargement to the 3,6-
dihydroazepin-2-one and the hydrogen shift to the final
product are apparently much faster reactions (see Scheme 2).
For an estimation of the influence of the substitution pat-
tern on the rate of the 3,3-sigmatropic rearrangement,
Sperling (19)4 performed DFT calculations (B3LYP/6-31G*)
with two model systems 39 and 40. The transformation of
these compounds into 3,6-dihydroazepin-2-ones 41 and 42,
respectively, have to surpass only slightly different barriers
that are in the order of 70 kJ/mol indicating that these rear-
rangements can occur at relatively low temperature — prob-
ably considerably lower than the applied 80 °C. In contrast,
the reaction enthalpies are much more influenced by the sub-
stitution pattern: the cyclopropanol derivative 40 undergoes
a much more exothermic reaction, which is likely due to the
destabilization of the cyclopropane stage by this substituent
and (or) the gain of conjugation in the product. These calcu-
lated energies suggest that the transition structures of the
Methyl t-2-tert-butyldimethylsiloxy-c-2-(1-cyclohexenyl)-
1-methyl-r-1-cyclopropanecarboxylate (5)
According to the general procedure described in ref. 21,
2-siloxycyclopropanecarboxylate 1 (2.68 g, 9.60 mmol) was
deprotonated with LDA (14.4 mmol) and alkylated with
methyliodide (7.04 g, 49.6 mmol) in THF (100 mL) at
−78 °C for 17 h. Purification of the crude product (0.915 g)
by Kugelrohr distillation (125 °C, 0.015 mbar (1 bar = 105
Pa) yielded 1.90 g (60%) of 6 as a colorless oil that slowly
crystallized at room temperature (rt) (mp 38–42 °C). IR
(cm–1): 2935, 2855 (C-H), 1725 (C=O), 1250 (Si-C), 1305,
1
1150 (C-O). H NMR (CDCl3, 300 MHz) δ: 5.66 (mc, 1H,
2′-H), 3.57 (s, 3H, CO2Me), 2.25–1.99, 1.68–1.42 (2m, 8H,
3′-H to 6′-H), 1.88 (d, J = 5.8 Hz, 1H, 3-Htrans), 1.40 (s, 3H,
1-Me), 0.86 (s, 9H, t-Bu), 0.73 (d, J = 5.8 Hz, 1H, 3-Hcis),
4 J. Fabian and D. Sperling. Unpublished results.
© 2004 NRC Canada

Reissig et al.
171
0.07, 0.06 (2s, 6H, SiMe2). 13C NMR (CDCl3, 75.5 MHz) δ:
173.5, 51.6 (s, q, CO2Me), 135.0 (s, C-1′), 125.8 (d, C-2′),
68.8 (s, C-2), 30.5 (s, C-1), 25.7, 18.1 (q, s, t-Bu), 25.0,
24.1, 22.6*,5 22.4 (4 t, C-3, C-3′ to C-6′), 15.1 (q, 1-Me),
–3.9, –4.3 (2 q, SiMe2). Anal. calcd. for C18H32O3Si (324.5):
C 66.32, H 9.94; found: C 66.80, H 10.32.
(0.196 g, 42%) as a colorless solid, mp 106–110 °C. IR (cm–1):
3450 (CO2H), 2960–2930 (CH), 1690 (C=O), 1260 (Si-C).
1H NMR (CDCl3, 300 MHz) δ: 7.35–7.08 (m, 5H, Ph), 5.46,
5.10 (2 s, 1H each, 2′-H), 1.93, (d, J = 5.9 Hz, 1H, 3-Htrans),
1.44 (s, 3H, 1-Me), 0.83 (d, J = 5.9 Hz, 1H, 3-Hcis), 0.63 (s,
9H, t-Bu), –0.04, –0.24 (2 s, 6H, SiMe2). 13C NMR (CDCl3,
75.5 MHz) δ: 177.7 (s, CO2H), 144.9 (s, C-1′), 137.7, 127.8,
127.4, 127.1 (s, 3d, Ph), 115.0 (t, C-2′), 67.9 (s, C-2), 31.9
(s, C-1), 25.6, 18.0 (q, s, t-Bu), 24.6 (t, C-3), 14.8 (q, 1-Me),
–4.0, –4.3 (2q, SiMe2). Anal. calcd. for C19H28O3Si (332.5):
C 68.63, H 8.49; found: C 68.46, H 8.68.
Methyl t-2-tert-butyldimethylsiloxy-c-2-(1-phenyl-
ethenyl)-1-methyl-r-1-cyclopropanecarboxylate (6)
According to the general procedure described in ref. 21,
2-siloxycyclopropanecarboxylate 2 (0.922 g, 2.77 mmol)
was deprotonated with LDA (4.00 mmol) and alkylated with
methyliodide (1.09 g, 7.68 mmol) in THF (50 mL) at –78 °C
for 19 h. Purification of the crude product (0.915 g) by col-
umn chromatography (heptane/EtOAc, 10:1) yielded 0.559 g
(60%) of 6 as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ:
7.40–7.07 (m, 5H, Ph), 5.55, 5.19 (2s, 1H each, 2′-H), 3.17
(s, 3H, CO2Me), 1.96 (d, J = 5.9 Hz, 1H, 3-Htrans), 1.45 (s,
3H, 1-Me), 0.84 (d, J = 5.9 Hz, 1H, 3-Hcis), 0.64 (s, 9H, t-
Bu), 0.00, –0.24 (2s, 6H, SiMe2). 13C NMR (CDCl3,
75.5 MHz) δ: 172.6, 51.5 (s, q, CO2Me), 145.5 (s, C-1′),
137.6, 127.8, 127.4, 126.9 (s, 3d, Ph), 115.0 (t, C-2′), 67.3
(s, C-2), 31.8 (s, C-1), 25.4, 18.0 (q, s, t-Bu), 24.3 (t, C-3),
15.0 (q, 1-Me), –4.0, –4.3 (2q, SiMe2).
t-2-tert-Butyldimethylsiloxy-c-2-isopropenyl-1-methyl-r-1-
cyclopropanecarboxylic acid (12)
According to general procedure 1, methyl cyclopropane-
carboxylate 7 (0.284 g, 1.00 mmol) and KOSiMe3 (0.385 g,
3.00 mmol) in toluene (5 mL) were heated for 2 h at 100 °C
and yielded 12 (0.225 g, 84%) as a colorless solid, mp 63–
67 °C. IR (cm–1): 3450 (OH), 2960–2830 (CH), 1700
(C=O), 1650 (C=C), 1260 (SiC). 1H NMR (CDCl3,
300 MHz) δ: 11.75 (br. s, 1H, CO2H), 4.83, 4.80 (2 s, 1H
each, 2′-H), 1.91 (d, J = 5.9 Hz, 1H, 3-Htrans), 1.70, 1.39
(2 s, 3H each, 1-Me, 1′-Me), 0.85 (s, 9H, t-Bu), 0.76 (d, J =
5.9 Hz, 1H, 3-Hcis), 0.06 (s, 6H, SiMe2). 13C NMR (CDCl3,
75.5 MHz) δ: 179.5 (s, CO2H), 141.7 (s, C-1′), 114.6 (t, C-
2′), 69.4 (s, C-2), 30.8 (s, C-1), 25.6, 18.1 (q, s, t-Bu), 25.0
(t, C-3), 19.3 (q, 1′-Me), 14.7 (q, 1-Me), –4.2, –4.3 (2q,
SiMe2). Anal. calcd. for C14H24O3Si (268.4): C 62.18, H
9.01; found: C 62.40, H 9.26.
Saponification with KOSiMe3 (general procedure 1)
To a solution of methyl cyclopropanecarboxylate (1 equiv.)
in toluene (5 mL/mmol ester) was added KOSiMe3
(3 equiv.) and the solution was heated (time and temperature
are indicated in individual experiments). The mixture was
cooled to room temperature, quenched with saturated aque-
ous ammonium chloride solution and the product was ex-
tracted with diethyl ether. The combined organic layers were
dried over MgSO4 and concentrated.
t-2-tert-Butyldimethylsiloxy-1-methyl-c-2-vinyl-r-1-cyclo-
propanecarboxylic acid (13)
According to general procedure 1, methyl cyclopropane-
carboxylate 8 (0.270 g, 1.00 mmol) and KOSiMe3 (0.385 g,
3.00 mmol) in toluene (5 mL) were heated for 2 h at 100 °C
and yielded 13 (0.179 g, 70%) as a colorless solid, mp 55–
57 °C. IR (cm–1): 3450 (CO2H), 2960, 2930 (CH), 1690
t-2-tert-Butyldimethylsiloxy-c-2-(1-cyclohexenyl)-1-methyl-
r-1-cyclopropanecarboxylic acid (10)
1
(C=O). H NMR (CDCl3, 300 MHz) δ: 5.78 (dd, J = 17.0,
According to general procedure 1, methyl cyclopropane-
carboxylate 5 (1.86 g, 5.74 mmol) and KOSiMe3 (2.21 g,
17.2 mmol) in toluene (60 mL) were heated for 3 h at
100 °C and yielded 10 (1.70 g, 96%) as a colorless solid, mp
115–120 °C. IR (cm–1): 3400 (CO2H), 2930, 2860 (C-H),
1690 (C=O), 1305, 1245 (Si-C). 1H NMR (CDCl3,
300 MHz) δ: 5.76 (mc, 1H, 2′-H), 2.25–2.11 (m, 1H, 3′-H),
2.00 (br. s, 2H, 6′-H), 1.89 (d, J = 5.8 Hz, 1H, 3-Htrans),
1.72–1.60 (m, 1H, 3′-H), 1.53 (mc, 4H, 4′-H, 5′-H), 1.40 (s,
3H, 1-Me), 0.87 (s, 9H, t-Bu), 0.79 (d, J = 5.8 Hz, 1H, 3-
Hcis), 0.07, 0.06 (2s, 6H, SiMe2). 13C NMR (CDCl3,
75.5 MHz) δ: 179.7 (s, CO2H), 134.5 (s, C-1′), 126.5 (d, C-
2′), 69.9 (s, C-2), 30.1 (s, C-1), 25.7, 18.1 (q, s, t-Bu), 25.2,
25.0, 22.6*,5 22.3 (4 t, C-3, C-3′ to C-6′), 14.8 (q, 1-Me),
–3.8, –4.3 (2 q, SiMe2). Anal. calcd. for C17H30O3Si (310.5):
C 65.76, H 9.73; found: C 65.89, H 10.01.
10.7 Hz, 1H, 1′-H), 5.18 (dd J = 17.0, 1.5 Hz, 1H, 2′-H),
5.02 (dd, J = 10.7, 1.5 Hz, 1H, 2′-H), 1.73 (d, J = 6.1 Hz,
1H, 3-Htrans), 1.31 (s, 3H, 1-Me), 0.92 (d, J = 6.1 Hz, 1H, 3-
Hcis), 0.79 (s, 3 H, t-Bu), 0.01, –0.03 (2 s, 6H, SiMe2). 13C
NMR (CDCl3, 75.5 MHz) δ: 178.1 (s, CO2H), 136.4 (d, C-
1′), 115.7 (t, C-2′), 65.8 (s, C-2), 32.4 (s, C-1), 26.4 (t, C-3),
25.8, 18.2 (q, s, t-Bu), 14.9 (q, 1-Me), –3.42, –3.56 (2q,
SiMe2). Anal. calcd. for C13H24O3Si (256.4): C 60.84, H
9.70; found: C 60.93, H 9.43.
1-Allyl-c-2-tert-butyldimethylsiloxy-t-2-vinyl-r-1-cyclopro-
panecarboxylic acid (14)
According to general procedure 1, methyl cyclopropane-
carboxylate 9 (0.879 g, 2.96 mmol) and KOSiMe3 (1.12 g,
8.73 mmol) in toluene (20 mL) were heated for 2 h at
110 °C. After extraction with diethyl ether, the combined or-
ganic layers were successively washed with 2 N HCl, satd.
t-2-tert-Butyldimethylsiloxy-c-2-(1-phenylethenyl)-1-
methyl-r-1-cyclopropanecarboxylic acid (11)
According to general procedure 1, methyl cyclopropane-
carboxylate 6 (0.492 g, 1.42 mmol) and KOSiMe3 (0.528 g,
4.12 mmol) in toluene (14 mL) were heated for 2 h at
110 °C. Recrystallization of the crude product yielded 11
aq. NaHCO3, and water. Yield: 14 (0.413 g, 49%) as a color
-
less solid, mp 65–70 °C. IR (cm–1): 3450 (CO2H), 2960–
2930 (C-H), 1690 (C=O), 1650 (C=C), 1260 (Si-C). 1H
NMR (CDCl3, 300 MHz) δ: 5.94–5.80 (m, 2H, 1′-H, 2′′-H),
5.18 (dd, J = 17.2, 1.3 Hz, 1 H, 2′-H), 5.15 (dd, J = 10.7,
5 * Indicates that the signal has double intensity.
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Can. J. Chem. Vol. 82, 2004
1.3 Hz, 1 H, 2′-H), 5.10 (dd, J = 17.2, 1.7 Hz, 1H, 3′′-H),
5.02 (dd, J = 10.4, 1.7 Hz, 1H, 3′′-H), 2.90 (ddd, J = 15.6,
6.2, 1.3 Hz, 1H, 1′′-H), 2.27 (dd, J = 15.6, 6.8 Hz, 1H, 1′′-
H), 1.85 (d, J = 6.3 Hz, 1H, 3-Htrans), 1.09 (d, J = 6.3 Hz,
1H, 3-Hcis), 0.91 (s, 9 H, t-Bu), 0.12, 0.09 (2 s, 6H, SiMe2).
13C NMR (CDCl3, 75.5 MHz) δ: 177.7 (s, CO2H), 136.1,
135.6 (2d, C-1′, C-2′′), 116.0 (t, C-3"), 115.9 (t, C-2′), 66.0
(s, C-2), 36.9 (s, C-1), 32.5 (t, C-1"), 25.8, 18.2 (q, s, t-Bu),
24.3 (t, C-3), –3.4, –3.6 (2q, SiMe2). Anal. calcd. for
C15H26O3Si (282.4): C 63.80, H 9.28; found: C 63.78, H
9.33.
1.5 Hz, 1H, 2′-H), 1.85 (d, J = 6.2 Hz, 1H, 3-Htrans), 1.29 (s,
3H, 1-Me), 0.95 (d, J = 6.2 Hz, 1H, 3-Hcis), 0.79 (s, H, t-
Bu), 0.01, –0.03 (2s, 6H, SiMe2). 13C NMR (CDCl3,
75.5 MHz) δ: 179.3 (s, C=O), 135.7 (d, C-1′), 116.0 (t, C-2′),
67.0 (s, C-2), 35.4 (s, C-1), 26.7 (t, C-3), 25.8, 18.2 (q, s, t-
Bu), 14.9 (q, 1-Me), –3.5, –3.6 (2q, SiMe2).
t-2-tert-Butyldimethylsiloxy-c-2-(1-cyclohexenyl)-1-methyl-
r-1-cyclopropanecarbonyl azide (16)
According to general procedure 2, cyclopropanecar-
boxylic acid 10 (0.304 g, 0.979 mmol), NEt3 (0.124 g,
1.22 mmol) and DPPA (0.299 g, 1.09 mmol) in toluene
(3 mL) were stirred for 1 h at 0 °C. Filtration (diethyl ether/
pentane, 10:1) of the crude product yielded 0.248 g (76%)
16 as colorless crystals, mp 37–39 °C. IR (cm–1): 2950
Preparation of cyclopropanecarbonyl azide (general
procedure 2)
To a solution of the cyclopropanecarboxylic acid (1 equiv.)
in toluene (3–5 mL/mmol acid) was added NEt3 (1.3–
1.7 equiv.) and DPPA (1.1–1.7 equiv.). After stirring at 0 °C
for 1–3 h the solvent was removed in vacuo and the residue
was filtered (silica gel, diethyl ether/pentane).
1
(CH), 2135 (N3), 1695 (C=O), 1640 (C=C), 1250 (Si-C). H
NMR (CDCl3, 300 MHz) δ: 5.62 (mc, 1H, 2′-H), 2.26–2.09
(m, 1H, 3′-H), 2.00 (mc, 2H, 6′-H), 1.93 (d, J = 5.7 Hz, 1H,
3-Htrans), 1.59–1.47 (m, 5H, 3′-H, 4′-H, 5′-H), 1.37 (s, 3H, 1-
Me), 0.79 (s, 9H, tBu), 0.77 (d, J = 5.7 Hz, 1H, 3-Hcis), 0.07,
0.06 (2s, 6H, SiMe2). 13C NMR (CDCl3, 75.5 MHz) δ: 179.3
(s, C=O), 134.1 (s, C-1′), 127.0 (d, C-2′), 71.3 (s, C-2), 33.4
(s, C-1), 25.6, 18.1 (q, s, t-Bu), 25.8, 25.0, 22.6, 22.3 (4t, C-
3′ to C-6′), 14.9 (q, 1-Me), –3.9, –4.3 (2q, SiMe2). Anal.
calcd. for C17H29N3O2Si (284.5): C 60.86, H 8.71, N 12.52;
found: C 61.64, H 9.25, N 12.27. No better elemental analy-
sis could be obtained.
One-pot procedure for synthesis of 1,3-dihydroazepin-2-
ones (general procedure 3)
The corresponding cyclopropanecarboxylic acid (1 equiv.)
was dissolved in toluene (10–30 mL/mmol acid) and cooled
to 0 °C. After addition of NEt3 (5.2–6 equiv.) and DPPA
(1.8–3 equiv.) the mixture was allowed to warm up to room
temperature. The solution was stirred for 2 to 3 h at this
temperature and then heated to 80 °C for 2 to 3 h. Removal
of the solvent in vacuo gave the crude product that was puri-
fied by column chromatography (silica gel, heptane/EtOAc,
2:1 to 0:1) or by recrystallization (heptane/EtOAc).
2-Aza-1-oxo-3-methyl-5-tert-butyldimethylsiloxy-4,5-
dihydrobicyclo[4.5.0]decane (19)
Carbonyl azide 16 (0.206 g, 0.614 mmol) was heated in
toluene (5 mL) for 3 h to 80 °C under an argon atmosphere.
Removal of the solvent in vacuo and purification of the re-
sulting residue by recrystallization (heptane) gave 0.128 g
(68%) of azepinone 19 as colorless crystals, mp 125–
129 °C. IR (cm–1): 3420 (NH), 2940–2850 (CH), 1670
(C=O), 1640 (C=C), 1260 (Si-C). 1H NMR (CDCl3,
300 MHz) δ: 7.88 (br. s, 1H, NH), 5.49 (s, 1H, 4-H), 2.82–
2.78 (m, 1H, 9-H), 2.39 (d, J = 6.8 Hz, 1H, 9a-H), 2.24 (mc,
1H, 8-H), 1.96 (s, 3H, 3-Me), 1.84 (mc, 1H, 9-H), 1.71–1.61
(m, 3H, 7-H, 6-H), 1.51–1.44 (m, 1H, 8-H), 1.35–1.28 (m,
1H, 7-H), 0.92 (s, 9H, t-Bu), 0.07, 0.00 (2s, 6H, SiMe2). 13C
NMR (CDCl3, 75.5 MHz) δ: 172.8 (s, C=O), 143.8 (s, C-5),
133.6 (s, C-3), 112.5 (s, C-5a), 111.4 (d, C-4), 39.2 (d, C-
9a), 25.8, 18.1 (q, s, t-Bu), 23.7 (t, C-9), 23.2 (t, C-8), 22.9
(t, C-7), 22.1 (t, C-6), 21.8 (q, 3-Me), –3.9, -4.3 (2q, SiMe2).
Anal. calcd. for C17H29NO2Si (307.5): C 66.41, H 9.51, N
4.56: found: C 66.84, H 9.73, N 4.51.
t-2-tert-Butyldimethylsiloxy-1-methyl-c-2-vinyl-r-1-
cyclopropanecarbonyl azide (15)
Method A
To a solution of cyclopropanecarboxylic acid 13 (0.120 g,
0.503 mmol) in acetone (5 mL) NEt3 (0.074 g, 0.73 mmol)
and ethyl chloroformiate (0.084 g, 0.77 mmol) were slowly
added at 0 °C. After 20 min at 0 °C, NaN3 (0.060 g,
0.90 mmol) dissolved in water (5 mL) was added dropwise
to the solution and stirred at this temperature for a further
2 h. The reaction mixture was poured into a mixture of
ice/water and extracted with chloroform. The combined or-
ganic layers were washed with water and dried over Na2SO4.
Removal of the solvent in vacuo gave 0.076 g (54%) of 15
as colorless oil.
Method B
One-pot procedure
According to general procedure 2, cyclopropanecarboxy-
lic acid 13 (0.100 g, 0.39 mmol), NEt3 (0.190 g, 1.88 mmol)
and DPPA (0.266 g, 0.966 mmol) in toluene (5 mL) were
stirred for 1.5 h at 0 °C. The resulting mixture was diluted
with diethyl ether (25 mL) and water (5 mL) and the
aqueous phase was extracted with diethyl ether (2 × 20 mL).
The combined organic phases were washed with satd. aq.
NaHCO3 solution and brine (5 mL each) and dried
over MgSO4. Purification by flash chromatography
(heptane/EtOAc, 2:1) gave 0.024 g (22%) of 15 as a yellow
According to general procedure 3, cyclopropanecarboxy-
lic acid 10 (0.312 g, 1.00 mmol), NEt3 (0.526 g, 5.20 mmol)
and DPPA (0.523 g, 1.90 mmol) in toluene (10 mL) were
stirred for 1 h at 0 °C and then heated for 2.5 h to 80 °C. Pu-
rification by column chromatography (heptane/EtOAc, 2:1)
yielded 0.147 g (48%) azepinone 19 as colorless crystals,
mp 126–130 °C.
5-tert-Butyldimethylsiloxy-7-methyl-4-phenyl-1,3-
dihydroazepin-2-one (20)
1
oil and 0.116 g (43%) of DPPA. Compound 15: H NMR
(CDCl3, 300 MHz) δ: 5.73 (dd, J = 17.0, 10.7 Hz, 1H, 1′-H),
5.17 (dd J = 17.0, 1.5 Hz, 1H, 2′-H), 5.04 (dd, J = 10.7,
According to general procedure 3, cyclopropanecarboxy-
lic acid 11 (0.064 g, 0.192 mmol), NEt3 (0.112 g,
© 2004 NRC Canada

Reissig et al.
173
1.11 mmol), and DPPA (0.161 g, 0.585 mmol) in toluene
(5 mL) were stirred for 1 h at 0 °C and then heated for 2 h to
80 °C. Purification by column chromatography (heptane/
EtOAc, 2:1 to 0:1) yielded 0.030 g (47%) of azepinone 20 as
7-Allyl-3,4-dihydro-1H-azepin-2,5-dione (24) and 7-(E)-
(1-propenyl)-3,4-dihydro-1H-azepin-2,5-dione (25)
According to general procedure 3, cyclopropanecarboxy-
lic acid 14 (22) (0.074 g, 0.262 mmol), NEt3 (0.144 g,
1.42 mmol), and DPPA (0.161 g, 0.585 mmol) in toluene
(5 mL) were stirred for 1 h at 0 °C and then heated for 2 h to
80 °C. Purification by by column chromatography (heptane/
EtOAc, 1:1) yielded 0.018 g (42%) of a mixture of aze-
pindiones 24 and 25 as a colorless solid (ratio of 24:25, ca.
1
a colorless solid. H NMR (CDCl3, 300 MHz) δ: 7.90 (br. s,
1H, NH), 7.68–7.28 (m, 5H, Ph), 5.78 (s, 1H, 6-H), 3.24 (s,
2H, 3-H), 2.21 (s, 3H, 7-Me), 0.93 (s, 9H, t-Bu), 0.15 (s, 6H,
SiMe2). 13C NMR (CDCl3, 75.5 MHz) δ: 169.8 (s, C=O),
145.2 (s, C-5), 139.5 (s, C-7), 134.7, 128.5, 127.7, 126.2 (s,
3d, Ph), 112.7 (d, C-6), 111.3 (s, C-4), 39.7 (t, C-3), 25.6,
18.0 (q, s, t-Bu), 22.2 (q, 7-Me), -4.3 (q, SiMe2). Anal.
calcd. for C19H27NO2Si (329.5): C 69.26, H 8.26, N 4.25;
found: C 68.68, H 7.89, N 4.40.
1
1:1.2). Signals assigned to compound 24: H NMR (CDCl3,
500 MHz) δ: 7.80 (br. s, 1H, NH), 5.79 (mc, 1H, 2′-H), 5.50
(s, 1H, 6-H), 5.26 (dd, J = 7.8, 1.3 Hz, 1H, 3′-H), 2.84–2.63
(m, 4H, 3-H, 4-H).
Isomerization of 24 to 25
5-tert-Butyldimethylsiloxy-4,7-dimethyl-1,3-dihydroazepin-
2-one (21)
The mixture of 24/25 (0.016 g, 0.097 mmol) was stirred
with NEt3 (5 drops) in dichloromethane (2 mL) at room tem-
perature for 24 h. Removal of the solvent in vacuo and puri-
fication of the residue by column chromatography
(heptane/EtOAc, 1:2) yielded 0.016 g (37% from 14) of
According to general procedure 3, cyclopropanecarboxylic
acid 12 (0.600 g, 2.22 mmol), NEt3 (1.35 g, 13.3 mmol), and
DPPA (1.16 g, 4.13 mmol) in toluene (20 mL) were stirred
for 1 h at 0 °C and then heated for 3 h to 80 °C. Purification
by column chromatography (hexane/EtOAc, 4:1 to 1.1)
yielded 0.445 g (75%) of azepinone 21 as colorless needles,
mp 141–143 °C. IR (cm–1): 3500 (NH), 1685 (C=O), 1650
(C=C), 1250 (Si-C), 1200 (C-O). 1H NMR (CDCl3,
300 MHz) δ: 7.45 (br. s, 1H, NH), 5.39 (s, 1H, 6-H), 2.61 (s,
2H, 3-H), 1.90, 1.75 (2 s, 3H each, 4-Me, 7-Me), 0.86 (s,
9H, t-Bu), 0.00 (s, 6H, SiMe2). 13C NMR (CDCl3,
75.5 MHz) δ: 169.0 (s, C=O), 144.1 (s, C-5), 133.3 (s, C-7),
111.9 (d, C-6), 108.6 (s, C-4), 39.9 (t, C-3), 25.7, 18.1 (q, s,
t-Bu), 21.9, 17.5 (2q, 4-Me, 7-Me), –4.1 (q, SiMe2). Anal.
calcd. for C14H25NO2Si (267.4): C 62.87, H 9.42, N 5.24;
found: C 62.73, H 9.18, N 5.20.
1
azepindione 25 as colorless crystals, mp 122–130 °C. H
NMR (CDCl3, 500 MHz) δ: 7.64 (br. s, 1H, NH), 6.31 (dq,
J = 15.7, 6.8 Hz, 1H, 2′-H), 5.94 (dd, J = 15.7, 1.6 Hz, H, 1′-
H), 5.53 (s, 1H, 6-H), 2.73 (mc, 2H, 3-H), 2.32 (mc, 2H, 4-
H), 1.89 (dd, J = 6.8, 1.6 Hz, 3H, 3′-H). 13C NMR (CDCl3,
126 MHz) δ: 197.7 (s, C-5), 174.1 (s, C-2), 142.8 (s, C-7),
133.9 (d, C-1′), 128.7 (d, C-2′), 112.0 (d, C-6), 36.3 (t, C-3),
30.6 (t, C-4), 18.5 (q, C-3′). Due to the small amount of 25
no further characterization was possible.
t-2-tert-Butyldimethylsiloxy-1-methyl-c-2-phenyl-r-1-
cyclopropanecarboxylic acid (27)
According to general procedure 1, the corresponding
methyl cyclopropanecarboxylate (0.173 g, 0.540 mmol) and
KOSiMe3 (0.209 g, 1.62 mmol) in toluene (5 mL) were
heated for 2.5 h to 100 °C and yielded 27 (0.144 g, 83%) as
light yellow crystals, mp 140–145 °C (recrystallization from
heptane/EtOAc). IR (cm–1): 3450 (CO2H), 2960 (CH), 1690
5-tert-Butyldimethylsiloxy-7-methyl-1,3-dihydroazepin-2-
one (22) and 7-methyl-3,4-dihydro-1H-azepin-2,5-dione (23)
According to general procedure 3, cyclopropanecar-
boxylic acid 13 (0.261 g, 1.02 mmol), NEt3 (0.543 g,
5.47 mmol), and DPPA (0.502 g, 1.82 mmol) in toluene
(30 mL) were stirred for 1 h at 0 °C and then heated for
2 h to 80 °C. Purification by column chromatography
(heptane/EtOAc, 4:1 to 1:3) yielded 0.056 g (23%) of
azepinone 22 as a colorless solid and 0.037 g (27%) of
azepindione 23 as colorless crystals, mp 179–184 °C. Com-
pound 22: IR (cm–1): 3400 (NH), 2950–2800 (CH), 1690
(C=O), 1640 (C=C), 1430 (C-O), 1235 (Si-C). 1H NMR
(CDCl3, 300 MHz) δ: 8.26 (br. s, 1H, NH), 5.33 (s, 1H, 6-
H), 4.66 (t, J = 7 Hz, 1H, 4-H), 2.59 (d, J = 7 Hz, 2H, 3-H),
1.87 (s, 3H, 7-Me), 0.79 (s, 9H, t-Bu), 0.00 (s, 6H, SiMe2).
13C NMR (CDCl3, 75.5 MHz) δ: 170.0 (s, C=O), 151.3 (s,
C-5), 135.5 (s, C-7), 111.0 (d, C-6), 97.8 (d, C-4), 33.1 (t,
C-3), 25.7, 18.2 (q, s, t-Bu), 22.2 (q, 7-Me), –4.7, –4.9 (2q,
SiMe2). Anal. calcd. for C13H23NO2Si (253.4): C 61.61, H
9.15, N 5.53; found: C 59.13, H 9.00, N 9.88. No better ele-
mental analysis could be obtained. Compound 23: IR (cm–1):
1
(C=O), 1255 (SiC). H NMR (CDCl3, 300 MHz) δ: 7.32–
7.21 (m, 5H, Ph), 2.16 (d, J = 6.0 Hz, 1H, 3-Htrans), 1.51 (s,
3H, 1-Me), 1.01 (d, J = 6.0 Hz, 1H, 3-Hcis), 0.83 (s, 9H, t-
Bu), 0.00, –0.37 (2s, 6H, SiMe2). 13C NMR (CDCl3,
75.5 MHz) δ: 178.4 (s, CO2H), 138.8, 128.7, 127.7, 127.6 (s,
3d, Ph), 67.7 (s, C-2), 31.8 (s, C-1), 25.6, 18.0 (q, s, t-Bu),
24.8 (t, C-3), 14.8 (q, 1-Me), –4.2*5 (q, SiMe2). Anal. calcd.
for C17H26O3Si (306.5): C 66.62, H 8.55; found: C 67.06, H
8.67.
t-2-tert-Butyldimethylsiloxy-1-methyl-c-2-phenyl-r-1-cyclo-
propanecarbonyl azide (28)
According to general procedure 2, cyclopropanecar-
boxylic acid 27 (0.301 g, 0.982 mmol), NEt3 (0.158 g,
1.56 mmol), and DPPA (0.300 g, 1.09 mmol) in toluene
(5 mL) were stirred for 1 h at 0 °C. Filtration (pentane/di-
ethyl ether, 10:1) of the crude product yielded 0.226 g (70%)
of 28 as colorless crystals, mp 40–42 °C. IR (cm–1): 2900
(CH), 2145 (N3), 1695 (C=O), 1255 (SiC). 1H NMR
(CDCl3, 300 MHz) δ: 7.32–7.23 (m, 5H, Ph), 2.35 (d, J =
6.1 Hz, 1H, 3-Htrans), 1.56 (s, 3H, 1-Me), 1.11 (d, J =
6.1 Hz, 1H, 3-Hcis), 0.84 (s, 9H, t-Bu), 0.01, –0.36 (2 s, 6H,
SiMe2). 13C NMR (CDCl3, 75.5 MHz) δ: 179.2 (s, C=O),
138.3, 128.8, 128.0, 127.8 (s, 3d, Ph), 68.9 (s, C-2), 34.8 (s,
1
3400 (NH), 2950 (CH), 1700 (C=O), 1650, 1615 (C=C). H
NMR (CDCl3, 300 MHz) δ: 8.23 (br. s, 1H, NH), 5.47 (s,
1H, 6-H), 2.72 (mc, 4H, 3-H, 4-H), 2.07 (s, 3H, 7-Me). 13C
NMR (CDCl3, 75.5 MHz) δ: 196.9 (s, C-5), 174.8 (s, C-2),
145.9 (s, C-7), 111.7 (d, C-6), 35.5, 30.3 (2t, C-3, C-4), 24.3
(q, 7-Me). Anal. calcd. for C7H9NO2 (139.1): C 60.42, H
6.52, N 10.07; found: C 60.34, H 6.76, N 10.03.
© 2004 NRC Canada

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Can. J. Chem. Vol. 82, 2004
C-1), 25.5, 17.9 (q, s, t-Bu), 25.4 (t, C-3), 14.9 (q, 1-Me),
–4.2 (q, SiMe2). Anal. calcd. for C17H25N3O2Si (331.5): C
61.60, H 7.60, N 12.68; found: C 62.08, H 7.54, N 12.40.
4.9 Hz, 1H, 3-Hcis). 13C NMR (CDCl3, 75.5 MHz) major
isomer, δ: 170.8, 51.5 (s, q, CO2Me), 139.1 (s, C-1′), 145.5,
138.1, 128.3, 127.9, 127.8, 127.1, 126.5, 126.3 (2s, 6d, Ph),
114.9 (t, C-2′), 40.0 (s, C-2), 27.6 (d, C-1), 17.8 (t, C-3); mi-
nor isomer δ: 170.7, 51.5 (s, q, CO2Me), 150.7, 143.1 (2s,
Ph), 139.3 (s, C-1′), 129.4, 128.0, 127.7, 127.5, 127.3, 126.7
(6d, Ph), 118.0 (t, C-2′), 38.7 (s, C-2), 29.8 (d, C-1), 23.1 (t,
C-3). Anal. calcd. for C19H18O2 (278.4): C 81.98, H 6.52;
found: C 81.68, H 6.66.
t-2-tert-Butyldimethylsiloxy-1-methyl-c-2-phenyl-r-1-
cyclopropylisocyanate (29)
Carbonyl azide 28 (0.126 g, 0.380 mmol) was heated in
toluene (3 mL) for 2 h at 80 °C under an argon atmosphere.
Removal of the solvent in vacuo and purification of the re-
sulting crude product by filtration (silica gel, diethyl
ether/pentane) gave 0.102 g (88%) of isocyanate 29 as a red-
dish oil. IR (cm–1): 3080–2880 (CH), 2235 (NCO). 1H NMR
(CDCl3, 300 MHz) δ: 7.43–7.25 (m, 5H, Ph), 1.64 (s, 3H, 1-
Me), 1.62 (d, J = 7.2 Hz, 1H, 3-Htrans), 1.03 (d, J = 7.2 Hz,
1H, 3-Hcis), 0.84 (s, 9H, t-Bu), 0.00, –0.31 (2s, 6H, SiMe2).
13C NMR (CDCl3, 75.5 MHz) δ: 138.7, 128.6, 128.4, 128.3
(s, 3d, Ph), 120.4 (br. s, NCO), 65.1 (s, C-2), 41.6 (s, C-1),
25.4 (t, C-3), 25.6, 17.9 (q, s, tBu), 19.8 (q, 1-Me), –3.7,
–4.0 (2q, SiMe2). Anal. calcd. for C17H25NO2Si (303.5): C
67.29, H 8.30, N 4.68; found: C 67.26, H 8.25, N 4.56.
t/c-2-Phenyl-c/t-2-(1-phenylethenyl)-r-1-cyclopropanecar-
boxylic acid (32)
Methyl cyclopropanecarboxylate 31 (1.94 g, 6.95 mmol,
ratio of isomers = 47:53) was added to a solution of KOH
(1.52 g, 25.0 mmol) in methanol (30 mL) and heated for 5 h
under reflux. After removal of the solvent in vacuo, water
was added to the residue and extracted several times with di-
ethyl ether. The aqueous layer was acidified with a 2 N HCl
solution under ice cooling to pH 2 to 3, extracted with di-
ethyl ether (5 times), and the combined organic layers were
dried over Na2SO4. Purification of the crude product by
recrystallization (methanol) gave 32 (1.52 g, 83%, cis:trans
= 45:55) as a colorless solid, mp 154–156 °C. For analytical
data of cis- and trans-32 see the next section.
3-Methyl-2H-benzo[c]azepin-2,5-dione (30)
Analogously to ref. 23, isocyanate 29 (0.058 g,
0.185 mmol) was treated with boron trifluoride etherate
(1 mL, ≈0.8 mmol) at 0 °C for 2.5 h. The reaction mixture
was allowed to warm to room temperature and was then
quenched with water (2 mL). The aqueous phase was ex-
tracted several times with diethyl ether and the combined
organic phases were dried over MgSO4. Purification of the
resulting crude product by column chromatography
(chloroform/methanol, 60:1) yielded 10 mg (28%) of
azepindione 30 as colorless needles, mp 150–155 °C (lit.
Iodolactonization of carboxylic acid cis-32
According to a procedure described in the literature (17)
cyclopropanecarboxylic acid 32 (1.61 g, 6.09 mmol,
cis:trans = 48:52) was dissolved in a 1:1 mixture of
1.6 mol/L NaHCO3 and satd. aq. Na2CO3 solution (6 mL
each) and cooled to 0 °C. To this mixture a 0.7 mol/L solu-
tion of I2 in 2.5 mol/L KI solution (5.6 mL, 3.92 mmol) was
added dropwise over a period of 3 h. After stirring for
30 min at this temperature the precipitate (iodolactone 33)
was filtered off and washed with water. The resulting filtrate
was extracted twice with chloroform, acidified with a 2 N
HCl solution, and finally extracted with diethyl ether. Both
organic phases were combined and dried over MgSO4 and
the solvent was removed to provide trans-32. Yield: 0.798 g
(34%, with respect to cis-32: 71%) of iodolactone 33 as a
solid, mp 59–64 °C, and 0.466 g (29%, with respect to
trans-32: 56%) of trans-32 as a colorless oil.
1
(16) mp 120–122 °C). H NMR (CDCl3, 500 MHz) δ: 8.10–
8.04 (m, 2H, Ar), 7.74–7.66 (m, 1H, Ar), 7.58–7.50 (m, 1H,
Ar), 7.50 (br. s, 1H, NH), 6.57 (s, 1H, 6-H), 2.41 (s, 3H, 7-
Me). 13C NMR (CDCl3, 126 MHz) δ: 192.5 (s, C-5), 182.9
(s, C-2), 135.4, 131.2, 129.2, 129.0, 128.9, 128.6, 128.3 (3s,
4d, Ar, C-7), 97.4 (d, C-6), 24.8 (q, 7-Me). Due to the low
amount of 30 no further characterization could be per-
formed.
Methyl t/c-2-phenyl-c/t-2-(1-phenylethenyl)-r-1-cyclopro-
panecarboxylate (31)
Cyclopropane 31 was prepared according to the general
procedure described in the literature (21) by slow addition of
methyl diazoacetate (2.88 g, 28.0 mmol) to a refluxing sus-
pension of Cu(acac)2 (0.131 g, 0.500 mmol) and 2,3-
diphenyl-1,3-butadiene (5.15 g, 25.0 mmol) in EtOAc
(80 mL) (reaction time: 19 h). Purification was achieved by
column chromatography (silica gel, heptane/EtOAc (6:1)).
Fraction 1: 1.98 g (39%) starting material; fraction 2: 3.38 g
(48%) of 31 (ratio of isomers = 57:43) as a colorless oil. IR
(cm–1): 3090 (CH), 1735 (C=O), 1380, 1170 (C-O). 1H
NMR (CDCl3, 300 MHz) major isomer δ: 7.42–7.14 (m,
10H, Ph), 5.46 (s, 2H, 2′-H), 3.41 (s, 3H, CO2Me), 2.52 (dd,
J = 8.2, 5.8 Hz, 1H, 1-H), 2.17 (dd, J = 6.1, 5.8 Hz, 1H, 3-
4-Iodomethyl-4,5-diphenyl-3-oxa-bicyclo[3.1.0]hexan-2-
one (33)
A 1:1 mixture of two diastereomers. IR (cm–1): 1765
(C=O), 1445, 1185, 990, 965, 760. 1H NMR (CDCl3,
300 MHz) δ: 7.45–7.08 (m, 20H, Ph), 3.96, 3.86, 3.72, 3.53
(4 d, J = 11.4 Hz, 1H each, 4-CH2), 2.53 (dd, J = 8.4,
4.2 Hz, 1H, 1-H*6), 2.47 (dd, J = 9.0, 3.1 Hz, 1H, 1-H*6),
1.75 (dd, J = 4.9, 3.1 Hz, 1H, 6-H*6), 1.37–1.30 (m, 3H, 6-
H*6). 13C NMR (CDCl3, 75.5 MHz) δ: 174.3, 174.2 (2 s,
C=O), 139.5, 139.4, 134.4, 134.2, 131.5, 130.7, 129.0,
128.7, 128.5, 128.4, 128.3, 128.3, 128.1, 127.9, 125.7, 125.0
(4s, 12d, Ph), 88.1, 86.5 (2s, C-5), 42.3, 40.4 (2s, C-4),
25.9*5 (d, C-1), 19.2, 19.0 (2t, C-6), 14.3, 7.9 (2t, C-1′) HR-
MS (80 eV) calcd. for C18H25O2I: 390.0117; found:
390.0132.
H
trans), 1.46 (dd, J = 8.2, 6.1 Hz, 1H, 3-Hcis); minor isomer
δ: 7.42–7.14 (m, 10H, Ph), 5.89, 5.49 (2s, 1H each, 2′-H),
3.37 (s, 3H, CO2Me), 2.60 (dd, J = 8.1, 6.2 Hz, 1H, 1-H),
2.00 (dd, J = 6.2, 4.9 Hz, 1H, 3-Htrans), 1.54 (dd, J = 8.1,
6 * Indicates that the assignment may be exchanged.
© 2004 NRC Canada

Reissig et al.
175
3-H). 13C NMR (CDCl3, 75.5 MHz) δ: 168.1 (s, C-2), 140.8,
140.0, 135.8, 128.2 (4s, Ph, C-4, C-5), 130.1, 120.0, 127.9,
127.8, 127.0, 126.8, 125.6 (7d, Ph, C-7), 118.3 (d, C-6),
44.2 (t, C-3). Anal. calcd. for C18H15NO (261.3): C 82.37, H
5.78, N 5.36; found: C 82.01, H 5.70, N 5.26.
c-2-Phenyl-t-2-(1-phenylethenyl)-r-1-cyclopropanecarboxy-
lic acid (trans-32)
1H NMR (CDCl3, 300 MHz) δ: 7.44–7.09 (m, 10H, Ph),
6.90 (br. s, 1H, CO2H), 5.44 (s, 2H, 2′-H), 2.47 (dd, J = 8.1,
5.8 Hz, 1H, 1-H), 2.11 (t, J = 5.5 Hz, 1H, 3-Htrans), 1.50 (dd,
J = 8.1, 4.9 Hz, 1H, 3-Hcis). Anal. calcd. for C18H16O2
(264.3): C 81.79, H 6.10; found: C 81.61, H 6.10.
4,5-Dimethyl-1,3-dihydro-azepin-2-one (37)
According to general procedure 2, cyclopropanecarboxy-
lic acid cis-34 (0.240 g, 1.71 mmol), NEt3 (0.288 g,
2.85 mmol), and DPPA (0.554 g, 2.01 mmol) in toluene
(5 mL) were stirred for 3 h at 0 °C. Filtration (diethyl
ether/pentane 20:1) of the crude product yielded 0.194 g
(70%) of c-2-isopropenyl-t-2-methyl-r-1-cyclopropanecar-
bonyl azide as a colorless oil. IR (cm–1): 2975 (CH), 2160
(N3), 1705 (C=O), 1650 (C=C), 1375, 1195. 1H NMR
(CDCl3, 300 MHz) δ: 4.96 (q, J = 1.5 Hz, 1H, 2′-H), 4.91 (s,
1H, 2′-H), 1.73 (br. s, 3H, 1′-Me), 1.70–1.64 (m, 2H, 1-H, 3-
H), 1.29 (s, 3H, 2-Me), 1.11–1.07 (m, 1H, 3-H). 13C NMR
(CDCl3, 75.5 MHz) δ: 177.4 (s, C=O), 143.3 (s, C-1′), 114.3
(t, C-2′), 37.0 (s, C-2), 30.4, 25.1, 20.8 (d, 2q, C-1, 1′-Me, 2-
Me), 22.3 (t, C-3). Anal. calcd. for C8H11N3O (165.2): C
58.17, H 6.71, N 25.44; found: C 57.39, H 6.61, N 23.42.
The crude product (0.042 g, 0.274 mmol) was heated in
toluene (2 mL) for 2 h to 100 °C under an argon atmo-
sphere. Removal of the solvent gave 0.033 g (88%) of
azepinone 37 as a colorless solid. 1H NMR (CDCl3,
300 MHz) δ: 8.26 (br. s, 1H, NH), 6.09 (dd, J = 8.8, 4.4 Hz,
1H, 7-H), 5.73 (d, J = 8.8 Hz, 1H, 6-H), 2.78 (s, 2H, 3-H),
1.91, 1.80 (2s, 3H each, 4-Me, 5-Me). 13C NMR (CDCl3,
75.5 MHz) δ: 168.3 (s, C-2), 127.9, 124.4 (2d, C-6, C-7),
122.7, 111.9 (2s, C-4, C-5), 43.7 (t, C-3), 20.7, 17.9 (2q, 4-
Me, 5-Me). Due to the low amount of 37 no elemental anal-
ysis could be performed.
t-2-Phenyl-c-2-(1-phenylethenyl)-r-1-cyclopropanecarboxy-
lic acid (cis-32)
According to a procedure described in the literature (18)
zinc dust (0.395 g, 6.23 mmol) was added to a hot solution
of AgOAc (0.0039 g, 0.0234 mmol) and glacial acid (15
drops) and stirred for 30 min. After removal of the glacial
acid the residue was washed with diethyl ether (5 times). To
the resulting Ag/Zn couple were added the iodolactone 33
(0.700 g, 1.79 mmol) dissolved in diethyl ether (15 mL),
ethanol (4.25 mL), and few drops of glacial acid and the sus-
pension was heated under reflux for 7 h. The cooled suspen-
sion was filtered and the filtrate was successively washed
with satd. aq. NaHCO3 solution and brine. Drying of the or-
ganic layer with MgSO4 and removal of the solvent gave
0.146 g of the crude product, which was purified by column
chromatography (heptane/EtOAc, 4:1). Yield: 0.327 g (69%)
of cis-32 as a colorless oil. IR (cm–1): 3400 (CO2H), 2925
(CH), 1700 (C=O), 1440, 1225. 1H NMR (CDCl3, 300 MHz)
δ: 10.21 (br. s, 1H, CO2H), 7.36–7.13 (m, 10H, Ph), 5.76,
5.42 (2s, 1H each, 2′-H), 2.52 (dd, J = 8.1, 6.1 Hz, 1H, 1-H),
1.90 (dd, J = 6.1, 5.0 Hz, 1H, 3-Htrans), 1.56 (dd, J = 8.1,
5.0 Hz, 1H, 3-Hcis). 13C NMR (CDCl3, 75.5 MHz) δ: 176.9
(s, C=O), 145.2 (s, C-1′), 142.9, 139.5, 128.4, 128.0, 127.6,
127.4, 126.7, 126.5 (2s, 6d, Ph), 118.1 (t, C-2′), 39.8 (s, C-
2), 36.1 (d, C-1), 23.1 (t, C-3). HR-MS (80 eV) calcd.:
264.1150; found: 264.1163. Anal. calcd. for C18H16O2
(264.3): C 81.79, H 6.10; found: C 80.93, H 6.17.
4,5,7-Trimethyl-1,3-dihydroazepin-2-one (38)
According to general procedure 2, cyclopropanecar-
boxylic acid cis-35 (0.254 g, 1.65 mmol), NEt3 (0.231 g,
2.28 mmol), and DPPA (0.488 g, 1.77 mmol) in toluene
(5 mL) were stirred for 1 h at 0 °C. Filtration (diethyl
ether/pentane, 20:1) of the crude product yielded 0.159 g
(53%) of c-2-isopropenyl-t-1,2-dimethyl-r-1-cyclopropane-
carbonyl azide as a colorless oil. IR (cm–1): 2970 (CH),
2135 (N3), 1705 (C=O), 1680 (C=C). 1H NMR (CDCl3,
300 MHz) δ: 4.84, 4.01 (2m, 1H each, 2′-H), 1.90 (d, J =
4.8 Hz, 1H, 3-Htrans), 1.73 (br. s, 3H, 1′-Me), 1.40, 1.32 (2s,
3H each, 2-Me, 1-Me), 0.68 (d, J = 4.8 Hz, 1H, 3-Hcis). 13C
NMR (CDCl3, 75.5 MHz) δ: 180.3 (s, C=O), 145.3 (s, C-1′),
113.3 (t, C-2′), 38.2 (s, C-2), 32.4 (s, C-1), 27.0 (t, C-3),
20.8, 20.7, 16.0 (3q, 2-Me, 1′-Me, 1-Me). Anal. calcd. for
C9H13N3O (179.2): C 60.32, H 7.31, N 23.45; found: C
60.53, H 7.89, N 21.70.
4,5-Diphenyl-1,3-dihydroazepin-2-one (36)
According to general procedure 2, cyclopropanecarboxy-
lic acid cis-32 (0.258 g, 0.976 mmol), NEt3 (0.335 g,
3.32 mmol), and DPPA (0.170 g, 1.68 mmol) in toluene
(20 mL) were stirred for 2 h at 0 °C. Filtration (diethyl
ether/pentane, 20:1) of the crude product yielded 0.184 g
(65%) of t-2-phenyl-c-2-(1-phenylethenyl)-r-1-cyclopropane-
carbonyl azide as a colorless oil. IR (cm–1): 3060, 2950
(CH), 2135 (N3), 1710 (C=O), 1495 (CH). 1H NMR (CDCl3,
300 MHz) δ: 7.39–7.16 (m, 10H, Ph), 5.92, 5.50 (2 s, 1H
each, 2′-H), 2.58 (dd, J = 8.0, 6.1 Hz, 1H, 1-H), 2.08 (dd,
J = 6.1, 5.0 Hz, 1H, 3-Htrans), 1.64 (dd, J = 8.0, 5.0 Hz, 1H,
3-Hcis). 13C NMR (CDCl3, 75.5 MHz) δ: 176.5 (C=O), 144.6
(s, C-1′), 142.2, 139.0, 128.4, 128.0, 127.5, 126.7, 126.6,
126.3 (2s, 6d, Ph), 118.6 (t, C-2′), 41.5 (s, C-2), 32.3 (d, C-
1), 24.4 (t, C-3). Anal. calcd. for C18H15N3O (298.3): C
74.72, H 5.22, N 14.52; found: C 74.46, H 5.13, N 13.86.
The azide (0.192 g, 0.446 mmol) was heated in toluene
(10 mL) for 2 h to 100 °C under an argon atmosphere. Re-
moval of the solvent in vacuo and purification of the result-
ing product by recrystallization (heptane/EtOAc) gave
0.098 g (84%) of azepinone 36 as colorless crystals, mp
181–183 °C. IR (cm–1): 3205 (NH), 3080 (CH), 1675
The azide (0.068 g, 0.379 mmol) was heated in toluene
(3 mL) for 2 h to 80 °C under an argon atmosphere. Re-
moval of the solvent in vacuo and recrystallization
(heptane/EtOAc) gave 0.045 g (79%) of azepinone 38 as col-
orless crystals, mp 130–132 °C. IR (cm–1): 3500–3400 (NH)
3080, 2950–2850 (CH), 1650 (C=O), 1610 (C=C), 1380
1
(CH). H NMR (CDCl3, 300 MHz) δ: 8.36 (br. s, 1H, NH),
5.56 (s, 1H, 6-H), 2.76 (s, 2H, 3-H), 1.99, 1.87, 1.75 (3s, 3H
each, 4-Me, 5-Me, 7-Me). 13C NMR (CDCl3, 75.5 MHz) δ:
167.7 (s, C-2), 131.7, 127.9, 122.2 (3s, C-4, C-5, C-7), 117.3
(d, C-6), 43.4 (t, C-3), 22.1, 20.4, 18.0 (3q, 4-Me, 5-Me, 7-
1
(C=O), 1625 (C=C). H NMR (CDCl3, 300 MHz) δ: 9.18
(br. s, 1H, NH), 7.43–6.93 (m, 10H, 2 Ph), 6.36 (dd, J = 8.9,
4.7 Hz, 1H, 7-H), 5.96 (d, J = 8.9 Hz, 1H, 6-H), 3.38 (s, 2H,
© 2004 NRC Canada

176
Can. J. Chem. Vol. 82, 2004
Me). Anal. calcd. for C9H13NO. 0.75 H2O (164.7): C 65.63,
H 8.87, N 8.50; found: C 65.91, H 8.69, N 8.38.
7. G. Böttcher. Ph.D. Dissertation, Technische Universität
Dresden, Dresden, Germany.1999.
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466 (1970); (b) P. Müller and H. Imogai. Helv. Chim. Acta,
82, 315 (1999); (c) T.T. Raj and M.R. Eftink. Synth. Commun.
28, 3787 (1998); our preliminary communication: G. Böttcher
and H.-U. Reissig. Synlett, 725 (2000).
10. E. Kunkel, I. Reichelt, and H.-U. Reissig. Liebigs Ann. Chem.
512 (1984).
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(1982); for more details see ref. 4a.
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Acknowledgements
Generous support of this work by the Deutsche
Forschungsgemeinschaft (Struktur-Eigenschafts-Beziehungen
bei Heterocyclen) and the Fonds der Chemischen Industrie is
gratefully appreciated. We thank Ute Hain and Luise
Schefzig for experimental assistance, Dr. Margit Gruner for
measurements and help during interpretations of numerous
NMR spectra and, in particular, Prof. Dr. Jürgen Fabian and
Dr. Dirk Sperling for the DFT calculation and their interest
in this and related types of cyclopropane rearrangements.
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© 2004 NRC Canada