The synthesis of baclofen and GABOB via Rh(II) catalyzed intramolecular C-H insertion of α-diazoacetamides

Article abstract of DOI:10.1016/j.tet.2004.11.077

The synthesis of baclofen and GABOB is reported via hydrolysis of the corresponding N-tert-butyl γ-lactams, which were obtained from Rh(II) catalyzed intramolecular C-H insertion of α-diazoacetamides.

Full text of DOI:10.1016/j.tet.2004.11.077

Tetrahedron 61 (2005) 1579–1586
The synthesis of baclofen and GABOB via Rh(II) catalyzed
intramolecular C–H insertion of a-diazoacetamides
Zhenliang Chen,a,b Zhiyong Chen,a Yaozhong Jianga and Wenhao Hua,
*
aKey Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan Province and Union Laboratory of Asymmetric Synthesis,
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
bGraduate School of Chinese Academy of Sciences, Beijing, China
Received 15 March 2004; revised 14 November 2004; accepted 15 November 2004
Available online 18 December 2004
Abstract—The synthesis of baclofen and GABOB is reported via hydrolysis of the corresponding N-tert-butyl g-lactams, which were
obtained from Rh(II) catalyzed intramolecular C–H insertion of a-diazoacetamides.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
preparation of GABA analogues,1–4 there is still increasing
interests for general and practical synthetic approaches.
g-Amino butyric acid (GABA) is an important central
nervous system neurotransmitter.1 It has profound impact
on many important biological functions. Hence, GABA
analogues, such as gabapentin,2 baclofen3 and g-amino
b-hydroxy butyric acid (GABOB)4 (Fig. 1), have been well
explored as medicines to treat various diseases associated
with GABA receptors. For instance, gabapentin (1) has been
used for the treatment of cerebral diseases such as epilepsy,
faintness attacks, hypokinesis and cranial traumas.2b
Although many methods have been developed for the
In the transition metal catalyzed C–H insertion of a-diazo-
acetamide, regioselectivity has remained a major challenge.
It has been well documented that regioselectivity depends
highly on the substitutents of diazo carbon, the N-sub-
stitutents on the amide moiety, and the electrophilicity of
the catalysts.5 In the past twenty years, some examples have
been reported on the application of the intramolecular C–H
insertion of a-diazoacetamide.6 High regioselectivity has
been achieved with N-tert-butyl a-diazoacetamide, initially
reported by Padwa and co-workers.7 In our previous
communication, we found that the tert-butyl protecting
group can be easily removed in hydrochloric acid and
gabapentin (1) was prepared accordingly (Scheme 1).7e
Excellent selectivity and high reactivity of N-tert-butyl
a-diazoacetamides shed lights on the potential application
as a general method to other GABA analogues. We report
here our detail study of this approach towards b-substi-
tuted GABA analogues such as (G)-baclofen (2) and
(G)-GABOB (3) (Scheme 2).
Figure 1.
Scheme 1.
Keywords: C–H Insertion; g-Lactam; Gabapentin; Baclofen; GABA.
* Corresponding author. Fax: C86 28 85229250; e-mail: huwh@cioc.ac.cn
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.077

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Z. Chen et al. / Tetrahedron 61 (2005) 1579–1586
Scheme 2. (i) Diketene, THF; p-ABSA, DBU, THF; LiOH, H2O, THF, 75–86% yield. (ii) Rh2(cap)4 (1 mol%), refluxing CH2Cl2, 55–94% yield. (iii) 2: 28%
HCl, reflux, 95% yield; 3: 25% HCl, 90 8C, 95% yield.
2. Results and discussion
namely aromatic cycloaddition, which was suppressed by
using Rh2(cap)4 catalyst.
2.1. Preparation of GABA analogues
2.3. Catalyst efficiency and substrate reactivity
a-Diazoacetatamides (7) were prepared from N-tert-butyl
amine (6) according to the literature procedure.8 Catalyzed
by 1 mol% of Rh2(cap)4, intramolecular C–H insertion of 7
gave corresponding g-lactam (8) in good yield and excellent
regioselectivity. Hydrolysis of g-lactam 8 under refluxing
aqueous HCl afforded the desired b-substituted GABA
products as corresponding hydrochloride salt (Scheme 2). In
this way, tert-butyl protecting group was easily introduced
and removed (Table 1).
The catalytic efficiency of this C–H insertion process was
examined by lowering catalyst loading of dirhodium acetate
(Table 3). For a-diazoacetamide (4), with substrate/catalyst
ratio of 5000, g-lactam (5) was obtained in 89% yield.7e
When the same catalyst loading applied to 7g, g-lactam (8g)
was obtained in 68% yield with 25% starting material
recovered, thus reaction with even lower catalyst loading
was not further examined.
Table 1. Synthesis of a-diazoacetamides (7) and g-lactams (8)a
Table 3. Dirhodium acetate catalyzed C–H insertion of a-diazoacetamides
(4 and 7g) with different catalyst loadinga
Entry
R
Yield of 7 (%)
Yield of 8 (%)
Entry
Substrate/catalyst
Yield of 5 (%)b
Yield of 8g (%)b
1
2
3
4
5
6
7
p-Chlorophenyl
m-Chlorophenyl
p-Nitrophenyl
p-Methoxphenyl
o-Methylphenyl
m-Methylphenyl
Benzyloxy
84
77
77
75
81
81
86
77
65
1
2
3
4
100
500
1000
5000
95
88
89
89
91
55 (61)b
71 (68)b
88
89
78c
68c
74
94
a Reactions were carried out in refluxing CH2Cl2 for 3 h according to the
general experimental procedure.
a Isolated yield after column chromatography purification.
b Isolated yield after column chromatography purification.
c Reactions were carried out in refluxing CH2Cl2 for 12 h according to the
general experimental procedure.
b The yield was reported in literature 7b (catalyzed by Rh2(OAc)4).
2.2. Catalyst effect
2.4. The effect of nitrogen protecting group on
regioselectivity
In the intramolecular C–H insertion of the a-diazoaceta-
mides, the choice of the catalysts was important. Intra-
molecular C–H insertion of a-diazoacetamide (7a) with
Rh2(cap)4 gave g-lactam (8a) in 77% yield, while only 51%
yield was obtained with Rh2(OAc)4. In addition to Rh(II)
catalyst, Cu(OTf)2 was also effective to catalyze the
reaction, however, in lower yield (Table 2). Low yield of
8a compared with 5 and 8g was due to a side reaction,
Other N-protecting groups such as p-methoxyphenyl,9a
p-nitrophenyl,6a and BTMSM (bis(trimethyl-silyl)methyl)9b
have been reported in the intramolecular C–H insertion of
a-diazoacetamides. In order to further demonstrate the
effect of N-protecting group on regioselectivity of the C–H
insertion, N-benzyl protected a-diazoacetamides (9a and
Table 2. Catalyst effect on intramolecular C–H insertion of a-diazoacetamidesa
Entry
Catalyst
Yield of 5 (%)b
Yield of 8a (%)b
Yield of 8g (%)b
1
2
3
Rh2(OAc)4
Rh2(cap)4
Cu(OTf)2
95
96
88
51
77
31
91
93
79
a All the reactions were carried out in refluxing CH2Cl2 for 3 h according to general experimental procedure.
b Isolated yield after column chromatography purification.

Z. Chen et al. / Tetrahedron 61 (2005) 1579–1586
1581
Scheme 3.
9b) were subjected to diazo decomposition in the presence
of 1 mol% of dirhodium acetate. The desired g-lactam (10)
was obtained in only 44% (10a) and 27% (10b) yield,
respectively. The major side reaction was found to be the
intramolecular aromatic cycloaddition reaction, in which
attacking of metal carbene to the benzyl protecting group
occurred producing compound 11 in 54% (11a) and 40%
(11b) yield, respectively (Scheme 3). The side reaction also
occurred with Rh2(cap)4 (Scheme 3). In contrast, there was
no side reaction occurred to the N-tert-butyl protecting
group in a-diazoacetamides (4 and 7).
3. Conclusion
We have described a new approach for the synthesis of
(G)-baclofen and (G)-GABOB from ring opening of
g-lactams, which were obtained in good yield from Rh(II)
(1 mol%) catalyzed intramolecular C–H insertion of tert-
butyl protected a-diazoacetamides. Given the successful
g-lactam formation from other N-tert-butyl a-diazoaceta-
mides reported in the literature,7a,b this approach can be a
general method for the synthesis of b-substituted g-amino
butyric acid.
2.5. Hydrolysis of g-lactams
4. Experimental
TfOH10a and H2SO4
have been successfully used to
10b
4.1. General methods
remove N-tert-butyl group from amides or carbamates.
Unfortunately, by using the similar procedures, we were
unable to obtain either deprotected product of 5 or the
desired product 1. However, aqueous hydrochloric acid was
found to be effective to remove the tert-butyl group in our
previous investigation,7e where the lactam ring was opened
simultaneously to give the corresponding hydrochloride
salt. Applying this protocol to hydrolyze g-lactam 8g, the
debenzylation occurred with the g-lactam ring opening
and further dehydration was a side reaction producing
a,b-unsaturated g-amino butyric acid (12). Fortunately, the
dehydration was found to be temperature dependent (Table
4). At 90 8C (oil bath temperature), (G)-GABOB hydro-
chloride salt was obtained in 95% yield. Compound 3 and
12 can be readily separated by the preparation of the
corresponding N-Boc derivatives (N-Boc-GABOB (13) and
N-Boc-12).
NMR spectra were recorded on a Bruker-300 MHz
spectrometer. HRMS (ESI) mass spectra were recorded on
BRUKER FT-MS. Mass spectra were recorded on a
VG7070E instrument. Infrared spectra were measured on
a Nicolet 200SXV FT-IR spectrometer. Melting points were
determined on a digital melting point apparatus and
uncorrected. Dichloromethane and dimethyl sulfoxide
were distilled over calcium hydride. Tetrahydrofuran was
distilled over sodium. N,N-Dimethylformamide was dried
˚
over 4 A molecular sieves.
4.1.1. N-tert-Butyl-N-cyclohexylmethyl amine. To cyclo-
hexane carboxaldehyde (5 mL, 40.5 mmol) in ethanol
(40 mL) was added tert-butyl amine (6.89 mL,
58.5 mmol) and the solution was stirred at room temperature
for 1 h. To the solution was added, 5% palladium on
Table 4. Temperature effect on hydrolysis of 8g with 25% HCl (without any organic solvent)
Entry
Oil bath temperature (8C)
Time (h)
Yield (%)a
Ratio of 3/12b
1
2
3
120
100
90
11
17
18
89
93
95
90/10
94/6
O95/5
a Combined yield of compound 3 (as the corresponding hydrochloride salt) and 12.
1
b Determined by H NMR.

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Z. Chen et al. / Tetrahedron 61 (2005) 1579–1586
charcoal catalyst (1.4 g) and followed 1 atm hydrogen. The
reaction mixture was stirred at 50 8C for 12 h. After cooling
to room temperature, the catalyst was filtered off and the
solvent was removed under reduced pressure. The resulting
clear oil was purified by silica gel column chromatography
(petroleum ether/ethyl acetate, 5:1 v/v) to afforded N-tert-
butyl-N-cyclohexylmethyl amine as an colorless oil (6.1 g,
88% yield). 1H NMR (300 MHz, CDCl3) d 2.36 (d, 2H, JZ
6.6 Hz), 1.77–1.68 (m, 5H), 1.37–1.16 (m, 5H), 1.08 (s, 9H),
0.90–0.87 (m, 2H); 13C NMR (75 MHz, CDCl3) d 50.9,
50.1, 39.6, 32.5, 29.8, 27.6, 26.9; HRMS (ESI) calcd for
C11H24N [MCH]C: 170.1909, found: 170.1900.
(4!20 mL), dried over sodium sulfate, filtered and
concentrated with a rotary evaporator. The residue was
purified by silica gel column chromatography (petroleum
ether/ethyl acetate, 5:1 v/v) to give N-tert-butyl-N-benzyl-
oxyethyl amine (6g) (2.8 g, 66% yield). Pale yellow oil. 1H
NMR (300 MHz, CDCl3) d 7.31–7.19 (m, 5H), 4.46 (s, 2H),
3.54 (t, 2H, JZ5.4 Hz), 2.71 (t, 2H, JZ5.4 Hz), 1.04 (s,
9H); 13C NMR (75 MHz, CDCl3) d 138.4, 128.4, 127.7,
127.6, 73.1, 70.6, 49.9, 42.2, 28.9; HRMS (ESI) calcd For
C13H22NO [MCH]C: 208.1701, found: 208.1689.
Other N-tert-butyl amines (6b–6f) were prepared in a
similar manner.
4.1.2. N-tert-Butyl-N-p-chlorophenylethyl amine (6a). To
anhydrous N,N-dimethylformamide (15 mL) was added
potassium carbonate (1.6 g, 11.6 mmol). The resulting
white suspension was vigorously stirred for 10 min. tert-
Butyl amine (2.5 mL, 23.6 mmol), p-chlorophenylethyl
bromide (2.3 g, 10.5 mmol) and potassium iodide (0.1 g,
0.6 mmol) were added to the white suspension in sequence.
The reaction mixture was stirred at 60 8C for 24 h. After
cooling to room temperature, water (20 mL) and ethyl
acetate (30 mL) were added. The aqueous layer was
extracted with ethyl acetate (2!30 mL). The combined
organic layer was washed with saturated sodium chloride
(4!20 mL), dried over sodium sulfate. Solvent was
removed under reduced pressure to give a yellow oil. Silica
gel column chromatography purification (petroleum ether/
ethyl acetate, 2:1 v/v) yield a pale yellow oil (1.1 g, 47%
4.1.4. N-tert-Butyl-N-m-chlorophenylethyl amine (6b).
1
Yield 31.5%. Yellow oil. H NMR (300 MHz, CDCl3) d
7.24–7.08 (m, 4H), 2.84–2.71 (m, 4H), 1.08 (s, 9H); 13C
NMR (75 MHz, CDCl3) d 142.2, 134.0, 129.5, 128.6, 126.7,
126.2, 50.2, 43.7, 36.8, 28.9; HRMS (ESI) calcd for
C12H19NCl [MCH]C: 212.1206, found: 212.1201.
4.1.5. N-tert-Butyl-N-p-nitrophenylethyl amine (6c).
Yield: 55.7%. Yellow oil. H NMR (300 MHz, CDCl3) d
1
8.15 (dt, 2H, JZ9.2, 2.2 Hz), 7.37 (dt, 2H, JZ9.2, 2.2 Hz),
2.86 (s, 4H), 1.07 (s, 9H); 13C NMR (75 MHz, CDCl3) d
148.3, 146.6, 129.5, 123.6, 50.4, 43.5, 37.2, 28.9.
4.1.6. N-tert-Butyl-N-p-methoxyphenylethyl amine (6d).
Yield 49.5%. Yellow oil. H NMR (300 MHz, CDCl3) d
1
1
7.15–7.11 (m, 2H), 6.86–6.81 (m, 2H), 3.78 (s, 3H), 2.82–
2.77 (m, 2H), 2.73–2.68 (m, 2H), 1.06 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 157.9, 132.2, 129.5, 113.8, 55.2, 50.2,
44.2, 36.3, 28.9.
yield). H NMR (300 MHz, CDCl3) d 7.20 (d, 2H, JZ
8.3 Hz), 7.09 (d, 2H, JZ8.3 Hz), 2.78–2.66 (m, 4H), 1.02 (s,
9H); 13C NMR (75 MHz, CDCl3) d 138.5, 131.6, 129.5,
128.3, 50.1, 43.7, 36.4, 28.8; HRMS (ESI) calcd for
C12H19NCl [MCH]C: 212.1206, found: 212.1201.
4.1.7. N-tert-Butyl-N-o-methylphenylethyl amine (6e).
Yield 49.8%. Yellow oil. H NMR (300 MHz, CDCl3) d
7.19–7.11 (m, 4H), 2.78 (s, 4H), 2.33 (s, 3H), 1.1 (s, 9H);
13C NMR (75 MHz, CDCl3) d 138.4, 136.2, 130.2, 129.0,
126.2, 125.9, 50.3, 42.9, 34.9, 29.0, 19.4.
1
4.1.3. N-tert-Butyl-N-Benzyloxyethyl amine (6g). An
oven dried, 150 mL, one-necked round-bottom flask
equipped with a magnetic stirring bar was flashed with
argon. Dichloromethane (50 mL) was added. The flask inlet
was sealed with a rubber septum and cooled to 0 8C in an
ice bath. To this flask was added triethylamine (3.5 mL,
25 mmol), benzyloxyethyl alcohol (3.1 g, 20.4 mmol) and
methanesulfonyl chloride (2 mL, 25.8 mmol). The resulting
solution was stirred at room temperature for 2 h and then
quenched by adding 20 mL ice water. The organic layer was
separated and washed successively with saturated aqueous
sodium bicarbonate (20 mL) and brine (2!20 mL). The
organic layer was dried over magnesium sulfate, filtered and
concentrated with a rotary evaporator to give crude
benzyloxyethyl methanesulfonate. The crude methane-
sulfonate was directly used in the next step without further
purification. To another oven dried, 100 mL, one necked
round-bottom flask containing a magnetic stirring bar and a
rubber septum inlet was flashed with argon and charged with
potassium iodide (200 mg). The crude methanesulfonate
in dimethyl sulfoxide (20 mL) was added to the flask and
followed by addition of tert-butyl amine (6 mL,
56.8 mmol). The resulting solution was stirred at 50 8C
for 8 h and then allowed to cool to room temperature. The
reaction solution was poured into a separatory funnel
containing 30 mL of 1% aqueous sodium hydroxide. The
resulting mixture was extracted with ethyl acetate (2!
30 mL). The combined organic layer are washed with brine
4.1.8. N-tert-Butyl-N-m-methylphenylethyl amine (6f).
Yield 45.1%. Yellow oil. H NMR (300 MHz, CDCl3) d
1
7.22–7.16 (m, 1H), 7.04–7.01 (m, 3H), 2.86–2.80 (m, 2H),
2.77–2.72 (m, 2H), 2.34 (s, 3H), 1.09 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 140.3, 138.1, 129.6, 128.4, 126.9,
125.8, 50.4, 44.3, 37.3, 29.1, 21.5.
4.1.9. N-Benzyl-N-cyclohexylmethyl amine. Yield 42%.
Pale yellow oil. H NMR (300 MHz, CDCl3) d 7.32–7.19
1
(m, 5H), 3.77 (s, 2H), 2.46 (d, 2H, JZ6.6 Hz), 1.77–1.68
(m, 5H), 1.47–1.19 (m, 5H), 0.91–0.88 (m, 2H); 13C NMR
(75 MHz, CDCl3) d 140.7, 128.3, 128.0, 126.7, 56.2, 54.2,
38.0, 31.4, 26.7, 26.0.
4.1.10. N-Benzyl-N-benzyloxyethyl amine. Yield 24%.
Pale yellow oil. H NMR (300 MHz, CDCl3) d 7.37–7.22
1
(m, 10H), 4.52 (s, 2H), 3.80 (s, 2H), 3.62 (t, 2H, JZ5.2 Hz),
2.84 (t, 2H, JZ5.2 Hz); 13C NMR (75 MHz, CDCl3) d
140.3, 138.3, 128.4, 128.3, 128.1, 127.7, 127.6, 126.9, 73.2,
69.7, 53.9, 48.8.
4.1.11. N-tert-Butyl-N-cyclohexylmethyl a-diazoaceta-
mide (4). To N-tert-butyl-N-cyclohexylmethyl amine

Z. Chen et al. / Tetrahedron 61 (2005) 1579–1586
1583
(4.3 g, 25 mmol) in tetrahydrofuran (30 mL) was added
diketene (2 mL, 25 mmol). The mixture was stirred at 0 8C
for 0.5 h, then allowed to warm to room temperature and
stirred overnight. To the resulting brown reaction mixture
was added 4-acetamidobenzene sulfonyl azide (7.3 g,
29 mmol), followed by adding of 1,8-diazabicyclo[5,4,0]
undec-7-ene (4.4 mL, 29 mmol). The resulting solution was
stirred at room temperature for 8 h. A solution of lithium
hydroxide (LiOH$H2O, 4 g, 95 mmol) in water (50 mL) was
added and the resulting orange-brown mixture was stirred
vigorously for 8 h. The reaction mixture was diluted with
ethyl acetate (60 mL) and the organic layer was washed with
water (2!30 mL), dried over MgSO4. Solvent was removed
under reduced pressure to yield a red-brown mixture. Silica
gel column chromatography (petroleum ether/ethyl acetate,
5:1 v/v) yield a yellow solid (4.6 g, 77% overall yield from
N-tert-butyl-N-cyclohexylmethyl amine), mp: 73.6–
mp: 70.5–71.5 8C. 1H NMR (300 MHz, CDCl3) d 7.10–7.06
(m, 2H), 6.88–6.84 (m, 2H), 4.96 (s, 1H), 3.79 (s, 3H), 3.29–
3.23 (m, 2H), 2.80–2.75 (m, 2H), 1.51 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 166.4, 158.4, 130.3, 129.4, 114.2, 57.8,
55.3, 48.6, 47.2, 37.1, 29.3; FT-IR (KBr, cmK1): 2113
(C]N2).
4.1.16. N-tert-Butyl-N-o-methylphenylethyl a-diazo-
acetamide (7e). Yield: 81.1% overall yield from N-tert-
butyl-N-o-methylphenylethyl amine (6e), yellow solid, mp:
72.2–73.2 8C. 1H NMR (300 MHz, CDCl3) d 7.18–7.11 (m,
4H), 5.01 (s, 1H), 3.32–3.26 (m, 2H), 2.88–2.83 (m, 2H),
2.37 (s, 3H), 1.53 (s, 9H); 13C NMR (75 MHz, CDCl3) d
166.4, 136.8, 135.8, 130.6, 129.0, 126.9, 126.4, 57.9, 48.6,
45.7, 35.3, 29.4, 19.7; HRMS (ESI) calcd for C15H22N3O
[MCH]C: 260.1764, found: 260.1763.
1
74.7 8C. H NMR (300 MHz, CDCl3) d 4.98 (s, 1H), 2.93
4.1.17. N-tert-Butyl-N-m-methylphenylethyl a-diazo-
acetamide (7f). Yield: 80.7% overall yield from N-tert-
butyl-N-m-methylphenylethyl amine (6f). Yellow viscous
oil. 1H NMR (300 MHz, CDCl3) d 7.26–7.19 (m, 1H), 7.08–
7.05 (m, 1H), 6.98–6.96 (m, 2H), 4.99 (s, 1H), 3.32–3.26
(m, 2H), 2.83–2.77 (m, 2H), 2.35 (s, 3H), 1.52 (s, 9H); 13C
NMR (75 MHz, CDCl3) d 166.3, 138.5, 138.2, 129.1, 128.7,
127.5, 125.3, 57.8, 48.6, 46.9, 37.9, 29.3, 21.3; HRMS (ESI)
calcd for C15H22N3O [MCH]C: 260.1763, found:
260.1763.
(d, 2H, JZ7.2 Hz), 1.78–1.75 (m, 5H), 1.37–1.34 (m, 1H),
1.47 (s, 9H), 1.25–1.16 (m, 3H), 0.89–0.86 (m, 2H); 13C
NMR (75 MHz, CDCl3) d 166.5, 57.5, 51.2, 48.9, 39.7,
30.8, 29.0, 26.1, 25.9; FT-IR (KBr, cmK1): 2113 (C]O);
HRMS (ESI) calcd for C13H24N3O [MCH]C: 238.1919,
found: 238.1918.
Other a-diazoacetamides (7a–7b) and (9a–9b) were
prepared in a similar manner.
4.1.12. N-tert-Butyl-N-p-chlorophenylethyl a-diazo-
acetamide (7a). Yield: 84% overall yield from N-tert-
butyl-N-p-chlorophenylethyl amine (6a), yellow solid, mp:
4.1.18. N-tert-Butyl-N-benzyloxyethyl a-diazoacetamide
(7g). Yield: 78% overall yield from N-tert-butyl-N-benzyl-
oxyethyl amine (6g). Yellow viscous oil. 1H NMR
(300 MHz, CDCl3) d 7.31–7.19 (m, 5H), 5.11 (s, 1H),
4.45 (s, 2H), 3.44 (t, 2H, JZ6.3 Hz), 3.26 (t, 2H, JZ
6.3 Hz), 1.35 (s, 9H); 13C NMR (75 MHz, CDCl3) d 167.2,
137.6, 128.4, 127.8, 127.5, 73.3, 70.2, 57.6, 48.4, 44.7, 29.1;
FT-IR (KBr, cmK1): 2102 (C]N2); HRMS (ESI) calcd for
C15H22N3O [MCH]C: 276.1712, found: 276.1711.
1
113.5–114.5 8C. H NMR (300 MHz, CDCl3) d 7.32–7.28
(m, 2H), 7.13–7.11 (m, 2H), 4.95 (s, 1H), 3.31 (t, 2H, JZ
7.4 Hz), 2.83 (t, 2H, JZ7.4 Hz), 1.53 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 173.8, 141.2, 132.7, 128.9, 128.0, 54.2,
52.9, 40.5, 36.4, 27.7; FT-IR (KBr, cmK1): 2100 (C]N2);
HRMS (ESI) calcd for C14H19N3ClO [MCH]C: 280.1217,
found: 280.1218.
4.1.19. N-Benzyl-N-cyclohexylmethyl a-diazoacetamide
(9a). Yield: 75% overall yield from N-benzyl-N-cyclo-
hexylmethyl amine. Yellow viscous oil. 1H NMR
(300 MHz, CDCl3) d 7.36–7.19 (m, 5H), 4.94 (s, 1H),
4.45 (wide, 2H), 3.24–2.9 (wide, 2H), 1.71–1.67 (m, 6H),
1.28–1.16 (m, 3H), 0.93–0.85 (m, 2H); 13C NMR (75 MHz,
CDCl3) d 166.3, 128.7, 127.4, 53.3, 50.4, 46.9, 37.1, 31.0,
26.3, 25.8; FT-IR (cmK1): 2105 (C]N2); HRMS (ESI)
calcd for C16H22N3O [MCH]C: 272.1763, found:
272.1761.
4.1.13. N-tert-Butyl-N-m-chlorophenylethyl a-diazo-
acetamide (7b). Yield: 76.8% overall yield from N-tert-
butyl-N-m-chlorophenylethyl amine (6b), yellow solid, mp:
92.2–93.2 8C. 1H NMR (300 MHz, CDCl3) d 7.29–7.04 (m,
4H), 4.97 (s, 1H), 3.33–3.27 (m, 2H), 2.84–2.79 (m, 2H),
1.53 (s, 9H); 13C NMR (75 MHz, CDCl3) d 166.3, 140.2,
134.6, 130.1, 128.5, 127.0, 126.6, 57.9, 48.7, 46.6, 37.6,
29.4; FT-IR (KBr, cmK1): 2099 (C]N2); HRMS (ESI)
calcd for C14H19N3ClO [MCH]C: 280.1217, found:
280.1218.
4.1.20. N-Benzyl-N-bezyloxyethyl a-diazoacetamide
(9b). Yield: 78% overall yield from N-benzyl-N-benzyl-
oxyethyl amine. Yellow viscous oil. H NMR (300 MHz,
CDCl3) d 7.38–7.19 (m, 10H), 5.10 (wide, 1H), 4.57 (s, 2H),
4.47 (s, 2H), 3.47–3.32 (wide, 4H); 13C NMR (75 MHz,
CDCl3) d 166.6, 137.9, 137.3, 128.7, 128.4, 127.9, 127.7,
127.6, 127.4, 73.3, 67.5, 49.6, 47.1, 46.9; FT-IR (cmK1):
2105 (C]N2); HRMS (ESI) calcd for C18H20N3O2 [MC
H]C: 310.1556, found: 310.1543.
4.1.14. N-tert-Butyl-N-p-nitrophenylethyl a-diazoaceta-
mide (7c). Yield: 77.3% overall yield from N-tert-butyl-N-
p-nitrophenylethyl amine (6c), yellow solid, mp: 148.3–
1
1
149.3 8C. H NMR (300 MHz, CDCl3) d 8.20 (dt, 2H, JZ
9.2, 2.2 Hz), 7.35 (dt, 2H, JZ9.2, 2.2 Hz), 4.97 (s, 1H),
3.39–3.33 (m, 2H), 2.99–2.93 (m, 2H), 1.52 (s, 9H); 13C
NMR (75 MHz, CDCl3) d 166.2, 146.9, 145.9, 129.3, 124.1,
57.8, 48.9, 46.2, 37.7, 29.5; FT-IR (KBr, cmK1): 2106
(C]N2).
4.2. General procedure for a-diazoacetamide
decomposition
4.1.15. N-tert-Butyl-N-p-methoxyphenylethyl a-diazo-
acetamide (7d). Yield: 74.6% overall yield from N-tert-
butyl-N-p-methoxyphenylethyl amine (6e), yellow solid,
To a solution of Rh2(cap)4 (1 mol%) in the CH2Cl2 (5 mL)

1584
Z. Chen et al. / Tetrahedron 61 (2005) 1579–1586
at reflux was added the a-diazoacetamide (1.0 mmol) in the
CH2Cl2 (5 mL) via a syringe pump over 2 h period. After
the addition was complete, the reaction solution was stirred
for an additional 30 min, then the solvent was removed
under reduced pressure. Silica gel column chromatography
purification (petroleum ether/ethyl acetate, 3:1 v/v) yielded
the g-lactam as a pale yellow (or colorless) oil.
4.2.7. N-tert-Butyl-b-m-methylphenyl-g-lactam (8f).
Yield 74%. Colorless oil. H NMR (300 MHz, CDCl3) d
1
7.25–7.19 (m, 1H), 7.07–6.96 (m, 3H), 3.83–3.79 (m, 1H),
3.44–3.37 (m, 2H), 2.73 (dd, 1H, JZ15.8, 8.8 Hz), 2.58–
2.34 (m, 1H), 2.34 (s, 3H), 1.43 (s, 9H); 13C NMR (75 MHz,
CDCl3) d 174.2, 142.5, 138.4, 128.7, 127.7, 127.5, 123.7,
54.1, 53.1, 40.6, 36.9, 27.7, 21.4; HRMS (ESI) calcd for
C15H22NO [MCH]C: 232.1701, found: 232.1693.
4.2.1. N-tert-Butyl-b-cyclohexyl-g-lactam (5). Yield 96%.
Pale yellow oil. 1H NMR (300 MHz, CDCl3) d 3.17 (s, 2H),
2.20 (s, 2H), 1.46–1.36 (m, 19H); 13C NMR (CDCl3,
75 MHz) d 175.1, 68.7, 58.3, 54.4, 37.4, 35.9, 28.5, 26.5,
26.4, 23.6; FT-IR (cmK1): 1686 (C]O); HRMS (ESI) calcd
for C13H24NO [MCH]C: 210.1858, found: 210.1854.
4.2.8. N-tert-Butyl-b-benzyloxy-g-lactam (8g). Yield
93%. Pale yellow oil. 1H NMR (300 MHz, CDCl3) d
7.31–7.19 (m, 5H), 4.48 (d, 1H, JZ11.8 Hz), 4.38 (d, 1H,
JZ11.8 Hz), 4.06–4.04 (m, 1H), 3.59 (dd, 1H, JZ10.6,
6.4 Hz), 3.40 (dd, 1H, JZ10.6, 3.3 Hz), 2.53 (dd, 1H, JZ
17.1, 6.9 Hz), 2.42 (dd, 1H, JZ17.1, 4.0 Hz), 1.32 (s, 9H);
13C NMR (75 MHz, CDCl3) d 172.6, 137.6, 128.5, 127.9,
127.7, 70.8, 70.4, 53.9, 52.1, 39.8, 27.7; HRMS (ESI) calcd
for C15H22NO2 [MCH]C: 248.1651, found: 248.1647.
4.2.2. N-tert-Butyl-b-p-chlorophenyl-g-lactam (8a).
Yield 77%. Pale yellow oil. H NMR (300 MHz, CDCl3)
1
d 7.29 (d, 2H, JZ8.4 Hz), 7.18 (d, 2H, JZ8.4 Hz), 3.84 (t,
1H, JZ8.7 Hz), 3.43–3.34 (m, 2H), 2.76 (dd, 1H, JZ16.5,
8.7 Hz), 2.49 (dd, 1H, JZ16.8, 8.4 Hz), 1.43 (s, 9H); 13C
NMR (75 MHz, CDCl3) d 173.8, 141.2, 132.7, 128.9, 128.0,
54.2, 52.9, 40.5, 36.4, 27.7; FT-IR (cmK1): 1685 (C]O);
HRMS (ESI) calcd for C14H19NClO [MCH]C: 252.1155,
found: 252.1157.
4.2.9. N-Benzyl-b-cyclohexyl-g-lactam (10a). Yield 50%.
Pale yellow oil. H NMR (300 MHz, CDCl3) d 7.36–7.21
1
(m, 5H), 4.43 (s, 2H), 2.99 (s, 2H), 2.31 (s, 2H), 1.47–1.42
(m, 10H); 13C NMR (75 MHz, CDCl3) d 174.0, 136.6,
128.6, 128.0, 127.5, 58.1, 46.4, 44.0, 36.9, 36.1, 25.5, 22.8;
HRMS (ESI) calcd for C16H22NO [MCH]C: 244.1701,
found: 244.1696.
4.2.3. N-tert-Butyl-b-m-chlorophenyl-g-lactam (8b).
Yield 65.4%. Pale yellow oil. 1H NMR (300 MHz,
CDCl3) d 7.27–7.21 (m, 3H), 7.13–7.10 (m, 1H), 3.84–
3.82 (m, 1H), 3.45–3.36 (m, 2H), 2.75 (dd, 1H, JZ16.6,
8.9 Hz), 2.50 (dd, 1H, JZ16.6, 8.9 Hz), 1.43 (s, 9H); 13C
NMR (75 MHz, CDCl3) d 173.7, 144.7, 134.6, 130.1, 127.1,
126.9, 124.8, 54.2, 52.7, 40.4, 36.7, 27.7; FT-IR (cmK1):
1683 (C]O); HRMS (ESI) calcd for C14H19NClO
[MCH]C: 252.1155, found: 252.1157.
4.2.10. N-Benzyl-b-benzyloxy-g-lactam (10b). Yield
25%. Pale yellow oil. 1H NMR (300 MHz, CDCl3) d
7.34–7.25 (m, 10H), 4.52–4.42 (m, 4H), 4.23–4.20 (m, 1H),
3.47 (dd, 1H, JZ10.7, 6.1 Hz), 3.32 (dd, 1H, JZ10.7,
2.9 Hz), 2.75–2.58 (m, 2H); 13C NMR (75 MHz, CDCl3) d
172.4, 137.4, 136.1, 128.7, 128.5, 128.2, 128.0, 127.9,
127.7, 127.6, 70.9, 70.8, 52.7, 46.2, 38.2; HRMS (ESI) calcd
for C18H20NO2 [MCH]C: 282.1494, found: 282.1486.
4.2.4. N-tert-Butyl-b-p-nitrophenyl-g-lactam (8c). Yield
55.4%. Yellow solid, mp: 67.3–68.1 8C. 1H NMR
(300 MHz, CDCl3) d 8.21 (dt, 2H, JZ9.2, 2.2 Hz), 7.40
(dt, 2H, JZ9.2, 2.2 Hz), 3.91 (dd, 1H, JZ9.6, 7.9 Hz),
3.62–3.52 (m, 1H), 3.42 (dd, 1H, JZ9.6, 6.6 Hz), 2.83
(dd, 1H, JZ16.7, 8.9 Hz), 2.52 (dd, 1H, JZ16.7, 7.8 Hz),
1.43 (s, 9H); 13C NMR (75 MHz, CDCl3) d 173.3, 150.3,
146.9, 127.6, 124.1, 54.4, 52.5, 40.3, 36.8, 27.7; FT-IR
(KBr, cmK1): 1684 (C]O).
4.2.11. N-Cyclohexylmethyl-2-aza-bicyclo[5,3,0]-decane-
4,6,8-triene-1-one (11a). Yield 48% (white solid, easily
decomposed in air). H NMR (300 MHz, CDCl3) d 6.50–
1
6.44 (m, 2H), 6.20–6.14 (m, 2H), 5.29 (dd, 1H, JZ9.8,
3.9 Hz), 4.19 (s, 2H), 3.23 (d, 2H, JZ7.4 Hz), 3.09 (s, 1H),
1.76–1.61 (m, 6H), 1.25–1.17 (m, 3H), 1.05–0.97 (m, 2H);
13C NMR (75 MHz, CDCl3) d 174.3, 130.3, 129.8, 129.5,
126.8, 120.9, 119.3, 51.7, 48.8, 46.4, 35.8, 30.7, 30.6, 26.3,
25.7; FT-IR (KBr, cmK1): 3023, 2931, 2915, 2848, 1680,
1649, 1637, 1479, 1463, 1446, 1438, 1422, 1365, 1318,
1273, 1231, 940, 884, 817, 791, 719, 684.
4.2.5. N-tert-Butyl-b-p-methoxyphenyl-g-lactam (8d).
Yield 71%. Colorless oil. H NMR (300 MHz, CDCl3) d
1
7.18–7.13 (m, 2H), 6.89–6.83 (m, 2H), 3.79 (s, 3H), 3.38–
3.35 (m, 2H), 2.73 (dd, 1H, JZ16.5, 8.8 Hz), 2.50 (dd, 1H,
JZ16.6, 8.5 Hz), 1.42 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 174.2, 158.4, 134.5, 129.6, 127.6, 114.1, 55.2, 53.9, 53.3,
40.9, 36.3, 27.7; FT-IR (KBr, cmK1): 1685 (C]O).
4.2.12. N-Benzyloxyethyl-2-aza-bicyclo[5,3,0]-decane-
4,6,8-triene-1-one (11b). Yield 39% (white solid, easily
decomposed in air). H NMR (300 MHz, CDCl3) d 7.34–
1
4.2.6. N-tert-Butyl-b-o-methylphenyl-g-lactam (8e).
Yield 87.9%. Colorless oil. H NMR (300 MHz, CDCl3) d
1
7.26 (m, 5H), 6.50–6.46 (m, 2H), 6.15–6.12 (m, 2H), 5.26
(dd, 1H, JZ9.5, 3.8 Hz), 4.51 (s, 2H), 4.33 (s, 2H), 3.68–
3.59 (m, 4H), 3.07 (s, 1H); 13C NMR (75 MHz, CDCl3) d
174.1, 137.8, 130.1, 129.8, 129.7, 128.6, 128.3, 128.1,
127.8, 127.6, 127.5, 126.8, 120.5, 119.1, 72.9, 68.3, 52.5,
46.1, 42.5; FT-IR (KBr, cmK1): 3024, 2918, 2861, 1690,
1479, 1434, 1450, 1356, 1315, 1278, 1208, 1104, 1026, 738,
704.
7.27–7.14 (m, 4H), 3.83 (dd, 1H, JZ9.5, 7.9 Hz), 3.66–3.63
(m, 1H), 3.41 (dd, 1H, JZ9.5, 6.2 Hz), 2.76 (dd, 1H, JZ
16.7, 9.0 Hz), 2.50 (dd, 1H, JZ16.7, 7.6 Hz), 2.34 (s, 3H),
1.43 (s, 9H); 13C NMR (75 MHz, CDCl3) d 174.2, 140.8,
135.6, 130.5, 126.7, 126.5, 125.0, 54.1, 52.3, 40.2, 32.6,
27.7, 19.7; FT-IR (cmK1): 1682 (C]O); HRMS (ESI) calcd
for C15H22NO [MCH]C: 232.1701, found: 232.1693.

Z. Chen et al. / Tetrahedron 61 (2005) 1579–1586
1585
4.3. General procedure for hydrolysis of g-lactam
(5, 8a, 8g)
Acknowledgements
We acknowledge the financial support from the Chinese
Academy of Sciences and the National Science Foundation
of China (Grant No. 20202011).
A mixture of g-lactam (0.85 mmol) in 25–28% HCl aqueous
(6 mL) was heated at 90–120 8C for 18 h. After cooled to
room temperature, the solution was extracted with diethyl
ether (3!20 mL). The water was removed under reduced
pressure to give the desired products (as the corresponding
hydrochloride salt).
References and notes
4.3.1. Gabapentin hydrochloride (1). Yield 84% (white
solid). H NMR (300 MHz, D2O) d 3.00 (s, 2H), 2.43 (s,
1. (a) Yuen, P. W.; Kanter, G. D.; Taylor, C. P.; Vertanian, M. G.
Bioorg. Med. Chem. Lett. 1994, 4, 823–826. (b) Silverman,
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Vartanian, M. G. J. Med. Chem. 1991, 34, 2295–2298.
1
2H), 1.40–1.30 (m, 10H); 13C NMR (75 MHz, D2O) d
176.9, 47.5, 40.7, 35.5, 33.6, 25.9, 21.4.
´
(c) Moglioni, A. G.; Brousse, B. N.; Alvarez-Larena, A.;
Moltrasio, G. Y.; Ortun˜o, R. M. Tetrahedron: Asymmetry
2002, 13, 451–454. (d) Bryans, J. S.; Davies, N.; Gee, N. S.;
Dissanayake, V. U. K.; Ratcliffe, G. S. J. Med. Chem. 1998,
41, 1838–1845.
4.3.2. (G)-Baclofen hydrochloride (2). Yield 95% (white
solid). 1H NMR (300 MHz, D2O) d 7.45 (d, 2H, JZ8.4 Hz),
7.35 (d, 2H, JZ8.5 Hz), 3.49–3.25 (m, 3H), 2.86 (dd, 1H,
JZ16.1, 5.9 Hz), 2.74 (dd, 1H, JZ16.1, 8.6 Hz); 13C NMR
(75 MHz, D2O) d 177.8, 139.7, 136.0, 132.1, 131.9, 46.3,
42.0, 40.8.
2. (a) Satzinger, G.; Hartenstein, J.; Herrmann, M.; Heldt, W.
U.S. Pat. Appl. US 4,024,175, 1977. (b) Geibel, W.;
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4.3.3. (G)-GABOB hydrochloride (3). Yield 95% (white
solid). 1H NMR (300 MHz, D2O) d 4.35–4.26 (m, 1H), 3.22
(dd, 1H, JZ10.8, 2.3 Hz), 3.05–2.98 (m, 1H), 2.71 (dd, 1H,
JZ16.1, 4.6 Hz), 2.59 (dd, 1H, JZ16.1, 8.2 Hz); 13C NMR
(75 MHz, D2O) d 174.3, 64.0, 43.5, 38.9.
4.3.4. (G)-N-Boc-GABOB (13) and N-Boc-a,b-unsatu-
rated g-amino butyric acid (N-Boc-12). A mixture of
g-lactam 8g (1.7 g, 6.8 mmol) in 25% aqueous HCl (24 mL)
was heated in an oil bath (120 8C) for 18 h. After cooling to
room temperature, the solution was extracted with diethyl
ether (3!20 mL). The water was removed under reduced
pressure. The residue was dissolved in water (30 mL). To
the solution, potassium carbonate (1.5 g, 108.5 mmol) and
di-tert-butyl dicarbonate (1.5 g, 6.8 mmol) were added in
sequence. The resulting mixture was stirred at room
temperature for 12 h. After being acided by saturated
sodium sulfate solution to pH 3–4 in ice-bath, the mixture
was extracted with diethyl ether (3!20 mL). The combined
organic layer was dried over sodium sulfate, filtered and
concentrated with a rotary evaporator. The residue was
purified by silica gel column chromatography (petrol ether/
ethyl acetate, 3:1 v/v) to give (G)-N-Boc-GABOB and
N-Boc-a,b-unsaturated g-amino butyric acid.
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Tetrehedron: Asymmetry 2003, 14, 581–586. (m) Wee,
A. G. H.; Shi, Q.; Wang, Z.; Hatton, K. Tetrehedron:
Asymmetry 2003, 14, 897–909. (n) Licandro, E.; Maiorana,
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mp: 97.5–98.5 8C. H NMR (300 MHz, CDCl3) d 5.29 (s,
1H), 4.16–4.09 (m, 1H), 3.44–3.23 (m, 1H), 3.20–3.11 (m,
1H), 2.54–2.46 (m, 2H), 1.45 (s, 9H); 13C NMR (75 MHz,
CDCl3) d 175.6, 157.1, 80.2, 67.8, 45.5, 38.4, 28.3; MS (EI):
219 [MC].
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1
N-Boc-a,b-unsaturated g-amino butyric acid (N-Boc-12).
75 mg, 5% yield, white solid, mp: 132.5–133.5 8C.
1H NMR (300 MHz, CDCl3) d 7.05–6.97 (m, 1H), 5.98–
5.92 (m, 1H), 4.73 (s, 1H), 3.95 (s, 2H), 1.45 (s, 9H); 13C
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41.4, 28.2.
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