Identification of 1,5,7-Triazabicyclododecene and Polystyrene-Supported Superbases as Efficient Hydroxylaminolysis Agents of Sterically Hindered and Epimerizable Esters

Article abstract of DOI:10.1055/s-0036-1591551

In modern pharmaceutical research, the need for reliable protocols for the preparation of chemical libraries in a controlled manner is quintessential to driving the Design-Make-Test cycle in drug discovery programs. In this letter, we communicate the iden

Full text of DOI:10.1055/s-0036-1591551

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
en
R. Pierre et al.
Letter
Synlett
Identification of 1,5,7-Triazabicyclododecene and Polystyrene-
Supported Superbases as Efficient Hydroxylaminolysis Agents of
Sterically Hindered and Epimerizable Esters
Boc
Romain Pierre
N
H
N
O
O
R
O
Frédéric Gaigne
Ghizlane El-Bazbouz
Grégoire Mouis
Gilles Ouvry
R
Nuc
Nucleophile, MeOH, r.t.
R
R =
NH2OH, MeOH, r.t.
S
OH
Ph
N
O
O
H
O
H
H
N
N
N
N
N
3 examples
up to 90% yield
4 examples
up to 78% yield
N
N
N
O
O
TBD
TBD
or PS-DBU
Ph
N
H
Ph
N
H
Loic Tomas*
0
0
0
0
0-
0
0
3
3-
9
9
0
3-
7
5
2
99:1 er
94:6 er
screening of
11 organobases and 10 solvents
Craig S. Harris*
Nestlé Skin Health R&D, 2400 Route de Colles,
06410 Biot, France
Loic.tomas@galderma.com
Craig.harris@galderma.com
Received: 07.12.2017
Accepted after revision: 18.02.2018
Published online: 13.04.2018
O
H
N
N
H
OH
DOI: 10.1055/s-0036-1591551; Art ID: st-2017-d0882-l
O
H
H
N
N
S
OH
Abstract In modern pharmaceutical research, the need for reliable
protocols for the preparation of chemical libraries in a controlled man-
ner is quintessential to driving the Design-Make-Test cycle in drug dis-
covery programs. In this letter, we communicate the identification of
1,5,7-triazabicyclododecene and polystyrene-supported superbases as
efficient hydroxylaminolysis agents of sterically hindered and epimeriz-
able esters and, to some extent, amides, using iChem Explorer® as the
conditions scouting tool.
Vorinostat
O
O
O
Belinostat
O
OH
N
H
H
N
HN
Panobinostat
Key words hydroxylaminolysis, hydroxamic acid, TBD, polymer-sup-
ported superbases, superbases, non-racemizing process
Figure 1 Pan-HDAC inhibitors having the hydroxamic acid functional-
ity recently approved by the FDA
With the recent approvals of the histone deacetylase
(HDAC) inhibitors1 Voronistat,2 Belinostat,3 and Panobinos-
tat4 for the treatment of cutaneous T cell lymphoma (CTCL),
peripheral T-cell lymphoma and multiple myeloma, the hy-
droxamic acid group has come under the spotlight (Figure
1).5 The hydroxamic acid group binds to the zinc ion pres-
ent in the active site of HDAC proteins. Inhibition of HDAC
modifies cellular events such as proliferation, differentia-
tion, and apoptosis, thereby making it a particularly attrac-
tive target for cancer therapies.6
In a recent letter, we disclosed the advantages of using
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in solution to re-
duce reaction times and increase yields of hydroxamic acids
from carboxylic acid esters.7 In this letter, we describe the
discovery that 1,5,7-triazabicyclododecene (TBD) signifi-
cantly accelerates the hydroxylaminolysis of hindered
esters even more and report its utilization for common
aminolysis reactions. Moreover, we show that the hydroxyl-
aminolysis process using polymer-supported superbases, in
particular polymer-supported DBU, proceeds with minimal
in situ epimerization while significantly accelerating the re-
action rate compared with the standard protocol.
Our first screening, using iChem Explorer® as the scout-
ing tool,8 focused on the choice of base to examine whether
we could improve further the crude reaction profiles com-
pared with that obtained with DBU using hindered ester 1
as the substrate.7 Table 1 summarizes the results obtained
from a selection of common nucleophilic and non-nucleop-
hilic organobases with a large range of pKa.9
Nucleophilic aromatic bases such as pyridine and DMAP
give no trace of product. Both DIPEA and DABCO also result-
ed in no conversion (entries 4 and 5). Perhaps surprisingly,
the weaker amidine base DBN (entry 7) afforded just 35% of
hydroxamic acid product 3 compared with 70% when DBU
was used (entry 6). However, cyclic guanidine bases, 1,5,7-
triazabicyclododecene (TBD) and 7-methyl-1,5,7-triazabi-
cyclo(4.4.0)dec-5-ene (MTBD) proved superior to DBU,
completing the reaction after just 30 h vs. 48 h and gave the
best ratio of hydroxamic acid product to carboxylic acid by-
product (entries 8, 9 vs. 6). Finally, acyclic guanidine bases
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
R. Pierre et al.
Letter
Synlett
Table 1 Effect of Base on Hydroxamic Acid Formation
O
O
O
O
O
O
O
O
O
N
N
N
base (3 equiv)
O
O
O
O
O
O
H
50% NH2OH (aq)
(10 equiv)
MeOH (4 vol)
0 °C to r.t.
S
O
S
N
S
OH
Ph
N
Ph
N
OH
Ph
N
H
H
H
1
2
3
Ratio (%)b
Yield of 3 (%)
a
Entry
Base
pKa
Time(h)
1
2
3
1
2
none
48
48
48
48
48
48
48
30
30
48
48
48
100
100
100
100
100
–
–
–
–
–
pyridine
12.5
17.9
18.5c
18.3
24.3
23.8
26.0
25.4
23.3
25.3
26.9
–
–
3
N,N-dimethylaminopyridine (DMAP)
N,N-diisopropylethylamine (DIPEA)
–
–
–
4
–
–
–
5
1,4-diazabicyclo[2.2.2]octane (DABCO)
–
–
–
6
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
1,5-diazabicyclo[4.3.0]non-5-ene (DBN)
1,5,7-triazabicyclododecene (TBD)
30
65
22
31
71
75
35
70
35
78
69
29
25
65
59
–
7
–
8
–
64
–
9
7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD)
1,1,3,3-tetramethylguanidine (TMG)
–
10
11
12
–
–
2-tert-butyl-1,1,3,3-tetramethylguanidine
–
–
tert-butylimino-tris(dimethylamino)phosphorane (P1-t-Bu)
–
–
a Values in MeCN.
b Conversion determined by UPLC-MS.
c Actual value not found; estimated value.
(entries 10 and 11) afforded less than 30% conversion to the
desired hydroxamic acid product but the phosphazene base
P1-t-Bu afforded an acceptable conversion to the desired
product 3 (entry 12).
TBD both in solution and on solid support for hydroxylami-
nolysis on enantiomerically pure substrates rather than ex-
amining substrate scope, which we expected to be very
similar to that with DBU.7 We chose methyl benzoyl-L-
phenylalaninate (4) and methyl benzoyl-L-phenylglycinate (6),
which were readily prepared from benzoyl chloride and the
corresponding α-amino ester. Little racemization of 4 or 6
was observed during amide bond formation as verified by
chiral HPLC.10 For 4, DBU, TBD, and MTBD in solution accel-
erated greatly the reaction and there was no racemization
in situ (entries 3–5 vs. 1). As expected, polymer-supported
DBU and TBD also worked, but the reaction was significant-
ly slower (entries 3, 4 vs. 6, 7). In all our experiments, full
conversion was observed with very little formation of car-
boxylic acid side-product and even in the presence of
NaOH, no erosion of the stereogenic center was observed
(Table 3).
With these results in hand, we chose TBD as the base
and looked at the effect of changing the solvent on product
distribution. From Table 2, among the dipolar aprotic sol-
vents, only dimethyl sulfoxide (DMSO) afforded a positive
ratio of 3 to 2 (entry 1) whereas N,N-dimethylformamide
(DMF) and sulfolane gave more carboxylic acid by-product
(2) (entries 2 and 3). All ethereal solvents screened favored
conversion to the hydroxamic product 3 (entries 4–6). In
terms of protic solvents, as expected, water gave a poor ra-
tio (entry 7), which we presume is due to saponification in
situ to the undesired carboxylic acid. However, alcoholic
solvents (entries 8 and 9) afforded the best ratios, with
MeOH clearly giving the best conversion (entry 9). We also
carried out the reaction in an ionic liquid with the aim of
recovering the solvent after the reaction was complete but,
unfortunately, the carboxylic acid impurity was the major
product (entry 10).
To differentiate between the reaction conditions, we
turned our attention to methyl benzoyl-L-phenylglycinate
(6), which we anticipated would be much more sensitive to
epimerization because of the lower pKa of the proton α to
the phenyl group (Table 4). In summary, sodium hydroxide,
DBU, TBD, and MTBD in solution all afforded 7 very rapidly
Encouraged by our screening results on hindered sub-
strate 1, we carried out a comparative study of DBU and
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
R. Pierre et al.
Letter
Synlett
Table 2 Effect of Solvent on Hydroxamic Acid Formation
case of polymer-supported DBU, however, a significant
change was observed using just 0.5 equiv, whereby a final
enantiomeric ratio of 89:11 was achieved (entries 9–11).11
As we anticipated that the rate of hydroxylaminolysis was
much greater than the rate of epimerization, and epi-
merization was occurring through deprotonation of the
benzylic proton of the starting ester (6), we reversed the or-
der of addition and added the ester to the reaction mixture.
To our satisfaction, the enantiomeric ratio was improved
from 78:22 to 85:15 and 94:6 at r.t. and at 0 °C, respectively,
by using a syringe pump (entry 6 vs. entries 12 and 13).12
O
O
O
O
O
O
O
O
O
N
N
N
solvent (see table)
O
O
O
O
O
O
H
S
OH
S
O
S
N
50% NH2OH (aq)
(10 equiv)
TBD (3 equiv)
0 °C to r.t., 48 h
Ph
N
Ph
N
Ph
N
OH
H
H
H
3
2
1
Entry
Solvent
Ratio (%)a
2
3
Table 4 Racemization of 6 during the Hydroxylaminolysis Process
1
2
DMSO
DMF
41
53
57
45
43
42
76
38
22
71
59
47
43
55
57
58
34
62
78
29
3
sulfolane
O
O
base (see table)
H
O
N
4
tetrahydrofuran (THF)
N
N
OH
H
H
50% NH2OH (aq) (10 equiv)
MeOH (4 vols), r.t.
O
5
MeTHF
O
6, S/R = 98:2
7
6
1,2-dimethoxyethane (DME)
7
water
Entry Base
Equiv
Time
Conv.
(%)a
Enantiomer-
ic ratio
8
i-PrOH
MeOH
1
2
none
–
12 h
2 h
98
97
95
99
96
98
97
93
93
99
88
88
91
85:15
59:41
65:35
54:46
54:46
78:22
81:19
82:18
78:22
81:19
89:11
85:15
94:6
9
2N NaOH (aq)
DBU
3
10
3-methyl-1-octylimidazolium hexafluorophosphate
a Conversion determined by LCMS.
3
3
<10 min
<10 min
<10 min
30 min
1 h
4
TBD
3
5
MTBD
3
Table 3 Epimerization of 4 during the Hydroxylaminolysis Process
6
PS-TBD
PS-TBD
PS-TBD
PS-DBU
PS-DBU
PS-DBU
PS-DBUb
PS-DBUc
3
7
1
O
O
base (see table)
8
0.5
3
4 h
H
O
N
N
N
OH
9
30 min
1 h
H
50% NH2OH (aq) (10 equiv)
MeOH (4 vols), r.t.
H
O
O
10
11
12
13
1
4, S/R = 99:1
5
0.5
3
4 h
20 min
1 h
Entry Base (equiv)
Time (h) Conv. (%)
Enantiomeric ratio
3
1
2
3
4
5
6
7
none
12
2
98
97
95
95
96
93
99
99:1
99:1
99:1
99:1
99:1
99:1
99:1
a Based on LCMS analysis.
b Solution of 6 added at r.t. to a suspension of the resin and hydroxylamine
over 2 min.
2N NaOH (aq) (3)
DBU (3)
c Solution of 6 added at 0 °C via a syringe pump over 1 h.
0.5
0.5
0.5
1
TBD (3)
Finally, we examined the use of other nucleophiles in
the reaction to establish whether TBD could give access to
simple amides under similar conditions directly from the
carboxylic ester.13 For this trial, we used the least hindered
substrate, methyl benzoyl-L-phenylalaninate (4), as we an-
ticipated that 1 would be far too hindered to observe any
reaction. From Table 5, it is clear that there are significant
advantages of having TBD present. Hydrazinolysis is signifi-
cantly accelerated, as expected (entry 1 vs. 2), but TBD also
significantly improved conversion to 9 for weaker nucleop-
hiles such as piperidine (entries 3 vs. 4), O-benzylhydroxyl-
amine (entries 5 vs. 6) and ammonia (entries 7 vs. 8), albeit
with poor overall conversions and isolated yields.
MTBD (3)
PS-DBU (3)a
PS-TBD (3)a
1
a Reaction carried out in the presence of 1 additional volume of CH2Cl2.
but with significant epimerization in each case (entries 2–
5) compared with the control reaction (entry 1). As expect-
ed, the rate of hydroxylaminolysis decreased when using
polymer-supported DBU or TBD but epimerization was also
significantly reduced to just 20% (entries 3 and 4 vs. 9 and
6). Reducing the quantity of polymer-supported base in the
case of TBD had little effect on the enantiomeric ratio and
reduced significantly the reaction rate (entries 6–8). In the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
R. Pierre et al.
Letter
Synlett
Table 5 Use of TBD with Nucleophiles other than Hydroxamic Acid
O
O
O
Nucleophile
O
OH
Nuc
N
H
N
H
N
H
MeOH (4 vols)
r.t., 16 h
O
O
O
8
9
4
Entry
Nucleophile (equiv)
Time (h)
Ratio (%)a
Yield 9 (%)
4
8
9
1
2
3
4
5
6
7
8
hydrazine (10), TBD (2), MeOH
hydrazine (10), MeOH
4
18
8
–
2
2
98
92
41
–
78
–
5
piperidine (10), TBD (2), MeOH
piperidine (10), MeOH
44
88
39
91
44
78
15
12
26
8
35
–
8
O-benzylhydroxylamine (10), TBD (2), MeOH
O-benzylhydroxylamine (10), MeOH
NH3 (7N in MeOH) (10), TBD (2), MeOH
NH3 (7N in MeOH) (10), MeOH, r.t.
16
16
24
24
35
1
23
–
20
20
36
2
31
–
a Conversion determined by UPLC-MS.
Although we have not studied the mechanism in detail,
we propose the possibility that TBD and MTBD act as nucle-
ophilic acylation catalysts based on existing studies on DBU
and TBD.14 Nucleophilic attack of TBD or MTBD on the
methyl ester 10 affords an activated intermediate 11. Attack
by hydroxylamine affords the tetrahedral intermediate 12.
Here, we speculate that the significant rate enhancement
between DBU and TBD or MTBD could be explained by the
presence of the extra nitrogen atom. We postulate that the
nitrogen atom participates in the mechanism, accelerating
the breakdown of 12 to the hydroxamic product 13 through
intramolecular proton abstraction (Scheme 1).
In conclusion, we have extended our knowledge on su-
perbase-mediated hydroxylaminolysis of esters and identi-
fied TBD and polymer-supported TBD and DBU as efficient
bases for the formation of hydroxamic acids, hydrazides
and, to some extent, amides. We also have shown that poly-
mer-supported superbases can be employed for hydroxam-
ic acid formation with little in situ racemization using sub-
strates very prone to racemization.15
Funding Information
The work communicated in this letter was part of a short laboratory
project carried out by Romain Pierre in support of obtaining the qual-
ification of Diplome d’Ingenieur from the CNAM (Conservatoire Na-
O
O
R
R'
N
tional des Arts et Métiers), Paris.
)(
R
O
N
10
N+
Supporting Information
11
H2N OH
Supporting information for this article is available online at
R'
https://doi.org/10.1055/s-0036-1591551.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
N
N
TBD, R' = H
MTBD, R' = CH3
N
References and Notes
OH
R
HN
O
H
(1) (a) Lane, A. A.; Chabner, B. A. J. Clin. Oncol. 2009, 27, 5459.
(b) Haberland, M.; Montgomery, R. L.; Olson, E. N. Nat. Rev.
Genet. 2009, 10, 32. (c) Dokmanovic, M.; Clarke, C.; Marks, P. A.
Mol. Cancer Res. 2007, 5, 981.
(2) (a) Richon, V. M. Br. J. Cancer 2006, 95, S2–S6. (b) Marks, P. A.;
Breslow, R. Nat. Biotechnol. 2007, 25, 84.
(3) Gimsing, P. Expert Opin. Invest. Drugs 2009, 18, 501.
(4) Laubach, J. P.; Moreau, P.; San-Miguel, J. F.; Richardson, P. G.
Clin. Cancer Res. 2015, 21, 4767.
R'
N
N
O
N+
OH
12
R
N
H
13
Scheme 1 Proposed mechanism for the hydroxylaminolysis of esters
using TBD or MTBD
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

E
R. Pierre et al.
Letter
Synlett
(5) (a) Pal, D.; Saha, S. J. Adv. Pharm. Technol. Res. 2012, 3, 92.
(b) Muri, E. M. F.; Nieto, M. J.; Sindelar, R. D.; Williamson, J. S.
Curr. Med. Chem. 2002, 9, 1631. (c) Kontogiorgis, C. A.;
Papaioannou, P.; Hadjipavlou-Litina, D. J. Curr. Med. Chem. 2005,
12, 339.
(6) (a) Manal, M.; Chandrasekar, M. J. N.; Priya, J. G.; Nanjan, M. J.
Bioorg. Chem. 2016, 67, 18. (b) Rochea, J.; Bertrand, P. Eur. J. Med.
Chem. 2016, 121, 451.
(7) (a) Beillard, A.; Bhurruth-Alcor, Y.; Bouix-Peter, C.; Bouquet, K.;
Chambon, S.; Clary, L.; Harris, C. S.; Millois, C.; Mouis, G.; Ouvry,
G.; Pierre, R.; Reitz, A.; Tomas, L. Tetrahedron Lett. 2016, 57,
2165. (b) Typical procedure: To a stirred solution of the methyl
ester (1 equiv) in MeOH (4 vol), was added DBU (3 equiv) and
50% v/v aqueous solution NH2OH (aq) (10 equiv) at room tem-
perature. The reaction mixture was stirred for 48 h or until full
conversion. The crude product was then purified directly using
a mass-triggered preparative LCMS Waters X-Terra reverse-
phase column (C-18, 5μ silica, 19 mm diameter, 100 mm length,
flow rate of 40 mL/min) and decreasing polar mixtures of water
(containing 0.1% formic acid) and acetonitrile as eluent. The
fractions containing the desired compound were evaporated to
dryness to afford the final compounds, usually as crystalline
solids.
(8) The iChem Explorer® is compatible with Agilent 1100 and 1200
HPLC systems. This heating/cooling stirring module allows the
progress of reactions in up to 57 vials to be closely monitored
during a single run (http://www.ichemexplorer.com/Articles/
iChemExplorerFeatures.html).
(9) (a) Ishikawa, T.; Harwood, L. M. Synlett 2013, 24, 2507.
(b) Ishikawa, T. Superbases for Organic Chemistry; John Wiley &
Sons: Weinheim, 2009. (c) Leito, I.; Koppel, I. A.; Koppel, I.;
Kaupmees, K.; Tshepelevitsh, S.; Saame, J. Angew. Chem. Int. Ed.
2015, 54, 9262.
ethyl)benzamide (7; 90 mg, 90%) as a beige solid. LCMS (tR =
1.01 min) purity: 100%; MS (ES+): m/z = 285.04 [M+H]+; 1H NMR
(400 MHz, DMSO-d6): δ = 11.02 (s, 1 H), 9.01 (s, 1 H), 8.85 (d, J =
8.1 Hz, 1 H), 8.06–7.79 (m, 2 H), 7.62–7.20 (m, 9 H), 5.62 (d, J =
8.2 Hz, 1 H); 13C NMR (101 MHz, DMSO): δ = 166.74, 166.27,
138.50, 133.91, 131.47, 128.30, 128.21, 127.79, 127.66, 127.45,
54.68.
(13) Evaluation of TBD as an acylation catalyst with other nucleo-
philes; General Procedure
To a stirred solution of nucleophile (10 equiv) and 1,5,7-triazab-
icyclo[4.4.0]dec-5-ene (3 equiv) (supported or in solution) in
MeOH (4 vols) at r.t., was added methyl benzoyl-L-phenylala-
ninate (4; 50 mg, 0.18 mmol, 1 equiv) and the crude reaction
mixture was stirred for 1–24 h and purified directly by mass-
trigger Prep LCMS to obtain 9.
(S)-N-(1-Hydrazineyl-1-oxo-3-phenylpropan-2-yl)ben-
zamide: Yield: 40 mg (78%); LCMS (tR = 0.87 min) purity: 100%;
1
MS (ES+): m/z = 284.02 [M+H]+; H NMR (400 MHz, DMSO-d6):
δ = 9.30 (s, 1 H), 8.56 (d, J = 8.5 Hz, 1 H), 7.85–7.72 (m, 2 H),
7.56–7.47 (m, 1 H), 7.47–7.39 (m, 2 H), 7.39–7.30 (m, 2 H), 7.26
(dd, J = 8.3, 6.7 Hz, 2 H), 7.20–7.11 (m, 1 H), 4.67 (td, J = 8.7,
6.0 Hz, 1 H), 3.07–2.98 (m, 2 H).
(S)-N-(1-Oxo-3-phenyl-1-(piperidin-1-yl)propan-2-yl)ben-
zamide: Yield: 21 mg (35%); LCMS (tR = 1.16 min) purity: 100%;
1
MS (ES+): m/z = 337.12 [M+H]+; H NMR (400 MHz, DMSO-d6):
δ = 8.75 (d, J = 8.2 Hz, 1 H), 7.78–7.87 (m, 2 H), 7.47–7.58 (m,
1 H), 7.21–7.34 (m, 4 H), 7.13–7.21 (m, 1 H), 5.12 (td, J = 8.3,
6.4 Hz, 1 H), 3.43 (dd, J = 6.8, 4.4 Hz, 4 H), 2.89–3.13 (m, 2 H),
1.13–1.63 (m, 6 H).
(S)-N-(1-((Benzyloxy)amino)-1-oxo-3-phenylpropan-2-
yl)benzamide: Yield: 15 mg (23%); LCMS (tR = 1.13 min) purity:
100%; MS (ES+): m/z = 375.10 [M+H]+; 1H NMR (400 MHz,
DMSO-d6): δ = 11.41 (s, 1 H), 8.68 (d, J = 8.2 Hz, 1 H), 7.73–7.96
(m, 2 H), 7.07–7.62 (m, 14 H), 4.67–4.83 (m, 2 H), 4.56 (td, J =
8.7, 6.2 Hz, 1 H), 2.93–3.09 (m, 2 H).
(10) Chiral HPLC conditions: PIC Solutions Chiral SFC; Column ID,
5 μm ×4.6×250 mm; scCO2 / 25% i-PrOH; flow rate: 4 mL/min;
wavelength: 210 nm; tR = 3.4 (R), 4.5 (S) min.
(S)-N-(1-Amino-1-oxo-3-phenylpropan-2-yl)benzamide:
Yield: 15 mg (31%); LCMS (tR = 0.91 min) purity: 100%; MS
(11) The authors recognize that a catalytic amount of base could be
employed for this reaction, which is in accordance with the pro-
posed mechanism. In the interest of our medicinal chemistry
projects, whereby we were looking for high throughput process
to prepare diverse libraries, we preferred to use an excess of
superbase to assure rapid and complete hydroxylaminolysis.
(12) Hydroxylaminolysis of methyl (S)-2-benzamido-2-phenylac-
etate (6); General Procedure
1
(ES+): m/z = 269.05 [M+H]+; H NMR (400 MHz, DMSO-d6): δ =
8.49 (d, J = 8.5 Hz, 1 H), 7.74–7.83 (m, 2 H), 7.48–7.61 (m, 2 H),
7.40–7.47 (m, 2 H), 7.34 (d, J = 7.2 Hz, 2 H), 7.25 (t, J = 8.5 Hz,
1 H), 7.13–7.20 (m, 1 H), 7.11 (s, 1 H), 4.64 (dd, J = 8.5, 4.1 Hz,
1 H), 2.90–3.20 (m, 2 H).
(14) (a) Fu, X.; Tan, C. H. Chem. Commun. 2011, 8210. (b) Shieh, W.-
C.; Dell, S.; Repič, O. J. Org. Chem. 2002, 67, 2188. (c) Horn, H.
W.; Jones, G. O.; Wei, D. S.; Fukushima, K.; Lecuyer, J. M.; Coady,
D. J.; Hedrick, J. L.; Rice, J. E. J. Phys. Chem. A 2012, 116, 12389.
(15) (a) Noguchi, T.; Jung, S.; Imai, N. Tetrahedron Lett. 2014, 55, 394.
(b) Ivkovic, J.; Lembacher-Fadum, C.; Breinbauer, R. Org. Biomol.
Chem. 2015, 13, 10456.
To a stirred solution of 50 wt. % NH2OH (aq) (216 μL, 3.53 mmol,
10 equiv) and the base (0.5–3 equiv) was added methyl
benzoyl-D/L-phenylalaninate (100 mg, 0.35 mmol, 1 equiv) and
the reaction mixture was stirred at r.t. until completion (<10
min to 12 h) and purified directly by mass-triggered prepara-
tive LCMS to afford N-(2-(hydroxyamino)-2-oxo-1-phenyl-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E