Potassium phosphate promoted aza-Markovnikov addition of N-heterocycles to vinyl esters

Article abstract of DOI:10.1055/s-2007-983733

Anhydrous potassium phosphate promoted the aza-Markovnikov addition of a variety of N-heterocycles to vinyl esters in DMF at room temperature in moderate to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983733

PAPER
1933
Potassium Phosphate Promoted Aza-Markovnikov Addition of N-Heterocycles
to Vinyl Esters
K
PO -Promo
o
n
ovnikov Add
g
ition of
N
-H
-
eterocyc
w
les to
V
inyl
E
ster
e
s
n Lin,a Qi Sun,a Run-tao Li,*a,b Tie-ming Cheng,a Ze-mei Ge*a
3
4
a
School of Pharmaceutical Sciences, Peking University, Beijing 100083, P. R. of China
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100083,
b
P. R. of China
Fax +86(10)82716956; E-mail: zmge@bjmu.edu.cn
Received 5 February 2007; revised 27 April 2007
Br
Br
N
N
O
R1
Abstract: Anhydrous potassium phosphate promoted the aza-
Markovnikov addition of a variety of N-heterocycles to vinyl esters
in DMF at room temperature in moderate to excellent yields.
Br
O
R2
O
N
Cl
R2
O
R1
Key words: aza-Markovnikov addition, anhydrous K3PO4, N-het-
erocycles, vinyl esters, 1-[N-(N-heterocycle)]alkyl esters
B
A
R4
N
R3
R5
O
As a subset of heterocyclic compounds, 1-[N-(N-hetero-
cycle)]alkyl esters possess valuable biological activities
and can act as, amongst others, acaricides (A),1a,b antimi-
crobials (B),1c antitumor drugs (C)1d and (H+-K+)-ATPase
inhibitors (D)1e (Figure 1). Their preparation is usually
through the nucleophilic substitution of N-heterocycles to
1-haloalkyl esters and acetals,1c–e,2 acylation of N-hy-
droxyalkyl heterocycles,1e,2b,3 reaction of N-acyl heterocy-
cles with aldehydes,4 and aza-Markovnikov addition of N-
heterocycles to vinyl esters.5 Among these approaches,
aza-Markovnikov addition of N-heterocycles to vinyl es-
ters has recently received much attention. Such aza-Mark-
ovnikov additions were traditionally performed under
harsh reaction conditions in which bases, acids and strong
heating were usually used to promote the reaction. In or-
der to avoid these disadvantages, Lin and co-workers de-
veloped two effective methods, one was the use of ionic
liquid as a catalyst and reaction medium,6 and the second
was the use of acylases as biocatalysts.7 Nevertheless, a
mild and more general method for performing such aza-
Markovnikov additions was still desirable.
F
N
HN
X
O
O
N
O
N
R1
O
R2
R1
O
R2
D
C
Figure 1
nyl acetate (2a, 4 mmol), in the presence of anhydrous
K3PO4 (0.3 mmol), in acetone as solvent, at room temper-
ature, and found that the expected compound 3a was
formed in 84% yield.
O2N
O
N
N
base, solvent
r.t.
O2N
+
O
N
O
N
H
O
1a
2a
3a
Over the past few years, anhydrous potassium phosphate
(K3PO4) has been widely used as mild base in reactions
such as Suzuki cross-coupling,8 transition metal catalyzed
C–N coupling9 and oxidative coupling of thiols to disul-
fides.10 Using anhydrous K3PO4 as base, our group has
successfully carried out the syntheses of tetra-O-acetyl-
glycosides,11 dithiocarbamates,12 thiazolidines13,14 and
1,3,4-thiadiazoles.14 Here, as an extension of this work,
we would like to report a mild and efficient anhydrous
K3PO4-promoted aza-Markovnikov addition of N-hetero-
cycles to vinyl esters.
Scheme 1
Encouraged by this result, we then employed this reaction
as a template with which to optimize the reaction condi-
tions (Scheme 1). Firstly, the reaction was performed in a
range of solvents such as acetone, methanol, chloroform
and dimethylformamide (Table 1, entries 1–4), with the
latter being found to be best in terms of both yield and re-
action time (95%, 10 h). Six weak bases were then exam-
ined using DMF as solvent (Table 1, entries 4–9).
Comparing the results, anhydrous K3PO4 was found to be
the most efficient base, giving the product 3a in 95%
yield. Other weak inorganic bases, such as K2HPO4,
K2CO3, KHCO3, afforded lower yields even with longer
reaction times, while KH2PO4 and the organic base Et3N,
gave only a trace of product. Upon examining the influ-
ence of the amount of anhydrous K3PO4 on the reaction, it
Initially, we evaluated the feasibility of aza-Markovnikov
addition of 2-methyl-5-nitroimidazole (1a, 1 mmol) to vi-
SYNTHESIS 2007, No. 13, pp 1933–1938
x
x.
x
x
.
2
0
0
7
Advanced online publication: 18.06.2007
DOI: 10.1055/s-2007-983733; Art ID: F02707SS
© Georg Thieme Verlag Stuttgart · New York

1934
S.-w. Lin et al.
PAPER
Table 1 Markovnikov Addition of 2-Methyl-5-nitroimidazole (1a) to Vinyl Acetate (2a)a
Entry
1
Solvent
Acetone
MeOH
CHCl3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Base
Time (h)
72
1a:2a:base (equiv)
1:4:0.3
1:4:0.3
1:4:0.3
1:4:0.3
1:4:0.3
1:4:0.3
1:4:0.3
1:4:0.3
1:4:0.3
1:4:0.2
1:4:0.5
1:4:1
Yield (%)b
K3PO4
K3PO4
K3PO4
K3PO4
K2HPO4
KH2PO4
K2CO3
KHCO3
Et3N
84
2
30
56
3
30
38
4
10
95
5
48
78
6
48
trace
94
7
36
8
48
80
9
48
trace
85
10
11
12
13
14
15
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
30
10
94
10
91
20
1:3:0.3
1:2:0.3
1:1:0.3
89
48
84
60
75
a All reactions were run at r.t. using 1a (1.0 mmol) in the indicated solvent (2 mL).
b Isolated yields.
was found that 0.3 equivalent of anhydrous K3PO4 was that this is the first time benzotriazole has been success-
sufficient to promote the reaction. In the presence of less fully used as a donor in Markovnikov addition to vinyl es-
than this amount, the yield dropped dramatically, even if ters.15 Furthermore, 5-fluorouracil acted as a novel donor
longer reaction times were used (Table 1, entry 10). When for Markovnikov addition, to give a moderate yield (51%)
the amount of anhydrous K3PO4 was increased over 0.3 of 3k at 50 °C in 24 hours (Table 2, entry 11), which con-
equivalent, however, neither the yield nor the reaction stitutes a significant improvement over the best literature
time was improved (Table 1, entries 11 and 12). Finally, results, i.e. using the ionic liquid method6a (35% yield ) or
the influence of the amount of vinyl acetate relative to 2- the biocatalytic method (24%).7c In addition to the various
methyl-5-nitroimidazole was investigated. The best result heterocycle donors, we also investigated the Markovnik-
was obtained when a 4:1 equivalent of the former to the ov additions of 2-methyl-5-nitroimidazole to representa-
latter was used (Table 1, entries 13–15 vs. entry 4).
tive vinyl esters. Compared with vinyl acetate, excellent
yields were also obtained for vinyl butyrate (entry 12,
94%, 30 h) and vinyl benzoate (entry 13, 93%, 30 h) by
prolonging the reaction time and/or raising the reaction
temperature, though their reactivity was lower than that of
vinyl acetate.
With optimized experimental conditions in hand, we pro-
ceeded to investigate the substrate generality of the reac-
tion system; the results are summarized in Table 2. A
variety of N-heterocycles, such as imidazoles, pyrrole,
1,2,4-triazole, benzotriazole and benzimidazole, reacted
smoothly with vinyl acetate at room temperature, to afford On the basis of the experimental results, a possible mech-
the corresponding Markovnikov adducts in good to excel- anism for the formation of compounds 3 is proposed in
lent yields. Even 1H-imidazole-4-carbaldehyde, with an Scheme 2. The N-heterocycle anion (Nu–), formed from
oxidant-sensitive formyl group (entry 5, 90%) and methyl N-heterocycle 1 through the action of K3PO4, could react
3-(1H-imidazol-4-yl) acrylate, with both a base/acid-sen- with vinyl ester 2, affording the N-acyl heterocycle 4 and
sitive ester group and an oxidant-sensitive C=C bond, acetaldehyde (5). Acetaldehyde (5) would then be at-
gave excellent yields of product (entry 6, 94%). Benzotri- tacked by Nu– to form the hemiaminal 6. The target prod-
azole provided the N-1 adduct (3i-1, 78%) and the N-2 ad- ucts 3 would be generated from the reaction of 6 with the
duct (3i-2, 17%) with a total yield of 95%. It is noteworthy formerly formed N-acyl heterocycle 4.
Synthesis 2007, No. 13, 1933–1938 © Thieme Stuttgart · New York

PAPER
K3PO4-Promoted Aza-Markovnikov Addition of N-Heterocycles to Vinyl Esters
1935
Table 2 Markovnikov Addition of N-Heterocycles to Vinyl Esters Promoted by Anhydrous K3PO4 in DMFa
Entry
1
Nu-H
R
Product
Time (h)
10
Yield (%)b
95
O2N
Me
3a
N
N
O2N
N
H
N
O
O
2
3
4
Me
Me
Me
3b
3c
3d
24
24
10
88
82
97
N
N
N
N
H
O
O
N
N
N
O
N
N
H
O
O2N
O2N
N
N
N
O
H
O
5
6
Me
Me
3e
3f
10
10
90
94
OHC
OHC
N
N
N
N
O
H
O
MeO2C
MeO2C
N
N
N
N
O
H
O
7
8
Me
Me
3g
3h
24
10
78
97
N
O
N
H
O
N
N
N
N
N
N
O
H
O
9c
Me
3i-1
3i-2
10
78
17
N
N
N
N
N
O
N
H
O
N
N
N
O
O
10
Me
Me
3j
10
24
79
51
N
N
N
O
N
H
O
11d
3k
O
O
F
F
HN
HN
O
N
O
N
O
H
O
Synthesis 2007, No. 13, 1933–1938 © Thieme Stuttgart · New York

1936
S.-w. Lin et al.
PAPER
Table 2 Markovnikov Addition of N-Heterocycles to Vinyl Esters Promoted by Anhydrous K3PO4 in DMFa (continued)
Entry
12
Nu-H
R
Product
Time (h)
30
Yield (%)b
n-Pr
3l
94
N
O2N
O2N
N
N
H
N
N
O
O
O
n-Pr
13d
Ph
3m
30
93
N
O2N
O2N
N
N
H
O
Ph
a Reactions were carried out at r.t. on 1.0 mmol scale of N-heterocycles with vinyl esters (4 equiv) and anhyd K3PO4 (0.3 equiv) in DMF (2 mL).
b Isolated yields.
c 3i-1 was the N-1 adduct formed with a yield of 78%, while 3i-2 was the N-2 adduct formed with a yield of 17%.
d Reaction was performed at 50 °C.
K3PO4
92% (20 h) in the presence of 1, 2 and 4 equivalents of ac-
Nu
O
etaldehyde, respectively. These results demonstrate that
acetaldehyde must form as an intermediate during the re-
action.
O
Nu–
Nu-H
O
R
O
R
2
1
3
In addition, in order to clarify whether the hemiaminal in-
termediate 6 preferentially attacked the N-acyl heterocy-
cle 4 in the process of reaction, we mixed 1a, 2a and 7
with an equivalent ratio of 1:4:1 in DMF at room temper-
ature and monitored the reaction by TLC (Scheme 4). It
was found that 3m was the major product, with only a
trace of 3a being detected before 10 hours. After about 10
hours, the amount of reagent 7 began to decrease and the
amount of 3a began to increase. These results indicate that
the acyl group of product 3 comes from the N-acyl hetero-
cycle 4, rather than from the vinyl ester.
Nu-COR
Nu-COR
4
Nu
4
MeCHO
O–
5
6
Nu–
Scheme 2
If this mechanism were reasonable, addition of excess
acetaldehyde would be expected to accelerate the rate of
reaction. Hence, we selected the reaction of 2-methyl-5-
nitroimidazole with vinyl benzoate at room temperature in
order to examine the influence of acetaldehyde on the re-
action rate and yield (Scheme 3). It was found that 3m
was obtained with yields of 59% (48 h), 93% (48 h) and
In summary, we have developed an anhydrous K3PO4-
promoted aza-Markovnikov addition of a variety of N-
heterocycles to vinyl esters. This procedure offers several
advantages including mild condition, high yields, inex-
pensive catalyst, wide scope of substrates and operational
simplicity.
O2N
N
O
N
K3PO4, DMF
O2N
+
MeCHO
+
N
O
O
Ph
N
r.t.
H
O
Ph
1a
2m
5
3m
Scheme 3
O2N
O2N
N
N
O
N
N
O2N
K3PO4, DMF
r.t.
N
O2N
+
+
+
N
O
O
N
O
N
H
O
Ph
O
Ph
O
1a
2a
7
3a
3m
Scheme 4
Synthesis 2007, No. 13, 1933–1938 © Thieme Stuttgart · New York

PAPER
K3PO4-Promoted Aza-Markovnikov Addition of N-Heterocycles to Vinyl Esters
1937
All reagents and solvents were obtained from commercial sources.
Melting points were determined on a X4 microscope. IR spectra
were recorded on a NEXUS-470 FTIR spectrophotometer. 1H NMR
was performed on a VXR 300 (300 MHz) instrument. Elemental
analyses were performed on a Vario EL III (Germany).
1-(Pyrrol-1-yl)ethyl Acetate (3g)6a
Colorless oil.
IR (film): 3105, 1741, 1565, 1520 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.76 (d, J = 6.3 Hz, 3 H), 2.06 (s,
3 H), 6.19 (d, J = 2.3 Hz, 2 H), 6.66 (q, J = 6.3 Hz, 1 H), 6.89 (d,
J = 2.3 Hz, 2 H).
aza-Markovnikov Addition; General Procedure
A mixture of N-heterocycle (1 mmol), vinyl ester (4 mmol) and an-
hyd K3PO4 (64 mg, 0.3 mmol) in DMF (2 mL) was stirred at r.t. for
the time indicated in Table 2. H2O (20 mL) was added and the mix-
ture was extracted with EtOAc (3 × 20 mL). The combined organic
layers were washed with sat. NaCl (20 mL), dried over anhyd
MgSO4, filtered and evaporated under reduced pressure. The resi-
due was purified by flash column chromatography [silica gel;
EtOAc–PE (60–90 °C)] to provide the desired product 3 (Table 2).
1-(1,2,4-Triazol-1-yl)ethyl Acetate (3h)6a
Colorless oil.
IR (film): 3124, 3001, 1753, 1508 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.89 (d, J = 6.3 Hz, 3 H), 2.08 (s,
3 H), 6.86 (q, J = 6.3 Hz, 1 H), 7.98 (s, 1 H), 8.33 (s, 1 H).
1-(Benzotriazol-1-yl)ethyl Acetate (3i-1)
Colorless oil.
IR (film): 3091, 3029, 1753, 1610, 1590 cm–1.
1-(2-Methyl-4-nitro-1H-imidazol-1-yl)ethyl Acetate (3a)
Colorless solid; mp 138–139 °C.
1H NMR (300 MHz, CDCl3): d = 2.07 (s, 3 H), 2.12 (d, J = 6.3 Hz,
3 H), 7.40 (m, 2 H), 7.54 (m, 1 H), 7.75 (d, J = 8.1 Hz, 1 H), 8.08
(d, J = 8.4 Hz, 1 H).
IR (KBr): 3144, 1754, 1546, 1501 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.76 (d, J = 6.3 Hz, 3 H), 2.10 (s,
3 H), 2.53 (s, 3 H), 6.63 (q, J = 6.3 Hz, 1 H), 7.84 (s, 1 H).
Anal. Calcd for C10H11N3O2: C, 58.53; H, 5.40; N, 20.48. Found: C,
58.48; H, 5.30; N, 20.28.
Anal. Calcd for C8H11N3O4: C, 45.07; H, 5.20; N, 19.71. Found: C,
45.24; H, 5.37; N, 19.74.
1-(Benzotriazol-2-yl)ethyl Acetate (3i-2)
Colorless oil.
IR (film): 3067, 3000, 1757, 1563, 1501 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.04 (d, J = 6.2 Hz, 3 H), 2.12 (s,
3 H), 7.40 (m, 3 H), 7.89 (m, 2 H).
1-(Imidazol-1-yl)ethyl Acetate (3b)6a
Yellow oil.
IR (film): 3116, 1746, 1495 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.75 (d, J = 6.3 Hz, 3 H), 2.03 (s,
3 H), 6.69 (q, J = 6.3 Hz, 1 H), 7.06 (d, J = 1.5 Hz, 1 H), 7.11 (d,
J = 1.5 Hz, 1 H), 7.72 (s, 1 H).
Anal. Calcd for C10H11N3O2: C, 58.53; H, 5.40; N, 20.48. Found: C,
58.57; H, 5.60; N, 20.21.
1-(2-Methyl-1H-imidazol-1-yl)ethyl Acetate (3c)6a
Yellow oil.
1-(Benzimidazol-1-yl)ethyl Acetate (3j)
Colorless oil.
IR (film): 3090, 1748, 1614, 1495 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.95 (d, J = 6.3 Hz, 3 H), 2.06 (s,
3 H), 7.04 (q, J = 6.3 Hz, 1 H), 7.32 (m, 2 H), 7.60 (m, 1 H), 7.81
(m, 1 H), 8.12 (s, 1 H).
IR (film): 3111, 1744, 1535, 1500 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.71 (d, J = 6.3 Hz, 3 H), 2.06 (s,
3 H), 2.47 (s, 3 H), 6.66 (q, J = 6.3 Hz, 1 H), 6.94 (d, J = 1.5 Hz,
1 H), 7.02 (d, J = 1.5 Hz, 1 H).
1-(4-Nitro-1H-imidazol-1-yl)ethyl Acetate (3d)6a
Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92; N, 13.72. Found: C,
64.45; H, 5.88; N, 13.47.
Colorless solid; mp 83–84 °C (Lit.6a 82–83 °C).
IR (KBr): 3135, 1741, 1547, 1514 cm–1.
1-(5-Fluorouracil-1-yl)ethyl Acetate (3k)6a
1H NMR (300 MHz, CDCl3): d = 1.86 (d, J = 6.3 Hz, 3 H), 2.11 (s,
3 H), 6.70 (q, J = 6.3 Hz, 1 H), 7.69 (d, J = 1.5 Hz, 1 H), 7.95 (d,
J = 1.5 Hz, 1 H).
Colorless solid; mp 172–174 °C (Lit.6a 171–172 °C).
IR (KBr): 3734, 3170, 3086, 3049, 1752, 1730, 1702, 1662, 1225
cm–1.
1-(4-Formyl-1H-imidazol-1-yl)ethyl Acetate (3e)
Yellow oil.
IR (film): 3121, 2830, 2755, 1750, 1691, 1538, 1498 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.54 (d, J = 6.3 Hz, 3 H), 2.05
(s, 3 H), 6.76 (q, J = 6.3 Hz, 1 H), 8.20 (d, JH–F = 7.2 Hz, 1 H), 11.90
(s, 1 H).
1H NMR (300 MHz, CDCl3): d = 1.83 (d, J = 6.3 Hz, 3 H), 2.09 (s,
3 H), 6.72 (q, J = 6.3 Hz, 1 H), 7.83 (s, 2 H), 9.90 (s, 1 H).
1-(2-Methyl-4-nitro-1H-imidazol-1-yl)ethyl Butyrate (3l)
Light-yellow oil.
IR (film): 3164, 3114, 1745, 1547, 1504 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.93 (t, J = 7.5 Hz, 3 H), 1.66 (m,
2 H), 1.77 (d, J = 6.3 Hz, 3 H), 2.33 (t, J = 7.8 Hz, 2 H), 2.56 (s,
3 H), 6.65 (q, J = 6.3 Hz, 1 H), 7.85 (s, 1 H).
Anal. Calcd for C8H10N2O3: C, 52.74; H, 5.53; N, 15.38. Found: C,
52.50; H, 5.57; N, 15.43.
Methyl 1-(1-Acetoxyethyl)-4-urocanoate (3f)
Yellow oil.
IR (film): 3127, 1747, 1711, 1642, 1535, 1496 cm–1.
Anal. Calcd for C10H15N3O4: C, 49.79; H, 6.27; N, 17.42. Found: C,
49.88; H, 6.28; N, 17.18.
1H NMR (300 MHz, CDCl3): d = 1.80 (d, J = 6.3 Hz, 3 H), 2.06 (s,
3 H), 3.78 (s, 3 H), 6.58 (d, J = 15.6 Hz, 1 H), 6.67 (q, J = 6.3 Hz,
1 H), 7.30 (s, 1 H), 7.54 (d, J = 15.6 Hz, 1 H), 7.74 (s, 1 H).
1-(2-Methyl-4-nitro-1H-imidazol-1-yl)ethyl Benzoate (3m)
Colorless solid; mp 149–150 °C.
IR (KBr): 3143, 3089, 3017, 1725, 1603, 1547, 1504, 1451 cm–1.
Anal. Calcd for C11H14N2O4: C, 55.46; H, 5.92; N, 11.76. Found: C,
55.69; H, 5.88; N, 11.53.
Synthesis 2007, No. 13, 1933–1938 © Thieme Stuttgart · New York

1938
S.-w. Lin et al.
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Synthesis 2004, 1257.
1H NMR (300 MHz, CDCl3): d = 1.93 (d, J = 6.3 Hz, 3 H), 2.63 (s,
3 H), 6.91 (q, J = 6.3 Hz, 1 H), 7.49 (m, 2 H), 7.64 (m, 1 H), 7.96
(s, 1 H), 8.02 (m, 2 H).
Anal. Calcd for C13H13N3O4: C, 56.72; H, 4.76; N, 15.27. Found: C,
56.63; H, 5.02; N, 15.20.
Acknowledgment
The authors thank the Natural Science Foundation of China for the
financial support (NSFC 20472008).
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