An efficient multi-component synthesis of N-1-alkylated 5-nitrouracils from α-amino acids

Article abstract of DOI:10.1016/j.tetlet.2016.04.039

The preparation of N-1 selectively alkylated uracil intermediates usually requires selective protection at N-3 followed by alkylation at N-1 and subsequent removal of the protecting group. In this Letter, we show the limitations of this approach when quaternary C centres at N-1 became a key target for the programme. To access this key substructure, we developed an efficient multi-component reaction (MCR) from readily available α-amino acid precursors.

Full text of DOI:10.1016/j.tetlet.2016.04.039

Tetrahedron Letters 57 (2016) 2367–2371
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient multi-component synthesis of N-1-alkylated
5-nitrouracils from a-amino acids
Jean-Guy Boiteau, Claire Bouix-Peter, Sandrine Chambon, Laurence Clary, Sebastien Daver,
⇑
Laurence Dumais, Jean-François Fournier, Craig S. Harris , Kenny Mebrouk, Corinne Millois,
Romain Pierre, Nicolas Rodeville, Sandrine Talano, Loïc Tomas
Galderma R&D, 2400 Route de Colles, 06410 Biot, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of N-1 selectively alkylated uracil intermediates usually requires selective protection at
N-3 followed by alkylation at N-1 and subsequent removal of the protecting group. In this Letter, we show
the limitations of this approach when quaternary C centres at N-1 became a key target for the pro-
gramme. To access this key substructure, we developed an efficient multi-component reaction (MCR)
Received 23 March 2016
Revised 9 April 2016
Accepted 12 April 2016
Available online 22 April 2016
from readily available a-amino acid precursors.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Multi-component reaction (MCR)
Cyclocondensation
5-Nitrouracil
During a recent project on an undisclosed target, we targeted
the uracil core scaffold from which to explore the 3 key vectors
from N-1 & N-3 and C-5 to deliver the target design set. Retrosyn-
thetic analysis gave the obvious synthon 5-nitrouracil. From which
we envisaged a selective alkylation strategy to introduce the alkyl
groups at N-1 and N-3 followed by reduction of the nitro group and
amide bond formation (Fig. 1).
Consequently, our first strategy relied upon selective N-3-pro-
tection of 5-nitrouracil with the benzhydryl group1 followed by
N-1 alkylation to prepare 2 in acceptable yields.2 Subsequent
deprotection of the benzhydryl group under hydrolytic conditions1
gave access to 3 for exploration from the N-3 vector. Alkylation of
N-3 followed by reduction of the nitro group under dissolving
metal conditions3 and subsequent amide bond formation using
to introduce a quaternary C centre under classical alkylation (entry
4)7 or Mitsunobu-type8 conditions from ethyl 2-hydroxy-2-methyl-
propanoate (entry 5)9 failed affording no signs of alkylated product.
Disappointed by the fact that we failed to apply alkylation
chemistry often cited for phenolic substrates,5,9 we focused our
efforts on the preparation of the more accessible cyclopropyl
derivative 8 following established protocol to prepare 1-aminocy-
clopropane-1-carboxylic acid starting from phthalimide.10 Alkyla-
tion of 1 with either the triflate or the alcohol, under Mitsunobu
conditions, proceeded in acceptable yields to afford 6. Ring-open-
ing of the resulting lactone 6 with HBr followed by esterification
of the resulting carboxylic acid moiety afforded 7. Subsequent
cyclisation to the cyclopropyl derivative proceeded in acceptable
yields in the presence of NaH after significant optimisation. Finally,
cleavage of the benzhydryl group under acidic conditions and
N-alkylation with Me-I afforded 8 albeit in just 1.2% overall yield.
Furthermore, attempts to exploit 8 to prepare our desired libraries
failed whereby saponification led to ring opening of the cyclo-
propyl moiety to afford 9 and hydrolysis of the ester worked but
also led to cleavage of the amide vector affording 11 (Scheme 2).
Next, we turned our attention to an alternative cyclisation strat-
COMU
(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethy-
lamino-morpholino-carbenium hexafluorophosphate)4 as the cou-
pling agent afforded our key scaffold 5 (Scheme 1).
From Table 1, alkylation with unhindered alkyl bromides such as
ethyl bromoacetate (entry 1) afforded consistently high yields of
selectively N-1 alkylated product with no signs of O-alkylation as
determined by NMR. After screening several conditions, we found
that alkylation with triflate derived lactate derivatives (entries 2
and 3)5 proceeded in acceptable yields and little epimerisation dur-
ing the process as confirmed by chiral HPLC.6 However, all attempts
egy10 starting from
a-amino acid ester precursors. We envisaged
that we could access the desired scaffold 3 using ethyl nitroacetate
as the key starting material depending on a 3 MCR (multi-compo-
nent reaction) with just the primary urea precursor (12) to prepare
from readily-available amino acid substrates 13 using either
TMS-isocyanate11 or potassium cyanate (Fig. 2).12
⇑
Corresponding author. Tel.: +33 (0)4 93 95 7042; fax: +33 (0)4 93 95 7071.
E-mail address: craig.harris@galderma.com (C.S. Harris).
http://dx.doi.org/10.1016/j.tetlet.2016.04.039
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

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J.-G. Boiteau et al. / Tetrahedron Letters 57 (2016) 2367–2371
O
Ph
Ph
Ph
Ph
LG
H
N
TMSO
NTMS
O
O
O
O
N
N
Ph
Ph
R
R'
O
+
NH
O
N+
O-
Br
Conditions
(see table 1)
cat. I2, MeCN,
r.t., 24 h, 77%
NH
N
R
O
O
N+
O-
N+
O-
O
O
R'
O
1
O
2
5-nitrouracil
TFA-TfOH (2:1),
r.t., 95%
R''
N
R''
1. Fe(s), NH4Cl, THF,
EtOH, H2O, 98%
H
O
O
N
O
N
O
O
O
R''-X
O
N
N
O
N
R
O
N+
O-
O
N
H
R'''
N+
O-
O
Cs2CO3, DMF,
r.t.-70°C, 50-80%
2. COMU, NMM, DMF,
r.t., 30-95%
O
R
R'
O
R R'
O
4
R'
O
3
5
Scheme 1. General scheme developed to access the scaffold 5.
intermediates 15–22 with ethyl nitroacetate in the presence of tri-
ethylorthoformate afforded consistently good yields of the surpris-
ingly stable intermediates 23–30 (E/Z ratio ꢀ 6:4) that could be
purified by normal phase chromatography if necessary, but often
they were pure enough to be used in the cyclisation step without
further purification (Table 2, entries 1–8).
R''
N
H
N
O
O
1. Selective alkylation
O
O
N
R''''
NH
O
N
H
N+
O-
N
2. Nitro group reduction
3. Amide bond formation
R'''
H
R
R'
O
O
Target set
5-nitrouracil
With the precursors 23–30 in hand, we turned our attention to
finding appropriate cyclisation conditions. Looking in the literature
there exists several reported cyclisation conditions published for
simple symmetrical urea substrates under strongly basic10,13 or
acidic conditions.14 Table 3 shows a selection of conditions that
were screened using the cyclopropyl derivative 26 as the substrate
(entry 4, Table 2).
With the isolated advanced intermediate 26 in hand and just
one step from the uracil derivative, we were surprised by how dif-
ficult it was to obtain the cyclised uracil product based on litera-
ture precedent.10,13,14 Briefly, the results from screening a large
Figure 1. Retrosynthetic analysis of key scaffolds.
The preparation of the primary urea components 15–22 was
fast and required no chromatography. Starting from -amino acid
esters 13, we used TMS-isocyanate affording yields 73–95%
(Scheme 3; Table 2, entries 1, 2, 5 and 7).11 From
-amino acids
a
a
14, we adopted a 2-step process using potassium cyanate followed
by protection of the carboxylic acid moiety by alkylation
(Scheme 3; Table 2, entries 3, 4 and 8).12 Condensation of the urea
Table 1
First generation of conditions employed to alkylate 1
O
Ph
Ph
Ph
Ph
LG
R''
O
O
O
N
N
R
R'
O
Conditions
R''
NH
N
O
O
N+
O-
N+
O-
O
R
R'
O
O
2
1
Entry
Alkylating agent
Conditions*
Yield % (e.r.)
96
O
1
K2CO3, DMF, rt
K2CO3, MeCN, rt
Br
O
O
TfO
2
3
64 (97/3)
61 (95/5)
O
O
TfO
K2CO3, MeCN, rt
O
Et
O
Extensive base & solvent screen, rt to 150 °C in the
LG
4
5
—
—
microwave using various leaving groups (LG)
O
O
Mitsunobu: DTAD, TPP, toluene, rt to 120 °C or Mitsunobu-
Tsunoda: CMPP or CMBP, toluene, 120 °C
HO
O
*
DTAD = di-tert-butyl azodicarboxylate; TPP = triphenylphosphine; CMPP = cyanomethyltriphenylphosphorane; CMBP = cyanomethyltributylphosphorane.

J.-G. Boiteau et al. / Tetrahedron Letters 57 (2016) 2367–2371
2369
Ph
Ph
N
Ph
Ph
N
Ph
Ph
O
X
O
O
O
O
N
N
N
O
O
c
O
NH
O
O
N+
O-
N+
O-
N+
O-
d
O
a or b
O
O
7
O
O
1
6
Br
N
O
N
O
O
N+
O-
OH
h
O
N
O
9
O
e
N
O
OH
N+
O-
O
O
f , g
i-j
N
O
N
O
O
O
8
O
O
k
+
N
N
OH
OH
H2N
R
O
N
H
R
O
11
O
10
Scheme 2. Preparation of cyclopropyl analogue 8. Conditions: (a) when X = OTf, K2CO3, MeCN, rt, 42%; (b) when X = OH, DIAD, TPP, DCM, rt, 40%; (c) HBr in AcOH, 70 °C, 75%;
(d) cat. Sulfuric acid, MeOH-DME, 45%; (e) NaH 60%, THF, rt, 1 h, 82%; (f) TFA, TfOH, rt, 10 min, 50%; (g) CH3I, K2CO3, DMF, rt, 3 h, 21%; (h) 1 M LiOH (aq), THF, 100%; (i) H2, Pd-
C, EtOAc, rt, 74%; (j) RCOOH, HATU, DIPEA, DMF, rt, 65%; (k) 2 M HCl (aq) EtOH, reflux, 16 h.
OEt
OEt
H
O
H2N
H
N
O
N
C
N
O
O
OEt
O
O
3 MCR
TMS
HN
R''
or
H2N
R''
O
O
N
R''
O
O
O
N+
O-
O
N+
O-
R
R'
Base cat.
OK
R
R'
13
R
R'
O
O
3
12
Figure 2. Retrosynthetic analysis proposed to access scaffold 3 with hindered quaternary C centres at N-1.
O
O
H
N
H2N
H2N
R''
OH
O
O
a , b
c
O
R'
R
O
R'
R
H
N
NH
d
14
R''
H2N
O
O
O
O
R'
R
N+
O-
O
O
O
N+
O-
R''
15-22
O
O
23-30
R'
R
13
Scheme 3. Preparation of intermediates 23–30. Reagents and conditions: (a) 3–5 equiv KOCN, water, reflux, 3–5 h; (b) R-X, DIPEA, DMF, rt, 16 h, 33–42%; (c) TMS-isocyanate,
DCM, rt, 16 h, 71–95%; (d) triethylorthoformate, toluene, 90 °C to reflux, 3–16 h, 46–93%.
Table 2
Results for the preparation of cyclisation precursor 23–30
Entry
R0, R00
R
Urea step(s) yield (%)
Compound
Condensation step yield (%)
Compound
1*
2
3
4
5
6
7
8
H,H
Et
Et
80
73
71
39
87
33
95
42
15
16
17
18
19
20
21
22
93
55
46
97
92
82
46
62
23
24
25
26
27
28
29
30
H, CH3 (S)
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)3–
CH3, CH3
CH3, CH3
Me
Allyl
t-Bu
Me
Me
Allyl
*
Compound 15 was prepared from ethyl isocyanatoacetate and a solution of NH3 in IPA.

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J.-G. Boiteau et al. / Tetrahedron Letters 57 (2016) 2367–2371
Table 3
Selected results from the cyclisation screening
O
H
N
Allyl
H
N
O
O
O
O
O
O
Conditions
NH
N
Allyl
+
O
NO2
O
N+
O-
O
O
O
O
N+
O-
N+
O-
O
O
35
O
26
31
Entry
Conditions
Yield of 35 (%)
Yield of 31* (%)
1
2
3
4
5
2 equiv NaH, DMF, rt to 80 °C
2 equiv t-BuOK, DMF, rt to 90 °C
2 equiv DIPEA, DMF, rt to 120 °C
2 equiv DBU, DMF, rt to 90 °C
2 equiv K2CO3, DMF, rt to 90 °C
AcOH, rt to reflux
—
—
—
—
Traces
—
67
35
—
52
75
—
6
7
8
9
10
BF3ꢁEt2O, DCM, rt to reflux
—
5
78
84
35
56
6
2 equiv Cs2CO3, toluene, rt to 120 °C
2 equiv Cs2CO3, MeCN, rt–reflux, 2 h
2 equiv Cs2CO3, DMF, rt to 95 °C, 2 h
5
*
Only 31 was clearly identified as a major impurity by LCMS and 1H NMR.
Table 4
Selected results for the preparation of N-1 alkylated uracils
O
H
N
R''
O
O
H
O
N
R
R'
NH
O
2 eq Cs2CO3, DMF
90 °C, 1-4 h
N
R''
O
N+
O-
O
O
O
N+
O-
R
R'
O
O
23-30
32-38
Entry
Compound
R0, R00
H,H
R
Dilution (volumes)
Yield (%) [S/R]
1
2
3
4
5
6
7
8
32
33
33
33
33
33
34
35
36
37
38
Et
10
10
20
95
H, CH3 (S)
H, CH3 (S)
H, CH3 (S)
H, CH3 (S)
H, CH3 (S)
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)3–
CH3, CH3
CH3, CH3
Et
Et
Et
Et
Et
84 [78:22]
84 [91:9]
79 [94:6]
66 [95:5]
20*
40*
60*
10
58 [>99:1]
Me
84
97
92
82
25
0
Allyl
t-Bu
Me
Me
Allyl
10
10
10
10
9
10
11
12
10
*
Reactions carried out using MeCN as solvent.
panel of conditions identified Cs2CO3 as the most effective base in
either DMF or MeCN as the solvent (Table 3, entries 9, and 10). All
the other conditions afforded, at best, only trace quantities of the
desired product 35. The ethyl nitroacetate dimer 31 was the only
major impurity that we identified which we believe was coming
from decomposition 26 in situ.
Table 4 confirms that the cyclisation process is very sensitive to
steric hindrance at N-1. As steric hindrance increases (entries 1–
11), the process becomes less efficient. This was particularly evi-
dent for the case of the gem-dimethyl intermediate (entries 11
and 12) whereby only poor yields were obtained despite extensive
conditions’ screening looking at solvent and base combinations. In
addition, we demonstrate that we can control epimerisation during
the cyclisation process (entries 2–6). Briefly, by diluting the pro-
cess by 2 fold in DMF we reduce the undesired R enantiomer by
13% (entries 2 vs 3). Switching from DMF to MeCN also reduced
epimerisation (entries 3 vs 4). Finally, by further diluting the pro-
cess to 60 volumes, we managed to eliminate epimerisation albeit
with a 16% loss in chemical yields (entries 4–6).7
Finally, to check the robustness of our process we performed
the synthesis of 35 on a 100 g scale (Scheme 4). The synthesis
started with 200 g of 1-aminocyclopropane carboxylic acid using
KOCN in refluxing water; crystallisation of the intermediate acid
was performed by addition of concentrated hydrochloric acid at
3 °C to afford the acid 39 in 80% yield. To avoid use of CMR solvents
such as DMF, alkylation with allyl bromide was performed in a
mixture of THF-water retaining DIPEA as a base. The MCR reaction
was performed as described and 26 was crystallised by adding
heptane to yield a stable yellow amorphous powder in 79% yield.
For the cyclisation step, we managed to replace DMF with MeCN
while maintaining a comparable isolated yield and an operating
temperature of below 100 °C. The latter point was particularly

J.-G. Boiteau et al. / Tetrahedron Letters 57 (2016) 2367–2371
2371
O
O
O
H
H
H2N
N
b
a
H2N
N
H2N
O
OH
OH
O
O
18
39
O
H
N
O
O
H
N
O
NH
O
c
d
N
O
O
O
N+
O-
N+
O-
O
O
O
26
35
Scheme 4. Large-scale preparation of 35. Reagents and conditions: (a) KOCN, water, reflux, 78%; (b) Allyl bromide, DIPEA, THF–H2O (10:1), reflux, 18 h, 68%; (c) ethyl
nitroacetate, triethyl orthoformate, toluene, reflux, 16 h, 79%; (d) Cs2CO3, MeCN, reflux, 30 min, 73%.
6. Real time chiral analysis was carried out by coupling the chiral column to the
important as safety assessment of compounds 26 and 35 by DSC
iChem Explorer (http://www.ichemexplorer.com/). Conditions: Column = IB
(differential scanning calorimetry) showed
a decomposition
Chiralpak 4.6 ꢃ 250,
5 lM; solvent = heptane/EtOH (9/1) + 0.3% TFA; flow
enthalpy of about ꢂ800 J/g starting at 188 °C and 250 °C, respec-
tively.15 In conclusion, we obtained an overall yield of 30.6% over
4 steps without any chromatography.
In conclusion, we have discovered an efficient way to prepare
selectively N-1-alkylated 5-nitrouracils with quaternary carbon
centres in poor to excellent yields from readily available a-amino
acids. Work is currently ongoing to improve the substrate scope
of the cyclisation step.
rate = 1.4 mL/min; temperature of column oven = 35 °C; run time = 20 min.
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Supplementary data
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Supplementary data (full experimental procedures and sup-
porting LCMS and 1H NMR characterisation data) associated with
this article can be found, in the online version, at http://dx.doi.
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