Facile synthesis of the isoquinoline alkaloids doryanine and oxyhydrastinine

Article abstract of DOI:10.1055/s-0033-1341158

Starting from 4,5-(methylenedioxy)homophthalic acid, a concise and efficient synthesis of the isoquinoline alkaloids doryanine and oxyhydrastinine is described via the corresponding homophthalimide utilizing a one-pot regioselective reductive dehydration

Full text of DOI:10.1055/s-0033-1341158

1954▌
PAPER
paper
Facile Synthesis of the Isoquinoline Alkaloids Doryanine and Oxyhydrastinine
Doryanine and Oxyhydrastinine
Ravi Jangir, Smita R. Gadre, Narshinha P. Argade*
Division of Organic Chemistry, National Chemical Laboratory (CSIR), Pune 411 008, India
E-mail: np.argade@ncl.res.in
Received: 06.02.2014; Accepted after revision: 20.03.2014
The homophthalic acids 1a and 1b were initially stirred
Abstract: Starting from 4,5-(methylenedioxy)homophthalic acid, a
with excess 40% aqueous methylamine solution at 25 °C
concise and efficient synthesis of the isoquinoline alkaloids dory-
for few minutes to form the corresponding salt. The ob-
anine and oxyhydrastinine is described via the corresponding ho-
tained dry salts on vigorous reflux in o-dichlorobenzene
for 10 hours provided the corresponding precursor ho-
mophthalimides 2a and 2b in very good yields via amide
formation followed by intramolecular dehydrative cycli-
zation.8 The regioselective sodium borohydride reduction
of the more reactive unconjugated imide carbonyl group
in imides 2a and 2b formed the corresponding geminal
aminohydrin intermediates 3a and 3b. Herein the boron
atom selectively complexes with an oxygen atom from the
more electron-rich unconjugated imide carbonyl group re-
sulting in complete regioselectivity. These aminohydrin
intermediates exhibit ring-chain tautomerism and were
prone to decomposition. During the course of the reduc-
tion we also noticed the formation of undesired acyclic
overreduced product, which is in accordance with the ob-
servation of Cheng et al.8b Therefore, in situ dehydration
with the periodic addition of a controlled amount of hy-
drochloric acid was performed to obtain the desired model
compound 4a and the natural product doryanine (4b) di-
rectly in nearly 75% yields. A similar protocol was earlier
employed by Iida et al. en route to doryanine (4b), how-
ever the complete experimental details are not available;4f
on completion of the sodium borohydride reduction reac-
tion, they acidified the reaction mixture with 10% hydro-
chloric acid. In our studies, the periodic addition of
hydrochloric acid to the reaction mixture is essential to
ensure completion of the reaction and resolve yield issues.
It also helps to avoid decomposition and the formation of
mophthalimide utilizing
dehydration and catalytic hydrogenation pathway.
a one-pot regioselective reductive
Key words: homophthalic acid, homophthalimide, regioselective
reduction, dehydration, isoquinoline alkaloids
The isoquinoline alkaloids are an important class of com-
pounds and they exhibit a broad range of biological activ-
ity.1 The alkaloid doryanine is isolated from Cryptocarya
chinensis, Doryphora sassafras, and Mitragyna speciosa
species.2 The alkaloid oxyhydrastinine is wide spread in
Nature and it is isolated from Argemone mexicana,
Hunnemania fumariaefolia, Hydrastis canadensis, Hype-
coum erectum, Hypecoum leptocarpum, Fumaria agrar-
ia, Fumaria bastardii, Fumaria indica, Fumaria sepium,
and Papaveraceae species. It is known to possess antibac-
terial, antitubercular, and immunostimulant activity.3
Several good synthesis of these two simple natural prod-
ucts are known in the literature.4,5 They have been de-
signed by employing several new C–C and C–N bond-
forming reactions. Continuing our studies from the last
two decades on cyclic anhydrides and their derivatives as
bioactive natural products,6 we reasoned that 4,5-(methy-
lenedioxy)homophthalic anhydride7 would be a potential
precursor for the synthesis of doryanine and oxyhydrasti-
nine. In this context, now we herein report a practical syn-
thesis of the target compounds (Scheme 1).
O
O
R
COOH
COOH
R
R
Me
O
R
Me
OH
MeNH2, o-C6H4Cl2
(i) NaBH4
EtOH, 0 °C
N
N
reflux, 10 h
R
R
1a R = H
1b R–R = OCH2O
2a R = H (78%)
2b R–R = OCH2O (76%)
3a R = H
3b R–R = OCH2O
O
O
R
Me
R
R
Me
Pd(OH)2, EtOH, H2, reflux, 24 h
(ii) EtOH–HCl (2 M) (4:1)
0 °C, 6 h
N
N
R
4a R = H (74%)
doryanine 4b R–R = OCH2O (73%)
5a R = H (98%)
oxyhydrastinine 5b R–R = OCH2O (90%) .
Scheme 1 Synthesis of isoquinoline alkaloids doryanine and oxyhydrastinine
SYNTHESIS 2014, 46, 1954–1956
Advanced online publication: 10.04.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1341158; Art ID: SS-2014-Z0092-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Doryanine and Oxyhydrastinine
1955
13C NMR (50 MHz, CDCl3): δ = 26.8, 36.3, 125.3, 127.1, 127.7,
129.1, 133.6, 134.0, 165.1, 170.2.
MS (ESI): m/z (%) = 175.89 (7) [M + H]+.
undesired overreduction product. Next, we performed the
reduction of the C=C bond in heterocyclic ring B in com-
pound 4a using palladium-on-carbon in ethyl acetate and
obtained the desired second prototypical compound 5a in
quantitative yield. Our above-specified hydrogenation re-
action at room temperature under 2 bars of hydrogen pres-
sure was very slow and it took almost three days to go to
completion (monitored by 1H NMR). The same reduction
reaction with substrate 4b was not feasible and the starting
material remained completely unreacted. We also at-
tempted the palladium-on-carbon catalyzed reduction of
compound 4b at room temperature in other solvents, such
as methanol, ethanol, and petroleum ether, using a hydro-
genation Parr shaker under 4.5 bars of hydrogen pressure.
The results were not encouraging and we always ended up
with isolation of the starting material. We feel that the
cause for failure could be the relatively lower reactivity of
substrate 4b bearing the oxymethylene bridge. Finally, the
palladium hydroxide induced hydrogenation of both com-
pounds 4a and 4b under a balloon pressure hydrogen at-
mosphere in refluxing ethanol delivered the desired
compound 5a and natural product oxyhydrastinine (5b) in
nearly quantitative yields. The analytical and spectral data
obtained for synthetic 4b and 5b were in complete agree-
ment with the reported data.2–5 Thus starting from 4,5-
(methylenedioxy)homophthalic acid, we completed the
two-step synthesis of doryanine and three-step synthesis
of oxyhydrastinine in decent overall yields.
6-Methyl[1,3]dioxolo[4,5-g]isoquinoline-5,7(6H,8H)-dione (2b)
Following the typical procedure for 2a using acid 1b gave the prod-
uct as a faint yellow solid; yield: 1.33 g (76%); mp 142–144 °C.
IR (CHCl3): 1708, 1665 cm–1.
1H NMR (200 MHz, CDCl3): δ = 3.34 (s, 3 H), 3.94 (s, 2 H), 6.06
(s, 2 H), 6.66 (s, 1 H), 7.59 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 26.7, 36.4, 102.1, 106.4, 107.9,
119.4, 130.2, 147.8, 152.5, 164.5, 170.2.
MS (ESI): m/z (%) = 219.86 (80) [M + H]+.
2-Methylisoquinolin-1(2H)-one (4a); Typical Procedure
To a stirred solution of imide 2a (1.20 g, 6.85 mmol) in EtOH (20
mL) was added portionwise NaBH4 (2.08 g, 54.80 mmol) at 0 °C.
The mixture was stirred under argon at 0 °C with periodic addition
of HCl–EtOH soln [EtOH (8 mL) and 2 M HCl (2 mL)] (2 drops) at
15 min intervals. At the end of 6 h, excess NaBH4 was quenched at
0 °C by the addition of 2 M HCl–EtOH until the mixture became
acidic. The solvent was removed in vacuo and the obtained residue
was dissolved in EtOAc (25 mL). The organic layer was washed
with H2O (20 mL), brine (20 mL), and dried (Na2SO4). Concentra-
tion of the organic layer in vacuo followed by purification of the res-
idue by column chromatography (silica gel, 40% EtOAc–PE) gave
pure 4a as a thick oil; yield: 806 mg (74%).
IR (CHCl3): 1646, 1595 cm–1.
1H NMR (200 MHz, CDCl3): δ = 3.60 (s, 3 H), 6.47 (d, J = 8 Hz, 1
H), 7.06 (d, J = 8 Hz, 1 H), 7.40–7.67 (m, 3 H), 8.43 (d, J = 6 Hz, 1
H).
13C NMR (50 MHz, CDCl3): δ = 36.9, 105.9, 125.8, 126.0, 126.7,
127.6, 131.9, 132.3, 137.1, 162.6.
MS (ESI): m/z (%) = 159.93 (3) [M + H]+.
In summary, we have described the well-organized syn-
thesis of doryanine and oxyhydrastinine alkaloids. Our
present approach to this isoquinoline class of compound is
general in nature and will be useful to design a focused
mini-library of their analogues and congeners for SAR
studies.
6-Methyl[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one (Doryanine,
4b)
Following the typical procedure for 4a using imide 2b gave the
product as a faint yellow solid; yield: 812 mg (73%); mp 158–160
°C.
Melting points are uncorrected. 1H NMR spectra were recorded in
CDCl3 using TMS as an internal standard on a 200 MHz NMR spec-
trometer. 13C NMR spectra were recorded on a 200 NMR spectrom-
eter (50 MHz) and 400 NMR spectrometer (100 MHz). MS were
taken on an MS-TOF mass spectrometer. IR spectra were recorded
on a FT-IR spectrophotometer. Column chromatographic separa-
tions used silica gel (60–120 mesh); petroleum ether = PE. Com-
mercially available homophthalic acid, MeNH2, o-dichlorobenzene,
NaBH4, Pd/C, and Pd(OH)2 were used. 4,5-(Methylenedioxy)ho-
mophthalic acid (1b) was prepared by using known procedures.7
IR (CHCl3): 1653, 1581 cm–1.
1H NMR (200 MHz, CDCl3): δ = 3.59 (s, 3 H), 6.07 (s, 2 H), 6.37
(d, J = 8 Hz, 1 H), 6.85 (s, 1 H), 6.99 (d, J = 8 Hz, 1 H), 7.78 (s, 1 H).
13C NMR (50 MHz, CDCl3): δ = 37.0, 101.6, 103.6, 105.5, 105.8,
121.6, 131.2, 134.3, 147.8, 151.6, 161.8.
MS (ESI): m/z (%) = 226.06 (100) [M + Na]+.
2-Methyl-3,4-dihydroisoquinolin-1(2H)-one (5a); Typical Pro-
cedure
To a stirred solution of lactam 4a (636 mg, 4.00 mmol) in EtOH (20
mL) was added a catalytic amount of Pd(OH)2 (25 mg, 0.20 mmol)
and the mixture was refluxed under a balloon pressure H2 atmo-
sphere for 24 h. The mixture was allowed to cool to r.t. and then it
was filtered through a pad of Celite to remove the catalyst and con-
centrated in vacuo. The crude product was purified by column chro-
matography (silica gel, 40% EtOAc–PE) to provide 5a as a thick
oil; yield: 631 mg (98%).
2-Methylisoquinoline-1,3(2H,4H)-dione (2a); Typical Proce-
dure
To homophthalic acid (1a, 1.80 g, 10.00 mmol) was added 40% aq
MeNH2 (5 mL) and the mixture was stirred for 5 min. The mixture
was then concentrated in vacuo and dried on a vacuum pump. To the
obtained salt was added o-dichlorobenzene (20 mL) and the mixture
was vigorously refluxed for 10 h. The mixture was allowed to cool
to r.t. and subjected directly to column chromatographic (silica gel,
EtOAc–PE) to give pure product 2a as a white solid; yield: 1.36 g
(78%); mp 119–121 °C.
IR (CHCl3): 1643, 1606 cm–1.
1H NMR (200 MHz, CDCl3): δ = 2.99 (t, J = 8 Hz, 2 H), 3.15 (s, 3
H), 3.56 (t, J = 8 Hz, 2 H), 7.16 (d, J = 8 Hz, 1 H), 7.25–7.45 (m, 2
H), 8.08 (dd, J = 8, 2 Hz, 1 H).
13C NMR (50 MHz, CDCl3): δ = 27.7, 35.0, 48.0, 126.7, 126.8,
127.9, 129.2, 131.4, 137.8, 164.6.
IR (CHCl3): 1710, 1664 cm–1.
1H NMR (200 MHz, CDCl3): δ = 3.38 (s, 3 H), 4.06 (s, 2 H), 7.28
(d, J = 8 Hz, 1 H), 7.45 (t, J = 8 Hz, 1 H), 7.60 (dt, J = 8, 2 Hz, 1 H),
8.23 (dd, J = 8, 2 Hz, 1 H).
MS (ESI): m/z (%) = 162.01 (4) [M + H]+.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1954–1956

1956
R. Jangir et al.
PAPER
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a crystalline solid; yield: 629 mg (90%); mp 95–97 °C.
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H), 3.52 (t, J = 8 Hz, 2 H), 5.99 (s, 2 H), 6.61 (s, 1 H), 7.54 (s, 1 H).
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Acknowledgment
R.J. thanks CSIR, New Delhi for the award of a research fellowship
and N.P.A. thanks Department of Science and Technology, New
Delhi for financial support.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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Synthesis 2014, 46, 1954–1956
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