Synthesis of N-Pyridyl Hydroxylamines via Copper-Catalyzed Cross-Coupling

Article abstract of DOI:10.1055/s-0037-1611836

N -Pyridyl hydroxylamine derivatives were prepared via copper-catalyzed cross-coupling of orthogonally functionalized hydroxylamines with iodopyridines. Various amino- and hydroxyl-protecting groups were tolerated. A total of 20 examples were synthesized in 28-90percent yield.

Full text of DOI:10.1055/s-0037-1611836

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–F
psp
A
en
C. Torruellas et al.
PSP
Synthesis
Synthesis of N-Pyridyl Hydroxylamines via Copper-Catalyzed
Cross-Coupling
Carilyn Torruellas*
Cu2O (10 mol%)
DMEDA (20 mol%)
X
X
PG
Fu-Lian Hsu
PG
HN
+
R
N
I
R
N
N
Andrew J. Walz
K2CO3 (2 equiv), 3Å MS
toluene, 80 °C, 18 h
OPG
OPG
R = I, H
X = C, N
20 examples
up to 90% yield
CCDC Chemical Biological Center, 8198 Blackhawk Rd.,
Aberdeen Proving Ground, MD 21010, United States
carilyn.torruellaspagan.civ@mail.mil
Received: 21.03.2019
Accepted after revision: 26.04.2019
Published online: 15.05.2019
O
O
Cu2O
DMEDA
Ph
Py
Py
Ph
Py
I
+
HN
N
T. Kukosha et al.
DOI: 10.1055/s-0037-1611836; Art ID: ss-2019-m0188-psp
OMe
+
OMe
Cu2O
DMEDA
Abstract N-Pyridyl hydroxylamine derivatives were prepared via cop-
per-catalyzed cross-coupling of orthogonally functionalized hydroxyl-
amines with iodopyridines. Various amino- and hydroxyl-protecting
groups were tolerated. A total of 20 examples were synthesized in 28–
90% yield.
PG
PG
N
Py
I
HN
OPG
This work
OPG
Scheme 1 Copper-catalyzed coupling of iodopyridines
Key words copper, cross-coupling, hydroxylamines, protecting
groups, pyridine
leophilic attack. The reactions were carried out using 10
mol% of copper(II) oxide, DMEDA as the ligand, and potassi-
um carbonate as the base in toluene at 80 °C. Coupling
products were obtained from moderate to excellent yields
(28–90%). Most protecting groups were tolerated. While N-
arylation of N-tosyl-O-benzyl hydroxamates is inefficient
via conventional coupling methods,13 it was accomplished
using 2-iodopyridine under the studied conditions (Table 1,
entry 4). No coupling product was isolated from the reac-
tion using N-formyl hydroxamate (entry 6) with decompo-
sition of the hydroxylamine being observed. Similarly, no
products were observed using O-silyl ether hydroxamates
(entries 15 and 16) but starting material was recovered.
Kukosha had previously coupled 3-iodopyridine using
N-methoxy-2-phenylacetamide as coupling partner under
the studied conditions.12 However, in our hands, no product
was observed when treated with N-acetyl-O-benzyl hy-
droxamate. 4-Iodopyridine was also evaluated, using N-ace-
tyl-O-benzyl hydroxylamine, and the coupling product was
not observed.
N-Pyridyl hydroxylamine scaffold is found in antibacte-
rial,1 antiviral,2 anti-osteoclastogenic,3 and anticancer
agents.4 N-Pyridyl hydroxylamines are conventionally pre-
pared through palladium-catalyzed hydrogenation,5 stoi-
chiometric reduction of nitropyridines,6 aromatic nucleop-
hilic substitution,7 N-alkylation of nitrosopyridines,1a,8–10
Buchwald–Hartwig amination,11 and N-arylation of hydrox-
ylamines.12 Kukosha et al. studied the N-arylation of N,O-
functionalized hydroxylamines using copper(II) oxide and
N,N′-dimethylethylenediamine (DMEDA).12 This methodol-
ogy provided only two examples of pyridine substrates and
the hydroxamate coupling partners were limited to amides
(Scheme 1). In order to expand the scope of this process,
different protecting groups for the hydroxylamine coupling
partner and several other N-heteroaromatic systems were
examined using this methodology. Herein, we report our
findings on copper-catalyzed coupling of iodopyridines and
of N,O-protected hydroxylamines.
The coupling of various N,O-protected hydroxamates
and 2-iodopyridine was examined (Table 1). Orthogonal
amino- and hydroxyl-protecting groups were chosen to al-
low selective deprotection using: Lewis acid, aqueous acidic
hydrolysis, metal-catalyzed de-allylation, and fluoride nuc-
Similar to Kukosha’s12 and Tomkinson’s13 results on the
copper-catalyzed coupling of other aryl halides, 2-chloro-
pyridine and 2-bromopyridine using N-Boc-O-benzyl hy-
droxamate did not result in the isolation of the coupling
product.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

B
C. Torruellas et al.
PSP
Synthesis
Table 1 Copper-Catalyzed Coupling of Various N,O-Protected Hydrox-
Table 2 Copper-Catalyzed Coupling of Various Iodo-Heteroaryl Sub-
ylamine and 2-Iodopyridine
strates
Cu2O (10 mol%)
DMEDA (20 mol%)
Cu2O (10 mol%)
DMEDA (20 mol%)
R2
R2
Py
R2
HN
HN
OR1
N
R2
+
PyI
+
OR1
N
I
N
N
OR1
K2CO3 (2 equiv), 3Å MS
toluene, 80 °C, 18 h
K2CO3 (2 equiv), 3Å MS
toluene, 80 °C, 18 h
OR1
3r–x
1
2a–q
3a–q
Entry Heteroaryl iodide
Product
Yield
(%)a
Entry
R1
R2
Product
Yield (%)a
1
2
Bn
Bn
Bn
Bn
Bn
Bn
Ac
3a
3b
3c
3d
3e
3f
82
69
81
83
64
0
Boc
Teocb
Ts
R2
I
N
N
3
OR1
4
1
R1 = Bn, R2 = Ac
R1 = Bn, R2 = Boc
R1 = THP, R2 = Ac
3r
3s
3u
59
55
58
I
N
I
5
Ms
2
3
6
CHO
Ac
7
THP
THP
THP
THP
allyl
allyl
allyl
allyl
TBS
3g
3h
3i
90
28
66
48
69
50
45
82
0
8
Boc
Teocb
Cbz
Ac
N
N
9
OR1
N
I
10c
11
12
13
14
15
16
17
3j
4b
5b
R1 = Bn
3v
58
76
I
3k
3l
R1 = THP
3w
Boc
Teocb
Cbz
Ac
N
3m
3n
3o
3p
3q
Ac
N
N
N
OTHP
6
N
I
3x
73
a Isolated yields.
b MeCN and N-acetyl-O-protected hydroxylamine were used as solvent and
TBDPS
CH2CH2TMS
Ac
0
coupling partner, respectively.
Ac
43
a Isolated yields.
b Teoc: 2-(Trimethylsilyl)ethoxycarbonyl.
c Using 4 equiv of K2CO3 and heating for 42 h.
Exploration of several different iodo-heteroaryl part-
ners is shown in Table 2. Selective monocouplings were
achieved when coupling 2,6-diiodopyridine with 1 equiva-
lent of N,O-protected hydroxylamines (Table 2, entries 1–3).
Doubling the amount of hydroxylamine, catalyst, ligand,
and base generated the corresponding bis-coupled product
(see Table 1 in the Supporting Information). Interestingly,
coupling of a methylated iodopyridine salt proceeded but
provided only the deacetylated uncharged O-protected ox-
imes (entries 4 and 5). N-Acetyl-O-THP hydroxylamine cou-
pling with N-methyl pyridine salt (entry 5) as well as py-
rimidine (entry 6) produced the coupling product in good
yield.
In summary, Kukosha’s methodology was expanded to
include the coupling of 2-iodopyridines and other iodohet-
erocycles with protected hydroxylamines. Various N- and
O-protecting groups were chosen to allow selective removal
for broader synthetic versatility. This methodology is also
suitable for selected iodopyridines, pyrimidines, and bi-
functional substrates.
Starting materials, reagents, and solvents were purchased from com-
mercial sources and used without further purification. The prepara-
tion of functionalized hydroxylamines 2e,h,j,k,l,m,o,q is provided in
the Supporting Information. All non-aqueous reactions were carried
out under anhydrous conditions using oven dried glassware and an
inert atmosphere of argon, unless otherwise indicated. K2CO3 was
dried at 100 °C under vacuum prior to use. When indicated, solvents
and reagents were degassed by bubbling argon through the liquids for
1 h. Flash chromatography was performed using Reveleris X2 system
(Büchi Labortechnik AG; Flawil, Switzerland). Melting points were re-
corded on a Thomas Hoover capillary melting point apparatus (Phila-
delphia, PA) and reported uncorrected. 1H and 13C NMR spectra were
recorded with a 400 MHz JEOL NMR spectrometer (JEOL USA, Inc.;
Peabody, MA). IR spectra was recorded using a PerkinElmer FT-IR
spectrophotometer (Boston, MA). High-resolution mass spectroscopy
(HRMS) was measured using a ThermoFinnigan Q-Exactive instru-
ment (Thermo Fisher Scientific; Waltham, MA) with electron spray
ionization (ESI) and gas chromatography mass spectrometer chemical
ionization time of flight (CI/TOF, Agilent Technologies; Santa Clara,
CA).
Coupling of Iodopyridines with Functionalized Hydroxylamines;
General Procedure
Hydroxamate (0.90 mmol), iodopyridine (1.34 mmol, 1.0–1.5 equiv),
Cu2O (0.90 mmol), dry K2CO3 (1.79 mmol), and 3 Å molecular sieves
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

C
C. Torruellas et al.
PSP
Synthesis
(100% weight to the hydroxamate) were placed in a pressure tube.
The tube was purged with argon three times. Degassed anhyd toluene
(9.0 mL) and degassed DMEDA (0.18 mmol) were added to the flask.
The vessel was sealed, and the mixture was stirred at 80 °C for 16 h.
The mixture was cooled to r.t. and filtered. The filtrate was collected
and eluted through a small silica plug, then concentrated under re-
duced pressure. The crude residue was purified by chromatography
on silica gel using a gradient of 0–20% EtOAc/CH2Cl2 to yield the prod-
uct.
13C NMR (CDCl3, 100 MHz):  = 154.1, 148.5, 145.0, 137.6, 135.0,
131.0, 129.9, 129.4 (d), 128.6, 128.4, 122.5, 119.0, 79.9, 21.8.
HRMS (ESI): m/z [M + H]+ calcd for C19H19N2O3S: 355.1111; found:
355.1106.
N-(Benzyloxy)-N-(pyridin-2-yl)methanesulfonamide (3e)
Yellow oil; yield: 445 mg (64%).
IR (neat): 3034, 2937, 1588, 1461, 1431, 1348, 1162, 962, 767, 741,
698, 540 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 8.47 (m, 1 H), 7.65–7.61 (m, 1 H), 7.35–
7.34 (m, 2 H), 7.26 (m, 3 H), 7.21–7.19 (m, 1 H), 7.11 (d, J = 6.8 Hz, 1
H), 5.16 (s, 2 H), 3.11 (s, 3 H).
N-(Benzyloxy)-N-(pyridin-2-yl)acetamide (3a)
Tan solid; yield: 606 mg (82%); mp 81−82 °C.
IR (neat): 1673, 1570, 1462, 1428, 1371, 1331, 1278, 1147, 964, 781,
13C NMR (CDCl3, 100 MHz):  = 154.1, 149.0, 138.3, 134.9, 130.0,
734, 697, 589 cm–1
.
128.8, 128.4, 123.4, 121.1, 79.9, 34.9.
HRMS (ESI): m/z [M + H]+ calcd for C13H15N2O3S: 279.0798; found:
279.0794.
1H NMR (CD3OD, 400 MHz):  = 8.46 (m, 1 H), 7.88–7.84 (m, 1 H), 7.58
(d, J = 8.2 Hz, 1 H), 7.41–7.39 (m, 2 H), 7.34–7.32 (m, 3 H), 7.30–7.27
(m, 1 H), 4.96 (s, 2 H), 2.21 (s, 3 H).
13C NMR (CD3OD, 100 MHz):  = 171.4, 151.7, 148.0, 138.5, 134.4,
129.7, 128.8, 128.3, 122.1, 118.9, 77.3, 21.1.
HRMS (ESI): m/z [M + H]+ calcd for C14H15N2O2: 243.1125; found:
243.1128.
N-(Pyridin-2-yl)-N-[(tetrahydro-2H-pyran-2-yl)oxy]acetamide
(3g)
Yellow oil; yield: 1.31 g (91%).
IR (neat): 2941, 2869, 1686, 1585, 1466, 1431, 1366, 1320, 1276,
1035, 896, 874, 777 cm–1
.
tert-Butyl (Benzyloxy)(pyridin-2-yl)carbamate (3b)
Brown solid; yield: 187 mg (69%); mp 51–53 °C.
1H NMR (CDCl3, 400 MHz):  = 8.43 (m, 1 H), 7.72–7.68 (m, 1 H), 7.56–
7.54 (m, 1 H), 7.13–7.11 (m, 1 H), 5.03 (s, 1 H), 3.74–3.73 (m, 1 H),
3.34–3.31 (m, 1 H), 2.30 (s, 3 H), 1.84–1.79 (m, 3 H), 1.53–1.51 (m, 3
H).
13C NMR (CDCl3, 100 MHz):  = 171.2, 153.1, 148.3, 137.8, 121.8,
119.3, 104.0, 63.6, 28.6, 24.9, 22.9, 19.5.
IR (neat): 2974, 1702, 1582, 1466, 1432, 1339, 1289, 1252, 1117,
1020, 760, 704 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 8.49 (m, 1 H), 7.68–7.64 (m, 1 H), 7.49
(d, J = 8.3 Hz, 1 H), 7.46–7.44 (m, 2 H), 7.35–7.32 (m, 3 H), 7.09–7.04
(m, 1 H), 5.03 (s, 2 H), 1.53 (s, 9 H).
13C NMR (CDCl3, 100 MHz):  = 153.4 (d), 148.4, 137.6, 135.1, 129.8,
128.7, 128.4, 120.6, 116.8, 82.7, 77.9, 28.3.
HRMS (ESI): m/z [M + H]+ calcd for C12H17N2O2: 237.1234; found:
237.1230.
HRMS (ESI): m/z [M + H]+ calcd for C17H21N2O3: 301.1547; found:
301.1543.
tert-Butyl Pyridin-2-yl[(tetrahydro-2H-pyran-2-yl)oxy]carba-
mate (3h)
White solid; yield: 74.5 mg (28%); mp 59–60 °C.
2-(Trimethylsilyl)ethyl (Benzyloxy)(pyridin-2-yl)carbamate (3c)
Colorless oil; yield: 489 mg (81%).
IR (neat): 2970, 1709, 1585, 1567, 1461, 1439, 1329, 1279, 1155,
1114, 1096, 1024, 948, 900, 874, 795, 753 cm–1
.
IR (neat): 2956, 1713, 1585, 1465, 1387, 1327, 1288, 1249, 1114,
1H NMR (CDCl3, 400 MHz):  = 8.45–8.43 (m, 1 H), 7.65 (td, J = 1.88,
7.8 Hz, 1 H), 7.40 (d, J = 8.2 Hz, 1 H), 7.09–7.06 (m, 1 H), 5.15 (s, J = 3.0
Hz, 1 H), 3.79–3.73 (m, 1 H), 3.37–3.35 (m, 1 H), 1.90–1.69 (m, 3 H),
1.57–1.45 (m, 3 H), 1.47 (s, 9 H).
13C NMR (CDCl3, 100 MHz):  = 154.2 (d), 148.3, 137.4, 121.3, 119.3,
102.7, 82.7, 62.2, 28.3, 25.2, 18.4.
1061, 858, 835, 750, 697 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 8.47 (m, 1 H), 7.67 (t, J = 8.2 Hz, 1 H),
7.50 (d, J = 8.2 Hz, 1 H), 7.46–7.44 (m, 2 H), 7.33–7.32 (m, 3 H), 7.08 (t,
J = 5.5 Hz, 1 H), 5.08 (s, 2 H), 4.35–4.30 (m, 2 H), 1.11–1.07 (m, 2 H),
0.04 (s, 9 H).
13C NMR (CDCl3, 100 MHz):  = 154.6, 153.1, 148.4, 137.8, 135.0,
129.8, 128.7, 128.4, 120.8, 116.8, 78.2, 65.3, 17.8, –1.4.
HRMS (ESI): m/z [M + H]+ calcd for C15H23N2O4: 295.1652; found:
295.1647.
HRMS (CI/TOF): m/z [M]+ calcd for C18H25N2O3Si: 345.1629; found:
345.1626.
2-(Trimethylsilyl)ethyl Pyridin-2-yl[(tetrahydro-2H-pyran-2-
yl)oxy]carbamatecarbamate (3i)
N-(Benzyloxy)-4-methyl-N-(pyridin-2-yl)benzenesulfonamide
(3d)
Off-white solid; yield: 171 mg (66%); mp 45–46 °C.
IR (neat): 2955, 1708, 1585, 1461, 1439, 1387, 1316, 1290, 1259,
1245, 1181, 1114, 1049, 1016, 956, 904, 861, 835, 795, 769, 747, 694
Off-white solid; yield: 212 mg (83%); mp 73–74 °C.
IR (neat): 1582, 1428, 1360, 1169, 1087, 990, 807, 784, 708, 696, 664,
cm–1
.
592, 567, 540 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 8.43–8.41 (m, 1 H), 7.66–7.62 (m, 1 H),
7.42 (d, J = 8.2 Hz, 1 H), 7.07 (dd, J = 4.6, 7.3 Hz, 1 H), 5.13 (s, 1 H),
4.28–4.24 (m, 2 H ), 3.77–3.74 (m, 1 H ), 3.37–3.34 (m, 1 H), 1.90–1.69
(m, 3 H), 1.53–1.47 (m, 3 H), 1.03–0.98 (m, 2 H), –0.04 (s, 9 H).
1H NMR (CDCl3, 400 MHz):  = 8.32–8.31 (m, 1 H), 7.57 (td, J = 1.8, 7.8
Hz, 1 H), 7.47 (d, J = 8.3 Hz, 2 H), 7.37–7.35 (m, 2 H), 7.26–7.24 (m, 3
H), 7.17 (d, J = 7.8 Hz, 2 H), 7.11–7.08 (m, 2 H), 5.18 (s, 2 H), 2.35 (s, 3
H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

D
C. Torruellas et al.
PSP
Synthesis
13C NMR (CDCl3, 100 MHz):  = 155.4, 153.9, 148.4, 137.6, 121.5,
Benzyl (Allyloxy)(pyridin-2-yl)carbamate (3n)
119.2, 102.8, 65.2, 62.3, 28.2, 25.1, 18.4, 17.7, –1.5.
HRMS (CI/TOF): m/z [M]+ calcd for C16H27N2O4Si: 339.1735; found:
339.1740.
Clear-blue oil; yield: 225 mg (82%).
IR (neat): 3074, 1713, 1585, 1464, 1432, 1385, 1329, 1288, 1118 cm–1
1H NMR (CDCl3, 400 MHz):  = 8.45 (s, 1 H), 7.68–7.63 (m, 1 H), 7.54
(d, J = 8.2 Hz, 1 H), 7.40–7.27 (m, 5 H), 7.08–7.05 (m, 1 H), 6.01–5.91
(m, 1 H), 5.29, (s, 2 H), 5.29 (d, J = 6.4 Hz, 1 H), 5.20 (d, J = 10.1 Hz, 1
H), 4.53 (d, J = 6.9 Hz, 2 H).
.
Benzyl Pyridin-2-yl[(tetrahydro-2H-pyran-2-yl)oxy]carbamate
(3j)
Colorless oil; yield: 125 mg (48%).
13C NMR (CDCl3, 100 MHz):  = 154.3, 152.9, 148.4, 137.9, 135.7,
IR (neat): 3049, 2963, 2869, 1718, 1578, 1469, 1424, 1379, 1320,
131.9, 128.6, 128.4, 128.2, 121.0, 120.8, 116.9, 77.3, 68.2.
HRMS (ESI): m/z [M + H]+ calcd C16H17N2O3: 285.1234; found:
285.1299.
1268, 1203, 1112, 1024, 941, 872, 791, 735, 556, 455 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 8.47 (m, 1 H), 7.71–7.67 (m, 1 H), 7.47
(d, J = 8.2 Hz, 1 H), 7.36–7.29 (m, 5 H), 7.12 (dd, J = 4.6, 7.4 Hz, 1 H),
5.25 (s, 2 H), 5.19 (m, 1 H), 3.76 (td, J = 3.2, 11.0 Hz, 1 H), 3.37–3.32
(m, 1 H), 1.93–1.71 (m, 3 H), 1.58–1.45 (m, 3 H).
13C NMR (CDCl3, 100 MHz):  = 155.1, 153.7, 148.5, 137.7, 135.7,
128.6, 128.3, 128.0, 121.7, 119.2, 102.9, 68.2, 62.3, 28.2, 25.1, 18.4.
N-(Pyridin-2-yl)-N-(2-(trimethylsilyl)ethoxy)acetamide (3q)
Yellow oil; yield: 124 mg (43%).
IR (neat): 1686, 1585, 1465, 1431, 1368, 1328, 1281, 1150, 943, 777,
580 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C18H21N2O: 329.1496; found:
329.1491.
1H NMR (CDCl3, 400 MHz):  = 8.43 (br, 1 H), 7.70–7.67 (m, 2 H), 7.09
(br, 1 H), 4.02–4.00 (m, 2 H), 2.34 (s, 3 H), 1.07–1.05 (m, 2 H), –0.01 (s,
9 H).
13C NMR (CDCl3, 100 MHz):  = 170.4, 152.0, 148.2, 137.8, 121.0,
177.2, 73.4, 22.7, 16.8, –1.5.
N-(Allyloxy)-N-(pyridin-2-yl)acetamide (3k)
Green oil; yield: 151 mg (66%).
IR (neat): 2983, 2938, 1729, 1684, 1585, 1461, 1430, 1367, 1282,
HRMS (CI/TOF): m/z [M + H]+ calcd C12H21N2O2Si: 253.1367; found:
253.1367.
1153, 964, 909, 777 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 8.40 (m, 1 H), 7.65–7.61 (m, 2 H), 7.06
(s, 1 H), 5.94 (m, 1 H), 5.31–5.25 (m, 2 H) 4.45–4.43 (m, 2 H), 2.29 (s, 3
H).
13C NMR (CDCl3, 100 MHz):  = 170.7, 151.8, 148.3, 137.9, 131.3, 121.2
(d), 117.6, 76.6, 22.8.
HRMS (ESI): m/z [M + H]+ calcd C10H13N2O2: 193.0971; found:
N-(Benzyloxy)-N-(6-iodopyridin-2-yl)acetamide (3r)
Off-white solid; yield: 263 mg (59%); mp 75–76 °C.
IR (neat): 3034, 1679, 1555, 1415, 1364, 1308, 1159, 1125, 780, 743,
694, 578 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 7.79 (d, J = 8.2 Hz, 1 H), 7.54–7.50 (m, 3
H), 7.40–7.38 (m, 3 H), 7.31 (t, J = 8.2 Hz, 1 H), 5.04 (s, 2 H), 2.35 (s, 3
193.0969.
H).
tert-Butyl (Allyloxy)(pyridin-2-yl)carbamate (3l)
Brown oil; yield: 59.2 mg (50%).
13C NMR (CDCl3, 100 MHz):  = 171.0, 151.3, 139.2, 134.0, 131.7,
130.0, 129.3, 128.7, 115.5, 114.7, 78.0, 23.1.
HRMS (ESI): m/z [M + H]+ calcd C14H14IN2O2: 369.0094; found:
369.0091.
IR (neat): 2983, 1710, 1585, 1464, 1432, 1336, 1290, 1152, 1122, 777,
758 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 8.43 (s, 1 H), 7.64 (m, 1 H), 7.49–7.47
(m, 1 H), 7.04–7.03 (m, 1 H), 6.00–5.98 (m, 1 H), 5.33 (d, J = 8.8 Hz, 1
H), 5.22 (d, J = 10.0 Hz, 1 H), 4.51 (m, 2 H), 1.52 (s, 9 H).
13C NMR (CDCl3, 100 MHz):  = 153.4, 153.3, 148.3, 137.6, 132.2,
120.5, 120.4, 116.8, 82.7, 77.1, 28.3.
tert-Butyl (Benzyloxy)(6-iodopyridin-2-yl)carbamate (3s)
Yellow solid; yield: 216 mg (55%); mp 76–78 °C.
IR (neat): 2978, 1713, 1568, 1551, 1423, 1313, 1155, 1130, 747, 698
cm–1
.
HRMS (ESI): m/z [M + H]+ calcd C13H19N2O3: 251.1390; found:
251.1387.
1H NMR (CDCl3, 400 MHz):  = 7.58 (d, J = 8.2 Hz, 1 H), 7.55–7.53 (m, 2
H), 7.47 (d, J = 7.8 Hz, 1 H), 7.40–7.30 (m, 3 H), 7.25 (t, J = 7.8 Hz, 1 H),
5.07 (s, 2 H), 1.55 (s, 9 H).
13C NMR (CDCl3, 100 MHz):  = 152.8, 152.6, 138.8, 134.8, 131.0,
130.0, 128.9, 128.5, 114.7 (d), 83.2, 78.0, 28.3.
2-(Trimethylsilyl)ethyl (Allyloxy)(pyridin-2-yl)carbamate (3m)
Yellow oil; yield: 122 mg (43%).
IR (neat): 1714, 1585, 1468, 1434, 1386, 1328, 1288, 1151, 1117, 836,
HRMS (ESI): m/z [M + H]+ calcd C17H20IN2O3: 427.0513; found:
427.0506.
777, 754 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 8.43 (m, 1 H), 7.66–7.63 (m, 1 H), 7.52
(d, J = 8.2 Hz, 1 H), 7.08–7.06 (m, 1 H), 6.02–5.94 (m, 1 H), 5.30 (d, J =
17.0 Hz, 1 H), 5.22 (d, J = 11.0 Hz, 1 H), 4.54–4.52 (m, 2 H), 4.35–4.30
(m, 2 H), 1.10–1.06 (m, 2 H), 0.02 (s, 9 H).
13C NMR (CDCl3, 100 MHz):  = 154.6, 153.1, 148.3, 137.8, 132.0,
120.8, 120.6, 116.9, 65.3, 17.8, –1.4.
Di-tert-butyl Pyridine-2,6-diylbis[(benzyloxy)carbamate] (3s2)
The corresponding biscoupled product was also formed.
Yellow oil; yield: 30 mg.
IR (neat): 2978, 1711, 1582, 1439, 1313, 1152, 1121, 751, 697 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 7.64 (t, J = 8.0 Hz, 1 H), 7.44–7.42 (m, 4
H), 7.37 (d, J = 8.2 Hz, 2 H), 7.29–7.27 (m, 6 H), 5.10 (s, 4 H), 1.54 (s, 18
H).
HRMS (CI/TOF): m/z [M]+ calcd C14H23N2O3Si: 295.1473; found:
295.1467.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

E
C. Torruellas et al.
PSP
Synthesis
13C NMR (CDCl3, 100 MHz):  = 153.0, 151.6, 139.1, 135.2, 129.8,
13C NMR (CDCl3, 100 MHz):  = 170.2, 159.8, 158.2, 118.3, 104.3, 63.2,
128.6, 128.4, 112.4, 82.7, 77.9, 28.4.
28.4, 24.9, 23.9, 19.0.
HRMS (ESI): m/z [M + H]+ calcd C29H36N3O6: 522.2599; found:
HRMS (ESI): m/z [M + H]+ calcd C11H16N3O3: 238.1186; found:
522.2591.
238.1185.
N-(6-Iodopyridin-2-yl)-N-[(tetrahydro-2H-pyran-2-yl)oxy]acet-
amide (3u)
Funding Information
Yellow solid; yield: 263 mg (58%); mp 87–90 °C.
U.S. Defense Threat Reduction Agency Joint Science and Technology
Office (DTRA-JSTO, CB10243) is acknowledged for the financial sup-
IR (neat): 2918, 2862, 1682, 1555, 1415, 1367, 1286, 1159, 1125,
1035, 1016, 780, 723, 581 cm–1
.
port.
D
ef
e
nse
T
hreat
R
e
d
u
cti
o
n
A
g
e
n
c
y
(D
T
R
A-J
S
T
O
C
B
1
0
2
4
3)
1H NMR (CDCl3, 400 MHz):  = 7.67 (d, J = 7.8 Hz, 1 H), 7.53 (d, J = 7.3
Hz, 1 H), 7.32 (t, J = 7.8 Hz, 1 H), 5.03 (m, 1 H), 3.95–3.89 (m, 1 H),
3.46–3.42 (m, 1 H), 2.38 (s, 3 H), 1.92–1.84 (m, 3 H), 1.63–1.56 (m, 3
H).
13C NMR (CDCl3, 100 MHz):  = 171.5, 152.3, 139.0, 132.0, 116.8,
114.4, 104.8, 63.9, 28.7, 25.0, 23.2, 19.6.
Acknowledgment
Dr. Joy Ginter, Dr. Kevin Shefcheck, and Dr. Bruce King are gratefully
acknowledged for obtaining accurate mass data.
HRMS (ESI): m/z [M + H]+ calcd C12H16IN2O3: 363.0200; found:
363.0195.
Supporting Information
Supporting information for this article is available online at
(Z)-1-Methylpyridin-2(1H)-one O-Benzyl Oxime (3v)
Brown oil; yield: 150 mg (58%).
https://doi.org/10.1055/s-0037-1611836.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
IR (neat): 3030, 2911, 2851, 1644, 1556, 1454, 1347, 1045, 938, 730,
697 cm–1
.
References
1H NMR (CDCl3, 400 MHz):  = 7.41 (d, J = 6.9 Hz, 2 H), 7.35–7.25 (m, 3
H), 6.86–6.83 (m, 1 H), 6.79–6.76 (m, 2 H), 5.55–5.51 (m, 1 H), 4.96 (s,
2 H), 3.22 (s, 3 H).
(1) (a) Wencewicz, T. A.; Yang, B.; Rudloff, J. R.; Oliver, A. G.; Miller,
M. J. J. Med. Chem. 2011, 54, 6843. (b) Krchnak, V.; Zajicak, J.;
Miller, P. J. Org. Chem. 2011, 75, 10249.
13C NMR (CDCl3, 100 MHz):  = 154.9, 138.8, 137.7, 133.8, 128.3 (d),
(2) (a) Culyba, M.; Hwang, Y.; Attar, S.; Madrid, P. B.; Bupp, J.;
Huryn, D.; Sanchez, L.; Grobler, J.; Miller, M. D.; Bushman, F. D.
Nucleic Acids Res. 2012, 40, 1. (b) Zhao, Z. X.; Smith, S. J.;
Metifiot, M.; Johnson, B. C.; Marchand, C.; Pommier, Y.; Hugher,
S. H.; Burke, T. R. J. Med. Chem. 2014, 57, 1573. (c) Zhao, Z. X.;
Smith, S. J.; Metifiot, M.; Marchand, C.; Boyer, P. L.; Pommier, Y.;
Hugher, S. H.; Burke, T. R. J. Med. Chem. 2014, 57, 5190. (d) Zhao,
Z. X.; Smith, S. J.; Maskell, D. P.; Metifiot, M.; Pye, V. E.; Fesen, K.;
Marchand, C.; Pommier, Y.; Hugher, S. H.; Burke, T. R. J. Med.
Chem. 2017, 60, 7315. (e) Zhao, Z. X.; Smith, S. J.; Maskell, D. P.;
Metifiot, M.; Pye, V. E.; Fesen, K.; Marchand, C.; Pommier, Y.;
Cherepanov, P.; Hugher, S. H.; Burke, T. R. ACS Chem. Biol. 2016,
11, 1074.
127.5, 111.1, 100.9, 75.6, 39.1.
HRMS (ESI): m/z [M
+
H]+ calcd C13H15N2O: 215.1179; found:
215.1176.
(Z)-1-Methylpyridin-2(1H)-one O-Tetrahydro-2H-pyran-2-yl Ox-
ime (3w)
Yellow oil; yield: 200 mg (76%).
IR (neat): 2934, 2847, 1647, 1558, 1348, 1155, 1106, 1034, 984, 945,
813, 731 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 6.88 (d, J = 9.1 Hz, 1 H), 6.84–6.78 (m, 2
H), 5.56 (td, J = 1.37, 6.9 Hz, 1 H), 5.13–5.12 (m, 1 H), 3.95–3.88 (m, 1
H), 3.60–3.54 (m, 1 H), 3.28 (s, 3 H), 1.99–1.71 (m, 3 H), 1.60–1.55 (m,
3 H).
(3) Tseng, C. H.; Lin, R. W.; Chen, Y. L.; Wang, G. J.; Ho, M. L.; Tzeng,
C. C. J. Med. Chem. 2011, 54, 3103.
13C NMR (CDCl3, 100 MHz):  = 155.4, 137.9, 134.1, 111.0, 101.3,
100.7, 63.1, 39.3, 29.6, 25.5, 20.4.
(4) Disadee, W.; Ploypradith, P.; Aree, T.; Chaichit, N.; Ruchirawat,
S. Tetrahedron Lett. 2011, 52, 6142.
(5) Hand, E. S.; Paudler, W. W. J. Heterocycl. Chem. 1975, 12, 1063.
(6) Kuzmich, D.; Mulrooney, C. Synthesis 2003, 1671.
(7) (a) Tomazic, A.; Tisler, M.; Stanovik, B. Tetrahedron 1981, 37,
1787. (b) Demeunynck, M.; Tohme, N.; Lhomme, M. F.;
Lhomme, J. J. Heterocycl. Chem. 1984, 21, 501.
(8) Examples of nitroso ene and nitroso aldol reactions: (a) Yang,
B.; Miller, M. Tetrahedron Lett. 2010, 51, 328. (b) Li, Y.;
Chakrabarty, S.; Armido, S. Angew. Chem. Int. Ed. 2015, 54, 3587.
(9) Turbo Grignard reactions: (a) Bogart, J. A.; Lee, H. B.; Boreen, M.
A.; Jun, M.; Schelter, E. J. J. Org. Chem. 2013, 78, 6344.
(b) Okazawa, A.; Nogami, T.; Ishida, T. Chem. Mater. 2007, 19,
2733.
HRMS (ESI): m/z [M + H]+ calcd C11H17N2O2: 209.1284; found:
209.1281.
N-(Pyrimidin-2-yl)-N-[(tetrahydro-2H-pyran-2-yl)oxy]acetamide
(3x)
Brown oil; yield: 219 mg (73%).
IR (neat): 2938, 2866, 1695, 1564, 1405, 1368, 1298, 1245, 1034, 971,
894, 873 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 8.72 (m, 2 H), 7.14–7.12 (m, 1 H), 5.19
(m, 1 H), 3.93–3.90 (m, 1 H), 3.38–3.35 (m, 1 H), 2.42 (s, 3 H), 1.90–
1.85 (m, 3 H), 1.62–1.55 (m, 3 H).
(10) Nitroso Diels–Alder reaction: Krchnak, V.; Moellmann, U.;
Dahse, H. M.; Miller, M. J. J. Comb. Chem. 2008, 10, 104.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

F
C. Torruellas et al.
PSP
Synthesis
(11) (a) Hartwig, J. F. Acc. Chem Res. 2008, 41, 1534. (b) Muci, A. R.;
Buchwald, S. L. Cross-Coupling Reactions: A Practical Guide, In
Topics in Current Chemistry, Vol. 219; Miyaura, N., Ed.; Springer:
Berlin, 2002, 131. (c) Wagaw, S.; Buchwald, S. J. Org. Chem. 1996,
61, 7240.
(12) Kukosha, T.; Trufilkina, N.; Belyakov, S.; Katkevics, M. Synthesis
2012, 44, 2413.
(13) Jones, K. L.; Porzelle, A.; Hall, A.; Woodrow, M. D.; Tomkinson, N.
C. O. Org. Lett. 2008, 10, 797.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F