Oxidative C-C bond cleavage of N-alkoxycarbonylated cyclic amines by sodium nitrite in trifluoroacetic acid

Article abstract of DOI:10.1016/j.tetlet.2008.09.067

Oxidative carbon-carbon bond cleavage of N-alkoxycarbonylated cyclic amines was accomplished by NaNO₂ in TFA to afford ω-amino carboxylic acid in high yield. Optically active 3-hydroxypiperidine derivatives and 3-pipecolinate were converted to

Full text of DOI:10.1016/j.tetlet.2008.09.067

Tetrahedron Letters 49 (2008) 6728–6731
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxidative C–C bond cleavage of N-alkoxycarbonylated cyclic
amines by sodium nitrite in trifluoroacetic acid
*
Osamu Onomura , Atsushi Moriyama, Kazuhiro Fukae, Yutaka Yamamoto,
Toshihide Maki, Yoshihiro Matsumura, Yosuke Demizu
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Oxidative carbon–carbon bond cleavage of N-alkoxycarbonylated cyclic amines was accomplished by
Received 25 August 2008
Revised 11 September 2008
Accepted 12 September 2008
Available online 17 September 2008
NaNO2 in TFA to afford
x-amino carboxylic acid in high yield. Optically active 3-hydroxypiperidine deriv-
atives and 3-pipecolinate were converted to enantiomerically pure (R)-4-amino-3-hydroxybutanoic acid
(GABOB) and (S)-2-pyrrolidone-4-carboxylate, respectively.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Carbon–carbon cleavage
Cyclic amines
Trifluoroacetic acid
Sodium nitrite
x
-Amino acid
It is well known that trifluoroacetic acid (TFA) acts as an effi-
ried out in TFA (5 mL) containing NaNO2 (2 mmol) and H2O
(10 mmol) under aerobic condition. The oxidation smoothly pro-
ceeded at 0 oC to rt for 3 h to afford an oxidative ring-opened prod-
uct 2a in 98% yield.6
cient medium for oxidation of hydrocarbons.1 Recently, we found
that efficient oxidation of adamantanes to 1-adamantanols was
catalyzed by sodium nitrite (NaNO2) under oxygen atmosphere
in TFA.2 In addition, 2 equiv of NaNO2 in TFA3 oxidized acyclic
and cyclic secondary alcohols to the corresponding ketones and
NaNO2 (2 equiv)
CO2H
H2O (10 equiv)
-dicarboxylic acid, respectively.4 In the latter case, oxidative
-car-
CHO
a,
x
N
N
ð2Þ
in TFA
cleavage of cyclic secondary alcohols occurred between the
a
CO2Ph
CO2Ph
0 ºC to rt 3h
bon and the b-carbon. We report herein that this oxidizing agent
works well as demonstrated by a unique reaction of N-alkoxycarb-
onylated cyclic amines 1, which reacted with NaNO2 to afford the
ring-opened products 25 and its application to preparation of opti-
cally active compounds 3e and 4 (Eq. 1).
under air
1a
2a, 98%
The oxidative cleavages of N-protected pyrrolidines 1b–d
and piperidines 1e–i with NaNO2 in TFA were examined to
β
( )n
CO2Et
CHO
( )
n CO2H
CHO
NaNO2
α
HO2C
N
N
N
CO2R
H2O in TFA
ð1Þ
OAc CO2Bn
O
N
CO2R
CHO
3e
4
2
1
A typical example for the oxidative carbon–carbon (C–C) bond
cleavage is shown in Eq. 2. The oxidation of 1a (1 mmol) was car-
clarify generality of substrates (Eq. 3). The results are summarized
in Table 1.
* Corresponding author. Tel.: +81 95 819 2429; fax: +81 95 819 2476.
E-mail address: onomura@nagasaki-u.ac.jp (O. Onomura).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.067

O. Onomura et al. / Tetrahedron Letters 49 (2008) 6728–6731
6729
Table 1
The yields of the cleaved products 2j–m may have interrelation
with the oxidation potentials of 1j–m. That is, easily oxidizable
prolinol derivative 1j was converted into the corresponding
cleaved product 2j in excellent yield (entry 1), while compounds
1k,l, which have relatively high oxidation potential, afforded
2k,l in moderate yields (entries 2 and 3). However, proline
derivative 1m with high oxidation potential was not oxidized at
all (entry 4).
Oxidative cleavage of N-protected cyclic amines 1b–i with NaNO2 in TFA
Entry
Substrate
PG
Yield (%)
n
2
6
7
1
1
2
3
4
5
6
7
8
0
0
0
1
1
1
1
1
CO2Me
CO2Ph
CO2CH2CF3
CO2Me
CO2CH2CF3
CHO
1b
1c
1d
1e
1f
1g
1h
1i
74
83
88
79
99
0
9
0
0
0
0
0
0
0
11
11
0
15
0
0
0
0
0
0
0
0
0
We then subjected 2, or 3, or 4-methylated piperidines 1n–s to
same reaction conditions (Eq. 5). The results are summarized in
Table 3.
>99
>99
>99
COMe
COPh
0
0
NO2
( )n
CO2H
CHO
NaNO2 (2 equiv)
H2O (10 equiv)
( )n
( )n
( )n
N
+
+
N
PG
N
PG
N
PG
O
ð3Þ
ð5Þ
in TFA
PG
0 ºC to rt 3 h
under air
1b-i
2b-i
6b-i
7b-i
R3
R3
N
PG
2n-s
R3
N
PG
7n-s
R3
O
O
R2
R1
R2
R1
R2
R1
NO2
+
NaNO2 (2 equiv)
H2O (10 equiv)
CO2H
CHO
R2
R1
4
5
6
3
2
+
N
PG
1n-s
N
PG
8n-s
in TFA
0 ºC to rt 3 h
under air
N-Alkoxycarbonylated pyrrolidines 1b–d were transformed
into the corresponding ring-opened products 2b–d in good to high
yields along with a small amount of pyrrolidine-2-ones 6b–d
(entries 1–3). The oxidation of N-methoxycarbonylpiperidine 1e
Trifluoroethoxycarbonyl served as a better protecting group
than methoxycarbonyl in all cases (entries 1–6). In the cases where
2-methylpiperidines 1n and 1o were oxidized, C–C bond cleavage
occurred exclusively between the 5th and 6th position to afford 2n
and 2o (entries 1 and 2), while for 3-methylpiperidines 1p and 1q,
cleavage occurred between the 5th and 6th position to afford 2p
and 2q or at the 2nd and 3rd position to afford 8p and 8q, respec-
tively (entries 3 and 4).
afforded
x-amino acid in good yield and 3-nitroenamine 7e as a
by-product (entry 4), while electron-withdrawing groups7 such
as phenoxyl and trifluoroethoxyl groups were more efficient than
methoxycarbonyl group (Eq.
2 and entry 5). Interestingly,
N-formylated and acylated piperidines 1g–i were not oxidized at
all under the reaction conditions (entries 6–8). This may be due
to the formation of protonated species for 1g–i in TFA,8 which
are hardly oxidizable.
Next, the oxidative cleavages of substituted pyrrolidines 1j–m
were examined (Eq. 4). The results are summarized in Table 2.
To obtain insight into the mechanism for our reaction, the ki-
netic isotope effect was measured using 2,2-dideuteriopiperidines
1t,u (Eq. 6). The kH/kD values for the oxidation of 1t,u was found to
be almost similar with those of electrochemical oxidation.9 These
results strongly suggest that our oxidation proceeds via single elec-
tron transfer.
CO2H
CHO
NaNO2 (2 equiv)
H2O (10 equiv)
CO2H
CHO
CO2H
CDO
R
NaNO2 (2 equiv)
N
PG
R
+
N
ð4Þ
D
D
H
in TFA
N
PG
N
N
PG
H2O (10 equiv)
in TFA
D
D
H
0 ºC to rt 3 h
PG
2t-D
2u-D
PG
2t-H
2u-H
1j-m
2j-m
under air
0 ºC to rt 3 h
under air
1t : PG = CO2CH2CF3
1u : PG = CO2Me
kH
kH
/
/
k
k
D=2t-D : 2t-H = 2.07 : 1
D=2u-D : 2u-H = 2.10 : 1
Table 2
Oxidative cleavage of
a
-substituted pyrrolidines 1j–m with NaNO2 in TFA
-2e
+
D
H
D
H
Entry
Substrate
R
Oxidation potentiala (V)
Yield (%)
N
N
PG
D
OMe
MeO
H
4 F/mol , 50 mA , at 0 ºC
Et4NBF4 (0.1M) in MeOH
PG
9t-D
9u-D
PG
2
1
9t-H
9u-H
1
2
3
4
CO2Me
CO2CH2CF3
CO2Me
CH2OAc
1j
1k
1l
2.24
2.50
2.39
2.82
96
41
52
<1
0
CH2OAc
CO2Me
CO2Me
59
47
>99
kH
kH
/
/
k
k
D=9t-D : 9t-H = 2.03 : 1
D=9u-D : 9u-H = 2.01 : 1
CO2CH2CF3
1m
ð6Þ
a
Versus Ag/AgNO3.

6730
O. Onomura et al. / Tetrahedron Letters 49 (2008) 6728–6731
Table 3
Table 4
Oxidative cleavage of N-protected piperidines 1n–s with NaNO2 in TFA
Oxidative cleavage of N,O-protected 3-hydroxypiperidines 10
Entry
Substrate
Yield (%)
Entry
Substrate
Yield (%) of 3
PG
R1
R2
R3
2
7
8
PG
R
1
2
3
4
5
6
CO2Me
CO2CH2CF3
CO2Me
CO2CH2CF3
CO2Me
CO2CH2CF3
Me
Me
H
H
H
H
H
Me
Me
H
H
H
H
H
Me
Me
1n
1o
1p
1q
1r
47
79
42
74
43
76
52
20
Trace
0
45
0
0
11
10
0
1
2
3
4
5
6
7
8
CO2Ph
CO2Ph
CO2Me
CO2Me
Cbz
Cbz
Cbz
Cbz
Ac
Bz
Ac
Bz
Ac
Bz
COEt
Piv
10a
10b
10c
10d
10e
10f
Trace
Trace
68
59
66
11
63
>99
H
H
1s
15
0
10g
10h
Plausible reaction mechanism is shown in Scheme 1. NO+ gen-
erated from NaNO2 and TFA plays an important role as an oxidant
for 1 and intermediate A as well as a nitrosation agent for enamine
C. NO might be oxidized to NO+ by molecular O2,10 while nitroso
compound E is changed into oxime F, whose hydrated form G
smoothly affords ring-opened intermediate I. Finally, hydrolysis
Use of phenoxycarbonyl as N-protecting group led to only trace
amount of the desired cleaved product 3a,b (entries 1 and 2).
Change of the protecting group to methoxycarbonyl led to
improvement in yields to 68% for 3c and 59% for 3d (entries 3
and 4). The ease of deprotection made us decide to try benzyloxy-
carbonyl as N-protecting group, which gave comparable result to
methoxycarbonyl (entries 3 and 5). To further improve the yield,
we tried various O-protecting groups (entries 5–8), and enantio-
merically pure 3e5d,11 was obtained from 10e in good yield (entry
5). Pivaloyl12 emerged as the best protecting group to afford 3h13
in quantitative yield.
of I gives
x-N-formylamino carboxylic acid 2.
Enantiomerically pure 3e as a precursor for GABOB is of essence.
Therefore, we examined the suitability of different protecting
groups for both N and O toward exclusive oxidative cleavage be-
tween the 5th and 6th position of 3-hydroxypiperidine derivatives
10 (Eq. 7). The results are summarized in Table 4.
Also, oxidative carbon–carbon cleavage of 3-pipecolinate 1114
proceeded smoothly to afford 12, which was transformed into
enantiomerically pure 415,16 (Eq. 8).
RO
NaNO2 (2 equiv)
H2O (10 equiv)
RO
CO2H
CHO
In summary, oxidative C–C bond cleavage of N-alkoxycarbony-
lated cyclic amines was accomplished by NaNO2 in TFA to afford
N
PG
ð7Þ
N
in TFA
0 ºC 12 h
PG
x
-amino carboxylic acid in high yield. Optically active 3-hydroxy-
under air
3
10
piperidine derivative and 3-pipecolinate were converted to
- H2O
NO+ CF3CO2 + CF3CO2Na
O2
-
NaNO2 + 2CF3CO2H
O2
NO+
NO
NO+
NO
H
- H+
NO+
N
PG
1
N
PG
A
N
PG
B
N
PG
C
H
-e
-e
+ H+
-H+
OH
NHOH
NO
NO
OCOCF3
NOH
+ H2O
- H2O
-
+ CF3CO2
N
PG
G
OCOCF3
N
PG
D
N
N
OCOCF3
-
- CF3CO2
PG
PG
F
E
H
N
HO
HO
NH
CHO
OCOCF3
COOH
CHO
- CF3CO2H
+ H2O
- NH3
N
PG
O
H
N
PG
N
PG
I
2
H
Scheme 1. Plausible reaction mechanism.
1) H2 (1 atm)
cat.10% Pd-C in MeOH
EtO2C
EtO2C
NaNO2 (2 equiv)
H2O (10 equiv)
CO2H
CHO
4
N
Cbz
N
in TFA
0 ºC 12 h
under air
2) p-TsOH (0.4 equiv)
in toluene, 1,4-dioxane
at 110 ºC
ð8Þ
Cbz
11
12
53% yield
62% yield

O. Onomura et al. / Tetrahedron Letters 49 (2008) 6728–6731
6731
9. Shono, T.; Hamaguchi, H.; Matsumura, Y. J. Am. Chem. Soc. 1975, 97, 4264–
4268.
10. The oxidation of 1a under nitrogen atmosphere gave 2a in 25% yield along with
recovered 1a in 69% yield.
enantiomerically pure precursor for (R)-4-amino-3-hydroxybuta-
noic acid (GABOB) and (S)-2-pyrrolidone-4-carboxylate, respec-
tively. The mechanistic study and further synthetic application
are underway.
11. Enantiomerically pure (R)-3-acetoxy-4-[(N-benzyloxycarbonyl-N-formyl)amino]-
butanoic acid (3e): Colorless oil; IR(neat) 3567 (br), 2963, 1730, 1698,
1333, 1237 cmꢀ1
; d 1.92 (s, 3H), 2.64 (d,
1H NMR (300 MHz, CDCl3)
J = 6.9 Hz, 2H), 3.89 (dd, J = 3.6, 14.4 Hz, 1H), 4.02 (dd, J = 6.6, 11.4 Hz, 1H),
5.32 (s, 2H), 5.45 (m, 1H), 7.40 (m, 5H), 9.24 (s, 1H); 1H NMR (300 MHz,
DMSO-d6) d 1.80 (s, 3H), 2.60 (d, J = 8.8 Hz, 2H), 3.71 (dd, J = 10.6 Hz, 1H),
3.86 (dd, J = 5.7, 10.8 Hz, 1H), 5.00 (m, 1H), 5.30 (m, 2H), 7.34–7.45 (m,
5H), 9.13 (s, 1H), 12.31 (br s, 1H); 13C NMR (75 MHz, CDCl3) d 20.3, 36.2,
References and notes
1. Some examples: (a) Deno, N. C.; Messer, L. A. J. Chem. Soc., Chem. Commun.
1976, 1051; (b) Stewart, R.; Spitzer, U. D. Can. J. Chem. 1978, 56, 1273–1279; (c)
Nomura, K.; Uemura, S. J. Chem. Soc. Chem. Commun. 1994, 129–130; (d)
Murahashi, S.; Komiya, N.; Oda, Y.; Kuwabara, T.; Naota, T. J. Org. Chem. 2000,
65, 9186–9193.
2. Onomura, O.; Yamamoto, Y.; Moriyama, N.; Iwasaki, F.; Matsumura, Y. Synlett
2006, 2415–2418.
3. Oxidation of dodeca-substituted porphyrins by 6 equiv of NaNO2 in TFA:
Ongayi, O.; Fronczek, F. R.; Vincente, M. G. Chem. Commun. 2003, 2298–2299.
4. Matsumura, Y.; Yamamoto, Y.; Moriyama, N.; Furukubo, S.; Iwasaki, F.;
Onomura, O. Tetrahedron Lett. 2004, 45, 8221–8224.
42.4, 67.7, 69.0, 128.2, 128.4, 128.6, 134.1, 153.4, 163.0, 170.7, 173.2; ½a D20
ꢁ
+9.3 (c 1.0, CHCl3); MS [HR-EI]: m/z calcd for C15H17NO7 [M]+ 323.1005:
found 323.0993. Optical purity was determined by HPLC analysis
employing
a Daicel Chiralcel OJ-H column (4.6 mm ø, 250 mm). n-
Hexane/ethanol = 5:1, 0.1% TFA, wavelength: 220 nm, flow rate: 1.0 mL/
min, retention time: 27.3 min (R), 30.9 min (S).
12. Oxidation potential (vs Ag/AgNO3): 2.17 V for 10h.
13. Enantiomerically pure (R)-3-pivaloyloxy-4-[(N-benzyloxycarbonyl-N-formyl)-
amino]butanoic acid (3h): Colorless oil; IR (neat) 3200 (br), 2975, 1732,
5. Ru porphyrin/2,6-dichloropyridine N-oxide system-catalyzed oxidative ring
cleavage of N-acylated cyclic amines has been reported: (a) Ito, R.; Umezawa,
N.; Higuchi, T. J. Am. Chem. Soc. 2005, 127, 834–835; (b) Ru-catalyzed oxidative
1701, 1339, 1152, 1042 cmꢀ1 1H NMR (300 MHz, CDCl3) d 1.11 (s, 9H),
;
2.65 (d, J = 6.9 Hz, 2H), 3.79 (dd, J = 3.6, 14.4 Hz, 1H), 4.07 (dd, J = 7.8,
14.1 Hz, 1H), 5.32 (s, 2H), 5.44 (m, 1H), 7.39 (m, 5H), 9.21 (s, 1H); 1H
ring cleavage of N-alkoxycarbonyl a,b-unsaturated cyclic amines, see: (c) Torii,
NMR (300 MHz, DMSO-d6)
d 1.00 (s, 9H), 2.64 (d, J = 9.5 Hz, 2H), 3.66
S.; Inokuchi, T.; Kondo, K. J. Org. Chem. 1985, 50, 4980–4982; (d) Sakagami, H.;
Kamikubo, T.; Ogasawara, O. Synlett 1997, 221–222. Ozonolysis of them, see:
(e) Gnad, F.; Poleschak, M.; Reiser, O. Tetrahedron Lett. 2004, 45, 4277–4280.
Degradative autooxidation of N-acyl-3-piperidinones, see: (f) Schirmann, P. J.;
Matthews, R. S.; Dittmer, D. C. J. Org. Chem. 1983, 48, 4426–4427.
(d, J = 10.6 Hz, 1H), 3.92 (m, 1H), 5.29 (m, 3H), 7.36–7.43 (m, 5H), 9.12
(s, 1H), 12.39 (br s, 1H); 13C NMR (100 MHz, CDCl3) d 26.9, 36.8, 38.6,
42.9, 67.3, 69.3, 128.5, 128.8, 128.9, 134.4, 153.6, 162.6, 175.2, 177.7.
½ ꢁ
a D20 +3.0 (c 1.0, CHCl3); MS [HR-EI]: m/z calcd for C18H23NO7 [M]+
365.1474: found 365.1474. Optical purity was determined by HPLC
analysis employing a Daicel Chiralcel OJ-H column (4.6 mm ø, 250 mm),
n-Hexane/ethanol = 5:1, 0.1% TFA, wavelength: 220 nm, flow rate:
1.0 mL/min, retention time: 10.1 min (R), 10.9 min (S).
6. Under anhydrous condition, oxidation of 1a,e,f smoothly proceeded to give
x
-amino nitriles 5a,e,f in good to high yields. The reaction of x-amino nitriles
5a,e,f with NaNO2 (2 equiv) and H2O (10 equiv) in TFA did not proceed at all.
NaNO2 (2 equiv)
14. Oxidation potential (vs Ag/AgNO3): 2.21 V for 11.
CN
CHO
15. Enantiomerically pure ethyl (S)-N-formyl-2-pyrrolidinone-4-carboxylate (4):
(CF3CO)2O (7 equiv)
Colorless oil; IR (neat) 1887, 1767, 1717, 1476, 1399 cmꢀ1
;
1H NMR
5a: 85% yield
5e: 63% yield
5f : 87% yield
1a,e,f
N
in TFA
(300 MHz, CDCl3) d 1.30 (t, J = 7.2 Hz, 3H), 2.84 (dd, J = 9.6, 18.6 Hz, 1H), 2.97
(dd, J = 7.2, 18.3 Hz, 1H), 3.30 (m, 1H), 3.94 (m, 2H), 4.23 (q, J = 7.2 Hz, 2H), 9.09
(s, 1H); 13C NMR (100 MHz, CDCl3) d 14.1, 34.9, 35.7, 44.3, 61.9, 159.8, 171.6,
174.2. a2D0 +23.6 (c 1.0, CHCl3); MS [HR-EI]: m/z calcd for C8H11NO4 [M]+
185.0688: found 185.0667. Optical purity was determined by HPLC analysis
employing a Daicel Chiralcel OD-H column (4.6 mm ø ꢂ 250 mm). n-Hexane/
ethanol = 15:1, wavelength: 220 nm, flow rate: 1.0 mL/min, retention time:
27.4 min (S), 29.3 min (R).
0 ºC to rt 3 h
PG
under air
.
7. Oxidation potentials (vs Ag/AgNO3): 2.16 V for 1a, 2.10 V for 1e, 2.33 V for 1f.
8.
-
CF3CO2
N
16. Chemoenzymatic approach: Felluga, F.; Pitacco, G.; Prodan, M.; Pricl, S.;
Visintin, M.; Valentin, E. Tetrahedron: Asymmetry 2001, 12, 3241–3249.
HO
R
.