Facile synthesis of ortho-halo-substituted 4-aryl-2-aminobutyric acids

Article abstract of DOI:10.1055/s-2008-1032194

Herein we describe an efficient and practical route for the regioselective synthesis of 4-(5-bromo/chloropyrazol-1-yl)-2-aminobutyric acids. The compounds have been prepared by regioselective C-5 halogenation of 1-(3,3-dimethoxypropyl) -1H-pyrazole followed by a Strecker synthesis. In addition, Boc-protected 2-amino-4-(2-chlorophenyl)butyric acid and 2-amino-4-(3-chloropyridin-2-yl) butyric acid have been synthesized. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032194

PAPER
883
Facile Synthesis of ortho-Halo-Substituted 4-Aryl-2-Aminobutyric Acids
S
ynthesis of 4-(
o
-H
l
aloary
e
l)-2-Amino
x
butyric
A
cidander Heim-Riether*
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA
Fax +1(203)7916072; E-mail: alexander.heim-riether@boehringer-ingelheim.com
Received 15 October 2007; revised 13 December 2007
halogenation with simultaneous deoxygenation.3 Alkyl-
pyrazole-2-oxides can be accessed through regioselective
N-alkylation of hydroxypyrazole (5) with alkyl bromides.
For example, heating 5 and n-butyl bromide in chloroform
Abstract: Herein we describe an efficient and practical route for
the regioselective synthesis of 4-(5-bromo/chloropyrazol-1-yl)-2-
aminobutyric acids. The compounds have been prepared by regiose-
lective C-5 halogenation of 1-(3,3-dimethoxypropyl)-1H-pyrazole
followed by a Strecker synthesis. In addition, Boc-protected 2-ami- at 100 °C has been reported to furnish 1-butylpyrazole-2-
no-4-(2-chlorophenyl)butyric acid and 2-amino-4-(3-chloropyri-
oxide in 49% yield.
din-2-yl)butyric acid have been synthesized.
Key words: amino acids, 1-alkyl-5-halopyrazole, Strecker synthe-
sis, Heck reaction, Grignard reaction
N+
O
N
O–
R
N
Br
O
N
N
N
OH
a)
POR3
BocHN
5
+
O
O
In the course of our research, we required a general meth-
od for the preparation of ortho-substituted 4-aryl-2-ami-
nobutyric acids, particularly when aryl equals pyrazole.
While chemistry to prepare amino acid derivatives con-
taining (hetero)aryl side chains is known,1 none of the re-
ported methods appeared to allow the ready incorporation
of different ortho-substituents on the (hetero)aryl ring. For
the synthesis of a pyrazole-containing amino acid deriva-
tive such as 3, we initially focused on alkylation of the an-
ion of 5-substituted pyrazoles 1 (R = Cl, CN) with alkyl
bromide 2. As expected,2 this alkylation produced a regio-
isomeric mixture of the 1,5- and 1,3-substituted pyrazoles
3 and 4 that proved difficult to separate (Scheme 1). Sub-
sequently, we investigated an alternative synthesis of 3
with R = Br, with the intention of exploiting the bromine
functionality in subsequent cross-coupling reactions.
BocHN
BocHN
O
O
3
2
6
N
N
O
R = Cl, Br
O
BocHN
O
7
Scheme 2 O-Alkylation instead of N-alkylation. Reagents and
conditions: (a) CHCl3, 100 °C, 24 h, sealed tube.3
In our hands, heating a mixture of 5 and 2 in chloroform
at 100 °C provided exclusively O-alkylated product 7 in-
stead of the desired product 6 (Scheme 2). We attributed
this failure to the functional groups present in 2 compared
to non-functionalized alkyl bromides. Therefore, 3-bro-
mo-1,1-dimethoxypropane (9), a less functionalized alkyl
bromide, which could subsequently be converted into an
amino acid, was evaluated. Reaction of hydroxypyrazole
with 9 afforded the desired N-alkylated pyrazole-2-oxide,
but only in less than 10% yield (major product: O-alkyla-
tion).
R
N
N
N
R
R
N
Br
O
N
N
H
+
+
O
O
O
BocHN
BocHN
BocHN
O
Since the pyrazole oxide route was unsuccessful, we in-
vestigated a second general method, which involves
ortho-lithiation of 1-alkylpyrazoles.4 Starting from alkyl
bromide 9, we envisioned 5-halopyrazole 11a would be
readily accessible and undergo a subsequent Strecker re-
action to convert the aldehyde into the amino acid. Thus,
alkylation of the anion of pyrazole (8) with commercially
available bromide 9 provided acetal 10 in 75% yield.
Lithiation of 10 at –78 °C with n-butyllithium, followed
by addition of bromine, led to 5-bromopyrazole 11a. The
best yields (72%) were obtained when the reaction was
quenched below –30 °C with saturated aqueous sodium
carbonate; this avoided over-bromination of the pyrazole.
Cleavage of the acetal with perchloric acid5 afforded alde-
hyde 12a. In a one pot sequence, aldehyde 12a was first
O
1
2
3
4
R = Cl, CN
desired isomer
Scheme 1 Regioisomeric mixture formed through direct alkylation
Two general routes are reported that regioselectively in-
troduce a halogen at the 5-position of 1-alkylpyrazoles.
One method constitutes the conversion of 1-alkylpyra-
zole-2-oxides (cf. 6, Scheme 2) into 5-halo-1-alkylpyra-
zoles (cf. 3, R = Cl, Br) via an oxyhalide-mediated
SYNTHESIS 2008, No. 6, pp 0883–0886
x
x
.
x
x
.2
0
0
8
Advanced online publication: 28.02.2008
DOI: 10.1055/s-2008-1032194; Art ID: M07707SS
© Georg Thieme Verlag Stuttgart · New York

884
A. Heim-Riether
PAPER
converted into the aminonitrile,6 which was hydrolyzed by Bell et al. for mono-halogenated pyridines.9 Applying
under acidic conditions to the free amino acid. Subsequent these conditions, reaction of doubly halogenated pyridine
Boc-protection provided the expected 4-(5-bromopyra- 18 and commercially available Grignard reagent 19 fur-
zol-1-yl)-2-aminobutyric acid 13a in an overall yield of nished acetal 20 in 56% yield. Subsequent transforma-
81% over three steps (Scheme 3).
tions provided the Boc-protected 2-amino-4-(3-chloro-
pyridin-2-yl)butyric acid (21) in 19% yield over three iso-
lated steps (Scheme 5).
Br
N
N
R
N
O
N
O
a
b
+
N
N
H
MgBr
O
N
N
O
O
Cl
Cl
N
O
O
R
Cl
a
b, c
8
9
10
Br
+
O
OH
11a: R = Br
11b: R = Cl
BocHN
O
O
O
21
N
N
18
19
20
R
N
H
N
c
d
Scheme 5 Reagents and conditions: (a) CuBr, THF, 56%; (b)
HClO4, THF, 76%; (c) (i) TMSCN, NH3, cat. ZnI2; (ii) 6N HCl; (iii)
NaHCO3, Boc2O, 45%.
OH
O
BocHN
O
12a: R = Br
12b: R = Cl
13a: R = Br
13b: R = Cl
In summary, an efficient and practical regioselective route
to access 5-halopyrazole substituted 2-aminobutyric acids
has been developed. Furthermore, this general route, start-
ing from readily available materials, was applied to the
syntheses of 2-chlorophenyl and 3-chloropyridyl contain-
ing amino acids by expanding known chemistry.
Scheme 3 Reagents and conditions: (a) NaH, THF, 75%; (b) 11a:
n-BuLi, Br2, 72%; 11b: n-BuLi, C2Cl6, 75%; (c) HClO4, THF, 12a:
84%; 12b: 92%; (d) (i) TMSCN, NH3, cat. ZnI2; (ii) 6N HCl; (iii)
NaHCO3, Boc2O, 13a: 81%; 13b: 70%.
The corresponding chloro-analogue 11b was prepared in
a similar manner, using hexachloroethane in the halogena-
tion step. Both compounds 13a and 13b were obtained in
36% yield starting from pyrazole over four isolated steps.
All chemicals used, including anhydrous solvents, were of reagent
grade and used as supplied. Chromatography was carried out on sil-
ica gel; TLC were carried out on silica plates (Merck, Art. 5554). In
general, the course of reactions was followed by TLC and/or LC-
Based on this route, which provided us with a reliable se- MS. NMR spectra were obtained on a Bruker DPX-400 spectrome-
ter at 400 MHz. LC-MS data was recorded utilizing the electrospray
quence to access 5-halopyrazole-containing amino acids,
we investigated the synthesis of analogous amino acids
(ESI) technique. Values for m/z are given; the mass ion quoted is
[M + H]+, which refers to the protonated mass ion. HRMS data was
with six-membered aryl rings such as phenyl 17
acquired using an Agilent LCMSD-TOF in the positive and nega-
(Scheme 4)7 and 2-pyridyl 21 (Scheme 5). Aldehyde 16
tive ESI ionization modes. This instrument achieved a mass resolu-
tion of greater than 13,000 measured at m/z = 2722.
was prepared from 2-chloroiodobenzene (14) and allyl al-
cohol (15) in 73% yield by a Heck-type reaction devel-
oped by Jeffery.8 Subsequent Strecker reaction gave
butyric acid 17 in 55% yield (Scheme 4).
1-(3,3-Dimethoxypropyl)-1H-pyrazole (10)
To a solution of pyrazole (1.67 g, 24.6 mmol) in DMF (25 mL) at
r.t. was added NaH (0.98 g, 60% in mineral oil, 24.6 mmol) in one
portion. The resulting white suspension was stirred for 15 min be-
fore 3-bromo-1,1-dimethoxypropane (5.00 g, 90%, 24.6 mmol) was
added. The reaction mixture was heated at 80 °C for 3 h. After cool-
ing to r.t., the reaction was quenched with H2O (25 mL) and the
mixture was extracted with EtOAc (2 × 50 mL). The organic layer
was washed with brine (20 mL), dried over MgSO4, filtered and
concentrated under reduced pressure to give a pale-yellow oil. Puri-
fication on silica gel (EtOAc–hexane, 0→50%) gave 10.
Cl
Cl
Cl
+
b
a
I
OH
OH
BocHN
O
H
O
17
14
15
16
Yield: 3.16 g (75%); colorless oil; Rf = 0.5 (EtOAc–hexane, 75%).
Scheme 4 Reagents and conditions: (a) Pd(OAc)2, NaHCO3,
TBACl, DMF, 73%; (b) (i) TMSCN, NH3, cat. ZnI2; (ii) 6N HCl;
(iii) NaHCO3, Boc2O, 55%.
1H NMR (400 MHz, CDCl3): d = 7.51 (d, J = 2.0 Hz, 1 H), 7.37 (d,
J = 2.0 Hz, 1 H), 6.23 (t, J = 2.0 Hz, 1 H), 4.26 (t, J = 5.8 Hz, 1 H),
4.20 (t, J = 7.0 Hz, 2 H), 3.32 (s, 6 H), 2.16 (dt, J = 7.0, 5.8 Hz,
2 H).
In case of the pyridine analogue 21, the corresponding al-
dehyde precursor could not be prepared from 2-bromo-3-
chloropyridine (18) and allyl alcohol (15). We decided to
revisit our strategy and investigated the synthesis of acetal
20 via a copper(I)-mediated Grignard addition as reported
13C NMR (100 MHz, CDCl3): d = 139.2, 129.1, 105.1, 101.9, 53.0,
47.6, 33.2.
HRMS (ESI): m/z [M + H]+ calcd for C8H14N2O2: 171.1128; found:
171.1134.
Synthesis 2008, No. 6, 883–886 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-(o-Haloaryl)-2-Aminobutyric Acid
885
5-Bromo-1-(3,3-dimethoxypropyl)-1H-pyrazole (11a)
Strecker Synthesis of Boc-Protected Amino Acids; General Pro-
cedure
To a solution of pyrazole 10 (3.15 g, 18.1 mmol) in THF (50 mL) at
–78 °C was added n-BuLi (8.9 mL, 2.5 M in hexane, 22.2 mmol)
dropwise. After stirring at –78 °C for 30 min, Br2 (1.14 mL, 22.2
mmol) was added. The reaction was stirred for 1 h at –78 °C and
was then allowed to reach –30 °C before sat. aq Na2CO3 (50 mL)
was added. The resultant mixture was extracted with EtOAc (2 × 50
mL). The organic layer was washed with H2O (25 mL), brine (20
mL), dried over MgSO4, filtered and concentrated under reduced
pressure to give a yellow oil. Purification on silica gel (EtOAc–hex-
ane, 0→50%) gave 11a.
In a pressure tube, TMS-CN (1.5 mmol) and a catalytic amount of
ZnI2 (~5 mol%) were added to a solution of aldehyde (1.0 mmol) in
anhydrous THF (2 mL). After stirring for 15 min at r.t., a solution
of NH3 in MeOH (7 M, 5 mL) was added. The tube was sealed and
the reaction mixture was stirred at 60 °C for 3 h, after which time
the formation of the aminonitrile intermediate was complete (mon-
itored by LC-MS). After evaporation of the solvent, HCl (6 N, 5
mL) was added to the residue and the mixture was heated to reflux
for 8 h (or until complete hydrolysis to the amino acid was observed
by LC-MS). After cooling to r.t., the mixture was cautiously neu-
tralized with sat. aq NaHCO3. Additional sat. aq NaHCO3 (15 mL)
and dioxane (20 mL), followed by Boc2O (4.0 mmol), were added.
After 4 h (reaction monitored by LC-MS) the mixture was extracted
with EtOAc (3 × 20 mL) and the organic layer was discarded. The
aqueous layer was acidified to pH 5 with HCl (2 N) and extracted
with EtOAc (3 × 25 mL). The organic layer was washed with H2O
(25 mL), brine (20 mL), dried over MgSO4, filtered and concentrat-
ed under reduced pressure to give the product in >90% purity. The
products could be further purified on silica gel (MeOH–CH2Cl2,
0→10%).
Yield: 3.30 g (72%); colorless oil; Rf = 0.9 (EtOAc–hexane, 75%,
KMnO4 stain).
1H NMR (400 MHz, CDCl3): d = 7.49 (d, J = 2.0 Hz, 1 H), 6.27 (d,
J = 2.0 Hz, 1 H), 4.36 (t, J = 5.8 Hz, 1 H), 4.24 (t, J = 7.0 Hz, 2 H),
3.34 (s, 6 H), 2.15 (dt, J = 7.0, 5.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 140.2, 112.6, 108.4, 101.9, 53.2,
46.0, 32.8.
HRMS (ESI): m/z [M + H]+ calcd for C8H13BrN2O2: 249.0233;
found: 249.0245.
5-Chloro-1-(3,3-dimethoxypropyl)-1H-pyrazole (11b)
Prepared according to the procedure for 11a from pyrazole 10 (2.14
g, 12.6 mmol), n-BuLi (6.03 mL, 15.1 mmol) and hexachloroethane
(2.98 g, 12.6 mmol).
4-(5-Bromopyrazol-1-yl)-2-tert-butoxycarbonylaminobutyric
Acid (13a)
According to the general Strecker procedure, aldehyde 12a (1.27 g,
6.3 mmol) gave product 13a.
Yield: 1.94 g (75%); colorless oil.
Yield: 1.76 g (81%); colorless, waxy solid.
1H NMR (400 MHz, CDCl3): d = 7.47 (d, J = 2.0 Hz, 1 H), 6.18 (d,
J = 2.0 Hz, 1 H), 4.35 (t, J = 5.8 Hz, 1 H), 4.20 (t, J = 7.0 Hz, 2 H),
3.33 (s, 6 H), 2.14 (dt, J = 7.0, 5.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 139.3, 126.8, 104.5, 101.9, 53.1,
44.8, 32.6.
1H NMR (400 MHz, CDCl3): d = 9.76 (br s, 1 H), 7.53 (d, J = 2.0
Hz, 1 H), 6.32 (d, J = 2.0 Hz, 1 H), 5.44 (d, J = 7.0 Hz, 1 H), 4.45–
4.26 (m, 3 H), 2.46–2.37 (m, 1 H), 2.32–2.23 (m, 1 H), 1.43 (s,
9 H).
13C NMR (100 MHz, CDCl3): d = 173.7, 155.5, 139.9, 114.0, 109.1,
80.3, 51.2, 46.5, 32.2, 28.3.
HRMS (ESI): m/z [M + H]+ calcd for C8H13ClN2O2: 205.0738;
found: 205.0748.
HRMS (ESI): m/z [M + H]+ calcd for C12H18BrN3O4: 348.0553;
found: 348.0569.
3-(5-Bromopyrazol-1-yl)propionaldehyde (12a)
Acetal 11a (1.87 g, 7.5 mmol) was dissolved in THF (10 mL) and
cooled to 0 °C before a solution of perchloric acid (4.0 mL, 70%) in
THF (15 mL) was added. H2O (5 mL) was then added and the reac-
tion was stirred at r.t. for 6 h, the mixture was poured into sat. aq
NaHCO3 and extracted with EtOAc (2 × 50 mL). The organic layer
was washed with H2O (25 mL), brine (20 mL), dried over MgSO4,
filtered and concentrated under reduced pressure to give a pale-yel-
low oil. Purification on silica gel (EtOAc–hexane, 0→50%) gave
12a.
2-tert-Butoxycarbonylamino-4-(5-chloropyrazol-1-yl)butyric
Acid (13b)
According to the general Strecker procedure, aldehyde 12b (1.39 g,
8.8 mmol) gave product 13b.
Yield: 1.86 g (70%); colorless, waxy solid.
1H NMR (400 MHz, CDCl3): d = 7.54 (d, J = 2.0 Hz, 1 H), 6.27 (d,
J = 2.0 Hz, 1 H), 5.44 (br s, 1 H), 4.48–4.39 (m, 1 H), 4.36–4.23 (m,
2 H), 2.34–2.27 (m, 2 H), 1.43 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 173.8, 155.5, 139.2, 128.0, 105.2,
80.2, 51.2, 45.3, 32.1, 28.3.
Yield: 1.30 g (84%); colorless oil; Rf = 0.3 (EtOAc–hexane, 75%;
KMnO4 stain).
1H NMR (400 MHz, CDCl3): d = 9.84 (s, 1 H), 7.48 (d, J = 2.0 Hz,
1 H), 6.28 (d, J = 2.0 Hz, 1 H), 4.48 (t, J = 7.0 Hz, 2 H), 3.05 (t,
J = 7.0 Hz, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C12H18ClN3O4: 304.1058;
found: 304.1073.
13C NMR (100 MHz, CDCl3): d = 198.9, 140.5, 112.8, 108.7, 43.5,
3-(2-Chlorophenyl)propionaldehyde (16)
In a pressure tube under argon, 2-chloroiodobenzene (5.86 g, 24.6
mmol), allyl alcohol (2.51 mL, 36.8 mmol), Pd(OAc)2 (0.11 g, 0.5
mmol), NaHCO3 (5.16 g, 61.4 mmol) and TBACl (6.83 g, 24.6
mmol) were mixed together in anhydrous DMF (100 mL). The mix-
ture was stirred at 30 °C for 24 h before H2O (100 mL) was added.
The mixture was extracted with EtOAc (3 × 40mL) and the organic
layer was washed with H2O (25 mL), brine (20 mL), dried over
MgSO4, filtered and concentrated under reduced pressure. The re-
sulting black residue was purified on silica gel (EtOAc–hexane,
0→50%) to give 16.
43.0.
HRMS (ESI): m/z [M + H]+ calcd for C6H7BrN2O: 202.9814; found:
202.9817.
3-(5-Chloropyrazol-1-yl)propionaldehyde (12b)
Acetal 11b (1.93 g, 9.5 mmol) was hydrolyzed under the conditions
described for 12a to provide 12b.
Yield: 1.39 g (92%); pale-yellow oil.
1H NMR (400 MHz, CDCl3): d = 9.84 (s, 1 H), 7.50 (d, J = 2.0 Hz,
1 H), 6.20 (d, J = 2.0 Hz, 1 H), 4.50 (t, J = 7.0 Hz, 2 H), 3.05 (t,
J = 7.0 Hz, 2 H).
Yield: 3.00 g (73%); colorless oil.
Synthesis 2008, No. 6, 883–886 © Thieme Stuttgart · New York

886
A. Heim-Riether
PAPER
1H NMR (400 MHz, CDCl3): d = 9.83 (t, J = 1.2 Hz, 1 H), 7.35 (dd,
J = 7.3, 2.0 Hz, 1 H), 7.24 (dd, J = 7.3, 2.0 Hz, 1 H), 7.22–7.14 (m,
2 H), 3.06 (t, J = 7.4 Hz, 2 H), 2.80 (dt, J = 7.4, 1.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 201.1, 138.0, 133.8, 130.5, 129.6,
127.9, 127.0, 43.5, 26.2.
Yield: 52 mg (45%); colorless, waxy solid.
1H NMR (400 MHz, CD3OD): d = 8.38 (d, J = 4.8 Hz, 1 H), 7.79 (d,
J = 8.2 Hz, 1 H), 7.25 (dd, J = 8.2, 4.8 Hz, 1 H), 4.10 (br s, 1 H),
3.10–3.02 (m, 1 H), 2.99–2.91 (m, 1 H), 2.29–2.20 (m, 1 H), 2.06–
1.97 (m, 1 H), 1.44 (s, 9 H).
MS (EI, 70 eV): m/z (%) = 210 (100) [M(H2O) + Na + H]+.
13C NMR (100 MHz, CD3OD): d = 178.7, 159.6, 157.9, 148.2,
138.9, 138.6, 132.6, 124.2, 80.3, 32.5, 32.0, 28.8.
2-tert-Butoxycarbonylamino-4-(2-chlorophenyl)butyric Acid
(17)
According to the general Strecker procedure, aldehyde 16 (2.20 g,
13.1 mmol) gave product 17.
HRMS (ESI): m/z [M + H]+ calcd for C14H19ClN2O4: 315.1087;
found: 315.1091.
Acknowledgment
Yield: 2.25 g (55%); pale-yellow, waxy solid.
1H NMR (400 MHz, CDCl3): d = 7.33 (dd, J = 7.4, 1.5 Hz, 1 H),
7.24–7.13 (m, 3 H), 5.07 (d, J = 5.9 Hz, 1 H), 4.35 (br s, 1 H), 2.83
(t, J = 7.9 Hz, 2 H), 2.26–2.16 (m, 1 H), 2.03–1.93 (m, 1 H), 1.46 (s,
9 H).
13C NMR (100 MHz, CD3OD): d = 174.9, 156.9, 138.7, 133.7,
130.5, 129.3, 127.7, 127.0, 79.4, 53.4, 31.7, 29.6, 27.5.
We thank Scott Leonard for confirming the regiochemistry of the
halogenation by NMR, and Keith McKellop for HRMS experimen-
tation. Additional thanks to Dr. Daniel Goldberg and Dr. Neil Moss
for proofreading the manuscript and Dr. Derek Cogan for helpful
discussions.
HRMS (ESI): m/z [M – H]– calcd for C15H20ClNO4: 312.1008;
found: 312.1004.
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1892.
3-Chloro-2-(2-[1,3]dioxan-2-ylethyl)pyridine (20)
Under argon, a mixture of anhydrous CuBr (1.79 g, 12.5 mmol), an-
hydrous THF (30 mL) and dioxan-2-yl-ethylmagnesium bromide
(50 mL, 0.5 M in THF, 25.0 mmol) was stirred at –78 °C for 20 min.
2-Bromo-3-chloropyrdine (0.60 g, 3.1 mmol) was added and the re-
action mixture was stirred for 3 h at –78 °C then allowed to warm
to r.t. overnight. The reaction mixture was quenched by dropwise
addition of NH4OH (5 M, 10 mL) and then extracted with EtOAc
(3 × 20 mL). The organic layer was washed with H2O (25 mL),
brine (20 mL), dried over MgSO4, filtered and concentrated under
reduced pressure to give a brown oil. Purification on silica gel
(EtOAc–hexane, 0→50%) gave 20.
Yield: 0.40 g (56%); colorless oil.
1H NMR (400 MHz, CDCl3): d = 8.38 (dd, J = 4.8, 1.5 Hz, 1 H),
7.57 (dd, J = 8.0, 1.5 Hz, 1 H), 7.04 (dd, J = 8.0, 4.8 Hz, 1 H), 4.58
(t, J = 5.0 Hz, 1 H), 4.09–4.05 (m, 2 H), 3.76–3.69 (m, 2 H), 3.03–
2.99 (m, 2 H), 2.11–1.99 (m, 3 H), 1.32–1.26 (m, 1 H).
(3) Eskildsen, J.; Vedsø, P.; Begtrup, M. Synthesis 2001, 1053.
(4) (a) Effenberger, F.; Krebs, A. J. Org. Chem. 1984, 49, 4687.
(b) Butler, D. E.; Alexander, S. M. J. Org. Chem. 1972, 37,
215.
(5) For acetal cleavage with HClO4, see: Heath, R. R.; Doolittle,
R. E.; Sonnet, P. E.; Tumlinson, J. H. J. Org. Chem. 1980,
45, 2910.
13C NMR (100 MHz, CDCl3): d = 158.6, 147.1, 136.5, 131.2, 122.2,
101.6, 66.9, 33.1, 29.7, 25.8.
HRMS (ESI): m/z [M + H]+ calcd for C11H14ClNO2: 228.0785;
found: 228.0792.
2-tert-Butoxycarbonylamino-4-(3-chloropyridin-2-yl)butyric
Acid (21)
Acetal 20 (192 mg, 0.8 mmol) was hydrolyzed under the conditions
described for 12a providing 3-(2-chloropyridin-2-yl)propionalde-
hyde.
(6) For synthesis of a-aminonotriles, see: Mai, K.; Patil, G.
Tetrahedron Lett. 1984, 25, 4583.
(7) A synthesis of 17 with Br instead of Cl has been reported
using a Pd-catalyzed coupling of an amino-functionalized
organozinc reagent with 2-bromoiodobenzene: Deboves, H.
J. C.; Hunter, C.; Jackson, R. F. W. J. Chem. Soc., Perkin
Trans. 1 2002, 733.
(8) Jeffrey, T. J. Chem. Soc., Chem. Commun. 1984, 1287.
(9) Bell, T. W.; Hu, L.-Y.; Patel, S. V. J. Org. Chem. 1987, 52,
3847.
Yield: 108 mg (76%); pale-yellow oil.
1H NMR (400 MHz, CDCl3): d = 9.80 (br s, 1 H), 8.42 (d, J = 4.5
Hz, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.14 (dd, J = 8.0, 4.5 Hz, 1 H),
3.30 (t, J = 7.0 Hz, 2 H), 2.94 (dt, J = 7.0, 1.2 Hz, 2 H).
MS (EI, 70 eV): m/z (%) = 170.4 (100) [M + H]+.
According to the general Strecker procedure, 3-(2-chloropyridin-2-
yl)propionaldehyde (62 mg, 0.4 mmol) gave product 21.
Synthesis 2008, No. 6, 883–886 © Thieme Stuttgart · New York