Conversion of alanine and phenylalanine into weinreb amides by using different protecting groups

Article abstract of DOI:10.14233/ajchem.2014.16621

Efficient conversions of amino acids into Weinreb amides were achieved by treatment of amino acids with N,O-dimethylhydroxylamine hydrochloride in basic media. The amino group (-NH₂) of amino acids were protected with p-toluene sulphonyl chlori

Full text of DOI:10.14233/ajchem.2014.16621

Asian Journal of Chemistry; Vol. 26, No. 20 (2014), 6733-6736
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.16621
Conversion of Alanine and Phenylalanine into Weinreb Amides by Using Different Protecting Groups
*
ZULFIQAR ALI , SYEDA RUBINA GILANI, HABIB HUSSAIN and IMDAD HUSSAIN
Department of Chemistry, University of Engineering and Technology, Lahore, Pakistan
*Corresponding author: Tel: +92 321 4947884; E-mail: zulfi_ali_4@yahoo.com
Received: 1 November 2013;
Accepted: 17 January 2014;
Published online: 25 September 2014;
AJC-16000
Efficient conversions of amino acids into Weinreb amides were achieved by treatment of amino acids with N, O-dimethylhydroxylamine
hydrochloride in basic media. The amino group (-NH2) of amino acids were protected with p-toluene sulphonyl chloride (-OTs) and
diphenyl phosphinic chloride (-dpp) to get high yield of the product. The products were purified by flash chromatography and characterized
by spectroscopic techniques.
Keywords: Weinreb amides, p-Toluene sulphonyl chloride, Diphenyl phosphinic chloride.
INTRODUCTION
EXPERIMENTAL
Weinreb and Nahm1 designed a method in 1981 to synthe-
size N-methoxy-N-methylamides (Weinreb amides) and
ketones. This functional group has been widely used as versa-
tile synthetic intermediates in organic synthesis2. Recently,
increasing attention has been paid to N-methoxy-N-methyl-
amides (Weinreb amides) owing to their versatile reactivity
with nucleophiles and selective reduction to aldehydes.
Weinreb amides derived from amino acids have found exten-
sive use in the preparation of α-amino aldehydes3 and α-amino
ketones4. Most direct conversions of carboxylic acids into the
corresponding Weinreb amides have utilized peptide-coupling
reagents such as benzotriazol-1-yl-N-oxy-tris- (dimethyl-
amino) phosphonium hexafluorophosphate (BOP)5 N,N'-dicyclo-
hexylcarbodiimide (DCC)6 or propylphosphonic anhydride/
N-ethyl morpholine7.
Carboxylic acids including alanine, phenyl alanine, p-
toluene sulphonyl chloride, diphenyl phosphinic chloride, N,
N-dicyclohexyl carbodiimide and other solvents of analytical
grade were purchased from sigma Aldrich.
Synthesis of tosyl alanine (Fig. 1) (3): To the suspension
of D-alanine (1 g, 11.2 mmol) in 25 mL water at room tempe-
rature, NaOH (1.34 g, 33.6 mmol) and p-toluene sulfonyl
chloride (2.56 g, 13.4 mmol) were added10. The mixture was
stirred at 60 °C for 6 h. The combined basic layers were cooled
to 0 °C and acidified (pH = 1) by the addition of conc. HCl.
The precipitates were collected by filtration, washed with cold
water and air dried to give tosyl alanine as a white solid (0.90 g,
33 %).
Ts
O
O
In synthetic organic chemistry appropriate protecting
groups are required to prevent the formation of undesired bonds
and side reactions8,9. However tosyl group (-OTs) is extensively
used in -NH2 protection and -OH protection in amino acids
and amino alcohols. Tosylamine is the intermediate, when
-NH2 group is protected with tosyl group. This intermediate
leads to form weinreb amides and other novel annulated
products. At the end of the reaction -Ts group is removed in
acidic media. Since diphenyl phosphinic chloride (-dpp)
protected weinreb amides are not reported in the literature. In
this research along with tosyl group, -dpp group is used in
protection of -NH2 group which leads to form weinreb amides.
At the end of the reaction -dpp group is removed in very weak
acidic media.
H2O
HN
+
Cl
S
OH
NaOH
NH2
O
O
OH
(1)
(3)
(2)
Fig. 1. Synthesis of tosylalanine
Synthesis of weinreb amide of tosyl alanine (Fig. 2)
(5): A solution of D or L-Tosyl alanine (1 g, 4.11 mmol), N-
methyl morpholine (0.45 g, 4.53 mmol), N,O-dimethyl-
hydroxylamine. HCl (0.44 g, 4.53 mmol) in anhydrous CH2Cl2
(16.6 mL) is cooled to 0 °C under argon and treated with N,N-
dicyclohexyl carbodiimide (0.93 g, 4.53 mmol) portion wise
over 10 min11. Stirring was done at 0 °C for 3 h followed by a

6734 Ali et al.
Asian J. Chem.
O
Ts
O
O
OH
+
H
N
N-m.morpholine
HN
CH
3
CH3
N
CH
3
DCM
CH3
+
OH
.HCl
3
NH
Ts
N
NH
.HCl
NH
OCH
CH Cl
2
OCH3
HN
OCH3
2
N .m.morpholine
Ts
OCH
O
Ts
(7)
3
(4)
(5)
(4)
(3)
(8)
Fig. 2. Synthesis of weinreb amide
Fig. 4. Synthesis of weireb amide of phenylalanine
further 15 h at room temperature, then filtered through celite
and concentrated under reduced pressure. The residue was then
dissolved in CH2Cl2 (50 mL) and washed with saturated
aqueous NaHCO3 (2 × 10 mL), brine (1 × 10 mL) and dried
with MgSO4. The resulting crude oil was then purified by flash
chromatography, eluting with 50 % EtOAc/ Pet. Ether to give
desired Weinreb amide as opaque oil after concentration under
reduced pressure (0.55 g, 47 % yield).
dpp
O
O
Et3N
HN
Ph
P
Cl
+
OMe
Cl
CH2Cl2
Ph
NH3
(9)
O
OMe
(11)
(10)
Fig. 5. Synthesis of dpp-alanine methyl ester
diphenyl phosphonic chloride (1.6 mL, 8.60 mmol) in the
presence of triethyl amine (3 mL, 21.50 mmol) at 0 °C12. The
stirring of whole reaction mixture was done at about 4 h at
room temperature. Completion of the reaction mixture was
determined by LC-MS. The reaction mixture was quenched
with saturated aq. NaHCO3 and the product was extracted with
CH2Cl2 (3 × 10 mL). The organic layers were combined, dried
with MgSO4. Crude product (2.07 g, 95 % yield) was obtained
by evaporating dichloromethane.
Synthesis of tosyl phenylalanine (Fig. 3) (7): To the sus-
pension of D-phenylalanine (1 g, 6 mmol) in 25 mL water at
room temperature, NaOH (0.72 g, 18 mmol) and p-toluene
sulfonyl chloride (1.37 g, 7.2 mmol) were added10. The mix-
ture was stirred at 60 °C for 6 h. Acid base washed method
was used to collect product from the reaction mixture. 3M
Conc. HCl and EtOAc were added to the reaction mixture.
The starting material (D-phenylalanine) was protonated and
shifted to the aqueous phase and product was shifted to the
organic phase at pH = 1. Product was then deprotonated by
adding by adding 2M NaOH aqueous solution to the organic
phase and it was come back to the aqueous phase at pH =11-
12. At the end, product was protonated by adding 3M HCl
and was collected in organic phase. The organic phase is
washed with brine, dried with MgSO4 and product was ob-
tained (1.80 g, 95 %) by evaporating the solvent.
Basic hydrolysis of dpp-alanine methyl ester
hydrochloride (Fig. 6) (12): Dpp-alanine methylester (1 g,
3.30 mmol) was suspended in freshly distilled 1,4-dioxane
(7.7 mL) and 2M sodium hydroxide (1.9 mL) was added13.
The reaction mixture was stirred for 5 min at room temperature;
colourless solution was stirred for 1 h. Consumption of the
starting material was monitored by TLC. The reaction was
acidified to pH 3-4 with saturated aqueous citric acid causing
a white gum to separate which was extracted with ethyl acetate
(3 × 10 mL). The combined organic phase was washed with
water (1 × 50 mL), brine (2 × 50 mL) and dried with anhydrous
MgSO4. Evaporation of the solvent gave crude (0.93 g, 98 %
yield).
O
O
OH
O
S
OH
NH
H2O
+
Cl
NH2
NaOH
O
Ts
dpp
HN
dpp
HN
(2)
Fig. 3. Synthesis of tosyl phenylalanine
(7)
(6)
R.T
+
NaOH
1,4-dioxane
O
OH
O
OMe
Synthesis of weinreb amide of tosyl phenylalanine (Fig.
4) (8): A solution of D-tosylphenylalanine (0.9 g, 2.5 mmol),
N-methyl morpholine (0.25 g, 2.47 mmol), N,O-dimethyl-
hydroxy-lamine. HCl (0.24 g, 2.46 mmol) in anhydrous CH2Cl2
(15 mL) is cooled to 0 °C under argon and treated with N,N-
dicyclohexyl carbodiimide (0.52 g, 2.52 mmol) portion wise
over 10 min11. The reaction mixture was stirred at 0 °C for 3 h
followed by a further 15 h at room temperature, then filtered
through celite and concentrated under reduced pressure. The
CH2Cl2 (50 mL) was used to dissolve residue, washed with
saturated aqueous NaHCO3 (2 × 10 mL), brine (1 × 10 mL)
and dried with MgSO4. The resulting crude oil was then purified
by flash chromatography, eluting with 50 % EtOAc/ Pet. Ether
to give desired Weinreb amide as opaque oil after concentration
under reduced pressure (0.54 g, 59 % yield).
(12 )
(11)
Fig. 6. Synthesis of dpp-alanine
Synthesis of weinreb amide of diphenylphosphinyl
Alanine (Fig. 7) (13): A solution of dpp-alanine (1 g, 3.45 mmol),
N-methyl morpholine (0.42 mL, 3.80 mmol), N,O-dimethyl-
hydroxy-lamine. HCl (0.38 g, 3.80 mmol) in anhy-drous CH2Cl2
(14 mL) is cooled to 0 °C under argon and treated with N,N-
dicyclohexyl carbodiimide (0.78 g, 3.80 mmol) portion wise over
10 min11. The reaction mixture was stirred at 0 °C for 3 h followed
by a further 15 h at room temperature, then filtered through silica
plug and concentrated under reduced pressure. The residue was
dissolved in CH2Cl2 (50 mL) and washed with saturated aqueous
NaHCO3 (2 × 10 mL), brine (1 × 10 mL) and dried with MgSO4.
The resulting crude oil was purified by flash chromatography,
eluting with 5 % MeOH in DCM to give desired Weinreb amide
after concentration under reduced pressure (0.47 g, 41 % yield).
Synthesis of dpp-alanine methyl ester hydrochloride
(Fig. 5) (11): D-alanine methyl ester hydrochloride (1 g, 7.16
mmol) in anhydrous CH2Cl2 (18 mL, 0.4 M) was treated with

Vol. 26, No. 20 (2014)
Conversion of Alanine and Phenylalanine into Weinreb Amides by Using Different Protecting Groups 6735
dpp
665 (CH bending). δH (300 MHz; CDCl3) 7.69 (2 H, d, J 8.3
O
H
N-m.morpholine
HN
CH3
ArH ), 7.23-7.26 (2 H, m, ArH), 5.63 (1 H, d, J 9.3, NH),
4.26-4.36 (1 H, dq, J 6.9, 9.3, CH), 3.52 (3 H, s, OCH3), 2.96
(3 H, s, CH3), 2.37 (3 H, s, ArCH3), 1.27 (3 H, d, J 6.9, CH3).
δC (75 MHz; CDCl3) 172.4 (CO), 143.5 (C), 137.2 (C), 129.6
(ArCH), 127.4 (ArCH), 127.2 (CH), 61.5 (OCH3), 48.9 (CH3),
21.6 (ArCH3), 20.0 (CH3). Rf 0.24 (EtOAC-P.E, 50:50).
Tosyl phenylalanine: IR (film, νmax, cm-1) 3321 (N-H
Stretch), 3030 (sp2 C-H Stretch), 2925(sp3 C-H Stretch), 1710
(C=O Stretch), 1455 (C=C Stretch), 1330 (C-N Stretch), 684
(CH bending). δH (300 MHz; CDCl3) 7.59 (2 H, d, J 8.3,ArH),
7.20-7.26 (5 H, m, ArH ), 7.06-7.09 (2 H, m, ArH), 5.00 (1 H,
d, J 8.6, NH ), 4.18-4.24 (1 H, ddd, J 11.7, 8.6,5.6, CH), 3.07-
3.13 (1 H, dq, J 13.7, 5.6, -ArCHHCH), 2.97-3.04 (1 H, dq,
J 13.7, 5.6, -ArCHHCH), 2.41 (3 H, s, ArCH3). δC (75 MHz;
CDCl3) 173.1 (CO), 143.2 (C), 137.7 (C), 136.5 (C), 129.2
(ArCH), 128.1 (ArCH), 126.8 (ArCH), 126.6 (ArCH), 57.5
(CH), 38.7 (CH2), 20.3 (ArCH3). Rf 0.23 (EtOAC-P.E, 50:50).
N
CH3
+
.HCl
NH
dpp
N
OCH3
CH2Cl2
O
OH
OCH3
(13)
(4)
Fig. 7. Synthesis of weinreb amide
(12)
IR spectra were recorded on a Perkin-Elmer FT-IR 783
spectrophotometer. Varian NMR (400 MHz) spectrometer
(model DMX 400) was used for 1H NMR and 13C NMR measure-
ments. For protons, the chemical shifts were measured relative
to tetramethylsilane (TMS) at δ = 0 ppm.
RESULTS AND DISCUSSION
Table-1 comprises the product and their yield.
TABLE-1
PRODUCT WITH THEIR YIELDS
Weinreb amide of tosyl phenylalanine: IR (film, νmax
,
Entry
Number
Starting Material
Product
Yield (%)
33
cm-1) 3236 (N-H Stretch), 2928 (sp3 C-H Stretch), 1647 (C=O
Stretch), 1454 (C=C Stretch), 1331 (C-N Stretch), 1155 (C-O
Stretch), 665 (CH bending). δH (300 MHz; CDCl3) 7.60 (2 H,
d, J 8.2, ArH ), 7.07-7.26 (7 H, m, ArH), 5.56-5.59 (1 H, d, J
9.6, NH), 4.48-4.55 (1 H, dt, J 13.3, 9.6, 7.0, CH), 3.40 (3 H,
s, OCH3), 2.95-2.99 (1 H, dd, J 13.3, 7.5, -ArCHHCH), 2.93
(3 H, s, CH3), 2.81-2.86 (1 H, dd, J 13.3, 7.5, -ArCHHCH),
2.36(3 H, s, ArCH3). δC (75 MHz; CDCl3) 171.3 (CO), 143.4
(C), 137.0 (C), 135.9 (C), 129.7 (ArCH), 128.5 (ArCH), 127.3
(ArCH), 127.01 (ArCH), 61.4 (CH), 54.2 (CH2), 39.8 (OCH3),
32.2 (CH3), 21.6 (ArCH3). Rf 0.32 (EtOAC-Pet.Ether, 50:50).
m.p around room temperature; m/z (ESI) 362 ; HRMS (ESI)
calcd for C18H22N2O4S; C18H22N2O4SNa+ 385.11 Mass analysis
for mass 385.1181000 and found to be 385.1192490.
O
Ts
HN
1
2
OH
NH2
O
OH
Ts
O
H
N
HN
CH
3
47
95
Ts
N
OCH3
O
OH
O
O
OH
OH
NH2
3
4
NH
Ts
O
O
OH
CH3
N
59
HN
OCH3
NH
dpp-Alanine methyl ester hydrochloride: IR (film, νmax
,
Ts
cm-1) 3166 (N-H Stretch), 2987(sp2 C-H Stretch), 2880(sp3
C-H Stretch), 1737 (C=O Stretch), 1454 (C=C Stretch), 1331
(SO2 Stretch), 1155 (SO2 Stretch), 721 (P=O Stretch), 665 (CH
bending). δH (400 MHz; CDCl3) 7.73-7.91 (5 H, m,ArH), 7.41-
7.49 (5 H, m,ArH), 4.06-4.13 (1 H, dq, J 14.4, 6.8, CH3CHNH-),
3.91 (1H, d, J 6.8, CH3CHNH-), 3.69 (3 H, s, CH3O-), 1.42 (3
H, d, J 6.8, CH3CHNH-); δC (100 MHz; CDCl3) 174.6 (-CO),
132.8-133.4 (m,ArC), 131.9-132.3 (m,ArC), 131.2-131.7 (m,
ArC), 128.5-128.7 (dd, J 12.7, 4, ArC), 52.5 (-OCH3), 49.3
(CH3CHNH-), 22.0 (CH3CHNH-), Rf 0.18 (EtOAC-P.E, 50:50).
dpp-Alanine: IR (film, νmax, cm-1) 3343(-OH Stretch),
3060 (N-H Stretch), 2973(sp2 C-H Stretch), 2876(sp3 C-H
Stretch), 1723 (C=O Stretch), 1438 (C=C Stretch), 1284 (SO2
Stretch), 1123 (SO2 Stretch), 726 (P=O Stretch), 691 (CH
bending). δH (400 MHz; CDCl3) 9.8 ( 1 H, br. s, -OH), 7.84-
7.96 (4 H, m, ArH), 7.40-7.57 (6 H, m, ArH), 3.90 (d, J 5.1
Hz, CH3CHNH-), 3.78-3.85 (1 H, m, CH3CHNH-), 1.39 (3 H,
d, J 6.8, CH3CHNH-), δC (100 MHz; CDCl3) 175.2 (-CO),
132.9-133.2 (m,ArC), 132.4-132.7 (m,ArC), 131.5-131.7 (m,
ArC), 128.6-128.8 (dd, J 13.2, 5.5, ArC), 49.6 (CH3CHNH-),
21.3 (CH3CHNH-), Rf 0.46 (EtOAC-P.E, 9:1).
Ts
dpp
O
HN
OMe
Cl
5
6
7
95
98
41
N H3
O
OMe
OH
dpp
HN
d pp
H N
O
O
d pp
H N
OMe
O H
O
H
N
CH3
dpp
N
OCH3
O
Tosyl alanine: IR (film, νmax, cm-1) 3270 (N-H Stretch),
3068 (sp2 C-H Stretch), 2981(sp3 C-H Stretch), 1710 (C=O
Stretch), 1423 (C=C Stretch), 1340 (C-N Stretch), 678 (CH
bending). δH (300 MHz; CDCl3) 9.39 (1 H, s, COOH), 7.73 (2
H, d, J 8.3,ArH ), 7.28 (2 H, d, J 8.3, ArH), 5.35-5.38 (1 H, d,
J 8.3, NH), 3.95-4.05 (1 H, dq, J 7.2, 8.3, CH), 2.41 (3 H, s,
ArCH3), 1.40 (3 H, d, J 7.2, CH3). δC (75 MHz; CDCl3) 177.1
(CO), 144.1 (C), 136.8 (C), 129.9 (ArCH), 127.3 (ArCH), 51.2
(CH), 21.6 (ArCH3), 19.7 (CH3).
Rf 0.30 (EtOAC-P.E, 50:50).
Weinreb amide of diphenylphos-phinyl alanine: IR
(film, νmax, cm-1) 3269 (N-H Stretch), 3057(sp2 C-H Stretch),
2979 (sp3 C-H Stretch), 1654 (C=O Stretch), 1438 (C=C
Stretch), 1384 (SO2 Stretch), 1195 (SO2 Stretch), 724 (P=O
Winreb amide of tosyl alanine: IR (film, νmax, cm-1) 3260
(N-H Stretch), 2978 (sp3 C-H Stretch), 1651 (C=O Stretch),
1416 (C=C Stretch), 1331 (C-N Stretch), 1152 (C-O Stretch),

6736 Ali et al.
Asian J. Chem.
Stretch), 698 (CH bending). δH (400 MHz; CDCl3) 7.82-7.93
(4 H, m, ArH), 7.38-7.51 (6 H, m, ArH), 4.18-4.28 (1 H, m,
CH3CHNH-),3.94-3.99 (1H, t, J 10.3, CH3CHNH-), 3.37 (3
H, s,-NOCH3), 3.14 (3 H, s, -NCH3), 1.36 (3 H, d, J 6.8,
CH3CHNH-), δC (100 MHz; CDCl3) 174.4 (-CO), 133.0-133.4
(m,ArC), 132.1-132.4 (m,ArC), 131.7-131.9 (m,ArC), 128.4-
128.6 (dd, J 12.5, 1.6, ArC), 61.2 (CH3CHNH-), 46.3
(-NOCH3), 32.0 (-NCH3), 21.8 (CH3CHNH-), Rf 0.41 (MeOH-
DCM, 5:95); m.p. 89-90 °C; m/z (ESI) 332.13; HRMS (ESI) calcd.
for C17H21N2O3PH+ 332.13, found 333.13; C17H21N2O3PNa+
335.11 Mass analysis for mass 355.1174520 and found to be
355.1182002.
is clear from above results that yield of -dpp protectedWeinreb
amide is low as compared to -OTs protected Weinreb amides.
This is due to the large steric bulk of -dpp group than -OTs
group. Similarly some amount of -dpp protected Weinreb
amide was decomposed during product purification.
ACKNOWLEDGEMENTS
The authors are thankful to Higher Education Commission
of Pakistan for providing research funds and moreover thankful
to the Department of Chemistry, University of Engineering
and Technology, Lahore, Pakistan and School of Chemistry,
University of Bristol, UK for guidance, research and laboratory
facilities.
Three different Weinreb amides were prepared 5, 8 and
13 by using different protecting groups and excellent results
were obtained. In synthesize of Weinreb amides -NH2 group
was protected in amino acids. Since amino acids and alcohols
have poor leaving groups in SN2 reactions. This is the reason
for tosylate group must be introduced. Since -OTs group can
be deprotected easily in acidic media so tosylamines are
converted into corresponding Weinreb amides 5,8.
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product remained in celite and deprotected due to its acidic
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Conclusion
Diphenyl phosphinic chloride (dpp-) protection was stable
to bases and catalytic hydrogenation but sensitive to acids. It
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