Synthesis of (-)-(S)-norlaudanosine, (+)-(R)-O,O-dimethylcoclaurine, and (+)-(R)-salsolidine by alkylation of an α-aminonitrile

Article abstract of DOI:10.1002/ejoc.200700261

A short asymmetric synthesis of 1-substituted 1,2,3,4- tetrahydroisoquinoline alkaloids by deprotonation of an unprotected α-aminonitrile and alkylation of the resulting carbanion followed by spontaneous elimination of HCN and asymmetric reduction is described. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700261

FULL PAPER
DOI: 10.1002/ejoc.200700261
Synthesis of (–)-(S)-Norlaudanosine, (+)-(R)-O,O-Dimethylcoclaurine, and
(+)-(R)-Salsolidine by Alkylation of an α-Aminonitrile
Frank Werner,[a] Nancy Blank,[a] and Till Opatz*[a]
Keywords: Alkaloids / Heterocycles / Umpolung / Asymmetric catalysis / Aminonitriles
A short asymmetric synthesis of 1-substituted 1,2,3,4-tetra- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
hydroisoquinoline alkaloids by deprotonation of an unprotec-
ted α-aminonitrile and alkylation of the resulting carbanion
followed by spontaneous elimination of HCN and asymmet-
ric reduction is described.
Germany, 2007)
Introduction
Amines and nitrogen heterocycles are key structural ele-
ments found in an exceedingly large number of pharmaceu-
ticals and agrochemicals.[1] Both synthetic compounds and
natural products containing nitrogen frequently exhibit po-
tent biological activities.[2] An example is the large group of
tetrahydroisoquinoline alkaloids, several members of which
have become classical targets for the development of new
synthetic methodologies.[3–7] Here we report on a short
asymmetric approach to α-branched secondary amines and
its application to the synthesis of 1-substituted 1,2,3,4-tetra-
hydrosioquinoline alkaloids.
While investigating methods for the reversible Umpolung
of the reactivity of the C=N bond,[8–10] we recently found
that unprotected α-aminonitriles possessing a primary or
secondary amino group can be deprotonated in the α-posi-
tion without inducing elimination of HCN by means of a
retro-Strecker reaction if a stabilizing α-substituent such as
an aromatic or heteroaromatic ring is present. The resulting
stabilized carbanions can be used as starting materials for
the preparation of pyrrolidines, pyrroles, γ-amino acids, 1,2-
diamines, or indoles in one-pot reaction procedures.[11–16]
C-Alkylation of deprotonated unprotected aminonitriles 1
affords α-branched products 2, from which HCN can be
eliminated to form ketimines 3.[17] Depending on the struc-
ture of the compound 3, this elimination may occur sponta-
neously. Hydrolysis of imines 3 produces ketones, while
their reduction furnishes α-branched amines 4. In combina-
tion with methods for the enantioselective reduction of ket-
imines,[18] this reaction sequence can also be used for the
asymmetric synthesis of compounds 4 (Scheme 1).
Scheme 1. Asymmetric synthesis of α-branched amines via α-ami-
nonitriles.
Results and Discussion
The stable, crystalline 6,7-dimethoxy-1,2,3,4-tetrahydro-
isoquinoline-1-carbonitrile (6; Scheme 2) is readily access-
ible by Bischler–Napieralski cyclization of N-formyl homo-
veratrylamine, to provide dihydroisoquinoline 5, and subse-
quent addition of HCN.[19–21] Upon treatment with
KHMDS in THF at –78 °C, the aminonitrile 6 is deproton-
ated in the α-position without induction of the elimination
of HCN.[13] Addition of alkyl halides and warming to ambi-
ent temperature results directly in the formation of the 1-
alkylated dihydroisoquinolines 8. Apparently, the 1-substi-
tuted nitriles 7 are unstable and spontaneously eliminate
HCN. Attempts to convert imines 8 into the aminonitriles
7 by treatment with HCN or TMSCN and various catalysts
failed.
[a] Institut für Organische Chemie, Universität Mainz,
Duesbergweg 10–14, 55128 Mainz, Germany
Fax: +49-6131-392-4786
E-Mail: opatz@uni-mainz.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 3911–3915
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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F. Werner, N. Blank, T. Opatz
FULL PAPER
Scheme 2. Asymmetric synthesis of tetrahydroisoquinoline alkaloids from aminonitrile 6.
The asymmetric reduction of dihydroisoquinolines with
The alkylation of deprotonated aminonitriles and asym-
a chiral triacyloxyborohydride derived from N-benzyloxy- metric reduction of the imines resulting from spontaneous
carbonyl--proline described by Yamada and co-workers or induced elimination of HCN from the reaction products
proved suitable for the in situ reduction of compounds 8 provides a short path to chiral α-branched amines. The re-
without prior workup.[22] The enantiomeric excess of the action sequence does not require the isolation or purifica-
obtained (S)-O,O-dimethylcoclaurine (10a[23]) amounted to tion of the intermediates and, if cyanide-insensitive reduc-
69%, but the isolated yield was unsatisfactory. A similar ing agents are used, it can be performed as a one-pot pro-
reduction technique using a triacyloxyborohydride derived cedure. Although compounds 10 have previously been di-
from N-phthaloyl--leucine has been described by Hajipour rectly synthesized by Bischler–Napieralski cyclization of
and Hantehzadeh.[24] While these authors report high yields amides from homoveratrylamine, our protocol permits the
and optically pure products obtained under solid-state con- introduction of acid-sensitive side chains – which are in-
ditions (grinding of the reagents with alumina in a mortar), compatible with the harsh cyclization conditions – at C1.
we did not observe any reduction of crude or purified com-
pounds 8 on using this procedure. On the other hand, the
Experimental Section
asymmetric transfer hydrogenation of 8 with Noyori’s cata-
lyst (9) and formic acid/triethylamine as the hydrogen
source effected essentially quantitative reduction and was
highly enantioselective for all synthesized compounds.[25]
All reactions were carried out under argon unless stated otherwise.
THF was dried by distillation from Na/benzophenone. 3,4-Dimeth-
oxybenzyl bromide,[26,27] 2,3,4,6-tetra-O-acetyl-β--glucopyranosyl
With the (S,S)-enantiomer of the catalyst, (R)-configured isothiocyanate,[28] and (1R,2R)- and (1S,2S)-N-(4-tolylsulfonyl)-
1,2-diphenylethylenediamine[29,30] were prepared as described in the
literature. Ethyl acetate was distilled from potassium carbonate,
while petroleum ether (boiling range 40–70 °C) was distilled from
calcium hydride. All other solvents and reagents were purchased
from commercial suppliers and were used without further purifica-
tion. TLC was performed on TLC aluminium sheets (silica gel
60 F254, E. Merck). Flash chromatography was carried out on silica
gel (32–63 µm, 60 Å, MP Biomedicals GmbH). Analytical RP-
O,O-dimethylcoclaurine (10a) and salsolidine (10b) were
obtained with 96% and 91% ee, respectively. The (S) en-
antiomer of norlaudanosine (10c) was obtained in 93% ee
with the (R,R)-configured catalyst. Unfortunately, the
Noyori system turned out to be more sensitive than the rug-
ged Yamada reagent and both yield and optical purity of
the products were severely affected by the presence of cy-
anide ions. Therefore, removal of the cyanide from the reac-
tion mixture by extraction with a nickel chloride solution
proved necessary (Scheme 2).
HPLC separations were performed on a Luna C18(2), 5 µm (Phe-
nomenex) instrument using a Knauer MaxiStar K-1000 gradient
1
pump and a Knauer Variable Wavelength Monitor. H NMR and
3912
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3911–3915

Reversible Umpolung of the C=N Bond
FULL PAPER
13C NMR spectra were recorded on a Bruker AC 300 or Av-
ance 400 instrument. Chemical shifts were referenced to the resid-
ual solvent signal (CDCl3: δH = 7.24 ppm, δC = 77.0 ppm). FD-MS
spectra were recorded on a Finnigan MAT 95 at a desorption volt-
age of 5 kV and with a heater current ramp of 10 mAmin–1. IR
spectra were recorded on a Perkin–Elmer 1760X FTIR spectrome-
ter. Melting points were measured on a Dr. Tottoli apparatus and
are uncorrected. Determination of the enantiomeric excess was per-
formed as described for each compound. The racemic products
were prepared as reference compounds by one-pot reduction of the
crude dihydroquinolines with NaCNBH3.
terial was dissolved in methanol (30 mL) and after addition of a
solution of NiCl2·6H2O (300 mg) in water (30 mL), the mixture
was extracted with CH2Cl2 (3ϫ30 mL), the combined organic lay-
ers were washed with a solution of ammonia (10%, 30 mL) and
brine (30 mL) and dried with Na2SO4, and the solvent was removed
in vacuo to yield the cyanide-free crude imine 8a (656.0 mg). Tri-
ethylamine (27.6 µL, 196 µmol) was added to a solution of di-
chloro(p-cymene)ruthenium(II) dimer (12.9 mg, 21 µmol) and
(1S,2S)-N-(4-tolylsulfonyl)-1,2-diphenylethylenediamine (15.4 mg,
42 µmol) in dry DMF (0.44 mL). The solution was degassed by
ultrasonication under a slow stream of argon and was subsequently
heated to 80 °C for 1 h. The crude imine 8a, dissolved in degassed
dry DMF (4.2 mL), was added to the warm solution. After cooling
to 0 °C, formic acid/triethylamine azeotrope (5:2, 1.0 mL) was
added and the mixture was stirred for 3 h at ambient temperature.
After addition of saturated aq. K2CO3 solution (30 mL) and water
(20 mL), the reaction mixture was extracted with ethyl acetate
(3ϫ50 mL) and the combined organic layers were washed with
brine and dried with Na2SO4. Removal of the solvent in vacuo gave
the crude product (521.2 mg) as a brownish oil. A portion
(81.1 mg) of this material was purified by column chromatography
(silica, cyclohexane/CHCl3/Et2NH, 10:4:1) to give 10a as a slightly
brown oil (60.9 mg, 54.5%). [α]2D5 = +15.3 (c = 1, CHCl3); ref.[33]
+15.7 (c = 0.4, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.70 (br.
s, 1 H, NH), 2.63–2.79 (m, 2 H, 4-H2), 2.81–2.94 (m, 2 H, 3-H2),
3.12–3.24 (m, 2 H, ArCH2), 3.80, 3.82, 3.86 (3 s, 3ϫ3 H, OCH3),
4.10 (dd, J = 9.3, 4.4 Hz, 1 H, 1-H), 6.59, 6.63 (2 s, 2ϫ1 H, 5-H,
8-H), 6.87 (AAЈ-part of AAЈXXЈ system, 2 H, 3Ј,5Ј-H), 7.17 (XXЈ-
part of AAЈXXЈ system, 2 H, 2Ј,6Ј-H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 29.5 (C-4), 40.7, 41.8 (C-3, ArCH2), 55.2, 55.8, 55.9
(OCH3), 56.9 (C-1), 109.4, 111.8 (C-5, C-8), 114.0 (2 C, C-3Ј,5Ј),
127.3, 130.6, 131.0 (C-1Ј, C-4a, C-8a), 130.3 (2 C, C-2Ј,6Ј), 146.9,
6,7-Dimethoxy-3,4-dihydroisoquinoline (5): Formic acid (5.62 g,
122 mmol) was added with ice cooling to 3,4-dimethoxyphen-
ethylamine (16.05 g, 88.6 mmol). The light yellow mass was heated
to reflux (190 °C bath temperature) until TLC indicated complete
conversion (2 h). After cooling, the yellow reaction mixture was
diluted with toluene (75 mL). Phosphoryl chloride (27.4 g,
178 mmol) was added and the mixture was heated to reflux until
TLC indicated complete conversion (1 h). After removal of toluene
and excess phosphoryl chloride by distillation, the brown residue
was washed with petroleum ether (100 mL) and taken up in 1,4-
dioxane (30 mL).[31] The solution was poured onto ice (100 g) and
the resulting homogeneous solution was washed with diethyl ether
(2ϫ50 mL). The organic extracts were discarded and the aqueous
layer was basified to pH Ͼ12 by careful addition of solid NaOH
(cooling). Extraction with diethyl ether (4ϫ50 mL), drying over
Na2SO4, and removal of the solvent in vacuo furnished 5 (14.48 g,
85.5%) as an amber-colored oil. 1H NMR (300 MHz, CDCl3): δ =
2.64 (pseudo-t, Japp = 8.2 Hz, 2 H, 4-H2), 3.65 (pseudo-t, Japp
=
8.2 Hz, 2 H, 3-H2), 3.86, 3.87 (2 s, 2ϫ3 H, OCH3), 6.63 (s, 1 H,
5-H), 6.74 (s, 1 H, 8-H), 8.18 (br. s, 1 H, 1-H) ppm. IR (film): ν =
˜
2939, 2837, 1630, 1606, 1575, 1518, 1464, 1325, 1281, 1240, 1224,
147.4 (C-5, C-7), 158.2 (C-4Ј) ppm. IR (film): ν = 3332, 2996, 2933
˜
1121 cm–1.[32]
(sh), 2833, 1610, 1511, 1465 (sh), 1301, 1247 (sh), 1223, 1178, 1114,
1034 cm–1. These data are in accordance with the values reported
in the literature.[33]
6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile (6): A
solution of KCN (7.88 g, 121 mmol) in water (40 mL) and a few
crystals of bromophenol blue were added to a solution of 5 (7.33 g,
38.3 mmol) in MeOH (10 mL). The mixture was cooled to 0 °C,
and concentrated hydrochloric acid (40 mL) was added slowly. The
yellow reaction mixture turned green after 1 h and it was stirred at
ambient temperature overnight. HCN vapors were removed by use
of a slow stream of argon (caution!) and the mixture was poured
into saturated aq. NaHCO3 (200 mL). The mixture was made alka-
line (blue color) by addition of solid NaHCO3 and extracted with
CH2Cl2 (7ϫ70 mL). The combined organic layers were dried with
Na2SO4 and the solvent was removed in vacuo to give 6 (4.99 g,
59.7%) as light yellow crystals. m.p. 106–107 °C, lit. 109–110 °C.[19]
1H NMR (300 MHz, CDCl3): δ = 2.12 (br. s, 1 H, NH), 2.67 (dt,
2Jd = 16.2, 3Jt = 3.6 Hz, 1 H, 4-Ha), 2.86 (mc, 1 H, 4-Hb), 3.20–
3.29 (m, 2 H, 3-H2), 3.86, 3.87 (2 s, 2ϫ3 H, OCH3), 4.96 (s, 1 H,
Determination of the enantiomeric excess was carried out by
derivatization with 2,3,4,6-tetra-O-acetyl-β--glucopyranosyl iso-
thiocyanate and analytical HPLC. Eluent CH3CN/H2O 35:65,
1 mLmin–1, Rt (S derivative): 44.3 min, Rt (R derivative): 47.0 min.
Enantiomeric ratio = 48.2:1, ee = 96%.
(+)-(R)-Salsolidine (10b):
A solution of KHMDS (201.1 mg,
1.01 mmol) in dry THF (1.5 mL) was added at –78 °C to a solution
of 6 (200 mg, 0.916 mmol) in dry THF (7 mL). After 4 min, a solu-
tion of iodomethane (68.5 µL, 1.01 mmol) in dry THF (1.5 mL)
was added. After stirring for 3 h at –78 °C, the mixture was grad-
ually warmed to ambient temperature over the course of 7 h. After
addition of NaOH solution (1 , 30 mL), the mixture was extracted
with CH2Cl2 (3ϫ20 mL). The combined organic layers were dried
with Na2SO4 and the solvent was removed in vacuo to yield a red-
dish solid. This material was dissolved in methanol (20 mL) and,
after addition of a solution of NiCl2·6H2O (160 mg) in water
(20 mL), the mixture was extracted with CH2Cl2 (3ϫ30 mL), the
combined organic layers were washed with a 10% solution of am-
monia (20 mL) and brine (20 mL) and dried with Na2SO4, and the
solvent was removed in vacuo to yield the cyanide-free crude imine
8b (177.5 mg) as a reddish solid. Triethylamine (11.4 µL, 82 µmol)
was added to a solution of dichloro(p-cymene)ruthenium(II) dimer
(5.3 mg, 8.6 µmol) and (1S,2S)-N-(4-tolylsulfonyl)-1,2-diphenyl-
ethylenediamine (6.3 mg, 17.2 µmol) in dry DMF (0.44 mL). The
solution was degassed by ultrasonication under a slow stream of
argon and was subsequently heated to 80 °C for 1 h. The crude
imine 8b, dissolved in degassed dry DMF (1.8 mL), was added to
1-H), 6.60, 6.66 (2 s, 2ϫ1 H, 5-H, 8-H) ppm. IR (film): ν = 3334,
˜
2936 (sh), 2836, 2220 (w), 1611, 1520, 1464, 1264, 1226, 1109,
1029 cm–1.
(+)-(R)-O,O-Dimethylcoclaurine (10a): A solution of KHMDS
(502.7 mg, 2.52 mmol) in dry THF (3.8 mL) was added at –78 °C
to a solution of 6 (500 mg, 2.29 mmol) in dry THF (17.5 mL). After
4 min, a solution of 4-methoxybenzyl chloride (373 µL, 2.75 mmol)
in dry THF (3.8 mL) was added. After stirring for 3 h at –78 °C,
the mixture was gradually warmed to ambient temperature over
the course of 7 h. After addition of NaOH solution (1 , 60 mL),
the mixture was extracted with CH2Cl2 (4ϫ30 mL). The combined
organic layers were dried with Na2SO4 and the solvent was re-
moved in vacuo to yield a viscous reddish oil (704.5 mg). This ma-
Eur. J. Org. Chem. 2007, 3911–3915
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3913

F. Werner, N. Blank, T. Opatz
FULL PAPER
the warm solution. After cooling to 0 °C, formic acid/triethylamine
azeotrope (5:2, 0.5 mL) was added and the mixture was stirred for
3 h at ambient temperature. After addition of saturated aq. K2CO3
solution (9 mL) and water (6 mL), the reaction mixture was ex-
tracted with ethyl acetate (3ϫ15 mL) and the combined organic
layers were washed with brine and dried with Na2SO4. Removal of
the solvent in vacuo gave the crude product (156.3 mg) as a brown-
ish oil. A portion (45.6 mg) of this material was purified by column
chromatography (silica, petroleum ether/EtOAc/Et2NH 8:3:1, Rf =
0.13) to give 10b as a colorless oil (28.3 mg, 51.1%). [α]2D5 = +56.5
(c = 1, CHCl3); ref.[24] –59.5 (S enantiomer, c = 1, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 1.42 (d, J = 6.6 Hz, 3 H, CH3), 1.80
(br. s, 1 H, NH), 2.58–2.67, 2.72–2.82 (2 m, 2ϫ1 H, 4-Ha,b), 2.93–
3.02, 3.19–3.27 (2 m, 2ϫ1 H, 3-Ha,b), 3.83, 3.84 (2 s, 2ϫ3 H,
OCH3), 4.01 (q, J = 6.6 Hz, 1 H, 1-H), 6.55 (s, 1 H, 8-H), 6.61 (s,
1 H, 5-H) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 22.8 (CH3),
29.5 (C-4), 41.8 (C-3), 51.2 (C-1), 55.8, 55.9 (OCH3), 109.0, 111.7
(C-5, C-8), 126.8, 132.4 (C-4a, C-8a), 147.2, 147.3 (C-6, C-7) ppm.
CDCl3): δ = 29.6 (C-4), 41.0, 42.3 (ArCH2, C-3), 55.83, 55.85, 55.9,
56.0 (OCH3), 56.9 (C-1), 109.3 (C-8), 111.3, 111.8, 112.4 (C-5, C-
2Ј, C-5Ј), 121.4 (C-6Ј), 127.5 (C-4a), 130.5 (C-8a), 131.5 (C-1Ј),
147.0, 147.4, 147.6, 148.9 (C-6, C-7, C-3Ј, C-4Ј) ppm. IR (film): ν
˜
= 3327, 3010, 2935, 2833, 1609, 1590, 1515, 1464 (sh), 1262, 1235
(sh), 1112, 1028 cm–1. FD-MS: m/z = 366.2 [M + Na]+ (75%),
344.2 [M + H]+ (100%). These data are in accordance with the
values reported in the literature.[7]
Determination of the enantiomeric excess was carried out by 1H
NMR spectroscopy after derivatization with (S)-(α)-methylbenzyl
isocyanate (er Ͼ 99.5:0.5). Enantiomeric ratio: 26.7:1, ee = 93%.
Supporting Information (see also the footnote on the first page of
this article): 1H and 13C NMR spectra, as well as HPLC chromato-
grams.
Acknowledgments
IR (film): ν = 3315, 2933 (sh), 2832, 1610, 1511, 1464 (sh), 1372,
˜
1293, 1256, 1223, 1118 (sh), 1030, 858, 790 cm–1.These data are in
accordance with the values reported in the literature.[34]
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG) and the University of Mainz.
Determination of the enantiomeric excess was carried out by
derivatization with 2,3,4,6-tetra-O-acetyl-β--glucopyranosyl iso-
thiocyanate and analytical HPLC. Eluent CH3CN/H2O 35:65,
1 mLmin–1, Rt ((R) derivative): 64.7 min, Rt ((S) derivative):
68.0 min. Enantiomeric ratio = 20.9:1, ee = 91%.
[1] T. Henkel, R. M. Brunne, H. Müller, F. Reichel, Angew. Chem.
1999, 111, 688–691; Angew. Chem. Int. Ed. 1999, 38, 643–647.
[2] C. Kibayashi, Chem. Pharm. Bull. 2005, 53, 1375–1386.
[3] M. Chrzanowska, M. D. Rozwadowska, Chem. Rev. 2004, 104,
3341–3370.
(–)-(S)-Norlaudanosine (10c): A solution of KHMDS (301.6 mg, [4] V. G. Kartsev, Med. Chem. Res. 2004, 13, 325–336.
[5] K. W. Bentley, in Rodd’s Chemistry of Carbon Compounds, 2nd
ed., vol. 4 (Ed.: M. Sainsbury), Elsevier, Amsterdam, 1998, pp.
507–587.
1.51 mmol) in dry THF (2.3 mL) was added at –78 °C to a solution
of 6 (300 mg, 1.38 mmol) in dry THF (10.5 mL). After 4 min, a
solution of 3,4-dimethoxybenzyl bromide (333.6 mg, 1.44 mmol) in
dry THF (2.3 mL) was added. After stirring for 3 h at –78 °C, the
mixture was warmed to ambient temperature. As TLC indicated
incomplete conversion, another portion of KHMDS (274.2 mg,
1.38 mmol) in dry THF (2.3 mL) was added after 30 min and stir-
ring was continued for further 20 min. The reaction mixture was
poured into NaOH solution (1 , 45 mL) and the organic layer was
separated. The aqueous layer was extracted with CH2Cl2
(4ϫ25 mL) containing MeOH (10%).[35] The combined organic
layers were washed with a solution of NiCl2·6H2O (300 mg) in
water (30 mL), a solution of ammonia (10%, 30 mL), and brine
(30 mL). After drying over Na2SO4, the solvent was removed in
vacuo to yield the crude imine 8c as an orange oil (557.6 mg). Tri-
ethylamine (28.2 µL, 206 µmol) was added to a solution of
dichloro-p-cymene-ruthenium(II)-dimer (12.6 mg, 20.6 µmol) and
(1R,2R)-N-(4-tolylsulfonyl)-1,2-diphenylethylenediamine (15.2 mg,
41.2 µmol) in dry DMF (1.1 mL). The solution was degassed by
ultrasonication under a slow stream of argon and was subsequently
heated to 80 °C for 1 h.[36] The crude imine 8c, dissolved in de-
gassed dry DMF (3.8 mL), was added to the warm solution. After
cooling to 0 °C, formic acid/triethylamine azeotrope (5:2, 0.72 mL)
was added and the mixture was stirred for 4.5 h at ambient tem-
perature. Saturated aq. K2CO3 solution (9 mL) and water (6 mL)
were added and the mixture was extracted with ethyl acetate
(3ϫ10 mL). The combined organic layers were dried with Na2SO4
and the solvent was removed in vacuo to furnish a slightly brown
oil (514 mg), which was purified by column chromatography (silica,
eluent petroleum ether/EtOAc/Et2NH 8:2:1, Rf = 0.20) to give 10c
as a light yellow oil (368.1 mg, 77.9%). [α]2D5 = –21.9 (c = 1, CHCl3);
[6] K. W. Bentley, Nat. Prod. Rep. 2005, 22, 249–268.
[7] D. Mujahidin, S. Doye, Eur. J. Org. Chem. 2005, 2689–2693.
[8] D. Seebach, D. Enders, Angew. Chem. 1975, 87, 1–18; Angew.
Chem. Int. Ed. Engl. 1975, 14, 15–32.
[9] G. Stork, R. M. Jacobson, R. Levitz, Tetrahedron Lett. 1979,
9, 771–774.
[10] D. Enders, J. P. Shilvock, Chem. Soc. Rev. 2000, 29, 359–373.
[11] W. von Miller, J. Plöchl, Ber. Dtsch. Chem. Ges. 1898, 31, 2718–
2720.
[12] N. Meyer, F. Werner, T. Opatz, Synthesis 2005, 945–956.
[13] N. Meyer, T. Opatz, Eur. J. Org. Chem. 2006, 3997–4002.
[14] C. Kison, T. Opatz, Synthesis 2006, 3727–3738.
[15] C. Kison, N. Meyer, T. Opatz, Angew. Chem. 2005, 117, 5807–
5809; Angew. Chem. Int. Ed. 2005, 44, 5662–5664.
[16] T. Opatz, D. Ferenc, Org. Lett. 2006, 8, 4473–4475.
[17] J.-M. Mattalia, C. Marchi-Delapierre, H. Hazimeh, M.
Chanon, ARKIVOC 2006, 90–118.
[18] J. M. Brunel, Rect. Res. Devel. Org. Chem. 2003, 7, 155–190.
[19] J. Kobor, K. Koczka, Szegedi Tanarkepzo Foiskola Tudomanyos
Kozlemenyei 1969, 179–183.
[20] A. Bischler, B. Napieralski, Ber. Dtsch. Chem. Ges. 1893, 26,
1903–1908.
[21] T. Kanemitsu, Y. Yamashita, K. Nagata, T. Itoh, Synlett 2006,
1595–1597.
[22] K. Yamada, M. Takeda, T. Iwakuma, Tetrahedron Lett. 1981,
22, 3869–3872.
[23] S. Philipov, N. Ivanovska, R. Istatkova, M. Velikova, P. Tuleva,
Pharmazie 2000, 55, 688–689.
[24] A. R. Hajipour, M. Hantehzadeh, J. Org. Chem. 1999, 64,
8475–8478.
[25] N. Uematsu, A. Fujii, S. Hashiguchi, T. Ikariya, R. Noyori, J.
Am. Chem. Soc. 1996, 118, 4916–4917.
[26] J. B. Perales, F. Makino Narubumi, D. L. Van Vranken, J. Org.
Chem. 2002, 67, 6711–6717.
1
ref.[37] –21 (c = 1, CHCl3). H NMR (400 MHz, CDCl3): δ = 1.66
(br. s, 1 H, NH), 2.61–2.73, 2.77–2.92 (2 m, 2ϫ2 H, ArCH2, 4-
H2), 3.12–3.22 (m, 2 H, 3-H2), 3.81, 3.83, 3.83, 3.85 (4 s, 4ϫ3 H,
OCH3), 4.09 (mc, 1 H, 1-H), 6.57, 6.64 (2 s, 2ϫ1 H, 5-H, 8-H),
[27] M. Pinza, L. Dorigotti, G. Pifferi, Eur. J. Med. Chem. 1976,
11, 395–398.
6.73–6.82 (m, 3 H, 2Ј-H, 5Ј-H, 6Ј-H) ppm. 13C NMR (100.6 MHz, [28] H. Ogura, H. Takahashi, Heterocycles 1982, 17, 87–90.
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www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3911–3915

Reversible Umpolung of the C=N Bond
FULL PAPER
[29] G. J. Meuzelaar, M. C. A. Van Vliet, L. Maat, R. A. Sheldon,
Eur. J. Org. Chem. 1999, 2315–2321.
[30] L. F. Tietze, Y. Zhou, E. Töpken, Eur. J. Org. Chem. 2000,
2247–2252.
[35] Compounds 8 are oxidized in benzylic position by air. This
reaction proceeds much slower in the presence of alcoholic sol-
vents. See: G. J. Kapadia, N. J. Shah, R. J. Highet, J. Pharm.
Sci. 1964, 53, 1431–1432.
[31] R. D. Haworth, J. Chem. Soc. 1927, 2281–2284.
[32] E. Langhals, H. Langhals, C. Ruechardt, Chem. Ber. 1984, 117,
1436–1454.
[36] L. F. Tietze, N. Rackelmann, I. Müller, Chem. Eur. J. 2004, 10,
2722–2731.
[37] H. Corrodi, E. Hardegger, Helv. Chim. Acta 1956, 39, 889–897.
[33] R. Pedrosa, C. Andres, J. M. Iglesias, J. Org. Chem. 2001, 66,
Received: March 23, 2007
Published Online: June 19, 2007
243–250.
[34] G. D. Williams, R. A. Pike, C. E. Wade, M. Wills, Org. Lett.
2003, 5, 4227–4230.
Eur. J. Org. Chem. 2007, 3911–3915
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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