Access to Highly Substituted Pyrimidine N -Oxides and 4-Acetoxymethyl-Substituted Pyrimidines via the LANCA Three-Component Reaction-Cyclocondensation Sequence

Article abstract of DOI:10.1055/s-0040-1706020

The LANCA three-component reaction of lithiated alkoxy-allenes (LA), nitriles (N), and carboxylic acids (CA) smoothly provides β-alkoxy-β-ketoenamides in broad structural variety. The subsequent cyclocondensation of these compounds with hydroxylamine hydrochloride afforded a large library of pyrimidine N -oxides under mild conditions and in good yields. Their synthetic utility was further increased by the Boekelheide rearrangement leading to 4-acetoxymethyl-substituted pyrimidines. With trifluoroacetic anhydride the rearrangement proceeds even at room temperature and directly furnishes 4-hydroxymethyl-substituted pyrimidine derivatives. The key reactions are very robust and work well even in the presence of sterically demanding substituents.

Full text of DOI:10.1055/s-0040-1706020

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, A–N
paper
A
en
L. Schefzig et al.
Paper
Synthesis
Access to Highly Substituted Pyrimidine N-Oxides and 4-Acetoxy-
methyl-Substituted Pyrimidines via the LANCA Three-Component
Reaction–Cyclocondensation Sequence
Luise Schefziga
Timon Kurzawaa
Giaime Rancana
Igor Lindera
Stefan Leiseringa
Mrinal K. Beraa,b
Max Garta
OR1
•
R3
R3
O
Li
+
O
R3 NH
R2
O
Ac2O, Δ
NH2OH HCl
N
N
N
N
R2-C≡N
+
Boekelheide
R2
R2
rearrangement
OR1
OR1
OR1 OAc
R3-CO2H
0
0
0
0
-
0
0
0
3-4
3
8
2
-6
8
4
1
β-alkoxy-β-ketoenamides
pyrimidine N-oxides
21 examples
44–97%
14 examples
60–95%
LANCA
3-component
Reinhold Zimmer*a
Hans-Ulrich Reissig*a
reaction
0
0
0
0
-
0
0
0
2
-
1
9
1
2
-9
6
3
5
a Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustr. 3, 14195 Berlin, Germany
rzimmer@zedat.fu-berlin.de
hans.reissig@chemie.fu-berlin.de
b Department of Chemistry, Indian Institute of Engineering
Science and Technology, Shibpur, PO-Botanic Garden,
Howrah-711 103 (WB), India
Dedicated to Professor Heinz Heimgartner on the occasion of his 80th birthday
Corresponding Authors
Received: 10.12.2020
Accepted after revision: 13.01.2021
Published online: 09.02.2021
(Figure 1).7 Due to this high importance, the synthesis of
pyrimidines has attracted considerable attention and a
number of strategies for their synthesis are reported.1a–c To
date, beside cyclocondensations of -keto esters and vari-
ous nitrogen-containing C1-building blocks as the conven-
tional procedure, pyrimidines are also accessible using dif-
ferent approaches developed only recently,8 including cyc-
loaddition of alkynes and nitriles,9 gold-catalyzed
cyclizations of ynals and amidines,10 inverse electron de-
mand Diels–Alder reactions of heterocyclic aza-dienes,11
domino processes starting from activated skipped diynes
DOI: 10.1055/s-0040-1706020; Art ID: ss-2020-t0636-op
Abstract The LANCA three-component reaction of lithiated alkoxy-
allenes (LA), nitriles (N), and carboxylic acids (CA) smoothly provides
-alkoxy--ketoenamides in broad structural variety. The subsequent
cyclocondensation of these compounds with hydroxylamine hydrochlo-
ride afforded a large library of pyrimidine N-oxides under mild conditions
and in good yields. Their synthetic utility was further increased by the
Boekelheide rearrangement leading to 4-acetoxymethyl-substituted py-
rimidines. With trifluoroacetic anhydride the rearrangement proceeds
even at room temperature and directly furnishes 4-hydroxymethyl-sub-
stituted pyrimidine derivatives. The key reactions are very robust and
work well even in the presence of sterically demanding substituents.
H
F
N
N
Key words alkoxyallene, -alkoxy--ketoenamide, pyrimidine N-oxide,
Boekelheide rearrangement, oxidation
N
O
N
N
N
N
N
O
S
HN
R
N
N
N
H
Pyrimidines constitute one of the most important classes
of nitrogen-containing heterocycles and play a prominent
role in organic synthesis as well as in medicinal and agro-
chemistry.1 The pyrimidine core is for instance present in
pharmacologically interesting compounds possessing anti-
tubercular,2 antiproliferative,3 and CYP1A2 inhibitory activ-
ities.4 Derivatives of pyrimidines are identified as potent
dual M3 antagonists and PDE4 inhibitors5 and more recent-
ly they have been tested in multiple phase I/II trials for
treatment of cancer.6 In addition, pyrimidine derivatives
have also received a great attention from material science.
Numerous research groups have investigated their photo-
physical, electrochemical, and optoelectronic properties
O
O
novel class of
antitubercular agents
UCB-101333-3
dual M3 antagonist PEDH inhibitor
AZD6738, ATR inhibitor
Ar2
N
Ar1
N
N
N
N
N
N
N
Ar1
Ar1
Ar2
Ar1
Ph2N
O
NHPh
non-nucleotide P2Y14
receptor antagonist
donor-acceptor-
functionalized pyrimidines
tetraalkynyl-substituted
pyrimidines
Figure 1 Typical examples of highly functionalized pyrimidine deriva-
tives investigated as drug candidates or novel materials
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
L. Schefzig et al.
Paper
Synthesis
and amidines as nitrogen source12 as well as numerous
multicomponent reactions either metal-promoted13 or
metal-free14 versions.1g,15
furnishes pyrimidine N-oxides F under mild conditions.25 In
this account full details are reported exploring scope and
limitations of the method as well as the application of the
subsequent Boekelheide rearrangement leading to 4-acet-
oxymethyl-substituted pyrimidines.
Most of the studied -alkoxy--ketoenamides 3 are
known in the literature, but a few derivatives were newly
prepared for this study applying the known standard proce-
dure (see Supporting Information). Alkoxyallene 1 was
treated with n-butyllithium at low temperature and to the
generated lithiated alkoxyallene was subsequently added
the nitrile R2-CN providing the intermediate 2 (Scheme 2).
By addition of excess of the corresponding carboxylic acid a
reaction cascade was initiated17 that finally led to the de-
sired -alkoxy--ketoenamides 3. The LANCA three-compo-
nent reactions generally proceed in good to very good
yields, even in gram scale.
Among the many possible starting materials, com-
pounds with enamide and enamine substructure are effi-
cient precursors for the synthesis of pyrimidines.13b,f,14a
Enamides are generally very versatile polyfunctional build-
ing blocks frequently employed in organic synthesis.16 Our
group serendipitously found a new route to -alkoxy--ke-
toenamides (Scheme 1) by an intriguing one-pot three-
component reaction of lithiated alkoxyallenes (LA), nitriles
(N), and carboxylic acids (CA),17 subsequently explored this
LANCA process18,19 and established it as a versatile and
broadly applicable method. Its mechanism has been de-
scribed in detail in earlier publications.17
O
O
R3
R3
R3 NH
R2
O
R3
1) nBuLi
Et2O or THF
–78 °C
O
OR1
H
O
OR1
R2
N
O
3) R3-CO2H
R3
NH
O
A
B
•
•
O
R2
2) R2-CN
O
TFA
R2
OR1
Li
TFA
OR1
Li
N
C
L
•
1
2
3
R3
A
O
+
Scheme 2 Synthesis of -alkoxy--ketoenamides 3 by the LANCA
three-component reaction of lithiated alkoxyallenes, nitriles, and car-
boxylic acids
R3 NH
R2
O
N
R2-C≡N
+
N
R2
OH
OR1
D
R3
OR1
C
A
R3-CO2H
NH4X
β-alkoxy-β-ketoenamides
The cyclocondensation of the -alkoxy--ketoenamides
3 with hydroxylamine hydrochloride occurs in most cases
at room temperature using methanol as solvent providing
the desired pyrimidine N-oxides 4 in good to excellent
yields (Scheme 3, Table 1). The conceivable formation of ox-
azepine derivatives, the seven-membered isomers of 4, was
not observed. Most of the examples collected in Table 1
bear the methoxy group as alkoxy substituent OR1 (entries
1–12) since the parent compound methoxyallene is most
easily available and usually serves as a component to ex-
plore new reactions. Other alkoxy groups such as benzyloxy
or 2-(trimethylsilyl)ethoxy are also possible (entries 13–
17). With respect to the nitrile component and the carbox-
ylic acid simple or functionalized alkyl groups as well as
aryl or heteroaryl groups are compatible with the reaction
conditions and provide the product generally in satisfying
to excellent yields. The precursor -alkoxy--ketoenamides
3 are available in high yields if the components bear bulky
substituents R2 and R3.17,18 For this reason, many examples
can be found in Table 1 with sterically quite demanding
substituents such as tert-butyl or 1-adamantyl [see for in-
stance, compounds 4g (entry 7), 4j (entry 10), or 4q (entry
17)].
NH2OH HCl
R3
this work
N
N
R3
N
R2
Boekelheide
rearrangement
O
OR1
N
N
N
E
R2
R2
OR1 OR4
OR1
G
F
Scheme 1 The LANCA three-component approach to -alkoxy--keto-
enamides and subsequent products A–F derived from these polyfunc-
tionalized compounds
In a series of reports, we explored the high synthetic po-
tential of the -alkoxy--ketoenamides as versatile precur-
sors of 1,2-diketones A and (certain substitution patterns
given) for intriguing polycyclic compounds B.20 However,
the major synthetic importance of -alkoxy--ketoenam-
ides lies in cyclocondensation reactions leading to different
nitrogen-containing heterocycles, such as oxazoles C,21 pyr-
idines D17,22 (including bipyridine derivatives17e), or pyrimi-
dines E (Scheme 1).17f,i,23 While the synthesis and chemistry
of pyrimidines has attracted widespread interest, the syn-
thesis and application of pyrimidine N-oxides is much less
explored.24 We have already reported preliminary results
demonstrating that the cyclocondensation of -alkoxy--
ketoenamides with hydroxylamine hydrochloride smoothly
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N

C
L. Schefzig et al.
Paper
Synthesis
R3
O
Br
1)
O
R3 NH
O
NH2OH HCl, MeOH
rt, time
N
N
HO
2) tBuOK,tBuOH
reflux, 2 h
O
R2
R2
•
Bn2N
OR1
64%
(over 2 steps)
OR1
Bn2N
6
5
3
4
1) nBuLi
2) tBuCN
3) AcOH
Scheme 3 Cyclocondensation of -alkoxy--ketoenamides 3 with
hydroxylamine hydrochloride affording pyrimidine N-oxides 4
26%
O
O
NH2OH HCl
MeOH, 80 °C, 12 h
O
N
N
NH
Table 1 Preparation of Pyrimidine N-Oxides 4 from -Alkoxy--keto-
enamides 3 (according to Scheme 3)a
42%
O
O
Entry Precursor R1
R2
i-Pr
R3
Time
Product Yield
Bn2N
4r
Bn2N
3r
1
2
3a
3b
3c
3d
3e
3f
Me
Ph
c-Pr
1 d
2 d
4a
4b
4c
4d
4e
4f
61%
68%
69%
46%
81%
71%
65%
44%
97%
67%
58%
59%
38%
65%
50%
quant.
84%
Me
c-Pr
c-Pr
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Ad
Scheme 4 Synthesis of enantiopure alkoxyallene 6 and its conversion
into -alkoxy--ketoenamide 3r and subsequent cyclocondensation to
pyrimidine N-oxide 4r
3
Me
4-BrC6H4 1 d
4
Me
TMSE
Bn
1 d
1.5 d
2 d
1 d
1 d
1 d
1 d
1 d
1 d
2 d
1 d
1.5 d
2 d
1 d
5
Me
HO
N
6
Me
c-Pr
t-Bu
CH2Cl
Ph
O
O
NH2OH HCl
MeOH, 80 °C, 12 h
7
3g
3h
3i
Me
4g
4h
4i
NH
O
N
TBSO
tBu
8
Me
tBu
30%
OMe
3s
OMe
9
Me
4s
10
11
12
13
14
15
16
17
3j
Me
c-Pr
Ph
4j
3k
3l
Me
Ph
4k
4l
O
Me
2-Th
t-Bu
c-Pr
t-Bu
t-Bu
Ad
2-Th
c-Pr
c-Pr
Me
O
NH2OH HCl
MeOH, 80 °C, 12 h
NH
O
N
N
3m
3n
3o
3p
3q
Bn
4m
4n
4o
4p
4q
TMSE
TMSE
TMSE
TMSE
40%
OMe
3t
OMe
4t
Ph
Scheme 5 Conversion of enantiopure -alkoxy--ketoenamides 3s and
3t, respectively, into chiral pyrimidine N-oxides 4s and 4t
c-Pr
a Ad = 1-adamantyl, 2-Th = 2-thienyl, TMSE = 2-(trimethylsilyl)ethyl.
Finally, we included -alkoxy--ketoenamides without
the methyl ketone moiety in our investigations in order to
prepare pyrimidine N-oxides with different substituents in
the 6-position. Remarkably, precursor compounds with an
arylmethylcarbonyl group are directly available from aryl-
substituted propargylic ethers. Their deprotonation and re-
action with nitriles and carboxylic acids also provided the
desired target compounds although the exact mechanism
(requiring an intermediate proton transfer from the -posi-
tion to the -position) is not known.17d,21b,26 The reaction of
aryl-substituted propargyl ethers 7a and 7b with n-butyl-
lithium in diethyl ether followed by addition of pivalonitrile
and then trifluoroacetic acid afforded the desired -alkoxy-
-ketoenamides 8a and 8b in 40% and 36% yield, respective-
ly (Scheme 6). Their cyclocondensation reaction with hy-
droxylamine hydrochloride proceeded relatively slowly and
in both cases unconsumed starting material was re-isolated
(35% of 8a and 41% of 8b). The pyrimidine N-oxides 4u and
4v were obtained in 56% and 53% yield, showing that 6-ben-
zyl-substituted pyrimidine derivatives are smoothly acces-
sible via this route.
We also studied the applicability of the cyclocondensa-
tion protocol for the synthesis of pyrimidine N-oxides with
chiral substituents in different positions. The enantiopure
alkoxyallene 6 was readily accessible from N,N-dibenzyl-
protected (S)-alaninol 5 by O-alkylation with propargyl
bromide followed by base-promoted isomerization
(Scheme 4). After lithiation the LANCA reaction of this al-
lene with pivalonitrile and acetic acid provided the desired
-alkoxy--ketoenamide 3r in low yield. The reaction with
hydroxylamine hydrochloride required heating to 80 °C to
afford the pyrimidine N-oxide 4r in 42% yield. Both steps
were not optimized and may probably be improved.
The synthesis of -alkoxy--ketoenamides 3s and 3t
bearing the chirality at the amido group at the -position
was already described earlier.17g Their cyclocondensations
with hydroxylamine hydrochloride proceeded in methanol
under reflux and gave the pyrimidine N-oxides 4s and 4t,
respectively, in moderate yields (Scheme 5).
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N

D
L. Schefzig et al.
Paper
Synthesis
R3
R3
R3
1. 1.1 equiv nBuLi
O
Et2O, –40 °C
O
R
Ac2O
N
N
N
N
N
N
F3C
NH
O
OMe
+
2. tBu-CN, –40 °C
OAc
conditions
R2
R2
R2
R
3. CF3CO2H
–78 °C to rt
OR1
OR1
OR1
OMe
8a
8b
4
10
11
7a
7b
R = H, 40%
R = F, 36%
Scheme 8 Boekelheide rearrangement of pyrimidine N-oxides 4
leading to 4-acetoxymethyl-substituted pyrimidine derivatives 10 and
byproducts 11 (for details see Table 2)
NH2OH HCl, MeOH
reflux, 7 d
CF3
O
R
dine derivatives 11 were isolated as byproducts in 3% and
5% yield, respectively (entries 4, 7). The formation of this
type of compounds can be regarded as evidence of the par-
ticipation of radical intermediates during the rearrange-
ment process. The mechanism of the Boekelheide rear-
rangement is still controversially discussed and a study
with an emphasis on this aspect will be published separate-
ly.28
N
N
OMe
4u R = H 56%
4v R = F 53%
Scheme 6 Conversion of aryl-substituted propargyl ethers 7a and 7b,
respectively, into -alkoxy--ketoenamides 8a and 8b and subsequent
cyclocondensations leading to pyrimidine N-oxides 4u and 4v
Table 2 Conversion of Pyrimidine N-Oxides 4 into Acetoxymethyl-Sub-
stituted Pyrimidines 10 (according to Scheme 8)a
An obvious synthetic use of pyrimidine N-oxides is their
reductive deoxygenation which was demonstrated by sub-
jecting compound 4e to hydrogen in the presence of palla-
dium on carbon affording the expected pyrimidine deriva-
tive 9 in 50% yield (Scheme 7). Pyrimidines such as 9 can be
directly prepared from -alkoxy--ketoenamides and am-
monia sources.18b,23 The ‘detour’ via pyrimidine N-oxides
may have advantages in singular cases because the conden-
sation and the reduction step proceed at room temperature.
Entry Precursor R1
R2
R3
Method
Product
Yield
1
2
3
4
5
6
7
8
9
4c
4f
Me
c-Pr
4-BrC6H4 A: 120 °C, 3 h
10a
66%
Me
t-Bu
t-Bu
t-Bu
Ad
c-Pr
t-Bu
Ph
A: 120 °C, 3 h
A: 120 °C, 3 h
A: 120 °C, 3 h
A: 120 °C, 3 h
10b
78%
4g
4i
Me
10c
87%
Me
10d
Ph
N
69%b
Ph
N
O
H2, Pd/C
4j
Me
c-Pr
10e
89%
N
N
MeOH, rt
50%
tBu
tBu
4l
Me
2-Th 2-Th
B: C6H6, 80 °C, 4 h 10f
OMe
4e
OMe
67%
9
4m
4p
4q
Bn
t-Bu
t-Bu
Ad
c-Pr
Ph
A: 120 °C, 3 h
A: 120 °C, 3 h
10g
60%c
Scheme 7 Deoxygenation of pyrimidine N-oxide 4e leading to com-
pound 9
TMSE
TMSE
10h
94%
c-Pr
B: C6H6, 80 °C, 3 h 10i
95%
However, the focus of this study was to employ the N-
oxide unit for the functionalization of the adjacent alkyl
group in order to also allow variations at this position. This
objective could be smoothly accomplished by employing
the Boekelheide rearrangement, an elegant and synthetical-
ly valuable method to functionalize N-heterocycles such as
pyridine, pyrimidine, pyrazine, tetrahydroquinoline, or thi-
azole derivatives.27 Heating of typically substituted pyrimi-
dine N-oxides 4 with acetic anhydride at 120 °C for 3 hours
(method A) afforded the 4-acetoxymethyl-substituted py-
rimidine derivatives 10 generally in very good yields
(Scheme 8, Table 2, entries 1–5, 7, 8). Alternatively, the
transformation can also be achieved in refluxing benzene as
solvent at 80 °C and an excess of acetic anhydride (method
B, entries 6, 9). In two cases the ethyl-substituted pyrimi-
a Ad = 1-adamantyl, 2-Th = 2-thienyl, TMSE = 2-(trimethylsilyl)ethyl.
b + 3% of 11d.
c + 5% of 11g.
In Scheme 9 we have collected examples of pyrimidine
N-oxides with special substitution patterns needing sepa-
rate discussion. In the case of 4e the Boekelheide rearrange-
ment can either provide the ‘normal’ product 10j with an
acetoxymethyl group or pyrimidine derivative 10k where
the benzyl group was involved in the transformation. Actu-
ally, both compounds were formed in a ca. 1:1 ratio. The
missing regioselectivity of the rearrangement indicates that
the (assumed) electronic activation by the phenyl group
and the steric effect exhibited by this substituent are
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N

E
L. Schefzig et al.
Paper
Synthesis
AcO
N
Ph
N
Bn
Bn
Ac2O, C6H6
90 °C, 3 h
K2CO3
MeOH/CH2Cl2
O
O
N
N
N
N
N
N
N
N
N
+
OAc
sealed tube
87%
OH
tBu
tBu
tBu
tBu
tBu
rt, 3 h
70%
Ad
Ad
tBu
tBu
OMe
OMe OAc
OMe
OMe
OMe
4e
10j
(1:1)
10k
10e
Ph
12a
AcO
N
Ph
Ac2O, C6H6
90 °C, 3 h
N
N
K2CO3, MeOH
N
N
N
N
N
N
N
+
OAc
OH
OH
rt, 3 h
76%
sealed tube
64%
tBu
tBu
tBu
O
Bn2N
4r
CF3
O
OAc
OMe
OMe
O
10d
12b
Bn2N
Bn2N
10m
Ph
N
Ph
N
(CF3CO)2O
CH2Cl2
10l
(1:1)
O
N
CF3
Ac2O
rt, 3 h
85%
O
120 °C, 1 d
N
N
N
N
OMe
OMe
OAc
sealed tube
73%
tBu
tBu
4i
12b
OMe Ph
OMe Ph
Ph
N
Ph
N
4u
10n
(CF3CO)2O
CH2Cl2
O
N
Scheme 9 Boekelheide rearrangements of pyrimidine N-oxides 4e, 4r,
and 4u leading to the acetoxy-substituted pyrimidine derivatives 10j–10n
N
OH
rt, 3 h
72%
tBu
tBu
OMe
OMe
4e
12c
roughly in the same order. In the second case of Scheme 9,
two methyl groups in different positions of 4r compete
during the rearrangement process. Again a 1:1 mixture of
the two possible products 10l and 10m was isolated. The
last example of trifluoromethyl-substituted compound 4u
shows that the rearrangement is apparently retarded by
this electron-withdrawing substituent. After one day at 120 °C
product 10n was isolated in 73% yield.
The acetoxymethyl group of compounds 10a–10n al-
lows further transformations in this position which will be
the content of a separated report. The most trivial reaction
is the saponification of the acetic ester moiety which could
be smoothly achieved with potassium carbonate in metha-
nol as demonstrated by the conversion of 10e and 10d, re-
spectively, into the 4-hydroxymethyl-substituted com-
pounds 12a and 12b (Scheme 10). Remarkably, pyrimidine
derivatives of this type could be directly obtained by per-
forming the Boekelheide rearrangement of N-oxides 4 using
trifluoroacetic anhydride.29 The primarily formed trifluoro-
acetic esters undergo hydrolysis to the alcohols during
work-up and/or purification and therefore the saponifica-
tion step is not required. The three examples of Scheme 10
demonstrate that with the more electrophilic trifluoroace-
tic anhydride the Boekelheide rearrangement occurs al-
ready at room temperature, delivering the 4-hydroxymeth-
yl-substituted pyrimidine derivatives 12b–12d under mild
conditions and in very good yield.
tBu
tBu
(CF3CO)2O
CH2Cl2
O
N
N
N
N
OH
rt, 3 h
78%
tBu
tBu
OMe
OMe
4g
12d
Scheme 10 Synthesis of 4-hydroxymethyl-substituted pyrimidine
derivatives 12a–12d either by saponification of 4-acetoxymethyl-sub-
stituted compounds 10e and 10d, respectively, or by Boekelheide rear-
rangement of pyrimidine N-oxides 4e, 4g, and 4i with trifluoroacetic
anhydride
their cyclocondensation with hydroxylamine hydrochloride
works smoothly providing the desired pyrimidine N-oxides
4 generally in high yields. A subsequent Boekelheide rear-
rangement of 4 with acetic anhydride under heating allows
a functionalization of the methyl group adjacent to the N-
oxide moiety delivering 4-acetoxymethyl-substituted py-
rimidines 10 in good yield. With trifluoroacetic anhydride
the rearrangement proceeds even at room temperature and
directly furnishes 4-hydroxymethyl-substituted pyrimidine
derivatives 12. Bulky substituents do not lead to diminished
efficiency of the key reactions. The alkoxy substituent (in-
troduced via the allene component) also allows further sub-
stitutions at C-5 of the pyrimidine derivatives, in particular,
if benzyloxy or 2-(trimethylsilyl)ethoxy groups are em-
ployed. These subsequent transformations and other typi-
cal reactions of the prepared pyrimidine derivatives 4, 10,
or 12 will be presented in an upcoming report.
Our results clearly demonstrate that the LANCA ap-
proach to highly functionalized pyrimidine derivatives is
simple and very flexible. The required starting materials, -
alkoxy--ketoenamides 3, are available in large variety and
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N

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L. Schefzig et al.
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Synthesis
ers were dried (Na2SO4), filtered, and concentrated. Column chroma-
tography (silica gel, hexanes/EtOAc) provided the corresponding py-
rimidine N-oxide 4.
Reactions were generally performed under argon in flame-dried
flasks, and the components were added by syringe. Products were pu-
rified by flash chromatography on silica gel (230–400 mesh, Merck or
Macherey & Nagel). Unless otherwise stated, yields refer to analytical-
ly pure samples. 1H NMR [CHCl3 ( = 7.26), TMS ( = 0.00) as internal
standard] and 13C NMR spectra [CDCl3 ( = 77.0) as internal standard]
were recorded with Bruker AC 250, DRX 500, AV 700 or Jeol ECX 400
and Eclipse 500 instruments in CDCl3 solutions. Integrals are in accor-
dance with assignments; coupling constants are given in Hz. 13C NMR
spectra are proton-decoupled and the multiplicity of signals was de-
termined by DEPT spectra. IR spectra were measured with an FTIR
spectrophotometer Nicolet 5 SXC FTIR or a Nicolet Smart DuraSam-
plIR ATR spectrophotometer. MS and HRMS analyses were performed
with Finnigan MAT 711 (EI, 80 eV, 8 kV), MAT 95 (EI, 70 eV), MAT
CH7A (EI, 80 eV, 3 kV), or Agilent ESI-TOF 6210 (4 L/min, 1 bar, 4000
V) instruments. Optical rotations ([]D) were measured with a Perkin
Elmer 241 polarimeter in a 1 mL microcuvette at the temperature giv-
en. The elemental analyses were recorded with ‘Elemental-Analyzers’
(Perkin–Elmer or Carlo Erba).
4-Isopropyl-5-methoxy-6-methyl-2-phenylpyrimidine 1-Oxide
(4a)
According to general procedure (GP 1), -ketoenamide 4a (0.260 g,
0.821 mmol) and NH2OH·HCl (0.571 g, 8.21 mmol) in MeOH (15 mL)
were used; reaction time: 1 d. The crude product was purified by
chromatography (silica gel, hexanes/EtOAc, 3:1 to 1:1) to give 4a
(0.158 g, 61%) as a colorless oil.
IR (ATR): 3060–2870 (C–H), 1715–1570 cm–1 (C=C, C=N).
1H NMR (CDCl3, 500 MHz):  = 1.41 (d, J = 6.9 Hz, 6 H, iPr), 2.63 (s, 3 H,
Me), 3.44 (sept, J = 6.9 Hz, 1 H, iPr), 3.91 (s, 3 H, OMe), 7.53–7.55,
8.58–8.60 (2 m, 2 H, 3 H, Ph).
13C NMR (CDCl3, 125.8 MHz):  = 11.9 (q, Me), 21.4, 29.1 (q, d, iPr),
62.0 (q, OMe), 127.8, 130.0, 130.4, 132.6 (3 d, s, Ph), 148.3, 151.5,
151.6, 155.5 (4 s, C-2, C-4, C-5, C-6).
The preparation of starting materials 3a,17e 3b,23b 3e,17f 3i,17e 3j,25 3k,23
3l,17h 3m,21b 3o,21b 3q,21b 3s,17g 8a,17d and alkoxyallenes30 has been re-
ported earlier. The synthesis of other -alkoxy--ketoenamides is de-
scribed in the Supporting Information. All other chemicals are com-
mercially available and were used without further purification.
HRMS (ESI-ToF): m/z [M + H]+ calcd for C15H19N2O2: 259.1441; found:
259.1444.
Anal. Calcd for C15H18N2O2 (258.3): C, 69.74; H, 7.02; N, 10.84. Found:
C, 69.39; H, 7.40; N, 10.12.
2,4-Dicyclopropyl-5-methoxy-6-methylpyrimidine 1-Oxide (4b)
(E)-N-(4-Methoxy-2,2-dimethyl-5-oxohex-3-en-3-yl)cyclopropa-
necarboxamide (3f); Typical Procedure for the Synthesis of -
Alkoxy--ketoenamides 3
According to general procedure (GP1), -ketoenamide 3b (0.679 g,
3.04 mmol) and NH2OH·HCl (1.09 g, 15.6 mmol) in MeOH (10 mL)
were used; reaction time: 2 d. The crude product was purified by
chromatography (silica gel, hexanes/EtOAc, 3:1 to 1:1) to give 4b
(0.454 g, 68%) as a colorless oil.
IR (ATR): 3000–2880 (C–H), 1560 (C=C), 1475 cm–1 (C=N).
1H NMR (CDCl3, 500 MHz):  = 0.92–1.15 (m, 8 H, cPr), 2.16–2.19,
3.01–3.06 (2 m, 1 H each, cPr), 2.49 (s, 3 H, Me), 3.77 (s, 3 H, OMe).
13C NMR (CDCl3, 125.8 MHz):  = 10.0, 10.2 (2 t, CH2), 10.3, 10.8 (2 d,
CH), 11.5 (q, Me), 61.7 (q, OMe), 147.6, 149.5, 152.2, 158.1 (4 s, C-2,
C-4, C-5, C-6).
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C11H16N2NaO2: 243.1104;
found: 243.1115.
Methoxyallene (2.00 g, 28.5 mmol) was dissolved in Et2O (60 mL) and
n-BuLi (12.5 mL, 31.3 mmol, 2.5 M in hexanes) was added at –40 °C.
After 25 min at –50 °C to –40 °C pivalonitrile (4.70 mL, 43.0 mmol)
was added. The solution was stirred at –40 °C for 30 min and then
cooled to –78 °C. After stirring for 4 h at this temperature cyclopro-
panecarboxylic acid (3.40 mL, 43.0 mmol) was added and the mixture
was warmed up overnight to rt. The mixture was quenched with sat.
aq NaHCO3 solution (50 mL) and extracted with CH2Cl2 (3 × 50 mL).
The combined organic layers were dried (Na2SO4), filtered, and con-
centrated. Column chromatography (silica gel, hexane/EtOAc, 4:1, 1:1
to 1:3) provided 1f (2.68 g, 39%) as a pale yellow solid; mp 150 °C.
IR (ATR): 3285 (N–H), 2965–2840 (C–H), 1695 cm–1 (C=O).
1H NMR (CDCl3, 400 MHz):  = 0.69–0.79, 0.90–0.97 (m, 4 H each, cPr),
1.22 (s, 9 H, tBu), 1.40–1.51 (m, 1 H, cPr), 2.25 (s, 3 H, Me), 3.51 (s, 3 H,
OMe), 7.12 (br s, 1 H, NH).
13C NMR (CDCl3, 100.5 MHz):  = 7.6 (t, CH2), 14.3 (d, CH), 27.9 (q,
Me), 28.3, 36.5 (q, s, tBu), 58.8 (q, OMe), 134.1, 150.5 (2 s, C=C), 178.8
(s, CONH), 200.4 (s, C=O).
2-(4-Bromophenyl)-4-cyclopropyl-5-methoxy-6-methylpyrimi-
dine 1-Oxide (4c)
According to general procedure (GP 1), -ketoenamide 3c (1.42 g, 4.20
mmol) and NH2OH·HCl (1.17 g, 16.8 mmol) in MeOH (30 mL) were
used; reaction time: 1 d. The crude product was purified by chroma-
tography (silica gel, hexanes/EtOAc, 2:1) to give 4c (0.965 g, 69%) as
colorless crystals; mp 118 °C.
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C13H21NNaO3: 262.1419;
found: 262.1421.
IR (ATR): 3085–2835 (=C–H, C–H), 1585 (C=C), 1460 cm–1 (C=N).
1H NMR (CDCl3, 500 MHz):  = 1.07–1.11, 1.17–1.20 (2 m, 2 H each,
CH2), 2.27–2.34 (m, 1 H, CH), 2.52 (s, 3 H, Me), 3.85 (s, 3 H, OMe),
7.53–7.58, 8.32–8.39 (2 m, 2 H each, Aryl).
Anal. Calcd for C13H21NO3 (239.3): C, 65.25; H, 8.84; N, 5.85. Found: C,
65.22; H, 8.83; N, 5.84.
13C NMR (CDCl3, 125.8 MHz):  = 10.4 (t, CH2), 11.0, 11.5 (d/q, CH, Me),
61.7 (q, OMe), 124.9, 130.9, 131.2, 131.5 (s, d, s, d, Aryl), 149.1, 150.2,
151.0, 152.2 (4 s, C-2, C-4, C-5, C-6).
HRMS (ESI-ToF): m/z [M + H]+ calcd for C15H16BrN2O2: 335.0390,
337.0268; found: 335.0395, 337.0219.
5-Methoxy-6-methylpyrimidine 1-Oxides 4; General Procedure
(GP 1)
-Alkoxy--ketoenamide 3 (1 equiv) was dissolved in MeOH (12–24
mL/mmol) and NH2OH·HCl (3–10 equiv) was added. The mixture was
stirred at rt (or under reflux) for the time indicated in the individual
experiment. After addition of water (20 mL/mmol), the mixture was
extracted with CH2Cl2 (5 × 10 mL/mmol). The combined organic lay-
Anal. Calcd for C15H15BrN2O2 (335.2): C, 53.75; H, 4.51; N, 8.36. Found:
C, 53.76; H, 4.40; N, 8.33.
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L. Schefzig et al.
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Synthesis
4-tert-Butyl-5-methoxy-6-methyl-2-[2-(trimethylsilyl)ethyl]-
1H NMR (CDCl3, 400 MHz):  = 1.36, 1.50 (2 s, 9 H each, tBu), 2.50 (s, 3
pyrimidine 1-Oxide (4d)
H, Me), 3.76 (s, 3 H, OMe).
13C NMR (CDCl3, 125.8 MHz):  = 12.4 (q, Me), 29.2, 29.7, 38.2, 38.9 (2
q, 2 s, tBu), 61.7 (q, OMe), 149.9, 151.7, 154.7, 158.9 (4 s, C-2, C-4, C-5,
C-6).
HRMS (ESI-ToF): m/z [M + H]+ calcd for C14H25N2O2: 253.1911; found:
253.1919.
According to general procedure (GP1), -ketoenamide 3d (0.245 g,
0.810 mmol) and NH2OH·HCl (0.285 g, 4.10 mmol) in MeOH (3 mL)
were used; reaction time: 1 d. The crude product was purified by
chromatography (silica gel, hexanes/EtOAc, 3:1 to 1:1) to give 4d
(0.123 g, 46%) as a colorless oil.
IR (ATR): 2955–2870 (C–H), 1525 (C=C), 1475 cm–1 (C=N).
1H NMR (CDCl3, 500 MHz):  = –0.01 (s, 9 H, SiMe3), 0.98–1.04 (m, 2 H,
CH2Si), 1.36 (s, 9 H, tBu), 2.48 (s, 3 H, Me), 3.00–3.05 (m, 2 H, CH2),
3.75 (s, 3 H, OMe).
13C NMR (CDCl3, 125.8 MHz):  = –1.84 (q, SiMe3), 11.4 (t, SiCH2), 12.3
(q, Me), 26.7 (t, CH2), 29.1, 37.9 (q, s, tBu), 61.8 (q, OMe), 149.7, 150.2,
155.9, 156.5 (4 s, C-2, C-4, C-5, C-6).
4-tert-Butyl-2-(chloromethyl)-5-methoxy-6-methylpyrimidine 1-
Oxide (4h)
According to general procedure (GP1), -ketoenamide 3h (0.330 g,
1.33 mmol) and NH2OH·HCl (0.278 g, 4.00 mmol) in MeOH (5 mL)
were used; reaction time: 1 d. The crude product was purified by
chromatography (silica gel, hexanes/EtOAc, 3:1 to 1:1) to give 4h
(0.144 g, 44%) as a pale yellow oil.
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C15H28N2NaO2Si: 319.1812;
found: 319.1810.
IR (ATR): 2960–2865 (C–H), 1520 (C=C), 1480 cm–1 (C=N).
1H NMR (CDCl3, 400 MHz):  = 1.37 (s, 9 H, tBu), 2.51 (s, 3 H, Me), 3.80
2-Benzyl-4-tert-butyl-5-methoxy-6-methylpyrimidine 1-Oxide
(s, 3 H, OMe), 4.85 (s, 2 H, CH2Cl).
(4e)
13C NMR (CDCl3, 125.8 MHz):  = 12.2 (q, Me), 28.9, 37.9 (q, s, tBu),
40.8 (t, CH2Cl), 61.9 (q, OMe), 149.3, 151.1, 151.5, 156.9 (4 s, C-2, C-4,
C-5, C-6).
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C11H17ClN2NaO2: 267.0871;
found: 267.0867.
According to general procedure (GP1), -ketoenamide 3e (0.340 g,
1.18 mmol) and NH2OH·HCl (0.408 g, 5.88 mmol) in MeOH (5 mL)
were used; reaction time: 1.5 d. The crude product was purified by
chromatography (silica gel, hexanes/EtOAc, 2:1 to 1:2) to give 4e
(0.275 g, 81%) as a colorless oil.
IR (ATR): 3065–2865 (=CH, C–H), 1470–1350 cm–1 (C=N).
4-tert-Butyl-5-methoxy-6-methyl-2-phenylpyrimidine 1-Oxide
(4i)
1H NMR (CD3OD, 400 MHz):  = 1.32 (s, 9 H, tBu), 2.48 (s, 3 H, Me),
3.74 (s, 3 H, OMe), 4.37 (s, 2 H, CH2Ph), 7.17–7.21, 7.25–7.29, 7.40–
7.42 (3 m, 1 H, 2 H, 2 H, Ph).
13C NMR (CDCl3, 100.5 MHz):  = 12.5 (q, Me), 29.2, 37.9 (q, s, tBu),
38.4 (t, CH2Ph), 61.9 (q, OMe), 126.6, 128.3, 129.9, 136.2 (3 d, s, Ph),
150.2, 150.6, 153.6, 156.0 (4 s, C-2, C-4, C-5, C-6).
According to general procedure (GP 1), -ketoenamide 3i (1.70 g, 6.17
mmol) and NH2OH·HCl (1.35 g, 19.4 mmol) in MeOH (20 mL) were
used; reaction time: 1 d. The crude product was purified by chroma-
tography (silica gel, hexanes/EtOAc, 3:1 to 1:1) to give 4i (1.63 g, 97%)
as a colorless oil.
IR (ATR): 2960–2870 (C–H), 1600 (C=C), 1460 cm–1 (C=N).
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C17H22N2NaO2: 309.1579;
1H NMR (CDCl3, 400 MHz):  = 1.42 (s, 9 H, tBu), 2.57 (s, 3 H, Me), 3.86
found: 309.1584.
(s, 3 H, OMe), 7.45–7.48, 8.54–8.58 (2 m, 2 H, 3 H, Ph).
4-tert-Butyl-2-cyclopropyl-5-methoxy-6-methylpyrimidine
1-Oxide (4f)
13C NMR (CDCl3, 100.5 MHz):  = 12.6 (q, Me), 29.0, 38.0 (q, s, tBu),
61.8 (q, OMe), 127.7, 129.8, 130.3, 132.5 (3 d, s, Ph), 149.1, 150.0,
151.8, 156.4 (4 s, C-2, C-4, C-5, C-6).
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C16H20N2NaO2: 295.1417;
found: 295.1431.
According to general procedure (GP1), -ketoenamide 3f (0.998 g,
4.17 mmol) and NH2OH·HCl (0.733 g, 10.5 mmol) in MeOH (16 mL)
were used; reaction time: 2 d. The crude product was purified by
chromatography (silica gel, pentane/EtOAc, 2:1 to 1:1) to give 4f
(0.697 g, 71%) as a colorless oil.
IR (ATR): 2960–2870 (C–H), 1530 (C=C), 1475 cm–1 (C=N).
1H NMR (CDCl3, 400 MHz):  = 1.03–1.15 (m, 4 H, cPr), 1.32 (s, 9 H,
tBu), 2.51 (s, 3 H, Me), 3.04–3.23 (m, 1 H, cPr), 3.74 (s, 3 H, OMe).
4-(1-Adamantyl)-2-cyclopropyl-5-methoxy-6-methylpyrimidine
1-Oxide (4j)
According to general procedure (GP 1), -ketoenamide 3j (0.260 g,
0.820 mmol) and NH2OH·HCl (0.171 g, 2.46 mmol) in MeOH (3 mL)
were used; reaction time: 1 d. The crude product was purified by
chromatography (silica gel, hexanes/EtOAc, 2:1) to give 4j (0.172 g,
67%) as a pale yellow oil.
13C NMR (CDCl3, 100.5 MHz):  = 10.1, 10.4 (t, d, cPr), 12.8 (q, Me),
29.5, 37.6 (q, s, tBu), 62.7 (q, OMe), 149.4, 150.1, 155.6, 156.4 (4 s, C-2,
C-4, C-5, C-6).
IR (ATR): 2870–2870 (C–H), 1570 (C=C), 1460 cm–1 (C=N).
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C13H20N2NaO2: 259.1417;
1H NMR (CDCl3, 400 MHz):  = 1.08–1.18 (m, 4 H, cPr), 1.63–1.88,
1.95–2.11 (2 m, 6 H, 9 H, adamantyl-CH, -CH2), 2.51 (s, 3 H, Me), 3.05–
3.16 (m, 1 H, cPr), 3.75 (s, 3 H, OMe).
found: 259.1421.
2,4-Di-tert-butyl-5-methoxy-6-methylpyrimidine 1-Oxide (4g)
13C NMR (CDCl3, 100.5 MHz):  = 10.0, 10.5 (t, d, cPr), 12.5 (q, Me),
28.7, 36.8, 40.2, 40.3 (d, 2 t, s, adamantyl), 62.2 (q, OMe), 149.2, 150.3,
155.8, 156.2 (4 s, C-2, C-4, C-5, C-6).
HRMS (ESI-ToF): m/z [M + H]+ calcd for C19H27N2O2: 315.2072; found:
315.2081.
According to general procedure (GP 1), -ketoenamide 3g (0.960 g,
4.00 mmol) and NH2OH·HCl (0.830 g, 12.0 mmol) in MeOH (16 mL)
were used; reaction time: 1 d. The crude product was purified by
chromatography (silica gel, pentane/EtOAc, 5:1 to 2:1) to give 4g
(0.650 g, 65%) as a colorless oil.
IR (ATR): 2865–2870 (C–H), 1575 (C=C), 1460 cm–1 (C=N).
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N

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Synthesis
5-Methoxy-6-methyl-2,4-diphenylpyrimidine 1-Oxide (4k)
1H NMR (CDCl3, 250 MHz):  = –0.01 (s, 9 H, SiMe3), 0.93–1.23 (m, 10
H, cPr, CH2Si), 2.14–2.24, 3.03–3.13 (2 m, 1 H each, cPr), 2.49 (s, 3 H,
Me), 3.92–4.00 (m, 2 H, OCH2).
13C NMR (CDCl3, 100.5 MHz):  = 1.6 (q, SiMe3), 9.8, 10.0 (2 t, CH2),
10.1, 10.9 (2 d, CH), 11.8 (q, Me), 18.9 (t, CH2Si), 72.7 (t, OCH2), 146.5,
149.5, 152.0, 157.5 (4 s, C-2, C-4, C-5, C-6).
According to general procedure (GP1), -ketoenamide 3k (0.257 g,
0.870 mmol) and NH2OH·HCl (0.182 g, 2.61 mmol) in MeOH (5 mL)
were used; reaction time: 1 d. The crude product was purified by
chromatography (silica gel, hexanes/EtOAc, 3:1 to 1:1) to give 4k
(0.148 g, 58%) as a colorless oil.
IR (ATR): 2990–2870 (C–H), 1590 (C=C), 1450 cm–1 (C=N).
HRMS (ESI-ToF): m/z [M + H]+ calcd for C16H27N2O2Si: 307.1842;
1H NMR (CDCl3, 250 MHz):  = 2.53 (s, 3 H, Me), 3.89 (s, 3 H, OMe),
found: 307.1845.
7.35–7.50, 8.41–8.60 (2 m, 4 H, 6 H, Ph).
4-tert-Butyl-2,6-dimethyl-5-[2-(trimethylsilyl)ethoxy]pyrimi-
dine 1-Oxide (4o)
13C NMR (CDCl3, 100.5 MHz):  = 12.8 (q, Me), 61.5 (q, OMe), 127.6,
127.7, 129.7, 129.8, 130.3, 130.5, 132.5, 133.0 (6 d, 2 s, Ph), 149.5,
150.8, 151.7, 156.7 (4 s, C-2, C-4, C-5, C-6).
HRMS (ESI-ToF): m/z [M + H]+ calcd for C18H17N2O2: 293.1263; found:
293.1285.
According to general procedure (GP1), -ketoenamide 3o (0.302 g,
1.02 mmol) and NH2OH·HCl (0.213 g, 3.06 mmol) in MeOH (20 mL)
were used; reaction time: 1.5 d. The crude product was purified by
chromatography (silica gel, hexanes/EtOAc, 3:1 to 1:1) to give 4o
(0.152 g, 50%) as a pale yellow oil.
5-Methoxy-6-methyl-2,4-di(2-thienyl)pyrimidine 1-Oxide (4l)
IR (ATR): 3050–2890 (C–H), 1570 (C=C), 1490 cm–1 (C=N).
According to general procedure (GP1), -ketoenamide 3l (0.120 g,
0.391 mmol) and NH2OH·HCl (0.081 g, 1.17 mmol) in MeOH (3 mL)
were used; reaction time: 1 d. The crude product was purified by
chromatography (silica gel, hexanes/EtOAc, 1:1 to 1:2) to give 4l
(0.070 g, 59%) as a colorless oil.
1H NMR (CDCl3, 400 MHz):  = 0.06 (s, 9 H, SiMe3), 1.22–1.29 (m, 2 H,
CH2Si), 1.43 (s, 9 H, tBu), 2.45, 2.64 (2 s, 3 H each, 2 Me), 3.79–3.89 (m,
2 H, OCH2).
13C NMR (CDCl3, 100.5 MHz):  = –1.4 (q, SiMe3), 12.7 (q, Me), 18.9 (t,
CH2Si), 20.0 (q, Me), 29.3, 37.8 (q, s, tBu), 72.7 (t, OCH2), 148.9, 150.7,
152.4, 156.5 (4 s, C-2, C-4, C-5, C-6).
IR (Neat): 3065–2995 (=C–H, C–H), 1570–1465 cm–1 (C=N).
1H NMR (CDCl3, 400 MHz):  = 2.63 (s, 3 H, Me), 3.84 (s, 3 H, OMe),
7.17 (dd, J = 5.1, 3.8 Hz, 1 H, Thio), 7.23 (dd, J = 5.1, 4.0 Hz, 1 H, Thio),
7.54 (dd, J = 5.1, 1.2 Hz, 1 H, Thio), 7.59 (dd, J = 5.1, 1.3 Hz, 1 H, Thio),
8.06 (dd, J = 3.8, 1.2 Hz, 1 H, Thio), 8.45 (dd, J = 4.0, 1.3 Hz, 1 H, Thio).
HRMS (ESI-ToF): m/z [M + H]+ calcd for C15H29N2O2Si: 297.1993;
found: 297.1991.
4-tert-Butyl-6-methyl-2-phenyl-5-[2-(trimethylsilyl)ethoxy]py-
rimidine 1-Oxide (4p)
13C NMR (CDCl3, 100.5 MHz):  = 11.8 (q, Me), 61.2 (q, OMe), 126.6,
128.4, 129.5, 130.3, 131.9, 132.1, 132.2, 138.5 (2 s, 6 d, Thio), 141.2,
145.2, 147.5, 151.3 (4 s, C-2, C-4, C-5, C-6).
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C14H12N2NaO2S2: 327.0238;
found: 327.0244.
According to general procedure (GP1), -ketoenamide 3p (3.00 g, 8.27
mmol) and NH2OH·HCl (1.73 g, 24.9 mmol) in MeOH (200 mL) were
used; reaction time: 2 d. The crude product was purified by chroma-
tography (silica gel, hexanes/EtOAc, 3:1 to 1:1) to give 4p (3.01 g,
quant.) as a pale yellow oil.
5-(Benzyloxy)-4-tert-butyl-2-cyclopropyl-6-methylpyrimidine 1-
Oxide (4m)
IR (ATR): 3060–2850 (C–H), 1570 (C=C), 1485 cm–1 (C=N).
1H NMR (CDCl3, 400 MHz):  = 0.03 (s, 9 H, SiMe3), 1.19–1.24 (m, 2 H,
CH2Si), 1.35 (s, 9 H, tBu), 2.52 (s, 3 H, Me), 3.87–3.96 (m, 2 H, OCH2),
7.38–7.49, 8.48–8.56 (2 m, 3 H, 2 H, Ph).
13C NMR (CDCl3, 125.8 MHz):  = –1.3 (q, SiMe3), 12.8 (q, Me), 18.8 (t,
CH2Si), 29.1, 38.1 (q, s, tBu), 72.7 (t, OCH2), 127.7, 129.8, 130.2, 132.6
(3 d, s, Ph), 148.8, 148.9, 152.1, 156.5 (4 s, C-2, C-4, C-5, C-6).
According to general procedure (GP1), -ketoenamide 3m (1.37 g,
4.35 mmol) and NH2OH·HCl (0.907 g, 13.1 mmol) in MeOH (20 mL)
were used; reaction time: 2 d. The crude product was purified by
chromatography (silica gel, hexanes/EtOAc, 3:1 to 1:1) to give 4m
(0.520 g, 38%) as a pale yellow oil.
IR (ATR): 3090–2865 (C–H), 1525 (C=C), 1455 cm–1 (C=N).
HRMS (ESI-ToF): m/z [M + H]+ calcd for C20H31N2O2Si: 359.2149;
found: 359.2164.
1H NMR (CDCl3, 400 MHz):  = 1.05–1.15 (m, 4 H, cPr), 1.33 (s, 9 H,
tBu), 2.53 (s, 3 H, Me), 3.06–3.16 (m, 1 H, cPr), 4.84 (s, 2 H, OCH2),
7.30–7.50 (m, 5 H, Ph).
4-(1-Adamantyl)-2-cyclopropyl-6-methyl-5-[2-(trimethylsilyl)-
ethoxy]pyrimidine 1-Oxide (4q)
13C NMR (CDCl3, 100.5 MHz):  = 9.8 (t, CH2), 10.2 (d, CH), 12.6 (q,
Me), 29.0, 37.8 (q, s, tBu), 75.7 (t, OCH2), 126.9, 128.2, 128.5, 135.6 (3
d, s, Ph), 147.0, 150.3, 155.9, 156.1 (4 s, C-2, C-4, C-5, C-6).
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C19H24N2NaO2: 335.1730;
found: 335.1747.
According to general procedure (GP1), -ketoenamide 3q (0.379 g,
0.940 mmol) and NH2OH·HCl (0.196 g, 2.82 mmol) in MeOH (3 mL)
were used; reaction time: 1 d. The crude product was purified by
chromatography (silica gel, hexanes/EtOAc, 3:1 to 1:1) to give 4q
(0.313 g, 84%) as a pale yellow oil.
2,4-Dicyclopropyl-6-methyl-5-[2-(trimethylsilyl)ethoxy]pyrimi-
dine 1-Oxide (4n)
IR (ATR): 2950–2850 (C–H), 1530, 1465 cm–1 (C=C, C=N).
1H NMR (CDCl3, 400 MHz):  = 0.01 (s, 9 H, SiMe3), 1.02–1.11 (m, 4 H,
cPr), 1.17–1.25 (m, 2 H, CH2Si), 1.65–1.83, 1.93–2.12 (2 m, 6 H, 9 H,
adamantyl-CH, CH2), 2.51 (s, 3 H, Me), 3.06–3.16 (m, 1 H, cPr), 3.79–
3.89 (m, 2 H, OCH2).
13C NMR (CDCl3, 100.5 MHz):  = –1.5 (q, SiMe3), 9.8, 10.4 (t, d, cPr),
12.6 (q, Me), 18.7 (t, CH2Si), 28.6, 36.7, 40.0, 40.2 (d, 2 t, s, adamantyl),
72.8 (t, OCH2), 147.6, 150.6, 155.9, 156.0 (4 s, C-4, C-5, C-6, C-2).
According to general procedure (GP 1), -ketoenamide 3n (0.618 g,
2.00 mmol) and NH2OH·HCl (0.278 g, 4.00 mmol) in MeOH (5 mL)
were used; reaction time: 1 d. The crude product was purified by
chromatography (silica gel, hexanes/EtOAc, 3:1 to 1:1) to give 4n
(0.398 g, 65%) as a colorless oil.
IR (ATR): 3000–2850 (C–H), 1560 (C=C), 1480 cm–1 (C=N).
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HRMS (ESI-TOF): m/z [M + Na]+ calcd for C23H36N2O2SiNa: 423.2438;
found: 423.2467.
13C NMR (CDCl3, 125.8 MHz):  = 10.1, 10.2, 10.4 (3 t, CH2), 11.9, 12.1
(2 d, CH), 19.5 (q, Me), 29.6 (q, Me), 35.6 (q, MeCH), 62.1 (q, OMe),
147.5, 150.0, 155.0, 158.3 (4 s, C-2, C-4, C-5, C-6).
HRMS (ESI-ToF): m/z [M + H]+ calcd for C13H22N2O2: 237.1598; found:
(S)-4-tert-Butyl-5-[2-(dibenzylamino)propoxy]-2,6-dimethyl-
pyrimidine 1-Oxide (4r)
237.1591.
According to general procedure (GP1), -ketoenamide 3r (0.116 g,
0.265 mmol) and NH2OH·HCl (0.184 g, 2.65 mmol) in MeOH (5 mL)
were used; reaction time: 12 h at 80 °C. The crude product was puri-
fied by chromatography (silica gel, EtOAc/MeOH, 20:1) to give 4r
(0.045 g, 42%) as a yellow oil.
[]D22 –38.4 (c 0.31, CHCl3).
IR (ATR): 3080–2890 (C–H), 1570 (C=C), 1475 cm–1 (C=N).
1H NMR (CD3OD, 250 MHz):  = 1.22 (d, J = 6.3 Hz, 3 H, Me), 1.28 (s, 9
H, tBu), 2.31, 2.58 (2 s, 3 H each, Me), 3.24–3.39 (m, 1 H, CHN), 3.60 (d,
J = 14.3 Hz, 2 H, CH2Ph), 3.65–3.73 (m, 1 H, OCH2), 3.77 (d, J = 14.3 Hz,
2 H, CH2Ph), 3.90 (dd, J = 5.5, 8.7 Hz, 1 H, OCH2), 7.17–7.32, 7.37–7.44
(2 m, 6 H, 4 H, Ph).
13C NMR (CD3OD, 100.5 MHz):  = 11.3, 23.5, 27.7 (3 q, Me), 29.1, 37.6
(q, s, tBu), 52.8 (t, CHN), 54.4 (t, CH2Ph), 76.9 (t, OCH2), 127.0, 128.3,
128.8, 140.2 (3 d, s, Ph), 148.8, 150.4, 152.3, 155.8 (4 s, C-2, C-3. C-4,
C-5).
6-Benzyl-4-tert-butyl-5-methoxy-2-(trifluoromethyl)pyrimidine
1-Oxide (4u)
According to general procedure (GP 1), -ketoenamide 8a (0.036 g,
0.105 mmol) and NH2OH·HCl (0.073 g, 1.05 mmol) in MeOH (10 mL)
were used; reaction time: 7 d at 60 °C. The crude product was puri-
fied by chromatography (silica gel, hexanes/EtOAc, 10:1 to 4:1) to give
4u (0.020 g, 56%) as a yellow oil and precursor 8a (0.013 g, 35%).
IR (ATR): 3090–2870 (C–H), 1600 (C=C), 1480 cm–1 (C=N).
1H NMR (CDCl3, 500 MHz):  = 1.41 (s, 9 H, tBu), 3.82 (s, 3 H, OMe),
4.37 (s, 2 H, CH2), 7.20–7.24, 7.27–7.28 (2 m, 1 H, 4 H, Ph).
13C NMR (CDCl3, 100.5 MHz):  = 29.1 (q, tBu), 30.8 (t, CH2), 38.3 (s,
tBu), 63.5 (q, OMe), 127.2, 128.7, 128.9, 135.1 (3 d, s, Ph), 153.9, 155.2,
156.9 (3 s, C-4, C-5, C-6); the signals of CF3 and C-2 cannot be as-
signed unambiguously due to CF couplings.
19F NMR (471 MHz, CDCl3):  = –70.28 (s, 3 F, CF3).
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C17H19F3N2NaO2: 363.1296;
HRMS (ESI-ToF): m/z [M + H]+ calcd for C27H36N3O2: 434.2802; found:
437.2827.
found: 363.1309.
(S)-4-tert-Butyl-2-(1-hydroxyethyl)-5-methoxy-6-methylpyrimi-
dine 1-Oxide (4s)
N-[(E)-1-tert-Butyl-2-methoxy-3-oxo-4-(4-fluorophenyl)but-1-
enyl]-2,2,2-trifluoroacetamide (8b)
According to general procedure (GP 1), -ketoenamide 3s (0.068 g,
0.190 mmol) and NH2OH·HCl (0.066 g, 0.949 mmol) in MeOH (3 mL)
were used; reaction time: 12 h. The crude product was purified by
chromatography (silica gel, hexanes/EtOAc, 2:1) to give 4s (0.013 g,
30%) as a colorless oil.
[]D22 +6.0 (c 0.43, CHCl3).
IR (neat): 3335 (O–H), 2965–2880 (C–H), 1625–1465 cm–1 (C=C, C=N).
1H NMR (CDCl3, 500 MHz):  = 1.38 (s, 9 H, tBu), 1.62 (d, J = 6.6 Hz, 3
H, MeCH), 2.52 (s, 3 H, Me), 3.80 (s, 3 H, OMe), 5.15–5.41 (m, 1 H,
CHMe).
13C NMR (CDCl3, 125.8 MHz):  = 12.1 (q, Me), 18.7 (q, MeCH), 29.0,
38.1 (q, s, tBu), 62.0 (q, OMe), 67.1 (d, CHMe), 150.8, 151.3, 154.3,
157.4 (4 s, C-2, C-4, C-5, C-6).
In a flame-dried flask under argon atmosphere, propargyl ether 7b
(0.300 g, 1.83 mmol) was dissolved in Et2O (14 mL) and treated with
n-BuLi (0.77 mL, 1.92 mmol) at –40 °C for 30 min. Pivalonitrile (0.228
g, 2.74 mmol) was added and after 15 min the mixture was cooled to
–78 °C. Trifluoroacetic acid (0.32 mL, 4.20 mmol) was added and the
mixture was allowed to warm up to rt within 19 h. Sat. aq NaHCO3
solution was added (15 mL), the phases were separated and the aque-
ous phase was extracted with CH2Cl2 (2 × 15 mL). The combined or-
ganic phases were dried (Na2SO4) and concentrated in vacuo. The
crude product was purified by column chromatography (silica gel,
hexanes/EtOAc, 10:1 to 4:1) to furnish 8b (0.239 g, 36%) as a colorless
solid.
IR (ATR): 3285 (N–H), 3045–2845 (=C–H, C–H), 1720, 1700, 1535,
1510 cm–1 (C=O, C=C, C–N).
1H NMR (CDCl3, 500 MHz):  = 1.20 (s, 9 H, tBu), 3.53 (s, 3 H, OMe),
3.90 (s, 2 H, CH2), 6.96–7.01, 7.12–7.16 (2 m, 2 H each, Ar), 7.56 (br s,
1 H, NH).
13C NMR (CDCl3, 125.8 MHz):  = 28.4, 36.6 (q, s, tBu), 45.6 (t, CH2),
59.4 (q, OMe), 115.4 (dd, JCF = 21.7 Hz, Ar), 115.8 (q, JCF = 288.6 Hz,
CF3), 128.9 (d, JCF = 3.1 Hz, Ar), 130.2 (s, C-1), 131.4 (dd, JCF = 8.1 Hz,
Ar), 151.8 (s, C-2), 156.7 (q, JCF = 37.1 Hz, CF3CO), 162.1 (d, JCF = 245.5
Hz, Ar), 200.0 (d, JCF = 1.0 Hz, C-3).
19F NMR (CDCl3, 471 MHz):  = –115.7 (mc, 1 F, Ar-F), –75.9 (s, 3 F,
CF3).
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C17H19F4NO3Na: 384.1193;
found: 384.1206.
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C12H20N2O2SiNa: 263.1376;
found: 263.1377.
(S)-4-Butan-2-yl-2-cyclopropyl-5-methoxy-6-methylpyrimidine
1-Oxide (4t)
According to general procedure (GP1), -ketoenamide 3t (0.182 g,
0.762 mmol) and NH2OH·HCl (0.530 g, 7.62 mmol) in MeOH (20 mL)
were used; reaction time: 12 h at 80 °C. The crude product was puri-
fied by chromatography (silica gel, hexanes/EtOAc, 4:1 to 1:1) to give
4t (0.072 g, 40%) as a colorless oil.
IR (neat): 2995–2885 (C–H), 1615–1495 cm–1 (C=C, C=N).
1H NMR (CDCl3, 400 MHz):  = 0.77 (t, J = 7 Hz, 3 H, Me), 1.05–1.17,
1.48–1.56, 1.63–1.72 (3 m, 7 H, 1 H, 1 H, Me, 3xCH2), 2.51 (s, 3 H, Me),
2.99 (sext, J = 6.8 Hz, 1 H, CH), 3.10–3.15 (m, 1 H, CH), 3.72 (s, 3 H,
OMe).
Anal. Calcd for C17H19F4NO3 (361.3): C, 56.51; H, 5.30; N, 3.88. Found:
C, 56.48; H, 5.28; N, 3.79.
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Synthesis
4-tert-Butyl-6-(4-fluorobenzyl)-5-methoxy-2-(trifluoromethyl)-
pyrimidine 1-Oxide (4v)
IR (ATR): 3085–2870 (=C–H, C–H), 1755 (C=O), 1560 (C=C), 1455 cm–1
(C=N).
1H NMR (CDCl3, 400 MHz):  = 1.05–1.15, 1.20–1.33 (2 m, 2 H each,
CH2), 2.18 (s, 3 H, Me), 2.31–2.44 (m, 1 H, CH), 3.89 (s, 3 H, OMe), 5.26
(s, 2 H, OCH2), 7.46–7.61, 8.12–8.28 (2 m, 2 H each, Aryl).
13C NMR (CDCl3, 125.8 MHz):  = 11.1, 11.15 (2 t, CH2), 20.9 (q, Me),
61.8 (t, OCH2), 62.0 (q, OMe), 124.7, 129.6, 131.4, 136.5 (s, 2 d, s, Aryl),
149.4, 154.9, 158.2, 165.2 (4 s, C-2, C-4, C-5, C-6), 170.6 (s, CO2).
According to general procedure (GP1), -ketoenamide 8b (0.100 g,
0.291 mmol) and NH2OH·HCl (0.202 g, 2.91 mmol) were dissolved in
MeOH (25 mL); reaction time: 7 d at 60 °C. The crude product was
purified by chromatography (silica gel, hexanes/EtOAc, 10:1 to 4:1) to
give 4v (0.052 g, 53%) as a yellow oil and precursor 8b (0.041 g, 41%).
IR (KBr): 3075–2875 (=C–H, C–H), 1605, 1580, 1510, 1480, 1460 cm–1
(C=C, C=N).
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C17H17BrN2NaO3: 399.0315;
found: 399.0326.
1H NMR (CDCl3, 500 MHz):  = 1.41 (s, 9 H, tBu), 3.84 (s, 3 H, OMe),
4.32 (s, 2 H, CH2), 6.93–6.98, 7.25–7.30 (2 m, 2 H each, Ar).
13C NMR (CDCl3, 125.8 MHz):  = 29.1 (q, tBu), 30.0 (t, CH2), 38.4 (s,
tBu), 63.5 (q, OMe), 115.7 (dd, JCF = 21.7 Hz, Ar), 130.4 (dd, JCF = 8.0 Hz,
Ar), 130.7 (d, JCF = 3.1 Hz, Ar), 153.8, 155.1, 157.1 (3 s, C-4, C-5, C-6),
162.0 (d, JCF = 245.7 Hz, Ar); the signals of CF3 and C-2 cannot be as-
signed unambiguously due to CF couplings.
(6-tert-Butyl-2-cyclopropyl-5-methoxypyrimidin-4-yl)methyl
Acetate (10b)
According to general procedure (GP 2, method A), pyrimidine N-oxide
4f (1.00 g, 4.23 mmol), and Ac2O (10 mL) afforded after purification by
flash chromatography (silica gel, hexanes/EtOAc, 8:1) compound 10b
(0.920 g, 78%) as a colorless oil.
19F NMR (CDCl3, 471 MHz):  = –115.3 (mc, 1 F, Ar-F), –70.3 (s, 3 F,
IR (ATR): 3090–2870 (=C–H, C–H), 1560 (C=C), 1450 cm–1 (C=N).
CF3).
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C17H18F4N2O2Na: 381.1197;
found: 381.1218.
1H NMR (CDCl3, 400 MHz):  = 0.92–0.97, 0.99–1.05 (2 m, 2 H each,
CH2), 1.32 (s, 9 H, tBu), 2.12–2.20 (m, 4 H, CH, Me), 3.73 (s, 3 H, OMe),
5.15 (s, 2 H, OCH2).
2-Benzyl-4-tert-butyl-5-methoxy-6-methylpyrimidine (9)
13C NMR (CDCl3, 125.8 MHz):  = 10.4 (t, CH2), 17.7 (d, CH), 20.9 (q,
Me), 29.2, 38.2 (q, s, tBu), 61.8 (t, OCH2), 62.7 (q, OMe), 149.6, 155.9,
165.2, 169.2 (4 s, C-2, C-4, C-5, C-6), 170.8 (s, CO2).
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C15H22N2NaO3: 301.1523;
found: 301.1534.
To a solution of pyrimidine N-oxide 4e (0.045 g, 0.167 mmol) in
MeOH (2 mL) was added Pd/C (0.017 g, 0.042 mmol, 25% on charcoal)
and the resulting mixture was bubbled with H2 gas for 15 min. After
that the mixture was stirred for 24 h under H2 atmosphere. Metal res-
idue was filtered with a small silica gel pad and concentrated to give
pyrimidine 9 (0.024 g, 50%) as a colorless oil.
Anal. Calcd for C15H22N2O3 (278.4): C, 64.73; H, 7.97; N, 10.06. Found:
C, 64.82; H, 7.78; N, 9.97.
IR (ATR): 3065–2870 (=C–H, C–H), 1555–1375 cm–1 (C=N).
1H NMR (CDCl3, 400 MHz):  = 1.38 (s, 9 H, tBu), 2.46 (s, 3 H, Me), 3.73
(s, 3 H, OMe), 4.16 (s, 2 H, CH2Ph), 7.17–7.21 (m, 1 H, Ph), 7.26–7.30
(m, 2 H, Ph), 7.43–7.45 (m, 2 H, Ph).
13C NMR (CDCl3, 100.5 MHz):  = 19.7 (q, Me), 29.3, 38.0 (q, s, tBu),
45.4 (t, CH2Ph), 60.9 (q, OMe), 126.2, 128.2, 129.3, 139.2 (3 d, s, Ph),
150.3, 160.2, 162.4, 168.1 (4 s, C-2, C-4, C-5, C-6).
(2,6-Di-tert-butyl-5-methoxypyrimidin-4-yl)methyl Acetate (10c)
According to general procedure (GP 2, method A), pyrimidine N-oxide
4g (0.320 g, 1.29 mmol), and Ac2O (10 mL) afforded after purification
by flash chromatography (silica gel, hexanes/EtOAc, 10:1) compound
10c (0.330 g, 87%) as pale yellow crystals; mp 69.5–72 °C.
IR (ATR): 3020–2870 (=C–H, C–H), 1750 (C=O), 1545 (C=C), 1450 cm–1
(C=N).
HRMS (ESI-ToF): m/z [M + H]+ calcd for C17H23N2O: 271.1810; found:
271.1810.
1H NMR (CDCl3, 500 MHz):  = 1.34 (s, 9 H, tBu), 1.38 (s, 9 H, tBu), 2.18
(s, 3 H, Me), 3.78 (s, 3 H, OMe), 5.28 (s, 2 H, OCH2).
General Procedure for the Reaction of Pyrimidine N-Oxides 4 with
Acetic Anhydride (GP 2)
13C NMR (CDCl3, 125.8 MHz):  = 20.9 (q, Me), 29.4, 29.8, 38.4, 39.2 (2
q, 2 s, tBu), 61.8 (q, OMe), 62.3 (t, OCH2), 149.0, 155.7, 168.0, 170.3 (4
s, C-2, C-4, C-5, C-6), 170.9 (s, C=O).
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C16H26N2NaO3: 317.1835;
found: 317.1829.
Method A: In an ACE sealed tube, pyrimidine N-oxide 4 was dissolved
in Ac2O and the solution was heated at reflux at 120 °C for 3 h. After
cooling to rt, the excess Ac2O was removed under reduced pressure.
Purification of the crude product by column chromatography (silica
gel, hexanes/EtOAc) provided the rearranged product 10.
(6-tert-Butyl-5-methoxy-2-phenylpyrimidin-4-yl)methyl Acetate
(10d)
Method B: In an ACE sealed tube, pyrimidine N-oxide 4 (1 equiv) was
dissolved in benzene and Ac2O (3 equiv) was added. The solution was
heated at reflux at 90 °C for 3 h. After cooling to rt, Ac2O and benzene
were removed under reduced pressure. Purification of the crude
product by column chromatography (silica gel, hexanes/EtOAc) pro-
vided the rearranged product 10.
According to general procedure (GP 2, method A), pyrimidine N-oxide
4i (0.878 g, 3.22 mmol), and Ac2O (10 mL) afforded after purification
by flash chromatography (silica gel, hexanes/EtOAc, 8:1) compound
10d (0.699 g, 69%) as colorless crystals and compound 11d (0.028 g,
3%) as a colorless oil.
[2-(4-Bromophenyl)-6-cyclopropyl-5-methoxypyrimidin-4-yl]-
methyl Acetate (10a)
Compound 10d
Mp 59–61 °C.
According to general procedure (GP 2, method A), pyrimidine N-oxide
4c (0.071 g, 0.212 mmol), and Ac2O (2 mL) afforded after purification
by flash chromatography (silica gel, hexanes/EtOAc, 4:1) compound
10a (0.053 g, 66%) as a pale yellow oil.
IR (ATR): 2960–2865 (=C–H, C–H), 1750 (C=O), 1550 (C=C), 1450 cm–1
(C=N).
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1H NMR (CDCl3, 400 MHz):  = 1.48 (s, 9 H, tBu), 2.22 (s, 3 H, Me), 3.84
(s, 3 H, OMe), 5.32 (s, 2 H, OCH2), 7.43–7.62, 8.40–8.43 (2 m, 2 H, 3 H,
Ph).
13C NMR (CDCl3, 100.5 MHz):  = 20.9 (q, Me), 29.2, 38.4 (q, s, tBu),
61.7 (t, OCH2), 62.6 (q, OMe), 128.0, 128.3, 129.9, 137.7 (3 d, s, Ph),
150.4, 156.6, 157.8, 169.2 (4 s, C-2, C-4, C-5, C-6), 170.8 (s, C=O).
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C16H14N2NaO3S2: 369.0338;
found: 369.0334.
Anal. Calcd for C16H14N2O3S2 (346.4): C, 55.47; H, 4.07; N, 8.09; S,
18.51. Found: C, 55.06; H, 4.00; N, 7.94; S, 18.44.
[5-(Benzyloxy)-6-tert-butyl-2-cyclopropylpyrimidin-4-yl]methyl
Acetate (10g)
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C18H22N2NaO3: 337.1528;
found: 337.1540.
According to general procedure (GP 2, method A), pyrimidine N-oxide
4m (0.507 g, 1.62 mmol), and Ac2O (5 mL) afforded after purification
by flash chromatography (silica gel, hexanes/EtOAc, 6:1) compound
10g (0.363 g, 60%) and 11g (0.028 g, 5%) as pale yellow oils.
4-tert-Butyl-6-ethyl-5-methoxy-2-phenylpyrimidine (11d)
IR (ATR): 3090–2870 (=C–H, C–H), 1545 (C=C), 1445 cm–1 (C=N).
Compound 10g
1H NMR (CDCl3, 400 MHz):  = 1.55 (t, J = 7.5 Hz, 3 H, Me), 1.58 (s, 9 H,
tBu), 2.93 (q, J = 7.5 Hz, 2 H, CH2), 3.80 (s, 3 H, OMe), 7.45–7.56, 8.58–
8.62 (2 m, 2 H, 3 H, Ph).
IR (ATR): 3085–2845 (=C–H, C–H), 1740 (C=O), 1570 (C=C), 1455 cm–1
(C=N).
13C NMR (CDCl3, 125.8 MHz):  = 12.3 (q, Me), 25.2 (t, CH2), 29.6, 38.3
(q, s, tBu), 61.8 (q, OMe), 128.2, 128.5, 129.8, 138.5 (3 d, s, Ph), 150.6,
157.6, 164.7, 167.9 (4 s, C-2, C-4, C-5, C-6).
1H NMR (CDCl3, 400 MHz):  = 0.97–1.01, 1.05–1.08 (2 m, 2 H each,
CH2), 1.38 (s, 9 H, tBu), 2.14 (s, 3 H, Me), 2.16–2.23 (m, 1 H, CH), 4.89,
5.18 (2 s, 2 H each, OCH2), 7.33–7.48 (m, 5 H, Ph).
HRMS (ESI-ToF): m/z [M + H]+ calcd for C17H23N2O: 271.1810; found:
271.1791.
13C NMR (CDCl3, 100.5 MHz):  = 10.3 (t, CH2), 17.6 (d, CH), 20.7 (q,
Me), 29.3, 38.2 (q, s, tBu), 61.7 (t, OCH2), 76.7 (t, OCH2), 127.1, 128.2,
128.6, 136.2 (3 d, s, Ph), 148.0, 156.3, 165.2, 169.2 (4 s, C-2, C-4, C-5,
C-6), 170.6 (s, CO2).
[6-(1-Adamantyl)-2-cyclopropyl-5-methoxypyrimidin-4-yl]meth-
yl Acetate (10e)
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C21H26N2NaO3: 377.1836;
found: 377.1826.
According to general procedure (GP 2, method A), pyrimidine N-oxide
4j (0.520 g, 1.66 mmol), and Ac2O (3 mL) afforded after purification by
flash chromatography (silica gel, hexanes/EtOAc, 3:1) compound 10e
(0.527 g, 89%) as pale yellow crystals; mp 98 °C.
IR (ATR): 2940–2850 (=C–H, C–H), 1750 (C=O), 1555 (C=C), 1430 cm–1
(C=N).
1H NMR (CDCl3, 400 MHz):  = 0.91–1.10 (m, 4 H, cPr), 1.70–1.80,
2.03–2.10 (2 m, 6 H, 9 H, adamantyl-CH, -CH2), 2.12–2.21 (m, 4 H, cPr,
Me), 3.73 (s, 3 H, OMe), 5.15 (s, 2 H, OCH2).
13C NMR (CDCl3, 100.5 MHz):  = 10.3, 17.7 (t, d, cPr), 20.9 (q, Me),
28.6, 36.8, 40.0, 40.6 (d, 2 t, s, adamantyl), 61.7 (t, CH2O), 62.9 (q,
OMe), 149.9, 156.0, 165.2, 168.4 (4 s, C-2, C-4, C-5, C-6), 170.7 (s,
C=O).
5-(Benzyloxy)-4-tert-butyl-2-cyclopropyl-6-ethylpyrimidine (11g)
IR (ATR): 3070–2860 (=C–H, C–H), 1570 (C=C), 1460 cm–1 (C=N).
1H NMR (CDCl3, 400 MHz):  = 0.94–0.98, 1.06–1.10 (2 m, 2 H each,
CH2), 1.30 (t, J = 7 Hz, 3 H, Me), 1.38 (s, 9 H, tBu), 2.12–2.19 (m, 1 H,
CH), 2.78 (q, J = 7 Hz, 2 H, CH2), 4.82 (s, 2 H, OCH2), 7.34–7.49 (m, 5 H,
Ph).
13C NMR (CDCl3, 100.5 MHz):  = 10.2 (t, CH2), 12.2 (q, Me), 17.0 (d,
CH), 25.8 (t, CH2), 29.5, 37.3 (q, s, tBu), 75.8 (t, OCH2), 127.1, 128.2,
128.7, 136.2 (3 d, s, Ph), 147.5, 164.6, 164.8, 168.1 (4 s, C-2, C-4, C-5,
C-6).
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C20H26N2NaO: 333.1937;
found: 333.1920.
HRMS (ESI-ToF): m/z [M + H]+ calcd for C21H29N2O3: 357.2178; found:
357.2195.
{6-tert-Butyl-2-phenyl-5-[2-(trimethylsilyl)ethoxy]pyrimidin-4-
yl}methyl Acetate (10h)
Anal. Calcd for C21H28N2O3 (356.5): C, 70.76; H, 7.92; N, 7.86. Found:
C, 70.76; H, 7.91; N, 7.86.
According to general procedure (GP 2, method A), pyrimidine N-oxide
4p (0.132 g, 0.368 mmol), and Ac2O (1 mL) afforded after purification
by flash chromatography (silica gel, hexanes/EtOAc, 4:1) compound
10h (0.139 g, 94%) as a pale yellow oil.
IR (ATR): 3070–2920 (=C–H, C–H), 1755 (C=O), 1560 (C=C), 1460 cm–1
(C=N).
[5-Methoxy-2,6-di(2-thienyl)pyrimidin-4-yl]methyl Acetate (10f)
According to general procedure (GP 2, method B), pyrimidine N-oxide
4l (0.052 g, 0.171 mmol) and Ac2O (0.1 mL) in benzene (2 mL) afford-
ed after purification by flash chromatography (silica gel, hex-
anes/EtOAc, 4:1 to 3:1) compound 10f (0.040 g, 67%) as a colorless oil.
IR (Neat): 3020–2990 (=C–H, C–H), 1740 (C=O), 1550–1750 cm–1
(C=C).
1H NMR (CDCl3, 400 MHz):  = 2.24 (s, 3 H, Me), 3.85 (s, 3 H, OMe),
5.33 (s, 2 H, OCH2), 7.12 (dd, J = 5.0, 3.6 Hz, 1 H, Thio), 7.19 (dd, J = 5.0,
3.8 Hz, 1 H, Thio), 7.43 (dd, J = 5.0, 1.2 Hz, 1 H, Thio), 7.58 (dd, J = 5.0,
1.2 Hz, 1 H, Thio), 7.95 (dd, J = 3.6, 1.2 Hz, 1 H, Thio), 8.14 (dd, J = 3.8,
1.2 Hz, 1 H, Thio).
1H NMR (CDCl3, 400 MHz):  = 0.05 (s, 9 H, SiMe3), 1.21–1.28 (m, 2 H,
CH2Si), 1.47 (s, 9 H, tBu), 2.21 (s, 3 H, Me), 3.87–3.96 (m, 2 H, OCH2),
5.27 (s, 2 H, OCH2), 7.40–7.47, 8.37–8.43 (2 m, 3 H, 2 H, Ph).
13C NMR (CDCl3, 100.5 MHz):  = –1.5 (q, SiMe3), 18.9 (t, CH2Si), 20.9
(q, Me), 29.2, 38.4 (q, s, tBu), 61.8 (t, OCH2), 73.5 (t, OCH2), 128.0,
128.3, 129.8, 137.8 (3 d, s, Ph), 149.1, 156.8, 157.6, 169.3 (4 s, C-2, C-4,
C-5, C-6), 170.7 (s, CO2).
13C NMR (CDCl3, 100.5 MHz):  = 20.9 (q, Me), 61.2 (q, OMe), 61.5 (t,
OCH2), 128.2, 128.4, 128.8, 129.6, 131.0, 131.1, 138.5, 142.9 (2 s, 6 d,
Thio), 145.7, 152.2, 156.5, 158.3 (4 s, C-2, C-4, C-5, C-6), 170.8 (s, CO2).
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C22H32N2NaO3Si: 423.2074;
found: 423.2080.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N

L
L. Schefzig et al.
Paper
Synthesis
{6-(1-Adamantyl)-2-cyclopropyl-5-[2-(trimethylsilyl)ethoxy]-
pyrimidin-4-yl}methyl Acetate (10i)
EtOAc, 4:1) an inseparable mixture of compounds 10l and 10m
(0.463 g, 64%; 1:1) as a pale yellow oil.
IR (ATR): 3030–2850 (C–H), 1740 (C=O), 1560 (C=C), 1450 cm–1 (C=N).
According to general procedure (GP 2, method B), pyrimidine N-oxide
4q (0.041 g, 0.102 mmol), and Ac2O (0.5 mL) dissolved in benzene (2
mL) afforded after purification by flash chromatography (silica gel,
hexanes/EtOAc, 6:1) compound 10i (0.043 g, 95%) as a colorless oil.
IR (ATR): 3010–2845 (=C–H, C–H), 1750 (C=O), 1560 (C=C), 1430 cm–1
(C=N).
1H NMR (CDCl3, 500 MHz):  = 1.24, 1.25 (2 d, J = 6.3 Hz, 3 H, Me),
1.29, 1.30 (2 s, 9 H, tBu), 2.14, 2.19 (2 s, 3 H, Me), 2.34, 2.63 (2 s, 3 H,
Me), 3.26–3.38 (m, 1 H, CHN), 3.62 (d, J = 14.0 Hz, 2 H, CH2Ph), 3.68–
3.99 (m, 4 H, OCH2, CH2Ph), 5.01, 5.08 (AB system, JAB = 12.7 Hz, 1 H,
OCH2), 5.19 (s, 1 H, OCH2), 7.17–7.43 (m, 10 H, Ph).
1H NMR (CDCl3, 400 MHz):  = 0.04 (s, 9 H, SiMe3), 0.91–1.08, 1.18–
1.27 (2 m, 4 H, 2 H each, cPr, CH2Si), 1.70–1.78, 2.03–2.10 (2 m, 6 H, 9
H, adamantyl-CH, CH2), 2.04–2.20 (m, 4 H, cPr, Me), 3.78–3.88 (s, 2 H,
CH2O), 5.11 (s, 2 H, OCH2).
13C NMR (CDCl3, 100.5 MHz):  = –1.5 (q, SiMe3), 10.3, 17.6 (t, d, cPr),
28.6, 36.8, 40.0, 40.6 (d, 2 t, s, adamantyl), 61.8 (t, CH2O), 73.8 (t,
CH2O), 148.6, 156.2, 165.0, 168.6 (4 s, C-2, C-4, C-5, C-6), 170.7 (s,
C=O).
13C NMR (CDCl3, 100.5 MHz):  = 11.6, 11.7, 19.7, 20.8, 20.9, 25.5 (6 q,
Me), 29.1, 29.2, 37.9, 38.0 (2 q, 2 s, tBu), 52.6 (d, CHN), 54.2, 54.3 (2 t,
CH2Ph), 61.6, 66.0 (2 t, OCH2), 75.8, 78.0 (2 t, OCH2), 126.9, 128.3,
128.4, 128.7, 139.9, 140.0 (4 d, 2 s, Ph), 148.5, 149.8, 156.2, 157.0,
160.8, 161.5, 168.3, 169.4 (8 s, C-2, C-4, C-5, C-6), 170.5, 170.8 (2 s,
CO2).
HRMS (ESI-ToF): m/z [M + H]+ calcd for C29H36N3O3: 476.2908; found:
476.2912.
HRMS (ESI-ToF): m/z [M + H]+ calcd for C25H39N2O3Si: 443.2724;
found: 443.2739.
[6-tert-Butyl-5-methoxy-2-(trifluoromethyl)pyrimidin-4-yl](phe-
nyl)methyl Acetate (10n)
(2-Benzyl-6-tert-butyl-5-methoxypyrimidin-4-yl)methyl Acetate
(10j) and (4-tert-Butyl-5-methoxy-6-methylpyrimidin-2-yl)(phe-
nyl)methyl Acetate (10k)
According to general procedure (GP 2, method A, reaction time: 1 d),
pyrimidine N-oxide 4u (0.236 g, 0.693 mmol), and Ac2O (2 mL) afford-
ed after purification by flash chromatography (silica gel, hex-
anes/EtOAc, 10:1) compound 10n (0.192 g, 73%) as a pale yellow oil.
According to general procedure (GP 2, method B), pyrimidine N-oxide
4e (0.200 g, 1.00 mmol), and Ac2O (0.66 mL) in benzene (5 mL) afford-
ed after purification by flash chromatography (silica gel, hexanes/
EtOAc, 4:1) compound 10j and 10k (0.201 g, 87%, 2 isomers = 1:1) as a
pale yellow oil. A sample of the mixture was separated by a second
flash chromatography.
IR (ATR): 3030–2855 (=C–H, C–H), 1545–1520 cm–1 (C=C, C=N).
1H NMR (CDCl3, 400 MHz):  = 1.40 (s, 9 H, tBu), 2.19 (s, 3 H, Me), 3.95
(s, 3 H, OMe), 6.95 (s, 1 H, OCH), 7.33–7.39, 7.52–7.56 (2 m, 3 H, 2 H,
Ph).
13C NMR (CDCl3, 100.5 MHz):  = 21.1 (q, Me), 29.3, 38.7 (q, s, tBu),
1
63.0 (q, OMe), 72.3 (d, 6-CH), 119.7 (q, JCF = 275 Hz, CF3), 128.1,
Compound 10j
2
128.8, 129.2, 136.2 (3 d, s, Ph), 150.2 (q, JCF = 36.7 Hz, C-2), 152.1,
IR (ATR): 2995–2870 (C–H), 1735 (C=O), 1560 (C=C), 1440 cm–1 (C=N).
161.5, 171.0 (3 s, C-4, C-5, C-6), 171.9 (s, C=O).
19F NMR (CDCl3, 470 MHz):  = –69.5 (s, CF3).
HRMS (ESI-ToF): m/z [M + Na]+ calcd for C19H21F3N2NaO3: 405.1396;
found: 405.1404.
1H NMR (CDCl3, 500 MHz):  = 1.37 (s, 9 H, tBu), 2.11 (s, 3 H, Me), 3.77
(s, 3 H, OMe), 4.19 (s, 2 H, CH2), 5.18 (s, 2 H, OCH2), 7.17–7.30, 7.37–
7.40 (2 m, 3 H, 2 H, Ph).
13C NMR (CDCl3, 125.8 MHz):  = 20.9 (q, Me), 29.3, 38.3 (q, s, tBu),
45.3 (t, CH2), 61.7 (t, OCH2), 62.7 (q, OMe), 126.3, 128.2, 129.4, 138.9
(3 d, s, Ph), 150.1, 156.4, 163.1, 169.6 (4 s, C-2, C-4, C-5, C-6), 170.8 (s,
CO2).
[6-(1-Adamantyl)-2-cyclopropyl-5-methoxypyrimidin-4-yl]meth-
anol (12a)
To a solution of 10e (0.456 g, 1.28 mmol) in MeOH/CH2Cl2 (10:1 mL)
was added K2CO3 (0.708 g, 5.12 mmol) at rt and the mixture was
stirred for 3 h. After filtration, the solvent was removed under re-
duced pressure. The residue was purified by flash chromatography
(silica gel, hexanes/EtOAc, 3:1) to afford 12a (0.280 g, 70%) as color-
less crystals; mp 127 °C.
HRMS (ESI-ToF): m/z [M + H]+ calcd for C19H25N2O3: 329.1860; found:
329.1879.
Compound 10k
IR (ATR): 3030–2870 (C–H), 1745 (C=O), 1545 (C=C), 1460 cm–1 (C=N).
1H NMR (CDCl3, 500 MHz):  = 1.37 (s, 9 H, tBu), 2.20 (s, 3 H, Me), 2.45
(s, 3 H, Me), 3.73 (s, 3 H, OMe), 6.67 (s, 1 H, OCH), 7.25–7.35, 7.56–
7.58 (2 m, 3 H, 2 H, Ph).
13C NMR (CDCl3, 125.8 MHz):  = 19.8, 21.3 (2 q, 2 Me), 29.3, 38.1 (q, s,
tBu), 61.0 (q, OMe), 78.3 (d, OCH), 127.9, 128.3, 128.4, 138.3 (3 d, s,
Ph), 150.8, 159.8, 160.8, 168.2 (4 s, C-2, C-4, C-5, C-6), 170.6 (s, CO2).
IR (ATR): 3175 (O–H), 2930–2845 (C–H), 1565 (C=C), 1455 cm–1
(C=N).
1H NMR (CDCl3, 400 MHz):  = 0.94–1.00, 1.03–1.10 (2 m, 2 H each,
cPr), 1.69–1.79, 1.98–2.10 (2 m, 6 H, 9 H, adamantyl-CH, -CH2), 2.14–
2.23 (m, 1 H, cPr), 3.68 (s, 3 H, OMe), 4.19 (br s, 1 H, OH), 4.69 (s, 2 H,
CH2O).
HRMS (ESI-ToF): m/z [M + H]+ calcd for C19H25N2O3: 329.1860; found:
329.1900.
13C NMR (CDCl3, 100.5 MHz):  = 10.3, 17.6 (t, d, cPr), 28.6, 36.8, 40.0,
40.4 (d, 2 t, s, adamantyl), 59.3 (q, OMe), 61.8 (t, CH2O), 148.3, 159.5,
164.4, 167.5 (4 s, C-2, C-4, C-5, C-6).
HRMS (ESI-ToF): m/z [M + H]+ calcd for C19H27N2O2: 315.2072; found:
315.2082.
{(S)-6-tert-Butyl-5-[2-(dibenzylamino)propoxy]-2-methylpyrimi-
din-4-yl}methyl Acetate (10l) and {(S)-6-tert-Butyl-5-[2-(dibenzyl-
amino)propoxy]-4-methylpyrimidin-2-yl}methyl Acetate (10m)
Anal. Calcd for C19H26N2O2 (314.4): C, 72.58; H, 8.33; N, 8.91. Found:
C, 72.56; H, 8.23; N, 8.95.
According to general procedure (GP 2, , method B), pyrimidine N-ox-
ide 4r (0.520 g, 1.51 mmol), and Ac2O (1 mL) in benzene (5 mL) afford-
ed after purification by flash chromatography (silica gel, hexanes/
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N

M
L. Schefzig et al.
Paper
Synthesis
(6-tert-Butyl-5-methoxy-2-phenylpyrimidin-4-yl)methanol (12b)
Funding Information
Method A: To a solution of 10d (0.716 g, 2.25 mmol) in MeOH (15 mL)
was added K2CO3 (1.18 g, 8.53 mmol) at rt and the mixture was
stirred for 3 h. After filtration, the solvent was removed under re-
duced pressure. The residue was purified by flash chromatography
(silica gel, hexane/EtOAc, 3:1) to afford 12b (0.465 g, 76%) as a color-
less oil.
This work was generously supported by the Deutsche Forschungs-
gemeinschaft and BayerHealthCare.
B
ayer
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ealhtCare()D
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tsch
e
Forsch
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n
gsgemeinschaft()
Acknowledgment
Method B: To a solution of pyrimidine N-oxide 4i (0.430 g, 1.58 mmol)
in CH2Cl2 (10 mL) was added TFAA (1 mL) and the solution was stirred
at rt for 3 h. The excess TFAA and the solvent were removed under
reduced pressure. Purification of the crude product by column chro-
matography (silica gel, hexanes/EtOAc, 5:1) provided 12b (0.364 g,
85%) as a colorless oil.
We thank Evrim Altay, Giacomo Cassará, Gianmarco Paternicó, Emilio
Balcazar-Pust, and Dr. Roopender Kumar for experimental help.
Supporting Information
Supporting information for this article is available online at
IR (ATR): 3450 (O–H), 3090–2865 (=CH, C–H), 1555–1450 cm–1 (C=C).
https://doi.org/10.1055/s-0040-1706020.
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u
p
p
ortingInformati
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nS
u
p
p
ortingInformatio
n
1H NMR (CDCl3, 400 MHz):  = 1.44 (s, 9 H, tBu), 3.78 (s, 3 H, OMe),
4.30 (br s, 1 H, OH), 4.82 (s, 2 H, OCH2), 7.38–7.50, 8.41–8.50 (2 m, 2
H, 3 H, Ph).
13C NMR (CDCl3, 100.5 MHz):  = 29.3, 38.3 (q, s, tBu), 59.5 (t, OCH2),
61.5 (q, OMe), 127.9, 128.4, 130.1, 137.1 (3 d, s, Ph), 148.9, 156.9,
159.8, 168.5 (4 s, C-2, C-4, C-5, C-6),
References
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HRMS (ESI-ToF): m/z [M + Na]+ calcd for C16H20N2NaO2: 295.1418;
found: 295.1420.
(2-Benzyl-6-tert-butyl-5-methoxypyrimidin-4-yl)methanol (12c)
Pyrimidine N-oxide 4e (0.130 g, 0.488 mmol) and TFAA (0.190 g, 1.36
mmol) were dissolved in CH2Cl2 (4 mL) and the solution was stirred at
rt for 3 h. Then the solvent and the excess TFAA were removed under
reduced pressure. Purification of the crude product by column chro-
matography (silica gel, hexanes/EtOAc, 6:1 to 1:1) provided 12c
(0.094 g, 72%) as a colorless oil.
IR (ATR): 3185 (O–H), 2980–2880 (C–H), 1560 (C=C), 1460 cm–1
(C=N).
1H NMR (CDCl3, 400 MHz):  = 1.37 (s, 9 H, tBu), 3.77 (s, 3 H, OMe),
4.15 (br s, 1 H, OH), 4.25 (s, 2 H, CH2), 4.72 (s, 2 H, OCH2), 7.20–7.31,
7.37–7.42 (2 m, 3 H, 2 H, Ph).
13C NMR (CDCl3, 125.8 MHz):  = 29.1, 38.1 (q, s, tBu), 45.0 (t, CH2),
59.2 (t, OCH2), 61.4 (q, OMe), 126.3, 128.2, 129.2, 138.5 (3 d, s, Ph),
148.4, 159.7, 161.9, 168.8 (4 s, C-2, C-4, C-5, C-6).
HRMS (ESI-ToF): m/z [M + H]+ calcd for C17H23N2O2: 287.1754; found:
287.1728.
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Pytela, O.; Klikar, M.; Bureš, F.; Achelle, S. J. Org. Chem. 2018, 83,
11712. (e) Achelle, S.; Rodríguez-López, J.; Larbani, M.; Plaza-
Pedroche, R.; Robin-le Guen, F. Molecules 2019, 24, 1742.
(f) Pérez-Caaveiro, C.; Moreno Oliva, M.; López Navarrete, J. T.;
Pérez Sestelo, J.; Martínez, M. M.; Sarandeses, L. A. J. Org. Chem.
2019, 84, 8870; and references cited therein.
(2,6-Di-tert-butyl-5-methoxypyrimidin-4-yl)methanol (12d)
Pyrimidine N-oxide 4g (0.320 g, 1.29 mmol) and TFAA (0.810 g, 3.87
mmol) were dissolved in CH2Cl2 (10 mL) and the solution was stirred
at rt for 3 h. Then the solvent and the excess TFAA were removed un-
der reduced pressure. Purification of the crude product by column
chromatography (silica gel, hexanes/EtOAc, 20:1 to 15:1) provided
12d (0.260 g, 78%) as a colorless oil.
IR (ATR): 3150 (O–H), 2950–2860 (C–H), 1560 (C=C), 1455 cm–1
(C=N).
1H NMR (CDCl3, 500 MHz):  = 1.37, 1.38 (2 s, 9 H each, tBu), 3.74 (s, 3
(8) Reviews: (a) Stopka, T.; Adler, P.; Hagn, G.; Zhang, H.; Tona, V.;
Maulide, N. Synthesis 2019, 51, 194. (b) Maji, P. K. Curr. Org.
Chem. 2020, 24, 1055. (c) Elkanzi, N. A. A.; Zahou, F. M. Hetero-
cycl. Lett. 2020, 10, 131. (d) Nagata, T.; Obora, Y. Asian J. Org.
Chem. 2020, 9, 1532. See also: (e) Aquino, E. da. C.; Lobo, M. M.;
H, OMe), 4.20 (very br s, 1 H, OH), 4.74 (s, 2 H, OCH2).
13C NMR (CDCl3, 125.8 MHz):  = 29.3, 29.7, 38.4, 39.2 (2 q, 2 s, tBu),
59.5 (t, OCH2), 61.4 (q, OMe), 127.1, 128.2, 128.6, 136.2 (3 d, s, Ph),
147.7, 158.8, 167.6, 169.4 (4 s, C-2, C-4, C-5, C-6).
HRMS (ESI-ToF): m/z [M + H]+ calcd for C14H25N2O2: 253.1911; found:
253.1932.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N

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L. Schefzig et al.
Paper
Synthesis
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© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–N