A new approach to construction of isoindolo[1,2-a]isoquinoline alkaloids Nuevamine, Jamtine, and Hirsutine via IMDAF reaction

Tetrahedron 65 (2009) 3789–3803

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Tetrahedron

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A new approach to construction of isoindolo[1,2-a]isoquinoline alkaloids

Nuevamine, Jamtine, and Hirsutine via IMDAF reaction

,

a

Fedor I. Zubkov ^a, Julya D. Ershova , Anna A. Orlova , Vladimir P. Zaytsev , Eugeniya V. Nikitina ,

Alexandr S. Peregudov ^b, Atash V. Gurbanov ^d, Roman S. Borisov ^c, Victor N. Khrustalev ^b,

Abel M. Maharramov ^d, Alexey V. Varlamov ^a

*

^aOrganic Chemistry Department, Russian Peoples Friendship University, 6 Miklukho-Maklaya Street, Moscow 117198, Russian Federation

^bNesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilov Street, Moscow 119991, Russian Federation

^cA.V. Topchiev Institute of Petrochemical Synthesis, 29 Leninsky prospekt, Moscow 119991, Russian Federation

^dBaku State University, 23 Z. Khalilov Street, Baku AZ-1148, Azerbaijan

a r t i c l e i n f o

a b s t r a c t

Article history:

The interaction between 1-furyl-1,2,3,4-tetrahydroisoquinolines and unsaturated acids derivatives

(acryloyl, methacryloyl, and crotonoyl chloride, maleic and citraconic anhydride) was studied. It was

shown that the reaction proceeds via amide formation and subsequent intramolecular Diels–Alder

reaction of the furan (IMDAF). The [4þ2] cycloaddition proceeded under mild reaction conditions

(25–80 ^ꢀC) and afforded only the exo-adduct in a high yield. With this method, a new approach to the

isoindolo[1,2-a]isoquinoline system, the basic structural element of alkaloids Jamtine, Hirsutine, and

Nuevamine, is proposed.

Received 6 November 2008

Received in revised form 28 January 2009

Accepted 13 February 2009

Available online 20 February 2009

Keywords:

Intramolecular Diels–Alder

reaction of furan (IMDAF)

Isoindolo[1,2-a]isoquinolines

1-Furyltetrahydroisoquinolines

Alkaloids

Jamtine

Hirsutine

1. Introduction

Darwinii Hook (Southern Chile). Their structure was established

one year later⁶and there are several published methods of their

Recently our group has proposed several efﬁcient approaches to

potentially bioactive substances such as hydrogenated hydroxy-

isoquinolines,¹isoindolo[2,1-a]quinolines,²and isoindolo[2,1-

b]benzazepines³using commercially available furfurylamines as

starting materials. The intramolecular furan Diels–Alder reaction

(IMDAF)⁴between unsaturated acid derivatives and the furan core

of the amines was the key step of the transformations mentioned

above.

synthesis.⁷

(ꢁ)-Jamtine is probably the best-known substance amongst

isoindoloquinoline alkaloids. Its isolation was reported in 1987.⁸It

is produced by the climbing shrub Cocculus Hirsutus,⁹that grows in

Pakistan and India and is widely used in folk medicine.¹⁰

From all appearances Jamtine together with other bioactive

substances is responsible for the antihyperglycemic activity of

Trying to apply our chemistry to target natural products we

were attracted to isoindoloisoquinoline alkaloids. There are three

known natural products containing the isoindolo[2,1-a]isoquino-

line skeleton. These are the alkaloids Nuevamine, Jamtine (and its

N-oxide), and Hirsutine (Chart 1).

O

MeO

HO

N

O

H

O

N

MeO

MeO₂C

The lactams of (ꢁ)-Nuevamine, the ﬁrst known iso-

indoloquinoline alkaloids, were isolated in 1984⁵by Berberis

Jamtine-N-oxide

Hirsutine

Nuevamine

from Cocculus hirsutus (L.)

from Berberis

darwinii Hook

* Corresponding author. Tel.: þ7 095 955 0729; fax: þ7 095 952 2644.

E-mail address: fzubkov@sci.pfu.edu.ru (F.I. Zubkov).

Chart 1.

doi:10.1016/j.tet.2009.02.024

3790

F.I. Zubkov et al. / Tetrahedron 65 (2009) 3789–3803

O

hydroisoquinolines 3 and amides 4 (Scheme 1). It should be men-

NH₂

O

tioned that the two-stage procedure for preparation of 2-methyl-

1,2,3,4-tetrahydroisoquinolines 3, including alkylation with methyl

iodide and reduction under sodium borohydride, turned out to be

preferable (65–77% overall yield) over the single-stage reaction of

formic acid/formaldehyde mixture (45–55%).

N

O

CHO

MeO

O

The next step of our study implied the construction of the iso-

indolo[1,2-a]isoquinoline skeleton based on the interaction

between tetrahydroisoquinolines 2a,b and maleic (citraconic)

anhydride. Both reactions went smoothly and stereospeciﬁcally

under mild reaction conditions. As shown in Scheme 2 by an

example of adding citraconic anhydride to 1-furyl-1,2,3,4-tetrahyd

roisoquinoline 2a, the reaction ran via an initial maleinamides A (B)

formation (that was not isolated) followed by the stereoselective

intramolecular [4þ2] exo-cycloaddition reaction. The Diels–Alder

adductsd5,8,8a,9,10,12b-hexahydro-6H-10,12a-epoyisoindolo[2,1-

a]isoquinolines 5 (6), occur with the form of single diastereoisomer

with the cis-orientation^2,13,16of the 10,12a-epoxy bridge and sub-

stituents at C-8a and C-9 (J_8a-exo,9-exo¼8.8–9.3 Hz, J_9exo,10¼0 Hz). The

H-8a and H-12b protons have the cis-conﬁguration as well. This

conclusion was conﬁrmed by ¹H NMR NOE values indicating the

O

Nuevamine

N

O

MeO

O

Chart 2.

aqueous extract of C. Hirsutus leaves (L.).¹¹The ﬁrst synthesis of this

unusual alkaloid was reported by Padwa’s research group in 2002.¹²

Isolation of the isoindoloisoquinoline alkaloid (ꢁ)-Hirsutine was

ﬁrst reported in 1991¹³(also from C. Hirsutus). We were surprised to

have found no published synthesis of this substance. Possibly it can

be explained by the fact that another Corynanthe alkaloid of

indolo[2,3-a]quinolizidine series has the same name.¹⁴

h

increase of H_isignal intensity when H_jsignal was saturated ( {H_j},

H_i

%). The values of h_H-12b{H-8a}¼4–6.5% and h_H-8a{H-12b}¼4.5%

proved that H-8a and H-12b atoms in adducts 5a,b are situated on

the same side of the central pyrrolidone ring. In the case of cit-

raconic anhydride, a mixture of two regioisomers, which differ in

the position of the methyl group (at C-8a or C-9), was isolated from

the reaction mixture. Both isomeric pairs 6aA/6aB and 6bA/6bB

contained predominantly the regioisomers with Me group at the

position C-9. The ratio of isomers A/B was w1.3:1 according to the

¹H NMR spectroscopic data (see Experimental section) (Scheme 2).

These results could be explained by the fact that the nucleophilic

attack of 2a by nitrogen atom occurs preferentially at the C-5 car-

bon atom of citraconic anhydride rather than at C-2. The latter is

sterically bulkier and bears a lesser partial positive charge resulting

from the electron-donating effect of the Me-3 group.

2. Results and discussion

Our approach to the construction of isoindolo[1,2-a]isoquinol

ine frame involves three basic steps (Chart 2): Bischler–Napieralski

synthesis of 3,4-dihydro-1-furylisoquinoline, reduction, and then

cycloaddition of the resulting tetrahydroisoquinoline with either

maleic anhydride or an unsaturated acid chloride. Subsequent

transformations of the Diels–Alder adducts can lead to various

products including Nuevamine.

The initial 1-furylisoquinolines 2–4 were obtained by a three-

step procedure, which involves acylation of phenethylamines with

furoylchloride followed by Bischler–Napieralski reaction.¹⁵Con-

densation of furoylamides in an excess of phosphorus oxychloride

in boiling toluene gave the desired imines 1 in good overall yields.

Dimethoxy derivative 1b formed much faster (3–5 h) and in higher

yields (95–98%) than its unsubstituted analogue 1a (24–26 h, 85–

92%), that can be explained by the electron-donor effect of the

methoxy groups.

For Nuevamine synthesis it is necessary to be able to obtain the

isoindolo[1,2-a]isoquinoline skeleton without the carboxylic group

at C-9. To this end we had to turn to the interaction between tet-

rahydroisoquinolines

2 and chloranhydrides of acrylic acid

derivatives. The acylation and following cycloaddition of crotonoyl,

methacryloyl, and acryloyl chlorides with 1,2,3,4-tetrahydro-1-

furylisoquinolines 2a,b required more drastic reaction conditions

(Scheme 2) compared to maleic anhydride. While the maleic

In both cases no resiniﬁcation occurs. Subsequent alkylation/

reduction or reduction/acylation processes gave N-methyltetra-

R¹

NH₂

Cl

NMe

O

N

O

R²

R¹

O

3a (75%)

3b (65%)

4a-d

O

(69-77%)

H₂CO/

O

HCO₂H

2. NaBH₄

MeOH

r.t., 6 h

1. MeI

MeCN

r.t., 48 h

R¹

(R₂CO)₂O

Δ, 3−8 h

MeCN,

Py

r.t, 3 h

HN

R¹

quant.

R¹

NaBH₄

MeOH,

POCl₃

PhMe,

O

N

O

NH

O

R¹

Δ, 4 - 25 h

Δ, 8 h

1a (92%)

1b (98%)

2a (74%)

2b (97%)

1-3a: R¹= H; 1-3b: R¹= OMe; 4a,b: R¹= H;

4c,d: R¹= OMe; 4a,c: R²= Me; 4b,d: R²= CF₃

Scheme 1.

F.I. Zubkov et al. / Tetrahedron 65 (2009) 3789–3803

3791

5

4

R¹

a: R¹= H

6

Me

Cl

b: R¹= OMe

O

7

N

O

N

O

1

H

PhMe, 20 °C,

2 h

Et₃N, PhMe

Δ, 8 - 10 h

8a

12

O

Me

CO₂H

R¹

9

10

7a (19%)

7b (23%)

5a (97%)

5b (90%)

NH

O

R³

Cl

Me

R¹

N

R¹

O

2 a,b

O

N

O

+

H

Me

Et₃N, PhMe

Δ, 6 - 10 h

PhMe, 20 °C,

2 h

A

R³

O

CO₂H

O

R¹

8a R³= H (77%);

8b R³= H (56%);

9a R³= Me (61%);

9b R³= Me (76%)

N

O

Me

H

B

O

CO₂H

6a R¹= H (69%)

6b R¹= OMe (98%)

A/B = 1.3/1

N

O

Me

[4+2]

exo-

6Aa

A

better

O

CO₂H

Me

3

4

A

2

2a

O

1

5

+

Me

N

[4+2]

exo-

poorly

B

6Ba

O

CO₂H

O

B

Scheme 2.

anhydride, the cycloaddition proceeded at room temperature for

2 h, the reaction with acryloyl chloride derivatives required 8–10 h

heating at 110 ^ꢀC in toluene. In the case of the acylation of tetra-

hydroisoquinolines 2a,b with crotonoyl and acryloyl chlorides, the

reactions proceeded smoothly to give the corresponding 10,12b-

epoxyisoindolo[1,2-a]isoquinolines 8,9 in moderate yields (56–

77%) and with a high level of stereoselectivity. After solvent

removal a simple puriﬁcation process by recrystallization allowed

us to obtain pure exo-pentacycles 8a,b and 9a,b. The substituent R³

(Me-8a) in compounds 9 has endo-orientation, that was established

from the large NOE values of h_H-12b{Me-8a} or vice versa equal to

12–14%.

Unexpectedly, the analogous procedure with the initial product

2 and crotonoyl chloride under chosen reaction conditions gave the

target isoindoloisoquinolines 7 in poor yields (no more than 25%).

We cannot provide any acceptable explanation of this fact. The

structure of compounds 7 was established relying on the ¹H NMR

spectroscopic data. In particular, the H-8a and H-9 atoms of the

oxabicycloheptene fragment in these compounds gave the doublet

In the second part of our investigation we were interested in the

interaction between isoquinolines 1–4 and activated alkynes. Since

the isoquinolines 1–4 possess simultaneously the dienophilic furan

fragment and the nucleophilic nitrogen atom in their molecules,

two competing ways of the reaction are theoretically possible: the

Diels–Alder cycloaddition to the furan ring and the Michael addi-

tion to nitrogen.

We presume, that the formation of the tetrahydro-

benzo[d]azocines derivatives 12a,b proceeds via the Michael ad-

dition of the saturated nitrogen atom of isoquinolines 3a,b to the

triple bond of the DMAD (dimethyl acetylenedicarboxylate) mole-

cule, followed by the intramolecular SN reaction, leading to the

tetrahydropyridine ring expansion (Scheme 4). In a similar manner,

methyl propiolate addition to amines 3a,b led to the regioselective

Michael addition and subsequent cycle expansion to form benzo-

[d]azocines 13a,b. In either case, according to chromatography–

mass spectrometry data, no [4þ2] cycloaddition adduct was

observed in the crude reaction mixture. The formation mechanism

of octatomic cycles 12 and 13 is exempliﬁed in our previous papers.¹⁷

signals at

at 2.62–2.64 ppm with spin–spin coupling constants J_{8a-endo,9-exo}

3.8 Hz and J_10,9-exo¼4.5 Hz.

d 2.18–2.20 ppm and the doublet-doublet-quartet signals

d

¼

R¹

The carboxylic acids 5, 6 are colourless crystalline substances,

sparingly soluble in most organic solvents, and therefore hardly

analyzable by NMR. In this connection we carried out their esteri-

ﬁcation (Scheme 3) that permitted us to obtain the corresponding

esters 10, 11 and interrogate their spatial structures using ¹H–¹H

and ¹³C NMR methods. It was interesting to note that after esteri-

ﬁcation of the regioisomer mixture 6A/6B and isolation of esters 11,

the unique derivatives 11a (11b) with endo-orientation of the Me-

8a groups were obtained. Probably the puriﬁcation by

recrystallization protocol led to enrichment of less soluble Me-8a

regioisomers, and thus, we were unable to isolate the corre-

sponding Me-9 analogue.

MeOH / H⁺

Δ, 8 h

N

R¹

O

H

R⁴

5, 6A

O

10, 11

O

CO₂Me

CO₂H

+

R¹

10a: R¹= R⁴= H (96%);

N

R¹

10b: R¹= OMe, R⁴= H (91%);

11a: R¹= H, R⁴= Me (30%);

11b: R¹= OMe, R⁴= Me (45%)

O

Me

6B

O

CO₂H

Scheme 3.

3792

F.I. Zubkov et al. / Tetrahedron 65 (2009) 3789–3803

2

1

10

7

R¹

3

Me

CO₂Me

H

N

DMAD

MeCN, 20 °C

N

O

PhMe, Δ, 4 h

6

CO₂Me

for 2a,b

(X = H)

CO₂Me

O

R¹

14a (72%)

14b (68%)

12a (66%)

12b (60%)

N

O

X

for 3a,b

(X = Me)

2 - 4

R¹

Me

N

DMAD

≡

HC C-CO₂Me

PhMe

N

R²

R¹

MeO₂C

R¹

MeCN, 20 °C

Δ, 16-24 h

a: R¹= H

O

for 4a-d

CO₂Me

b: R¹= OMe

(X = COR²)

O

MeO₂C

13a (70%)

13b (72%)

15a R¹= H, R²= Me (31%);

15b R¹= H, R²= CF₃(33%);

15c R¹= OMe, R²= Me (45%);

15d R¹= OMe, R²= CF₃(68%)

Scheme 4.

The interaction between 1-furyl-1,2,3,4-tetrahydroisoquinol

ines 2a,b and double molar excess of DMAD proceeded smoothly in

boiling toluene (Scheme 4). Initially we expected alkylation of

nitrogen with alkyne to the N-vinyl derivative 14 that would un-

dergo further the [4þ2] cycloaddition with the second DMAD

molecule. But practically, only the ﬁrst stage was realized (most

likely, owing to the steric hindrance of the bulky N-vinyl fragment).

In much the same way N-acylated isoquinolines 4 cyclized in the

presence of DMAD giving adducts 15 in satisfactory yields. The

latter was isolated as a mixture of two geometrical isomers differ-

ing in the orientation of the H-1 relative to the 1⁰,4⁰-oxabridge. The

ratio of the two isomers was w6:1 according to the ¹H NMR

spectroscopic data.

8b was transformed into diacetyl compound 18 (Scheme 6). This

reaction was a result of opening of the oxabridge with subsequent

migration of the double bond. Its structure was established by ¹H

and ¹³C NMR spectroscopic data. Double bond migration to C-12-

position was proved by the presence of the quaternary carbon C-

12a at

d 141.9 ppm. It is a painful conclusion for us, since we relied

on the fact that the conjugate double bond would arise at the C-8a–

C-9 position (Jamtine skeleton). A relatively high (for diacetoxy-

substituted fragments) coupling constant ³J_10-H,11-H¼7.9 Hz

indicated the pseudoaxial positions of H-10 and H-11. It means that

the acetoxy groups had the trans-conﬁguration. This statement was

conﬁrmed by ¹H NMR NOE values h_H-12b{H-8a}¼6%, on the one

hand, and h_H-10{H-8a}¼5%, on the other hand, proved that the H-

12b, H-10, and H-8a atoms were situated on the same side of the

central pyrrolidone plane.

The reaction of 3,4-dihydroisoquinolines 1 with an excess of

DMAD or methyl propiolate gives an unusual reaction. In that case

the attack of acetylenedicarboxylate at the nitrogen atom of the

Then, the epoxidation of the double bond in 8a,b and 10a,b with

m-chloroperoxybenzoic acid was accomplished. The yields of

diepoxides 19, 20 were 65–85% (Scheme 6). As expected,^1a,19oxir-

ane ring of heptacycles 19, 20 was exo-annulated to the oxabicy-

cloheptane fragment. The endo-conﬁguration of H-1a, H-3(endo),

H-3a, and H-11d of the compound 19, 20 was concluded from the

imines 1 led to the relatively stable zwitterion 17 . The subsequent

*

[4þ2] cycloaddition of the next DMAD molecule to this ion closes

the six-membered cycle and forms product 17.¹⁸Methyl propiolate

reacts with 1 in the same way. No products of furan cycloaddition

or cycle expansion were isolated from the reaction mixture

(Scheme 5).

The last part of this article concerns the modiﬁcation of the

oxabicycloheptene moiety in epoxyisoindolo[1,2-a]isoquinolines

8,10. First, in the presence of BF₃$OEt₂in acetic anhydride epoxide

similarity

of

the

vicinal

constants

³J_1a,11d¼2.9–3.3 Hz,

3

³J_3a,3A(endo)¼8.9–9.2 Hz, and J_2,3A(endo)¼³J_2,1a(endo)¼0 Hz with the

literature data for analogous bridged systems with reliably estab-

lished conﬁgurations.²⁰According to these data, the coupling

R¹

HC≡C-CO₂Me

MeCN, Δ, 6 h

DMAD

N

E

N

O

N

R¹

MeCN, Δ, 2 h

1a,b

E

O

16b (28%)

17a (20%)

17b (28%)

DMAD

R¹

E = CO₂Me;

a R¹= H;

N

O

E

DMAD

b R¹= OMe

[4+2] cycloaddition

17*

Scheme 5.

F.I. Zubkov et al. / Tetrahedron 65 (2009) 3789–3803

3793

4

5

R¹

MeO

6

7

BF₃·OEt₂,

N

O

N

O

H

Ac₂O, 20 °C

1

H

for 8b (R⁵= H)

12

O

9

R⁵

8, 10

AcO

18 (30%)

OAc

m-CPBA

CH₂Cl₂, 20 °C

8

7

R¹

6

8a,20a: R¹= R⁵= H (79%);

5

N

8b,20b: R¹= OMe, R⁵= H (67%);

10a,19a: R¹= H, R⁵= CO₂Me (77%);

10b,19b: R¹=OMe, R⁵=CO₂Me (83%)

O

H

11

4

11d

R⁵

O

3

O

1

1a

2

19, 20

Scheme 6.

constant of the proton in the bridgehead (H-2) is very small (<1 Hz)

for R-endo-H, but it is higher than 3 Hz for R-exo-H, so the observed

spin coupling constants unambiguously prove the endo-orientation

of H-1a and H-3A(endo).

Figure 1. Molecular structure of 21a (only hydrogen atoms at the asymmetric centers

are shown).

The exposure of diepoxides 19b, 20b to BF₃$OEt₂in the presence

of acetic anhydride led to the opening of the oxirane ring in

accordance with the original Wagner–Meerwein skeleton rear-

rangement (Scheme 7). As a result polycycles 21a,b (with quite

six-membered (tetrahydropyridinone, tetrahydropyridine and

benzene) rings (Figs. 1 and 2). Both ﬁve-membered rings of the

bicyclic fragment have usual envelope conformations, and the two

central six-membered rings adopt the sofa (tetrahydropyridinone,

the C11A carbon atom is out of the plane through the other atoms of

the ring by 0.672 Å) and nonsymmetrical half-chair (tetrahydro-

pyridine, the C6 carbon and N7 nitrogen atoms are out of the plane

through the other atoms of the ring by ꢂ0.544 and 0.238 Å,

respectively) conformations. The nitrogen N7 atom has the tri-

gonal-planar geometry (sum of the bond angles is 359.4^ꢀ). The

dihedral angle between the planes of the tetrahydropyridinone and

tetrahydropyridine rings is 131.3^ꢀ. It is interesting to point out that

the two carboxylate substituents are in the sterically unfavourable

syn-periplanar conﬁguration relative to the tetrahydrofuran ring.

Such a disposition is explained by both the structure of the initial

epoxy compound 19b and the direction of the Wagner–Meerwein

rearrangement.

good yield) were formed via intermediate cations 19, 20b and 19,

*

20b^**. The formation mechanism of compounds 21a,b looks like

a typical Wagner–Meerwein rearrangement and it is exempliﬁed in

Scheme 7.

¹H and ¹³C NMR data for the compounds 21a,b conﬁrm their

structural similarity with the 4,6-epoxycyclopenta[c]pyridine

skeleton. But the absence of literature analogy of the structure of

the compounds 21a,b did not allow us to make a decisive choice

between several possible alternative structures relying only on

NMR data. Particularly the relative conﬁguration of hydrogen atoms

at C-11 and C-12a remained unclear.

Single crystals of 21a were grown by crystallization from

a mixture of ethanol with dimethylformamide, and its mole-

cular structure was unambiguously elucidated by X-ray data

(Fig. 1).

Compound 21a comprises a fused pentacyclic system containing

two ﬁve-membered (cyclopentane and tetrahydrofuran) and three

MeO

N

BF₃·OEt₂

O

H

O

H

Ac₂O, 20 °C

- AcO^-

R⁵

O

AcO

19b, 20b

19,20b*

H

10

11

MeO

AcO

9

H

13

AcO

H

O

N

O

H

O

H

R⁵

O

+ AcO^-

H

N

1

8

7

MeO

R₅

12a

6

AcO

4

5

21a: R⁵= H (62%);

21b: R⁵= CO₂Me (73%)

19,20b**

Figure 2. The H-bonded dimers of 21a (most hydrogen atoms are omitted for clarity);

Scheme 7.

hydrogen bonds are shown by dashed lines.

3794

F.I. Zubkov et al. / Tetrahedron 65 (2009) 3789–3803

The molecules of 21a are diastereomers and possess six asym-

Cambridge Crystallographic Data Center, CCDC 694217. Copies of this

information may be obtained free of charge from the Director, CCDC,

12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44 1223 336033; e-

mail: deposit@ccdc.cam.ac.uk or www.ccdc.cam.ac.uk).

metric centers at the C8A, C10, C11, C11A, C12, and C12A carbon

atoms. The crystal of 21a is racemate and consists of enantiomeric

pairs with the relative conﬁguration of the centers rac-

8AR

*

,10S

*

,11R

*

,11AR

*

,12R

*

,12AS . In the crystal, the enantiomers of

*

21a form the centrosymmetrical dimers via intermolecular C10–

3.3. 1-(2-Furyl)-3,4-dihydroisoquinoline (1a), 1-(2-furyl)-6,7-

dimethoxy-3,4-dihydroisoquinoline (1b)

H/p(C4–C4A) [ꢂx, 1ꢂy, ꢂz] hydrogen bonds (H/C4 3.04 Å,

:C10–H/C4 131^ꢀ; H/C4A 2.79 Å, :C10–H/C4A 151^ꢀ) (Fig. 2).

The dimers are packed in stacks along the a axis (see Supplemen-

tary data).

3.3.1. Compound 1a

Phosphoryl chloride (72 mL, 1 mol) was slowly added with

cooling to a stirred solution of amide 1a (43 g, 0.20 mol) in absolute

toluene (250 mL). The reaction mixture was then reﬂuxed for 24–

26 h. At the end of reaction, the reaction mixture was cooled and

poured into 300 mL ice and treated with 25% aqueous ammonia to

pH 9–10. Then the organic products were extracted with ethyl ac-

etate (3ꢃ150 mL), the organic layers were combined, dried over

MgSO₄, and evaporated. The residue was puriﬁed by column

chromatography on Al₂O₃(eluent ethyl acetate–hexane 1:10) to

give dihydroisoquinoline 1a as dark oil. Yield 33.3 g (92%); R_f(ethyl

Thus, herein we reported a facile new procedure, which en-

ables the synthesis of isoindolo[1,2-a]isoquinolines in three syn-

thetic steps with high levels of diastereoselectivity, from readily

available precursors: furfural, phenethylamines, and maleic an-

hydride. Some reactions of the adducts obtained have been per-

formed, and the regioselectivity of the reaction of activated

alkynes with hydrogenized 1-furylisoquinolines has been in-

vestigated. The suggested strategy for the isoindolo[1,2-a]iso-

quinoline construction offers a new short synthetic route to the

alkaloid Nuevamine and closely related structural analogs of the

alkaloids Jamtine and Hirsutine.

acetate) 0.35; IR 1735 (C]N) cm^ꢂ1

; EIMS (70 eV) m/z (rel

intensity): M^þ197 (87), 168 (100), 154 (11), 141 (57), 128 (14), 115

(82), 102 (16), 89 (31), 77 (43), 63 (58), 51 (64), 38 (99). ¹H NMR

3. Experimental

3.1. General

(CDCl₃, 400 MHz) d 7.71 (1H, dd, J_8,61.4, J_8,77.4 Hz, H-8), 7.58 (1H, br

d, J_{5 ,4}2.0 Hz, H-5⁰), 7.41 (1H, dt, J_6,5¼J_6,77.4, J_6,81.4 Hz, H-6), 7.33

(1H, dt, J_7,51.5, J_7,6¼J_7,87.4 Hz, H-7), 7.26 (1H, br dd, J_5,67.4, J_5,7

0

1.5 Hz, H-5), 6.85 (1H, br d, J_{3 ,4}3.4 Hz, H-3⁰), 6.52 (1H, dd, J_{4 ,3}3.4,

0

All reagents were purchased from Acros Chemical Co. All

solvents were used without further puriﬁcation. Melting points

were determined using a Fisher-Johns melting point apparatus

and are uncorrected. IR spectra were obtained in KBr pellets for

solids or in thin ﬁlm for oils using an IR-Fourier spectrometer

Infralum FT-801. ¹H (400 or 600 MHz) and ¹³C (100.6 MHz) NMR

spectra were recorded for solutions (2–5%) in deuteriochloro-

form or DMSO-d₆(6b and 19a) at 30 ^ꢀC and traces of chloroform

0

J_{4 ,5}2.0 Hz, H-4 ), 3.82 (2H, t, J_3,47.4 Hz, H-4), 2.74 (2H, t, J_3,47.4 Hz,

H-3). ¹³C NMR (CDCl₃, 100.6 MHz)

d

156.9 (C₂), 151.7 (C₁), 143.9

0

(C₅), 138.8 (C_4a), 130.7 (C₆), 127.53 (C_8a), 127.45 (C₈), 126.8 and 126.7

0

(C₅and C₇), 113.0 and 111.2 (C₃and C₄), 47.2 (C₃), 26.3 (C₄). Anal.

Calcd for C₁₃H₁₁NO: C, 79.16; H, 5.62; N, 7.10. Found: C, 79.20; H,

5.60; N, 7.11.

3.3.2. Compound 1b

(¹H NMR

d d

7.26 ppm) or DMSO-d₅H (¹H NMR 2.49 ppm and ¹³C

Phosphoryl chloride (13.1 mL, 0.18 mol) was slowly added drop-

wise with cooling to a stirred solution of amide 1a (10.0 g,

0.036 mol) in absolute toluene (70 mL). The reaction mixture was

then reﬂuxed for 3–5 h. After cooling, it was poured into 100 mL of

broken ice and basiﬁed with 25% aqueous ammonia to pH 9–10. The

mixture was extracted with ethyl acetate (3ꢃ100 mL). The extract

was dried over MgSO₄and concentrated in vacuo. The crude

product was recrystallized from mixture of hexane–ethyl acetate to

give dihydroisoquinoline 1b as pale-yellow rhombic crystals. Yield

9.0 g (98%); mp 99–101 ^ꢀC; R_f(ethyl acetate) 0.41; IR 1717

(C]N) cm^ꢂ1; EIMS (70 eV) m/z (rel intensity): M^þ257 (100), 242

(18), 228 (17), 212 (13), 184 (6), 115 (7), 77 (9), 63 (6), 51 (7), 39 (13).

NMR 39.43 ppm) were used as the internal standard. Mass

spectra were measured either on Thermo Focus DSQ II (electron

ionization, 70 eV, ion source temperature was 200 ^ꢀC, gas chro-

matographic inlet with Varian FactorFour VF-5ms column) or on

Thermo Trace DSQ (electron ionization, 70 eV, ion source tem-

perature was 200 ^ꢀC, direct inlet probe). The purity of the sub-

stances obtained and the composition of the reaction mixtures

were controlled by TLC Sorbﬁle plates. The separation of the

ﬁnal products was carried out by column chromatography on

Al₂O₃(activated, neutral, 50–200 mm) or by fractional

crystallization.

¹H NMR (CDCl₃, 400 MHz)

d

7.56 (1H, dd, J_{5 ,3}0.8, J_{5 ,4}₀1.3 Hz, H-5 ),

0

3.2. X-ray crystal structure determination

0

7.24 (1H, s, H-8), 6.82 (1H, dd, J_{3 ,4}3.4, J_{3 ,5}0.8 Hz, H-3 ), 6.74 (1H, s,

H-5), 6.51 (1H, dd, J_{4 ,3}3.4, J_{4 ,5}1.3 Hz, H-4 ), 3.92 (3H, s, H–OMe),

0

The crystal of 21a (C₂₂H₂₅NO₈, M¼431.43) is triclinic, space group

P-1, at T¼293 K: a¼9.5010(19), b¼10.792(2), c¼11.173(2) Å,

3.85 (3H, s, H–OMe), 3.77 (2H, t, J_3,47.4 Hz, H-3), 2.65 (2H, t, J_4,3

7.4 Hz, H-4). ¹³C NMR (CDCl₃, 100.6 MHz)

d

156.2 (C₂), 151.9 (C₆),

0

a

¼87.60(3),

b

¼74.90(3),

g

¼68.31(3)^ꢀ, V¼1025.9(4) Å³, Z¼2,

0

150.9 (C₇), 147.2 (C₁), 143.6 (C₅), 131.7 (C_4a), 120.2 (C_8a), 112.4 (C₅),

d_calcd¼1.397 g/cm³, F(000)¼456,

m

¼0.107 mm^ꢂ1

.

4041 total

0

111.1 (C₈), 110.7 (C₃), 110.3 (C₄), 56.1 and 55.8 (OMeꢃ2), 47.0 (C₃),

22.7 (C₄). Anal. Calcd for C₁₅H₁₅NO₃: C, 70.02; H, 5.88; N, 5.44.

Found: C, 70.05; H, 5.85; N, 5.42.

reﬂections (3794 unique reﬂections, R_int¼0.012) were measured on

an Enraf-Nonius CAD-4 four-circle automated diffractometer (l(Mo

K

a)-radiation,

b

-ﬁlter,

u/2

q

scan mode, 2q_max¼51^ꢀ). The structure

was determined by direct methods and reﬁned by full-matrix least

squares technique with anisotropic displacement parameters for

non-hydrogen atoms. The hydrogen atoms were placed in calculated

positions and reﬁned within riding model with ﬁxed isotropic dis-

placement parameters (U_iso(H)¼1.5U_eq(C) for the CH₃-groups and

U_iso(H)¼1.2U_eq(C) for the other groups). The ﬁnal divergence factors

3.4. 1-(2-Furyl)-1,2,3,4-tetrahydroisoquinoline (2a), 1-(2-

furyl)-6,7-dimethoxy-1,2,3,4-terahydroisoquinoline (2b).

Typical procedure

2-Fold molar excess of NaBH₄(3.33 g, 0.088 mol) was added to

an alcohol solution (150 mL, MeOH) of the corresponding dihy-

droisoquinoline (0.044 mol). The reaction mixture was then

reﬂuxed for 6–10 h (monitoring by TLC). At the end of the reaction,

the mixture was diluted with water (400 mL) and extracted with

were R₁¼0.031 for 2553 independent reﬂections with I>2

s(I) and

wR₂¼0.091 for all independent reﬂections, S¼1.039. All calculations

were carried out using the SHELXTL (PC version 6.12) program.²¹

Crystallographic data for 21a have been deposited with the

F.I. Zubkov et al. / Tetrahedron 65 (2009) 3789–3803

3795

chloroform (5ꢃ50 mL). The extract was dried over MgSO₄and

concentrated in vacuo to give 1,2,3,4-tetrahydroisoquinolines 2a,b.

then hexane–ethyl acetate (10:1, 5:1, 1:1) to give the corresponding

compounds 3.

3.4.1. Compound 2a

3.5.1. Compound 3a

White powder, yield 6.42 g (74%); mp 39–41 ^ꢀC; R_f(50% ethyl

acetate–hexane) 0.68; IR 3235 (NH) cm^ꢂ1; EIMS (70 eV) m/z (rel

intensity): M^þ199 (100), 170 (67), 141 (76), 130 (42), 115 (52), 103

Brown oil, yield: method Ad0.31 g (92%), method Bd0.79 g

(41%); R_f(30% ethyl acetate–hexane) 0.63; IR 1451 (C]C) cm^ꢂ1

;

EIMS (70 eV) m/z (rel intensity): M^þ213 (70), 185 (6), 170 (73), 140

(18), 77 (31), 55 (36), 39 (43). ¹H NMR (CDCl₃, 400 MHz)

d

7.38 (1H,

(100), 128 (13), 114 (35), 89 (7), 77 (7), 42 (13). ¹H NMR (CDCl₃,

br d, J_{5 ,3}0.7, J_{5 ,4}1.8 Hz, H-5 ), 7.10–7.20 (3H, m, H-5, H-6, and H-7),

400 MHz)

7.38 (1H, dd, J_{5 ,3}0.8, J_{5 ,4}1.6 Hz, H-5⁰), 7.09–7.15 (1H,

0 0 0 0

d

0

7.02 (1H, d, J_8,78.1 Hz, H-8), 6.29 (1H, dd, J_{4 ,3}3.0, J_{4 ,5}1.8 Hz, H-4 ),

m, H-5, 6, and 7), 6.88 (1H, br d, J_8,78.0 Hz, H-8), 6.34 (1H, dd, J_{4 ,5}

5.98 (1H, dd, J_{3 ,4}3.0, J_{3 ,5}0.7 Hz, H-3⁰), 5.22 (1H, s, H-1), 3.06–3.14

1.6, J_{4 ,3}3.0 Hz, H-4⁰), 6.21 (1H, dd, J_{3 ,5}0.8, J_{3 ,4}3.0 Hz, H-3⁰), 4.60

0

(2H, m, H-3), 2.86 (2H, m, H-4), 2.33 (1H, br s, NH). ¹³C NMR (CDCl₃,

(1H, s, H-1), 3.11 (2H, m, H-3), 2.92 (1H, m, H-4A), 2.68 (m, 1H, H-

4B), 2.38 (3H, s, NMe). ¹³C NMR (CDCl₃, 100.6 MHz)

d

155.1 (C₂),

0

100.6 MHz)

d

156.8 (C₂), 142.0 (C₅), 135.3 and 135.1 (C_4aand C_8a),

0

129.3, 127.8, 126.8, 125.6 (C_5,6,7,8), 109.9 and 108.3 (C₃and C₄), 58.0

(C₁), 42.2 (C₃), 29.0 (C₄). Anal. Calcd for C₁₃H₁₃NO: C, 78.36; H, 6.58;

N, 7.03. Found: C, 78.36; H, 6.59; N, 6.99.

142.2 (C₅), 135.3 and 134.4 (C_4aand C_8a), 128.7 (C₅), 127.7, 126.5,

0

125.7 (C_6,7,8), 109.8 and 109.6 (C₃and C₄), 63.1 (C₁), 50.3 (C₃), 43.8

(Me-2), 28.6 (C₄). Anal. Calcd for C₁₄H₁₅NO: C, 78.84; H, 7.09; N,

6.57. Found: C, 78.82; H, 7.08; N, 6.56.

3.4.2. Compound 2b

Viscous pale-red oil, yield 10.95 g (97%); R_f(50% ethyl acetate–

3.5.2. Compound 3b

hexane) 0.50; IR 3330 (NH) cm^ꢂ1; EIMS (70 eV) m/z (rel intensity):

M

Brown oil, yield: method Ad0.34 g (77%), method Bd1.28 g (52%);

R_f(ethyl acetate) 0.38; IR 1464 (C]C) cm^ꢂ1; EIMS (70 eV) m/z (rel

intensity): M^þ273 (77), 258 (13), 230 (100), 206 (54), 187 (17), 144

^þ259 (85), 258 (100), 244 (30), 230 (29), 228 (27), 201 (16), 192

(13), 115 (11), 77 (5). ¹H NMR (CDCl₃, 400 MHz)

d

7.39 (1H, br d, J_{5 ,3}

0 0

0.8, J_{5 ,4}1.8 Hz, H-5⁰), 6.61 (1H, s, H-5), 6.51 (1H, s, H-8), 6.29 (1H,

(17), 115 (33), 81 (44), 42 (58). ¹H NMR (CDCl₃, 400 MHz)

d

7.35 (1H,

0

dd, J_{4 ,3}3.2, J_{4 ,5}1.8 Hz, H-4 ), 5.98 (1H, dd, J_{3 ,4}3.2, J_{3 ,5}0.8 Hz, H-

3⁰), 5.15 (1H, s, H-1), 3.87 (3H, s, OMe), 3.76 (3H, s, OMe), 3.01–3.13

(2H, m, H-3), 2.86–2.71 (2H, m, H-4), 2.34 (1H, br s, NH). ¹³C NMR

0

dd, J_{5 ,3}0.8, J_{5 ,4}1.8 Hz, H-5 ), 6.60 (1H, s, H-8), 6.32 (1H, s, H-5), 6.30

(1H, dd, J_{4 ,5}1.8, J_{4 ,3}3.2 Hz, H-4⁰), 6.15 (1H, dd, J_{3 ,5}0.8, J_{3 ,4}3.2 Hz,

H-3⁰), 4.51 (1H, s, H-1), 3.83 (3H, s, OMe), 3.68 (3H, s, OMe), 3.04 (1H,

m, H-3A), 2.94 (1H, m, H-3B), 2.79 (1H, m, H-4A), 2.63 (1H, m, H-4B),

0

(CDCl₃, 100.6 MHz)

d 156.9 (C₂), 148.3 and 147.7 (C₆and C₇), 141.9

(C₅), 127.5 and 126.9 (C_4aand C_8a), 111.7 (C₅), 110.7 (C₈), 109.9 and

2.34 (3H, s, NMe). ¹³C NMR (CDCl₃,100.6 MHz)

d 155.1 (C₂),148.1 and

0

108.2 (C₃and C₄), 55.9 and 55.8 (OMeꢃ2), 54.0 (C₁), 40.3 (C₃), 28.8

(C₄). Anal. Calcd for C₁₅H₁₇NO₃: C, 69.48; H, 6.61; N, 5.40. Found: C,

69.51; H, 6.58; N, 5.42.

147.4 (C₆and C₇), 142.4 (C₅), 127.0 and 126.6 (C_4aand C_8a), 111.3

0

and 110.7 (C₅and C₈), 109.9 and 109.7 (C₃and C₄), 62.5 (C₁), 56.0 and

55.9 (OMeꢃ2), 50.1 (C₃), 43.6 (Me-2), 28.0 (C₄). Anal. Calcd for

C₁₆H₁₉NO₃: C, 70.31; H, 7.01; N, 5.12. Found: C, 70.28; H, 7.00; N, 5.11.

3.5. 1-(2⁰-Furyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline (3a),

1-(2⁰-furyl)-6,7-dimethoxy-2-methyl-1,2,3,4-

tetrahydroisoquinoline (3b)

3.6. 2-Acetyl-1-(2⁰-furyl)-1,2,3,4-tetrahydroisoquinoline (4a),

6,7-dimethoxy-2-acetyl-1-(2⁰-furyl)-1,2,3,4-

tetrahydroisoquinoline (4c). Typical procedure

Method A. To a solution of corresponding isoquinoline 1a,b

(1.9 mmol) in 35 mL of acetonitrile was added 0.12 mL (1.9 mmol)

of methyl iodide. The reaction mixture was stirred at room tem-

perature for 2 days (monitoring by TLC). At the end of the reaction

the solvent was evaporated. The residue was crystallized in ethyl

acetate to give intermediate N-methylisoquinoline iodides as yel-

low solids (yield 84%).

The corresponding tetrahydroisoquinoline 2a,b (0.014 mol) was

dissolved in 20 mL of acetic anhydride. The reaction mixture

was then reﬂuxed for 3 h. At the end of the reaction the mixture

was diluted with water (100 mL) and neutralized by saturated so-

lution of sodium carbonate (40 mL). Then the organic layer was

extracted with ethyl acetate (3ꢃ25 mL) and the extract was dried

over MgSO₄. After evaporation of the solvent, the residue was

chromatographed on Al₂O₃(1ꢃ45 cm, eluent: hexane).

Sodium borohydride 0.12 g (3.2 mmol) was slowly added to the

stirred solution of N-methy-3,4-dihydrolisoquinoline iodide

(1.6 mmol) in 30 mL of methanol at room temperature. The reaction

progress was monitored by TLC (until disappearance of the starting

compound’s spot). At the end of the reaction (36 h) the mixture was

poured into water (100 mL) and extracted with CH₂Cl₂(3ꢃ25 mL).

The organic layers were combined, dried (MgSO₄), and concen-

trated to give brown oil. The residue was puriﬁed by the column

chromatography on alumina (Al₂O₃, 45ꢃ1 cm), eluent: hexane,

then hexane–ethyl acetate (10:1, 5:1, 1:1) to give title compound 3.

Method B. Paraform 0.27 g (9.0 mmol) was added to a solution of

corresponding isoquinoline (9.0 mmol) in 20 mL of formic acid. The

reaction mixture was reﬂuxed for 4–6 h until the complete disso-

lution of paraformaldehyde. After the reaction mixture was cooled

an additional 1.08 g (0.036 mol) of paraform was added. The

resulted mixture was reﬂuxed additionally for 4–6 h. The formic

acid was removed under reduced pressure. The residue, brown oil,

was dissolved in ethyl acetate (50 mL) and washed with saturated

solution of sodium carbonate (2ꢃ20 mL). The organic layer was

separated, washed with water (2ꢃ20 mL), dried (MgSO₄), and

concentrated. The residue, brown oil, was puriﬁed by the column

chromatography on alumina (Al₂O₃, 45ꢃ1 cm), eluent: hexane,

3.6.1. Compound 4a

Yellow viscid oil, yield 2.33 g (69%); R_f(30% ethyl acetate–hex-

ane) 0.38; IR 1654 (NCO) cm^ꢂ1; EIMS (70 eV) m/z (rel intensity): M^þ

241 (41), 212 (40), 198 (18), 182 (16), 170 (67), 141 (37), 130 (25), 115

(48), 103 (16), 77 (23), 63 (17), 51 (23), 43 (100). ¹H NMR mixture of

two amide rotamers, data for major isomer (CDCl₃, 400 MHz)

d

7.32

0

(1H, dd, J_{5 ,3}0.8, J_{5 ,4}1.8 Hz, H-5 ), 7.16–7.25 (4H, m, C₆H₄), 6.84 (1H,

0

s, H-1), 6.26 (1H, dd, J_{4 ,5}1.8, J_{4 ,3}3.2 Hz, H-4 ), 6.03 (1H, dd, J_{3 ,5}0.8,

J_{3 ,4}3.2 Hz, H-3 ), 3.83 (1H, m, H-3A), 3.61 (1H, m, H-3B), 2.75–3.06

0

(2H, m, H-4), 2.19 (3H, s, MeCO). ¹³C NMR mixture of two amide

0

rotamers (CDCl₃, 100.6 MHz)

d

169.2 (COMe), 154.8 and 154.3 (C₂),

0

142.8 and 142.4 (C₅), 135.5 and 134.1 (C_4a), 126.2 and 126.5 (C₆),

129.4, 128.9, 128.5, 128.1, 127.8, 127.4 (C_5,7,8,8a), 110.2 and 110.1, 109.0

0

and 108.8 (C₃and C₄), 55.1 and 49.9 (C₁), 41.3 and 36.1 (C₃), 29.1

and 28.3 (C₄), 21.9 and 21.7 (COMe). Anal. Calcd for C₁₅H₁₅NO₂: C,

74.67; H, 6.27; N, 5.81. Found: C, 74.68; H, 6.25; N, 5.82.

3.6.2. Compound 4c

White large crystals, yield 3.12 g (74%); mp 122–124 ^ꢀC; R_f(ethyl

acetate) 0.46; IR 1649 (NCO) cm^ꢂ1; EIMS (70 eV) m/z (rel intensity):

3796

F.I. Zubkov et al. / Tetrahedron 65 (2009) 3789–3803

M^þ301 (19), 272 (22), 230 (10), 200 (10), 128 (9), 115 (17), 77 (12),

63 (10), 51 (13), 43 (100), 39 (15). ¹H NMR mixture of two amide

3.8. (8aS

hexahydro-6H-10,12a-epoxyisoindolo[1,2-a]isoquinoline-9-

carboxylic acid (5a), (8aS ,9R ,10S ,12aR ,12bR )-2,3-

*

,9R

*

,10S

*

,12aR

*

,12bR

*

)-8-Oxo-5,8,8a,9,10,12b-

rotamers, data for major isomer (CDCl₃, 400 MHz)

d

7.34 (1H, dd,

*

J_{5 ,3}0.8, J_{5 ,4}1.8 Hz, H-5⁰), 6.76 (1H, s, H-8), 6.65 (1H, s, H-5), 6.27

dimethoxy-8-oxo-5,8,8a,9,10,12b-hexahydro-6H-10,12a-

epoxyisoindolo[1,2-a]isoquinoline-9-carboxylic acid (5b),

0

(1H, dd, J_{4 ,5}1.8, J_{4 ,3}3.2 Hz, H-4⁰), 5.91 (1H, br dd, J_{3 ,5}0.8, J_{3 ,4}

0

3.2 Hz, H-3⁰), 5.91 (1H, s, H-1), 4.63 (1H, m, J_3A,3B14.1 Hz, H-3A),

3.87 (3H, s, OMe), 3.79 (3H, s, OMe), 3.54 (1H, m, J_3B,3A14.1 Hz, H-

3B), 2.91 (1H, m, H-4A), 2.77 (1H, m, H-4B), 2.18 (3H, s, COMe). ¹³C

(8aS

hexahydro-6H-10,12a-epoxyisoindolo[1,2-a]isoquinoline-9-

carboxylic acid (6a), (8aS ,9R ,10S ,12aR ,12bR )-9-methyl-2,3-

*

,9R

*

,10S

*

,12aR

*

,12bR

*

)-9-methyl-8-oxo-5,8,8a,9,10,12b-

*

NMR mixture of two amide rotamers (CDCl₃, 100.6 MHz)

d

169.2

dimethoxy-8-oxo-5,8,8a,9,10,12b-hexahydro-6H-10,12a-

epoxyisoindolo[1,2-a]isoquinoline-9-carboxylic acid (6b).

Typical procedure

0

and 168.7 (COMe), 154.7 and 154.2 (C₂), 148.5, 148.2,147.6, 147.8 (C₆

0

and C₇), 142.5 and 142.2 (C₅), 127.5, 126.1, 125.3, 124.1 (C_4aand C_8a),

0

111.4, 111.2, 110.9, 110.7, 110.0, 109.8, 108.8, 108.6 (C₅, C₈, C₃, C₄),

55.93, 55.87, 55.77 (OMeꢃ2), 54.4 and 49.2 (C₁), 40.9 and 35.6 (C₃),

28.4 and 27.6 (C₄), 21.7 and 21.4 (COMe). Anal. Calcd for C₁₇H₁₉NO:

C, 67.76; H, 6.36; N, 4.65. Found: C, 67.77; H, 6.35; N, 4.67.

The toluene (15 mL) solution of maleic anhydride (8.0 mmol) in

case of 5a,b or citraconic anhydride (8.0 mmol) in case of 6a,b was

added to the toluene solution (15 mL) of the corresponding tetra-

hydroisoquinoline 2a,b (7.10 mol). The reaction mixture was stirred

for 2–3 h at room temperature. At the end of the reaction toluene

was removed in vacuo, ether (10–20 mL) was added to the residue,

and the precipitate was ﬁltered off to give acids 5–6a,b as white

solids.

3.7. 2-Triﬂuoracetyl-1-(2⁰-furyl)-1,2,3,4-tetrahydro-

isoquinoline (4b), 6,7-dimethoxy-2-triﬂuoracetyl-1-(2⁰-furyl)-

1,2,3,4-tetrahydroisoquinoline (4d). Typical procedure

3.8.1. Compound 5a

The corresponding isoquinoline 2a,b (0.039 mol) was dissolved

in 50 mL of dichloromethane and then triethylamine (8.2 mL,

0.06 mol) was added in one portion to this solution. The resulted

mixture was ice-cooled and triﬂuoroacetic anhydride (7.0 mL,

0.05 mol) was added drop-wise. The reaction mixture was vigor-

ously stirred at room temperature for one day (TLC monitoring).

Then it was diluted with water (100 mL), neutralized by saturated

solution of sodium carbonate (15 mL), and then extracted with

dichloromethane (3ꢃ50 mL). The extract was dried over MgSO₄.

After solvent evaporation, the residue was crystallized in ether to

give isoquinolines 4a,b as white solids.

White powder, yield 1.96 g (97%); mp 219–221 ^ꢀC; IR 1657 (NCO)

and 1730 (CO₂H) cm^ꢂ1; EIMS (70 eV) m/z (rel intensity): M^þ297 (9),

279 (14), 251 (40), 224 (42), 198 (100), 184 (27), 170 (52), 132 (40),

103 (35), 76 (30), 54 (36), 43 (34). ¹H NMR (CDCl₃, 400 MHz)

d 12.05

(br s, CO₂H), 7.11–7.17 (4H, m, C₆H₄), 6.88 (1H, d, J_12,115.7 Hz, H-12),

6.45 (1H, dd, J_11,101.6, J_11,125.7 Hz, H-11), 5.44 (1H, br s, H-12b), 4.83

(1H, d, J_10,111.6 Hz, H-10), 4.00 (1H, ddd, J_6A,5B2.4, J_6A,5A5.7, J_6A,6B

12.9 Hz, H-6A), 3.01 (1H, m, H-6B), 2.97 (1H, br d, J_9endo,8a9.1 Hz, H-

9_endo), 2.71 (1H, m, H-5A), 2.60 (1H, m, H-5B), 2.48 (1H, d, J_8a,9endo

9.1 Hz, H-8a). ¹³C NMR (CDCl₃, 100.6 MHz)

d 173.3 (C₈), 169.6 (C–

CO₂H), 137.7 (C₁₁), 135.7 (C₁₂), 135.1 (C_4a), 132.9 (C_12c), 129.3 (C₄),

126.6–127.0 (C₁–C₃), 92.2 (C_12a), 81.2 (C₁₀), 56.3 (C_12b), 51.3 (C_8a),

45.5 (C₉), 36.9 (C₆), 28.7 (C₅). Anal. Calcd for C₁₇H₁₅NO₄: C, 68.68; H,

5.09; N, 4.71. Found: C, 68.90; H, 4.85; N, 4.48.

3.7.1. Compound 4b

Colourless oil, yield 8.81 g (77%); R_f(10% ethyl acetate–hexane)

0.85; IR 1692 (NCO) cm^ꢂ1; EIMS (70 eV) m/z (rel intensity): M^þ295

(100), 266 (69), 226 (14), 198 (49), 183 (17), 169 (19), 154 (16), 141

3.8.2. Compound 5b

(26), 115 (53), 77 (13). ¹H NMR (CDCl₃, 400 MHz)

d 7.38 (1H, dd, J_{5 ,3}

White powder, yield 2.18 g (90%); mp 230–232 ^ꢀC; IR 1677

(NCO) and 1715 (CO₂H) cm^ꢂ1; EIMS (70 eV) m/z (rel intensity): M^þ

357 (4), 258 (100), 244 (16), 228 (25), 187 (50), 141 (20), 76 (26), 54

0 0

0

0.8, J_{5 ,4}1.8 Hz, H-5 ), 7.16–7.30 (₀4H, m, C₆H₄), 6.73 (1H, s, H-1), 6.31

0

(1H, dd, J_{4 ,5}1.8, J_{4 ,3}2.6 Hz, H-4 ), 6.12 (1H, dd, J_{3 ,5}0.8, J_{3 ,4}2.6 Hz,

H-3⁰), 4.08 (1H, m, J_3A,3B12.7 Hz, H-3A), 3.67 (1H, m, J_3B,3A12.7 Hz,

H-3B), 3.10 (1H, m, H-4A), 2.92 (1H, m, H-4B). ¹³C NMR (CDCl₃,

(91), 43 (80). ¹H NMR (CDCl₃, 400 MHz)

d 7.93 (br s, CO₂H), 6.92 (1H,

d, J_12,115.7 Hz, H-12), 6.71 (1H, s, H-4), 6.65 (1H, s, H-1), 6.47 (1H, br

d, J_11,125.7 Hz, H-11), 5.35 (1H, br s, H-12b), 4.84 (1H, br s, H-10),

4.04 (1H, m, H-6A), 3.70 (3H, s, OMe), 3.64 (3H, s, OMe), 3.40 (1H, m,

H-6B), 2.98 (1H, br d, J_9endo,8a8.9 Hz, H-9_endo), 2.71 (1H, m, H-5A),

2.60 (1H, m, H-5B), 2.53 (1H, d, J_8a,9endo8.9 Hz, H-8a). ¹³C NMR

155.9 (q, ²J_C,F¼35.2 Hz, COCF₃), 153.0 (C₂), 143.2 (C₅),

0

100.6 MHz)

d

133.4 and 131.8 (C_4aand C_8a), 129.0, 128.4, 127.9, 126.8 (C_5,6,7,8),

1

0

116.6 (q, J_C,F¼288.0 Hz, COCF₃), 110.2 and 110.1 (C₃and C₄), 51.5

(C₁), 40.4 (br s, C₃), 29.2 (C₄). Anal. Calcd for C₁₅H₁₂F₃NO₂: C, 61.02;

H, 4.10; N, 4.74. Found: C, 61.11; H, 4.09; N, 4.79.

(CDCl₃, 100.6 MHz)

d 173.4 (C₈), 169.6 (CO₂H), 148.1 (C₂), 147.8 (C₃),

137.8 (C₁₁), 135.6 (C₁₂), 127.2 (C_4a), 124.4 (C_12c), 112.6 (C₄), 110.1 (C₁),

92.3 (C_12a), 81.2 (C₁₀), 56.1 and 56.0, 56.1 (C_12band C₂-OMe, C₃-

OMe), 51.3 (C_8a), 45.5 (C₉), 37.0 (C₆), 28.2 (C₅). Anal. Calcd for

C₁₉H₁₉NO₆: C, 63.86; H, 5.36; N, 3.92. Found: C, 63.59; H, 5.09; N,

4.20.

3.7.2. Compound 4d

White needle crystals, yield 9.88 g (71%); mp 106 ^ꢀC; R_f(15%

ethyl acetate–hexane) 0.29; IR 1698 (NCO) cm^ꢂ1; EIMS (70 eV) m/z

(rel intensity): M^þ355 (100), 326 (49), 311 (14), 286 (16), 258

(37), 243 (21), 199 (10), 128 (8), 115 (13), 77 (6). ¹H NMR (CDCl₃,

7.40 (1H, dd, J_{5 ,3}0.8, J_{5 ,4}1.8 Hz, H-5⁰), 6.73 (1H, s,

3.8.3. Compound 6a

0

400 MHz)

d

0

H-1), 6.66 (1H, s, H-8), 6.62 (1H, s, H-5), 6.33 (1H, dd, J_{4 ,5}1.8,

Regioisomer mixture 6Aa/6Ba 1.3:1 (according to ¹H NMR),

white powder, yield 1.46 g (69%); mp 178–182 ^ꢀC; IR (broad band)

1694 (NCO and CO₂H) cm^ꢂ1; EIMS (70 eV) m/z (rel intensity): M^þ

311 (4), 266 (7), 198 (73), 170 (45), 141 (31), 115 (61), 101 (19), 76

(36), 68 (100), 63 (35), 59 (64), 43 (38). ¹H NMR for major isomer A

J_{4 ,3}3.2 Hz, H-4⁰), 6.15 (1H, dd, J_{3 ,5}0.8, J_{3 ,4}3.2 Hz, H-3⁰), 4.04

(1H, m, J_3A,3B13.5 Hz, H-3A), 3.90 (3H, s, OMe), 3.82 (3H, s, OMe),

3.63 (1H, m, J_3B,3A13.5 Hz, H-3B), 3.06 (1H, m, H-4A), 2.85 (1H,

0

2

m, H-4B). ¹³C NMR (CDCl₃, 100.6 MHz)

d

155.6 (q, J_C,F¼35.2 Hz,

0

COCF₃), 153.0 (C₂), 148.8 and 148.0 (C₆and C₇), 143.1 (C₅), 125.5

and 123.5 (C_4aand C_8a), 119.4 (q, ¹J_C,F¼287.0 Hz, COCF₃), 111.2 and

(CDCl₃, 400 MHz) d 12.02 (br s, CO₂H), 7.13–7.19 (4H, m, C₆H₄), 6.92

(1H, d, J_12,115.7 Hz, H-12), 6.55 (1H, dd, J_11,101.8, J_11,125.7 Hz, H-11),

5.44 (1H, br s, H-12b), 4.76 (1H, d, J_10,111.8 Hz, H-10), 4.02 (1H, ddd,

J_6A,5B2.8, J_6A,5A6.0, J_6A,6B12.9 Hz, H-6A), 3.02 (1H, m, J_6B,5B3.9, J_6B,5A

11.2, J_6B,6A12.9 Hz, H-6B), 2.74 (1H, m, J_5A,6A6.0, J_5A,6B11.2, J_5,5

12.0 Hz, H-5A), 2.63 (1H, ddd, J_5B,6A2.8, J_5B,6B3.9, J_5,512.0 Hz, H-5B),

0

110.7 (C₅and C₈), 110.1 and 110.0 (C₃and C₄), 56.0 and 55.9

4

(OMeꢃ2), 51.1 (C₁), 40.2 (q, J_C,F¼4.5 Hz, C₃), 28.6 (C₄). Anal. Calcd

for C₁₇H₁₆F₃NO₄: C, 57.47; H, 4.54; N, 3.94. Found: C, 57.44; H,

4.55; N, 3.94.

F.I. Zubkov et al. / Tetrahedron 65 (2009) 3789–3803

3797

2.09 (1H, s, H-8a), 1.18 (3H, s, Me). ¹³C NMR for major isomer A

(CDCl₃, 100.6 MHz) 173.3 (C₈), 173.2 (CO₂H), 138.3 (C₁₁), 135.3

3.8, J_9,104.4, J_Me,97.1 Hz, H-9), 2.20 (d,1H, J_8a,12b0.8, J_8a,93.8 Hz, H-8a),

1.02 (3H, d, J_Me,97.1 Hz, Me). ¹³C NMR (CDCl₃,100.6 MHz)

173.0 (C₈),

d

(C_4a), 133.7 (C₁₂), 132.9 (C_12c), 129.3 (C₄), 126.6, 126.7, 127.0 (C₁, C₂,

C₃), 94.5 (C_12a), 80.7 (C₁₀), 57.26 (C₉), 54.9 (C_8a), 53.7 (C_12b), 36.9

(C₆), 28.7 (C₅), 21.7 (C₉-Me). Anal. Calcd for C₁₈H₁₇NO₄: C, 69.44; H,

5.50; N, 4.50. Found: C, 69.14; H, 5.72; N, 4.26.

136.0 (C₁₁), 134.7 (C_4a), 134.0 (C₁₂), 131.5 (C_12c), 129.3 (C₄), 126.0,

126.6, 127.2 (C₁, C₂, C₃), 93.1 (C_12a), 82.5 (C₁₀), 57.8 (C_12b), 56.1 (C_8a),

37.1 (C₆), 36.6 (C₉), 28.6 (C₅), 17.1 (Me). Anal. Calcd for C₁₇H₁₇NO₂: C,

76.38; H, 6.69; N, 5.01. Found: C, 76.62; H, 6.69; N, 5.01.

3.8.4. Compound 6b

3.9.2. Compound 7b

Regioisomer mixture 6Ab/6Bb 1.25:1 (according to ¹H NMR),

white powder, yield 2.47 g (98%); mp 189–192 ^ꢀC; IR (broad band)

1673 (NC]O) and 1738 (CO₂H) cm^ꢂ1; EIMS (70 eV) m/z (rel in-

tensity): [M^þꢂ46] 325 (2), 258 (81), 244 (36), 230 (67), 214 (30),

201 (58), 192 (47), 176 (38), 159 (35), 144 (34), 128 (33), 115 (60), 68

(100), 59 (83), 43 (86). ¹H NMR for major isomer A (CDCl₃,

White rhombic crystals, yield 0.44 g (23%); mp 149–151 ^ꢀC; R_f

(ethyl acetate) 0.57; IR 1682 (NCO) and 1611 (C]C) cm^ꢂ1; EIMS

(70 eV) m/z (rel intensity): M^þ327 (32), 298 (55), 270 (12), 258 (21),

244 (100), 115 (11), 69 (47), 41 (27). ¹H NMR (CDCl₃, 400 MHz)

d 6.75

(1H, d, J_12,115.7 Hz, H-12), 6.61 (1H, s, H-4), 6.59 (1H, s, H-1), 6.45 (1H,

dd, J_11,101.4, J_11,125.7 Hz, H-11), 5.28 (1H, br s, H-12b), 4.83 (1H, dd,

J_10,111.4, J_10,94.5 Hz, H-10), 4.38 (1H, ddd, J_6A,5B1.8, J_6A,5A5.6, J_6A,6B

12.7 Hz, H-6A), 3.83 (3H, s, OMe), 3.82 (3H, s, OMe), 3.02 (1H, m,

J_5A,6A5.6 Hz, H-5A), 2.88 (1H, m, J_5B,6A1.8 Hz, H-5B), 2.62 (1H, m, H-

6B), 2.62 (1H, ddd, J_9,8a3.7, J_9,104.5, J_Me,97.0 Hz, H-9), 2.18 (1H, br d,

J_8a,93.7 Hz, H-8a), 1.01 (3H, d, J_Me,97.0 Hz, Me). ¹³C NMR (CDCl₃,

400 MHz)

d 12.02 (br s, CO₂H), 6.98 (1H, d, J_12,115.7 Hz, H-12), 6.73

(1H, s, H-4), 6.70 (1H, s, H-1), 6.53 (1H, dd, J_11,101.8, J_11,125.7 Hz, H-

11), 5.44 (1H, br s, H-12b), 4.76 (1H, d, J_10,111.8 Hz, H-10), 4.04 (1H,

ddd, J_6A,5B2.6, J_6A,5A5.8, J_6A,6B12.7 Hz, H-6A), 3.72 (3H, s, OMe), 3.67

(3H, s, OMe), 2.95 (1H, dt, J_6B,5B4.0, J_6B,6A12.7 Hz, H-6B), 2.72 (1H,

m, J_5A,6A5.8 Hz, H-5A), 2.50 (1H, m, J_5B,6A2.6, J_5B,6B4.0 Hz, H-5B),

2.08 (1H, s, H-8a), 1.18 (3H, s, Me). ¹³C NMR for major isomers A

100.6 MHz) d 173.0 (C₈), 148.1 (C₂), 147.9 (C₃), 136.3 (C₁₁), 133.7 (C₁₂),

127.0 (C_4a), 131.5 (C_12c), 111.8 (C₄), 108.7 (C₁), 93.0 (C_12a), 82.4 (C₁₀),

56.1 (C_12b), 57.6, 55.8, and 55.9 (C_8a, C₂-OMe, and C₃-OMe), 37.1 (C₆),

36.6 (C₉), 28.1 (C₅), 17.1 (Me). Anal. Calcd for C₁₉H₂₁NO₄: C, 69.71; H,

6.47; N, 4.28. Found: C, 69.45; H, 6.25; N, 4.56.

(DMSO-d₆, 100.6 MHz)

d 172.6 and 172.3 (CO₂H and C₈), 147.8 and

147.5 (C₂and C₃), 137.7 and 133.0 (C₁₁and C₁₂), 127.2 and 124.0 (C_4a

and C_12c), 112.6 and 110.3 (C₁and C₄), 93.8 (C_12a), 80.0 (C₁₀), 56.5

(C_12b), 55.8 and 55.6 (OMeꢃ2), 54.1 and 53.4 (C_8aand C₉), 36.4 (C₆),

27.5 (C₅), 20.9 (Me-1). Anal. Calcd for C₂₀H₂₁NO₆: C, 64.68; H, 5.70;

N, 3.77. Found: C, 64.35; H, 5.48; N, 4.01.

3.9.3. Compound 8a

White rhombic crystals, yield 1.13 g (77%); mp 118–120 ^ꢀC; R_f

(ethyl acetate) 0.36; IR 1682 (NC]O) and 1619 (C]C) cm^ꢂ1; EIMS

(70 eV) m/z (rel intensity): M^þ253 (21), 224 (50), 185 (11), 141 (21),

115 (27), 94 (53), 85 (71), 76 (86), 66 (46), 55 (100), 42 (35). ¹H NMR

3.9. (8aS

tetrahydro-6H-10,12a-epoxyisoindolo[1,2-a]isoquinolin-

8(8aH)-one (7a), (8aS ,9S ,10S ,12aR ,12bR )-2,3-dimethoxy-9-

*

,9S

*

,10S

*

,12aR

*

,12bR

*

)-9-Methyl-5,9,10,12b-

*

(CDCl₃, 400 MHz) d 7.13–7.24 (4H, m, C₆H₄), 6.68 (1H, d, J_12,115.8 Hz,

methyl-5,9,10,12b-tetrahydro-6H-10,12a-epoxyisoindolo[1,2-

a]isoquinolin-8(8aH)-one (7b), (8aS,10R,12aR,12bR)-5,9,10,12b-

tetrahydro-6H-10,12a-epoxyisoindolo[1,2-a]isoquinolin-

H-12), 6.45 (1H, dd, J_11,101.7, J_11,125.8 Hz, H-11), 5.42 (1H, s, H-12b),

5.00 (1H, dd, J_10,9exo4.6, J_10,111.7 Hz, H-10), 4.37 (1H, ddd, J_6A,5A5.6,

J_6A,6B12.9, J_6A,5B2.4 Hz, H-6A), 3.09 (1H, m, J_6B,6A12.9 Hz, H-6B),

2.93 (1H, m, J_5A,6A5.6 Hz, H-5A), 2.74 (1H, m, J_5B,6A2.4 Hz, H-5B),

2.66 (1H, dd, J_8a,9exo3.5, J_8a,9endo8.8 Hz, H-8a), 2.23 (1H, ddd, J_9exo,8a

3.5, J_9exo,104.6, J_9exo,9endo11.8 Hz, H-9_exo), 1.61 (1H, dd, J_9endo,8a8.8,

8(8aH)-one (8a), (8aS

5,9,10,12b-tetrahydro-6H-10,12a-epoxyisoindolo[1,2-

a]isoquinolin-8(8aH)-one (8b), (8aS ,10R ,12aR ,12bR

methyl-5,9,10,12b-tetrahydro-6H-10,12a-epoxyisoindolo[1,2-

a]isoquinolin-8(8aH)-one (9a), (8aS ,10R ,12aR ,12bR )-2,3-

*

,10R

*

,12aR

*

,12bR

*

)-2,3-dimethoxy-

*

)-8a-

J_9endo,9exo11.8 Hz, H-9_endo). ¹³C NMR (CDCl₃, 100.6 MHz)

d 173.1 (C₈),

*

137.8 (C₁₁), 134.7 (C_4a), 132.8 (C₁₂), 131.6 (C_12c), 129.3 (C₄), 126.0,

126.7, 127.2 (C₁, C₂, C₃), 92.5 (C_12a), 79.0 (C₁₀), 57.8 (C_12b), 48.4 (C_8a),

37.2 (C₆), 28.6 (C₅), 28.2 (C₉). Anal. Calcd for C₁₆H₁₅NO₂: C, 75.87; H,

5.97; N, 5.53. Found: C, 75.52; H, 5.64; N, 5.26.

dimethoxy-8a-methyl-5,9,10,12b-tetrahydro-6H-10,12a-

epoxyisoindolo[1,2-a]isoquinolin-8(8aH)-one (9b). Typical

procedure

The corresponding isoquinoline 2a,b (w1.0 g, 3.90 mmol) was

dissolved in benzene (in case of 8a,b) or toluene (for 7a,b and 9a,b).

Triethylamine (1.1 mL, 7.80 mmol) was added in one portion to the

solution, then acryloyl chloride (0.47 mL, 5.80 mmol) in case of 8a,b

(crotonoyl chloride in case of 7a,b and methacryloyl chloride in

case of 9a,b) was rapidly added to the solution. The reaction mix-

ture was reﬂuxed for 10 h (TLC monitoring). At the end of the re-

action it was diluted with water (50 mL) and extracted with ethyl

acetate (4ꢃ30 mL). The extract was dried over MgSO₄and con-

centrated in vacuo. The residue solidiﬁed on standing and further

crystallization from hexane–ethyl acetate gave the corresponding

isoindoloisoquinolines 7–9a,b as white solids.

3.9.4. Compound 8b

White rhombic crystals, yield 1.02 g (56%); mp 140–142 ^ꢀC; R_f

(ethyl acetate) 0.42; IR 1715 (NC]O) and 1620 (C]C) cm^ꢂ1; EIMS

(70 eV) m/z (rel intensity): M^þ313 (54), 284 (100), 258 (20), 244

(64), 228 (7), 191 (11), 176 (13), 115 (7), 55 (16). ¹H NMR (CDCl₃,

400 MHz)

d 6.66 (1H, d, J_12,115.8 Hz, H-12), 6.60 (1H, s, H-4), 6.59

(1H, s, H-1), 6.45 (1H, dd, J_11,101.5, J_11,125.8 Hz, H-11), 5.35 (1H, br s,

H-12b), 5.00 (1H, dd, J_10,9exo4.4, J_10,111.5 Hz, H-10), 4.38 (1H, ddd,

J_6A,5A5.5, J_6A,6B12.6, J_6A,5B1.8 Hz, H-6A), 3.83 (3H, s, OMe), 3.81 (3H,

s, OMe), 3.03 (1H, dt, J_6B,6A12.6, J_6B,5B4.0 Hz, H-6B), 2.87 (1H, m,

J_5A,6A5.5 Hz, H-5A), 2.66 (1H, dd, J_8a,9endo8.8, J_8a,9exo3.6 Hz, H-8a),

2.64 (1H, m, J_5B,6A1.8, J_5B,6B4.0 Hz, H-5B), 2.22 (1H, ddd, J_9exo,8a3.6,

J_9exo,9endo11.8, J_9exo,104.4 Hz, H-9_exo), 1.60 (1H, dd, J_9endo,8a8.8,

3.9.1. Compound 7a

J_9endo,9exo11.8 Hz, H-9_endo). ¹³C NMR (CDCl₃, 100.6 MHz)

d 173.1 (C₈),

White rhombic crystals, yield 0.29 g (19%); mp 141–143 ^ꢀC; R_f

(ethyl acetate) 0.71; IR 1680 (NC]O) and 1615 (C]C) cm^ꢂ1; EIMS

(70 eV) m/z (rel intensity): M^þ267 (59), 238 (100), 210 (9), 198 (22),

184 (55), 170 (39), 141 (29), 115 (25), 69 (71). ¹H NMR (CDCl₃,

148.2 and 148.0 (C₂and C₃), 138.1 (C₁₁), 132.5 (C₁₂), 123.2 and 127.0

(C_4aand C_12c), 111.9 (C₄), 108.7 (C₁), 92.4 (C_12a), 79.0 (C₁₀), 57.6

(C_12b), 55.8 and 55.9 (OMeꢃ2), 48.4 (C_8a), 37.2 (C₆), 28.2 and 28.1

(C₉and C₅). Anal. Calcd for C₁₈H₁₉NO₄: C, 68.99; H, 6.11; N, 4.47.

Found: C, 68.70; H, 5.92; N, 4.25.

400 MHz)

d 7.16–7.26 (4H, m, C₆H₄), 6.89 (1H, d, J_12,115.8 Hz, H-12),

6.47 (1H, dd, J_11,101.5, J_11,125.8 Hz, H-11), 5.42 (1H, s, H-12b), 4.83 (1H,

dd, J_10,111.5, J_10,94.4 Hz, H-10), 4.38 (1H, ddd, J_6A,5B2.3, J_6A,5A5.8, J_6A,6B

12.9 Hz, H-6A), 3.08 (1H, m, J_5A,6A5.8 Hz, H-5A), 2.95 (1H, m, J_5B,6A

2.3 Hz, H-5B), 2.75 (1H, dt, J_6B,6A12.9 Hz, H-6B), 2.64 (1H, ddq, J_9,8a

3.9.5. Compound 9a

White rhombic crystals, yield 0.94 g (61%); mp 160–162 ^ꢀC; R_f

(ethyl acetate) 0.70; IR (broad band) 1675 (NC]O) cm^ꢂ1; EIMS

3798

F.I. Zubkov et al. / Tetrahedron 65 (2009) 3789–3803

(70 eV) m/z (rel intensity): M^þ267 (100), 238 (50), 224 (26), 210

(C₁₂), 135.0 (C_4a), 134.8 (C₁₁), 131.2 (C_12c), 129.4 (C₄),125.9,126.6,127.3

(C₁, C₂, C₃), 92.0 (C_12a), 81.3 (C₁₀), 57.0 (C_12b), 52.1 (C_8a), 51.8 (OMe),

45.3 (C₉), 37.4 (C₆), 28.8 (C₅). Anal. Calcd for C₁₈H₁₇NO₄: C, 69.44; H,

5.50; N, 4.50. Found: C, 69.78; H, 5.23; N, 4.25.

(20), 199 (40), 183 (37), 168 (23), 141 (46), 130 (42), 115 (30), 69 (48),

59 (29), 43 (38). ¹H NMR (CDCl₃, 400 MHz)

d 7.16–7.26 (4H, m,

C₆H₄), 6.68 (1H, d, J_12,115.9 Hz, H-12), 6.52 (1H, dd, J_11,101.5, J_11,12

5.9 Hz, H-11), 5.34 (1H, s, H-12b), 4.90 (1H, dd, J_10,9exo4.9, J_10,11

1.5 Hz, H-10), 4.38 (1H, ddd, J_6A,5A5.6, J_6A,6B12.7, J_6A,5B2.3 Hz,

H-6A), 3.11 (1H, br dt, J_6B,6A12.7, J_6B,5A11.6, J_6B,5B3.8 Hz, H-6B), 2.94

(1H, m, J_5A,6A5.6, J_5A,5B15.6, J_5A,6B11.6 Hz, H-5A), 2.75 (1H, ddd,

J_5B,6A2.3, J_5B,5A15.6, J_5B,6B3.8 Hz, H-5B), 2.50 (1H, dd, J_9exo,104.9,

J_9exo,9endo11.8 Hz, H-9_exo), 1.20 (3H, br s, Me), 1.15 (1H, d, J_9endo,9exo

3.10.2. Compound 10b

White powder, yield 1.69 g (91%); mp 162–164 ^ꢀC; IR 1691

(NC]O) and 1738 (CO₂Me) cm^ꢂ1; EIMS (70 eV) m/z (rel intensity):

M

^þ371 (8), 339 (6), 310 (20), 258 (100), 243 (13), 176 (18), 144 (30),

113 (60), 84 (95), 59 (98), 43 (50). ¹H NMR (CDCl₃, 400 MHz)

d 6.77

11.8 Hz, H-9_endo). ¹³C NMR (CDCl₃, 100.6 MHz)

d

177.1 (C₈), 138.1

(1H, d, J_12,115.8 Hz, H-12), 6.61 (1H, s, H-4), 6.58 (1H, s, H-1), 6.52 (1H,

dd, J_11,101.7, J_11,125.8 Hz, H-11), 5.33 (1H, br s, H-12b), 5.12 (1H, d, J_10,11

1.7 Hz, H-10), 4.34 (1H, ddd, J_5A,5A5.6, J_6A,5B3.4, J_6A,6B12.8 Hz, H-6A),

3.83 (3H, s, OMe), 3.81 (3H, s, OMe), 3.75 (3H, s, H-CO₂Me), 3.03 (1H,

m, J_5A,6A5.6 Hz, H-5A), 3.00 (1H, d, J_9endo,8a9.1 Hz, H-9_endo), 2.90 (1H,

m, H-5B), 2.75 (1H, d, J_8a,9endo9.1 Hz, H-8a), 2.64 (1H, m, J_6B,6A12.8,

(C₁₁), 135.0 (C_4a), 131.7 (C_12c), 131.3 (C₁₂), 129.3 (C₄), 126.0, 126.7,

127.2 (C₁, C₂, C₃), 94.7 (C_12a), 78.8 (C₁₀), 56.4 (C_12b), 53.4 (C_8a), 37.2

(C₆), 36.4 (C₉), 28.74 (C₅), 20.4 (Me). Anal. Calcd for C₁₇H₁₇NO₂: C,

76.38; H, 6.41; N, 5.24. Found: C, 76.15; H, 6.65; N, 5.51.

3.9.6. Compound 9b

J_6B,5B3.6 Hz, H-6B). ¹³C NMR (CDCl₃, 100.6 MHz)

d 172.1 (C₈), 169.6

White rhombic crystals, yield 1.44 g (76%); mp 59–61 ^ꢀC; R_f(50%

ethyl acetate–hexane) 0.52; IR 1686 (NCO) cm^ꢂ1; EIMS (70 eV) m/z

(rel intensity): M^þ327 (100), 312 (24), 298 (57), 284 (15), 258 (47),

(CO₂Me), 148.3 (C₃), 147.9 (C₂), 138.0 (C₁₂), 134.6 (C₁₁), 127.3 (C_12c),

122.8 (C_4a), 111.9 (C₄), 108.7 (C₁), 92.0 (C_12a), 81.3 (C₁₀), 56.8 (C_12b),

55.9 and 56.0 (C₂-OMe and C₃-OMe), 52.1 (C_8a), 51.7 (CO₂Me), 45.3

(C₉), 37.4 (C₆), 28.3 (C₅). Anal. Calcd for C₂₀H₂₁NO₆: C, 64.68; H, 5.70;

N, 3.77. Found: C, 64.41; H, 5.42; N, 3.55.

244 (21), 69 (34). ¹H NMR (CDCl₃, 400 MHz)

d 6.67 (1H, d, J_12,11

5.8 Hz, H-12), 6.63 (1H, s, H-4), 6.62 (1H, s, H-1), 6.53 (1H, dd, J_11,10

1.7, J_11,125.8 Hz, H-11), 5.28 (1H, br s, H-12b), 4.91 (1H, dd, J_10,9exo

4.8, J_10,111.7 Hz, H-10), 4.38 (1H, ddd, J_6A,5A5.7, J_6A,6B13.1, J_6A,5B

2.1 Hz, H-6A), 3.85 (3H, s, OMe), 3.84 (3H, s, OMe), 3.03 (1H, m,

J_5A,6A5.7 Hz, H-5A), 2.89 (1H, m, H-5B), 2.65 (1H, m, H-6B), 2.50

(1H, dd, J_9exo,9endo11.8, J_9exo,104.8 Hz, H-9_exo), 1.19 (3H, s, Me), 1.15

(1H, d, J_9endo,9exo11.8 Hz, H-9_endo). ¹³C NMR (CDCl₃, 100.6 MHz)

3.10.3. Compound 11a

White powder, yield 0.49 g (30%); mp 172–174 ^ꢀC; IR 1690

(NC]O), 1740 (CO₂Me) cm^ꢂ1; EIMS (70 eV) m/z (rel intensity): M^þ

325 (3), 296 (5), 266 (15), 198 (100), 168 (14), 141 (37), 130 (29), 115

(23), 84 (48), 69 (45), 59 (61), 43 (42). ¹H NMR (CDCl₃, 400 MHz)

d

177.0 (C₈), 148.1 (C₂), 147.9 (C₃), 138.4 (C₁₁), 130.9 (C₁₂), 127.2 (C_4a),

d 7.16–7.25 (4H, m, C₆H₄), 6.85 (1H, d, J_12,115.8 Hz, H-12), 6.57 (dd,

123.2 (C_12c), 111.8 (C₄), 108.6 (C₁), 94.6 (C_12a), 78.7 (C₁₀), 56.2 (C_12b),

55.8 and 55.8 (C₂-OMe and C₃-OMe), 53.4 (C_8a), 37.2 (C₆), 36.4 (C₉),

28.2 (C₅), 20.4 (Me₈). Anal. Calcd for C₁₉H₂₁NO₄: C, 69.71; H, 6.47; N,

4.28. Found: C, 69.48; H, 4.85; N, 4.02.

1H, J_11,101.8, J_11,125.8 Hz, H-11), 5.36 (1H, s, H-12b), 4.99 (1H, d, J_10,11

1.8 Hz, H-10), 4.35 (ddd, 1H, J_6A,5A5.5, J_6A,5B2.5, J_6A,6B12.8 Hz, H-

6A), 3.73 (3H, s, CO₂Me), 2.96 (1H, m, J_5A,6A5.5 Hz, H-6B), 2.76 (1H,

m, H-5A), 2.55 (1H, m, H-5B), 1.91 (1H, s, H-9), 1.30 (3H, s, Me-8a).

¹³C NMR (CDCl₃, 100.6 MHz)

d 173.7 (C₈), 172.4 (CO₂Me), 138.1 (C₁₁),

3.10. Methyl (8aS

hexahydro-6H-10,12a-epoxyisoindolo[1,2-a]isoquinoline-9-

carboxylate (10a), methyl (8aS ,9R ,10S ,12aR ,12bR )-2,3-

*

,9R

*

,10S

*

,12aR

*

,12bR

*

)-8-oxo-5,8,8a,9,10,12b-

135.2 (C_4a),133.0 (C₁₂),131.3 (C_12c),129.3 (C₄),125.9,126.6,127.3 (C₁,

C₂, C₃), 92.4 (C_12a), 80.6 (C₁₀), 57.7 (C_8a), 55.7 (C_12b), 53.5 (C_9a), 52.1

(CO₂Me), 37.3 (C₆), 28.8 (C₅), 21.3 (Me_8a). Anal. Calcd for C₁₉H₁₉NO₄:

C, 70.14; H, 5.89; N, 4.31. Found: C, 70.38; H, 5.64; N, 4.53.

*

dimethoxy-8-oxo-5,8,8a,9,10,12b-hexahydro-6H-10,12a-

epoxyisoindolo[1,2-a]isoquinoline-9-carboxylate (10b),

methyl (8aS

*

,9R

*

,10S

*

,12aR

*

,12bR

*

)-9-methyl-8-oxo-

3.10.4. Compound 11b

5,8,8a,9,10,12b-hexahydro-6H-10,12a-epoxyisoindolo[1,2-

a]isoquinoline-9-carboxylate (11a), methyl

White powder, yield 0.90 g (45%); mp 154–156 ^ꢀC; IR 1697 (NCO),

1737 (CO₂Me) cm^ꢂ1; EIMS (70 eV) m/z (rel intensity): M^þ385 (10),

(8aS

*

,9R

*

,10S

*

,12aR

*

,12bR

*

)-9-methyl-2,3-dimethoxy-8-oxo-

326 (14), 258 (100), 242 (16), 214 (13), 127 (37), 84 (34), 59 (35), 43

1

5,8,8a,9,10,12b-hexahydro-6H-10,12a-epoxyisoindolo[1,2-

a]isoquinoline-9-carboxylate (11b). Typical procedure

(27). H NMR (CDCl₃, 400 MHz)

d

6.70 (1H, d, J 5.8 Hz, H-12), 6.57

(1H, s, H-4), 6.54 (1H, s, H-1), 6.54 (1H, dd, J 5.8, J_10,111.8 Hz, H-11),

5.17 (1H, br s, H-12b), 4.96 (1H, d, J_10,111.8 Hz, H-10), 4.25 (1H, ddd,

J_6A,6B12.5, J_5A,6A5.4, J_5B,6A2.3 Hz, H-6A), 3.76 (3H, s, OMe-3), 3.71

(3H, s, CO₂Me), 3.78 (3H, s, OMe-2), 2.96 (1H, ddd, J_6A,6B12.5, J_5A,6B

11.6, J_5B,6B3.6 Hz, H-6B), 2.84 (1H, ddd, J 15.3, J_5A,6B11.6, J_5A,6A5.4 Hz,

H-5A), 2.57 (1H, dt, J_5A,5B15.3, J_5B,6B3.0, J_5B,6A3.0 Hz, H-5B), 1.89 (1H,

Adduct 5–6a,b (5.0 mmol) was then reﬂuxed in methanol

(20 mL) for 8 h in the presence of catalytic amount of concentrated

H₂SO₄. Then the reaction mixture was poured into 150 mL of water

and extracted with chloroform (3ꢃ70 mL). The extract was dried

over MgSO₄and concentrated in vacuo. The crude product was

recrystallized from mixture of hexane–ethyl acetate to give esters

10–11a,b as white solids.

s, H-9), 1.28 (3H, s, Me-8a). ¹³C NMR (CDCl₃, 100.6 MHz)

d 173.4 and

172.1 (s, C₈and 9-CO), 148.0 and 147.6 (s, C₂and C₃), 138.1 (d, J

177.5 Hz, C₁₁), 132.5 (d, J 176.5 Hz, C₁₂), 127.2 and 122.5 (s, C_4aand

C_12c),111.7 (d, J 156.2 Hz, C₄),108.3 (d, J 154.7 Hz, C₁), 94.1 (s, C_12a), 8.3

(d, J 168.5 Hz, C₁₀), 57.5 (s, C_8a), 55.7 and 55.6 (q, J 144.5 Hz, C₂-OMe

and C₃-OMe), 55.2 (d, J 139.5 Hz, C_12b), 53.2 (d, J 138.0 Hz, C_9a), 51.8

(q, J 146.5 Hz, CO₂Me), 37.0 (t, J 142.0 Hz, C₆), 28.0 (t, J 129.5 Hz, C₅),

21.0 (q, J 129.0 Hz, Me_8a). Anal. Calcd for C₂₁H₂₃NO₆: C, 65.44; H,

6.02; N, 3.63. Found: C, 65.68; H, 5.82; N, 3.40.

3.10.1. Compound 10a

White powder, yield 1.50 g (96%); mp 199–201 ^ꢀC; IR 1701

(NC]O) and 1724 (CO₂Me) cm^ꢂ1; EIMS (70 eV) m/z (rel intensity):

M

^þ311 (10), 280 (10), 251 (45), 223 (25), 198 (100), 168 (17), 141 (26),

130 (45), 115 (60), 84 (15), 55 (64), 43 (32). ¹H NMR (CDCl₃, 400 MHz)

7.13–7.23 (4H, m, C₆H₄), 6.76 (1H, d, J_12,115.7 Hz, H-12), 6.50 (1H, dd,

d

J_11,101.6, J_11,125.7 Hz, H-11), 5.38 (1H, s, H-12b), 5.10 (1H, d, J_10,111.6 Hz,

H-10), 4.31 (1H, ddd, J_6A,6B12.7, J_6A,5A5.4, J_6A,5B2.9 Hz, H-6A), 3.75

(3H, s, CO₂Me), 3.06 (1H, m, J_6B,6A12.7 Hz, H-6B), 2.99 (1H, br d,

J_9endo,8a9.2 Hz, H-9_endo), 2.95 (1H, m, J_5A,5B15.6, J_5A,6A5.4 Hz, H-5A),

2.75 (1H, d, J_8a,9endo9.2 Hz, H-8a), 2.72 (1H, dt, J_5B,5A15.6, J_5B,6A2.9 Hz,

3.11. Dimethyl 6-(2⁰-furyl)-3-methyl-1,2,3,6-tetrahydro-3-

benzoazocine-4,5-dicarboxylate (12a)

Isoquinoline 3a (2.78 g, 0.013 mol) was dissolved in 50 mL of

acetonitrile and then DMAD (1.76 mL, 0.014 mol) was added in one

portion to the solution. The reaction mixture was stirred at room

H-5B). ¹³C NMR (CDCl₃, 100.6 MHz)

d 172.2 (C₈), 169.6 (CO₂Me), 137.7

F.I. Zubkov et al. / Tetrahedron 65 (2009) 3789–3803

3799

temperature for 7–10 days (TLC monitoring). After removal of the

solvent and recrystallization from mixture of hexane–ethyl acetate

benzoazocine 12a was obtained as white crystals.

(70 eV) m/z (rel intensity): M^þ297 (100), 266 (17), 238 (84), 210

(22), 194 (25), 180 (24), 165 (28), 152 (17), 128 (38), 115 (15), 81 (8),

42 (19). ¹H NMR (CDCl₃, 400 MHz)

d

7.62 (1H, s, H-4), 7.33 (1H, s, H-

0

7), 7.31 (1H, dd, J_{5 ,3}0.8, J_{5 ,4}1.8 Hz, H-5 ), 7.20–7.23 (3H, m, H-8, 9,

0

0 0 0 0

and 10), 6.30 (1H, dd, J_{4 ,3}3.1, J_{4 ,5}1.8 Hz, H-4 ), 5.99 (1H, br s, H-6),

3.11.1. Compound 12a

White cubic crystals, yield 3.05 g (66%), mp 138 ^ꢀC, R_f(20% ethyl

acetate–hexane) 0.37; IR 1738 and 1679 (CO₂Me) cm^ꢂ1; EIMS (70 eV)

m/z (rel intensity): M^þ355 (69), 323 (24), 296 (72), 266 (24), 236

(100), 208 (13), 181 (18), 165 (27), 152 (19), 141 (12), 115 (19), 58 (26).

5.86 (1H, dd, J_{3 ,4}3.1, J_{3 ,5}0.8 Hz, H-3⁰), 3.75 (3H, s, CO₂Me), 3.65

(1H, ddd, J_2A,1B6.3, J_2A,1A12.0, J_2A,2B17.9 Hz, H-2A), 3.08 (1H, m,

J_2B,1B2.6, J_2B,2A17.9 Hz, H-2B), 3.08 (1H, m, J_1A,1B15.0, J_1A,2A12.0 Hz,

H-1A), 2.94 (3H, s, NMe), 2.92 (1H, ddd, J_1B,1A15.0, J_1B,2A6.3, J_1B,2B

0

¹H NMR (CDCl₃, 400 MHz)

d

7.31 (1H, dd, J_7,87.3, J_7,91.6 Hz, H-7), 7.26

2.6 Hz, H-1B). ¹³C NMR (CDCl₃, 100.6 MHz)

(C₂), 153.6 (C₄), 140.8 (C₅), 138.5 (C_6a), 136.8 (C_10a), 133.1 (C₁₀), 131.9

(C₇), 127.3 (C₈), 126.9 (C₉), 110.7 (C₃), 103.9 (C₄), 96.2 (C₅), 51.42

(CO₂Me), 51.1 (C₂), 45.0 (NMe), 43.94 (C₆), 36.6 (C₁). Anal. Calcd for

C₁₈H₁₉NO₃: C, 72.71; H, 6.44; N, 4.71. Found: C, 72.83; H, 6.40; N,

4.69.

d

170.4 (CO₂Me), 159.1

(1H, dd, J_{5 ,3}0.9, J_{5 ,4}1.9 Hz, H-5⁰), 7.22 (1H, dt, J_9,71.6,

J_9.8¼J_9,10¼7.3 Hz, H-9), 7.20 (1H, dt, J_8.9¼J_8.9¼7.3, J_8,101.6 Hz, H-8), 7.12

0

(1H, br d, J_10,81.6, J_10,97.3 Hz, H-10), 6.27 (1H, dd, J_{4 ,3}3.2, J_{4 ,5}1.9 Hz,

H-4⁰), 5.90 (1H, s, H-6), 5.89 (1H, dd, J_{3 ,4}3.2, J_{3 ,5}0.9 Hz, H-3⁰), 3.76

(3H, s, CO₂Me), 3.71 (3H, s, CO₂Me), 3.59 (1H, ddd, J_2A,1A11.6, J_2A,1B6.5,

J_2A,2B15.1 Hz, H-2A), 3.19 (1H, ddd, J_2B,1A7.8, J_2B,1B1.6, J_2B,2A15.1 Hz, H-

2B), 2.96 (1H, ddd, J_1A,1B15.9, J_1A,2A11.6, J_1A,2B7.8 Hz, H-1A), 2.81 (1H,

0

3.14. Methyl 6-(2⁰-furyl)-8,9-dimethoxy-3-methyl-1,2,3,6-

tetrahydro-3-benzoazocine-5-carboxylate (13b)

ddd, J_1B,1A15.9, J_1B,2A6.5, J_1B,2B1.6 Hz, H-1B), 2.53 (3H, s, NMe). ¹³

C

0

NMR (CDCl₃, 100.6 MHz)

d

167.0 and 169.3 (CO₂Meꢃ2), 157.1 (C₂),

0

155.9 (C₄), 141.0 (C₅), 137.4 (C_6a), 137.2 (C_10a), 133.2 (C₁₀), 131.1 (C₇),

Isoquinoline 3b (1.92 g, 7.0 mmol) was dissolved in 50 mL of

acetonitrile. Then the methyl propiolate (0.70 mL, 7.8 mmol) was

added in one portion to the solution. The reaction mixture was

stirred at room temperature for 10–12 days (TLC monitoring). After

removal of the solvent and recrystallization from mixture of hex-

ane–ethyl acetate benzoazocine 13b was obtained as white crystals.

0

127.5 (C₈), 127.4 (C₉), 110.5 (C₃), 105.0 (C₄), 101.9 (C₅), 55.0 (C₂), 51.9

and 52.6 (CO₂Meꢃ2), 47.0 (NMe), 38.0 (C₆), 34.4 (C₁). Anal. Calcd for

C₂₀H₂₁NO₅: C, 67.59; H, 5.96; N, 3.94. Found: C, 67.70; H, 5.95; N, 3.93.

3.12. Dimethyl 6-(2⁰-furyl)-8,9-dimethoxy-3-methyl-1,2,3,6-

tetrahydro-3-benzoazocine-4,5-dicarboxylate (12b)

3.14.1. Compound 13b

Isoquinoline 3b (0.33 g, 1.20 mmol) was dissolved in 30 mL of

acetonitrile and 0.15 mL (1.20 mmol) of DMAD was added in one

portion to the solution. The reaction mixture was stirred at room

temperature for 7–10 days (monitoring by TLC). After removal of

the solvent and recrystallization from mixture of hexane–ethyl

acetate benzoazocine 12b was obtained as white crystals.

White rhombuses, yield 1.81 g (72%), mp 126–128 ^ꢀC, R_f(50%

ethyl acetate–hexane) 0.42; IR 1671 (CO₂Me) and 1610 (C]C) cm^ꢂ1

;

EIMS (70 eV) m/z (rel intensity): M^þ357 (100), 342 (15), 326 (13),

314 (10), 298 (89), 282 (10), 270 (14), 255 (17), 243 (25), 212 (11), 164

(22), 128 (15), 42 (13). ¹H NMR (CDCl₃, 400 MHz)

d 7.61 (1H, s, H-4),

0

7.30 (1H, dd, J_{5 ,3}0.7, J_{5 ,4}1.8 Hz, H-5 ), 6.78 ₀(1H, s, H-10), 6.66 (1H, s,

0

H-7), 6.27 (1H, dd, J_{4 ,3}3.0, J_{4 ,5}1.8 Hz, H-4 ), 5.85 (1H, s, H-6), 5.82

(1H, dd, J_{3 ,4}3.0, J_{3 ,5}0.7 Hz, H-3⁰), 3.90 (3H, s, OMe), 3.88 (3H, s,

0

3.12.1. Compound 12b

White cubic crystals, yield 0.30 g (60%), mp 138–140 ^ꢀC, R_f(50%

ethyl acetate–hexane) 0.40; IR 1729 and 1685 (CO₂Me) cm^ꢂ1; EIMS

(70 eV) m/z (rel intensity): M^þ415 (15), 358 (32), 326 (10), 296 (9),

243 (9), 229 (8), 197 (14), 181 (14), 164 (22), 151 (24), 58 (100), 42 (12).

OMe), 3.74 (3H, s, CO₂Me), 3.59 (1H, m, H-2A), 3.00 (2H, m, H-1), 2.96

(3H, s, NMe), 2.88 (1H, m, H-1B). ¹³C NMR (CDCl₃, 100.6 MHz)

d

170.5

0

(CO₂Me),159.2 (C₂),153.4 (C₄),147.5 (C₈), 147.2 (C₉),140.8 (C₅),130.7

0

(C_6a), 128.7 (C_10a), 116.1 (C₁₀), 115.0 (C₇), 110.6 (C₃), 103.9 (C₄), 96.3

(C₅), 55.9 and 55.9 (OMeꢃ2), 51.4 (CO₂Me), 51.0 (C₂), 44.5 (NMe),

43.9 (C₆), 36.3 (C₁). Anal. Calcd for C₂₀H₂₃NO₅: C, 67.21; H, 6.49; N,

3.92. Found: C, 67.20; H, 6.47; N, 3.89.

¹H NMR (CDCl₃, 400 MHz)

7.28 (1H, dd, J_{5 ,3}0.8, J_{5 ,4}1.8 Hz, H-5⁰),

0 0 0 0

d

0

6.81 (1H, s, H-10), 6.62 (1H, s, H-7), 6.28 (1H, dd, J_{4 ,3}3.2, J_{4 ,5}1.8 Hz,

H-4⁰), 5.90 (1H, dd, J_{3 ,4}3.2, J_{3 ,5}0.8 Hz, H-3⁰), 5.82 (1H, s, H-6), 3.90

(3H, s, OMe), 3.88 (3H, s, OMe), 3.79 (3H, s, CO₂Me), 3.73 (3H, s,

CO₂Me), 3.56 (1H, m, J_2A,1B6.0, J_2A,2B15.2 Hz, H-2A), 3.19 (1H, ddd,

J_2B,1A7.6, J_2B,1B1.8, J_2B,2A15.2 Hz, H-2B), 2.90 (1H, m, J_1A,1B16.2, J_1A,2B

7.6 Hz, H-1A), 2.79 (1H, ddd, J_1B,1A16.2, J_1B,2A6.0, J_1B,2B1.8 Hz, H-1B),

0

3.15. Dimethyl (2E)-2-[1-(2-furyl)-3,4-dihydroisoquinolin-

2(1H)-yl]but-2-enedioate (14a), dimethyl (2E)-2-[1-(2-furyl)-

6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl]but-2-

enedioate (14b). Typical procedure

2.53 (3H, s, NMe). ¹³C NMR (CDCl₃, 100.6 MHz)

d

167.0 and 169.4

0

(CO₂Meꢃ2), 157.2 (C₂), 155.8 (C₄), 147.7 (C₈), 147.6 (C₉), 141.0 (C₅),

0

129.4 (C_6a), 129.2 (C_10a), 116.2 (C₁₀), 114.2 (C₇), 110.5 (C₃), 104.9 (C₄),

101.9 (C₅), 55.9 and 56.0 (OMeꢃ2), 55.0 (C₂), 51.9 and 52.6

(CO₂Meꢃ2), 46.7 (NMe), 38.1 (C₆), 34.1 (C₁). Anal. Calcd for

C₂₂H₂₅NO₇: C, 63.60; H, 6.07; N, 3.37. Found: C, 63.60; H, 6.09; N, 3.38.

Acetylenedicarboxylic ester (DMAD) (5 mL, 0.04 mol) was

added to a solution of isoquinolines 2a,b (0.01 mol) in 30 mL of

toluene. The resulted mixture was boiled for 2–6 h. The reaction

progress was monitored by TLC (until disappearance of the starting

compound). At the end of the reaction the mixture was cooled and

the solvent was evaporated. The residue was puriﬁed by column

chromatography on alumina (eluent ethyl acetate–hexane 1:10) to

give white crystals of isoquinolines 14a,b.

3.13. Methyl 6-(2⁰-furyl)-3-methyl-1,2,3,6-tetrahydro-3-

benzoazocine-5-carboxylate (13a)

Isoquinoline 3a (2.22 g, 0.01 mol) was dissolved in 50 mL of ace-

tonitrile. Thenmethyl propiolate(0.93 mL, 0.01 mol)was addedinone

portion to the solution. The reaction mixture was stirred at room

temperaturefor10–12days(monitoringbyTLC). Afterremovingofthe

solvent, residuewas chromatographed onAl₂O₃(eluent: hexane, ethyl

acetate–hexane 1:10) to give benzoazocine 13a as white crystals.

3.15.1. Compound 14a

White plates, yield 2.54 g (72%), mp 97–99 ^ꢀC, R_f(25% ethyl ac-

etate–hexane) 0.47; IR 1700 and 1747 (CO₂Me) cm^ꢂ1; EIMS (70 eV)

m/z (rel intensity): M^þ341 (13), 310 (15), 282 (100), 250 (15), 222

(48), 210 (6), 198 (8), 141 (17), 115 (13). ¹H NMR (CDCl₃, 400 MHz)

00 00

d

7.34 (1H, br d, J_{5 ,4}1.8 Hz, H-5⁰⁰), 7.12–7.23 (4H, m, H–Ar), 6.27

(1H, dd, J_{4 ,3}3.2, J_{4 ,5}1.8 Hz, H-4⁰⁰), 6.06 (1H, dd, J_{3 ,4}3.2, J_{3 ,5}

0.8 Hz, H-3⁰⁰), 5.64 (1H, s, H-1), 5.01 (1H, s, H-3⁰), 3.63 and 3.94 (3H,

s, OMe), 3.42–3.59 (2H, m, H-3), 3.06 (1H, m, H-4A), 2.83 (1H, m,

00 00

3.13.1. Compound 13a

White rhombuses, yield 2.08 g (70%), mp 84–86 ^ꢀC, R_f(20% ethyl

acetate–hexane) 0.30; IR 1678 (CO₂Me), 1615 (C]C) cm^ꢂ1; EIMS

3800

F.I. Zubkov et al. / Tetrahedron 65 (2009) 3789–3803

H-4B). ¹³C NMR (CDCl₃, 100.6 MHz)

d

168.2 (C₄in CO₂Me), 165.9

(12), 318 (16), 280 (23), 248 (15), 228 (100), 130 (21), 115 (38), 69

(14), 57 (9). ¹H NMR (CDCl₃, 400 MHz) complicated spectrum

(mixture of two isomers in the ratio w3:1), all data cite the major

0

00

(CO₂Me-2 ), 152.9 and 153.6 (C₂, C₂), 142.8 (C₅), 132.8 and 134.1

00

(C_4a, C_8a),126.5,127.8,127.8, and 128.8 (C₅,C₆, C₇, and C₈),110.2 (C₃),

00

0

109.0 (C₄), 86.0 (C₃), 55.9 (C₁), 53.9 and 53.0 (OMeꢃ2), 43.2 (C₃),

28.3 (C₄). Anal. Calcd for C₁₉H₁₉NO₅: C, 66.85; H, 5.61; N, 4.10.

Found: C, 66.63; H, 5.45; N, 3.99.

isomer

d

7.30 (1H, d, J_{6 ,5}5.2 Hz,₀H-6), 7.14–7.27 (4H, m, H–Ar), 7.10

0

(1H, dd, J_{5 ,4}2.0, J_{6 ,5}5.2 Hz, H-5 ), 6.47 (1H, s, H-1), 5.70 (1H, d, J_{4 ,5}

2.0 Hz, H-4⁰), 4.24 (1H, m, H-3A), 4.04 (1H, m, H-3B), 3.77 and 3.82

(3H, s, OMe), 2.93–3.08 (2H, m, H-4). ¹³C NMR (CDCl₃, 100.6 MHz)

2

3.15.2. Compound 14b

d

162.7 and 164.2 (CO₂Meꢃ2), 156.3 (q, COCF₃, J_C,F36.5 Hz), 153.0

White plates, yield 2.71 g (68%), mp 130–132 ^ꢀC, R_f(ethyl ace-

tate) 0.56; IR 1683 and 1743 (CO₂Me) cm^ꢂ1; EIMS (70 eV) m/z (rel

intensity): M^þ401 (10), 386 (8), 370 (14), 343 (21), 342 (100), 340

(18), 326 (8), 282 (17), 258 (12), 191 (14). ¹H NMR (CDCl₃, 400 MHz)

and 153.7 (C₂and C₃), 143.0 and 145.1 (C₆and C₅), 133.8 (C_4a),

0

130.58 (C_8a), 126.9, 127.2, 128.0, 129.0 (C₅, C₆, C₇, and C₈), 116.6 (q,

1

0

CF₃, J_C,F287.7 Hz), 101.2 (C₁), 84.0 (C₄), 52.8 (C₁), 52.0 and 52.5

(CO₂Meꢃ2), 41.1 (C₃), 28.7 (C₄). Anal. Calcd for C₂₁H₁₈F₃NO₆: C,

57.67; H, 4.15; N, 3.20. Found: C, 57.76; H, 4.18; N, 3.09.

00 00 00 00

d

7.35 (1H, dd, J_{5 ,3}0.8, J_{5 ,4}1.6 Hz, H-5⁰⁰), 6.60 (1H, s, H-5), 6.57

(1H, s, H-8), 6.27 (1H, dd, J_{3 ,4}3.2, J_{3 ,5}0.8 Hz, H-3⁰⁰), 6.06 (₀1H, dd,

00 00

00

00 00

J_{4 ,3}3.2, J_{4 ,5}1.8 Hz, H-4 ), 5.55 (1H, s, H-1), 5.02 (1H, s, H-3 ), 3.62,

3.78, 3.85, 3.94 (3H, four singlets, OMeꢃ4), 3.40–3.56 (2H, m, H-3),

3.00 (1H, m, H-4B), 2.70 (1H, m, H-4A). ¹³C NMR (CDCl₃, 100.6 MHz)

3.16.3. Compound 15c

White plates, yield 0.32 g (45%); mp 166–168 ^ꢀC, R_f(ethyl ace-

tate) 0.62; IR 1738, 1714 (CO₂Me), 1643 (NCO) cm^ꢂ1; EIMS (70 eV)

m/z (rel intensity): 426 [M^þꢂ17] (17), 384 (66), 352 (33), 301 (51),

272 (88), 258 (47), 230 (63), 192 (49), 176 (37), 111 (67), 79 (36), 59

d

168.2 and 166.0 (CO₂Meꢃ2), 147.7, 148.6, 153.1, and 153.6 (C₆, C₇,

0

00

C₂, and C₂), 142.9 (C₅), 124.4 and 126.3 (C_4a, C_8a), 110.4 and 111.2

(C₅and C₈), 110.2 (C₃), 109.2 (C₄), 85.8 (C₃), 55.9 and 56.1

(OMeꢃ2), 55.4 (C₁), 53.1 and 50.9 (CO₂Meꢃ2), 43.1 (C₃), 27.9 (C₄).

Anal. Calcd for C₂₁H₂₃NO₇: C, 62.83; H, 5.78; N, 3.49. Found: C,

62.95; H, 5.96; N, 3.69.

(100); ¹H NMR (CDCl₃, 400 MHz)

d

7.26 (1H, d, J_{6 ,5}5.4 Hz, H-6⁰),

00

0

7.11 (1H, dd, J_{5 ,4}2.0, J_{5 ,6}5.4 Hz, H-5 ), 6.69 (1H, s, H-8), 6.57 (1H, s,

0

H-5), 6.51 (1H, s, H-1), 5.68 (1H, d, J_{4 ,5}2.0 Hz, H-4 ), 4.02 (1H, m, H-

3A), 3.84 (3H, s, OMe), 3.83 (3H, s, OMe), 3.82 (3H, s, CO₂Me), 3.78

(1H, m, H-3B), 3.76 (3H, s, CO₂Me), 2.81 (2H, m, H-4), 2.15 (3H, s,

3.16. Dimethyl (1R

tetrahydroisoquinoline-1-yl]-7-oxabicyclo[2.2.1]hepta-2,5-

dien-2,3-dicarboxylate (15a), dimethyl (1R ,4S )-1-[2-

*

,4S )-1-[2-acetyl-1,2,3,4-

NCOMe). ¹³C NMR (CDCl₃, 100.6 MHz)

d

170.1 (NCOMe), 164.7 and

0

162.3 (CO₂Meꢃ2), 156.7 and 149.5 (C₂and C₃), 147.3 and 148.4 (C₇

0

*

and C₆), 144.2 and 144.5 (C₆and C₅), 126.7 (C_4a), 124.2 (C_8a), 110.3

0

triﬂuoroacetyl-1,2,3,4-tetrahydroisoquinolin-1-yl]-7-

oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate (15b),

and 111.5 (C₈and C₅), 102.5 (C₁), 83.8 (C₄), 55.7 and 56.0 (OMeꢃ2),

52.6 and 52.4 (CO₂Meꢃ2), 49.6 (C₁), 41.6 (C₃), 27.9 (C₄), 21.1

(NCOMe). Anal. Calcd for C₂₃H₂₅NO₈: C, 62.30; H, 5.68; N, 3.16.

Found: C, 62.28; H, 5.69; N, 3.17.

dimethyl (1R

tetrahydroisoquinolin-1-yl]-7-oxabicyclo[2.2.1]hepta-2,5-

diene-2,3-dicarboxylate (15c), dimethyl (1R ,4S )-1-[6,7-

*

,4S

*

)-1-[6,7-dimethoxy-2-acetyl-1,2,3,4-

*

dimethoxy-2-(triﬂuoroacetyl)-1,2,3,4-tetrahydroisoquinolin-

1-yl]-7-oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate

(15d). Typical procedure

3.16.4. Compound 15d

White plates, yield 0.54 g (68%); mp 130 ^ꢀC, R_f(50% ethyl acetate–

hexane) 0.63; IR 1733 and 1696 (CO₂Me), 1634 (NCO) cm^ꢂ1; EIMS

(70 eV) m/z (rel intensity): M^þ497 (9), 480 (16), 468 (13), 436 (21),

354 (41), 326 (19), 288 (100), 258 (19), 244 (11), 190 (11), 176 (26),

160 (6), 119 (6). ¹H NMR (CDCl₃, 400 MHz) complicated spectrum

(mixture of two isomers in the ratio w2:1), all data cite for major

DMAD (0.49 mL, 4.0 mmol) was added to the solution of cor-

responding tetrahydroisoquinoline 13a–d (1.6 mmol) in 30 mL of

toluene. The resulted mixture was reﬂuxed for 2–3 days (TLC

monitoring). At the end of the reaction the mixture was cooled and

toluene was evaporated. The residue was treated with ether (7–

10 mL) to give white solids. The obtained crystals were ﬁltered-off

and washed with ether. Further crystallization from hexane–ethyl

acetate gave the corresponding adducts 15 as a colourless crystals.

7.30 (1H, d, J_{6 ,5}5.3 Hz, H-6⁰), 7.14 (1H, br d, J_{5 ,6}5.3 Hz, H-

0 0 0 0

isomer d

5⁰), 6.72 (1H, s, H-8), 6.61 (1H, s, H-5), 6.40 (1H, s, H-1), 5.74 (br s, 1H,

H-4⁰), 4.20 (1H, br dt, J_3A,3B14.0, J_3A,4A12.7, J_3A,4B4.7 Hz, H-3A), 4.05

(1H, dd, J_3B,3A14.0, J_3B,4A6.4 Hz, H-3B), 3.87 (3H, s, OMe), 3.85 (3H, s,

OMe), 3.83 (3H, s, CO₂Me), 3.79 (3H, s, CO₂Me), 2.97 (1H, ddd, J_4A,3A

12.7, J_4A,3B6.4, J_4A,4B16.8 Hz, H-4A), 2.83 (1H, dd, J_4B,3A4.7, J_4B,4A

3.16.1. Compound 15a

16.8 Hz, H-4B). ¹³C NMR (CDCl₃, 100.6 MHz)

d

164.6 and 162.1

2

White powder, yield 0.19 g (31%); mp 184–186 ^ꢀC, R_f(30% ethyl

(CO₂Meꢃ2), 156.5 (q, COCF₃, J_C,F36.7 Hz), 150.1 and 155.1 (C₃and

0

acetate–hexane) 0.26; IR 1735, 1717 (CO₂Me), 1644 (NCO) cm^ꢂ1

;

C₂), 148.9 (C₆), 147.6 (C₇), 144.4 (C₅), 143.7 (C₆), 126.0 (C_4a), 122.6

0

EIMS (70 eV) m/z (rel intensity): 354 [M^þꢂ29] (16), 312 (22), 280

(C_8a), 116.53 (q, CF₃, ¹J_C,F288.3 Hz), 111.4 (C₅), 110.1 (C₈), 101.6 (C₁),

0

(27), 248 (13), 198 (8), 174 (23), 132 (100), 117 (16), 103 (13), 77 (17),

83.9 (C₄), 55.8 and 56.1 (OMeꢃ2), 52.6 (C₁), 51.7 and 52.5

59 (13), 43 (87); ¹H NMR (CDCl₃, 400 MHz)

d

7.27 (1H, d, J_{6 ,5}5.2 Hz,

(CO₂Meꢃ2), 41.1 (C₃), 28.2 (C₄). Anal. Calcd for C₂₃H₂₂F₃NO₈: C,

0

H-6⁰), 7.10–7.24 (1H, m, H-5, 6, 7, and 8), 7.09 (1H, dd, J_{5 ,4}1.8, J_{5 ,6}

55.54; H, 4.46; N, 2.82. Found: C, 55.53; H, 4.44; N, 2.85.

0

5.2 Hz, H-5⁰), 6.60 (1H, s, H-1), 5.65 (1H, d, J_{4 ,5}1.8 Hz, H-4⁰), 4.06

(1H, m, H-3A), 3.84 (3H, s, CO₂Me), 3.78 (1H, m, H-3B), 3.76 (3H, s,

CO₂Me), 2.88 (1H, m, H-4B), 2.88 (1H, m, H-4A), 2.15 (3H, s,

0

3.17. Dimethyl 11b-(2⁰-furyl)-7,11b-dihydro-6H-pyrido[2,1-

a]isoquinoline-1,3-dicarboxylate (16a), dimethyl 11b-(2⁰-

furyl)-9,10-dimethoxy-7,11b-dihydro-6H-pyrido[2,1-

a]isoquinoline-1,3-dicarbocylate (16b), tetramethyl 11b-(2⁰-

furyl)-7,11b-dihydro-6H-pyrido[2,1-a]isoquinoline-1,2,3,4-

tetracarboxylate (17a), tetramethyl 11b-(2⁰-furyl)-9,10-

dimethoxy-7,11b-dihydro-6H-pyrido[2,1-a]isoquinoline-

1,2,3,4-tetracarbocylate (17b). Typical procedure

NCOMe). ¹³C NMR (CDCl₃, 100.6 MHz)

d 170.1 (NCOMe), 162.3 and

0

164.7 (CO₂Meꢃ2), 156.7 (C₂), 149.6 (C₃), 144.8 (C₅), 144.1 (C₆),

134.5 (C_4a), 132.6 (C_8a), 129.1 (C₅), 127.7 (C₆), 127.5 (C₇), 126.1 (C₈),

0

102.5 (C₁), 83.7 (C₄), 52.4 and 52.6 (CO₂Meꢃ2), 50.0 (C₁), 41.7 (C₃),

28.5 (C₄), 21.1 (NCOMe). Anal. Calcd for C₂₁H₂₁NO₆: C, 65.79; H,

5.52; N, 3.65. Found: C, 65.78; H, 5.50; N, 3.60.

3.16.2. Compound 15b

DMAD (2.9 mL, 24.0 mmol, for 17) or methyl propiolate (2.1 mL,

24.0 mmol, for 16) was added to the solution of 12.0 mmol dihy-

droisoquinoline 1a,b in 40 mL of acetonitrile at room temperature

and the reaction mixture was reﬂuxed for 2–6 h. The reaction

White powder, yield 0.23 g (33%); mp 180–182 ^ꢀC, R_f(20% ethyl

acetate–hexane) 0.42; IR 1728 and 1710 (CO₂Me),1689 (NCO) cm^ꢂ1

;

EIMS (70 eV) m/z (rel intensity): M^þ437 (1), 408 (6), 377 (14), 349

F.I. Zubkov et al. / Tetrahedron 65 (2009) 3789–3803

3801

progress was monitored by TLC until disappearance of the starting

compound’s spot. At the end the solvent was evaporated to give

viscous oil residue. Further puriﬁcation by the column chroma-

tography on alumina (Al₂O₃, 45ꢃ1 cm, eluent: hexane, ethyl ace-

tate–hexane (1:10, 1:5, 1:1)) to give corresponding compounds 16

or 17.

3.18. (8aS

*

,10R

*

,11R

*

,12bS )-10,11-Diacetoxy-2,3-dimethoxy-

*

5,6,8,8a,9,10,11,12b-octahydroisoindolo[1,2-a]isoquinoline-8-

one (18)

BF₃$OEt₂0.2 mL (1.6 mmol) was added to solution of 0.25 g

(0.80 mmol) of isoindoloisoquinoline 8b in 10 mL of acetic

anhydride. The pale brown reaction mixture was stirred at

25 ^ꢀC for 10 h. Then it was diluted with water (60 mL), neu-

tralized with excess Na₂CO₃, and extracted with chloroform

(3ꢃ30 mL). The organic phase was dried by MgSO₄. After sol-

vent distillation, the substance was recrystallized from mixture

of ethyl acetate–hexane to give 0.10 g (0.24 mmol) of com-

pound 18.

3.17.1. Compound 16b

White needles, yield 1.43 g (28%); mp 188–190 ^ꢀC, R_f(ethyl ac-

etate) 0.77; IR 1708 and 1684 (CO₂Me), 1604 (C]C) cm^ꢂ1; EIMS

(70 eV) m/z (rel intensity): M^þ425 (59), 394 (4), 366 (100), 350 (16),

342 (11), 327 (6), 292 (3), 264 (3), 220 (2), 191 (2), 167 (3), 59 (2). ¹H

NMR (CDCl₃, 400 MHz)

d

7.76 (1H, s, H-4), 7.71 (1H, s, H-2), 7.33 (1H,

dd, J_{5 ,3}0.9, J_{5 ,4}1.8 Hz, H-5⁰), 7.00 (1H, s, H-8), 6.54 (1H, s, H-11),

0

6.29 (1H, dd, J_{4 ,3}3.3, J_{4 ,5}1.8 Hz, H-4⁰), 5.91 (1H, dd, J_{3 ,4}3.3, J_{3 ,5}

3.18.1. Compound 18

0

0.9 Hz, H-3⁰), 3.85 (3H, s, CO₂Me), 3.74 (3H, s, OMe), 3.70 (3H, s,

OMe), 3.58 (1H, ddd, J_6A,6B13.5, J_6A,7A7.2, J_6A,7B2.3 Hz, H-6A), 3.51

(3H, s, CO₂Me), 3.51 (3H, s, CO₂Me), 3.48 (1H, ddd, J_6B,6A13.5, J_6B,7A

10.7, J_6B,7B5.5 Hz, H-6B), 3.00 (1H, ddd, J_7A,6A7.2, J_7A,6B10.7, J_7A,7B

16.4 Hz, H-7A), 2.86 (1H, ddd, J_7B,6A2.3, J_7B,6B5.5, J_7B,7A16.4 Hz, H-

White rhombuses; yield (30%); mp 148–150 ^ꢀC, R_f0.69 (ethyl-

acetate); IR 1685 (N–C]O), 1705 and 1729 (O–C]O) cm^ꢂ1; EIMS

(70 eV) m/z (rel intensity): 415 [M^þ] (39), 356 (100), 324 (34), 296

(56), 264 (34), 244 (39), 43 (22). ¹H NMR (CDCl₃, 400 MHz)

d 6.61

(1H, s, H-1), 6.60 (1H, s, H-4), 5.59 (1H, m, J_11,123.1 Hz, H-12), 5.33

(1H, m, J_10,117.9, J_11,123.1 Hz, H-11), 5.23 (1H, br s, H-12b), 5.11 (1H,

ddd, J_9B,1012.4, J_10,117.9, J_9A,104.0 Hz, H-10), 4.38 (1H, ddd, J_6A,6B12.7,

J_5A,6A5.3, J_5B,6A1.5 Hz, H-6A), 3.81 (6H, s, 2-OMe, 3-OMe), 3.33 (1H,

m, J_8a,911.5 Hz, H-8a), 2.86 (1H, m, J_6A,6B12.7, J_5A,6B12.1, J_5B,6B

3.4 Hz, H-6B), 2.71 (1H, m, J_5A,5B15.4, J_5A,6B12.1, J_5A,6A5.3 Hz, H-5A),

2.56 (1H, dd, J_5A,5B15.4, J_5B,6B3.4 Hz, H-5B), 2.45 (1H, ddd, J_9A,9B

12.5, J_8a,9A5.3, J_9A,104.0 Hz, H-9A), 2.01 (3H, s, OAc), 1.99 (3H, s,

7B). ¹³C NMR (CDCl₃, 100.6 MHz)

d

164.3 and 167.1 (CO₂Meꢃ2),

0

157.9 (C₂), 155.3 (C₂and C₄), 152.3 (C₁), 148.7 and 147.7 (C₉and C₁₀),

0

142.3 (C₅), 127.2 and 125.6 (C_7aand C_11a), 110.1, 110.8, 111.1, 112.2

0

(C₃, C₃, C₈, C₁₁), 106.8 (C₄), 104.1, 55.8, and 55.9 (OMe-Arꢃ2), 50.7

and 51.0 (CO₂Meꢃ2), 41.9 (C₆), 29.8 (C₇). Anal. Calcd for C₂₃H₂₃NO₇:

C, 64.93; H, 5.45; N, 3.29. Found: C, 65.11; H, 5.43; N, 3.26.

3.17.2. Compound 17a

OAc), 1.54 (1H, ddd, J_9A,9B12.5, J_9B,1012.4, J_8a,9B11.5 Hz, H-9B). ¹³

NMR (CDCl₃, 100.6 MHz) 170.6 (s, C₈), 170.3 and 170.2 (s, C₁₀and

C

White needles, yield 1.15 g (20%); mp 140 ^ꢀC, R_f(50% ethyl ac-

d

etate–hexane) 0.40; IR 1732 and 1712 (CO₂Me), 1597 (C]C) cm^ꢂ1

;

C₁₁), 20.8 (q, 2C, J 130.0 Hz, OAcꢃ2),141.9 (s, C_12a), 28.3 (t, J 133.5 Hz,

C₉), 148.1 and 147.7 (s, C₂and C₃), 126.2 (s, C_4a), 123.0 (s, C_12c), 116.9

(d, J 165.0 Hz, C₁₂), 112.3 (d, J 156.5 Hz, C₄), 109.7 (d, J 155.0 Hz, C₁),

72.1 (d, J 149.0 Hz, C₁₁), 71.9 (d, J 148.5 Hz, C₁₀), 58.1 (d, J 140.5 Hz,

C_12b), 56.1 (q, J 144.5 Hz, C₂-OMe), 55.7 (q, J 144.5 Hz, C₃-OMe), 42.0

(d, J 129.0 Hz, C_8a), 36.7 (t, J 142.0 Hz, C₆), 28.7 (t, J 130.5 Hz, C₅).

Anal. Calcd for C₂₂H₂₅NO₇: C, 63.60; H, 6.07; N, 3.37; O, 26.96,

Found: C, 63.61; H, 6.05; N, 3.37; O, 26.95.

EIMS (70 eV) m/z (rel intensity): M^þ481 (10), 451 (53), 422 (100),

394 (21), 362 (33), 280 (24), 260 (62), 199 (54), 169 (23), 128 (24),

111 (42), 95 (43), 59 (92), 43 (57). ¹H NMR (CDCl₃, 400 MHz)

d

8.07

(1H, d, J_11,108.0 Hz, H-11), 7.38 (1H, dd, J_10,97.6, J_10,118.0 Hz, H-10),

0

7.27 (1H, t, J_9,8¼J_9,10¼7.6 Hz, H-9), 7.26 (1H, dd, J_{5 ,3}0.8, J_{5 ,4}1.7 Hz,

H-5⁰), 7.08 (1H, d, J_8,97.6 Hz, H-8), 6.38 (1H, dd, J_{3 ,4}3.3, J_{3 ,5}0.8 Hz,

0

H-3⁰), 6.21 (1H, dd, J_{4 ,3}3.3, J_{4 ,5}1.7 Hz, H-4 ), 3.98 (3H, s, CO₂Me),

3.74 (3H, s, CO₂Me), 3.72 (1H, m, J_6A,6B11.9 Hz, H-6A), 3.68 (3H, s,

CO₂Me), 3.52 (3H, s, CO₂Me), 3.45 (1H, ddd, J_6B,6A11.9, J_6B,7A9.2,

J_6B,7B4.9 Hz, H-6B), 2.88 (1H, m, J_7A,6B9.2 Hz, H-7A), 2.88 (1H, m,

0

3.19. Methyl (1aR

1a,2,3,3a,4,7,11b,11d-octahydro-6H-2,11c-epoxireno-

[6,7]isoindolo[1,2-a]isoquinolin-3-carboxylate (19a), methyl

*

,2R

*

,3R

*

,3aS

*

,11bR

*

,11cR

*

,11dR )-4-oxo-

*

J_7B,6B4.9 Hz, H-7B). ¹³C NMR (CDCl₃, 100.6 MHz)

d

165.0 and 167.2

0

(CO₂Meꢃ2), 164.2 (2C, CO₂Meꢃ2), 152.4 (C₂), 149.0 (C₄), 143.5 (C₅),

(1aR

*

,2R

*

,3R

*

,3aS

*

,11bR

*

,11cR

*

,11dR )-9,10-dimethoxy-4-oxo-

*

135.2 (C₂), 134.6 (C_7a), 133.5 (C_11a), 126.42, 128.2, 128.6, 128.7 (four

1a,2,3,3a,4,7,11b,11d-octahydro-6H-2,11c-epoxireno-

[6,7]isoindolo[1,2-a]isoquinoline-3-carboxylate (19b),

0

d, C₈–C₁₁), 116.6 (C₁), 112.7 (C₃), 110.1 (C₄), 99.9 (C₃), 62.8 (C₆), 51.7,

52.0, 52.5 and 53.3 (four q, CO₂Meꢃ4), 46.5 (C_11b), 29.4 (C₇). Anal.

Calcd for C₂₅H₂₃NO₉: C, 62.37; H, 4.82; N, 2.91. Found: C, 62.40; H,

4.83; N, 2.90.

(1aR

6H-2,11c-epoxireno[6,7]isoindolo[1,2-a]isoquinolin-4(2H)-

one (20a), (1aR ,2R ,3aS ,11bR ,11cR ,11dR )-9,10-dimethoxy-

*

,2R

*

,3aS

*

,11bR

*

,11cR

*

,11dR )-1a,3,3a,7,11b,11d-hexahydro-

*

1a,3,3a,7,11b,11d-hexahydro-6H-2,11c-epoxireno[6,7]-

isoindolo[1,2-a]isoquinolin-4(2H)-one (20b). Typical

procedure

3.17.3. Compound 17b

White needles, yield 1.82 g (28%); mp 196–197 ^ꢀC, R_f(50% ethyl

acetate–hexane) 0.33; IR 1735 and 1698 (CO₂Me), 1603

(C]C) cm^ꢂ1; EIMS (70 eV) m/z (rel intensity): M^þ541 (3), 510 (6),

482 (100), 438 (4), 408 (3), 349 (3), 304 (3), 260 (3), 241 (7), 190 (2),

A mixture of 4.80 mmol of isoindoloisoquinoline 8 (10) and

15 mL of dichloromethane was added to solution of 2.07 g

(12.0 mmol) of m-CPBA in 25 mL of dichloromethane. The resulted

reaction mixture was boiled for 1–3 days (monitoring by TLC). Then

it was cooled and diluted with water (50 mL), basiﬁed with NaHCO₃

to pH 9–10, and then extracted with CH₂Cl₂(3ꢃ50 mL). The organic

phase was dried over MgSO₄. After solvent distillation, the residue

(brown oil) was treated with ether (10 mL). The obtained solids

were ﬁltered-off and were recrystallized from mixture of hexane–

ethyl acetate to give corresponding diepoxides 19–20a,b as white

or pale-yellow crystals.

59 (5). ¹H NMR (CDCl₃, 400 MHz)

d 7.36 (1H, dd, J_{5 ,3}0.8, J_{5 ,4}1.8 Hz,

0 0 0 0

H-5⁰), 6.64 (1H, s, H-11), 6.63 (1H, s, H-8), 6.44 (1H, dd, J_{3 ,4}3.1, J_{3 ,5}

0

0.8 Hz, H-3⁰), 6.31 (1H, dd, J_{4 ,3}3.1, J_{4 ,5}1.8 Hz, H-4⁰), 3.93 (3H, s,

OMe), 3.90 (3H, s, OMe), 3.82 (3H, s, CO₂Me), 3.74 (1H, m, J_6A,7A

5.9 Hz, H-6A), 3.73 (3H, s, CO₂Me), 3.66 (3H, s, CO₂Me), 3.65 (1H, m,

J_6B,7A12.4 Hz, H-6B), 3.45 (3H, s, CO₂Me), 3.13 (1H, ddd, J_7A,6A5.9,

J_7A,6B12.4, J_7A,7B17.1 Hz, H-7A), 2.75 (1H, br d, J_7B,7A17.1 Hz, H-7B).

0

¹³C NMR (CDCl₃, 100.6 MHz)

147.4 (C₄), 148.7, 149.2, 152.5 (C₂), 143.5 (C₅), 134.7 (C₂), 126.9 (C₁),

d

164.2, 164.2, 165.2, 167.2 (CO₂Meꢃ4),

0

125.2 (C_7a), 117.2 (C_11a), 112.6 (C₇), 111.8, 110.95 (C₃), 110.1 (C₄), 99.7

(C₃), 62.6 (C_11b), 55.9 (2C, q, OMeꢃ2), 51.7, 52.2, 52.5, and 53.3 (four

s, CO₂Me), 46.5 (C₆), 28.9 (C₇). Anal. Calcd for C₂₇H₂₇NO₁₁: C, 59.89;

H, 5.03; N, 2.59. Found: C, 59.90; H, 5.02; N, 2.56.

3.19.1. Compound 19a

White crystals, yield 1.21 g (77%); mp 258–260 ^ꢀC; R_f(ethyl

acetate) 0.32; IR 1707 (NC]O) and 1737 (CO₂Me) cm^ꢂ1; EIMS

3802

F.I. Zubkov et al. / Tetrahedron 65 (2009) 3789–3803

(70 eV) m/z (rel intensity): M^þ327 (80), 326 (100), 295 (30), 266

(C₆), 31.0 (C₃), 27.9 (C₇). Anal. Calcd for C₁₈H₁₉NO₅: C, 65.64; H, 5.81;

N, 4.25. Found: C, 65.90; H, 6.02; N, 4.51.

(8), 238 (15), 210 (12), 168 (13), 130 (37), 103 (10), 77 (7), 59 (5). ¹H

NMR (CDCl₃, 400 MHz) d 7.34 (1H, br d, J_10,117.8 Hz, H-11), 7.28 (1H,

br t, J_9,8¼J_9,10¼7.8 Hz, H-9), 7.21 (1H, br t, J_10,9¼J_10,11¼7.8 Hz, H-10),

7.13 (1H, br d, J_8,97.8 Hz, H-8), 5.25 (1H, br s, H-2), 4.72 (1H, s, H-

11b), 4.20 (1H, ddd, J_6A,6B12.7, J_6A,7A5.5, J_6A,7B3.0 Hz, H-6A), 3.72

(1H, d, J_1a,11d3.3 Hz, H-1a), 3.71 (3H, s, CO₂Me), 3.47 (1H, d, J_11d,1a

3.3 Hz, H-11d), 3.18 (1H, br d, J_3endo,3a9.4 Hz, H-3_endo), 3.10 (1H, m,

J_6B,6A12.7 Hz, H-6B), 2.94 (2H, d, J_3a,3endo9.4 Hz, H-3a), 3.00 (1H, m,

H-7A), 2.74 (1H, m, J_7B,6A3.0 Hz, H-7B). ¹³C NMR (DMSO-d₆,

3.20. (8aR

*

,10S

*

,11aR

*

,12R

*

,12aS )-2,3-Dimethoxy-11-methyl-

*

8-oxo-5,8,8a,9,10,11,11a,12a-octahydro-10,12-

epoxycyclopenta[4,5]pyrido[2,1-a]isoquinoline-11,12-

diylacetate (21a), methyl (8aS

bis(acetoxy)-2,3-dimethoxy-11-methyl-8-oxo-

5,6,8,8a,9,10,11,11a,12,12a-decahydro-10,12-

*

,9S

*

,10S

*

,11aR

*

,12R

*

,12aS )-11,12-

*

100.6 MHz)

d

170.8 and 168.2 (CO₂H and C₄), 134.4 and 130.1 (C_7a

epoxycyclopenta[4,5]pyrido[2,1-a]isoquinoline-9-carboxilate

and C_11a),128.5 (C₈),126.7,126.2,126.0 (C_9,10,11), 87.1 (C_11c), 77.1 (C₂),

55.6, 53.4, 51.2, 49.1, 48.5, 46.8 (C_{1a,3,3a,11b,11d,CO2Me}), 36.7 (C₆), 28.0

(C₇). Anal. Calcd for C₁₈H₁₇NO₅: C, 66.05; H, 5.23; N, 4.28. Found: C,

66.28; H, 5.01; N, 4.53.

(21b). Typical procedure

BF₃$OEt₂(0.38 mL, 3.0 mmol) was added to solution of

1.50 mmol of corresponding epoxyisoindoloisoquinoline (19b, 20b)

in 10 mL of acetic anhydride with ice cooling. The mixture was

stirred for 1 h at 2–4 ^ꢀC and then at room temperature for 4 h

(monitoring by TLC). At the end of the reaction, the reaction mix-

ture was diluted with water (60 mL), and saturated sodium

hydrocarbonate solution was added to pH 9–10. Three 70 mL

extractions with chloroform were performed. The organic layers

were combined, washed with water (2ꢃ30 mL), and dried over

MgSO₄. After solvent distillation, the residue was crystallized in

ether (5 mL) to give compounds 21a,b as white powder. The sub-

sequent recrystallization from ethyl acetate gives the analytically

pure sample. A single crystal of the compound 21a for X-ray anal-

ysis was obtained by slow crystallization from the mixture meth-

anol–DMF.

3.19.2. Compound 19b

White crystals, yield 1.54 g (83%); mp 158–160 ^ꢀC; R_f(50% ethyl

acetate–hexane) 0.32; IR 1708 (NC]O) and 1734 (CO₂Me) cm^ꢂ1

;

EIMS (70 eV) m/z (rel intensity): M^þ387 (100), 372 (7), 356 (55),

258 (13), 190 (14), 43 (22). ¹H NMR (CDCl₃, 400 MHz)

6.81 (1H, s,

d

H-11), 6.59 (1H, s, H-8), 5.18 (1H, br s, H-2), 4.72 (1H, s, H-11b), 4.22

(1H, ddd, J_6A,6B13.0, J_6A,7A5.3, J_6A,7B3.0 Hz, H-6A), 3.88 (3H, s, OMe),

3.83 (3H, s, OMe), 3.71 (3H, s, CO₂Me), 3.71 (1H, d, J_1a,11d3.3 Hz, H-

1a), 3.47 (1H, d, J_11d,1a3.3 Hz, H-11d), 3.18 (1H, dd, J_3endo,3a9.3,

J_3endo,20.7 Hz, H-3_endo), 3.08 (1H, m, J_6B,6A13.0 Hz, H-6B), 2.94 (1H,

d, J_3a,3endo9.3 Hz, H-3a), 2.88 (1H, m, H-7A), 2.65 (1H, m, J_7B,6A

3.0 Hz, H-7B). ¹³C NMR (CDCl₃, 100.6 MHz)

d 170.3 (C₄), 168.2

(CO₂Me), 148.0 and 148.4 (C₁₀and C₉), 126.5 (C_11a), 122.2 (C_7a), 111.6

(C₈), 108.7 (C₁₁), 87.3 (C_11c), 77.8 (C₂), 56.5 (C_11b), 56.0 and 55.9

(OMeꢃ2), 53.9 (C₃), 52.2 (CO₂Me), 49.8 and 49.1 (C_1aand C_11d), 47.9

(C_3a), 37.6 (C₆), 28.0 (C₇). Anal. Calcd for C₂₀H₂₁NO₇: C, 62.01; H,

5.46; N, 3.62. Found: C, 62.30; H, 5.22; N, 3.90.

3.20.1. Compound 21a

White prisms, yield 0.4 g (62%); mp 262–264 ^ꢀC (decomp.); IR

1645 (NC]O), 1730 and 1754 (OC]O) cm^ꢂ1; EIMS (70 eV) m/z (rel

intensity): M^þ431 (2), 388 (16), 372 (40), 343 (14), 312 (100), 300

(13), 284 (65), 272 (24), 258 (21), 192 (36), 176 (20), 43 (24). ¹H NMR

3.19.3. Compound 20a

(CDCl₃, 400 MHz) d 7.35 (1H, s, H-1), 6.60 (1H, s, H-4), 5.44 (1H, br s,

Pale-yellow powder, yield 1.02 g (79%); mp 168–170 ^ꢀC; IR 1682

(NC]O) cm^ꢂ1; EIMS (70 eV) m/z (rel intensity): M^þ269 (100), 268

(98), 240 (17), 212 (7), 198 (7), 168 (6), 130 (21), 128 (7), 103 (8). ¹H

H-12a), 4.86 (1H, br d, J_11,11a1.4 Hz, H-11), 4.59 (1H, ddd, J_6A,5B2.5,

J_6A,5A7.0, J_6A,6B10.5 Hz, H-6A), 4.57 (1H, br t, J_9B,10¼J_11,10¼1.0 Hz, H-

10), 3.99 (1H, dd, J_11,11a1.4, J_8a,11a4.6 Hz, H-11a), 3.89 (3H, s, OMe),

3.84 (3H, s, OMe), 2.99 (1H, ddd, J_8a,9B4.0, J_8a,11a4.5, J_8a,9A11.8 Hz, H-

8a), 2.92 (2H, m, H-5), 2.63 (1H, m, H-6B), 2.20 (1H, ddd, J 0.8, J_8a,9A

11.8, J_9A,9B13.5 Hz, H-9A), 2.17 (3H, s, OAc), 2.14 (3H, s, OAc), 1.48

(1H, ddd, J_9B,100.8, J_8a,9B4.0, J_9A,9B13.5 Hz, H-9B). ¹³C NMR (CDCl₃,

NMR (CDCl₃, 400 MHz)

d 7.38 (1H, br d, J_10,117.8 Hz, H-11), 7.33 (1H,

br t, J_10,9¼J_9,8¼7.8 Hz, H-9), 7.23 (1H, br t, J_10,9¼J_10,11¼7.8 Hz, H-10),

7.17 (1H, br d, J_8,97.8 Hz, H-8), 5.31 (1H, s, H-11b), 4.58 (1H, d, J_3exo,2

4.9 Hz, H-2), 4.30 (1H, ddd, J_6A,6B12.8, J_6A,7A5.7, J_6A,7B2.8 Hz, H-6A),

3.71 (1H, d, J_1a,11d3.4 Hz, H-1a), 3.49 (1H, d, J_11d,1a3.4 Hz, H-11d), 3.15

(1H, m, J_6B,6A12.8 Hz, H-6B), 3.08 (1H, m, J_7A,6A5.7 Hz, H-7A), 2.95

(1H, dd, J_3a,3endo9.4, J_3a,3exo3.6 Hz, H-3a), 2.77 (1H, ddd, J_7B,6A2.8 Hz,

H-7B), 2.25 (1H, ddd, J_3exo,24.9, J_3exo,3endo12.7, J_3exo,3a3.6 Hz, H-3_exo),

1.88 (1H, dd, J_3endo,3exo12.7, J_3endo,3a9.4 Hz, H-3_endo). ¹³C NMR (CDCl₃,

100.6 MHz)

d

168.2, 169.3, 170.1 (C₈, CO₂Meꢃ2), 147.1 and 148.3 (C₃

and C₂), 128.9 (C_4a), 123.7 (C_12b), 111.6 (C₄), 110.3 (C₁), 107.2 (C₁₂),

80.0 (C₁₁), 77.8 (C₁₀), 58.9 (C_12a), 55.8 and 56.1 (OMe–Arꢃ2), 41.6

(C_11a), 41.0 (C₆), 35.4 (C_8a), 33.9 (C₉), 28.3 (C₅), 21.1 and 22.2

(OCOMeꢃ2). Anal. Calcd for C₂₂H₂₅NO₈: C, 61.25; H, 5.84; N, 3.25.

Found: C, 61.44; H, 5.68; N, 3.51.

100.6 MHz)

d 171.7 (C₄), 134.3 and 130.8 (C_7aand C_11a), 129.1 (C₈),

127.5, 126.9, 126.0 (C₉, C₁₀, C₁₁), 87.6 (C_11c), 75.5 (C₂), 57.3 (C_11b), 50.4,

50.1, 49.1 (C_1a, C_11d, C_3a), 37.4 (C₆), 30.9 (C₃), 28.5 (C₇). Anal. Calcd for

C₁₆H₁₅NO₃: C, 71.36; H, 5.61; N, 5.20. Found: C, 71.59; H, 5.39; N, 5.48.

3.20.2. Compound 21b

White prisms, yield 0.10 g (73%); mp 241–243 ^ꢀC; IR 1659

(NC]O), 1745 (OC]O) cm^ꢂ1; EIMS (70 eV) m/z (rel intensity): M^þ

489 (1), 430 (15), 429 (45), 371 (100), 342 (50), 272 (41), 192 (37),

3.19.4. Compound 20b

Pale-yellow powder, yield 1.06 g (67%); mp 196–198 ^ꢀC; IR 1690

(NC]O) cm^ꢂ1; EIMS (70 eV) m/z (rel intensity): M^þ329 (100), 328

(73), 314 (8), 298 (67), 286 (5), 272 (4), 190 (6), 176 (7). ¹H NMR

176 (22), 60 (24), 43 (41). ¹H NMR (CDCl₃, 400 MHz)

d 7.31 (1H, s,

H-1), 6.62 (1H, s, H-4), 5.44 (1H, br s, H-12a), 4.94 (1H, br s, H-

11), 4.80 (1H, m, H-9), 4.78 (1H, s, H-10), 4.13 (1H, dd, J_11,11a1.2,

J_8a,11a3.7 Hz, H-11a), 3.90 (3H, s, OMe), 3.87 (3H, s, OMe), 3.39

(3H, s, CO₂Me), 3.18–3.25 (3H, m, H-6 and H-8a), 2.87 (1H, m, H-

5A), 2.54 (1H, m, H-5B), 2.19 (3H, s, OAc), 2.17 (3H, s, OAc). ¹³C

(CDCl₃, 400 MHz) d 6.84 (1H, s, H-11), 6.63 (1H, s, H-8), 5.23 (1H, s, H-

11b), 4.58 (1H, d, J_3exo,24.7 Hz, H-2), 4.29 (1H, ddd, J 1.5, 3.7, 12.8 Hz,

H-6A), 3.91 (3H, s, OMe), 3.85 (3H, s, OMe), 3.70 (1H, d, J_1a,11d3.3 Hz,

H-1a), 3.50 (1H, d, J_11d,1a3.3 Hz, H-11d), 3.09 (1H, m, H-6B), 2.89 (1H,

dd, J_3exo,3a4.3, J_3endo,3a9.5 Hz, H-3a), 2.85–2.92 (1H, m, H-7A), 2.67

(1H, m, H-7B), 2.22 (1H, dt, J_3exo,24.3, J_3exo,3endo12.4 Hz, H-3_exo), 1.87

(1H, dd, J_3endo,3exo12.4, J_3endo,3a9.5 Hz, H-3_endo). ¹³C NMR (CDCl₃,

NMR (CDCl₃, 100.6 MHz)

d 164.9, 167.5, 169.2, 170.0 (C₈, CO₂Me,

OCOMeꢃ2), 146.7 and 147.9 (C₃and C₂), 128.8 (C_4a), 123.3 (C_12b),

111.5 (C₁), 109.9 (C₄), 107.3 (C₁₂), 81.7 (C₈), 76.4 (C₁₀), 59.9 (C_12a),

55.8 and 56.0 (OMe–Ar), 51.9 (CO₂Me), 46.4 (C_11a), 42.8 (C₉), 41.3

(C₆), 38.4 (C_8a), 27.4 (C₅), 21.0 and 22.2 (OCOMeꢃ2). Anal. Calcd

for C₂₄H₂₇NO₁₀: C, 58.89; H, 5.56; N, 2.86. Found: C, 58.70; H,

5.82; N, 2.99.

100.6 MHz)

d 171.8 (C₄), 148.4 and 148.1 (C₁₀and C₉), 126.2 (C_11a),

122.5 (C_7a), 111.6 (C₈), 108.6 (C₁₁), 87.5 (C_11c), 75.5 (C₂), 57.1 (C_11b),

55.9 and 55.9 (OMeꢃ2), 50.5, 50.1 and 49.0 (C_1a, C_3a, and C_11d), 37.4

F.I. Zubkov et al. / Tetrahedron 65 (2009) 3789–3803

3803

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The authors are grateful to the Russian Foundation for Basic Re-

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Supplementary data

Supplementary data containing tables of atom coordinates,

bond lengths and angles, anisotropic displacement parameters, and

crystal packing for 21a are provided. Crystal data are also given as

a CIF ﬁle. Supplementary data associated with this article can be

found in the online version, at doi:10.1016/j.tet.2009.02.024.

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Article Doi

A new approach to construction of isoindolo[1,2-a]isoquinoline alkaloids Nuevamine, Jamtine, and Hirsutine via IMDAF reaction

DOI: 10.1016/j.tet.2009.02.024

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