Simple and selective one-pot replacement of the N-methyl group of tertiary amines by quaternization and demethylation with sodium sulfide or potassium thioacetate: An application to the synthesis of pergolide

Article abstract of DOI:10.1039/b104843k

The paper describes a mild, selective, and rapid replacement of an N-methyl group of tertiary amines with other alkyl groups via a simple one-pot procedure. This transformation is easily achieved by preparation of the appropriate quaternary ammonium salt in sulfolane and in situ treatment with sodium sulfide or potassium thioacetate. The protocol is successfully applied to the transformation of dihydrolysergol, dextromethorphan and laudanosine (as models of ergot and opium N-methyl alkaloids) into various N-alkyl congeners.

Full text of DOI:10.1039/b104843k

View Article Online / Journal Homepage / Table of Contents for this issue
Simple and selective one-pot replacement of the N-methyl group of
tertiary amines by quaternization and demethylation with sodium
sulfide or potassium thioacetate: an application to the synthesis of
pergolide
1
Luigi Anastasia, Giuliana Cighetti and Pietro Allevi*
Dipartimento di Chimica e Biochimica Medica, Università di Milano, via Saldini 50,
I-20133 Milano, Italy. E-mail: pietro.allevi@unimi.it; Fax: (ϩ39)02 58356040
Received (in Cambridge, UK) 4th June 2001, Accepted 24th July 2001
First published as an Advance Article on the web 11th September 2001
The paper describes a mild, selective, and rapid replacement of an N-methyl group of tertiary amines with other alkyl
groups via a simple one-pot procedure. This transformation is easily achieved by preparation of the appropriate
quaternary ammonium salt in sulfolane and in situ treatment with sodium sulfide or potassium thioacetate. The
protocol is successfully applied to the transformation of dihydrolysergol, dextromethorphan and laudanosine (as
models of ergot and opium N-methyl alkaloids) into various N-alkyl congeners.
1
1
Introduction
homologue 1c, a key intermediate for the synthesis of the
pergolide mesylester 4 (8β-[(methylthio)methyl]-6-propylergo-
line mesylester; Permax ), a semisynthetic ergot alkaloid
clinically used as an adjunct to levodopa-carbidopa in the
The replacement of an N-methyl group of tertiary amines
with other alkyl groups is a crucial transformation especially
in alkaloid chemistry, as many clinically used compounds
possessing different N-alkyl groups are prepared from cheap N-
methyl-substituted analogues of compounds of natural origin.
®
12
treatment of symptoms of Parkinson’s disease.
1
Traditional processes, allowing the replacement of the N-
methyl group, imply involved protocols, consisting in the con-
version of N-methyl-substituted compounds to the correspond-
2
ing cyanamides (by the von Braun reaction with cyanogen
3
bromide), or carbamates [by reaction with alkyl carbono-
chlorides (alkyl chloroformates)] which are subsequently
cleaved to give N-noralkaloids. A successive N-alkylation
accomplishes the desired substitution. This procedure has been
recently improved, for the synthesis of opium alkaloids, by
4
using L-selectride as the N-demethoxycarbonylation agent.
An alternative procedure involves the intermediate quatern-
ization of the starting tertiary amine, by alkylation with the
appropriate alkyl halide, followed by a selective S 2 demethyl-
N
ation, which can be performed with variable results, using
cuprous [copper()] or sodium thiophenoxide in refluxing
5
6
7
pyridine, butanone or acetonitrile–butanone, thiopropoxide
8
in HMPA, or excess of thiomethoxide (freshly prepared) in
-methylpyrrolidin-2-one (NMP).
Our interest in the transformation of dihydrolysergol 1a into
9,10
1
its congeners having different alkyl groups on the aliphatic
nitrogen atom prompted us to seek for a simpler procedure for
the exchange of the N-methyl group of 1a. In particular we
were looking for a new procedure that would avoid some hassle
encountered with the known methods, caused by the use of
5
8
Results and discussion
pyridine or HMPA, the need of a large excess of freshly pre-
9,10
pared thioalkoxides, even in the best method to date, and the
long handling of hazardous intermediates.
The one-pot replacement of the N-methyl group of dihydro-
lysergol 1a with various alkyl groups (Table 1) was performed
by a quantitative quaternization of the tertiary N-methyl amine
of 1a, with the appropriate halogenoalkane (1.25 molar equiv.)
in sulfolane (tetramethylene sulfone) buffered by catalytic
amounts of K PO (0.1 molar equiv.), followed by addition of
As a result of our studies we herein report a simple protocol
for the selective one-pot exchange of the N-methyl group
of tertiary amines, applied to dihydrolysergol 1a, and also to
dextromethorphan 2a and laudanosine 3a, two compounds
chosen as representative models of opium alkaloids.
3
4
Na Sؒ9H O (1.0 molar equiv.) and heating at 120 ЊC for 5 h.
2
2
The synthetic utility of the method is demonstrated, inter
alia, by the transformation of dihydrolysergol 1a into its
The use of K PO4 in the quaternization reaction distinctly
improves both the level of conversion and the rate of the reac-
3
2
398
J. Chem. Soc., Perkin Trans. 1, 2001, 2398–2403
DOI: 10.1039/b104843k
This journal is © The Royal Society of Chemistry 2001

View Article Online
Table 2 Replacement of the methyl group of the dextromethorphan 2a
Table 1 Replacement of the methyl group of the dihydrolysergol 1a
b
Compound
(yield %)
Selectivity
1x : 1a
a
Entry
R-X
Nu
c
1
2
3
4
5
6
MeCH2I
Na2S
Na2S
Na2S
Na2S
Na2S
Na2S
1b
81 : 19
96 : 4
98 : 2
98 : 2
1.4 : 98.6
9 : 91
b
Compound
(yield %)
Selectivity
Me[CH ] I
1c (85)
1d (90)
1e (87)
1a (89)
1a (84)
a
2
2
Entry
R-X
Nu
2a : 2x : 5x
Me[CH ] I
2
3
Me[CH ] I
2
7
1
2
3
4
5
6
7
8
9
MeCH2I
Me[CH ] I
Me[CH ] I
Na2S
Na2S
Na2S
Na2S
5b (83)
5c (84)
5e (74)
2a (86)
1 : 2: 97
1 : 6 : 93
1 : 14 : 85
93 : 2 : 5
16 : 81 : 3
5 : 92 : 3
1 : 94 : 5
90 : 9 : 1
87 : 12 : 1
1 : 20 : 79
4 : 20 : 76
C H CH Br
6
5
2
2
2
CH ᎐CHCHBr
2
2
7
a
b
Isolated yields after rapid chromatography. Determined by GLC
and GLC-MS. Separable with difficulty from starting material 1a, an
analytical sample was obtained by traditional column chromatography.
C H CH Br
6 5 2
c
MeCH2I
Me[CH ] I
Me[CH ] I
MeCOSK 2b (75)
MeCOSK 2c (84)
MeCOSK 2e (86)
MeCOSK 2a (82)
MeCOSK 2a (78)
2
2
2
7
C H CH Br
6
5
2
CH ᎐CHCHBr
tion.† The selective removal of the methyl group occurs with
very good to excellent yields affording the desired congener
b–e (Table 1). On the other hand, in the case of benzyl- and
allyl-ammonium derivatives, the benzyl and allyl groups are
quantitatively eliminated with high selectivity (Table 1, entries
2
1
1
0
1
Me[CH ] I
Me[CH ] I
MeSNa
MeSNa
5c (70)
5c (69)
2
2
c
2
2
1
a
b
Isolated yields after rapid chromatography. Determined by GLC and
c
GLC-MS. In NMP at 100 ЊC for 6 h.
5
and 6) and the demethylation is not of synthetic utility.
This preferential removal of benzyl and allyl substituents is
in agreement with the results already observed using thio-
In order to evaluate the generality of our protocol we tested
its application to the replacement of the methyl group of
dextromethorphan 2a† and of laudanosine 3a. Unfortunately,
using sodium sulfide, a competitive Hofmann elimination
occurred and, in the case of dextromethorphan 2a, the desired
5,13
phenoxide
and could be due to electronic effects.
The use of the inorganic sodium sulfide as a selective
demethylation agent of quaternary ammonium salts is unprece-
dented, in spite of the fact that other organic sulfides, such as
thiophenoxides or thioalkoxides, are good dealkylants. This salt
S 2 products were obtained in negligible to poor amounts
N
2Ϫ
(2.0–14.0%, Table 2; entries 1–3) accompanied by the relative
elimination products 5b, 5c and 5e lacking the heterocyclic ring.
Superior but still modest results were obtained in the case of
laudanosine 3a. In fact, with this substrate, the desired com-
pounds of substitution (Table 3; entries 1–3) were formed as
major products in good yields (61–71%), but they were still
accompanied by significant amounts of Hofmann elimination
products, of assigned structures 6b, 6c and 6e.
was chosen for the high nucleophilicity of the sulfide ion (S ),
Ϫ
and because the thiomethoxide ion (CH S ), resulting from a
3
hypothetical S 2 attack, is still able to continue the dealkyl-
N
ation. Therefore, the selective dealkylation of the ammonium
salts was achieved using only a 1 : 1 molar ratio of Na S and the
2
ammonium salt, to afford tertiary amines with both high yields
and selectivity (Table 1). The selectivity of the demethylation
enhances with an increase in the steric hindrance of the alkyl
groups used as replacement of the starting methyl (Table 1).
Thus the method was also practically useful for a large-scale
preparation of the N-propyl compound 1c, a key intermediate
for the synthesis of pergolide 4. Starting from dihydrolysergol
The proposed structures 5 and 6 for the Hofmann elimin-
ation products were confirmed by MS (molecular ions) and
1
H-NMR data. In particular, the presence of only two olefinic
1
proton signals in the H-NMR spectra is diagnostic and allows
exclusion of any possible alternative structure. Moreover, the
couplings-constant values (16.0 Hz) associated with the olefinic
protons of compounds 6 are diagnostic for the E configuration
of the formed double bond.
1
a (10 g) the homologous compound 1c was obtained in high
yield (76%) and purity (99.2% by GLC), after a single crystal-
lization form diisopropyl ether. The replacement of the
11
alcoholic group of 1c with a thiomethoxy group affords,
first, highly pure pergolide (99.5% pure by GLC) after a single
crystallization, and successively the pergolide mesylester 4
Formation of an elimination product (20%) was already
observed for a similar N-methyl group exchange reaction per-
formed on quaternized thebaine, a compound structurally7
related to 2a, using thiophenoxide in butanone–acetonitrile.
Also the use of sodium thiomethoxide, a nucleophile which
(
(
99.6% pure by GLC as free base) in satisfactory overall yield
42%) from dihydrolysergol 1a.
These results clearly confirm the potentials of this new
9
shows good results with ergot ammonium salts, afforded,
protocol, and allowed us to achieve a new, simple and efficient
synthesis of pergolide mesylester 4, alternative to the best
in our hands, similar poor results due to the formation of con-
sistent amounts of elimination products (Table 2; entries 10
and 11).
In order to overcome this limitation of our method (as well
as of the previous ones), we decided to test the behaviour of a
less basic nucleophile. We found that treatment of quaternized
9
known method, which has a major drawback, since it requires
a tandem chromatographic purification to remove some by-
products closely related to pergolide.
†
Unfortunately any attempt to perform the N-alkylation of 1a or
2
a or 3a dissolved in sulfolane with commercial potassium
2
a with secondary halogenoalkanes was not successful due to the
thioacetate (3 molar equiv.) for 6 h at 120 ЊC, affords the desired
N-alkylamino homologues with high yields and selectivity
incomplete tetraalkylation of the starting amine. In fact the reaction
of 1a or 2a with 2-iodopropane (6 molar equiv.) in sulfolane or NMP
at 120 ЊC for 26 h afforded a mixture of the tetraalkyl compound
(
Table 2 and Table 3; entries 5–7). The reaction proceeded with
(
20–30%) and the unchanged starting amine (70–80%).
the same good results also when we used NMP in place of
J. Chem. Soc., Perkin Trans. 1, 2001, 2398–2403
2399

View Article Online
Table 3 Replacement of the methyl group of the (±)-laudanosine 3a
umn (12 m, 0.20 mm ID, 0.20 µm, He 65 kPa) for laudanosine
and dextromethorphan derivatives. Mass spectra were obtained
on a Hewlett-Packard 5988A, by using either electron impact
(
EI) or chemical ionization (CI) with NH as reagent gas. All
3
reactions were monitored by thin-layer chromatography (TLC)
carried out on 0.25 mm E. Merck silica gel plates (60 F254) using
UV light, 50% sulfuric acid and heat or iodine as developing
agent. E. Merck 230–400 mesh silica gel was used for rapid
14
column chromatography.
General procedure for the one-pot replacement of the N-methyl
group of tertiary amines
The starting tertiary amine (1a, 2a and 3a; 1.00 mmol) and the
appropriate halogenoalkane (1.25 mmol) were dissolved in
3
sulfolane (80 cm ) containing K PO ؒ3H O (0.1 mmol)
3
4
2
and the solution was heated at 110 ЊC for 2 h. At this time,
the disappearance of the starting amine was monitored (by
TLC), the nucleophile (Na Sؒ9H O, 1 mmol; MeSNa, 3 mmol;
2
2
MeCOSK, 9 mmol) was added and the mixture was heated
at 120 ЊC [for 5 h (Na Sؒ9H O, MeSNa) or 6 h (MeCOSK)].
2
2
3
The mixture was then poured in ice-cold water (10 cm ) and
the resulting suspension was extracted with ethyl acetate. The
organic layer was then washed with water, and dried over
Na SO to afford, after evaporation under reduced pressure, a
b
Compound
(yield %)
Selectivity
a
Entry
R-X
Nu
3a : 3x : 6x
2
4
crude residue which was finally chromatographed.
1
2
3
4
5
6
7
8
MeCH2I
Na2S
Na2S
Na2S
Na2S
MeCOSK
MeCOSK
MeCOSK
MeCOSK
3b (58)
3c (55)
3e (65)
3a (86)
3b (78)
3c (82)
3e (86)
3a (84)
18 : 62 : 20
6 : 61 : 33
6 : 71 : 23
95 : 4 : 1
11 : 85 : 4
7 : 88 : 5
1 : 94 : 5
93 : 6 : 1
Me[CH ] I
2
2
Me[CH ] I
(1) Using chloroethane, dihydrolysergol 1a and Na Sؒ9H O.
2 2
2
7
C H CH Br
The obtained crude product was a mixture of the starting
amine 1a and of its homologues 1b in a 19 : 81 ratio. Purifi-
cation by traditional chromatography on silica gel G-Celite
6
5
2
MeCH2I
Me[CH ] I
2
2
Me[CH ] I
2
7
(
1 : 1 v/v, starting elution with AcOEt and going on with
C H CH Br
6
5
2
addition of increasing amounts of MeOH), allowed the iso-
lation of an analytical sample of pure 1b as a solid (Found:
C, 75.3; H, 8.4; N, 10.5. C H N O requires C, 75.5; H, 8.2; N,
a
b
Isolated yields after rapid chromatography. Determined by GLC and
GLC-MS.
17
22
2
15
1
0.4%); mp 251–254 ЊC (from EtOH–CH Cl ) (lit., 252–254
2 2
ЊC); GLC (240 ЊC) t 2.22 min; δ (500 MHz; CDCl ) 0.86 (3 H,
R
H
3
sulfolane and appears to be a general and interesting alternative
to known methods, in particular for the modification of sub-
strates prone to suffer elimination.
t, J 7.1, NCH CH ), 0.92 (1 H, ddd, J 12.2, 12.2, 12.4, 9-Ha),
2
3
1
(
4
.89 (1 H, m, 8-H), 1.96 (1 H, dd, J 10.8 and 10.8, 7-Ha), 2.26
1 H, ddd, J 4.0, 9.6, 11, 5-H), 2.52–2.60 (3 H, overlapping,
-Ha, 9-Hb, NCHHCH ), 2.71–2.78 (2 H, overlapping, 10-H
Unfortunately, a limitation of our exchange protocol is rep-
resented by the impossibility to efficiently replace a methyl
group with a benzyl or allyl group since the new substituent is
preferably eliminated (Table 2; entries 4, 8 and 9 and Table 3;
entries 4 and 8). However, the clean and selective new protocol
for the debenzylation of the quaternary benzylammonium
salts promoted by potassium thioacetate herein reported is of
great interest, since it offers the possibility to regenerate, under
milder conditions, the starting amine in all cases in which its
protection as quaternary benzylammonium salt is required or
could be useful.
3
and NCHHCH ), 3.08 (1 H, dd, J 2.9 and 10.8, 7-Hb), 3.28
3
(
(
(
2 H, m, 8Ј-H ), 3.36–3.47 (overlapping DHO and 4-Hb), 4.53
1 H, dd, J 4.0 and 4.0, 8Ј-OH), 6.76 (1 H, d, J 6.8, 12-H), 6.95
2
1 H, br s, 2-H), 7.01 (1 H, dd, J 6.8 and 6.8, 13-H), 7.11 (1 H, d,
ϩ
J 6.8, 14-H), 10.80 (1 H, br s, 1-H); m/z (CI, NH ) 271 (M ϩ 1,
1
1
3
ϩ
00%); m/z (EI) 270 (M , 100%), 255 (14), 168 (14), 154 (49),
44 (34), 127 (18).
(
2) Using 1-chloropropane and dihydrolysergol 1a with
Na Sؒ9H O. Purification by rapid chromatography, eluting with
2
2
AcOEt–MeOH 75 : 25 v/v, afforded the amine 1c (241 mg, 85%)
as a solid (Found: C, 76.1; H, 8.6; N, 9.8. C H N O requires C,
18
24
2
Experimental
7
6.0; H, 8.5; N, 9.85%); mp 179–181 ЊC (from diisopropyl ether)
15
15
(
(
lit., 181–182 ЊC); [α] Ϫ52.2 (c 1 in MeOH) (lit., Ϫ66); GLC
240 ЊC) t 2.61 min; δ (500 MHz; CDCl ) 0.86 (3 H, t, J 7.3,
D
General
R
H
3
Mps were measured on a SMP3 mp apparatus (Stuart
Scientific, USA) and are not corrected. Proton nuclear
magnetic resonance spectra were recorded in CDCl or [ H ]-
NCH CH CH ), 0.92 (1 H, ddd, J 12.2, 12.2, 12.4, 9-Ha), 1.46
2 2 3
(2 H, m, NCH CH CH ), 1.88 (1 H, m, 8-H), 1.96 (1 H, dd,
2 2 3
2
3
6
J 11.0 and 11.0, 7-Ha), 2.27 (1 H, ddd, J 3.9, 9.6, 10.7, 5-H),
2.53–2.59 (3 H, overlapping, 4-Ha, 9-Hb, NCHHCH CH ),
DMSO at 303 K on Bruker AM-500 spectrometer operating at
00.13 MHz. Chemical shifts are reported as δ-values in ppm,
2
3
5
2.71–2.77 (2 H, overlapping, 10-H and NCHHCH CH ), 3.08
2 3
relative to residual CHCl (δ 7.24) or DMSO (δ 2.50) as internal
(1 H, dd, J 2.9 and 11.0, 7-Hb), 3.28 (2 H, m, 8Ј-H ), 3.36–3.46
3
2
standard. Multiplicities are described using the following
abbreviations: s = singlet, d = doublet, t = triplet, q = quartet.
Coupling constants (J) are reported in Hz. Optical rotations
were taken at 24 ЊC on a Perkin-Elmer 241 polarimeter and
(overlapping DHO and 4-Hb), 4.54 (1 H, dd, J 4.0 and 4.0,
8Ј-OH), 6.76 (1 H, d, J 6.8, 12-H), 6.95 (1 H, br s, 2-H), 7.00
(1 H, dd, J 6.8 and 6.8, 13-H), 7.10 (1 H, d, J 6.8, 14-H), 10.80
ϩ
(1 H, br s, 1-H); m/z (CI, NH ) 285 (M ϩ 1, 100%); m/z (EI)
3
Ϫ1
2
Ϫ1
ϩ
[
α] -values are given in 10 deg cm g . GLC analyses were
284 (M , 100%), 255 (81), 168 (22), 154 (69), 144 (22), 127 (24).
D
carried out on a Hewlett-Packard 5890 gas chromatography
equipped with an HP-5 (Hewlett-Packard) capillary column
(3) Using 1-chlorobutane, dihydrolysergol 1a and Na Sؒ9H O.
2
2
(
5 m, 0.32 mm ID, 0.25 µm, He 15 kPa) for dihydrolysergol
Purification by rapid chromatography, eluting with AcOEt–
MeOH 80 : 20 v/v, afforded the amine 1d (268 mg, 90%) as a
derivatives and with an HP-1 (Hewlett-Packard) capillary col-
2
400
J. Chem. Soc., Perkin Trans. 1, 2001, 2398–2403

View Article Online
solid (Found: C, 72.2; H, 9.0; N, 8.7. C H N OؒH O requires
ddd, J 3.3, 12.2, 12.6, 16-Ha), 2.32 (1 H, m, 6-Hb), 2.50–2.58
(4 H, overlapping, 10-Ha, 16-Hb, NCH CH ), 2.90 (1 H, dd,
J <1, 17.8, 10-Hb), 2.90 (1 H, ddd, J <1, 3.3, 4.4, 9-H), 3.76
19
26
2
2
C, 72.1; H, 8.9; N, 8.85%); mp 151–153 ЊC (from diisopropyl
2
3
15
15
ether) (lit., 152–154 ЊC); [α]D Ϫ51.4 (c 1 in MeOH) (lit.,
Ϫ68.2); GLC (240 ЊC) tR 2.88 min; δH (500 MHz; CDCl3)
(3 H, OMe), 6.66 (1 H, dd, J 2.7, 8.4, 2-H), 6.78 (1 H, d, J 2.7,
ϩ
0
1
.91 (3 H, t, J 7.3, N[CH ] CH ), 0.93 (1 H, ddd, J 12.2, 12.2,
4-H), 6.98 (1 H, d, J 8.4, 1-H); m/z (CI, NH ) 286 (M ϩ 1,
2
3
3
3
2.4, 9-Ha), 1.28 (2 H, tq, J 7.3 and 7.3, N[CH ] CH CH ), 1.42
100%). Further elution afforded the starting dextromethorphan
2a (35 mg, 13% recovery).
2
2
2
3
(
2 H, m, NCH CH CH CH ), 1.89 (1 H, m, 8-H), 1.97 (1 H,
2 2 2 3
dd, J 11.0 and 11.0, 7-Ha), 2.28 (1 H, ddd, J 3.8, 9.8, 10.8, 5-H),
2
2
.51–2.62 (3 H, overlapping, 4-Ha, 9-Hb, NCHH[CH ] CH ),
(8) Using 1-chloropropane and dextromethorphan 2a. (a)
With Na Sؒ9H O. Purification by rapid chromatography,
2
2
3
.73–2.82 (2 H, overlapping, 10-H and NCHH[CH ] CH ), 3.08
2
2
3
2
2
(
(
8
1 H, dd, J 3.0 and 10.3, 7-Hb), 3.29 (2 H, m, 8Ј-H ), 3.40–3.49
overlapping DHO and 4-Hb), 4.59 (1 H, dd, J 4.0 and 4.0,
Ј-OH), 6.76 (1 H, d, J 7.0, 12-H), 6.96 (1 H, br s, 2-H), 7.00
eluting with MeOH, afforded the elimination compound 5c
(263 mg, 84%) as an oil (Found: C, 80.5; H, 9.9; N, 4.5.
C H NO requires C, 80.5; H, 10.0; N, 4.5%); GLC (220 ЊC) t
R
2
21
31
(
(
1 H, dd, J 7.0 and 7.0, 13-H), 7.11 (1 H, d, J 7.0, 14-H), 10.82
3.34 min; δH (500 MHz; CDCl ) 0.79 (3 H, t, J 7.4, NCH -
CH CH ), 0.96 (1 H, dddd, J 2.7, 11.0, 12.1, 12.1, 8-Ha), 1.21
2 3
3
2
ϩ
1 H, br s, 1-H); m/z (CI, NH ) 299 (M ϩ 1, 100%).
3
(
1 H, m, 7-Ha), 1.29–1.43 (5 H, overlapping, 5-Ha, 6-Ha,
(
4) Using 1-chlorooctane, dihydrolysergol 1a and Na Sؒ9H O.
2 2
15-Ha, NCH CH CH ), 1.52–1.57 (3 H, overlapping, 5-Hb,
2
2
3
Purification by rapid chromatography, eluting with AcOEt–
MeOH 90 : 10 v/v, afforded the amine 1e (252 mg, 87%) as a
solid (Found: C, 78.0; H, 9.6; N, 7.9. C H N O requires C,
7
(
-Hb, 8-Hb), 1.91 (1 H, ddd, J 4.3, 11.9, 12.8, 15-Hb), 1.96–2.04
2 H, overlapping, 14-H and 16-Ha), 2.05 (3 H, s, NMe), 2.12
(2 H, t, J 7.4, NCH CH CH ), 2.28–2.35 (2 H, overlapping,
23
34
2
2
2
3
7
[
7.9; H, 9.7; N, 7.9%); mp 138–140 ЊC (from diisopropyl ether);
6
-Hb and 16-Hb), 3.79 (3 H, s, OMe), 5.78 (1 H, dd, J 6.1 and
α] Ϫ44.6 (c 1 in MeOH); GLC (240 ЊC) t 11.01 min; δ (500
D
R
H
9.5, 9-H), 6.27 (1 H, d, J 9.5, 10-H), 6.65 (1 H, dd, J 2.4 and
8.3, 2-H), 6.77 (1 H, d, J 2.4, 4-H), 6.95 (1 H, d, J 8.3, 1-H);
m/z (CI, NH ) 314 (M ϩ 1, 100%); m/z (EI) 313 (M , 1.0%),
MHz; CDCl ) 0.85 (3 H, t, J 6.7, NCH [CH ] CH ), 0.91 (1 H,
ddd, J 12.2, 12.2, 12.4, 9-Ha), 1.23–1.30 (10 H, overlapping,
× CH ), 1.43 (2 H, m, NCH CH [CH ] CH ), 1.87 (1 H, m,
-H), 1.95 (1 H, dd, J 10.3 and 11.0, 7-Ha), 2.26 (1 H, ddd,
J 4.0, 9.8, 10.9, 5-H), 2.51–2.62 (3 H, overlapping, 4-Ha, 9-Hb,
NCHH[CH ] CH ), 2.71–2.80 (2 H, overlapping, 10-H and
NCHH[CH ] CH ), 3.06 (1 H, dd, J 1.7 and 10.3, 7-Hb), 3.28
2 H, m, 8Ј-H ), 3.35–3.46 (overlapping DHO and 4-Hb), 4.56
1 H, dd, J 4.0 and 4.0, 8Ј-OH), 6.75 (1 H, d, J 7.1, 12-H), 6.96
1 H, br s, 2-H), 6.99 (1 H, dd, J 7.1 and 6.8, 13-H), 7.10 (1 H, d,
J 7.1, 14-H), 10.79 (1 H, br s, 1-H); m/z (CI, NH ) 355 (M ϩ 1,
00%); m/z (EI) 354 (M , 90%), 255 (100), 168 (21), 154 (62),
44 (21), 127 (16).
3
2
2 6
3
ϩ
ϩ
3
5
8
2 2 2 2 5 3
299 (0.6), 284 (1.0), 270 (8.7), 214 (44.2), 171 (100).
(
b) With MeCOSK. Purification by rapid chromatography,
eluting with MeOH, afforded the amine 2c (251 mg, 84%) as an
oil (Found: C, 80.1; H, 9.5; N, 4.7. C H NO requires C, 80.2;
H, 9.8; N, 4.7%); [α]D ϩ66.4 (c 1 in CHCl ); GLC (220 ЊC) tR
3.47 min; δH (500 MHz; CDCl ) 0.89 (3 H, t, J 7.3, NCH -
CH CH ), 1.10 (1 H, dddd, J 3.5, 12.3, 12.5, 12.5, 8-Ha), 1.25–
1
1.52 (3 H, overlapping, 5-Hb and NCH CH CH ), 1.62 (1 H, m,
2
6
3
20
29
2
6
3
3
(
(
(
2
3
2
2
3
.39 (5 H, overlapping, 5-Ha, 6-Ha, 7-Ha, 8-Hb, 15-Ha), 1.44–
ϩ
3
2
2
3
ϩ
1
1
7
-Hb), 1.70 (1 H, ddd, J 4.7, 12.6, 12.6, 15-Hb), 1.79 (1 H, ddd,
J 2.9, 3.3, 12.5, 14-H), 2.01 (1 H, ddd, J 3.2, 12.2, 12.6, 16-Ha),
.32 (1 H, m, 6-Hb), 2.41 (2 H, t, J 7.3, NCH CH CH ), 2.49
2
2
2
3
(
5) Using benzyl bromide, dihydrolysergol 1a and Na Sؒ9H O.
2 2
(
1 H, ddd, J 1.3, 4.7, 12.2, 16-Hb), 2.55 (1 H, dd, J 5.9, 18.0,
Purification by rapid chromatography, eluting with AcOEt–
MeOH 70 : 30 v/v, afforded the starting dihydrolysergol 1a
228 mg, 89% recovery); GLC (240 ЊC) t 2.02 min.
1
1
6
3
0-Ha), 2.85 (1 H, ddd, J <1, 3.3, 5.9, 9-H), 2.91 (1 H, dd, J <1,
8.0, 10-Hb), 3.76 (3 H, OMe), 6.66 (1 H, dd, J 2.8, 8.2, 2-H),
(
R
.78 (1 H, d, J 2.8, 4-H), 6.99 (1 H, d, J 8.2, 1-H); m/z (CI, NH )
3
ϩ
00 (M ϩ 1, 100%).
(
6) Using allyl bromide, dihydrolysergol 1a and Na Sؒ9H O.
2 2
(
c) With MeSNa. Rapid chromatography, eluting with
Purification by rapid chromatography, eluting with AcOEt–
MeOH 70 : 30 v/v, afforded the starting dihydrolysergol 1a
215 mg, 84% recovery); GLC (240 ЊC) t 2.02 min.
MeOH, afforded, first, the amine 2c (50 mg, 17%) and then the
elimination product 5c (219 mg, 70%).
(
R
(
d) With MeSNa in NMP at 100 ЊC for 6 h. Rapid chroma-
(
7) Using chloroethane and dextromethorphan 2a. (a) With
tography, eluting with MeOH, afforded, first, the amine 2c
(48 mg, 16%) and then the elimination product 5c (216 mg,
69%).
Na Sؒ9H O. Purification by rapid chromatography, eluting with
2
2
MeOH, afforded the elimination compound 5b (248 mg, 83%)
as an oil (Found: C, 80.4; H, 9.75; N, 4.8. C H NO requires C,
20
29
8
0.2; H, 9.8; N, 4.7%); GLC (220 ЊC) t 2.76 min; δ (500 MHz;
(9) Using 1-chlorooctane and dextromethorphan 2a. (a) With
Na Sؒ9H O. Purification by rapid chromatography, eluting with
R
H
CDCl ) 0.91 (3 H, t, J 7.0, NCH CH ), 0.97 (1 H, dddd, J 3.1,
3
2
3
2
2
1
1.2, 12.3, 12.3, 8-Ha), 1.21 (1 H, m, 7-Ha), 1.29–1.43 (3 H,
hexane–AcOEt 70–30 v/v, afforded the elimination compound
5e (283 mg, 74%) as an oil (Found: C, 81.6; H, 10.9; N, 3.7.
C H NO requires C, 81.4; H, 10.9; N, 3.65%); GLC (220 ЊC
overlapping, 5-Ha, 6-Ha, 15-Ha), 1.52–1.58 (3 H, overlapping,
5
1
-Hb, 7-Hb, 8-Hb), 1.92 (1 H, ddd, J 4.6, 12.0, 12.8, 15-Hb),
.97–2.04 (2 H, overlapping, 14-H and 16-Ha), 2.05 (3 H, s,
26
41
Ϫ1
for 5 min, 20 ЊC min until 290 ЊC) t 7.62 min; δ (500 MHz;
R
H
NMe), 2.25 (2 H, q, J 7.0, NCH CH ), 2.29–2.37 (2 H, over-
CDCl ) 0.77 (3 H, t, J 7.0, NCH [CH ] CH ), 0.96 (1 H, dddd,
2
3
3 2 2 6 3
lapping, 6-Hb and 16-Hb), 3.79 (3 H, s, OMe), 5.78 (1 H, dd,
J 6.1 and 9.5, 9-H), 6.27 (1 H, d, J 9.5, 10-H), 6.65 (1 H, dd,
J 2.4 and 8.3, 2-H), 6.77 (1 H, d, J 2.4, 4-H), 6.95 (1 H, d, J 8.3,
J 2.7, 11.0, 12.1, 12.1, 8-Ha), 1.16–1.26 (11 H, overlapping,
7-Ha and 5 × CH ), 1.29–1.46 (5 H, overlapping, 5-Ha, 6-Ha,
2
15-Ha, CH ), 1.52–1.57 (3 H, overlapping, 5-Hb, 7-Hb, 8-Hb),
2
ϩ
ϩ
1
-H); m/z (CI, NH ) 300 (M ϩ 1, 100%); m/z (EI) 299 (M ,
1.91 (1 H, ddd, J 4.0, 11.2, 12.3, 15-Hb), 1.96–2.04 (2 H, over-
lapping, 14-H and 16-Ha), 2.05 (3 H, s, NMe), 2.16 (2 H, t,
J 7.0, NCH [CH ] CH ), 2.28–2.35 (2 H, overlapping, 6-Hb and
3
0
.9%), 285 (1.2), 270 (5.6), 214 (39.7), 171 (100).
(
b) With MeCOSK. Rapid chromatography, eluting with
2
2 6
3
MeOH, afforded, first, the amine 2b (214 mg, 75%) as an oil
16-Hb), 3.79 (3 H, s, OMe), 5.78 (1 H, dd, J 6.0 and 9.5, 9-H),
6.27 (1 H, d, J 9.5, 10-H), 6.65 (1 H, dd, J 2.5 and 8.3, 2-H),
(
Found: C, 79.8; H, 9.6; N, 4.8. C H NO requires C, 79.95; H,
19 27
9
.6; N, 4.9%); [α] ϩ51.6 (c 1 in CHCl ); GLC (220 ЊC) t 2.86
6.77 (1 H, d, J 2.5, 4-H), 6.95 (1 H, d, J 8.3, 1-H); m/z (CI, NH )
384 (M ϩ 1, 100%); m/z (EI) 383 (M , 2.3%), 340 (0.6),
284 (3.4), 270 (1.7), 214 (97.1), 171 (100).
D
3
R
3
ϩ
ϩ
min; δ (500 MHz; CDCl ) 1.07 (3 H, t, J 7.1, NCH CH ), 1.11
H
3
2
3
(
1 H, dddd, J 3.4, 12.4, 12.5, 12.5, 8-Ha), 1.25–1.40 (5 H, over-
lapping, 5-Ha, 6-Ha, 7-Ha, 8-Hb, 15-Ha), 1.49 (1 H, ddd, J 2.6,
(b) With MeCOSK. Purification by rapid chromatography,
eluting with hexane–AcOEt 60 : 40 v/v, afforded the amine 2e
(317 mg, 86%) as an oil (Found: C, 81.1; H, 10.7; N, 4.2.
3
1
.3, 10.9, 5-Hb), 1.62 (1 H, m, 7-Hb), 1.71 (1 H, ddd, J 4.7, 12.6,
2.6, 15-Hb), 1.79 (1 H, ddd, J 2.9, 3.3, 12.5, 14-H), 1.98 (1 H,
J. Chem. Soc., Perkin Trans. 1, 2001, 2398–2403
2401

View Article Online
C H NO requires C, 81.25; H, 10.7; N, 4.3%); [α] ϩ111.6
9-Ha), 2.80–2.87 (2 H, overlapping, 3-Ha and 4-Hb), 3.05 (1 H,
25
39
D
Ϫ1
(
c 1 in CHCl ); GLC (220 ЊC for 5 min, 20 ЊC min until 290
dd, J 5.8 and 13.5, 9-Hb), 3.19 (1 H, ddd, J 4.2, 6.9, 13.6, 3-Hb),
3.57 (3 H, s, OMe), 3.74 (1 H, dd, J 5.8 and 7.6, 1-H), 3.78 (3 H,
s, OMe), 3.81 (3 H, s, OMe), 3.83 (3 H, s, OMe), 6.02 (1 H, s,
8-H), 6.53 (1 H, s, 5-H), 6.60 (1 H, d, J 1.5, 2Ј-H), 6.61 (1 H, dd,
3
ЊC) tR 8.10 min; δH (500 MHz; CDCl ) 0.86 (3 H, t, J 7.0,
3
NCH [CH ] CH ), 1.10 (1 H, dddd, J 3.2, 12.3, 12.5, 12.5,
2
2 6
3
8
-Ha), 1.23–1.39 (15 H, overlapping, 5-Ha, 6-Ha, 7-Ha, 8-Hb,
1
5-Ha, 5 × CH ), 1.45–1.52 (3 H, overlapping, 5-Hb and
J 1.5 and 7.7, 6Ј-H), 6.75 (1 H, d, J 7.7, 5Ј-H); m/z (CI, NH )
386 (M ϩ 1, 100%); m/z (EI) 234 (100%), 218 (9), 190 (5),
2
3
ϩ
CH ), 1.61 (1 H, m, 7-Hb), 1.74 (1 H, ddd, J 4.5, 12.6, 12.6,
2
1
5-Hb), 1.83 (1 H, ddd, J 3.0, 3.3, 12.5, 14-H), 2.03 (1 H,
151 (7).
ddd, J 3.2, 12.2, 12.6, 16-Ha), 2.32 (1 H, m, 6-Hb), 2.46 (2 H,
t, J 7.0, NCH CH CH ), 2.53 (1 H, ddd, J 1.3, 4.5, 12.2,
Further elution afforded the elimination products 6c (115
mg, 29%) as an oil (Found: C, 72.0; H, 8.4; N, 3.5. C H NO4
2
2
3
24 33
1
3
6-Hb), 2.58 (1 H, dd, J 5.9, 18.0, 10-Ha), 2.90 (1 H, ddd, J <1,
.3, 5.9, 9-H), 2.91 (1 H, dd, J <1, 18.0, 10-Hb), 3.76 (3 H,
requires C, 72.15; H, 8.3; N, 3.5%); GLC (250 ЊC) t 9.44 min;
R
δ (500 MHz; CDCl ) 0.87 (3 H, t, J 7.4, NCH CH CH ), 1.49
H
3
2
2
3
OMe), 6.66 (1 H, dd, J 3.0, 8.2, 2-H), 6.78 (1 H, d, J 3.0,
(2 H, tq, J 7.4 and 7.4, NCH CH CH ), 2.34 (3 H, s, NMe), 2.38
(2 H, t, J 7.4, NCH CH CH ), 2.56 (2 H, t, J 8.0, ArCH -
2 2 3 2
2 2 3
ϩ
4
-H), 6.99 (1 H, d, J 8.2, 1-H); m/z (CI, NH ) 370 (M ϩ 1,
3
1
00%).
CH N), 2.87 (2 H, t, J 8.0, ArCH CH N), 3.87 (3 H, s, OMe),
2
2
2
3
.88 (3 H, s, OMe), 3.91 (6 H, s, 2 × OMe), 6.68 (1 H, s,
(
10) Using benzyl bromide and dextromethorphan 2a. (a)
ArH), 6.83 (1 H, d, J 16.0, olefinic H), 6.84 (1 H, d, J 8.7,
ArH), 7.01–7.06 (2 H, overlapping, 2 × ArH), 7.08 (1 H, s,
ArH), 7.16 (1 H, d, J 16.0, olefinic H); m/z (CI, NH ) 400
With Na Sؒ9H O. Purification by rapid chromatography,
eluting with MeOH, afforded the starting dextromethorphan 2a
233 mg, 86% recovery); GLC (220 ЊC) t 2.52 min.
2
2
3
(
ϩ
ϩ
R
(M ϩ 1, 100%); m/z (EI) 399 (M , 5%), 313 (0.5), 297 (0.5),
82 (0.6), 86 (100).
b) With MeCOSK. Purification by rapid chromatography,
eluting with AcOEt–MeOH 70 : 30 v/v, afforded the amine 3c
300 mg, 78%), identical in all respects with the compound
above described.
(
b) With MeCOSK. Purification by rapid chromatography,
eluting with MeOH, afforded the starting dextromethorphan 2a
222 mg, 82% recovery); GLC (220 ЊC) t 2.52 min.
2
(
(
R
(
(
11) Using allyl bromide, dextromethorphan 2a and MeCOSK.
Purification by rapid chromatography, eluting with MeOH,
afforded the starting dextromethorphan 2a (211 mg, 78%);
GLC (220 ЊC) t 2.52 min.
(
14) Using 1-chlorooctane and (±)-laudanosine 3a. (a) With
R
Na Sؒ9H O. Rapid chromatography, eluting with hexane–
2
2
AcOEt 60 : 40 v/v, afforded, first, the amine 3e (296 mg, 65%) as
an oil (Found: C, 73.8; H, 9.0; N, 3.1. C H NO requires C,
(
12) Using chloroethane and (±)-laudanosine 3a. (a) With
Na Sؒ9H O. Rapid chromatography, eluting with AcOEt–
28 41
4
2
2
Ϫ1
7
3.8; H, 9.1; N, 3.1%); GLC (250 ЊC for 10 min, 20 ЊC min
MeOH 60 : 40 v/v, afforded, first, the amine 3b (215 mg, 58%) as
a solid (Found: C, 71.1; H, 7.8; N, 3.7. C H NO requires C,
1.1; H, 7.9; N, 3.8%); mp 86–88 ЊC (from EtOH) (lit., 89 ЊC);
GLC (250 ЊC) t 4.05 min; δ (500 MHz; CDCl ) 1.11 (3 H, t,
J 7.1, NCH CH ), 2.48 (1 H, ddd, J 3.9, 4.4, 13.1, 4-Ha), 2.68
2 H, q, J 7.1, NCH CH ), 2.72 (1 H, dd, J 7.8 and 13.5, 9-Ha),
.79–2.89 (2 H, overlapping, 3-Ha and 4-Hb), 3.07 (1 H, dd,
J 5.5 and 13.3, 9-Hb), 3.17 (1 H, ddd, J 4.4, 7.2, 13.7, 3-Hb),
.54 (3 H, s, OMe), 3.77 (3 H, s, OMe), 3.79 (1 H, dd, J 5.5 and
.8, 1-H), 3.81 (3 H, s, OMe), 3.82 (3 H, s, OMe), 5.98 (1 H, s,
-H), 6.35 (1 H, s, 5-H), 6.60 (1 H, d, J 1.5, 2Ј-H), 6.61 (1 H, dd,
J 1.5 and 7.7, 6Ј-H), 6.75 (1 H, d, J 7.7, 5Ј-H); m/z (CI, NH )
72 (M ϩ 1, 100%); m/z (EI) 220 (100%), 204 (16), 176 (6),
until 290 ЊC for 5 min) t 12.19 min; δ (500 MHz; CDCl ) 0.86
R
H
3
22
29
4
16
(3 H, t, J 6.9, NCH [CH ] CH ), 1.23–1.29 (10 H, overlapping,
2 2 6 3
7
5
4
× CH ), 1.48 (2 H, m, CH ), 2.45 (1 H, ddd, J 4.0, 4.3, 14.0,
2
2
R
H
3
-Ha), 2.57 (2 H, t, J 7.0, NCH [CH ] CH ), 2.72 (1 H, dd,
2
2 6
3
2
3
J 7.6 and 13.5, 9-Ha), 2.80–2.87 (2 H, overlapping, 3-Ha and
-Hb), 3.05 (1 H, dd, J 5.7 and 13.5, 9-Hb), 3.20 (1 H, ddd,
(
2
2 3
4
J 4.3, 7.1, 13.8, 3-Hb), 3.56 (3 H, s, OMe), 3.75 (1 H, dd, J 5.7
and 7.6, 1-H), 3.78 (3 H, s, OMe), 3.81 (3 H, s, OMe), 3.83 (3 H,
s, OMe), 6.02 (1 H, s, 8-H), 6.53 (1 H, s, 5-H), 6.61 (1 H, d, J 1.6,
3
7
8
2
5
Ј-H), 6.62 (1 H, dd, J 1.6 and 7.8, 6Ј-H), 6.74 (1 H, d, J 7.8,
ϩ
Ј-H); m/z (CI, NH ) 456 (M ϩ 1, 100%); m/z (EI) 304 (100%),
3
3
ϩ
288 (5), 260 (1), 151 (13).
Further elution afforded the elimination products 6e (70 mg,
3
1
51 (9).
17
15%) as an oil (Found: C, 74.1; H, 9.2; N, 2.9. C H NO4
Further elution afforded the elimination products 6b (65
mg, 17%) as an oil (Found: C, 71.6; H, 8.0; N, 3.6. C H NO
requires C, 71.6; H, 8.1; N, 3.6%); GLC (250 ЊC) t 7.95 min;
δ (500 MHz; CDCl ) 1.07 (3 H, t, J 7.1, NCH CH ), 2.33 (3 H,
s, NMe), 2.49 (2 H, q, J 7.1, NCH CH ), 2.55 (2 H, t, J 8.0,
ArCH CH N), 2.87 (2 H, t, J 8.0, ArCH CH N), 3.87 (3 H,
s, OMe), 3.89 (3 H, s, OMe), 3.91 (6 H, s, 2 × OMe), 6.68 (1 H,
s, ArH), 6.87 (1 H, d, J 16.0, olefinic H), 6.85 (1 H, d, J 9.0,
ArH), 7.02–7.04 (2 H, overlapping, 2 × ArH), 7.09 (1 H,
29 43
requires C, 74.2; H, 9.2; N, 3.0%); GLC (250 ЊC for 10 min, 20
23
31
4
Ϫ1
ЊC min until 290 ЊC for 5 min) tR 14.72 min; δH (500 MHz;
R
CDCl ) 0.85 (3 H, t, J 7.1, NCH [CH ] CH ), 1.22–1.26 (10 H,
3
2
2 6
3
H
3
2
3
overlapping, 5 × CH ), 1.46 (2 H, m, CH ), 2.33 (3 H, s, NMe),
2
2
2
3
2
.39 (2 H, t, J 7.1, NCH [CH ] CH ), 2.54 (2 H, t, J 7.8,
2 2 6 3
2
2
2
2
ArCH CH N), 2.86 (2 H, t, J 7.8, ArCH CH N), 3.87 (3 H, s,
2
2
2
2
OMe), 3.88 (3 H, s, OMe), 3.91 (6 H, s, 2 × OMe), 6.68 (1 H, s,
ArH), 6.83 (1 H, d, J 16.0, olefinic H), 6.84 (1 H, d, J 8.7, ArH),
7
.02–7.05 (2 H, overlapping, 2 × ArH), 7.08 (1 H, s, ArH), 7.16
s, ArH), 7.16 (1 H, d, J 16.0, olefinic H); m/z (CI, NH ) 386
3
ϩ
ϩ
ϩ
(1 H, d, J 16.0, olefinic H); m/z (CI, NH ) 470 (M ϩ 1, 100%);
m/z (EI) 469 (M , 4%), 313 (1), 297 (0.9), 282 (2), 156 (100).
(
2
M
ϩ 1, 100%); m/z (EI) 385 (M , 7%), 313 (0.4), 297 (0.4),
82 (0.6), 72 (100).
b) With MeCOSK. Purification by rapid chromatography,
eluting with AcOEt–MeOH 60 : 40 v/v, afforded the amine 3b
300 mg, 78%), identical in all respects with the compound
above described.
3
ϩ
(
b) With MeCOSK. Purification by rapid chromatography,
eluting with hexane–AcOEt 60 : 40 v/v, afforded the amine 3e
391 mg, 86%), identical in all respects with the compound
(
(
(
above described.
(
13) Using 1-chloropropane and (±)-laudanosine 3a. (a) With
(15) Using benzyl bromide and (±)-laudanosine 3a. (a) With
Na Sؒ9H O. Purification by rapid chromatography, eluting
Na Sؒ9H O. Rapid chromatography, eluting with AcOEt–
2
2
2
2
MeOH 70 : 30 v/v, afforded, first, the amine 3c (212 mg, 55%) as
with AcOEt–MeOH 60 : 40 v/v, afforded the starting (±)-
laudanosine 3a (308 mg, 86% recovery); GLC (250 ЊC) tR
3.53 min.
(b) With MeCOSK. Purification by rapid chromatography,
eluting with AcOEt–MeOH 60 : 40 v/v, afforded the starting
(±)-laudanosine 3a (300 mg, 84% recovery); GLC (250 ЊC) tR
3.53 min.
an oil (Found: C, 71.6; H, 8.1; N, 3.6. C H NO requires C,
2
3
31
4
16
7
6
0
1.7; H, 8.1; N, 3.6%); mp 68–70 ЊC (from aq. acetone) (lit.,
9–70 ЊC); GLC (250 ЊC) tR 4.78 min; δH (500 MHz; CDCl3)
.85 (3 H, t, J 7.3, NCH CH CH ), 1.50 (2 H, tq, J 7.3 and 7.3,
2
2
3
NCH CH CH ), 2.45 (1 H, ddd, J 3.8, 4.2, 14.0, 4-Ha), 2.55
2
2
3
(
2 H, t, J 7.3, NCH CH CH ), 2.73 (1 H, dd, J 7.6 and 13.5,
2 2 3
2
402
J. Chem. Soc., Perkin Trans. 1, 2001, 2398–2403

View Article Online
Synthesis of pergolide mesylester 4
stirring. Filtration of the suspension afforded a pink solid
7.33 g) which, after treatment with decolourizing carbon and
recrystallization from EtOH (180 cm ), gave pergolide mesyl-
(
A mixture of dihydrolysergol 1a (10 g, 39 mmol), 1-iodo-
propane (8.3 g, 48.8 mmol) and K PO ؒ3H O (1.04 g, 3.9 mmol)
3
3
4
2
ester 4 (6.67 g, 78.3%; 99.6% pure by GLC, as free base) as
3
in sulfolane (80 cm ) was heated at 110 ЊC under stirring,
becoming a dark solution within 45 min. Heating was con-
tinued (2 h) until 1a could no longer be detected by TLC
12
a white solid: mp 257–259 ЊC (decomp.) (lit., 258–260 ЊC);
12
[
α] Ϫ21.7 (c 1 in DMF) (lit., Ϫ18 to Ϫ23); GLC (240 ЊC) tR
D
3
.07 min (as free base); identical in all respects with authentic
(
development with MeOH; R 1a = 0.25). At this time solid
f
material.
Na Sؒ9H O (9.36 g, 39 mmol) was added and the mixture was
2
2
heated, with stirring, at 120 ЊC for 5 h. The mixture was then
3
slowly poured into water (400 cm ) under vigorous agitation.
The suspension was cooled to 0 ЊC under stirring and filtered.
Acknowledgements
This work was financially supported by Italian MURST
A green solid was obtained which was dried, dissolved in
3
(
Ministero dell’Università e della Ricerca Scientifica).
AcOEt–MeOH (1 : 1 v/v, 400 cm ), and treated with decolour-
izing carbon (4 g) for 30 min at room temperature. Filtration
and evaporation under reduced pressure gave a light yellow
solid (9.98 g), which was crystallized from diisopropyl ether to
afford pure N-propyl derivative 1c as a colourless solid (8.43 g,
References
1 For a review see: J. H. Cooley and E. J. Evain, Synthesis, 1989, 1.
2 J. von Braun, Ber. Dtsch. Chem. Ges., 1900, 33, 1438.
7
6%; 99.2% pure by GLC), with all physico-chemical properties
3
4
J. D. Hobson and J. G. McCluskey, J. Chem Soc. C, 1967, 2015.
A. Coop, J. W. Janetka, J. W. Lewis and K. C. Rice, J. Org. Chem.,
identical with those described above.
The obtained compound 1c (8.43 g, 29.7 mmol) was dis-
1
998, 63, 4392.
3
solved in pyridine (45 cm ) and the solution was chilled to
5
6
G. H. Posner and J.-S. Ting, Synth. Commun., 1974, 4, 355.
M. Shamma, N. C. Deno and J. F. Remar, Tetrahedron Lett., 1966,
1375.
3
Ϫ10 ЊC under argon. Methanesulfonyl chloride (4.65 cm ,
6
0 mmol) was then added dropwise at such a rate as to maintain
the temperature at below 0 ЊC (30 min). The mixture was stirred
7 T. S. Manoharan, K. M. Madyastha, B. B. Singh, S. P. Bhatnagar
3
and U. Weiss, Synthesis, 1983, 809.
R. O. Hutchins and F. J. Dux, J. Org. Chem., 1973, 38, 1961.
J. W. Misner, J. H. Kennedy and W. S. Biggs, Org. Process. Res. Dev.,
at 0 ЊC for 1 h and then was poured in water (450 cm ). The
8
9
white suspension was filtered and the resulting white solid
3
was washed with water (2 × 40 cm ) and dried at room tempera-
1
997, 1, 77.
ture under reduced pressure (6.7 pa) for 6 h, to give the crude
1
0 J. W. Misner, U.S. Pat., 5 463 060, 1995 (Chem. Abstr., 1994, 120,
270946v).
methanesulfonate (9.56 g, 89%), which was dissolved in DMF
3
(
200 cm ) and treated with commercial CH SNa (5.54 g, 79.1
11 E. C. Kornfeld and N. J. Bach, US Pat., 4 166 182, 1979 (Chem.
Abstr., 1980, 92, 181450q).
12 D. J. Sprankle and E. C. Jensen, in Analytical Profiles of Drug
Substances and Excipients, ed. H. G. Brittain, Academic Press, New
York, 1992, vol. 21, p. 375.
3
mmol). The resulting suspension was stirred at room tempera-
3
ture for 2 h and then poured into water (550 cm ). After filtra-
3
tion, the collected solid was washed with water (2 × 40 cm ),
dried at room temperature under reduced pressure (6.7 pa) for
1
3 T. Kametani, K. Kigasawa, M. Hiiragi, N. Wagatsuma and
K. Wakisaka, Tetrahedron Lett., 1969, 635.
3
6
h and triturated in boiling MeOH (300 cm ) to afford pure
pergolide (6.53 g, 78.8%; 99.5% pure by GLC).
14 W. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 1978, 43,
2
923.
The obtained pergolide (6.53 g, 20.8 mmol), suspended in
3
15 J. Krepelka, A. Cerny, R. Kotva and M. Semonsky, Collect. Czech.
Chem. Commun., 1977, 42, 1209.
MeOH (60 cm ), was treated with a solution of methane-
3
sulfonic acid (2.0 g, 20.8 mmol) in MeOH (60 cm ) and the
1
1
6 J. M. Z. Gladych and E. P. Taylor, J. Chem. Soc., 1962, 1481.
7 A. L. Mndzhoyan, V. A. Mnatsakanyan and L. S. Arutyunyan, Arm.
Khim. Zh., 1969, 22, 842 (Chem. Abstr., 1970, 72, 21808w).
mixture was heated under reflux. When the pergolide had com-
3
pletely dissolved, propan-2-ol (120 cm ) was added under
J. Chem. Soc., Perkin Trans. 1, 2001, 2398–2403
2403