Unusual skeletal rearrangement of unsaturated seven-membered lactams into fused pyrrolidinolactones

Article abstract of DOI:10.1002/ejoc.201300136

Unsaturated ε-lactams undergo a novel process involving a skeletal reorganization to give fused pyrrolidine-lactones by reaction with aromatic α-bromo ketones in the presence of 1,4-diazabicyclo[2.2.2]octane and a base. The process involves the formation

Full text of DOI:10.1002/ejoc.201300136

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FULL PAPER
DOI: 10.1002/ejoc.201300136
Unusual Skeletal Rearrangement of Unsaturated Seven-Membered Lactams
into Fused Pyrrolidinolactones
Silvia Álvarez,[a] Gema Domínguez,[a] Ana Gradillas,[a] and Javier Pérez-Castells*[a]
Keywords: Nitrogen heterocycles / Lactones / Lactams / Ylides / Diastereoselectivity / Rearrangement
Unsaturated ε-lactams undergo a novel process involving a
skeletal reorganization to give fused pyrrolidine-lactones by
reaction with aromatic α-bromo ketones in the presence of
1,4-diazabicyclo[2.2.2]octane and a base. The process in-
volves the formation of an ammonium salt and subsequently
a nitrogen ylide, which initiates the rearrangement reaction.
This species reduces undesired side-reactions such as
double-bond shifts or Morita–Baylis–Hilman-type processes.
The resulting products are structurally related to kainoids
and the transformation of the lactone moiety in the re-
arranged product paves the way to the synthesis of these po-
tentially bioactive natural products and their derivatives.
Introduction
Skeletal rearrangements are among the most fascinating
chemical transformations and the understanding of their re-
action mechanisms is often a challenge. In the course of our
studies on the synthesis of highly functionalized cyclopro-
panes by the cyclopropanation of unsaturated lactams with
nitrogen ylides, we discovered an unprecedented rearrange-
ment of a seven-membered unsaturated lactam.[1] This pro-
cess led to a bicyclic homoallylamine fused to a lactone ring
structurally related to natural products such as kainic acid
or radicamines (Scheme 1).
(–)-α-Kainic acid has attracted attention because of its
neuroexcitatory properties and also its insecticidal and an-
thelmintic activities.[2] The potent neuroexcitatory activity
of kainic acid is attributed to its action as a conformation-
ally restricted analogue of glutamic acid. The synthesis of
this product and potentially active derivatives will continue
to attract the attention of synthetic chemists for years to
come.[3] Some aryl kainic acid analogues have been reported
to show activity towards the human GluR6 receptor.[4] Ra-
dicamines A and B, isolated from Lobelia chinensis Lour,[5]
are pyrrolidine alkaloids that exhibit α-glucosidase inhibi-
tion and have received considerable synthetic attention.[6]
Therefore this new rearrangement could be a really inter-
esting chemical tool because it presents a new and unknown
reactivity. Herein we present all our synthetic efforts to in-
Scheme 1. Rearrangement of a seven-membered unsaturated lac-
tam to give homolallylamine 4a and structures of related natural
and bioactive products.
vestigate the scope and limitations of this new process by
varying the α-bromo ketone, the protecting group and the
ring size of the unsaturated lactam employed. We also envi-
sioned investigating the potential of applying this process,
as a starting point, to the synthesis of analogues of natural
products containing the pyrrolidine core. A plausible
mechanism for this reaction is proposed that postulates the
participation of nitrogen ylides as reagents. In addition to
the synthetically important phosphonium and sulfonium
ylides, ammonium ylides have been developed and reviewed
in recent years as important precursors in organic chemis-
try.[7] Although they are involved in many different types of
reactions, the cyclopropanation of activated double bonds
with nitrogen ylides is probably the most useful synthetic
reaction in which these species are involved.[8]
[a] Departamento de Química, Facultad de Farmacia, Universidad
San Pablo-CEU,
Urb. Montepríncipe, 28668 Boadilla del Monte, Madrid, Spain
Fax: +34-913-510496
E-mail: jpercas@ceu.es
Homepage:
http://ww2.uspceu.es/pro/pg/
verpg.aspx?cip=NTA3MTc1NDY=
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300136.
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Table 1. Scope of the rearrangement reaction of lactams 2.
Results and Discussion
To extend the study of the rearrangement of seven-mem-
bered unsaturated lactams, we optimized the synthesis of
the starting materials, the unsaturated lactams 2, by the
route shown in Scheme 2. The choice of the nitrogen pro-
tecting group was important because electron-withdrawing
properties seem to be necessary for the initiation of the re-
arrangement process. Thus, we prepared unsaturated lact-
ams 2a–d bearing sulfonamides and carbamate protecting
groups. ε-Caprolactam was transformed into compounds
1a and 1b, which were converted into the corresponding
α,β-unsaturated analogues by seleniation of the lactam
enolates, oxidation into the corresponding selenoxide and
elimination. Oxidation of the selenide with aqueous hydro-
gen peroxide generated the selenoxide, which spontaneously
eliminated PhSeOH to give the desired compounds in better
global yields than when the oxidation was performed with
m-CPBA.[9] In addition, we prepared the eight-membered
unsaturated lactam 2c following the same methodology
starting from azocin-2(1H)-one. For the synthesis of (+)-
2d it was necessary to carry out the protection step after
constructing the unsaturated lactam as the selenation pro-
cess did not take place with N-camphorsulfonylcaprolac-
tam. Therefore 2b was treated with TFA and the resulting
lactam 3 was treated with (+)-10-camphorsulfonyl chloride
to give (+)-2d in an overall yield of 43% starting from 2b.
Scheme 2. Synthesis of the starting unsaturated lactams 2a–d.
Thus, the reaction of phenacyl bromide with 1 equiv. of
1,4-diazabicyclo[2.2.2]octane (DABCO) followed by the ad-
dition after stirring for 1 h of 1.2 equiv. of Cs2CO3 and 2a
gave product 4a in 55% yield. It was necessary to form the
quaternary ammonium salt previous to the addition of the
base to avoid secondary reactions such as condensation and
double-bond shifts. Increasing the amount of base to
2 equiv. of Cs2CO3 raised the yield to 70%. If the lactam
2a was added 30 min after the addition of the base, the
reaction was cleaner and 4a was isolated in 79% yield (en-
try 1). The solvent of choice was acetonitrile because the
[a] Reaction conditions: DABCO (1 equiv.), α-bromo ketone
(1.1 equiv.), Cs2CO3 (2 equiv.), 2a or 2d (1 equiv.), anhydrous aceto-
nitrile, argon. [b] In pure product.
2
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Lactam Rearrangement into Fused Pyrrolidinolactones
yields were slightly lower with dichloroethane or dichloro- rearranged products 4j and 4k in a combined yield of 58%
methane whereas with THF or dioxane we detected impor- in a ratio of 1:1, which we were not able to separate by
tant amounts of side-products (see below). With these opti- chromatography.
mized conditions in hand, the scope of the reaction was
In an attempt to develop an asymmetric version of this
explored with various α-bromo ketones and the results are process we substituted DABCO by a chiral amine. Thus,
shown in Table 1. Conversion to the corresponding fused two isomers of (8-ethylquinuclidin-2-yl)methanol and 3-(–)-
heterocyclic compounds was observed for the aromatic α- (R)-quinuclidinol (commercial compounds) were acetylated
bromo ketones tested. Only lactams bearing sulfonamides to give the amines 5–7 depicted in Figure 1.[11] We treated
as protecting groups displayed desirable properties under these amines with (1-benzofuran-2-yl)-2-bromoethanone
the reaction conditions to yield the desired compounds as but in the first two cases we did not observe the formation
no rearrangement was observed for 2b. Phenyl derivatives of ammonium salts, possibly due to a steric effect. On the
bearing either an electron-withdrawing or -donating group other hand, the reaction of 7 gave the salt, which was
reacted well under the conditions (entries 2–7), but the reac- treated with 2a. Rearrangement occurred to give scalemic
tion is favoured by electronic-rich aromatic rings. Thus, 4b 4i in 57% yield with an ee of only 15%.[12]
and 4c were isolated in good yields, whereas 4e–g were
formed in much lower yields. The o-methoxy derivative 4d
was only obtained in moderate yield probably due to the
steric hindrance. Naphthalene and benzofuran derivatives,
following these trends, gave the corresponding products 4h
and 4i in good yields (entries 8 and 9).
The structures of compounds 4 were assigned according
to their NMR spectroscopic data. An X-ray diffraction
Figure 1. Chiral amines used for the reaction with (1-benzofuran-
2-yl)-2-bromoethanone and 2a.
analysis supported the structure of compound 4a and
The side-reactions detected in these reactions proved to
showed the cis stereochemistry of the ring fusion, which be interesting. In some reactions we detected mixtures of
was assigned to the rest of the series due to the similarity isomers of the starting lactam in which the double bond
of the NMR spectra.[10] Other α-bromo ketones without had shifted to various positions within the ring. Significant
aromatic rings were tested, but we did not observe conver- yields of these products were obtained when using the α-
sion into the rearranged products. In addition, secondary bromo ketones depicted in Scheme 3.[13] In addition, this
bromides did not react. These unreactive bromo ketones are was the only process observed when the eight-membered
shown in Scheme 3. Finally, we treated chiral substrate (+)- lactam 2c was treated with phenacyl bromide. With this
2d with (1-benzofuran-2-yl)-2-bromoethanone (entry 10) starting material we isolated 2e and 2f in variable yields
and isolated the corresponding mixture of diastereomeric depending on the reaction conditions. The other competing
reaction was a Morita–Baylis–Hillman-type (MBH) reac-
tion of lactam 2a, which gave product 8.[14] As indicated
above, acetonitrile was found to be the best solvent, with
THF and dioxane giving 8 as the major product (32% iso-
lated yield with dioxane) along with mixtures of 2g–i. The
use of harder bases (Na2CO3, NaOH) led to the formation
of variable amounts of 8 as a result of the MBH-type reac-
tion.
With these results we proposed a reaction pathway that
could explain the formation of the fused heterocyclic prod-
ucts 4 (Scheme 4). It is reasonable to assume the formation
of enolate A to start the reaction. This should subsequently
react with the carbonyl group of the preformed ammonium
salt and proceed to intermediate B. We checked that ammo-
nium salts are intermediates in this reaction by isolating 9,
which gave the corresponding product 4i in 75% yield upon
reaction with 2a and 2 equiv. of Cs2CO3. Moreover, if the
lactam was added before the formation of the ammonium
salt no rearrangement was observed and a mixture of
double-bond-shifted products was produced. In addition,
bases like NaOH or Na2CO3 resulted in MBH-type reac-
tions, which shows that the way in which the enolate is
formed is critical for a particular reaction course. This ten-
dency towards isomerization reactions was reduced or elim-
inated if the ammonium salt was stirred with the base prior
to the addition of the lactam. During this period bright-
Scheme 3. Main side-reactions in the reactions of lactams 2 with
bromo ketones.
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coloured species were formed, which indicates the forma- molecular 1,4-addition of the TosNH group to the α,β-un-
tion of nitrogen ylides. In view of these observations, we saturated lactone F could be possible (path b). Compounds
postulate that the formation of intermediate B might pro- 4 were shown to have cis stereochemistry.[10]
ceed via the transition state depicted in Scheme 4, the nitro-
The products obtained by this new rearrangement pro-
gen ylide being the species that removes the proton thereby cess have structural similarities with certain natural prod-
avoiding competitive side-reactions.
ucts as we have indicated above. Therefore we explored
some transformations leading to structures more closely re-
lated to kainoids and radicamines. Scheme 5 shows the re-
sults of these reactions with 4i. Reduction of the lactone
group with DIBAL-H allowed the selective synthesis of
both the diol 10 and the mixture of hemiacetals 11. If
5 equiv. of DIBAL-H were used and the reaction allowed
to reach room temp., the major product was 10 (72%),
whereas milder conditions (2 equiv. of reagent and lower
temperatures not above –40 °C) produced only the hemi-
acetals 11 in high yields (77%). Cleavage of the lactone to
give hydroxy acid 12 was accomplished by using EtONa
and we were able to obtain this product as a single spot on
TLC. However, after a few minutes in solution, this product
started to cyclize to 4i. Finally, we performed an aminolysis
reaction on 4i with pyrrolidine to obtain 13 in an excellent
yield (89%).[15]
Scheme 5. Transformations of product 4i.
Scheme 4. Proposed reaction pathway for the synthesis of the fused
heterocyclin products 4.
Conclusions
The protonation of B and an E1cB-type process would
The reactions of unsaturated seven-membered lactams
lead to C. Stabilization of the new double bond by the aro- with aromatic α-bromo ketones by a novel rearrangement
matic ring should be essential and this could be the reason process have been described herein. The reaction is medi-
for the lack of reactivity of non-aromatic reagents. Further- ated by tertiary amines, which form quaternary salts with
more, opening of the lactam to form D and conjugate at- the bromo ketones and subsequently nitrogen ylides that
tack of the amino group produces intermediate E (path a). initiate the rearrangement process. The participation of ni-
Cyclization assisted by the leaving of the ammonium group trogen ylides is postulated as necessary to avoid competitive
gives the final product 4. Alternatively, the addition of the side-reactions. Thus, new fused heterocyclic compounds re-
carboxylate anion in D to the new tetrasubstituted double lated to kainoids and other natural products such as radica-
bond with elimination of the tertiary amine and then intra- mines have been obtained. The transformation of the lact-
4
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Lactam Rearrangement into Fused Pyrrolidinolactones
1-{[(1S,4R)-7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl]methylsulf-
onyl}-6,7-dihydro-1H-azepin-2(5H)-one [(+)-2d]: A 1 m LiHMDS
solution (1.00 mL, 1.00 mmol) in THF was added to a 0.2 m solu-
tion of 6,7-dihydro-1H-azepin-2(5H)-one (3; 0.18 mL, 0.90 mmol)
in anhydrous THF under argon at –40 °C. The reaction mixture
was stirred for 1 h and then a 0.4 m solution of (1S)-(+)-10-cam-
phorsulfonyl chloride in THF (2.50 mL, 1.00 mmol) was added at
the same temperature. The reaction was stirred for a further 1 h
and then warmed to room temperature over 30 min. The mixture
was washed with a 1 n HCl aqueous solution (20 mL) and then
the aqueous layer was extracted three times with ethyl acetate (3ϫ
20 mL). The organic layers were combined, washed with a 10%
aqueous solution of NaHCO3 (20 mL) and brine (20 mL) and dried
with anhydrous MgSO4. Reaction time: 2.5 h, yield 190 mg (65%;
hexane/ethyl acetate, 6:1) of 2d as a white solid (m.p. 91–94 °C). [α]
one group present in the rearranged product paves the way
for the synthesis of these natural products and their deriva-
tives.
Experimental Section
General: Melting points (uncorrected) were determined with a Stu-
art Scientific SMP3 apparatus. 1H and 13C NMR spectra were
taken with a Bruker DPX 300 MHz BACS60. Chemical shifts (δ)
are expressed in parts per million relative to internal tetramethylsil-
ane at δ = 0.00 ppm. IR spectra were recorded with a Perkin-Elmer
Spectrum a 100 FT-IR spectrophotometer. Mass spectra were re-
corded with a 1100 HPLC (Xterra MS C18 5 mm reverse-phase
columns) coupled to MS (API-ES) with a 1946D Ms detector, all
from Agilent. Elemental analyses (C, H, N) were performed with
a LECO CHNS-932 apparatus at the Microanalyses Service of the
Universidad Complutense of Madrid. Thin layer chromatography
(TLC) analyses were performed on commercial aluminium sheets
bearing a 0.25 mm layer of Merck silica gel 60 F254. Merck silica
gel 60 of 230–400 mesh ASTM was used for standard column
chromatography. All solvents were purchased from VWR and dis-
tilled just before their use. Tetrahydrofuran was refluxed in the
presence of sodium/benzophenone and acetonitrile and dichloro-
methane in the presence of calcium hydride. All reactions were con-
ducted under argon in flame-dried flasks. All reagents were pur-
chased from Aldrich or Across Organics. The syntheses of com-
pounds 1a, 1b,[1] 1c,[16] 2a, 2b,[1] 3,[17] 2g, 2h and 2i[12] have been
described in the literature.
26
1
= +38 (c = 0.024, CH2Cl2). H NMR (300 MHz, CDCl3): δ =
D
0.91 (s, 3 H, CH3, camphor), 1.11 (s, 3 H, CH3, camphor), 1.42–
1.50 (m, 1 H, camphor), 1.75–1.85 (m, 1 H, camphor), 1.92 (d, J
= 18.5 Hz, 1 H, camphor), 2.01–2.13 (m, 4 H, CH2CH2CH2 and
camphor), 2.34–2.49 (m, 4 H, CH2CH= and camphor), 3.53 (d, J
= 14.9 Hz, 1 H, camphor), 3.67–3.77 (d, J = 6.0 Hz, 1 H, CH2N),
3.94–4.03 (d, J = 6.0 Hz, 1 H, CH2N), 3.99 (d, J = 14.9 Hz, 1 H,
camphor), 6.04 (d, J = 11.8 Hz, 1 H, HC=CO), 6.47–6.55 (m, 1 H,
CH2CH=) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.2 (2 CH3),
26.2 (CH2), 26.6 (CH2), 27.5 (CH2), 28.7 (CH2), 43.0 (CH2), 43.2
(CH), 45.2 (CH2), 48.9 (C), 52.5 (CH2), 59.4 (C), 127.1 (CH), 143.0
(CH), 170.2 (CO), 215.2 (CO) ppm. IR (KBr): ν = 1738, 1694 cm–1.
˜
MS (ESI): m/z = 326 [M + H]+. C16H23NO4S (325.42): calcd. C
59.05, H 7.12, N 4.30, S 9.85; found C 59.14, H 7.24, N 4.11.
(Z)-1-Tosyl-5,6,7,8-tetrahydroazocin-2(1H)-one
(2c):
A
1 m
(Z)-1-Tosyl-1,6,7,8-tetrahydroazocin-2(3H)-one (2e) and (Z)-1-Tos-
yl-3,4,7,8-tetrahydroazocin-2(1H)-one (2f): Following the general
procedure for the rearrangement reaction from 2-bromo-1-phenyl-
ethanone (77 mg, 0.39 mmol), Cs2CO3 (232 mg, 0.71 mmol),
DABCO (40 mg, 0.36 mmol) and 2c (100 mg, 0.36 mmol). Reaction
time: 16 h, yield 25 mg (25%; (hexane/ethyl acetate, 9:1) of 2e as a
yellow syrup and 10 mg (10%) of 2f as a yellow syrup unpurified
by 2e.
LiHMDS solution (3.00 mL, 3.0 mmol) in THF was added to a
0.2 m solution of 1-tosyl-2-azacyclooctanone (0.20 mL, 1.0 mmol)
in anhydrous THF under argon at –30 °C. The reaction mixture
was stirred for 1 h and then a 0.4 m solution of phenylselenyl chlor-
ide (383 mg, 2.0 mmol) was added at the same temperature. The
mixture was stirred for a further 1 h and then warmed up to room
temperature over 1 h and stirred 30 min more at this temperature.
The reaction mixture was washed with a 1 m HCl aqueous solution
(20 mL) and then the aqueous layer was extracted three times with
ethyl acetate. The organic layers were combined, washed with a
10% aqueous solution of NaHCO3 and brine, dried with anhydrous
MgSO4 and concentrated under reduced pressure. The resulting
crude product was dissolved in THF and a 30% aqueous solution
of hydrogen peroxide (0.34 mL, 3.00 mmol) was added to the mix-
ture at 0 °C. This mixture was stirred for 15 min at 0 °C and then
warmed up to room temperature over 30 min. The reaction mixture
was then dissolved in dichloromethane (15 mL) and washed with a
saturated aqueous solution of NaHCO3. The aqueous layer was
extracted three times with dichloromethane (15 mL). The organic
layers were combined, washed with brine, dried with anhydrous
MgSO4 and concentrated under reduced pressure. The residue was
purified by flash chromatography to give 2c as a white solid (m.p.
99–101 °C), yield 182 mg (65%; hexane/ethyl acetate, 6:1). 1H
NMR (300 MHz, CDCl3): δ = 1.56–1.71 (m, 2 H, CH2CH2CH=),
1
Data for 2e: H NMR (300 MHz, CDCl3): δ = 1.84–1.92 (m, 2 H,
CH2), 2.04–2.11 (m, 2 H, CH2), 2.43 (s, 3 H, CH3), 3.18 (dd, J1 =
5.1, J2 = 1.7 Hz, 2 H, CH2CO), 4.09 (t, J = 5.6 Hz, 2 H, CH2N),
5.47–5.54 (m, 1 H, HC=), 5.67–5.77 (m, 1 H, HC=), 7.30 (d, J =
8.2 Hz, 2 H, Ts), 7.91 (d, J = 8.4 Hz, 2 H, Ts) ppm. 13C NMR
(75 MHz, CDCl3): δ = 19.7 (CH2), 21.6 (CH3), 29.8 (CH2), 30.9
(CH2), 46.5 (CH2), 121.6 (CH), 129.0 (CH), 129.2 (CH), 136.2 (C),
141.1 (CH), 144.7 (C), 168.1 (CO) ppm. IR (NaCl): ν = 2930, 1632,
˜
1495 cm–1. C14H17NO3S (279.35): calcd. C 60.19, H 6.13, N 5.01,
S 11.48; found C 60.42, H 6.26, N 5.15.
1
Data for 2f: H NMR (300 MHz, CDCl3): δ = 0.83–0.88 (m, 4 H,
2 CH2), 2.43 (s, 3 H, CH3), 2.52–2.58 (m, 2 H, CH2CO), 4.06 (t, J
= 6.6 Hz, 2 H, CH2N), 5.85 (d, J = 9.8 Hz, 1 H, HC=), 6.77–6.83
(m, 1 H, HC=), 7.32 (d, J = 8.1 Hz, 2 H, Ts), 7.93 (d, J = 8.4 Hz,
2 H, Ts) ppm. IR (NaCl): ν = 2929, 1630, 1490 cm–1.
˜
1.95 (br. s, 2 H, CH2CH2N), 2.33 (br. s, 2 H, CH2CH2CH=), 2.43 General Procedure for the Rearrangement Reaction: DABCO
(s, 3 H, CH3), 4.11 (t, J = 11.3 Hz, 2 H, CH2CH2N), 5.65 (dt, J1 (1 equiv.) was added to solution of the α-bromo ketone
= 12.8, J2 = 1.9 Hz, 1 H, HC=CHCO), 6.13 (dt, J1 = 12.8, J2 (1.1 equiv.) in dry acetonitrile (0.20 m) under argon and the re-
5.2 Hz, 1 H, HC=CHCO), 7.31 (d, J = 8.1 Hz, 2 H, Ts), 7.94 (d, J sulting mixture was stirred at room temp. for 60 min. Then Cs2CO3
= 8.4 Hz, 2 H, Ts) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.7
(2 equiv.) was added and the mixture stirred for 30 min. Finally,
(CH2), 21.6 (CH3), 29.8 (CH2), 30.9 (CH2), 46.5 (CH2), 121.6 (CH), the corresponding lactam (1 equiv.) dissolved in dry acetonitrile
a
=
129.0 (CH), 129.2 (CH), 136.2 (C), 141.1 (CH), 144.7 (C), 168.1
(0.20 m) was added slowly over 30 min. The reaction mixture was
(CO) ppm. IR (KBr): ν = 2931, 1672, 1632, 1595 cm–1. MS (ESI): stirred at 80 °C. Once completed, as shown by TLC analysis, the
˜
m/z = 280 [M + H]+. C14H17NO3S (279.35): calcd. C 60.19, H 6.13, reaction was quenched by filtering through Celite and washing with
N 5.01, S 11.48; found C 60.32, H 6.03, N 4.86.
a 2.5% HCl aqueous solution (15 mL). The mixture was extracted
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with CH2Cl2 (3ϫ 15 mL) and the organic layers combined, washed
with brine, dried with anhydrous MgSO4, filtered and concentrated
under reduced pressure to give the product, which was purified by
flash chromatography.
(3aS*,6aR*)-6a-[1-(2-Methoxyphenyl)vinyl]-4-tosylhexahydro-2H-
furo[3,2-b]pyrrol-2-one (4d): Following the general procedure start-
ing from 1-(2-methoxyphenyl)-2-bromoethanone (95 mg,
0.42 mmol), Cs2CO3 (244 mg, 0.75 mmol), DABCO (43 mg,
0.38 mmol) and 2a (100 mg, 0.38 mmol). Reaction time: 16 h, yield
70 mg (45%; hexane/ethyl acetate, 9:1) of 4d as a yellow solid (m.p.
172–174 °C). 1H NMR (300 MHz, CDCl3): δ = 1.71–1.76 (m, 1 H,
CH2CH2N), 2.05–2.17 (m, 1 H, CH2CH2N), 2.39 (s, 3 H, CH3),
2.87–2.88 (m, 2 H, CH2CO), 3.47–3.54 (m, 2 H, CH2CH2N), 3.78
(s, 3 H, OCH3), 4.31 (dd, J1 = 3.8, J2 = 2.8 Hz, 1 H, CH), 5.01 (s,
1 H, H2C=C), 5.57 (s, 1 H, H2C=C), 6.84–6.89 (m, 3 H, Ar), 7.11
(d, J = 8.2 Hz, 2 H, Ts), 7.28–7.36 (m, 1 H, Ar), 7.43 (d, J = 8.3 Hz,
2 H, Ts) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.5 (CH3), 35.2
(CH2), 36.9 (CH2), 47.2 (CH2), 55.5 (OCH3), 63.2 (CH), 96.0 (C),
111.0 (CH), 118.5 (CH2), 120.6 (CH), 126.7 (CH), 128.5 (C), 129.6
(CH), 129.8 (CH), 131.2 (CH), 134.9 (C), 143.2 (C), 143.6 (C),
(3aS*,6aR*)-6a-(1-Phenylvinyl)-4-tosylhexahydro-2H-furo[3,2-b]pyr-
rol-2-one (4a): Following the general procedure starting from 2-
bromo-1-phenylethanone (84 mg, 0.42 mmol), Cs2CO3 (244 mg,
0.75 mmol), DABCO (43 mg, 0.38 mmol) and 2a (100 mg,
0.38 mmol). Reaction time: 16 h, yield 115 mg (79%; hexane/ethyl
acetate, 3:1) of 4a as a white solid (m.p. 236–240 °C). 1H NMR
(300 MHz, CDCl3): δ = 1.75–1.86 (m, 1 H, CH2CH2N), 2.05–2.13
(m, 1 H, CH2CH2N), 2.35 (s, 3 H, CH3), 2.66 (dd, J1 = 18.4, J2 =
6.1 Hz, 1 H, CH2CO), 2.84 (d, J = 18.4 Hz, 1 H, CH2CO), 3.43–
3.49 (m, 2 H, CH2CH2N), 4.27 (d, J = 6.6 Hz, 1 H, CH), 5.12 (s,
1 H, H2C=C), 5.41 (s, 1 H, H2C=C), 6.95 (d, J = 6.8 Hz, 2 H, Ph),
7.12–7.26 (m, 5 H, Ph and Ts), 7.47 (d, J = 8.3 Hz, 2 H, Ts) ppm.
13C NMR (75 MHz, CDCl3): δ = 21.5 (CH3), 34.8 (CH2), 36.6
(CH2), 47.1 (CH2), 62.8 (CH), 95.4 (C), 117.7 (CH2), 126.8 (CH),
128.0 (CH), 128.3 (CH), 128.4 (CH), 129.9 (CH), 134.5 (C), 138.1
156.5 (C), 174.9 (CO) ppm. IR (KBr): ν = 2924, 1792, 1695,
˜
1599 cm–1. MS (ESI): m/z = 414 [M + H]+, 436 [M + Na]+.
C22H23NO5S (413.49): calcd. C 63.90, H 5.61, N 3.39, S 7.75; found
C 63.99, H 5.74, N 3.20.
(C), 143.9 (C), 145.8 (C), 174.4 (CO) ppm. IR (KBr): ν = 2953,
˜
2900, 1789, 1696, 1597 cm–1. MS (ESI): m/z = 384 [M + H]+.
C21H21NO4S (383.46): calcd. C 65.78.05, H 5.52, N 3.65, S 8.36;
found C 65.73, H 5.48, N 3.47.
(3aS*,6aR*)-6a-[1-(4-Bromophenyl)vinyl]-4-tosylhexahydro-2H-
furo[3,2-b]pyrrol-2-one (4e). Following the general procedure start-
ing from 2-bromo-1-(4-bromophenyl)ethanone (117 mg,
0.42 mmol), Cs2CO3 (244 mg, 0.75 mmol), DABCO (43 mg,
0.38 mmol) and 2a (100 mg, 0.38 mmol). Reaction time: 16 h, yield
97 mg (55%; hexane/ethyl acetate, 9:1) of 4e as a yellow solid (m.p.
129–131 °C). 1H NMR (300 MHz, CDCl3): δ = 1.75–1.80 (m, 1 H,
CH2CH2N), 2.10–2.12 (m, 1 H, CH2CH2N), 2.47 (s, 3 H, CH3),
2.77 (dd, J1 = 18.4, J2 = 6.1 Hz, 1 H, CH2CO), 2.94 (d, J = 18.4 Hz,
1 H, CH2CO), 3.51–3.58 (m, 2 H, CH2CH2N), 4.27 (d, J = 5.9 Hz,
1 H, CH), 5.19 (s, 1 H, H2C=C), 5.50 (s, 1 H, H2C=C), 6.89 (d, J
= 8.4 Hz, 2 H, Ar), 7.24 (d, J = 8.1 Hz, 2 H, Ar), 7.38 (d, J =
8.4 Hz, 2 H, Ts), 7.53 (d, J = 8.3 Hz, 2 H, Ts) ppm. 13C NMR
(75 MHz, CDCl3): δ = 21.6 (CH3), 35.1 (CH2), 36.6 (CH2), 47.2
(CH2), 62.7 (CH), 95.1 (C), 118.3 (CH2), 122.5 (C), 126.9 (CH),
130.0 (CH), 130.1 (CH), 131.6 (CH), 134.6 (C), 137.0 (C), 144.3
(3aS*,6aR*)-6a-[1-(p-Tolyl)vinyl]-4-tosylhexahydro-2H-furo[3,2-b]-
pyrrol-2-one (4b): Following the general procedure starting from
2-bromo-1-(4-methylphenyl)ethanone (89 mg, 0.42 mmol), Cs2CO3
(244 mg, 0.75 mmol), DABCO (43 mg, 0.38 mmol) and 2a (100 mg,
0.38 mmol). Reaction time: 16 h, yield 113 mg (75%; hexane/ethyl
1
acetate, 9:1) of 4b as an orange solid (m.p. 114–116 °C). H NMR
(300 MHz, CDCl3): δ = 1.82–1.93 (m, 1 H, CH2CH2N), 2.11–2.17
(m, 1 H, CH2CH2N), 2.38 (s, 3 H, CH3), 2.43 (s, 3 H, CH3), 2.73
(dd, J1 = 18.3, J2 = 6.1 Hz, 1 H, CH2CO), 2.91 (d, J = 18.3 Hz, 1
H, CH2CO), 3.49–3.55 (m, 2 H, CH2CH2N), 4.35 (d, J = 6.0 Hz,
1 H, CH), 5.17 (s, 1 H, H2C=C), 5.44 (s, 1 H, H2C=C), 6.90 (d, J
= 8.0 Hz, 2 H, Ar), 7.06 (d, J = 8.0 Hz, 2 H, Ar), 7.21 (d, J =
8.2 Hz, 2 H, Ts), 7.55 (d, J = 8.3 Hz, 2 H, Ts) ppm. 13C NMR
(75 MHz, CDCl3): δ = 21.2 (CH3), 21.6 (CH3), 35.0 (CH2), 36.7
(CH2), 47.2 (CH2), 62.9 (CH), 95.5 (C), 117.5 (CH2), 127.0 (CH),
128.3 (CH), 129.1 (CH), 129.9 (CH), 134.8 (C), 135.3 (C), 137.9
(C), 145.0 (C), 174.1 (CO) ppm. IR (KBr): ν = 2922, 1783, 1694,
˜
1595 cm–1. MS (ESI): m/z = 462 [M + H]+. C21H20BrNO4S
(462.36): calcd. C 54.55, H 4.36, Br 17.28, N 3.03, S 6.94; found C
54.44, H 4.48, N 2.94.
(C), 143.9 (C), 145.9 (C), 174.5 (CO) ppm. IR (KBr): ν = 2924,
˜
1789, 1595 cm–1. MS (ESI): m/z = 398 [M + H]+. C22H23NO4S
(397.49): calcd. C 66.48, H 5.83, N 3.52, S 8.07; found C 66.18, H
5.62, N 3.71.
(3aS*,6aR*)-6a-[1-(3-Bromophenyl)vinyl]-4-tosylhexahydro-2H-
furo[3,2-b]pyrrol-2-one (4f): Following the general procedure start-
ing from 2-bromo-1-(3-bromophenyl)ethanone (117 mg,
0.42 mmol), Cs2CO3 (244 mg, 0.75 mmol), DABCO (43 mg,
0.38 mmol) and 2a (100 mg, 0.38 mmol). Reaction time: 16 h, yield
(3aS*,6aR*)-6a-[1-(4-Methoxyphenyl)vinyl]-4-tosylhexahydro-2H-
furo[3,2-b]pyrrol-2-one (4c): Following the general procedure start-
ing from 2-bromo-1-(4-methoxyphenyl)ethanone (95 mg,
0.42 mmol), Cs2CO3 (244 mg, 0.75 mmol), DABCO (43 mg,
0.38 mmol) and 2a (100 mg, 0.38 mmol). Reaction time: 16 h, yield
132 mg (84%; hexane/ethyl acetate, 9:1) of 4c as a yellow solid (m.p.
236–240 °C). 1H NMR (300 MHz, CDCl3): δ = 1.83–1.94 (m, 1 H,
CH2CH2N), 2.12–2.17 (m, 1 H, CH2CH2N), 2.43 (s, 3 H, CH3),
2.72 (dd, J1 = 18.4, J2 = 6.2 Hz, 1 H, CH2CO), 2.90 (d, J = 18.3 Hz,
1 H, CH2CO), 3.51–3.57 (m, 2 H, CH2CH2N), 3.83 (s, 3 H, OCH3),
4.34 (d, J = 6.0 Hz, 1 H, CH), 5.16 (s, 1 H, H2C=C), 5.43 (s, 1 H,
H2C=C), 6.76 (d, J = 8.6 Hz, 2 H, Ar), 6.95 (d, J = 8.8 Hz, 2 H,
Ar), 7.23 (d, J = 8.3 Hz, 2 H, Ts), 7.56 (d, J = 8.3 Hz, 2 H, Ts) ppm.
13C NMR (75 MHz, CDCl3): δ = 21.5 (CH3), 35.0 (CH2), 36.7
(CH2), 47.2 (CH2), 55.3 (OCH3), 62.9 (CH), 95.6 (C), 113.8 (CH),
117.4 (CH2), 127.0 (CH), 129.6 (CH), 130.0 (CH), 130.4 (C), 134.8
1
105 mg (60%; hexane/ethyl acetate, 9:1) of 4f as an orange oil. H
NMR (300 MHz, CDCl3): δ = 1.76–1.80 (m, 1 H, CH2CH2N),
2.13–2.14 (m, 1 H, CH2CH2N), 2.43 (s, 3 H, CH3), 2.79 (dd, J1 =
18.4, J2 = 6.1 Hz, 1 H, CH2CO), 2.95 (d, J = 18.4 Hz, 1 H,
CH2CO), 3.51–3.58 (m, 2 H, CH2CH2N), 4.29 (d, J = 5.9 Hz, 1 H,
CH), 5.19 (s, 1 H, H2C=C), 5.51 (s, 1 H, H2C=C), 6.97 (d, J =
7.7 Hz, 1 H, Ar), 7.14 (t, J = 7.8 Hz, 1 H, Ar), 7.19 (t, J = 1.7 Hz,
1 H, Ar), 7.23 (d, J = 8.1 Hz, 2 H, Ts), 7.47 (dt, J1 = 8.0, J2
=
1.8 Hz, 1 H, Ar), 7.54 (d, J = 8.3 Hz, 2 H, Ts) ppm. 13C NMR
(75 MHz, CDCl3): δ = 21.6 (CH3), 35.1 (CH2), 36.6 (CH2), 47.2
(CH2), 62.7 (CH), 95.0 (C), 118.7 (CH2), 122.6 (C), 126.9 (CH),
128.6 (CH), 129.3 (CH), 130.0 (CH), 131.2 (CH), 131.6 (CH), 134.5
(C), 140.2 (C), 144.2 (C), 144.8 (C), 174.1 (CO) ppm. IR (NaCl): ν
˜
= 2918, 1788, 1694, 1594 cm–1. MS (ESI): m/z = 462 [M + H]+.
C21H20BrNO4S (462.36): calcd. C 54.55, H 4.36, Br 17.28, N 3.03,
S 6.94; found C 54.71, H 4.25, N 3.13.
(C), 144.0 (C), 145.5 (C), 159.4 (C), 174.5 (CO) ppm. IR (KBr): ν
˜
= 2926, 1791, 1693, 1605 cm–1. MS (ESI): m/z = 414 [M + H]+.
C22H23NO5S (413.49): calcd. C 63.90, H 5.61, N 3.39, S 7.75; found
C 63.78, H 5.49, N 3.57.
4-{1-[(3aS*,6aR*)-2-Oxo-4-tosylhexahydro-2H-furo[3,2-b]pyrrol-
6a-yl]vinyl}benzonitrile (4g): Following the general procedure start-
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30136
/KAP1
Date: 05-04-13 10:28:12
Pages: 10
Lactam Rearrangement into Fused Pyrrolidinolactones
ing from 2-bromo-1-(4-cyanophenyl)ethanone (94 mg, 0.42 mmol),
Cs2CO3 (244 mg, 0.75 mmol), DABCO (43 mg, 0.38 mmol) and 2a
(100 mg, 0.38 mmol). Reaction time: 16 h, yield 54 mg (35%; hex-
ane/ethyl acetate, 9:1) of 4g as a yellow solid (m.p. 126–128 °C). 1H
NMR (300 MHz, CDCl3): δ = 1.77–1.88 (m, 1 H, CH2CH2N),
the general procedure starting from (1-benzofuran-2-yl)-2-bromo-
ethanone (82 mg, 0.34 mmol), Cs2CO3 (202 mg, 0.62 mmol),
DABCO (35 mg, 0.31 mmol) and 2d (100 mg, 0.31 mmol). Reac-
tion time: 4 h, yield 88 mg (58%; hexane/ethyl acetate, 9:1) of a
mixture of 4j and 4k as a brown syrup. 1H NMR (300 MHz,
2.17–2.22 (m, 1 H, CH2CH2N), 2.47 (s, 3 H, CH3), 2.77 (dd, J1 = CDCl3): δ = 0.88 and 0.91 (s, 3 H, CH3, camphor), 1.13 and 1.14
18.5, J2 = 6.3 Hz, 1 H, CH2CO), 2.94 (d, J = 18.5 Hz, 1 H, (s, 3 H, CH3, camphor), 1.40–1.49 (m, 1 H, camphor), 1.63–1.73
CH2CO), 3.48–3.56 (m, 1 H, CH2CH2N), 3.59–3.66 (m, 1 H, (m, 1 H, camphor), 1.96 and 1.97 (d, J = 24.8 and J = 24.4 Hz, 1
CH2CH2N), 4.33 (d, J = 5.9 Hz, 1 H, CH), 5.27 (s, 1 H, H2C=C), H, camphor), 2.01–2.14 (m, 2 H, camphor), 2.35–2.53 (m, 3 H,
5.53 (s, 1 H, H2C=C), 7.21 (d, J = 8.4 Hz, 2 H, Ar), 7.27 (d, J =
CH2CH2N and camphor), 2.61–2.77 (m, 1 H, camphor), 2.81–3.06
8.4 Hz, 2 H, Ar), 7.57 (d, J = 8.4 Hz, 2 H, Ar), 7.60 (d, J = 8.3 Hz, (m, 3 H, CH2CO and camphor), 3.50 and 3.54 (d, J = 30.1 and J
2 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.6 (CH3), 35.7
(CH2), 36.5 (CH2), 47.1 (CH2), 62.7 (CH), 94.7 (C), 112.4 (CN),
= 28.0 Hz, 1 H, camphor), 3.60–3.73 (m, 1 H, CH2CH2N), 3.91–
4.00 (m, 1 H, CH2CH2N), 4.92 and 5.01 (d, J = 5.8 and J = 7.9 Hz,
118.1 (C), 119.0 (CH2), 127.1 (CH), 129.2 (CH), 130.1 (CH), 132.2 1 H, CH), 5.71 (s, 1 H, H2C=C), 6.02 (s, 1 H, H2C=C), 6.90 and
(CH), 134.9 (C), 142.9 (C), 144.4 (C), 145.0 (C), 173.7 (CO) ppm.
6.91 (s, 1 H, Ar), 7.20–7.33 (m, 2 H, Ar), 7.46–7.55 (m, 1 H, Ar),
7.57 (d, J = 7.6 Hz, 1 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ
= 19.8 and 19.9 (CH3), 20.0 (both CH3), 25.2 and 25.3 (CH2), 26.8
and 26.9 (CH2), 36.2 (both CH2), 36.5 and 36.6 (CH2), 42.6 (both
CH2), 42.8 and 42.9 (CH), 47.3 and 47.5 (C), 47.9 (both CH2), 48.1
and 48.4 (CH2), 58.4 and 58.5 (C), 62.9 (both CH), 94.2 and 94.3
(C), 105.5 and 105.6 (CH), 111.2 and 111.3 (CH), 116.7 (both
CH2), 121.4 (both CH), 123.4 and 123.5 (CH), 125.4 (both CH),
128.0 and 128.1 (C), 135.3 and 135.4 (C), 152.1 and 152.2 (C),
154.4 and 154.5 (C), 174.1 and 174.2 (CO), 215.1 (both CO) ppm.
IR (KBr): ν = 2912, 2226, 1790, 1596 cm–1. MS (ESI): m/z = 409
˜
[M + H]+, 431 [M + Na]+. C22H20N2O4S (408.47): calcd. C 64.69,
H 4.94, N 6.86, S 7.85; found C 64.49, H 4.79, N 6.98.
(3aS*,6aR*)-6a-[1-(2-Naphthyl)vinyl]-4-tosylhexahydro-2H-
furo[3,2-b]pyrrol-2-one (4h): Following the general procedure start-
ing from 2-bromo-1-(2-naphthylethanone (105 mg, 0.42 mmol),
Cs2CO3 (244 mg, 0.75 mmol), DABCO (43 mg, 0.38 mmol) and 2a
(100 mg, 0.38 mmol). Reaction time: 2.5 h, yield 112 mg (68%; hex-
ane/ethyl acetate, 9:1) of 4h as a yellow syrup. 1H NMR (300 MHz,
CDCl3): δ = 1.81–1.86 (m, 1 H, CH2CH2N), 2.14–2.20 (m, 1 H,
CH2CH2N), 2.19 (s, 3 H, CH3), 2.84 (dd, J1 = 18.3, J2 = 5.8 Hz, 1
H, CH2CO), 2.96 (d, J = 18.2 Hz, 1 H, CH2CO), 3.51–3.56 (m, 2
H, CH2CH2N), 4.43 (d, J = 5.4 Hz, 1 H, CH), 5.27 (s, 1 H,
H2C=C), 5.60 (s, 1 H, H2C=C), 6.77 (d, J = 8.0 Hz, 2 H, Ar), 7.12
(d, J = 8.4 Hz, 1 H, Ar), 7.38 (d, J = 8.3 Hz, 2 H, Ar), 7.49 (s, 1
H, Ar), 7.55–7.58 (m, 2 H, Ar), 7.72–7.80 (m, 2 H, Ar), 7.87 (d, J
= 8.3 Hz, 1 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.3
(CH3), 35.0 (CH2), 36.7 (CH2), 47.2 (CH2), 62.8 (CH), 95.5 (C),
118.2 (CH2), 126.4 (CH), 126.7 (CH), 126.7 (CH), 126.8 (CH),
127.6 (CH), 127.7 (CH), 128.0 (CH), 128.1 (CH), 129.7 (CH), 132.7
(C), 132.9 (C), 134.4 (C), 135.6 (C), 143.8 (C), 145.9 (C), 174.4
IR (NaCl): ν = 2964, 1741, 1691 cm–1.
˜
(Z)-3-(2-Oxo-1-tosylazepan-4-yl)-1-tosyl-6,7-dihydro-1H-azepin-
2(5H)-one (8): Following the general procedure starting from 2-
bromo-1-phenylethanone (84 mg, 0.42 mmol), Cs2CO3 (244 mg,
0.75 mmol), DABCO (43 mg, 0.38 mmol) and 2a (100 mg,
0.38 mmol) in dioxane. Reaction time: 16 h, yield 32 mg (32%; hex-
ane/ethyl acetate, 3:1) of 8 as a yellow oil. 1H NMR (300 MHz,
CDCl3): δ = 1.63–1.70 (m, 2 H, CH2), 1.98–2.07 (m, 2 H, CH2),
2.16–2.26 (m, 2 H, CH2), 2.31–2.47 (m, 3 H, CH2CO and CH2),
2.42 (s, 6 H, 2 CH3), 2.63–2.70 (m, 1 H, CH), 2.77 (dd, J1 = 13.3,
J2 = 9.9 Hz, 1 H, CH2CO), 3.64–3.76 (m, 2 H, CH2N), 3.90 (dt, J1
= 14.9, J2 = 5.7 Hz, 1 H, CH2N), 4.32 (dd, J1 = 15.4, J2 = 7.2 Hz,
1 H, CH2N), 6.11 (t, J = 7.3 Hz, 1 H, HC=C), 7.28 (m, 4 H, Ts),
7.84 (d, J = 8.4 Hz, 2 H, Ts), 7.88 (d, J = 8.4 Hz, 2 H, Ts) ppm.
13C NMR (75 MHz, CDCl3): δ = 21.6 (CH3), 21.7 (CH3), 22.7
(CH2), 28.1 (CH2), 28.4 (CH2), 35.0 (CH), 37.5 (CH2), 43.6 (CH2),
44.5 (CH2), 45.9 (CH2), 128.4 (CH), 128.6 (CH), 129.3 (CH), 129.5
(CH), 133.4 (CH), 136.3 (C), 136.5 (C), 141.9 (C), 144.7 (2 C),
(CO) ppm. IR (NaCl): ν = 2912, 1789, 1695, 1543 cm–1. MS (ESI):
˜
m/z = 434, [M + H]+. C25H23NO4S (433.52): calcd. C 69.26, H
5.35, N 3.23, S 7.40; found C 69.15, H 5.25, N 3.38.
(3aS*,6aR*)-6a-[1-(Benzofuran-2-yl)vinyl]-4-tosylhexahydro-2H-
furo[3,2-b]pyrrol-2-one (4i): Following the general procedure start-
ing from 1-benzofuran-2-yl-2-bromoethanone (100 mg,
0.42 mmol), Cs2CO3 (244 mg, 0.75 mmol), DABCO (43 mg,
0.38 mmol) and 2a (100 mg, 0.38 mmol). Reaction time: 2.5 h, yield
137 mg (85%; hexane/ethyl acetate, 9:1) of 4i as a yellow syrup. 1H
NMR (300 MHz, CDCl3): δ = 2.35–2.42 (m, 2 H, CH2CH2N), 2.50
(s, 3 H, CH3), 2.82 (dd, J1 = 18.5, J2 = 6.1 Hz, 1 H, CH2CO), 3.08
(d, J = 18.5 Hz, 1 H, CH2CO), 3.64–3.78 (m, 2 H, CH2CH2N),
4.61 (d, J = 5.6 Hz, 1 H, CH), 5.61 (s, 1 H, H2C=C), 5.98 (s, 1 H,
H2C=C), 6.37 (s, 1 H, Ar), 7.20–7.30 (m, 3 H, Ar), 7.35 (d, J =
8.0 Hz, 2 H, Ts), 7.42 (dd, J1 = 7.1, J2 = 1.0 Hz, 1 H, Ar), 7.77 (d,
J = 8.3 Hz, 2 H, Ts) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.1
(CH3), 36.4 (CH2), 36.5 (CH2), 48.0 (CH2), 63.5 (CH), 94.4 (C),
105.4 (CH), 111.5 (CH), 117.1 (CH2), 121.6 (CH), 123.7 (CH),
125.7 (CH), 127.9 (CH), 128.3 (C), 130.6 (CH), 135.2 (C), 135.6
169.8 (CO), 172.9 (CO) ppm. IR (NaCl): ν = 2956, 2927, 1684,
˜
1596, 1353 cm–1. MS (ESI): m/z = 553 [M + Na]+. C26H30N2O6S2
(530.66): calcd. C 58.85, H 5.70, N 5.28, S 12.09; found C 59.12,
H 5.81, N 5.36.
1-[2-(Benzofuran-2-yl)-2-oxoethyl]-4-aza-1-azoniabicyclo[2.2.2]-
octane (9): DABCO (43 mg, 0.38 mmol) was added to a solution
of 1-benzofuran-2-yl-2-bromoethanone (91 mg, 0.38 mmol) in dry
acetonitrile (0.20 m) under argon and the mixture was stirred at
room temp. until the formation of a precipitate (1 h). The solvent
was eliminated under reduced pressure to give the salt 9 without
any further purification, yield 132 mg (99%) of 9 as a white solid
1
(m.p. 238–241 °C). H NMR (300 MHz, [D6]DMSO): δ = 3.18 (t,
J = 7.5 Hz, 6 H, +NCH2CH2N), 3.68 (t, J = 7.1 Hz, 6 H,
+NCH2CH2N), 5.13 (s, 2 H, CH2CO), 7.50 (t, J = 7.8 Hz, 1 H,
Ar), 7.70 (t, J = 8.3 Hz, 1 H, Ar), 7.86 (d, J = 8.4 Hz, 1 H, CH),
7.99 (d, J = 7.8 Hz, 1 H, Ar), 8.23 (s, 1 H, Ar) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 43.3 (CH2), 51.5 (CH2), 62.8 (CH2),
(C), 144.7 (C), 152.2 (C), 154.6 (C), 174.4 (CO) ppm. IR (NaCl): ν
˜
= 2924, 1799, 1694, 1596 cm–1. MS (ESI): m/z = 462 [M + K]+.
C23H21NO5S (423.48): calcd. C 65.23, H 5.00, N 3.31, S 7.57; found
C 65.11, H 4.87, N 3.39.
(3aR,6aS)- and (3aS,6aR)-6a-[1-(Benzofuran-2-yl)vinyl]-4- 111.2 (CH), 115.3 (CH), 123.0 (CH), 123.4 (CH), 125.2 (CH), 128.5
{[(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl]methylsulf-
onyl}hexahydro-2H-furo[3,2-b]pyrrol-2-one (4j and 4k): Following
(C), 149.1 (C), 154.1 (C), 179.8 (CO) ppm. IR (KBr): ν = 1732,
˜
1694, 1601, 1554 cm–1. MS (ESI): m/z = 271 [M]+.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O30136
/KAP1
Date: 05-04-13 10:28:12
Pages: 10
S. Álvarez, G. Domínguez, A. Gradillas, J. Pérez-Castells
(2S*,3R*)-3-[1-(Benzofuran-2-yl)vinyl]-2-(2-hydroxyethyl)-1-tosyl- (440 mg, 6.5 mmol) in absolute EtOH (2.2 mL), generated in situ,
FULL PAPER
pyrrolidin-3-ol (10): Compound 4i (100 mg, 0.24 mmol) was dis-
solved in anhydrous dichloromethane (0.9 mL) and cooled to
–78 °C. A solution of 1 m DIBAL-H in toluene (1.2 mL, 1.2 mmol)
was added dropwise to the reaction mixture. The solution was
warmed to room temperature and stirred for 1 h. Once completed,
as shown by TLC analysis, the reaction was quenched by adding a
1 m solution of NaOH (20 mL). The aqueous layer was extracted
with dichloromethane (4ϫ 15 mL) and the combined organic lay-
ers were dried with anhydrous MgSO4, filtered and concentrated
under reduced pressure. The resulting mixture was purified by flash
chromatography on silica gel (hexane/ethyl acetate, 3:1) to give
and the mixture was heated at reflux for 4 h. Then the mixture was
allowed to cool to room temperature and water (2 mL) was poured
over the mixture followed by ethyl acetate. The organic layer was
dried with anhydrous MgSO4 and concentrated under reduced
pressure. The residue was purified by flash chromatography, yield
65 mg (70%; hexane/ethyl acetate, 3:1) of 12 as a yellow syrup that
evolved in a few minutes to a mixture of 12 and 4i (data taken from
1
the mixture). H NMR (300 MHz, [D6]DMSO): δ = 2.12–2.23 (m,
2 H, CH2CH2N), 2.44 (s, 3 H, CH3), 2.59 (dd, J1 = 16.7, J2
=
4.5 Hz, 1 H, CH2CO), 2.81 (dd, J1 = 16.7, J2 = 6.4 Hz, 1 H,
CH2CO), 3.42–3.70 (m, 2 H, CH2CH2N), 4.27 (dd, J1 = 6.3, J2 =
compound 10 as a white solid (74 mg, 72%; m.p. 58–60 °C) along 4.5 Hz, 1 H, CH), 5.44 (s, 1 H, H2C=C), 5.65 (s, 1 H, H2C=C),
with 7 mg (7%) of 11. 1H NMR (300 MHz, CDCl3): δ = 1.99–2.12
6.67 (s, 1 H, Ar), 7.26–7.30 (m, 5 H, Ar and Ts), 7.42 (d, J =
(m, 1 H, CH2CH2N), 2.08 (t, J = 6.9 Hz, 2 H, CH2CH2OH), 2.25– 8.0 Hz, 1 H, Ar), 7.64 (d, J = 8.2 Hz, 2 H, Ts) ppm. 13C NMR
2.35 (m, 1 H, CH2CH2N), 2.43 (s, 3 H, CH3), 3.36 (dt, J1 = 14.0,
J2 = 10.7 Hz, 1 H, CH2CH2N), 3.67 (dt, J1 = 13.8, J2 = 10.7 Hz,
(75 MHz, [D6]DMSO): δ = 21.1 (CH3), 35.7 (CH2), 36.7 (CH2),
46.7 (CH2), 62.4 (CH), 79.7 (C), 104.9 (CH), 110.6 (CH), 116.0
1 H, CH2CH2N), 3.86–3.93 (m, 1 H, CH2CH2OH), 3.97–4.04 (m, (CH2), 121.0 (CH), 122.9 (C), 124.6 (CH), 127.3 (CH), 127.7 (CH),
1 H, CH2CH2OH), 4.17 (dd, J1 = 6.8, J2 = 5.1 Hz, 1 H, CH), 5.19 128.3 (C), 129.6 (CH), 134.0 (C), 139.2 (C), 143.3 (C), 153.2 (C),
(s, 1 H, H2C=C), 5.55 (s, 1 H, H2C=C), 6.63 (s, 1 H, Ar), 7.10 (d, 172.6 (CO) ppm. IR (NaCl): ν = 3480, 3250, 2900, 1720, 1590 cm–1.
˜
J = 8.0 Hz, 2 H, Ts) 7.20–7.40 (m, 3 H, Ar), 7.50–7.55 (m, 3 H, Ar
and Ts) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.6 (CH3), 32.9
(CH2), 36.9 (CH2), 46.7 (CH2), 58.2 (CH2), 64.5 (CH), 80.6 (C),
105.4 (CH), 110.8 (CH), 115.6 (CH2), 121.3 (CH), 123.0 (CH),
124.8 (CH), 127.5 (CH), 128.6 (C), 129.6 (CH), 134.2 (C), 139.9
2-{(2S*,3R*)-3-[1-(Benzofuran-2-yl)vinyl]-3-hydroxy-1-tosylpyrrol-
idin-2-yl}-1-(pyrrolidin-1-yl)ethanone (13): Et3N (1.00 mL) and pyr-
rolidine (0.42 mL, 5.00 mmol) were added to a solution of 4i
(106 mg, 0.25 mmol) under argon. The resulting mixture was
heated at reflux with stirring for 2 h, cooled and diluted with di-
ethyl ether (5 mL). Then it was treated with a solution of potassium
carbonate (10 mL) and the aqueous phase was extracted with two
portions of diethyl ether (2ϫ 10 mL). The organic extracts were
combined, dried with anhydrous MgSO4 and evaporated under re-
duced pressure to yield the crude product, which was purified by
flash chromatography, yield 110 mg (89 %; hexane/ethyl acetate,
4:1) of 13 as a brown syrup. 1H NMR (300 MHz, CDCl3): δ =
1.87–1.90 (m, 4 H, CH2CH2N and pyrrolidine), 2.13 (t, J = 6.9 Hz,
(C), 143.6 (C), 153.5 (C), 154.0 (C) ppm. IR (KBr): ν = 3469, 3337,
˜
2950, 1595 cm–1. MS (ESI): m/z = 428 [M + H]+. C23H25NO5S
(427.51): calcd. C 64.62, H 5.89, N 3.28, S 7.50; found C 64.48, H
5.95, N 3.07.
(2S*,3aS*,6aR*)- and (2R*,3aS*,6aR*)-6a-[1-(Benzofuran-2-yl)-
vinyl]-4-tosylhexahydro-2H-furo[3,2-b]pyrrol-2-ol (11a and 11b):
Compound 4i (100 mg, 0.24 mmol) was dissolved in anhydrous
dichloromethane (0.9 mL) and cooled to –78 °C. A solution of 1 m
DIBAL-H in toluene (0.48 mL, 0.48 mmol) was added dropwise to
the reaction mixture. The reaction was warmed to –40 °C and then
stirred for 1 h at this temperature. Then the reaction was quenched
by adding a solution of 1 m NaOH (20 mL). The aqueous layer
was extracted with dichloromethane (4ϫ 15 mL) and the combined
organic layers were dried with anhydrous MgSO4, filtered and con-
centrated under reduced pressure. The resulting mixture was puri-
fied by flash chromatography on silica gel (hexane/ethyl acetate,
3:1). A mixture of compounds 11a and 11b was obtained as a white
syrup (78 mg, 77%) together with 10 mg (10%) of compound 10.
1H NMR (300 MHz, CDCl3): δ = 2.05–2.30 (m, 3 H, CH2CH2N
and CH2CHOH), 2.49 and 2.51 (s, 3 H, CH3), 2.58 and 2.71 (d, J
= 14.5 Hz, and ddd, J1 = 14.3, J2 = 5.2, J3 = 2.1 Hz, 1 H,
CH2CHOH), 2.81 and 3.30 (d, J = 5.0 Hz, and d, J = 9.0 Hz, 1 H,
OH), 3.60–4.55 (m, 2 H, CH2CH2N), 4.39 and 4.53 (d, J = 5.0 Hz,
and dd, J1 = 5.7, J2 = 2.1 Hz, 1 H, NCH), 5.61 and 5.64 (s, 1 H,
H2C=C), 5.61 and 5.76 (m and q, J = 5.0 Hz, 1 H, CHOH), 5.90
and 5.92 (s, 1 H, H2C=C), 6.23 and 6.37 (s, 1 H, Ar), 7.19–7.42
(m, 6 H, Ar and Ts), 7.81 and 7.79 (d, J = 8.3 Hz, and d, J =
8.3 Hz, 2 H, Ts) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.7 (CH3),
36.6 and 37.6 (CH2), 39.9 and 41.2 (CH2), 48.1 and 48.3 (CH2),
66.7 (CH), 93.8 and 95.0 (C), 99.7 and 100.4 (CH), 104.5 and 104.8
(CH), 111.0 (CH), 116.1 (CH2), 120.9 (CH), 122.9 and 123.0 (CH),
124.8 and 124.8 (CH), 127.5 and 127.8 (CH), 128.3 and 128.5 (C),
130.0 and 130.0 (CH), 137.6 (C), 138.7 (C), 143.8 and 144.0 (C),
2 H, pyrrolidine), 2.43 (s, 3 H, CH3), 3.00 (dd, J1 = 14.9, J2
=
2.5 Hz, 1 H, CH2CO), 3.14 (dd, J1 = 14.9, J2 = 8.4 Hz, 1 H,
CH2CO), 3.25 (dt, J1 = 14.2, J2 = 10.3 Hz, 1 H, CH2CH2N), 3.50
(t, J = 7.1 Hz, 2 H, pyrrolidine), 3.55–3.59 (m, 1 H, pyrrolidine),
3.63 (dt, J1 = 13.1, J2 = 10.3 Hz, 1 H, CH2CH2N), 3.73–3.81 (m,
1 H, pyrrolidine), 4.27 (dd, J1 = 8.4, J2 = 2.6 Hz, 1 H, CH), 5.01
(s, 1 H, H2C=C), 5.58 (s, 1 H, H2C=C), 6.79 (s, 1 H, Ar), 6.86 (s,
1 H, OH), 7.14 (d, J = 8.0 Hz, 2 H, Ts), 7.20–7.31 (m, 2 H, Ar),
7.36 (d, J = 8.2 Hz, 1 H, Ar), 7.51 (d, J = 8.2 Hz, 1 H, Ar), 7.58
(d, J = 8.2 Hz, 2 H, Ts) ppm. 13C NMR (75 MHz, CDCl3): δ =
21.6 (CH3), 24.5 (CH2), 26.1 (CH2), 36.8 (CH2), 37.0 (CH2), 46.2
(CH2), 46.7 (CH2), 47.7 (CH2), 62.9 (CH), 80.9 (C), 105.5 (CH),
110.7 (CH), 115.8 (CH2), 121.2 (CH), 122.8 (CH), 124.6 (CH),
127.4 (CH), 128.8 (C), 129.7 (CH), 134.0 (C), 139.9 (C), 143.7 (C),
153.8 (C), 154.0 (C), 170.6 (CO) ppm. IR (NaCl): ν = 2944,
˜
1604 cm–1. MS (ESI): m/z = 495 [M + H]+. C27H30N2O5S (494.60):
calcd. C 65.57, H 6.11, N 5.66, S 6.48; found C 65.33, H 6.31, N
5.39.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 1C NMR spectra of compounds (+)-2d, 4a–k, 8–13;
ORTEP drawing of 4a.
Acknowledgments
153.2 (C), 154.1 (C) ppm. IR (NaCl): ν = 3505, 3298, 2951,
˜
1601 cm–1.
Funding of this project by the Spanish Ministerio de Educación
2-{(2S*,3R*)-3-[1-(Benzofuran-2-yl)vinyl]-3-hydroxy-1-tosylpyrrol- y Ciencia (MEC) (MINECO, project number CTQ2012-31063) is
idin-2-yl}acetic Acid (12): Compound 4i (90 mg, 0.21 mmol) in
EtOH/CH2Cl2 (2.4 mL, 1:1) was added to a solution of EtONa
acknowledged. S. A. thanks the Spanish Ministerio de Ciencia e
Innovación (MCINN) for a pre-doctoral fellowship.
8
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30136
/KAP1
Date: 05-04-13 10:28:12
Pages: 10
Lactam Rearrangement into Fused Pyrrolidinolactones
[8]
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Received: January 29, 2013
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Published Online: ᭿
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9

Job/Unit: O30136
/KAP1
Date: 05-04-13 10:28:12
Pages: 10
S. Álvarez, G. Domínguez, A. Gradillas, J. Pérez-Castells
FULL PAPER
Lactam Rearrangement
Unsaturated ε-lactams undergo a novel
skeletal reorganization to give fused pyr-
rolidine-lactones by reaction with aromatic
α-bromo ketones in the presence of
DABCO and a base. The process involves
the formation of an ammonium salt and
subsequently a nitrogen ylide, which in-
itiates the rearrangement reaction to pro-
duce compounds structurally related to
kainates and radicamines.
S. Álvarez, G. Domínguez, A. Gradillas,
J. Pérez-Castells* ............................ 1–10
Unusual Skeletal Rearrangement of Un-
saturated Seven-Membered Lactams into
Fused Pyrrolidinolactones
Keywords: Nitrogen heterocycles / Lact-
ones / Lactams / Ylides / Diastereoselectiv-
ity / Rearrangement
10
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