Application of the hypervalent iodine reagent to the synthesis of some pentasubstituted aporphine alkaloids

Article abstract of DOI:10.1055/s-2007-985596

The oxidative biaryl coupling of various N-substituted 1- benzyltetrahydroisoquinolines to the corresponding aporphines by the hypervalent iodine reagent was studied. The study sheds light on the unifying mechanism of the reaction illustrating the requirement of the p-p coupling via the six-membered transition state as the initial step. The finding was applied to the synthesis of some pentasubstituted aporphine alkaloids. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-985596

LETTER
2363
Application of the Hypervalent Iodine Reagent to the Synthesis of Some
Pentasubstituted Aporphine Alkaloids
U
se of Iodine Re
a
t
Synth
c
esis of
A
po
h
a
oids nok Pingaew,a Somsak Ruchirawat*a–c
a
b
c
Department of Chemistry, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
Chulabhorn Research Institute and Chulabhorn Graduate Institute, Vipavadee Rangsit Highway, Bangkok 10210, Thailand
Program on Research and Development of Synthetic Drugs, Institute of Science and Technology for Research and Development,
Mahidol University, Salaya Campus, Salaya 73170, Thailand
Fax +66(2)5740616; E-mail: somsak@cri.or.th
Received 25 June 2007
known.7–15 Thalicsimidine, norpurpureine and thalbaic-
alidine exhibited significant antiplatelet aggregation ac-
tivity.7,8
Abstract: The oxidative biaryl coupling of various N-substituted 1-
benzyltetrahydroisoquinolines to the corresponding aporphines by
the hypervalent iodine reagent was studied. The study sheds light on
the unifying mechanism of the reaction illustrating the requirement
of the p–p coupling via the six-membered transition state as the
initial step. The finding was applied to the synthesis of some penta-
substituted aporphine alkaloids.
Intramolecular oxidative coupling of 1-benzyltetra-
hydroisoquinoline with several heavy metal oxidizing re-
agents, such as Ru(IV),16 Pb(IV),17 V(III),18,19 and
Cr(III)20 is a frequently employed method for the prepara-
tion of aporphine alkaloid along with its biosynthetic
pathway. However, this synthetic method has serious
drawbacks associated with the highly toxic nature of
heavy-metal reagents and the use of harsh acidic condi-
tions. Possessing exceptionally mild, selective and
environmentally friendly properties, hypervalent iodine
reagents have been recognized as powerful oxidizing re-
agents in organic synthesis.21–23 To some varying extent,
the hypervalent iodines were successfully utilized to pro-
mote oxidative biaryl coupling reaction.24–30 Intramolecu-
lar oxidative coupling reaction of N-protected 1-
benzyltetrahydroisoquinolines using the hypervalent
iodine reagent has been reported by Badia,31 Lee,32 and
Kita.33,34 The oxidation of N-methyl- and N-acyl-1-ben-
Key words: aporphine, 1-benzyltetrahydroisoquinoline, neospir-
inedienone, hypervalent iodine, p–p coupling
Aporphine is a large group of the benzylisoquinoline-
derived alkaloids possessing a tetracyclic structure
(Figure 1). The aporphine alkaloids exhibited diverse in-
teresting pharmacological properties.1–6 Although glau-
cine, a tetrasubstituted structure, is probably the most
commonly known natural aporphine, some pentasubsti-
tuted aporphines, occurring in plants, such as Annona
(purpurea) Phoebe (pittieri, molicella, valeriana) and
Thalictrum (simplex, pedunculatum, baicalense) are also
R3
3
zyltetrahydroisoquinolines
using
phenyliodine(III)
4
R2
2
bis(trifluoroacetate) (PIFA)–BF3·Et2O afforded apor-
phine and neospirinedienone alkaloids respectively.31,32,34
On the other hand, morphinandienone alkaloids could be
obtained by employing the combination of PIFA and
heteropoly acid (HPA).33
5
NR4
R1
6
1
7
11
10
8
R6
9
Although the formation of aporphine, neospirinedienone
and morphinandienone alkaloids using the application of
hypervalent iodine has been reported, the direct p–p cou-
pling of 1-benzyltetrahydroisoquinoline has not been ob-
served.31–34 In order to learn more about the mechanistic
detail of the oxidative coupling for conversion of 1-ben-
zylisoquinolines to the corresponding aporphine, the oxi-
dative biaryl coupling of various N-substituted 1-
benzylisoquinolines 2a–h was investigated (Table 1).35
R5
1
glaucine: R1 = R2 = R5 = R6 = OMe, R3 = H, R4 = Me
nantenine: R1 = R2 = OMe, R3 = H, R4 = Me, R5–R6 = OCH2O
thalicsimidine: R1 = R2 = R3 = R5 = R6 = OMe, R4 = Me
phoebine: R1 = R2 = R3 = OMe, R4 = Me, R5–R6 = OCH2O
norpurpureine: R1 = R2 = R3 = R5 = R6 = OMe, R4 = H
norphoebine: R1 = R2 = R3 = OMe, R4 = H, R5–R6 = OCH2O
N-formyl purpureine: R1 = R2 = R3 = R5 = R6 = OMe, R4 = CHO
romucosine G: R1 = R2 = R3 = R5 = R6 = OMe, R4 = CO2Me
thalbaicalidine: R1 = R2 = R5 = R6 = OMe, R3 = OH, R4 = Me
thalbaicaline: R1 = R2 = R5 = R6 = OMe, R3 = OH, R4 = H
From our study, we found that aporphines 1 and neospir-
inedienones 3 were successfully synthesized by the oxida-
tive biaryl coupling using PIFA. The formation of
products depended on the substituents on the N atom and
the presence or the absence of the methoxy group at the 5-
position of the starting isoquinolines 2. In the case of
PIFA oxidation of N-methyltetrahydroisoquinolines 2a–c,
aporphines 1 were satisfactorily achieved irrespective of
Figure 1
SYNLETT 2007, No. 15, pp 2363–2366
Advanced online publication: 22.08.2007
DOI: 10.1055/s-2007-985596; Art ID: G16507ST
© Georg Thieme Verlag Stuttgart · New York
1
7
.0
9
.2
0
0
7

2364
R. Pingaew, S. Ruchirawat
LETTER
Table 1 PIFA-Mediated Oxidative Biaryl Coupling
R2
R2
OMe
4
3
4
5
O
MeO
R1
2
MeO
R1
6
5
6
7
PhI(OCOCF3)2
3
NR3
BF3·OEt2, –40 °C
NCHO
NR3
1
4a
or
7a
1
8
CH2Cl2, 1 h
8
12
9
R5
R5
R5
R4
R4
R4
3
2
1
Entry
2
R1
R2
R3
R4
R5
Yield (%)
1
3
–
–
–
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
OMe
OMe
H
H
H
Me
Me
Me
Me
OMe
OMe
36
36
34
OCH2O
OMe
OMe
H
OMe
OMe
OMe
a
H
OMe
–
OMe
OMe
H
H
CHO
CHO
CHO
CHO
OMe
–
91
94
–
H
OCH2O
OMe
–
2g
2h
OMe
H
OMe
OMe
42
a
H
OMe
–
a The reaction gave only a complex mixture.
Table 2 PIFA-Mediated Oxidative Biaryl Coupling
the presence of the methoxy group at C-5. However, when
N-formyltetrahydroisoquinolines 2e–g were oxidized un-
der the same condition, we discovered that the aporphines
1 were obtained only when methoxy group at the 5-posi-
tion was present. In the absence of methoxy group at C-5,
neospirinedienones 3 were obtained in high yields instead
of the aporphines 1. The NMR spectrum of the N-formyl
aporphine 1g was complex, owing to the resonances of
two rotational isomers due to restricted rotation around
the N-formyl group.8
OMe
OMe
MeO
MeO
MeO
MeO
PhI(OCOCF3)2
BF3·OEt2, –40 °C
NR1
NR1
CH2Cl2, 1 h
R3
R3
R2
R2
2
1
A plausible mechanistic pathway for aryl–aryl coupling of
N-substituted 1-benzyltetrahydroisoquinolines 2 to form
aporphines 1 or neospirinedienones 3 is proposed
(Scheme 1). The radical cation intermediate A was first
generated by single-electron-transfer (SET) process.36 For
isoquinolines 2a,b and 2e,f, bridgehead p–p coupling on
the radical cation A via six-membered transition state
gave morphinandienone intermediate B.33,34,37 For N-
methyltetrahydroisoquinolines 2a,b, the aziridinium in-
termediate C was possibly formed through the participa-
tion of the free electron-pair on nitrogen. Aryl migration
Entry 2
R1
R2
R3
1
Yield (%)
1
2
3
4
5
2i
2j
Me
OMe
OCH2O
OMe
OCH2O
OMe
OMe
OMe
OMe
1i
31
29
72
67
52
Me
1j
1k
1l
2k
2l
CHO
CHO
CO2Me
2m
1m
was governed by stereoelectronic factor, leading to pro- nandienone intermediate B may be due to the stability of
erythrinadienone intermediate D.38 Further aryl migration the resulting benzylic cation E.39 However, the oxidative
furnished the aporphines. However, in the cases where the biaryl coupling of N-substituted 1-benzyltetrahydroiso-
free electron-pair is not available through the formation of
the amide bond as in compounds 2e,f, the alkyl group
migration of the morphinandienone intermediate B was
observed to produce neospirinedienone 3. The preference
to alkyl migration rather than to aryl migration in morphi-
quinolines 2c and 2g possessing methoxy group at the 5-
position could undergo direct p–p coupling via a six-
membered transition state to afford directly the aporphine
alkaloids 1.
Synlett 2007, No. 15, 2363–2366 © Thieme Stuttgart · New York

LETTER
Use of Iodine Reagent in the Synthesis of Aporphine Alkaloids
2365
R2
5
OMe
OMe
4
6
7
MeO
R1
MeO
O
3
NR3
2
NCHO
NCHO
1
+
8
R5
R5
R5
R4
R4
R4
2
3
E
R3 = CHO
PhI(OCOCF3)2
BF3·OEt2
alkyl migration
+
R2
OMe
MeO
MeO
MeO
MeO
R1
+
.
R1 = OMe, R2 = H
R3 = Me
N
+
NR3
NR3
Me
bridgehead p-p coupling
R5
R5
R4
R4
radical cation A
R5
R4
B
C
R
1 = H, R2 = OMe
direct p-p coupling
aryl migration
R2
+
MeO
MeO
R1
NMe
NR3
MeO
R5
R5
R4
R4
D
1
Scheme 1 Possible reaction mechanism for the formation of aporphine 1 and neospirinedienone 3
The above finding on the direct p–p coupling has allowed oxidative process as well as the non-toxic property of
us to successfully synthesize many aporphine alkaloids the hypervalent iodine compound make this method very
(Table 2). N-Formyl purpureine 1k8 and romucosine G favorable for the synthesis of the aporphine alkaloids.
1m13 were successfully synthesized by using the appli-
cation of hypervalent iodine in 72% and 52% yields,
Acknowledgment
respectively. Thalicsimidine 1i7 and phoebine 1j12 could
We gratefully acknowledge the financial support from the Thailand
Research Fund (TRF) for the generous support of the research
program and the award of Senior Research Scholar to S.R. and the
Royal Golden Jubilee Ph.D. Program (Grant No. PHD/0205/2544)
to R.P.
be derived from either direct oxidative coupling using
PIFA (entries 1 and 2) or lithium aluminum hydride re-
duction of N-formyl aporphine 1k (76%) and 1l (75%), re-
spectively. Furthermore, norpurpureine7 (65%) and
norephoebine9 (59%) could be obtained after hydrolysis
of the corresponding N-formyl aporphines 1k and 1l with
potassium hydroxide in ethanol.
References and Notes
(1) Guinaudeau, H.; Leboeuf, M.; Cave, A. Lloydia 1975, 38,
In conclusion, we have found an application of PIFA as a
powerful oxidative biaryl coupling reagent for the synthe-
sis of aporphine and neospirinedienone. It is concluded
that the reaction mechanism takes place via p–p coupling
involving six-membered transition state in the initial step
followed by further reactions depending on the methoxy-
lation pattern on the aromatic ring and the nature of
the substituents on the nitrogen. The simplicity of the
275.
(2) Guinaudeau, H.; Leboeuf, M.; Cave, A. Lloydia 1979, 42,
325.
(3) Guinaudeau, H.; Leboeuf, M.; Cave, A. J. Nat Prod. 1983,
46, 761.
(4) Guinaudeau, H.; Leboeuf, M.; Cave, A. J. Nat Prod. 1988,
51, 389.
(5) Guinaudeau, H.; Leboeuf, M.; Cave, A. J. Nat Prod. 1994,
57, 1033.
Synlett 2007, No. 15, 2363–2366 © Thieme Stuttgart · New York

2366
R. Pingaew, S. Ruchirawat
LETTER
0.88 mmol) in CH2Cl2 (5 mL) at –40 °C under an argon
(6) Kametani, T.; Honda, T. In The Alkaloids, Vol. 24; Brossi,
A., Ed.; Academic Press: New York, 1985, 153.
(7) Chang, F.-R.; Wei, J.-L.; Teng, C.-M.; Wu, Y.-C.
Phytochemistry 1998, 49, 2015.
(8) Chang, F.-R.; Wei, J.-L.; Teng, C.-M.; Wu, Y.-C. J. Nat.
Prod. 1998, 61, 1457.
(9) Castro, O.; Lopez, C. J.; Vergara, G. A. Phytochemistry
1985, 24, 203.
(10) Stermitz, F. R.; Castro, C. O. J. Nat. Prod. 1983, 46, 913.
(11) Velcheva, M. P.; Petrova, R. R.; Samdanghiin, Z.;
Danghaaghiin, S.; Yansanghiin, Z.; Budzikiewicz, H.;
Hesse, M. Phytochemistry 1996, 42, 535.
(12) Castro, O.; Lopez, J.; Stermitz, F. R. J. Nat. Prod. 1986, 49,
1036.
(13) Chang, F.-R.; Chen, C.-Y.; Wu, P.-H.; Kuo, R.-Y.; Chang,
Y.-C.; Wu, Y.-C. J. Nat. Prod. 2000, 63, 746.
(14) Hussain, S. F.; Siddiqui, M. T.; Guinaudeau, H.; Shamma,
M. J. Nat. Prod. 1989, 52, 428.
(15) Maekh, S. K.; Yunusov, S. Y.; Boiko, E. V.; Starchenko, V.
M. Khim. Prir. Soedin. 1983, 4, 537.
(16) Landais, Y.; Robin, J. P. Tetrahedron 1992, 48, 7185.
(17) Hoshino, O.; Suzuki, M.; Ogasawara, H. Heterocycles 2000,
52, 751.
atmosphere. The reaction mixture was stirred at –40 °C for
1 h, then sat. NaHCO3 (30 mL) was added followed by
extraction with CH2Cl2 (3 × 30 mL). The combined CH2Cl2
extracts were dried over anhyd Na2SO4 and evaporated to
dryness in vacuo. The crude product was purified by PLC on
silica gel using 50% EtOAc–hexane as a developing solvent
to give aporphine 1g (62 mg, 42%). Recrystallization from
EtOAc afforded yellow needles; mp 193.0–193.6 °C. IR
(nujol): 1675, 1602, 1570, 1520 cm–1. 1H NMR (300 MHz,
CDCl3): d = 2.60–3.42 (m, 5 H, C4-H2, C5-H, C7-H2), 3.88–
3.95, 4.43–4.47 (2 × m, 1 H, C5-H), 3.86, 3.93, 3.95, 3.99,
4.00 (5 × s, 12 H, 4 × OMe), 4.59–4.64, 4.95–5.06 (2 × m, 1
H, C6a-H), 6.79, 6.82 (2 × s, 1 H, C8-H), 7.08, 7.12 (2 × s, 1
H, C1-H), 7.20 (s, 1 H, C11-H), 8.30, 8.42 (2 × s, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 23.73, 24.78 (C-4), 32.75,
36.77 (C-7), 36.02, 42.03 (C-5), 49.30, 53.06 (C-6a), 55.90,
56.00, 56.13, 56.34, 60.56, 60.66 (4 × OMe), 106.64, 106.78
(C-1), 107.09, 107.19 (C-11), 111.67, 112.06 (C-8), 123.43,
123.75, 125.90, 126.17, 126.92, 127.77, 128.08, 128.91,
130.12, 130.46 (C-1a, C-1b, C-3a, C-7a, C-11a), 145.10,
145.55 (C-3), 148.31, 148.65 (C-10), 148.83, 148.92 (C-9),
151.54, 151.86 (C-2), 161.89, 162.22 (CHO). LRMS (EI):
m/z (%) = 369 (8.28) [M]+, 337 (100.00), 309 (72.14).
HRMS (FAB): m/z [M + H]+ calcd for C21H24NO5:
(18) Kupchan, S. M.; Liepa, A. J.; Kameswaran, V.; Bryan, R. F.
J. Am. Chem. Soc. 1973, 95, 6861.
(19) Gottlieb, L.; Meyers, A. I. J. Org. Chem. 1990, 55, 5659.
(20) Czarnocki, Z.; Mieczkowski, J. B.; Ziolkowski, M.
Tetrahedron: Asymmetry 1996, 7, 2711.
370.1654; found: 370.1661. Anal. Calcd for C21H23NO5: C,
68.28; H, 6.28; N, 3.79. Found: C, 68.29; H, 5.94; N, 3.70.
Neospirinedienone 3e (130 mg, 91%) was obtained
(21) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123.
(22) Wirth, T.; Hirt, U. H. Synthesis 1999, 1271.
(23) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523.
(24) Moreno, I.; Tellitu, I.; Herrero, M. T.; SanMartín, R.;
Domínguez, E. Curr. Org. Chem. 2002, 6, 1433.
(25) Tohma, H.; Morioka, H.; Takizawa, S.; Arisawa, M.; Kita,
Y. Tetrahedron 2001, 57, 345.
(26) Herrero, M. T.; Tellitu, I.; Domínguez, E.; Hernandez, S.;
Moreno, I.; SanMartín, R. Tetrahedron 2002, 58, 8581.
(27) Churruca, F.; SanMartín, R.; Carril, M.; Urtiaga Miren, K.;
Solans, X.; Tellitu, I.; Domínguez, E. J. Org. Chem. 2005,
70, 3178.
(28) Dohi, T.; Morimoto, K.; Kiyono, Y.; Maruyama, A.; Tohma,
H.; Kita, Y. Chem. Commun. 2005, 2930.
(29) Faul, M. M.; Sullivan, K. A. Tetrahedron Lett. 2001, 42,
3271.
(30) Churruca, F.; SanMartín, R.; Tellitu, I.; Domínguez, E. Eur.
J. Org. Chem. 2005, 2481.
following the above procedure starting from isoquinoline 1e
(150 mg, 0.40 mmol); mp 242.3–243.8 °C. IR (nujol): 1663,
1647, 1623, 1588, 1513 cm–1. 1H NMR (300 MHz, CDCl3):
d = 1.93–2.28 (m, 2 H, C5-H2), 2.83–3.36 (m, 2 H, C8-H2),
3.26–3.81 (m, 2 H, C6-H2), 3.69, 3.71, 3.89, 3.90 (4 × s, 9 H,
3 × OMe), 4.26 (dd, J = 4.6, 8.1 Hz, 1 H, C7a-H), 4.54 (dd,
J = 2.5, 6.1 Hz, 1 H, C7a-H), 5.81, 5.86 (2 × s, 1 H, C4-H),
6.50, 6.62 (2 × s, 1 H, C1-H), 6.66, 6.67 (2 × s, 1 H, C9-H),
6.95, 7.02 (2 × s, 1 H, C12-H), 8.30, 8.48 (2 × s, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 32.11, 34.96 (C-8), 38.67,
40.99 (C-5), 41.68, 44.91 (C-6), 47.98, 49.23 (C-4a), 55.12,
55.18, 56.00, 56.04 (3 × OMe), 56.89, 59.32 (C-7a), 107.82,
107.98 (C-12), 110.67, 111.16 (C-9), 116.04, 117.87 (C-4),
123.15, 123.62 (C-1), 124.14, 126.18 (C-12a), 127.00,
128.16 (C-8a), 148.47, 148.61, 150.73, 151.18, 151.38,
151.75 (C-3, C-10, C-11), 156.13, 157.98 (C-1a), 160.59,
160.85 (CHO), 180.80, 180.92 (C-2). LRMS (EI): m/z (%) =
355 (47.82) [M]+, 327 (50.32), 297 (100.00).
(31) Anakabe, E.; Carrillo, L.; Badia, D.; Vicario, J. L.; Villegas,
M. Synthesis 2004, 1093.
(32) Huang, W.-J.; Singh, O. V.; Chen, C.-H.; Lee, S.-S. Helv.
Chim. Acta 2004, 87, 167.
(33) Hamamoto, H.; Shiozaki, Y.; Nambu, H.; Hata, K.; Tohma,
H.; Kita, Y. Chem. Eur. J. 2004, 10, 4977.
(34) Hamamoto, H.; Shiozaki, Y.; Hata, K.; Tohma, H.; Kita, Y.
Chem. Pharm. Bull. 2004, 52, 1231.
(35) Typical Procedure: To a stirred solution of N-formyl-
tetrahydroisoquinoline 2g (150 mg, 0.40 mmol) in CH2Cl2
(10 mL) was added a solution of bis(trifluoroacetoxy)iodo-
benzene (191 mg, 0.44 mmol) and BF3·OEt2 (0.12 mL,
(36) Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujita, S.;
Mitoh, S.; Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116,
3684.
(37) Kupchan, S. M.; Kameswaran, V.; Lynn, J. T.; Williams, D.
K.; Liepa, A. K. J. Am. Chem. Soc. 1975, 97, 5622.
(38) (a) Kupchan, S. M.; Kim, C.-K. J. Am. Chem. Soc. 1975, 97,
5623. (b) For a related migration involving stereoelectronic
factors, see: Evan, D. A.; Hart, D. J.; Koelsch, P. M. J. Am.
Chem. Soc. 1978, 100, 4593.
(39) Chen, W.; Wu, H.; Bernard, D.; Metcalf, M. D.; Deschamps,
J. R.; Flippen-Anderson, J. L.; MacKerell, A. D. Jr.; Coop,
A. J. Org. Chem. 2003, 68, 1929.
Synlett 2007, No. 15, 2363–2366 © Thieme Stuttgart · New York