Alkaloids of the flora of Siberia and Altai: XX. Synthesis of 5-aryl(hetaryl)-substituted anthranilic acid esters

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 7, pp. 960–972. © Pleiades Publishing, Ltd., 2014. Original Russian Text © V.E. Romanov, G.R. Sabankulova, M.M. Shakirov, E.E. Shul’ts, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 7, pp. 979–990.

960

Alkaloids of the Flora of Siberia and Altai: XX.* Synthesis of 5-Aryl(hetaryl)-Substituted Anthranilic Acid Esters

V. E. Romanova, b, G. R. Sabankulovaa, M. M. Shakirova, and E. E. Shul’tsa

a Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, pr. Akademika Lavrent’eva 9, Novosibirsk, 630090 Russia

e-mail: [email protected] b Novosibirsk State University, ul. Pirogova 2, Novosibirsk, 630090 Russia

Received December 20, 2013

Abstract—Cross-coupling of methyl 2-acetylamino-5-bromobenzoate and 5′-bromolappaconitine with aryl-, furyl-, pyridyl-, and 5-acetylthiophen-2-ylboronic acids or 1-(2-fluoroquinolin-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane gave the corresponding 5-aryl(hetaryl)-substituted anthranilic acid derivatives. The use of the two-phase toluene–water system as reaction medium and addition of tetrabutylammonium bromide allows the cross-coupling to be accomplished under mild conditions. The catalytic system Pd(dba)2–AsPh3 was found to be efficient in the cross-coupling of methyl 2-acetylamino-5-bromobenzoate with furyl- and pyridylboronic acids, whereas the system Pd(OAc)2–(o-Tol)3P ensured good results in the reactions of 5′-bromolappaconitine with hetarylboronic acids. Facile esterification at the C8-OH and C9-OH groups of the aconitane skeleton was observed in the reactions of 5′-bromolappaconitine and 5′-phenyllappaconitine with phenylboronic acid. 5′-Bromo-8,9-O-(phenylboranediyl)lappaconitine under the Suzuki reaction conditions underwent hydrolysis of the boronic ester moiety with formation of the cross-coupling product of 5′-bromolappaconitine with phenyl-boronic acid.

* For communication XIX, see [1].

Substituted symmetrical and unsymmetrical biaryls are being extensively studied, and their derivatives are used in the synthesis of drugs, polymers, molecular wires, and liquid crystals, as well as for building up chiral skeletons of asymmetric catalysts. Apart from classical methods of synthesis of biaryls based on the Ullmann and Stille reactions, Suzuki–Miyaura cross-couplings have found wide application [2, 3] since organoboron acids are more advantageous reagents. They are stable in aqueous media and are converted into nontoxic products which can be readily separated from target compounds.

Development of the Suzuki–Miyaura procedure made it possible to successfully synthesize polyfunc-tionalized biaryls, in particular those based on anthra-nilic acid derivatives, including natural anthranilic acid esters such as accessible diterpene alkaloids. An ex-ample of the latter is alkaloid lappaconitine (I). We previously described modification of lappaconitine (I) at the aromatic fragment, which reduced its toxicity

and enhanced anti-arrhythmic activity [4, 5]. A few syntheses of aryl-substituted anthranilic acid deriva-tives interesting as biologically active compounds have been reported [6, 7].

In the present work we have synthesized 5-aryl-(hetaryl)-substituted anthranilic acid esters via palla-dium-catalyzed cross-coupling of methyl 2-acetyl-

DOI: 10.1134/S1070428014070070

I, R = H; III, R = Br.

OMe

NMe

O

OH

OMeHO

OMe

O NHAc

R

OMe

O

NHAc

Br

I, III II

ALKALOIDS OF THE SIBERIAN AND ALTAI FLORA: XX.

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 7 2014

961

IV, V, R1 = R2 = R3 = R4 = H; VI, VII, R1 = Me, R2 = R3 = R4 = H; VIII, X, R1 = H, R2 = R3 = R4 = OMe; IX, XI, R1 = R4 = H, R2 = R3 = OMe; i: Pd(PPh3)4, K2CO3, Bu4NBr, dioxane; ii: Pd(PPh3)4, K2CO3, Bu4NBr, toluene–water; iii: Pd(OAc)2, P(o-Tol)3, K2CO3,

Bu4NBr, toluene–water; iv: Pd(dba)2, AsPh3, K2CO3, Bu4NBr, DMF.

II +

R1

R2

R3

R4

B(OH)2

IV, VI, VIII, IX

i–iv, 100°C

R1

R2

R3

R4

NHAc

COOMe

V, VII, X, XI

1

23

4

5

1'

2'3'

4'

5'6'

6

Scheme 1.

amino-5-bromobenzoate (II) and 5′-bromolappaco-nitine (III) [5] with aryl(hetaryl)boronic acids and 1-(2-fluoroquinolin-3-yl)-4,4,5,5-tetramethyl-1,3,2-di-oxaborolane.

The reaction of methyl 2-acetylamino-5-bromoben-zoate (II) with phenylboronic acid (IV) in dioxane in the presence of Pd(PPh3)4 (which is widely used as catalyst in the Suzuki couplings), potassium carbonate (3 equiv) as base, and 10 mol % of tetrabutylammo-nium bromide (10 h, i) [8] gave methyl 2-acetylamino-5-phenylbenzoate (V) (Scheme 1). Compound V was isolated in 89% yield when the reaction time was pro-longed to 20 h. Longer reaction time led to consider-able tarring and reduced yield of V. Fritzson et al. [7] described the alkaline hydrolysis product of 2-acetyl-amino-5-phenylbenzoic acid which was also synthe-sized by the Suzuki reaction. It should be noted that the conversion of II in the reaction with 2-methyl-phenylboronic acid (VI) under analogous conditions (i) was much lower (29%).

According to Miyaura et al. [9], the yield of cross-coupling products increases when the reaction is carried out in the two-phase toluene–water system. The reaction of methyl 2-acetylamino-5-bromobenzoate (II) with phenylboronic acid (IV) in the presence of Pd(PPh3)4 (5 mol %), K2CO3, and Bu4NBr in a 4 : 1 toluene–water mixture was characterized by complete conversion of II, which was attained in 8 h at 100°C (ii). However, in the reaction of II with 2-methyl-phenylboronic acid (VI) under analogous conditions, compound VII was isolated in 27% yield. The use of Pd(PPh3)4 complicates the isolation procedure because of the necessity of removing triphenylphosphine oxide Ph3PO, so that the yield of the target products consid-erably decreases.

Bromide II reacted with 3,4,5-trimethoxyphenyl-boronic (VIII) and 3,4-dimethoxyphenylboronic acids (IX) in the presence of Pd(OAc)2–P(o-Tol)3 as cata-lytic system (iii) to produce the corresponding biaryls

X and XI which were isolated in 14 and 46% yield, respectively.

Successful Suzuki and Stille palladium-catalyzed cross-couplings with the use of triphenylarsine as ligand were reported [10]. We found that the reaction of methyl 2-acetylamino-5-bromobenzoate (II) with 2-methylphenylboronic acid (VI) in DMF in the pres-ence of 5 mol % of Pd(dba)2, 10 mol % of AsPh3, and 1 equiv of K2CO3 (100°C, 6 h) afforded compound VII as the major product (yield 58%). Increase of the reaction time to 12 h raised the yield of VII to 64%, but appreciable tarring was observed. The reaction with excess 2-methylphenylboronic acid (VI) was ac-companied by formation of the homocoupling product, 2,2′-dimethylbiphenyl (XII) [11]. When Bu4NBr was added to the reaction mixture (120°C, 6 h; iv), com-pound VII was isolated as the only product in 68% yield. It is known that Bu4NBr stabilizes colloidal palladium particles formed in situ and prevents their aggregation to larger inactive particles [12]. The effect of tetraalkylammonium salts as phase transfer catalysts was also discussed [13]. The reaction of II with phenylboronic acid (IV) under the above conditions (iv) smoothly produced compound V (yield 64%).

The conversion of II in the reaction with furan- 2-ylboronic acid (XIII) (iii) was complete, but the product, compound XIV, was isolated in 10% yield (Scheme 2). The reaction of II with furan-3-ylboronic acid XV in the presence of Pd(OAc)2–P(o-Tol)3 gave 40% of methyl 2-acetylamino-5-(furan-3-yl)benzoate (XVI). Compounds XIV and XVI were also formed in the reactions carried out according to procedure i, but the yield did not exceed 5%. The catalytic system Pd(dba)2–AsPh3 (iv) ensured good results in the reac-tions of II with furylboronic acids XIII and XV, as well as with pyridin-3-yl- and pyridin-4-ylboronic acids XVII and XVIII. The yields of the correspond-ing methyl 2-acetylamino-5-(hetaryl)benzoates XIV, XV, XIX, and XX ranged from 42 to 52%.


ROMANOV et al. 962

Scheme 2.

II +O B(OH)2

XIII

i, iii, ivNHAc

COOMe

O

XIV

II + O B(OH)2

XV

i, iii, ivNHAc

COOMeO

XVI

II +

XVII

iv

N

B(OH)2NHAc

COOMe

N

XIX

II +

XVIII

iv

N

B(OH)2NHAc

COOMeN

XX

II +S B(OH)2

XXI

iii, v, vi

Ac

NHAc

COOMe

S

XXII

Ac +

NHAc

COOMe

XXIII

v: PdCl2(dppf), K2CO3, Bu4NBr, toluene–water, 100°C; vi: Pd(PPh3)2, K2CO3, DMF–water, 65 or 100°C.

In the reaction of II with 5-acetylthiophen-2-yl-boronic acid (XXI) (ii), the conversion of II was 50%. According to the 1H NMR data, the reaction mixture contained methyl 2-acetylamino-5-(5-acetylthiophen-2-yl)benzoate (XXII, 38%), unreacted bromide II, and methyl 2-acetylaminobenzoate (XXIII), the latter being the product of reductive debromination of II. When the reaction with the same compounds was carried out in

the presence of PdCl2(dppf) [dppf = 1,1′-bis(diphenyl-phosphino)ferrocene] [14] (Scheme 2, v), the conver-sion of II decreased to 38%, and a considerable amount of hydrodebromination product XXIII was obtained. The complete conversion of II was achieved in the system DMF–water. In the presence of 3 equiv of K2CO3, the product ratio XXII/XXIII was 1 : 1. Reduction of the amount of the base to 1.5 equiv

vii: Et2O, Na2SO4, 20°C, 24 h.

N

B(OH)2

F

+

XXIV

OH

Me

HO

MeMe

Me

XXVI

vii

N

B

F

XXV, 71%

O

OMeMe

MeMe

N F

II + XXVb

NHAc

COOMe

XXVII

1

2

5

1'

3'

5'

8'

Scheme 3.



963

Scheme 4.

OMe

NMe

O

O

OMeO

OMe

O

NHAc

IIIIV (2 equiv), ii B

Ph

XXIX

IV (1 equiv), ii

MeO

NMe

O

OH

OMeHO

OMe

O

NHAc

XXVIII

1''5'

1'

2'

12

3 45

67

8910

11

1213

14

15

1617

19

IV, vii, viii

OMe

NMe

O

O

OMeO

OMe

O

NHAc

Br

BPh

XXX

MeO

NMe

O

O

OMeO

OMe

O

NHAc

BPh

XXXI

IVI, viiXXVIII, vii

XXIX

1312

11 1014

157

6a

3a13b

13a

12

14

16

177a

9

34

5

6

8

XXXii

XXVIII + XXIX + IIIii

XXVIII + III

viii: K2CO3, Bu4NBr, toluene–water, 100°C.

changed the ratio XXII/XXIII to 2 : 1, and in the reac-tion at lower temperature (65°C, 30 h; vi) the fraction of cross-coupling product XXII increased to 91% (yield 38% after chromatographic purification). Ex-amples of dehalogenation under the Suzuki reaction conditions have been reported in the literature [15].

Attempted cross-coupling of (2-fluoroquinolin-3-yl)boronic acid (XXIV) with methyl 2-acetylamino-5-bromobenzoate (II) under the above conditions was unsuccessful. Obviously, this is related to low stability of compound XXIV. In order to perform cross-cou-pling with unstable hetarylboronic acid, 2,2-dimethyl-propane-1,3-diol, 2,3-dimethylbutane-2,3-diol [16], and N-methyliminodiacetic acid [17] are converted into stable boron esters, trifluoroborate salts [18], or

cyclic triborates [19]. Cyclic 2-fluoroquinolin-3-yl-boronic acid ester (XXV) was smoothly prepared by reaction of 2-fluoroquinolin-3-ylboronic acid (XXIV) with 2,3-dimethylbutane-2,3-diol (XXVI) in the pres-ence of anhydrous sodium sulfate (Scheme 3). By heating compound XXV with bromide II in toluene–water in the presence of Pd(PPh3)4, K2CO3, and Bu4NBr (ii) we obtained methyl 2-acetylamino-5-(2-fluoroquinolin-3-yl)benzoate (XXVII) in 15% yield.

Thus, cross-couplings of methyl 2-acetylamino-5-bromobenzoate (II) with aryl- and hetarylboronic acids or cyclic esters derived from hetarylboronic acids and pinacol allow preparation of anthranilic acid deriva-tives containing various aryl or hetaryl substituent in the 5-position of the aromatic ring.


ROMANOV et al. 964

Scheme 5.

OMe

NMe

O

OH

OMeHO

OMe

O

NHAc

IIIXIII, iii

XXXV

IV, VI, VIII, IX, iii

MeO

NMe

O

OH

OMeHO

OMe

O

NHAc

XXVIII, XXXII, XXXIV

XV, iii

OMe

NMe

O

O

OMeO

OMe

O

NHAc

BPh

XXXVI

O

R1

R2

R3R4

O

XXVIII, R1 = R2 = R3 = R4 = H; XXXII, R1 = Me, R2 = R3 = R4 = H; XXXIII, R1 = H, R2 = R3 = R4 = MeO; XXXIV, R1 = R4 = H, R2 = R3 = MeO.

The reaction of 5′-bromolappaconitine (III) with an equimolar amount of phenylboronic acid (IV) in the system Pd(PPh3)4–K2CO3–Bu4NBr–PhMe–H2O (Scheme 4, ii) in 10 h smoothly afforded 5′-phenyllap-paconitine (XXVIII) (75% according to the 1H NMR data). The use of 2 equiv of IV ensured complete con-version of substrate III with formation of 5′-phenyl-8,9-O-(phenylboranediyl)lappaconitine (XXIX), i.e., the cross-coupling was accompanied by esterification of phenylboronic acid with the 8,9-diol fragment of the diterpene fragment of III (87%, according to the 1H NMR data). Compound XXIX was also synthesized independently by reaction of 5′-phenyllappaconitine (XXVIII) with phenylboronic acid (IV) in the pres-ence of anhydrous sodium sulfate (vii). 5′-Bromo-8,9-O-(phenylboranediyl)lappaconitine (XXX) was formed in 89% yield (1H NMR) in the reaction of bromide III with phenylboronic acid (IV) in the absence of Pd(PPh3)4. Lappaconitine (I) itself was also converted into the corresponding 8,9-ester XXXI on treatment with boronic acid IV in diethyl ether in the presence of sodium sulfate. Thus, we have revealed facile forma-tion of phenylboronic acid esters with participation of the cis-8,9-diol moiety of lappaconitine and its derivatives.

We also studied the behavior of 5′-bromo-8,9-O-(phenylboranediyl)lappaconitine (XXX) under the

Suzuki reaction conditions. Heating of XXX for 10 h (procedure ii) led to the formation of a mixture of products consisting of 5′-bromolappaconitine (III, 38%), 5′-phenyllappaconitine (XXVIII, 19%), and 5′-phenyl-8,9-O-(phenylboranediyl)lappaconitine (XXIX, 24%) together with unreacted initial com-pound XXX (19%). When the resulting mixture was heated for an additional 10 h, the fractions of com-pounds XXVIII and III increased to 60 and 40%, respectively, i.e., the reaction involved cleavage of the ester bonds in the 8,9-positions of aconitane alkaloids and formation of the cross-coupling product.

Taking into account difficult separation of the cross-coupling products from triphenylphosphine oxide in the reactions carried out in the presence of Pd(PPh3)4, 5′-bromolappaconitine (III) was brought into reactions with phenylboronic acids IV, VI, VIII, and IX and furylboronic acids XIII and XV using Pd(OAc)2–P(o-Tol)3 as catalytic system (Scheme 5, iii). In these cases, the corresponding cross-coupling products XXVIII and XXXII–XXXVI were obtained in 45–83% yield. The best yields were observed with the use of methoxy-substituted phenylboronic acids VIII and IX. The yield of XXVIII was 65%, which is comparable with the result of the cross-coupling cata-lyzed by Pd(PPh3)4 (ii, 68%). It is seen that 5′-bromo-lappaconitine (III) is highly reactive in the cross-cou-



965

plings with aryl- and furylboronic acids. The catalytic system Pd(dba)2–AsPh3 (Scheme 1, iv) which ensured good results in the reactions with bromide II turned out to be inefficient for the synthesis of aryl-substitut-ed derivatives from 5′-bromolappaconitine (III). In the latter case, the conversion did not exceed 10–15%.

The structure of the isolated compounds was deter-mined on the basis of their spectral parameters and elemental compositions. The 1H and 13C NMR spectra of methyl 2-acetylaminobenzoate derivatives V, VII, X, XI, XIV, XVI, XIX–XXI, and XXVII and 5′-sub-stituted lappaconitine derivatives XXVIII, XXIX, XXXII–XXXVI displayed only one set of signals from the aryl (hetaryl) substituent. The formation of compounds XXIX and XXX was confirmed by the presence of a signal at δB 31.78 ppm in the 11B NMR spectrum of XXX. Compounds XXIX–XXXI charac-teristically showed in the 13C NMR spectra a consider-able downfield shift of the C8 and C9 signals (∆δC = 8–9 ppm) and upfield shifts of the signals from C15 (∆δC = 6–7 ppm) and C14, C10 (∆δC = 3–4 ppm).

In summary, accessible methyl 2-acetylamino-5-bromobenzoate (II) and 5′-bromolappaconitine (III) have been successfully used to synthesize various aryl and hetaryl-substituted derivatives of anthranilic acid and lappaconitine. Specific features of the cross-cou-pling reactions have been revealed, depending on the catalytic system and solvent. Facile esterification of the cis-8,9-diol fragment of lappaconitine (I) and its derivatives with excess phenylboronic acid (IV) has been observed.

EXPERIMENTAL

The NMR spectra were recorded from solutions in CDCl3 on Bruker AV-300 (300.13 and 75.47 MHz for 1H and 13C, respectively), Bruker AV-400 (400.13 and 100.78 MHz), and Bruker AV-600 (600.30 and 150.96 MHz) spectrometers. The chemical shifts were measured relative to tetramethylsilane. The multiplic-ities of signals in the 13C NMR spectra were deter-mined using standard J-modulation techniques. In the description of the NMR spectra of lappaconitine deriv-atives XXVIII–XXXVI, atom numbering of the aconi-tane skeleton was used (see structure XXVIII in Scheme 4. The signals were assigned with account taken of the data for lappaconitine (I) [20]; only char-acteristic signals in the 1H NMR spectra of XXVIII–XXXVI are given because of difficult assignment of all signals. The IR spectra were recorded in KBr on a Bruker Vector-22 instrument. The UV spectra were

measured on an HP 8453 UV Vis spectrophotometer from solutions in ethanol. The optical rotations [α]D

20 were determined using a PolAAr3005 polarimeter. The molecular weights and elemental compositions were determined from the high-resolution mass spectra which were obtained on DFS Thermo Scientific and Finnigan MAT-8200 mass spectrometers (electron impact, 70 eV; vaporizer temperature 210–280°C). The molecular weight of XXIX was determined by HPLC/MS analysis of its solution in ethanol on an Agilent 1200 liquid chromatograph coupled with a Bruker micrOTOF-Q hybrid quadrupole time-of-flight mass spectrometer (atmospheric pressure elec-trospray ionization; solvent flow rate 0.3 mL/min; nebulizer gas nitrogen, flow rate 10 L/min, 30 psi; 340°C). The elemental analyses were obtained on a Carlo Erba 1106 CHN analyzer (Italy).

The progress of reactions and the purity of products were monitored by TLC on Silufol UV-254 plates using chloroform–ethanol (20 : 1) as eluent. Silica gel (70–230 μm, Acros Organics) was used for column chromatography. Analytical samples were isolated by thin-layer chromatography on 20 × 20-cm glass plates coated with KSK silica gel (0–70 μm) or Acros silica gel (0.035–0.70 mm, pore diameter 6 nm), layer thick-ness 1 mm; eluent chloroform or chloroform–ethanol (20 : 1). Commercial PdCl2(dppf) (Alfa Aesar) was used; Pd(PPh3)4, Pd(OAc)2, and Pd(dba)2 were synthe-sized according to the procedures described in [21–23]. Arylboronic acids IV, VI, VIII, and IX, hetaryl-boronic acids XIII, XV, XVII, XVIII, XXI, and XXIV, tris(o-tolyl)phosphine, and tetrabutylammo-nium bromide were commercial products (Alfa Aesar).

The solvents used (toluene, dioxane, diethyl ether, DMF) were purified by standard methods and were distilled in a stream of argon just before use.

Methyl 2-acetylamino-5-bromobenzoate (II) and 5′-bromolappaconitine (III) were prepared as reported in [5].

Methyl 5-aryl(hetaryl)-2-acetylaminobenzoates (general procedures). i. A reaction vessel was charged with 1 mmol (272 mg) of methyl 2-acetylamino-5-bromobenzoate (II), 1.3 mmol of aryl(hetaryl)boronic acid IV , VI , XIII , or XV , 60 mg (5 mol %) of Pd(PPh3)4, 32 mg (10 mol %) of Bu4NBr, 3 mmol (414 mg) of K2CO3, and 5 mL of anhydrous dioxane; the vessel was evacuated and filled with argon, and this procedure was repeated twice. The mixture was heated for 20 h under reflux with stirring and evaporat-ed, the residue was dissolved in chloroform, and the


ROMANOV et al. 966

solution was applied onto a glass chromatographic plate coated with silica gel. The plate was eluted with chloroform−ethanol (20 : 1), the zone strongly absorb-ing in the UV region was separated, the product was washed off with ethanol, the solution was evaporated, and the residue was dried under reduced pressure.

ii. A reaction vessel was charged with 1 mmol (272 mg) of compound II, 1.3 mmol of aryl(hetaryl)-boronic acid IV, VI, XIII, or XV, 60 mg (5 mol %) of Pd(PPh3)4, 32 mg (10 mol %) of Bu4NBr, 3 mmol (414 mg) of K2CO3, 4 mL of toluene, and 1 mL of water. The vessel was evacuated and filled with argon, and this procedure was repeated twice. The mixture was heated under stirring to 100°C, kept for 6 h at that temperature, and evaporated, the residue was dissolved in chloroform, the solution was washed with water, and dried over MgSO4, the solvent was distilled off, and the residue was subjected to silica gel column chromatography using chloroform as eluent.

iii. A reaction vessel was charged with 1 mmol (272 mg) of compound II, 1 mmol of aryl(hetaryl)-boronic acid VIII, IX, XV, or XVII, 12 mg (5 mol %) of Pd(OAc)2, 31 mg (10 mol %) of P(o-Tol)3, 32 mg (10 mol %) of Bu4NBr, 3 mmol (414 mg) K2CO3, 4 mL of toluene, and 1 mL of water. The system was evacuated and filled with argon, and this procedure was repeated twice. The mixture was heated to 100°C under stirring, kept for 9 h at that temperature, and evaporated. The residue was dissolved in chloroform, the solution was washed with water, and dried over MgSO4, the solvent was distilled off, and the residue was subjected to silica gel column chromatography using chloroform as eluent.

iv. A reaction vessel was charged with 1 mmol (272 mg) of compound II, 1 mmol of aryl(hetaryl)-boronic acid IV, VI, XIII, XV, XVII, or XVIII, 30 mg (5 mol %) of Pd(dba)2, 30 mg (10 mol %) of AsPh3, 1 mmol (138 mg) of K2CO3, 1 mmol (230 mg) of Bu4NBr, and 5 mL of anhydrous DMF. The system was evacuated and filled with argon, and this proce-dure was repeated twice. The mixture was heated to 120°C under stirring, kept for 6 h at that temperature, cooled, and poured into a Petri dish to allow DMF to evaporate. The dry residue was subjected to chroma-tography on a plate coated with silica gel (chloroform–ethanol, 19 : 1). The colorless zone strongly absorbing in the UV region was separated, the product was washed off with ethanol, and the solution was evaporated.

v. A reaction vessel was charged with 1 mmol (272 mg) of compound II, 1 mmol (170 mg) of

5-acetylthiophen-2-ylboronic acid (XXI), 28 mg (5 mol %) of PdCl2(dppf), 32 mg (10 mol %) of Bu4NBr, 3 mmol (414 mg) K2CO3, 4 mL of toluene, and 1 mL of water. The system was evacuated and filled with argon, and this procedure was repeated twice. The mixture was heated for 9 h at 100°C under stirring and evaporated, the residue was dissolved in chloroform, and the solution was washed with water and dried over MgSO4.

vi. A reaction vessel was charged with 1 mmol (272 mg) of compound II, 1 mmol (170 mg) of boronic acid XXI, 60 mg (5 mol %) of Pd(PPh3)4, 3 or 1.5 mmol (414 or 207 mg) of K2CO3, 4 mL of DMF, and 1 mL of water. The system was evacuated and filled with argon, and this procedure was repeated twice. The mixture was heated to 100°C, kept for 9 h at that temperature or for 30 h at 65°C, and evaporated, the residue was dissolved in chloroform, the solution was washed with water and dried over MgSO4, the solvent was distilled off, and the residue was subjected to silica gel column chromatography using chloroform as eluent.

Methyl 2-acetylamino-5-phenylbenzoate (V). Yield 89 (a), 60 (b), 64% (d); amorphous powder (after evaporation of chloroform), mp 133–135°C. IR spec-trum, ν, cm–1: 3298, 3265, 3030, 2993, 2947, 1699, 1684, 1595, 1520, 1441, 1288, 1234, 1092, 854, 789, 764, 694, 656, 604. 1H NMR spectrum, δ, ppm (J, Hz): 2.30 s (3H, CH3CO), 3.99 s (3H, OCH3), 7.38 t (1H, 4′-H, J = 8), 7.48 t (2H, 3′-H, 5′-H, J = 8), 7.60 d (2H, 2′-H, 6′-H, J = 8), 7.79 d.d (1H, 4-H, J = 2.2, 8), 8.29 d (1H, 6-H, J = 2.2), 8.80 d (1H, 3-H, J = 8), 11.10 s (1H, NH). 13C NMR spectrum, δC, ppm: 25.37 (CH3CO), 52.26 (OCH3), 114.96 (C1), 120.61 (C3), 126.57 (C2′, C6′), 127.29 (C4), 128.74 (C3′, C5′), 128.95 (C4′), 132.93 (C6), 135.13 (C5), 139.42 (C1′), 140.55 (C2), 168.56 (CH3CO), 168.93 (C=O). Mass spectrum: m / z 269 .1045 [M ] +. C 16H 15NO 3. Ca lcu l a t ed: M 269.1047.

Methyl 2-acetylamino-5-(2-methylphenyl)ben-zoate (VII). Yield 18 (a), 27 (b), 67% (d); amorphous powder (after evaporation of chloroform), mp 124–125°C. IR spectrum, ν, cm–1: 3300, 3265, 3044, 3005, 2953, 1697, 1686, 1593, 1520, 1487, 1427, 1394, 1321, 1294, 1285, 1234, 1086, 953, 849, 791, 770, 739, 731, 654. 1H NMR spectrum, δ, ppm (J, Hz): 2.25 s (6H, CH3CO, CH3), 3.90 s (3H, OCH3), 7.19–7.25 m (4H, 3′-H, 4′-H, 5′-H, 6′-H), 7.51 d.d (1H, 4-H, J = 2.1, 8), 7.98 d (1H, 6-H, J = 2.1), 8.71 d (1H, 3-H, J = 8), 11.05 s (1H, NH). 13C NMR spectrum, δC, ppm: 20.31 (CH3), 25.38 (CH3CO), 52.24 (OCH3), 114.47 (C1),



967

119.98 (C3), 125.81 (C4), 127.45 (C5′), 129.56 (C6′), 130.31 (C4′), 131.14 (C3′), 135.25 (C6), 135.51 (C1′), 136.01 (C2′), 140.23 (C2, C5), 167.50 (CH3CO), 168.97 (C=O) . Mass spec t rum: m / z 283 .1201 [M ]+. C17H17NO3. Calculated: M 283.1203.

Methyl 2-acetylamino-5-(3,4,5-trimethoxyphe-nyl)benzoate (X). Yield <5 (a), 14% (c); amorphous powder (after evaporation of chloroform), mp 134–136°C. IR spectrum, ν, cm–1: 3319, 3275, 3049, 2957, 2843, 1686, 1593, 1504, 1464, 1456, 1437, 1296, 1242, 1130, 1096, 1003, 924, 829, 800, 629. 1H NMR spectrum, δ, ppm (J, Hz): 2.24 s (3H, COCH3), 3.87 s (3H, OCH3), 3.92 s (6H, 3′-OCH3, 5′-OCH3), 3.92 s (3H, 4′-OCH3), 6.72 s (2H, 2′-H, 6′-H), 7.69 d.d (1H, 4-H, J = 2.3, 8), 8.16 d (1H, 6-H, J = 2.3), 8.74 d (1H, 3-H, J = 8), 11.03 s (1H, NH). 13C NMR spectrum, δC, ppm: 25.09 (CH3CO), 52.03 (OCH3), 55.90 (3′-OCH3, 5′-OCH3), 60.55 (4′-OCH3), 103.83 (C2′, C6′), 114.67 (C1), 120.36 (C3), 128.55 (C4), 132.68 (C6), 135.09 (C5), 135.26 (C1′), 137.44 (C4′), 140.27 (C2), 153.16 (C3 ′, C5 ′), 168.22 (CH3CO), 168.61 (C=O). Mass spectrum: m/z 359.1361 [M]+. C19H21NO6. Calculated: M 359.1363.

Methyl 2-acetylamino-5-(3,4-dimethoxyphenyl)-benzoate (XI). Yield <5 (a), 46% (c); amorphous powder (after evaporation of chloroform), mp 175–177°C. IR spectrum, ν, cm–1: 3119, 3005, 2957, 2939, 2910, 2839, 1690, 1593, 1508, 1464, 1317, 1296, 1238, 1175, 1142, 1092, 1026, 910, 845, 808, 717, 669, 600. 1H NMR spectrum, δ, ppm (J, Hz): 2.22 s (3H, COCH3), 3.89 s (3H, OCH3), 3.93 s (6H, 3′-OCH3, 4′-OCH3), 6.90 d (1H, 5′-H, J = 6), 7.03 d (1H, 3′-H, J = 1.9), 7.07 d.d (1H, 6′-H, J = 1.9, 6), 7.68 d.d (1H 4-H, J = 2, 6), 8.16 d (1H, 6-H, J = 2), 8.71 d (1H, 3-H, J = 6), 11.00 s (1H, NH). 13C NMR spectrum, δC, ppm: 25.38 (CH3CO), 52.29 (OCH3), 55.87 and 55.93 (3′-OCH3, 5′-OCH3), 109.93 (C5′), 111.39 (C6′), 114.96 (C1), 119.03 (C2′), 120.62 (C3), 128.55 (C4), 132.52 (C1′), 132.70 (C6), 135.07 (C5), 140.18 (C2), 148.64 (C3 ′), 149.14 (C4 ′), 168.58 (CH3CO), 168.87 (C=O). Mass spectrum: m/z 329.1254 [M]+. C18H19NO5. Calculated: M 329.1258.

Methyl 2-acetylamino-5-(furan-2-yl)benzoate (XIV). Yield <5 (a), 10 (c), 51% (d), amorphous powder (after evaporation of chloroform), mp 130–132°C. IR spectrum, ν, cm–1: 3319, 3119, 3007, 2955, 1690, 1593, 1522, 1323, 1439, 1410, 1369, 1298, 1242, 1159, 1092, 1015, 845, 797, 658. 1H NMR spec-trum, δ, ppm (J, Hz): 2.23 s (3H, CH3CO), 3.94 s (3H, OCH3), 6.47 m (1H, 4′-H), 6.61 d (1H, 3′-H, J = 4),

7.46 d (1H, 5′-H, J = 4), 7.78 d.d (1H, 4-H, J = 2.1, 8), 8.29 d (1H, 6-H, J = 2.1), 8.71 d (1H, 3-H, J = 8), 11.04 s (1H, NH). 13C NMR spectrum, δC, ppm: 25.36 (CH3CO), 52.30 (OCH3), 104.78 (C3′), 111.63 (C4′), 114.84 (C1), 120.46 (C3), 125.27 (C5), 125.73 (C6), 129.63 (C4), 140.37 (C2), 141.99 (C5′), 152.59 (C2′), 168.41 (C=O), 168.84 (CH3CO). Mass spectrum: m / z 259 .0836 [M ] +. C 14H 13NO 4. Ca lcu la t ed: M 259.0839.

Methyl 2-acetylamino-5-(furan-3-yl)benzoate (XVI). Yield <5 (a), 40 (c), 52% (d); amorphous powder (after evaporation of chloroform), mp 72– 75°C. IR spectrum, ν, cm–1: 3319, 3276, 3006, 2956, 2850, 1762, 1689, 1591, 1517, 1438, 1369, 1328, 1244, 1164, 1296, 1089, 1020, 875, 844, 667. 1H NMR spectrum, δ, ppm (J, Hz): 2.21 s (3H, CH3CO), 3.92 s (3H, OCH3), 6.67 d (1H, 4′-H, J = 2), 7.45 m (1H, 2′-H), 7.32 d (1H, 5′-H, J = 2), 7.59 d.d (1H, 4-H, J = 2, 8), 8.08 d (1H, 6-H, J = 2), 8.67 d (1H, 3-H, J = 8), 11.03 s (1H, NH). 13C NMR spectrum, δC, ppm: 25.33 (CH3CO), 52.28 (OCH3), 108.46 (C4′), 115.00 (C1), 120.67 (C3), 125.13 (C5), 126.72 (C3′) 127.64 (C6), 131.76 (C4), 138.30 (C2′), 140.19 (C2), 143.71 (C5′), 168.44 (C=O), 168.87 (COCH3). Mass spec-trum: m/z 259.0835 [M]+. C14H13NO4. Calculated: M 259.0839.

Methyl 2-acetylamino-5-(pyridin-3-yl)benzoate (XIX). Yield 41% (d), amorphous powder (after evap-oration of chloroform), mp 86–88°C. IR spectrum, ν, cm–1: 634, 856, 871, 1022, 1058, 1161, 1242, 1299, 1325, 1359, 1415, 1431, 1514, 1583, 1681, 1766, 2850, 2942, 3001, 3276, 3310. 1H NMR spectrum, δ, ppm (J, Hz): 2.12 s (3H, CH3CO), 3.91 s (3H, OCH3), 7.49 d.d (1H, 5′-H, J = 1.9, 8), 7.63 d.d (1H, 4-H, J = 1.9, 8), 7.84 d (1H, 6-H, J = 2.1), 7.97 d (1H, 4′-H, J = 2.1) 8.75 d (1H, 3-H, J = 8), 8.85 s (1H, 2′-H), 11.07 s (1H, NH). 13C NMR spectrum, δC, ppm: 25.41 (CH3CO), 52.11 (OCH3), 113.56 (C1), 117.66 (C3), 121.50 (C5′), 127.43 (C4), 132.51 (C6), 132.78 (C4′), 140.23 (C5), 140.33 (C3′), 142.37 (C2′), 150.36 (C6′), 169.10 (C=O), 169.45 (CH3CO). Mass spectrum: m/z 270.2831 [M]+. C15H14N2O3. Calculated: M 270.2833.

Methyl 2-acetylamino-5-(pyridin-4-yl)benzoate (XX). Yield 42% (d); amorphous powder (after evap-oration of chloroform), mp 91–92°C. IR spectrum, ν, cm–1: 3315, 3270, 2998, 2941, 2852, 1760, 1686, 1581, 1513, 1434, 1355, 1329, 1295, 1249, 1162, 1051, 1028, 875, 851, 636. 1H NMR spectrum, δ, ppm (J, Hz): 2.12 s (3H, CH3CO), 3.91 s (3H, OCH3), 7.57 d (2H, 3′-H, 5′-H, J = 1.9), 7.68 d.d (1H, 4-H, J =


ROMANOV et al. 968

2, 8), 7.87 d (1H, 6-H, J = 2), 8.71 d (1H, 3-H, J = 8), 8.67 d (2H, 2′-H, 6′-H, J = 1.9), 11.01 s (1H, NH). 13C NMR spectrum, δC, ppm: 25.31 (CH3CO), 52.09 (OCH3), 114.34 (C1), 118.44 (C3), 121.61 (C3′, C5′), 127.22 (C4), 133.15 (C6), 138.74 (C5), 146.79 (C4′), 147.40 (C2′, C6′), 147.76 (C2), 169.11 (C=O), 169.47 (COCH3). Mass spectrum: m/z 270.2835 [M]+. C15H14N2O3. Calculated: M 270.2833.

Methyl 2-acetylamino-5-(5-acetylthiophen-2-yl)-benzoate (XXII). Yield 38% (f), amorphous powder (after evaporation of chloroform), mp 177–179°C. IR spectrum, ν, cm–1: 3317, 3277, 3007, 2928, 2853, 1692, 1657, 1535, 1514, 1448, 1410, 1366, 1300, 1275, 1238, 1090, 1003, 964, 894, 843, 806, 665. 1H NMR spectrum, δ , ppm (J , Hz): 2.24 s (3H, COCH3), 2.54 s (3H, 5′-COCH3), 3.95 s (3H, OCH3), 7.27 d (1H, 4′-H, J = 4), 7.62 d (1H, 3′-H, J = 4), 7.76 d.d (1H, 4-H, J = 2.2, 8), 8.28 d (1H, 6-H, J = 2.2), 8.75 d (1H, 3-H, J = 8), 11.08 s (1H, NH). 13C NMR spectrum, δC, ppm: 25.44 (CH3CO), 26.43 (5′-COCH3) 52.52 (OCH3), 115.03 (C1), 120.76 (C3), 123.64 (C3′), 127.43 (C2′), 128.35 (C4), 131.82 (C4′), 133.35 (C6), 141.82 (C2), 142.97 (C5), 151.02 (C5′), 168.08 (COCH3), 169.02 (C=O), 190.36 (5′-COCH3). Mass spectrum: m/z 317.0713 [M]+. C16H15NO4S. Cal-culated: M 317.0716.

2-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-lan-2-yl)quinoline (XXV). 2-Fluoroquinolin-3-ylbor-onic acid (XXIV), 1.5 mmol, was dissolved in 5 mL of diethyl ether, 1.5 mmol (135 mg) of 2,3-dimethyl-butane-2,3-diol (XXVI) and excess Na2SO4 were added, and the mixture was stirred at room temperature until the reaction was complete (TLC). The precipitate was filtered off and washed with diethyl ether, and the filtrate was combined with the washings and used in further syntheses without additional purification.

Methyl 2-acetylamino-5-(2-fluoroquinolin-3-yl)-benzoate (XXVII). Yield 15% (b), amorphous powder (after evaporation of chloroform), mp 190–192°C. IR spectrum, ν, cm–1: 3319, 3277, 3009, 2957, 2930, 2853, 1690, 1591, 1520, 1460, 1427, 1402, 1371, 1354, 1300, 1252, 1092, 1014, 1005, 970, 957, 914, 894, 847, 704. 1H NMR spectrum, δ, ppm (J, Hz): 2.25 s (3H, COCH3), 3.95 s (3H, OCH3), 7.52 t (1H, 6′-H, J = 2.1), 7.69 t (1H, 7′-H, J = 2.1), 7.79 d.d (1H, 4-H, J = 8, 2) 7.85 d (1H, 5′-H, J = 8), 7.93 d (1H, 8′-H, J = 8), 8.23 d (1H, 6-H, J = 8), 8.31 s (1H, 4′-H), 8.82 d (1H, 3-H, J = 8), 11.03 s (1H, NH). 13C NMR spectrum, δC, ppm: 25.44 (CH3CO), 52.47 (OCH3), 114.90 (C1), 120.57 (C3), 122.93 (C3′), 126.47 (C8′), 127.44 (C6′), 127.72 (C4), 128.02 (C4′a), 130.46 (C5′),

131.20 (C7′), 137.87 (C6), 139.98 (C4′), 141.56 (C5), 144.64 (C2), 144.87 (C8 ′a), 156.48 (C2 ′), 168.30 (COCH3), 169.09 (C=O). Mass spectrum: m/z 338.1064 [M]+. C19H15N2O3F. Calculated: M 338.1061.

5′-Aryl(hetaryl)benzoyloxyaconitanes XXVIII, XXIX, and XXXII–XXXVI were synthesized accord-ing to procedures ii and iii using 1 mmol (663 mg) of 5′-bromolappaconitine (III).

vii. A reaction vessel was charged with 1 mmol (663 mg) of 5′-bromolappaconitine (III), 1.3 mmol of phenylboronic acid (IV), 32 mg (10 mol %) of Bu4NBr, 3 mmol (414 mg) of K2CO3, 4 mL of toluene, and 1 mL of water. The vessel was evacuated and filled with argon, and this procedure was repeated twice. The mixture was heated to 100°C, stirred for 6 h at that temperature, cooled, and evaporated, the residue was dissolved in chloroform, the solution was washed with water and dried over MgSO4, the solvent was distilled off, and the residue was subjected to silica gel column chromatography using chloroform as eluent.

viii. Compound I, III, or XXVIII, 0.5 mmol, was dissolved in 5 mL of diethyl ether, 0.5 mmol (61 mg) of phenylboronic acid (IV) and excess Na2SO4 were added, and the mixture was stirred at room temperature until the reaction was complete (TLC). The precipitate was filtered off and washed with diethyl ether, the filtrate was combined with the washings and evaporat-ed, the residue was dissolved in chloroform, and the solution was passed through a thin layer of silica gel to isolate compounds XXIX–XXXI.

(8β,9β-Dihydroxy-1α,14α,16β-trimethoxy-20-ethylaconitan-4β-yl) 2-acetylamino-5-phenylbenzo-ate (XXVIII). Yield 68% (b), amorphous powder (after evaporation of chloroform), mp 112–115°C. IR spectrum, ν, cm–1: 3498, 3400, 3313, 2925, 2875, 2819, 1701, 1681, 1591, 1519, 1232, 1147, 1114, 1087, 761, 698. 1H NMR spectrum, δ, ppm (J, Hz): 1.11 t (3H, C22H3, J = 6), 1.58 d.d (1H, 6-HB, J = 15, 7), 1.75 m (1H, 3-HB), 2.22 s (3H, COCH3), 2.64 m (1H, 6-HA), 3.00 s (1H, 17-H), 3.18 d.d (1H, 1β-H, J = 10.4, 6); 3.29 s, 3.31 s, and 3.41 s (3H each, 1-OCH3, 14-OCH3, 16-OCH3); 3.41 d (1H, 14β-H, J = 5), 3.55 d (1H, 19-HA, J = 11), 7.33 t (1H, 4″-H, J = 8), 7.43 t (2H, 3″-H, 5″-H, J = 8), 7.51 d (2H, 2″-H, 6″-H, J = 8), 7.70 d.d (1H, 4′-H, J = 2.0, 8), 8.10 d (1H, 6′-H, J = 2.0), 8.72 d (1H, 3′-H, J = 8), 11.05 s (1H, NH). 13C NMR spectrum, δC, ppm: 13.45 (C22), 23.96 (C6), 25.48 (COCH3), 26.12 (C2), 26.73 (C12), 31.78 (C3), 36.25 (C13), 44.81 (C15), 47.52 (C7), 48.29 (C5), 48.88 (C21), 49.72 (C10), 50.95 (C11), 55.50 (C19), 56.04



969

(16-OCH3), 56.44 (1-OCH3), 57.86 (14-OCH3), 61.41 (C17), 75.54 (C8), 78.45 (C9), 82.81 (C16), 84.09 (C1), 84.92 (C4), 90.09 C14), 116.11 (C1′), 120.64 (C3′), 126.73 (C2″, C6″), 127.26 (C4′), 128.81 (C3″, C5″), 129.09 (C4″), 132.83 (C6′), 135.23 (C5′), 139.70 (C1″), 140.68 (C2′), 167.29 (C=O), 168.81 (COCH3). Mass spectrum: m/z 659.3314 [M]+. C38H47N2O8. Calculated: M 660.3405.

(2R,3S,3aS,6aS,7aR,10R,13S,13aS)-8-Ethyl-3,13,17-trimethoxy-5-phenyldodecahydro-10,13a,7-(epiethane[1,1,2]triyl)-2,6a-ethano[1,3,2]dioxa-borolo[4′,5′:7,7a]indeno[5,4-b]azocin-10-yl 2-acetyl-amino-5-phenylbenzoate [XXIX, 5′-phenyl-8,9-O-(phenylboranediyl)lappaconitine]. Yield 82 (ii), 81% (viii); amorphous powder (after evaporation of chloro-form), mp 111–114°C. IR spectrum, ν, cm–1: 3658, 3400, 3313, 2985, 2931, 2875, 1685, 1595, 1521, 1496, 1440, 1352, 1319, 1255, 1230, 1180, 1087, 1026, 945, 906, 858, 667, 638. 1H NMR spectrum, δ, ppm (J, Hz): 1.14 t (3H, C22H3, J = 7), 1.74 d.d (1H, 6-HB, J = 15, 7), 1.75 m (1H, 3-HB), 2.19 s (3H, COCH3), 2.55 m (1H, 6-HA), 3.09 s (1H, 17-H), 3.24 d.d (1H, 1β-H, J = 10.8, 6); 3.29 s, 3.31 s, and 3.34 s (3H each, 1-OCH3, 14-OCH3, 16-OCH3); 3.40 d (1H, 14β-H, J = 5), 3.57 d (1H, 19-HA, J = 11), 7.09 t (2H, 3′′′-H, 5′′′-H, J = 8), 7.20 t (1H, 4′′′-H, J = 8), 7.33 d (2H, 2″-H, 6″-H, J = 8), 7.38 t (2H, 3″-H, 5″-H, J = 8), 7.44 d (1H, 4″-H, J = 8), 7.67 d.d (1H, 4′-H, J = 2.3, 8), 7.82 d (2H, 2′′′-H, 6′′′-H, J = 8), 8.02 d (1H, 6′-H, J = 2.3), 8.69 d (1H, 3′-H, J = 8), 10.94 s (1H, NH). 13C NMR spectrum, δC, ppm: 13.35 (C22), 25.19 (C6), 25.41 (COCH3), 26.12 (C2), 27.03 (C12), 31.66 (C3), 35.16 (C13), 37.77 (C15), 46.84 (C7), 46.95 (C5), 47.45 (C10), 48.84 (C21), 51.12 (C11), 55.67 (C19), 56.27 (16-OCH3), 56.57 (1-OCH3), 58.31 (14-OCH3), 59.95 (C17), 82.90 (C16), 84.16 (C1), 84.42 (C4), 84.47 (C8), 86.40 (C14), 87.54 (C9), 115.87 (C1′), 120.60 (C3′), 126.24 (C2′′, C6′′), 127.26 (C4′), 127.68 (C2′′′, C6′′′), 128.72 (C3″, C5″), 129.17 (C4″), 132.83 (C4′′′), 135.51 (C6′), 134.84 (C3′′′, C5′′′), 139.70 (C1″, C1′′′), 139.16 (C5′), 140.68 (C2′), 167.04 (C=O), 168.83 (COCH3). Mass spectrum (Agilent, positive ion detection): m/z 747.379 [C44H51N2O8B + H]+. Calculated: M + H 747.378.

(2R,3S,3aS,6aS,7aR,10R,13S,13aS)-8-Ethyl-3,13,17-trimethoxy-5-phenyldodecahydro-10,13a,7-(epiethane[1,1,2]triyl)-2,6a-ethano[1,3,2]dioxaboro-lo[4′,5′:7,7a]indeno[5,4-b]azocin-10-yl 2-acetyl-amino-5-bromobenzoate [XXX, 5′-bromo-8,9-O-(phenylboranediyl)lappaconitine]. Yield 78 (vii),

82% (viii); amorphous powder (after evaporation of chloroform), mp 119–122°C, [α]D

20 = +110° (c = 0.10, CHCl3). IR spectrum, ν, cm–1: 3492, 3311, 2997, 2877, 2823, 1685, 1600, 1581, 1510, 1450, 1438, 1357, 1394, 1311, 1257, 1224, 1145, 1130, 1085, 1026, 943, 902, 835, 663, 636. UV spectrum, λmax, nm (log ε): 259 (5.20), 326 (4.71). 1H NMR spectrum, δ, ppm (J, Hz): 1.11 t (3H, C22H3, J = 7), 1.60 d.d (1H, 6-HB, J = 15, 7), 2.15 s (3H, COCH3), 2.64 m (1H, 6-HA), 3.06 s (1H, 17-H), 3.22 d.d (1H, 1β-H, J = 10.8, 5.6); 3.29 s, 3.31 s, and 3.41 s (3H each, 1-OCH3, 14-OCH3, 16-OCH3); 3.39 d (1H, 14β-H, J = 5), 3.57 d (1H, 19-HA, J = 11), 7.33 t (2H, 3″-H, 5″-H, J = 8), 7.42 d (1H, 4″-H, J = 8), 7.53 d.d (1H, 4′-H, J = 2.2, 8), 7.80 d (2H, 2″-H, 6″-H, J = 8), 7.85 d (1H, 6′-H, J = 2.2), 8.56 d (1H, 3′-H, J = 8), 10.86 s (1H, NH). 13C NMR spectrum, δC, ppm: 12.98 (C22), 24.86 (C6), 25.08 (COCH3), 26.27 (C2), 26.74 (C12), 31.29 (C3), 34.83 (C13), 37.45 (C15), 46.18 (C7), 46.50 (C5), 46.56 (C10), 48.48 (C21), 50.93 (C11), 55.54 (C19), 55.97 (16-OCH3), 56.26 (1-OCH3), 57.99 (14-OCH3), 59.64 (C17), 82.56 (C16), 83.79 (C1), 84.15 (C8), 84.09 (C4), 86.06 (C14), 87.17 (C9), 114.20 (C1″), 116.84 (C1′), 121.51 (C3′), 127.30 (C2″, C6″), 130.88 (C4′), 132.90 (C4″), 134.47 (C3″, C5″), 136.66 (C6′), 140.19 (C2′, C5′), 167.29 (C=O), 168.81 (COCH3). 11B NMR spectrum: δB 31.78 ppm. Found, %: C 58.96; H 6.07; Br 10.70; N 3.70. C38H46BBrN2O8. Calculated, %: C 60.90; H 6.19; Br 10.66; N 3.74.

(2R,3S,3aS,6aS,7aR,10R,13S,13aS)-8-Ethyl-3,13,17-trimethoxy-5-phenyldodecahydro-10,13a,7-(epiethane[1,1,2]triyl)-2,6a-ethano[1,3,2]dioxa-borolo[4′,5′:7,7a]indeno[5,4-b]azocin-10-yl 2-acetyl-aminobenzoate [XXXI, 8,9-O-(phenylboranediyl)-lappaconitine]. Yield 57% (viii), amorphous powder (after evaporation of chloroform), mp 119–122°C, [α]D

20 = +140° (c = 0.1, CHCl3). IR spectrum, ν, cm–1: 3311, 3271, 2997, 2931, 2875, 1683, 1604, 1589, 1525, 1500, 1448, 1394, 1357, 1311, 1298, 1269, 1234, 1143, 1132, 1085, 1026, 964, 945, 902, 848, 665. UV spectrum, λmax, nm (log ε): 254 (5.41), 313 (5.00). 1H NMR spectrum, δ, ppm (J, Hz): 1.11 t (3H, C22H3, J = 7), 1.63 d.d (1H, 6-HB, J = 15, 7), 2.17 s (3H, COCH3), 2.66 m (1H, 6-HA), 3.06 s (1H, 17-H), 3.21 d.d (1H, 1β-H, J = 11.0, 5.8); 3.27 s, 3.31 s, and 3.33 s (3H each, 1-OCH3, 14-OCH3, 16-OCH3); 3.39 d (1H, 14β-H, J = 5), 3.58 d (1H, 19-HA, J = 11), 6.93 t (1H, 5′-H, J = 8), 7.36 t (2H, 3″-H, 5″-H, J = 8), 7.45 t (1H, 4″-H, J = 8), 7.79 d (1H, 6′-H, J = 8), 7.81 d (2H, 2″-H, 6″-H, J = 8), 8.60 d (1H, 3′-H,


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J = 8), 10.96 s (1H, NH). 13C NMR spectrum, δC, ppm: 13.29 (C22) , 25 .01 (C6) , 25.40 (COCH3), 26.63 (C2), 27.04 (C12), 31.56 (C3), 35.08 (C13), 37.79 (C15), 46.79 (C5,7), 47.30 (C10), 48.79 (C21), 51.18 (C11), 55.65 (C19), 56.24 (16-OCH3), 56.53 (1-OCH3), 58.29 (14-OCH3), 59.93 (C17), 82.88 (C16), 84.13 (C1), 84.35 (C8), 84.42 (C9), 86.43 (C14), 87.56 (C4), 115.50 (C1′), 120.08 (C3′), 122.25 (C4′), 127.60 (C2″, C6″), 130.90 (C4″), 131.17 (C6′), 134.25 (C5′), 134.87 (C3″, C5″), 137.87 (C1″), 141.46 (C2′), 167.23 (C=O), 168.83 (COCH3). Found, %: C 66.91; H 7.01; N 4.18. C38H47BN2O8. Calculated, %: C 68.06; H 7.06; N 4.18.

20-Ethyl-8β,9β-dihydroxy-1α,14α,16β-trime-thoxyaconitan-4β-yl 2-acetylamino-5-(2-methyl-phenyl)benzoate (XXXII). Yield 53% (iii), amorphous powder (after evaporation of chloroform), mp.129–132°C. IR spectrum, ν, cm–1: 607, 665, 848, 902, 943, 964, 1016, 1035, 1087, 1147, 1222, 1234, 1294, 1323, 1392, 1452, 1483, 1517, 1591, 1679, 2823, 2875, 2931, 3010, 3309, 3539. 1H NMR spectrum, δ, ppm (J, Hz): 1.11 t (3H, C22H3, J = 7), 1.51 d.d (1H, 6-HB, J = 15, 7), 1.75 m (1H, 3-HB), 2.23 s (6H, COCH3, 2″-CH3), 2.61 m (1H, 6-HA), 2.98 s (1H, 17-H), 3.16 d.d (1H, 1β-H, J = 11, 6); 3.27 s, 3.28 s, and 3.37 s (3H each, 1-OCH3, 14-OCH3, 16-OCH3); 3.41 d (1H, 14β-H, J = 5), 3.51 d (1H, 19-HA, J = 11), 7.16–7.25 m (4H, 3″-H, 4″-H, 5″-H, 6″-H), 7.46 d.d (1H, 4′-H, J = 4, 8), 7.85 d (1H, 6′-H, J = 2.2), 8.68 d (1H, 3′-H, J = 8), 11.07 s (1H, NH). 13C NMR spectrum, δC, ppm: 13.36 (C22), 20.38 (2″-CH3), 23.90 (C6), 25.45 (COCH3), 26.12 (C2), 26.61 (C12), 31.68 (C3), 36.22 (C13), 44.76 (C15), 47.46 (C7), 48.29 (C5), 48.91 (C21), 49.68 (C10), 50.90 (C11), 55.53 (C19), 56.03 (16-OCH3), 56.42 (1-OCH3), 57.84 (14-OCH3), 61.43 (C17), 75.51 (C8), 78.38 (C9), 82.78 (C16), 84.01 (C1), 84.71 (C4), 90.03 (C14), 115.46 (C1′), 120.01 (C3′), 125.91 (C4′), 127.43 (C5″), 129.65 (C6″), 130.41 (C4″), 131.17 (C3″), 135.04 (C6′), 135.32 (C1″), 135.89 (C2″), 140.31 (C2′, C5′), 167.28 (COCH3), 168.98 (C=O). Mass spectrum: m /z 673.3477 [M ]+. C 39H49N2O8. Calculated: M 674.3562.

20-Ethyl-8β,9β-dihydroxy-1α,14α,16β-trime-thoxyaconitan-4β-yl) 2-acetylamino-5-(3,4,5-trime-thoxyphenyl)benzoate (XXXIII). Yield 64% (iii), amorphous powder (after evaporation of chloroform), mp 128–129°C. IR spectrum, ν, cm–1: 3541, 3311, 2935, 2875, 1681, 1593, 1508, 1463, 1328, 1296, 1251, 1174, 1143, 1087, 1028, 945, 908, 842, 669, 601. 1H NMR spectrum, δ, ppm (J, Hz): 1.11 t (3H, C22H3, J = 7), 1.58 d.d (1H, 6-HB, J = 15, 7), 1.75 m

(1H, 3-HB), 2.23 s (3H, COCH3), 2.65 m (1H, 6-HA), 2.99 s (1H, 17-H), 3.18 d.d (1H, 1β-H, J = 11, 6); 3.28 s, 3.29 s, and 3.39 s (3H each, 1-OCH3, 14-OCH3, 16-OCH3); 3.41 d (1H, 14β-H, J = 5), 3.49 d (1H, 19-HA, J = 11); 3.90 s, 3.91 s, and 3.93 s (3H each, 3″-OCH3, 4″-OCH3, 5″-OCH3); 6.72 s (2H, 2″-H, 6″-H), 7.69 d.d (1H, 4′-H, J = 1.8, 8), 8.16 d (1H, 6′-H, J = 1.8), 8.74 d (1H, 3′-H, J = 8), 10.99 s (1H, NH). 13C NMR spectrum, δC, ppm: 13.41 (C22), 24.03 (C6), 25.41 (C2), 25.46 (COCH3), 26.18 (C12), 29.95 (C3), 36.23 (C15), 36.31 (C13), 44.80 (C7), 47.50 (C21), 48.92 (C5), 49.70 (C11), 50.93 (C10), 55.48 (16-OCH3), 55.69 (1-OCH3); 55.79, 55.80, 55.82 (3″-OCH3, 4″-OCH3, 5″-OCH3); 55.94 (C19), 57.81 (14-OCH3), 61.36 (C17), 75.48 (C8), 78.41 (C9), 82.78 (C16), 84.02 (C1), 84.70 (C4), 90.06 (C14), 109.88 (C5″), 111.58 (C6″), 116.06 (C1′), 118.97 (C2″), 120.64 (C3′), 128.84 (C4′), 132.33 (C1″), 132.39 (C6′), 134.99 (C5′), 140.27 (C2′), 141.65 (C3″), 149.14 (C4″), 167.21 (C=O), 168.90 (COCH3). Mass spectrum: m/z 750.8040 [M]+. C41H54N2O11. Cal-culated: M 750.8043.

20-Ethyl-8β,9β-dihydroxy-1α,14α,16β-trime-thoxyaconitan-4β-yl) 2-acetylamino-5-(3,4-dime-thoxyphenyl)benzoate (XXXIV). Yield 83% (iii), amorphous powder (after evaporation of chloroform), mp 123–125°C. IR spectrum, ν, cm–1: 3541, 3314, 2932, 2871, 2833, 1688, 1590, 1511, 1467, 1323, 1286, 1253, 1174, 1140, 1081, 1027, 935, 917, 842, 665, 612. 1H NMR spectrum, δ, ppm (J, Hz): 1.11 t (3H, C22H3, J = 7), 1.58 d.d (1H, 6-HB, J = 15, 7), 1.75 m (1H, 3-HB), 2.23 s (3H, COCH3), 2.65 m (1H, 6-HA), 2.99 s (1H, 17-H), 3.18 d.d (1H, 1β-H, J = 11, 6); 3.28 s, 3.29 s, and 3.39 s (3H each, 1-OCH3, 14-OCH3, 16-OCH3); 3.41 d (1H, 14β-H, J = 5), 3.49 d (1H, 19-HA, J = 11), 3.90 s and 3.93 s (3H each, 3″-OCH3, 4″-OCH3), 6.91 d (1H, 5″-H, J = 8), 7.03 s (1H, 2″-H), 7.06 d (1H, 6″-H, J = 8), 7.70 d.d (1H, 4′-H, J = 2.0, 8), 8.08 d (1H, 6′-H, J = 8), 8.69 d (1H, 3′-H, J = 8), 10.99 s (1H, NH). 13C NMR spectrum, δC, ppm: 13.41 (C22), 24.03 (C6), 25.41 (C2), 25.46 (COCH3), 26.18 (C12), 29.95 (C3), 36.23 (C15), 36.31 (C13), 44.80 (C7), 47.50 (C21), 48.92 (C5), 49.70 (C11), 50.93 (C10), 55.48 (16-OCH3), 55.69 (1-OCH3), 55.79 and 55.82 (3″-OCH3, 4″-OCH3), 55.94 (C19), 57.81 (14-OCH3), 61.36 (C17), 75.48 (C8), 78.41 (C9), 82.78 (C16), 84.02 (C1), 84.70 (C4), 90.06 (C14), 109.88 (C5″), 111.58 (C6″), 116.06 (C1′), 118.97 (C2″), 120.64 (C3′), 128.84 (C4′), 132.33 (C1″), 132.39 (C6′), 134.99 (C5′), 140.27 (C2′) 141.65 (C3″), 149.14 (C4″), 167.21 (C=O), 168.90 (COCH3). Mass spectrum: m/z 720.8480 [M]+. C40H52N2O10. Calculated: M 720.8483.



971

20-Ethyl-8β,9β-dihydroxy-1α,14α,16β-trime-thoxyaconitan-4β-yl) 2-acetylamino-5-(furan-2-yl)-benzoate (XXXV). Yield 52% (iii), amorphous powder (after evaporation of chloroform), mp 128–130°C. IR spectrum, ν, cm–1: 3539, 3311, 3006, 2933, 2875, 2823, 1681, 1591, 1519, 1450, 1367, 1323, 1296, 1257, 1236, 1215, 1145, 1087, 1014, 943, 894, 844, 669. 1H NMR spectrum, δ, ppm (J, Hz): 1.21 t (3H, C22H3, J = 7), 1.59 d.d (1H, 6-HB, J = 15, 7), 1.75 m (1H, 3-HB), 2.22 s (3H, COCH3), 2.68 m (1H, 6-HA), 3.01 s (1H, 17-H), 3.19 d.d (1H, 1β-H, J = 11, 6); 3.29 s, 3.30 s, and 3.40 s (3H each, 1-OCH3, 14-OCH3, 16-OCH3); 3.42 d (1H, 14β-H, J = 5), 3.57 d (1H, 19-HA, J = 11), 6.43 m (1H, 4″-H), 6.57 d (1H, 3″-H, J = 3.2), 7.44 d (1H, 5″-H, J = 1.8), 7.76 d.d (1H, 4′-H, J = 2.1, 8), 8.15 d (1H, 6′-H, J = 2.1), 8.68 d (1H, 3′-H, J = 8), 11.03 s (1H, NH). 13C NMR spectrum, δC, ppm: 13.31 (C22), 23.92 (C6), 25.48 (COCH3), 26.18 (C2), 26.71 (C12), 31.53 (C3), 36.23 (C13), 44.75 (C15), 47.76 (C7), 48.29 (C5), 48.97 (C21), 49.66 (C10), 50.93 (C11), 55.52 (C19), 56.05 (16-OCH3), 56.44 (1-OCH3), 57.87 (14-OCH3), 61.40 (C17), 75.53 (C8), 78.39 (C9), 82.76 (C16), 83.86 (C1), 84.81 (C4), 90.04 (C14), 104.85 (C3″), 111.58 (C4″), 115.94 (C1′), 120.48 (C3′), 125.27 (C5′), 125.93 (C6′), 129.49 (C4′), 140.46 (C2′), 142.05 (C5″), 152.59 (C2″), 167.09 (C=O), 168.88 (CH3CO). Mass spectrum: m/z 649.3115 [M]+. C36H45N2O9. Calculated: M 650.3198.

20-Ethyl-8β,9β-dihydroxy-1α,14α,16β-trime-thoxyaconitan-4β-yl) 2-acetylamino-5-(furan-3-yl)-benzoate (XXXVI). Yield 45% (iii), amorphous powder (after evaporation of chloroform), mp 130–133°C. IR spectrum, ν, cm–1: 3541, 3311, 3006, 2931, 2875, 1681, 1589, 1516, 1467, 1450, 1367, 1328, 1296, 1261, 1228, 1211, 1145, 1085, 1018, 945, 875, 844, 663. 1H NMR spectrum, δ, ppm (J, Hz): 1.21 t (3H, C22H3, J = 7), 1.56 d.d (1H, 6-HB, J = 15, 7), 1.80 m (1H, 3-HB), 2.21 s (3H, COCH3), 2.67 m (1H, 6-HA), 3.01 s (1H, 17-H), 3.16 d.d (1H, 1β-H, J = 11, 6); 3.28 s, 3.29 s, and 3.39 s (3H each, 1-OCH3, 14-OCH3, 16-OCH3); 3.41 d (1H, 14β-H, J = 5), 3.57 d (1H, 19-HA, J = 11), 6.63 m (1H, 4″-H), 7.45 d (1H, 5″-H, J = 1.8), 7.59 d.d (1H, 4-H, J = 2.2, 8), 7.67 d (1H, 2″-H, J = 1.8), 7.96 d (1H, 6-H, J = 2.2), 8.65 d (1H, 3-H, J = 8), 10.96 s (1H, NH). 13C NMR spec-trum, δC, ppm: 13.30 (C22) , 23.90 (C6) , 25.38 (COCH3), 26.11 (C2), 26.53 (C12), 31.61 (C3), 36.25 (C13), 44.74 (C15), 47.47 (C7), 48.29 (C5), 48.89 (C21), 49.67 (C10), 50.92 (C11), 55.46 (C19), 56.00 (16-OCH3), 56.36 (1-OCH3), 57.83 (14-OCH3), 61.33 (C17), 75.48 (C8), 78.38 (C9), 82.74 (C16), 83.88 (C1), 84.74 (C4),

90.03 (C14), 108.60 (C3″), 116.04 (C4″), 120.63 (C1′), 125.13 (C3′), 126.64 (C5′), 127.82 (C6′), 131.56 (C4′), 138.27 (C2′), 140.24 (C5″), 143.65 (C2″), 167.02 (C=O), 168.78 (COCH3). Mass spectrum: m/z 649.3116 [M]+. C36H45N2O9. Calculated: M 650.3198.

This study was performed under financial support by the Russian Foundation for Basic Research (project no. 12-03-00 535) and by the President of the Russian Federation (program for support of leading scientific schools, project no. NSh-2625.2014.3).

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