Electroreductive Intermolecular Coupling of Uracils with Aromatic Ketones: Synthesis of 6-Substituted and cis-5,6-Disubstituted 5,6-Dihydro-1,3-dimethyluracils and Their Transformation to 6-Substituted 1,3-Dimethyluracils, trans-5,6-Disubstituted 5,6-Dihydro-1,3-dimethyluracils, and 4,5,5-Trisubstituted 3-Methyloxazolizin-2-ones

Article abstract of DOI:10.1021/acs.joc.6b00670

The electroreductive coupling of 1,3-dimethyluracil, thymine, and 5-fluorouracil with aromatic ketones in the presence of TMSCl gave 6-substituted and cis-5,6-disubstituted 5,6-dihydro-1,3-dimethyluracils. The dehydrotrimethylsiloxylation of the adducts afforded 6-substituted and 5,6-fused 1,3-dimethyluracils. The detrimethylsilylation of the adducts with TBAF or 1 M HCl-MeOH gave 4,5,5-trisubstituted 3-methyloxazolizin-2-ones or 3-methyloxazolizin-2-imines in addition to simply desilylated alcohols. The cis-5,6-disubstituted 5,6-dihydro-1,3-dimethyluracils were isomerized to the corresponding trans-isomers by heating in the presence of cat. DMAP. The cis- and trans-5,6-disubstituted 5,6-dihydro-1,3-dimethyluracils were assigned by the coupling constants J_5,6 of their ¹H NMR spectra.

Full text of DOI:10.1021/acs.joc.6b00670

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Article
Electroreductive Intermolecular Coupling of Uracils with Aromatic
Ketones: Synthesis of 6-Substituted and cis-5,6-Disubstituted
5,6-Dehydro-1,3-dimethyluracils and Their Transformation to 6-
Substituted 1,3-Dimethyluracils, trans-5,6-Disubstituted 5,6-Dihydro-1,3-
dimethyluracils and 4,5,5-Trisubstituted 3-Methyloxazolizin-2-ones
Naoki Kise, Yusuke Hamada, and Toshihiko Sakurai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00670 • Publication Date (Web): 12 May 2016
Downloaded from http://pubs.acs.org on May 13, 2016
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Electroreductive Intermolecular Coupling of Uracils with Aromatic Ketones:
Synthesis of 6ꢀSubstituted and cisꢀ5,6ꢀDisubstituted 5,6ꢀDehydroꢀ1,3ꢀdimethyluracils
and Their Transformation to 6ꢀSubstituted 1,3ꢀDimethyluracils, transꢀ5,6ꢀDisubstituted
5,6ꢀDihydroꢀ1,3ꢀdimethyluracils and 4,5,5ꢀTrisubstituted 3ꢀMethyloxazolizinꢀ2ꢀones
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Naoki Kise,* Yusuke Hamada, and Toshihiko Sakurai
Department of Chemistry and Biotechnology, Graduate School of Engineering,
Tottori University, 4ꢀ101, Koyamaꢀcho Minami, Tottori 680ꢀ8552, Japan
ABSTRACT
The electroreductive coupling of 1,3ꢀdimethyluracil, thymine, and 5ꢀfluorouracil with
aromatic ketones in the presence of TMSCl gave 6ꢀsubstituted and cisꢀ5,6ꢀdisubstituted
5,6ꢀdehydroꢀ1,3ꢀdimethyluracils. The dehydrotrimethylsiloxylation of the adducts afforded
6
ꢀsubstituted and 5,6ꢀfused 1,3ꢀdimethyluracils. The detrimethylsilylation of the adducts
with TBAF or 1M HClꢀMeOH gave 4,5,5ꢀtrisubstituted 3ꢀmethyloxazolizinꢀ2ꢀones or
2ꢀimines in addition to simply desilylated alcohols. The cisꢀ5,6ꢀdisubstituted
,6ꢀdehydroꢀ1,3ꢀdimethyluracils were isomerized to the corresponding transꢀisomers by
ꢀ
5
heating in the presence of cat. DMAP.
The cisꢀ and transꢀ5,6ꢀdisubstituted
1
5
,6ꢀdehydroꢀ1,3ꢀdimethyluracils were assigned by the coupling constants J5,6 of their H
NMR spectra.
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INTRODUCTION
To date, a number of 5ꢀ and 6ꢀsubstituted uracils have been investigated as
pharmacologically and biologically active compounds, since they are analogs of primary
1
,2
nucleicꢀacid bases.
Therefore, the selective synthesis of 5ꢀ and 6ꢀsubstituted uracils
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3
,4
attracts much interest from the synthetic chemists.
In this context, we reported the
reductive twoꢀtoꢀone coupling of benzophenones with 1,3ꢀdimethyluracils by lowꢀvalent
titanium as the first example of the reductive coupling of uracils with carbonyl compounds
5
(
Scheme 1). In addition, we recently reported the electroreductive oneꢀtoꢀone coupling
between
aromatic
ketones
and
1,3ꢀdimethyluracils
to
give
6ꢀsubstituted
5,6ꢀdehydroꢀ1,3ꢀdimethyluracils and their transformation to 6ꢀsubstituted 1,3ꢀdimethyluracils
6
(
X = H, Me) or 5,6ꢀfused 1,3ꢀdimethyluracils (X = F). It is noted that cisꢀ5,6ꢀdisubstituted
5
,6ꢀdehydroꢀ1,3ꢀdimethyluracils were formed stereoselectively from 1,3ꢀdimethylthymine (X
=
Me) and 5ꢀfluoriuracil (X = F). In this paper, we report our further study on the
electroreductive coupling of 1,3ꢀdimethyluracils with aromatic ketones and the
detrimethylsiloxylation of the adducts. Moreover, we found that the adducts can be
transformed to 4,5,5ꢀtrisubstituted 3ꢀmethyloxazolizinꢀ2ꢀones, 3ꢀmethyloxazolizinꢀ2ꢀimines,
and transꢀ5,6ꢀdisubstituted 5,6ꢀdihydroꢀ1,3ꢀdimethyluracils (Scheme 2).
Successive
ringꢀclosure and opening of the adducts proceeded by treatment with TBAF in THF or HCl in
MeOH to give Nꢀmethylꢀ2ꢀ(3ꢀmethylꢀ2ꢀoxoꢀ5,5ꢀdiaryloxazolidinꢀ4ꢀyl)acetamides (X = H, Me,
F) or methyl 3ꢀmethylꢀ2ꢀ(methylimino)ꢀ5,5ꢀdiaryloxazolidinꢀ4ꢀyl)propanoates (X = Me),
respectively. Furthermore, cisꢀ5,6ꢀdisubstituted 5,6ꢀdehydroꢀ1,3ꢀdimethyluracils (X = Me,
F) were isomerized to the corresponding transꢀisomers by heating at 150 ºC in the presence of
cat. DMAP. These results provide a new method for the stereoselective synthesis of cisꢀ and
transꢀ5,6ꢀdisubstituted 5,6ꢀdehydroꢀ1,3ꢀdimethyluracils. The both geometric isomers were
1
readily assigned by the coupling constants J5,6 of their H NMR spectra.
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Scheme 1. Previous Works: Reductive Coupling of Uracils with Benzophenones
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Scheme 2. Transformation of 6ꢀSubstituted (X = H) and cisꢀ5,6ꢀDisubstituted
5,6ꢀDehydroꢀ1,3ꢀDimethyluracils (X = Me, F)
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RESULTS AND DISCUSSION
1. Electroreductive Coupling of Uracils with Aromatic Ketones.
The electroreduction of 1,3ꢀdimethyluracils 1aꢀc and benzophenones 2aꢀg (2 equiv.) were
carried out in THF in the presence of TMSCl (5 equiv.) and TEA (5 mmol) using a Pt cathode
to give 6ꢀsubstituted 1,3ꢀdimethylꢀ5,6ꢀdihydrouracils 3aꢀn as the adducts (Table 1).6 As the
cathode material, Pt, Pb, Au, Ag, Cu, Zn, and Sn afforded almost the same yields of 3a
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(
72ꢀ77%) in the reaction of 1a and 2a. The presence of TMSCl is indispensable for the
electroreductive coupling,7 since no crossꢀcoupled product was produced by the
electroreduction of 1a and 2a in the absence of TMSCl; 1,1,2,2ꢀtetraphenylethaneꢀ1,2ꢀdiol was
obtained as an only product by the pinacol coupling of 2a. On the other hand, the presence of
TEA is not crucial for the reductive coupling but brought about steady results. The role of
TEA is probably to neutralize hydrogen chloride generated from TMSCl and trace amounts of
water remaining in the solvent and reagents. From 1,3ꢀdimethylthymine (1b) and
1,3ꢀdimethylꢀ5ꢀfluorouracil (1c), cisꢀ5,6ꢀdisubstituted 1,3ꢀdimethylꢀ5,6ꢀdihydrouracils cisꢀ3hꢀn
were produced with complete stereoselectivity (runs 8ꢀ14). The stereostructures of cisꢀ3hꢀn
1
were determined by Xꢀray crystallographic and H NMR analyses (vide infra).
The electroreductive coupling of 1aꢀc with alkyl aryl ketones 4aꢀe were also effected
6
under the same conditions (Table 2). All of the products 5aꢀi were formed as mixtures of
two diastereomers. Fortunately, it was confirmed by Xꢀray crystallographic analysis of the
corresponding detrimethylsilylated alcohols as described below that the major isomers of 5e
(X = H) and 5h (X = F) were erythro and cis-erythro, respectively, and the minor isomer of 5g
(X = Me) was cisꢀthreo. These results suggest that the major isomers of 5dꢀi formed from
cyclic ketones, 1ꢀtetralone (4d) and 1ꢀindanone (4e), were erythro (runs 4ꢀ9) and the both
isomers of 5fꢀi (X = Me, F) were cis (runs 6ꢀ9). The cisꢀstereoconfiguration of both isomers
1
of 5fꢀi was also supported by H NMR analysis (vide infra).
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Table 1. Electroreductive Coupling of Uracils with Benzophenones
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% yield of 3a
run
1
1
2
3
3a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
1c
1c
1c
2a
2b
2c
2d
2e
2f
77b
62b
57b
65b
58
2
3b
3
3c
4
3d
5
3e
6
3f
44
7
2g
2a
2b
2c
2a
2b
2c
2d
3g
52
8
cisꢀ3h
cisꢀ3i
cisꢀ3j
cisꢀ3k
cisꢀ3l
cisꢀ3m
cisꢀ3n
63b
45b
9
10
80b
67b
11
12
54b
49b
68b
13
14
b
a
Isolated yields. Reported data in ref. 6.
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Table 2. Electroreductive Coupling of Uracils with Alkyl Aryl Ketones
O
O
+
2e
X
TMSCl
MeN
O
MeN
O
Ph
Ph
+
OTMS
R
N
O
THF
N
Me
Me
Ph
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11
12
13
14
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20
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22
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1
a
4a R = Me
4b R = Et
5a
R = Me
(
1 mmol)
5b R = Et
4c R = i-Pr
5c R = i-Pr
(2 mmol)
O
O
O
+2e
X
X
TMSCl
MeN
O
MeN
O
OTMS
+
N
N
n
THF
Me
Me
1a X = H
b X = Me
1c X = F
4d n = 2
4e n = 1
(2 mmol)
n
5d,e X = H
cis-5f,g X = Me
cis-5h.i X = F
1
(1 mmol)
run
1
1
4
5
5a
% yield (dr) of 5a
b
1a
1a
1a
1a
1a
1b
1b
1c
1c
4a
4b
4c
4d
4e
4d
4e
4d
4e
52 (50:50)
b
2
5b
49 (55:45)
b
3
5c
71 (67:33)
b.c
4
5d
75 (73:27)
52 (55:45)c
5
5e
6
cisꢀ5f
cisꢀ5g
cisꢀ5h
76 (85:15)c,d
53 (67:33)c,d
7
8
60 (70:30)c,d
42 (55:45)c,d
9
cisꢀ5i
b
c
a
Isolated yields. Reported data in ref 6. Major isomers were erythro.
d
Both isomers were cis.
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6
As described in the previous report, the cisꢀstereoselective formation of 3hꢀn and 5fꢀi
can be explained by the assumption that the protonation to the 5ꢀposition of 6ꢀsubstituted silyl
enol ethers occurs from the lessꢀhindered side, that is, opposite side of the 6ꢀsubstituent
predominantly. Next, the presumed reaction mechanism of the electroreductive coupling of
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6
1
a with 4d is illustrated in Scheme 3, according to the reported mechanism. Carbanion A is
generated by the twoꢀelectron transfer to 4d and Oꢀtrimethylsilylation, The nucleophilic
addition of A proceeds at the 6ꢀposition of 1a through transition states TS and subsequent
Oꢀsilylation produce silyl enol ether B. During workup, the desilylation of silyl enol ether
moiety in B affords 5d. Therefore, we calculated the transition states TS to give erythroꢀ
and threoꢀ5d by the DFT method at the B3LYP/6ꢀ311+(2d,p) level using the IEFPCM model
in THF to elucidate the erythroꢀselectivity in the electroreductive coupling of 1a with 4d.
As exhibited in Figure 1, two transition states erythroꢀTS and threoꢀTS were found and
erythroꢀTS is lower in energy than threoꢀTS (1.42 kcal/mol corresponding to 83:17 dr). The
energy deference is probably due to the steric repulsion between trimethylsiloxy group and
1ꢀmethyl group in threoꢀTS. Although the calculation results somewhat overestimate the
diastereomeric ratio compared to the experimental result (73:27 dr), the erythroꢀselectivity in
the formation of 5d is supported by the DFT calculations.
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Scheme 3. Presumed Reaction Mechanism of Electroreductive Coupling of 1a with 4d
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Figure 1. Optimized Structures and Relative Energies of erythro-TS and threoꢀTS
Calculated at the B3LYP/6ꢀ311+G(2d,p) Level Using the IEFPCM Model in THF
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2. Detrimethylsiloxylation of the Adducts.
The results of the detrimethylsiloxylation of 3aꢀn by reflux in a benzenoid solvent in the
presence of cat. TsOH are summarized in Table 3. From 3aꢀj (X = H, Me) except for 3f, the
corresponding 6ꢀdiarylmethylꢀ1,3ꢀdimethyluracils 6aꢀe,g (X = H) and 6hꢀj (X = Me) were
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0
obtained in moderate to high yields (runs 1ꢀ5 and 7ꢀ10).
6ꢀ(9ꢀanthracenyl)ꢀ5,6ꢀdihydouracil 6f was formed as a product (run 6). However, 5,6ꢀfused
,3ꢀdimethyluracils 7kꢀn were given by the reactions of cisꢀ3kꢀn (X = F) under the same
From 3f,
1
conditions (runs 11ꢀ14).
The results of the detrimethylsiloxylation of 5aꢀi are shown in Table 4. From 5aꢀc
derived from acetophenones 4aꢀc, 6ꢀalkenylꢀ1,3ꢀdimethylꢀ5,6ꢀdihydrouracils 8aꢀc were
obtained as the major products together with 6ꢀalkylꢀ1,3ꢀdimethyluracils 9aꢀc (runs 1ꢀ3). In
contrast, the reactions of 5dꢀi formed from cyclic ketones 4d,e selectively yielded 8dꢀi (runs
4ꢀ9).
Dehydration
of
8d
and
cisꢀ8f,h
with
DDQ
gave
6ꢀ(1ꢀnaphthyl)ꢀ1,3ꢀdimethylꢀ5,6ꢀdihydroutacils 10d and cisꢀ10f,h, respectively (Scheme 4).
The stereoconfiguration of cisꢀ8f,h was completely retained in cisꢀ10f,h.
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Table 3. Detrimethylsiloxylation of 3aꢀn to 6aꢀj or 7aꢀd
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
run
3
solvent
time
6
% yield
7
% yield
of 6a
of 7a
86b
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
toluene
toluene
toluene
toluene
toluene
xylene
12 h
12 h
1 h
6a
6b
6c
6d
6e
6fc
6g
6h
6i
6j
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
82b
93b
94b
66
12 h
12 h
1 h
62
3g
xylene
24 h
12 h
12 h
2 h
94
83b
cisꢀ3h toluene
cisꢀ3i toluene
cisꢀ3j toluene
cisꢀ3k toluene
cisꢀ3l toluene
cisꢀ3m toluene
69b
95b
10
11
12 h
12 h
1 h
ꢀ
ꢀ
ꢀ
7k
7l
70b
51b
1
2
3
ꢀ
1
ꢀ
7m
7n
72b
90b
14
cisꢀ3n benzene
12 h
b
a
c
Isolated yields. Reported data in ref 6. The structure of 6f was shown below.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 4. Detrimethylsiloxylation of 5aꢀi to 8aꢀi or 9aꢀc
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
run
5
solvent time
8
% yield (gr)
9
% yield
of 8a
of 9a
1
2
3
4
5
6
7
8
9
5a
5b
xylene
xylene
xylene
xylene
toluene
12 h
12 h
72 h
2 h
8a
8b
8c
8d
8e
81b
9a
9b
9c
6b
8b
50 (70:30)b
5c
28b
89b
90
85
73
78
76
11b
5dc
5ec
2 h
cisꢀ5fc
toluene 12 h cisꢀ8f
cisꢀ5gc toluene
cisꢀ5hc toluene
3 h
3 h
2 h
cisꢀ8g
cisꢀ8h
cisꢀ8i
cisꢀ5ic
toluene
b
c
aIsolated yields. Reported data in ref 6. Diastereomeric mixtures obtained in Table 2.
Scheme 4. Dehydration of 8d,f,h to 10d,f,h
O
O
X
X
MeN
O
DDQ
MeN
O
N
N
benzene
Me
Me
8d
X = H
10d
86%
cis-8f X = Me
cis-8h X = F
cis-10f 90%
cis-10h 93%
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9
3. Detrimethylsilylation of the Adducts with TBAF.
The results of the detrimethylsilylation of 3aꢀn with TBAF in THF are summarized in
Table 5. The reactions were typically performed until almost all of 3aꢀn were consumed.
The treatment of 3aꢀe (X = H) at 25 ºC for 15 min gave 4ꢀsubstituted
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
,5ꢀdiaryloxazolidinꢀ2ꢀones 12aꢀe (runs 1ꢀ5), while simply detrimethysilylated alcohols 11f,g
were obtained from 3f,g (X = H) under the same conditions (runs 6 and 7). The reaction of
cisꢀ3h (X = Me) at 25 ºC for 15 min afforded almost transꢀisomerized 11h and diastereomeric
mixture of 12h in 26% (3:97 dr) and 58% (70:30 dr) yields, respectively (run 8). When the
reaction was carried out at
0
ºC for 15 min, cisꢀ11h was obtained as the major product (86:14
ºC brought about
dr) in 88% yield (run 9). The prolonged reaction time (12 h) at
0
considerable isomerization of cisꢀ11h to transꢀ11h (72%, 31:69 dr) and slight formation of 12h
(15%, 80:20 dr) from 11h (run 10). The desilylation of cisꢀ3i,j (X = Me) was slower than that
of cisꢀ3h (runs 11ꢀ13). The treatment of cisꢀ3i,j at 25 ºC for 12 h afforded completely
transꢀisomerized 11i,j as minor products and diastereomeric mixtures of 12i,j as major
products (run 11 and 13). From cisꢀ3kꢀn (X = F), 12kꢀn were obtained by treatment at 25 ºC
for 15 min as single stereoisomers (runs 14ꢀ17). Since the stereostructure of the obtained
12kꢀn was determined to be threo by Xꢀray crystallography, the stereoconfiguration of cisꢀ3kꢀn
was completely reflected in threoꢀ12kꢀn.
The results of the detrimethylsilylation of 5dꢀi with TBAF in THF are shown in Table 6.
The treatment of both isomers of 5d,e (X = H) gave the corresponding desilylated alcohols
13d,e (runs 1ꢀ4). While transꢀisomers of erythroꢀ13f,g and diastereomeric mixtures of
oxazolinꢀ2ꢀones 14f,g were formed from cis-erythro-5f,g (runs 5 and 7), only
transꢀisomerized threoꢀ13f,g were obtained from cisꢀthreoꢀ5f,g (runs 6 and 8). In contrast,
the reactions of both isomers of cis-5h,i (X = F) afforded 14h,i selectively (runs 9ꢀ11).
Although the stereostructures of 14i obtained from cis-erythro- and cis-threo-5i could not be
confirmed (runs 10 and 11), they were assumed to be erythro-threo and threo-threo,
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
respectively, from the completely stereoselective formation of threoꢀ12kꢀn (runs 14ꢀ17 in
Table 5).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 5. Detrimethylsilylation of 3aꢀn to 11fꢀj, 12aꢀe, and 12hꢀm with TBAF
run
3
temp.
time
11
% yield of 11a
cis trans
12
% yield of
a
(
:
)
12 (dr)
f1
2
3a
3b
25 ºC
25 ºC
25 ºC
25 ºC
25 ºC
25 ºC
25 ºC
25 ºC
0 ºC
15 min
15 min
15 min
15 min
15 min
15 min
15 min
15 min
15 min
12 h
12a
12b
12c
12d
12e
87
69
83
84
85
3
3c
4
3d
5
3e
6
3f
11f
11g
11h
11h
11h
11i
81
88
7
3g
8
cisꢀ3h
cisꢀ3h
cisꢀ3h
cisꢀ3i
cisꢀ3j
cisꢀ3j
cisꢀ3k
cisꢀ3l
cisꢀ3m
cisꢀ3n
26 (3:97)
88 (86:14)
72 (31:69)
34 (<1:99)
90 (29:71)
19 (<1:99)
12h
58 (70:30)b
9
10
0 ºC
12h
12i
15 (80:20)b
54 (78:22)b
11
25 ºC
25 ºC
25 ºC
25 ºC
25 ºC
25 ºC
25 ºC
12 h
12
13
14
15
16
15 min
12 h
11j
67 (45:55)b
11j
12j
12k
12l
15 min
15 min
15 min
15 min
63 (>99:1)c
49 (>99:1)c
12m
12n
82 (>99:1)c
82 (>99:1)c
17
aIsolated yields. bErythro
:
threo in parentheses. Obtained as threo only.
c
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Table 6. Detrimethylsilylation of 5dꢀi to 13dꢀg and 14fꢀi with TBAF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
run
5 (cisꢀ5fꢀi)
time
13
% yield
of 13a
91
14
% yield of
a
(
transꢀ13f,g)
14 (dr)
1
2
3
4
5
6
7
8
9
eryrthroꢀ5d
threoꢀ5d
eryrthroꢀ5e
threoꢀ5e
15 min eryrthroꢀ13d
15 min
15 min
15 min
30 min
30 min
2 h
threoꢀ13d
eryrthroꢀ13e
threoꢀ13e
65
78
79
eryrthroꢀ5f
threoꢀ5f
eryrthroꢀ13f
threoꢀ13f
41b
eryrthroꢀ14f
eryrthroꢀ14g
50 (68:32)
15 (73:27)
70b
eryrthroꢀ5g
threoꢀ5g
5hc
eryrthroꢀ13g
threoꢀ13g
63b
58b
2 h
15 min
15 min
15 min
14h
70 (60:40)
83 (>99:1)
68 (>99:1)
10
eryrthroꢀ5i
threoꢀ5i
eryrthroꢀ14i
threoꢀ14i
11
a
Isolated yields. Obtained as trans only. cErythro:threo = 70:30.
b
The presumed reaction mechanism of the transformation of 3 to 12 is shown in Scheme 5.
Detrimethylsilylation of 3 with TBAF generates Oꢀanion C. Intramolecular nucleophilic
addition of the Oꢀanion to the carbonyl group at the 2ꢀposition in C forms bicyclo[3.2.1]
Oꢀanion D. Ring opening of the sixꢀmembered ring in D and subsequent protonation of
resultant anion E produce oxazolizinꢀ2ꢀones 12. When the stereoconfiguration of 3hꢀn (X =
Me, F) is retained, cisꢀisomers of 3hꢀn are transformed to erythroꢀ12hꢀj (X = Me) and
threoꢀ12kꢀn (X = F). The relative energies of E to C (Ar = Ph, X = H, Me, F) calculated by
the DFT method at the B3LYP/6ꢀ311+(2d,p) level using the IEFPCM model in THF are
summarized in Table 7. These results show that anions Ea,h,k are much lower in energy
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
than anions Ca,h,k and therefore suggest the spontaneous transformation from C to E. It
seems to be possible that alternative intramolecular nucleophilic addition of the Oꢀanion to
the carbonyl group at the 4ꢀposition in Ca and subsequent ringꢀopening of resultant Da’ to
give Ea’. However, Ea’ is higher in energy than Ca (3.20 kcal/mol). This result shows
that the alternative route from Ca to Ea’ is unlikely. Since the transformation of cisꢀ11hꢀj
(X = Me) to erythroꢀ12hꢀj is slow compared with those of cisꢀ11aꢀe (X = H) and cisꢀ11kꢀn (X
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
=
F) probably due to steric and electronic effects of the 5ꢀMe group in cisꢀ11hꢀj, the
isomerization of cisꢀ11hꢀj to transꢀ11hꢀj occurs. Unsurprisingly, transꢀCh (Ar = Ph, X =
Me) is much lower in energy (−5.78 kcal/mol) than cisꢀCh and this result elucidates the
straightforward isomerization of cisꢀ11hꢀj and cisꢀ13f,g to their transꢀisomers.
The
transformation of transꢀ11hꢀj with TBAF gave threoꢀ12hꢀj as described below.
Scheme 5. Presumed Reaction Mechanism of the Transformation of 3 to 12
O
O
O
+
F
X
X
X
O
O
MeN
-
TMSF
MeN 4
2
MeN
2
Ar
Ar
Ar
Ar
O
O
N
O
N
O
N
Me
Me
Me
Ar
OTMS
Ar
3 X = H, Me, F
C
D
O
C NMe
NMe
C NHMe
+H
X
X
NMe
Ar
Ar
Ar
O
O
O
12 X = H
O
Ar
X = Me: erythro
X = F: threo
E
O
O
O
C NMe
MeN
O
MeN 4
MeN
O
Ph
Ph
O
Ph
O
N
N
Me
Ph
O
Me
O
Ph
Ph
Ca
Da'
Ea'
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Table 7. Relative Energies of E to C (Ar = Ph, X = H, Me, F) Calculated at the
B3LYP/6ꢀ311+G(2d,p) Level Using the IEFPCM Model in THF
X
C
E
relative energy of E
to C (kcal/mol)
−5.71
H
H
Ca
Ca
Ea
Ea’
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3.20
Me
cisꢀCha
cisꢀCk
erythroꢀEh
threoꢀEk
−6.71
F
−10.09
a
Relative energy to transꢀCh is 5.78 kcal/mol.
4. Detrimethylsilylation of the Adducts with 1M HCl in MeOH
The results of the detrimethylsilylation of 3aꢀg (X = H) and cisꢀ3kꢀn (X = F) with 1M
HCl in MeOH at 25 ºC or 0 ºC are summarized in Table 8. The reactions were carried out
until almost all of 3 were consumed. Except for 3c and 3f, the corresponding desilylated
alcohols 11a,b,d,e,g,kꢀn were obtained in good to high yields (runs 1,2,5,6,8ꢀ12). From 3c
6 4
(Ar = 4ꢀMeOC H ), methyl ether 11c’ (23%) was also formed with 11c (63%) by the
substitution of 11c with methanol even at 0 ºC for 30 min (run 3). Although the desilylation
needed prolonged reaction time (6 h), 11c was formed as the sole product (85%) by treatment
with 1M HCl aq/dioxane (1/1) at 25 ºC (run 4). In the reaction of 3f, dehydrated product 6f
(26%) was also obtained with 11f (35%) even at 0 ºC for 30 min (run 7). Stereoconfiguration
of cisꢀ3kꢀn was completely retained in cisꢀ11kꢀn (runs 9ꢀ12).
On the contrary, cisꢀ3h,i (X = Me) were transformed to cisꢀ11h,i, transꢀ3,4ꢀdisubstituted
5
,5ꢀdiarylꢀγꢀbutyrolactones transꢀ15h,i, and 4ꢀsubstituted 5,5ꢀdiaryloxazolidinꢀ2ꢀimines 16h,i
by treatment with 1M HCl in MeOH depending on the reaction conditions (Table 9). The
treatment of cisꢀ3h with 1M HCl in MeOH at 0 ºC for 12 h gave cisꢀ11h (50%) and transꢀ15h
(
25%) (run 1). The reaction at 25 ºC accelerated the isomerization of cisꢀ11h to transꢀ15h
and brought about the formation of 16h (runs 2 and 3). Under the same conditions, the
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
product converged with 16h (90%) after 120 h (run 4). The transformation of cisꢀ3h to 16h
was completed at reflux temperature within 3 h (run 5). The treatment of cisꢀ3i at 0 ºC for 8
h gave cisꢀ11i (42%) and transꢀ15i (24%) (run 6) and that at 25 ºC or reflux temperature did
16i (89% or 90%) as a sole product (runs 7 and 8). Similarly to the reaction of 3c, methyl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ether cisꢀ11j’ was formed as a major product (52%) with a small amount of cisꢀ11j (8%) and 16j
(11%) from cisꢀ3j under the conditions at 0 ºC for 6 h (run 9). The alcohol cisꢀ11j was
obtained predominantly (59%) with a small amount of transꢀ15j (15%) by treatment with 1M
HCl aq/dioxane (1/1) at 25 ºC for 12 h (run 10). The products 11hꢀj, 15hꢀj and 16hꢀj were all
formed as single stereoisomers and the stereostructures of 11hꢀj and 15hꢀj were confirmed to
be cis and trans, respectively, by Xꢀray and 1H NMR analyses.
stereoconfiguration of 16hꢀj could not be determined, it seemed that the erythroꢀisomers of
6hꢀj were obtained exclusively with retaining the stereochemistry. Moreover, it is probable
that ꢀimines of 16hꢀj (erythroꢀZ) were formed preferentially, since ꢀimines are expected to
be thermodynamically more stable than ꢀimines. Even after the reaction of cisꢀ3h was
Although the
1
Z
Z
E
carried out in refluxing 1M HCl aq/dioxane (1/1) for 24 h, the carboxylic acid corresponding
to 16h could not be obtained; cisꢀ11h (45%) and transꢀ15h (30%) was afforded (Scheme 6).
In contrast, the corresponding ethyl ester 16’ (90%) was formed from cisꢀ3h after reflux in
1M HClꢀEtOH for 3 h.
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Table 8. Detrimethylsilylation of 3aꢀg and 3kꢀn to 11aꢀg and 11kꢀn with 1M HCl in
MeOH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
run
1
3
3a
temp.
25 ºC
25 ºC
0 ºC
time
15 min
30 min
30 min
6 hc
11
11a
% yield of 11a
93
2
3b
11b
92
63b
3
3c
11c
4
3c
25 ºC
0 ºC
11c
85
81
70
35d
88
91
93
80
84
5
3d
30 min
3 h
11d
6
3e
25 ºC
0 ºC
11e
7
3f
30 min
30 min
2 h
11f
8
3g
0 ºC
11g
9
cisꢀ3k
cisꢀ3l
cisꢀ3m
cisꢀ3n
25 ºC
25 ºC
25 ºC
cisꢀ11k
cisꢀ11l
cisꢀ11m
cisꢀ11n
10
6 h
11
12 h
12
25 ºC
6 h
a
b
c
Isolated yields. Obtained with 11c’ (23%). In 1M HCl aq/dioxane (1/1).
dObtained with 6f (26%).
O
MeN
OMe
O
N
Me
C6H4OMe-4
C H OMe-4
6
4
11c'
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5
5
5
5
5
5
5
6
Table 9. Detrimethylsilylation of cisꢀ3hꢀj to cisꢀ11hꢀj, transꢀ15hꢀj and 16hꢀj with 1M HCl
in MeOH
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
run cisꢀ
3
temp. time cisꢀ11
% yield transꢀ15 % yield
16
% yield
of 16a
of 11a
of 15a
1
2
3
4
5
6
7
8
9
3h
0 ºC
25 ºC
25 ºC
12 h
4 h
11h
11h
11h
50
15h
15h
15h
25
3h
3h
3h
3h
3i
25
49
16h
16h
16h
16h
16
57
90
90
12 h
15
24
25 ºC 120 h
reflux
0 ºC
3 h
8 h
11i
42
8b
15i
24
3i
25 ºC
reflux
0 ºC
72 h
3 h
16i
16i
16j
89
90
11
3i
3j
6 h
11j
11j
10
3j
25 ºC 12 hc
59
15j
15
a
b
c
Isolated yields. Obtained with 11j’ (52%). In 1M HCl aq/dioxane (1/1).
On the other hand, the treatment of 5dꢀj with 1M HCl in MeOH at 0 ºC for 1ꢀ3 h gave the
corresponding desilylated alcohols 13dꢀj selectively (Table 10). From cisꢀ5fꢀi (X = Me, F),
cisꢀisomers of 13fꢀi were formed exclusively with keeping the stereostructure of cisꢀ5fꢀi (runs
5ꢀ11).
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Scheme 6. Treatment of cis
ꢀ
3h with refluxing 1M HCl aq/dioxane (1/1) and 1M
HClꢀEtOH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
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37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 10. Detrimethylsilylation of 5dꢀi to 13dꢀi with 1M HCl in MeOH
run
1
5 (cisꢀ5fꢀi)
eryrthroꢀ5d
threoꢀ5d
eryrthroꢀ5c
threoꢀ5e
time 13 (cisꢀ13fꢀi)
% yield of 13a
1 h
1 h
2 h
2 h
1 h
1 h
1 h
2 h
3 h
1 h
1 h
eryrthroꢀ13d
threoꢀ13d
eryrthroꢀ13e
threoꢀ13e
eryrthroꢀ13f
threoꢀ13f
82
65
87
83
80
74
68
61
77c
70
64
2
3
4
5
eryrthroꢀ5f
threoꢀ5f
6
7
eryrthroꢀ5g
threoꢀ5g
eryrthroꢀ13g
threoꢀ13g
13h
8
9
5hb
10
eryrthroꢀ5i
threoꢀ5i
eryrthroꢀ13i
threoꢀ13i
11
aIsolated yields. bErythro:threo = 70:30. cErythro:threo = 73:27.
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1
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2
2
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2
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5
5
5
5
5
5
5
5
6
The presumed reaction mechanism of the transformation of cisꢀ3h to transꢀ15h and 16h
erythro-Z) is shown in Scheme 7. Initially, acid catalyzed detrimethylsilylation of cisꢀ3h in
(
MeOH generates alcohol cisꢀ11h. After protonation to the carbonyl group at the 4ꢀposition
in cisꢀ11h, intramolecular nucleophilic addition of the hydroxy group to the 4ꢀposition forms
bicyclo[3.2.1] cation G. After proton migration to the nitrogen at the 3ꢀposition in G, ringꢀ
opening of the sixꢀmembered ring in resultant H to I and subsequent deprotonation from I
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
afford γꢀlactone trans-15h.
Under reflux conditions, intramolecular nucleophilic
substitution of the urea carbonyl oxygen atom to the 5ꢀposition in the protonated transꢀ15h (I)
proceeds through carbocation J to give carboxylic acid L after deprotonation of resultant K.
Finally, acid catalyzed esterification of L produces methyl ester 16h. The relative energies
of cisꢀ11h, trans-11h, trans-15h, L (erythro-Z and erythro-E), and 16h (erythro-Z) were
calculated by the DFT method at the B3LYP/6ꢀ311+(2d,p) level using the IEFPCM model in
MeOH are shown in Table 11.
The calculation results show that trans-15h is
thermodynamically more stable (4.49 kcal/mol) than cisꢀ11h whereas L (erythro-Z) is much
more unstable (18.63 kcal/mol) than trans-15h. As expected above, L (erythro-Z) is more
stable (5.97 kcal/mol) than L (erythro-E). Accordingly, in the reaction of 11h with 1M HCl
aq/dioxane (1/1) (Scheme 6), L was not formed at all. Predictably, transꢀ11h is more stable
(4.41 kcal/mol) than cisꢀ11h and, therefore, isomerization of cisꢀ11h to trans-11h was
observed under the reflux conditions in 1M HCl aq/dioxane (1/1) as shown in Scheme 6.
Under the conditions in 1M HClꢀMeOH, the equilibrium between cisꢀ11h, trans-15h, L, and
16h was completely moved to 16h by esterification of L (runs 4 and 5 in Table 9). The
driving force of the isomerization of cisꢀ11hꢀj to transꢀ15hꢀj seems to be release of steric
hindrance, since this type of isomerization could not be observed for 3aꢀg, cisꢀ3kꢀn (Table 8),
and transꢀ11hꢀj (vide infra).
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9
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1
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1
1
1
1
1
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3
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4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 7. Presumed Reaction Mechanism of the Transformation of cisꢀ3h to transꢀ15h
and 16h
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 11. Relative Energies of 11h, 15h, L, and 16h Calculated at the
B3LYP/6ꢀ311+G(2d,p) Level Using the IEFPCM Model in MeOH
relative energy
(
kcal/mol)
0
cisꢀ11h
transꢀ11h
transꢀ15h
−4.41
−4.49
14.14
20.15
11.58
L (erythro
L (erythro
h (erythro MeOH + H O
ꢀZ)
ꢀE)
6
ꢀ
Z)
̶
2
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5. Isomerization of cisꢀ5,6ꢀDisubstituted 1,3ꢀDimethylꢀ5,6ꢀdihydrouracils to
transꢀIsomers and Their Desilylation.
The results of the isomerization of cisꢀ3hꢀk,m (X = Me, F) to the corresponding
transꢀisomers transꢀ3hꢀk,m by heating at 150 ºC in the presence of cat. DMAP are
summarized in Table 12. The isomerization of cisꢀ3hꢀj (X = Me) was completed after
heating for 24 h (runs 1ꢀ3), while that of cisꢀ3k,m (X = F) was finished within 8 h (runs 4 and
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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53
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60
5). Similarly, the isomerization of cisꢀ8f,h and cisꢀ10f was effected under the same
conditions (Scheme 8). However, a dehydrofluorinated product 17h was the only product in
the reaction of cisꢀ10h under the same conditions. Incidentally, transꢀ10h was obtained by
dehydration of transꢀ8h with DDQ.
Table 12. Isomerization from 3hꢀk,m to transꢀ3hꢀk,m
run
1
cisꢀ3
cisꢀ3h
cisꢀ3i
cisꢀ3j
cisꢀ3k
cisꢀ3m
time
24 h
24 h
24 h
8 h
transꢀ3
transꢀ3h
transꢀ3i
transꢀ3j
transꢀ3k
transꢀ3m
% yield of transꢀ3a
67
63
75
70
82
2
3
4
5
8 h
aIsolated yields.
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9
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1
1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
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3
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3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 8. Isomerization of 8f,h and 10f,h
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The results of detrimethylsilylation of transꢀ3hꢀk,m with TBAF are shown in Table 13.
Whereas mixtures of transꢀ11hꢀj and threoꢀ12hꢀj (X = Me) were obtained from transꢀ3hꢀj
(runs 1ꢀ3), erythroꢀ12k,m (X = F) were only products from transꢀ3k,m (runs 4 and 5). The
stereoconfiguration of transꢀ3hꢀk,m was completely reflected in threoꢀ12hꢀj and
erythroꢀ12k,m. On the other hand, detrimethylsilylation of transꢀ3hꢀk,m with 1M HCl
aq/dioxane (1/1) at 25 ºC selectively gave transꢀ11hꢀk,m in high yields (Table 14). The
isomerization of transꢀ11hꢀj to γꢀlactone 15 as described above could not be observed at all.
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Table 13. Detrimethylsilylation of transꢀ3hꢀl,k,m with TBAF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
run
transꢀ
3
transꢀ11
% yield of
12
% yield
of 12a
34
transꢀ11a
1
2
3
4
5
transꢀ3h
transꢀ3i
transꢀ3j
transꢀ3k
transꢀ3m
transꢀ11h
transꢀ11i
transꢀ11j
56
63
52
threo12h
threo12i
25
threoꢀ12j
28
erythroꢀ12k
erythroꢀ12m
87
92
aIsolated yields.
Table 14. Detrimethylsilylation of transꢀ3hꢀk,m with 1M HCl aq/dioxane (1/1)
O
O
X
X
1M HCl aq
MeN
O
MeN
O
OH
Ar
OTMS
Ar
N
N
dioxane
25 °C
Me
Me
Ar
Ar
trans-11h-j X = Me
trans-11k,m X = F
trans-3h-j X = Me
trans-3k,m X = F
run
transꢀ
3
time
transꢀ11
% yield of
transꢀ11a
1
2
3
4
5
transꢀ3h
transꢀ3i
transꢀ3j
transꢀ3k
transꢀ3m
12 h
12 h
12 h
8 h
transꢀ11h
transꢀ11i
transꢀ11j
transꢀ11k
transꢀ11m
96
94
84
95
92
8 h
aIsolated yields.
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5
5
6
6.
Assignment
of
Geometric
Isomers
of
5,6ꢀDisubstituted
1,3ꢀDimethylꢀ5,6ꢀdihydrouracils.
1
Table 15 exhibits H NMR chemical shifts of 6ꢀΗ and coupling constants between 5ꢀH
and 6ꢀH (J5,6) of 5,6ꢀcisꢀ and transꢀsubstituted 5,6ꢀdihydroꢀ1,3ꢀdimethyluracils obtained in
this paper. These results indicate that the J5,6 values of 5,6ꢀdisubstituted uracils are within
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5.3~8.0 Hz for cis and 0~2.6 Hz for trans. Consequently, the geometric structure of
1
5,6ꢀdisubstituted 5,6ꢀdihydrouracils can readily be assigned by the J5,6 values of their H
NMR spectra.
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Table 15. H NMR Chemical Shifts of 6ꢀH and Coupling Constants (J5,6) of 5,6ꢀcisꢀ and
transꢀSubstituted 1,3ꢀDimethylꢀ5,6ꢀdihydrouracils
cis
trans
6
ꢀH (δ)
4.45
4.24
4.41
4.16
4.38
4.13
J
5,6 (Hz)
6.3
5.8
6ꢀH (δ)
4.09
3.93
4.03
3.86
4.02
3.83
J
5,6 (Hz)
0a
0a
3h
1h
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
31
32
33
34
35
36
37
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39
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
i
6.3
5.4a
0
0
1
1i
3j
1j
1j’
6.9
0
0a
1
5.9
1
4.41a
4.96
4.71
4.90
4.67
4.88
4.63
4.71
4.61
3.77
3.52
4.72
5.45
3.90
3.90
3.68
3.22
4.56
3.75
3.37
3.97
3.84
5.03
5.75
4.22
3.93
3.99
3.54
4.93
4.13
3.66
6.7
3k
8.0
4.61
4.44
0
0
11k
6.9
7.7a
3l
11l
6.9
8.0
3m
4.53
4.34
0
0
11m
6.9
7.7a
3n
11n
6.7a
6.3
5.3
7.0
7.3
6.3a
6.0
6.2
5.9
6.9
6.1
5.6a
6.7
6.2
6.9a
7.5
6.9a
6.6
6.9
6.7
6.9a
7.0
6.9
erythroꢀ5f
threoꢀ5f
8f
4.21
4.95
3.40
3.41
0
2.3
0
10f
erythroꢀ13f
threoꢀ13f
erythroꢀ5g
threoꢀ5g
8g
0
erythroꢀ13g
threoꢀ13g
erythroꢀ5h
threoꢀ5h
3.36
3.07
1.1
0a
8
h
4.83
5.54
2.5
2.6
10h
erythroꢀ13h
threoꢀ13h
erythroꢀ5i
threoꢀ5i
8
i
erythroꢀ13i
threoꢀ13i
a
Confirmed by Xꢀray crystallography.
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