Synthesis of 1,6-dihydropyrimidines via copper-catalyzed multistep cascade reactions between O-propargylic aldoximes and isocyanates

Article abstract of DOI:10.1016/j.tetlet.2013.12.105

Multi-step cascade reactions of O-propargylic oximes with isocyanates were carried out in the presence of copper catalysts to afford the corresponding 1,6-dihydropyrimidines in good yields. The multi-step reactions consisted of a 2,3-rearrangement, a [3+2] cycloaddition, decarboxylative ring opening involving a 1,4-hydrogen shift, and a 6π-electrocyclization.

Full text of DOI:10.1016/j.tetlet.2013.12.105

Tetrahedron Letters 55 (2014) 1178–1182
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Tetrahedron Letters
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Synthesis of 1,6-dihydropyrimidines via copper-catalyzed multistep
cascade reactions between O-propargylic aldoximes and isocyanates
b
b
a,b
Itaru Nakamura a, , Toshiki Onuma , Dong Zhang , Masahiro Terada
⇑
a Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
b Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Multi-step cascade reactions of O-propargylic oximes with isocyanates were carried out in the presence
of copper catalysts to afford the corresponding 1,6-dihydropyrimidines in good yields. The multi-step
reactions consisted of a 2,3-rearrangement, a [3+2] cycloaddition, decarboxylative ring opening involving
Received 1 November 2013
Revised 9 December 2013
Accepted 25 December 2013
Available online 3 January 2014
a 1,4-hydrogen shift, and a 6p-electrocyclization.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Cascade reaction
Copper-catalyzed
Rearrangement
Alkyne
Oximes
Multi-step cascade reactions have been proven to provide
highly efficient transformations in the synthesis of highly elaborate
molecules starting from readily available compounds in a single
operation.1 The attractive feature of such methodology can be
attributed to the continuous generation of reactive and often elu-
sive intermediates that are kinetically or thermodynamically
unstable and/or difficult to prepare.1 In many cases, such cascade
N-O bond
cleavage
C
O
C
N
C
C
C
(a)
N
C
1,3-oxygen
migration
[3+2]
O
•
O
N
M
N
O
ref. 4f
•
2,3
O
C
N
O
C
N
A
O
(b)
heterocycle
?
N
reactions can be triggered by p-acidic metal catalysts that can gen-
N-O bond
cleavage
- CO2
[3+2]
erate the reactive species in the initial step, under mild reaction
conditions, under high tolerances of various functional groups.2,3
Recently, we reported that N-allenylnitrone intermediate A can
•
This work
B
be efficiently generated from O-propargylic oximes via
p-acidic
Scheme 1. [3+2] Cycloaddition followed by N–O bond cleavage for N-allenylnitrone
intermediate A with (a) olefins and (b) isocyanates (present work).
copper-catalyzed 2,3-rearrangement (Scheme 1).4 More recently,
we carried out the intermolecular cascade reactions involving elec-
tron-deficient olefins such as maleimides and fumaric acid esters
(Scheme 1a).4f The reactions proceeded via a [3+2] cycloaddition
between N-allenylnitrone A and the olefin, followed by a N–O bond
cleavage resulting in a 1,3-oxygen migration. In contrast, we
envisioned that the sequence of [3+2] cycloaddition/N–O bond
cleavage should proceed differently for reactions involving isocya-
nates as the dipolarophile because N-allenyloxadiazolidinone
species B would favor the liberation of CO2 rather than undergo a
1,3-oxygen migration (Scheme 1b).5,6 Herein, we report on the
copper-catalyzed reactions of O-propargylic aldoximes 1 and iso-
cyanates 2, in which the multi-step cascade sequence proceeded
via a 2,3-rearrangement, a [3+2] cycloaddition, decarboxylative
ring opening involving a 1,4-hydrogen migration, and a 6p-electro-
cyclization, to afford the corresponding 1,6-dihydropyrimidines 3
in good yields (Eq. 1).
R3
H
R3
R4
R4
R2
cat. CuBr / SPhos
N
N
N
O
•
+
O
N
ð1Þ
R1
R2
H
3
R1
1
2
Initially, the reaction conditions were optimized using (E)-1a
and N-(p-toluenesulfonyl)isocyanate 2a (1.2 equiv), as summa-
rized in Table 1. The reaction was carried out in 1,2-dichloroethane
⇑
Corresponding author. Tel.: +81 22 795 6754; fax: +81 22 795 6602.
E-mail address: itaru-n@m.tohoku.ac.jp (I. Nakamura).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.105

I. Nakamura et al. / Tetrahedron Letters 55 (2014) 1178–1182
1179
Table 1
Optimization of the reaction conditions
H
Ph
Ph
10 mol % [catalyst]
R4
R4
Ph
O
N
10 mol % [ligand]
R4
N
N
N
N
O
N
+
+
+
•
O
DCE (0.5 M)
80 °C
Ph
Ph Ph
Ph
Ph
Ph
H
3
Ph
2
(E)-1a
4
5a
(1.2 equiv)
3a (R4 = Ts)
2a (R4 = Ts)
4
(R4 = p-FC6H4SO2)
3b
3c
3d
2b
2c
2d
(R = p-FC6H4SO2)
(R4 = Bz)
(R4 = Bz)
4
(R4 = p-O2NC6H4)
(R = p-O2NC6H4)
Catalyst
Ligand
2
Time (h)
Yielda (%)
3
4
5
1
2
3
4
5
6
7
8
CuCl
CuBr
CuI
[CuCl(cod)]2
Cu(OAc)2
[Cu(CH3CN)4]PF6
none
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuCl
Cu(OAc)2
CuBr
None
None
None
None
None
None
None
None
None
None
PtBu3
PCy3
SPhos
PPh3
SPhos
SPhos
SPhose
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2a
2a
2a
2a
2a
2a
2a
7
5
21
2
4
44
15
21
18
25
8
20
4
36
<1
6
19
18
16
18
13
9
12
6
5
43
42
33
45
36
<1
24
<1
10
48
45
51
33
40
44
b
7
13
<1
<1
6
<1
25
6
9
7
24
<1
14
<1
2
48c
12
48
10
6
9
10
11
12
13
14
15
16
17d
6
12
23
24
12
18
58f
16
a
b
c
d
e
f
The yields were determined by 1H NMR using dibromomethane as an internal standard.
5 mol %.
65% of 1a was recovered.
0.25 M.
11 mol % of SPhos was used.
9% of 6a was obtained.
H
R4
N
N
PCy2
OMe
MeO
Ph
Ph
Ph
6
SPhos
Table 2
Substitution effects at the oxime moietya
H
O
R3
R3
H
10 mol % CuBr
11 mol % SPhos
Ts
Ts
Ts
N
N
Ts
N
N
N
N
+
+
+
•
O
N
R3
DCE, 80 °C
Ph
Ph
Ph
Ph
Ph
H
3
R3
6
4
Ph
1
2a
(E)-
1
R3
Time (h)
Product (% yield)
3b
6c
4c
1
2
3
4
5
1b
p-F3CC6H4
p-ClC6H4
Ph
p-MeOC6H4
Cy
24
14
18
12
6
3e (39)
3f (51)
3a (56)
3g (52)
3h (30)
6e (4)
6f (7)
6a (8)
6g (21)
—
4e (21)
4f (18)
4a (16)
4g (11)
4h (17)
1c
1a
1d
1e
a
The reactions of (E)-1 (0.20 mmol) and N-tosylisocyanate 2a (0.24 mmol) were carried out in the presence of CuBr
(10 mol %) and SPhos (11 mol %) in 1,2-dichloroethane (0.8 mL) at 80 °C.
b
Isolated yields.
c
The yields were determined by 1H NMR using dibromomethane as an internal standard.
(DCE), in the presence of CuBr (10 mol %), at 80 °C to afford 2,4,6-
triphenyl-1-tosyl-1,6-dihydropyrimidine 3a (43% yield), along
with N-tosylbenzaldimine 4a (21% yield), and the four-membered
cyclic nitrone 5a (6% yield) (entry 2).7 Cu(I) and Cu(II) salts such
as CuCl, CuI, and Cu(OAc)2 exhibited comparable catalytic
activities, whereas the use of [CuCl(cod)]2 or [Cu(CH3CN)4]PF6 re-
sulted in a lower yield (entries 1–6). The use of transition metal
salts such as AgOTf, AuCl, PtCl2, and InCl3 did not promote the pres-
ent reaction (See Supporting information). The reaction in the ab-
sence of copper catalysts did not afford the desired product 3a at

1180
I. Nakamura et al. / Tetrahedron Letters 55 (2014) 1178–1182
all; a trace amount (4%) of the imine 4a was obtained along with
65% of the recovered 1a (entry 7). The reaction of arenesulfonyl
isocyanate 2b, which possesses an electron-deficient aryl group,
resulted in the predominant formation of the undesired imine
4b, while those of N-benzoyl- and N-(p-nitrophenyl)isocyanate
were sluggish (entries 8–10). In terms of the ligands, bulky and
electron-donating phosphine ligands such as t-Bu3P and SPhos8 re-
sulted in higher yields of 3a (entries 11–13). Reaction conditions,
such as concentration and loading amounts of SPhos, were opti-
mized to ultimately afford 3a in an acceptable yield (entry 17).
During the optimization process, we noticed the formation of a
small amount of byproduct 6 due to the migration of the phenyl
group in all entries in Table 1, except for entries 7 and 9. For exam-
ple, 6a (R4 = Ts) was obtained in 9% yield under the optimized reac-
tion conditions (entry 17).
The ratio between the hydrogen-migration product 3 and the
aryl-migration product 6 is apparently dependent on the electronic
character of the oxime substituent R3, as summarized in Table 2.
Substrates 1b and 1c, which possess an electron-deficient aromatic
group, selectively favored hydrogen-migration, whereas substrates
with electron-rich aromatic groups shifted the reaction towards
aryl-migration (entries 1–4). It should be noted that, for the reac-
tions between 1e and 2a (entry 5), the migration of the cyclohexyl
group was not observed.
Next, the substitution effects on the propargyl group of oxime
(E)-1 were investigated, as summarized in Table 3. For substituents
on the alkyne terminus, the reaction was able to tolerate both aryl
and alkyl substituents (entries 1–4). Substitution at the propargylic
position by an electron-donating anisyl group resulted in a rapid
reaction, affording the desired product 3m in a good yield (entry
5). Arylaldoxime 1l, which possesses an electron-withdrawing
p-trifluoromethylphenyl group at R2, was converted in the absence
of SPhos into product 3o in an acceptable yield (entry 7); the
reaction of 1l and 2a in the presence of SPhos resulted in lowering
the chemical yield (34%). Substrate 1m, which possesses an alkyl
group at the propargylic position was significantly less reactive,
with the recovery of 70% of 1m (entry 8). It should be noted that
for every reaction (listed in Table 3), byproducts were also
detected; specifically, phenyl-migration product 6 (ca. 5–10%)
and N-tosylimine 4a (ca. 10–20%) (see Supporting information).
Using the optimized reaction conditions, the reaction of Z oxime
(Z)-1b and 2a afforded the same dihydropyrimidine 3e as that of E
oxime (E)-1b (Eq. 2 and Table 2, entry 1). In the absence of the
copper catalyst, however, the reaction favored the formation of
tosylimine 4e rather than 3e.
Ar
H
Ar
Ts
Ph
Ts
w/ or w/o Cu catalyst
DCE, 80°C
N
N
N
N
Ts
O
+
+
•
O
N
Ph
Ar
Ph
ð2Þ
H
4e
Ph
2a
(1.2 equiv)
3e
(Z)-1b
Ar: p-F3CC6H4
w/ CuBr, SPhos
w/o Cu catalyst
30%
<1 %
20%
43%
To gain insight into the mechanisms of the reaction, specifically
that of the hydrogen atom at the oxime moiety, the reaction was
carried out using deuterium-labeled substrates (Eqs. 3 and 4).
The reaction of deuterated (E)-1a-d (99%-deuterated at the oxime
moiety) with N-tosylisocyanate 2a afforded 3a-d (15% yield, 99%-
deuterated at the 5-position), along with the phenyl-migration
product 6a-d (15% yield) and N-tosylimine 4a-d (Eq. 3). The results
clearly indicate that the hydrogen atom at the 5-position of dihy-
dropyrimidine 3 is attributable to the aldoxime hydrogen atom
of substrate 1. Because the yield was significantly affected by deu-
terium-labeling (lower yield of 3a-d versus 3a, Table 1, entry 17),
the reaction was repeated using a 1:1 mixture of 1a and 1a-d (total
amount, 1 mmol) with isocyanate (1.2 mmol) under standard con-
ditions (Eq. 4). The results showed that the deuterium content of
the product 3a-d at the 5-position was 29%, suggesting that the
hydrogen-migration step was decelerated by deuterium-labeling.
Accordingly, the deuterium-to-hydrogen ratio of the phenyl-
migration product 6a-d, which formed without involving C-H(D)
bond cleavage, was higher than 50%. Furthermore, because the
deuterium content of recovered substrate 1a was 50%, there is no
difference in the consumption rate of 1a and 1a-d, which implies
that the hydrogen migration process occurs (at the least) after
the irreversible elemental process(es).
D
Ph
10 mol % CuBr
11 mol % SPhos
Ts
N
•
O
N
O
+
DCE (0.25 M), 80 ºC
18 h
Ph
2a
Ph
1a-d
(99% D)
Ph
D
ð3Þ
Ts
Ts
Ts
D
N
N
N
N
N
+
+
Ph
Ph
Ph
Ph
Ph
D
Ph
6a-d
15% yield
(99% D)
3a-d
15% yield
(99% D)
4a-d
23% yield
(99% D)
Table 3
Cu-catalyzed reactions of 1f–m and N-tosylisocyanate 2aa
H
Ph
Ph
H
O
Ph
D
O
Ph
10 mol % CuBr
Ts
11 mol % SPhos
N
Ts
N
N
N
N
Ts
O
+
+
•
+
O
N
as above
2 h
•
N
O
DCE, 80 °C
R2
R1
R2
Ph
Ph
H
3
R1
2a
Ph
Ph
2a
1.20 mmol
1
(E)-
1a
1a
-d
0.50 mmol
0.50 mmol
1
R1
R2
Time (h)
3
Yieldb (%)
ð4Þ
H/D
Ph
Ph
H/D
1
2
3
4
5
1f
p-MeOC6H4
p-ClC6H4
p-F3CC6H4
Cy
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
10
18
12
24
6
10
12
48
3i
3j
51
45
48
55
64
63
43
7d
Ts
Ts
Ts
N
O
1g
1h
1i
N
N
N
N
N
+
+
+
3k
3l
3m
3n
3o
3p
Ph
H/D
Ph
Ph
Ph
Ph
Ph
H/D
Ph
Ph
1j
p-MeOC6H4
p-MeC6H4
p-F3CC6H4
Cy
6
1k
1l
1m
1a
3a
6a
-d
0.10 mmol
(H/D=36/64)
4a
-d
0.14 mmol
(H/D=71/29)
-d
7c
8
0.26 mmol
0.14 mmol
(H/D=50/50)
(H/D=36/64)
a
The reactions of (E)-1 (0.20 mmol) and N-tosylisocyanate 2a (0.24 mmol) were
Based on our experimental results, a probable reaction mecha-
nism between 1 and 2a is illustrated in Scheme 2, which is based
on the -acidity and on the single-electron redox ability of the cop-
per catalyst. First, the -acidic copper catalyst coordinates to the
triple bond of 1 to form -complex 7. Next, the enhanced electro-
carried out in the presence of CuBr (10 mol %) and SPhos (11 mol %) in 1,2-dichlo-
roethane (0.8 mL) at 80 °C.
p
b
Isolated yields.
Without SPhos.
70% of 1m was recovered.
c
p
d
p

I. Nakamura et al. / Tetrahedron Letters 55 (2014) 1178–1182
1181
O
Ts
H
N
R3
O
R3
N
Ts
R2
R3
N
N
[Cu]
[Cu]
R1
•
R1
N
O
R2
10
H
R2
13
CO2
[Cu]
TsNCO
R1
6π
1
2a
Ts
[Cu]
N
N
R3
Ts
H
R3
H
N
R3
Ts
R2
O
N
R3
N
N
R3
R1
H
N
R1
R1
•
R1
•
R2
N
H
O
R2
12
R2
R3
R1
9
3
R2
11
N
O
R1
R2
[Cu]
Ts
Cu
4π
Ts
R3
H
[Cu]
H
N
N
7
[Cu]
Ts
N
N
H
N
N
R3
O
8
R3
N
R2
R1
R1
R1
R3
R2
R1
R2
R2
5
6
11'
12'
Scheme 2. A plausible mechanism.
philic triple bond undergoes a nucleophilic attack by the oxime
nitrogen atom to form cyclized intermediate 8. Subsequent cleav-
age of the C–O bond and elimination of the copper catalyst gener-
ates the N-allenylnitrone intermediate 9, which immediately
undergoes a [3+2] cycloaddition with isocyanate 2a to give 2-alle-
nyl-1,2,4-oxadiazolidin-5-one 10. Cleavage of the N–O bond via
single-electron transfer from the copper catalyst followed by
decarboxylation leads to aminyl radical species 11. The subsequent
1,4-hydrogen-migration9 and elimination of the copper catalyst af-
cascade reaction involves a 2,3-rearrangement, a [3+2] cycloaddi-
tion, decarboxylative ring opening with a 1,4-hydrogen migration,
and a 6p-electrocyclization, to afford the corresponding 1,6-dihy-
dro-pyrimidines 3 in good yields. Dihydropyrimidines are often em-
ployed as synthetic intermediates of heterocyclic compounds,13
although previous preparation methods are still limited in the sub-
stitution pattern and required higher reaction temperature.14
Therefore, the present methodology may prove to be highly useful
and effective for synthesis of a new class of 1,6-dihydropyrimidines.
ford 1,3-diazatriene 13, which undergoes a 6p-electrocyclization
step to form product 3.10 As a note, the formation of 1,4,5,6-tetra-
substituted dihydropyrimidine 6 is attributable to the 1,4-aryl-
migration11 from 11, instead of a 1,4-hydrogen-migration. The
preferential migration of electron-rich aryl groups is in good agree-
ment with our proposed mechanism (Table 2). The reaction be-
tween (Z)-1b and 2a in the absence of copper catalysts gave
neither the desired product 3e nor the four-membered cyclic nit-
rone 5b (Eq. 2), despite our knowledge that both 2,3-rearrange-
ment of (Z)-1b and following [3+2] cycloaddition, which is faster
Acknowledgments
We thank Prof. Takeaki Iwamoto and Prof. Shintaro Ishida
(Tohoku University, Japan) for X-ray crystallographic expertise.
This work was supported by a Grant-in-Aid for Scientific Research
on Innovative Areas ‘Molecular Activation Directed toward
Straightforward Synthesis’ from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
than 4p-electrocyclization, proceed even in the absence of the cop-
Supplementary data
per catalyst.4d This result strongly suggests that the decarboxyla-
tive re-cyclization process from 10 to 3 is also promoted by the
copper catalyst.12 In addition, only copper salts exhibited catalytic
activity toward the present reaction, perhaps because copper cata-
Supplementary data (experimental procedures and character-
ization of the products 3 and 6) associated with this article can
be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.12.105.
lyst efficiently serves as not only
p-acidic metal catalyst to pro-
mote the first catalytic cycle from 1 to 9 but also single-electron
redox catalyst from 10 to 3. It is possible that the bulky and elec-
tron-donating SPhos would promote the N–O bond cleavage pro-
cess from 10 to 11 and stabilize the intermediate 11, suppressing
unfavorable decomposition pathways. Presumably, N-tosylimine
4 is formed via several reaction pathways, such as thermal decom-
position of oxadiazolidin-5-one 10, elimination from radical inter-
mediate 11, and reaction between the iminium intermediate 8
with tosylamine (TsNH2), which is generated by hydrolysis of tosy-
lisocyanate 2a. Low reactivity of the substrate 1m (Table 3, entry 8)
is probably because the C–O bond cleavage process from the vinyl-
copper intermediate 8 to the N-allenylnitrone 9 is decelerated by
the alkyl substituent at the propargylic position.4d Further mecha-
nistic studies are underway in our laboratory.
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aldoximes 1 and isocyanates 2. Our copper-catalyzed multi-step

1182
I. Nakamura et al. / Tetrahedron Letters 55 (2014) 1178–1182
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Dtsch. Chem. Ges. 1890, 23, 3319; (c) Black, D. S. C.; Crozier, R. F.; Davis, V. C.
Synthesis 1975, 7, 205; (d) Ritter, T.; Carreira, E. M. Angew. Chem., Int. Ed. 2005,
44, 936.
10.
6
p
-Electrocyclization of 1,3-diaza-1,3,5-triene Rossi, E.; Abbiati, G.; Pini, E.
Synlett 1999, 1265.
11. 1,4-Aryl shift (a) Studer, A.; Bossart, M. Tetrahedron 2001, 57, 9649; (b)
Senboku, H.; Hasegawa, H.; Orito, K.; Tokuda, M. Tetrahedron Lett. 2000, 41,
5699.
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Matsuoka, T.; Suematsu, F.; Ohizumi, N. Chem. Pharm. Bull. 1985, 33, 1869; (c)
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7. The positions of the substituent were unambiguously assigned using the X-ray
crystallographic analysis of 3q, which was obtained from the reaction of 1n
(R1 = p-anisyl, R2 = Ph, R3 = p-F3CC6H4) and N-tosylisocyanate 2a.
8. Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc.
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12. In contrast to the Z oxime (Z)-1, the E oxime (E)-1a resulted in the recovery of
(E)-1a under thermal reaction conditions in the absence of copper catalysts
(Table 1, entry 7). This is because concerted 2,3-rearrangement from 1 to 9 was
interfered by the oxime substituent at the E position. See Ref. 4d.
13. Weis, A. L.; van der Plas, H. C. Heterocycles 1986, 24, 1433.
14. Synthesis of 1,6-dihydropyrimidines (a) Kunckell, F.; Sarfert, O. Chem. Ber.
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Cho, H.; Nishimura, Y.; Yasui, Y.; Yamaguchi, M. Tetrahedron Lett. 2012, 53,
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9. 1,4-Hydrogen shift (a) Chen, S.-H.; Huang, S.; Gao, Q.; Golik, J.; Farina, V. J. Org.
Chem. 1994, 59, 1475; (b) Montevecchi, P. C.; Navacchia, M. L. Tetrahedron Lett.