Efficient Approaches for the Synthesis of Diverse α-Diazo Amides

Article abstract of DOI:10.1055/s-0039-1690905

Metal-catalysed carbenoid chemistry can be exploited for the synthesis of diverse ranges of small molecules from α-diazo carbonyl compounds. In this paper, three synthetic approaches to α-diazo amides are described, and their scope and limitations are determined. On the basis of these synthetic studies, recommendations are provided to assist the selection of the most appropriate approach for specific classes of product. The availability of practical and efficient syntheses of diverse α-diazo acetamides is expected to facilitate the discovery of many different classes of bioactive small molecules.

Full text of DOI:10.1055/s-0039-1690905

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–L
paper
A
en
S. Chow et al.
Paper
Synthesis
Efficient Approaches for the Synthesis of Diverse -Diazo Amides
Shiao Chowa,b
Adam I. Greena,b
R1
NH
R2
A: Acylation and elimination
Christopher Artera,b
Samuel Livera,b
Abbie Leggotta,b
Luke Traska,b
George Karageorgisa,b
Stuart Warrinera,b
14 examples
21–97% yield
O
C: Diazo transfer
10 examples
22–82% yield
B: α-Substitution
12 examples
34–85% yield
R1
R3
N
R2
N2
O
O
Adam Nelson*a,b
0
0
0
0-0
0
0
3-3
8
8
6-3
6
3
X
R1
N
R1
R3
N
R2
N2
R2
a School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK
b Astbury Centre for Structural Molecular Biology, University of
Leeds, Leeds, LS2 9JT, UK
a.s.nelson@leeds.ac.uk
Received: 05.11.2019
Accepted after revision: 04.01.2020
Published online: 06.02.2020
be complementary, and enable the efficient synthesis of a
wide range of substrates.
We envisaged three general synthetic approaches to -
diazo amides 1 (Scheme 1): acylation with an appropriate
reagent followed by elimination (Approach A); -substitu-
tion of -diazo acetamides 2 (Approach B); and diazo trans-
fer (Approach C). Here, we describe the development and
demonstrate the scope and limitations of practical methods
for the synthesis of -diazo amides (and some related com-
pounds) from readily available starting materials.
DOI: 10.1055/s-0039-1690905; Art ID: ss-2019-t0491-op
Abstract Metal-catalysed carbenoid chemistry can be exploited for
the synthesis of diverse ranges of small molecules from -diazo carbon-
yl compounds. In this paper, three synthetic approaches to -diazo am-
ides are described, and their scope and limitations are determined. On
the basis of these synthetic studies, recommendations are provided to
assist the selection of the most appropriate approach for specific class-
es of product. The availability of practical and efficient syntheses of di-
verse -diazo acetamides is expected to facilitate the discovery of many
different classes of bioactive small molecules.
R1
NH
R2
Key words diazo compounds, molecular diversity, carbenoid chemis-
try
A: Acylation and elimination
Metal-catalysed carbenoid chemistry can enable the
synthesis of many different classes of small molecule.1 The
diversity of the possible products stems from the many dif-
ferent patterns of reactivity that are possible, and the scope
for both inter- and intramolecular reactions. The diverse
patterns of possible reactivity include insertion into C–H,
O–H and N–H bonds, cyclopropanation and ylide forma-
tion; some of these processes also enable subsequent
chemistry such as cycloaddition or rearrangement reac-
tions.2–4 Crucially, judicious choice of catalyst can provide
control over stereochemistry, chemoselectivity (e.g., a par-
ticular C–H bond in a complex substrate) and reaction fate
(e.g., which mode of reactivity is favoured).5–10 The diversity
of possible reaction outcomes can enable the parallel dis-
covery of diverse bioactive chemotypes.11,12
O
R1
R3
N
R2
B: α-Substitution
C: Diazo transfer
O
N2
1
O
R1
R1
N
R2
R3
N
R2
N2
2
3
Scheme 1 Overview of synthetic approaches to -diazo amides
Approach A: Synthesis by Acylation and Elimination
We developed a one-pot synthesis of -diazo amides
from readily available amines that was based on an estab-
lished synthesis of -diazoacetic esters.13,14 Glyoxylic acid
(4a) and phenylglyoxylic acid (4b) were initially converted
into the corresponding toluenesulfonyl hydrazones 5. Sub-
sequent treatment with thionyl chloride in toluene at 90 °C
gave the corresponding acid chlorides 6 that were used
without purification (Scheme 2). The acid chlorides 6a and
6b were orange and yellow amorphous solids respectively,
We therefore investigated a suite of methods for the
synthesis of -diazo amides and some related compounds.
These methods would ideally enable the efficient synthesis
of structurally diverse diazo compounds from readily avail-
able substrates without the need for purification of any in-
termediates. Overall, the developed methods would ideally
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S. Chow et al.
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Synthesis
acetamide 2h, for example, was spectroscopically identical
after storage for more than a year.
Ts
Ts
O
R
NH
NH
TsNHNH2
THF
SOCl2
toluene
N
N
OH
The acid chloride 6b was exploited in the synthesis of an
-diazo -phenyl acetamide (Scheme 4). After coupling
with pyrrolidine (3.3 equiv) in the presence of N,N-dimeth-
ylaniline, elimination was induced by treatment with a
12 M aqueous solution of sodium hydroxide and the phase-
transfer catalyst trioctylmethylammonium chloride
(Aliquat® 336; 1 mol%). We had investigated the use of
trimethylamine and DBU in the elimination step with little
success, even at elevated temperature, before arriving at
these optimal conditions.16 We demonstrated that, with
pyrrolidine, good yields of the corresponding -diazo -
phenyl acetamide 8 could be obtained.
OH
Cl
R
R
O
O
O
4a, R = H
4b, R = Ph
5a, R = H, 99%
5b, R = Ph, 76%
6a, R = H
6b, R = Ph
Scheme 2 Synthesis of the acid chlorides 6 that were used without pu-
rification
and were stored in vacuo at room temperature for a maxi-
mum of 12 hours prior to use.
The acid chloride 6a was exploited in the synthesis of -
diazo acetamides. Accordingly, a solution of the acid chlo-
ride 6a in dichloromethane at 0 °C was treated with the
requisite amine and N,N-dimethylaniline under a nitrogen
atmosphere; after 2 hours, triethylamine was added to in-
duce elimination to yield the corresponding -diazo acet-
amide (Scheme 3). Although DBU has been used in synthe-
ses of related products,15 we found triethylamine enabled
more facile product purification.
O
1. 6b, N,N-dimethylaniline
H
N
CH2Cl2, 0 °C
Ph
N
2. Aliquat-336 (1 mol%)
NaOH (12 M)
63%
N2
8
Scheme 4 One-pot synthesis of a -diazo -phenyl acetamide 8
The approach enabled the synthesis of a wide range of
-diazo acetamides. In particular, a primary amine (→ 2a),
secondary amines (→ 2b–g) and anilines/hetarylamines (→
2h–m) were successful as substrates. In the case of sterical-
ly hindered secondary amines, prolonged coupling and/or
elimination was necessary to yield the corresponding -di-
azo acetamides (e.g., 2f). The -diazo acetamides 2a–m
were stored at –20 °C; under these conditions, the -diazo
Approach B: Synthesis by -Arylation of the Correspond-
ing -Diazo Acetamide
We have also developed a method for the -arylation of
-diazo acetamides 2 (Scheme 5).17 The beneficial effect of
Ag2CO3 was found following a limited additive screen, and
is in line with previous studies involving related sub-
strates.17b In each case, Pd(PPh3)4 (5 mol%) and Ag2CO3 (0.5
equiv) were placed in oven-dried glassware under a nitro-
TsHN
Cl
A
N
1.
O
R1
R1
6a
O
NH
R2
N
R2
N,N-dimethylaniline
CH2Cl2, 0 °C
N2
7
2
2. Et3N
O
O
O
O
O
O
B
N
N
N
N
N
H
N2
N2
O
N2
N2
N2
Ph
2a, 79%
2b, 83%
2c, 78%
2d, 63%
2e, 90%
O
NC
O
O
O
N
N
Ph
N
N
F3C
N2
iPr
O
S
N2
N2
N2
NH
O
2f, 26%a,b
2g, 97%
2h, 80%
2i, 79%
iPr
iPr
O
TBSO
TBSO
O
O
O
Ph
N
N
H
O
N
H
N
H
N
N2
N2
N2
N2
2j, 71%
2k, 24%
2l, 50%
2m, 79%
Scheme 3 One-pot synthesis of -diazo acetamides. Panel A: General synthetic scheme. Panel B: Structures of the -diazo acetamides prepared. a
A
prolonged reaction (24 h) between the amine and the acid chloride was required. b A prolonged reaction time (48 h) for the elimination was required.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

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Synthesis
gen atmosphere, and anhydrous toluene, the aryl halide (1
equiv), triethylamine and a solution of the -diazo acet-
amide 2 (1.3 equiv) in anhydrous toluene were added se-
quentially. The reactions were stirred at room temperature,
generally for 4 hours.
extended (48 h) reaction times, product purification was
difficult due to the poor conversions. In addition, couplings
with aryl bromides were successful with electron-deficient
substrates (e.g., → 9c and 9d); however, there was no evi-
dence of conversion by TLC with bromobenzene, 1-bromo-
3-methoxybenzene, 1-bromo-4-methoxybenzene and 3-
bromopyridine, even with extended reaction times.
We also developed a procedure in which the synthesis
of the -diazo acetamide was telescoped with subsequent
-arylation (Scheme 6). The telescoped procedure was suc-
cessful with a bridged secondary amine as a substrate (→
10a).
A
ArI, Pd(PPh3)4 (5 mol%)
Et3N, Ag2CO3 (0.5 equiv)
O
O
R1
R1
Ar
N
R2
N
R2
toluene
N2
N2
9
2
B
CN
CN
O
O
N
CF3
N
CF3
1. 6a
N,N-dimethylaniline
A
N2
N2
O
CH2Cl2, 2 h
then Et3N
9a, 82%a
9b, 77%a
R1
NH
R2
R1
Ar
NO2
N
R2
O
2. ArI, Pd(PPh3)4 (2 mol%)
Et3N, Ag2CO3 (0.5 equiv)
toluene
O
N2
7
10
N
N
N2
N2
B
CN
8, 85%a
9c, 57%b
O
Boc
N
N
CF3
CN
O
O
N2
N
NO2
N
N2
10a, 44%
N2
9d, 47%b
Scheme 6 Telescoped synthesis of -aryl -diazo acetamides from
amines and a lactam. Panel A: General synthetic scheme. Panel B: An
example of an -aryl -diazo acetamide prepared by this route.
9e, 48%
N2
Cl
Cl
N
O
O
N
N
CF3
Approach C: Synthesis by Diazo Transfer
N2
The synthesis of -diazo carbonyl compounds by diazo
transfer has been demonstrated with a range of substrate
classes.18,19 We initially adopted this approach with cyclic
1,3-dicarbonyl compounds (Scheme 7). In our preliminary
studies, we had found that the use of triethylamine as the
base, rather than DBU, enabled more facile product purifi-
cation. Accordingly, triethylamine (1.2 equiv) was added
dropwise to a solution of the appropriate 1,3-dicarbonyl
compound and 4-acetamidobenzenesulfonyl azide (p-ABSA)
(1.5 equiv) in anhydrous acetonitrile at –10 °C, and the re-
action then stirred at room temperature. Under these opti-
mal conditions, diazo transfer was rapid and was accompa-
nied by precipitation of 4-acetamidobenzenesulfonamide.20
Efficient diazo transfer was observed with a range of 1,3-di-
carbonyl compounds including 1,3-dimethylbarbituric acid
(→ 12a), a -keto lactam (→ 12b), a 1,3-diketone (→ 12c)
and Meldrum’s acid (→ 12d).
9g, 49%c
9f, 34%
Cl
N
N2
N2
O
O
NO2
CF3
9h, 47%c
9i, 53%c
N2
N
O
Cl
CF3
9j, 50%c
Scheme 5 Palladium-catalysed synthesis of -aryl -diazo acetamides.
Panel A: General synthetic scheme. Panel B: The prepared -aryl -di-
azo acetamides. a Prepared by method B2 (see the Supporting Informa-
tion), with a 1:1 stoichiometry of diazo compound to aryl iodide.
b Prepared from the corresponding aryl bromide. c Prepared from the
-diazo acetamides described in the Supporting Information.
We also investigated the diazo transfer reactions of acy-
clic -keto amides (Scheme 8). A range of structurally di-
verse -keto amide derivatives was prepared by reaction of
the appropriate nitrogen nucleophile with 2,2,6-trimethyl-
1,3-dioxin-4-one (1.1 equiv) under microwave irradiation
(110 °C, max 200 W, max 300 psi) for 1.5–2 hours.21 Our
previous experience11,12 had shown that it was possible to
telescope the acylation step with a subsequent diazo trans-
The demonstrated scope of the method is shown in
Scheme 5 (Panel B). Couplings were successful with a wide
range of aryl iodides including iodobenzene (→ 8) and elec-
tron-deficient substrates (e.g., → 9a, 9b and 9e–i); it was
found that the coupling proceeded most rapidly with elec-
tron-deficient substrates. Couplings with 5-iodoindole and
4-iodoanisole showed slow conversion by TLC and, despite
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A
A
O
1.
N2
O
O
O
O
p-ABSA, Et3N
O
O
R1
R2
MeCN
R1
R2
O
O
–10 °C → RT
MW, 110 °C
toluene
11
12
R1
R1
NH
R2
N
B
N2
2. p-ABSA, Et3N
MeCN
R2
N2
N2
O
O
7
13
O
O
0 °C → RT
N
N
B
HN
O
Cl
O
O
O
O
O
12a, 88%
12b, 33%
Cl
N
N
O
N2
N2
N2
13b, 64% (over two steps)a
Ph
O
O
13a, 42% (over two steps)a
N2
O
O
O
O
O
Cl
O
O
12c, 76%
12d, 91%
N
N
N2
Scheme 7 Diazo transfer with cyclic 1,3-dicarbonyl substrates
N2
fer reaction. Accordingly, treatment of the crude acylation
products and p-ABSA with triethylamine at 0 °C resulted in
smooth diazo transfer. Significantly extended reaction
times (20–24 h) were required to yield the diazo products
13d, 13f and 13g. Remarkably, the approach was successful
with a wide range of nitrogen nucleophiles including ani-
lines (→ 13a–c), a secondary amine (→ 13d), lactams (→
13e and 13f) and an oxazolidinone (→ 13g).
13c, 67% (over two steps)a
13d, 22% (over two steps)a
O
O
O
O
O
O
O
O
O
N
N
N
O
N2
N2
N2
Ph
iPr
13e, 29%
(over two steps)a
13f, 40%
(over two steps)a
13g, 53%
(over two steps)a
The synthesis of -aryl -diazo acetamides 9 by diazo
transfer was also investigated (Scheme 9). Although similar
-aryl -diazo acetamides 9 had previously been prepared
using diphenyl phosphoryl azide (DPPA) and LDA,22 we rec-
ognised the advantages of p-ABSA in terms of both safety
and ease of product purification. We found DBU to be an ef-
fective base for the transformation. Accordingly, DBU (2
equiv) was added dropwise to a solution of the appropriate
-aryl acetamide and p-ABSA (1.1 equiv); the reactions
were then allowed to warm to room temperature over 4
hours. The method was successful with -aryl acetamides
derived from both anilines (→ 9k and 9l) and a secondary
amine (→ 9f).
-Diazo amides have diverse reactivity that can be har-
nessed in the synthesis of a wide range of molecular scaf-
folds. Indeed, we have previously exploited metal-catalysed
reactions of -diazo amides in the activity-directed synthe-
sis of diverse androgen receptor agonists. The scope of
three synthetic approaches has been determined, and a
summary of our recommendations for which approach is
most suitable for specific classes of product is provided in
Figure 1.
Scheme 8 Synthesis of -diazo -keto amides by diazo transfer.
Panel A: General synthetic scheme. Panel B: The prepared -diazo
-keto amides. a Telescoped yield.
A
O
O
p-ABSA, DBU
R1
Ar
R1
Ar
N
R2
N
R2
MeCN
0 °C → RT
N2
14
9
B
Cl
Cl
O
N
N2
9f, 82%
Cl
Cl
Cl
O
O
Ph
N
Cl
N
N2
9k, 53%
N2
9l, 35%
Scheme 9 Synthesis of -aryl -diazo acetamides by diazo transfer.
Panel A: General synthetic scheme. Panel B: The prepared -aryl -di-
azo acetamides.
We demonstrated that Approach A (synthesis by acyla-
tion with an acid chloride 6 and subsequent elimination)
enables the synthesis of a wide range of -diazo acet-
amides. The value of the approach is likely to be extremely
high because of the very wide availability of primary
amine, secondary amine and aniline substrates.
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dures B2 and C3 are included in the Supporting Information. Flash
column chromatography was carried out using silica gel 60 (35–70
m particles) supplied by Merck. Thin-layer chromatography was car-
ried out using commercially available pre-coated aluminium plates
(Merck silica gel 60 F254). A UV lamp (max = 254 nm) and KMnO4
were used for visualisation. Infrared spectra were recorded on a
Bruker Alpha ATR FR-IR spectrophotometer; absorptions are reported
in wavenumbers (cm–1). 1H and 13C NMR spectra were collected on
Bruker Avance 500, Bruker DPX500, DPX400 or DPX300 spectrome-
ters using an internal deuterium lock. NMR spectra were recorded at
300 K unless otherwise stated. Chemical shifts are quoted in parts per
million down field of trimethylsilane and coupling constants (J) are
given in Hz. High-resolution mass spectrometry (HRMS) was per-
formed using electrospray ionisation on a Bruker MaXis Impact spec-
trometer.
O
• Approach A widely exemplified. Many primary
amine, secondary amine and aniline starting
materials available
R1
N
R2
N2
• Approach A exemplified for Ar = Ph, but limited by
the availability of α-aryl α-keto carboxylic acids
• Approach B widely exemplified with aryl iodides,
but limited to electron-deficient aryl bromides
• Approach C widely exemplified but reliant on the
availability of α-aryl carboxylic acid deriviatives
O
R1
Ar
N
R2
N2
O
O
• Approach C widely exemplified with R3 = Me but
otherwise reliant on the availability of β-keto amides
R1
N
R2
R3
N2
Figure 1 Scope of the approaches for the synthesis of -diazo amides.
Approach A: Synthesis by acylation and elimination. Approach B: Syn-
thesis by -arylation of the corresponding -diazo acetamide. Approach
C: Synthesis by diazo transfer.
Synthesis of Diazo Compounds Using Acid Chloride Reagents; Gen-
eral Procedure A
Toluenesulfonyl hydrazone 5a or 5b (1 equiv) was dissolved in anhy-
drous toluene (25 mL) and purged with N2 for 5 min. Thionyl chloride
(2 equiv) was added dropwise at RT and the solution was stirred vig-
orously and slowly heated to 90 °C over 30 min. After 4 h, the reaction
mixture was cooled to RT, the solvent was removed under reduced
pressure and the crude product was dried under vacuum.
All three of the approaches can enable the synthesis of
-aryl -diazo amides. The poor availability of -aryl -keto
carboxylic acids means that Approach A is likely to be most
useful for the synthesis of phenyl-substituted analogues.
Approach B (synthesis by Pd-catalysed -arylation of -di-
azo acetamides), on the other hand, enables the introduc-
tion of a very broad range of (het)aryl substituents. Howev-
er, although many aryl iodides are competent substrates,
the scope of the approach is less broad with (more general-
ly available) aryl bromides. Finally, Approach C (synthesis
by diazo transfer) is successful with a range of -aryl acet-
amides and enables the synthesis of a wide range of -diazo
-keto amides. The approach is particularly valuable for -
diazo -keto butanamides because the required substrates
may be easily prepared by acylation of the appropriate ni-
trogen nucleophile (including amines, anilines, lactams and
oxazolidinones).
The crude product (1 equiv) was dissolved in anhydrous CH2Cl2 (3
mL/mmol) and cooled to 0 °C. A solution of amine (2 equiv) in CH2Cl2
(0.5 mL/mmol) and a separate solution of dimethylaniline (1 equiv)
were added slowly under an N2 atmosphere. The reaction mixture
was stirred overnight before Et3N (5 equiv) was added dropwise over
10 min. The reaction mixture was allowed to return to RT gradually
and the solution was stirred overnight. The reaction mixture was
washed with aqueous sodium bicarbonate solution and brine solution
successively. The organic layer was collected, dried (MgSO4), filtered
and concentrated under reduced pressure to afford the crude diazo
amides 2a–k, 8.
Synthesis of Diazo Acetamides; General Procedure B1
The appropriate diazo compound (1.3 equiv) as a solution in dry tolu-
ene was added to a stirred suspension of the appropriate aryl iodide
(1 equiv), Pd(PPh3)4 (5 mol%), Ag2CO3 (0.5 equiv) and Et3N (1.3 equiv)
in dry toluene under an N2 atmosphere. The syringe was washed
twice with dry toluene and the washings were added to the reaction
mixture for a final concentration of 0.25 M. After 4 h, the reaction
mixture was filtered through a silica plug (2 × Ø2 cm) eluting with
EtOAc (2 × 10 mL). The filtrate was concentrated under reduced pres-
sure and the crude residue was purified by flash column chromatog-
raphy to yield compounds 9c–j.
Overall, the availability of practical and efficient ap-
proaches for the synthesis of -diazo acetamides is expect-
ed to facilitate the discovery of diverse bioactive small mol-
ecules.
CAUTION! Diazo compounds are potentially explosive and must be
handled with care. For concentration of material under reduced pres-
sure, a maximum water bath temperature of 40 °C was used. Contact
with metal was avoided during syntheses. No problems were encoun-
tered during our synthetic studies on the scales that are described be-
low.
Synthesis of Diazo Compounds by Diazo Transfer; General Proce-
dure C1
A solution of dicarbonyl compound (1 equiv) and p-ABSA (1.5 equiv)
in anhydrous MeCN was cooled to –10 °C. Et3N (1.2 equiv) was added
dropwise over 5–10 min and the mixture was stirred at RT under a N2
atmosphere. After 0.5–1 h (when a solid precipitated out of solution
and the starting material had been consumed according to TLC), the
solvent was removed under reduced pressure and the crude residue
was dissolved in Et2O (30 mL/mmol), filtered and the resulting solid
rinsed with CH2Cl2 (30 mL/mmol). The filtrate was concentrated and
purified by flash column chromatography to yield compounds 12a–d.
Details regarding the syntheses and structures of precursors S1–11
can be found in the Supporting Information. All non-aqueous reac-
tions were carried out under an atmosphere of nitrogen unless other-
wise stated and water-sensitive reactions were performed in anhy-
drous solvents (obtained from a PureSolv MD5 Purification System) in
oven-dried glassware and cooled under nitrogen before use. All other
solvents and reagents were of analytical grade and used as supplied.
Ether refers to diethyl ether and petrol refers to petroleum spirit (bp
40–60 °C) unless otherwise stated. Solvents were removed under re-
duced pressure using an IKA RV 10 rotary evaporator. General proce-
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Synthesis of Diazo Compounds by Acylation Followed by Diazo
Transfer; General Procedure C2
1H NMR (300 MHz, acetone-d6):  = 5.34 (s, 1 H, diazo acetamide 2-
H1), 3.48–3.18 (app br m, 4 H, morpholine 2-HAB, 6-HAB), 1.99–1.74
(m , 4 H, morpholine 3-HAB, 5-HAB).
13C NMR (75 MHz, acetone-d6):  = 164.0, 46.4, 26.5, 25.2.
HRMS (ESI): m/z [M + H]+ calcd for C6H10N3O2: 156.0773; found:
2,2,6-Trimethyl-4H-1,3-dioxin-4-one (1.1 equiv) was added to a solu-
tion of aniline 7 (1 equiv) in toluene and the mixture was reacted un-
der microwave irradiation (110 °C, max 200 W, max 300 psi). After
1.5–2 h, the solvent was removed under reduced pressure. p-ABSA
(1.5 equiv) was added followed by anhydrous MeCN and the solution
was cooled to 0 °C. Et3N (1.2 equiv) was added dropwise over 5–10
min and the mixture was stirred at RT under an N2 atmosphere. After
4 h, the solvent was removed under reduced pressure and the crude
residue was purified by flash column chromatography to yield com-
pounds 13a–g.
156.0768.
2-Diazo-1-(3-phenylpyrrolidin-1-yl)ethan-1-one (2c)
By employing general procedure A, the reaction of 6a (3.4 mmol, 884
mg) and 3-phenylpyrrolidine (6.8 mmol, 1.0 g) gave a crude material
that was purified by column chromatography eluting with CH2Cl2 for
three column volumes and then CH2Cl2–Et2O (9:1) to yield the diazo
acetamide 2c as a bright orange oil (574 mg, 78%).
2-(4-Methylbenzenesulfonamido)imino Acetic Acid (5a)
Rf = 0.32 (Et2O).
IR (CH2Cl2): 2095, 1600, 1417, 1166 cm–1
Glyoxylic acid (0.08 mol, 7.4 g) and p-toluenesulfonylhydrazide (0.05
mol, 10.0 g) were dissolved in THF (70 mL) and the mixture stirred
vigorously at RT for 24 h. The solvent was removed under reduced
pressure and the resulting residue was triturated with cold water. The
solid was air-dried for two days to attain the crude product, which
was recrystallised in EtOAc to afford pure product 5a as a white amor-
phous solid (12.80 g, 99%).
.
1H NMR (500 MHz, CD2Cl2):  = 7.33 (dd, J = 8.0, 7.0 Hz, 2 H), 7.26 (m,
3 H), 4.89 (s, 1 H), 4.02–3.81 (m, 1 H), 3.61–3.23 (m, 4 H), 2.35–2.29
(m, 1 H), 2.07–2.01 (m, 1 H).
13C NMR (125 MHz, CD2Cl2):  (rotamers A/B) = 163.8 (A/B), 141.4 (B),
141.1 (A), 129.9 (B), 129.8 (A), 128.7 (A/B), 127.14 (A/B), 52.5 (A/B),
52.3 (A/B), 46.2 (A), 45.8 (B), 44.6 (A), 42.9 (B), 33.4 (A), 33.1 (B).
IR (neat): 3170, 2892, 1695, 1595 cm–1
.
1H NMR (400 MHz, acetone-d6):  = 11.01 (s, 1 H, OH), 7.82 (d, J = 8.0
Hz, 2 H, phenyl 3-H, 5-H), 7.43 (d, J = 8.0 Hz, 2 H, phenyl 2-H, 6-H),
7.32 (s, 1 H, 2-H), 2.42 (s, 3 H, Me).
HRMS (ESI): m/z [M + H]+ calcd for C12H14N3O: 216.1137; found:
216.1127.
13C NMR (100 MHz, acetone-d6):  = 206.3, 163.8, 145.3, 137.3, 130.6,
128.5, 21.4.
HRMS (ESI): m/z [M + Na]+ calcd for C9H10N2O4SNa: 265.0254; found:
265.0252.
2-Diazo-1-(pyrrolidin-1-yl)ethan-1-one (2d)
By employing general procedure A, the reaction of 6a (1.5 mmol, 390
mg) and pyrrolidine (3 mmol, 246 L) gave a crude material that was
purified by column chromatography eluting with CH2Cl2–Et2O (9:1) to
yield the diazo acetamide 2f as a yellow oil (132 mg, 63%).
2-Diazo-N-(prop-2-en-1-yl)acetamide (2a)
Rf = 0.20 (Et2O).
By employing general procedure A, the reaction of 6a (3 mmol, 780
mg) with allylamine (6 mmol, 448 L) gave a crude material that was
purified by column chromatography eluting with CH2Cl2–Et2O (9:1) to
yield the diazo acetamide 2a as a yellow oil (298 mg, 79%).
IR (neat): 3063, 2974, 2875, 2096, 1594, 1425 cm–1
.
1H NMR (400 MHz, CDCl3):  = 4.80 (s, 1 H, diazo acetamide 2-H), 3.52
(app br s, 2 H, pyr 2-HA, 5-HA), 3.20 (app br s, 2 H, pyr 2-HB, 5-HB), 1.94
(app br s, 2 H, pyr 3-HA, 4-HA), 1.87 (app br s, 2 H, pyr 3-HB, 4-HB).
13C NMR (100 MHz, CDCl3):  = 163.2, 63.2, 45.5, 17.8, 14.8.
HRMS (ESI): m/z [M + Na]+ calcd for C6H9N3ONa: 162.0643; found:
Rf = 0.40 (Et2O).
IR (film): 3291, 3089, 2925, 2103, 1618, 1542 cm–1
.
1H NMR (400 MHz, acetone-d6):  = 6.91 (br s, 1 H, NH), 5.85 (ddt,
J = 17.2, 10.6, 5.4 Hz, 1 H, propenyl 2-H), 5.72 (s, 1 H, diazo acetamide
2-H1), 5.16 (dq, J = 17.2, 1.6 Hz, 1 H, propenyl 3-Htrans), 5.04 (dq,
J = 10.3, 1.6 Hz, 1 H, propenyl 3-Hcis), 3.86 (tt, J = 5.7, 1.6 Hz, 2 H, pro-
penyl 1-H).
13C NMR (100 MHz, acetone-d6):  = 165.7, 136.4, 115.5, 46.8, 42.5.
HRMS (ESI): m/z [2 M + Na]+ calcd for C10H14N6O2Na: 273.1076;
162.0638.
2-Diazo-N-methyl-N-(oxan-4-yl)acetamide (2e)
By employing general procedure A, the reaction of 6a (4.3 mmol, 1.12
g) and N-methyl-N-tetrahydro-2H-pyran-4-ylamine (4.3 mmol, 495
mg) gave a crude material that was purified by column chromatogra-
phy eluting with CH2Cl2–Et2O (9:1) for 3 column volumes an then
Et2O to afford the diazo acetamide 2h as a bright orange oil (708 mg,
90%).
found: 273.1069.
2-Diazo-1-(morpholin-4-yl)ethan-1-one (2b)
Rf = 0.10 (Et2O).
By employing general procedure A, the reaction of 6a (1.5 mmol, 390
mg) and morpholine (3 mmol, 260 L) gave a crude material that was
purified by column chromatography eluting with CH2Cl2–Et2O (9:1) to
yield the diazo acetamide 2d as a yellow oil (193 mg, 83%).
IR (CH2Cl2): 2098, 1600, 1410, 1256, 1144, 1086 cm–1
.
1H NMR (500 MHz, CD2Cl2):  = 5.01 (s, 1 H), 3.98 (d, J = 4.6 Hz, 1 H),
3.96 (d, J = 4.6 Hz, 1 H), 3.44 (t, J = 11.4 Hz, 2 H), 2.70 (s, 3 H), 1.77–
1.73 (m, 3 H), 1.55–1.52 (m, 2 H).
13C NMR (125 MHz, CD2Cl2):  (rotamers A/B) = 165.9 (A/B), 130.0 (A),
126.6 (B), 104.6 (A/B), 67.8 (A/B), 46.8 (A/B), 30.7 (A/B).
Rf = 0.24 (Et2O).
IR (film): 3056, 2973, 2036, 1647, 1488 cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C8H13N3O2Na: 206.0905; found:
206.0892.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

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S. Chow et al.
Paper
Synthesis
2-Diazo-1-(1-isopropyl-1H,3H,4H,9H-pyrido[3,4-b]indol-2-
yl)ethan-1-one (2f)
1H NMR (400 MHz, acetone-d6):  = 8.11 (d, J = 8.4 Hz, 1 H, Ar 5-H),
8.05 (d, J = 2.0 Hz, 1 H, Ar 2-H), 7.89 (dd, J = 8.4, 2.0 Hz, 1 H, Ar 6-H),
5.56 (s, 1 H, diazo acetamide 2-H), 3.40 (s, 3 H, NMe).
13C NMR (101 MHz, acetone-d6):  = 166.4, 148.9, 137.0, 130.4, 125.2,
125.1, 116.0, 48.7, 36.8.
By employing general procedure A, the reaction of 6a (6.2 mmol, 1.61
g) and 1-isopropyl-1H,2H,3H,4H,9H-pyrido[3,4-b]indole (12.4 mmol,
2.66 g) gave a crude material that was purified by flash column chro-
matography eluting with CH2Cl2–MeOH (99:1) to give the diazo acet-
amide 2f as a yellow amorphous solid (0.457 g, 26%).
HRMS (ESI): m/z [M + H]+ calcd for C11H8F3N4O: 269.0690; found:
269.0619.
Rf = 0.39 (CH2Cl2–MeOH, 99:1).
IR (film): 3194, 2967, 2103, 1580, 1467, 1428, 1349 cm–1
The spectroscopic data match with the literature.12
.
1H NMR (300 MHz, CD2Cl2):  = 7.48 (d, J = 7.5 Hz, 1 H, ind 5-H), 7.36
(d, J = 7.5 Hz, 1 H, ind 8-H), 7.21–7.08 (m, 2 H, ind 6-H, 7-H), 5.58 (d,
J = 14.4 Hz, 1 H, ind 1-H), 5.25 (s, 1 H, 2-H), 3.50 (br m, 2 H, ind 3-H),
2.84–2.69 (m, 2 H, ind 4-H), 2.14 (dt, J = 14.4, 6.7, 6.7 Hz, 1 H, iPr H),
1.15 (d, J = 6.7 Hz, 3 H, iPr Ha), 0.99 (d, J = 6.7 Hz, 3 H, iPr Hb); iPr =
isopropyl, ind = indolyl.
13C NMR (126 MHz, CD2Cl2):  = 166.1, 136.7, 134.7, 127.1, 121.9,
119.5, 118.2, 111.6, 107.7, 56.2, 47.1, 41.2, 33.7, 22.3, 20.2, 20.1.
HRMS (ESI): m/z [M – N2]+ calcd for C16H18N2O: 254.1414; found:
254.1486.
2-Diazo-N-phenylacetamide (2j)
By employing general procedure A, the reaction of 6a (3 mmol, 780
mg) and aniline (6 mmol, 545 L) gave a crude material that was puri-
fied by column chromatography eluting with CH2Cl2–Et2O (9:1) to
yield the diazo acetamide 2j as an orange solid (682 mg, 71%).
Rf = 0.52 (CH2Cl2–Et2O, 9:1).
IR (CH2Cl2): 3085, 2093 (diazo), 1631, 1600, 1548, 1442, 1369.
1H NMR (400 MHz, acetone-d6):  = 8.88 (s, 1 H, acetamide NH), 7.62–
7.58 (m, 2 H, Ar 3-H, 5-H), 7.30–7.24 (m, 2 H, Ar 2-H, 6-H), 7.04–6.99
(m, 1 H, Ar 4-H), 5.40 (s, 1 H, diazo acetamide 2-H).
13C NMR (100 MHz, acetone-d6):  = 164.4, 140.7, 129.6, 123.7, 119.7,
119.6, 48.6.
HRMS (ESI): m/z [M + H]+ calcd for C8H8N3O: 162.0667; found:
162.0655.
2-Diazo-1-(1,1-dioxidothiomorpholino)ethan-1-one (2g)
By employing general procedure A, the reaction of 6a (1.5 mmol, 390
mg) and thiomorpholine-1,1-dioxide (3 mmol, 405 mg) gave a crude
material that was purified by column chromatography eluting with
CH2Cl2–Et2O (9:1) to yield the diazo acetamide 2g as a yellow solid
(295 mg, 97%).
The spectroscopic data match with the literature.23
2-Diazo-N-(3-methylisoxazol-5-yl)acetamide (2k)
Rf = 0.34 (pentane–Et2O, 1:1).
1H NMR (400 MHz, acetone-d6):  = 5.88 (s, 1 H, diazo acetamide 2-H),
3.95–3.87 (m, 4 H, 2-HAB, 6-HAB), 3.12–3.08 (m, 4 H, 3-HAB, 5-HAB).
By employing general procedure A, the reaction of 6a (4.3 mmol, 1.12
g) and 5-amino-3-methylisoxazole (4.3 mmol, 422 mg) gave a crude
material that was purified by column chromatography eluting with
CH2Cl2–Et2O (9:1) to yield the diazo acetamide 2k as a bright orange
oil (170 mg, 24%).
13C NMR (100 MHz, acetone-d6):  = 165.6, 52.42, 46.9, 43.2 cm–1
.
HRMS (ESI): m/z [M + Na]+ calcd for C6H9N3O3SNa: 226.0262; found:
226.0255.
Rf = 0.49 (Et2O).
IR (CH2Cl2): 3205, 2109 (diazo), 1648, 1551, 1381, 1364, 1197, 1155
2-Diazo-N-methyl-N-phenylacetamide (2h)
cm–1
.
By employing general procedure A, the reaction of 6a (3 mmol, 780
mg) and N-methylaniline (6 mmol, 650 L) gave a crude material that
was purified by column chromatography eluting with CH2Cl2–Et2O
(9:1) to yield the diazo acetamide 2h as an orange oil (419 mg, 80%).
1H NMR (500 MHz, acetone-d6):  = 10.17 (s, 1 H, acetamide NH), 6.13
(s, 1 H, isoxazol 4-H), 5.99 (s, 1 H, diazo acetamide 2-H), 2.19 (s, 3 H,
methyl 3-H).
13C NMR (125 MHz, acetone-d6):  (rotamers A/B) = 162.7 (A), 162.6
(B), 162.2 (A), 162.1 (B), 161.6 (A/B), 88.7 (A), 88.6 (B), 49.3 (A/B), 11.6
(A/B).
Rf = 0.45 (pentane–Et2O, 1:1).
IR (neat): 3118, 3061, 2934, 2101, 1621 cm–1
.
1H NMR (400 MHz, acetone-d6):  = 7.48–7.28 (m, 2 H, Ar 3-H, 5-H),
7.28–7.18 (m, 1 H, Ar 4-H), 7.20–7.16 (m, 2 H, Ar 2-H, 6-H), 4.81 (s, 1
H, diazo acetamide 2-H), 3.12 (s, 3 H, NMe).
HRMS (ESI): m/z [M + Na]+ calcd for C6H6N4O2Na: 189.0388; found:
189.0379.
13C NMR (100 MHz, acetone-d6):  = 165.7, 144.4, 130.5, 128.4, 128.2,
47.4, 37.1.
The spectroscopic data match with the literature.15b
N-{4-[(tert-Butyldimethylsilyl)oxy]-3-(propan-2-yl)phenyl}-2-di-
azoacetamide (2l)
By employing general procedure A1, the reaction of 6a (2.7 mmol, 700
mg) and aniline S3 (500 mg, 1.9 mmol) gave a crude material that was
purified by column chromatography eluting with pentane–Et2O (1:1)
to yield the diazo acetamide 2l as a yellow solid (333 mg, 50%).
N-[4-Cyano-3-(trifluoromethyl)phenyl]-2-diazo-N-methylacet-
amide (2i)
By employing general procedure A, the reaction of 6a (1 mmol, 260
mg) and N-methyl-4-cyano-3-trifluoromethylaniline (2 mmol, 400
mg) gave a crude material that was purified by column chromatogra-
phy eluting with CH2Cl2–Et2O (9:1) to yield the diazo acetamide 2i as
a yellow solid (212 mg, 79%).
Rf = 0.2 (pentane–Et2O, 1:1).
IR (film): 3279, 3085, 2959, 2929, 2886, 2858, 2101, 1622, 1602,
1550, 1490, 1471 cm–1
.
1H NMR (500 MHz, acetone-d6):  = 8.72 (br s, 1 H, NH), 7.42 (d, J = 2.6
Hz, 1 H, 2-H), 7.37 (dd, J = 8.6, 2.6 Hz, 1 H, 6-H), 6.77 (d, J = 8.6 Hz, 1 H,
5-H), 5.36 (s, 1 H, diazo acetamide 2-H), 3.33 (sept, J = 6.9 Hz, 1 H,
propan-2-yl 2-H), 1.18 (d, J = 6.9 Hz, 6 H propan-2-yl 1-H, 3-H), 1.04
(s, 9 H, tert-butyl-H), 0.25 (s, 6 H, dimethyl-H).
Rf = 0.43 (Et2O).
IR (neat): 3091, 2231, 2108, 1605, 1377 cm–1
.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

H
S. Chow et al.
Paper
Synthesis
13C NMR (125 MHz, acetone-d6):  = 164.1, 149.2, 139.8, 134.7, 119.3,
HRMS (ESI): m/z [M + H]+ calcd for C16H18F3N4O: 339.1433; found:
118.4, 118.3, 48.4, 27.5, 26.3, 23.3, 19.0, –3.9.
339.1423
HRMS (ESI): m/z [M + H]+ calcd for C17H28N3O2Si: 334.1951; found:
334.1949.
4-[1-Diazo-2-oxo-2-(pyrrolidin-1-yl)ethyl]-2-(trifluorometh-
yl)benzonitrile (9b)
By employing general procedure B2 (0.5 mmol scale), the reaction of
2d (0.5 mmol, 70mg) and 4-iodo-2-(trifluoromethyl)benzonitrile (0.5
mmol, 149 mg) gave a crude material that was purified by column
chromatography eluting with CH2Cl2–Et2O (9:1) to yield the diazo ac-
etamide 9b as a red solid (119 mg, 77%).
N-{4-[(tert-Butyldimethylsilyl)oxy]-3-(propan-2-yl)phenyl}-2-di-
azo-N-methylacetamide (2m)
By employing general procedure A1, the reaction of 6a (2.7 mmol, 700
mg) and aniline S4 (1.8 mmol, 500 mg) gave a crude material that was
purified by column chromatography eluting with pentane–Et2O (8:2)
to yield the diazo acetamide 2m as a yellow solid (500 mg, 79%).
Rf = 0.33 (Et2O).
Rf = 0.4 (pentane–Et2O, 8:2).
IR (neat): 2899, 2848, 2193, 2045, 1675, 1390 cm–1
.
IR (film): 3280, 3085, 2959, 2930, 2859, 2101, 1622, 1602, 1549, 1491
1H NMR (400 MHz, acetone-d6): 8.09 (d, J = 2.0 Hz, 1 H, Ar 3-H), 7.99
(d, J = 8.4 Hz, 1 H, Ar 6-H), 7.77 (dd, J = 8.4, 2.0 Hz, 1 H, Ar 5-H), 3.54–
3.50 (m, 4 H, 2-HAB, 5-HAB), 2.00–1.81 (m, 4 H, 3-HAB, 4-HAB).
13C NMR (101 MHz, acetone-d6):  = 161.5, 136.9, 135.9, 132.5, 127.2,
125.5, 122.3, 121.9, 116.5, 105.0, 48.3, 25.9 (1 signal missing).
cm–1
.
1H NMR (500 MHz, acetone-d6):  = 7.15 (d, J = 2.7 Hz, 1 H, 2-H), 7.00
(dd, J = 8.5, 2.7 Hz, 1 H, 6-H), 6.91 (d, J = 8.5 Hz, 1 H, 5-H), 4.77 (s, 1 H,
diazo acetamide 2-H), 3.35 (sept, J = 6.9 Hz, 1 H, propan-2-yl 2-H),
3.21 (s, 3 H, methyl-H), 1.21 (d, J = 6.9 Hz, 6 H, propan-2-yl 1-H, 3-H),
1.05 (s, 9 H, tert-butyl-H), 0.29 (s, 6 H, dimethyl-H).
HRMS (ESI): m/z [M + Na]+ calcd for C14H11F3N4ONa: 331.0783; found:
331.0776.
13C NMR (126 MHz, acetone-d6):  = 166.0, 153.0, 141.3, 137.8, 126.4,
126.4, 120.0, 47.3, 37.4, 27.7, 26.3, 23.2, 19.0, –3.9.
HRMS (ESI): m/z [M + H]+ calcd for C18H30N3O2Si: 348.2107; found:
348.2112.
2-Diazo-2-(4-nitrophenyl)-1-(pyrrolidin-1-yl)ethan-1-one (9c)
By employing general procedure B1 (1.53 mmol scale), the reaction of
2d (2 mmol, 280 mg) and 4-iodo-1-nitrobenzene (1.53 mmol, 310
mg) gave a crude material that was purified using column chromato-
graphy eluting with CH2Cl2–Et2O (9:1) to yield the diazo acetamide 9c
as a dark orange solid (226 mg, 57%).
2-Diazo-2-phenyl-1-(pyrrolidin-1-yl)ethan-1-one (8)
By employing general procedure A, the reaction of 6b (1.5 mmol, 500
mg) and pyrrolidine (3 mmol, 250 L) gave a crude material that was
purified by column chromatography eluting with CH2Cl2–Et2O (9:1) to
yield the diazo acetamide 8 as a yellow oil (274 mg, 63%).
Rf = 0.6 (CH2Cl2–Et2O, 9:1).
IR (neat): 2062, 1625, 1525, 1391, 1346, 1235, 1170, 826 cm–1
.
1H NMR (501 MHz, DMSO-d6):  = 7.77–7.74 (app m, J = 9.1, 2.0 Hz, 2
H, Ar 3-H, 5-H), 7.14–7.11 (app m, J = 9.1, 2.0 Hz, 2 H, Ar 2-H, 6-H),
2.97 (app m, 4 H, pyr 2-Hab, 5-Hab), 1.44–1.39 (m, 4 H, pyr 3-Hab, 4-
Rf = 0.34 (pentane–Et2O, 1:1).
IR (neat): 2925, 2101, 1646 cm–1
.
H
ab); pyr = pyrrolidinyl.
1H NMR (400 MHz, acetone-d6):  = 7.99–7.95 (m, 2 H, Ar 2-H, 6-H),
7.74 (tt, J = 7.2, 1.2 Hz, 1 H, Ar 4-H), 7.61 (app t, J = 7.2 Hz, 2 H, Ar 3-H,
5-H), 3.77–3.71 (m, 4 H, pyr 2-HAB, 5-HAB), 3.63–3.60 (m, 2 H, pyr 3-
13C NMR (126 MHz, DMSO-d6):  = 160.93, 144.40, 136.97, 131.52,
130.73, 64.05, 47.88, 25.31.
H
AB), 3.39–3.37 (m, 2 H, pyr 4-HAB).
HRMS (ESI): m/z [M + Na]+ calcd for C12H12N4O3Na: 283.0807; found:
283.0800.
13C NMR (101 MHz, acetone-d6):  = 165.2, 134.7, 129.4, 129.1, 128.6,
127.3, 66.4, 66.2, 46.0, 41.2.
4-[1-Diazo-2-oxo-2-(pyrrolidin-1-yl)ethyl]-3-methylbenzonitrile
(9d)
2-[4-Cyano-3-(trifluoromethyl)phenyl]-2-diazo-N,N-dipropyl-
acetamide (9a)
By employing general procedure B1 (1 mmol scale), the reaction of 2d
(1.3 mmol, 180 mg) and 4-bromo-3-methylbenzonitrile (1 mmol, 196
mg) gave a crude material that was purified by column chromatogra-
phy eluting with CH2Cl2–Et2O (9:1) to yield the diazo acetamide 9d as
a pale yellow solid (119 mg, 47%).
By employing general procedure B2 (1 mmol scale), the reaction of
S11 (1 mmol, 169 mg) and 4-iodo-2-(trifluoromethyl)benzonitrile (1
mmol, 297 mg) gave a crude material that was purified by column
chromatography eluting with CH2Cl2–Et2O (19:1) to yield the diazo
acetamide 9a as a red solid (277 mg, 82%).
Rf = 0.46 (CH2Cl2–Et2O, 9:1).
Rf = 0.52 (pentane–Et2O, 1:1).
IR (neat): 2960, 2937, 2878, 2228, 2068, 1632, 1434 cm–1
1H NMR (400 MHz, acetone-d6):  = 8.00 (d, J = 8.4 Hz, 1 H, Ar 5-H),
7.86 (d, J = 1.9 Hz, 1 H, Ar 2-H), 7.68 (dd, J = 8.4, 2.0 Hz, 1 H, Ar 6-H),
3.43–3.35 (m, 4 H, Pr 1-H), 1.65 (sext, J = 7.4 Hz, 4 H, Pr 2-H), 0.89 (t,
J = 7.4 Hz, 6 H, Pr 3-H); Pr = propyl.
IR (neat): 2231, 1685, 1637, 1444, 1220, 1012, 848, 708 cm–1
1H NMR (501 MHz, acetone-d6):  = 7.78 (d, J = 8.1 Hz, 1 H, 5-H), 7.66
(app s, 1 H, 2-H), 7.63 (app d, J = 8.1 Hz, 1 H, 5-H), 3.42–3.38 (m, 4 H,
pyr 2-Hab, 5-Hab), 2.48 (s, 3 H, Me CH3), 1.85–1.83 (m, 4 H, pyr 3-Hab
4-Hab); pyr = pyrrolidinyl.
13C NMR (126 MHz, acetone-d6):  = 192.8, 164.1, 141.2, 136.4, 135.3,
132.1, 129.7, 117.6, 115.9, 46.4, 45.2, 25.7, 23.6, 19.8.
HRMS (ESI): m/z [M – N2]+ calcd for C14H15N2O: 227.1184); found:
227.1177.
.
.
,
13C NMR (101 MHz, acetone-d6): 162.3, 137.2, 136.1, 132.9 (q, 2JCF = 32
1
Hz), 127.1, 123.0 (q, JCF = 222 Hz), 121.0, 116.4, 105.0, 49.8, 21.3,
11.5.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

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S. Chow et al.
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Synthesis
2-Diazo-2-(4-methyl-3-nitrophenyl)-1-(pyrrolidin-1-yl)ethan-1-
one (9e)
2-Diazo-N,N-diethyl-2-[4-(trifluoromethyl)phenyl]acetamide
(9h)
By employing general procedure B1 (0.83 mmol scale), the reaction of
2d (1.1 mmol, 153 mg) and 4-iodo-1-methyl-2-nitrobenzene (0.83
mmol, 218 mg) gave a crude material that was purified by column
chromatography eluting with CH2Cl2–Et2O (9:1) to yield the diazo ac-
etamide 9e as an orange solid (118 mg, 48%).
By employing general procedure B1 (2 mmol scale), the reaction of S9
(2.6 mmol, 366 mg) and 4-trifluoromethyliodobenzene (2 mmol, 294
L) gave a crude material that was purified by column chromatogra-
phy eluting with CH2Cl2–Et2O (9:1) to yield the aryl diazo acetamide
9h as a bright orange oil (264 mg, 47%).
Rf = 0.55 (CH2Cl2–Et2O, 9:1).
Rf = 0.45 (CH2Cl2–Et2O, 9:1).
IR (neat): 2066, 1627, 1590, 1510, 1393, 1337, 1111, 850, 751 cm–1
.
IR (film): 3083, 2111, 1644, 1204 cm–1
.
1H NMR (501 MHz, acetone-d6):  = 7.94 (d, J = 2.0 Hz, 1 H, 2-H), 7.37
(dd, J = 8.2, 2.0 Hz, 1 H, 5-H), 7.30 (d, J = 8.2 Hz, 1 H, 6-H), 3.33–3.31
(m, 4 H, pyr 2-Hab, 5-Hab), 2.36 (s, 3 H, Me CH3), 1.80–1.77 (m, 4 H, pyr
3-Hab, 4-Hab); pyr = pyrrolidinyl.
1H NMR (400 MHz, CDCl3):  = 7.52 (d, J = 8.4 Hz, 2 H, Ar 3-H, 5-H),
7.24 (d, J = 8.4 Hz, 2 H, Ar 2-H, 6-H), 3.34 (q, J = 7.1 Hz, 4 H, Et 1-H),
1.13 (t, J = 7.1 Hz, 6 H, Et 2-H).
2
13C NMR (125 MHz, CDCl3):  = 163.6, 132.4, 127.6 (q, JC–F = 29 Hz),
13C NMR (126 MHz, acetone-d6):  = 161.8, 149.8, 133.0, 129.3, 127.9,
125.9 (q, JC–F = 4 Hz), 125.5 (q, JC–F = 277 Hz), 61.5, 41.9, 13.2 (2 sig-
3
1
119.9, 47.5, 25.1, 18.7.
nals missing).
HRMS (ESI): m/z [M + Na]+ calcd for C13H14N4O3Na: 297.0963; found:
HRMS (ESI): m/z [M + H – N2]+ calcd for C13H15F3NO: 258.1100; found:
297.0960.
258.1102.
2-Diazo-2-(3,4-dichlorophenyl)-1-(pyrrolidin-1-yl)ethan-1-one
(9f)
2-Diazo-N,N-diethyl-2-(4-nitrophenyl)acetamide (9i)
By employing general procedure B1 (2 mmol scale), the reaction of S9
(2.6 mmol, 366 mg) and 4-nitroiodobenzene (2 mmol, 498 mg) gave a
crude material that was purified by column chromatography eluting
with CH2Cl2–Et2O (9:1) to yield the aryl diazo acetamide 9i as a bright
orange amorphous solid (277 mg, 53%).
By employing general procedure B1 (1 mmol scale), the reaction of 2d
(1.3 mmol, 180 mg) and 1,2-dichloro-4-iodobenzene (1 mmol, 273
mg) gave a crude material that was purified by column chromatogra-
phy eluting with CH2Cl2–Et2O (9:1) to yield the diazo acetamide 9f as
an orange oil (96 mg, 34%).
Rf = 0.45 (CH2Cl2–Et2O, 9:1).
Rf = 0.51 (CH2Cl2–Et2O, 9:1).
IR (film): 2062, 1626, 1474, 1388, 1338, 1135, 1027, 735 cm–1
1H NMR (501 MHz, acetone-d6):  = 7.70 (app d, J = 2.2 Hz, 1 H, 5-H),
7.56–7.53 (app m, 1 H, 2-H), 7.32-7.30 (m, 1 H, 6-H), 3.48-3.44 (app
m, 4 H, pyr 2-Hab, 5-Hab), 1.95-1.92 (m, 4 H, pyr 3-Hab, 4-Hab); pyr =
pyrrolidinyl.
13C NMR (126 MHz, acetone-d6):  = 161.7, 132.2, 130.6, 129.4, 127.8,
125.8, 123.7, 54.1, 47.4, 25.1.
HRMS (ESI): m/z [M + Na]+ calcd for C12H11Cl2N3Ona: 306.0177;
IR (film): 3029, 2119, 1659, 1503 cm–1
.
.
1H NMR (400 MHz, CDCl3):  = 8.13 (d, J = 9.1 Hz, 2 H, Ar 3-H, 5-H),
7.27 (d, J = 9.1 Hz, 2 H, Ar 2-H, 6-H), 3.36 (q, J = 7.1 Hz, 4 H, Et 1-H),
1.16 (t, J = 7.1 Hz, 6 H, Et 2-H).
13C NMR (125 MHz, CDCl3):  = 162.7, 144.8, 136.3, 124.4, 123.3, 62.2
(verified through HMBC), 42.0, 13.2.
HRMS (ESI): m/z [M + H – N2]+ calcd for C12H15N2O3: 235.1077; found:
235.1074.
found: 306.0170.
N-[2-(4-Chlorophenyl)ethyl]-2-diazo-N-methyl-2-[4-(trifluoro-
methyl)phenyl]acetamide (9j)
N-[(4-Chlorophenyl)methyl]-2-diazo-N-methyl-2-[4-(trifluoro-
methyl)phenyl]acetamide (9g)
By employing general procedure B1 (4 mmol scale), the reaction of
S10 (5.2 mmol, 1.23 g) and 4-trifluoromethyliodobenzene (4 mmol,
589 L) gave a crude material that was purified by column chroma-
tography eluting with CH2Cl2–Et2O (9:1) to yield the aryl diazo acet-
amide 9j as a bright orange oil (769 mg, 50%).
By employing general procedure B1 (3 mmol scale), the reaction of S8
(3.9 mmol, 872 mg) and 4-trifluoromethyliodobenzene (3 mmol, 440
L) gave a crude material that was purified by column chromatogra-
phy eluting with CH2Cl2–Et2O (9:1) to yield aryl diazo acetamide 9g as
a bright orange oil (535 mg, 49%).
Rf = 0.52 (CH2Cl2–Et2O, 9:1).
IR (film): 3087, 2113, 1652, 1199 cm–1
.
Rf = 0.5 (CH2Cl2–Et2O, 9:1).
1H NMR (400 MHz, CDCl3):  = 7.49 [d, J = 8.3 Hz, 2 H, Ar(F) 3-H, 5-H],
7.20 [d, J = 8.3 Hz, 2 H, Ar(F) 2-H, 6-H], 7.09 [d, J = 8.1 Hz, 2 H, Ar(Cl)
3-H, 5-H], 7.06 [d, J = 8.1 Hz, 2 H, Ar(Cl) 2-H, 6-H], 3.57 (t, J = 7.3 Hz, 2
H, ArCH2CH2), 2.86–2.81 (m, 5 H, ArCH2CH2 and N-CH3).
13C NMR (125 MHz, CDCl3):  = 164.4, 136.7, 132.6, 131.9, 130.1,
128.8, 127.6 (q, 2JC–F = 29 Hz), 125.9 (q, 3JC–F = 3 Hz), 123.8, 62.4 (veri-
fied through HMBC), 50.7, 36.6, 33.1.
IR (film): 3096, 2107, 1632, 1208 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.54 [d, J = 8.4 Hz, 2 H Ar(F) 3-H, 5-H],
7.29–7.25 [m, 4 H, Ar(F) 2-H, 6-H and Ar(Cl) 3-H, 5-H], 7.16 [d, J = 8.5
Hz, 2 H Ar(Cl) 2-H, 6-H], 4.51 (s, 2 H, ArCH2), 2.80 (s, 3 H, N-CH3).
13C NMR (125 MHz, CDCl3):  = 164.5, 134.9, 133.8, 131.9, 129.4,
3
129.1, 126.1 (q, JC–F = 4 Hz), 123.9, 62.7 (verified through HMBC),
52.1, 36.1 (2 signals missing).
HRMS (ESI): m/z [M + Na]+ calcd for C17H13ClF3N3ONa: 390.0591;
HRMS (ESI): m/z [M + H]+ calcd for C18H16ClF3N3O: 382.0929; found:
382.0924.
found: 390.0586.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

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S. Chow et al.
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Synthesis
tert-Butyl (1R,5S)-8-{[4-Cyano-3-(trifluoromethyl)phenyl](di-
azo)acetyl}-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (10a)
crude material was purified by column chromatography eluting with
CH2Cl2 to give the diazo compound as a yellow amorphous solid (446
mg, 76%).
By telescoping general procedures A and B2 (0.25 mmol scale), a
crude material was obtained and purified by column chromatography
eluting with CH2Cl2–Et2O (9:1) to yield the diazo acetamide 10a as a
yellow oil (49 mg, 44%).
Rf = 0.40 (CH2Cl2).
IR (neat): 2119, 1688, 1594, 1350, 1329, 1265, 1188, 738, 709 cm–1
.
1H NMR (501 MHz, CD2Cl2):  = 7.84–7.79 (m, 2 H, 4-H, 7-H), 7.78–
7.74 (m, 2 H, 5-H, 6-H).
13C NMR (126 MHz, CD2Cl2):  = 182.39, 137.57, 135.17, 122.88, 70.39.
Rf = 0.10 (Et2O).
1H NMR (400 MHz, acetone-d6):  = 7.91-7.88 (m, 2 H, Ar 5-H, 2-H),
7.69-7.66 (m, 1 H, Ar 6-H), 4.29 (app s, 2 H, 3-H, 6-H), 3.77-3.72 (m, 2
H, 2-HA, 7-HA), 3.05-2.85 (m, 2 H, 2-HB, 7-HB), 1.83-1.79 (m, 2 H, 4-HA,
5-HA), 1.66-1.61 (m, 2 H, 4-HB, 5-HB), 1.32 (s, 9 H, tert-butyl).
HRMS (ESI): molecular ion not found.
The spectroscopic data match with the literature.26
13C NMR (101 MHz, acetone-d6):  = 163.3, 156.0, 136.4, 136.2, 127.5,
122.3, 116.4, 105.4, 80.1, 55.4, 27.3.
5-Diazo-2,2-dimethyl-1,3-dioxane-4,6-dione (12d)
HRMS (ESI): m/z [M + Na]+ calcd for C21H22F3N5O3Na: 472.1572;
found: 472.1564.
By employing general procedure C1, to 2,2-dimethyl-1,3-dioxane-4,6-
dione (3.5 mmol, 500 mg) and p-ABSA (5.25 mmol, 1.26 g) in MeCN
(0.12 M, 30 mL) was added Et3N (4.20 mmol, 0.58 mL) dropwise at
–10 °C and the resulting mixture was allowed to react at room
temperature for 30 min. The crude material was purified by column
chromatography eluting with CH2Cl2 to give the diazo compound as a
colourless amorphous solid (541 mg, 91%).
5-Diazo-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (12a)
By employing general procedure C1, to 1,3-dimethylpyrimidine-
2,4,6(1H,3H,5H)-trione (6.4 mmol, 1.00 g) and p-ABSA (9.6 mmol,
2.30 g) in MeCN (0.12 M, 54 mL) was added Et3N (1.10 mL, 7.68
mmol) dropwise at –10 °C and the resulting mixture was allowed to
react at room temperature for 30 min. The crude material was puri-
fied by column chromatography eluting with EtOAc–petrol (1:1) to
give the diazo compound as a pale yellow amorphous solid (1.025 g,
88%).
Rf = 0.38 (CH2Cl2).
IR (neat): 2175, 1706, 1308, 1296, 1191, 1165, 1026, 977, 905 cm–1
1H NMR (501 MHz, CD2Cl2):  = 1.76 (s, 6 H, 2 × CH3).
13C NMR (126 MHz, CD2Cl2):  = 158.65, 107.40, 64.39, 26.95.
HRMS (ESI): molecular ion not found.
.
Rf = 0.55 (EtOAc–petrol, 1:1).
The spectroscopic data match with the literature.27
IR (neat): 2155, 1710, 1638, 1468, 1415, 1372, 1291, 1245, 1066 cm–1
1H NMR (501 MHz, CD2Cl2):  = 3.27 (s, 6 H, 2 × CH3).
13C NMR (126 MHz, CD2Cl2):  = 158.5, 150.9, 71.9, 28.6.
HRMS (ESI): molecular ion not found.
.
N-(3-Chloro-4-methoxyphenyl)-2-diazo-N-methyl-3-oxobutana-
mide (13a)
By employing general procedure C2, 3-chloro-4-methoxy-N-meth-
ylaniline (3.5 mmol, 600 mg) in toluene (1.4 M, 2.5 mL) and 2,2,6-
trimethyl-1,3-dioxin-4-one (3.85 mmol, 510 L) were reacted under
microwave irradiation at 110 °C for 1.5 h. The crude material was pu-
rified by column chromatography eluting with CH2Cl2–MeOH (98:2)
to give the butanamide (840 mg, 94%). By employing general proce-
dure C3, to the butanamide (840 mg, 3.28 mmol) and p-ABSA (1.20 g,
4.92 mmol) in MeCN (0.12 M, 28 mL) was added Et3N (0.55 mL, 3.94
mmol) to give a crude material. Purification by column chromatogra-
phy eluting with CH2Cl2–Et2O (9:1) gave the diazo compound as a
light yellow, low melting solid (412 mg, 45%).
The spectroscopic data match with the literature.24
3-Diazo-2,4-piperidinedione (12b)
By employing general procedure C1, to 2,4-piperidinedione (4.42
mmol, 500 mg) and p-ABSA (6.63 mmol, 1.59 g) in MeCN (0.12 M, 37
mL) was added Et3N (0.73 mL, 5.30 mmol) dropwise at –10 °C and the
resulting mixture allowed to react at room temperature for 30 min.
The crude material was purified by column chromatography eluting
with CH2Cl2–MeOH (9:1). The product was further purified by col-
umn chromatography eluting with Et2O to give the diazo compound
as a colourless amorphous solid (204 mg, 33%).
Rf = 0.43 (CH2Cl2–Et2O, 9:1).
IR (film): 3360, 2110, 1642, 1499, 1361, 1265, 1247, 1062, 1020 cm–1
.
Rf = 0.08 (Et2O).
1H NMR (501 MHz, CD2Cl2):  = 7.27 (d, J = 2.6 Hz, 1 H, Ar 2-H), 7.12
(dd, J = 8.7, 2.6 Hz, 1 H, Ar 6-H), 6.97 (d, J = 8.7 Hz, 1 H, Ar 5-H), 3.91
(s, 3 H, CH3O), 3.29 (s, 3 H, N-CH3), 2.44 (s, 3 H, CH3).
13C NMR (126 MHz, CD2Cl2):  = 191.6, 161.1, 155.1, 136.5, 128.7,
126.6, 123.7, 113.2, 74.0, 56.8, 38.7, 28.6.
IR (film): 3183, 3045, 2905, 2150, 1650, 1461, 1416, 1347, 1291, 1039
cm–1
.
1H NMR (501 MHz, CD2Cl2):  = 6.96 (s, 1 H, NH), 3.45 (td, J = 6.5, 2.8
Hz, 2 H, 6-H), 2.60 (t, J = 6.5 Hz, 2 H, 5-H).
13C NMR (126 MHz, CD2Cl2):  = 188.56, 163.72, 75.41, 37.36, 36.68.
HRMS (ESI): m/z [M + Na]+ calcd for C12H12ClN3ONa: 304.0460; found:
304.0456.
HRMS (ESI): molecular ion not found.
The spectroscopic data match with the literature.25
N-(4-Chlorophenyl)-2-diazo-N-methyl-3-oxobutanamide (13b)
2-Diazoindan-1,3-dione (12c)
By employing general procedure C2, 4-chloro-N-methylaniline (8.3
mmol, 1.00 mL) in toluene (8 mL) and 2,2,6-trimethyl-1,3-dioxin-4-
one (12.5 mmol, 1.66 mL) were reacted under microwave irradiation
at 110 °C for 30 min. The crude material was then treated with p-
ABSA (9.1 mmol, 2.20 g) and Et3N (1.30 mL, 9.1 mmol) and the reac-
tion allowed to warm to room temperature over 16 hours. A white
By employing general procedure C1, to 1,3-indandione (3.4 mmol,
500 mg) and p-ABSA (5.1 mmol, 1.22 g) in MeCN (0.12 M, 30 mL) was
added Et3N (0.57 mL, 4.08 mmol) dropwise at –10 °C and the result-
ing mixture was allowed to react at room temperature for 1 h. The
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

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S. Chow et al.
Paper
Synthesis
precipitate formed, which was removed by filtration, and the solvent
then removed under reduced pressure to give a dark red oil. Purifica-
tion by column chromatography eluting with CH2Cl2 and then CH2Cl2–
Et2O (9:1) gave the diazo compound 13b as a yellow oil that solidified
on standing (1.34 g, 64%).
2.83–2.79 (m, 1 H, allyl 1-Ha), 2.63–2.60 (m, 1 H, py 3-Ha), 2.36–2.33
(m, 1 H, py 3-Hb), 2.24–2.21 (m, 1 H, allyl 1-Hb), 2.21 (s, 3 H, butane 4-
H); py = pyridinyl.
13C NMR (75 MHz, acetone-d6):  = 189.0, 164.0, 144.0, 136.4, 130.2,
129.2, 127.5, 127.5, 121.4, 118.5, 76.1, 58.3, 54.8, 38.8, 29.4, 27.3.
Rf = 0.10 (CH2Cl2).
IR (CH2Cl2): 2184 (diazo), 1636, 1590, 1487, 1356 cm–1
HRMS (ESI): m/z [M + Na]+ calcd for C18H19N3O2Na: 332.1370; found:
332.1369.
.
1H NMR (400 MHz, CDCl3):  = 7.39 (d, J = 8.7 Hz, 2 H, Ar 3-H, 5-H),
7.14 (d, J = 8.7 Hz, 2 H, Ar 2-H, 6-H), 3.34 (s, 3 H, N-methyl), 2.46 (s, 3
H, oxobutanamide 4-H).
2-Diazo-1-{3-oxo-2-azabicyclo[2.2.1]hept-5-en-2-yl}butane-1,3-
dione (13e)
13C NMR (100 MHz, CDCl3):  = 191.4, 161.1, 157.1, 141.7, 133.9,
130.6, 127.5, 38.6, 28.5.
HRMS (ESI): m/z [M + Na]+ calcd for C11H10ClN3O2Na: 274.0359;
found: 274.0350.
By employing general procedure C2 and 2-azabicyclo[2,2,1]hept-5-
en-3-one (500 mg, 4.6 mmol), the diazo transfer was performed for
24 h, followed by purification by column chromatography eluting
with petrol–EtOAc (7:3) to give the diazo compound 13e as a yellow
oil (0.29 g, 29%).
Rf = 0.27 (petrol–EtOAc, 7:3).
IR (film): 2955, 2139, 1745, 1651, 1302 cm–1
1-(6-Chloro-3,4-dihydro-2H-quinolin-1-yl)-2-diazobutane-1,3-di-
one (13c)
.
By employing general procedure C2, to 6-chloro-1,2,3,4-tetrahydro-
quinoline (3.0 mmol, 500 mg) in toluene (1 M, 3.00 mL) was added
2,2,6-trimethyl-1,3-dioxin-4-one (3.3 mmol, 440 L) and the result-
ing solution was reacted under microwave irradiation at 110 °C for 1.5
h. The crude product was purified by silica gel column chromatogra-
phy eluting with CH2Cl2–Et2O (9:1) to give the butanamide (744 mg,
99%). By employing general procedure C3, to the butanamide (0.70 g,
2.78 mmol) and p-ABSA (1.00 g, 4.17 mmol) in MeCN (0.12 M, 23 mL)
was added Et3N (0.46 mL, 3.34 mmol). After 4 h, the crude material
was purified by column chromatography eluting with CH2Cl2–Et2O
(9:1) to give the diazo compound as a light yellow, low melting solid
(439 mg, 57%).
1H NMR (400 MHz, CDCl3):  = 6.91 (dd, J = 5.2, 2.3 Hz, 1 H, 5-H), 6.48
(dd, J = 5.2, 3.3 Hz, 1 H, 6-H), 4.83–4.82 (m, 1 H, 4-H), 3.39–3.38 (m, 1
H, 1-H), 2.30 (s, 3 H, CH3), 2.21 (dt, J = 8.8, 1.4 Hz, 1 H, 7-Ha), 2.11 (dt,
J = 8.8, 1.3 Hz, 1 H, 7-Hb).
13C NMR (400 MHz, CDCl3):  = 189.8, 175.6, 160.3, 140.6, 136.1, 62.2,
53.7, 53.0, 28.4.
HRMS (ESI): m/z [M + Na]+ calcd for C10H9N3O3Na: 242.0538; found:
242.0535.
2-Diazo-1-(4-isopropyl-2-oxopyrrolidin-1-yl)butane-1,3-dione
(13f)
By employing general procedure C2 and 4-isopropylpyrrolidin-2-one
(500 mg, 3.93 mmol), the diazo transfer was performed for 24 h fol-
lowed by purification by column chromatography eluting with
CH2Cl2–MeOH (99:1) to give the diazo compound 13f as a yellow
amorphous solid (0.376 g, 40%).
Rf = 0.43 (CH2Cl2–Et2O, 9:1).
IR (film): 2950, 2891, 2107, 1632, 1484, 1345, 1255, 1197, 1170,
1090, 946 cm–1
.
1H NMR (501 MHz, methanol-d4):  = 7.32 (d, J = 8.6 Hz, 1 H, qui 5-H),
7.25 (d, J = 2.5 Hz, 1 H, qui 8-H), 7.17 (dd, J = 8.6, 2.5 Hz, 1 H, qui 7-H),
3.75 (t, J = 6.5 Hz, 2 H, qui 2-H), 2.74 (t, J = 6.5 Hz, 2 H, qui 4-H), 2.32
(s, 3 H, CH3), 1.98 (quin, J = 6.5 Hz, 2 H, qui 3-H); qui = quinolinyl.
Rf = 0.24 (CH2Cl2–MeOH, 99:1).
IR (film): 2962, 2133, 1732, 1650, 1316, 1204 cm–1
.
1H NMR (400 MHz, acetone-d6):  = 3.89 (dd, J = 10.8, 7.8 Hz, 1 H, pyr
5-Ha), 3.51 (dd, J = 10.8, 9.2 Hz, 1 H, pyr 5-Hb), 2.64 (dd, J = 17.4, 8.3
Hz, 1 H, pyr 3-Ha), 2.42 (dd, J = 17.4, 8.3 Hz, 1 H, pyr 3-Hb), 2.39 (s, 3 H,
butane 4-H), 2.14 (td, J = 17.4, 8.3 Hz, 1 H, pyr 4-H), 1.68–1.64 (m, 1 H,
iPr H), 0.96 (d, J = 6.7 Hz, 6 H, iPr H); pyr = pyrrolidinyl, iPr = isopro-
pyl.
13C NMR (126 MHz, methanol-d4):  = 191.1, 162.5, 138.4, 135.8,
131.7, 129.7, 127.9, 124.9, 77.4, 45.9, 27.6, 27.4, 24.8.
HRMS (ESI): m/z [M + Na]+ calcd for C13H12ClN3O2Na: 300.0511;
found: 300.0508.
2-Diazo-1-[(2R,6S)-2-allyl-6-phenyl-1,2,3,6-tetrahydropyridin-1-
yl]butane-1,3-dione (13d)
13C NMR (101 MHz, acetone-d6):  = 190.2, 174.5, 160.6, 79.2, 51.0,
38.8, 38.1, 32.6, 28.6, 20.7, 20.3.
By employing general procedure C2 and (2R,6S)-2-allyl-6-phenyl-
1,2,3,6-tetrahydropyridine (996 mg, 5 mmol), the diazo transfer was
performed for 24 h followed by purification by column chromatogra-
phy eluting with CH2Cl2 to give the diazo compound 13d as a yellow
oil (0.339 g, 22%).
HRMS (ESI): m/z [M – N2 + Na]+ calcd for C11H15NO3Na: 232.0944;
found: 232.0942.
2-Diazo-1-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]butane-1,3-
dione (13g)
Rf = 0.14 (CH2Cl2).
By employing general procedure C2 and (4S)-4-phenyl-1,3-oxazoli-
din-2-one (1.5 g, 9.2 mmol), the diazo transfer was performed for 24
h followed by purification by column chromatography eluting with
CH2Cl2 to give the diazo compound 13g as a white amorphous solid
(1.280 g, 53%).
IR (film): 3033, 2114, 1697, 1655, 1611, 1493, 1449 cm–1
.
1H NMR (501 MHz, acetone-d6):  = 7.33 (d, J = 7.9 Hz, 2 H, Ph 2-H, 6-
H), 7.27 (app t, J = 7.9 Hz, 2 H, Ph 3-H, 5-H), 7.17 (app t, J = 7.9 Hz, 1 H,
Ph 4-H), 5.87 (ddt, J = 17.1, 10.1, 7.4 Hz, 1 H, allyl 2-H), 5.76 (dd,
J = 10.0, 2.3 Hz, 1 H, py 5-H), 5.69 (dt, J = 10.0, 3.0 Hz, 1 H, py 4-H),
5.21 (d, J = 2.3 Hz, 1 H, py 6-H), 5.14 (d, J = 17.1 Hz, 1 H, allyl 3-Htrans),
5.09 (dd, J = 10.1, 2.0 Hz, 1 H, allyl 3-Hcis), 4.29–4.28 (m, 1 H, py 2-H),
Rf = 0.17 (CH2Cl2).
IR (film): 3058, 2136, 1775, 1656, 1308, 1207 cm–1
.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L

L
S. Chow et al.
Paper
Synthesis
1H NMR (400 MHz, CD2Cl2):  = 7.44–7.38 (m, 5 H, Ph 2-H, 3-H, 4-H,
5-H, 6-H), 5.59 (t, J = 8.8 Hz, 1 H, ox 4-H), 4.77 (app t, J = 8.8 Hz, 1 H,
ox 5-Ha), 4.25 (app t, J = 8.8 Hz, 1 H, ox 5-Hb), 2.37 (s, 3 H, butane 4-
H); ox = oxazolidinyl.
13C NMR (101 MHz, CD2Cl2):  = 189.7, 160.0, 153.6, 137.3, 129.6,
129.5, 127.1, 80.0, 70.8, 59.2, 28.8.
References
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HRMS (ESI): m/z [M – N2 + Na]+ calcd for C13H11NO4Na: 268.0580;
found: 268.0577.
2-Diazo-2-(3,4-dichlorophenyl)-N-methyl-N-phenylacetamide
(9k)
(6) Doyle, M. P.; Winchester, W. R.; Hoorn, J. A. A.; Lynch, V.;
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By employing general procedure C3 (1 mmol scale), the reaction of 2-
(3,4-dichlorophenyl)-N-methyl-N-phenylacetamide (293 mg,
mmol) and p-ABSA (264 mg, 1.1 mmol) gave a crude material that
was purified by column chromatography eluting with CH2Cl2–Et2O
(9:1) to yield the diazo acetamide 9k as an orange oil (252 mg, 53%).
1
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Rf = 0.67 (pentane–Et2O, 1:1).
1H NMR (400 MHz, acetone-d6):  = 7.63 (d, J = 2.3 Hz, 1 H, Ar 2-H),
7.48 (d, J = 8.5 Hz, 1 H, Ar 5-H), 7.44–7.39 (m, 2 H, Ph 3-H, 5-H), 7.35–
7.33 (m, 2 H, Ph 2-H, 6-H), 7.30-7.26 (m, 1 H, Ph 4-H), 7.18 (dd, J = 8.5,
2.3 Hz, 1 H, Ar 6-H), 3.38 (s, 3 H, NMe).
13C NMR (101 MHz, acetone-d6):  = 164.2, 145.0, 132.9, 131.4, 130.8,
130.1, 128.9, 127.7, 127.0, 126.6, 124.6, 112.7, 38.7.
HRMS (ESI): m/z [M – N2 + H]+ calcd for C15H12Cl2NO: 292.0296;
found: 292.0277.
N,2-Bis(4-chlorophenyl)-2-diazo-N-methylacetamide (9l)
By employing general procedure C3, the reaction of N,2-bis(4-chloro-
phenyl)-N-methylacetamide (300 mg, 1.0 mmol) and p-ABSA (269
mg, 1.1 mmol) gave a viscous orange oil that was purified by flash col-
umn chromatography eluting with pentane–Et2O (9:1) to give the di-
azo compound 9l as an orange oil (114 mg, 35%).
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Rf = 0.14 (pentane/Et2O, 1:1).
IR (CH2Cl2): 2066 (diazo), 1635, 1490, 1313 cm–1
.
1H NMR (400 MHz, acetone-d6):  = 7.42–7.30 (m, 8 H, Ar), 3.36 (s, 3
H, N-methylacetamide).
13C NMR (101 MHz, acetone-d6):  = 164.9, 144.2, 132.7, 131.7, 130.8,
130.0, 129.7, 128.3, 127.7, 127.2, 38.7.
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342.0165.
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Funding Information
We thank the Engineering and Physical Sciences Research Council
(EPSRC) (EP/N025652/1), the Biotechnology and Biological Sciences
Research Council (BBSRC), GlaxoSmithKline (GSK) and LifeArc for
funding.
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(25) Wang, Z.; Bi, X.; Liao, P.; Zhang, R.; Liang, Y.; Dong, D. Chem.
Commun. 2012, 48, 7076.
Acknowledgment
(26) Coffrey, K. E.; Murphy, G. K. Synlett 2015, 26, 1003.
(27) Nikolaev, V. A.; Shevchenko, V. V.; Platz, M. S.; Khimich, N. N.
Russ. J. Org. Chem. 2006, 42, 815.
We thank Christopher Tinworth, Richard Bayliss and members of the
Nelson group for useful discussions.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690905.
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–L