Synthesis of advanced intermediates of lennoxamine analogues

Article abstract of DOI:10.1055/s-2007-965950

A simple and convenient method for synthesis of advanced isoindolone intermediates of lennoxamine and analogues is described in this paper. The intramolecular Diels-Alder reaction of furan is used as a key step in this synthesis. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-965950

PAPER
1091
Synthesis of Advanced Intermediates of Lennoxamine Analogues
Synthesis of
A
r
dvanced
a
Intermedia
j
tes of
L
ennoxamin
k
e
Analogue
t
a S. Sarang,a Arun A. Yadav,a Prashant S. Patil,a Urlam Murali Krishna,b Girish K. Trivedi,*a
Manikrao M. Salunkhe*a
a
Department of Chemistry, The Institute of Science, 15 Madam Cama Road, Mumbai 400032, India
Fax +91(22)22816750; E-mail: mmsalunkhe@hotmail.com; E-mail: snehgkt@yahoo.com
Indian Institute of Technology, Bombay Powai, Mumbai 400076, India
b
Received 9 December 2006; revised 12 January 2007
MeO
OMe
Abstract: A simple and convenient method for synthesis of ad-
vanced isoindolone intermediates of lennoxamine and analogues is
described in this paper. The intramolecular Diels–Alder reaction of
furan is used as a key step in this synthesis.
O
N
O
Me
N
MeO
Key words: isoindolone, lennoxamine, Diels–Alder, imine, cyclo-
O
adduct
MeO
MeO
O
O
The isoindolone ring system has gradually acquired sig-
nificant importance due to its presence in both natural
products and synthetic pharmaceuticals with biological
activity. Lennoxamine, aristoyagonine, nuevamine, and
chilenine are few examples of important alkaloids whose
skeleton contains the very important isoindolone system
(Figure 1). Though the alkaloids chilenine and lennox-
amine are not known to have any potent pharmacological
profile, their unique structural features have attracted the
attention of organic chemists and, over the last few de-
cades, many synthetic strategies have been put forward
for the synthesis of these very attractive and synthetically
challenging targets.1,2 Apart from being an integral part of
natural products, isoindolones are well known for their bi-
ological activity like antihypertensive,3a antipsychotic,3b
antiviral,3c and antileukemic.3d
lennoxamine
aristoyagonine
MeO
OMe
O
O
O
N
HO
O
N
O
OMe
O
O
OMe
nuevamine
chilenine
Figure 1
In light of the numerous methods known for the synthesis
of biologically important isoindolones,4 we wish to dis-
close here a simple and convenient method based on the
intramolecular Diels–Alder reaction of furan approach to
the synthesis of isoindolone derivatives. These isoindol-
one derivatives could, in turn, be transmuted to lennox-
amine and analogues. The retrosynthetic approach of our
synthesis is outlined in Scheme 1.
ductive amination and the intramolecular Diels–Alder
reaction of furan sequence (Scheme 2). Amination of fur-
fural (4) resulted in the formation of Schiff base 5, which,
due to its instability, was reduced in situ with sodium
borohydride to give the corresponding secondary furyl-
amines 6 in quantitative yield. Capitalizing on the reactiv-
Intramolecular Diels–Alder reactions of furan are of con-
tinuing interest, since molecules with a high degree of
structural diversity can be easily constructed in a single
step. These initial cycloadducts can then be manipulated,
leading to a variety of interesting precursors for natural
products.5 We were particularly interested in applying the
intramolecular Diels–Alder reaction of furan as a key step
in the synthesis of isoindolone precursors of lennoxamine
and analogues. The first facet of our synthesis was to pre-
pare cycloadduct 2, which could easily be effected by re-
O
O
COOH
R
N
COOH
R
N
O
1
2
CHO
+
O
R-NH2
SYNTHESIS 2007, No. 7, pp 1091–1095
Advanced online publication: 20.02.2007
x
x
.
x
x
.2
0
0
7
3
4
DOI: 10.1055/s-2007-965950; Art ID: Z25706SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

1092
P. S. Sarang et al.
PAPER
ity of the furan nucleus towards dienophiles in the Diels– However, an independent confirmation of the structure
Alder reaction, these furylamines were subsequently was necessary due to the intriguing IR features of oxo-
treated with maleic anhydride to furnish the stereochemi- isoindolecarboxylic acids 1. The presence of a carboxy
cally pure tricyclic cycloadducts 2. The formation of cy- function was confirmed by converting 1 into their corre-
cloadducts 2 proceeded smoothly via initial N-acylation sponding methyl esters. (Scheme 4).
followed by intramolecular Diels–Alder cycloaddition re-
O
action (one-pot reaction). The intramolecular Diels–Alder
O
O
R
R
cycloaddition reaction was highly stereoselective and pro-
COOH
N
N
vided only the exo-product.6
OMe
CHO
1
7
O
N
R
a
R-NH2
+
Scheme 4 Reagents and conditions: (a) MeOH, concd H2SO4,
O
reflux, 6 h, 58–60%.
5
3
4
Finally, the structure of the carboxylic acid 1c was unam-
biguously established by single crystal X-ray
crystallography8 (Figure 2). Though the structure was as
expected, it was found that the unit cell contained two
molecules. For the sake of clarity however, the structure
of only one molecule is given here.
b
O
COOH
R
O
c
N
N
H
R
O
2a–e
6
2a R =
2c R =
2b R =
2d R =
MeO
MeO
Figure 2 ORTEP drawing of the X-ray structure of 1c.
2e R =
N
H
Since isoindolone derivatives such as 8 (Figure 3) have
recently been transformed to give the naturally occurring
lennoxamine class of alkaloid,9 the isoindolone deriva-
tives 1 reported in this paper may be considered as the ad-
vanced intermediates for the synthesis of analogues of the
lennoxamine class of alkaloids.
Scheme 2 Reagents and conditions: (a) toluene, reflux, 3 h, (b)
NaBH4, MeOH, 0 °C, 2 h; (c) maleic anhydride, benzene, 84–95%.
The next step in our strategy was ring opening of the ep-
oxy bridge, followed by aromatization to furnish isoindo-
lones. Influenced by the methodology adopted for the ring
opening of epoxyisoindolones,7 we deliberately subjected
cycloadduct 2 to 4-toluenesulfonic acid in refluxing tolu-
ene conditions. As expected, the epoxyisoindolones of
type 2 undergo a ring-opening reaction and are subse-
R1O
O
N
R2O
R3
quently aromatized to isoindolone derivatives
(Scheme 3).
1
R3
8a–c
8a R1–R2 = CH2, R3 = OMe
8b R1 = R2 = R3 = OMe
8c R1 = R2 = Me, R3 = H
O
O
COOH
R
COOH
R
N
N
a
O
Figure 3
2a–e
1a–e
Thus, we have described herein a very simple and conve-
nient method for the synthesis of isoindolone derivatives
that may prove to be a practical approach for the synthesis
of lennoxamine and analogues. Further transformations of
Scheme 3 Reagents and conditions: (a) PTSA, toluene, reflux, 44–
55%.
Synthesis 2007, No. 7, 1091–1095 © Thieme Stuttgart · New York

PAPER
Synthesis of Advanced Intermediates of Lennoxamine Analogues
1093
HRMS: m/z [M + H]+ calcd for C16H16NO4: 286.1079; found:
286.1091.
these compounds towards the construction of valuable
molecular entities will be reported in due course.
4-Oxo-3-phenethyl-10-oxa-3-azatricyclo[5.2.1.01,5]dec-8-ene-6-
carboxylic Acid (2c)
White solid; yield: 90%; mp 89–90 °C.
Melting points were determined on a Laboratory Devices MEL-
TEMP II melting-point apparatus and are uncorrected. IR spectra
were recorded on a Perkin-Elmer FTIR spectrophotometer. 1H and
13C NMR spectra were measured on JEOL 300 MHz spectrometer
using TMS as an internal reference in CDCl3 and DMSO-d6. HRMS
were recorded on Micromass Q-Tof micro spectrometer. TLC was
performed on silica gel plates prepared by coating thin film of glass
plate and the components were visualized by observing under I2 va-
pors and UV light. Column chromatography was performed on sil-
ica gel (60–120 mesh). All chemicals used in this study were
commercially available. Homoveratrylamine and tryptamine were
purchased from Sigma Aldrich Chemicals and used as received.
IR (KBr): 3456, 1735, 1663, 1177 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.3 (m, 5 H), 6.4 (dd, 1 H), 6.4 (d,
1 H), 5.3 (s, 1 H), 5.01 (br s, 1 H), 3.8–3.6 (m, 3 H), 3.5–3.4 (m, 1
H), 2.9–2.7 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 173.0, 172.4, 138.2, 137.2, 134.7,
128.7, 128.6, 128.6, 126.6, 88.9, 82.4, 50.4, 49.7, 45.9, 44.8, 33.5.
HRMS: m/z [M + H]+ calcd for C17H18NO4: 300.1236; found:
300.1236.
3-[2-(3,4-Dimethoxyphenyl)ethyl]-4-oxo-10-oxa-3-azatricy-
clo[5.2.1.01,5]dec-8-ene-6-carboxylic Acid (2d)
White solid; yield: 84%; mp 134–135 °C.
IR (KBr): 3454, 1737, 1666, 1180 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.8 (m, 3 H), 6.47 (m, 2 H), 5.3 (s,
1 H), 3.8 (s, 3 H), 3.8 (s, 3 H), 3.7 (m, 2 H), 3.6 (m, 1 H), 3.5 (m, 1
H), 2.8 (m, 4 H).
N-Substituted 2-Furylmethanimine 5; General Procedure
Imines 5 were prepared by refluxing a mixture of freshly distilled
furfuraldehyde 4 (79.21 mmol) and the appropriate amine 3 (71.95
mmol) in toluene using a Dean–Stark apparatus; reflux was contin-
ued for 3 h. Toluene was distilled off on a rotary evaporator and the
crude imine was used in the next step without purification.
N-Substituted 2-Furylmethylamine 6; General Procedure
NaBH4 (81 mmol) was added in small portions to a soln of imine 5
(81 mmol) in MeOH at 0 °C. When the addition was complete, the
mixture was stirred at 0 °C for 30 min and at r.t. for 3 h and then
acidified with 10% HCl to pH 1. The resulting mixture was adjusted
to pH 11 with aq NH3 soln and extracted with CH2Cl2 (3 ×). The
combined organic layers were washed with brine, dried (Na2SO4),
and concentrated in vacuo to give viscous oil 6, which was used di-
rectly in the next step.
13C NMR (75 MHz, CDCl3): d = 173.0, 172.5, 149.0, 147.8, 137.2,
134.8, 130.8, 120.6, 112.1, 111.4, 88.9, 88.8, 55.9, 50.6, 45.9, 45.0,
33.2.
HRMS: m/z [M + H]+ calcd for C19H22NO6: 360.1447; found:
360.1454.
3-[2-(1H-Indol-3-yl)ethyl]-4-oxo-10-oxa-3-azatricy-
clo[5.2.1.01,5]dec-8-ene-6-carboxylic Acid (2e)
White solid; yield: 86%; mp 179–180 °C.
IR (KBr): 3376, 3330, 1739, 1642, 1432, 1215 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 12.1 (br s, 1 H), 10.8 (s, 1 H),
7.5 (d, 1 H), 7.3 (d, 1 H), 7.1 (d, 1 H), 7.0–6.9 (td, 2 H), 6.5 (d, 1 H),
6.4 (dd, 1 H), 4.9 (s, 1 H), 4.0 (d, 1 H), 3.6 (d, 1 H), 2.9 (t, 2 H), 2.7
(d, 1 H), 2.5–2.4 (m, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 173.1, 170.3, 136.8, 136.3,
135.7, 127.2, 122.9, 121.1, 118.4, 118.3, 111.5, 111.2, 88.5, 81.2,
50.4, 48.1, 44.5, 42.8, 23.0.
3-Substituted 4-Oxo-10-oxa-3-azatricyclo[5.2.1.01,5]dec-8-ene-
6-carboxylic Acids 2; General Procedure
To a stirred soln of amine 6 (64.17 mmol) in anhyd benzene was
added maleic anhydride (64.17 mmol) at r.t. The soln was stirred at
r.t. for 10 h. The product was filtered and washed with benzene to
yield the cycloadduct 2. Recrystallization (hexane–EtOAc) gave
desired acid 2 as a colorless solid.
3-Butyl-4-oxo-10-oxa-3-azatricyclo[5.2.1.01,5]dec-8-ene-6-car-
boxylic Acid (2a)
White solid; yield: 87%; mp 119–120 °C.
HRMS: m/z [M + H]+ calcd for C19H19N2O4: 339.1345; found:
339.1345.
IR (KBr): 3075, 1739, 1629, 1369 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.50 (s, 2 H), 5.35 (s, 1 H), 4.02
(d, 1 H), 3.75 (d, 1 H), 3.4–3.3 (m, 2 H), 2.89 (m, 2 H), 1.55 (m, 2
H), 1.34 (m, 2 H), 0.91 (t, 3 H).
13C NMR (75 MHz, CDCl3): d = 173.5, 172.4, 136.9, 135.1, 87.0,
82.1, 51.0, 48.8, 45.4, 42.8, 29.0, 19.7, 13.7.
HRMS: m/z [M + K]+ calcd for C13H17KNO4: 290.0795; found:
290.0780.
Isoindolones 1; General Procedure
A mixture of cycloadduct 2 (1 mmol), toluene, and PTSA (3 mmol)
in a flask equipped with a reflux condenser was stirred at reflux tem-
perature. The progress of the reaction was monitored by TLC.
When the reaction was complete, toluene was distilled off on a ro-
tary evaporator. The resulting residue was dissolved in CH2Cl2 and
washed thoroughly with H2O. The organic layer was washed with
brine, dried (Na2SO4), and concentrated in vacuo to give a viscous
mass, which was purified by column chromatography (EtOAc–
CHCl3) to give the desired product.
3-Benzyl-4-oxo-10-oxa-3-azatricyclo[5.2.1.01,5]dec-8-ene-6-car-
boxylic Acid (2b)
White solid; yield: 95%; mp 150 °C.
IR (KBr): 3459, 1739, 1662, 1178 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.3 (m, 5 H), 6.5 (m, 2 H), 5.3 (s,
1 H), 4.7 (d, 1 H), 4.43 (d, 1 H), 3.9 (d, 1 H), 3.6 (d, 1 H), 2.8–3.0
(m, 2 H).
2-Butyl-3-oxo-2,3-dihydro-1H-isoindole-5-carboxylic Acid (1a)
White solid; yield: 50%; mp 134–135 °C.
IR (KBr): 1709, 1606, 1498, 742 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.4 (d, 1 H), 7.7 (m, 2 H), 4.5 (s,
2 H), 3.7 (t, 2 H), 1.7 (m, 2 H), 1.4 (m, 2 H), 0.91 (t, 3 H).
13C NMR (75 MHz, CDCl3): d = 173.1, 172.5, 137.2, 135.2, 134.8,
128.9, 128.0, 127.9, 88.8, 82.4, 77.4, 50.7, 48.5, 47.0, 45.9.
13C NMR (75 MHz, CDCl3): d = 169.6, 165.5, 141.7, 133.4, 132.2,
129.8, 129.3, 126.8, 50.9, 43.1, 30.1, 20.0, 13.6.
Synthesis 2007, No. 7, 1091–1095 © Thieme Stuttgart · New York

1094
P. S. Sarang et al.
PAPER
HRMS: m/z [M + H]+ calcd for C13H16NO3: 234.1130; found:
IR (KBr): 1735, 1661, 1517, 1135, 746 cm–1.
234.1126.
1H NMR (300 MHz, CDCl3): d = 7.5 (m, 3 H), 6.7 (m, 3 H), 4.1 (s,
2 H), 4.0 (s, 3 H), 3.85 (s, 3 H), 3.83 (s, 2 H), 3.80 (s, 3 H), 2.9 (t, 2
H).
13C NMR (75 MHz, CDCl3): d = 167.1, 165.6, 148.3, 147.0, 141.4,
130.6, 130.2, 129.6, 129.4, 127.0, 124.3, 119.9, 111.1, 110.7, 55.2,
55.1, 52.09, 49.7, 33.6, 33.5.
HRMS: m/z [M + H]+ calcd for C20H22NO5: 356.1498; found:
356.1505.
2-Benzyl-3-oxo-2,3-dihydro-1H-isoindole-5-carboxylic Acid
(1b)
White solid; yield: 55%; mp 164–165 °C.
IR (KBr): 1707, 1609, 1495, 1452, 1279, 743 cm–1.
1H NMR (300 MHz, CDCl3): d = 16.0 (br s, 1 H), 8.3 (d, 1 H), 7.6
(t, 1 H), 7.6 (d, 1 H), 7.3 (m, 5 H), 4.8 (s, 2 H), 4.4 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 169.6, 165.4, 141.5, 135.1, 133.5,
132.4, 129.4, 129.1, 128.4, 128.3, 126.9, 50.4, 47.3.
Acknowledgment
HRMS: m/z [M + H]+ calcd for C16H14NO3: 268.1256; found:
268.1251.
We thank the Council of Scientific and Industrial Research, New
Delhi, Lady Tata Memorial Trust (Mumbai) and University Grants
Commission, New Delhi for the financial support of this project and
the National Single Crystal X-ray Diffraction facility at IIT Bombay
for the X-ray crystal structure of 1c.
3-Oxo-2-phenethyl-2,3-dihydro-1H-isoindole-5-carboxylic
Acid (1c)
White solid; yield: 48%; mp 140–141 °C.
IR (KBr): 1710, 1612, 1498, 1316, 745 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.36 (d, 1 H), 7.68 (m, 2 H), 7.29
(m, 5 H), 4.33 (s, 2 H), 3.96 (t, 2 H), 3.09 (t, 2 H).
References
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13C NMR (75 MHz, CDCl3): d = 170.3, 169.6, 141.9, 137.7, 133.2,
132.2, 129.4, 129.0, 128.8, 128.5, 126.9, 51.6, 45.0, 34.3.
2-[2-(3,4-Dimethoxyphenyl)ethyl]-3-oxo-2,3-dihydro-1H-iso-
indole-5-carboxylic Acid (1d)
White solid; yield: 44%; mp 179–180 °C.
IR (KBr): 3435, 1710, 1610, 1251 cm–1.
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Rigdon, G. C. J. Med. Chem. 1996, 39, 149.
1H NMR (300 MHz, CDCl3): d = 8.36 (d, 1 H), 7.65 (m, 2 H), 6.78
(m, 3 H), 4.33 (s, 2 H), 3.97 (t, 2 H), 3.85 (s, 3 H), 3.81 (s, 3 H), 3.01
(t, 2 H).
13C NMR (75 MHz, CDCl3): d = 169.5, 165.5, 149.3, 147.8, 142.0,
133.0, 132.2, 130.1, 129.4, 128.9, 127.0, 120.5, 111.5, 111.3, 55.8,
51.7, 44.9, 33.8, 31.9.
HRMS: m/z [M + H]+ calcd for C19H20NO5: 342.1341; found:
342.1343.
2-Substituted Methyl 3-Oxo-2,3-dihydro-1H-isoindole-5-car-
boxylates 7; General Procedure
A mixture of acid 1 (1 mmol), concd H2SO4 (0.5 mL), and abs
MeOH (10 mmol) in a flask equipped with reflux condenser was re-
fluxed gently for 6 h. Excess MeOH was distilled off by rotary
evaporator. The resulting mixture was diluted with EtOAc and
washed with aq NaHCO3 (2 ×). The organic layer was washed with
brine, dried (Na2SO4), and concentrated in vacuo to give the corre-
sponding ester. This was purified by column chromatography
(EtOAc–CHCl3) to give the desired product 7.
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Methyl 2-Benzyl-3-oxo-2,3-dihydro-1H-isoindole-5-carboxyl-
ate (7b)
White solid; yield: 60%; mp 99–100 °C.
IR (KBr): 1730, 1686 1295, 1133, 790 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.5 (m, 3 H), 7.3 (m, 5 H), 4.7 (s,
2 H), 4.2 (s, 2 H) 4.0 (s, 3 H).
(g) Gutierrez, A. J.; Shea, K. J.; Svoboda, J. J. J. Org. Chem.
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Zwanenburg, B. Tetrahedron 1985, 41, 6063. (k) Aubert,
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58, 1740. (m) Camilleri, P.; Cassola, A. J. Chem. Soc.,
Chem. Commun. 1978, 807. (n) Rowe, R. K.; Shelton, B. R.
13C NMR (75 MHz, CDCl3): d = 167.7, 166.2, 142.1, 136.7, 131.0,
130.5, 129.8, 129.1, 128.8, 128.3, 127.7, 125.0, 52.7, 49.0, 46.4.
HRMS: m/z [M + H]+ calcd for C17H16NO3: 282.1521; found:
282.1528.
Methyl 2-[2-(3,4-Dimethoxyphenyl)ethyl]-3-oxo-2,3-dihydro-
1H-isoindole-5-carboxylate (7d)
White solid; yield: 58%; mp 114–115 °C.
Synthesis 2007, No. 7, 1091–1095 © Thieme Stuttgart · New York

PAPER
Synthesis of Advanced Intermediates of Lennoxamine Analogues
1095
J. Org. Chem. 1990, 55, 4603. (o) Takeuchi, H.; Eguchi, S.
(8) Crystallographic data for the structure in this paper has been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication No. CCDC 63347. Copies of
the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44
(1223)336033 or E-mail: deposit@ccdc.cam.ac.uk]. Some
selected crystallographic data: crystal system, space group:
triclinic, P-1, bond lengths [Å] and angles [°]: N1–C8
1.322(2), N1–C9 1.457(3), N1–C10 1.458(3), O1–C(1)
1.213(2), O2–C1 1.311(3), O2–H2 1.03(4), O3–C8
1.247(2).
J. Chem. Soc., Perkin Trans. 1 1989, 2149.
(5) Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997,
53, 14179.
(6) (a) Zylber, J.; Tubul, A.; Brun, P. Tetrahedron: Asymmetry
1995, 6, 377. (b) Mukaiyama, T.; Iwasawa, N. Chem. Lett.
1981, 29. (c) Prajapati, D.; Borthakur, D. R.; Sandhu, J. S. J.
Chem. Soc., Perkin Trans. 1 1993, 1197. (d) Murali, R.;
Surya Prakash Rao, H.; Scheeren, H. W. Tetrahedron 2001,
57, 3165.
(7) (a) Zubkov, F. I.; Boltkhina, E. V.; Turchin, K. F.;
Varlamov, A. V. Tetrahedron 2004, 60, 8455. (b) Zubkov,
F. I.; Boltkhina, E. V.; Turchin, K. F.; Borisov, R. S.;
Varlamov, A. V. Tetrahedron 2005, 61, 4099.
(9) Sahakitpichan, P.; Ruchirawat, S. Tetrahedron 2004, 60,
4169.
Synthesis 2007, No. 7, 1091–1095 © Thieme Stuttgart · New York