Synthesis of functionalized nitrogen heterocycles from β- And γ-amino acids by radical decarboxylation

Article abstract of DOI:10.1016/j.tetlet.2004.07.111

The radical decarboxylation of β- and γ-amino acids on treatment with PhI(OAc)₂a-I₂ is a mild and efficient methodology to synthesize halogenated or oxygenated nitrogen heterocycles. The reaction was applied to the synthesis of bioactive products, such as opioid analogues, iminosugars and new antifungic agents.

Full text of DOI:10.1016/j.tetlet.2004.07.111

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6841–6845
Synthesis of functionalized nitrogen heterocycles from b- and
c-amino acids by radical decarboxylation
a,
a
b
Alicia Boto,a, Rosendo Hernandez, Yolanda de Leon, Jose R. Murguıa and
*
*
´
Abigail Rodrıguez-Afonso
´
´
´
b
´
a
´
´
´
Instituto de Productos Naturales y Agrobiologıa del C.S.I.C., Avda. Astrofısico Fco. Sanchez 3, 38206 La Laguna, Tenerife, Spain
b
´
Unidad de Investigacion, Hospital Universitario de Canarias, Ofra s/n, 38320 La Laguna, Tenerife, Spain
Received 22 June 2004; revised 19 July 2004; accepted 24 July 2004
Abstract—The radical decarboxylation of b- and c-amino acids on treatment with PhI(OAc)2–I2 is a mild and efficient methodology
to synthesize halogenated or oxygenated nitrogen heterocycles. The reaction was applied to the synthesis of bioactive products, such
as opioid analogues, iminosugars and new antifungic agents.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The presence of functionalized piperidine and pyrrol-
idine rings in the structure of many natural products1
and synthetic drugs2 has elicited a growing interest in
these nitrogen heterocycles.
Cl
HO
Among the compounds containing them (Fig. 1), there
are simple structures such as that of coniine 1,1a the
active principle in the hemlock poison, or the potent
antipsychotic haloperidol 2,2a to complex alkaloids from
the Amarillydaceae family.1j Furthermore, these hetero-
cycles are also of interest in synthetic organic chemistry
as ligands and chiral auxiliaries, such as compound 3.3
As a result, many synthetic methodologies to obtain
these heterocycles have been developed.4
N
N
PPh2
N
H
H
O
(CH2)3
Ph-pF
( )-2
(+)- or (-)-3
( )-1
Figure 1. Piperidine and pyrrolidine rings in natural products,
synthetic drugs and ligands.
We report now on a mild, efficient preparation of func-
tionalized nitrogen heterocycles from b- and c-amino
acids, using a radical decarboxylation as the key step.5
The starting amino acids are readily prepared from com-
mercial products. For instance, the b-amino acid 4
(Scheme 1) was prepared in two steps from dimethyl
itaconate,6a in excellent yields. The models 5 and 6 were
synthesized by acylation of commercial pyrrolidine or
piperidine derivatives,6b,c and compound 7 was obtained
in three steps from isonipecotic acid.6d
The aryl acid 8 was formed from commercial 4-cyano 4-
phenylpiperidineÆHCl.6e,f Many other a-aryl acids can
be synthesized by palladium-catalyzed arylation of ester
enolates, followed by saponification.7 They can also be
synthesized in two steps from commercial aryl acetic
esters and nitrogen mustards.8
When the b- or c-amino acids 4–8 were treated with
(diacetoxyiodo)benzene (DIB) and iodine, a radical
decarboxylation took place and the iodinated or oxy-
genated products 9–13 were obtained (Scheme 1).9
Keywords: Radicals; Piperidines; Arylpiperidines; Pyrrolidines; Decar-
boxylation; Amino acids; Antifungic.
*
The decarboxylation of substrate 4 afforded the iodo
derivative 9 in good yield. Remarkably, due to the mild
Corresponding authors. Tel.: +34 922 260112; fax: 34 922 260135;
e-mail addresses: alicia@ipna.csic.es; rhernandez@ipna.csic.es
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.111

6842
A. Boto et al. / Tetrahedron Letters 45 (2004) 6841–6845
logues. These oxygenated derivatives are usually synthe-
I
COOH
Ph
sized by addition of Grignard reagents to ketones,11c,f,g
conditions not compatible with aryl substituents such
as Br, I, O-acyl, etc. Our methodology could offer an
alternative route towards new members of this class of
compounds.
i
O
O
N
N
Ph
( )-4
(81%)
( )-9
Following our current interest in biologically active
products, we decided to apply the decarboxylation reac-
tion to the synthesis of iminosugars. Many iminosugars
are potent glycosidase inhibitors, and possess antiviral,
antitumoural and hypoglucaemic activities.12 In order
to modulate their activity or improve their bioavailabil-
ity, the development of new derivatives is of great
interest.
I
H
COOH
H
i
( )n
( )n
N
Z
N
Z
(66%)
(72%)
( )-10 n = 0, Z = BOC
( )-11 n = 1, Z = CO2Me
( )-5 n = 0, Z = BOC
( )-6 n = 1, Z = CO2Me
The decarboxylation product 11 can be transformed
into different iminosugars in a few steps.13 For example,
by treatment of 11 with DBU the alkene 14 (Scheme 2)
was obtained in good yields. The product 14 underwent
dihydroxylation affording the iminosugar ( )-15 in satis-
factory yields.
I
MeOOC
COOH
MeOOC
i
N
N
CO2Me
CO2Me
The decarboxylation of c-amino acids was also applied
to the development of new antifungic agents. Thus, the
decarboxylation–elimination product 14 (Scheme 3)
was epoxidated and then treated with piperidine, afford-
ing the alcohols ( )-[16a and 16b].14,15a Similarly, by
epoxidation and treatment with 6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline, the alcohols ( )-[17a and 17b]
were isolated as a mixture; however, their benzoate es-
ters ( )-[18a and 18b] were easily separated.14,15b
( )-7
(41%)
( )-12
OAc
COOH
i
N
N
CO2
-tBu
CO2-tBu
Products ( )-[18a and 18b] showed potent activity
against opportunistic fungi of the genus Saccharomyces.
IC50 = (14 7) · 10À3 lmol/mL for compound ( )-18a,
IC50 = (10 4) · 10À3 lmol/mL for compound ( )-
18b). In contrast, the activity of their analogues ( )-
[16a and 16b] was considerably smaller (IC50 = (105
(48%)
( )-8
( )-13
Scheme 1. Reagents and conditions: (i) PhI(OAc)2 (2equiv), I2
(1equiv), CCl4, hm (irradiation with two 80W tungsten lamps), reflux.
Yields are given for products purified by chromatography on silica gel.
9) · 10À3 lmol/mL for compound ( )-16a, IC50
=
(108 9) · 10À3 lmol/mL for compound ( )-16b). We
are currently synthesizing other derivatives in order to
study their activity against different strains of patho-
genic fungi. The complete biological results will be pub-
lished elsewhere.
reaction conditions, no elimination was observed. The
amino acid analogues 5 and 6 were treated under similar
conditions, affording the desired iodo derivatives 10 and
11.
Similarly, the malonate derivative 7 yielded the a-iodo
ester 12, although in moderate yield. However, the prep-
aration of this quaternary iodo compound is difficult by
other methodologies, since an elimination reaction usu-
ally takes place to give the a,b-unsaturated ester.10
In summary, the decarboxylation of b- and c-amino
acids is a mild and efficient methodology to synthesize
halogenated or oxygenated piperidines and pyrrolidines.
These functionalized nitrogen heterocycles are useful
intermediates in the synthesis of a variety of com-
To our surprise, when the radical decarboxylation was
carried out with the phenyl derivative 8, the main prod-
uct was the acetate 13, and no iodo derivatives were iso-
lated. This result could be explained by initial formation
of a tertiary benzylic iodide followed by nucleophilic
substitution by acetate ions from the reagent.
OH
OH
i
ii
11
N
N
BOC
BOC
The formation of the oxygenated derivative 13 seemed
promising, since similar structures can be found in drugs
with a potent action on the nervous system,11 such as the
widely used antipsychotic 2 and several new opiate ana-
14
( )-15
Scheme 2. Reagents and conditions: (i) DBU, CH2Cl2, 84%; (ii) OsO4,
NMO, acetone–H2O, 57%.

A. Boto et al. / Tetrahedron Letters 45 (2004) 6841–6845
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N
N
OH
N
OH
N
i, ii
+
14
CO2Me
( )-16a
CO2Me
( )-16b
i, iii
OMe
OMe
OR
N
N
OR
N
OMe
OMe
+
N
CO2Me
CO2Me
( )-17b R = H
( )-18b R = Bz
( )-17a R = H
( )-18a R = Bz
iv
iv
Scheme 3. Synthesis of antifungic agents. Reagents and conditions: (i)
MCPBA, CH2Cl2, 98%; (ii) piperidine, EtOH, Et3N, reflux, 53%, (16a/
b 3:2); (iii) 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, EtOH, Et3N,
reflux, then (iv) BzCl, CH2Cl2, Et3N, DMAP (cat.), 61%, (18a/b, 2:1).
´
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Acknowledgements
This work was supported by the Investigation Pro-
grammes PPQ2000-0728 and PPQ2003-01379 of the
´
Plan Nacional de Investigacion Cientıfica, Desarrollo e
Innovacion Tecnologica, Direccion General de Investi-
´
´
´
´
´
´
gacion, Ministerio de Ciencia y Tecnologıa, Spain. We
also acknowledge financial support from FEDER funds.
Y.R. thanks Gobierno de Canarias for a fellowship.
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9. Compounds 9–13 were characterized by 1H and 13C
NMR, MS, HRMS, IR and elemental analysis. 2D-COSY
and HSQC experiments were also carried out. Selected
NMR and analysis data are given. Compound 9: 1H NMR
(500MHz, CDCl3) d 7.34 (2H, dd, J = 7.0, 7.5Hz), 7.29
(1H, dd, J = 7.1, 7.3Hz), 7.26 (2H, d, J = 7.2Hz), 4.52
(1H, d, J = 14.8Hz), 4.45 (1H, d, J = 14.8Hz), 4.39 (1H,
dddd, J = 5.0, 5.0, 6.8, 6.8Hz), 3.74 (1H, dd, J = 6.5,
11.4Hz), 3.56 (1H, dd, J = 4.4, 11.5Hz), 3.06 (1H, dd,
J = 7.6, 17.7Hz), 2.88 (1H, dd, J = 5.1, 17.7Hz); 13C
NMR (100.6MHz, CDCl3): d 171.8 (C), 135.6 (C), 128.8
(2 · CH), 128.2 (2 · CH), 127.8 (CH), 58.0 (CH2), 46.4
(CH2), 44.7 (CH2), 9.7 (CH). Anal. Calcd for C11H12 NIO:
C, 43.88; H, 4.02; N, 4.65. Found: C, 44.16; H, 4.19; N,
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1
4.89. Compound 10: H NMR (500MHz, CDCl3) d 4.35
13. Chang, D.; Heringa, M. F.; Witholt, B.; Li, Z. J. Org.
Chem. 2003, 67, 8599–8606.
(1H, m), 3.81 (1H, m), 3.74 (1H, m), 3.57 (1H, m), 3.42
(1H, m), 2.25 (1H, m), 2.21 (1H, m), 1.46 (9H, s); 13C
NMR (125.7MHz, CDCl3, 2 6ꢁC). Mixture of two rota-
mers: d 79.7 (C), 57.3/57.0 (CH2), 45.0/44.7 (CH2), 38.3/
37.5 (CH2), 28.4 (3 · CH3), 19.8 (CH). The signal for the
CO group was not observed. However, in the IR spectrum
its absorption band appears at 1688.3cmÀ1. Anal. Calcd
for C9H16INO2: C, 36.38; H, 5.43; N, 4.71. Found: C,
36.56; H, 5.23; N, 4.60. Compound 11: 1H NMR
(500MHz, CDCl3) d 4.41 (1H, dddd, J = 5.8, 5.9, 5.9,
5.9Hz), 3.64 (3H, s), 3.57 (2H, m), 3.31 (2H, ddd, J = 5.5,
5.5, 11.6Hz), 1.98 (4H, m); 13C NMR (100.6MHz, CDCl3,
26ꢁC): d 155.7 (C), 52.6 (CH3), 43.7 (2 · CH2), 37.0
(2 · CH2), 27.1 (CH). Anal. Calcd for C7H12INO2: C,
31.25; H, 4.50; N, 5.21. Found: C, 31.41; H, 4.38; N, 5.25.
14. (a) The proposed structures are supported by the 1H
NMR, DEPT, COSY and HSQC experiments, as well as
the IR and mass spectra. 1H NMR (500MHz, CDCl3,
70ꢁC) and HRMS data for compounds ( )-[16a and 16b,
18a and 18b]: Compound ( )-16a: dH 4.43 (1H, d,
J = 9.7Hz), 4.25 (1H, d, J = 12.6Hz), 3.69 (3H, s), 3.45
(1H, ddd, J = 5.1, 10.0, 10.1Hz), 2.74 (2H, m), 2.69 (1H,
ddd, J = 2.5, 12.8, 13.2Hz), 2.58 (1H, dd, J = 10.5,
12.4Hz), 2.47 (2H, m), 2.40 (1H, m), 1.77 (1H, m), 1.66
(4H, m), 1.46 (2H, m), 1.44 (1H, m); HRMS calcd for
C12H22N2O3 242.1630, Obs. 242.1667. Compound ( )-
16b: dH 4.25 (1H, d, J = 11.8Hz), 4.13 (1H, d,
J = 13.7Hz), 3.69 (3H, s), 3.57 (1H, ddd, J = 4.6, 10.3,
10.3Hz), 2.82 (2H, ddd, J = 3.5, 7.2, 11.1Hz), 2.71 (1H,
ddd, J = 2.8, 13.3, 13.3Hz), 2.65 (1H, dd, J = 11.7,
12.5Hz), 2.47 (2H, ddd, J = 3.4, 6.9, 10.7Hz), 2.28 (1H,
ddd, J = 4.1, 10.7, 10.8Hz), 2.05 (1H, dddd, J = 2.6, 2.6,
4.9, 12.8Hz), 1.65 (4H, m), 1.47 (3H, m); HRMS calcd for
C12H22N2O3 242.1630, Obs. 242.1655. Compound ( )-
18a: dH 7.98 (2H, d, J = 7.3Hz), 7.53 (1H, dd, J = 7.4,
7.5Hz), 7.41 (2H, dd, J = 7.6, 7.7Hz), 6.53 (1H, s), 6.50
(1H, s), 5.32(1H, m), 4.24 (1H, m), 3.90 (1H, m), 3.9–3.7
(2H, m), 3.80 (6H, s), 3.70 (3H, s), 3.22 (1H, dd, J = 8.1,
13.2Hz), 3.16 (1H, ddd, J = 3.3, 10.2, 13.4Hz), 3.05 (1H,
m), 3.00 (1H, m), 2.90 (1H, m), 2.81 (1H, m), 2.71 (1H, m),
2.08 (1H, m), 1.83 (1H, m). HRMS calcd for C25H30N2O6
454.2104, Obs. 454.2103. Compound ( )-18b: dH 8.00 (2H,
d, J = 7.1Hz), 7.52(1H, dd, J = 7.4, 7.5Hz), 7.40 (2H, dd,
J = 7.7, 7.8Hz), 6.53 (1H, s), 6.50 (1H, s), 5.44 (1H, ddd,
J = 4.3, 8.7, 8.8Hz), 4.11 (1H, ddd, J = 3.0, 4.2, 13.7Hz),
1
Compound 12: H NMR (500MHz, CDCl3) d 3.80 (3H,
s), 3.70 (2H, m), 3.68 (3H, s), 3.32 (2H, ddd, J = 3.1, 8.8,
13.4Hz), 2.27 (2H, m), 1.84 (2H, ddd, J = 3.9, 8.8,
13.4Hz); 13C NMR (100.6MHz, CDCl3, 2 6ꢁC): d 172.2
(C), 155.7 (C), 53.2(CH 3), 52.8 (CH3), 42.5 (2 · CH2),
42.0 (C), 38.2 (2 · CH2). Anal. Calcd for C9H14INO4: C,
33.05; H, 4.31; N, 4.28. Found: C, 33.39; H, 4.44; N, 3.92.
1
Compound 13: H NMR (500MHz, CDCl3) d 7.35–7.30
(5H, m), 4.12 (2H, m), 3.11 (2H, m), 2.48 (2H, d,
J = 12.3Hz), 2.06 (3H, s), 1.93 (2H, ddd, J = 4.8, 13.3,
13.6Hz), 1.47 (9H, s); 13C NMR (125.7MHz, CDCl3,
26ꢁC): d 169.4 (C), 154.8 (C), 143.8 (C), 128.4 (2 · CH),
127.4 (CH), 124.4 (2 · CH), 80.3 (C), 79.6 (C), 40.1
(2 · CH2), 35.3 (2 · CH2), 28.4 (3 · CH3), 21.9 (CH3).
Anal. Calcd for C18H25NO4: C, 67.69; H, 4.39; N, 7.89.
Found: C, 67.58; H, 7.96; N, 4.53.

A. Boto et al. / Tetrahedron Letters 45 (2004) 6841–6845
6845
3.93 (1H, m), 3.90 (1H, d, J = 14Hz), 3.83 (1H, d,
J = 14Hz), 3.82(3H, s), 3.80 (3H, s), 3.73 (3H, s), 3.27
(1H, dd, J = 9.1, 13.7Hz), 3.18 (1H, ddd, J = 3.3, 10.2,
13.5Hz), 3.06 (1H, ddd, J = 5.4, 5.7, 11.4Hz), 2.88 (2H,
m), 2.74 (1H, ddd, J = 5.6, 5.7, 16.7Hz), 2.67 (1H, ddd,
J = 5.2, 5.3, 15.8Hz), 2.23 (1H, m), 1.73 (1H, m); HRMS
calcd for C25H30N2O6 454.2104, Obs. 454.2040.
15. (a) For compounds related to 16a and 16b, see: Efange, S.
M. N.; Khare, A. B.; Foulon, C.; Akella, S. K.; Parsons, S.
M. J. Med. Chem. 1994, 37, 2574–2582, and references
cited therein; (b) For compounds related to 18a and 18b,
see: Kubota, H.; Kakefuda, A.; Watanabe, T.; Taguchi,
Y.; Ishii, N.; Masuda, N.; Sakamoto, S.; Tsukamoto, S.-I.
Bioorg. Med. Chem. Lett. 2003, 13, 2155–2158.