C
Synthesis
B. C. Hamper et al.
PSP
1
H NMR (500 MHz, CDCl , 50 °C): δ = 9.25 (br s, 1 H), 6.36 (d, J =
6.8 Hz, 1 H), 6.20 (br s, 1 H), 5.66 (d, J = 10.9 Hz, 1 H), 4.95 (s, 1 H),
.94 (t, J = 10.0 Hz, 1 H), 3.59 (m, 1 H), 1.78 (m, 3 H), 1.60 (m, 3 H).
All reactions were carried out in oven-dried glassware under an at-
mosphere of nitrogen unless otherwise noted. Dichloromethane
3
1
3
(
CH Cl ) was dried over calcium hydride (CaH ). Commercial reagents
2
2
2
13
of high purity were purchased and used without further purification.
Hydroxylamine, polymer bound on Wang resin, was obtained from
NovaBiochem (Millipore Sigma, PN 8.55117; 1.9 mmol/g). Reactions
were monitored by thin-layer chromatography (TLC) using TLC silica
C NMR (125 MHz, CDCl , 50 °C): δ = 164.6 (C=O, very br s), 127.6
3
(br s), 103.1, 63.0, 34.2, 28.4, 25.3, 19.0.
MS (FAB+): m/z (%) = 194 (40) [M + Na], 176 (40), 73 (100).
HRMS (FAB+): m/z calcd for C H NO Na: 194.0793; found: 194.0790.
gel 60 Å 254 nm plates and visualizing with UV light or KMnO stain.
8
13
3
4
Silica gel (230–400 mesh) was used for flash column chromatography.
IR spectra were obtained with a Thermo Nicolet Avatar 360 FTIR
spectrophotometer. NMR spectra were recorded in CDCl or DMSO-d
Anal. Calcd for C H NO : C, 56.13; H, 7.65; N, 8.18. Found: C, 56.39;
8 13 3
H, 7.73; N, 8.16.
3
6
1
13
1
at 300 or 500 ( H) and 75 or 125 ( C) MHz, respectively. H NMR
Acrylohydroxamic Acid (1)
spectra were referenced to residual CHCl (7.27 ppm) or DMSO-d6
3
To a solution of 4 (1.71 g) in MeOH (40 mL) was added p-toluenesul-
13
(
2.54 ppm), C NMR spectra were referenced to the center line of
fonic acid monohydrate (TsOH·H O; 200 mg). After 90 min, the reac-
2
CDCl (77.2 ppm) or DMSO (40.4 ppm). Coupling constants, J, are re-
3
tion was complete as determined by TLC [R = 0.40 (EtOAc)]. The mix-
f
ported in Hz. Reverse-phase HPLC analysis was conducted with an
Agilent 1100 system equipped with UV diode array and ELS detectors.
A Zorbax XBD-C18 column was employed using gradient of 95%
H O/5% CH CN to 95% CH CN over 6 min followed by a hold of 95%
ture was concentrated at r.t. to give an oil, which was purified by
chromatography (silica; EtOAc) to give 1.
Yield: 0.51 g (58.6%); white solid; mp 83–84 °C.
2
3
3
CH CN for 3 min. Mobile phase solvents were prepared from HPLC
IR (ATR): 3202 (NH), 3032, 2811, 1650 (C=O), 1596 (C=C), 1547, 1054,
969 cm .
3
–1
grade CH CN and H O containing 0.1% TFA.
3
2
1
H NMR (300 MHz, DMSO-d ): δ = 10.82 (br s, 1 H), 9.08 (br s, 1 H),
6
O-Resin-Bound Acrylohydroxamic Acid (4)
6.14 (m, 2 H), 5.66 (dd, J=8.1, 3.6 Hz, 1 H).
A mixture of hydroxylamine Wang resin (NovaBiochem PN 8.55117;
13
C NMR (75 MHz, DMSO-d ): δ = 163.2 (C=O), 129.7, 125.9.
6
0
.53 g, 1.9 mmol/g, 1.0 mmol) in CH Cl (10 mL) was prepared in a
2 2
MS (FAB+): m/z (%) = 219 (100) [M+Cs], 176 (40), 110 (30) [M + Na].
peptide reactor and agitated for 10 min. The resulting suspension was
treated sequentially with triethylamine (0.35 mL, 0.253 g; 2.5 mmol)
and acryloyl chloride (0.16 mL, 0.181 g, 2.0 mmol). The reaction was
agitated for 2 h, filtered, and retreated with CH Cl (10 mL), triethyl-
HRMS (FAB+): m/z calcd for C H NO Cs: 219.9375; found: 219.9375.
3
5
2
Anal. Calcd for C H NO : C, 41.38; H, 5.79; N, 16.09. Found: C, 41.58;
H, 5.85; N, 16.03.
3
5
2
2
2
amine (0.35 mL) and acryloyl chloride (0.16 mL). After agitation for
h, the mixture was filtered and washed sequentially three times
each with CH Cl , MeOH, DMF, MeOH, and CH Cl . The resin was dried
A sample for X-ray crystallography was prepared by room-tempera-
ture recrystallization. A solution of 1 in EtOAc was treated slowly with
hexanes and allowed to crystallize over a period of 7 days to afford
long needles of a white, crystalline solid (mp 83–84 °C). Spectral
properties were identical to those of the previously obtained materi-
2
2
2
2
2
overnight in a vacuum oven at r.t. to afford 4 as an amber resin.
IR (ATR): 3026, 2920, 1751, 1698, 1612.
al. Crystal data: Monoclinic space group C2/c; a = 11.6765(9) Å, b =
Treatment of resin 4 (94 mg) with a 1:1 mixture of CDCl and TFA (1
3
3
8.7896(6) Å, c = 8.0357(5) Å, β = 100.178(5)°; V = 811.74(10) Å ; R1 =
mL) afforded direct cleavage of the products in an NMR compatible
1
0.0471, wR2 = 0.136.
solvent. Analysis of the filtrate by H NMR showed a mixture of prod-
ucts corresponding to acrylic acid and the desired acrylohydroxamic
acid (1). Further attempts at chromatographic purification or crystal-
lization led to a loss of product 1.
Funding Information
This work was supported by a contract from ALKYMOS, Inc. Funding
for the ApexII diffractometer was provided by the National Science
N-(Tetrahydro-2H-pyran-2-yloxy)acrylamide (5)
To a solution of acrylic acid (0.72 g, 10 mmol) and O-(tetrahydro-2H-
Foundation (MRI, CHE-0420497).
N
oaitn
a
l
Secince
F
o
u
n
d
oaitn
C(
H
E-0
4
2
0
4
9
7)
pyran-2-yl)hydroxylamine (THP-ONH ; 1.29 g (11.0 mmol) in CH Cl
2
2
2
(15 mL) cooled in an ice-water bath was added dropwise a solution of
N,N′-dicyclohexylcarbodiimide (DCC; 2.27 g, 11.0 mmol) in CH Cl2
2
Acknowledgment
(
20 mL). The addition rate was controlled to keep the reaction tem-
perature below 5 °C. After stirring for 1 h, the reaction mixture was
filtered through Celite and concentrated to give an oily, white solid.
Recrystallization from CCl4 (25 mL) afforded 5 (1.38 g, 80.6%) as a
white, crystalline solid (mp 100–101 °C). Further purification by sili-
ca chromatography (50%, EtOAc/hexanes) gave the product.
We thank Mr. Joe Kramer and Professor R.E.K. Winter for mass spec-
tra.
Supporting Information
Yield: 1.06 g (61.9%); white solid; mp 102.5–103 °C; HPLC (C18 reverse
Supporting information for this article is available online at
phase): t = 1.037 min (>98% by UV210 and 254); TLC: R = 0.71 (100%
R
f
https://doi.org/10.1055/s-0036-1589103.
S
u
p
p
ortioIgnfmr oaitn
S
u
p
p
o
nrtogI
i
f
rm oaitn
EtOAc).
IR (ATR): 3181 (NH), 2989, 2946, 1656 (C=O), 1626 cm–1
.
NMR data was obtained at 50 °C to overcome broad resonance peaks
due to hindered rotation.
References
(1) Roy, S.; Sutivisedak, N.; Hamper, B. C.; Lyss, A. M.; Spilling, C. D.
Synthesis 2015, 47, 3669.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–D