New synthesis of 3-arylpyrrolines

Article abstract of DOI:10.1016/j.tetlet.2005.12.008

We present an easy and straightforward synthesis of 3-arylpyrrolines 4a-g by repeated treatment of 4-aryl-1,2,5,6-tetrahydropyridines 2a-g with m-chloroperoxybenzoic acid (MCPBA) and boron trifluoride etherate (BF ₃-OEt₂). The transformation proceeds via epoxidation, ring contraction, Baeyer-Villiger oxidation and elimination reaction and affords 3-arylpyrrolines 4a-g with 61-70% yield. This facile strategy was also used to synthesize racemic baclofen (6).

Full text of DOI:10.1016/j.tetlet.2005.12.008

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 855–859
New synthesis of 3-arylpyrrolines
Meng-Yang Chang,a,* Chun-Li Paib and Yung-Hua Kunga
aDepartment of Applied Chemistry, National University of Kaohsiung, Kaohsiung 811, Taiwan
bDepartment of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
Received 4 November 2005; revised 28 November 2005; accepted 2 December 2005
Available online 20 December 2005
Abstract—We present an easy and straightforward synthesis of 3-arylpyrrolines 4a–g by repeated treatment of 4-aryl-1,2,5,6-tetra-
hydropyridines 2a–g with m-chloroperoxybenzoic acid (MCPBA) and boron trifluoride etherate (BF3-OEt2). The transformation
proceeds via epoxidation, ring contraction, Baeyer–Villiger oxidation and elimination reaction and affords 3-arylpyrrolines 4a–g
with 61–70% yield. This facile strategy was also used to synthesize racemic baclofen (6).
ꢀ 2005 Elsevier Ltd. All rights reserved.
Synthesis of 3-pyrrolines and its analogs has been
largely inspired by the structural relationship of this
heterocycle to the ubiquitous pyrrolidine and pyrrole.1,2
These substituted and functionalized 3-pyrrolines are
often used as key intermediates for the synthesis of
nitrogen containing heterocyclic natural products and
potential biological activity compounds.3 For example,
3-arylpyrrolines with different substitutents are reported
to act as irreversible mechanism-based inactivators or
inhibitors of various enzymes.4
O
B
ring-closing
metathesis
O
Ar
Suzuki coupling
(ref. 11)
Ar
(ref. 12a)
our work
Ar
N
R
N
R
N
R
metal ion induced
cyclization
(ref. 6a)
Ar
C
H2C
Development of a general and novel procedure for 3-
pyrrolines provides an expedient entry point. Basically,
the adopted synthetic strategies of 3-pyrrolines and its
related analogs can be summarized in transition metal-
promoted, for example, palladium(0, II),5 silver(I),6
mercury(II),7 gold(III),8 organolanthanide9 and phos-
phine-catalyzed10 cyclization and cycloisomerization of
a heteroatom onto an allene moiety, Suzuki coupling,11
and ring-closing metathesis reaction12 (Fig. 1). In this
letter, we develop an easy and straightforward strategy
to 3-arylpyrrolines by repeated treatment of 4-aryl-
1,2,5,6-tetrahydropyridines with m-chloroperoxybenzoic
acid (MCPBA) and boron trifluoride etherate (BF3-
OEt2).
HN
R
N
R
Figure 1.
1. 4-Aryl-1,2,5,6-tetrahydropyridines 2a–f were pre-
pared by the four-step standard protocol and described
as follows: (i) N-tosylation of 4-hydroxypiperidine with
OH
O
Ar
1) TsCl, Et3N
1) ArMgBr
2) Jones ox.
(two-step 90%)
2) BF3-OEt2
N
H
N
N
Ts
Ts
4-Hydroxypiperidine was chosen as the starting material
in the synthesis of 3-arylpyrrolines as shown in Scheme
1
2a, Ar=C6H5 (80%)
2b, Ar=4-FC6H4 (71%)
2c, Ar=4-ClC6H4 (70%)
2d, Ar=4-MeOC6H4 (81%)
2e, Ar=3-MeOC6H4 (79%)
2f, Ar=4-C6H5C6H4 (82%)
Keywords:
3-Arylpyrrolines;
4-Aryl-1,2,3,6-tetrahydropyridines;
m-Chloroperoxybenzoic acid; Boron trifluoride etherate.
*
Corresponding author. Tel.: +886 7 5919464; fax: +886 7 5919348;
e-mail: mychang@nuk.edu.tw
Scheme 1.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.008

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M.-Y. Chang et al. / Tetrahedron Letters 47 (2006) 855–859
triethylamine and p-toluenesulfonyl chloride in dichloro-
methane at 0 ꢁC for 1 h, (ii) oxidation of the resulting
alcohol with excess Jones reagent in acetone at 0 ꢁC
for 15 min, (iii) Grignard addition of 1-tosylpiperidin-
4-one (1) with different arylmagnesium bromide reagent
(a, Ar = C6H5; b, Ar = 4-FC6H4; c, Ar = 4-ClC6H4; d,
Ar = 4-MeOC6H4; e, Ar = 3-MeOC6H4; f, Ar = 4-
C6H5C6H4) in tetrahydrofuran at À78 ꢁC for 2 h, (iv)
dehydration of the resulting tertiary alcohols with
BF3-OEt2 in dichloromethane at 0 ꢁC for 15 min. Thus,
compounds 2a–f were provided from compound 1 after
two recrystallizations in 70–82% overall yield.13
Ar
Ar
CHO
Ar
1) MCPBA
1) MCPBA
2) BF3-OEt2
2) BF3-OEt2
N
N
N
Ts
Ts
Ts
2a-f
3a-f
4a, Ar=C6H5 (64%)
4b, Ar=4-FC6H4 (64%)
4c, Ar=4-ClC6H4 (61%)
4d, Ar=4-MeOC6H4 (66%)
4e, Ar=3-MeOC6H4 (70%)
4f, Ar=4-C6H5C6H4 (65%)
Scheme 3.
To initiate our work, reaction of compound 2a was trea-
ted with excess MCPBA at rt for ca. 170 h in dichloro-
methane followed by treatment of BF3-OEt2 at 0 ꢁC
for 15 min. 3-Phenylpyrroline was separated in only
18% yield via the one-pot reaction with a series of func-
tional group transformations. This is an interesting
result. The possible reaction mechanism has been
proposed as shown in Scheme 2. Presumably, epoxide
of olefin 2a was first generated. After MCPBA-mediated
conversion of pinacol to pinacolone and following
Baeyer–Villiger oxidation of the resulting aldehyde 3a,
formyl acid was then eliminated by the addition of
BF3-OEt2 in dichloromethane, providing compound
4a. During the one-pot process, 2-pyrroline framework
was not observed under this combination of MCPBA
and BF3-OEt2 conditions.
reaction of the resulting formyl group with BF3-OEt2
at 0 ꢁC for 15 min. The continuous reaction showed
shorter overall reaction time and higher reaction effi-
ciency. For the transformation, 3-arylpyrrolines 4a–f
were obtained in 61–70% yield by only column chroma-
tography purification on silica gel.16 The total synthetic
procedure must be monitored by TLC until the reaction
was complete within a working day.
We had tried to study the synthesis of 3-methylpyrroline
by repeated treatment of 4-methyl-1,2,5,6-tetrahydro-
pyridine with MCPBA and BF3-OEt2, but 3-methylpyrr-
oline was provided in trace yield. Especially, many
products were produced by the treatment of 4-methyl-
3,4-epoxypiperidine with BF3-OEt2. Although the syn-
thetic application has been decreased, the present work
is complementary to existing methodology.
With the above results and enough amounts of com-
pounds 2a–f, we examined and investigated the integrity
of ring contraction reaction sequence in the synthesis of
3-arylpyrrolines as shown in Scheme 3. This repeated
combination of MCPBA and BF3-OEt2 could provide
an easy and straightforward standard operation proto-
col with better yields from compounds 2a–f to com-
pounds 4a–f.
Racemic baclofen17 (Lioresalꢂ; Baclonꢂ) [4-amino-3-
(4-chlorophenyl)butanoic acid] is a lipophilic analog of
the inhibitory neurotransmitter c-aminobutyric acid
(GABA). During the last decade, a number of specific
agonists or antagonists for the GABAB receptor site
have been developed. However, baclofen is the only
selective and therapeutically useful GABAB agonist.
Baclofen is used in the treatment of spasticity caused
by disease of the spinal cord, particularly traumatic
lesions. Due to its biological and pharmacological
importance, there have been several reports on the total
synthesis of baclofen.18
The related overall procedure for synthesizing com-
pounds 4a–f is described as follows. First, aldehydes
3a–f were first provided by epoxidation of compounds
2a–f with MCPBA at rt for 3 h and followed by
rearrangement reaction of the resulting epoxides with
BF3-OEt2 at 0 ꢁC for 15 min.14,15 Next, Baeyer–Villiger
reaction of aldehydes 3a–f was further treated with
MCPBA at rt for 3 h and followed by the elimination
Here, we report a new approach for the synthesis of
racemic baclofen from compound 2g as shown in
Scheme 4. Under the repeated combination of MCPBA
4-ClC6H4
4-ClC6H4
C6H5
C6H5
O
1) MCPBA
1) MCPBA
C6H5
CHO
CHO
MCPBA
2) BF3-OEt2
2) BF3-OEt2
(65% from 2g)
N
N
epoxidation
ring contraction
BF3-OEt2
N
N
Cbz
Cbz
N
Ts
Ts
2a
Ts
2g
3g
3a
4-ClC6H4
4-ClC6H4
C6H5
C6H5
OCHO
4-ClC6H4
H2, Pd/C
1) RuCl3, NaIO4
Baeyer-Villiger
oxidation
formic acid
elimination
one-pot reaction
Boc2O
(75%)
2) 2N HCl
( 42%)
HO2C
N
N
N
N
NH2
Cbz
Boc
Ts
Ts
4a
4g
baclofen (6)
(18% from 2a)
5
Scheme 2.
Scheme 4.

M.-Y. Chang et al. / Tetrahedron Letters 47 (2006) 855–859
857
Mou, Q. Y.; Chen, J.; Zhu, Y. C.; Zhou, D. H.; Chi, Z. Q.;
Long, Y. Q. Bioorg. Med. Chem. Lett. 2002, 12, 2287; (f)
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124, 12135.
and BF3-OEt2 condition, compound 4g was provided in
65% yield from compound 2g. In view of the experimen-
tal simplicity, the preparation of compound 4g was also
conducted in a multigram scale (10 mmol) with 51%
overall yield. Compound 5 was yielded by the treatment
of compound 4g with hydrogen and di-tert-butyl di-
carbonate in the presence of a catalytic amount of 10%
palladium on activated carbon.19 Selective oxidation of
compound 5 with ruthenium oxide and subsequent
hydrolysis with aqueous hydrochloric acid yielded bac-
lofen (6) in 42% yield.20
5. (a) Ma, S.; Yu, F.; Gao, W. J. Org. Chem. 2003, 68, 5943;
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Chem. Commun. 1987, 243.
In summary, we present an easy and straightforward
synthesis of 3-arylpyrrolines 4a–g by repeated treatment
of 4-aryl-1,2,5,6-tetrahydropyridines 2a–g with MCPBA
and BF3-OEt2. The transformation proceeds via epoxi-
dation, ring contraction, Baeyer–Villiger oxidation and
elimination reaction and affords 3-arylpyrrolines 4a–g
with 61–70% yield. This facile strategy was also used
to synthesize racemic baclofen (6). We are currently
studying the scope of this process as well as additional
applications of the methodology to the synthesis of pip-
eridines, indolizidines, quinolizidines and indoles.
7. Fox, D. N. A.; Lathbury, D.; Mahon, M. F.; Molly, K. C.;
Gallagher, T. J. Chem. Soc., Chem. Commun. 1989, 1073.
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Chem. Soc. 1998, 120, 4871.
Acknowledgements
The authors would like to thank the National Science
Council (NSC 94-2113-M-390-001) of the Republic of
China for financial support.
10. (a) Xu, Z.; Lu, X. J. Org. Chem. 1998, 63, 5031; (b) Xu, Z.;
Lu, X. Tetrahedron Lett. 1997, 38, 3461; (c) Zhu, X. F.;
Henry, C. E.; Kwon, O. Tetrahedron 2005, 61, 6276.
11. Hercouet, A.; Neu, A.; Peyronel, J.-F.; Carboni, B. Synlett
2002, 829.
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Hodgeson, A.; Morris, J.; Sridharan, V. Tetrahedron Lett.
2001, 42, 8673; (b) Grigg, R.; Hodgeson, A.; Morris, J.;
Sridharan, V. Tetrahedron Lett. 2003, 44, 1023; (c) Kim, J.
M.; Lee, K. Y.; Lee, S.; Kim, J. N. Tetrahedron Lett. 2004,
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Briot, A.; Bujard, M.; Gouverneur, V.; Nolan, S. P.;
Mioskowski, C. Org. Lett. 2000, 2, 1517.
Supplementary data
1
Photocopies of H NMR (CDCl3 or D2O) spectral data
for compounds 2a–g, 3g, 4a–g and 5–6 were supported.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.12.008.
13. A representative procedure of 2a–g is as follows: A
solution of arylmagnesium bromide (2.6 mmol) in tetra-
hydrofuran (10 mL) was added to a stirred solution of
piperidin-4-one (2.23 mmol) in tetrahydrofuran (20 mL) at
À78 ꢁC. The reaction mixture was stirred at rt for 2 h.
Water (5 mL) was added to the reaction mixture and
the mixture was filtered through a short plug of Celite.
The filtrate was concentrated under reduced pressure. The
residue was extracted with ethyl acetate (3 · 50 mL). The
combined organic layers were washed with brine, dried,
filtered and evaporated to afford crude product under
reduced pressure. Without further purification, a solution
of boron trifluoride etherate (1 mL) in dichloromethane
(5 mL) was added to a stirred solution of the crude
product in dichloromethane (50 mL) at 0 ꢁC. The reaction
mixture was stirred at rt for 15 min. Saturated sodium
bicarbonate solution (10 mL) was added to the reaction
mixture and the solvent was concentrated under reduced
pressure. The residue was extracted with ethyl acetate
(3 · 50 mL). The combined organic layers were washed
with brine, dried, filtered and evaporated to afford crude
product under reduced pressure. Recrystallizations from
hexane and ethyl acetate (ca. 2:1) yielded 2a–f. Purification
on silica gel (hexane/ethyl acetate = 4:1–2:1) afforded 2g.
Representative data for 2a: 1H NMR (500 MHz, CDCl3) d
References and notes
1. Bird, C. W.; Cheeseman, G. W. H. In Comprehensive
Heterocyclic Chemistry; Katrizky, A. R., Rees, C. W.,
Eds.; Pergamon: Oxford, 1984; Vol. 4, p 89.
2. For recent reviews of pyrrole, pyrroline and pyrrolidine
containing natural products see: (a) OÕHagan, D. Nat.
Prod. Rep. 2000, 17, 435; (b) Mauger, A. B. J. Nat. Prod.
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Garcia, A. L. L.; Carpes, M. J. S.; de Oca, A. C. B. M.;
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858
M.-Y. Chang et al. / Tetrahedron Letters 47 (2006) 855–859
7.72 (d, J = 8.5 Hz, 2H), 7.35–7.26 (m, 7H), 5.97–5.95 (m,
product under reduced pressure. Without further purifi-
cation, a solution of boron trifluoride etherate (1 mL) in
dichloromethane (5 mL) was added to a stirred solution of
the resulting crude product in dichloromethane (50 mL) at
0 ꢁC. The reaction mixture was stirred at rt for 15 min.
Saturated sodium bicarbonate solution (10 mL) was added
to the reaction mixture and the solvent was concentrated
under reduced pressure. The residue was extracted with
ethyl acetate (3 · 50 mL). The combined organic layers
were washed with brine, dried, filtered and evaporated to
afford crude product under reduced pressure. Purification
on silica gel (hexane/ethyl acetate = 2:1–1:1) afforded 4a–
g. Representative data for 4a: 1H NMR (500 MHz,
CDCl3) d 7.77 (d, J = 8.5 Hz, 2H), 7.33–7.27 (m, 7H),
6.01 (t, J = 2.0 Hz, 1H), 4.49 (td, J = 2.0, 4.0 Hz, 2H),
4.31 (td, J = 2.0, 4.0 Hz, 2H), 2.42 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 143.56, 137.34, 134.08, 132.48,
129.83 (2·), 128.68 (2·), 128.43, 127.47 (2·), 125.38 (2·),
118.86, 55.66, 54.90, 21.50; HRMS (ESI) m/z calcd for
C17H18NO2S (M++1) 300.1058, found 300.1058. For 4b:
1H NMR (500 MHz, CDCl3) d 7.77 (d, J = 8.0 Hz, 2H),
7.33 (d, J = 8.0 Hz, 2H), 7.27–7.24 (m, 2H), 7.02 (t,
J = 8.5 Hz, 2H), 5.94 (t, J = 2.0 Hz, 1H), 4.46–4.44 (m,
2H), 4.31–4.28 (m, 2H), 2.42 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 163.59, 161.62, 143.62, 136.28, 133.99, 129.85
(2·), 127.45 (2·), 127.13, 127.06, 118.64, 115.77, 115.59,
55.60, 54.92, 21.50; HRMS (ESI) m/z calcd for
C17H17FNO2S (M++1) 318.0964, found 318.0963. For
4c: 1H NMR (500 MHz, CDCl3) d 7.77 (d, J = 8.5 Hz,
2H), 7.33 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H),
7.21 (d, J = 8.5 Hz, 2H), 6.00 (t, J = 2.0 Hz, 1H), 4.45 (td,
J = 2.0, 4.5 Hz, 2H), 4.30 (td, J = 2.0, 5.0 Hz, 2H), 2.42 (s,
3H); 13C NMR (125 MHz, CDCl3) d 143.66, 136.30,
134.22, 133.98, 130.94, 129.86 (2·), 128.87 (2·), 127.45
(2·), 126.63 (2·), 119.60, 55.62, 54.77, 21.52; HRMS (ESI)
m/z calcd for C17H17ClNO2S (M++1) 334.0669, found
334.0670.
1H), 3.77 (dd, J = 2.5, 6.0 Hz, 2H), 3.33 (t, J = 6.0 Hz,
2H), 2.63–2.61 (m, 2H), 2.44 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 143.63, 140.11, 135.39, 133.14, 129.67 (2·),
128.44 (2·), 127.77 (2·), 127.52, 124.97 (2·), 118.98, 45.24,
43.01, 27.55, 21.53; HRMS (ESI) m/z calcd for
C18H20NO2S (M++1) 314.1215, found 314.1213. For 2b:
1H NMR (300 MHz, CDCl3) d 7.73–7.69 (m, 2H), 7.33 (d,
J = 8.4 Hz, 2H), 7.28–7.22 (m, 2H), 7.03–6.96 (m, 2H),
5.89 (td, J = 1.8, 3.6 Hz, 1H), 3.74 (dd, J = 3.0, 6.0 Hz,
2H), 3.33–3.29 (m, 2H), 2.59–2.55 (m, 2H), 2.43 (s, 3H);
HRMS (ESI) m/z calcd for C18H19FNO2S (M++1)
332.1121, found 332.1122. For 2g: 1H NMR (500 MHz,
CDCl3) d 7.40–7.27 (m, 9H), 5.99 (br s, 1H), 5.18 (s, 2H),
4.16 (d, J = 2.0 Hz, 2H), 3.72 (t, J = 5.5 Hz, 2H), 2.52 (br
s, 2H); HRMS (ESI) m/z calcd for C19H19ClNO2 (M++1)
328.1104, found 328.1106.
14. (a) Nagai, Y.; Hino, K.; Uno, H.; Minami, S. Chem.
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16. A representative procedure of 4a–g is as follows: A
solution of m-chloroperoxybenzoic acid (510 mg, 75%,
2.2 mmol) in dichloromethane (10 mL) was added to a
solution of 2a–g (2.0 mmol) in dichloromethane (20 mL).
The reaction mixture was stirred at rt for 3 h. Saturated
sodium carbonate solution (10 mL) was added to the
reaction mixture and the solvent was concentrated under
reduced pressure. The residue was extracted with ethyl
acetate (3 · 50 mL). The combined organic layers were
washed with brine, dried, filtered and evaporated to afford
crude product under reduced pressure. Without further
purification, a solution of boron trifluoride etherate
(1 mL) in dichloromethane (5 mL) was added to a stirred
solution of the resulting crude epoxide product in dichloro-
methane (50 mL) at 0 ꢁC. The reaction mixture was stirred
at rt for 15 min. Saturated sodium bicarbonate solution
(10 mL) was added to the reaction mixture and the solvent
was concentrated under reduced pressure. The residue was
extracted with ethyl acetate (3 · 50 mL). The combined
organic layers were washed with brine, dried, filtered and
evaporated to afford crude products 3a–g under reduced
pressure. Without further purification, a solution of m-
chloroperoxybenzoic acid (510 mg, 75%, 2.2 mmol) in
dichloromethane (10 mL) was added to a solution of
resulting aldehyde 3a–g and sodium bicarbonate (750 mg,
8.93 mmol) in dichloromethane (20 mL). The reaction
mixture was stirred at rt for 3 h. Saturated sodium
carbonate solution (10 mL) was added to the reaction
mixture and the solvent was concentrated under reduced
pressure. The residue was extracted with ethyl acetate
(3 · 50 mL). The combined organic layers were washed
with brine, dried, filtered and evaporated to afford crude
17. (a) Kerr, D. I. B.; Ong, J. Med. Res. Revs. 1992, 12, 593;
(b) Berthelot, P.; Vaccher, C.; Flouquet, N.; Debaert, M.;
Luyckx, M.; Brunet, C. J. Med. Chem. 1991, 34, 2557; (c)
Kerr, D. I. B.; Ong, J.; Doolette, D. J.; Abbenante, J.;
Prager, R. H. Eur. J. Pharmacol. 1993, 96, 239.
18. (a) Felluga, V.; Gombac, G.; Pitacco, G.; Valentin, E.
Tetrahedron: Asymmetry 2005, 16, 1341, and references
cited herein; (b) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu,
X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119, and
references cited herein.
19. The synthetic procedure of 5 is as follows: 10% palladium
on activated carbon (10 mg) was added to a solution of
4g (100 mg, 0.32 mmol) and di-tert-butyl dicarbonate
(110 mg, 0.5 mmol) in methanol (10 mL). Then, hydrogen
was bubbled into the mixture for 10 min, and the
reaction mixture was continued to stir at rt for 10 h.
The catalyst was filtered through a short plug of Celite
and washing with methanol (2 · 10 mL). The combined
organic layers were evaporated under reduced pressure
to yield the crude compound. Purification on silica
gel (hexane/ethyl acetate = 3:1) afforded 5. 1H NMR
(300 MHz, CDCl3) d 7.38–7.15 (m, 4H), 3.85–3.72 (br s,
1H), 3.70–3.52 (br s, 1H), 3.42–3.20 (m, 3H), 2.32–2.18
(br s, 1H), 2.01–1.83 (m, 1H), 1.65 (s, 9H); HRMS (ESI)
m/z calcd for C15H21ClNO2 (M++1) 282.1261, found
282.1263.
20. The synthetic procedure of baclofen-HCl (6) is as follows:
Compound 5 (56 mg, 0.2 mmol) was dissolved in carbon
tetrachloride (2 mL), acetonitrle (2 mL) and water (3 mL)
with vigorous stirring. Then, sodium periodate (210 mg,
1.0 mmol) and ruthenium (III) chloride hydrate (5 mg)
were added. The reaction was stopped after 6 h, diluting

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859
with dichloromethane (20 mL) and the organic layer was
separated. The aqueous layer was then extracted with
dichloromethane (2 · 10 mL) and the organic layers were
filtered on a Celite pad, collected and concentrated to yield
lactam as the major product. 1H NMR (400 MHz, CDCl3)
d 7.32 (br s, 1H), 7.27–7.24 (m, 2H), 7.14–7.13 (m, 2H),
3.76–3.72 (m, 1H), 3.65–3.57 (m, 1H), 3.33 (dd, J = 7.2,
9.4 Hz, 1H), 2.68 (dd, J = 9.0, 16.9 Hz, 1H), 2.40 (dd,
J = 8.6, 16.9 Hz, 1H). 13C NMR (100 MHz, CDCl3) d
177.73, 140.64, 132.70, 128.85 (2·), 128.02 (2·), 49.42,
39.51, 37.98. A mixture of the resulting lactam product in
aqueous hydrogen chloride solution (2 N, 10 mL) was
refluxed for 12 h. The solvent was evaporated under
reduced pressure and the residue was triturated in isopro-
panol yielding baclofen-HCl (6). 1H NMR (400 MHz,
D2O) d 7.49 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H),
3.42–3.24 (m, 3H), 2.67 (dd, J = 6.4, 14.6 Hz, 1H), 2.57
(dd, J = 8.4, 14.6 Hz, 1H); 13C NMR (100 MHz, D2O) d
175.71, 138.62, 133.49, 129.88 (2·), 129.66 (2·), 44.55,
42.66, 41.22.