Synthesis of substituted 4-azaisoindoles - New tacrine analogues

Article abstract of DOI:10.1139/V06-180

The regioselective Friedlaender reaction of 3-amino-4-cyanopyrroles with a series of cyclic ketones has enabled the first reported synthesis of substituted 4-azaisoindoles. Structurally, this new class of compounds stands for the first reported 4-azaisoin

Full text of DOI:10.1139/V06-180

1
Synthesis of substituted 4-azaisoindoles — New
tacrine analogues
Henri Bekolo and Gilbert Kirsch
Abstract: The regioselective Friedländer reaction of 3-amino-4-cyanopyrroles with a series of cyclic ketones has en-
abled the first reported synthesis of substituted 4-azaisoindoles. Structurally, this new class of compounds stands for the
first reported 4-azaisoindole tacrine analogues. A reaction mechanism for the formation of the reported 4-azaisoindoles
is proposed.
Key words: 4-azaisoindoles, tacrine, Friedländer reaction, pyrroles, mechanism.
Résumé : La réaction de Friedländer des 3-amino-4-cyanopyrroles avec une série de cétones cycliques a permis la syn-
thèse d’une nouvelle famille de composés: les 4-azaisoindoles substituées. Ces nouveaux composés sont de nouveaux
analogues de la tacrine soit les 4-azaisoindoles analogues de la tacrine dont nous proposons aussi le mécanisme de for-
mation.
Mots-clés : 4-azaisoindoles, tacrine, réaction de Friedländer, pyrroles, mécanisme.
Bekolo and Kirsch
6
Introduction
Scheme 1. Friedländer synthesis of 3 from 1 and 2.
We have previously developed an efficient synthesis of 3-
amino-4-cyanopyrrole derivatives (1–3) and have set out to
investigate their reactivity. Herein we give a preliminary ac-
count of our investigations, since pyrroles 1a (1) and 1b (3)
have proven to be good synthons for the preparation of sub-
stituted 4-azaisoindoles 3 (Scheme 1).
NH2
SMe
SMe
CN
AlCl3
n
n
RN
+
RN
1, 2 DCE
reflux
O
NH2
Z
N
Z
CO2
Et
CO2Et
3
1
2, Z = any
While the derivatives of 4-azaindole have been extensively
synthesized (4), the synthesis of the derivatives of the iso-
meric 4-azaisoindole seems to have been neglected despite
their possible potential as bioactive molecules. A related ex-
ample is the potent antitumor agent camptothecin, whose B
and C rings system is a reduced tautomeric form of 4-
azaisoindole (5). This lack of interest in the synthesis of 4-
azaisoindoles stems from the current research endeavour
aimed at developing a potent side effect free anti-
Alzheimers’s disease drug based on a tacrine analogue lead
compound. Many research groups have been synthesizing
and screening various kinds of heterocyclic system tacrine
analogues for biological activities, but none has ever re-
ported a synthesis nor a biological evaluation of 4-
azaisoindole tacrine analogues, or any other “pyrrolo”
tacrines (6–14), i.e., tacrine analogues having a pyrrole ring
in place of the benzene ring of tacrine 4 (Fig. 1).
1a: R = H
1b: R = Ph
upset, represent an important drawback. Despite these limi-
tations, tacrine appears as an important reference (9). So, a
great synthetic and pharmacological research effort has been
undertaken to design a tacrine analogue, which would be a
more potent and side effect free drug.
Results and discussion
We have prepared 4-azaisoindole tacrine analogues 3a–3q
(Tables 1–8) in which, as in the previously reported ana-
logues, the cyclohexane-fused ring (3b, 3h) has been con-
tracted (3a), enlarged (3c, 3d), and replaced by
functionalized cyclohexane rings (3e, 3f, 3g, 3l, 3m, 3n, and
3p) (14), a nitrogen-containing six-membered heterocyclic
ring (3j) (14), and unlike the previously reported analogues,
replaced by a pyran (3q) and a thiopyran ring (3i).
In most cases the Friedländer cyclizations (9) (Scheme 1)
were complete within 2 h, yielding the 4-azaisoindoles 3 in
good to quantitative yields, which is noteworthy as the pri-
mary amino group of 1 is expected to be weakly
nucleophilic (15) and the “pyridine ring” might form at ei-
ther substituent ortho to the primary amino group.
Tacrine was the first drug approved in the USA for the
palliative treatment of Alzheimer’s disease. However, its se-
vere side effects, such as hepatotoxicity and gastrointestinal
Received 28 August 2006. Accepted 20 November 2006.
Published on the NRC Research Press Web site at
http://canjchem.nrc.ca on 5 January 2007.
H. Bekolo1 and G. Kirsch. Laboratoire d’Ingénierie
Moléculaire et Biochimie Pharmacologique – 1, Boulevard
Arago, 57078 Metz, France.
The α tetralone-type ketones 2e, 2f, 2n, and 2o were slow
to react and required higher reagent–reactant concentrations.
Considering the mechanistic pathway 2 (Scheme 2) that we
have postulated, this slowness is probably the result of the
1Corresponding author (e-mail: hbekolo@hotmail.com).
Can. J. Chem. 85: 1–6 (2007)
doi:10.1139/V06-180
© 2007 NRC Canada

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Can. J. Chem. Vol. 85, 2007
Table 4. Reaction of ketones 2b–2j with pyrrole 1b.
Fig 1. Tacrine 4.
NH2
NH2
SMe
X
X
PhN
O
N
N
4
CO2Et
Table 1. Reaction of ketones 2a–2d with pyrrole 1a.
Ketone
Time (h)
Product
Yield (%)a
NH2
SMe
2b: X = CH2
2i: X = S
2j: X = N-Ts
1
1
2
3h: X = CH2
3i: X = S
3j: X = N-Ts
76
77
70
n
HN
n
O
N
aIsolated yields.
CO2Et
Ketone
Time (h)
Product
Yield (%)a
Table 5. Reaction of ketone 2l with pyrrole 1b.
2a: n = 0
2b: n = 1
2c: n = 2
2d: n = 3
1
1
2
2
3a: n = 0
3b: n = 1
3c: n = 2
3d: n = 3
81
92
80
100
O
NH2
O
SMe
PhN
O
N
aIsolated yields.
CO2Et
Yield (%)a
80
Table 2. Reaction of ketones 2e and 2f with pyrrole 1a.
Ketone
Time (h)
2
Product
NH2
SMe
2l
3l
aIsolated yields.
HN
O
N
CO2Et
R1
R1
Table 6. Reaction of ketone 2m with pyrrole 1b.
NH2
SMe
Ketone
Time (h)
Product
Yield (%)a,b
O
2e: R1 = H
8
15
3e: R1 = H
50
55
PhN
2f: R1 = OMe
3f: R1 = OMe
O
N
CN
aIsolated yields.
CO2Et
HN
b1,2 DCE (5 mL) was used.
SMe
NPh
EtO2C
Table 3. Reaction of ketone 2g with pyrrole 1a.
Ketone
Time (h)
2
Product
Yield (%)a
25
NH2
SMe
2m
3m
aIsolated yields.
HN
O
N
CO2Et
Table 7. Reaction of ketones 2n–2p with pyrrole 1b.
Ketone
Time (h)
2
Product
Yield (%)a
73
NH2
SMe
2g
3g
aIsolated yield.
O
PhN
X
N
X
CO2Et
reduced electrophilicity of the corresponding aluminium
chloride coordinated carbonyls 5 whose α aromatic rings act
by mesomeric effects as electron suppliers to the developing
positive charge induced at the benzylic position by AlCl3,
thus slowing the enamine formation steps. As can be seen in
Tables 2 and 7, the formations of azaisoindoles 3e and 3f as-
sembled from 1a, and 3n and 3o assembled from 1b, required
longer reaction times than those of 3b and 3h, respectively.
In the case of the formation of 3e and 3f, many unidenti-
fied by-products were detected, which would account for the
modest obtained isolated yields of 50% and 55%, respec-
tively.
Ketone
Time (h) Product
Yield (%)a,b
2n: X = O
2o: X = NH
2p: X = N-SO2Ph
15
24
2
3n: X = O
3o: X = NH
3p: X = N-SO2Ph 40
67
5
aIsolated yield.
b1,2 DCE (5 mL) was used.
In line with our reasoning, ketone 2o, whose α pyrrole
ring has a greater electron supplying ability than the furan
ring of 2n, reacted poorly with 1b even after 24 h of reflux
© 2007 NRC Canada

Bekolo and Kirsch
3
Scheme 2. Possible mechanistic pathways for the Friedländer cyclization of α tetralone-type ketones.
AlCl3
N
AlCl3
N
SMe
SMe
Pathway 1
C
RN
RN
NH2
O
HO
Ar
Ar
NH2
H
CO2Et
EtO
C
7
O
1
NH2
SMe
8
RN
N
Ar
CO2Et
9
SMe
AlCl3
N
CN
SMe
Pathway 2
C
RN
O
AlCl3
Ar
RN
NH2
CO2Et
N
H
Ar
5
1
CO2Et
6
Table 8. Reaction of ketone 2q with pyrrole 1b.
Fig 2. The likely intermediates 6p and 6m.
SMe
CN
SMe
NH2
SMe
CN
O
PhN
PhN
O
PhN
O
N
H
N
H
NSO2Ph
N
CO2Et
CO2Et
O
CO2Et
6m
6p
Yield (%)a
86
Fig 3. Ketone 2k and pyrrole 1c.
Ketone
Time (h)
2
Product
3q
SMe
2q
CN
aIsolated yield.
NAc
PhN
O
N
H
O
2k
CO2Et
to yield traces (5%) of the corresponding azaisoindole 3o
along with the remaining starting materials 1b and 2o. A
prolonged reaction time (5 days) resulted in recovering 1b
and 2o; the expected product 3o was not detected under
these reaction conditions.
To gain further insight into the mechanistic pathway 2, we
made the pyrrole ring of 2o electron-deficient by protecting
its NH group as the benzenesulfonylamide 2p, which, as ex-
pected, reacted with 1b within 2 h, more rapidly than did 2o.
All these facts have supported our proposed mechanistic
pathway 2 for the formation of the 4-azaisoindoles of type 9,
and we have made it general for the formation of com-
pounds 3.
1c
coordinated to AlCl3 on both oxygen atoms. The aluminium
chloride coordinated pyran ring oxygen would have made
the carbonyl group somewhat more electrophilic by an
electron-withdrawing inductive effect. The subsequent
intramolecular enamine cyclization would have occured
within an enamine species whose pyran ring oxygen was
free of AlCl3. This presumed positive electronic effect was
probably less beneficial to the reactivity of ketone 2f whose
p-methoxy group oxygen is relatively far from the carbonyl
group.
The 4-azaisoindole 3p was isolated in only 40% yield.
This is propably due to the slow intramolecular cyclization
of the presumed enamine intermediate 6p (Fig. 2), whose
benzenesulfonyl group raises the energy barrier for the
cyclization. Therefore, the uncyclized enamine 6p might
have enough time to undergo competing side reactions. A
similar reasoning would account for the low isolated yield
(25%) obtained in the case of 3m; the CO group α to the
corresponding enamine intermediate (6m) double bond
would compare to the benzenesulfonyl group in 6p. For sim-
ilar reasons, the “pyridine ring” nitrogen atom might have
prevented the possible further intramolecular cyclization of
3m by raising the energy barrier for cyclization.
The mixture of 1b, AlCl3, and N-acetyl-4-piperidone (2k)
(Fig. 3) was insoluble in refluxing 1,2 dichloroethane (1,2
DCE) and had to be heated for 24 h for complete consump-
tion of pyrrole 1b. We postulated that the amide functional-
ity (Lewis base) part of piperidone 2k was sufficiently basic
to coordinate to AlCl3 (Lewis acid) to form an insoluble
complex, which plagued the reaction and led to the acylation
of pyrrole 1b as we isolated pyrrole 1c (Fig. 3) as the major
product (25%) among numerous by-products we could not
separate. Not surprisingly, the basic 1-methyl-4-piperidone
and 2,2,6,6-tetramethyl-4-piperidone that we attempted to
react with 1b and AlCl3 in refluxing 1,2 DCE formed insolu-
ble mixtures from which we could isolate what seemed to be
1
The good reactivity of the α tetralone-type ketone 2q may
then be surprising. We believe that the presumed corre-
sponding enamine intermediate might have formed from 2q
degradation products from the H NMR of the material we
obtained after flash chromatography. We then prepared the
less basic N-tosyl-4-piperidone (2j), which refluxed in a
© 2007 NRC Canada

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Can. J. Chem. Vol. 85, 2007
homogeneous reaction mixture to provide 3j cleanly in 70%
isolated yield within 2 h.
The combined extracts were dried (MgSO4) and concen-
trated. Purification by flash chromatography (FC) on silica
gel (MeOH–CH2Cl2, 6:94) afforded 3.
In our effort to improve the yield (5%) of 3o, the reaction
was run in nitrobenzene as solvent at a higher temperature
(130 °C) for 1 h, and we isolated some undentified material
besides the remaining pyrrole 1b and ketone 2o. The use of
extra pure H2SO4 as the catalyst, instead of AlCl3, in
refluxing 1,2 DCE led to complete consumption of 1b and
2o and the formation of a presumed new product, whose
structure could not be determined by 1H NMR. The acid cat-
alyst, p-toluenesulfonic, did not help effect the desired trans-
formation; 1b and 2o were recovered after 6 h of reflux in
1,2 DCE.
8-Amino-1-methylsulfanyl-2,5,6,7-tetrahydro-2,4-diaza-s-
indacene-3-carboxylic acid ethyl ester (3a)
Yield 81%; yellow crystals; mp 170 °C. 1H NMR (CDCl3)
δ: 6.51 (br s, 2H, NH2), 4.35 (q, J = 7.12 Hz, 2H), 2.99 (t,
J = 7.62, 2H), 2.75 (t, J = 7.32 Hz, 2H), 2.48 (s, 3H), 2.25–
2.05 (m, 2H), 1.35 (t, J = 7.01 Hz, 3H). 13C NMR (CDCl3)
δ: 149.2, 138.4, 114.2, 111.3, 110.8, 59.6, 32.0, 26.5, 22.6,
20.5, 13.9. HRMS calcd. for C14O2N3H17S [MH]+:
292.111 42; found: 292.1116.
Attempts to improve the reactivity of 1-methyl-4-
piperidone were made. Thus, acetic acid was used as
cosolvent. It was believed that its presumed in situ
protonated amino group would not coordinate to AlCl3. Un-
fortunately, the expected cyclization did not proceed under
these conditions as 1b and the piperidone were recovered es-
sentially after a 3 h reflux in CH3CO2H–1,2 DCE (1.5:8.5).
The mixture of 1-methyl-4-piperidone, 1b, and AlCl3 in
nitrobenzene as solvent at 110 °C resulted in complete dis-
appearance of both reactants within 1 h, and no product was
detected by TLC analysis. The use of polyphosphoric acid,
instead of AlCl3, in refluxing 1,2 DCE for 3 h was not help-
ful; only the two reactants were detected in the crude mix-
ture by TLC analysis.
9-Amino-1-methylsulfanyl-5,6,7,8-tetrahydro-2H-
pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester (3b)
Yield 92%; yellow crystals; mp 195 °C. 1H NMR (CDCl3)
δ: 4.36 (q, J = 7.12 Hz, 2H), 2.80–2.60 (m, 2H), 2.44 (s,
5H), 1.95–1.75 (m, 4H), 1.37 (t, J = 7.01 Hz, 3H). 13C NMR
(CDCl3) δ: 164.9, 151.6, 144.0, 136.3, 127.7, 114.0, 110.6,
104.5, 59.5, 28.7, 21.9, 21.4, 21.3, 20.4, 14.7. HRMS calcd.
for C15O2N3H19S [MH]+: 306.127 07; found: 306.1271.
10-Amino-1-methylsulfanyl-2,5,6,7,8,9-hexahydro-2,4-
diaza-cyclohepta[f]indene-3-carboxylic acid ethyl ester
(3c)
Yield 80%; yellow crystals; mp 185 °C. 1H NMR (CDCl3)
δ: 6.84 (br s, 2H, NH2), 4.37 (q, J = 7.12 Hz, 2H), 2.95–2.80
(m, 2H), 2.75–2.60 (m, 2H), 2.47 (s, 3H), 1.83 (m, 2H), 1.71
(m, 2H), 1.59 (m, 2H), 1.38 (t, J = 7.01 Hz, 3H). 13C NMR
(CDCl3) δ: 164.9, 150.9, 150.6, 135.6, 127.5, 114.3, 111.0,
109.7, 59.5, 35.7, 31.5, 26.5, 25.8, 24.4, 20.6, 14.7. HRMS
calcd. for C16O2N3H21S [MH]+: 320.142 72; found:
320.1427.
Conclusion
In summary, the standard Friedländer cyclization has en-
abled the first reported preparation of substituted 4-
azaisoindoles and the first reported 4-azaisoindole tacrine
analogues that we plan to have tested for biological evalua-
tion.
8-Amino-6-methylsulfanyl-2,5-diaza-tricyclo[7.6.0.03,7]-
pentadeca-1,3,6,8-tetraene-4-carboxylic acid ethyl ester
(3d)
Experimental
General
Melting points were determined on a Stuart Scientific
SMP 3 capillary melting apparatus and were uncorrected. 1H
and 13C spectra were recorded on a Brucker AC250 spec-
trometer using CHCl3 as internal standard. The chemical
shifts (δ) are reported in ppm. Commercially available ke-
tones and AlCl3 were used as purchased. Ketones 2j (16)
and 2p were prepared using standard procedures. Pyrroles
1a (1) and 1b (3) were prepared as previously reported. For
indications on the preparation of 1b, please see the follow-
ing.
Yield quant; yellow crystals; mp 205 °C. 1H NMR
(CDCl3) δ: 6.69 (br s, 2H, NH2), 4.38 (q, J = 7.12 Hz, 2H),
2.85 (t, J = 6.10 Hz, 2H), 2.70 (t, J = 6.40 Hz, 2H), 2.49 (s,
3H), 1.79 (m, 2H), 1.68 (m, 2H), 1.49 (m, 2H), 1.43–1.25
(m, 5H). 13C NMR (CDCl3) δ: 165.0, 151.1, 148.0, 136.4,
127.7, 114.3, 110.9, 106.8, 59.4, 33.0, 30.6, 27.8, 25.9, 25.7,
23.0, 20.4, 14.7. HRMS calcd. for C17O2N3H23S [MH]+:
334.158 37; found: 334.1583.
7-Amino-8-methylsulfanyl-5,9-dihydro-6H-
benzo[h]pyrrolo[3,4-b]quinoline-10-carboxylic acid ethyl
ester (3e)
Typical procedure for the preparation of 4-
azaisoindoles 3
A mixture of pyrrole 1 (0.62 mmol), ketone 2 (3.1 mmol),
and AlCl3 (anhyd. granules, 99%, 3.1 mmol) in distilled
1,2 DCE (10 mL) was placed in an oil bath held at 115–
120 °C for 2 h. After cooling to RT, a solution of aq. NaOH
(pH 14) – THF (1:2, 15 mL) was added. The mixture was
stirred for 15 min. Solvents were removed under reduced
pressure. To the residue, CH2Cl2 (15 mL) and aq. NaOH
(20 mL, pH 14) were added. The layers were separated and
the aqueous layer was extracted with CH2Cl2 (3 × 15 mL).
The reaction was carried out in 1,2 DCE (5 mL). FC
(MeOH–CH2Cl2, 3:97). Yield 50%; yellow crystals; mp
185 °C. H NMR (CDCl3) δ: 7.75 (m, 1H), 7.45–7.25 (m,
3H), 6.77 (br s, 2H, NH2), 4.41 (q, J = 7.12 Hz, 2H), 2.96 (t,
J = 7.31 Hz, 2H), 2.76 (t, J = 6.97 Hz, 2H), 2.49 (s, 3H),
1.42 (t, J = 7.31 Hz, 3H). 13C NMR (CDCl3) δ: 138.5, 130.6,
128.6, 127.4, 122.7, 114.7, 111.2, 104.8, 59.7, 29.6, 27.8,
20.7, 20.2, 14.7. HRMS calcd. for C19O2N3H19S [MH]+:
354.127 07; found: 354.1271.
1
© 2007 NRC Canada

Bekolo and Kirsch
5
3H), 2.06 (s, 3H), 0.90 (t, J = 7.32 Hz, 3H). 13C NMR
(CDCl3) δ: 159.6, 156.2, 144.4, 143.7, 142.1, 138.7, 133.2,
129.7, 128.8, 128.3, 127.9, 127.6, 119.4, 116.0, 111.6,
102.0, 60.0, 43.6, 43.2, 33.7, 21.5, 13.8. HRMS calcd. for
C27O4N4H28S2 [MH]+: 537.162 47; found: 537.1624.
7-Amino-3-methoxy-8-methylsulfanyl-5,9-dihydro-6H-
benzo[h]pyrrolo[3,4-b]quinoline-10-carboxylic acid ethyl
ester (3f)
The reaction was carried out in 1,2 DCE (5 mL). FC
(MeOH–CH2Cl2, 3:97). Yield 55%; reddish crystals; mp
1
184 °C. H NMR (CDCl3) δ: 7.70 (d, J = 7.92 Hz, 1H),
8-Tetrahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid
ethyl ester (3l)
6.95–6.80 (m, 2H), 6.65 (br s, 2H, NH2), 4.42 (q, J =
7.12 Hz, 2H), 3.85 (s, 3H), 2.95 (t, J = 7.01 Hz, 2H), 2.73 (t,
J = 7.01 Hz, 2H), 2.50 (s, 3H), 1.43 (t, J = 7.02 Hz, 3H). 13
C
FC (MeOH–CH2Cl2, 1:99). Yield 80%; white crystals; mp
1
164 °C. H NMR (CDCl3) δ: 7.60–7.35 (m, 3H), 7.24–7.14
NMR (CDCl3) δ: 161.4, 150.6, 140.7, 136.5, 124.1, 121.0,
114.4, 113.8, 112.7, 110.7, 103.6, 59.5, 55.3, 28.1, 20.5,
20.0, 14.7. HRMS calcd. for C20O3N3H21S [MH]+:
384.137 64; found: 384.1377.
(m, 2H), 7.09 (br s, 2H, NH2), 3.98 (q, J = 7.31 Hz, 2H),
2.55 (t, J = 6.10 Hz, 2H), 2.47–2.25 (m, 5H), 2.20–2.00 (m,
2H), 0.89 (t, J = 7.31 Hz, 3H). 13C NMR (CDCl3) δ: 198.2,
160.4, 159.1, 137.6, 130.5, 129.5, 128.8, 104.0, 60.8, 36.4,
29.3, 21.6, 18.4, 13.4. HRMS calcd. for C21O3N3H21S
[MH]+: 396.137 64; found: 396.1376.
11-Amino-10-methylsulfanyl-5,9-dihydro-6H-7,9-diaza-
cyclopenta[b]phenanthrene-8-carboxylic acid ethyl ester (3g)
AlCl3 (4 equiv.) and ketone (2 equiv.) were used. Yield
9-Amino-5-(4-cyano-5-ethoxycarbonyl-2-methylsulfanyl-1-
phenyl-1H-pyrrol-3-ylamino)-1-methylsulfanyl-2-phenyl-
7,8-dihydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid
ethyl ester (3m)
1
73%; greenish crystals; mp 190 °C. H NMR (CDCl3) δ:
7.81 (d, J = 7.95 Hz, 1H), 7.36–7.04 (m, 3H), 6.86 (br s, 2H,
NH2), 4.38 (q, J = 7.12 Hz, 2H), 3.05–2.70 (m, 4H), 2.50 (s,
3H), 1.36 (t, J = 7.01 Hz, 3H). 13C NMR (CDCl3) δ: 137.0,
131.3, 128.3, 126.9, 126.4, 124.0, 114.5, 112.0, 105.2, 59.8,
28.2, 20.5, 14.5. HRMS calcd. for C19O2N3H19S [MH]+:
354.127 07; found: 354.1271.
1
FC (100% CH2Cl2). Yield 25%; viscous yellow oil. H
NMR (CDCl3) δ: 7.45 (br s, 1H, NH), 7.60–7.35 (m, 6H),
7.25–7.10 (m, 4H), 6.54 (t, J = 4.57 Hz, 1H), 5.06 (br s, 2H,
NH2), 4.10–3.90 (m, 4H), 2.59 (t, J = 6.40 Hz, 2H), 2.39 (s,
3H), 2.32 (s, 3H), 2.20–2.00 (m, 2H), 1.10–0.80 (m, 6H).
13C NMR (CDCl3) δ: 194.8, 159.6, 145.7, 139.5, 138.0,
134.5, 128.8, 128.7, 128.4, 128.3, 127.9, 127.8, 126.3, 60.0,
59.4, 37.4, 24.2, 23.0, 18.5, 17.9, 13.6, 13.5, 12.8.
9-Amino-1-methylsulfanyl-2-phenyl-5,6,7,8-tetrahydro-2H-
pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester (3h)
The reaction mixture refluxed for 1 h. Yield 76%; yellow
1
crystals; mp 100 °C. H NMR (CDCl3) δ: 7.55–7.40 (m,
3H), 7.35–7.20 (m, 2H), 4.15 (q, J = 7.12 Hz, 2H), 3.00 (t,
J = 5.8 Hz, 2H), 2.53 (t, J = 6.10 Hz, 2H), 2.08 (s, 3H),
1.98–1.75 (m, 4H), 1.08 (t, J = 7.01 Hz, 3H). 13C NMR
(CDCl3) δ: 159.0, 154.7, 151.8, 136.4, 131.9, 129.8, 128.7,
127.6, 110.1, 109.4, 108.7, 61.1, 29.4, 22.9, 21.5, 20.9, 20.8,
13.7. HRMS calcd. for C21O2N3H23S [MH]+: 382.158 37;
found: 382.1585.
6-Amino-7-methylsulfanyl-8-phenyl-5,8-dihydro-4H-3-oxa-
8,10-diaza-dicyclopenta[a,g]naphthalene-9-carboxylic acid
ethyl ester (3n)
The reaction was carried out in 1,2 DCE (5 mL). FC
(MeOH–CH2Cl2, 3:97). Yield 67%; yellow crystals; mp
180 °C. 1H NMR (CDCl3) δ: 7.85–7.64 (m, 3H), 7.58 (d, J =
1.82 Hz, 1H), 7.55–7.40 (m, 2H), 7.25 (d, J = 1.82 Hz, 1H),
5.90 (br s, 2H, NH2), 4.44 (q, J = 7.12 Hz, 2H), 3.35–3.00
(m, 4H), 2.32 (s, 3H), 1.48 (t, J = 7.01 Hz, 3H). 13C NMR
(CDCl3) δ: 160.2, 156.3, 152.9, 143.8, 142.5, 141.9, 138.8,
128.6, 128.3, 128.0, 121.2, 119.7, 116.4, 112.6, 107.7,
103.1, 60.0, 21.6, 21.3, 14.0. HRMS calcd. for C23O3N3H21S
[MH]+: 420.137 64; found: 420.1375.
9-Amino-1-methylsulfanyl-2-phenyl-2,5,6,8-tetrahydro-7-
thia-2,4-diaza-cyclopenta[b]naphthalene-3-carboxylic acid
ethyl ester (3i)
Yield 77%; yellow crystals; mp 105 °C. 1H NMR (CDCl3)
δ: 7.52 (m, 3H), 7.26 (m, 2H), 5.86 (br s, 2H, NH2), 4.14 (q,
J = 6.72 Hz, 2H), 3.65 (s, 2H), 3.32 (t, J = 6.10 Hz, 2H),
2.97 (t, J = 6.41 Hz, 2H), 2.12 (s, 3H), 0.84 (t, J = 6.40 Hz,
3H). 13C NMR (CDCl3) δ: 159.6, 159.3, 144.4, 141.3, 138.6,
128.2, 127.8, 127.7, 119.8, 115.5, 112.0, 105.6, 59.9, 35.3,
25.2, 22.5, 21.4, 13.7. HRMS calcd. for C20O2N3H21S
[MH]+: 400.1148; found: 400.1148.
6-Amino-7-methylsulfanyl-8-phenyl-3,4,5,8-tetrahydro-
3,8,10-triaza-dicyclopenta[a,g]naphthalene-9-carboxylic
acid ethyl ester (3o)
The reaction was carried out in 1,2 DCE (5 mL). FC
(MeOH–CH2Cl2, 1.5:98.5). Yield 5%, white crystals. 1H
NMR (CDCl3) δ: 8.52 (br s, 1H, NH), 7.55–7.40 (m, 4H),
7.30–7.15 (m, 2H), 6.67 (d, J = 1.85 Hz, 1H), 3.96 (q, J =
7.12 Hz, 2H), 2.75 (t, J = 6.10 Hz, 2H), 2.50 (t, J = 6.10 Hz,
2H), 2.40 (s, 3H), 0.93 (t, J = 7.01 Hz, 3H). 13C NMR δ:
167.2, 159.3, 138.6, 138.0, 129.0, 128.9, 128.6, 128.5,
128.0, 127.9, 119.1, 114.5, 105.5, 59.8, 37.8, 29.6, 23.9,
23.5, 22.6, 18.4, 13.7.
9-Amino-1-methylsulfanyl-2-phenyl-7-(toluene-4-sulfonyl)-
5,6,7,8-tetrahydro-2H-2,4,7,-triaza-cyclopenta[b]naphtha-
lene-3-carboxylic acid ethyl ester (3j)
After refluxing, CH2Cl2 (15 mL) and aq. NaOH (pH 14,
15 mL) were added, respectively. The two layers were sepa-
rated. The aqueous layer was extracted with CH2Cl2 (2 ×
15 mL). The combined organic layers were dried (MgSO4)
and concentrated. FC (MeOH–CH2Cl2, 3:97). Yield 70%;
6-Amino-3-benzenesulfonyl-7-methylsulfanyl-8-phenyl-
3,4,5,8-tetrahydro-3,8,10-triaza-dicyclopenta[a,g]naphtha
1
yellow crystals; mp 162 °C. H NMR (CDCl3) δ: 7.74 (d,
-
J = 8.52 Hz, 2H), 7.60–7.40 (m, 3H), 7.35–7.05 (m, 4H),
5.90 (br s, 2H, NH2), 4.21 (s, 2H), 4.12 (q, J = 7.32 Hz, 2H),
3.43 (t, J = 5.80 Hz, 2H), 3.15 (t, J = 5.80 Hz, 2H), 2.39 (s,
lene-9-carboxylic acid ethyl ester (3p)
The reaction was carried out in 1,2 DCE (5 mL). After
refluxing, the same work-up is used as for 3j. FC (cyclohexane–
© 2007 NRC Canada

6
Can. J. Chem. Vol. 85, 2007
1
CH2Cl2, 2:8). Yield 40%; white crystals; mp 185 °C. H
NMR (CDCl3) δ: 7.87 (d, J = 7.32 Hz, 2H), 7.75–7.40 (m,
6H), 7.29 (d, J = 3.65 Hz, 1Hz), 7.25–7.10 (m, 2H), 6.80 (d,
J = 3.67 Hz, 1H), 3.92 (q, J = 7.12 Hz, 2H), 2.50–2.35 (m,
5H), 0.85 (t, J = 7.01 Hz, 3H). 13C NMR (CDCl3) δ: 194.2,
166.0, 159.0, 138.8, 138.5, 137.9, 134.5, 134.3, 129.6,
129.1, 128.8, 128.7, 128.5, 127.8, 127.0, 126.9, 124.6,
122.3, 114.1, 109.0, 60.0, 37.3, 28.9, 22.6, 13.6.
5 days. Yield 70%; white crystals; mp 147–149 °C. 1H
NMR (CDCl3) δ: 7.17–7.50 (m, 5H), 5.06 (br s, 2H, NH2),
4.01 (q, J = 7.20 Hz, 2H), 2.40 (s, 3H), 0.94 (t, J = 7.20 Hz,
3H).
Acknowledgments
HB thanks Professor G. Kirsch for providing us with
space and chemicals and graduate student David Thomae for
helpful discussions.
7-Amino-8-methylsulfanyl-9-phenyl-6H,9H-5-oxa-9,11-
diaza-cyclopenta[b]phenanthrene-10-carboxylic acid ethyl
ester (3q)
References
FC (MeOH–CH2Cl2, 3:97). Yield 86%; yellow crystals;
mp 215 °C. H NMR (CDCl3) δ: 8.44 (d, J = 7.92 Hz, 1H),
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7.60–7.45 (m, 3H), 7.40–7.20 (m, 3H), 7.10 (t, J = 7.62 Hz,
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To a solution of 2o (0.3 g, 2.2 mmol, 1 equiv.) in 1,2 DCE
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8.8 mmol, 4 equiv.), Et3N (1.8 g, 17.6 mmol, 8 equiv.) in 1,2
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ganic layers were dried (MgSO4) and concentrated. Purifica-
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1
73%; beige solid; mp 122 °C. H NMR (CDCl3) δ: 7.85 (d,
J = 7.92 Hz, 2H), 7.75–7.45 (m, 3H), 7.23 (d, J = 3.05 Hz,
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© 2007 NRC Canada