Solvent-enhanced diastereo- and regioselectivity in the pd IIcatalyzed synthesis of six- and eight-membered heterocycles via cis-aminopalladation

Article abstract of DOI:10.1002/chem.200900477

The Pd^II-catalyzed intramolecular oxidative cyclization of tosyl-protected cis- and frans-N-allyl-2-aminocyclohexanecarboxamides was examined, and efficient syntheses of cyclohexane-fused pyrimidin-4-ones and l,5-diazocin-6-ones were developed.

Full text of DOI:10.1002/chem.200900477

DOI: 10.1002/chem.200900477
II
Solvent-Enhanced Diastereo- and Regioselectivity in the Pd -Catalyzed
Synthesis of Six- and Eight-Membered Heterocycles via
cis-Aminopalladation
[
a]
[a]
[a]
[c]
ꢀ
rpꢁd Balꢁzs, Anasztꢁzia Hetꢂnyi, Zsolt Szakonyi, Reijo Sillanpꢃꢃ, and
[a, b]
Ferenc Fꢄlçp*
II
Abstract: The Pd -catalyzed intramolecular oxidative cyclization of tosyl-protected
cis- and trans-N-allyl-2-aminocyclohexanecarboxamides was examined, and effi-
cient syntheses of cyclohexane-fused pyrimidin-4-ones and 1,5-diazocin-6-ones
were developed. In the course of the research, a marked solvent effect was ob-
Keywords: allylic compounds
amination domino reactions
oxidation · palladium
·
·
·
II
served on both the regio- and diastereoselectivity. Additionally, a novel Pd -medi-
ated domino oxidation, oxidative amination reaction was discovered. Our experi-
mental and theoretical findings suggest that the reactions proceed via a cis-amino-
palladation mechanism.
[
4]
Introduction
ing marked solvent and base effects, together with our par-
ticular interest in the synthesis and transformation of alicy-
II
[5]
The Pd -mediated intramolecular oxidative “Wacker-type”
cyclization is an efficient and valuable method for the con-
struction of diverse nitrogen-containing heterocycles.
clic b-amino acid derivatives, the aim of the present work
was to investigate the cyclization properties of cis- and
trans-N,N-diallyl- (5, 7) and N-allyl-N-methyl-2-tosylamino-
[1]
II
Since, the olefin moiety is preserved in the product, this
type of transformation is also important for target- and di-
cyclohexanecarboxamides (6, 8) in Pd -catalyzed intramo-
lecular oxidative aminations. We have paid special attention
to the possible stereochemical outcome of the transforma-
tions and to the effects of the marked difference between
the calculated pK values of the tosyl-protected cyclohexyla-
mine-type nitrogen and the analogous aniline-type nitro-
[2]
versity-oriented synthesis. However, the exact mechanism
underlying this transformation has not been fully revealed
[1k]
to date, though it would be a powerful tool for the devel-
a
II
[3]
opment of enantioselective Pd -catalyzed cyclizations.
[4]
In view of the report by Beccalli et al. on the oxidative
Pd -mediated cyclization of N-allylanthranilamides, involv-
gen (9.9 vs 7.2).
II
Results and Discussion
[
a] ꢀ. Balꢁzs, Dr. A. Hetꢂnyi, Dr. Z. Szakonyi, Prof. Dr. F. Fꢃlçp
Institute of Pharmaceutical Chemistry
University of Szeged
The synthetic route towards the starting carboxamides 5–8 is
depicted in Scheme 1. Tosylation of the starting racemic cis-
and trans-2-aminocyclohexanecarboxylic acids (1, 2), fol-
lowed by transformation into their acyl chlorides and subse-
quent reaction with allylamines, led to the desired protected
6
720 Szeged, Eçtvçs u. 6 (Hungary)
Fax : (+36)62-545-705
E-mail: fulop@pharm.u-szeged.hu
[
b] Prof. Dr. F. Fꢃlçp
Stereochemistry Research Group
of the Hungarian Academy of Sciences
University of Szeged
[5]
amides 5–8 in acceptable overall yields (36–41%).
Application of the cyclization conditions reported by Bec-
6
720 Szeged, Eçtvçs utca 6 (Hungary)
[4]
calli et al. (10 mol% Pd
ACHTUNGENTRNUNG( OAc) , 1 equiv NaOAc, DMSO,
2
[
c] Prof. Dr. R. Sillanpꢄꢄ
Department of Chemistry, University of Jyvꢄskylꢄ
1
008C) to 5 resulted in the rapid formation of palladium
black and recovery of the unreacted starting material. Since
the application of a phase-transfer catalyst had proved bene-
4
0351 Jyvꢄskylꢄ (Finland)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900477.
[6]
ficial in Pd-mediated transformations, an additional one
7376
ꢅ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 7376 – 7381

FULL PAPER
Table 2. Investigation of the effect of the solvent on the cyclization of trans-car-
boxamides.
T
Reaction
time [h]
Entry Compound R
Solvent
[
8C]
[
a]
[b]
1
2
3
4
5
6
7
8
7
7
7
7
7
8
8
16
allyl
allyl
allyl
allyl
allyl
Me
110 DMSO 2
110 toluene 0.5
42 (32)
21
58 (44)
79
87 (72)
55
Scheme 1. Synthesis of the starting allyl carboxamides 5–8.
82 MeCN
110 DMF 1.5
110 NMP 1.5
110 DMSO 3
4
13 (6)
45
equivalent of nBu NCl was utilized, which led to the forma-
4
33
66
tion of 9 as a single diastereomer in 45% yield (Scheme 2).
Finally, performing the reaction under an atmosphere of O2
64 (54)
28 (12)
15 (9)
36 (21)
72 (61)
85 (67)
Me
82 MeCN
4
4
[
c]
PMB 82 MeCN
(
balloon) provided 9 in 69% yield at 1108C (Table 1,
1
entry1).
[a] Calculated ratio based on H NMR. [b] Isolated yields in parenthesis.
[
c] PMB=p-methoxybenzyl.
Table 1. Investigation of the effect of the solvent on the cyclization of
cis-carboxamides.
Entry Compound
R
T [8C] Solvent Reaction Product Yield [%]
time [h]
1
2
3
4
5
5
6
6
Allyl 110
Allyl 110
Me 130
Me 110
DMSO
4
9
69
76
52
84
[
a]
toluene 1.5
DMSO 20
toluene 2.5
9+11
10
10
[
a] Combined yield of C-2 epimers.
II
Scheme 3. Pd -mediated oxidative cyclization of trans-carboxamides.
studies and X-ray crystallography as trans-cyclohexane-fused
1
,5-diazocin-6-one (Figure 1).
Since, Pd-catalyzed 8-endo-trig cyclization is rare and the
synthesis of medium-sized heterocycles is always a challeng-
II
Scheme 2. Pd -mediated oxidative cyclization of cis-carboxamides.
Reaction of cis-N-allyl-N-methyl analogue 6 with the opti-
mized conditions gave the single diastereomer 10 in 52%
yield, even after prolonged heating (Table 1, entry 3). Be-
cause of the significant solvent effect on this type of trans-
[4]
formation, we also performed the reaction in refluxing tol-
uene. Full conversion of 5 was observed within 1.5 h, and a
55:45 C-2 epimeric mixture of 9 and 11 was isolated in 76%
combined yield (Table 1, entry 2). In order to exclude the
possibility of product isomerization, 9 was subjected to iden-
tical conditions as shown in entry 2, but no formation of 11
was detected even after 2 h. The transformation of 6 in re-
fluxing toluene gave 10 in an excellent yield (84%) within
Figure 1. Ortep view of 14. Thermal displacement parameters are drawn
at 20% probability.
2.5 h (Table 1, entry 4).
When the optimized conditions were applied to the cycli-
zation of trans-amides 7 and 8 (Scheme 3), the reaction was
first performed in DMSO at 1108C and reached completion
within 2 h (Table 2, entry 1).
ing task, we targeted the selective preparation of the diazo-
cinone structure obtained. This uncommon structure is also
valuable as concerns natural product and peptidomimetic
[7]
[8]
The transformation provided a close to 1:1 mixture of two
products. The first-eluted compound 12 was identified as the
transanellated analogue of 9. However, the latter-eluted
component 14 was identified by two-dimensional NMR
synthesis. In an investigation of the effect of the reaction
medium on the regioselectivity, the H NMR spectrum of
the crude product indicated that diazocinone 14 was formed
as the major product in refluxing toluene in an approximate
1
Chem. Eur. J. 2009, 15, 7376 – 7381
ꢅ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7377

F. Fꢃlçp et al.
ratio of 4:1 with compound 12 (Table 2, entry 2). In reflux-
ing acetonitrile, a ratio of 87:13 was achieved, and diazoci-
none 14 was isolated in 72% yield (Table 2, entry 3). To
confirm that the observed regioselectivity is truly solvent-de-
pendent, but not temperature-dependent, a control experi-
ment was performed in toluene at 808C. The outcome was a
ratio of 4:1, identical to that observed in refluxing toluene.
Further efforts to make the reaction more selective resulted
in lower ratios (Table 2, entries 4 and 5). In the reaction on
the N-allyl-N-methyl-substituted compound 8, acetonitrile
displayed a lower regioselectivity for compound 15 (Table 2,
entry 7). Interestingly, the cyclization of 8 in DMSO gave
the pyrimidinone derivative 13 as the major product in a
ratio of 64:36 (Table 2, entry 6). In order to broaden the
scope of the transformation, p-methoxybenzyl-substituted
compound 16 was synthesized according to Scheme 1. The
cyclization was complete in 4 h (Table 2, entry 8) and diazo-
cinone derivative 18 was isolated in 67% yield together with
Scheme 5. cis- vs trans-Aminopalladation in the formation of diazoci-
nones 14, 15 and 18.
Intermediate E is formed via aminopalladation of the
[1k]
double bond, and subsequent syn-b-hydride elimination
1
7 (9% yield).
from intermediate F results in compounds 14, 15 and 18. In
the case of trans-aminopalladation, intermediate G would
form and syn-b-hydride elimination could occur with either
With regards the underlying mechanism, if the reactions
proceeded via a p-allyl-palladium intermediate, seven-mem-
bered heterocycles would also have been formed, in accord
with the results of Beccalli et al. In view of the marked dif-
ference between the electron density of the tosyl-protected
aniline-type nitrogen and the protected cyclohexylamine-
type nitrogen, we suggest that, after a Pd-mediated double
1
2
H or H resulting in the double bond isomer 19 too, but
this was not observed in our experiments. However, com-
pounds 14 and 15 are thermodynamically more stable than
[
4]
À1
19 by 12 and 14 kcalmol , respectively.
The presumed mechanisms are supported by gas-phase
DFT calculations at the level of b3pw91/lanl2dz for the tran-
sition states A and C shown in Scheme 4 and E in Scheme 5.
The calculations demonstrated that, for cis-carboxamides 5
[9,10]
bond migration,
the ring-closure towards 9–13 and 17
[1k]
takes place via cis-aminopalladation, due to the stronger
coordination of the protected cyclohexylamine-type nitrogen
to the palladium moiety. (Scheme 4).
and 6, cis-aminopalladation is not favored by 15 and
À1
1
6.7 kcalmol , respectively, in the formation of intermedi-
ates 5E and 6E (see Supporting Information, Table S1).
Moreover, the calculations confirmed that in the formation
of quinazolines 10, 12, 13 and 17, cis-aminopalladation takes
place via an “upper-face” attack rather than via the “lower-
face”. In contrast, for compound 5, the calculations indicat-
ed, that aminopalladation can take place from both the
À1
“
upper” and the “lower” face (<2 kcalmol difference) as
we observed in the non-coordinating toluene. The fact that
in DMSO only compound 9 can be isolated in 69% yield re-
veals the dramatic effect of the solvent on the geometry of
the transition state, resulting in an “upper-face” attack.
As mentioned above, no formation of diazepine-type
product was observed in our experiments, which might serve
as further evidence of cis-aminopalladation. Our suggested
mechanism is depicted in Scheme 6.
Scheme 4. Proposed mechanism for the formation of quinazolinones 9–13
and 17 via cis-aminopalladation.
The formation of a diazepine-type product via cis-amino-
palladation would take place by aminopalladation of the
double bond in intermediate H,
though b-hydride elimination
would require a 1208 rotation
An initial hydropalladation involving b-hydride elimina-
tion would give intermediates A and C; subsequent cis-ami-
nopalladation of the isomerized double bond from either
the “upper” (A) or the “lower” (C) face, and a final b-hy-
dride elimination from intermediates B and D would furnish
quinazolinones 9–13 and 17.
For diazocinones 14, 15 and 18, we propose the catalytic
pathway shown in Scheme 5.
It appears feasible to assume that the reaction takes place
via cis-aminopalladation rather than trans-aminopalladation.
of the palladium moiety around
the CÀC bond (intermediate I),
which was found to be a critical
barrier and thus a potential
rate-determining step by Keith
[11]
et al.
Furthermore, the coor-
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ꢅ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 7376 – 7381

Synthesis of Six- and Eight-Membered Heterocycles
FULL PAPER
Since quinazolinone-type products 13 and 23 are also
formed, we suggest that first an aminopalladation/ring-clo-
sure catalytic cycle (cycle I) takes place, identical to that
[12]
shown in Scheme 4. According to Keith et al. and Popp
[13]
et al., at the end of such a cycle, re-oxidation of the cata-
lyst can take place via either direct oxygen insertion or a
palladium peroxo species. Both of these pathways result in
the palladium hydroperoxo intermediate L before regenera-
tion of the original catalyst. On the basis of literature
[14]
data, we propose that this species can undergo a 1,3-dipo-
lar cycloaddition to result in intermediate M, which is trans-
formed to the allylic alcohol derivative N via syn-b-hydride
elimination. Next, allylic alcohol derivative N undergoes
[
15]
ring-closure aminopalladation
similar to that shown in
Scheme 6. Mechanistic proposal for the formation of diazepinone-type
products.
Scheme 5, to produce the diazocinedione derivative 24. The
fact that the formerly introduced hydroxy group is not elimi-
nated in the final b-elimination step (intermediate P) sug-
gests that the 1,3-dipolar cycloaddition step is diastereose-
lective and creates steric hindrance for the aminopalladation
step (intermediate O), which thus occurs from the opposite
side. Piera et al. recently reported a palladium-catalyzed oxi-
dative transformation in which water was the source of
oxygen built into the final product. In order to investigate
this possibility, a control experiment was performed in the
presence of water, although all our previous experiments
were performed in dry media. However, the addition of one
equivalent of water did not improve the yield or the ratio of
compound 24. Performance of the reaction with stoichio-
dination of the non-bonding electron pair of the oxygen
[1k]
atom
in the tosyl group would stabilize intermediate I,
subsequently increasing the energy barrier of the transfor-
mation.
However, trans-aminopalladation in intermediate J would
provide an opportunity for syn-b-hydride elimination from
intermediate K, but diazepinone 20 was not observed in our
experiments.
[16]
Finally, we set out to obtain experimental evidence to sup-
3
port our theory that no h -allyl–palladium complex is in-
volved in these transformations. In view of our finding that,
in the presence of the Hoveyda–Grubbs 2nd-generation cat-
alyst, under microwave irradiation, allylamides tend to iso-
merize to the corresponding propenyl derivatives, we pre-
pared compounds 21 and 22, in a ratio of 5:1, from 8
[17]
2
metric Pd
A
H
U
G
R
N
U
G
under argon to exclude any source of
oxygen yielded quinazolinone derivatives 13 and 23 exclu-
sively, in a close to 1:1 ratio. Hereby, experimental evidence
has been provided for our theory that a p-allyl–palladium
intermediate is not involved in these transformations. Other-
wise, diazocine 15 would also have been formed in the stoi-
chiometric reaction. As proposed by one of the Referees,
we prepared the cis-analogue of 21, but its reaction failed to
furnish the cis-analogue of 24, as we had expected from our
theoretical calculations, which had indicated that cis-anella-
tion of a six- and eight-membered ring system is thermody-
namically less favored than trans-anellation. On the other
hand, compound 25 (the PMB-substituted analogue of 21),
isomerized from 16 according to Scheme 7, gave the corre-
sponding diazocinedione 26 in 63% yield.
(
Scheme 7).
Scheme 7. Microwave-assisted allyl to propenyl isomerization of com-
pound 8.
It was presumed that subjecting 21 to the conditions
shown in Table 2, entry 3 would result in the exclusive for-
mation of 13. The reaction was complete in 2 h, though it re-
sulted in a mixture of three substances. Two of them were
identified as compound 13 and its (2S*) diastereomer 23,
but they were isolated in a combined yield of only 10%.
The third compound, 24, was isolated in 64% yield and
identified as a cyclic imide derivative of 15. Since no such
side-reaction was observed in our previous experiments, we
suggest that the oxygen incorporation step takes place prior
to the ring-closing aminopalladation step. Accordingly, we
presume that 24 is formed via a domino oxidation–oxidative
amination cascade reaction. The proposed mechanism is de-
picted in Scheme 8.
Conclusion
II
In conclusion, a highly diastereoselective and efficient Pd -
catalyzed method is reported for the preparation of cyclo-
hexane cis-fused 2-vinylpyrimidinones in an O atmosphere.
Starting from trans-carboxamide derivatives, a highly sol-
vent-dependent and unexpected formation of 1,5-diazocin-6-
ones was observed. Both the experimental findings and the
theoretical considerations suggest that the reactions proceed
via cis-aminopalladation, favoring “upper-face” attack,
thereby controlling the stereochemical outcome of the trans-
formation. Experimental evidence is presented that no p-
2
Chem. Eur. J. 2009, 15, 7376 – 7381
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7379

F. Fꢃlçp et al.
solution was extracted with cold 5%
HCl solution (2ꢇ75 mL) and with cold
5
% NaOH solution (2ꢇ75 mL). The
organic layer was dried over anhy-
drous Na SO and evaporated to dry-
2
4
ness under reduced pressure. Isopropyl
ether (15 mL) was added to the crude
product and the solid was filtered off,
resulting in compounds 5–8 and 16.
General procedure for the cyclization
of carboxamides 5–8, 16 and 21: A
1
00 mL three-necked round-bottomed
flask was charged with carboxamide
5
1
1
0
–8 or 16 (1.3 mmol), NaOAc (106 mg,
.3 mmol),
.3 mmol),
nBu
4
NCl
(362 mg,
(29 mg,
Pd(OAc)
A
H
U
G
R
N
N
2
.13 mmol) and the appropriate sol-
vent (20 mL) and placed under an at-
mosphere of O (balloon). After heat-
2
ing at 1108C (reflux in the event of
MeCN) for the time specified in
Scheme 8. Proposed mechanism for the formation of diazocine-dione 24 and 26.
Tables
1 and 2, the mixture was
quenched with brine (25 mL), filtered
through a short pad of Celite and ex-
allyl–palladium intermediate is involved in these transforma-
tions. Furthermore, a novel Pd -catalyzed domino oxidation,
tracted with Et
EtOAc (1ꢇ25 mL). The combined organic phase was dried over anhy-
drous Na SO and evaporated to dryness under reduced pressure. The
residue was purified by column chromatography (n-hexane/ethyl acetate
:1), which provided pure compounds 9–15, 17, 18, 23 and 24.
2
O (2ꢇ25 mL) and
II
2
4
oxidative amination reaction was discovered, resulting in an
eight-membered cyclic imide compound. These results may
4
II
facilitate a better understanding of Pd -mediated oxidative
*
*
*
(
2R ,4aR ,8aR )-3-Allyl-1-tosyl-2-vinyl-2,3,4a,5,6,7,8,8a-octahydro-1H-
transformations, particularly stereoselective ones.
quinazolin-4-one (9): Prepared in DMSO according to the general proce-
dure for 4 h. White solid (336 mg, 69%); m.p. 95–978C; H NMR
1
(
600 MHz, [D
6
]DMSO): d=7.75 (d, J=8.3 Hz, 2H, Ar), 7.43 (d, J=
.0 Hz, 1H, Ar), 5.98 (ddd, J=17.2, 10.1, 7.5 Hz, 1H, CH-CH ), 5.63–
.56 (m, 1H, CH -CH-CH ), 5.37 (d, J=16.9 Hz, 1H, CH-CH ), 5.34 (d,
), 5.16 (dd, J=10.3, 1.2 Hz, 1H, CH -CH-CH ),
4.97 (dd, J=17.3, 1.4 Hz, 1H, CH -CH-CH ), 4.43–4.38 (m, 1H, CH
CH-CH ), 4.13–4.09 (m, 1H, CH-NH), 3.43 (dd, J=15.7, 6.9 Hz, 1H,
CH -CH-CH ), 2.40 (s, 3H, Me), 2.18 (d, J=13.3 Hz, 1H, CH ), 1.98 (s,
1H, CH-CO), 1.67–1.61 (m, 2H, CH ), 1.61–1.53 (m, 1H, CH ), 1.36 (d,
J=13.2 Hz, 1H, CH ), 1.26–1.18 (m, 2H, CH ), 0.86 ppm (tq, J=13.3,
]DMSO): d=21.0, 21.4, 24.7,
8
5
2
Experimental Section
2
2
2
J=10.1 Hz, 1H, CH-CH
2
2
2
1
13
General methods: H and C NMR spectra were recorded on a Bruker
DRX 400, DRX 500 or AV600 spectrometer. Chemical shifts are ex-
pressed in ppm (d) relative to TMS as internal reference. J values are
given in Hz. Melting points were determined on a Kofler apparatus and
are uncorrected. FT-IR spectra were recorded on KBr plates on a
Perkin-Elmer Spectrum 100 instrument. Elemental analyses were per-
formed with a Perkin-Elmer 2400 CHNS elemental analyser. Low-resolu-
tion CR=1000–1500 mass spectra were run on a Finnigan MAT95S
double-focusing mass spectrometer. Samples were introduced directly
into the ion source. The electron impact ion source conditions were: tem-
perature 1708C; electron energy 20 eV; ion current 150 mA. Merck alu-
minium oxide 90 active neutral (0.063–0.200 mm) was used for column
chromatography and Merck Kieselgel 60F254 plates for thin-layer chroma-
tography. Anhydrous toluene was distilled from sodium metal and stored
2
2
2
-
2
2
2
2
2
2
2
2
1
3
2 6
3.1 Hz, 1H, CH ); C NMR (150 MHz, [D
24.9, 30.9, 39.9, 45.3, 53.0, 69.8, 117.5, 119.9, 126.8, 130.1, 132.4, 136.4,
136.9, 144.0, 166.7 ppm; IR (KBr): n˜ =3079, 2960, 2942, 2865, 1935, 1655,
À1
+
1445, 1343, 1246, 1168, 1090 cm ; MS m/z: 374 [M ]; elemental analysis
calcd (%) for C20
7.12, N 7.33.
26 2 3
H N O S: C 64.14, H 7.00, N 7.48; found: C 64.02, H
trans-5-Allyl-1-tosyl-1,2,6a,7,8,9,10,10a-octahydro-5H-benzo[b]-
AHCTUNGERTG[NNUN 1,5]diazocin-6-one (14): Prepared in MeCN according to the general
1
procedure for 4 h. White solid (351 mg, 72%); m.p. 136–1388C; H NMR
600 MHz, [D ]DMSO): d=7.62 (d, J=8.3 Hz, 2H, Ar), 7.38 (d, J=
.0 Hz, 2H, Ar), 5.77 (td, J=9.9, 1.9 Hz, 1H, N-CH -CH-CH-N), 5.73–
.65 (m, 1H, CH -CH-CH ), 5.13 (dd, J=17.3, 1.6 Hz, 1H, CH -CH-
over sodium wire. Anhydrous CH
pentoxide and stored over 4 ꢆ molecular sieve. Pd
2
Cl
2
was distilled from phosphorus
(OAc) and Hoveyda–
(
6
A
H
U
T
E
N
N
2
8
5
2
Grubbs 2nd-generation catalyst were purchased from Sigma-Aldrich.
2
2
2
CCDC 709671 (14) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif
2 2 2
CH ), 5.07 (dd, J=10.3, 1.5 Hz, 1H, CH -CH-CH ), 5.04 (ddd, J=9.9,
3.7, 2.5 Hz, 1H, N-CH -CH-CH-N), 4.24 (d, J=20.1 Hz, 1H, N-CH -CH-
2
2
CH-N), 3.86–3.80 (m, 3H, N-CH -CH-CH-N, CH -CH-CH ), 3.72 (dt, J=
2
2
2
11.7, 3.4 Hz, 1H, CH-N), 2.89 (dt, J=11.3, 4.0 Hz, 1H, CH-CO), 2.38 (s,
3H, Me), 1.70–1.49 (m, 4H, CH ), 1.17–1.28 (m, 3H, CH ), 1.16–
); C NMR (150 MHz, [D ]DMSO): d=21.4, 23.9,
24.9, 28.6, 28.7, 41.9, 44.4, 49.4, 58.2, 117.1, 118.1, 126.9, 127.0, 130.3,
Starting materials: cis- and trans-2-Aminocyclohexanecarboxylic acids (1,
2
2
1
3
2
) and 2-tosylaminocyclo-hexanecarboxylic acids (3, 4) were prepared ac-
1.07 ppm (m, 1H, CH
2
6
[
5]
cording to literature processes.
1
1
34.1, 138.8, 143.4, 171.8 ppm; IR (KBr): n˜ =3085, 3067, 2924, 2864, 1935,
834, 1654, 1445, 1396, 1336, 1221, 1154, 1090 cm ; MS m/z: 374 [M ];
General procedure for the preparation of 2-tosylaminocyclohexanecar-
boxamides 5–8 and 16: To a stirred solution of 3 or 4 (16.8 mmol) in an-
À1
+
elemental analysis calcd (%) for C20
found: C 64.01, H 6.82, N 7.30.
26 2 3
H N O S: C 64.14, H 7.00, N 7.48;
hydrous toluene (125 mL), SOCl
stirring for 3 h at 608C, the solution was evaporated to dryness under re-
duced pressure. The residue was taken up in anhydrous CH Cl (80 mL)
and the solution was added dropwise to a stirred solution containing the
appropriate allylamine (2 equiv) and Et N (2 equiv) in of anhydrous
CH Cl (50 mL). After completion of the reaction according to TLC, the
2
(1.3 equiv) was added dropwise. After
trans-5-Methyl-1-tosyl-2,3,6a,7,8,9,10,10a-octahydro-1H,5H-benzo[b]-
AHCTUNGTERG[NNUN 1,5]diazocine-4,6-dione (24): Prepared according to the general proce-
dure for the cyclization of carboxamides, starting from 21 (100 mg,
2
2
3
2
2
0.285 mmol) in refluxing dry MeCN (8 mL). Colorless oil (66 mg, 64%);
7380
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ꢅ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 7376 – 7381

Synthesis of Six- and Eight-Membered Heterocycles
FULL PAPER
1
H NMR (500 MHz, CDCl
H, Ar), 4.12–3.99 (m, 2H, N-CH
N-CH -CH -CO), 3.44–3.38 (m, 1H, N-CH
1.4 Hz, 1H, CH-CO), 2.99 (s, 3H, N-Me), 2.94–2.82 (m, 1H, N-CH
CH -CO), 2.43–2.39 (m, 4H, Me, CH ), 2.07–0.78 ppm (m, 7H, CH );
C NMR (125 MHz, CDCl ): d=21.0, 24.3, 24.7, 29.3, 29.4, 31.2, 38.1,
3
): d=7.59–7.55 (m, 2H, Ar), 7.29–7.25 (m,
-CH -CO, CH-N), 3.56–3.47 (m, 1H,
-CH -CO), 3.24 (dt, J=3.4,
Chem. Rev. 2007, 107, 5318–5365; n) Z. Zhang, J. Zhang, J. Tan, Z.
Wang, J. Org. Chem. 2008, 73, 5180–5182; o) Z. Zhang, J. Tan, Z.
Wang, Org. Lett. 2008, 10, 173–175.
2
2
2
2
2
2
2
1
2
-
[2] S. L. Schreiber, Science 2000, 287, 1964–1969.
2
2
2
[3] a) T. Shinohara, M. A. Arai, K. Wakita, T. Arai, H. Sasai, Tetrahe-
dron Lett. 2003, 44, 711–714; b) R. M. Trend, Y. K. Ramtohul, E. M.
Ferreira, B. M. Stoltz, Angew. Chem. 2003, 115, 2998–3001; Angew.
Chem. Int. Ed. 2003, 42, 2892–2895; c) L. F. Tietze, H. Ila, H. P.
Bell, Chem. Rev. 2004, 104, 3453–3516; d) R. M. Trend, Y. K. Ram-
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4] E. M. Beccalli, G. Broggini, G. Paladino, A. Penoni, C. Zoni, J. Org.
Chem. 2004, 69, 5627–5630.
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1
3
3
3
2
[
9.2, 49.7, 58.4, 126.7, 129.3, 135.5, 143.2, 170.7, 174.0 ppm; IR (KBr): n˜ =
À1
925, 2854, 1704, 1655, 1465, 1373, 1328, 1158, 1066 cm ; MS m/z: 364
+
M ]; elemental analysis calcd (%) for C18
H
24
N
2
O
4
S: C 59.32, H 6.64, N
7
.69; found: C 59.19, H 6.75, N 7.81.
Microwave-assisted allyl to propenyl isomerization of compound 8 to 21
and 22: A 10 mL CEM Discover microwave vial was charged with 8
(
1
ated at 1008C for 20 min. After completion of the reaction, the solvent
was evaporated off and the residue was dissolved in EtOAc (20 mL) and
extracted with water (2ꢇ15 mL). The organic phase was dried over anhy-
2 4
drous Na SO , evaporated to dryness and purified by column chromatog-
raphy, using n-hexane/ethyl acetate 2:1, to yield 21 and 22.
[
[
[
[
100 mg, 0.285 mmol), Hoveyda–Grubbs 2nd-generation catalyst (1.8 mg,
mol%), dry MeOH (2 mL) and a magnetic stir bar. The vial was irradi-
3
34.
6] a) E. Beccalli, G. Broggini, M. Martinelli, G. Palladino, Synlett 2006,
3–76; b) J. Muzart, Tetrahedron 2005, 61, 4179–4212.
7] a) S. Bienz, P. Bisegger, A. Guggisberg, M. Hesse, Nat. Prod. Rep.
005, 22, 647–658; b) B. Rasmussen, A.-J. Nkurunziza, M. Witt,
H. A. Oketch-Rabah, J. W. Jaroszewski, D. Stærk, J. Nat. Prod. 2006,
9, 1300–1304.
7
2
trans-N-Methyl-N-((E)-prop-1-enyl)-2-tosylaminocyclohexanecarboxa-
mide (21): White solid (72 mg, 72%); m.p. 71–738C; two rotamers in a
ratio of 1:0.4; H NMR (400 MHz, CDCl
7
1
1
6
1
[8] K. A. Oppong, C. D. Ellis, M. C. Laufersweiler, S. V. OꢉNeil, Y.
Wang, D. L. Soper, M. W. Baize, J. A. Wos, B. De, G. K. Bosch,
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muth, Jr., Bioorg. Med. Chem. Lett. 2005, 15, 4291–4294.
3
): d=7.76–7.68 (m, 4H, Ar),
.31–7.25 (m, 4H, Ar), 7.08 (d, J=14.7 Hz, 1H, N-CH=CH), 6.54 (d, J=
3.3 Hz, 1H, N-CH=CH), 5.11–5.03 (m, 1H, N-CH=CH), 5.02–4.94 (m,
H, N-CH=CH), 4.75 (d, J=6.1 Hz, 1H, NH), 4.67 (d, J=6.1 Hz, 1H,
[
3d]
II
[
9] Trend et al.
reported a Pd -catalyzed transformation where the
NH), 3.50–3.41 (m, 2H, CH-NH), 3.03 (s, 3H, N-Me), 2.91 (s, 3H, N-
ring-closure product could be
formed only via a p-allyl–palladi-
um intermediate, but isolated the
title compound in <5% yield.
They therefore rejected this
mechanism. In our case, we sug-
gest that the amide moiety plays
a key role in stabilizing the iso-
merized product through a cross-conjugated p-system.
Me), 2.78–2.70 (m, 2H, CH-CO), 2.41 (s, 6H, Me), 2.13–2.04 (m, 2H,
CH
CH
2
), 1.81–1.65 (m, 12H, N-CH=CH-Me, CH
2
), 1.49–1.16 ppm (m, 6H,
1
3
2
); C NMR (100 MHz, CDCl
3
): d=15.9, 21.9, 25.0, 25.1, 29.4, 29.6,
3
1
1
0.1, 31.0, 32.7, 32.9, 47.0, 47.4, 55.4, 55.5, 106.7, 109.2, 127.5, 128.5, 129.0,
29.8, 138.8, 143.4, 172.3 ppm; IR (KBr): n˜ =3211, 2927, 2858, 1621, 1451,
À1
+
330, 1161, 1095 cm ; MS m/z: 350 [M ]; elemental analysis calcd (%)
for C18
H
26
N
2
O
3
S: C 61.69, H 7.48, N 7.99; found: C 61.78, H 7.35, N 7.91.
II
[
10] References that highlight double bond migration in Pd -mediated
transformations: a) E. Thiery, C. Chevrin, J. Le Bras, D. Harakat, J.
Muzart, J. Org. Chem. 2007, 72, 1859–1862; b) M. J. Schultz, M. S.
Sigman, J. Am. Chem. Soc. 2006, 128, 1460–1461.
Acknowledgements
We are grateful to the Hungarian Research Foundation (OTKA
T049407) for financial support. The computational resources of HPC U-
Szeged (ALAP4-00092/2005) are acknowledged. The authors are thank-
ful to Dr. Andrꢁs Kotschy for his helpful remarks.
[
[
[
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1
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604.
[
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2
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2
Am. Chem. Soc. 2005, 127, 7690–7691; g) J. Streuff, C. H. Hçvel-
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1
4587; h) M. M. Rogers, J. E. Wendland, I. A. Guzei, S. S. Stahl,
[17] In the presence of benzoquinone as catalyst oxidant, no cyclization
took place and only unreacted starting material was isolated from
the mixture.
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Y. Zhu, D. Yang, J. Am. Chem. Soc. 2006, 128, 3130–3131; j) V.
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l) A. Minatti, K. MuÇiz, Chem. Soc. Rev. 2007, 36, 1142–1152;
Received: February 20, 2009
m) E. M. Beccalli, G. Broggini, M. Martinelli, S. Sottocornola,
Published online: June 23, 2009
Chem. Eur. J. 2009, 15, 7376 – 7381
ꢅ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7381