A Cascade Process of Hydroxamates Renders 1,6-Dioxa-3,9-diazaspiro[44]nonane-2,8-diones

Article abstract of DOI:10.1055/s-0040-1706660

A cascade route to 1,6-dioxa-3,9-diazaspiro[4.4]nonane-2,8-diones from N, O -diacyl hydroxylamines consisting of a two-step procedure is described. The key transformation is a [3,3]-sigmatropic rearrangement of N, O -diacyl hydroxylamines promoted by form

Full text of DOI:10.1055/s-0040-1706660

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, A–K
paper
A
en
Z. Nazarian, C. M. Forsyth
Paper
Synthesis
A Cascade Process of Hydroxamates Renders 1,6-Dioxa-3,9-
diazaspiro[4.4]nonane-2,8-diones
Zohreh Nazarian*
Craig M. Forsyth*
0
0
0
0
-
0
0
0
2
-
5
8
6
7
-
3
8
6
0
H3C
O
O
H3C
O
O
N
N
O
CH3
R2
H
tBu
N
N
School of Chemistry, Monash University, Victoria, Melbourne,
3800, Australia
nazarianzohreh@yahoo.com.au
craig.forsyth@monash.edu
N
R2
H
tBu
Stereoselective synthesis
One-pot process
*
O
*
O
*
R2
R1
O
O
R
R
N
O
O
R
R1
Metal-free conditions
TBSOTf (2.5 equiv)
Et3N (2.5 equiv)
–78 °C to r.t
*
O
O
R1
OTBS
O
CH3
ZCSeMcorhahaiorgiCeolMholncroaN.arfzFeiaaCgoszrh.prafisoeoarymnirntaszdhnyiositnhthrgr@y
e
A,mhMu@otohynnaoaahrsssho
h
o.e.Udconumive.arusity, Victoria, Melbourne, 3800, Australia
[3,3]-SR
N
Cyclization, followed by
Spirocyclization
tBu
O
H
*
R2
HO
R
N
O
TBSO
R1
O–
O–
Received: 29.10.2020
Accepted after revision: 08.12.2020
Published online: 19.01.2021
OTMS
OTMS
R1
R2
R1
R2
R1
R2
R1
R2
O
NR1
O
NR1
NR
NR
NR
NR
DOI: 10.1055/s-0040-1706660; Art ID: ss-2020-f0559-op
O–
O–
OTMS
OTMS
Abstract A cascade route to 1,6-dioxa-3,9-diazaspiro[4.4]nonane-
2,8-diones from N,O-diacyl hydroxylamines consisting of a two-step
procedure is described. The key transformation is a [3,3]-sigmatropic
rearrangement of N,O-diacyl hydroxylamines promoted by formation of
a silylketenaminal followed by an intramolecular cyclization and a final
spirocyclization. The optimum reaction conditions employ a one-fold
excess of each reagent and are utilized to prepare a range of structurally
diverse examples of this class of compound.
Anionic rearrangement6
Neutral rearrangement using a mild
base and a Lewis acid7
R1
R1
R1
R1
O
N
O
O
O
O
NR2
O
O
NR2
O
NR
R2
R2
R
R
R
OH
OH
Thermal rearrangement8
OTMS
OTMS
Neutral rearrangement using a mild
base and a Lewis acid11
Key words [3,3]-sigmatropic rearrangement, cascade process, N,O-
diacyl hydroxylamines, 3-azaspirocyclic orthoamides, 1,6-dioxa-3,9-di-
azaspiro[4.4]nonane-2,8-diones
Scheme 1 Some examples of previous work on [3,3]-SRs of N,O-diacyl
hydroxylamines and N,N-diacyl hydrazine
The utility of [3,3]-sigmatropic rearrangement ([3,3]-
SR) in systems containing a heteroatom is reasonably well
understood.1–3 However, less well-known are [3,3]-SRs of
systems comprising bis-enolates or their analogues. In fact,
only a few studies have focused on this subject (Scheme
1).4–11
Conventional methods for enolate coupling typically use
a strong base followed by metal salts such as Cu(OAc)2 or Ti-
Cl4. However, these harsh conditions often result in poor
yields and diastereoselectivities and limit the range of sub-
strates.12–14 On the other hand, [3,3]-SR has emerged as a
reliable approach for the coupling of enolates and C–C bond
formation. Recently, the generation of -acyloxyamides, in
addition to cyclic orthoamides, via [3,3]-SR of N,O-diacyl
hydroxylamines11 has been disclosed. The reported meth-
odology described the attempted stereoselective synthesis
of -acyloxyamides using a chiral auxiliary at the O-acyl
moiety to be rather ineffective to build diastereoselectivity
during the rearrangement.
Accordingly, in connection with this previous research,
the current study was directed towards controlling the ste-
reochemical outcome of these rearrangements, and to con-
struct stereoselectivity during rearrangement of N,O-diacyl
hydroxylamines. Although this aim was achieved, the pro-
cess resulted in the serendipitous formation of 1,6-dioxa-
3,9-diazaspiro[4.4]nonane-2,8-diones rather than the ex-
pected acyloxyamides or cyclic orthoamides. The first re-
port on the synthesis of this class of compounds was pub-
lished in 2016.15
Initially, it was sought to prepare chiral N,O-diacyl hy-
droxylamine substrates. Thus, N,O-diacyl hydroxylamines
were readily prepared via coupling of the appropriate hy-
droxamic acid 2 (1.0 equiv) with the corresponding N-Boc-
N-methyl amino acid 3 mediated by EDCI (1.6 equiv) in the
presence of a catalytic amount of DMAP (0.1 equiv). The de-
sired -amino acid substituted analogs 4a–m were ob-
tained in modest to excellent yields (46–95%) (Table 1).
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Z. Nazarian, C. M. Forsyth
Paper
Synthesis
Table 1 (continued)
Table 1 Synthesis of N,O-Diacyl Hydroxylamines
Entry
2
3
Product
Yield (%)
80
R1
R
N
(i) Et3N (1.3 equiv)
NHOH
·HCl
CF3
Bn
HO
R
O
H3C
O
O
N
N
2a–i
(ii) acid chloride
or
anhydride
11
3a
3a
3a
4k
HO
N
1a R = Bn
1b R = Me
O
(64–81%)
(i) Et3N (1.3 equiv)
R2
tBu
2g
+
(S)
(1.0 equiv)
CH2Cl2, 0 °C to r.t
(ii) EDCI (1.6 equiv)
DMAP (0.1 equiv)
CH2Cl2, 0 °C to r.t
H
O
H3C
O
O
R
R1
CH3
O
N
Bn
N
R2
H
O
12
13
4l
85
88
(S)
tBu
O
HO
O
4a–m
2h
HO
3a R2 = H
Ph
3b R2 = CH3
3c R2 = iPr
3d R2 = Bn
H3C
N
4m
HO
O
2i
Entry
1
2
3
Product
Yield (%)
88
The majority of these compounds were isolated as a
mixture of two rotamers, resulting from restricted rotation
in N,O-diacyl hydroxylamine systems.16 As a result, in the
proton NMR spectra of these compounds a pair of signals
could be assigned to a single proton. Similarly, in their car-
bon NMR spectra, more than one peak could be attributed
to a single carbon. However, elevation of the temperature
from 25 °C to 50 °C during the 1H NMR and 13C NMR experi-
ments overcame restricted rotation.
With N,O-diacyl hydroxylamines 4 in hand, compound
4b was initially exposed to the previously reported condi-
tions for the preparation of acyloxy amides and cyclic orth-
oamides.10 However, with this precursor, the reported con-
ditions led to significant recovery of the starting material.
Upon changing the Lewis acid from TMSOTf to TBSOTf, the
conversion of the starting N,O-diacyl hydroxylamine in-
creased significantly. Under the optimized conditions, 4b
was allowed to react with different ratios of the Lewis acid
and base. Employing 1.0 equivalent of the reagent mainly
resulted in no identifiable product, whereas using a one-
fold excess of the reagent furnished a compound which did
not have the expected scaffold of the rearranged product.
Indeed, NMR studies revealed the serendipitous formation
of a 1,6-dioxa-3,9-diazaspiro[4.4]nonane-2,8-dione (Scheme
2).
Ph
Ph
Ph
Ph
Bn
N
N
N
N
N
N
N
N
3a
4a
HO
O
O
O
O
O
O
O
O
2a
Bn
2
3
4
5
6
7
8
3b
3c
3d
3b
3a
3a
3b
4b
4c
4d
4e
4f
92
90
93
95
46
70
74
HO
2a
Bn
HO
2a
Bn
HO
2a
C10H7
C6H4NO2
C4H3S
C4H3S
CH3
Bn
HO
2b
Bn
HO
2c
Bn
4g
4h
HO
The appearance of a singlet at 5.53 ppm in the 1H NMR
spectrum of 6b was assigned to the CH7 proton, suggesting
that substrate 4b(i) had initially undergone a [3,3]-SR17 to
form silyl iminoether 5b(i), followed by a cyclization and
subsequent spirocyclization to generate spirocyclic com-
pounds 6b and 7b (Scheme 2). The 1H NMR data also
matched the values previously reported for the spirocyclic
compound 6b, with further spectroscopic data (i.e., 13C
NMR, COSY, HSQC, HMBC and HRMS) corroborating the
proposed structure. Assignment of relative stereochemistry
to the product was confirmed by a crystal structure analy-
sis of 6b, which revealed the absolute configuration of the
newly formed stereogenic centers at C5 and C7 to be R, in
accord with a previous assignment made from X-ray crystal
2d
Bn
HO
2d
Bn
9
3a
3a
4i
4j
80
86
N
N
HO
O
O
2e
CH3
Bn
10
HO
2f
Thieme. All rights reserved. Synthesis 2021, 53, A–K

C
Z. Nazarian, C. M. Forsyth
Paper
Synthesis
ration profile during crystal growth. A trivial increase in
yield was noticed when instead of H, a CH3 group was em-
ployed at R2 in substrate 4b. Purification via column chro-
matography on silica gel afforded two diastereomers, 6b
and 7b, in 55% combined yield and 1.7:1 dr. When the bulky
amino acid derivative 4c was employed, the reaction oc-
curred with 100% conversion, giving spirocyclic 6c and 7c in
45% total yield and 1.3:1 dr. The observed lower yield com-
pared to 6b is possibly due to the increased steric hindrance
of isopropyl versus methyl at R2 in precursor 4c. The failure
of the reaction with substrate 4d, where Boc-protected
phenylalanine was used at the O-acyl moiety, confirms that
steric hindrance at R2 is a determining factor in inhibiting
the reaction. Precursor 4e, bearing a 2-naphthyl substituent
at R1, performed well under the standard conditions leading
to an improved 66% yield of spirocyclic 6e; this represents
the highest yield in this series of compounds. In this case, a
small amount of cyclic orthoamide 8e was also isolated in
9–10% yield. Unfortunately, due to the instability of the iso-
lated compound 8e, assignment of the configuration was
not possible. The use of precursor 4f led to a marked drop in
yield (23%), presumably due to the presence of an electron-
withdrawing NO2 group at the para position of the phenyl
substituent at R1. Purification of the crude product via flash
chromatography on silica gel gave solely the spirocycle 6f.
Most of the spirocyclic orthoamides were stable in CDCl3,
however, compound 6f proved to be unstable and isomeri-
zed fairly rapidly, giving a 50:50 isomeric mixture when
stored in a solution of CDCl3. Which stereocenter of the spi-
rocycle isomerized remained ambiguous. Our attempts to
prevent isomerization by using basified CDCl3 were unsuc-
cessful. As a result, we switched to C6D6 as an alternative
solvent. Surprisingly, we found that isomerization of 6f did
not occur, even when left overnight in a solution of C6D6.
This is presumably due to the inability of C6D6 to coordinate
with the spirocycle through H-bonding or dipole–dipole in-
teractions that would facilitate isomerization.
H3C
O
O
H3C
4
O
O
O
CH3
O
CH3
H
N
N
N
N
N
N
H3C
H
tBu
tBu
H3C
4
H
CH3
O
O
5
H
S
O
O
CH3
R
O
Ph
Bn
N
O
O
Ph
Bn
N
O
+
R
5.5 ppm
7
Bn
O
Bn
OTBS
4b(i)
O
Ph
O
Ph
4b
6b
7b
i) TBSOTf (2.5 equiv)
ii) Et3N (2.5 equiv)
[3,3]-SR
–78 °C to r.t
13–14 h
O
CH3
4
N
tBu
O
H
CH3
O
Bn
N
O
~6.0 ppm
7
TBSO
Ph
5b(i)
Scheme 2 Formation of a spirocyclic orthoamide via silylketenaminal
4b(i)
structure analysis of the same compound generated from
the double cyclization of (R)-2-(benzylamino)-2-oxo-1-
phenylethyl (S)-2-[(tert-butoxycarbonyl)(methyl)amino]-
propanoate (Figure 1).15
O
N
CH3
4
H
CH3
O
5
Bn
N
O
7
O
Ph
6b
Figure 1 Crystal structure of (4S,5R,7R)-9-benzyl-3,4-dimethyl-7-phe-
nyl-1,6-dioxa-3,9-diazaspiro[4,4]nonane-2,8-dione (6b) (see the Sup-
porting Information)
Identification of the second diastereomer was not possi-
ble, as it was separated either as a mixture of two diastereo-
mers or as a liquid diastereomer, which was obtained in in-
sufficient quantity for a 2D NMR experiment (i.e., a NOESY
experiment). Nevertheless, determination of the ratio was
carried out by using the integral ratio of diagnostic signals
in the 1H NMR spectrum of the crude mixture.
A similar analysis carried out for other compounds
based upon the observed configuration of the major diaste-
reomer of 6b enabled proposition of the configuration of
the major isolated diastereomer (see below). To investigate
the generality of the process, various N,O-diacyl hydroxyl-
amines were subjected to the above conditions.
Upon subjecting 4a to the optimized conditions, two di-
astereomers, 6a and 7a, were formed in 50% combined yield
and a dr of 1.5:1 (Scheme 3). It is notable that attempted
crystallization of 6a in hot EtOH resulted in isomerization
and formation of crystals of the racemic (R,R/S,S) diastereo-
mers,18 presumably due to the thermal instability of the
spirocyclic nonane and a subsequent change in the configu-
Reaction of 4g, where R = benzyl, R1 = thienyl and R2 = H,
gave two diastereomers, 6g and 7g, in 20% combined yield
and a dr of 1.2:1. Separation of the diastereomers was suc-
cessfully achieved via flash chromatography on silica gel.
The effect of adding a methyl substituent at R2 in 4h im-
proved the overall yield, mirroring the observations for the
R1 = Ph series above. Chromatography on silica gel afforded
a single diastereomer of 6h in 32% yield along with relative-
ly impure cyclic orthoamide 8h in 5–6% yield. Similar to 8e,
compound 8h was highly unstable and decomposed within
a few hours at room temperature. The presence of an alke-
nyl substituent at R1 in 4i provided spirocyclic compounds
6i and 7i in a 1.2:1 dr and a combined yield of 42%, with a
trivial drop in yield compared to the corresponding phenyl-
substituted starting material. Less polar spirocyclic com-
pound 6i was isolated as a single isomer, whereas more po-
lar spirocycle 7i was isolated as a mixture of two isomers.
Upon changing R1 from phenyl (4a–f) to CH3 (4j), the overall
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

D
Z. Nazarian, C. M. Forsyth
Paper
Synthesis
H3C
O
O
O
CH3
O
CH3
CH3
N
N
N
HN
R2
H
tBu
R1
H
TBSOTf (2.5 equiv),
Et3N (2.5 equiv)
H
O
O
TBSO
H
R2
R2
R2
+
+
O
R
N
O
R
N
O
Bn
N
O
O
R
–78 °C to r.t
13–14 hr
N
R1
O
R1
O
O
R1
O
4a-m
(major isomer: 6a–c, 6e–j)
(minor isomer: 7)
8
O
CH3
HN
CH3
H
O
CH3
H
O
CH3
CH3
H
N
N
N
HN
CH3
O
TBSO
O
N
O
TBSO
Bn
CH3
H
CH3
4kb
4lc
CH3
ND
NR
NR
4e
4a
Bn
N
O
Bn
N
O
4h
Bn
O
Bn
N
O
N
O
O
O
O
O
O
S
S
6h (32%)
8h (5%)
6e (66%)
8e (9%)
6a (dr: 1.5:1, 50%)
O
CH3
O
N
CH3
H
4m
O
CH3
N
N
O
O
O
4b
4f
CH3
4i
Bn
N
O
Bn
N
O
Bn
N
O
O
O
O
6i (dr: 1.2:1, 42%)
6b (dr: 1.7:1, 55%)
6f (23%)
O
CH3
NO2
N
O
CH3
H
O
CH3
O
N
N
O
CH3
4j
O
Bn
N
O
4c
Bn
N
O
4g
Bn
N
O
CH3
O
CH3
6j (dr: 1.2:1, 30%)
O
O
S
6g (dr: 1.2:1, 20%)
6c (dr: 1.3:1, 45%)
4da
NR
Scheme 3 Scope of the 1,6-dioxa-3,9-diazaspiro[4,4]nonane-2,8-diones. a Starting material was recovered (NR: no reaction). b Spirocyclic compounds
were not detected (ND: not detected). c Starting material was recovered. Stereocenters in structures 6 & 7 are tagged with different colors to differenti-
ate them in their stereochemistries.
yield of the two spirocyclic orthoamides 6j and 7j dropped
to 30% with a dr of 1.2:1. Two of the substrates, namely 4k
and 4l with CF3 and H substituents at R1, respectively, did
not furnish spirocyclic products despite the starting mate-
rials being consumed completely.
For 4l, forcing thermal conditions or using an increased
amount of the reagents was also ineffective. These results
highlight the need for a readily enolizable proton next to
the carbonyl of the amide in the transition state.
In determining the effect of the N-acyl substituent on
the reaction, N,O-diacyl hydroxylamine 4m was evaluated
to see whether an N-methyl substituent would be tolerated.
The results showed that in this case the reaction failed to
produce any of the desired product. In general, the above
results indicate that the process tolerates a wide spectrum
of variations at R1 and R2, but not at R.
As is shown in Scheme 4, it is postulated that the trans-
formation proceeds via a cascade route, where initially hy-
droxamate 4(i) undergoes a [3,3]-SR to give Boc-protected
acyloxyamides 5(i), forming two possible diastereomers as
a result of the rearrangement. In theory each of these dias-
tereomers can form two spirocyclic isomers. Consequently,
the cyclization and ultimate spirocyclization of 5(i) can
generate spirocyclic compounds with four possible stereo-
chemistries. In practice, however, only two spirocyclic iso-
mers were isolated, indicating that only some stereoselec-
tivities are involved in the process (Scheme 4). Whilst the
stereochemistry of one of the spirocyclic products was un-
ambiguously established by X-ray crystal structure analy-
sis, the stereochemistry of the second spirocyclic product
remained undefined. Nonetheless, it may have adopted one
of the three possibilities shown in dashed circles in Scheme
4.
From the mechanism point of view, it can be postulated
that Boc-protected silyl iminoether 5(i) converts into the
corresponding tert-butyldimethylsilyloxy carbonyl deriva-
tive 5(ii) upon using 1.0 equivalent each of the reagents as
discussed previously.15 In the presence of an excess amount
of the reagents, the silyl carbamate can further proceed to
generate spirocyclic orthoamides. Alternatively, loss of the
tert-butyldimethylsilyloxy carbonyl group (COOTBS) results
in the cyclized products (i.e., 8e and 8h). It appears that a
similar intermediate is responsible for the generation of the
spirocyclic compound and the cyclic product, since in cases
where the cyclic product was detected, only a single spiro-
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

E
Z. Nazarian, C. M. Forsyth
Paper
Synthesis
This work
Previous work
H3C
O
O
O
O
CH3
H3C
N
O
O
O
O
CH3
O
O
CH3
O
CH3
O
O
CH3
O
O
CH3
N
(S)
N
N
N
N
N
N
R2
tBu
TBS
Bn
tBu
R2
tBu
tBu
H
tBu
H
H
(S)
(S)
tBu
O
H
TBS
Bn
H
R2
H
R2
R2
H
R2
[3,3]SR
H
O
O
O
O
R2
O
R2
O
when R = Bn
i
O
O
O
R
R1
O
N
R1
Bn
Bn
+
NH
O
R
N
O
(R)
R1
N
O
(S)
R1
Bn
NH
O
N
O
N
O
N
TBSOTf (1.0 equiv)
Et3N (1.0 equiv)
when R = Bn
OTBS
R
O
O
R1
TBSO
TBSO
R1
TBSO
R1
O
TBSO
R1
4
4i
5i
5i
5i
5ii
was detected
when R = Bn
TBSOTf (2.5 equiv)
Et3N (2.5 equiv)
i) TBSOTf (2.5 equiv), Et3N (2.5 equiv)
–78 °C to r.t, 13–14 hr
O
O
CH3
N
O
O
CH3
O
CH3
O
O
CH3
O
O
CH3
N
N
N
N
tBu
TBS
TBS
H
H
O
H
H
H
2
R2
R2
R2
O
(S)
O
TBS
Bn
O
R2
R
(S)
(R)
Bn
N
O
Bn N (S) O
(S)
R1
Bn
Bn
N
O
N
O
N
O
CH3
(R)
R1
HN
O
O
R1
TBSO
R1
TBSO
R1
TBSO
TBSO
H
confirmed by X-ray
(4S, 5R, 7R)
R2
+
Bn
N
O
– COOTBS
CH3
+
+
O
R1
occasionally was detected
O
CH3
O
CH3
O
CH3
O
CH3
N
HN
N
N
N
H
H
H
H
O
TBSO
Bn
H
O
O
O
R2
R2
R2
R2
R2
(S)
(S)
(S)
Bn
N
O
N
O
Bn
N
O
(R)
Bn
N
O
Bn
N
O
+
(S)
R1
(R)
R1
O
R1
O
R1
occasionally was detected
O
R1
O
O
two diastereomers were detected
Only two diastereomers were detected
Scheme 4 The structures of the four possible stereochemistries of 1,6-dioxa-3,9-diazaspiro[4.4]nonane-2,8-diones formed via [3,3]-SR. The mecha-
nism for the formation of the spirocycles using this procedure mainly relies on the recent mechanism reported for synthesis of these compounds via
Boc-protected -acyloxyamide derivatives.
cyclic compound was isolated. Overall, the proposed mech-
anism in this work mainly relies on the recently reported
mechanism15 (see previous work in Scheme 4).
parts per million downfield relative to the center line of the triplet of
CDCl3 at  77.0 and/or (CD3)2CO at  205.1 and  30.1. 19F NMR spectra
were determined at 377 MHz with trichlorofluoromethane as the in-
ternal reference ( 0.00). Accurate mass determinations were made
on an Agilent G6220A LC-TOF system.
In summary, a new synthetic approach towards the
preparation of 1,6-dioxa-3,9-diazaspiro[4.4]nonane-2,8-di-
ones has been disclosed. The process reveals that a [3,3]-SR
occurs as a crucial step in the construction of a carbon–het-
eroatom bond. Apart from reducing the number of required
manipulations, this cascade process allows several transfor-
mations via a simple synthetic route. Thus, this pathway
represents a relatively short procedure for preparing a se-
ries of structurally diverse 3-azaspirocyclic orthoamides.
Additionally, the formation of two of the four possible dias-
tereomers offers the potential to generate these products in
stereochemically enriched forms.18
Hydroxamic Acids 2; General Procedure (GP1)
To a magnetically stirred solution of N-alkyl hydroxylamine hydro-
chloride (3.0 mmol) in dry CH2Cl2 (20 mL) under N2 was added Et3N
(7.5 mmol, 1.0 mL) dropwise via a syringe at 0 °C. While in an ice
bath, the reaction was stirred for 20 min. Next, the freshly prepared
corresponding acid chloride or acid anhydride (3.0 mmol) in dry
CH2Cl2 (30 mL) was added slowly over a 10 min period. The resulting
mixture was then warmed to room temperature and allowed to stir
for a further 4–5 h. The solvent was removed in vacuo and the residue
was taken up in CH2Cl2 and washed with HCl (1.0 M) and brine. The
organic layer was dried over MgSO4, filtered and concentrated under
reduced pressure.19 Purification of the crude residue was accom-
plished by flash column chromatography with an appropriate solvent
system (EtOAc/hexanes) to afford the desired hydroxamic acids 2a–i.
All reactions were performed under N2 or Ar unless otherwise stated.
All solvents were distilled from appropriate drying agents prior to
use. Unless otherwise noted, commercially available chemicals were
used as received. Melting points were measured on a Reichert hot
stage melting point apparatus. Optical rotations were obtained at 20
°C using a 1 dm cell at a wavelength of 589 nm (sodium D line), quot-
ed as: []D, concentration c (g/100 mL), solvent. 1H NMR spectra were
recorded at 300, 400 or 600 MHz and chemical shifts are reported in
ppm relative to internal tetramethylsilane (TMS,  0.0) or with the
solvent reference relative to TMS employed as the internal standard
[CDCl3,  7.26; (CD3)2CO,  2.09; C6D6,  7.16]. 13C NMR spectra were
recorded at 75, 100 or 150 MHz and chemical shifts are reported in
N-Benzyl-N-hydroxy-2-phenylacetamide (2a)
Prepared using N-benzyl hydroxylamine hydrochloride (1a) (3.0
mmol, 0.48 g) and phenylacetyl chloride (3.0 mmol, 0.40 mL), in ac-
cordance with GP1.
Yield: 0.58 g (80%); off-white solid; mp 94–95 °C (Lit.19 96–97 °C).
1H NMR (400 MHz, CDCl3):  = 7.32–7.26 (m, 10 H), 4.81 (s, 2 H), 3.85–
3.76 (br s, 2 H).
ESI-MS: m/z [M + Na]+ calcd for C15H15NO2Na: 264.09; found: 264.1.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

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Z. Nazarian, C. M. Forsyth
Paper
Synthesis
N-Benzyl-N-hydroxy-2-(naphthalene-2-yl)acetamide (2b)
N-Benzyl-N-hydroxypropionamide (2f)
Prepared using N-benzyl hydroxylamine hydrochloride (1a) (3.0
mmol, 0.48 g) and 2-(naphthalen-2-yl)acetyl chloride (3.0 mmol, 0.61
mL), in accordance with GP1.
Prepared using N-benzyl hydroxylamine hydrochloride (1a) (3.0
mmol, 0.48 g) and propionyl chloride (3.0 mmol, 0.3 mL) in accor-
dance with GP1.
Yield: 0.73 g (78%); off-white crystalline solid; mp 140–141 °C.
Yield: 0.39 g (65%); off-white crystalline solid; mp 60–61 °C; Rf = 0.37
(35% EtOAc/hexanes).
IR (Diamond-ATR, neat): 3059, 3030, 2923, 2853, 1641, 1495, 1453,
1422, 1144, 1078, 1029, 939, 804, 755, 731, 691 cm–1
.
IR (Diamond-ATR, neat): 3179, 2978, 2939, 2361, 2336, 1615, 1453,
1232 cm–1
.
1H NMR (600 MHz, acetone-d6):  (mixture of two rotamers) = 8.17
(br s, 1 H), 7.80–7.66 (m, 3 H), 7.44–7.26 (m, 9 H), 5.92 and 4.83 (2 × s,
2 H), 3.99–3.92 (m, 2 H).
1H NMR (400 MHz, CDCl3):  (mixture of two rotamers) = 7.92–7.10
(m, 5 H), 4.79 (s, 2 H), 2.52–2.34 (br m, 2 H), 1.25–1.08 (m, 3 H).
13C NMR (150 MHz, acetone-d6):  (mixture of two rotamers) =
171.96, 137.74, 135.43, 134.19, 134.09, 132.87, 132.09, 130.15,
129.52, 128.89, 128.81,128.73, 128.71, 128.54, 128.51, 128.32,
128.03, 127.98, 127.70, 126.35, 125.88, 52.48, 52. 57, 40.01.
13C NMR (100 MHz, CDCl3):  (mixture of two rotamers) = 175.6,
168.5, 136.2, 134.5, 128.5, 128.0, 127.6, 127.0, 52.5 and 52.1, 25.6 and
24.7, 9.3 and 8.8.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H13NO2Na: 202.0838;
found: 202.0831.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H18NO2: 292.1332; found:
292.1333.
N-Benzyl-3,3,3-trifluoro-N-hydroxypropanamide (2g)
N-Benzyl-N-hydroxy-2-(4-nitrophenyl)acetamide (2c)
Prepared using N-benzyl hydroxylamine hydrochloride (1a) (3.0
mmol, 0.48 g) and 3,3,3-trifluoropropanoyl chloride (3.0 mmol, 0.44
mL) in accordance with GP1.
Prepared using N-benzyl hydroxylamine hydrochloride (1a) (3.0
mmol, 0.48 g) and 2-(4-nitrophenyl)acetyl chloride (3.0 mmol, 0.6
mL) in accordance with GP1.
Yield: 0.51 g (67%); off-white crystalline solid; mp 99–100 °C; Rf =
Yield: 0.67 g (79%); off-white crystalline solid.
0.47 (35% EtOAc/hexanes).
IR (Diamond-ATR, neat): 3169, 1606, 1518, 1495, 1453, 1346 cm–1
1H NMR (300 MHz, acetone-d6):  = 9.17 (br s, 1 H), 8.17 (d, J = 8.7 Hz,
2 H), 7.57 (d, J = 8.7 Hz, 2 H), 7.30 (s, 5 H), 4.81 (s, 2 H), 4.04 (s, 2 H).
13C NMR (75 MHz, acetone-d6):  = 170.7, 147.2, 144.3, 137.3, 131.1,
128.6, 127.7, 123.4, 52.1, 39.0.
.
IR (Diamond-ATR, neat): 3221, 1648, 1625, 1452, 1271, 1243, 1142,
1114, 726, 697 cm–1
.
1H NMR (400 MHz, acetone-d6):  = 9.31 (s, 1 H), 7.35–7.27 (m, 5 H),
4.80 (s, 2 H), 3.64 (q, JH–F = 10.8 Hz, 2 H).
13C NMR (100 MHz, acetone-d6):  = 163.6, 135.9, 127.7, 126.8, 125.7,
122.9, 50.8, 36.1 (q, JC–F = 28.9 Hz).
HRMS (ESI-TOF): m/z [M – H]+ calcd for C15H13N2O4: 285.0881; found:
285.0888.
19F NMR (377 MHz, acetone-d6):  = –58.0 (t, J = 10.8 Hz, 3 F).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H10F3NO2Na: 256.0556;
found: 256.0556.
N-Benzyl-N-hydroxy-2-(thiophen-2-yl)acetamide (2d)
Prepared using N-benzyl hydroxylamine hydrochloride (1a) (3.5
mmol, 0.56 g) and 2-(thiophen-2-yl)acetyl chloride (3.5 mmol, 0.43
mL) in accordance with GP1.
Yield: 0.70 g (81%); off-white crystalline solid; mp 95–96 °C (Lit.19
N-Benzyl-N-hydroxyacetamide (2h)
Prepared using N-benzyl hydroxylamine hydrochloride (1a) (3.0
mmol, 0.48 g) and acetyl chloride (3.0 mmol, 0.21 mL) in accordance
with to the GP1.
97–98 °C); Rf = 0.34 (35% EtOAc/hexanes).
1H NMR (400 MHz, CDCl3):  = 7.34–7.21 (m, 7 H), 6.96–6.92 (m, 2 H),
4.84 (br s, 2 H), 3.97 (br d, J = 14.8 Hz, 2 H).
Yield: 0.39 g (78%); off-white crystalline solid; mp 105 °C (Lit.20 108–
109 °C); Rf = 0.2 (50% EtOAc/hexanes).
1H NMR (400 MHz, CDCl3):  = 7.33–7.26 (m, 5 H), 3.75 (s, 2 H), 3.31
(s, 3 H); a signal due to OH was not observed.
(E)-N-Benzyl-N-hydroxybut-2-enamide (2e)
ESI-MS: m/z [M + Na]+ calcd for C9H11NO2Na: 188.06; found: 188.1.
Prepared using N-benzyl hydroxylamine hydrochloride (1a) (3.0
mmol, 0.48 g), crotonic anhydride (3.0 mmol, 0.44 mL) and Et3N (7.5
mmol, 1.0 mL) in accordance with GP1.
N-Hydroxy-N-methyl-2-phenylacetamide (2i)
Yield: 0.44 g (77%), off-white solid; mp 83–86 °C; Rf = 0.37 (50%
EtOAc/hexanes).
Prepared using N-methylhydroxylamine hydrochloride (1b) (3.0
mmol, 0.25 g) and phenylacetyl chloride (3.0 mmol, 0.4 mL) in accor-
dance with GP1.
Yield: 0.32 g (64%); off-white crystalline solid; mp 54 °C (Lit.19 54–55
°C).
1H NMR (300 MHz, CDCl3, 60 °C):  = 7.36–7.26 (m, 5 H), 3.73 (s, 2 H),
3.31 (s, 3 H); signal due to OH was not observed.
IR (Diamond-ATR, neat): 2359, 2341, 1683, 1602, 1455, 1228, 1155,
668 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.35–7.26 (m, 5 H), 7.00 (dq, J = 13.9,
6.9 Hz, 1 H), 6.24 (br s, 1 H), 4.86 (s, 2 H), 1.90 (dd, J = 7.0, 1.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 143.2, 135.4, 128.8, 128.0, 52.2, 18.3;
signals corresponding to CO and COCH were not observed.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H14NO2: 192.1019; found:
N,O-Diacyl Hydroxylamines Bearing N-Boc-N-methyl -Amino
Acid; General Procedure (GP2)
192.1020.
To a stirring solution of N-hydroxy-N-alkyl acetamide 2a–i (1.0 equiv)
in dry CH2Cl2 (10 mL) at 0 °C were added N-Boc-N-methyl -amino
acid 3a–d (1.0 equiv), EDCI·HCl (1.6 equiv) and DMAP (0.1 equiv) un-
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

G
Z. Nazarian, C. M. Forsyth
Paper
Synthesis
der an atmosphere of N2. To the resulting suspension was added Et3N
(1.3 equiv) dropwise via a syringe, after which the mixture was al-
lowed to warm to room temperature and stirred overnight. The mix-
ture was diluted with CH2Cl2, washed with HCl (1.0 M) and water, and
then dried over MgSO4. The crude residue was purified via flash chro-
matography to yield products 4a–m.
(S)-tert-Butyl {1-[(N-Benzyl-2-phenylacetamido)oxy]-1-oxo-3-
phenylpropan-2-yl}(methyl)carbamate (4d)
Yield: 0.58 g (93%); colorless liquid; Rf = 0.35 (0.35% EtOAc/hexanes);
[]D20 –34.8 (c 1.0, CH2Cl2).
IR (Diamond-ATR, neat): 3244, 2977, 2933, 1790, 1688, 1480, 1392,
1367, 1157 cm–1
.
1H NMR (400 MHz, CDCl3):  (mixture of two rotamers) = 7.28–7.10
(m, 15 H), 4.88–4.80 (m, 3 H), 3.57 (ABq, J = 12.8 Hz, 2 H), 3.10–2.82
(m, 2 H), 2.62 and 2.56 (2 × s, 3 H), 1.36 and 1.27 (2 × s, 9 H).
13C NMR (100 MHz, CDCl3):  (mixture of two rotamers) = 169.07,
168.58, 155.45, 136.31, 136.14, 134.88, 133.77, 129.41, 129.18,
129.02, 128.90, 128.60, 128.52, 127.93, 126.97, 80.67, 58.86, 52.30,
39.82 and 39.45, 35.13 and 34.83, 32.29, 28.19.
tert-Butyl {2-[(N-Benzyl-2-phenylacetamido)oxy]-2-oxoeth-
yl}(methyl)carbamate (4a)
Yield: 0.60 g (88%); colorless liquid; Rf = 0.25 (20% EtOAc/hexanes).
IR (Diamond-ATR, neat): 2976, 1791, 1682, 1496, 1455, 1389, 1366,
1153, 1060, 731, 698 cm–1
.
1H NMR (300 MHz, CDCl3):  (mixture of two rotamers) = 7.34–7.26
(m, 10 H), 4.81 (s, 2 H), 3.84 (d, J = 11.4 Hz, 2 H), 3.69 (s, 2 H), 2.81 (s,
3 H), 1.36 and 1.30 (2 × s, 9 H).
13C NMR (100 MHz, CDCl3):  (mixture of two rotamers) = 171.24,
167.96 and 167.60, 155.86 and 154.86, 134.81 and 134.56, 133.79 and
133.44, 129.33, 129.16, 128.68, 128.60, 128.56, 128.16, 128.02,
127.22, 127.00, 80.81 and 80.69, 52.24, 49.08 and 48.89, 39.90 and
39.74, 35.66 and 35.33, 28.25.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C30H34N2O5Na: 525.2360;
found: 525.2364.
(S)-tert-Butyl (1-{[N-Benzyl-2-(naphthalen-2-yl)acetamido]oxy}-
1-oxopropan-2-yl)(methyl)carbamate (4e)
Yield: 0.54 g (95%); colorless liquid; Rf = 0.44 (20% EtOAc/hexanes);
[]D20 –131.7 (c 1.0, CH2Cl2).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C23H28N2O5Na: 435.1890;
found: 435.1894.
IR (Diamond-ATR, neat): 3337, 3057, 3030, 2975, 2932, 1789, 1681,
1478, 1454, 1388, 1366, 1153, 1060, 986, 860, 804, 777, 699 cm–1
.
1H NMR (400 MHz, CDCl3):  (mixture of two rotamers) = 7.74–7.58
(m, 4 H), 7.43–7.12 (m, 8 H), 4.89 (ABq, J = 15.6 Hz, 1 H), 4.78 (ABq, J =
15.4 Hz, 1 H), 4.68–4.57 (m, 1 H), 3.76 and 3.65 (2 × s, 2 H), 2.62 (s, 3
H), 1.34 (s, 9 H), 1.21 (d, J = 3.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 170.36, 155.70, 134.85, 133.47,
133.40, 132.48, 131.36, 128.84, 128.57, 128.47, 128.45, 128.29,
128.10, 127.98, 127.79, 127.69, 127.62, 127.14, 126.78, 126.44,
126.08, 125.99, 125.68, 124.73, 80.64, 52.79, 52.79, 52.28, 39.69,
39.11, 30.75, 30.14, 28.29, 15.29, 14.58.
(S)-tert-Butyl {1-[(N-Benzyl-2-phenylacetamido)oxy]-1-oxopro-
pan-2-yl}(methyl)carbamate (4b)
Yield: 0.77 g (92%); colorless liquid; Rf = 0.42 (35% EtOAc/hexanes);
[]D20 –28 (c 1.0, CH2Cl2).
IR (Diamond-ATR, neat): 2976, 2931, 1789, 1682, 1455, 1389, 1153,
1060, 872, 731, 698 cm–1
.
1H NMR (400 MHz, CDCl3):  (mixture of two rotamers) = 7.30–7.24
(m, 10 H), 4.87 (ABq, J = 15.6 Hz, 1 H), 4.76 (ABq, J = 15.6 Hz, 1 H), 4.62
(br m, 1 H), 3.58 (s, 2 H), 2.63 (s, 3 H), 1.34 (br s, 9 H).
13C NMR (100 MHz, CDCl3):  (mixture of two rotamers) = 170.32,
155.67, 154.71, 134.86, 133.83, 129.40, 129.01, 128.90, 128.54,
127.97, 126.77, 80.60, 53.07, 52.69, 39.52, 30.70, 30.08, 29.69, 28.28,
15.29,14.59.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C28H32N2O5Na: 499.2203;
found: 499.2214.
(S)-tert-Butyl (2-{[N-Benzyl-2-(4-nitrophenyl)acetamido]oxy}-2-
oxoethyl)(methyl)carbamate (4f)
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C24H30N2O5Na: 449.2047;
found: 449.2042.
Yield: 0.24 g (46%); yellow oil.
IR (Diamond-ATR, neat): 3032, 1795, 1680, 1518, 1366, 1344, 1238,
1151, 1095, 733, 700 cm–1
.
tert-Butyl {1-[(N-Benzyl-2-phenylacetamido)oxy]-3-methyl-1-
oxobutan-2-yl}(methyl)carbamate (4c)
1H NMR (400 MHz, CDCl3):  (mixture of two rotamers) = 8.15 (d, J =
8.4 Hz, 2 H), 7.42 (d, J = 8.4 Hz, 2 H), 7.28 (m, 5 H), 4.90 (s, 2 H), 3.96
(ABq, J = 13.6 Hz, 2 H), 3.76 (ABq, J = 18.2 Hz, 2 H), 2.85 (s, 3 H), 1.45
and 1.38 (2 × s, 9 H).
Yield: 0.59 g (90%); colorless liquid; Rf = 0.5 (20% EtOAc/hexanes);
[]D20 –54.5 (c 1.0, CH2Cl2).
IR (Diamond-ATR, neat): 3332, 3032, 2971, 2932, 1786, 1692, 1455,
13C NMR (100 MHz, CDCl3):  (mixture of two rotamers) = 168.20 and
167.75, 156.00, 147.29 and 147.14, 141.45 and 140.84, 134.43 and
134.16, 130.57, 128.70, 128.42, 128..25, 123.78, 123.62, 80.95, 52.16,
49.19, 38.95, 35.96 and 35.44, 28.24. The signal corresponding to car-
bon in NCH2PhOC was not observerd.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C23H27N3O7Na: 480.1741;
found: 480.1746.
1391, 1368, 1161 cm–1
.
1H NMR (400 MHz, CDCl3):  (mixture of two rotamers) = 7.32–7.23
(m, 10 H), 4.97–4.79 (m, 2 H), 4.47 and 4.19 (2 × d, J = 11.2 Hz, 1 H),
3.69–3.63 (m, 2 H), 2.66 (s, 3 H), 2.24–2.11 (m, 1 H), 1.42 and 1.41 (2 ×
s, 9 H), 0.91–0.80 (m, 6 H).
13C NMR (100 MHz, CDCl3):  (mixture of two rotamers) = 170. 96,
168.97 and 168.29, 155.90 and 154.88, 134.78 and 134.57, 133.68 and
133.49, 129.49, 129.25, 128.58, 128.51, 128.06, 127.93, 127.12,
127.02, 80.85, 80.63, 63.15 and 61.67, 52.18, 39.20 and 30.12, 28.27
and 27.27, 19.59 and 19.36 and 19.12, 18.55 and 18.36.
tert-Butyl (2-{[N-Benzyl-2-(thiophen-2-yl)acetamido]oxy}-2-oxo-
ethyl)(methyl)carbamate (4g)
Yield: 0.55 g (70%); yellow oil; Rf = 0.39 (35% EtOAc/hexanes).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C26H34N2O5Na: 477.2360;
found: 477.2367.
IR (Diamond-ATR, neat): 3307, 2975, 2930, 1757, 1671, 1538, 1481,
1454, 1391, 1366, 1297, 1244, 1179, 1148 cm–1
.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

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Z. Nazarian, C. M. Forsyth
Paper
Synthesis
1H NMR (400 MHz, CDCl3):  (mixture of two rotamers) = 7.49–7.26
(m, 5 H), 7.24–7.17 (m, 1 H), 7.02–6.97 (m, 1 H), 6.44 (s, 1 H), 4.62–
4.34 (m, 2 H), 4.19 and 3.80 (ABq, J = 17.6 Hz, 2 H), 2.94 and 2.91 (2 ×
s, 3 H), 1.62 and 1.36 and 1.33 (3 × s, 9 H), a signal corresponding to
the CH2 protons of NCH2Ph was not observed.
13C NMR (100 MHz, CDCl3):  = 168.29, 167.36, 156.90, 137.85,
137.02, 128.83, 128.76, 128.55, 127.84, 127.65, 127.35, 126.92,
126.63, 126.16, 80.88, 71.98, 71.43, 51.35, 51.05, 43.66, 43.40, 36.41,
35.57, 28.23, 28.11. The signal corresponding to the methylene car-
bon of NCH2Ph was not observed.
1H NMR (400 MHz, CDCl3):  (mixture of two rotamers) = 7.35–7.27
(m, 5 H), 4.88 and 4.81 (2 × s, 2 H), 3.96 (d, J = 15.9 Hz, 2 H), 2.82 (s, 3
H), 2.32 (q, J = 7.5 Hz, 2 H), 1.45 and 1.40 (2 × s, 9 H), 1.14 (ddd, J =
13.4, 9.2, 5.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  (mixture of two rotamers) = 174.00,
168.07 and 167.78, 155.82 and 154.84, 135.03 and 134.80, 128.65,
128.58, 128.38, 128.07, 127.94, 80.76 and 80.66, 52.10, 49.20 and
48.91, 35.61 and 35.37, 28.19, 25.71, 8.38.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H26N2O5Na: 373.1734;
found: 373.1742.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C21H26N2O5SNa: 441.1455;
found: 441.1457.
(S)-tert-Butyl {1-[(N-Benzyl-3,3,3-trifluoropropanamido)oxy]-1-
oxopropan-2-yl}(methyl)carbamate (4k)
(S)-tert-Butyl (1-{[N-Benzyl-2-(thiophen-2-yl)acetamido]oxy}-1-
Yield: 0.37 g (80%); colorless liquid; Rf = 0.22 (20% EtOAc/hexanes);
[]D20 –10.4 (c 0.5, CH2Cl2).
oxopropan-2-yl)(methyl)carbamate (4h)
20
Yield: 0.52 g (74%); yellow oil; Rf = 0.22 (20% EtOAc/hexanes); []D
IR (Diamond-ATR, neat): 3225, 2980, 1796, 1684, 1453, 1393, 1368,
–37.6 (c 1.3, CH2Cl2).
1329, 1259, 1155 cm–1
.
IR (Diamond-ATR, neat): 3297, 2975, 2930, 1746, 1662, 1537, 1453,
1H NMR (400 MHz, CDCl3):  (mixture of two rotamers) = 7.36–7.27
(m, 5 H), 4.90 (s, 2 H), 4.61 and 4.41–4.37 (br s and m, 1 H), 3.29–3.22
(m, 2 H), 2.75 (s, 3 H), 1.42 (s, 9 H), 1.30 (d, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 169.8, 158.4, 134.3, 128.9, 128.7,
128.3, 125.2, 122.4, 81.0, 53.6 and 53.0, 51.6, 37.2 (q, JC–F = 117.2 Hz),
31.5, 28.2, 14.4; the signal corresponding to CO in NCH2PhOCO was
not observed.
1390, 1366, 1149, 1087, 697 cm–1
.
1H NMR (400 MHz, CDCl3):  (mixture of two rotamers) = 7.74–7.69
and 7.54–7.51 (2 × m, 1 H), 7.33–7.27 and 7.22–7.16 (2 × m, 5 H), 6.42
and 6.32 (2 × s, 1 H), 4.70 and 4.16 (br q, J = 6.8 Hz, 1 H), 4.60–4.36 (m,
2 H), 2.92 and 2.78 (2 × s, 3 H), 1.48–1.43 (m, 3 H), 1.34 (s, 9 H); a
signal corresponding to the CH2 protons of NCH2Ph was not observed.
13C NMR (100 MHz, CDCl3):  (mixture of two rotamers) = 170.97 and
170.48, 167.7 and 167.64, 156.94 and 156.25, 138.02 and 137.91,
137.43, 128.68, 128.53, 128.45, 127.79, 127.75, 127.42, 127.31,
127.19, 126.87, 126.85, 126.38, 80.79 and 80.70, 72.56 and 71.89,
56.57 and 54.41, 43.37, 33.82 and 31.10, 28.27, 14.60 and 14.15. The
signal corresponding to the CH2 carbon of NCH2Ph was not observed.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C19H25F3N2O5Na: 441.1608;
found: 441.1612.
tert-Butyl {2-[(N-Benzylacetamido)oxy]-2-oxoethyl}(methyl)car-
bamate (4l)
Yield: 0.47 g (85%); colorless liquid.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C22H28N2O5SNa: 455.1611;
found: 455.1602.
IR (Diamond-ATR, neat): 2976, 2932, 1795, 1685, 1452, 1389, 1367,
1242, 1151, 1100, 1058, 1032, 879, 699 cm–1
.
1H NMR (400 MHz, CDCl3):  (mixture of two rotamers) = 7.34–7.30
(m, 5 H), 4.88 and 4.82 (2 × s, 2 H), 3.96 (d, J = 11.8 Hz, 2 H), 2.94 and
2.83 (2 × s, 3 H), 2.08 (s, 3 H), 1.42 and 1.40 (2 × s, 9 H).
13C NMR (100 MHz, CDCl3):  (mixture of two rotamers) = 171.80,
168.08 and 167.73, 155.85 and 154.84, 134.91 and 134.66, 128.69,
128.61, 128.14, 128.00, 80.80 and 80.70, 51.93, 49.16 and 48.95, 35.68
and 35.36 , 28.23, 20.49.
(E)-tert-Butyl {2-[(N-Benzylbut-2-enamido)oxy]-2-oxoethyl}-
(methyl)carbamate (4i)
Yield: 0.54 g (80%); colorless liquid; Rf = 0.53 (35% EtOAc/hexanes).
IR (Diamond-ATR, neat): 3031, 2975, 1793, 1690, 1699, 1635, 1445,
1387, 1366, 1236, 1151, 1095, 1055, 963, 921, 881, 699 cm–1
.
1H NMR (400 MHz, CDCl3):  (mixture of two rotamers) = 7.33–7.27
(m, 5 H), 7.07 (dt, J = 14.5, 6.9 Hz, 1 H), 6.16 and 6.05 (2 × d, J = 15.2
Hz, 1 H), 4.93 (s, 2 H), 3.97 (ABq, J = 12.8 Hz, 2 H), 2.82 (s, 3 H), 1.89
and 1.87 (dd, J = 7.0, 1.6 Hz, 3 H), 1.44 and 1.40 (2 × s, 9 H).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H24N2O5Na: 359.1577;
found: 359.1581.
13C NMR (100 MHz, CDCl3):  (mixture of two rotamers) = 168.13 and
167.67, 166.41 and 166.09, 155.87 and 154.86, 145.19 and 144.97,
135.05 and 134.81, 128.64, 128.55, 128.53, 128.30, 128.03, 127.89,
119.68 and 119.34 , 80.69 and 80.65, 52.42 and 52.12, 49.17 and
49.00, 35.66 and 35.30, 28.23 and 28.19, 18.28 and 18.25.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C19H26N2O5Na: 385.1734;
found: 385.1737.
tert-Butyl Methyl{2-[(N-Methyl-2-phenylacetamido)oxy]-2-oxo-
ethyl}carbamate (4m)
Yield: 0.56 g (88%); colorless liquid.
IR (Diamond-ATR, neat): 3222, 2927, 1770, 1625, 1490, 1434, 1395,
1192, 1105 cm–1
.
1H NMR (400 MHz, CDCl3):  (mixture of two rotamers) = 7.31–7.23
(m, 5 H), 4.02 (d, J = 18.4 Hz, 2 H), 3.66 (s, 2 H), 3.33 and 3.32 (2 × s, 3
H), 2.92 (s, 3 H), 1.47 and 1.43 (2 × s, 9 H).
tert-Butyl {2-[(N-Benzylpropionamido)oxy]-2-oxoethyl}(meth-
13C NMR (100 MHz, CDCl3):  (mixture of two rotamers) = 167.88 and
167.64, 155.91 and 154.91, 133.86 and 133.50, 129.20, 129.05,
128.72, 128.61, 127.19, 127.01, 80.89 and 80.81, 49.32 and 49.00,
39.83 and 39.70, 35.86 and 35.67, 28.27.
yl)carbamate (4j)
Yield: 0.59 g, 86%, colorless liquid; Rf = 0.4 (35% EtOAc/hexanes).
IR (Diamond-ATR, neat): 3089, 3064, 1793, 1685, 1453, 1389, 1366,
1306, 1237, 1150, 1099, 806, 633 cm–1
.
HRMS (ESI-TOF): m/z [M – H]+ calcd for C17H23N2O5: 335.1607; found:
335.1971.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

I
Z. Nazarian, C. M. Forsyth
Paper
Synthesis
1,6-Dioxa-3,9-diazaspiro[4.4]nonane-2,8 diones 6 and 7; General
Procedure (GP3)
9-Benzyl-4-isopropyl-3-methyl-7-phenyl-1,6-dioxa-3,9-di-
azaspiro[4,4]nonane-2,8-dione (6c, 7c)
To an oven-dried round-bottomed flask containing dry CH2Cl2 at –78
°C was added N,O-diacyl hydroxylamine 4a–m (1.0 equiv) under an
atmosphere of N2. To this solution was added TBSOTf (2.5 equiv)
dropwise via a microsyringe through a septum, followed after 5 min
by Et3N (2.5 equiv). The reaction was maintained at –78 °C for about
15–20 min while stirring vigorously and was then removed from the
dry ice bath and allowed to stir at room temperature for an additional
13–14 h. After the reaction was deemed complete (via TLC), the sol-
vent was evaporated under reduced pressure and the crude product
was then applied directly to a silica gel column and eluted with the
appropriate solvent system.
Prepared using 4c (0.39 mmol, 0.18 g), TBSOTf (0.97 mmol, 0.26 mL)
and Et3N (0.97 mmol, 0.14 mL) in accordance with GP3.
Yield: 66 mg (45% combined yield); dr = 1.3:1.
Less polar spirocyclic 6c15 (major product): off-white solid; mp 153–
155 °C; Rf = 0.25 (20% EtOAc/hexanes).
1H NMR (400 MHz, CDCl3):  = 7.45–7.25 (m, 10 H), 5.54 (s, 1 H), 5.12
(d, J = 15.9 Hz, 1 H), 4.06 (d, J = 15.9 Hz, 1 H), 3.32 (d, J = 2.3 Hz, 1 H),
2.80 (s, 3 H), 2.08 (m, 1 H), 0.91 (d, J = 6.9 Hz, 3 H), 0.83 (d, J = 7.4 Hz, 3
H).
13C NMR (100 MHz, CDCl3):  = 170.7, 155.0, 135.9, 133.6, 129.3,
128.9, 128.3, 127.6, 127.1, 113.8, 78.2, 66.3, 43.8, 30.7, 27.5, 19.8,
16.6.
9-Benzyl-3-methyl-7-phenyl-1,6-dioxa-3,9-di-
azaspiro[4,4]nonane-2,8-dione (6a, 7a)
More polar spirocycle 7c was isolated as a mixture of two diastereo-
Prepared using 4a (0.46 mmol, 0.19 g), TBSOTf (1.15 mmol, 0.31 mL)
mers.
and Et3N (1.15 mmol, 0.16 mL) in accordance with GP3.
Yield: 78 mg (50% combined yield); dr = 1.5:1.
Less polar spirocyclic 6a15 (major product): off-white solid; Rf = 0.32
9-Benzyl-3,4-dimethyl-7-(naphthalene-2-yl)-1,6-dioxa-3,9-di-
azaspiro[4,4]nonane-2,8-dione (6e)
Prepared using 4e (0.46 mmol, 0.22 g), TBSOTf (1.1 mmol, 0.28 mL)
(40% EtOAc/hexanes).
and Et3N (1.05 mmol, 0.146 mL) in accordance with GP3.
1H NMR (400 MHz, CDCl3):  = 7.54–7.24 (m, 10 H), 5.46 (s, 1 H), 5.02
(d, J = 15.6 Hz, 1 H), 4.08 (d, J = 15.7 Hz, 1 H), 3.53 (d, J = 11.1 Hz, 1 H),
3.22 (d, J = 11.1 Hz, 1 H), 2.77 (s, 3 H).
Yield: 120 mg (66%); off-white solid; mp 174–175 °C; Rf = 0.32 (40%
EtOAc/hexanes); []D20 –75.8 (c 1.0, CH2Cl2).
The more polar isomer 7a15 was isolated as a mixture of two diaste-
reomers.
IR (Diamond-ATR, neat): 3059, 3032, 2979, 2938, 1773, 1737, 1452,
1429, 1398, 922 cm–1
.
1H NMR (600 MHz, CDCl3):  = 7.96–7.87 (m, 4 H), 7.56–7.52 (m, 2 H),
7.50 (dd, J = 8.4, 1.8 Hz, 1 H), 7.38–7.31 (m, 5 H), 5.70 (s, 1 H), 5.14 (d,
J = 16.2 Hz, 1 H), 4.16 (d, J = 16.2 Hz, 1 H), 3.59 (q, J = 6.6 Hz, 1 H), 2.77
(s, 3 H), 1.20 (d, J = 6.6 Hz, 3 H).
1H NMR (400 MHz, CDCl3):  (mixture of 6a and 7a) = 7.54 (d, J = 6.9
Hz, 14 H),7.54–7.25 (m, 10 H), 5.52 (s, 1 H), 5.47 (s, 1 H), 5.09 (d, J =
15.6 Hz, 1 H), 5.03 (d, J = 15.5 Hz, 1 H), 4.11 (s, 1 H), 4.07 (s, 1 H), 3.33
(d, J = 11.1 Hz, 1 H), 3.23 (d, J = 11.0 Hz, 1 H), 2.79 (s, 3 H), 2.78 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 171.1, 154.5, 135.4, 133.8, 133.1,
131.3, 129.1, 129.0, 128.3, 127.8, 127.4, 127.0, 126.9, 126.7, 123.5,
113.5, 78.1, 57.6, 43.8, 28.3, 12.5.
13C NMR (100 MHz, CDCl3):  = 170.42, 169.72, 154.55, 154.49,
135.42, 135.25, 134.21, 133.90, 129.11, 129.05, 128.92, 128.82,
128.71, 128.58, 128.52, 128.20, 127.90, 126.52, 124.11, 112.21,
111.75, 79.50, 79.38, 54.76, 54.25, 43.77, 43.67, 30.22, 30.18.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C24H23N2O4: 403.1652; found:
403.1656.
9-Benzyl-3,4-dimethyl-7-phenyl-1,6-dioxa-3,9-di-
azaspiro[4,4]nonane-2,8-dione (6b, 7b)
3-Benzyl-2-[(tert-butyldimethylsilyl)oxy]-2-[(S)-1-(methylami-
Prepared using 4b (0.47 mmol, 0.20 g), TBSOTf (1.2 mmol, 0.31 mL)
no)ethyl]-5-(naphthalen-1-yl)oxazolidin-4-one (8e)
and Et3N (1.2 mmol, 0.16 mL) in accordance with GP3.
Yield: 20 mg (9%); yellow oil; Rf = 0.6 (40% EtOAc/hexanes).
Yield: 90 mg (55% combined yield); dr = 1.7:1 dr.
Less polar spirocyclic 6b15 (major product): off-white solid; Rf = 0.32
IR (Diamond-ATR, neat): 3326, 2953, 2928, 2855, 1714, 1434, 1413,
1359, 1252, 1165, 838 cm–1
.
1H NMR (600 MHz, CDCl3):  = 8.11 (s, 1 H), 7.87–7.82 (m, 3 H), 7.72
(dd, J = 8.5, 1.6 Hz, 1 H), 7.50–7.49 (m, 4 H), 7.48–7.29 (m, 3 H), 5.75
(s, 1 H), 4.95 (d, J = 14.9 Hz, 1 H), 4.25 (d, J =14.9 Hz, 1 H), 2.52 (q, J =
6.4 Hz, 1 H), 1.86 (s, 3 H), 1.18 (d, J = 6.4 Hz, 3 H), 0.88 (s, 9 H), 0.16 (s,
3 H), –0.19 (s, 3 H).
13C NMR (150 MHz, CDCl3):  = 170.1, 137.4, 133.1, 133.0, 128.8,
128.6, 128.2, 128.0, 127.7, 127.7, 126.2, 126.1, 125.7, 124.7, 112.4,
79.5, 62.0, 43.5, 33.7, 25.7, 18.1, 13.3, –3.0, –4.1.
(40% EtOAc/hexanes).
1H NMR (400 MHz, CDCl3):  = 7.45–7.23 (m, 10 H), 5.53 (s, 1 H), 5.10
(d, J = 16.0 Hz, 1 H), 4.13 (d, J = 16.0 Hz, 1 H), 3.56 (q, J = 6.6 Hz, 1 H),
2.76 (s, 3 H), 1.17 (d, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 171.0, 154.3, 135.8, 133.9, 129.2,
129.1, 128.9, 128.2, 127.3, 126.8, 113.4, 77.9, 57.5, 43.7, 28.3, 12.4.
More polar spirocyclic 7b:15 colorless liquid; Rf = 0.18 (40% EtO-
Ac/hexanes).
1H NMR (400 MHz, CDCl3):  = 7.54–7.27 (m, 10 H), 5.45 (s, 1 H), 5.01
(d, J = 15.8 Hz, 1 H), 4.16 (d, J = 15.8 Hz, 1 H), 3.45 (q, J = 6.5 Hz, 1 H),
2.74 (s, 3 H), 1.18 (d, J = 6.6 Hz, 3 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C29H39N2O3Si: 491.2724;
found: 491.2727.
9-Benzyl-3-methyl-7-(4-nitrophenyl)-1,6-dioxa-3,9-di-
azaspiro[4,4]nonane-2,8-dione (6f)
13C NMR (100 MHz, CDCl3):  = 170.1, 154.3, 135.6, 134.4, 129.1,
129.1, 128.9, 128.4, 127.7, 126.5, 113.7, 79.7, 58.3, 43.8, 28.3, 12.2.
Prepared using 4f (0.47 mmol, 0.22 g), TBSOTf (1.1 mmol, 0.29 mL)
and Et3N (1.1 mmol, 0.16 mL) in accordance with GP3.
Yield: 41 mg (23%); pale yellow solid; mp 133–134 °C; []D20 +1.20 (c
0.77, CH2Cl2).
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

J
Z. Nazarian, C. M. Forsyth
Paper
Synthesis
IR (Diamond-ATR, neat): 3389, 1776, 1736, 1522, 1398, 1414, 1348,
978 cm–1
3-Benzyl-2-[(tert-butyldimethylsilyl)oxy]-2-[1-(methylami-
no)ethyl]-5-(thiophen-2-yl)oxazolidin-4-one (8h)
.
1H NMR (400 MHz, C6D6):  = 7.83-7.79 (d, J = 8.9 Hz, 2 H), 7.10-7.05
(d, J = 8.9 Hz, 2 H), 6.97-6.94 (m, 3 H) , 6.92-6.90 (m, 2 H), 4.83 (s, 1 H),
4.66 (d, J = 15.6 Hz, 2 H), 3.62 (d, J = 15.6 Hz, 2 H), 2.70 (ABq, J = 11.2
Hz, 2 H), 2.15 (s, 3 H).
Yield: 12 mg (5%); yellow oil; Rf = 0.6 (20% EtOAc/hexanes).
1H NMR (400 MHz, CDCl3):  = 7.47–7.26 (m, 7 H), 7.01 (m, 1 H), 5.78
(s, 1 H), 4.91 (d, J = 14.8 Hz, 1 H), 4.20 (d, J = 15.6 Hz, 1 H), 2.44 (q, J =
6.4 Hz, 1 H), 1.81 (s, 3 H), 1.12 (d, J = 6.4 Hz, 3 H), 0.88 (s, 9 H), 0.12 (s,
3 H), –0.14 (s, 3 H).
13C NMR (100 MHz, C6D6):  = 168.5, 153.7, 148.2, 140.5, 135.7, 128.8,
13C NMR (100 MHz, CDCl3):  = 169.3, 137.2, 128.9, 127.9, 127.0,
126.6, 126.5, 126.0, 125.6, 112.5, 61.7, 43.6, 33.7, 25.7, 18.0, 14.1,
–3.2, –4.4.
126.3, 123.4, 111.2, 76.4, 53.3, 43.3, 29.3.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H18N3O6: 384.1190; found:
384.1192.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C23H35N2O3SSi: 447.2132;
9-Benzyl-3-methyl-7-(thiophen-2-yl)-1,6-dioxa-3,9-di-
azaspiro[4,4]nonane-2,8-dione (6g, 7g)
found: 447.2128.
Prepared using 4g (0.52 mmol, 0.22 g), TBSOTf (1.3 mmol, 0.34 mL)
and Et3N (1.3 mmol, 0.18 mL) in accordance with GP3.
9-Benzyl-3-methyl-7-vinyl-1,6-dioxa-3,9-diazaspiro[4.4]nonane-
2,8-dione (6i, 7i)
Prepared using 4i (0.49 mmol, 0.18 g), TBSOTf (1.3 mmol, 0.32 mL)
Yield: 35 mg (20% combined yield); dr = 1.2:1.
and Et3N (1.3 mmol, 0.17 mL) in accordance with GP3.
Less polar isomer 6g (major product): pale yellow solid; mp 142–143
°C; Rf = 0.32 (40% EtOAc/hexanes); []D20 +1.47 (c 0.44, CH2Cl2).
Yield: 60 mg (42% combined yield); dr = 1.2:1.
Less polar diastereomer 6i (major product); off-white solid; Rf = 0.32
(40% EtOAc/hexanes).
IR (Diamond-ATR, neat): 3348, 2928, 1773, 1736, 1414, 1398, 1362,
1291, 977 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.40–7.26 (m, 6 H), 7.25–7.23 (m, 1 H),
7.06 (dd, J = 5.1, 3.6 Hz, 1 H), 5.78 (s, 1 H), 5.11 (d, J = 15.8 Hz, 1 H),
4.10 (d, J = 15.7 Hz, 1 H), 3.54 (d, J = 11.2 Hz, 1 H), 3.30 (d, J = 11.2 Hz,
1 H), 2.78 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 169.0, 154.4, 136.4, 135.2, 128.9,
128.2, 127.5, 127.4, 127.1, 127.0, 111.5, 75.0, 54.3, 43.8, 30.2.
IR (Diamond-ATR, neat): 3353, 3063, 3031, 2927, 1773, 1726, 1393,
1362, 1311, 986 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.35–7.25 (m, 5 H), 5.96 (ddd, J = 17.1,
10.5, 5.8 Hz, 1 H), 5.61 (ddd, J = 17.1, 1.5, 0.9 Hz, 1 H), 5.42 (ddd, J =
10.5, 1.5, 0.9 Hz, 1 H), 5.01 (d, J = 15.6 Hz, 1 H), 4.93 (dt, J = 5.8, 1.5 Hz,
1 H), 4.03 (d, J = 15.6 Hz, 1 H), 3.46 (d, J = 11.2 Hz, 1 H), 3.18 (d, J = 11.2
Hz, 1 H), 2.74 (s, 3 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H17N2O4S: 345.0904;
found: 345.0900.
13C NMR (100 MHz, CDCl3):  = 169.8, 154.5, 135.3, 130.7, 129.0,
128.5, 128.1, 127.9, 120.1, 112.1, 78.6, 54.4, 43.7, 30.1.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H17N2O4: 289.1183; found:
More polar spirocyclic 7g: yellow liquid; Rf = 0.18 (40% EtOAc/hex-
anes); []D20 –3.69 (c 0.26, CH2Cl2).
289.1182.
IR (Diamond-ATR, neat): 3345, 2966, 1771, 1735, 1671, 1496, 1400,
1396, 1292, 976 cm–1
.
More polar isomer 7i was isolated as a mixture of two diastereomers.
1H NMR (400 MHz, CDCl3):  (mixture of 6i and 7i) = 7.51–7.23 (m, 10
H), 6.00–5.89 (m, 2 H), 5.63–5.53 (m, 2 H), 5.46–5.41 (m, 2 H), 5.04
(m, 1 H), 5.00 (d, J = 4.4 Hz, 2 H), 4.93 (m, 1 H), 4.06 (d, J = 4.4 Hz, 1 H),
4.02 (d, J = 4.4 Hz, 1 H), 3.48 (d, J = 4.8 Hz, 1 H), 3.45 (d, J = 4.4 Hz, 1 H),
3.24 (ABq, J = 11.2 Hz, 1 H), 3.19 (ABq, J = 11.2 Hz, 1 H), 2.78 (s, 3 H),
2.76 (s, 3 H).
1H NMR (400 MHz, CDCl3):  = 7.39–7.25 (m, 7 H), 7.01 (dd, J = 5.0, 3.6
Hz, 1 H), 5.68 (s, 1 H), 5.06 (d, J = 15.5 Hz, 1 H), 4.12 (d, J = 15.5 Hz, 1
H), 3.52 (d, J = 11.1 Hz, 1 H), 3.21 (d, J = 11.1 Hz, 1 H), 2.77 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 168.9, 154.4, 136.2, 135.1, 129.1,
128.6, 128.2, 127.3, 127.2, 127.1, 112.1, 75.5, 54.5, 44.0, 30.2.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H17N2O4S: 345.0904;
found: 345.0899.
9-Benzyl-3,7-dimethyl-1,6-dioxa-3,9-diazaspiro[4,4]nonane-2,8-
dione (6j, 7j)
9-Benzyl-3,4-dimethyl-7-(thiophen-2-yl)-1,6-dioxa-3,9-di-
azaspiro[4,4]nonane-2,8-dione (6h)
Prepared, using 4j (0.57 mmol, 0.20 g), TBSOTf (1.43 mmol, 0.38 mL)
and Et3N (1.43 mmol, 0.20 mL) in accordance with GP3.
Prepared using 4h (0.46 mmol, 0.20 g), TBSOTf (1.1 mmol, 0.28 mL)
and Et3N (1.1 mmol, 0.02 mL) in accordance with GP3.
Yield: 47 mg (30% combined yield); dr = 1.2:1.
Less polar isomer 6j15 (major product): off-white solid; Rf = 0.51 (50%
EtOAc/hexanes).
1H NMR (400 MHz, CDCl3):  = 7.37–7.23 (m, 5 H), 5.00 (d, J = 16.0 Hz,
1 H), 4.61 (q, J = 12.0 Hz, 1 H), 4.03 (d, J = 16.0 Hz, 1 H), 3.40 (d, J = 12.0
Hz, 1 H), 3.22 (d, J = 12.0 Hz, 1 H), 2.76 (s, 3 H), 1.50 (d, J = 8.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 172.7, 154.8, 135.5, 129.0, 129.0,
128.4, 127.8, 123.3, 111.6, 101.7, 54.1, 43.5, 30.2, 17.2.
Yield: 53 mg (32%); light yellow solid; mp 159–160 °C; Rf = 0.32 (40%
EtOAc/hexanes); []D20 –4.81 (c 0.022, CH2Cl2).
IR (Diamond-ATR, neat): 3346, 3064, 3032, 2935, 1774, 1739, 1432,
1399, 1338, 925 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.34–7.24 (m, 7 H), 7.00 (dd, J = 5.1, 3.6
Hz, 1 H), 5.72 (s, 1 H), 5.03 (d, J = 16.0 Hz, 1 H), 4.06 (d, J = 16.0 Hz, 1
H), 3.45 (q, J = 6.8 Hz, 1 H), 2.74 (s, 3 H), 1.04 (d, J = 6.4 Hz, 3 H).
More polar isomer 7j was isolated as a mixture of two diastereomers.
13C NMR (100 MHz, CDCl3):  = 169.9, 154.2, 136.3, 135.6, 129.1,
128.3, 128.0, 127.3, 127.1, 113.3, 74.7, 57.6, 43.8, 28.3, 12.4.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H19N2O4S: 359.1060;
found: 359.1054.
1H NMR (400 MHz, CDCl3):  (mixture of 6j and 7j) = 7.38–7.30 (m, 5
H), 7.29–7.21 (m, 5 H), 5.01 (d, J = 7.6 Hz, 1 H), 4.97 (d, J = 7.7 Hz, 1 H),
4.62 (q, J = 6.8 Hz, 1 H), 4.55 (q, J = 7.0 Hz, 1 H), 4.04 (d, J = 3.8 Hz, 1 H),
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K

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Z. Nazarian, C. M. Forsyth
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Synthesis
4.00 (d, J = 3.7 Hz, 1 H), 3.41 (d, J = 3.0 Hz, 1 H), 3.38 (d, J = 3.0 Hz, 1 H),
3.22 (d, J = 11.1 Hz, 1 H), 3.16 (d, J = 11.0 Hz, 1 H), 2.75 (s, 3 H), 2.74 (s,
3 H), 1.54 (d, J = 7.0 Hz, 3 H), 1.50 (d, J = 6.8 Hz, 3 H).
(7) Miller, S. J.; Bayne, C. D. J. Org. Chem. 1997, 62, 5680.
(8) Al-Faiyz, Y. S. S.; Clark, A. J.; Filik, R. P.; Peacock, J. L.; Thomas, G.
H. Tetrahedron Lett. 1998, 39, 1269.
(9) Clark, A. J.; Al-Faiyz, Y. S. S.; Broadhurst, M. J.; Patel, D.; Peacock,
J. L. J. Chem. Soc., Perkin Trans. 1 2000, 1117.
(10) Clark, A. J.; Al-Faiyz, Y. S. S.; Patel, D.; Broadhurst, M. J. Tetrahe-
dron Lett. 2001, 42, 2007.
Funding Information
(11) Lagiakos, H. R.; Aguilar, M.-I.; Perlmutter, P. J. Org. Chem. 2009,
74, 8001.
The authors are grateful for financial support from Monash University
through the award of a Ph.D. scholarship to Z.N.
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ash
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iversiyt()
(12) Ito, Y.; Konoike, T.; Saegusa, T. J. Am. Chem. Soc. 1975, 97, 2912.
(13) Paquette, L. A.; Bzowej, E. I.; Branan, B. M.; Stanton, K. J. J. Org.
Chem. 1995, 60, 7277.
(14) Matsumura, Y.; Nishimura, M.; Hiu, H.; Watanabe, M.; Kise, N.
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(15) Nazarian, Z.; Forsyth, C. RSC Adv. 2016, 6, 55534.
(16) Price, B. J.; Sutherland, I. O. Chem. Commun. (London) 1967,
1070.
(17) Parallel research in our laboratory revealed that N,O-diacyl
hydroxyl amine derivatives can undergo 3,3-sigmatropic rear-
rangement under different conditions.
(18) Forsyth, C. M.; Nazarian, Z. IUCrData 2019, 4, x190520.
(19) Hoffman, R. V.; Nayyar, N. K.; Chen, W. J. Org. Chem. 1992, 57,
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1706660.
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© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–K