Synthesis of tetrahydroisoquinoline alkaloids via anodic cyanation as the key step

Article abstract of DOI:10.1021/jo100714y

We report a new route to tetrahydroisoquinoline (THIQ) alkaloids involving the alkylation of α-aminonitrile 2 as a key step. The latter compound was prepared by anodic cyanation of the corresponding tertiary amine 1. Reductive decyanation of α-aminonitriles 6a-c proceeded diastereoselectively (up to 95% de) to deliver the C1-substituted alkaloids precursors 9a-c. The syntheses of (±)-carnegine, (±)-norlaudanosine, and (±)-O,O- dimethylcoclaurine have been achieved.

Full text of DOI:10.1021/jo100714y

pubs.acs.org/joc
found in the biosynthetic pathway of alkaloids. In organic
synthesis, SET reactions can be effected by one-electron
Synthesis of Tetrahydroisoquinoline Alkaloids via
Anodic Cyanation as the Key Step
1
oxidants, photochemically, or electrochemically.
2
3-8
In
the first step, one electron is removed from the substrate to
†
,‡
Fadila Louafi, Jean-Pierre Hurvois,* Aı
†
ssa Chibani, and
¨
4-7
9
desilylated, or
‡
yield a radical cation that is deprotonated,
Thierry Roisnel
8
decarboxylated to yield an R-amino radical, which is readily
oxidized to produce an immonium ion which is trapped
in situ by a variety of nucleophiles (Nu) to form stable
R-alkoxylated (Nu=OR) or R-acyloxylated (Nu=OCOR)
‡
Sciences Chimiques de Rennes, Catalyse et
Organom eꢀ talliques, UMR 6226, CNRS-Universit eꢀ de
Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France,
†
and D eꢀ partement de Chimie, Facult eꢀ des Sciences Exactes,
10
products. In this context, the photochemical or electro-
1
1
Universit eꢀ Mentouri de Constantine, Route de Ain El Bey,
5000 Constantine, Alg eꢀ rie
chemical direct synthesis of R-aminonitrile systems has
occupied an interesting, although often understated position
in organic chemistry. In that case, stronger nucleophiles such
as cyanide anions intervene in the SET process to intercept
the unstable iminium cation to yield the stable R-aminoni-
trile compound. Despite its synthetic utility this process has
received little attention due to a general lack of regioselec-
tivity. Indeed, oxidation of nonsymmetrical amines can give
rise to two different iminium species (Scheme 3) and hence
2
jean-pierre.hurvois@univ-rennes1.fr
Received April 13, 2010
1
1e
two regioisomers.
In a series of papers, we have shown that problems
associated with the nonselective deprotonation at both the
N-CH positions can be avoided by the right selection of
1
1c,d
amine N-substituent.
As a part of our program in the
elaboration of new R-aminonitrile systems, we became inter-
ested in the anodic cyanation of tetrahydroisoquinoline 1
(Scheme 1). If successful, this strategy would provide a new
pathway for the synthesis of C1-substituted tetrahydroiso-
1
2
We report a new route to tetrahydroisoquinoline (THIQ)
alkaloids involving the alkylation of R-aminonitrile 2as a key
step. The latter compound was prepared by anodic cyanation
of the corresponding tertiary amine 1. Reductive decyanation
of R-aminonitriles 6a-c proceeded diastereoselectively (up
to 95% de) to deliver the C1-substituted alkaloids precursors
quinolines (THIQs). However, several questions about the
electrochemical behavior of 1 needed to be addressed. First,
the anodic oxidation reaction could lead to the formation of
a radical cation that could arise from the nitrogen atom or
1
3
from the electron-rich catechol moiety. In other words, can
the electrode act as a selective oxidant so that a single product
9
a-c. The syntheses of (()-carnegine, (()-norlaudanosine,
and (()-O,O-dimethylcoclaurine have been achieved.
(6) For the R-methoxylation of sulfinylamines, see: Turcaud, S.; Sierecki,
E.; Martens, T.; Royer, J. J. Org. Chem. 2007, 72, 4882.
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Matsumara, Y.; Tsubata, K.; Uchida, K.; Kanazawa, T.; Tsuda, K. J. Org.
Chem. 1984, 49, 3711. (b) Bodman, K.; Bug, T.; Steinbeisser, S.; Kreuder, R.;
Reiser, O. Tetrahedron Lett. 2006, 47, 2061.
Nitrogen oxidation that proceeds through a single electron
transfer (SET) mechanism is an ubiquitous process that is
(
8) For the R-methoxylation of N-acylated amino acids, see: (a) Iwasaki,
T.; Horikawa, H.; Matsumoto, K.; Miyoshi, M. J. Org. Chem. 1979, 44,
552. (b) Matsumura, Y.; Shirakawa, Y.; Satoh, Y.; Umino, M.; Tanaka, T.;
1
(1) (a) Chen, C.-K.; Hortman, A. G.; Marzabadi, M. R. J. Am. Chem. Soc.
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Angew. Chem., Int. Ed. Engl. 1986, 9, 843.
1
3
307. (c) For a recent overview, see: Li, C.-J. Acc. Chem. Res. 2009, 2, 335.
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Gil, L.; Ferroud, C.; Gateau-Olesker, A.; Martin, M.-T.; Marazano, C.
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2009, 7, 351. (b) Tajima, T.; Nakajima, A. J. Am. Chem. Soc. 2008, 130,
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van de Weghe, P.; Roisnel, T. Eur. J. Org. Chem. 2008, 4622. (d) Girard, N.;
Pouchain, L.; Hurvois, J.-P.; Moinet, C. Synlett, 2006, 1679 and references
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(c) Bentley, K. W. Nat. Prod. Rep. 2003, 20, 342.
(2) (a) Kim, H. J.; Yoon, U. C.; Jung, Y.-S.; Park, N. S.; Cederstrom,
E. M.; Mariano, P. S. J. Org. Chem. 1998, 63, 860. (b) Ferroud, C.; Cocquet,
G.; Guy, A. Tetrahedron Lett. 1999, 40, 5005.
(
3) (a) Yoshida, J.-I.; Kataoka, K.; Horcajada, R.; Nagaki, A. Chem. Rev.
008, 108, 2265. (b) Sperry, J. B.; Wright, D. L. Chem. Soc. Rev. 2006, 35, 605.
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2
(
(4) For the R-methoxylation of amides, see: (a) Asher, V.; Becu, C.;
Anteunis, M. J. O.; Callens, R. Tetrahedron Lett. 1981, 22, 141. (b) Moeller,
K. D.; Wang, P. W.; Tarazi, S.; Marzabadi, M. R.; Wong, P. L. J. Org. Chem.
1
991, 56, 1058. (c) Tong, Y.; Fobian, Y. M.; Wu, M.; Boyd, N. D.; Moeller,
K. D. J. Org. Chem. 2000, 65, 2484.
5) For the R-methoxylation of carbamates, see: (a) Dooms, C.; Laurent,
P.; Daloze, D.; Pasteels, J.; Nedved, O.; Braekman, J. C. Eur. J. Org. Chem.
005, 1378. (b) Dhimane, H.; Vanucci-Bacqu ꢀe , C.; Hamon, L.; Lhommet, G.
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991, 69, 211. (d) Shono, T.; Hamaguchi, H.; Matsumura, Y. J. Am. Chem.
(
2
(13) (a) Miller, L. L.; Stermitz, F. R.; Falck, J. R. J. Am. Chem. Soc. 1971, 93,
5941. (b) Miller, L. L.; Stermitz, F. R.; Falck, J. R. J. Am. Chem. Soc. 1973, 95,
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Miller, L. L.; Stermitz, F. R. J. Electroanal. Chem. 1976, 68, 181.
1
Soc. 1975, 97, 4264. (e) Kirira, P. G.; Kuriyama, M.; Onomura, O. Chem.—
Eur. J. 2010, 16, 3970. (f) Libendi, S. S.; Demizu, Y.; Matsumura, Y.;
Onomura, O. Tetrahedron 2008, 64, 3935.
DOI: 10.1021/jo100714y
r 2010 American Chemical Society
Published on Web 07/21/2010
J. Org. Chem. 2010, 75, 5721–5724 5721

Louafi et al.
JOCNote
SCHEME 1. Electrochemical Synthesis of r-Aminonitrile 2
TABLE 1. Peak Potentials from Cyclic Voltammograms of Compounds
1
, 3, and 4
entry
compd
EpA
EpB
a
b
a
a
a
b
1
2
3
4
a
1
1
3
4
þ0.90
þ0.95
þ0.95
þ1.45
þ1.30
þ1.30
b
In the absence of NaCN. In the presence of 4 equiv of NaCN.
SCHEME 2. Synthesis of THIQ 1
TABLE 2. Anodic Cyanation of THIQ 1
compd
(mmol/L)
NaCN
(equiv)
AcOH
(equiv)
yield
(%)
a,b
b
entry
products
1
2
3
4
a
4
30
22
22
6.0
6.0
2
2
2 (9); 5 (1)
2
2
75
50
75
85
SCHEME 3. Electrochemical Pathway for the Formation of
r-Aminonitriles 2 and 5
2.5
0.5
The regioisomer ratios are in parentheses and were determined by
1
b
integration of the H NMR signals in the crude precipitate. Yield
represents a mass balance of the isolated regioisomers. In all cases the
electrolyses went to completion.
-1
sweep rate of 50 mV s . Peak potentials expressed in V vs SCE
-
1
are collected in Table 1. THIQ 1(20mmolL ) was dissolved in
a 0.1 M LiClO in MeOH electrolyte solution. In the absence of
4
NaCN, compound 1 displayed two successive irreversible peaks
at EpA=þ0.90 V and EpB=þ1.30 V (entry 1, Table 1). After
the addition of 4 equiv of NaCN per mol of substrate, two
successive distinct irreversible peaks were recorded at EpA =
þ0.95 V and EpB=þ1.30 V (entry 2, Table 1).
Previous studies in our laboratory have shown that the first
oxidation peak was attributable to the oxidation of the amine
into the corresponding iminium cation, while the second oxida-
tion peak could be attributed to the oxidation of the catechol
moiety. As a confirmation, the first oxidation peak was present
in the voltammograms of 2-(1-phenylethyl)-1,2,3,4-tetrahyd-
roisoquinoline (3) (EpA=þ0.95 V, entry 3, Table 1) and the
second one was recorded for veratrole (4) (EpB = þ1.45 V,
13e
entry 4, Table 1). Then, the anodic cyanation of 1 was first
-
1
effected on a 4 mmol L scale (entry 1, Table 2) in an undivided
cell with a vitreous carbon anode (see the schematic diagram in
the SI), at a controlled potential of þ0.95 V vs SCE. Amine 1was
could be formed during the anodic process? Second, the
regiochemical preferences for the deprotonation step (i.e. at
dissolved in a 0.1 M LiClO in MeOH electrolyte solution in the
4
presence of 4 equiv per mol of NaCN. After the consumption of
2.1 F/mol of substrate, the completion of the reaction was
0
C1, C1 , or C3) under our electrolysis conditions are unknown.
We were also curious to investigate the influence of the asym-
metric carbon on the stereochemical outcome of the subsequent
attested by the disappearance of the first oxidation peak and
workup afforded the ring cyanated product 2 (75%) after
crystallization in hot ethanol. Single crystals were also obtained
in this way, and the X-ray diffraction study revealed the presence
of a single diastereoisomer, the configuration of which was
1
4
chemical manipulations. With these questions in mind, we
report here the electrochemical synthesis of R-aminonitrile 2,
and its use in the synthesis of C1-substituted THIQs. In this
study, all compounds are racemic, and all the stereogenic
centers are represented in a relative configuration.
1
found to be R*,R*. Surprisingly, when the H NMR spec-
trum of these crystals was recorded in CDCl we noticed the
3
As outlined in Scheme 2, our synthesis began with the
presence of two diastereoisomers in a 42/58 ratio. This observa-
tion pointed out that 2 exists in a single configuration in the solid
state and it was also felt that epimerization of C1 may take place
Pictet-Spengler cyclization of homoveratrylamine accord-
1
5
ing to the protocol described by Fukuyama. The inter-
mediary tetrahydro-6,7-dimethoxyisoquinoline was then
condensed with 1.1 equiv of (1-bromo)ethylbenzene to form
1
rapidly in CDCl . Indeed, when the H NMR spectrum of 2 was
3
recorded in [D ]benzene, within 5 min, we observed the presence
6
of a single adduct as shown by the presence of one singlet
resonance signal at δ 4.73. We can observe that a slow epimer-
1
in an overall 80% yield.
Analytical Study and Anodic Cyanation. Then, an analyti-
cal study was carried out at a vitreous carbon electrode at a
ization also occurred in [D ]benzene. After standing for 48 h at
6
2
5 °C in this solvent, the sample was analyzed and found to be a
(
14) For 1,3-stereoinduction, see: Juaristi, E.; Le oꢀ n-Romo, J. L.; Reyes,
A.; Escalante, J. Tetrahedron: Asymmetry 1999, 10, 2441.
15) Okano, K.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2006,
28, 7136.
mixture (45/55) of two diastereoisomers as shown by the pre-
sence of an additional singlet resonance signal at δ 5.12. The
subsequent electrolyses were carried out at higher NaCN and
(
1
5
722 J. Org. Chem. Vol. 75, No. 16, 2010

Louafi et al.
JOCNote
TABLE 3. Synthesis of R-Aminonitriles 6a-c
TABLE 4. Reductive Decyanation of R-Aminonitriles 6a-c
a
b
entry
product
9a, R = Me
9b, 4-MeO-Ph-CH
9c, 3,4-(MeO) -Ph-CH
% yield
% de
producta,
% yield
b
entry
RX, equiv
% de
1
2
3
a
76
85
88
98
80
80
2
1
2
3
4
a
MeI, 2.0
MeI, 6.0
4-MeO-Ph-CH
6a, 40
6a, 67
6b, 77
6c, 75
80
80
80
80
2
2
Br (7), 1.5
Br (8), 1.5
Yields are of isolated products after column chromatography.
2
b
1
Determined by H NMR spectroscopy.
3,4-(MeO) -Ph-CH
2
2
Yields are of isolated products after crystallization in ethanol.
b
1
Determined by H NMR spectroscopy.
yield was poor (30-40%). However, addition of a large excess
(6 equiv) of iodomethane (entry 2, Table 3) gave the C1-methyl
product 6a as a yellow powder in an improved 67% yield.
19
amine concentration values (up to 30 mmol/L, entry 2, Table 2)
and failed to reproduce the first results. Yields were generally
lower and ring cyanated products 2 and 5 were obtained as a
mixture (9/1) of regioisomers which could not be separated by
column chromatography. Fortunately, after several chemical
manipulations (for a detailed procedure, see the SI) R-aminoni-
trile 5 could be obtained as colorless plates. An X-ray diffraction
experiment revealed an R*,R* relative configuration of both the
stereogenic centers.
Interestingly, single crystals could be obtained from a slow
crystallization in ethanol and the X-ray diffraction study
revealed a R*,R* configuration of the two stereogenic cen-
ters. Having successfully installed a methyl group at the C1
carbon atom we turned our efforts to the synthesis of
R-aminonitriles 6b,c, which are potential precursors of O,O-
dimethylcoclaurine and norlaudanosine, respectively. This
involved the condensation of the benzyl bromides 7 and 8
which were readily prepared by reacting the corresponding
The product distribution 2/5 provided a direct indication of
the site of deprotonation of the intermediary radical cation A
alcohols with PBr according to a modified version of the
3
1
6
Van Vranken’s procedure. Treatment of the anion solution
of 2 with a THF solution of bromide 7 afforded the bifunc-
tional R-aminonitrile 6b as a yellow powder in a 77% yield.
Likewise, the alkylation of 2 with bromide 8 afforded the
adduct 6c as a yellow powder in a 75% yield. Single crystals
of adducts 6b and 6c were obtained from a slow crystal-
lization in ethanol, and the X-ray diffraction studies revealed
that these adducts displayed a R*,R* relative configuration.
Reductive Decyanation. The reductive decyanation of
R-aminonitrile systems is a common procedure that consists
of the neat replacement of the cyano group by a hydrogen atom.
According to the reducing agent, the reaction proceeds through
(
Scheme 3). Albeit obtained in low yields, the presence of the
unwanted regioisomer 5 in the crude reaction mixture suggests
that a competitive kinetic deprotonation occurred at C3 in the
presence of a high concentration of NaCN or in the presence of
an electrogenerated base produced at the cathode. With this in
mind, the reaction conditions were altered in order to increase
the 2/5 ratio. This was first accomplished by decreasing the
concentration of NaCN. Indeed, when the reaction was allowed
-1
to proceed in a 20 mmol L scale in the presence of 2.0 equiv of
NaCN, the adduct 2was obtained as a sole product in 75% yield
(entry 3, Table 2). Finally, the addition of 0.5 equiv of AcOH
(entry 4, Table 2) led to the formation of 2 in an improved 85%
yield. Under these reaction conditions, it seemed likely that the
HCN/CN buffer system should balance the excess of base that
was produced at the cathode. In addition, one cannot exclude
the formation of an intermediary unstable N-O geminated
compound that results from the reversible condensation be-
17
a ionic or a radical pathway. In the first mode of reactivity, the
R-aminonitrile yields an iminium cation that is reduced in situ
-
2
0
21
by a variety of hydride donors such as NaBH , BH , AgBF /
4
3
4
22
23
24
Zn(BH4)2, NaBH CN, or NaBH(OAc)3. In the second
3
mode, the R-aminonitrile is reduced by a two-electron-transfer
2
5
26
27
18
mechanism involving Li/NH3, Na/NH3, or LiDBB as
tween MeOH and the iminium cation.
Alkylation. The condensation of the lithiated R-aminonitrile
with requisite alkyl halides is the key step in our synthetic
reducing agents. Therefore, the reduction of R-aminonitriles
6
4
a-c was carried out at -20 °C in ethanol in the presence of
2
equiv of NaBH ; results are collected in Table 4. THIQ 9a was
4
approach (Table 3). The lithiation procedure was carried out at
a temperature of -80 °C by the slow addition of a solution of 1.3
equiv of LDA (prepared from n-BuLi 2.5 M and diisopropyl-
amine) on a stirred suspension of R-aminonitrile 2 in anhydrous
and oxygen free THF. Then, the clear red anion solution was
allowed to warm to -20 °C over a 2 h period, and the electro-
philes were added at a temperature of -80 °C. After workup,
the R-aminonitriles 6a-c were obtained in yields ranging from
(
19) For the alkylation of R-cyanocarbanions, see: (a) Bare, T. M.;
Hershey, N. D.; House, H. O.; Swain, C. G. J. Org. Chem. 1972, 37, 997.
(b) Opatz, T. Synthesis 2009, 12, 1941.
(20) (a) Bonin, M.; Romero, J. R.; Grierson, D. S.; Husson, H.-P.
Tetrahedron Lett. 1982, 23, 3369. (b) Polniaszek, R. P.; Belmont J. Org.
Chem. 1991, 56, 4868.
(21) Ogura, K.; Shimamura, Y.; Fujita, M. J. Org. Chem. 1991, 56, 2920.
(22) (a) Ratovelomanana, V.; Royer, J.; Husson, H.-P. Tetrahedron Lett.
985, 26, 3803. (b) Guerrier, L.; Royer, J.; Grierson, D. S.; Husson, H.-P.
1
J. Am. Chem. Soc. 1983, 105, 7754.
(23) (a) Maloney, K. M.; Danheiser, R. L. Org. Lett. 2005, 7, 3115.
6
7% and 77%. When 2 equiv of iodomethane was introduced
onto the intermediary R-amino carbanion (entry 1, Table 3), the
(
b) Amat, M.; G oꢀ mez-Esqu ꢀe , A.; Escolano, C.; Santos, M. M. M.; Molins,
E.; Bosch, J. J. Org. Chem. 2009, 74, 1205. (c) Bergner, I.; Wiebe, C.; Meyer,
N.; Opatz, T. J. Org. Chem. 2009, 74, 8243.
(24) Nakamura, Y.; Burke, A. M.; Kotani, S.; Ziller, J. W.; Rychnovsky,
S. C. Org. Lett. 2010, 12, 72.
(25) Rychnovsky, S. D.; Swensson, S. S. J. Org. Chem. 1997, 62, 1333.
(26) Bunnelle, W. H.; Shelvin, C. G. Tetrahedron Lett. 1989, 30, 4203.
(27) Bahde, R. J.; Rychnovsky, S. D. Org. Lett. 2008, 10, 4017.
(
16) Perales, J. B.; Makino, N. F.; Van Vranken, D. L. J. Org. Chem.
002, 67, 6711.
17) Mattalia, J.-M.; Marchi-Delapierre, C.; Hazidem, H.; Chanon, M.
ARKIVOC 2006, 90.
18) Gladych, J. M. Z.; Hartley, D. In Comprehensive Organic Chemistry;
Sutherland, I. O., Ed.; Pergamon Press: Oxford, UK, 1979; Vol. 2, p 94.
2
(
(
J. Org. Chem. Vol. 75, No. 16, 2010 5723

Louafi et al.
JOCNote
TABLE 5. Hydrogenolysis of THIQs 9a-c
Experimental Section
: THIQ 1 (2.0 g, 6.72 mmol) was dissolved in a 0.1 M LiClO4
2
in MeOH electrolyte solution (0.3 L), in the presence of 0.82 g
16.73 mmol) of NaCNand 0.19 mL (0.19g, 3.32 mmol) of glacial
(
acetic acid. The working potential was adjusted to þ1.0 V/SCE
and after the consumption of 1360 C (2.1 F/mol), the electrolysis
was stopped. Then, water (150 mL) was added (Caution: LiClO
4
a
entry
product
10a, R = Me
10b, 4-MeO-Ph-CH
10c, 3,4-(MeO) -Ph-CH
Yields are of isolated products after column chromatography.
% yield
may lead to severe explosions when the material is evaporated to
dryness; the cyanide anions were destroyed by the addition of an
excess of KMnO ; due to the possible release of HCN, the
electrolyses should be carried out under a well-ventilated hood)
and methanol was evaporated under reduced pressure at þ50 °C.
The resulting aqueous phase was extracted with dichloromethane
1
2
3
a
95
80
90
2
4
2
2
(
MgSO and concentrated in vacuo. The resulting white solid was
triturated with diethyl ether and was recrystallized from 50 mL of
hot ethanol to give 1.87 g (86%) of 2 as crystalline white powder.
3 ꢀ 50 mL) and the combined organic layers were dried over
obtained as a single diastereoisomer as evidenced by the
presence of a set of 18 independent resonance lines in the
13
C
4
1
NMR spectrum. Likewise, the H NMR spectrum exhibits two
distinct doublet systems at δ 1.31 and 1.38 ppm. However, the
relative configuration of the stereogenic centers could not be
Colorless plates, mp 172-174 °C (ethanol); R
f
(diethyl ether/
1
petroleum ether, 70:30) 0.3. H NMR (C D , 500 MHz) δ 1.37 (d,
6 6
1
determined from the H NMR spectrum. Similarly, compound
9b was obtained as a solid in an improved 85% yield but in a
J = 6.5 Hz, 3 H), 2.46 (dd, J = 16.5, 3.5 Hz, 1 H), 2.79 (td, J =
11.8, 3.8 Hz, 1 H), 2.96 (ddd, J = 16.5, 11.8, 6.3Hz, 1 H), 3.15 (s, 3
H), 3.21 (ddm, J = 11.8, 6.3 Hz, 1 H), 3.46 (s, 3 H), 3.97 (q, J =
lower diastereoselectivity (80% de). Fortunately, single crystals
were obtained from a slow crystallization of 9b in ethanol and
the subsequent X-ray diffraction study revealed that compound
6
6
.5 Hz, 1 H), 4.73 (s, 1 H), 6.12 (s, 1 H), 6.42 (s, 3 H), 7.20 (tt, J =
.8, 1.5 Hz, 1 H), 7.29, (tm, J = 6.8 Hz, 2 H), 7.55 (dm, J = 6.8
1
3
Hz, 2 H) ppm. C NMR (C
6 6
D , 125 MHz) δ 21.7, 28.6, 42.8,
9b displayed a R*,R* relative configuration.
Hydrogenolysis. In the last step, a selective catalytic hy-
5
1
3
4.1, 55.2, 55.3, 62.1, 110.1, 112.0, 117.1, 122.1, 126.3, 129.1,
43.9, 148.7, 149.91 ppm. HRMS (C20
22.1681, found 322.1679. C H N O : calcd C 74.51, H 6.88,
þ
22 2 2
H N O [M ]) calcd
drogenolysis of benzylic amines 9a-c was cleanly achieved
in the presence of 10% Pd/C in a mixture of ethanol and
hydrochloric acid under 3 atm of H . After workup, THIQs
2
2
0
22
2
2
N 8.69; found C 74.29, H 6.82, N 8.74.
1
(
0a-c were obtained in yields ranging from 80% to 95%
Table 5).
Acknowledgment. This work was supported by the Pro-
gramme Franco-Alg ꢀe rien de Formation Sup ꢀe rieure en
France (PROFAS).
A reliable route to THIQ alkaloids (()-carnegine (32%),
()-norlaudanosine (40%), and (()-O,O-dimethylcoclaur-
(
ine (35%) has been developed from homoveratrylamine. In
this process, the R-C1H bond of the THIQ nucleus has been
activated regioselectively by a SET process to produce a
stable R-aminonitrile system that serves to construct the new
C1-CR bonds.
Supporting Information Available: General procedures for
the synthesis of compounds; H NMR and C NMR spectra of
1
13
1
, 2, 5, 6a-c, 7, 8, 9a-c, and 10a-c; crystallographic data of 2, 5,
6a-c, and 9b. This material is available free of charge via the
Internet at http://pubs.acs.org.
5
724 J. Org. Chem. Vol. 75, No. 16, 2010