Suzuki cross-coupling/reductive debenzyloxycarbonylation sequence for the syntheses of [c]annulated isoquinolines: Application for the syntheses of pancratistatin-like isoquinolines

Article abstract of DOI:10.1021/jo801761f

(Chemical Equation Presented) A two-step strategy involving Suzuki cross-coupling of boronic acids with a diverse array of α-iodoenones followed by hydrogenation is developed for the construction of [c]annulated isoquinolines. This mild and efficient proc

Full text of DOI:10.1021/jo801761f

SCHEME 1. Two Different Modes of Aza-Interactions
Suzuki Cross-Coupling/Reductive
Debenzyloxycarbonylation Sequence for the
Syntheses of [c]Annulated Isoquinolines:
Application for the Syntheses of
Pancratistatin-like Isoquinolines
Ganesh Pandey* and Madhesan Balakrishnan
DiVision of Organic Chemistry, National Chemical
Laboratory, Dr. Homi Bhabha Road, Pune-411008, India
gp.pandey@ncl.res.in
ReceiVed August 11, 2008
A two-step strategy involving Suzuki cross-coupling of
boronic acids with a diverse array of R-iodoenones followed
by hydrogenation is developed for the construction of
[c]annulated isoquinolines. This mild and efficient procedure
is also applied to the synthesis of highly oxygenated
isoquinolines.
alkyl,5b-d aroyl,5e alkenyl,5f and fluoroalkyl5g at the 3,4-
positions. Later, nickel-catalyzed annulations of the same starting
materials were also developed which were claimed to make the
process more efficient, mild, and highly regioselective.6 The
transition-metal chemistry focusing on isoquinoline syntheses
has further been expanded by exploring other elements (Zr,7
Rh,8 and Cu9) of this series for their usefulness. Other important
strategies in this regard concern the photochemical-mediated
cascade iminyl radical addition/intramolecular cyclization with
internal alkyne10 and organolithium addition to 2-(2-methoxy-
ethenyl)benzonitrile.11
While exploring the strategy for the construction of alkaloid
skeleton 5 through base-induced intramolecular aza-Michael
reaction (n-BuLi, THF/HMPA, -78 °C) of 3a (Scheme 1, path
a), we also investigated the mode of interaction of the corre-
sponding free amine of this substrate. Thus, reductive removal
of benzyl carbamate (1 atm of H2, 10% Pd/C) from 3a produced
an isoquinoline 7a in 46% yield, possibly by involving
intermediate 6 (path b).
Isoquinolines and their dihydro and tetrahydro derivatives are
the structural component of several biologically active natural
alkaloids.1 They are also known to serve as important molecular
scaffolds for the syntheses of complex natural products.2 Over
the last two decades, there has been growing interest to develop
mild and efficient syntheses of isoquinolines against tedious and
conventional approaches.3 Research toward this end has pro-
moted the exploration of heteroannulation of aldimines with
internal alkynes for the construction of 3,4-disubstituted iso-
quinolines employing stoichiometric amounts of palladacycles.4
Although this approach was initially thought to be efficient but
expensive, development of catalytic version5a subsequently, has
produced diverse array of isoquinolines substituted with aryl,5b-d
(1) The Chemistry of Hetrocyclic Compounds: Isoquinolines; Coppola, G. M.,
Schuster, H. F. , Eds.; John Wiley & Sons: New York, 1981; Vol. 38, Part 3.
(b) Phillipson, J. D.; Roberts, M. F.; Zenk, M. H. The Chemistry and Biology of
Isoquinoline Alkaloids; Springer-Verlag: New York, 1985. (c) Bentley, K. W.
The Isoquinoline Alkaloids; Harwood Academic Publishers: Amsterdam, 1998;
Vol. 1.
(2) For examples, see: (a) Magnus, P.; Matthews, K. S. J. Am. Chem. Soc.
2005, 127, 12476. (b) Su, S.; Porco, J. A., Jr. Org. Lett. 2007, 9, 4983.
(3) (a) Whaley, W. M.; Govindachari, T. R. In Organic Reactions; Adams,
R., Ed.; Wiley: New York, 1951; Vol. 6, pp 151-190. (b) Whaley, W. M.;
Govindachari, T. R. In Organic Reactions; Adams, R., Ed.; Wiley: New York,
1951; Vol. 6, pp 74-150. (c) Gensler, W. J. In Organic Reactions; Adams, R.,
Ed.; Wiley: New York, 1951; Vol. 6, pp 191-206.
(5) (a) Roesch, K. R.; Larock, R. C. J. Org. Chem. 1998, 63, 5306. (b)
Roesch, K. R.; Larock, R. C. Org. Lett. 1999, 1, 553. (c) Dai, G.; Larock, R. C.
Org. Lett. 2001, 3, 4035. (d) Roesch, K. R.; Zhang, H.; Larock, R. C. J. Org.
Chem. 2001, 66, 8042. (e) Dai, G.; Larock, R. C. J. Org. Chem. 2002, 67, 7042.
(f) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2003, 68, 980. (g)
Konno, T.; Chae, J.; Miyabe, T.; Ishihara, T. J. Org. Chem. 2005, 70, 10172.
(6) Korivi, R. P.; Cheng, C.-H. Org. Lett. 2005, 7, 5179.
(7) Ramakrishna, T. V. V.; Sharp, P. R. Org. Lett. 2003, 5, 877.
(8) Lim, S.-G.; Lee, J. H.; Moon, C. W.; Hong, J.-B.; Jun, C.-H. Org. Lett.
2003, 5, 2759.
(9) Wang, B.; Lu, B.; Jiang, Y.; Zhang, Y.; Ma, D. Org. Lett. 2008, 10,
2761.
(10) Alonso, R.; Campos, P. J.; Garc´ıa, B.; Rodr´ıguez, M. A. Org. Lett. 2006,
8, 3521.
(4) (a) Girling, I. R.; Widdowson, D. A. Tetrahedron Lett. 1982, 23, 4281.
(b) Maassarani, F.; Pfeffer, M.; Le Borgne, G. J. Chem. Soc., Chem. Commun.
1987, 8, 565. (c) Wu, G.; Geib, S. J.; Rheingold, A. L.; Heck, R. F. J. Org.
Chem. 1988, 53, 3238.
(11) Kobayashi, K.; Shiokawa, T.; Omote, H.; Hashimoto, K.; Morikawa,
O.; Konishi, H Bull. Chem. Soc. Jpn. 2006, 79, 1126.
8128 J. Org. Chem. 2008, 73, 8128–8131
10.1021/jo801761f CCC: $40.75 2008 American Chemical Society
Published on Web 09/23/2008

TABLE 2. Syntheses of Isoquinolines Using Suzuki
Cross-Coupling/Reductive Debenzyloxycarbonylation Sequence
FIGURE 1. Few naturally occurring annulated isoquinolines.
TABLE 1. Optimization of Conditions for Reductive
Debenzyloxycarbonylation
entry
catalysta
10% Pd/C
pressure (atm)
time (h)
yield (%)
46b
1
2
3
4
5
1
4
28
12
12
12
8
10% Pd/C
52
W-2 Raney Ni
W-2 Raney Ni
20% Pd(OH)2/C
1
no reaction
39
96
15c
1
a All hydrogenations were performed with 20 mol % of the catalysts
consistently. b 3a was recovered in 48% yield. c Hydrogenation was
conducted in a Parr reactor.
This unexpected observation, led us to explore the utility of
this reaction for the syntheses of annulated isoquinilines as, to
the best of our knowledge, there was no straightforward and
easy approach to access annulated isoquinolines. We report
herein a mild two-step synthesis of [c]annulated isoquinolines
involving Suzuki cross-coupling/reductive debenzyloxycarbo-
nylation sequence (Scheme 1) between 1a and iodoenone 2a.
[c]Annulated isoquinolines of type 7a are valuable synthetic
precursor in the synthesis of trispheridine (8),12 a naturally
occurring phenanthridine alkaloid from the Amaryllidaceae plant
family (Figure 1). Palladium catalyzed dehydrogenation of 7a
in refluxing xylene have been reported to produce 8.13 However,
7a was synthesized via µ-wave assisted aza-6π-electrocycliza-
tion of 6-cyclohexenyl piperonal O-methyl oxime. Compound
7a also shares close structural relationship with other alkaloids
such as bicolorine (9)14 and roserine (10).15
a Suzuki cross-coupling reactions16 were carried out by refluxing (80
°C) a mixture of 1a,b (1.0 mmol) and 2a-c (1.0 mmol) along with 5
mol % of Pd[PPh3]4 in benzene/ethanol (2:1, 15 mL) for 1-2 h.
b Freshly purified 3b-d were reduced in ethanol using optimized
hydrogenation conditions defined in entry 5, Table 1. c Isolated yield.
compound 7d is previously known.17
SCHEME 2. Access of Requisite Boronic Acids (1)
Driven by the easy access of annulated isoquinoline 7a
through the above route, we examined the in situ generation of
free amine by the reductive removal of benzyloxycarbonyl
moiety of 3a to obtain the maximum yield of 7a, and the results
of the optimization studies are listed in Table 1. During the
course of the hydrogenation, the conversion of 3a was observed
to be incomplete in the presence of catalytic 10% Pd/C under
1 atm of hydrogen and gave only 46% isolated yield of 7a even
after 28 h of the reaction. Therefore, we raised the hydrogen
pressure to 4 atm, and although the reaction was complete in
12 h, the yield of 7a did not improve significantly due to the
formation of several undesired products. It was also noticed that
3a remained inactive to Raney Ni mediated hydrogenation at 1
atm pressure of hydrogen but produced a complex reaction
mixture along with required isoquinoline 7a in small amounts
(39%, entry 4) when the reaction was conducted at high pressure
(15 atm). Pleasingly, the use of catalytic 20% Pd(OH)2/C cleanly
effected complete conversion of 3a at atmospheric pressure of
the hydrogen and afforded 7a in 96% yield (8 h, entry 5).
The generality of the Suzuki cross-coupling/reductive de-
benzyloxycarbonylation sequence was evaluated by synthesizing
isoquinolines 7b-d. The corresponding coupling partners (1a,b
and 2a-c), coupling products (3b-d), and respective yields of
these reactions are summarized in Table 2.
The requisite starting materials of this reaction sequence were
easily obtained through established procedures. While R-io-
doenones (2) were readily obtained using Johnson’s iodination
protocol,18 the other coupling partner (1) was easily synthesized
from 12 using lithiation followed by boronation protocol
(Scheme 2). The requisite bromide 12 were synthesized from
the corresponding aldehyde 11 adopting Dube´’s reductive
N-alkylation of carbamate strategy.19 It should be noticed that
(12) Abdel-Halim, O. B.; Morikawa, T.; o, S.; Matsuda, H.; Yoshikawa, M.
J. Nat. Prod. 2004, 67, 1119.
(13) Kumemura, T.; Choshi, T.; Yukawa, J.; Hirose, A.; Nobuhiro, J.; Hibino,
S. Heterocycles 2005, 66, 87.
(14) Viladomat, F.; Bastida, J.; Tribo, G.; Codina, C.; Rubiralta, M.
Phytochemistry 1990, 29, 1307.
(15) Bastida, J.; Codina, C.; Viladomat, F.; Rubiralta, M.; Quirion, J.-C.;
Weniger, B. J. Nat. Prod. 1992, 55, 134.
(16) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513.
(17) Beugelmans, R.; Chastanet, J.; Roussi, G. Tetrahedron 1984, 40, 311.
(18) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, B. W.;
Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron Lett. 1992, 33, 917.
(19) Dube´, D.; Scholte, A. A. Tetrahedron Lett. 1999, 40, 2295.
J. Org. Chem. Vol. 73, No. 20, 2008 8129

SCHEME 3. Syntheses of Oxygenated Isoquinolines
FIGURE 2. Pancratistatin-like isoquinolines.
compounds (20 and 21) for their anticancer activity against
murine P388 lymphocytic leukemia and two other human
cancerous cell linessMCF-7 (breast adenocarcinoma) and
THP-1 (promonocytic leukemia). However, they exhibited
>100-fold less activity (IC50 values in the order of >40 µg/
mL) in these cell lines in comparison to natural 22.
In summary, we have developed a mild, two-step strategy to
synthesize [c]annulated isoquinolines involving Suzuki cross-
coupling/reductive debenzyloxycarbonylation sequence. The
practical viability of the strategy for isoquinoline synthesis is
appropriately acknowledged by the catalytic nature and opera-
tional simplicity of both the steps involved and also by the easy
accessibility of starting materials. The method was successfully
applied to the syntheses of range of both substituted and
unsubstituted cycloalkene-fused isoquinolines.
most of the o-bromo aldehydes 11 are commercially available
for the syntheses of various aromatic substituted boronic acids.
Since the success of any methodology is defined by its
application to the syntheses of complex molecule, we investi-
gated the efficacy of this reaction sequence for the synthesis of
15. Highly oxygenated R-iodoenone 13 was derived in 29%
overall yield from the commercially available D-(-)-quinic
acid.20 The Suzuki cross-coupling of 13 with 1a delivered 14
in 81% yield (Scheme 3), which upon hydrogenation afforded
trialkoxycyclohexene annulated isoquinoline (15, 86%). It should
be mentioned that oxygenated isoquinoline of this type has not
been synthesized previously and would be difficult to obtain
via classical approaches, as known approaches utilized normally
strong acidic conditions. In order to demonstrate further the
application of our methodology for the synthesis of isoquiniline
of this series (e.g., 19), we initially attempted the preparation
of required hydrogenation precursor by coupling iodoenone 1621
with 1a. However, it was disappointing to note that it did not
produce the expected coupling product and gave some com-
pletely aromatized product, possibly by ꢀ-alkoxy elimination
followed by aromatization under the basic reaction conditions.
Therefore, we employed corresponding silyl protected iodoenone
1722 which was well suited to obtain 18 as well as isoquinoline
19 (77% combined yield).
Experimental Section
General Procedure for Suzuki Cross-Coupling Reactions. To
a solution of iodoenone (2/13/17, 2 mmol) in benzene (20 mL)
was added a predissolved solution of boronic acid (1, 2 mmol) in
ethanol (10 mL), aqueous 2 M Na2CO3 (5 mL), and a catalytic
amount of Pd[PPh3]4 (0.1 mmol). The vigorously stirring yellow
solution was heated in an oil bath set at 65-80 °C for 20 min-2
h under an atmosphere of argon. The dark reddish mixture produced
was cooled, diluted with water (15 mL), and extracted with EtOAc
(3 × 25 mL). The combined organic extracts were dried (Na2SO4),
filtered, and concentrated under reduced pressure. The residue
obtained was purified by column chromatography to afford 3/14/
18.
Benzyl (6-(6-oxocyclohex-1-enyl)benzo[d][1,3]dioxol-5-yl)m-
ethylcarbamate (3a): yield 82%, colorless solid; mp 123-124 °C;
IR (CHCl3) 2947, 1712, 1694, 1504, 1230, 1040 cm-1; H NMR
1
(benzene-d6, 500 MHz) δ 7.32 (s, 1H), 7.31 (s, 1H), 7.21-7.11
(m, 3H), 7.00 (s, 1H), 6.52 (s, 1H), 6.40 (t, J ) 4.1 Hz, 1H), 5.54
(bs, 1H), 5.43 (s, 2H), 5.16 (s, 2H), 4.21 (bs, 2H), 2.24 (t, J ) 6.4
Hz, 2H), 1.83 (m, 2H), 1.54 (quintet, J ) 6.4 Hz, 2H); 13C NMR
(benzene-d6, 125 MHz) δ 197.6, 156.5, 149.4, 148.0, 147.2, 140.6,
137.6, 131.7, 130.3, 128.5, 128.3, 127.9, 110.4, 109.4, 101.1, 66.5,
43.3, 38.6, 26.1, 22.8; MS (ESI) 402 (M + Na+, 55), 272 (55),
258 (52), 244 (100). Anal. Calcd for C22H21NO5: C, 69.64; H, 5.58;
N, 3.69. Found: C, 69.48; H, 5.51; N, 3.79.
Removal of the protecting groups from 15 as well as 19 using
6 N HCl in MeOH afforded isoquinolines 20 [87%, mp
Benzyl (6-((3S,4S,5R)-3,4,5-tris(methoxymethoxy)-6-oxocy-
clohex-1-enyl)benzo[d][1,3]dioxol-5-yl)methylcarbamate (14):
239-241 °C, [R]27 +48.5 (c 0.5, DMF)] and 21 [91%, mp
yield 81%; [R]27 +69.5 (c 1.16, CHCl3); IR (neat) 2895, 1730,
D
D
1713, 1693, 1504, 1485, 1371, 1240, 1042 cm-1; 1H NMR (CDCl3,
200 MHz) δ 7.32 (s, 5H), 6.90 (s, 1H), 6.81 (d, J ) 3.7 Hz, 1H),
6.51 (s, 1H), 5.93 (s, 2H), 5.39 (bs, 1H), 5.07 (s, 2H), 4.86 (d, J )
7.0 Hz, 1H), 4.81-4.70 (m, 6H), 4.50 (d, J ) 7.6 Hz, 1H), 4.27
(dd, J ) 7.5, 2.9 Hz, 1H), 4.02 (bs, 2H), 3.41 (s, 3H), 3.40 (s, 3H),
3.37 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 194.8, 156.2, 147.9,
146.8, 145.1, 139.3, 136.6, 131.1, 128.2, 127.8, 127.5, 109.6, 109.3,
101.2, 96.9, 96.8, 96.4, 77.2, 76.9, 71.4, 66.5, 55.9, 55.6, 55.5, 42.7;
MS (ESI) 583 (MH + Na+, 29), 582 (M + Na+, 100), 577 (M +
NH4+, 12), 560 (13). Anal. Calcd for C28H33NO11: C, 60.10; H,
5.94; N, 2.50. Found: C, 60.24; H, 5.76: N, 2.43.
286-291 °C, [R]27D -43.1 (c 0.5, DMF)], respectively (Figure
2). These isoquinolines (20 as well as 21) bear considerable
structural similarity with 7-deoxypancratistatin (22),23 a naturally
occurring and promising anticancer agent from plants of the
Amaryllidaceae family. Therefore, we also screened both these
(20) Pandey, G.; Balakrishnan, M.; Swaroop, P. S. Eur. J. Org. Chem.,
submitted for publication.
(21) Sha, C.-K.; Hong, A.-W.; Huang, C.-M. Org. Lett. 2001, 3, 2177.
(22) (a) Iodoenone 23 has been synthesized from the corresponding enone
utilizing Johnson’s iodination protocol18 in quantitative yield. For enone synthesis,
see: (b) Pandey, G.; Murugan, A.; Balakrishnan, M Chem Commun. 2002, 624
(23), 22.
General Procedure for the Syntheses of Isoquinolines. A
solution of Suzuki cross-coupling product (3/14/18, 0.5 mmol) in
ethanol (25 mL) was hydrogenated at atmospheric pressure in the
(23) Ghosal, S.; Singh, S.; Kumar, Y.; Srivastava, R. S Phytochemistry 1989,
28, 611.
8130 J. Org. Chem. Vol. 73, No. 20, 2008

presence of 20% Pd(OH)2 on charcoal (50 mg). The reaction was
monitored for its starting material consumption (TLC analysis, 9-14
h). After complete disappearance of starting material, the reaction
mixture was passed through a short pad of Celite. The solvent was
removed by rotary evaporation and the residue was purified by
column chromatography to produce 7/15/19.
4.50-4.40 (m, 2H), 3.47 (s, 3H), 3.46 (s, 3H), 3.32 (dd, J ) 16.0,
6.3 Hz, 1H), 3.30 (s, 3H), 3.15 (dd, J ) 16.0, 10 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ 151.3, 149.4, 148.2, 144.7, 133.1, 125.1,
123.9, 103.7, 101.7, 99.3, 97.2, 96.6, 95.4, 78.8, 75.4, 71.3, 55.9,
55.5, 55.54, 27.6; MS (ESI) 408 (MH+, 100), 228 (68), 214 (66).
Anal. Calcd for C20H25NO8: C, 58.96; H, 6.18; N, 3.44. Found: C,
58.92; H, 6.24; N, 3.32.
1,2,3,4-Tetrahydro[1,3]dioxolo[4,5-j]phenanthridine (7a):
yield 96%, colorless solid; mp 89-91 °C; IR (CHCl3) 3053, 2306,
1
1460, 1265 cm-1; H NMR (CDCl3, 400 MHz) δ 8.73 (s, 1H),
Acknowledgment. The cytotoxic evaluation data from Dr.
Dhiman Sarkar and Ms. Sampa Sarkar are gratefully acknowl-
edged. M.B. thanks CSIR, New Delhi, for the award of a
Research Fellowship.
7.07 (s, 2H), 6.02 (s, 2H), 2.98 (s, 2H), 2.87 (s, 2H), 1.88 (m, 4H);
13C NMR (CDCl3, 100 MHz) δ 150.8, 149.2, 147.7, 147.0, 133.6,
124.2, 123.8, 103.5, 01.3, 98.5, 32.5, 25.1, 23.0, 22.7; MS (ESI)
250 (M + Na+, 100). Anal. Calcd for C14H13NO2: C, 73.99; H,
5.77; N, 6.16. Found: C, 73.92; H, 5.68; N, 6.26.
Supporting Information Available: Experimental proce-
dures, characterization details, and copies of 1H NMR and 13
C
(2S,3S,4S)-2,3,4-Tris(methoxymethoxy)-1,2,3,4-
tetrahydro[1,3]dioxolo[4,5-j]phenanthridine (15): yield 86%;
NMR spectra of compounds 1-3, 5, 7, 12-15, and 17-21.
This material is available free of charge via the Internet at
http://pubs.acs.org.
[R]27D +118.1 (c 1.1, CHCl3); IR (CHCl3) 3433, 2360, 1643 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 8.88 (s, 1H), 7.21 (s, 1H), 7.15 (s,
1H), 6.08 (d, J ) 2.3 Hz, 2H), 5.12 (d, J ) 6.8 Hz, 1H), 4.92 (d,
J ) 3.5 Hz, 1H), 4.90-4.78 (m 4H), 4.73 (d, J ) 6.8 Hz, 1H),
JO801761F
J. Org. Chem. Vol. 73, No. 20, 2008 8131