Synthesis of new quinoxaline derivatives by reductive cyclization of various 1-(2-nitrophenyl)-2-cyanoamines

Article abstract of DOI:10.1002/1099-0690(200103)2001:5<987::AID-EJOC987>3.0.CO;2-B

The electrochemical cyanation of various six-membered N-(2-nitrophenyl) heterocyclic amines, including piperidine, morpholine, thiomorpholine, and N-Boc-protected piperazine derivatives, was investigated. The expected cyanoamines 5 were obtained in good y

Full text of DOI:10.1002/1099-0690(200103)2001:5<987::AID-EJOC987>3.0.CO;2-B

FULL PAPER
Synthesis of New Quinoxaline Derivatives by Reductive Cyclization of Various
1-(2-Nitrophenyl)-2-cyanoamines
Tristan Renaud,[a] Jean-Pierre Hurvois,*[b] and Philippe Uriac[a]
Keywords: CϪC coupling / Cyclizations / Electrochemistry / Nitrogen heterocycles / Reductions
The electrochemical cyanation of various six-membered N-
(2-nitrophenyl) heterocyclic amines, including piperidine,
morpholine, thiomorpholine, and N-Boc-protected piperaz-
studied for the cases both of trans-5f, in which the 2-cyano
substituent was axial and the 4-methyl substituent equator-
ial, and of cis-5f, in which both the 2-cyano and the 4-methyl
ine derivatives, was investigated. The expected cyanoamines substituents were equatorial. The expected tetrahydroquino-
5 were obtained in good yields and subjected to catalytic hy- xalines 3 were conveniently prepared in a following step by
drogenation to afford the corresponding cyclic amidine N-
oxides 6. The reductive cyclization proceeded through the
formation of a hydroxylamine, which cyclized onto the cyano
moiety. The stereoselectivity of the cyclization reaction was
the catalytic hydrogenation of cyclic amidines 6 in the pres-
ence of Pearlman’s catalyst at five atmospheres of hydrogen
pressure.
Introduction
The synthesis of new tetrahydroquinoxaline derivatives is
of interest due to the fact that such systems are models for
tetrahydrofolic acid.[1] Earlier studies of the formation of
such systems were based on the reductive cyclization of
suitably substituted quinoxalines, which could be prepared
directly by condensation of 1,2-diaminobenzene with the
desired 1,2-dicarbonyl compounds.[2a] A more recent ap-
proach, aimed at the preparation of chiral tetrahydro-2-vi-
nylquinoxalines, showed that such derivatives could also be
directly prepared by Pd0-catalyzed condensation between
substituted 1,2-diaminobenzenes and (Z)-1,4-bis(methoxy-
carbonyloxy)but-2-ene.[2b] Essentially, reductive ring-clos-
ure of nitro acids 1, followed by the reduction of the inter-
mediate lactam 2, was used to synthesize the desired molec-
ules 3.[2cϪ2e] Up to now, only commercially available amino
acids like proline (X ϭ 0) or pipecolic acid (X ϭ CH2) have
been used as starting materials for such a synthetic purpose.
The difficulties found in the synthesis of modified amino
acids (X ϭ S,[3a,3b] O,[3c] NH[3d]) might be the cause of their
limited synthetic use as suitable starting materials in the
synthesis of modified quinoxalines 3.
cyclic six-membered amidines 6 in good yield.[4] In this pa-
per we report the extension of this methodology to nitro-
aryl-substituted amines 4, which were selected as starting
materials for the preparation of a set of amidines 6. Finally,
these amidines were hydrogenated in the presence of
Pearlman’s catalyst to afford their corresponding tetrahy-
droquinoxalines 3.
In earlier papers, we described the synthesis of various
cyanoamines of type 5 which, after reduction of their nitro
group under protic conditions, yielded the corresponding
Results and Discussion
The starting nitroamines 4a؊d and 4f were prepared
without difficulty by direct treatment of 1-fluoro-2-nitro-
benzene with the requisite amines, as detailed elsewhere.[2c]
The synthesis of 4e was performed in two consecutive steps,
starting with the condensation of 1-fluoro-2-nitrobenzene
with an equimolar amount of piperazine in a two-phase
system (CH2Cl2/40% aq. NaOH), and followed by the intro-
duction of a Boc protecting group at the resulting second-
ary amino function. This common mode of protection is
[a]
Laboratoire de Chimie Pharmaceutique,
´
Universite de Rennes I,
´
Avenue du Professeur Leon Bernard, 35043 Rennes Cedex,
France
[b]
´
Laboratoire dЈElectrochimie et dЈOrganometalliques,
U.M.R. 6509, Campus de Beaulieu, 35042 Rennes Cedex,
France
Fax: (internat.) ϩ33-2/9928-1660
E-mail: Jean-Pierre.Hurvois@univ-rennes1.fr
Eur. J. Org. Chem. 2001, 987Ϫ996
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0305Ϫ0987 $ 17.50ϩ.50/0
987

T. Renaud, J.-P. Hurvois, P. Uriac
FULL PAPER
necessary to avoid overoxidation of the unprotected second- tions might be performed at the first oxidation peak of
ary amino group at the anode (Scheme 1).
amines 4a؊f.
Oxidation of Amines 4a؊f
Firstly, we decided to focus on the electrochemical be-
havior of amines that differ from each other either by the
size of their ring (compounds 4a؊b), or by the presence of
a heteroatom (X ϭ O, S, N-Boc) in the position γ to the
nitrogen atom (compounds 4c؊e). The oxidation of amines
4a؊e (up to 3 g) was effected in a divided cell apparatus
fitted with a planar vitreous carbon electrode (diameter 60
mm) as anode, and a carbon rod as cathode. Experiments
were performed in methanol at a controlled potential (de-
pending on the nature of the substrate, see Experimental
Section), in the presence of LiClO4 (20 g/L) as supporting
electrolyte and four equivalents of NaCN as cyanating
agent. After the consumption of 2.0Ϫ2.7 mol of electrons
per mol of substrate, the completion of the reaction was
attested to by the disappearance of the first oxidation peak.
The addition of water resulted in the precipitation of the
crude material, and cyanoamines 5a؊e were obtained in
54Ϫ89% isolated yield after crystallization or rapid passage
through a silica column (Scheme 2).
Scheme 1. Synthesis of nitroamines 4a؊f
Electrochemical Investigations
Prior to macroscale electrolysis, analytical investigations
were performed at a glassy carbon electrode, using meth-
anol as solvent and lithium perchlorate (20 g/L) as sup-
porting electrolyte. Peak potentials, expressed in V. vs. SCE,
are collected in Table 1.
Table 1. Voltammetric investigations: glassy carbon electrode (dia-
meter 4.5 mm); solvent: MeOH; supporting electrolyte: LiClO4 (20
g/L); product concentration 10Ϫ2 mol/L, scan rate: 0.1 V/s; reaction
conditions: (1): in absence of NaCN, (2): in presence of 4 equiv. of
NaCN per mol of substrate
Product
EpA(1)
EpB(1)
EpA(2)
EpB(2)
4a
4b
4c
4d
4e
4f
1.40
1.55
1.60
Ϫ
Ϫ
Ϫ
1.10
1.10
1.25
1.25
1.15
1.15
1.50
1.50
1.65
1.65
1.55
1.55
1.20
1.60[a]
1.40[a]
1.50[a]
1.30
1.55
[a] In the case of compounds 4c؊e peaks EpA(1) and EpB(1) were su-
perimposed.
Scheme 2. Synthesis of cyanoamines 5a؊f
In the absence of sodium cyanide, compounds 4a؊b and
4f displayed two successive irreversible peaks in the range
1
In all cases, the H NMR spectra were consistent with a
of EpA(1) ϭ ϩ1.20Ϫ1.40 V and EpB(1) ϭ ϩ1.55Ϫ1.60 V, ring cyanation and included a characteristic 2-H signal at
while compounds 4c؊e exhibited a single irreversible peak δ ϭ 4.40Ϫ4.70, which appeared as a triplet or a broadened
EpA(1) ϭ ϩ1.40Ϫ1.60 V (see footnote of Table 1), the height singlet. The 13C NMR spectra exhibited a characteristic C-
of which was twice that reported for EpA(1). Previous stud- 2 doublet resonance system found in the region δ ϭ 52Ϫ55
ies performed in our laboratory have shown that the first and a quaternary CN signal in the region δ ϭ 116Ϫ119.
oxidation peak [EpA(1)] was attributable to the amine Ǟ With the exception of 5e, a weak absorption at 2220 cmϪ1
iminium transformation,[5] whilst the oxidation of the in the IR spectra indicated the presence of the cyano group.
aminoether (resulting from the addition of methanol to the The chemistry of such compounds has received much atten-
iminium species) occurred either at the second oxidation tion since the discovery that they represent a valuable
peak [EpB(1)] or at EpA(1) (compounds 4c؊e; see footnote source of iminium cations, but it has also been reported
of Table 1). The addition of sodium cyanide (four equiv. that problems may arise from their instability.[6] Therefore,
per mol of substrate) caused a significant shift of the first we were please to find that cyanoamines 5a؊e proved to be
oxidation peak towards less positive values [EpA(2)
ϭ
extremely stable and could be handled without difficulties
ϩ1.10Ϫ1.25 V] and a splitting of the single oxidation peaks and stored for a month under normal conditions without
[EpA(1); see footnote of Table 1] into two, recorded at EpA(2) loss of quality.
and EpB(2) ϭ ϩ1.50Ϫ1.65 V. These observations are con-
A C-4 methyl-substituted piperidine derivative seemed to
sistent with the iminium species electrogenerated at EpA(2) be a convenient substrate on which to study the stereochem-
being trapped by cyanide anions, leading to a new com- ical outcome of the cyanation procedure. Compound 4f was
pound (identified as the corresponding cyanoamine), that selected as the model compound and, after being elec-
can be oxidized at EpB(2). As confirmation, a similar oxida- trolyzed, afforded an 80:20 diastereomeric mixture. Both
tion peak [EpB(2)] was recorded on voltammograms of cy- adducts, trans- and cis-5f, could easily be separated by care-
anoamines 5a؊f under similar reaction conditions. Taken ful filtration on a silica column, with a mixture of petro-
together, these results indicated that selective transforma- leum ether and diethyl ether (2:1) as eluent. The major iso-
988
Eur. J. Org. Chem. 2001, 987Ϫ996

Synthesis of New Quinoxaline Derivatives
FULL PAPER
mer trans-5f (64%) was eluted first, followed by the more electronically controlled mode so as to avoid energetically
polar cis-5f (16%).
unfavorable boat-like transition states.[7aϪ7c] This mechan-
The configuration of the major isomer trans-5f was deter- ism accounts for the formation of either the major isomer
mined by examination of selected 1H-1H coupling con- trans-5f or the minor isomer cis-5f (after the ring-inversion
stants. Evidence for the equatorial disposition of 2-H was of III owing to unfavorable 1Ϫ3 diaxial interactions be-
given by a broad singlet signal at δ ϭ 4.50. On irradiation tween the methyl and the cyano substituent).
at δ ϭ 2.98 (6-Ha), a vicinal coupling of 4.5 Hz was lost
from the resonance of 5-Ha (δ ϭ 1.37), which appeared as
a large quadruplet (J ϭ 13.0 Hz) signal, indicating that
both the vicinal protons 6-Hb and 4-H were axial and,
therefore, an equatorial disposition for the 4-methyl sub-
stituent. The 1H NMR spectrum of cis-5f displayed a signi-
ficant doublet of doublets system [3J(2,3a) ϭ 8.0 Hz,
3J(2,3b) ϭ 4.0 Hz] at δ ϭ 4.14, placing 2-H in a pseudoaxial
orientation. On irradiation at δ ϭ 3.42 (6-Hb), a vicinal
coupling constant of 3.0 Hz was lost from the resonance
system of 5-Ha, which appeared as a doublet of triplets
[2J(5a,5b) ϭ 14.0 Hz, 3J(5a,6a) ϭ 3J(5a,4) ϭ 8.5 Hz] system
at δ ϭ 1.55. The magnitudes of these coupling constants
were in agreement with an equatorial disposition of the
methyl group at C-4. The formation of these two diastereo-
mers can be understood if one considers the formation of
the iminium species I, in which the methyl group is pseudo-
Reductive Cyclization of Cyanoamines 5a؊f
Our first experiment was devoted to the reduction of the
nitro group under protic conditions. Treatment of 5a with
Zn/HCl in boiling ethanol resulted in the formation of a
mixture of unidentified products. At this point, it was clear
that the carbonϪnitrile bond had been cleaved affording
the iminium species, which proved to be unstable under
these reaction conditions. To overcome this drawback, cata-
lytic hydrogenation of the aromatic nitro group seemed to
us to be a promising possibility. After several attempts, the
best yields and reaction rates were found to be obtained
when the catalytic hydrogenation of 5a؊d was performed
over Pd(OH)2 [8] in ethanol at atmospheric pressure. The N-
oxide derivatives 6a؊d (Scheme 4) were obtained, providing
evidence of the partial reduction of the nitro group into the
corresponding hydroxylamine.
Scheme 4. Reductive cyclization of cyanoamines 5a؊e
Conversely, the syntheses of 6a؊e could readily be
achieved by means of the electrochemical reduction of 5a؊e
at controlled potentials in a batch cell at a mercury pool
cathode. The electrolysis was performed in ethanol in the
presence of acetic buffer as supporting electrolyte and con-
sumed four mol of electron per mol of substrate; this is a
direct indication of the partial reduction of the nitro group
into the corresponding hydroxylamine. The products ob-
tained in this way (50 to 70% yield) proved to be identical
in all respects to those obtained from the catalytic hydro-
genation of 5a؊e.
Hydrogenation of the N-Boc-protected cyanoamine 5e at
one atm. H2 resulted in the formation of the corresponding
amidine-N-oxide 6e, together with the saturated quinoxa-
line 3e in 25% yield. Attempts to reduce the formation of
3e by using limited amounts of catalyst did not produce any
alteration in the original experimental results and, in this
case only, overreduction of the intermediate amidine into
the corresponding saturated quinoxaline could not be tot-
ally avoided. The 1H NMR spectrum of 6e recorded in
Scheme 3. Cyanide addition onto iminiums I and II
equatorial (Scheme 3). Several studies have shown that the [D4]methanol was temperature dependent and, with the ex-
former species can be in equilibrium with the alternate iso- ception of the resonance system of 4a-H, displayed coales-
mer II, in which the methyl substituent is pseudo-axial.[6] It cent signals at δ ϭ 2.95Ϫ3.20 (3 H), 3.90Ϫ4.00 (2 H), and
is important to note that in both of these two cases the 4.17Ϫ4.25 (1 H). In keeping with these observations, the
approach of the cyanide anions will be from the axial direc- 13C NMR spectrum of 6e, recorded at 298 K, exhibited co-
tion (path a and aЈ for I and II, respectively) and in a stereo- alescent signals at δ ϭ 41 and 44. Heating of the sample at
Eur. J. Org. Chem. 2001, 987Ϫ996
989

T. Renaud, J.-P. Hurvois, P. Uriac
FULL PAPER
343 K induced decoalescence of these broad peaks and a buffer at a scan rate of 0.1 V/s. On the first cathodic scan,
sharpening of all signals. At that temperature, two doublets the reduction of the nitro group of trans-5f into the corres-
of multiplets were recorded at δ ϭ 3.92 and 4.00 for 1-Hb ponding hydroxylamine IV occurred at Epc ϭ Ϫ0.60 V. On
and 2-Hb, respectively. Similarly, sharp signals at δ ϭ 41.7 the reversed cathodic scan, oxidation of the latter species
(C-2) and 44.2 (C-4) were recorded in the 13C NMR spec- into the corresponding nitroso derivative occurred at Epa ϭ
trum. In a subsequent step, concomitant deprotection and ϩ0.05 V. On the other hand, the voltammogram of cis-5f
formation of the hydrochloride salt of 7e were performed displayed a single reduction peak at Epc ϭ Ϫ0.85 V, attrib-
by direct treatment of 6e with a 3  ethanolic HCl solution. uted to the NO2 Ǟ NHOH transformation, whereas the
1
The H NMR spectrum of 7e was recorded in D2O and peak corresponding to the NHOH Ǟ NO oxidation was
displayed a typical doublet signal (J ϭ 11.0 Hz), attributed not observed during the reversed cathodic scan. This result
to the axial proton 4a-H at δ ϭ 5.06. Likewise, the 1H indicated not only that, in the case of cis-5f, the interme-
NMR spectra of the hydrochloride salts of 6a؊d were re- diate hydroxylamine VII cyclized faster than IV, but also
corded in D2O and displayed a similar doublet (J ϭ that an equatorially oriented cyano group is preferred, in-
12.0 Hz) signal in the region δ ϭ 4.25Ϫ4.55.
ducing a rapid condensation between the nitrogen nucle-
In order to acquire more fundamental information con- ophile and the cyano group.
cerning the stereochemical outcome of the cyclization reac-
The catalytic reduction of trans-5f was performed as de-
tion, we decided to study the behavior of the two adducts scribed above, affording trans-6f in 58% yield. The 1H
trans- and cis-5f. As mentioned earlier, the C-2 cyano sub- NMR spectrum of trans-6f displayed a typical doublet of
stituent could adopt either an axial or an equatorial ori- doublets [3J(6a,7b) ϭ 12.0 Hz, J(6a,7a) ϭ 3.0 Hz] system
3
entation. Therefore, one might expect a noticeable differ- at δ ϭ 4.54, placing 6a-H in an axial orientation. A large
ence between the cyclization rates of the two hy- triplet of doublets [2J(7b,7a) ϭ 3J(7b,6a) ϭ 12.0 Hz,
droxylamines IV and VII (Scheme 5).
3J(7b,8) ϭ 4.5 Hz] system at δ ϭ 1.98 was found for 7-Hb,
which is a direct indication that in this molecule 8-CH3 is
axial, as shown in Scheme 5. This relative orientation sug-
gests that a ring reversal followed by a nitrogen inversion
had taken place during the trans-5f Ǟ trans-6f transforma-
tion.[9a][9b] It is also well established that conjugation of a
nitrogen lone pair with a π system decreases the barrier to
inversion of the nitrogen atom,[10] and this accounts for the
pyramidal instability of the intermediate derivative V. One
should also keep in mind that IV and V are in a dynamic
equilibrium and that conformational mobility and nitrogen
inversion allow the cyano group in the requisite conforma-
tion to react with the nitrogen nucleophile, shifting the equi-
librium as the reaction proceeds.
The reduction of cis-5f was totally complete after a reac-
tion time of five hours, demonstrating once more that the
ring-forming reaction had taken place more rapidly in the
1
case of cis-5f. The H NMR spectrum of the hydrochloride
salt of cis-6f was measured in D2O and the coupling con-
stants [3J(6-a,7a) ϭ 12.0 Hz and 3J(6-a,7b) ϭ 2.0 Hz] found
at δ ϭ 4.31 were indicative of the axial orientation of 6a-
H, and hence an equatorial disposition for 8-CH3. Interest-
ing in the 13C resonance systems was the significant γ-shift
produced by the axially oriented methyl group at C-8.[11]
For example, in the spectrum of trans-6f, the C-6a and C-
10 resonance systems were found at δ ϭ 55.9 and 44.2, re-
spectively, whereas those observed for their counterparts in
cis-6f resonated at δ ϭ 60.5 and 48.4 (Table 2).
Reduction of Amidine N-Oxides 6a؊e
Interestingly, when the cyanoamines 6a؊c were reduced
at atmospheric pressure, the derivatives 3a؊c were obtained
in moderate yields (up to 25%). As a further extension of
this study, it was of interest to examine whether this reduc-
tion might represent a new means of access to the tetrahy-
Scheme 5. Stereochemical pathway for the reductive ring-closure of
trans- and cis-5f
Cyclic voltammograms were performed at a hanging mer- droquinoxaline ring system. We first examined the direct
cury electrode in a 1:1 mixture of ethanol and 0.5  acetic reduction of cyanoamines 5a؊c under rather forcing condi-
990
Eur. J. Org. Chem. 2001, 987Ϫ996

Synthesis of New Quinoxaline Derivatives
FULL PAPER
Table 2. Selected 13C chemical shifts for amidines trans-, cis-6f, and at δ ϭ 2.89 (6a-H) a large coupling constant [3J (7a,6-a) ϭ
12.0 Hz] was lost from the resonance system of 7-Ha. The
tetrahydroquinoxalines trans-, cis-3f
B/C ring junction of quinoxalines 3a؊c was presumably
Product
C-6a
C-7
C-8
8-CH3
C-9
C-10
trans, despite the fact that no Bohlmann bands could be
found in the 2700Ϫ2800 cmϪ1 region in the IR spectra of
3a؊c.[12] Several studies have shown that compounds in
which the nitrogen lone pair is delocalized over aromatic
ring orbitals do not give rise to such IR absorptions.[13] In
a related field of research, NMR spectroscopic studies have
demonstrated the influence of the bridgehead nitrogen lone
pair on the chemical shift of α-axial protons, which ab-
sorbed at δ Ͻ 3.8, as compared to α-equatorial protons,
trans-6f
cis-6f
55.9
60.5
48.5
53.9
33.2
35.5
35.6
38.5
27.7
30.9
25.0
30.2
19.0
23.8
17.2
22.0
28.6
33.0
31.0
33.7
44.2
48.4
42.5
47.0
trans-3f
cis-3f
tions [Pd(OH)2, 5 atm. H2] and soon observed that partial
reductive decyanation occurred together with the reduction
of the nitro group. Thus, it was felt that the reductive cyc-
lization should take place first, and that reduction of the
resulting amidine function should be effected in a sub-
sequent step. Therefore, the two-step preparation of the
tetrahydroquinoxaline derivatives was carried out in meth-
anol [Pd(OH)2, 1 atm. H2] in such a way that the resulting
N-oxides 6a؊c could easily be recovered from the meth-
anolic solution and directly hydrogenated at five atmo-
spheres H2 at room temperature. The reduction proceeded
sluggishly (5 days) and the expected tetrahydroquinoxalines
3a؊c were obtained in yields ranging between 52% and
66% (Scheme 6).
1
which absorbed at δ Ͼ 3.8. In our case, in the H NMR
spectra of tetrahydroquinoxalines 3a؊c (see Experimental
Section), absorptions attributable to the α-antiperiplanar
protons were found in the region δ ϭ 2.53Ϫ3.06, while
those attributable to the corresponding α-equatorial pro-
tons resonated in the region δ ϭ 3.49Ϫ3.82. These observa-
tions are in agreement with a trans B/C ring junction in
which the bridgehead nitrogen lone pair is partially delocal-
ized towards the antiperiplanar, axially oriented CϪH
bond. However, delocalization of the nitrogen lone pair
over the benzene ring will partially or totally deactivate the
α-antiperiplanar shielding effect. In our case, and in
1
others,[12] determination, by IR or H NMR spectroscopy,
of whether the configuration of the B/C ring junction is cis
or trans is not straightforward.
When the same reaction was conducted on the amidine
6d, no reduction to the expected tetrahydroquinoxaline 3d
was observed. All other attempts performed at more elev-
ated pressure conditions (up to 10 atm. H2) were also un-
successful, and resulted in the formation in 52% yield of the
corresponding amidine derivative. Catalytic hydrogenation
has been widely studied in N-oxide chemistry and numerous
examples of removal of the N-oxide group to afford the
parent heterocycle have been reported.[14] However, it
should be noted that the presence of a sulfur atom in 6d
should diminish the reducing power of the catalyst[15] and
account for the absence of the saturated quinoxaline 3d.
The synthesis of the quinoxaline 8e[16] was effected with-
out difficulty by means of a two-step procedure starting
from the cyanoamine 5e. As with 3c, the reductive cycliza-
tion was performed at 1 atm. H2, and followed by the reduc-
tion of the amidine function at 5 atm. H2 to afford 3e in
52% isolated yield. The removal of the Boc protecting
group was performed in ethanol with dry HCl, affording
the hydrochloride salt of 8e.
Hydrogenation of cis-6f was performed at five atmo-
spheres H2 and resulted in clean formation of the saturated
Scheme 6. Synthesis of the tetrahydroquinoxalines 3
It is worth noting that reduction of the amidine function quinoxaline cis-3f as a single diastereomer in 70% yield.
resulted in the elimination of one molecule of ammonia per The catalytic reduction of trans-6f was performed as de-
molecule of substrate. Indeed, a characteristic smell of scribed above and, after a reaction time of six days and
ammonia was observed on opening the reaction vessel. The rapid filtration through a silica column, afforded the ex-
1
1H NMR spectra of 3a؊c were well resolved and a com- pected material as an oil in 73% yield. H NMR analysis
plete attribution of all the protons could be performed. The revealed that this oil was a mixture (9:1) of the correspond-
axial orientation of the 6a-H proton, for example, was un- ing trans-3f (as the major compound), together with cis-3f.
ambiguously determined from examination of the 1H NMR Further evidence of the presence of cis-3f was provided by
spectrum of 3a, in which it was found that upon irradiation analysis of the 13C NMR spectrum, in which all the signals
Eur. J. Org. Chem. 2001, 987Ϫ996
991

T. Renaud, J.-P. Hurvois, P. Uriac
FULL PAPER
eV were used. LSIMSϪHRMS (Csϩ) were obtained with a Zab-
Spec TOF Micromass instrument with a source temperature of 40
°C, using a m-nitrobenzyl alcohol matrix.
arising from the minor isomer cis-3f were found. The axial
orientation of the 8-CH3 substituent in trans-3f was de-
duced by examination of the 1H NMR signal of 8-H, which,
after irradiation of the C-8 methyl signal at δ ϭ 1.05, ap-
peared as a quintet signal (J ϭ 4.0 Hz). Also interesting
was the fact that the presence of the axial CH3 group in
Caution: LiClO4 may cause severe explosions when the solvent is
evaporated to dryness. The addition of water (a threefold excess) to
the methanolic solution resulted in precipitation of the cyanoamine
trans-3f caused a significant upfield shift (Ϫ5 ppm, relative during the evaporation of the solvent. After precipitation, the crude
material was extracted with classical solvents such as CH2Cl2 or
diethyl ether.
to cis-3f, see Table 2) of the C-10 resonance triplet signal,
providing further evidence that the CH3 group was axial in
this compound. The reduction of amidines 6a؊f has the
potential to yield several intermediate species, among which
we can postulate an enediamine, produced after the reduc-
tion of the N-oxide group. The hydrogenation at C-6a at
1-(2-Nitrophenyl)piperidine-2-carbonitrile (5a): A methanolic solu-
tion (100 mL) of 4a (3 g, 14.5 mmol), containing LiClO4 (20 g/L)
as supporting electrolyte, was oxidized (Ep ϭ ϩ1.30 V, Q ϭ 2.71
F/mol) in the presence of NaCN (4 equiv.) in a batch cell fitted
the less-hindered side (opposite to the axial CH3) of that with a vitreous carbon electrode. Water (200 mL) was added to
the resulting solution and MeOH was evaporated under reduced
pressure. The aqueous layer was extracted with 200 mL of CH2Cl2;
the organic fraction was then dried over K2CO3 and evaporated.
Addition of a mixture of diethyl ether and petroleum ether (8:2)
led to the crystallization of 5a (3 g, 89%) as a pale yellow powder.
Ϫ M.p. 56 °C (diethyl ether/petroleum ether). Ϫ Rf ϭ 0.5 (diethyl
ether/petroleum ether, 3:7). Ϫ IR (KBr): ν˜ ϭ 2228 cmϪ1 (CN). Ϫ
1H NMR (CDCl3, 500 MHz): δ ϭ 1.69Ϫ1.84 (m, 4 H), 1.95Ϫ1.98
(m, 1 H), 2.11Ϫ2.16 (m, 1 H), 2.97 (dm, J ϭ 12.0 Hz, 1 H), 3.35
(td, J ϭ 12.0, 3.0 Hz, 1 H), 4.50 (s, br., 1 H), 7.29 (t, J ϭ 7.0 Hz,
1 H), 7.48 (d, J ϭ 7.0 Hz, 1 H), 7.60 (t, J ϭ 7.0 Hz, 1 H), 7.80 (d,
J ϭ 7.0 Hz, 1 H). Ϫ 13C NMR (CDCl3, 125 MHz): δ ϭ 19.9, 25.2,
28.8, 48.6, 54.3, 117.1, 124.4, 125.2, 125.6, 133.7, 144.1, 146.3. Ϫ
HRMS (C12H13N3O2 [Mϩ]): calcd. 231.10077; found 231.10111. Ϫ
C12H13N3O2: calcd. C 62.33, H 5.67, N 18.17, O 13.84; found C
62.44, H 5.53, N 18.20, O 13.92.
enediamine might be the origin of the formation of small
amounts of cis-3f during the catalytic hydrogenation of
trans-6f.
Conclusion
The first part of this study was devoted to the anodic
cyanation of various six-membered N-aryl heterocycles,
which were successfully transformed into their correspond-
ing cyanoamines. Once formed, such substrates proved to
be effective for the preparation of novel tetrahydroquinoxa-
line derivatives by a two-step reaction sequence involving:
a) reductive cyclization between the cyano substituent and
the nitrogen nucleophile, and b) the reduction of the amid-
ine moiety at a more elevated hydrogen pressure. Both the
starting cyanoamines and the final tetrahydroquinoxaline
derivatives are suitable precursors for further transforma-
tions, and work in this area is currently in progress.
1-(2-Nitrophenyl)azepane-2-carbonitrile (5b): Compound 4b (1 g,
4.5 mmol) and NaCN (0.8 g) were dissolved in MeOH (100 Ml)
containing LiClO4 (20 g/l). The resulting solution was electrolyzed
at Ep ϭ ϩ1.10 V and, after the passage of 876 C (2.0 F/mol), the
cyanoamine 5b was treated as described above to give a pale orange
powder (0.760 g, 68%). Ϫ Rf ϭ 0.28 (diethyl ether/petroleum ether,
2:8). Ϫ IR (neat): ν˜ ϭ 2226 cmϪ1 (CN). Ϫ 1H NMR (CDCl3,
500 MHz): δ ϭ 1.56Ϫ1.62 (m, 1 H), 1.65Ϫ1.85 (m, 5 H), 1.94Ϫ2.02
(m, 1 H), 2.25Ϫ2.31 (m, 1 H), 3.20 (dt, J ϭ 14.0, 5.0 Hz, 1 H),
3.43 (ddd, J ϭ 14.0, 10.0, 3.0 Hz, 1 H), 4.42 (tm, J ϭ 6.0 Hz, 1 H),
7.29 (t, J ϭ 7.0 Hz, 1 H), 7.54 (t, J ϭ 7.0 Hz, 1 H), 7.59 (d, J ϭ
7 Hz, 1 H), 7.66 (d, J ϭ 7 Hz, 1 H). Ϫ 13C NMR (CDCl3,
125 MHz): δ ϭ 23.6, 27.5, 29.1, 33.27, 52.4, 56.2, 118.9, 124.2,
125.9, 127.2, 133.3, 144.7, 147.5. Ϫ HRMS (C13H15N3O2 [Mϩ]):
calcd. 245.11643; found 245.11749. Ϫ C13H15N3O2: calcd. C 63.66,
H 6.16, N 17.13, O 13.05; found C 63.40, H 6.04, N 16.68, O 13.92.
Experimental Section
General: Purification by column chromatography was performed
using 70Ϫ230 mesh silica gel (Merck). Ϫ TLC analyses were car-
ried out on alumina sheets precoated with 60F254 silica gel; Rf
values are given for guidance. Ϫ Elemental analyses were per-
´
formed at the ‘‘Service Central dЈAnalyse, Departement Analyse
´
Elementaire (Vernaison)’’. Ϫ IR spectra were recorded with a Nico-
let 205 FT-IR instrument or a PerkinϪElmer FT-IR 16PC machine
(KBr powder or dichloromethane). Ϫ 1H and 13C NMR spectra
were recorded with a Bruker AH 300 FT (300 MHz and 75 MHz
4-(2-Nitrophenyl)morpholine-3-carbonitrile (5c): As described
1
for H and 13C, respectively), or Bruker DMX 500 (500 MHz and above, 4c (1.50 g, 7.2 mmol) was electrolyzed at Ep ϭ ϩ1.10 V.
125 MHz for 1H and 13C, respectively) spectrometer at the ‘‘Centre
After the disappearance of the first anodic wave and the consump-
tion of 1390 C (Q ϭ 2.0 F/mol), electrolysis was stopped. Water
(100 mL) was added to the resulting solution, and the usual
workup afforded 5c (0.760 g, 68%) as an orange powder. Ϫ M.p.
125 °C (diethyl ether/petroleum ether). Ϫ Rf ϭ 0.13 (diethyl ether/
petroleum ether, 2:8). Ϫ IR (KBr): ν˜ ϭ 2230 cmϪ1 (CN). Ϫ 1H
NMR (CDCl3, 500 MHz): δ ϭ 2.82 (d, J ϭ 12.0 Hz, 1 H), 3.66
(td, J ϭ 11.0, 3.0 Hz, 1 H), 3.75 (td, J ϭ 11.0, 3.0 Hz, 1 H), 3.99
(dd, J ϭ 12.0, 3.0 Hz, 1 H), 4.02 (dm, J ϭ 12.0 Hz, 1 H), 4.08 (dm,
J ϭ 12.0, Hz, 1 H), 4.40 (s, br., 1 H), 7.36 (t, J ϭ 8.0 Hz, 1 H),
7.52 (d, J ϭ 8.0 Hz, 1 H), 7.66 (t, J ϭ 8.0 Hz, 1 H), 7.84 (d, J ϭ
8.0 Hz, 1 H). Ϫ 13C NMR (CDCl3, 125 MHz): δ ϭ 47.7, 53.9,
67.0, 68.0, 116.0, 124.4, 125.4, 126.5, 134.0, 142.5, 146.7. Ϫ HRMS
´
Regional de Mesures Physiques de lЈOuest (CRMPO)’’. Chemical
shifts are expressed in ppm downfield from TMS: s, d, dd, t, q,
quint, sext, and m designate singlet, doublet, doublet of doublets,
triplet, quadruplet, quintet, sextet, and multiplet; coupling con-
stants (J) in Hz. The assignments were made on the basis of chem-
ical shifts and coupling constants (1J and long range coupling).
1H NMR: AB systems are presented in the following order: Ha (δ
centered) the more shielded, Hb (δ centered) the more deshielded.
13C NMR: broad band and gated decoupling spectra were re-
corded. EI-HRMS were obtained with a Mat 311 double focusing
instrument at the CRMPO, with a source temperature of 170 °C.
An ion-accelerating potential of 3 kV and ionizing electrons of 70
992
Eur. J. Org. Chem. 2001, 987Ϫ996

Synthesis of New Quinoxaline Derivatives
FULL PAPER
(C11H11N3O3 [Mϩ]): calcd. 233.08003; found 233.08066.
Ϫ
Rf ϭ 0.38 (diethyl ether/petroleum ether, 1:2) Ϫ IR (KBr): ν˜ ϭ
C11H11N3O3: calcd. C 56.65, H 4.75, N 18.02, O 20.58; found C 2242 cmϪ1(CN). Ϫ 1H NMR (CDCl3, 300 MHz): δ ϭ 1.14 (d, J ϭ
55.44, H 4.57, N 17.31, O 18.95.
6.5 Hz, 3 H, 4-CH3), 1.46Ϫ1.57 (m, 1 H, 5-Ha), 1.70Ϫ1.85 (m, 3
H, 3-Ha, 4-H, 5-Hb), 2.21 [dt, 2J(3b,3a) ϭ 11.50 Hz, 3J(3b,2) ϭ
(3b,4) ϭ 4.0 Hz, 1 H, 3-Hb], 2.69 [ddd, 2J(6a,6b) ϭ 12.0 Hz,
4-(2-Nitrophenyl)thiomorpholine-3-carbonitrile (5d): Compound 4d
(0.404 g, 1.8 mmol) was electrolyzed (Ep ϭ ϩ1.20 V, Q ϭ 2.0 F/
mol) at a carbon electrode to afford the cyano adduct 5d (0.241 g,
54%) as a pale orange powder. Ϫ M.p. 91 °C (diethyl ether/petro-
leum ether). Ϫ Rf ϭ 0.69 (CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 2228 cmϪ1
(CN). Ϫ 1H NMR (CDCl3, 500 MHz): δ ϭ 2.58 (dm, J ϭ 14.0 Hz,
1 H), 2.77 (dt, J ϭ 14.0, 3.0 Hz, 1 H), 2.98 (ddd, J ϭ 13.0, 12.0,
3.0 Hz, 1 H), 3.20 (dt, J ϭ 13.0, 3.0 Hz, 1 H), 3.36 (dd, J ϭ 13.0,
3.5 Hz, 1 H), 3.68 (td, J ϭ 12.0, 3.0 Hz, 1 H), 4.70 (t, J ϭ 4.0 Hz,
1 H), 7.37 (td, J ϭ 8.5, 1.0 Hz, 1 H), 7.54 (dd, J ϭ 8.0, 1.0 Hz, 1
H), 7.64 (td, J ϭ 8.0, 1.0 Hz, 1 H), 7.80 (dd, J ϭ 8.0, 1.0 Hz, 1 H).
3
3J(6a,5b) ϭ 8.5 Hz, J(6a,5a) ϭ 3.0 Hz, 1 H, 6-Ha], 3.42 (m, 1 H,
3
6-Hb), 4.14 [dd, 3J(2,3a) ϭ 8.0 Hz, J(2,3b) ϭ 4.0 Hz, 1 H, 2-H],
7.32 (t, J ϭ 8.0 Hz, 1 H), 7.43 (d, J ϭ 8.0 Hz, 1 H), 7.60 (t, J ϭ
8.0 Hz, 1 H), 7.77 (d, J ϭ 8.0 Hz, 1 H). Ϫ 13C NMR (CDCl3,
75 MHz): δ ϭ 20.2 (4-CH3), 27.9 (C-4), 32.5 (C-5), 36.8 (C-3), 51.2
(C-2), 51.4 (C-6), 118.5 (CN), 124.9, 124.9 (C-6Ј or C-4Ј) 126.3 (C-
3Ј), 133.2 (C-5Ј), 143.6 (C-1Ј), 147.7 (C-2Ј).
7,8,9,10-Tetrahydro-6aH-5-oxypyrido[1,2-a]quinoxalin-6-ylamine
Hydrochloride (6a): PearlmanЈs catalyst (0.15 g), 5a (0.670 g,
2.9 mmol), and dioxane (4 mL) were placed in a low-pressure hy-
drogenator. Air was removed from the reactor by alternately filling
it with hydrogen and venting it three times. The desired hydrogen
pressure (7.35 ϫ 102 Torr) was applied, and the reaction mixture
was stirred for 48 h at room temperature. The catalyst was filtered
off and washed with methanol (20 mL). The combined solutions
were evaporated under reduced pressure to afford the amidine 6a
(0.602 g, 91%) as a white powder. Addition of diethyl ether satur-
ated with gaseous HCl resulted in the formation of the hydro-
chloride salt of 6a. Ϫ M.p. 155Ϫ160 °C (dec.). Ϫ IR (KBr): ν˜ ϭ
740, 1658, 3082 (br.) cmϪ1. Ϫ 1H NMR (D2O, 500 MHz): δ ϭ
1.40Ϫ1.65 (m, 5 H), 1.73Ϫ1.80 (br. d, 1 H), 2.81 (quint, J ϭ 8.0 Hz,
1 H), 3.67 (d, J ϭ 14.0 Hz, 1 H), 4.23 (d, J ϭ 12.0 Hz, 1 H), 6.78
(d, J ϭ 8.0 Hz, 1 H), 6.86 (t, J ϭ 8.0 Hz, 1 H), 7.11 (t, J ϭ 8.0 Hz,
1 H), 7.30 (d, J ϭ 8.0 Hz, 1 H). Ϫ 13C NMR (D2O): δ ϭ 20.3,
23.6, 25.6, 46.2, 58.2, 114.0, 114.9, 119.8, 125.6, 128.1, 134.8, 156.4.
Ϫ HRMS (FAB ϩ): calcd. for C12H16N3O [M ϩ Hϩ] 218.1293;
found 218.1292.
Ϫ
13C NMR (CDCl3, 125 MHz): δ ϭ 27.6, 30.4, 49.7, 54.7, 115.9,
125.1, 125.2, 126.7, 133.8, 143.7, 146.9. HRMS
(C11H11N3O2S [Mϩ]): calcd. 249.05719; found 249.05780.
Ϫ
Ϫ
C11H11N3O2S: calcd. C 53.00, H 4.45, N 16.86, O 12.84, S 12.86;
found C 52.78, H 4.41, N 16.38, O 12.67, S 13.18.
3-Cyano-4-(2-nitrophenyl)piperazine-1-carboxylic Acid tert-Butyl
Ester (5e): Compound 4e (1 g, 3.3 mmol) was dissolved in methanol
(100 mL) in the presence of LiClO4 and electrolyzed at Ep ϭ ϩ1.25
V. After the passage of 628 C (2.15 F/mol), electrolysis was stopped.
Usual workup led to an oil, which crystallized upon addition of a
mixture of diethyl ether and petroleum ether to afford 5e as an
orange powder (0.815 g, 76%). Ϫ M.p. 103 °C (diethyl ether/petro-
leum ether). Ϫ Rf ϭ 0.44 (CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 2226 cmϪ1
1
(CN, weak). Ϫ H NMR (C6D6, 70 °C, 500 MHz): δ ϭ 1.21 (s, 9
H), 1.90 (d, J ϭ 11.5 Hz, 1 H), 2.30 (t, J ϭ 11.5 Hz, 1 H), 2.66 (d,
J ϭ 12.0 Hz, 1 H), 2.79 (t, J ϭ 11.0 Hz, 1 H), 3.56 (s, 1 H), 3.75
(s, coal., 2 H), 6.37 (t, J ϭ 8.0 Hz, 1 H), 6.65 (t, J ϭ 8.0 Hz, 1 H),
6.73 (d, J ϭ 8.0 Hz, 1 H), 7.09 (d, J ϭ 8.0 Hz, 1 H). Ϫ 13C NMR
(C6D6, 70 °C, 125 MHz): δ ϭ 28.4, 43.1, 46.7, 47.4, 53.6, 80.5,
115.8, 124.9, 125.3, 126.2, 133.5, 143.0, 147.1, 154.1. Ϫ HRMS
(C16H20N4O4 [Mϩ]): calcd. for 332.14844; found 332.14789. Ϫ
C16H20N4O4: calcd. C 57.82, H 6.07, N 16.86, O 19.26; found C
57.80, H 6.08, N 16.64, O 19.27.
6a,7,8,9,10,11-Hexahydro-5-oxyazepino[1,2-a]quinoxalin-6-yl-
amine·HCl (6b): Compound 5b (0.26 g, 1.06 mmol) was dissolved
in ethanol (4 mL) and placed in a low-pressure catalytic hydro-
genator in the presence of Pearlman’s catalyst (0.1 g). The desired
hydrogen pressure (7.35 ϫ 102 Torr, 1 bar) was applied and after
stirring (24 h) at room temperature, the catalyst was removed, and
washed with methanol. The resulting solutions were evaporated to
dryness and the crude material was taken up with diethyl ether to
afford 6b as a white powder (0.210 g, 86%). The hydrochloride salt
of 6b was obtained as described above. Ϫ M.p. 170Ϫ175 °C (dec.).
Electrolysis of 4f: The electrolysis of 4f was performed as described
above (1.35 g, 6.13 mmol, Ep ϭ ϩ1.20 V, Q ϭ 2.12 F/mol) to afford
a mixture (80:20) of diastereomers. The crude material (1.3 g, 85%)
was chromatographed through a silica column (eluent: diethyl
ether/petroleum ether, 1:2) to give trans-5f (1.02 g, 64%), followed
by the more polar cis-5f (0.250 g, 16%).
1
Ϫ IR (KBr): ν˜ ϭ 1506, 1668 cmϪ1. Ϫ H NMR (D2O, 500 MHz):
δ ϭ 1.38Ϫ1.45 (m, 1 H), 1.60Ϫ1.85 (m, 5 H), 1.87Ϫ1.95 (m, 1 H),
2.15Ϫ2.22 (m, 1 H), 3.19Ϫ3.26 (m, 1 H), 3.87 (ddd, J ϭ 13.0, 4.0,
1.0 Hz, 1 H), 4.55 (dd, J ϭ 11.5, 4.0 Hz, 1 H), 6.90Ϫ7.00 (m, 2 H),
7.25 (t, J ϭ 8.0 Hz, 1 H), 7.44 (d, J ϭ 8.0 Hz, 1 H). Ϫ 13C NMR
(D2O, 125 MHz): δ ϭ 25.2, 25.9, 27.8, 32.1, 49.1, 59.9, 112.6, 114.9,
118.2, 124.3, 128.1, 134.9, 155.1. Ϫ HRMS (FAB ϩ): calcd. for
C13H18N3O [M ϩ Hϩ] 232.1450; found 232.1452.
(2R*,4R*)-4-Methyl-1-(2-nitrophenyl)piperidine-2-carbonitrile
(trans-5f): Yellow powder, m.p. 74 °C (diethyl ether/petroleum
ether). Ϫ Rf ϭ 0.71 (diethyl ether/petroleum ether, 1:2) Ϫ IR (KBr):
ν˜ ϭ 2225 cmϪ1(CN). Ϫ 1H NMR (CDCl3, 300 MHz): δ ϭ 1.02 (d,
J ϭ 6.0 Hz, 3 H, 4-CH3), 1.37 [qd, 2J(5a,5b) ϭ 3J(5a,6b) ϭ
3
3J(5a,4) ϭ 13.0 Hz, J(5a,6a) ϭ 4.5 Hz, 1 H, 5-Ha], 1.70Ϫ2.00 (m,
2
4 H, 3-H, 4-H, 5-Hb), 2.98 [dm, J(6a,6b) ϭ 12.0 Hz, 1 H, 6-Ha],
3.37 [td, 2J(6b,6a) ϭ 3J(6b,5a) ϭ 12.0 Hz, 3J(6b,5b) ϭ 2.5 Hz, 1 H,
6-Hb], 4.50Ϫ4.53 (m, 1 H, 2-H), 7.29 (td, J ϭ 9.0, 2.0 Hz, 1 H),
7.48 (dd, J ϭ 8.0, 2.0 Hz, 1 H), 7.60 (td, J ϭ 9.0, 2.0 Hz, 1 H),
7.90 (dd, J ϭ 8.0, 2.0 Hz, 1 H). Ϫ 13C NMR (CDCl3, 75 MHz):
δ ϭ 21.3 (4-CH3), 26.8 (C-4), 33.7 (C-3), 36.6 (C-5), 48.4 (C-6),
54.2 (C-2), 117.2 (CN), 124.4, 125.2, 125.6 (C-4Ј or C-5Ј or C-6Ј),
1,3,4,10a-Tetrahydro-9-oxy-2-oxa-4a,9-diazaphenanthren-10-
ylamine·HCl (6c): Compound 5c (0.5 g, 2.14 mmol) was dissolved
in ethanol (5 mL) and reduced in the presence of Pearlman’s cata-
lyst (0.130 g). The desired hydrogen pressure (7.35 102 Torr, 1 bar)
was applied and, after 6 hours stirring at room temperature, the
catalyst was filtered off by suction and the crude material was
washed with diethyl ether to afford the amidine 6c as a white pow-
der. Addition of diethyl ether saturated with gaseous HCl resulted
in the formation of the hydrochloride salt of 6c (0.3 g, 62%). Ϫ
M.p. 170Ϫ175 °C (dec.). Ϫ IR (KBr): ν˜ ϭ 1278, 1492, 1672, 3048
133.7 (C-3Ј), 143.9 (C-1Ј), 146.3 (C-2Ј).
Ϫ
HRMS
(C13H15N3O2 [Mϩ]): calcd. 245.11642; found 245.11553.
Ϫ
C13H15N3O2: calcd. C 63.66, H 6.16, N 17.13, O 13.05; found C
63.60, H 6.06, N 17.06, O 13.17.
1
(2R*,4S*)-4-Methyl-1-(2-nitrophenyl)piperidine-2-carbonitrile (cis-
5f): Orange powder, m.p. 92 °C (diethyl ether/petroleum ether) Ϫ
(br.) cmϪ1. Ϫ H NMR (D2O, 500 MHz): δ ϭ 3.02 (td, J ϭ 13.0,
3.0 Hz, 1 H), 3.59 (d, J ϭ 13.0 Hz, 1 H), 3.63Ϫ3.70 (m, 2 H), 3.94
Eur. J. Org. Chem. 2001, 987Ϫ996
993

T. Renaud, J.-P. Hurvois, P. Uriac
FULL PAPER
(dd, J ϭ 13.0, 3.0 Hz, 1 H), 4.11 (dd, J ϭ 12.0, 2.0 Hz, 1 H), 4.30
(dd, J ϭ 10.5, 3.5 Hz, 1 H), 6.90 (d, J ϭ 8.0 Hz, 1 H), 7.02 (t, J ϭ
of Pearlman’s catalyst (0.375 g). The desired hydrogen pressure
(7.35·102 Torr) was applied and, after 48 h stirring at room temper-
7.0 Hz, 1 H), 7.24 (t, J ϭ 7.0 Hz, 1 H), 7.39 (d, J ϭ 8.0 Hz, 1 H). ature, the usual workup resulted in the precipitation of the hydro-
Ϫ
13C NMR (D2O, 125 MHz): δ ϭ 45.4, 55.3, 64.7 (2 carbons),
chloride salt of trans-6f (0.401 g, 58%). Ϫ M.p. 170Ϫ175 °C (dec.).
1
113.8, 115.1, 121.1, 126.0, 128.3, 135.1, 153.9. Ϫ HRMS (FAB ϩ):
Ϫ IR (KBr): ν˜ ϭ 1286, 1493, 1644, 2955 (br) cmϪ1. Ϫ H NMR
calcd. for C11H14N3O2 [M ϩ Hϩ] 220.1086; found 220.1086.
(D2O, 300 MHz): δ ϭ 1.10 (d, 3J ϭ 7.0 Hz, 3 H, 8-CH3), 1.32 [dm,
2
2J(9a,9b) ϭ 12.0 Hz, 1 H, 9-Ha], 1.49 [dm, J(7a,7b) ϭ 12.0 Hz, 1
2
3
H, 7-Ha], 1.88 [tm, J(9b,9a) ϭ J(9b,10a) ϭ 12.0 Hz, 1 H, 9-Hb],
1,3,4,10a-Tetrahydro-9-oxy-2-thia-4a,9-diazaphenanthren-10-
ylamine·HCl (6d): Compound 5d (0.570 g, 2.3 mmol) was dissolved
in ethanol (6 mL) and placed in a low-pressure hydrogenator in the
presence of Pearlman’s catalyst (0.3 g). The desired hydrogen pres-
sure (7.35 102 Torr, 1 bar) was applied and, after 24 h stirring at
room temperature, the usual workup led to the precipitation of the
hydrochloride salt of 6d (0.538 g, 99%), m.p. 160Ϫ165 °C (dec.). Ϫ
IR (KBr): ν˜ ϭ 1298, 1502, 1674, 3036 (br) cmϪ1. Ϫ 1H NMR (D2O,
500 MHz): δ ϭ 2.28 (d, J ϭ 13.5 Hz, 1 H), 2.35 (d, J ϭ 13.0 Hz,
1 H), 3.08 (dd, J ϭ 15.5, 11.5 Hz, 1 H), 3.18 (td, J ϭ 13.0, 2.0 Hz,
1 H), 3.56 (ddd, J ϭ 14.0, 12.5, 3.0 Hz, 1 H), 4.28 (d, J ϭ 15.0 Hz,
1 H), 5.00 (dd, J ϭ 11.5, 2.0 Hz, 1 H), 7.00Ϫ7.08 (m, 2 H), 7.31
(t, J ϭ 7.0 Hz, 1 H), 7.47 (d, J ϭ 7.0 Hz, 1 H). Ϫ 13C NMR (D2O,
125 MHz): δ ϭ 19.8, 23.6, 47.1, 59.6, 114.4, 115.2, 119.9, 125.6,
128.5, 133.2, 153.1. Ϫ HRMS (FAB ϩ): calcd. for C11H14N3OS [M
ϩ Hϩ] 236.0858; found 236.0860.
2
3
3
1.98 [td, J(7b,7a) ϭ J(7b,6a) ϭ 12.0 Hz, J(7b,8) ϭ 3.5 Hz, 1 H,
7-Hb], 2.03Ϫ2.15 (m,
1 ϭ
H, 8-H), 3.17 [td, 2J(10a,10b)
3J(10a,9b) ϭ 12.0 Hz, J(10a,9a) ϭ 3.0 Hz, 1 H, 10-Ha], 3.53 [dt,
3
2J(10b,10a) ϭ 12.0 Hz, 3J(10b,9b) ϭ J(10b,9a) ϭ 3.5 Hz, 1 H, 10-
3
Hb], 4.54 [dd, 3J(6a,7b) ϭ 12.0 Hz, 3J(6a,7a) ϭ 3.0 Hz, 1 H, 6a-H],
6.97Ϫ7.03 (m, 2 H), 7.23 (t, 1 H), 7.40 (d, 1 H). Ϫ 13C NMR (D2O,
75 MHz): δ ϭ 19.0, 27.7, 28.6, 33.2, 44.2, 55.9, 117.4, 117.7, 123.2,
129.0, 130.5, 137.4, 159.5.
Ϫ HRMS (FAB ϩ): calcd. for
C13H18N3O [M ϩ Hϩ] 232.1450; found 232.1452.
(6aR*,8S*)-7,8,9,10-Tetrahydro-6aH-8-methyl-5-oxopyrido[1,2-a]-
quinoxalin-6-ylamine·HCl (cis-6f): Compound cis-5f (0.368 g,
1.5 mmol) was dissolved in ethanol (5 mL) and placed in a low-
pressure hydrogenator in the presence of Pearlman’s catalyst (0.368
g). After 5 h stirring at room temperature, the usual workup re-
sulted in the precipitation of the hydrochloride salt of cis-6f (0.242
g, 70%). Ϫ M.p. 175Ϫ180 °C (dec.). Ϫ IR (KBr): ν˜ ϭ 1496, 1648,
3100 (br) cmϪ1. Ϫ 1H NMR (D2O, 300 MHz) δ ϭ 0.82 (d, 3J ϭ
7.0 Hz, 3 H, 8-CH3), 1.11Ϫ1.29 (m, 2 H, 7-Ha, 9-Ha), 1.54 [dm,
Synthesis of 7e: Compound 5e (0.228 g, 0.7 mmol) was dissolved
in a 1:1 mixture of ethanol and dioxane (3.0 mL) and placed in a
low-pressure hydrogenator in the presence of Pearlman’s catalyst
(0.067 g). The desired hydrogen pressure (7.35 ϫ 102 Torr, 1 bar)
was applied and, after 20 h stirring at room temperature, the addi-
tion of diethyl ether resulted in the precipitation of 6e (0.127 g,
60%), which was further purified by rapid filtration through a silica
column, with a mixture (80:20) of dichloromethane and methanol
as eluent. Addition of HCl in ethanol (3 , 8 mL) to the resulting
powder resulted in the precipitation of the hydrochloride salt of 7e.
2
2J(9b,9a) ϭ 14.0 Hz, 1 H, 9-Hb], 1.67 [dm, J(7b,7a) ϭ 14.0 Hz, 1
H, 7-Hb], 1.70Ϫ1.80 (m, 1 H, 8-H), 2.90 [t, 2J(10a,10b) ϭ
3J(10a,9a) ϭ 13.0 Hz, 1 H, 10-Ha], 3.82 [dm, 2J(10b,10a) ϭ
13.0 Hz, 1 H, 10-Hb], 4.31 [dd, 3J(6a,7a) ϭ 12.0 Hz, 3J(6a,7b) ϭ
2.0 Hz, 1 H, 6a-H], 6.89Ϫ6.96 (m, 2 H), 7.19 (t, 1 H), 7.35 (d, 1
H), Ϫ 13C NMR (D2O, 75 MHz): δ ϭ 23.8, 30.9, 33.0, 35.5, 48.4,
60.5, 116.9, 117.4, 122.6, 128.5, 130.5, 137.2, 159.1.
5-Amino-1,2,4,4a-tetrahydropyrazino[1,2-a]quinoxaline-3-carboxylic
Acid tert-Butyl Ester (6e): M.p. 170Ϫ175 °C (dec.). Ϫ Rf ϭ 0.8
(CH2Cl2/MeOH, 80:20). Ϫ IR (KBr): ν˜ ϭ 744, 1654 (CϭN), 1688
6,6a,7,8,9,10-Hexahydro-5H-pyrido[1,2-a]quinoxaline (3a): The am-
idine N-oxide 6a (0.680 g, 3.1 mmol) was dissolved in methanol
(50 mL) and placed in a high-pressure hydrogenation apparatus in
the presence of Pearlman’s catalyst (0.345 g). The desired pressure
(3.75·103 Torr) was applied and the resulting solution was shaken
for 7 days at room temperature. The catalyst was removed by filtra-
tion and washed with methanol. The combined solutions were
evaporated to dryness. The crude material was further chromato-
graphed on silica (eluent: CH2Cl2) to afford 3a as a colorless oil,
which solidified upon cooling (0.33 g, 56%). Ϫ Pale yellow powder,
m.p. 97 °C (diethyl ether/petroleum ether). Ϫ Rf ϭ 0.33 (CH2Cl2).
Ϫ IR (KBr): ν˜ ϭ 740, 1500,3330 cmϪ1 (NH). Ϫ 1H NMR (CDCl3,
500 MHz): δ ϭ 1.24Ϫ1.44 (m, 2 H, 8-Ha and 7-Ha), 1.56Ϫ1.68 (m,
2 H, 7-Hb and 9-Ha), 1.74Ϫ1.84 (m, 2 H, 8-Hb and 9-Hb), 2.53 [td,
1
(CϭO) cmϪ1. Ϫ H NMR (CD3OD, 300 MHz, 55 °C): δ ϭ 1.49
(s, 9 H, (CH3)3ϪC), 2.95Ϫ3.16 (m, 3 H, 1-Ha, 2-Ha, 4-Ha), 3.92
[dm, 2J(1b,1a) ϭ 13.0 Hz, 1 H, 1-Hb], 4.00 [dm, 2J(2b,2a) ϭ
13.0 Hz, 1 H, 2-Hb], 4.24 [dm, 2J(4b,4a) ϭ 13.0 Hz, 1 H, 4-Hb],
4.33 [dd, 3J(4-a,4a) ϭ 11.0 Hz, 2J(4-a,4b) ϭ 4.0 Hz, 1 H, 4a-H],
6.87Ϫ6.95 (m, 2 H), 7.15 (t, 1 H), 7.74 (d, 1 H). Ϫ 13C NMR
(CD3OD, 75 MHz, 55 °C): δ ϭ 28.5 [(CH3)3ϪC], 41.7 (coalescent,
C-2), 44.2 (coalescent, C-4), 46.0 (C-1), 57.1 (C-4a), 82.1
[(CH3)3ϪC], 113.4, 117.7, 120.6, 128.2, (C-7, C-8, C-9, C-10),
129.7, (C-6a), 136.3 (C-10a), 147.3 (C-5), 156.2 (CϭO). Ϫ HRMS
(FAB ϩ): calcd. for C16H23N4O3 [M ϩ Hϩ] 319.1770; found
319.1769.
3
2J(10a,10b) ϭ J(10a,9a) ϭ 12.0 Hz, 3J(10a,9b) ϭ 3.0 Hz, 1 H, 10-
Ha], 2.88Ϫ2.95 (m, 1 H, 6a-H), 3.19Ϫ3.26 (m, 2 H, 6-H),
3.40Ϫ3.50 (s, br., 1 H, NH), 3.80 [dm, 2J(10b,10a) ϭ 12.0 Hz, 1 H,
10-Hb], 6.43 (dd, J ϭ 7.5, 1.5 Hz, 1 H), 6.57Ϫ6.65 (m, 2 H), 6.73
(d, J ϭ 8.0 Hz, 1 H). Ϫ 13C NMR (CDCl3, 75 MHz): δ ϭ 22.6 (C-
8), 24.2 (C-9), 29.0 (C-7), 46.2 (C-10), 46.8 (C-6), 53.2 (C-6a), 111.7
and 113.1 (C-1 or C-4), 117.5 and 117.9 (C-2 or C-3), 134.1 and
134.7 (C-4a or C-10b).
188.1313; found 188.1313. Ϫ C12H16N2: calcd. C 76.55, H 8.57, N
14.88; found C 76.31, H 8.43, N 14.43.
2,3,4,4a-Tetrahydro-1H-6-oxypyrazino[1,2-a]quinoxalin-5-ylamine
(7e): M.p. 200Ϫ205 °C (dec.). Ϫ IR (KBr): ν˜ ϭ 1508, 1602, 1672,
2486, 3006 cmϪ1. Ϫ 1H NMR (D2O, 300 MHz): δ ϭ 3.30Ϫ3.60
(m, 5 H), 4.22 (d, J ϭ 15.0 Hz, 1 H), 5.06 (dd, J ϭ 11.0, 3.0 Hz, 1
H), 7.07 (d, 1 H), 7.13 (t, 1 H), 7.36 (t, 1 H), 7.53 (d, 1 H). Ϫ 13C
NMR (D2O, 75 MHz): δ ϭ 42.0, 43.1, 44.7, 56.6, 116.5, 118.2,
123.9, 128.3, 131.2, 135.1, 154.4. Ϫ HRMS (FAB ϩ): calcd. for
C11H15N4O [M ϩ Hϩ] 219.1246; found 219.1246.
Ϫ
HRMS (C12H16N2 [Mϩ]): calcd.
(6aR*,8R*)-7,8,9,10-Tetrahydro-6aH-8-methyl-5-oxopyrido[1,2-
a]quinoxalin-6-ylamine·HCl (trans-6f): Compound trans-5f (0.736 g, 5,6,6a,7,8,9,10,11-Octahydroazepino[1,2-a]quinoxaline (3b): Com-
3.0 mmol) was dissolved in a 1:1 mixture of ethanol and dioxane
(3.0 mL) and placed in a low-pressure hydrogenator in the presence
pound 6b (0.5 g, 2.16 mmol) was dissolved in methanol (35 mL),
and placed in a high-pressure apparatus in the presence of
994
Eur. J. Org. Chem. 2001, 987Ϫ996

Synthesis of New Quinoxaline Derivatives
FULL PAPER
Pearlman’s catalyst (0.511 g). The hydrogen pressure was applied C16H23N3O2:calcd. C 66.41, H 8.01, N 14.52; found C 66.43, H
at 3.75 ϫ 103 Torr, and the reaction mixture was shaken for 7 days
at room temperature. Workup as described above gave 3b as a col-
orless oil (0.29 g, 66%). Ϫ Rf ϭ 0.33 (CH2Cl2). Ϫ IR (KBr): ν˜ ϭ
8.09, N 14.43.
2,3,4,4a,5,6-Hexahydro-1H-pyrazino[1,2-a]quinoxaline·2HCl (8e):
M.p. 170Ϫ180 °C (dec.). Ϫ IR (KBr): ν˜ ϭ 756, 1610, 2392 cmϪ1
.
1281, 1509, 1597, 3379 cmϪ1 (NH).
Ϫ
1H NMR (CDCl3,
1
Ϫ H NMR (D2O, 300 MHz): δ ϭ 3.03Ϫ3.16 (m, 2 H, 4-Ha and
1-Ha), 3.29 [td, 2J(2a,2b) ϭ 3J(2a,1a) ϭ 13.0 Hz, 3J(2a,1b) ϭ
4.0 Hz, 1 H, 2-Ha], 3.39 [dd, 2J(5a,5b) ϭ 12.0 Hz, 3J(5a,4a) ϭ
10.0 Hz, 1 H, 5-Ha], 3.58Ϫ3.61 (m, 2 H, 4-Hb and 2-Hb), 3.67Ϫ3.80
300 MHz): δ ϭ 1.40Ϫ1.63 (m, 5 H, 8-H, 9-H, 10-Ha), 1.70Ϫ1.80
2
(m, 2 H, 7-H), 1.90Ϫ2.23 (m, 1 H, 10-Hb), 3.01 [dd, J(6a, 6b) ϭ
3
2
10.5 Hz, J(6a,6-a) ϭ 3.5 Hz, 1 H, 6-Ha], 3.06 [ddd, J(11a,11b) ϭ
15.0 Hz, 3J(11a,10b) ϭ 10.5 Hz, 3J(11a, 10a) ϭ 3.5 Hz, 1 H, 11-
(m, 2 H, 4a-H and 5-Hb), 4.10 [dm, J(1b,1a) ϭ 12.0 Hz, 1 H, 1-
2
Ha], 3.25 [dd, J(6b, 6a) ϭ 10.5 Hz, J(6b, 6-a) ϭ 3.5 Hz, 1 H, 6-
2
3
Hb], 6.93 (t, 3J ϭ 7.0 Hz, 1 H), 7.09 (d, 3J ϭ 8.0 Hz, 1 H), 7.21 (d,
Hb], 3.40Ϫ3.55 (m, 2 H, 6a-H and NH), 3.75 [dt, J (11b,11a) ϭ
2
3J ϭ 7.0 Hz, 1 H), 7.35 (t, J ϭ 8.0 Hz, 1 H). Ϫ 13C NMR (D2O,
3
15.0 Hz, 3J (11b,10) ϭ 4.5 Hz, 1 H, 11-Hb], 6.45Ϫ6.51 (m, 3 H),
6.60Ϫ6.65 (m, 1 H). Ϫ 13C NMR (CDCl3, 75 MHz): δ ϭ 25.4,
26.9, 27.2, 34.7, 45.2, 48.9, 56.8, 109.5, 113.7, 115.5, 119.3, 132.5,
75 MHz): δ ϭ 45.3 (C-1), 45.4 (C-5), 45.6 (C-2), 47.0 (C-4), 51.2
(C-4a), 118.0, 120.7, 123.1, 126.1, 133.3, 141.7.
Ϫ HRMS
(C11H15N3 [Mϩ]): calcd. 189.1266; found 189.1269.
134.7.
Ϫ
HRMS (C13H18N2 [Mϩ]): calcd. 202.1470; found
202.1477. Ϫ C13H18N2: calcd. C 77.18, H 8.97, N 13.85; found C
77.23, H 8.74, N 13.83.
(6aR*,8R*)-6,6a,7,8,9,10-Hexahydro-5H-8-methylpyrido[1,2-a]-
quinoxaline (trans-3f): The amidine trans-6f (0.245 g, 1.06 mmol)
was dissolved in methanol (40 mL) and placed in a high-pressure
apparatus in the presence of Pearlman’s catalyst (0.51 g). Hydrogen
pressure was applied at 3.75 ϫ 103 Torr and the solution was
shaken for 6 days at room temperature. The catalyst was removed
by suction and the resulting solution was evaporated under reduced
pressure. The crude reaction mixture was chromatographed
through a silica column (eluent CH2Cl2) to afford trans-3f as pale
yellow oil (0.157 g, 73%). Ϫ Rf ϭ 0.39 (CH2Cl2). Ϫ IR (neat): ν˜ ϭ
735, 1503, 1598, 3389 (NH) cmϪ1. Ϫ 1H NMR (CDCl3, 300 MHz):
δ ϭ 1.05 (d, 3J ϭ 7.0 Hz, 3 H, 8-CH3), 1.50Ϫ1.62 (m, 3 H, 7-H
and 9-Ha), 1.90 [tt, 2J(9b,9a) ϭ 3J(9b,10a) ϭ 12.0 Hz, 3J(9b,10b) ϭ
3J(9b,8) ϭ 5.0 Hz, 1 H, 9-Hb], 2.04 (m, 1 H, 8-H), 2.85 [td,
1,3,4,9,10,10a-Hexahydro-2-oxa-4a,9-diazaphenanthrene (3c): The
cyanoamine 5c (1.03 g, 4.44 mmol) was dissolved in methanol
(25 mL), and placed in a high-pressure apparatus in the presence
of Pearlman’s catalyst (0.5 g). The hydrogen pressure was applied
at 7.35 ϫ 102 Torr and the reaction mixture was shaken for 1 day
at room temperature. The hydrogen pressure was raised to 3.75 ϫ
103 Torr, and the solution was shaken for 7 additional days. The
crude reaction mixture was chromatographed over a silica column
(eluent: CH2Cl2) to afford 3c as a white solid (0.515 g, 65%). Ϫ
M.p. 116 °C. Ϫ Rf ϭ 0.56 (CH2Cl2). Ϫ IR (KBr): ν˜ ϭ 744, 1501,
1
2859, 3334 cmϪ1 (NH). Ϫ H NMR (CDCl3, 300 MHz): δ ϭ 2.83
2
3
3
[td, J(4a,4b) ϭ J(4a,3a) ϭ 12.0 Hz, J(4a,3b) ϭ 4.0 Hz, 1 H, 4-
3
2J(10a,10b) ϭ J(10a,9b) ϭ 12.0 Hz, 1 H, 10-Ha], 3.17Ϫ3.22 (m, 3
Ha], 3.09Ϫ3.22 (m, 3 H, 10-H, 10a-H), 3.26 [t, 2J(1a,1b) ϭ
H, 6-H and 6a-H), 3.50 [dt, 2J(10b,10a) ϭ 12.0 Hz, 3J(10b,9) ϭ
5.0 Hz, 1 H, 10-Hb], 6.44Ϫ6.48 (m, 1 H), 6.60Ϫ6.67 (m, 2H),
6.75Ϫ6.80 (m, 1 H). Ϫ 13C NMR (CDCl3, 75 MHz): 17.2 (8-CH3),
25.0 (C-8), 31.0 (C-9), 35.6 (C-7), 42.5 (C-10), 47.4 (C-6), 48.5 (C-
6a), 113.6, 114.1 (C-1 or C-4), 118.3, 119.4 (C-2 or C-3), 135.3,
135.9 (C-4a or C-10a). Ϫ HRMS (C13H18N2 [Mϩ]): calcd. for
202.1470; found 202.1466.
3J(1a,10-a) ϭ 10.0 Hz, 1 H, 1-Ha], 3.49 [dm, J(4b,4a) ϭ 12.0 Hz,
2
1 H, 4-Hb], 3.71 [td, J(3a,3b) ϭ J(3a,4a) ϭ 12.0 Hz, J(3a,4b) ϭ
3.0 Hz, 1 H, 3-Ha], 3.87 [dm, 2J(1b,1a) ϭ 10.0 Hz, 1 H, 1-Hb], 4.03
[dm, 2J(3b,3a) ϭ 12.0 Hz, 1 H, 3-Hb], 6.45Ϫ6.50 (m, 1 H),
6.64Ϫ6.68 (m, 3 H). Ϫ 13C NMR (CDCl3, 75 MHz): δ ϭ 43.0 (C-
10), 46.1 (C-4), 52.2 (C-10a), 66.9 (C-3), 69.3 (C-1), 112.1, 114.0
(C-5 or C-8), 118.3, 119.9 (C-6 or C-7), 134.5, 134.7 (C-4b or C-8a).
Ϫ HRMS (C11H14N2O [Mϩ]): calcd. 190.11060; found 190.1105. Ϫ
C11H14N2O: calcd. C 69.45, H 7.42, N 14.73, O 8.41; found C
69.35, H 7.70, N 14.68, O 8.15.
2
3
3
(6aR*,8S*)-6,6a,7,8,9,10-Hexahydro-5H-8-methylpyrido[1,2-a]-
quinoxaline (cis-3f): The amidine cis-6f (0.250 g, 1.08 mmol) was
dissolved in methanol (25 mL) and placed in a high-pressure appar-
atus in the presence of Pearlman’s catalyst (0.45 g). Hydrogen pres-
sure was applied at 3.75 ϫ 103 Torr and the solution was shaken
for 5 days at room temperature. The catalyst was removed by suc-
tion and the resulting solution was evaporated under reduced pres-
sure. The crude reaction mixture was chromatographed through a
silica column (eluent CH2Cl2) to afford cis-3f as pale yellow solid,
(0.148 g, 70%). Ϫ M.p. 55 °C (CH2Cl2) Ϫ Rf ϭ 0.23 (CH2Cl2). Ϫ
IR (CH2Cl2): ν˜ ϭ 735, 1598, 3380 (NH) cmϪ1. Ϫ 1H NMR
(CDCl3, 300 MHz): δ ϭ 0.96 (d, J ϭ 6.5 Hz, 3 H, 8-CH3), 0.98 [q,
Synthesis of 8e: The cyanoamine 5e (0.8g, 2.41 mmol) was dissolved
in methanol (25 mL), and placed in a high-pressure apparatus in
the presence of Pearlman’s catalyst (0.4 g). Hydrogen pressure was
applied at 7.35 ϫ 102 Torr for 1 day at room temperature; the rate
of the reductive cyclization was monitored by TLC. After comple-
tion, the hydrogen pressure was raised to 3.75 ϫ 103 Torr and the
solution was shaken for 5 additional days. Workup as described
above produced 3e (m.p. 124 °C) as a pale yellow solid (0.364 g,
52%). The addition of 3  ethanolic HCl solution (8 mL) resulted
in the precipitation of 8e as a gray hygroscopic solid.
3
3
2J(7a,7b) ϭ J(7a,6a) ϭ J(7a,8) ϭ 12.0 Hz, 1 H, 7-Ha], 1.28 [qd,
3
3
2J(9a,9b) ϭ J(9a,10a) ϭ J(9a,8) ϭ 12.5 Hz, 3J(9a,10b) ϭ 4.5 Hz,
tertButyl 1,2,4a,5-Tetrahydro-4H,6H-pyrazino[1,2-a]quinoxaline-3-
1 H, 9-Ha], 1.50Ϫ1.63 (m, 1 H, 8-H), 1.66 [dq, 2J(7b,7a) ϭ 12.5 Hz,
carboxylate (3e): Ϫ Rf ϭ 0.19 (CH2Cl2). Ϫ IR (CH2Cl2): ν˜ ϭ 735, 3J(7b,6-a) ϭ 3J(7b,8) ϭ 4J(7b,9b) ϭ 3.0 Hz, 1 H, 7-Hb], 1.76
1255, 1680 (CO), 3373 cmϪ1 (NH).
Ϫ
1H NMR (CDCl3,
[dquint, 2J(9b,9a) ϭ 13.0 Hz, 3J(9b,10a) ϭ 3J(9b,10b) ϭ 3J(9b,8) ϭ
3.0 Hz, ϭ
H, 9-Hb], 2.57 [td, 2J(10a,10b)
500 MHz): δ ϭ 1.47 [s, 9 H, C(CH3)], 2.60Ϫ2.65 (coalescent, 1 H), 4J(9b,7b)
ϭ
1
2.71 (td, J ϭ 12.0, 3.0 Hz, 1 H), 3.00Ϫ3.10 (m, 2 H), 3.24 (dd, J ϭ 3J(10a,9a) ϭ 12.5 Hz, 3J(10a,9b) ϭ 3.0 Hz, 1 H, 10-Ha], 2.91Ϫ3.00
11.0, 8.0 Hz, 1 H), 3.36 (dd, J ϭ 11.0, 3.0 Hz, 1 H), 3.68 (d, J ϭ (m, 1 H, 6a-H), 3.20Ϫ3.32 (m, 3 H, NH and 6-H), 3.82 [dm,
8.5 Hz, 1 H), 4.00Ϫ4.20 (coalescent, 2 H), 6.48Ϫ6.52 (m, 1 H),
2J(10b,10a) ϭ 12.0 Hz, 1 H, 10-Hb], 6.46 (dd, J ϭ 7.0, 2.0 Hz, 1
6.65Ϫ6.68 (m, 2 H), 6.72Ϫ6.73 (m, 1 H). Ϫ 13C NMR (CDCl3, H), 6.60 (td, J ϭ 7.0, 2.0 Hz, 1 H), 6.64 (td, J ϭ 7.0, 2.0 Hz, 1 H),
125 MHz): δ ϭ 28.4, 42.0 (coalescent), 44.5, 46.4, 47.0 (coalescent),
52.7, 80.0, 112.9, 114.4, 118.7, 119.9, 134.5, 134.8, 154.6. Ϫ HRMS
6.75 (dd, J ϭ 7.0, 2.0 Hz, 1 H). Ϫ 13C NMR (CDCl3, 75 MHz):
22.0 (8-CH3), 30.2 (C-8), 33.7 (C-9), 38.5 (C-7), 47.0 (C-10), 47.8
(C-6), 53.9 (C-6a), 112.8, 114.1 (C-1 or C-4), 118.6, 119.0 (C-2 or
(C16H23N3O2 [Mϩ]): calcd. 289.1790; found 289.1797.
Ϫ
Eur. J. Org. Chem. 2001, 987Ϫ996
995

T. Renaud, J.-P. Hurvois, P. Uriac
FULL PAPER
C-3), 135.0, 135.6 (C-4a or C-10b). Ϫ HRMS (C13H18N2 [Mϩ]):
Ϫ
[6c] C. Yue, I. Gaultier, J. Royer, H. P. Husson, J. Org. Chem.
1996, 61, 4949Ϫ4954.
calcd. for 202.1470; found 202.1466.
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P. Deslongchamps, in Stereoelectronic Effects in Organic
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V. Stevens, A. W. M. Lee, J. Am. Chem. Soc. 1979, 101,
7032Ϫ7035.
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