Decyanation of 6,7-Diphenylindolizine-5

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One-Pot Oxidative Coupling/Decyanation of 6,7-Diphenylindolizine-5carbonitriles and 2,3-Diphenylquinolizine-4-carbonitriles Yi-Hsuan Chen, Rong-Shiow Tang, Li-Yuan Chen, and Ta-Hsien Chuang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00041 • Publication Date (Web): 13 Mar 2019 Downloaded from http://pubs.acs.org on March 13, 2019

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The Journal of Organic Chemistry

One-Pot Oxidative Coupling/Decyanation of 6,7-Diphenylindolizine5-carbonitriles and 2,3-Diphenylquinolizine-4-carbonitriles Yi-Hsuan Chen, Rong-Shiow Tang, Li-Yuan Chen, and Ta-Hsien Chuang* School of Pharmacy, China Medical University, Taichung 40402, Taiwan Supporting Information Placeholder OCH3

R

N CN

R' OCH3

( )n

Method A: VOF3/TFA, DCM -20 o C; 1 h then, NaOH/H2O

OCH3

R

Method B: BTI/BF3.OEt2 DCM; -50 oC; 4 h R' then, NaOH/H2O

R; R' = H or OCH3; n = 1 or 2

N

( )n

O OCH3 52–89% yields

ABSTRACT: The one-pot oxidative coupling/decyanation reactions of 6,7-diphenylindolizine-5-carbonitriles and 2,3-diphenylquinolizine-4-carbonitriles were investigated using aryl−aryl oxidative coupling reagents. The phenanthroindolizidinones and phenanthroquinolizidinones were produced in 52−89% yields under VOF3/trifluoroacetic acid or [bis(trifluoroacetoxy)iodo]benzene/BF3mediated conditions. This represents a mild and efficient approach to construct these types of pentacyclic skeletons from the corresponding cyano group-activated aza-Diels−Alder cycloadducts. A plausible mechanism of the one-pot oxidative coupling/decyanation reaction was proposed.

Tylophorine, a phenanthroindolizidine alkaloid, was first isolated from Tylophora asthmatica (Asclepiadaceae) in 1935.1 Phenanthroindolizidines and phenanthroquinolizidines exhibit significant biological activities such as anticancer, antiamoebic, antibacterial, and antifungal activities. Some comprehensive reviews on their isolation, synthesis, and biological activities have been published.2−9 Recently, we developed a synthetic strategy based on reductive decyanation of cyano-promoted intramolecular aza-Diels−Alder (IADA) cycloadducts 1 and 2 followed by aryl−aryl coupling (Scheme 1). Pentacyclic alkaloids 3 and 4 were produced for anticancer structure−activity relationship (SAR) studies that focused on varying the substitution patterns around the phenanthrene core.10 However, the harsh reaction conditions of the key decyanation step in this synthetic strategy may not be suitable for scale-up. Therefore, milder methods to remove cyano group from 1 and 2 are still needed. Formation of an aryl−aryl bond between two electron-rich aromatic rings can be accomplished by oxidative coupling.11 VOF3,10 thallium(III) triflouroacetate (TTFA),12 and [bis(trifluoroacetoxy)iodo]benzene (BTI)13 have proven to be efficient reagents for intramolecular bi-aryl oxidative coupling reactions of 6,7-diphenylindolizines and 7,8-diphenylquinolizines. Moreover, VOCl3 was found to be a more effective oxidative coupling reagent for the transformation of 6,7-diphenylindolizinone to the corresponding phenanthroindolizidinone.14 Therefore, we decided to examine the intramolecular oxidative aryl−aryl coupling reactions of 6,7-diphenylindolizine-5-carbonitriles 1 and 2,3-diphenylquinolizine-4-carbonitriles 2 using some common oxidative coupling reagents to construct the phenanthrene ring.

Scheme 1. Previous Synthesis of Pentacyclic Alkaloids 3 and 4 and Their Retrosynthetic Analysis Previous synthesis: harsh conditions NaBH4 Ar Ar ( )n (10 equiv) N N 2-propanol Ar Ar 100-120 °C CN 1 (n = 1) OCH3 2 (n = 2) R This work:

one-pot oxidative coupling/ decyanation

OCH3 R VOF3/TFA ( )n DCM -20-0 °C R'

N

( )n

3 (n = 1) OCH3 4 (n = 2) reduction

N R'

( )n

O 5 (n = 1) OCH3 6 (n = 2)

Initially, 2,3-diphenylquinolizine-4-carbonitrile (2a) was chosen as a model substrate to determine the feasibility of the intramolecular aryl−aryl oxidative coupling reaction. Surprisingly, treatment of 2a with 5 equiv VOF3 and 14 equiv trifluoroacetic acid (TFA) at 0 °C in dichloromethane (DCM) produced a lactam product, phenanthroquinolizidione 6a (75%), instead of a 9a-azabenzo[b]triphenylene-9-carbonitrile derivative (Table 1, entry 1). Even at the lower temperature (−20 °C), lactam 6a was obtained in 87% yield (Table 1, entry 2). This suggests that the oxidative coupling reaction and decyanation can be carried out in a one-pot fashion. Some common bi-aryl oxidative coupling reagents, such as BTI, TTFA, and meta-chloroperbenzoic acid (m-CPBA), were used to investigate the unusual oxidative coupling/decyanation reaction, and the results are shown in Table 1. Treatment of cycloadduct 2a with 1.1 equiv BTI and BF3·OEt2 in DCM at −78 °C for 4 h afforded lactam 6a in 26%

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yield because of incomplete conversion (entry 3). Starting material 2a may be consumed completely by treatment with 2.2 equiv BTI and BF3·OEt2 at −50 °C for 4 h and the desired product 6a was obtained in 89% yield (entry 4). Although this reaction was completed within 1 h at room temperature, only a trace amount of product 6a was observed from the crude 1H NMR spectrum (entry 5). In addition, we found that 2.5 equiv TTFA in TFA could convert 2a to lactam 6a at 0 °C in 55% yield (entry 6). However, product 6a was somewhat difficult to purify because of the presence of trace amounts of over-oxidized product 7 which had similar polarity to 6a.15 We also reduced the amount of TTFA used, but it did not prevent the formation of dehydro side product 7 (entry 7). On the other hand, we found that m-CPBA may not be efficient for the transformation of cycloadduct 2a into lactam 6a. Employing m-CPBA/TFA, which has been used for oxidative coupling of 1,2-diarylethylenes,16 led to only trace amounts of product 6a (12%, entry 8). Table 1: One-Pot Oxidative Coupling/Decyanation Reaction of 1a Under Different Reaction Conditions H3CO reagent N CN

H3CO OCH3

N

acid, DCM O

H3CO

2a

OCH3

methods (Table 2, entries 1, 2, 7, and 8). Second, when the indolizine-5-carbonitrile 1b with a 3"-methoxyphenyl group and a 3',4'-dimethoxyphenyl group was utilized, phenanthroindolizidinone 5b was obtained in a moderate yield using method A (55%, entry 3). When using method B, product 5b was obtained in higher yield (64%, Table 2, entry 4). In addition, quinolizine4-carbonitriles 2b, having the same number and positions for the methoxy groups as 1b, produced phenanthroquinolizidinone 6b (54%, method A, entry 9; 75%, method B, entry 10) and a few molecules of geometric isomer 8 (15%, method A, entry 9; 8%, method B, entry 10). Table 2: Oxidative Coupling/Decyanation Reactions of Compounds 1 and 2 Using Methods A and B OCH3

OCH3 R

4"

3" 2" 1"

N

( )n

1'

R'

2' 4'

CN

3'

OCH3 1a: R = R' = OCH3; n = 1 1b: R = H; R' = OCH3; n = 1 1c: R = OCH3; R' = H; n = 1 2a: R = R' = OCH3; n = 2 2b: R = H; R' = OCH3; n = 2 2c: R = OCH3; R' = H; n = 2

OCH3

OCH3 H3CO

Page 2 of 6

OCH3

R

Method A: VOF3/TFA; DCM -20 o C; 1 h

N

Method B: BTI/BF3.OEt2 DCM; -50 oC; 4 h

O

R' OCH3

5a: R = R' = OCH3; n = 1 5b: R = H; R' = OCH3; n = 1 5c: R = OCH3; R' = H; n = 1 6a: R = R' = OCH3; n = 2 6b: R = H; R' = OCH3; n = 2 6c: R = OCH3; R' = H; n = 2 OCH3

H3CO

6a

( )n

H3CO H3CO

N

N

N

O

H3CO OCH3

entry

reagent (equiv) + acid (equiv)

temp (°C)

time (h)

6a (%)

1

VOF3 (5) + TFA (14)

0

1

75

2

VOF3 (5) + TFA (14)

−20

1

87

3

BTI (1.1) + BF3·OEt2 (1.1)

−78

4

26a

4

BTI (2.2) + BF3·OEt2 (2.2)

−50

4

89

5

BTI (2.2) + BF3·OEt2 (2.2)

rt

1

trace

6

TTFA (2.5) + TFAb

0

1

55c

7

TTFA (2) + TFAb

rt

1

59c

8

m-CPBA (2.5) + TFAb

rt

1

12c

aRecovered

starting material 2a (70%). bTFA was used as a solvent. cCombined with a trace amount of over-oxidized product 7.

Based on the results described above, all the oxidative coupling/decyanation reactions were conducted using methods A and B. A metallic coupling reagent was used for method A: a solution of cycloadducts 1 and 2, 5 equiv VOF3, and 14 equiv TFA in DCM was stirred at −20 °C under nitrogen for 1 h. Method B took advantage of a non-metallic coupling reagent: 2.2 equiv BTI and 2.2 equiv BF3·OEt2 were added to a solution of cycloadducts 1 and 2 in DCM at −78 °C under nitrogen, and the mixture was stirred at −50 °C for 4 h. The results of one-pot oxidative coupling/decyanation reactions of IADA cycloadducts 1 and 2 to give the corresponding lactams 5 and 6 are shown in Table 2. First, for 1a and 2a that contain two 3,4-dimethoxyphenyl groups, the yields of the oxidative coupling/decyanation reaction were excellent (ranging from 84% to 89%) by the two

O

O

H3CO

7

OCH3

entry

reactant

method

1

1a

2

( )n

OCH3

8

substituent

2 9: n = 1 10: n = 2

product (%)

R

R'

A

OCH3

OCH3

5a (84)

-

1a

B

OCH3

OCH3

5a (89)

-

3

1b

A

H

OCH3

5b (55)

-

4

1b

B

H

OCH3

5b (64)

-

5

1c

A

OCH3

H

5c (52)

9 (29)

6

1c

B

OCH3

H

5c (54)

9 (18)

7

2a

A

OCH3

OCH3

6a (87)

-

8

2a

B

OCH3

OCH3

6a (89)

-

9

2b

A

H

OCH3

6b (54)

8 (15)

10

2b

B

H

OCH3

6b (75)

8 (8)

11

2c

A

OCH3

H

6c (55)

10 (29)

12

2c

B

OCH3

H

6c (72)

10 (10)


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The Journal of Organic Chemistry To our surprise, when compound 2c was subjected to method A or method B, in addition to the expected product 6c, a unique side product, dimer 10, was formed (entries 11 and 12). A similar result was also observed when indolizine-5-carbonitrile 1c, which has a 3",4"-dimethoxyphenyl group and a 3'-methoxyphenyl group, was used (entries 5 and 6). These results show that the efficiency of the oxidative coupling/decyanation reaction carried out under the BTI/BF3-mediated conditions was slightly better than that under the VOF3/TFA-mediated conditions. In addition, the amounts of sterically hindered geometric isomer 8 and that of dimers 9 and 10 produced decreased when the reaction was conducted at lower temperatures using method B. This result indicates that the side products may be the thermodynamically favored products. The plausible mechanism for the formation of lactams 5 and 6 through the VOF3 or BTI-induced oxidative coupling/decyanation reaction of 6,7-diphenylindolizine-5-carbonitriles 1 and 2,3-diphenylquinolizine-4-carbonitriles 2 is proposed in Scheme 2. First, VOF3 and BTI are believed to induce the single-electron-transfer (SET) from an electron-rich substrate to vanadium(V) or hypervalent iodine(III).17 It is important to note here that TFA is an effective medium for these oxidations, particularly with moisture sensitive oxidants (i.e. VOF3),18 and the electrophilicity of BTI can be enhanced by Lewis acid, BF3·OEt2.19 The SET process would lead to initial formation of the radical-cation 11+., which can be stabilized by the conjugated amino group. Subsequently, radical-cation 11+. might undergo an intramolecular nucleophilic attack from the phenyl group to form the key aryl−aryl bond, followed by an additional SET and dehydro-aromatization to yield intermediate 12.20 Again, the SET oxidation of 12 by VOF3 or BTI produced radical-cation 12+.. Then, a SET from radical-cation 12+. to the oxidant followed by dehydro-aromatization lead to the formation of iminium ion 13. Finally, the reaction of intermediate 13 with hydroxide, followed by elimination of HCN during the basic work-up, provided the final products 5 and 6. Dimers 9 and 10 were obtained in the cases of 1c and 2c (R=OCH3; R'=H), but not 1b and 2b (R= H; R'= OCH3), indicating the existence of key radical-cation intermediate 12+.. Moreover, we also worked-up the one-pot oxidative coupling/decyanation reaction of 2a with 20% Na18OH in H218O solution to afford 18O-labeled lactam 6a-18O.21 This result revealed that the final lactam products 1 and 2 could be formed by the hydrolysis of intermediate 13 with a sodium hydroxide water solution.22 Scheme 2. Plausible Mechanism of One-Pot Oxidative Coupling/Decyanation Reaction of 1 and 2 OCH3

OCH3

R

R [O] 1 and 2

H

e-

N

SET

( )n

N

- e-; - 2H+

CN

R'

H

nucleophilic attack

CN

R' OCH3

OCH3 11+.

( )n

12

SET [O]

N R' OCH3

R

R basic work-up + OH-

R

H N

( )n - HCN

O 5: n = 1 6: n = 2

e-

OCH3

OCH3

OCH3

CN

R' OCH3

13

( )n - e

N

- H+

CN

R' OCH3

12+.

( )n

Finally, reduction of six lactams 5a−5c and 6a−6c with sodium bis(2-methoxyethoxy)aluminum hydride (SBAH) yielded the corresponding phenanthroindolizidines 3a−3c and phenanthroquinolizidines 4a−4c in high yields (Figure 1). OCH3

OCH3

OCH3

H3CO

H3CO

N H3CO

( )n

N

( )n

N

( )n

H3CO OCH3 3a: n = 1 (90%) 4a: n = 2 (92%)

OCH3 3b: n = 1 (86%) 4b: n = 2 (85%)

OCH3 3c: n = 1 (85%) 4c: n = 2 (87%)

Figure 1. Phenanthroindolizidines 3 and phenanthroquinolizidines 4 were obtained by reduction of lactams 5 and 6. In summary, this paper is the first to describe the one-pot oxidative coupling/decyanation reaction of 6,7-diphenylindolizine-5-carbonitriles 1 and 2,3-diphenylquinolizine-4-carbonitriles 2 to give the corresponding phenanthroindolizidinones 3 and phenanthroquinolizidinones 4 using VOF3 and BTI as oxidative coupling reagents under acidic conditions. Moreover, BTI is a more efficient and environmental friendly reagent than VOF3 for the one-pot oxidative coupling/decyanation reaction. This method will prove helpful for the synthesis of natural products and bioactive alkaloids via the cyano group-activated IADA reaction.

EXPERIMENTAL SECTION All reagents and solvents were purchased from commercial sources and were used as received without further purification. Melting points (°C) were uncorrected. 1H and 13C spectra were recorded on 500 MHz FT-NMR spectrometer. These 13C NMR spectra were obtained with complete proton decoupling. All chemical shifts (δ) were expressed in ppm using tetramethylsilane as the internal standard. IR spectra were reported in wave numbers (cm-1), and obtained on an FT-IR spectrometer using KBr pellets. Mass spectra were recorded on a double-focusing spectrometer. High-resolution electron ionization mass spectra (HREI-MS) were recorded on a high-resolution E/B mass spectrometer using a double-focusing magnetic-sector mass analyzer. Orbitrap mass analyzer was used for HRESI-MS measurements. Flash chromatography was performed on 230−400 mesh silica gel. General Procedures (Method A and Method B) for the Oxidative Coupling/Decyanation Reaction of 6,7Diphenylindolizine-5-carbonitriles 1 and 2,3Diphenylquinolizine-4-carbonitriles 2. Method A: A 0.04 M solution of cycloadducts 1 (and 2, 0.2 mmol) in dry DCM (5 mL) was added to VOF3 (124.0 mg, 1.0 mmol) at −20 °C and the mixture was stirred for 15 min. TFA (218 µL, 2.8 mmol) was added and the purple mixture was stirred at −20 °C for another 1 h. Method B: BTI (189.2 mg, 0.44 mmol) and BF3·OEt2 (56 µL, 0.44 mmol) were added to a solution of cycloadducts 1 (and 2, 0.2 mmol) in dry DCM (5 mL) at −78 °C under nitrogen, and the mixture was warmed to −50 °C and stirred for a further 4 h. The reaction mixture was quenched with 20% aqueous NaOH (1 mL). The resulting mixture was allowed to warm to room temperature and stirred for another 5 min. The biphasic H2O/DCM mixture was separated and the H2O layer was extracted with DCM (3 × 5 mL). The combined DCM extracts were dried over anhydrous MgSO4 and filtered. The filtrate was concentrated, and the residue was purified by column chromatography over silica gel and eluted with CHCl3−MeOH (100:1) to give pure phenanthroindolizidiones 5 (and phenanthroquinolizidiones 6). The full spectral data of 5a−5c, 6a−6c, and 8−10 are as follows.



9-Oxotylophorine (5a).23 Method A: Yield 84% (68.5 mg); method B: Yield 89% (72.6 mg); white powder, mp 282−284 °C. 1H NMR (500 MHz, CDCl ) δ 1.85−2.02 (2H, m), 2.14−2.21 (1H, 3 m), 2.39−2.47 (1H, m), 2.91 (1H, dd, J = 15.2, 14.0 Hz), 3.56 (1H, dd, J = 15.2, 3.9 Hz), 3.76−3.95 (3H, m), 4.04 (3H, s), 4.08 (3H, s), 4.11 (3H, s), 4.13 (3H, s), 7.30 (1H, s), 7.75 (1H, s), 7.79 (1H, s), 9.03 (1H, s); 13C NMR (125 MHz, CDCl3) δ 23.5, 32.5, 33.8, 45.3, 55.1, 55.8 (3 × C), 55.9, 102.3, 103.1, 104.8, 108.0, 122.4, 123.1, 124.3, 124.4, 126.6, 133.2, 148.6, 148.7, 148.9, 150.2, 164.6; IR (KBr) 3109, 2947, 1624, 1528, 1512 cm-1; EIMS m/z (rel. int.) 407 (100, M+); HREIMS m/z calcd for C24H25NO5: 407.1733; found: 407.1739 [M]+. 2,6,7-Trimethoxy-11,12,12a,13-tetrahydro-10H-9aazacyclopenta[b]triphenylen-9-one (5b). Method A: yield 55% (41.6 mg); method B: yield 64% (48.4 mg); pale yellow powder, mp 227−229 °C. 1H NMR (500 MHz, CDCl3) δ 1.86−2.02 (2H, m), 2.14−2.22 (1H, m), 2.40−2.47 (1H, m), 2.93 (1H, t, J = 15.6 Hz), 3.61 (1H, d, J = 15.6 Hz), 3.76−3.97 (3H, m), 3.98 (3H, s), 4.08 (3H, s), 4.10 (3H, s), 7.33 (1H, d, J = 9.1 Hz), 7.38 (1H, s), 7.89 (1H, s), 8.48 (1H, d, J = 9.1 Hz), 8.98 (1H, s); 13C NMR (125 MHz, CDCl3) δ 23.6, 32.4, 33.9, 45.4, 55.3, 55.5, 55.8, 55.9, 102.3, 105.2, 108.1, 118.0, 123.6, 124.5, 124.8, 125.3, 125.9, 129.7, 132.2, 148.8, 149.0, 157.8, 164.5; IR (KBr) 3109, 2924, 1636, 1504 cm-1; EIMS m/z (rel. int.) 377 (100, M+); HREIMS m/z calcd for C23H23NO4: 377.1627; found: 377.1624 [M]+. 2,3,7-Trimethoxy-11,12,12a,13-tetrahydro-10H-9aazacyclopenta[b]triphenylen-9-one (5c). Method A: yield 52% (39.3 mg); method B: yield 54% (40.8 mg); pale yellow powder, mp 234−235 °C. 1H NMR (500 MHz, CDCl3) δ 1.85−2.02 (2H, m), 2.13−2.22 (1H, m), 2.40−2.48 (1H, m), 2.93 (1H, dd, J = 15.5, 14.4 Hz), 3.58 (1H, dd, J = 15.5, 3.3 Hz), 3.76−3.97 (3H, m), 4.00 (3H, s), 4.04 (3H, s), 4.11 (3H, s), 7.24 (1H, dd, J = 9.2, 1.8 Hz), 7.32 (1H, s), 7.91 (1H, s), 8.39 (1H, d, J = 9.2 Hz), 8.95 (1H, d, J = 1.8 Hz); 13C NMR (125 MHz, CDCl3) δ 23.6, 32.8, 33.9, 45.3, 55.1, 55.4, 55.9 (2 × C), 103.2, 104.9, 107.4, 117.4, 122.7, 122.9, 123.3, 123.9, 127.6, 130.3, 135.6, 148.8, 150.6, 158.1, 164.6; IR (KBr) 3105, 2920, 1628, 1512 cm-1; EIMS m/z (rel. int.) 377 (100, M+); HREIMS m/z calcd for C23H23NO4: 377.1627; found: 377.1637 [M]+. 2,3,6,7-Tetramethoxy-10,11,12,13,13a,14-hexahydro-9aazabenzo[b]triphenylen-9-one (6a).15 Method A: yield 87% (73.4 mg); method B: yield 89% (75.1 mg); white powder, mp 201−202 °C. 1H NMR (500 MHz, CDCl3) δ 1.41−1.54 (1H, m), 1.54−1.71 (2H, m), 1.85−1.95 (2H, m), 1.96−2.05 (1H, m), 2.88 (1H, t, J = 12.7 Hz), 2.96 (1H, dd, J = 15.9, 11.2 Hz), 3.38 (1H, d, J = 15.9 Hz), 3.50−3.61 (1H, m), 4.03 (3H, s), 4.10 (9H, s), 4.71 (1H, d, J = 12.7 Hz), 7.26 (1H,s), 7.73 (2H, s), 9.37 (1H, s); 13C NMR (125 MHz, CDCl3) δ 22.9, 24.6, 32.9, 33.0, 42.7, 52.7, 55.8, 55.9 (2 × C), 56.0, 102.5, 103.1, 104.6, 108.7, 120.1, 122.8, 124.6, 124.7, 126.8, 133.4, 148.4, 148.8, 148.9, 150.5, 167.5; IR (KBr) 3001, 2928, 1624, 1531, 1504 cm-1; EIMS m/z (rel. int.) 421 (100, M+); HREIMS m/z calcd for C25H27NO5: 421.1889; found: 421.1881 [M]+. 2,6,7-Trimethoxy-10,11,12,13,13a,14-hexahydro-9aazabenzo[b]triphenylen-9-one (6b). Method A: yield 54% (42.3 mg); method B: yield 75% (58.8 mg); pale yellow powder, mp 198−200 °C. 1H NMR (500 MHz, CDCl3) δ 1.44−1.56 (1H, m), 1.56−1.71 (2H, m), 1.86−1.97 (2H, m), 1.99−2.07 (1H, m), 2.91 (1H, td, J = 13.0, 2.4 Hz), 3.03 (1H, dd, J = 16.3, 11.0 Hz), 3.47 (1H, dd, J = 16.3, 4.4 Hz), 3.56−3.66 (1H, m), 3.98 (3H, s), 4.09 (3H, s), 4.10 (3H, s), 4.72 (1H, d, J = 13.0 Hz), 7.33 (1H, d, J = 9.3 Hz), 7.38 (1H, s), 7.90 (1H, s), 8.47 (1H, d, J = 9.3 Hz), 9.32 (1H, s); 13C NMR (125 MHz, CDCl3) δ 22.9, 24.6, 32.7, 32.9, 42.8, 52.8, 55.5, 55.7, 55.9, 102.4, 105.3, 108.7, 118.2, 122.4, 124.0, 124.4, 125.5, 126.0, 129.4, 133.4, 148.7 (2 × C), 157.8, 167.3; IR (KBr) 3005, 2928, 1636, 1616, 1501 cm-1; EIMS m/z rel. int.) 391 (100,

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M+); HREIMS m/z calcd for C24H25NO4: 391.1784; found: 391.1785 [M]+. 2,3,7-Trimethoxy-10,11,12,13,13a,14-hexahydro-9aazabenzo[b]triphenylen-9-one (6c). Method A: yield 55% (43.1 mg); method B: yield 72% (56.4 mg); pale yellow powder, mp 200−202 °C. 1H NMR (500 MHz, CDCl3) δ 1.44−1.55 (1H, m), 1.56-1.70 (2H, m), 1.87−1.95 (2H, m), 1.99−2.07 (1H, m), 2.90 (1H, td, J = 13.0, 3.1 Hz), 3.02 (1H, dd, J = 16.3, 11.0 Hz), 3.44 (1H, dd, J = 16.3, 4.7 Hz), 3.55−3.63 (1H, m), 4.01 (3H, s), 4.04 (3H, s), 4.11 (3H, s), 4.72 (1H, d, J = 13.0 Hz), 7.23 (1H, dd, J = 9.2, 2.4 Hz), 7.31 (1H, s), 7.90 (1H, s), 8.40 (1H, d, J = 9.2 Hz), 9.29 (1H, d, J = 2.4 Hz); 13C NMR (125 MHz, CDCl3) δ 22.9, 24.7, 32.9, 33.2, 42.7, 52.7, 55.4, 55.9, 56.0, 103.2, 104.7, 108.2, 117.0, 120.5, 122.4, 123.3, 124.0, 127.7, 130.8, 135.8, 148.8, 150.9, 158.2, 167.4; IR (KBr) 3136, 2924, 1628, 1612, 1504 cm-1; EIMS m/z (rel. int.) 391 (100, M+); HREIMS m/z calcd for C24H25NO4: 391.1784; found: 391.1785 [M+H]+. 4,6,7-Trimethoxy-10,11,12,13,13a,14-hexahydro-9aazabenzo[b]triphenylen-9-one (8). Method A: yield 15% (11.8 mg); method B: yield 8% (6.3 mg); pale yellow powder, mp 204−206 oC. 1H NMR (500 MHz, CDCl ) δ 1.46−1.54 (1H, m), 1.56−1.70 (2H, 3 m), 1.87−1.95 (2H, m), 1.99−2.07 (1H, m), 2.94 (1H, td, J = 13.0, 3.3 Hz), 3.07 (1H, dd, J = 16.4, 11.1 Hz), 3.52 (1H, dd, J = 16.4, 4.7 Hz), 3.56−3.64 (1H, m), 4.08 (3H, s), 4.10 (3H, s), 4.11 (3H, s), 4.69 (1H, dd, J = 13.0, 1.8 Hz), 7.21 (1H, d, J = 8.2 Hz), 7.52 (1H, t, J = 8.2 Hz), 7.73 (1H, d, J = 8.2 Hz), 9.25 (1H, s), 9.27 (1H, s); 13C NMR (125 MHz, CDCl ) δ 22.7, 24.6, 32.8, 33.6, 42.6, 52.6, 3 55.5, 55.8, 56.3, 107.9, 109.1, 110.2, 117.2, 122.5, 122.8, 125.1, 125.7, 125.8, 130.7, 133.7, 147.4, 148.3, 157.9, 167.1; IR (KBr) 3009, 2947, 1624, 1612, 1501 cm-1; EIMS m/z (rel. int.) 391 (100, M+); HREIMS m/z calcd for C24H25NO4: 391.1784; found: 391.1782 [M]+. 2,3,7,2',3',7'-Hexamethoxy-11,12,12a,13,11',12',12'a,13'octahydro-10H,10'H-[6,6']bi[9a-azacyclopenta[b]triphenylenyl]-9,9'-dione (9). Method A: yield 29% (21.9 mg); method B: yield 18% (13.6 mg); pale yellow powder, mp > 300 oC. 1H NMR (500 MHz, CDCl3) δ 1.88−2.05 (4H, m), 2.15−2.23 (2H, m), 2.41−2.49 (2H, m), 2.95 (2H, dd, J = 15.4, 13.7 Hz), 3.60 (2H, dd, J = 15.4, 3.6 Hz), 3.79−3.96 (6H, m), 3.98 (6H, s), 4.03 (12H, s), 7.33 (2H, s), 7.93 (2H, s), 8.46 (2H, s), 9.10 (2H, s); 13C NMR (125 MHz, CDCl3) δ 23.6, 32.8, 33.8, 45.3, 55.2, 55.8 (2 × C), 56.1, 103.4, 104.8, 107.1, 122.7, 122.8, 123.6, 124.7, 127.5, 128.6, 130.0, 135.5, 148.7, 150.5, 156.6, 164.6; IR (KBr) 3094, 2924, 1632, 1524, 1508 cm-1; ESIMS m/z (rel. int.) 753 (100, [M+H]+); HRESIMS m/z calcd for C46H45N2O8: 753.3170; found: 753.3179 [M+H]+. 2,3,7-Trimethoxy-6-(2,6,7-trimethoxy-14-oxo-9,10,11,12,13,14hexahydro-9aH-13a-aza-benzo[b]triphenylen-3-yl)10,11,12,13,13a,14-hexahydro-9a-aza-benzo[b]triphenylen-9-one (10). Method A: yield 29% (22.7 mg); method B: yield 10% (7.8 mg); pale yellow powder, mp > 300 oC. 1H NMR (500 MHz, CDCl3) δ 1.47−1.73 (6H, m), 187−1.98 (4H, m), 2.01−2.09 (2H, m), 2.92 (1H, td, J = 13.0, 3.2 Hz), 3.08 (2H, dd, J = 16.4, 10.5 Hz), 3.49 (2H, dd, J = 16.4, 4.5 Hz), 3.62 (2H, tt, J = 10.5, 4.5 Hz), 4.00 (6H, s), 4.03 (6H, s), 4.05 (6H, s), 4.76 (2H, d, J = 13.0 Hz), 7.34 (2H, s), 7.92 (2H, s), 8.46 (2H, s), 9.46 (2H, s); 13C NMR (125 MHz, CDCl3) δ 23.0, 24.8, 33.0, 33.2, 42.9, 52.9, 55.9, 56.0, 56.1, 103.5, 104.8, 107.9, 120.4, 122.6, 123.8, 124.7, 127.8, 128.6, 130.5, 135.6, 148.8, 150.9, 156.7, 167.5; IR (KBr) 3140, 2936, 1636, 1620, 1524, 1501 cm-1'; ESIMS m/z (rel. int.) 781 (46, [M+H]+), 154 (100); HRESIMS m/z calcd for C48H49N2O8: 781.3483; found:781.3495 [M+H]+. General Procedure for the Reduction of Phenanthroindolizidiones 5 and Phenanthroquinolizidiones 6. A 3.5 M solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene (2.8 mmol) was added to a solution of phenanthroindolizidiones 5 (and phenanthroquinolizidiones 6, 0.2


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The Journal of Organic Chemistry mmol) in dry dioxane (10 mL) and the mixture was refluxed for 2 h in the dark. After evaporation of the solvents, the residue was diluted with H2O (10 mL) and then basified with 10% aqueous NaOH. The mixture was extracted with CHCl3 (5 × 20 mL), and the combined extracts were washed with H2O, dried over anhydrous MgSO4, and filtered. The filtrate was concentrated, and the residue was purified by column chromatography over silica gel and eluted with CHCl3−MeOH (50:1) to give pure phenanthroindolizidines 3 (and phenanthroquinolizidines 4). The full spectral data of 3a−3c and 4a−4c are described as follows. Tylophorine (3a).24 Yield 90% (70.9 mg); white powder, mp 270 °C (decomp.). 1H NMR (500 MHz, CDCl3) δ 1.77−1.83 (1H, m), 1.92−1.97 (1H, m), 2.03−2.07 (1H, m), 2.22−2.28 (1H, m), 2.49−2.58 (2H, m), 2.93 (1H, d, J = 15.2, 11.4 Hz), 3.35 (1H, d, J = 15.2 Hz), 3.48 (1H, t, J = 7.5 Hz), 3.68 (1H, d, J = 14.7 Hz), 4.04 (3H, s), 4.05 (3H, s), 4.11 (6H, s), 4.64 (1H, d, J = 14.7 Hz), 7.12 (1H, s), 7.29 (1H, s), 7.81 (2H, s) 13C NMR (125 MHz, CDCl3) δ 21.6, 31.1, 33.5, 53.8, 55.0, 55.8, 55.9, 56.0 (2 × C), 60.2, 103.1, 103.4, 103.5, 104.0, 123.4, 123.7, 124.3, 125.6, 125.7, 126.2, 148.5, 148.6, 148.7 (2 × C); IR (KBr) 3092, 2922, 1614, 1516 cm-1; EIMS m/z (rel. int.) 393 (24, M+), 324 (100); HREIMS m/z calcd for C24H27NO4: 393.1940; found: 393.1946 [M]+. 2,6,7-Trimethoxy-11,12,12a,13-tetrahydro-10H-9aazacyclopenta[b]triphenylene (3b).10 Yield 86% (62.5 mg); white powder, mp 186−188 °C. 1H NMR (500 MHz, CDCl3) δ 1.76−1.80 (1H, m), 1.84−1.98 (1H, m), 2.02−2.11 (1H, m), 2.23−2.29 (1H, m), 2.46−2.51 (2H, m), 2.93 (1H, dd, J = 16.0, 11.7 Hz), 3.36 (1H, d, J = 16.0 Hz), 3.49 (1H, t, J = 8.3 Hz), 3.67 (1H, d, J = 14.8 Hz), 3.99 (3H, s), 4.06 (3H, s), 4.12 (3H, s), 4.63 (1H, d, J = 14.8 Hz), 7.15 (1H, s), 7.25 (1H, dd, J = 9.0, 2.4 Hz), 7.35 (1H, d, J = 2.4 Hz), 7.94 (1H, s), 8.45 (1H, d, J = 9.0 Hz); 13C NMR (125 MHz, CDCl3) δ 21.6, 31.2, 33.4, 53.9, 55.1, 55.4, 55.8, 55.9, 60.1, 103.1, 103.3, 104.4, 115.5, 123.4, 123.7, 123.9, 124.1, 126.4, 128.0, 132.0, 148.5, 148.6, 157.7; IR (KBr) 3090, 2918, 1614, 1508 cm-1; EIMS m/z (rel. int.) 294 (100), 363 (21, M+); HREIMS m/z calcd for C23H25NO3: 363.1834; found: 363.1832 [M]+. Desmethoxytylophorine (3c).25 Yield 85% (61.8 mg); white powder, mp 196−197 °C. 1H NMR (500 MHz, CDCl3) δ 1.73−1.80 (1H, m), 1.83−1.95 (1H, m), 2.01−2.06 (1H, m), 2.20−2.26 (1H, m), 2.42−2.49 (2H, m), 2.90 (1H, dd, J = 15.6, 10.5 Hz), 3.34 (1H, dd, J = 15.6, 2.4 Hz), 3.46 (1H, td, J = 8.6, 1.8 Hz), 3.63 (1H, d, J = 14.7 Hz), 3.96 (3H, s), 4.04 (3H, s), 4.09 (3H, s), 4.62 (1H, d, J = 14.7 Hz), 7.19 (1H, d, J = 2.5 Hz), 7.22 (1H, dd, J = 9.0, 2.5 Hz), 7.29 (1H, s), 7.91 (1H, s), 8.44 (1H, d, J = 9.0 Hz); 13C NMR (125 MHz, CDCl3) δ 21.6, 31.3, 33.9, 53.9, 55.1, 55.4, 55.8, 55.9, 60.1, 103.2, 103.7, 104.0, 115.3, 123.2, 124.0, 124.3, 125.3, 126.1, 128.6, 130.6, 148.5, 148.7, 157.7.; IR (KBr) 3011, 2932, 1616, 1508 cm1; EIMS m/z (rel. int.) 294 (100), 363 (66, M+); HREIMS m/z calcd for C23H25NO3: 363.1834; found: 363.1835 [M]+. 7-Methoxycryptopleurine (4a).26 Yield 92% (69.3 mg); white powder, mp 245−246 °C (decomp.). 1H NMR (500 MHz, CDCl3) δ 1.38−1.55 (2H, m), 1.75−1.80 (2H, m), 1.86−1.89 (1H, m), 1.98−2.01 (1H, m), 2.24−2.33 (2H, m), 2.84 (1H, dd, J = 16.0, 10.5 Hz), 3.03 (1H, dd, J = 16.0, 3.5 Hz), 3.26 (1H, d, J = 10.5 Hz), 3.52 (1H, d, J = 15.1 Hz), 4.02 (3H, s), 4.03 (3H, s), 4.10 (6H, s), 4.30 (1H, d, J = 15.1 Hz), 7.07 (1H, s), 7.19 (1H, s), 7.76 (1H, s), 7.77 (1H, s); 13C NMR (125 MHz, CDCl3) δ 24.4, 26.0, 33.8, 34.9, 55.9, 56.0, 56.1 (2 × C), 56.3, 56.4, 57.6, 103.1, 103.4, 103.6, 103.9, 123.4, 123.5, 123.9, 125.0, 125.3 (2 × C), 148.4, 148.5, 148.7 (2 × C); IR (KBr) 3093, 2922, 1616, 1516 cm-1; EIMS m/z (rel. int.) 407 (23, M+), 324 (100); HREIMS m/z calcd for C25H29NO4: 407.2097; found: 407.2099 [M]+. 2,6,7-Trimethoxy-10,11,12,13,13a,14-hexahydro-9H-9aazabenzo[b]triphenylene (4b).10 Yield 85% (64.2 mg); white powder, mp 182−183 °C. 1H NMR (500 MHz, CDCl3) δ 1.42−1.57 (2H, m), 1.76−1.81 (2H, m), 1.87−1.89 (1H, m), 1.99−2.02 (1H, m), 2.26−2.36 (2H, m), 2.87 (1H, dd, J = 16.0, 10.6 Hz), 3.06 (1H,

dd, J = 16.0, 3.4 Hz), 3.27 (1H, d, J = 10.6 Hz), 3.56 (1H, d, J = 15.5 Hz), 3.96 (3H, s), 4.02 (3H, s), 4.08 (3H, s), 4.33 (1H, d, J = 15.5 Hz), 7.09 (1H, s), 7.21 (1H, dd, J = 9.1, 2.5 Hz), 7.26 (1H, d, J = 2.5 Hz), 7.90 (1H, s), 8.41 (1H, d, J = 9.1 Hz); 13C NMR (125 MHz, CDCl3) δ 24.4, 26.0, 33.8, 34.7, 55.4, 55.9, 56.0, 56.3 (2 × C), 57.5, 103.1, 103.4, 104.5, 115.3, 123.3, 123.4, 124.0, 124.1, 125.4, 127.2, 131.6, 148.5, 148.6, 157.7; IR (KBr) 3090, 2927, 1616, 1508 cm-1; EIMS m/z (rel. int.) 294 (100), 377 (21, M+); HREIMS m/z calcd for C24H27NO3: 377.1991; found: 377.1987 [M]+. 2,3,7-Trimethoxy-10,11,12,13,13a,14-hexahydro-9H-9aazabenzo[b]triphenylene (4c).10 Yield 87% (65.7 mg); white powder, mp 156−158 °C. 1H NMR (500 MHz, CDCl3) δ 1.42−1.57 (2H, m), 1.77−1.90 (3H, m), 2.01−2.03 (1H, m), 2.27−2.35 (2H, m), 2.88 (1H, dd, J = 16.4, 11.1 Hz), 3.07 (1H, d, J = 16.4 Hz), 3.27 (1H, d, J = 11.1 Hz), 3.56 (1H, d, J = 15.2 Hz), 3.95 (3H, s), 4.04 (3H, s), 4.08 (3H, s), 4.34 (1H, d, J = 15.2 Hz), 7.15 (1H, s), 7.20−7.22 (2H, m), 7.90 (1H, s), 8.42 (1H, d, J = 9.2 Hz); 13C NMR (125 MHz, CDCl3) δ 24.3, 25.9, 33.7, 34.9, 55.4, 55.8, 55.9, 56.1, 56.2, 57.4, 103.3, 103.8, 103.9, 115.0, 123.1, 124.0, 124.2, 124.6, 125.0, 127.5, 130.2, 148.5, 148.7, 157.6; IR (KBr) 3094, 2930, 1616, 1506 cm-1; EIMS m/z (rel. int.) 377 (33, M+), 294 (100); HREIMS m/z calcd for C24H27NO3: 377.1991; found: 377.1982 [M]+.

ASSOCIATED CONTENT Supporting Information Available: Copies of 1H and 13C NMR spectra of 3a−3c, 4a−4c, 5a−5c, 6a−6c, and 8−10 are available free of charge on the ACS Publications website.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected].

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT The authors would like to thank the Ministry of Science and Technology, Taiwan (MOST 107-2113-M-039-007) and China Medical University, Taiwan for financial support. We are also grateful to the National Center for High-performance Computing for computer time and facilities.

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Decyanation of 6,7-Diphenylindolizine-5

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