Two-carbon ring enlargement of five-, six-, and seven-membered 1-aza-2-vinylcycloalk-2-enes with dimethyl acetylenedicarboxylate and subsequent thermal isomerization reactions

Article abstract of DOI:10.1515/znb-2006-0404

2-Aminodienes, in which the enamine function is incorporated in a five-, six-, or seven-membered ring, react with dimethyl acetylenedicarboxylate in a sequence of [2+2] cycloaddition and electrocyclic ring-opening to form the two-carbon ring expanded unsa

Full text of DOI:10.1515/znb-2006-0404

Two-Carbon Ring Enlargement of Five-, Six-, and Seven-Membered
1-Aza-2-vinylcycloalk-2-enes with Dimethyl Acetylenedicarboxylate
and Subsequent Thermal Isomerization Reactions*
Gerhard Maas, Robert Reinhard, and Hans-Georg Herz
Abteilung Organische Chemie I, Universita¨t Ulm, Albert-Einstein-Allee 11, D-89081 Ulm
Reprint requests to Prof. Dr. G. Maas. Fax: +49(731)5022803. E-mail: gerhard.maas@uni-ulm.de
Z. Naturforsch. 61b, 385 – 395 (2006); received October 6, 2005
2-Aminodienes, in which the enamine function is incorporated in a five-, six-, or seven-membered
ring, react with dimethyl acetylenedicarboxylate in a sequence of [2+2] cycloaddition and elec-
trocyclic ring-opening to form the two-carbon ring expanded unsaturated heterocycles, i.e., 3,4-
dicarboxylate substituted 6,7-dihydro-1H-azepines 3, 8 and 21, 1,6,7,8-tetrahydroazocines 22, and
6,7,8,9-tetrahydro-1H-azonines 13. Similarly, 2-[(2-thienyl)ethynyl]-4,5,6,7-tetrahydro-1H-azepine
9 is converted into 2-[(2-thienyl)ethynyl]-6,7,8,9-1H-azonine-3,4-dicarboxylate 10 which was char-
acterized by X-ray structure determination. The eight- and nine-membered azaheterocycles 22 and
13, which have not been isolated, undergo thermal isomerization at elevated temperatures. Thus,
ring contraction by a 6π-electrocyclic reaction takes place for N-methyl substituted azonine 13,
while the N-allyl moiety of azocines 22 engages in an intramolecular Diels-Alder reaction or a 1,7-
electrocyclization reaction.
Key words: Enamines, 2-Aminodienes, Medium-Sized Aza Heterocycles, Ring Enlargement,
Ring Contraction
Introduction
The two-carbon ring expansion of enamines de-
rived from cyclic ketones (i. e. 1-(dialkylamino)cyclo-
alkenes) with electron-deficient alkynes, in particular
acetylenic esters, has often been applied to the syn-
thesis of medium-sized carbocyclic and heterocyclic
compounds (Scheme 1, type I); see lit. [1] and cited
references. Careful investigations have shown that in
an unpolar solvent, [2+2] cycloaddition initially gener-
ates 3-amino-cyclobutenes which undergo conrotatory
ring opening to form cis,trans-cycloalkadienes [1].
The condensed cyclobutenes derived from five- and
six-membered enamines could be isolated under care-
ful work-up conditions and were found to rearrange
slowly into the cis,cis-cycloalkadienes, while the lat-
ter were obtained directly from larger-sized amino-
cycloalkenes. The cis,trans-dienes underwent thermal
isomerization to form cis,cis-cycloalkadienes more or
less readily, depending on the ring size.
Scheme 1. Ring expansion of 1-amino-cycloalkenes (type 1)
and 1-aza-2-cycloalkenes (type 2) with acetylenedicarboxy-
lates (E = CO2Me).
The two-carbon ring expansion strategy can also
be used to convert endocyclic enamines into unsatu-
rated seven-, eight-, and nine-membered azaheterocy-
cles (Scheme 1, type II) [2 – 5]. Some years ago, we
have worked out a method to prepare 1-aza-2-vinyl-
cycloalk-2-enes, i. e., semicyclic 2-amino-1,3-dienes,
with the enamine functionality incorporated in five-,
six-, and seven-membered rings [6]. We report now on
the ring expansion of these cyclic enamines with di-
methyl acetylenedicarboxylateand on subsequent ther-
mally induced isomerization reactions [7].
* Presented in part at the 7th Conference on Iminium Salts
(ImSaT-7), Bartholoma¨/Ostalbkreis, September 6 – 8, 2005.
c
0932–0776 / 06 / 0400–0385 $ 06.00 ꢀ 2006 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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G. Maas et al. · Two-Carbon Ring Enlargement
Results and Discussion
The 2-alkenyl-4,5-dihydropyrroles 1a – c were pre-
pared from the corresponding 1-((het)aryl)-2-(1-meth-
ylpyrrolidin-2-ylidene)ethan-1-one in three steps [6].
The reaction with dimethyl acetylenedicarboxylate
(DMAD) was conducted in diethyl ether below room
temperature to obtain the bicyclic [2+2] cycloaddi-
tion products 2 (Scheme 2). However, the latter could
not be separated from the reaction mixture. When the
work-up was done by Kugelrohr distillation, yellow
◦
oils distilled at ≥ 200 C/0.005 mbar which yielded
yellow crystals (45– 65% yield) that were identified as
6,7-dihydro-1H-azepine-3,4-dicarboxylates 3a – c. On
the other hand, work-up of the reaction mixture ob-
tained from 1a, b by column chromatography over sil-
ica gel yielded the (dihydropyrrolyl)maleates or fu-
marates 4a, b; since only one diastereomer was ob-
tained, the available NMR data did not allow to as-
sign the configuration at the ester-substituted olefinic
bond (δ(=CH) = 4.92 ppm). Thus, the initially formed
cycloaddition products 2 undergo the expected electro-
Scheme 3. Synthe-
sis of aminodienes
6/7 and reaction
with DMAD. Yield
of 8: 56% from 5.
substructure. Analogous reactions take place when
cyclic cyclobutene ring-opening/ring expansion reac- [2+2] cycloaddition products of 1-dialkylamino-cyclo-
alkenes and acetylenic esters are dissolved in methanol
or CDCl3 [1a, 1b, 8, 9].
tion on thermal impact, while the formation of dihy-
dropyrroles 4 can be interpreted as a proton-catalyzed
ring-opening of the push-pull-substituted cyclobutene
When the tert-butyl group in aminodienes 1 is re-
placed by a methyl group, a tautomeric equilibrium be-
tween the semicyclic 2-aminodiene form 6 and the ex-
ocyclic 1-aminodiene form 7 is possible (Scheme 3). In
contrast to the tert-butyl analogues 1, 1-aminodiene 7
(Ar = 4-chlorophenyl and 2-thienyl) has been observed
exclusively by 1H NMR spectroscopy [6]. The same is
true for the 2-furyl substituted aminodiene (7, Ar = 2-
furyl) which we have now prepared by dimethylcuprate
addition to propyne iminium salt 5 (Scheme 3). Since
7 could not be isolated in pure form, the crude prod-
uct was directly combined with DM◦AD and the mix-
ture was subsequently heated at 200 C. By analogy to
the transformation 1 → 3, dihydroazepine 8 was iso-
lated in 58% yield. This result suggests indeed that
DMAD does not react with the 1-aminodiene 7 but
rather with the minute amount of the semicyclic amin-
odiene 6 which is in dynamic equilibrium with 7.
A 7 → 9 ring expansion took place when the 2-[(2-
thienyl)ethynyl]-4,5,6,7-tetrahydro-1H-azepine 9 [10]
◦
was exposed to DMAD at ≤ 20 C (Scheme 4). Ex-
traction of the reaction mixture with ether and crystal-
◦
Scheme 2. Reaction conditions: a) Et2O, −40 C → r. t.;
b) no solvent, bulb-to-bulb distillation at 200 – 240 ◦C /
lization yielded the tetrahydro-1H-azoninedicarboxyl-
0.005 mbar (45 – 62% yield from 1a – c); c) chromatographic ate 10 in 83% yield. Again, the initial [2+2] cycload-
work-up (silica gel) (76 – 82% yield from 1a, b).
dition product was not observed because the electro-
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G. Maas et al. · Two-Carbon Ring Enlargement
387
Scheme 4. 7 → 9 Ring expansion of tetrahydroazepine 9.
Scheme 5. 7 → 9 Ring expansion of dihydroazepine 11 and
subsequent thermal isomerization. Yield of 14: 61% from
11/12.
3-aminocyclobutene-1-carboxylates may undergo the
ring opening by a disrotatory concerted electrocyclic
process [11] or stepwise via a dipolar intermediate [12]
(see also lit. [1]).
The crystal structure analysis of 10 shows that the
tetrahydro-1H-azonine ring adopts a distorted boat
conformation (Fig. 1). The dienamine moiety is not
fully conjugated, because the torsion angle between the
two double bonds (C2–C3–C4–C5) arises to −54.3◦.
On the other hand, the torsion angles of the enam-
inoester moiety N–C=C–COOMe allow extended π-
conjugation with the expected bond length changes due
to the push-pull character of this conjugated system.
In contrast to the five-membered enamine 6, the
Fig. 1. Solid-state structure of 10; ellipsoids of thermal vibra-
tion are shown at the 30% probability level. Selected bond
◦
˚
lengths [A] and torsion angles [ ]: N–C2 1.367(6), C2–C3
1.375(7), C3–C16 1.470(7), C3–C4 1.486(6), C4–C18
1.504(7), C4–C5 1.334(7), C2–C10 1.441(7), C10–C11
1.195(7); C9–N–C2–C3 −25.4(7), N–C2–C3–C4 −5.6(8),
C2–C3–C4–C5 −54.3(7). The thiophene ring is probably
disordered over two position, with a minor component re-
lated to the major one by a 180◦ rotation around the C11–C12
bond. However, this disorder model was not included in the
refinement.
cyclic ring-opening took place already at room temper- seven-membered analogue 11 is the major component
ature or below. The NMR data of 10 did not allow to in the tautomeric equilibrium with the 1-aminodiene
firmly establish the configuration of the double bonds form 12 (11:12 ≈ 2.7:1) [6] (Scheme 5). Trapping of
in the azonine ring. A crystal structure determination the more reactive 2-aminodiene form 11 with DMAD
revealed the cis,cis-configuration of 10 (Fig. 1). It is was expected to furnish tetrahydroazonine 13 by anal-
interesting to note that the reaction of 1-dialkylamino- ogy with the conversion 9 → 10. As 13 could not
cycloheptenes and -cyclooctenes with DMAD at room be isolated in pure form from the reaction mixture
temperature generates the expected two-carbon ring- by crystallization or chromatography, a bulb-to-bulb
expanded cycloalka-1,3-dienes with cis,trans config- distillation was applied which unexpectedly gave the
uration [1] which have been isolated and were trans- acyclic hexatriene 14 as a 3:1 mixture of diastere-
formed into the cis,cis-isomer on heating. Thus, it is omers. The structure of 14 was elucidated by X-ray
not clear whether cis,cis-10 is formed via the cis,trans- diffraction analysis of a crystal taken from the mixture
1
isomer, the latter resulting from an orbital symmetry- of diastereoisomers (Fig. 2). The H chemical shifts of
allowed conrotatory ring-opening of the initial [2+2] the two diastereomers are quite similar except for the
cycloaddition product (see Introduction). The possi- significantly different values of the olefinic proton at
bility has been discussed that push-pull substituted the thienyl-substituted double bond. The chemical shift
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388
G. Maas et al. · Two-Carbon Ring Enlargement
Scheme 6. Possible mechanism for the formation of triene
14; Ar = 2-thienyl, E = CO2Me.
Fig. 2. Solid-state structure of (1E,2E,4E)-14; ellipsoids
of thermal vibration are shown at the 30% probabil◦ity
figuration of 13, and the case of azonine 10, as de-
scribed above, shows that the cis,cis-form is formed al-
ready at room temperature. The electrocyclic ring con-
˚
level. Selected bond lengths [A] and torsion angles [ ]:
N–C2 1.352(4), C2–C7 1.379(5), C7–C13 1.466(5), C7–C8
1.480(4), C8–C15 1.492(4), C8–C9 1.355(5), C9–C10
1.435(4), C10–C11 1.343(5); N–C2–C7–C8 −22.1(5), C2– traction of cis,cis-13a would generate cis-fused 15A;
C7–C8–C9 −52.2(5), C7–C8–C9–C10 −0.9(5), C8–C9–
a suprafacial H shift of the latter would lead to trans-
C10–C11 172.1(4), C9–C10–C11–C17 179.3(3), C10–C11–
disubstituted 15b from which Z(3,4)-14 would result
C17–C18 172.3(3). The thiophene ring is probably disor-
after disrotatory opening of the N–C bond in the five-
dered over two position, with a minor component related to
the major one by a 180◦ rotation around the exocyclic C–C
bond. However, this disorder model was not included in the
refinement.
membered ring. Thus, if the thermal isomerization re-
ally starts with cis,cis-azonine 13, at least one of the
three steps cannot be under the predicted stereochemi-
cal control. For example, an isomerization of cis-fused
15a to trans-disubstituted 15b could be caused by (in-
termolecular) proton transfer, and the ring opening of
15b could be a thermally induced homolytic process.
The ring contraction 13 → 15a could also be con-
sidered as a transannular nucleophilic addition of the
ring nitrogen atom to the electron-deficient 4,5-double
bond. The nucleophilicity of the nitrogen atom may be
considered too low because of the partial delocaliza-
tion of its lone pair of electrons in the enaminoester
moiety (see the structure of 10 discussed above),
but conformational changes at elevated temperatures
may change this situation. Transannular interactions of
medium-sized azaheterocycles with carbonyl functions
are known [13] and have been studied by molecular
mechanics calculations [14]. Transannular cyclization
reactions such as the electrophile-induced cyclization
of unsaturated nine- and ten-membered N-benzyl lac-
tams [15] and N-nucleophilic epoxide-ring opening re-
actions of nine-membered ring lactams [16] have re-
cently been used for the synthesis of quinolizidine and
indolizidine ring systems.
of this proton is found at δ = 6.27 ppm for the major
diastereomer and at δ = 6.62 ppm for the minor, corre-
sponding to the Z and E configuration, respectively, in
line with the assignment made for the starting material,
aminodiene 11 [6]. Thus, a partial geometrical isomer-
ization of the thienyl-substituted double bond has oc-
curred, and the crystal structure has been determined
for the minor diastereoisomer 1E,2E,4E-14.
The formation of piperidinylidene-hexatriene 14
can be explained by a thermally induced isomeriza-
tion of azonine 13 (Scheme 6). Ring contraction by
transannular formation of an N–C bond yields betaine
15A which rearranges to ylide 15B by a hydrogen
shift. Ring-opening of the cyclopentene ring finally
generates 14. It should be noted that this rearrange-
ment can occur by a series of three concerted peri-
cyclic processes with defined stereochemistry: disro-
tatory 6π electrocyclization of 13, suprafacial [1,4-H]
shift of 15a, and disrotatory six-electron ring open-
ing of 15B. In order to arrive at the observed E(2,3)-
configuration of triene 14, this sequence must begin
with the cis,trans-azonine 13 which undergoes elec-
trocyclization to form trans-fused 15A. However, we
Next, we were interested to learn whether the pres-
have no spectroscopic proof of the double bond con- ence of an allyl instead of a methyl substituent on the
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G. Maas et al. · Two-Carbon Ring Enlargement
389
Scheme 7. Preparation of semicyclic N-allyl-aminodienes 18
and 19.
nitrogen atom of compounds such as dihydroazepines
3 would open other pathways for thermal isomeriza-
tion reactions. To this end, we prepared N-allyl-2,3-
dihydropyrroles 18 and N-allyl-1,2,3,4-tetrahydropyr-
idines 19 by organocuprate addition to the semicyclic
propyniminium triflates 16 and 17 [17], respectively
(Scheme 7). In all cases, only one diastereoisomer was
found to which the E configuration of the tert-butyl-
substituted C=C bond could be assigned by NOE NMR
experiments.
As none of the 2-aminodienes 18 and 19 could be
isolated in pure form, the crude products were treated
◦
directly with DMAD at ≤ 20 C. Starting from 18a, b
and by full analogy with the behavior of the N-methyl
analogues 1 (see Scheme 2), the expected initial cy-
cloaddition products 20 (n = 1) were not isolated and
the crude product mixture was heated in toluene at
120 ◦C (Scheme 8). This procedure yielded the 6,7-di-
Scheme 8. 6 → 8 Ring expansion of aminodienes 18 and
19 and subsequent thermal isomerization reactions (E =
CO2Me); (a) toluene, 120 ◦C, 5 h; (b) toluene, 160 ◦C, 5 h.
˙
hydro-1H-azepine-3,4-dicarboxylates 21a, b in 47 and
52% yield. The characteristic NMR data match those
of 3a – c. In addition, the allyl NCH2 protons were
found to be diastereotopic which indicated the persis-
tance of a chiral conformation. As the strongly broad-
ened signals of both the o,o’- and m,m’-CH groups
in 21a indicated that these nuclei were on the way
to chemical nonequivalence, it can be concluded that
steric hindrance between the N-allyl substituent and
the alkenyl group attached to C-2 restricts the free ro-
tation around the ring/substituent bonds.
tra (see Experimental Section). It is obvious that 24
and 25 are derived from N-allylazocines by subsequent
thermally induced isomerization. Conversion of mono-
cyclic 22 into tetracyclic 25 occurs by an intramolecu-
lar Diels-Alder reaction with the 2-vinylthiophene unit
as the diene component. If no suitable diene unit is
present (Ar = 4-chlorophenyl), a [1,6] shift of an al-
lylic NCH hydrogen atom generates the conjugated
azomethine ylide 23 which yields bicyclic 24 by an 8π
1,7-electrocyclic ring closure. 1,7-Electrocyclizations
of conjugated 1,3-dipoles are an established route to
seven-membered heterocycles [18].
The reaction of aminodienes 19a, b with DMAD
and subsequent heating at 160 ◦C in toluene did not fur-
nish the expected tetrahydroazocines 22 (Scheme 8).
From 4-chlorophenyl-substituted19a, the azepino[1,2-
In conclusion, semicyclic 2-amino-1,3-dienes in
a]azocine 24 was obtained in 68% yield (relative to which the enamine function is incorporated in a five-,
the precursor of 19a, iminium salt 17a), while thienyl- six-, or seven-membered ring were found to react with
substituted 19b gave the tetracyclic azocino[2,1-a]thi- DMAD at the enamine C=C bond to give two-carbon
eno[3,2-f]isoindole 25 in 42% yield. The structure of ring-expanded products, while a [4+2] cycloaddition
24 and 25 was established by X-ray crystal structure was not observed. 6,7-Dihydro-1H-azepines could be
1
determination (Figs 3 and 4) and all H and 13C NMR isolated in good yield and were thermally quite sta-
chemical shifts were assigned from 1D and 2D spec- ble at high temperatures, surviving treatment at more
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G. Maas et al. · Two-Carbon Ring Enlargement
cent alkenyl substituents. The greater conformational
flexibility of the eight- and nine-membered ring sys-
tems is likely to favor these thermal isomerization reac-
tions. The results reported here indicate once more that
the two-carbon ring expansion of endocyclic enamines
is a suitable method to prepare functionalized seven-,
eight-, and nine-membered azaheterocycles. The latter
two classes in particular, representing typical medium-
sized ring systems, have been studied relatively lit-
tle and are found only in a limited number of natural
products [2, 19]. However, some azonine and azocine
derivatives are known to have interesting pharmaceuti-
cal properties.
Fig. 3. Solid-state structure of 24; ellipsoids of thermal vibra-
tion are shown at the 30% probability level. Selected bond
Experimental Section
◦
◦
˚
lengths [A], bond angles [ ], and torsion angles [ ]: C1–C2
1.342(2), C1–C13 1.504(3), C2–C15 1.494(3), C1–C12
1.500(3), C11–C12 1.340(2), C7–C8 1.328(3); C6–N–C12
120.73(16), C6–N–C7 115.90(17), C7–N–C12 123.37(16);
C13–C1–C2–C15 1.9(3), C10–C11–C12–N −3.4(3), C6–
N–C12–C1 −32.0(2).
General methods: Solvents were dried by standard meth-
ods and were stored under an argon atmosphere. The
petroleum ether used had a boiling point range of 40 –
◦
60 C. Dimethyl acetylenedicarboxylate (DMAD) was dis-
tilled prior to use. All reactions involving aminodienes were
carried out in rigorously dried glassware and under an argon
atmosphere. Column chromatography was performed using
hydrostatic pressure (silica gel 60, Macherey-Nagel, 0.063 –
0.2 mm) or under elevated pressure using Merck Lichro-
prep Si60 columns (particle size 40 – 63 µm, two columns
of size A and B connected), a gradient pump (Merck-Hitachi
L6200) and UV detection (Gilson Spectrochrom M, λ =
254 nm). For the bulb-to-bulb distillation experiments, the
temperature of the heating mantle is given. The NMR spectra
were recorded in CDCl3 solution using as the internal stan-
dard tetramethylsilane for 1H spectra (δ = 0 ppm) and resid-
ual solvent signal (δ(CHCl3) = 77.0 ppm) for 13C spectra;
mc = centered multiplet. The signal assignment was based
on proton-coupled 13C spectra (1J(C,H) multiplicities are
given with the spectra), H,H COSY, and C,H (1J) as well as
C,H (2J, 3J) correlation spectra. IR spectra were recorded on
Perkin Elmer IR 883 and IR 1310 spectrometers. Microanal-
yses were carried out in the Analytical Laboratories of the
Universities of Ulm and Kaiserslautern.
Dimethyl 2-[(Z)-2-(4-chlorophenyl)-3,3-dimethylbut-1-
enyl]-6,7-dihydro-1-methyl-1H-azepine-3,4-dicarboxylate
(3a): A solution of aminodiene 1a◦[6] (0.83 g, 3.0 mmol) in
ether (10 ml) was cooled at −40 C and DMAD (0.41 ml,
3.3 mol) was added. The cooling bath was removed and
the mixture was stirred overnight. After removal of the
solvent at 0.01 mbar, the residual oil was submitted to
a Kugelrohr distillation. Excess DMAD was distilled
off at 120 ◦C/0.005 mbar. The temperature was raised
until a yellow oil distilled over at 220 ◦C/0.005 mbar. It
was dissolved in ether, and pentane was added until the
solution started to become turbid. Crystallization at −30 ◦C
Fig. 4. Solid-state structure of 25; ellipsoids of ther-
mal vibration are shown at the 30% probability level.
◦
˚
Selected bond lengths [A], bond angles [ ], and tor-
sion angles [◦]: C10–C11 1.338(2), C11–C12 1.488(2),
C11–C23 1.500(2), C12–C21 1.462(2), C12–C13 1.380(2),
C13–N 1.356(2), N–C6 1.458(2), C15–C16 1.337(3), C1–C2
1.315(3); C6–N–C7 117.46(15), C6–N–C13 114.21(14),
C7–N–C13 127.75(15), C11–C12–C13–N 10.3(3), C10–
C11–C12–C13 39.4(3).
than 200 ◦C (3a– c) or at 120 ◦C (21a, b). On the other
hand, the homologous azocine and azonine deriva-
tives were found to undergo a variety of thermally
induced isomerization reactions, including transannu-
lar reaction as well as cyclization or cycloaddition re-
actions involving the exocyclic N-allyl and the adja- furnished yellow crystals (0.56 g, 45%), m. p. 93 ◦C. –
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391
IR (KBr): ν = 2940 (m), 1730 – 1630 (s, broad) cm−1. – marate) (4a): The reaction of aminodiene 1a (0.83 g,
1H NMR (400.13 MHz): δ = 1.16 (s, 9 H, tBu), 1.80 – 2.15 3.0 mmol) and DMAD (0.41 ml, 3.3 mmol) was conducted
(m, br, 2 H, 6-H2), 2.67 (s, 3 H, NCH3), 2.60 – 2.85 (m, as described above for 3a. After stirring overnight, the sol-
◦
2 H, NCH2), 3.65 (s, 3 H, OCH3), 3.69 (s, 3 H, OCH3), vent was evaporated at 25 C/0.01 mbar, and the residue
6.52 (t, 1 H, J = 6.1 Hz, 5-H), 6.54 (s, 1 H, =CHexcycl.), was worked up by column chromatography (silica gel,
6.94/7.26 (AA’BB’, 4 Haryl). – 13C NMR (100.61 MHz):
δ = 27.7 (C-6), 29.2 (CMe3), 36.3 (CMe3), 41.1 (NCH3),
50.9 (OCH3), 51.9 (OCH3), 57.7 (C-7), 99.7 (s, NC=C),
124.8 (d), 127.3 (d), 129.7 (d), 132.6 (s), 133.5 (s), 135.0
(d, C-5), 138.2 (s), 151.2 (s), 157.9 (s), 168.9 (C=O), 169.9
(C=O). – C23H28ClNO4 (417.93): calcd. C 66.10, H 6.75,
N 3.35; found C 66.1, H 6.8, N 3.3.
ether/CH2Cl2 (1:1)). Crystallization from ether yielded 4a
as a yellow powder (0.95 g, 76%), m. p. 103 ◦C. – IR (KBr):
ν = 2970 (s), 2945 (s), 2920 (s), 2900 (s), 1725 (vs), 1685 (s)
cm−1. – 1H NMR (200.1 MHz): δ = 1.15 (s, 9 H, tBu),
2.25 – 2.50 (unresolved m, 2 H), 2.64 (s, 3 H, NCH3), 3.10
(t, 2 H, NCH2), 3.66 (s, 3 H, OCH3), 3.95 (s, 3 H, OCH3),
4.92 (s, 1 H, =CH–CO2Me, 5.92 (s, 1 H, CH=C–Aryl),
7.11/7.21 (AA’BB’, 4 Haryl). – 13C NMR (100.61 MHz): δ =
28.4 (NCH2CH2), 29.2 (CMe3), 35.1 (NCH3), 36.9 (CMe3),
50.8 (OCH3), 52.2 (NCH2), 52.6 (OCH3), 101.3 (CH–
CO2Me), 105.6 (s, NC=C), 113.7 (CH=C–Aryl), 127.3 (d),
130.0 (d), 132.9 (s), 136.9 (s), 146.0 s), 155.7 (s), 158.8 (s),
167.6 (C=O), 169.8 (C=O). – C23H28ClNO4 (417.93): calcd.
C 66.10, H 6.75, N 3.35; found C 65.9, H 6.8, N 3.3.
Dimethyl
2-[(Z)-2-(furan-2-yl)-3,3-dimethylbut-1-en-
yl]-6,7-dihydro-1-methyl-1H-azepine-3,4-dicarboxylate
(3b): Prepared as described for 3a, from aminodiene 1b
[6] (0.70 g, 3.0 mmol) and DMAD (0.41 ml, 3.3 mmol).
◦
Kugelrohr distillation at 200 C/0.005 mba◦r. Yellow micro-
crystalline solid (0.59 g, 53%), m. p. 84 C. – IR (KBr):
ν = 3100 (w), 2940 (s), 1710 (s), 1685 (s) cm−1. – 1H NMR
(200.1 MHz): δ = 1.22 (s, 9 H, tBu), 2.36 (virtual q, 2 H,
6-H2), 2.62 (s, 3 H, NCH3), 2.99 (m, 2 H, NCH2), 3.62 (s,
3 H, OCH3), 3.71 (s, 3 H, OCH3), 6.12 (dd, J = 3.2, 0.6 Hz,
1 H, 3-Hfuryl), 6.32 (mc, 1 H, 4-Hfuryl), 6.53 (t, J = 5.7 Hz,
1 H, 5-H), 6.58 (s, 1H, =CHexcycl.), 7.37 (dd, J = 1.7, 0.6 Hz,
1 H, 5-Hfuryl). – 13C NMR (100.61 MHz): δ = 28.5 (C-6),
29.1 (CMe3), 36.4 (CMe3), 41.0 (NCH3), 50.5 (OCH3),
51.6 (OCH3), 57.7 (C-7), 98.9 (s, NC=C), 109.5 (d),
110.0 (d), 126.5 (d), 133.5 (d, J = 160.0 Hz, C-5), 141.3
(d, J = 211.3 Hz, 5-Cfuryl), 143.6 (s), 152.3 (s), 158.5 (s),
168.7 (C=O), 170.2 (C=O). – C21H27NO5 (373.45): calcd.
C 67.54, H 7.29; N 3.75; found C 67.2, H 7.2, N 3.7.
Dimethyl 2-{2-[(Z)-2-(2-furanyl)-3,3-dimethylbut-1-en-
yl]-4,5-dihydro-1-methyl-1H-pyrrol-3-yl}maleate (or fuma-
rate) (4b): The reaction of aminodiene 1b [6] (0.69 g, 3.0
mmol) and DMAD (0.41 ml, 3.3 mmol) was conducted as de-
scribed above for 3a. After stirring overnight, the solvent was
evaporated at 25 ◦C/0.01 mbar, and the residue was worked
up by column chromatography (silica gel, ether/CH2Cl2
(1:1)). Crystallization from ether yielded 4b as light-red
crystals (0.92 g, 82%), m. p. 164 ◦C. – IR (KBr): ν =
1
2960 (m), 2900 (m), 1715 (vs), 1670 (s) cm−1. – H NMR
(400.13 MHz): δ = 1.26 (s, 9 H, tBu), 2.42 (s, 3 H, NCH3),
2.61 (mc, 2 H), 3.20 – 3.40 (unresolved m, 2 H), 3.65 (s, 3 H,
OCH3), 3.84 (s, 3 H, OCH3), 4.99 (s, 1 H, =CH–CO2Me),
5.92 (s, 1 H, CH=C–Aryl), 6.32 (dd, J = 3.3, 1.7 Hz, 1 H,
4-Hfuryl), 6.42 (dd, J = 3.3, 0.7 Hz, 1 H, 3-Hfuryl), 7.38 (dd,
1 H, J = 1.8, 0.8 Hz, 5-Hfuryl). – 13C NMR (100.61 MHz):
δ = 28.2 (NCH2CH2), 29.4 (CMe3), 33.9 (NCH3), 36.9
(CMe3), 50.6 (OCH3), 52.1 (OCH3), 52.7 (NCH2), 100.4
(=CH–CO2Me), 105.8 (s, NC=C), 110.6 (d), 111.4 (d), 115.1
(CH=C–Aryl), 141.6 (d, J = 201.8 Hz, C-5furyl), 146.2 (s),
149.5 (s), 151.6 (s), 155.7 (s), 167.6 (C=O), 169.8 (C=O). –
C21H27NO5 (373.45): calcd. C 67.54, H 7.29, N 3.75; found
C 67.0, H 7.4, N 3.6.
Dimethyl
6,7-dihydro-1-methyl-2-[(Z)-3,3-dimethyl-2-
(thiophen-2-yl)but-1-enyl]-1H-azepine-3,4-dicarboxylate
(3c): Prepared as described for 3a, from aminodiene 1c
[6] (0.74 g, 3.0 mmol) and DMAD (0.41 ml, 3.3 mmol);
Kugelrohr distillation at 240 ◦C/0.005 mbar. Yellow crystals
(0.76 g, 65%), m. p. 72 ◦C. – IR (KBr): ν = 3100 (w),
2940 (m), 1710 (s), 1680 (s), 1625 (m) cm−1. – 1H NMR
(400.13 MHz): δ = 1.22 (s, 9 H, tBu), 2.0 – 2.2 (m, 2 H,
6-H2), 2.69 (s, 3 H, NCH3), 2.7 – 3.1 (unresolved m, 2 H,
NCH2), 3.62 (s, 3 H, OCH3), 3.68 (s, 3 H, OCH3), 6.55
(t, J = 6.0 Hz, 1 H, 5-H), 6.62 (s, 1 H, =CHexocycl.), 6.73
(dd, J = 3.4, 1.2 Hz, 1 H, 3-Hthienyl), 6.94 (mc, 1 H,
4-Hthienyl), 7.21 (dd, J = 5.1, 1.1 Hz, 5-Hthienyl). – 13C NMR
(100.61 MHz): δ = 27.6 (C-6), 28.8 (CMe3), 36.0 (CMe3),
40.7 (NCH3), 50.3 (OCH3), 51.3 (OCH3), 57.8 (C-7),
99.4 (s, NC=C), 124.1 (d), 125.6 (d), 125.7 (d), 126.9 (d),
133.6 (s), 134.6 (d, J = 160.1 Hz, C-5), 138.9 (s), 154.3 (s),
157.4 (s), 168.4 (C=O), 169.4 (C=O). – C21H27NO4S
(389.51): calcd. C 64.75, H 6.99, N 3.60; found C 64.5,
H 7.0, N 3.5.
Dimethyl 2-[(Z)-2-(furan-2-yl)-3,3-dimethylbut-1-enyl]-
6,7-dihydro-1-methyl-1H-azepine-3,4-dicarboxylate (8):
(2E)-2-[2-(Furan-2-yl)prop-2-en-1-ylidene]-2,3,4,5-tetrahy-
dro-1-methyl-1H-pyrrole (7) was prepared according to a
procedure for similar aminodienes [6] and was used with-
out purification. The reaction of crude aminodiene 7 (0.57 g,
3.0 mmol) and DMAD (0.41 ml, 3.3 mmol) was car-
ried out as described above for 3a. Bulb-to-bulb distil-
lation at 200 ◦C/0.005 mbar followed by crystallization
Dimethyl 2-{2-[(Z)-2-(4-chlorophenyl)-3,3-dimethylbut-1 from ether/pentane furnished a yellow, microcrystalline solid
◦
-enyl]-4,5-dihydro-1-methyl-1H-pyrrol-3-yl}maleate (or fu- (0.58 g, 58%), m. p. 93 C. – IR (KBr): ν = 2950 (s), 1710
Unauthenticated
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392
G. Maas et al. · Two-Carbon Ring Enlargement
(sh), 1695 (s) cm−1. – 1H NMR (200.1 MHz): δ = 2.20 (d, 1 H, 4-Hthienyl), 7.11 (d, J = 3.6 Hz, 1 H, 3-Hthienyl), 7.21
4J = 1.1 Hz, 3 H, =C-CH3), 2.61 (mc, 2 H, 6-H), 2.88 (s, (d, J = 5.1 Hz, 1 H, 5-Hthienyl), 7.51 (d, J = 11.6 Hz, 1 H,
3 H, NCH3), 3.40 (t, 2 H, NCH2), 3.54 (s, 3 H, OCH3), 3.72 ester–C=CH); (1(2’)E,2E,4E)-14: δ = 6.62 (d, J = 11.6 Hz,
(s, 3 H, OCH3), 6.41 (mc, 1 H), 6.42 (“s”, 4J coupling not re- CH=C-Thienyl). – 13C (100.61 MHz): δ = 16.1 (=C–CH3),
solved, 1 H, =CHexocycl.), 6.50 (t, 1 H, J = 5.4 Hz, 5-H), 6.84 20.5 (CH2), 22.8 (CH2), 29.8 (CH2), 44.4 (NCH3), 50.5
(mc, 1 H), 7.41 (mc, 1 H). – 13C NMR (100.61 MHz): δ =
(OCH3), 51.4 (CH2), 51.7 (OCH3), 93.0 (s, NC=C), 121.3
(d, CH=C-Thienyl), 124.4 (d), 125.0 (d), 127.5 (d), 130.2 (d,
ester–C=CH), 131.3 (s), 135.7 (s), 146.5 (s), 164.1 (s, NC=),
169.36 (C=O), 169.40 (C=O). – C20H25NO4S (375.49):
calcd. C 63.98, H 6.71, N 3.73; found C 64.0, H 6.8, N 3.9.
14.3 (=C–CH3), 29.2 (C-6), 40.7 (NCH3), 50.7 (OCH3), 51.8
(OCH3), 55.6 (C-7), 98.5 (s, NC=C), 107.6 (d), 111.2 (d),
121.5 (d), 131.0 (s), 131.9 (d, J = 156.4 Hz, C-5), 133.4 (s),
142.4 (d, J = 202.4 Hz, C-5furyl) 154.7 (s), 157.5 (s), 168.9
(C=O), 170.8 (C=O). – C18H21NO5 (331.37): calcd. C 65.24,
H 6.39, N 4.23; found C 64.0, H 6.7, N 3.8.
1-Allyl-5-[(Z)-2-(4-chlorophenyl)-3,3-dimethylbut-1-en-
yl]-2,3-dihydro-1H-pyrrole (18a): To a stirred suspension
of copper(I) bromide dimethylsulfide (0.432 g, 2.1 mmol)
Dimethyl 6,7,8,9-tetrahydro-1-methyl-2-[(thiophen-2-yl)
ethynyl]-1H-azonine-3,4-dicarboxylate (10): A solution of in THF (10 ml), cooled at −70 ◦C, was slowly added a
alkynyl-enamine 9 [10] (0.65 g, 3.0 mmol) in ether (10 ml) 1.7 M solution of tert-butyl lithium in hexane (2.37 ml,
was cooled at −40 ◦C and DMAD (0.41 ml, 3.3 mmol) was 4.2 mmol). The yellow suspension was then brought at
◦
added dropwise. The cooling bath was removed and the so- −40 C within 10 min and kept at this temperature until a
lution was stirred overnight. After evaporation of the sol- homogeneous pale-yellow solution had formed which was
vent at 25 ◦C/0.01 mbar, the residue was extracted with ether cooled again at −70 ◦C. A solution of iminium salt 16a [17]
(4 × 50 ml). The extracts were combined, the solvent was (0.788 g, 2.0 mmol) in THF (10 ml) was added dropwise.
removed, and the residue was crystallized by addition of The mixture was warmed at −40 ◦C within 15 min and
CH2Cl2/ether and cooling at −30 ◦C. Yellow crystals (0.89 g, kept at this temperature for 1 h, then brought to r. t. within
◦
83%), m. p. 114 C. – IR (KBr): ν = 3060 (w), 2920 (s), 2 h, whereupon a black color appeared. The solvent was
2180 (s, C ≡ C), 1700 (vs), 1670 (vs) cm−1. – 1H NMR evaporated at 0.01 mbar and the residue was extracted with
(400.13 MHz): δ = 1.60 – 1.88 (m, 4 H), 2.26 (mc, 2 H), pentane (3 × 50 ml). The extracts were combined and the
3.03 (s, 3 H, NCH3), 3.34 (mc, 2 H, NCH2), 3.68 (s, 3 H, solvent was completely evaporated at 0.01 mbar to leave
OCH3), 3.73 (s, 3 H, OCH3), 6.98 (t, J = 9.2 Hz, 1 H, 5- a yellow oil which could not be purified further and was
H), 7.02 (dd, J = 5.2, 3.8 Hz, 1 H, 4-Hthienyl), 7.33 (dd, used directly (vide infra). Yield of crude 18a: 0.520 g
J = 3.5, 1.1 Hz, 1 H, 3-Hthienyl), 7.37 (dd, J = 5.2, 1.1 Hz, (1.72 mmol, 86%). – IR (film): ν = 2960 (m), 2867 (m),
1643 (m), 1487 (m), 1171 (m), 1091 (m) cm−1. – 1H NMR
(500.14 MHz): δ = 1.09 (s, 9 H, tBu), 2.19 (mc, 2 H, 3-H2),
2.87 (t, 2 H, 2-H2), 3.40 (d, 2 H, NCH2CH=), 3.91 (mc, 1 H,
4-H), 5.12 (dd, 3J = 10.2, 2J = 1.6 Hz, 1 H, CH2CH=CH2),
5.19 (dd, 3J = 17.2, 2J = 1.6 Hz, 1 H, CH2CH=CH2),
5.83 (mc, 1 H, CH2CH=CH2), 5.95 (s, 1 H, 5-CH=),
6.95/7.26 (AA’BB’, 4 Haryl). – 13C NMR (125.77 MHz):
δ = 29.0 (C-3), 29.6 (CMe3), 36.7 (CMe3), 52.4 (C-2),
55.3 (NCH2CH=), 104.9 (C-4), 115.4 (CH=C–Aryl), 116.8
(CH2CH=CH2), 127.7 (d), 130.9 (d), 132.2 (s, C-Cl), 135.8
(CH2CH=CH2), 139.0 (s), 147.6 (CH=C–Aryl), 153.0 (s,
C-5). – C19H24ClN (301.86).
1 H, 5-Hthienyl). – 13C NMR (100.61 MHz): δ = 22.7 (CH2),
24.9 (CH2), 27.5 (CH2), 41.1 (NCH3), 49.8 (CH2), 51.1
(OCH3), 51.8 (OCH3), 88.4 and 91.7 (C≡C), 104.4 (s, C-3),
122.0 (s), 127.1 (d), 128.7 (d), 132.4 (s), 132.9 (d), 142.0 (d,
J = 156.8 Hz, C-5), 142.2 (s), 168.0 (C=O), 168.2 (C=O). –
C19H21NO4S: calcd. C 63.49, H 5.89, N 3.90; found C 63.5,
H 5.8, N 3.9.
Dimethyl (1(2’)E,2E,4Z)- and (1(2’)E,2E,4E)-1-(1-meth-
ylpiperidin-2-ylidene)-5-(thiophen-2-yl)hexa-2,4-diene-1,2-
dicarboxylate (14): A solution of aminodiene 11/12 [6]
◦
(0.70 g, 3.0 mmol) in ether (10 ml) was cooled at −40 C
and DMAD (0.41 ml, 3.3 mmol) was added dropwise. The
solution was brought to r. t. and submitted to a Kugelrohr
1-Allyl-5-[(Z)-3,3-dimethyl-2-(thiophen-2-yl)but-1-enyl]-
distillation. Excess DMAD was distilled off at 100 – 2,3-dihydro-1H-pyrrole (18b): The synthesis was achieved
120 ◦C/0.005 mbar. At 230 ◦C/0.005 mbar, a red oil distilled as described for 18a, from a solution of (t-Bu)2CuLi·LiBr
over from which orange crystals were obtained after crys- (4.2 mmol) in THF (10 ml) and a solution of iminium
tallization from ether/pentane. Yield: 0.69 g (61%); mixture salt 16b [17] (0.731 g, 2.0 mmol) in THF (10 ml). An
of diastereomers, (1(2’)E,2E,4Z):(1(2’)E,2E,4E) = 3:1. orange oil was obtained which could not be purified further
M. p. 119 ◦C. – IR (KBr): ν = 2930 (m), 1670 (s, br) and was used directly (vide infra). Yield of crude 18b:
cm−1. – 1H NMR (400.13 MHz) of (1(2’)E,2E,4Z)-14: 0.494 g (90%). – IR (film): ν = 3070 (w), 2962 (m),
δ = 1.72 – 1.84 (m, 4 H, NCH2CH2CH2), 2.30 (s, 3 H, 2865 (m), 1613 (m), 1462 (m), 1224 (m) cm−1. – 1H NMR
=C-CH3), 2.56 (s, 3 H, NCH3), 3.06 – 3.19 (m, 4 H), 3.59 (500.14 MHz): δ = 1.14 (s, 9 H, tBu), 2.20 (t, 2 H, 3-H2),
(s, 3 H, OCH3), 3.75 (s, 3 H, OCH3), 6.27 (broadened d, 2.90 (t, 2 H, 2-H2), 3.39 (d, 2 H, NCH2CH=), 4.20 (t, 1 H,
3J = 11.6 Hz, CH=C–Thienyl), 6.99 (dd, J = 5.1, 3.7 Hz, 4-H), 5.11 (dd, 3J = 10.3, 2J = 1.6 Hz, 1 H, CH2CH=CH2),
Unauthenticated
Download Date | 11/18/19 3:17 AM

G. Maas et al. · Two-Carbon Ring Enlargement
393
5.18 (dd, 3J = 17.1, 2J = 1.8 Hz, 1 H, CH2CH=CH2),
Dimethyl 1-allyl-2-[(Z)-2-(4-chlorophenyl)-3,3-dimeth-
5.83 (mc, 1 H, NCH2CH=), 6.06 (s, 1 H, CH=C–Thienyl), ylbut-1-enyl]-6,7-dihydro-1H-azepine-3,4-dicarboxylate
3
4
6.69 (dd, J = 3.4, J = 1.2 Hz, 1 H, 3-Hthienyl), 6.94 (dd, (21a): Freshly prepared crude aminodiene 18a (0.520 g,
3J = 5.0, J = 3.4 Hz, 1 H, 4-Hthienyl), 7.21 (dd, J = 5.0,
4J = 1.0 Hz, 1 H, 5-Hthienyl). – 13C NMR (125.77 MHz):
δ = 29.0 (C-3), 29.5 (CMe3), 36.8 (CMe3), 52.3 (C-2), 55.4
(NCH2CH=), 104.2 (C-4), 116.6 (CH2CH=CH2), 119.9
(CH=C–Thienyl), 124.4 (C-5thienyl), 126.0 (C-4thienyl), 126.5
(C-3thienyl), 135.8 (NCH2CH=), 140.3 (C-2thienyl), 146.6
(CH=C–Thienyl), 147.7 (s, C-5). – C17H23NS (273.44).
1-Allyl-6-[(Z)-2-(4-chlorophenyl)-3,3-dimethylbut-1-en-
yl]-1,2,3,4-tetrahydropyridine (19a): The synthesis was per-
formed as described for 18a, from a solution of (t-
Bu)2CuLi·LiBr (4.2 mmol) in THF (10 ml) and a solu-
tion of iminium salt 17a [17] (0.759 g, 2.0 mmol) in THF
(10 ml). A yellow oil was obtained which could not be pu-
rified further and was used directly (see below). Yield of
crude 19a: 0.555 g (88%). – IR (film): ν = 3074 (w), 2960,
1686, 1591, 1487, 1392, 1245 (all m) cm−1. – 1H NMR
(500.14 MHz): δ = 1.08 (s, 9 H, tBu), 1.48 (quin, 2 H,
3-H2), 1.73 (mc, 2 H, 4-H2), 2.79 (t, 2 H, 2-H2), 3.48
(d, 2 H, NCH2CH=), 4.08 (s, 1 H, 5-H), 5.09 (d, 3J =
10.3 Hz, 1 H, CH2CH=CH2), 5.14 (d, 3J = 17.4 Hz, 1 H,
CH2CH=CH2), 5.76 (mc, 1 H, CH2CH=CH2), 6.00 (s, 1 H,
CH=C–Aryl), 6.94/7.21 (AA’BB’, 4 H, Haryl). – 13C NMR
(125.77 MHz): δ = 21.1 (C-3), 22.7 (C-4), 29.7 (CMe3),
36.3 (CMe3), (C-2), 54.8 (NCH2CH=), 104.0 (C-5), 116.1
(CH2CH=CH2), 123.3 (CH=C–Aryl), 127.0 (d), 131.1 (d),
131.6 (C-Cl), 136.4 (CH2CH=CH2), 138.6 (s), 141.6 (C-6),
151.2 (CH=C–Aryl). – C20H26ClN (315.88).
3
3
1.7 mmol) was dissolved in ether (15 ml) and cooled at
−70 ◦C. DMAD (0.233 ml, 1.9 mmol) was added dropwise
and the mixture was allowed to come to r. t. over 12 h. The
solvent was replac◦ed by toluene (5 ml) and the solution
was heated at 120 C during 5 h in a thick-walled Schlenk
tube. Evaporation of the solvent left an oil which was
first submitted to flash chromatography (10 g of silica gel,
CH2Cl2), then to column chromatography (Merck Lobar
columns, ether/petroleum ether 1:4→1:1). Yield of 21a:
0.412 g (47% rel. to iminium salt 16a); dark-yellow oil. –
1H NMR (500.14 MHz, 253 K): δ = 1.16 (s, 9 H, tBu),
1.83 – 1.92 (m, 1 H, 6-H), 2.23 – 2.41 (m, 2 H, 6-H, 7-H),
2.85 – 2.93 (m, 1 H, 7-H), 3.06 (dd, 2J = 15.1, 3J = 8.1 Hz,
1 H, NCH2CH=), 3.68 (s, 3 H, OCH3), 3.72 (s, 3 H, OCH3),
4.34 (d, 2J = 14.8 Hz, 1 H, NCH2CH=), 5.10 – 5.19 (m,
2 H, CH2CH=CH2), 5.61 (mc, 1 H, CH2CH=CH2), 6.52
(t, 1 H, 5-H), 6.56 (s, 1 H, CH=C-Aryl), 6.80 – 7.00 (broad
coalescing signal, 2 Haryl), 7.24 – 7.35 (m, 2 H, Haryl). –
13C NMR (125.77 MHz, 253 K): δ = 28.9 (CMe3), 29.5
(C-6), 36.2 (CMe3), 51.1 (OCH3), 52.1 (OCH3), 54.8
(C-7), 56.9 (NCH2CH=), 99.9 (C-3), 117.8 (CH2CH=CH2),
123.9 (CH=C-Aryl), 127.2 (broadened d, o/m-Caryl), 132.2
(s, 2 C, C1aryl, C-4), 134.0 (CH2CH=CH2), 135.1 (d,
C-5), 137.7 (s, C-Cl), 151.6 (s, C-2), 158.0 (s, =C–Aryl),
169.1 (C=O), 170.4 (C=O). – C25H30ClNO4 (443.97):
calcd. C 67.63, 6.81, N 3.15; found C 68.19, H 6.69,
N 3.17.
1-Allyl-6-[(Z)-3,3-dimethyl-2-(thiophen-2-yl)but-1-en-
Dimethyl 1-allyl-2-[(Z)-3,3-dimethyl-2-(thiophen-2-yl)-
yl]-1,2,3,4-tetrahydropyridine (19b): As described above but-1-enyl]-6,7-dihydro-1H-azepine-3,4-dicarboxylate
for 18a, the compound was prepared from a solution of (21b): The preparation was carried out as described for 21a,
(t-Bu)2CuLi·LiBr (4.2 mmol) in THF (10 ml) and a solution from crude aminodiene 18b (0.494 g, 1.8 mmol) and
of iminium salt 17b [17] (0.759 g, 2.0 mmol) in THF DMAD (0.246 ml, 2.0 mmol) in ether (15 ml). Yield of
(10 ml). A yellow oil was obtained which could not be 21b: 0.434 g (52% rel. to iminium salt 16b); yellow oil. –
purified further and was used directly (vide infra). Yield IR (film): ν = 2950 (m), 1720 (s), 1536 (m), 1434 (m),
of 19b: 0.523 g (91%). – IR (film): ν = 3070 (w), 2954, 1252 (s), 1123 (m) cm−1. – 1H NMR (500.14 MHz, 253 K):
2833, 1632, 1462, 1434, 1360, 1225, 1171, 1129 (all m) δ = 1.21 (s, 9 H, tBu), 2.02 – 2.12 (m, 1 H, 6-H), 2.24 – 2.35
cm−1. – 1H NMR (500.14 MHz): δ = 1.14 (s, 9 H, tBu), (m, 1 H, 6-H), 2.53 (pseudo-t, 1 H, 7-H), 2.88 – 2.97 (m,
1.55 (quin, 2 H, 3-H2), 1.79 (mc, 2 H, 4-H2), 2.84 (t, 2 H, 1 H, 7-H), 3.18 (dd, 2J = 15.0 Hz, 3J = 8.1 Hz, 1 H,
2-H2), 3.48 (d, 2 H, NCH2CH=), 4.29 (s, br, 1 H, 5-H), NCH2CH=), 3.68 (s, 3 H, OCH3), 3.73 (s, 3 H, OCH3), 4.23
5.10 (dd, 3J = 10.2, 2J = 1.8 Hz, 1 H, CH2CH=CH2), 5.16 (broadened, 2J ≈ 15 Hz, 1 H, NCH2CH=), 5.09 – 5.18 (m,
(dd, 3J = 17.1, 2J = 1.7 Hz, 1 H, CH2CH=CH2), 5.80 (mc, 2 H, CH2CH=CH2), 5.63 (mc, 1 H, CH2CH=CH2), 6.54
1 H, NCH2CH=), 6.09 (s, 1 H, CH=C–Thienyl), 6.71 (dd, (t, 1 H, J = 5.4 Hz, 5-H), 6.63 (s, 1 H, CH=C–Thienyl),
4
3
3
4
3J = 3.5, J = 1.1 Hz, 1 H, 3-Hthienyl), 6.92 (dd, J = 5.1, 6.70 (dd, J = 3.5, J = 1.2 Hz, 1 H, 3-Hthienyl), 6.96 (dd,
3J = 3.5 Hz, 1 H, 4-Hthienyl), 7.18 (dd, 3J = 5.1, 4J = 1.2 Hz, 3J = 5.1, J = 3.5 Hz, 1 H, 4-Hthienyl), 7.22 (dd, J = 5.1,
1 H, 5-Hthienyl). – 13C NMR (125.77 MHz): δ = 21.1 (C-3), 4J = 1.2 Hz, 1 H, 5-Hthienyl). – 13C NMR (125.77 MHz,
22.9 (C-4), 29.7 (CMe3), 36.6 (CMe3), 47.5 (C-2), 55.3 253 K): δ = 28.9 (CMe3), 30.1 (C-6), 36.4 (CMe3), 51.1
(NCH2CH=), 103.4 (C-6), 116.2 (CH2CH=CH2), 123.8 (OCH3), 52.1 (OCH3), 54.6 (C-7), 56.7 (NCH2CH=),
(C-5thienyl), 125.8 (C-4thienyl), 126.5 (CH=C–Thienyl), 126.7 100.0 (s, C-3), 118.1 (CH2CH=CH2), 124.5 (C-5thienyl),
(C-3thienyl), 136.6 (NCH2CH=), 140.8 (s, C-2thienyl), 142.1 126.0 (d, 2 C, C-3thienyl, C-4thienyl), 126.4 (CH=C–thienyl),
3
3
(s, C-6), 145.0 (CH=C–Thienyl). – C18H25NS (287.46).
132.1 (s, C-4), 134.1 (CH2CH=CH2), 134.9 (d, C-5),
Unauthenticated
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394
G. Maas et al. · Two-Carbon Ring Enlargement
Table 1. Summary of crystallographic data and structure refinement for compounds 10, (1E,2E,4E)-14, 24, and 25.
10
(1(2’)E,2E,4E)-14 24
25
Empirical formula
Formula weight
Temperature (K)
Crystal size [mm]
Crystal system
Space group
C19H21NO4S
359.43
293(2)
C20H25NO4S
375.47
C26H32ClNO4
457.98
293(2)
C24H31NO4S × 0.5C3H6O a
458.60
293(2)
293(2)
0.75×0.50×0.35 0.60×0.35×0.25 0.38×0.19×0.12 0.54×0.27×0.11
orthorhombic
P bca
triclinic
monoclinic
P 21/n
monoclinic
P 21/n
P -1
˚
a [A]
14.536(3)
11.447(2)
22.273(4)
90
90
90
8.807(2)
10.463(2)
10.776(2)
97.20(3)
93.77(3)
96.40(3)
975.8(3)
2
12.637(2)
13.786(1)
14.149(2)
90
100.41(2)
90
6.3962(4)
22.652(1)
17.276(1)
90
99.93(9)
90
˚
b [A]
˚
c [A]
α [◦]
β [◦]
γ [◦]
3
˚
Volume [A ]
Z
3706.1(12)
8
2424.4(5)
4
2465.3(3)
4
ρber [g·cm−3
]
1.288
1.278
1.255
1.235
µ(Mo-Kα ) [cm−1
]
0.20
0.19
0.19
0.16
θ Range [◦]
2.20 – 23.50
−1 ≤ h ≤ 16
−1 ≤ k ≤ 12
−24 ≤ l ≤ 1
3496
1.91 – 24.00
−1 ≤ h ≤ 10
−11 ≤ k ≤ 11
−12 ≤ l ≤ 12
3730
1.99 – 25.96
−14 ≤ h ≤ 15
−16 ≤ k ≤ 16
−17 ≤ l ≤ 17
18673
2.16 – 25.92
−7 ≤ h ≤ 7
−27 ≤ k ≤ 27
−21 ≤ l ≤ 21
21317
Index ranges
Reflections collected
Independent reflections (R
)
27408 (0.0302)
99.9
3054 (0.0345)
99.8
4691 (0.0707)
98.8
4582 (0.0277)
95.6
int
Completeness to θmax [%]
Data / restraints / parameters
2740/ 0 / 265b
1.057
3054 / 0 / 332c
1.050
4691 / 0 / 294d
0.764
4582 / 3 / 303d
0.913
Goodness-of-fit on F2
e
Final R indices [I > 2σ(I)]: R1, wR2
R Indices (all data): R1, wR2
0.0757, 0.1869
0.1278, 0.2224
0.49, −0.70
0.0615, 0.1671
0.0842, 0.1856
0.48, −0.43
0.0376, 0.0714
0.0977, 0.0816
0.14, −0.17
b
0.0395, 0.1121
0.0568, 0.1226
0.33, −0.20
f
−3
˚
Largest diff. peak and hole [e·A
]
a
Acetone hemisolvate; the acetone molecule is disordered around an inversion centre;
hydrogen atom positions at the azonine ring
were taken from a ∆F map and refined freely; all other hydrogen positions were calculated and treated as riding on their bond neighbors;
c
all hydrogen atom positions were taken from a ∆F map and refined with isotropic temperature factors, except for H(18) (calculated
d
position, riding model);
hydrogen atoms were calculated geometrically and treated as riding on their bond neighbors; the H atoms of
the disordered acetone molecule in 26 were not located; refinement based on F2 values;
Fc2)2)/Σw(Fo2)2]1/2
R1 = ΣꢀFo|−|Fcꢀ/Σ|Fo|; wR2 = [Σ(w(Fo −
e
f
2
.
3
139.0 (s, C-2thienyl), 146.5 (s, =C–thienyl), 158.3 (s, C-2), t, 1 H, 4-H), 5.50 (d, J = 9.8 Hz, 1 H, 5-H), 5.54 (s, 1 H,
169.1 (C=O), 170.6 (C=O). – C23H29NO4S (415.55): 1-H), 7.12 – 7.24 (m, 4 H, Haryl). – 13C NMR (125.77 MHz,
calcd. C 66.48, H 7.03, N 3.37; found C 66.68, H 6.95, 250 K): δ = 23.2 (t, C-8), 24.9 (t, C-9), 25.8 (broadened q,
N 3.58.
CMe3) 25.8 (t, C-10), 31.7 (t, C-3), 36.7 (CMe3), 50.0 (t,
C-7), 52.6 (OCH3), 52.7 (OCH3), 54.7 (s, C-2), 102.3 (d, C-
4), 119.3 (d, C-1), 126.1/126.5 (both d, o-Caryl), 129.7 (d,
C-5), 130.4 (s, C-Cl), 130.8/132.8 (both d, m-Caryl), 134.9
(s, C-11), 137.0 (s, C-12a), 140.3 (s, C-12), 142.7 (s, C-
1aryl), 167.7 (C=O), 170.0 (C=O). – C26H32ClNO4 (458.00):
calcd. C 68.19, H 7.04, N 3.06; found C 68.00, H 7.17,
N 2.97.
Dimethyl 2-(tert-butyl)-2-(4-chlorophenyl)-2,3,7,8,9,10-
hexahydroazepino[1,2-a]azocine-11,12-dicarboxylate (24):
The preparation was carried out as described for 21a, from
crude aminodiene 19a (0.555 g, 1.76 mmol) and DMAD
(0.233 ml, 1.90 mmol)◦in ether (15 ml). Conditions for ther-
molysis: toluene, 160 C, 5 h. The product was purified by
flash chromatography (10 g of silica gel, CH2Cl2) and re-
crystallized from ethanol. Yield of 24: 0.626 g (68% rel.
13-(tert-Butyl)-3a,4,4a,5,7,8,9,12b-octahydroazocino-
◦
to iminium salt 17a); light-yellow crystals, m. p. 124 C. – [2,1-a]thieno[3,2-f]isoindole-11,12-dicarboxylate (25): The
IR (KBr): ν = 3045 (w), 2952 (m), 1731 (s), 1713 (s), preparation was carried out as described for 21a, from crude
1432 (m), 1263 (s) cm−1. – 1H NMR (500.14 MHz, 250 K): aminodiene 19b (0.523 g, 1.8 mmol) and DMAD (0.246 ml,
δ = 0.85 (broadened s, 9 H, tBu), 1.26 – 1.37 (m, 2 H, 8-H, 2.0 mmol) in ether (15 ml). Conditions for thermolysis:
9-H), 1.63 – 1.76 (m, 1 H, 8-H), 1.86 (quin, 1 H, 9-H), 2.40 – toluene, 160 ◦C, 5 h. The product was purified by flash
2.51 (m, 2 H, 3-H, 10-H), 2.58 – 2.70 (m, 2 H, 7-H, 10-H), chromatography (10 g of silica gel, CH2Cl2) followed by
2.92 (d, J = 15.2, 8.4 Hz, 1 H, 3-H), 3.27 (virtual t, 1 H, 7- column chromatography (silica gel, ethyl acetate/petroleum
H), 3.82 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3), 4.53 (virtual ether 1:3) and was recrystallized from acetone/petroleum
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G. Maas et al. · Two-Carbon Ring Enlargement
395
ether. Yield of 25: 0.364 g (42% rel. to iminium salt X-ray crystal structure determinations
17b); light-yellow crystals, m. p. 124 ◦C. – IR (KBr):
ν = 2940 (m), 1713 (s), 1550 (s), 1241 (vs) cm−1. –
Data collection was performed on a four-circle diffrac-
tometer (Siemens P4) for 10 and (1(2’)E,2E,4E)-14 and on
an imaging-plate diffractometer (STOE IPDS) for 24 and
25, using monochromatized Mo-Kα radiation. No absorp-
tion correction was applied. The structures were solved by
direct methods and refined by a full-matrix least-squares
procedure based on F2 values using the program package
SHELX-97 [20]. Crystallographic data and refinement de-
tails are given in Table 1.
CCDC-281834 (10), -281835 (1(2’)E,2E,4E-14),
-281836 (24) and -281837 (25) contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html [or from the Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge CB2 1EZ,
UK; fax: (internat.) +44-1223/336-033; E-mail: deposit@
ccdc.cam.ac.uk].
1H NMR (500.14 MHz): δ = 1.08 – 1.19 (m, 1 H, 8-H),
1.33 (s, 9 H, tBu), 1.35 – 1.45 (m, 1 H, 4-H), 1.67 – 1.83 (m,
2 H, 8-H, 4-H), 1.92 – 2.01 (m, 1 H, 4a-H), 2.29 – 2.47 (m,
2 H, 9-H), 2.87 (dd, J = 14.1, 3.6 Hz, 1 H, 7-H), 3.04 (d,
J = 9.8 Hz, 1 H, 5-H), 3.57 (dd, J = 9.8, 4.9 Hz, 1 H, 5-H),
3.52 (s, 3 H, OCH3), 3.69 (s, 3 H, OCH3), 3.98 (t, 1 H, 7-H),
4.17 – 4.24 (m, 1 H, 3a-H), 4.30 (d, J = 6.0 Hz, 1 H, 12b-H),
5.63 (dd, J = 6.2, 2.8 Hz, 1 H, 3-H), 6.14 – 6.20 (m, 2 H,
2-H, 10-H). – 13C NMR (125.77 MHz): δ = 13.5 (t, C-8),
24.9 (t, C-9), 28.7 (CMe3), 31.3 (d, C-4a), 36.0 (CMe3),
37.6 (t, C-4), 44.5 (t, C-7), 50.9 (d, C-3a), 51.1 (OCH3), 51.5
(d, C-12b), 51.9 (OCH3), 59.6 (t, C-5), 89.4 (s, C-12), 124.0
(d, C-2), 125.6 (d, C-3), 131.3 (d, C-10), 135.2 (s, 2 C, C-11,
C-13a), 135.4 (s, C-13), 159.9 (s, C-12a), 169.6 (C=O),
169.9 (C=O). – C24H31NO4S (429.57): calcd. C 67.10,
H 7.27, N 3.26; found C 66.03, H 7.29, N 3.02.
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Unauthenticated
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