Functionalization of a Pyridine Framework through Intramolecular Reissert-Henze Reaction of N-(Carbamoyloxy)pyridinium Salts and Unexpected Insertion of Ethereal Solvents

Article abstract of DOI:10.1002/ejoc.201500443

A new strategy for synthesis of the 2-pyridyl carbamates is reported. This strategy exploits a new intramolecular transformation of an acyloxy group from N-carbamoyloxypyridinium salts (Reissert-Henze-type reaction) as the key step. Addition of a silver salt effectively accelerates the intramolecular attack of the carbonyl oxygen at the 2-position of the pyridine ring. Additionally, a new rearrangement of the acyloxy group, combined with insertion of an ethereal solvent to give pyridine derivatives having a coordinating tether, is reported. A new strategy that gives 2-pyridyl carbamates upon treatment of N-(carbamoyloxy)pyridinium salts with silver oxide is reported. Additionally, a new rearrangement of the acyloxy group, combined with insertion of an ethereal solvent to give pyridine derivatives with a coordinating tether, is reported.

Full text of DOI:10.1002/ejoc.201500443

FULL PAPER
DOI: 10.1002/ejoc.201500443
Functionalization of a Pyridine Framework through Intramolecular Reissert–
Henze Reaction of N-(Carbamoyloxy)pyridinium Salts and Unexpected
Insertion of Ethereal Solvents
Haruyasu Asahara,*[a,b] Asuka Kataoka,[a] Shotaro Hirao,[c] and Nagatoshi Nishiwaki*[a]
Keywords: Synthetic methods / Rearrangement / Insertion / Nitrogen heterocycles / N,O ligands
A new strategy for synthesis of the 2-pyridyl carbamates is
ular attack of the carbonyl oxygen at the 2-position of the
reported. This strategy exploits a new intramolecular trans- pyridine ring. Additionally, a new rearrangement of the
formation of an acyloxy group from N-carbamoyloxypyridin-
ium salts (Reissert–Henze-type reaction) as the key step. Ad-
dition of a silver salt effectively accelerates the intramolec-
acyloxy group, combined with insertion of an ethereal sol-
vent to give pyridine derivatives having a coordinating
tether, is reported.
nating amino group to increase the nucleophilicity at the
carbonyl oxygen; (2) the addition of a silver salt to keep the
chloride counteranion away through the formation of stable
silver chloride, which has a small dissociation constant, and
so to increase the electrophilicity of the pyridine ring.
Introduction
Functionalized pyridines are widely found in biologically
active compounds,[1] ligands,[2] optical materials,[3] and so
on. Nonetheless, direct functionalization of the pyridine
ring is still challenging, due to the relatively low electron
density and high Lewis basicity of the ring nitrogen, which
prevents functionalization by electrophilic processes. N-
Acylation is one of the most important ways to activate the
pyridine ring; this approach facilitates nucleophilic addition
to functionalize the 2-position. This is known as the Reis-
sert-type reaction.[4,5] However, the products are nonaro-
matic dihydropyridines (Scheme 1). This disadvantage is
overcome by using the Reissert–Henze-type reaction,[6]
using an N-acyloxypyridinium halide, which gives 2-func-
tionalized pyridines by rearomatization, accompanied by
elimination of a carboxylic acid. Although this reaction is
applicable to a wide range of nucleophiles, to the best of
our knowledge, no intramolecular rearrangement of the
carbonyl oxygen has been reported. In this context, intra-
molecular attack of the carbonyl oxygen at the 2-position
may occur when other nucleophiles are absent, which is a
hitherto unknown process. To carry out the desired trans-
formation, the following strategies were implemented:
(1) the use of a carbamoyl chloride having an electron-do-
[a] School of Environmental Science and Engineering, Kochi
University of Technology,
Scheme 1.
Kami, Kochi 782-8502, Japan
E-mail: nishiwaki.nagatoshi@kochi-tech.ac.jp
https://sites.google.com/site/kutnishiwakilab2/nishiwakilab
[b] Research Center for Material Science and Engineering, Kochi
University of Technology,
In this paper, we report a new method for the synthesis
of 2-functionalized pyridines through the reaction between
pyridine N-oxides 1 and carbamoyl chlorides 2 in the pres-
ence of silver salts. In this study, we demonstrate a new
acyloxy group rearrangement, accompanied by insertion of
ethereal solvents.
Kami, Kochi 782-8502, Japan
[c] Department of Applied Chemistry, Faculty of Engineering,
Oita University,
Dannohara, Oita-shi, Oita 870-1192, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500443.
3994
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 3994–3999

Functionalization of a Pyridine Framework
1
The structure of 5Aa was determined as follows: in the H
Results and Discussion
NMR spectrum of 5Aa, signals for four nonequivalent
Initially, we investigated the reaction of pyridine N-oxide methylene protons were observed between δ = 3.76 and
(1A) with N,N-dimethylcarbamoyl chloride (2a). N-Acyl- 4.47 ppm in addition to signals closely related to those of
oxypyridinium salt 3Aa was formed as a white precipitate 4Aa. In the 13C NMR and IR spectra, a signal at δ =
when 2 equiv. of 2a was added to a benzene solution of 164.1 ppm and an absorption peak at 1697 cm–1 for a carb-
pyridine N-oxide. After stirring the mixture at room tem- onyl group, respectively, were observed, which indicated
perature, AgNO3 (1.0 equiv.) was added, and the resulting that the product contains a carbonate ester group. Ad-
mixture was heated at 150 °C in a sealed tube for 1 h. The ditionally, the MS data of 5Aa (m/z = 254 [M]+) indicated
desired product, 2-pyridinyl N,N-dimethylcarbamate (4Aa), that a C4H8O2 (Mr = 88) moiety had been added to the
was obtained by this process, albeit in just 4% yield framework of 4Aa (Mr = 166). These data clearly indicated
(Table 1, entry 1). On the other hand, control experiments the insertion of a dioxane molecule into the side-chain, ac-
showed that no reaction took place in the absence of the companied by ring opening.
silver salt (Table 1, entries 2 and 3). Screening of various
A plausible mechanism for this transformation is shown
silver salts demonstrated that silver(I) oxide was the most in Scheme 2. Addition of the silver salt accelerates the intra-
effective, and that its use increased the yield of 4Aa to 51% molecular attack of the carbonyl oxygen at the 2-position
(Table 1, entries 1, 4–6). When methyl chloroformate or of the pyridine ring to give the highly electrophilic diox-
benzoyl chloride was used instead of carbamoyl chloride, azolopyridine 7, which is a common intermediate for the
the N-oxide was recovered without any detectable amount formation of both 4Aa and 5Aa. Deprotonation at the
of the 2-functionalized pyridine. These results imply that bridgehead position induces rearomatization to give 4Aa
the electron-donating amino group plays an important role (route a), or alternatively attack of a 1,4-dioxane molecule
in the intramolecular transformation. Screening of several occurs competitively, leading to the formation of adduct
solvents for the reaction revealed that 1,4-dioxane was supe- intermediate
8 (route b). During rearomatization of
rior to other solvents for the formation of 4Aa (Table 1, the pyridine ring, rearrangement of the dimethylamino
entries 5–8). Lowering the reaction temperature to 60 °C group results in dioxane ring opening to give 5Aa. To selec-
produced slightly higher yields (Table 1, entries 11 and 12), tively obtain this intriguing product 5, we reinvestigated
although longer reaction times were required. Therefore, the reaction conditions, including the solvent, the tempera-
the optimized reaction conditions for the intramolecular ture, the reaction time, the amount of silver oxide, and
transformation of the acyloxy group were 2 equiv. of the concentration. Despite considerable efforts, the simulta-
carbamoyl chloride and an equimolar amount of Ag2O in neous production of 4Aa could not be suppressed, and the
1,4-dioxane at 60 °C. This strategy gave the pyridyl carb- product ratio of 4/5 was little changed. The difficulty in
amate through a new intramolecular Reissert–Henze-type controlling the reaction pathway could be attributed
reaction.
to the fact that both products were formed from the same
It is noteworthy that 5Aa was formed by a competitive intermediate (i.e., 7). We also studied the interconversion of
reaction when the reaction was carried out in 1,4-dioxane. the two isolated products (i.e., 4 and 5) under the reac-
Table 1. Optimization of the intramolecular transformation of the acyloxy group.
Entry
Additive
Solvent
Temp. [°C]
Time [h]
Yield [%][a]
4Aa
5Aa
1
2
3
4
5
6
7
8
AgNO3
none
Cu(OAc)2
AgOAc
Ag2CO3
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
benzene
benzene
benzene
benzene
benzene
benzene
acetonitrile
cyclohexane
CPME[b]
1,4-dioxane
benzene
150
150
150
150
150
150
150
150
150
150
60
1
1
1
1
1
1
1
1
1
4
0
0
–
–
–
–
–
–
–
–
–
15
47
51
33
22
48
52
50
61
9
10
11
12
1
24
24
20
–
33
Ag2O
Ag2O
1,4-dioxane
60
[a] Yield by NMR spectroscopy. [b] Cyclopentyl methyl ether.
Eur. J. Org. Chem. 2015, 3994–3999
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3995

H. Asahara, A. Kataoka, S. Hirao, N. Nishiwaki
FULL PAPER
tion conditions, but both products were stable and did not
change.
This transformation was carried out using another ethe-
real solvent, THF. A similar reaction occurred to give 6Aa
(32%) in addition to 4Aa (61%) (Table 2, entry 2). We then
examined the effect of substituents on the nitrogen atom of
the carbamoyl chloride when the reaction was run in THF
(Table 2). Even substrates with bulkier substituents on the
nitrogen atom, i.e., N,N-dialkylcarbamoyl chlorides 2b and
2c, underwent similar reactions in THF, without loss of to-
tal yield or selectivity (Table 2, entries 3 and 4).
Next, we attempted to extend the scope of this reaction
to substituted pyridines, as shown in Table 3. This reaction
was considerably influenced by the electronic properties of
the substituent, as reflected in the product yields and re-
gioselectivity. Specifically, substrates 1B and 1C, with an
electron-donating methyl group, gave the desired products
in low yields, whereas pyridine N-oxides with electron-with-
drawing groups, 1D and 1E, gave products 4 in higher
yields. Notably, the reaction of 3-chloropyridine N-oxide 1E
with 2a gave the desired product (i.e., 4Ea) in a total yield
of 77%, and with good regioselectivity (2-position/6-posi-
tion = 90:10). This may be attributed to the inductive effect
of the chloro group, and the fact that the 2-position of the
pyridine ring was more electrophilic.
The 2-functionalization of quinoline N-oxide (9) and
pyrimidine N-oxide (10) with carbamoyl chloride 2a was
Scheme 2. A plausible mechanism of the insertion of 1,4-dioxane.
Table 2. Substituent effect of the carbamoyl group.
Entry
2
R
Solvent
Yield [%][a]
4
5/6
Total
1
2
3
4
2a
2a
2b
2c
Me
Me
Et
1,4-dioxane
THF
THF
4Aa (61)
4Aa (61)
4Ab (53)
4Ac (62)
5Aa (33)
6Aa (32)
6Ab (31)
6Ac (29)
94
93
84
91
iPr
THF
[a] Yield by NMR spectroscopy.
Table 3. Substituent effect of the pyridine moiety.
Entry
1
R
Yield [%][a,b]
4
5
1
2
3
4
1B
1C
1D
1E
4-Me
3-Me
4-CN
3-Cl
10
trace
14 (50:50)
trace
29 (38:62)
39
77 (90:10)
trace
[a] Yield by NMR spectroscopy. [b] Ratio of regioselectivity (2-position/6-position) were shown in the parentheses.
3996 Eur. J. Org. Chem. 2015, 3994–3999
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Functionalization of a Pyridine Framework
also tested under the standard reaction conditions idyl carbamates 4 through an intramolecular Reissert–
(Scheme 3). In the presence of the silver salt, the reaction Henze-type reaction of N-(carbamoyloxy)pyridinium salts.
between substrate 9 and 2a gave the desired 2-quinolyl di- Addition of a silver salt effectively increased the electro-
methylcarbamate (i.e., 11) in 20% yield, along with 80% philicity of the pyridine ring by keeping the chloride
of 2-quinolonol as a byproduct. The low efficiency of the counteranion away as silver chloride. Moreover, unexpected
transformation of substrate 9 is probably due to steric re- insertion of ethereal solvents into the side-chain of the pyr-
pulsion from the peri hydrogen. On the other hand, pyrim- idine ring, leading to pyridyl carbonates 5 and 6, was de-
idine N-oxide (10) gave a complex mixture under the same tected. Products 4 and 5/6 were both formed from a com-
reaction conditions, and 12 was not detected.
mon dioxazolopyridine intermediate 7. Since these products
have multiple coordination sites, they are expected to serve
as new ligands.
Experimental Section
General Information: Pyridine N-oxides 1A–1E and carbamoyl
chlorides 2a–2c were purchased from commercial suppliers, and
1
were used without further purification. H and 13C NMR spectra
were recorded with a Bruker DPX-400 spectrometer (400 and
100 MHz, respectively) in CDCl3 using tetramethylsilane as an in-
ternal standard. 1H NMR spectroscopic data is reported as follows:
chemical shift (δ, ppm), chemical shift mutiplicities: s = singlet, d
= doublet, t = triplet, q = quartet, m = multiplet, integration, cou-
pling constant (Hz). 13C NMR spectroscopic data is reported in
terms of chemical shift (δ, ppm). NMR signal assignments of diox-
ane inserted product 5Aa were based on additional 2D NMR spec-
troscopy (e.g., COSY, NOESY, HSQC, and HMBC). Infrared spec-
tra were recorded with a Horiba FT-200 IR spectrometer, and data
are reported in frequency of absorption (wavenumbers). High-reso-
lution mass spectra were obtained with a JEOL JMS-700N mass
spectrometer. Melting points were recorded with a Yanaco micro
melting point apparatus.
Scheme 3. 2-Functionalization of other substrates.
To demonstrate the utility of the ethereal-solvent-in-
serted products, we studied the binding ability of these
products to metal ions. Figure 1 shows the changes in the
1H NMR spectrum of 5Aa in CD3CN upon the addition
of magnesium ions. A shift of both the ethylene and pyr-
idine proton signals was observed upon the addition of
Mg(ClO4)2, which suggests that binding of 5Aa to the mag-
nesium ion occurred through both ring nitrogens and a
Typical Procedure for the Reaction of Pyridine N-Oxide 1 with
Carbamoyl Chloride 2: Carbamoyl chloride 2 (0.8 mmol) was added
to a solution of pyridine N-oxide 1a (38 mg, 0.4 mmol) in solvent
tether at the 2-position. Details of the binding ability of (3 mL), and the resulting mixture was stirred at ambient tempera-
ture for several minutes. Then the silver salt (0.4 mmol) was added.
The solution was heated at 60 °C for 24 h, then the precipitate was
removed by filtration, and washed with dichloromethane (2ϫ
10 mL). The combined filtrates were concentrated under reduced
pressure. The yield of the product was determined by integration
of the 1H NMR spectrum of the crude product, using 1,1,2,2-tetra-
chloroethane as an internal standard. Further purification was
achieved by flash column chromatography on silica gel (hexane/
EtOAc, 50:50). The known carbamate products 4 were assigned
by comparison with those of authentic samples. For several of the
substituted pyridine N-oxides, attempts to isolate the pure product
failed due to low yields and the presence of by-products with close
Rf values.
the products and the structure of the corresponding metal
complexes are now under investigation.
2-Pyridyl N,N-Dimethylcarbamate (4Aa):[7] Brown oil. Rf = 0.15
1
(silica gel, hexane/EtOAc, 1:1). H NMR (400 MHz, CDCl3): δ =
3.02 (s, 3 H), 3.13 (s, 3 H), 7.10 (ddd, J = 0.7, 0.9, 7.3 Hz, 1 H),
7.17 (ddd, J = 0.9, 4.9, 7.3 Hz, 1 H), 7.75 (ddd, J = 2.0, 7.3, 7.3 Hz,
1 H), 8.36 (ddd, J = 0.7, 2.0, 4.9 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 36.7 (CH3), 36.8 (CH3), 116.4 (CH), 121.4
(CH), 139.4 (CH), 148.4 (CH), 154.1 (C), 158.8 (C) ppm. IR
Figure 1. NMR spectral changes of 5Aa upon addition of
Mg(ClO4)2 in CD3CN.
(NaCl): ν = 1728, 1225, 1161 cm–1.
˜
2-Pyridyl N,N-Diethylcarbamate (4Ab):[7] Brown oil. Rf = 0.17 (sil-
ica gel, hexane/EtOAc, 1:1). 1H NMR (400 MHz, CDCl3): δ = 1.21
(t, J = 7.1 Hz, 3 H), 1.27 (t, J = 7.1 Hz, 3 H), 3.40 (q, J = 7.1 Hz,
2 H), 3.48 (q, J = 7.1 Hz, 2 H), 7.11 (d, J = 8.8 Hz, 1 H), 7.16 (dd,
Conclusions
In conclusion, we have demonstrated a new method for
the functionalization of the pyridine framework to give pyr- J = 4.9, 7.4 Hz, 1 H), 7.75 (ddd, J = 2.0, 7.4, 8.8 Hz, 1 H), 8.37
Eur. J. Org. Chem. 2015, 3994–3999
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3997

H. Asahara, A. Kataoka, S. Hirao, N. Nishiwaki
FULL PAPER
(dd, J = 2.0, 4.9 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 7.1 Hz, 1 H), 6.84 (ddd, J = 1.2, 5.1, 7.1 Hz, 1 H), 7.55 (ddd, J =
13.4 (CH3), 14.3 (CH3), 42.2 (CH2), 42.3 (CH2), 116.5 (CH), 121.3 2.0, 7.1, 7.1 Hz, 1 H), 8.13 (ddd, J = 0.8, 2.0, 5.1 Hz, 1 H) ppm.
(CH), 139.3 (CH), 148.4 (CH), 153.5 (C), 158.9 (C) ppm. IR
13C NMR (100 MHz, CDCl3): δ = 25.9 (CH2), 26.1 (CH2), 36.0
(CH3), 36.5 (CH3), 65.2 (CH2), 65.5 (CH2), 111.2 (CH), 116.7
(CH), 138.6 (CH), 147.0 (CH), 156.9 (C), 164.1 (C) ppm. IR
(ATR): ν = 1713, 1209, 1148 cm–1.
˜
2-Pyridyl N,N-Diisopropylcarbamate (4Ac):[8] Reddish orange solid.
Rf = 0.16 (silica gel, hexane/EtOAc, 1:1). 1H NMR (400 MHz,
CDCl3): δ = 1.25–1.45 (m, 12 H), 3.95–4.16 (m, 2 H), 7.10 (d, J =
8.2 Hz, 1 H), 7.16 (dd, J = 4.8, 7.5 Hz, 1 H), 7.74 (ddd, J = 2.0,
7.5, 8.2 Hz, 1 H), 8.39 (dd, J = 2.0, 4.8 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 20.6 (CH3), 21.6 (CH3), 46.9 (CH), 116.7
(CH), 121.2 (CH), 139.2 (CH), 148.5 (CH), 152.9 (C), 158.8 (C)
(ATR): ν = 1697, 1285, 1182 cm–1. HRMS (EI): calcd. for
˜
C12H18N2O3 238.1317; found 238.1314.
8-Aza-8-ethyl-1,3-dioxa-2-oxo-1-(2-pyridyl)decane (6Ab): Brown oil.
Rf = 0.30 (silica gel, hexane/EtOAc, 1:1). 1H NMR (400 MHz,
CDCl3): δ = 1.11 (t, J = 7.1 Hz, 6 H), 1.77–1.90 (m, 4 H), 3.18–
3.40 (m, 4 H), 4.14 (t, J = 6.2 Hz, 2 H), 4.32 (t, J = 6.2 Hz, 2 H),
6.72 (d, J = 9.4 Hz, 1 H), 6.84 (ddd, J = 0.8, 5.0, 7.5 Hz, 1 H), 7.55
(ddd, J = 1.7, 7.5, 9.4 Hz, 1 H), 8.13 (dd, J = 1.7, 5.0 Hz, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 13.8 (CH3), 14.0 (CH3),
26.0 (CH2), 25.9 (CH2), 41.4 (CH2), 41.7 (CH2), 64.9 (CH2), 65.5
(CH2), 111.2 (CH), 116.7 (CH), 138.6 (CH), 147.0 (CH), 156.2 (C),
ppm. IR (ATR): ν = 1697, 1200, 1148 cm–1.
˜
4-Methylpyridin-2-yl N,N-Dimethylcarbamate: Brown oil. Rf = 0.17
1
(silica gel, hexane/EtOAc, 1:1). H NMR (400 MHz, CDCl3): δ =
2.23 (s, 3 H), 3.02 (s, 3 H), 3.13 (s, 3 H), 7.14 (d, J = 4.9 Hz, 1 H),
8.30 (d, J = 4.9 Hz, 1 H), 8.32 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 15.8 (CH3), 36.6 (CH3), 37.0 (CH3), 125.7 (CH), 139.8
(C), 144.2 (CH), 146.6 (CH), 147.4 (C), 154.1 (C) ppm. IR (NaCl):
164.1 (C) ppm. IR (ATR): ν = 1694, 1269, 1169 cm–1. HRMS (EI):
˜
calcd. for C14H22N2O3 266.1630; found 266.1621.
ν = 1717, 1246, 1151 cm–1. HRMS (EI): calcd. for C H N O
Quinolin-2-yl N,N-Dimethylcarbamate (11):[9] Brown oil. Rf = 0.18
˜
9
12
2
2
1
180.0899; found 180.0895.
(silica gel, hexane/EtOAc, 1:1). H NMR (400 MHz, CDCl3): δ =
3.05 (s, 3 H), 3.18 (s, 3 H), 7.24 (d, J = 8.7 Hz, 1 H), 7.52 (ddd, J
= 1.2, 7.0, 9.2 Hz, 1 H), 7.70 (ddd, J = 1.0, 7.0, 9.1 Hz, 1 H), 7.83
(dd, J = 1.2, 9.1 Hz, 1 H), 8.00 (dd, J = 1.0, 9.2 Hz, 1 H), 8.20 (d,
J = 8.7 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 36.8
(CH3), 36.9 (CH3), 116.1 (CH), 126.3 (CH), 127.1 (C), 127.6 (CH),
128.7 (CH), 130.1 (CH), 139.8 (CH), 146.7 (C), 154.2 (C), 157.2
4-Cyanopyridin-2-yl N,N-Dimethylcarbamate: Yellowish brown so-
lid, m.p. 127–129 °C. Rf = 0.13 (silica gel, hexane/EtOAc, 1:1). H
NMR (400 MHz, CDCl3): δ = 3.05 (s, 3 H), 3.14 (s, 3 H), 7.40 (dd,
J = 1.7, 5.0 Hz, 1 H), 7.41 (dd, J = 0.9, 1.7 Hz, 1 H), 8.53 (dd, J
= 0.9, 5.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 36.8
(CH3), 37.0 (CH3), 116.0 (C), 119.0 (CH), 122.9 (CH), 123.4 (C),
1
(C) ppm. IR (NaCl): ν = 1717, 1223, 1148 cm–1.
˜
149.7 (CH), 153.2 (C), 159.3 ppm. IR (ATR): ν = 2201 (CN), 1715,
˜
1250, 1142 cm–1. HRMS (EI): calcd. for C9H9N3O2 191.0695;
found 191.0697.
[1] For selected reviews, see: a) G. Jones, Comprehensive Heterocy-
clic Chemistry II, vol. 5 (Eds.: A. R. Katritzky, C. W. Rees,
E. F. V. Scriven), Pergamon, Oxford, UK, 1996, p. 167; b) R. C.
Larock, Comprehensive Organic Transformations: A Guide to
Functional Group Preparations, Wiley-VCH, New York, 1999;
c) G. D. Henry, Tetrahedron 2004, 60, 6043–6061.
[2] For recent reviews, see: a) G. de Ruiter, M. Lahav, M. E.
van der Boom, Acc. Chem. Res. 2014, 47, 3407–3416; b) G.
Chelucci, Coord. Chem. Rev. 2013, 257, 1887–1932; c) C. G.
Arena, G. Arico, Curr. Org. Chem. 2010, 14, 546–580; d) A. J.
Pardey, C. Longo, Coord. Chem. Rev. 2010, 254, 254–272.
[3] For a review, see: a) H. L. Bozec, T. Renouard, Eur. J. Inorg.
Chem. 2000, 229–239; For selected recent examples, see: b)
A. W. Woodward, A. Frazer, A. R. Morales, J. Yu, A. F.
Moore, A. D. Campiglia, E. V. Jucov, T. V. Timofeeva, K. D.
Belfield, Dalton Trans. 2014, 43, 16626–16639; c) A. P.
Menezes, A. Jayarama, S. W. Ng, J. Mol. Struct. 2015, 1088,
85–94.
3-Chloropyridin-2-yl N,N-Dimethylcarbamate: Yellow solid, m.p.
109–110 °C. Rf = 0.34 (silica gel, hexane/EtOAc, 1:1). 1H NMR
(400 MHz, CDCl3): δ = 3.04 (s, 3 H, 1-H), 3.16 (s, 3 H, 2-H), 7.18
(dd, J = 4.8, 7.8 Hz, 1 H, 4-H), 7.80 (dd, J = 1.7, 7.8 Hz, 1 H, 3-
H), 8.28 (dd, J = 1.7, 4.8 Hz, 1 H, 5-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 36.8 (CH3), 36.9 (CH3), 122.8 (CH), 124.2 (C), 139.6
(CH), 146.3 (CH), 153.1 (C), 154.9 (C) ppm. IR (ATR): ν = 1705,
˜
1234, 1153 cm–1. HRMS (EI): calcd. for C8H9ClN2O2 200.0353;
found 200.0354.
9-Aza-9-methyl-1,3,6-trioxa-2-oxo-1-(2-pyridyl)decane (5Aa)
[4] A. Reissert, Ber. Dtsch. Chem. Ges. 1905, 38, 1603.
[5] For reviews of Reissert-type reactions, see: a) W. E. McEwen,
R. L. Cobb, Chem. Rev. 1955, 55, 511–549; b) F. D. Popp, W.
Blount, P. Melvin, J. Org. Chem. 1961, 26, 4930–4932; c) F. D.
Popp, B. C. Uff, Heterocycles 1985, 23, 731–740; d) M. A. G.
Berg, H. W. Gibson, J. Org. Chem. 1992, 57, 748–750; e) D. L.
Comins, S. O’Connor, R. S. Al-awar, in: Comprehensive Hetero-
cyclic Chemistry III, 1st ed. (Eds.: A. R. Katritzky, C. A.
Ramsden, E. F. V. Scriven, R. J. K. Taylor), Elsevier, 2008, vol.
7, chapter 7.02, p. 41–99.
[6] For Reissert–Henze-type reactions, see: a) A. Reissert, Ber.
Dtsch. Chem. Ges. 1905, 38, 3415–3435; b) M. Henze, Ber.
Dtsch. Chem. Ges. 1936, 69, 1566–1568; c) L. H. Klemm,
D. R. J. Muchiri, Heterocycl. Chem. 1983, 20, 213–218; d) N.
Nishiwaki, S. Minakata, M. Komatsu, Y. Ohshiro, Chem. Lett.
1989, 773–776; e) T. Storz, M. D. Bartberger, S. Sukits, C.
Wilde, T. Soukup, Synthesis 2008, 2, 201–214; f) T. Shoji, K.
Okada, S. Ito, K. Toyota, N. Morita, Tetrahedron Lett. 2010,
51, 5127–5130; g) W. J. Lominac, M. L. D’Angelo, M. D.
Smith, D. A. Ollison, J. M. Hanna Jr., Tetrahedron Lett. 2012,
Yellow oil. Rf = 0.24 (silica gel, hexane/EtOAc, 1:1). 1H NMR
(400 MHz, CDCl3): δ = 2.89 (br. s, 6 H, k-H), 3.76 (t, J = 4.8 Hz,
2 H, j-H), 3.85 (t, J = 4.8 Hz, 2 H, i-H), 4.24 (t, J = 4.8 Hz, 2 H,
h-H), 4.47 (t, J = 4.8 Hz, 2 H, g-H), 6.77 (ddd, J = 0.9, 1.7, 7.1 Hz,
1 H, d-H), 6.85 (ddd, J = 1.7, 5.0, 7.1 Hz, 1 H, b-H), 7.55 (ddd, J
= 2.0, 7.1, 7.1 Hz, 1 H, c-H), 8.12 (ddd, J = 0.9, 2.0, 5.0 Hz, 1 H,
a-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 36.1 (CH3, C-k), 36.6
(CH3, C-k), 64.7 (CH2, C-j), 65.1 (CH2, C-i), 69.8 (CH2, C-h), 69.9
(CH2, C-g), 111.5 (CH, C-d), 116.9 (CH, C-b), 138.7 (CH, C-c),
146.9 (CH, C-a), 156.6 (C, C-e), 163.8 (C, C-f) ppm. IR (ATR): ν
˜
= 1697, 1273, 1186 cm–1. HRMS (EI): calcd. for C12H18N2O4
254.1267; found 254.1272.
8-Aza-8-methyl-1,3-dioxa-2-oxo-1-(2-pyridyl)nonane (6Aa): Yellow
1
oil. Rf = 0.25 (silica gel, hexane/EtOAc, 1:1). H NMR (400 MHz,
CDCl3): δ = 1.77–1.90 (m, 4 H), 2.89 (br. s, 6 H), 4.14 (t, J =
6.3 Hz, 2 H), 4.32 (t, J = 6.3 Hz, 2 H), 6.71 (ddd, J = 0.8, 1.2,
3998
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Eur. J. Org. Chem. 2015, 3994–3999

Functionalization of a Pyridine Framework
53, 906–909; h) R. P. Farrell, M. V. S. Elipe, M. D. Bartberger,
J. S. Tedrow, F. Vounatsos, Org. Lett. 2013, 15, 168–171; i) A.
Velavan, D. Mondal, S. Survase, Bull. Korean Chem. Soc. 2013,
34, 3459–3462.
[8] R. E. Miller, T. Rantanen, K. A. Ogilvie, U. Groth, V. Snieckus,
Org. Lett. 2010, 12, 2198–2201.
[9] J. M. Jacquelin, Y. Robin, A. Godard, G. Queguiner, Can. J.
Chem. 1988, 66, 1135–1140.
[7] L. Yue, C. Guo, Y. Chai, X. Yin, Y. Pan, Tetrahedron 2014, 70,
Received: April 7, 2015
Published Online: May 15, 2015
9500–9505.
Eur. J. Org. Chem. 2015, 3994–3999
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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