Facile synthesis of substituted isoquinolines

Article abstract of DOI:10.1016/j.tetlet.2012.02.045

A facile three-step protocol toward methoxy isoquinolines 7 starting with substituted 2-allylbenzaldehydes 9 was described. The overall synthetic process of skeleton 7 was carried out using the Grignard addition, PCC-oxidation, and one-pot oxidative cleavage of the olefinic group of skeleton 9 with OsO ₄-NaIO₄ followed by the condensation of the resulting 1,5-dicarbonyl compounds with NH₄OAc. Skeleton 9 was prepared in high yield via the known Claisen rearrangement of skeleton 8 and O-methylation. Papaverine 2 is also synthesized via the simple three-step synthetic protocol.

Full text of DOI:10.1016/j.tetlet.2012.02.045

Tetrahedron Letters 53 (2012) 2125–2128
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of substituted isoquinolines
⇑
Meng-Yang Chang , Ming-Hao Wu, Nein-Chia Lee, Ming-Fang Lee
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile three-step protocol toward methoxy isoquinolines 7 starting with substituted 2-allylbenzaldehy-
des 9 was described. The overall synthetic process of skeleton 7 was carried out using the Grignard addi-
tion, PCC-oxidation, and one-pot oxidative cleavage of the olefinic group of skeleton 9 with OsO4–NaIO4
followed by the condensation of the resulting 1,5-dicarbonyl compounds with NH4OAc. Skeleton 9 was
prepared in high yield via the known Claisen rearrangement of skeleton 8 and O-methylation. Papaverine
2 is also synthesized via the simple three-step synthetic protocol.
Received 2 January 2012
Revised 7 February 2012
Accepted 10 February 2012
Available online 18 February 2012
Keywords:
Isoquinoline
Ó 2012 Elsevier Ltd. All rights reserved.
Claisen rearrangement
One-pot combination reaction
Papaverine
Introduction
rearrangement followed by the O-methylation (Scheme 1).5 Under
the reaction condition, compound 9a and its regioisomer (4-allyl-3-
Natural products that contain an isoquinoline nucleus often ex-
hibit biological activity, such as antimalarial, anti-HIV, antitumor,
antimicrobial, and antibacterial.1 As a result, there is much interest
in the synthesis of substituted isoquinolines.2 Functionalized iso-
quinolines are prevalent scaffolds that serve as crucial building
blocks for numerous syntheses of natural products, as shown in
Fig. 1, such as nigellimine (1),3a papaverine (2),3b necatorone
(3),3c refescine (4),3d decumbenine B (5),3e and bererine (6).3f In
the context of a program directed toward the synthesis of isoquin-
oline-containing analogues (Fig. 2), our aim is to prepare a diverse
array of substituted isoquinolines partners 7.4
methoxybenzaldehyde) were isolated in nearly a 2:3 ratio. Com-
pound 9b was provided as a sole isomer. By controlling the reaction
temperature at 190 °C, compound 9c with one rearrangement and
its double-rearranged isomer was isolated in a ratio of almost 3/1
(for 3 h). To increase the reaction time from 3 to 6 h, the ratio value
of compound 9d obtained with a double rearrangement and the one
rearrangement of the isomer was 12/1 under the above-mentioned
condition. Therefore, after adjusting the reaction time, compounds
9c–9d and their isomers were observed in different ratios. With
compounds 9a–9d in hand, the investigation continued.
Herein, a facile three-step route toward methoxy isoquinolines
7 starting with different substituted 2-allylbenzaldehydes 9 is
described via the synthetic sequence of Grignard addition, PCC-oxi-
dation, and one-pot oxidative cleavage of the olefinic group of skel-
eton 9 with OsO4–NaIO4 followed by the condensation of the
resulting 1,5-dicarbonyl compounds with NH4OAc. Skeleton 9
was prepared in high yield via the known Claisen rearrangement
of skeleton 8 and O-methylation.
OMe
MeO
MeO
MeO
MeO
HO
MeO
MeO
N
N
N
N
O
Me MeO
N
MeO
OH
OMe
nigellimine (1)
papaverine (2)
necatorone (3)
refescine (4)
Results and discussion
O
O
The starting materials, 2-allylbenzaldehydes 9a–9d, were
isolated from commercially available compounds 8a and 8b in
44–55% overall yields of three-steps according to the reported pro-
cedures with the reaction sequence of O-allylation and the Claisen
O
X
R
O
1
4
O
Y
Z
O
N
N
N
1
2
MeO
HO
OMe
R
decumbenine B (5)
berberine (6)
7
⇑
Corresponding author. Tel.: +886 7 3121101x2220.
E-mail address: mychang@kmu.edu.tw (M.-Y. Chang).
Figure 1. Structures of natural polyoxygenated isoquinolines.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.045

2126
M.-Y. Chang et al. / Tetrahedron Letters 53 (2012) 2125–2128
To initiate the synthetic work of methoxy isoquinolines 7, one-
C4-C4a: Pormeranz-Fitsch reaction
4
4a
8a
pot oxidative cleavage of the olefinic group of model substrates 9a
and 9b with OsO4–NaIO4 followed by the condensation of the
resulting 1,5-dicarbonyl compounds with NH4OAc was examined.
Reports in the literature have described the improved procedure
for the oxidative cleavage of olefins by the OsO4–NaIO4 system.6
Our experimental conditions are as follows. First, the OsO4-medi-
ated bond cleavage of model substrates 9a and 9b with NMO
(2.2 equiv) provided a diol product in the co-solvent of THF and
water (v/v = 1:1) at 50 °C in 30 min. After the model substrate
was consumed (by TLC), NaIO4 (1.2 equiv) was then added to the
reaction mixture at 50 °C. No attempts were made to separate or
isolate the intermediate. Rather, condensation of the crude dialde-
hydes to the corresponding isoquinoline derivatives was further
examined. After 10 min, NH4OAc (1.5 equiv) and NaOAc (1.5 equiv)
were added to the reaction mixture at 50 °C for 20 min. The subse-
quent ring-closure was easily formed on the isoquinoline skeleton
and compounds 7a and 7b were isolated in 88% and 80% yields,
respectively (Scheme 2).7 The overall synthetic procedure had to
be monitored by TLC until the reaction was completed within ca.
1 h.
C1-N-C3: NH -mediated condensation
4
N
C1-N: Pitect-Spengler reaction
1
C1-C8a: Bischler-Napieralski reaction
Figure 2. Synthetic routes of substituted isoquinolines.
OH
X
R
1
1) allylBr, K2CO3
Y
Y
Z
R
2) decalin, reflux
3) MeI, K2CO3
CHO
8a, Y = H, R = H
CHO
9a, X = OMe, Y = Z = R = R = H (54%)
1
1
8b, Y = OMe, R = H
9b, X = Y = OMe, Z = R = R = H (44%)
1
1
9c, X = Y = OMe, Z = R = H, R = Me (55%)
1
9d, X = R =H, Y = Z = OMe, R = Ph (48%)
1
Scheme 1. Synthetic route of skeleton 9.
For preparing another skeleton 7, skeleton 9 was further trans-
formed to skeleton 10 via two steps: the Grignard addition with
R2MgBr (R2 = Me, C10H21, Bn, Ph, 2-Me-Ph, 4-F-Ph, 4-MeO-Ph)
and oxidation with PCC. Compounds 10a–10n were easily isolated
X
X
OsO , NaIO ,
4
4
Y
Y
in 78–90% yields by the two steps. The yields were based on the a-
NH OAc
4
N
allylbenzaldehydes 9 used as the starting materials and were fairly
consistent across the variety of substrates employed. Under the
above-mentioned one-pot combination condition, compounds
7c–7p with different alkyl groups and electron-withdrawing and
electron-donating aryl substituents were provided in 72–90%
CHO
9a, X = OMe, Y = H
9b, X = Y = OMe
7a, X = OMe, Y = H (88%)
7b, X = Y = OMe (80%)
Scheme 2. One-pot synthetic route of isoquinolines 7a and 7b.
Table 1
Synthesis of methoxy isoquinolines 7a,b
X
R
X
R
R
X
R
R
1
1
1
1) R2MgBr,THF
2) PCC, DCM
OsO , NMO
4
Y
Y
Z
Y
Z
R
R
NaIO , NH OAc
4
4
O
N
Z
CHO
9
10
7
2
2
Entry
1
Product 10/yield (%)
Product 7/yield (%)
Entry
2
Product 10/yield (%)
Product 7/yield (%)
OMe
MeO
OMe
MeO
OMe
MeO
OMe
MeO
O
N
O
N
Me
Me
10a / 82
7c / 78
10b / 80
10d / 88
7d / 80
OMe
MeO
OMe
OMe
OMe
OMe
MeO
MeO
MeO
MeO
MeO
O
N
O
O
N
3
4
10c / 86
10e / 78
7e / 82
7g / 84
7f / 88
OMe
MeO
OMe
OMe
MeO
N
O
N
5
6
Me
Me
F
F
10f / 83
7h / 87

M.-Y. Chang et al. / Tetrahedron Letters 53 (2012) 2125–2128
2127
Table 1 (continued)
Entry Product 10/yield (%)
OMe
Product 7/yield (%)
Entry
Product 10/yield (%)
Product 7/yield (%)
OMe
MeO
OMe Me
MeO
OMe Me
MeO
MeO
O
N
O
N
7
8
10h / 80
7j / 86
7l / 89
OMe
OMe
10g / 90
7i / 90
OMe Me
OMe Me
MeO
MeO
MeO
Ph
MeO
MeO
O
N
MeO
O
N
9
10
10j / 85
OMe
O
OMe
N
10i / 84
7k / 84
MeO
MeO
MeO
MeO
MeO
MeO
MeO
Ph
Ph
Ph
O
N
MeO
11
13
12
14
OMe
OMe
N
F
F
10l / 88
10n / 87
7n / 85
7p / 80
10k / 82
7m / 87
7o / 81
MeO
MeO
MeO
MeO
MeO
MeO
MeO
Ph
O
N
O
MeO
10m / 80
a
For the best one-pot reaction conditions: (i) olefins 10 (1.0 equiv), OsO4 (2.5% in THF, 1 mL), NMO (50% in H2O, 2.2 equiv), THF/H2O (v/v = 1:1, 10 mL), 50 °C, 30 min, (ii)
NaIO4 (1.2 equiv), 50 °C, 10 min, and (iii) NH4OAc (1.5 equiv), NaOAc (1.5 equiv), 50 °C, 20 min.
b
The isolated products were >95% pure as determined by 1H NMR analysis.
OMe
OMe
OsO , then
4
MeO
MeO
O
R
NaIO , HOAc
4
O
O
R
2
2
10a, R = Me
11a, R = Me (77%)
2
2
10b, R = C
H
10 21
11b, R = C H (80%)
11c, R = Bn (82%)
2
2
2 10 21
10c, R = Bn
2
Scheme 3. One-pot synthetic route of skeleton 11.
MeO
Ph
1) 3,4-MeO2PhCH2MgBr
OsO4, NaIO4,
O
MeO
MeO
9d
2
NH4OAc (77%)
2) PCC, DCM
(66% of two-step)
MeO
12
Scheme 4. Synthesis of papaverine (2).
route to prepare the substituted isoquinoline bearing the potential
biological activities.9
Interestingly, with the OsO4-promoted reaction of model sub-
strates 10a–10c with different alkyl groups (R2 = Me, C10H21, Bn)
with the addition of NaIO4–HOAc, compounds 11a–11c were iso-
lated in 77–82% yields, as shown in Scheme 3. HOAc was an impor-
tant factor in generating the formation of the ketal group on
skeleton 11 via the intramolecular protection. Overall, the OsO4–
NaIO4–HOAc system was demonstrated to be a convenient method
Figure 3. X-ray structure of compound 7i.
yields, as shown in Table 1. The structure of compound 7i was
determined using single-crystal X-ray analysis (Fig. 3).8 With the
successful results in mind, the efficient synthetic OsO4–NaIO4–
NH4OAc combination provided the one-pot facile and high-yield

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M.-Y. Chang et al. / Tetrahedron Letters 53 (2012) 2125–2128
3. For nigellimine (1), see: (a) Atta-ur-Rahman; Malik, S.; Zaman, K. J. Nat. Prod.
1992, 55, 676; For papaverine (2), see: (b) Falck, J. R.; Manna, S.; Mioskowski, C. J.
Org. Chem. 1981, 46, 3742; For necatorone (3), see: (c) Klamann, J.-D.; Fugmann,
B.; Steglich, W. P. Phytochemistry 1989, 28, 3519; For refescine (4), see: (d)
Menachery, M. D.; Muthler, C. D.; Buck, K. T. J. Nat. Prod. 1987, 50, 726; For
decumbenine B (5), see: (e) Zhang, J.; Zhu, D.; Hong, S. Phytochemistry 1995, 39,
435; For berberine (6), see: (f) Wang, Y.-X.; Wang, Y.-P.; Zhang, H.; Kong, W.-J.;
Li, Y.-H.; Liu, F.; Gao, R.-M.; Liu, T.; Jiang, J.-D.; Song, D.-Q. Bioorg. Med. Chem. Lett.
2009, 19, 6004.
4. (a) Gensler, W. J. In Org. React; Adams, R., Ed.; Wiley: New York, 1951; Vol. 6, pp
191–206; (b) Whaley, W. M.; Govindachari, T. R. In Organic Reactions; Adams, R.,
Ed.; Wiley: New York, 1951; Vol. 6, pp 74–150; (c) Whaley, W. M.; Govindachari,
T. R. In Organic Reactions; Adams, R., Ed.; Wiley: New York, 1951; Vol. 6, pp 154–
190.
for the one-pot synthesis of protected ketal skeleton 11 from skel-
eton 9. However, there is no example for the one-pot dihydroxyla-
tive ketalation.
On the basis of the three-step protocol, papaverine 2 was cho-
sen as the next synthetic target. Furthermore, ketone 12 was ob-
tained from the Grignard addition of aldehyde 9d followed by
oxidation with PCC in a 66% yield of two steps (Scheme 4). By
the efficient one-pot OsO4–NaIO4–NH4OAc combination, papaver-
ine 2 with analgesic activities was prepared in a 77% yield from ke-
tone 12.
5. (a) Chattopadhyay, S. K.; Biswas, T.; Maity, S. Synlett 2006, 2211; (b) Tsai, J.-C.; Li,
S.-R.; Chen, L.-Y.; Chen, P. Y.; Jhong, J. Y.; Shu, C.-J. .; Lo, Y.-F.; Lin, C.-N.; Wang, E.-
C. J. Chin. Chem. Soc. 2008, 55, 1317.
Conclusion
6. (a) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217; (b) Nielsen, T.
E.; Meldal, M. Org. Lett. 2005, 7, 2695; (c) Nielsen, T. E.; Le Quement, S. T.;
Meldal, M. Org. Lett. 2007, 9, 2469.
7. (a) Huang, X.; Tanaka, K. S. E.; Bennet, A. J. J. Am. Chem. Soc. 1997, 119, 11147; (b)
Schiess, P.; Huys-Francotte, M.; Vogel, C. Tetrahedron Lett. 1985, 26, 3959; (c)
Pongo, L.; Agai, B.; Faigl, F.; Reiter, J.; Simig, G. J. Heterocycl. Chem. 2006, 43,
1539; (d) Bringmann, G. Liebigs Ann. Chem. 1985, 2126; (e) Li, Y.-L.; Combs, A. P.;
Yue, E. W.; Li, H.-Y. WO patent 2011075630.
8. CCDC 860022 (7i) contains the Supplementary crystallographic data for this
Letter. This data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax:
44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk)
A synthetic methodology for producing a series of methoxy iso-
quinoline 7 has been successfully presented from skeleton 9 using
the Grignard addition, PCC-oxidation, and one-pot OsO4–NaIO4–
NH4OAc combination-promoted oxidative cleavage of olefins/con-
densation. Under the three-step protocol, papaverine (2) was also
synthesized.
Acknowledgment
9. A representative procedure of skeleton 7 is as follows: A solution of 2.5% OsO4
(1 mL, in THF) was added to a solution of skeleton 10 (1.0 mmol) in the co-
solvent of THF (10 mL) and water (10 mL). NMO (50% in water, 500 mg,
2.2 mmol) was added to the reaction mixture at rt. The reaction mixture was
stirred at 50 °C for 30 min. Then, NaIO4 (257 mg, 1.2 mmol) was added to the
reaction mixture at 50 °C. The reaction mixture was stirred at 50 °C for 10 min.
NH4OAc (115 mg, 1.5 mmol) and NaOAc (123 mg, 1.5 mmol) were added to the
reaction mixture at 50 °C. The reaction mixture was stirred at 50 °C for 20 min.
The overall synthetic procedure had to be monitored by TLC until the reaction
was completed within a period of 1 h. 10% NaHSO3 (aq) (5 mL) was added to the
reaction mixture and the solvent was concentrated. The residue was diluted
with water (10 mL) and the mixture was extracted with EtOAc (3 Â 20 mL). The
combined organic layers were washed with brine, dried, filtered, and evaporated
to yield crude compound. Purification on silica gel (hexanes/EtOAc) afforded
skeleton 7. For compound 7i: Yield 90% (265 mg); White solid; mp = 112–113 °C
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C18H18NO3
296.1287, found 296.1289; 1H NMR (400 MHz): d 8.51 (d, J = 6.0 Hz, 1H), 7.90
(dd, J = 0.8, 9.6 Hz, 1H), 7.86 (dd, J = 0.8, 6.0 Hz, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.27
(d, J = 9.6 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 4.01 (s, 6H), 3.88 (s, 3H); 13C NMR
(100 MHz): d 159.99, 159.89, 150.93, 142.14, 141.39, 132.88, 132.01, 131.10
(2Â), 124.64, 122.59, 114.84, 113.63 (2Â), 113.06, 61.09, 56.35, 55.27; Anal.
Calcd for C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.46; H, 5.98; N, 4.97.
Single-crystal X-Ray diagram: crystal of compound 7i was grown by slow
diffusion of EtOAc into a solution of compound 7i in DCM to yield colorless
prism. The compound crystallizes in the monoclinic crystal system, space group
P1 21/c 1, a = 7.9935(3) Å, b = 7.3253(2) Å, c = 25.8167(8) Å, V = 1507.80(8) Å3,
Z = 4, dcalcd = 1.301 g/cm3, F(000) = 624, 2h range 2.55–26.38°, R indices (all
data) R1 = 0.0996, wR2 = 0.1722.
The authors would like to thank the National Science Council of
the Republic of China for its financial support (NSC 99-2113-M-
037-006-MY3).
Supplementary data
Supplementary data (Experimental procedure and scanned
photocopies of 1H and 13C NMR (CDCl3) spectral data were sup-
ported.) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2012.02.045.
References and notes
1. For reviews on the synthesis of isoquinolines, see: (a) Chrzanowska, M.;
Rozwadowska, M. D. Chem. Rev. 2004, 104, 3341; (b) Larghi, E. L.; Bohn, M. L.;
Kaufman, T. S. Tetrahedron 2009, 65, 4257; (c) Rozwadowska, M. D. Heterocycles
1994, 39, 903; (d) Brase, S.; Gil, C.; Knepper, K. Bioorg. Med. Chem. 2002, 10, 2415.
2. (a) Flyer, A. N.; Si, C.; Myers, A. G. Nat. Chem. 2010, 2, 886; (b) Guimond, N.;
Fagnou, K. J. Am. Chem. Soc. 2009, 131, 12050; (c) Sha, F.; Huang, X. Angew. Chem.,
Int. Ed. 2009, 48, 3458; (d) Watanabe, Y.; Aoki, S.; Tanabe, D.; Setiawan, A.;
Kobayashi, M. Tetrahedron 2007, 63, 4074; (e) Wei, X.; Zhao, M.; Du, Z.; Li, X. Org.
Lett. 2011, 13, 4636; (f) Todorovic, N.; Awuah, E.; Albu, S.; Ozimok, C.; Capretta,
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