Straightforward carbamoylation of nucleophilic compounds employing organic azides, phosphines, and aqueous trialkylammonium hydrogen carbonate

Article abstract of DOI:10.1016/j.tet.2010.01.017

In the presence of aqueous trialkylammonium hydrogen carbonate, the Staudinger reaction leads to the intermediate formation of the corresponding isocyanate, which, in turn, reacts further with a nucleophilic reagent also present in the mixture and results in carbamoylation with good yield. On the basis of this reaction a practical carbamoylation procedure was devised and a comparative study on suitability of different solvents and phosphorus (III) derivatives for carbamoylation reaction was conducted. The versatility of the method was demonstrated by examples with different classes of nucleophilic compounds that included the aminomethyl resin and natural compounds that display poor solubility in organic solvents.

Full text of DOI:10.1016/j.tet.2010.01.017

Tetrahedron 66 (2010) 2210–2221
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Tetrahedron
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Straightforward carbamoylation of nucleophilic compounds employing organic
azides, phosphines, and aqueous trialkylammonium hydrogen carbonate
,
,
,b,
Andrey Yagodkin a b, Kerstin Lo¨schcke a y, Janne Weisell c, Alex Azhayev a
*
a School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, FI-70211 Kuopio, Finland
b Metkinen Chemistry, Microkatu 1, Microtower, Osa R, FI-70211 Kuopio, Finland
c Department of Biosciences, Biocenter Kuopio, Faculty of Science and Forestry, University of Eastern Finland, FI-70211 Kuopio, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
In the presence of aqueous trialkylammonium hydrogen carbonate, the Staudinger reaction leads to the
intermediate formation of the corresponding isocyanate, which, in turn, reacts further with a nucleo-
philic reagent also present in the mixture and results in carbamoylation with good yield. On the basis of
this reaction a practical carbamoylation procedure was devised and a comparative study on suitability of
different solvents and phosphorus (III) derivatives for carbamoylation reaction was conducted. The
versatility of the method was demonstrated by examples with different classes of nucleophilic com-
pounds that included the aminomethyl resin and natural compounds that display poor solubility in
organic solvents.
Received 1 September 2009
Received in revised form 23 November 2009
Accepted 4 January 2010
Available online 20 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
the action of rhodium complexes and carbon monoxide at high
pressures (150–300 atm) and high temperatures (160–180 ꢀC) in
The carbamoylation of nucleophilic compounds gives rise to
various useful derivatives. Ureas, for example, are useful in many
biological activities; e.g., as pharmaceutical products and their
precursors, agroprotective agents, and plant growth regulators.1
In pharmaceuticals, the urea moiety can be found in anti-convul-
sants, tranquillizers,1 antineoplastics,2,3 anti-malaria agents,4 anti-
diabetic drugs,5,6 and HIV-1 protease inhibitors.7,8
The conventional procedures to generate ureas are the reaction
of various amines with the highly toxic phosgene or sophisticated
phosgene derivatives.9 Alternatively, another approach is to per-
form carbamoylation of nucleophilic compounds, e.g., to synthesize
non-symmetrical substituted ureas,10 generated by the addition of
nucleophilic compounds to isocyanates. Hence, there is a clear need
to obtain straightforward methods for isocyanate synthesis.
In 1968, Bennet and Hardy published a synthesis for phenyl-
isocyanate that was based on the formation of nitrene from an
azide compound, which reacted with carbon monoxide11 at high
temperatures (160–180 ꢀC) and high pressures (200–300 atm).
Near the same time, Collman et al. reported the syntheses of
isocyanates from azides and carbon monoxide in the presence of
iridium complexes.12,13 Phenyl azide has also been shown to
undergo a carbamoylation reaction in a catalytic process involving
the formation of phenylisocyanate.14,15 Based on these initial find-
ings, Langstrom et al. successfully developed methods for the
synthesis of various 11C-labeled compounds via isocyanates.16,17
Phosphinimines (iminophosphoranes) have been claimed to be
useful in the preparation of alkyl- and arylisocyanates in early
1980s. Molina et al.18 described an efficient method for the
conversion of alkyl- and aryliminophosphoranes (generated from
the corresponding amines and triphenylphosphine dibromide) into
isocyanates, where a key step was the reaction of phosphinimine
with carbon dioxide, which was passed through a solution in
boiling benzene. This approach allowed for the preparation of eight
isocyanates in high yield. A similar approach was used by Kovacs
et al.19,20 to prepare cyclic carbamates by simultaneous bubbling of
carbon dioxide into the reaction mixture. The same approach was
employed by Marsura et al. for the preparation of b-cyclodextrin
‘dimers’ with the use of urea linkers.21 An extension of this method
utilized a polymer assisted one-pot phosphinimine reaction with
a polymer-bound triphenylphosphine to generate various cyclo-
dextrin urea derivatives.22 Another modification of this one-pot
phosphinimine reaction used supercritical carbon dioxide (sCO2) as
a solvent and reagent.23 Indeed, sCO2 in the presence of triphe-
nylphosphine or polymer-bound triphenylphosphine resulted in
the desired urea cyclodextrin derivatives within reasonable times
and in good yields.
* Corresponding author. Tel.: þ358 407364885.
E-mail address: Alex.Azhayev@uef.fi (A. Azhayev).
The present report also depicts carbamoylation of nucleophilic
compounds, employing organic azides as well as triphenylphos-
phine, polymer-bound triphenylphosphine, and some triaryl- or
y
Present address: Pharmaceutical Institute, University of Bonn, An der Immen-
burg 4, 53112 Bonn, Germany.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.017

A. Yagodkin et al. / Tetrahedron 66 (2010) 2210–2221
2211
alkyldiaryl phosphines. However, the new procedure, described
here in detail, employs an aqueous trialkylammonium hydrogen
carbonate buffer (triethylammonium hydrogen carbonate, TEAB or
trimethylammonium hydrogen carbonate, TMAB), added to an
organic solvent as a convenient source of carbon dioxide. We
believe that the possibility to perform carbamoylation reactions via
the formation of an isocyanate intermediates in solutions,
containing aqueous buffer, considerably broadens the application
of such an approach for the synthesis of derivatives of a number of
compounds with extremely low solubility in organic solvents that
tends to improve in the presence of water. It should be noted that
this procedure appears to be extremely simple. It does not require
any special equipment for generation of sCO2, transition metal
complexes or, more importantly, there is no need to use hazardous
highly toxic gases such as phosgene or carbon monoxide. We
believe that this procedure may be carried out in any chemical
laboratory.
reaction in the presence of aqueous 2 M TEAB. Figure 1 demon-
strates the changes in the 1H NMR spectrum of benzylazide–tri-
phenylphosphine mixture in dioxane in the presence of water at
room temperature and at different time points.
2. Results and discussion
Figure 1. 1H NMR spectra of benzylazide–triphenylphosphine mixture at different
time points in dioxane-d8 in the presence of D2O at room temperature.
Earlier, while studying various conditions required for the
removal of a 4-azidobutiryl group, which served as a protection of
the hydroxyl function,24 we noticed that the use of a triphenyl-
phosphine–dioxane–aqueous 1 M TEAB combination (instead of
the conventional triphenylphosphine–dioxane–water mixture)
resulted in the formation of an anomalous product at a high yield.
This product proved to be a symmetrical urea, bearing the sub-
stituent R contained in the initial azido-compound (Scheme 1).
dioxane, Ph3P,
R N3
RNH NHR
O
1M TEAB
Scheme 1.
In order to explain this phenomenon, we suggested that the
formation of the corresponding intermediate isocyanate followed
Staudinger’s generation of the phosphinimine from the azide.25
With the aim to support this assumption and to verify the limits
of the approach we performed a detailed investigation of the
reaction, employing a number of organic azides, nucleophilic
compounds, and phosphines.
Figure 2. 1H NMR spectra of a benzylazide–triphenylphosphine mixture at different
time points in dioxane-d8 in the presence of 3 M TEAB, prepared in D2O, at room
temperature.
Initially, we decided to study the simple model reaction of
benzylazide and triphenylphosphine in the presence of TEAB.
Theoretically, in our case (Scheme 2) the phosphinimine 1, gener-
ated from benzylazide may undergo a reaction with either water
(from the buffer) to form the corresponding benzylamine 2 or with
CO2 (from the TEAB) to give rise to the corresponding reactive
isocyanate 3. Alternatively, compound 1 may undergo both trans-
formations at the same time.
H2O
Ph NH2
2
Ph N C O
3
+
O
4
Ph
Ph
Ph
Ph
N3
+
P
+
Ph N P Ph N2
Ph
Ph
N
H
N
H
Ph
1
Ph
Scheme 3.
CO2
(TEAB)
H2O
Ph NH2
2
Ph
P
Ph
Ph
Ph
R N C O
Ph
Ph
O P
Ph
N
+ Ph N C O
3
R' XY
H2O
O
O
R
RNH XR'
O
NH2
Scheme 2.
X = NH2, NH-alkyl, NH-NH2,
Thus, we have compared the courses of these two reactionsda
textbook Staudinger reaction of benzylazide with triphenylphos-
phine in dioxane in the presence of water and the same Staudinger
CH=NOH, SH, OH
Scheme 4.

2212
A. Yagodkin et al. / Tetrahedron 66 (2010) 2210–2221
Table 1
Carbamoylation of basic nucleophilic compounds (free bases, entries 1–13), employing procedure Aa
Entry
Organic Azide (R-N3)
Nucleophilic compound
Yield
Product
b
c
%
%
NHPr
BnNH
5
1
BnN3
PrNH2
>99
71
64
O
N
N
BnNH
6
2
3
BnN3
BnN3
O
90
HN
O
O
O
94
68
BnNH
7
HN
O
O
O
NH
HO
O
N
NH
HO
4
5
6
96
73
O
N
HN
O
HN
8
N
N3
O
O
N
NH
O
N
HO
HO
NH
O
O
O
BnNH2
93
76
HO
O
O
HN
9
NHBn
N3
O
N
NH
O
N
O
NH
O
O
O
94
85
HO
HO
O
HN
O
HN
10
N
O
N3
O
N
HN
O
N
O
O
OH
O
NH
NH
O
O
O
7
8
HO
97
96
65
63
O
O
N
N
H
N
H
O
O
N
NH
HO
11
O
N3
NH2
O
O
N
PhN3
PhNH
HN
12
O
O
O
N
NH
NH
HO
HO
O
N
O
O
O
O
9
BnNH2
81
56
13
O
O
O
O
N3
N
NHBn
H

A. Yagodkin et al. / Tetrahedron 66 (2010) 2210–2221
2213
Table 1 (continued)
Entry
Organic Azide (R-N3)
Nucleophilic compound
Yield
Product
b
c
%
%
O
NH
N
H
N3
DMTO
HO
DMTO
O
O
O
Cl
O
OH
10
H2N
91
55
O
Cl
14
O
Cl
Cl
O
N
NH
O
HO
O
NH
O
NH2
11
12
76
59
15
CF3(CF2)7
HO
O
N
O
H
N
HN
(CF2)7CF3
N3
O
O
PrHN
N3
NH
O
PrNH2
80
78
O
COOH
16
COOH
O
O
N
NH
NH
13
AMPSd
d
87e
DMTO
DMTO
O
N
O
O
O
O
17
O
O
O
O
N
H
N
N3
H
a
See Experimental and Supplementary data for details.
b
Yields were determined by integration of all RP HPLC peaks at 260 nm, with the exception of peaks of the initial compounds and the corresponding triphenylphosphine
oxide.
c
Isolated yield.
d
e
AMPS¼macroporous aminomethylpolystyrene.
Isolated yield was calculated as % ratio of the amount of AMPS bound DMT groups versus DMT groups of the 50-O-DMT-30-O-(4-azidobutiryl)thymidine.
One can observe the gradual decrease of the singlet intensity at
evidence, i.e., no doublet, corresponding to the –CH2– group of
phosphinimine 1 observed. In this case, one can detect the
appearance of two new signalsdone singlet at 4.56 ppm and an-
other singlet at 4.40 ppm within less than 1 min of reaction time. As
supported by 1H NMR measurements with authentic samples,
whereas the singlet at 4.56 ppm corresponds to the CH2-group of
isocyanate 3 (Schemes 2 and 3), the singlet at 4.40 ppm corre-
sponds to the CH2-groups of N,N0-dibenzylurea 4 (Scheme 3).
Figure 2 allows assuming that during the course of reaction the
concentration of isocyanate 3 remains nearly proportional to that of
the initial benzylazide. The concentrations of both compounds
gradually decline, with signal corresponding to 3 (4.56 ppm)
becoming practically non-detectible after 45 min and signal of
benzylazide (4.41 ppm) becoming very small after 60 min. In par-
allel, the concentration of urea 4 gradually increases. The singlet at
4.40 ppm, corresponding to the N,N0-dibenzylurea 4, reaches its
maximum within 12 h. This singlet appears to be the only
CH2-group related signal in the reaction mixture, indicating that
the reaction is complete.
about 4.4 ppm (corresponding to the –CH2– group of the initial
benzylazide) within the first 60 min in parallel with the gradual
growth of the doublet intensity (4.33 ppm, JP–H¼16 Hz) corre-
sponding to the –CH2– group of phosphinimine 1 along with the
appearance of a low intensity singlet at 3.79 ppm corresponding to
the –CH2– group of benzylamine 2. Further monitoring of the
reaction demonstrated that the singlet corresponding to benzyl-
azide was completely absent after 4 h, while the doublet, corre-
sponding to phosphinimine appears to be present even 5 h after the
start of the reaction. Eventually, after 12 h, only one singlet can be
found, which corresponds to benzylamine in this region of 1H NMR
spectrum. Evidently, both processes, the Staudinger reaction of
phosphinimine formation as well as generation of benzylamine
from the phosphinimine by hydrolysis appear to be relatively slow
reactions, which take several hours to complete.
Interestingly, the Staudinger reaction gives completely different
products in the presence of aqueous triethylammonium hydrogen
carbonate buffer (Fig. 2).
As in the previous case (Fig. 1), one can observe the gradual
decrease of the singlet intensity at 4.41 ppm (corresponding to the
–CH2– group of the initial benzylazide) within more than 60 min.
However, in contrast to the previous experiment, there is no
The results of the experiments outlined in Figure 2 makes it
possible to draw the following conclusion. The rate limiting step of
the reaction appears to be the formation of the phosphinimine 1. In
the presence of aqueous 3 M TEAB, rather than being hydrolyzed to

2214
A. Yagodkin et al. / Tetrahedron 66 (2010) 2210–2221
Table 2
Carbamoylation of weakly basic nucleophilic compounds (entry 14), salts of basic nucleophilic compounds (entries 17, 21, 26), non-basic nucleophilic compounds (entries 15,
16, 18–20,22,23,27) or in situ generated basic nucleophilic compounds (entries 24,25), employing procedure Ba
Entry
14
Organic Azide (R-N3)
Nucleophilic compound
Yield
Product
b
c
%
%
NHNHPh
18
BnNH
BnN3
PhNHNH2
87
69
O
O
NH
O
HO
NH
N
O
O
15
16
PhSH
95
83
58
48
HO
O
19
N
O
HN
SPh
N3
O
S
BnNH
OH
OH
HS
BnNH3
20
O
O
NH
O
N
HO
O
NH
N
O
17
CH3ONHCH3$HCl
84
76
HO
HO
21
O
O
HN
N(Me)OMe
N3
O
O
NH
O
N
HO
O
O
22
N
NH
O
N
18
19
64
94
43
53
O
N
OH
O
NH
N
O
N3
N
N
COOH
N
BnN3
BnHN
23
COOH
H
O
O
NH
O
N
HO
O
N
NH
O
O
24
COOH
N
20
97
57
HO
O
O
H
HN
N
N3
COOH
OH
OH
NH
N
O
O
O
O
O
O
21
PhN3
92
69
HCl
NH
25
O
O
O
O
N
O
N
NH
NH
HO
O
22d
Methanol
77
57
O
HO
O
26
O
HN
OMe
N3
O

A. Yagodkin et al. / Tetrahedron 66 (2010) 2210–2221
2215
Table 2 (continued)
Entry
Organic Azide (R-N3)
Nucleophilic compound
Yield
Product
b
c
%
%
DMTO
27
NH
O
N3
DMTO
23
24
d
d
76
98
66
64
O
OH
BnNH
NHBn
4
BnN3
O
O
N
HN
O
N
O
OH
NH
O
O
O
25
d
93
87
69
67
HO
O
O
N
H
N
O
NH
N
H
HO
11
O
N3
BnNH
NH2
28
26
27
BnN3
Ammonium acetate
O
O
N
O
N
NH
NH
PhOH
51
31
HO
O
O
HO
O
29
O
HN
OPh
N3
O
a
See Supplementary data for experimental details.
b
Yields were calculated by integration of all RP HPLC peaks at 260 nm, with the exception of peaks of the initial compounds and the corresponding triphenylphosphine
oxide.
c
Isolated yield.
d
Synthesis of carbamate 26 was performed in methanol as the solvent (see also Table 4), using procedure B.
Table 3
the benzylamine 2, the iminophosphorane 1 undergoes a rapid
(at least on the time scale of NMR experiment) addition with CO2 to
give rise to the benzylisocyanate 3 (Scheme 1).
Carbamoylation of weakly basic nucleophilic compounds (entries 28, 29) and an in
situ generated basic nucleophilic compound (entry 30), employing polymer-bound
triphenylphosphine and procedure Ca
Subsequently, benzylisocyanate 3, which is subjected to partial
hydrolysis, forms benzylamine 2, which in turn instantly reacts
with the remaining isocyanate 3 to give the urea 4 as a final product
(Scheme 3). As shown in a separate experiment with an authentic
sample of benzylisocyanate, the complete conversion of 3 into 4
under the same reaction conditions requires less than the time
needed to undertake one 1H NMR spectrum measurement. On the
basis of this proposed mechanism, we postulated that if a com-
pound with a nucleophilicity higher than that of water is present in
the mixture from the very start, then the reaction will lead to the
formation of the corresponding carbamoyl derivative. Thus, this
method could provide simple access to a number of non-sym-
metrical ureas, thiocarbamates, and carbamates (Scheme 4).
Our present work demonstrates examples of carbamoylation
for different types of nucleophilic compounds while employing
the trialkylammonium hydrogen carbonate buffer as a conve-
nient source of carbon dioxide. Both buffers tested; i.e., TEAB and
TMAB, perform equally well in the new method, and gave similar
yields of the target compounds. The synthetic procedures A–C,
employed to generate compounds in Tables 1–3 are described in
detail in the Experimental. Entries 1–12, in Table 1, show car-
bamoylation of basic nucleophilic compounds (synthetic pro-
cedure A), including the carbamoylation of a polymer-bound
basic nucleophilic compounddaminomethylpolystyrene (entry
13, Table 1).
Entry
Azide
(R-N3)
Nucleophilic
compound
Yield
Product
b
c
%
%
BnNH
NHPh
30
28
BnN3
PhNH2
75
57
O
O
O
NH
HO
O
N
29
AZTd
PhNH2
86
89
52
59
31
NHPh
HN
O
O
BnNH
NHBn
4
30
BnN3
d
a
See Supplementary data for experimental details.
Yields were calculated by integration of all RP HPLC peaks at 260 nm, with the
b
exception of peak, corresponding to aniline.
c
Isolated yield.
30-Azido-30-deoxythymidine.
d
entries 15, 16, 18–20, 22–25 and 27, in Table 2 show reaction with
non-basic nucleophilic compounds or strong nucleophiles gener-
ated in situ by hydrolysis of the intermediate isocyanate, resulting
in the corresponding symmetrical ureas. Examples of carbamoy-
lation of weakly basic nucleophilic compounds (entries 28 and 29,
Table
2 corresponds to synthetic procedure B. Several
entriesd14, 17, 21, and 26, in Table 2 show the reaction with
weakly basic nucleophiles or salts of basic nucleophiles, and

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A. Yagodkin et al. / Tetrahedron 66 (2010) 2210–2221
Table 3) or in situ generated basic nucleophilic compound (entry
30, Table 3) employing a polymer-bound triphenylphosphine are
also depicted as synthetic procedure C.
alcohols may participate in the reaction under certain circum-
stances; e.g., methyl carbamate 26 (Table 2) with an excess of
methanol, or the formation of a cyclic product, carbamate 27
(Table 2). The reaction with phenol and AZT gave the corre-
sponding phenyl carbamate 29 in a satisfactory yield (Table 2).
Conversely, no corresponding carbamates were found in the
reaction mixture with p-nitrophenol or pentafluorophenol and
30-azido-30-deoxythymidine (AZT). In the case with p-nitro-
phenol this approach gave symmetrical urea in high yields, be-
ing virtually the single product, excluding the initial
triphenylphosphine and the corresponding phosphine oxide. In
It is worth noting that procedure Bdcarbamoylation,
employing a weakly basic, non-basic or an in situ generated
strong basic nucleophilic compound, may be described here as
general. This procedure consists of mixing the componentsde.g.,
organic azide, weakly basic, non-basic or no nucleophilic com-
pound, triphenylphosphine and TEAB or TMAB buffer and
allowing the reaction to run to completion at rt in a tightly closed
vessel. Procedure A utilizes amines as basic nucleophilic com-
pounds. Obviously, addition of strongly basic amines to a mixture
containing aqueous trialkylammonium hydrogen carbonate re-
sults in the conversion of hydrogen carbonate into carbonate,
which will diminish the concentration of free carbon dioxide in
solution and, consequently reduce the yield. Therefore, it is es-
sential that aliphatic amines, when employed as nucleophilic
compounds, must be initially neutralized. If a salt of the required
amine appears to be readily available, it may be introduced into
the carbamoylation reaction as such. As most of the amines in
Table 1 are usually available in the form of free bases, procedure
A incorporates the preliminary conversion of these bases into the
corresponding hydrogen carbonates by saturation of the amine
solution in TEAB or TMAB with gaseous carbon dioxide. Pro-
cedure C, being similar to procedure B, utilizes the polymer-
bound triphenylphosphine (Table 3), which requires the reaction
to be run at elevated temperatures due to the reduced reactivity
of the latter compound.
In order to investigate the range of utility for the present ap-
proach, we conducted a comparative study of the reaction between
benzylazide with triphenylphosphine in the presence of 2 M TEAB
in various solvents to produce N,N0-dibenzylurea 4 (Table 4).
From the values presented in Table 4, dioxane appears to be the
optimum solvent for the carbamoylation reaction. However, the use
of acetonitrile, 2-propanol, bis-(2-methoxyethyl)-ether, and ace-
tone also provides satisfactory yields of 4. When ethanol and
methanol are employed as solvents, the formation of the target
urea (70% and 23% correspondingly) was accompanied by the for-
mation of the corresponding ethylcarbamate (16%) and methyl
carbamate (59%) (Table 4). Therefore, this approach may serve as
a convenient method for the synthesis of methyl carbamates, when
the appropriate method of separation of products is elaborated.
the case with pentafluorophenol
a mixture of two com-
poundsdsymmetrical urea (24%) along with the corresponding
30-amino-30-deoxythymidine (76%) were found as two products
of the reaction.
We also compared the potency of the various phosphines in the
reaction with benzylazide in the presence of 2 M TEAB in dioxane
(Table 5).
Table 5
Yields of N,N0-dibenzylurea 4, synthesized by the carbamoylation reaction, em-
ploying benzylazide, various phosphines, 2 M TEAB, and dioxanea
Phosphine
Yieldb%
Triphenylphosphine
98%
95%
89%
Methyldiphenylphosphine
3-(Diphenylphosphino)benzenesulphonic acid
sodium salt
Diphenyl-2-pyridylphosphine
Dimethylphenylphosphine
Tributylphosphine
Methoxydiphenylphosphine
Dimethoxyphenylphosphine
Tri-2-furylphosphine
78%
71% (0.7)c
37% (0.65)c
29% (0.7)c
5% (0.15)c
1%
a
See Supplementary data for experimental details.
b
Yields were accessed by integration of RP HPLC peaks at 260 nm, with the ex-
ception of peaks of the initial phosphines and the corresponding phosphine oxides.
Yields given in Table 5 are approximate since yield calculation was based on the
assumption that the extinction coefficients of all compounds in the reaction mixture
(excluding peaks of the initial phosphines and the corresponding phosphine oxides)
are equal.
c
The ratios of peak areas for target compound 4 in reactions using various
phosphines in dioxane to the peak area of 4 in a control reaction, employing tri-
phenylphoshpine in dioxane, are given in brackets.
From the values presented in Table 5, triphenylphosphine
appears to be a superb reagent in the carbamoylation process,
while methyldiphenylphosphine, 3-(diphenylphosphino)-benze-
nesulphonic acid sodium salt, and diphenyl-2-pyridylphosphine
also proved to be effective reagents in this carbamoylation pro-
cedure. The possibility of performing the carbamoylation of nu-
cleophilic compounds, using solvents that are more polar than
dioxane and employing phosphines that demonstrate a better
solubility in aqueous organic solvents, e.g., 3-(diphenylphosphino)-
benzenesulphonic acid sodium salt and diphenyl-2-pyri-
dylphosphine, seems to be especially important if this method is to
be applied with the different natural compounds (amino acids,
modified nucleosides, and even oligonucleotides), that display
a limited solubility in organic solvents.
Table 4
Yields of N,N0-dibenzylurea 4, synthesized by the carbamoylation reaction,
employing benzylazide, triphenylphosphine, 2 M TEAB, and various solventsa
Solvent
Yield of urea 4b%
1,4-Dioxane
98
2-Propanol
94
Acetonitrile
81
bis-(2-Methoxyethyl)-ether
Acetone
81
79
N-Methylpyrrolidinone
Ethanol
Dimethylsulfoxide
Methanol
67
70 (þ16% of ethyl benzylcarbamate)
49
23 (þ59% of methyl benzylcarbamate)
DMF
0
a
See Supplementary data for experimental details.
Yields were calculated by integration of all RP HPLC peaks at 260 nm, with the
3. Conclusion
b
exception of peaks of the initial triphenylphosphine and the corresponding
triphenylphosphine oxide. Yields given in Table 4 are approximations, as yield
calculations were based on the assumption that the extinction coefficients of all
compounds in the reaction mixture (excluding peaks of the initial triphenylphos-
phine and the corresponding triphenylphosphine oxide) are equal.
In summary, novel approach proved to be a convenient and
efficient method to carbamoylate various nucleophilic functions
(Scheme 5).
Due to the simplicity of substitution with the azide ion, the
preparation of organic azides can be readily accomplished in many
cases. The novel straightforward procedure, which does not require
special equipment for the in situ transformation of azides into in-
termediate isocyanates in polar aqueous organic media, is expected
Carbamoylation of nitrogen and sulfur nucleophilic com-
pounds resulted in good to excellent yields of products (Tables
1–3). Moreover, even weakly nucleophilic hydroxyl groups of

A. Yagodkin et al. / Tetrahedron 66 (2010) 2210–2221
2217
bound polymer 17 (entry 13, Table 1), the resin was filtered, thor-
oughly washed with dioxane, and finally dried in vacuo.
X
P Y
Z
X
R N3
R
N P Y
Z
4.3. Synthetic procedure B
aqueous trialkylammonium
Carbamoylation, employing a weakly basic, non-basic or in situ
generated strong basic nucleophilic compounds. The organic azide
(0.75 mmol) was added to a mixture of the freshly saturated 2 M
trialkylammonium hydrogen carbonate buffer (1 ml) and 12 ml of
dioxane (synthesis of compounds 4, 11, 18–21, 25–29) or 12 ml of
2-propanol (synthesis of compounds 22–24), in the presence or
absence of a nucleophilic component (1 mmol). Triphenylphos-
phine (1.33 mmol) was added to the reaction mixture, the reaction
flask was tightly closed, vigorously shaken until complete dissolu-
tion of components, and then left for 24 h at rt. In the case of
heterogeneous reaction mixtures (entries 17–19, Table 2), vigorous
shaking was continued for 24 h. The reaction mixture was evapo-
rated to dryness. The resulting products were isolated, using silica
gel flash chromatography (compound 17) or reverse phase flash
chromatography (compounds 19, 26) or crystallization from
appropriate solvents (compounds 4,11,17,18, 24, 25, 29). In the case
hydrogen carbonate
NuH
RNH Nu
O
R N C O
Scheme 5.
to expand the synthetic availability for various classes of carbamoyl
derivatives.26 This statement may be especially relevant for natural
compounds displaying poor solubility in moderately polar organic
solvents (e.g., amino acids, nucleosides, etc.).
It is worth noting that this approach works well with modified
solid surfaces and polymers that have nucleophilic functional
groups.
We believe that such a simple method could be of broad interest
for synthetic and medicinal chemists.
of
L-proline derivatives 22 and 23, the reaction mixtures were
4. Experimental procedures
4.1. General
evaporated to dryness, the residue was dissolved in dichloro-
methane, extracted with 5% aqueous ammonium hydroxide,
aqueous extracts were acidified with hydrochloric acid to produce
pure viscous pale yellow oily products.
Gradient column chromatography was run using two C-601
pump modules, a C-615 pump controller, and borosilicate glass
4.4. Synthetic procedure C
columns (Bu¨chi). Lichroprep RP-18 (40–63
mm) or Silicagel 60
(40–63 m) (Merck) was employed for flash column chromatog-
m
Carbamoylation, employing polymer-bound triphenylphos-
phine (Table 3). The organic azide (0.5 mmol) was added to a mix-
ture of the freshly saturated 2 M TEAB (0.8 ml) and dioxane (10 ml),
in the presence or absence of a nucleophilic component (2.5 mmol).
Polymer-bound triphenylphosphine (2.0 g, 0.8 mmol/g triphenyl-
phosphine residues loading) was added to the reaction mixture.
The reaction flask was tightly closed and vigorously shaken for 48 h
at 40 ꢀC. The resin was filtered, washed with 3 ml of dioxane. The
combined filtrate and washings were evaporated to dryness and
the products were isolated using reverse phase flash chromatog-
raphy (compounds 30, 31) or crystallization from the appropriate
solvent (compound 4).
raphy using gradient of acetonitrile in water or methanol in
dichloromethane for the purification of compounds reported
herein. Analytical RP HPLC was performed employing a gradient
Waters ‘Breeze’ chromatograph on
a mm,
xBridgeÒ RP18 (5
4.6ꢁ150 mm, Waters) column using a gradient elution with ace-
tonitrile (from 0 to 80% over 30 min) in 0.1 M triethylammonium
acetate, pH 8.5, followed by isocratic elution with 80% acetonitrile
in 0.1 M triethylammonium acetate, pH 8.5; flow rate 1 ml/min.
NMR spectra were collected with an Avance 500 spectrometer
(Bruker) in DMSO-d6, CDCl3, CD3CN or dioxane-d8. High resolution
mass spectra (HRMS) were obtained with Applied Biosystems
QSTAR XL instrument using ESI. Exact masses of compounds were
calculated using the built in calculator of Analyst QS software.
Whereas characterization data for novel compounds is given
herein, the corresponding data for all compounds synthesized by
the present method, along with 1H and 13C NMR spectra may be
found in Supplementary data.
4.5. Testing various solvents
Generation of N,N0-dibenzylurea 4, employing benzylazide,
triphenylphosphine, 2 M TEAB, and various solvents was per-
formed as described above for Synthetic procedure B. The results of
these experiments are given in Table 4.
4.2. Synthetic procedure A
4.6. Testing various phosphines
Carbamoylation, employing basic nucleophilic compounds. A
mixture of basic nucleophilic compound (1 mmol) or amino-
methylpolystyrene (AMPS, 0.25 mmol/g of amino group loading,
4 g) and freshly prepared 2 M trialkylammonium hydrogen
carbonate buffer (TEAB or TMAB), pH 7.5–8.0 (1 ml) was saturated
with carbon dioxide at 0 ꢀC. Dioxane (12 ml) and organic azide
(0.75 mmol), followed by triphenylphosphine (1.33 mmol) were
quickly added to the reaction mixture. The reaction flask was
tightly closed, vigorously shaken until complete dissolution of
components, and then left for 24 h at rt. In case of heterogeneous
reaction mixtures (entries 10, 11, and 13, Table 1) the vigorous
shaking was continued for 24 h. The reaction mixture was evapo-
rated to dryness. The resulting products were isolated, using silica
gel flash chromatography (compounds 9, 13–15), reverse phase
flash chromatography (compounds 6–8, 10) or crystallization from
appropriate solvents (compounds 5, 11, 16). In case of nucleoside
Generation of N,N0-dibenzylurea 4, employing benzylazide,
dioxane, 2 M TEAB, and various phosphines was performed as
described above for Synthetic procedure B. The results of these
experiments are given in Table 5.
4.7. N-((2S,3S,5R)-2-(Hydroxymethyl)-5-(5-methyl-2,4-dioxo-
3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-
yl)piperidine-1-carboxamide (8)
Purified by crystallization from acetonitrile to give white crys-
tals. Mp 205–206 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d 11.26 (1H, s,
NH-3 of pyrimidine), 7.77 (1H, s, H-5 of pyrimidine), 6.65 (1H, d,
J¼7.0 Hz, terahydrofuran–NHCON), 6.19 (1H, t, J¼6.5 Hz, H-1 of
tetrahydrofuran), 5.01 (1H, t, J¼5.3 Hz, OH), 4.22 (1H, m, H-3 of
tetrahydrofuran), 3.78 (1H, m, H-4 of tetrahydrofuran), 3.63 (1H, m,

2218
A. Yagodkin et al. / Tetrahedron 66 (2010) 2210–2221
H-5a of tetrahydrofuran), 3.55 (1H, m, H-5b of tetrahydrofuran),
3.27 (4H, m, H-2a,b and H-6a,b of piperidine), 2.15 (2H, m, H-2a,b of
tetrahydrofuran), 1.78 (3H, s, CH3), 1.52 (2H, H-4a,b of piperidine),
1.41 (4H, m, H-3a,b and H-5a,b of piperidine). 13C NMR (125 MHz,
of pyrimidine), 7.75 (2H, s, 2ꢁH-5 of pyrimidine), 6.37 (2H, d,
J¼7.2 Hz, NHCONH), 6.14 (2H, t, J¼6.2 Hz, 2ꢁH-1 of tetrahydrofu-
ran), 5.06 (2H, t, J¼4.8 Hz, 2ꢁOH), 4.17 (2H, m, 2ꢁH-3 of tetrahy-
drofuran), 3.72 (2H, m, 2ꢁH-4 of tetrahydrofuran), 3.65 (2H, m,
2ꢁH-5a of tetrahydrofuran), 3.54 (2H, m, 2ꢁH-5b of tetrahydro-
furan), 2.19 (2H, m, 2ꢁH-2a of tetrahydrofuran), 2.01 (2H, m, 2ꢁH-
2b of tetrahydrofuran), 1.78 (6H, s, 2ꢁCH3). 13C NMR (125 MHz,
DMSO-d6): d 164.2 (s, C-4 of pyrimidine), 157.5 (s, NHCON), 150.9 (s,
C-2 of pyrimidine), 136.7 (s, C-6 of pyrimidine), 109.8 (s, C-5 of
pyrimidine), 85.9 (s, C-1 of tetrahydrofuran), 83.9 (s, C-4 of tetra-
hydrofuran), 61.9 (s, C-5 of tetrahydrofuran), 50.3 (s, C-3 of tetra-
hydrofuran), 44.7 (s, C-2 and C-6 of piperidine), 37.9 (s, C-2 of
tetrahydrofuran), 25.8 (s, C-3 and C-5 of piperidine), 24.6 (s, C-4 of
piperidine), 12.7 (s, CH3). HRMS ESI (m/z): [(MþH)þ] calcd for
C16H25N4O5, 353.1825; found, 353.1840.
CD3CN):
d
164.2 (s, 2ꢁC-4 of pyrimidine), 157.7 (s, NHCON), 150.9 (s,
2ꢁC-2 of pyrimidine), 136.6 (s, 2ꢁC-6 of pyrimidine), 109.8 (s, 2ꢁC-
5 of pyrimidine), 85.8 (s, 2ꢁC-1 of tetrahydrofuran), 83.8 (s, 2ꢁC-4
of tetrahydrofuran), 61.7 (s, 2ꢁC-5 of tetrahydrofuran), 50.2 (s,
2ꢁC-4 of tetrahydrofuran), 38.1(s, 2ꢁC-2 of tetrahydrofuran), 12.7
(s, 2ꢁCH3). HRMS ESI (m/z): [(MþH)þ] calcd for C21H29N6O9,
509.1996; found, 509.1991.
4.8. 1-Benzyl-3-((2S,3S,5R)-2-(hydroxymethyl)-5-(5-methyl-
2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-
yl)urea (9)
4.11. (2R,3S,5R)-2-(Hydroxymethyl)-5-(5-methyl-2,4-dioxo-
3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl-4-(3-
benzylureido)butanoate (13)
Purified by crystallization from acetonitrile to give white crys-
tals. Mp 173–176 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d 11.26 (1H, br s,
H-5 of pyrimidine), 7.76 (1H, s, H-5 of pyrimidine), 7.35–7.15 (4.4H,
m, phenyl), 6.46 (1H, d, J¼7.3 Hz, terahydrofuran–NHCONH), 6.35
(1H, t, J¼5.7 Hz, NHCONH–benzyl), 6.15 (1H, t, J¼6.3 Hz, H-1 of
tetrahydrofuran), 5.06 (1H, t, J¼5.2 Hz, OH), 4.20 (3H, m, CH2 of
benzyl and H-3 of tetrahydrofuran), 3.73 (1H, m, H-4 of tetrahy-
drofuran), 3.65 (1H, m, H-5a of tetrahydrofuran), 3.56 (1H, m, H-5b
of tetrahydrofuran), 2.21 (1H, m, H-2a of tetrahydrofuran), 3.27 (4H,
m, H-2a,b and H-6a,b of piperidine), 2.21 (1H, m, H-2a of tetrahy-
drofuran), 2.10 (1H, m, H-2b of tetrahydrofuran), 1.78 (3H, s, CH3).
Purified by crystallization from acetone to give white crystals. Mp
162–165 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d 11.25 (0.9H, NH-3 of
pyrimidine), 7.74 (1H, s, H-5 of pyrimidine), 7.34–7.18 (4.4H, m,
phenyl), 6.30 (1H, t, J¼5.9 Hz, NHCONH–Bn), 6.19 (1H, dd, J¼6.0 Hz,
J¼8.5 Hz, H-1 of tetrahydrofuran), 6.00 (1H, t, J¼5.6 Hz,
CO(CH2)3NHCONH), 5.27–5.17 (2H, m, H-3 of tetrahydrofuran and
OH), 4.20 (2H, d, J¼5.9 Hz, CH2–phenyl), 3.97 (1H, m, H-4 of tetra-
hydrofuran), 3.63 (2H, br s, H-5a and H-5b of tetrahydrofuran), 3.04
(2H, dt, J¼6.5 Hz, J¼12.7, CH2CH2CH2NH), 2.34 (2H, t, J¼7.4,
COCH2CH2CH2), 2.31–2.19(2H, m, H-2aandH-2boftetrahydrofuran),
1.78 (3H, s, CH3),1.65 (2H, m, J¼7.0 Hz, J¼14.2, CH2CH2CH2). 13C NMR
13C NMR (125 MHz, DMSO-d6):
d 164.2 (s, C-4 of pyrimidine), 158.2
(s, NHCONH), 150.9 (s, C-2 of pyrimidine), 141.2 (s, C-1 of phenyl),
136.6 (s, C-6 of pyrimidine), 128.7 (s, C-3 and C-5 of phenyl), 127.4
(s, C-2 and C-6 of phenyl), 127.02 (s, C-4 of phenyl), 109.8 (s, C-5 of
pyrimidine), 86.0 (s, C-1 of tetrahydrofuran), 83.8 (s, C-4 of tetra-
hydrofuran), 61.7 (s, C-5 of tetrahydrofuran), 50.3 (s, C-3 of tetra-
hydrofuran), 43.4 (s, CH2 of benzyl), 38.2(s, C-2 of tetrahydrofuran),
12.7 (s, CH3). HRMS ESI (m/z): [(MþH)þ] calcd for C18H23N4O5,
365.1668; found, 365.1661.
(125 MHz, DMSO-d6):
d 172.8 (s, OCOCH2), 164.1 (s, C-4 of pyrimi-
dine), 158.5 (s, NHCONH),150.9 (s, C-2 of pyrimidine),141.4 (s, C-1 of
phenyl),136.3 (s, C-6 of pyrimidine), 128.6 (s, C-3 and C-5 of phenyl),
127.5 (s, C-2 and C-6 of phenyl), 127.0 (s, C-4 of 2,4-dichlorophenyl),
110.2 (s, C-5 of pyrimidine), 85.1 (s, C-1 of tetrahydrofuran), 84.2 (s, C-
4 of tetrahydrofuran), 75.1 (s, C-3 of tetrahydrofuran), 61.8 (s, C-5 of
tetrahydrofuran), 43.4 (s, CH2-phenyl), 39.0 (s, OCOCH2CH2CH2NH),
37.0 (s, C-2 of tetrahydrofuran), 31.4 (s, OCOCH2CH2CH2NH), 25.9 (s,
OCOCH2CH2CH2NH), 12.7 (s, CH3). HRMS ESI (m/z): [(MþH)þ] calcd
for C22H29N4O7, 461.2036; found, 41.2046.
4.9. 5,9 N-((2S,3S,5R)-2-(Hydroxymethyl)-5-(5-methyl-2,4-
dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-
yl)morpholine-4-carboxamide (10)
4.12. 1-(Bis(4-methoxyphenyl)(phenyl)methoxy)-3-
(3-(3-hydroxypropyl)ureido)propan-2-yl-2-(2,4-
dichlorophenoxy)acetate (14)
Purified by crystallization from acetonitrile to give white crys-
tals. Mp 156–159 ꢀC. 1H NMR (500 MHz, CD3CN):
d 9.60(1H, s, NH-3
of pyrimidine), 7.70 (1H, s, H-5 of pyrimidine), 6.17 (1H, dd,
J¼5.3 Hz and J¼6.6 Hz, H-1 of tetrahydrofuran), 5.62 (1H, d,
J¼6.9 Hz, terahydrofuran–NHCON), 4.33 (1H, m, H-3 of tetrahy-
drofuran), 3.93 (1H, t, J¼5.8 Hz, OH), 3.77 (2H, m, H-4 and H-5a of
tetrahydrofuran), 3.69 (1H, m, H-5b of tetrahydrofuran), 3.60 (4H, t,
J¼4.7 Hz, H-2a,b and H-6a,b of morpholine), 3.31 (4H, t, J¼4.7 Hz,
H-3a,b and H-5a,b of morpholine), 2.35 (2H, m, H-2a,b of tetrahy-
Purified by flash reverse phase column chromatography to give
pale yellow oil. 1H NMR (500 MHz, CD3CN):
d 7.5–6.82 (16H, m, phe-
nyl, 2ꢁ4-methoxyphenyl, 2,4-dichlorophenyl), 5.13 (1H, m, 2,4-
dichlorophenoxyacetyl-OCH), 5.07 (2H, m, 2ꢁNH), 4.79 (1H, s, 2,4-
dichlorophenyl-OCHa, 4.78(1H, s, 2,4-dichlorophenyl-OCHb, 3.76 (6H,
s, 2ꢁOCH3), 3.45–3.12 (9H, m, bis(4-methoxyphenyl)(phenyl)methyl-
drofuran), 1.85 (3H, s, CH3). 13C NMR (125 MHz, CD3CN):
d
164.1 (s,
OCH2,
NHCH2CH2CH2OH,
OH,
2,4-dichlorophenoxyacetyl-
C-4 of pyrimidine), 157.9 (s, NHCON), 150.7 (s, C-2 of pyrimidine),
136.3 (s, C-6 of pyrimidine), 109.9 (s, C-5 of pyrimidine), 85.7 (s, C-1
of tetrahydrofuran), 83.9 (s, C-4 of tetrahydrofuran), 66.1 (s, C-2 and
C-6 of morpholine), 61.3 (s, C-5 of tetrahydrofuran), 50.1 (s, C-3 of
tetrahydrofuran), 43.9 (s, C-3 and C-5 of morpholine), 37.3 (s, C-2 of
tetrahydrofuran), 11.7 (s, CH3). HRMS ESI (m/z): [(MþH)þ] calcd for
C15H23N4O6, 355.1618; found, 355.1611.
OCHCH2NH), 1.51 (2H, m, NHCH2CH2CH2OH). 13C NMR (125 MHz,
CD3CN):
167.9 (s, COO), 158.9 (s, NHCONH), 158.7(s, 2ꢁC-4 of 4-
d
methoxyphenyl), 152.6 (s, C-1 of 2,4-dichlorophenyl), 145.0 (s, C-1 of
phenyl),135.8 (s, 2ꢁC-1 of 4-methoxyphenyl),130.0 (s, C-3 and C-5 of
phenyl), 129.8 (s, C-3 of 2,4-dichlorophenyl), 128.0 (s, C-2 and C-6 of
phenyl),127.9 (s, C-2 and C-6 of 4-methoxyphenyl),127.8 (s, C-5 of 2,4-
dichlorophenyl), 126.9 (s, C-4 of 2,4-dichlorophenyl), 126.0 (s, C-4 of
phenyl), 123.2 (s, C-2 of 2,4-dichlorophenyl), 114.9 (s, C-6 of 2,4-
dichlorophenyl),113,1 (s, C-3 andC-5 of4-methoxyphenyl), 86.0[s, (4-
methoxyphenyl)2phenyl)-C, 73.8 (s, 2,4-dichlorophenoxyacetyl-
OCH), 66.0 (s, (4-methoxyphenyl)2phenyl)methyl-OCH2), 62.7 (s, 2,4-
dichlorophenyl-OCH2CO), 58.5 (s, NHCH2CH2CH2O), 54.9 (s, 2ꢁ–
OCH3), 40.13 (s, 2,4-dichlorophenoxyacetyl-OCHCH2NH), 36.3 (s,
NHCH2CH2CH2O), 33.1 (s, NHCH2CH2CH2O). HRMS ESI (m/z):
4.10. 1,3-Bis((2S,3R,5R)-2-(hydroxymethyl)-5-(5-methyl-2,4-
dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-
yl)urea (11)
Purified by crystallization from acetone to give white crystals.
Mp 204–208 ꢀC. 1H NMR (500 MHz, CD3CN):
d
11.28 (2H, s, 2ꢁNH-3

A. Yagodkin et al. / Tetrahedron 66 (2010) 2210–2221
2219
[(MþNa)þ] calcd for C36H38N2O8Cl2Na, 719.1903; found, 719.1901;
4.17. S-Phenyl (2S,3S,5R)-2-(hydroxymethyl)-5-(5-methyl-2,4-
dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-
ylcarbamothioate (19)
[(MþK)þ] calcd for C36H38N2O8Cl2K, 735.1642; found, 735.1640.
4.13. 1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorodecyl)-
3-((2S,3S,5R)-2-(hydroxymethyl)-5-(5-methyl-2,4-dioxo-3,4-
dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl)urea (15)
Purified by crystallization from acetone to give white crystals.
Mp 120–124 ꢀC. 1H NMR (500 MHz, CD3CN):
d 9.38 (1H, s, NH-3 of
pyrimidine), 7.63 (1H, s, H-5 of pyrimidine), 7.55–7.40 (4.2H, m, S-
phenyl), 6.93 (1H, d, J¼6.5 Hz, SCONH–tetrahydrofuran), 6.20 (1H, t,
J¼6.3 Hz, H-1 of tetrahydrofuran), 4.45 (1H, m, H-3 of tetrahydro-
furan), 3.88 (1H, m, H-4 of tetrahydrofuran), 3.79 (1H, d, J¼11.6 Hz,
H-5a of tetrahydrofuran), 3.68 (1H, d, J¼11.9 Hz, H-5b of tetrahy-
drofuran), 3.29 (0.9H, m, OH), 2.32 (2H, m, H-2a,b of tetrahydro-
Purified by flash silica gel column chromatography to give pale
yellow foam. 1H NMR (500 MHz, CD3CN–DMSO-d6, 5:1):
d 10.62
(0.7H, br s, NH-3 of pyrimidine), 7.69 (1H, d, J¼1 Hz, H-5 of pyrimi-
dine), 6.29 (1H, d, J¼7.3 Hz, NHCONH–tetrahydrofuran), 6.16 (1H, t,
J¼6.1 Hz, H-1 of tetrahydrofuran), 5.80 (1H, t, J¼5.8 Hz, OH), 4.54
(0.9H, br s, heptadecafluorodecyl–NHCONH), 4.24 (1H, m, H-3 of
tetrahydrofuran), 3.75–3.68 (3H, m, H-4 and H-5a of tetrahydrofu-
ran), 3.64 (1H, m, H-5b of tetrahydrofuran), 3.41 (2H, q, J¼6.7 Hz,
NHCH2CH2(CF2)7CF3, 2.37) (2H, m, NHCH2CH2(CF2)7CF3), 2.27–2.12
(2H, m, H-2a and H-2b of tetrahydrofuran),1.82 (3H, d, J¼1 Hz, CH3).
furan), 1.82 (3H, s, CH3). 13C NMR (125 MHz, CH3CN):
d 165.6 (s,
NHCOS), 164.0 (s, C-4 of pyrimidine), 150.6 (s, C-2 of pyrimidine),
136.3 (s, C-6 of pyrimidine), 135.3 (s, C-1 of S-phenyl), 129.3 (s, C-2
and C-6 of S-phenyl), 129.1 (s, C-3 and C-5 of S-phenyl), 128.3 (s, C-4
of S-phenyl), 110.2 (s, C-5 of pyrimidine), 84.8 (s, C-1 of tetrahy-
drofuran), 84.3 (s, C-4 of tetrahydrofuran), 61.3 (s, C-5 of tetrahy-
drofuran), 51.1 (s, C-3 of tetrahydrofuran), 37.1 (s, C-2 of
tetrahydrofuran), 11.6 (s, CH3). HRMS ESI (m/z): [(MþH)þ] calcd for
C17H20N3O5S, 378.1124; found, 378.1124.
13C NMR (125 MHz, DMSO-d6):
d 164.2 (s, C-4 of pyrimidine), 158.1
(s, NHCONH), 150.9 (s, C-2 of pyrimidine), 136.0 (s, C-6 of pyrimi-
dine),122.0–107.0 (m, (CF2)7CF3),109.9 (s, C-5 of pyrimidine), 85.9 (s,
C-1 of tetrahydrofuran), 83.8 (s, C-4 of tetrahydrofuran), 61.4 (s, C-5
of tetrahydrofuran), 49.7 (s, C-3 of tetrahydrofuran), 37.8 (s, C-2 of
tetrahydrofuran), 32.0 (m, CH2CH2(CF2)7CF3, 31.2 (t, J¼20.7 Hz,
CH2CH2(CF2)7CF3, 11.8 (s, CH3). HRMS ESI (m/z): [(MþH)þ] calcd for
C21H20F17N4O5, 731.1162; found, 731.1163.
4.18. 3-((2S,3S,5R)-2-(Hydroxymethyl)-5-(5-methyl-2,4-dioxo-
3,4-dihydropyrimidin-1(2H)-yl) tetrahydrofuran-3-yl)-1-
methoxy-1-methylurea (21)
Purified by crystallization from acetonitrile to give white crys-
tals. Mp 170–173 ꢀC. 1H NMR (500 MHz, CD3CN):
d 9.36 (1H, s, NH of
4.14. 2-(4-((3-Propylureido)methyl)phenoxy)acetic acid (16)
pyrimidine), 7.67 (1H, d, J¼1.1 Hz, H-6 of pyrimidine), 6.55 (1H, d,
J¼7.4 Hz, NHCON(CH3)OCH3), 6.19 (1H, dd, J¼5.1 Hz, J¼6.9 Hz, H-1
of tetrahydrofuran), 4.35 (1H, m, H-3 of tetrahydrofuran), 3.84–3.77
(2H, m, H-4, H-5a of tetrahydrofuran), 3.70–3.66 (1H, m, H-5b of
tetrahydrofuran), 3.65 (3H, s, NHCON(CH3)OCH3), 3.55 (1H, t,
J¼5.9 Hz, OH), 3.03 (3H, s, NHCON(CH3)OCH3), 2.42–2.36 (1H, m, H-
2a of tetrahydrofuran), 2.34–2.28 (1H, m, H-2b of tetrahydrofuran),
Purified by crystallization from dichloromethane to give white
crystals. Mp 162–165 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d 12.97
(0.9H, br s, COOH), 7.15 (2H, d, J¼7.2 Hz, H-3, H-5 of 1,4-substituted
phenyl), 6.84 (2H, d, J¼7.1 Hz, H-2, H-5 of 1,4-substituted phenyl),
6.19 (1H, br s, NH), 5.88 (1H, br s, NH), 4.63 (2H, s, CH2O–C6H4–
CH2NH), 4.12 (2H, m, CH2O–C6H4–CH2NH), 2.96 (2H, m,
CH2CH2CH3), 1.37 (2H, m, CH2CH2CH3), 0.84 (3H, t, J¼6.9 Hz,
1.85 (1H, d, J¼1.1 Hz, CH3). 13C NMR (125 MHz, CH3CN):
d 163.9 (s,
C-4 of pyrimidine), 160.2 (s, NHCON(CH3)OCH3), 150.6 (s, C-2 of
pyrimidine), 136.3 (s, C-6 of pyrimidine), 110.0 (s, C-5 of pyrimi-
dine), 85.2 (C-1 of tetrahydrofuran), 84.1 (C-4 of tetrahydrofuran),
61.2 (s, NHCON(CH3)OCH3), 61.1 (C-5 of tetrahydrofuran), 49.2 (C-3
of tetrahydrofuran), 37.3 (C-2 of tetrahydrofuran), 34.7 (s,
NHCON(CH3)OCH3), 11.6 (s, CH3). HRMS ESI (m/z): [(MþH)þ] calcd
for C13H21N4O6, 329.1461; found, 329.1470; [(MþNa)þ] calcd for
C13H20N4O6Na, 351.1281; found, 351.1271.
CH2CH2CH3). 13C NMR (125 MHz, DMSO-d6):
d 170.7 (s, COOH),
158.5 (s, NHCONH), 157.0 (s, (s, C-1 of 1,4-substituted phenyl),),
133.91 (s, C-4 of 1,4-substituted phenyl),128.7 (s, C-3 and C-5 of 1,4-
substituted phenyl), 114.6 (s, C-2 and C-6 of 1,4-substituted phenyl),
65.0 (s, CH2O–C6H4–CH2NH), 42.8 (s, CH2O–C6H4–CH2NH), 41.6 (s,
CH2CH2CH3), 23.7 (s, CH2CH2CH3), 11.8 (s, CH2CH2CH3). HRMS ESI
(m/z): [(MþH)þ] calcd for C13H19N2O4, 267.1345; found, 267.1339.
4.19. (Z)-Picolinaldehyde O-(2S,3S,5R)-2-(hydroxymethyl)-5-
(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
yl)tetrahydrofuran-3-ylcarbamoyl oxime (22)
4.15. Thymidine bound solid support for oligonucleotide
synthesis (17)
Solid support 17 contained 32 mmol of DMT groups per gram of
resin27 and performed well in oligonucleotide synthesis.28
Purified bycrystallization from acetonitrile to give white crystals.
Mp 218–219 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d 11.32 (1H, s, NH of
pyrimidine), 8.68 (0.8H, d, J¼3.6 Hz, H-6 of picoline), 8.48 (0.7H, s,
NHCOO N]CH–picoline), 8.12–8.02 (1.9H, m, H-6 of pyrimidine and
H-3 of picoline), 7.95 (1H, m, H-4 of picoline), 7.78 (1H, s, NHCOO
N]CH–picoline), 7.53 (0.9H, m, H-5 of picoline), 6.23 (1H, t,
J¼5.9 Hz, H-1 of tetrahydrofuran), 5.12 (1H, m, OH), 4.30 (1H, m, H-3
of tetrahydrofuran), 3.91 (1H, m, H-4 of tetrahydrofuran), 3.67 (1H,
m, H-5a of tetrahydrofuran), 3.59 (1H, m, H-5b of tetrahydrofuran),
4.16. N-Benzyl-2-phenylhydrazinecarboxamide (18)
Purified by crystallization from 1,2-dichloroethane to give white
crystals. Mp 133–135 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d 7.86 (1H,
s, NHNH–phenyl), 7.61 (1H, s, NHNH–phenyl), 7.30–7.10 (6H, m,
phenyl–CH2 and H-3, H-5 of NHNH–phenyl), 7.03 (1H, br m, NHCH2-
phenyl), 6.73 (3H, m, H-2, H-6 and H-4 of NHNH–phenyl), 4.23 (2H,
2.28 (2H, m, H-2a and H-2b of tetrahydrofuran),1.79 (3H, s, CH3). 13
NMR (125 MHz, DMSO-d6): 164.2 (s, C-4 of pyrimidine), 154.7 (s,
C
d, J¼6.3 Hz, phenyl–CH2). 13C NMR (125 MHz, DMSO-d6):
d
159.8 (s,
d
NHCONHNH), 150.0 (s, C-1 of NHNH–phenyl), 141.4 (s, C-1 of CH2–
phenyl), 129.2 (s, C-3,C-5 of NHNH–phenyl), 128.5 (s, C-3 and C-5 of
CH2–phenyl), 127.4 (s, C-2 and C-6 of CH2–phenyl), 126.9, (s, C-4 of
CH2-phenyl),119.2 (s, C-4 of NHNHCH2-phenyl),112.8 (s, C-2 and C-6
of NHNHCH2-phenyl), 42.9 (s, CH2-phenyl). HRMS ESI (m/z):
[(MþH)þ] calcd for C14H16N3O, 242.1293; found, 242.1292.
NHCOON]CH–picoline), 154.3 (s, NHCOON]CH–picoline), 150.9
(C-2 of picoline), 150.4 (s, C-2 of pyrimidine), 150.1 (C-6 of picoline),
137.6 (s, C-6 of pyrimidine), 136.8 (C-4 of picoline), 126.2 (C-5 of
picoline),122.4 (C-3 of picoline),109.9 (s, C-5 of pyrimidine), 84.8 (C-
1 of tetrahydrofuran), 83.9 (C-4 of tetrahydrofuran), 61.6 (C-5 of
tetrahydrofuran), 51.3 (C-3 of tetrahydrofuran), 37.5 (C-2 of

2220
A. Yagodkin et al. / Tetrahedron 66 (2010) 2210–2221
tetrahydrofuran), 12.7 (s, CH3). HRMS ESI (m/z): [(MþH)þ] calcd for
122.1 (s, C-6 of 1,2-phenylene), 121.4 (s, C-3 of 1,2-phenylene),
120.1 (s, C-2 and C-6 of phenyl), 71.1 (s, CHOH), 57.1 (s, CH2N),
39.5 (s, (CH3)3C), 39.0 (s, (CH3)3C), 36.4 (s, CH3N), 27.3 (s,
2ꢁ(CH3)3C). HRMS ESI (m/z): [(MþH)þ] calcd for C26H35N2O6,
471.2495; found, 471.2485; [(MþNa)þ] calcd for C26H34N2O6Na,
493.2315; found, 493.2291.
C17H20N5O6, 390.1414; found, 390.1409.
4.20. (S)-1-(Benzylcarbamoyl)pyrrolidine-2-carboxylic
acid (23)
Upon the completion of reaction, the mixture was evaporated
to dryness, the residue was dissolved in dichloromethane,
extracted with 5% aqueous ammonium hydroxide, aqueous ex-
tracts were acidified with hydrochloric acid to give pure product
4.23. Methyl (2S,3S,5R)-2-(hydroxymethyl)-5-(5-methyl-2,4-
dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-
ylcarbamate (26)
as pale yellow oil. 1H NMR (500 MHz, CDCl3):
d 9.25 (1H, br s,
COOH), 7.35–7.25 (4.1H, m, phenyl), 5.11 (0.8H, br s, NH), 4.48 (1H,
m, H-2 of pyrrolidine), 4.45 (2H, s, CH2C6H5), 3.37 (1H, m, H-5a of
pyrrolidine), 3.21 (1H, m, H-5b of pyrrolidine), 2.49 (1H, m, H-3a
of pyrrolidine), 2.05 (3H, m, H-3a of pyrrolidine and H-4a,b of
Purified by crystallization from acetonitrile to give white
crystals. Mp 102–105 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d 11.26
(1H, s, NH-3 of pyrimidine), 7.75 (1H, s, H-6 of pyrimidine), 7.57
(1H, d, J¼6.9 Hz, NH–CO–NH–tetrahydrofuran), 6.14 (1H, t,
J¼6.4 Hz, H-1 of tetrahydrofuran), 5.05 (1H, t, J¼5.1 Hz, of tetra-
hydrofuran), 4.12 (1H, m, H-3 of tetrahydrofuran), 3.77 (1H, m,
H-4 of tetrahydrofuran), 3.64 (1H, m, H-5a of tetrahydrofuran),
3.54 (3H, s, CH3O), 3.52 (1H, m, H-5b of tetrahydrofuran), 2.20
(1H, m, H-2a of tetrahydrofuran), 2.11 (1H, m, H-2b of tetrahy-
drofuran), 2.07 (3H, s, CH3). 13C NMR (125 MHz, DMSO-d6):
pyrrolidine). 13C NMR (125 MHz, CDCl3):
d 173.2 (s, COOH), 158.8
(s, NHCO–pyrrolidine), 138.5 (s, C-1 of phenyl), 128.7 (s, C-3 and
C-5 of phenyl), 127.7 (s, C-3 and C-5 of phenyl), 127.6 (s, C-4 of
phenyl), 60.1 (s, C-2 of pyrrolidine), 46.2 (s, C-5 of pyrrolidine),
44.9 (s, CH2-phenyl), 27.5 (s, C-3 of pyrrolidine), 24.7 (s, C-4 of
pyrrolidine). HRMS ESI (m/z): [(MþH)þ] calcd for C13H17N2O3,
249.1239; found, 249.1241; [(MþNa)þ] calcd for C13H16N2O3Na,
271.1058; found, 271.1056.
d
164.2 (s, C-4 of pyrimidine), 156.7 (s, NHCOO), 150.8 (s, C-2 of
pyrimidine), 136.7 (s, C-6 of pyrimidine), 109.8 (s, C-5 of py-
rimidine), 85.2 (s, C-1 of tetrahydrofuran), 83.9 (s, C-4 of tetra-
hydrofuran), 61.6 (s, C-5 of tetrahydrofuran), 51.9 (s, CH3O), 51.0
(s, C-3 of tetrahydrofuran), 37.7 (s, C-2 of tetrahydrofuran), 12.7
(s, CH3). HRMS ESI (m/z): [(MþH)þ] calcd for C12H18N3O6,
300.1195; found, 300.1206; [(MþNa)þ] calcd for C12H17N3O6Na,
322.1015; found, 322.1017.
4.21. (S)-1-((2S,3S,5R)-2-(Hydroxymethyl)-5-(5-methyl-2,4-
dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-
ylcarbamoyl)pyrrolidine-2-carboxylic acid (24)
Upon the completion of reaction, the mixture was evaporated
to dryness, the residue was dissolved in dichloromethane,
extracted with 5% aqueous ammonium hydroxide, aqueous ex-
tracts were acidified with hydrochloric acid to give pure product
4.24. 5-((Bis(4-methoxyphenyl)(phenyl)methoxy) methyl)
oxazolidin-2-one (27)
as pale yellow oil. 1H NMR (500 MHz, DMSO-d6):
d 11.29 (1H, s, NH
of pyrimidine), 7.77 (1H, d, J¼0.9 Hz, H-6 of pyrimidine), 6.58 (1H,
d, J¼7.1 Hz, NHCO–pyrrolidine), 6.20 (1H, t, J¼6.5 Hz, H-1 of tet-
rahydrofuran), 5.03 (1H, br s, OH), 4.30–4.10 (2H, m, H-3 of tet-
rahydrofuran and H-2 of pyrrolidine), 3.75 (1H, m, H-4 of
tetrahydrofuran), 3.62 (1H, m, H-5a of tetrahydrofuran), 3.53 (1H,
m, H-5b of tetrahydrofuran), 3.28 (2H, H-5a and H-5b of pyrroli-
dine), 2.25–2.05 (3H, m, H-5a and H-5b of tetrahydrofuran and H-
3a of pyrrolidine), 1.91–1.80 (3H, m, H-3b and H-4a and H-4b of
pyrrolidine), 1.77 (3H, br s, CH3). 13C NMR (125 MHz, DMSO-d6):
Purified by flash reverse phase column chromatography to
give pale yellow oil. 1H NMR (500 MHz, CD3CN):
d 7.50–7.20 (9H,
m, H-2, H-3, H-4, H-5, H-6 of phenyl and 2ꢁH-2, 2ꢁH-6 of 4-
methoxyphenyl), 6.85 (4H, m, 2ꢁH-3, 2ꢁH-5 of 4-methox-
yphenyl), 5.66 (1H, br s, NH), 4.70 (1H, m, H-5 of oxazolidin-2-
one), 3.79 (6H, s, 2ꢁCH3O), 3.53 (1H, t, J¼8.8 Hz, OCHaHb-oxa-
zolidin-2-one), 3.29 (2H, m, OCHaHb-oxazolidin-2-one and H-4a
of oxazolidin-2-one), 3.14 (1H, dd, J¼4.9 Hz and J¼10.5 Hz, H-4b
of oxazolidin-2-one). 13C NMR (125 MHz, CH3CN):
d 159.1 (s,
d
174.9 (s, COOH), 164.2 (s, C-4 of pyrimidine), 156.4 (s, NHCO–
NHCOO), 158.7 (s, 2ꢁC-4 of 4-methoxyphenyl), 145.0 (s, C-1 of
phenyl), 135.8 (s, 2ꢁC-1 of 4-methoxyphenyl), 130.0 (s, 2ꢁC-2
and 2ꢁC-6 of 4-methoxyphenyl), 128.0 (s, C-3 and C-5 of phenyl),
127.9 (s, C-2 and C-6 of phenyl), 126.9 (s, C-4 of 4-methox-
yphenyl), 113.12 (s, 2ꢁC-3 and 2ꢁC-5 of 4-methoxyphenyl), 85.9
(s, (CH3OC6H4)2C6H5C), 75.1 (s, C-5 of oxazolidin-2-one), 64.4 (s,
OCH2-oxazolidin-2-one), 54.9 (s, 2ꢁCH3O), 41.9 (s, C-3 of oxazo-
lidin-2-one). HRMS ESI (m/z): [(MþNa)þ] calcd for C25H25NO5Na,
442.1630; found, 442.1617; [(MþK)þ] calcd for C25H25NO5K,
458.1370; found, 458.1355.
pyrrolidine), 150.9 (s, C-2 of pyrimidine), 136.8 (s, C-6 of pyrimi-
dine), 109.8 (s, C-5 of pyrimidine), 86.0 (C-1 of tetrahydrofuran),
83.9 (C-4 of tetrahydrofuran), 61.8 (C-5 of tetrahydrofuran), 59.0
(s, C-2 of pyrrolidine), 50.7 (C-3 of tetrahydrofuran), 46.1 (s, C-5 of
pyrrolidine), 37.8 (C-2 of tetrahydrofuran), 29.7 (s, C-3 of pyrroli-
dine), 24.5 (s, C-4 of pyrrolidine), 12.7 (s, CH3). HRMS ESI (m/z):
[(MþH)þ] calcd for C16H23N4O7, 383.1567; found, 383.1571.
4.22. 4-(1-Hydroxy-2-(1-methyl-3-phenylureido)ethyl)-1,2-
phenylene bis(2,2-dimethylpropanoate) (25)
4.25. Phenyl (2S,3S,5R)-2-(hydroxymethyl)-5-(5-methyl-2,4-
dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-
ylcarbamate (29)
Purified by crystallization from acetonitrile to give white
crystals. Mp 206–208 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d 8.40
(1H, s, OH), 7.44 (2.0H, d, J¼7.9 Hz, H-2 and H-6 of phenyl),
7.33–7.19 (5.0H, m, H-3, H-4, H-5 of phenyl and H-3, H-6 of 1,2-
phenylene), 6.93 (1H, t, J¼7.2 Hz, H-5 of 1,2-phenylene), 5.93
(1H, s, NH), 4.88 (1H, m, phenylene–CH(OH)–CH2), 3.46 (2H, d,
J¼5.7 Hz, CH2), 2.92 (3H, s, NHCONCH3), 1.29 (9H, s, (CH3)3C),
Purified crystallization from dichloromethane–acetonitrile, 9:1
to give white crystals. Mp 194–197 ꢀC. 1H NMR (500 MHz, DMSO-
d6):
d
11.30 (1H, s, NH-3 of pyrimidine), 8.23 (1H, d, J¼7.5 Hz,
OCONH–tetrahydrofuran), 7.78 (1H, s, H-5 of pyrimidine), 7.42–
7.10 (4.2H, m, O-phenyl), 6.21 (1H, t, J¼6.6 Hz, H-1 of tetrahydro-
furan), 5.12 (1H, t, J¼5.1 Hz H-3 of tetrahydrofuran), 4.20 (0.9H, m,
OH), 3.88 (1H, m, H-4 of tetrahydrofuran), 3.68 (1H, m, H-5a of
tetrahydrofuran), 3.60 (1H, d, H-5b of tetrahydrofuran), 2.28 (2H,
m, H-2a,b of tetrahydrofuran), 1.78 (3H, s, CH3). 13C NMR
1.28 (9H, s, (CH3)3C). 13C NMR (125 MHz, DMSO-d6):
d 175.8 (s,
COO), 175.7 (s, COO), 156.3 (s, NHCON), 142.9 (s, C-1 of 1,2-
phenylene), 142.4 (s, C-2 of 1,2-phenylene), 141.6 (s, C-1 of
phenyl), 141.0 (s, C-4 of 1,2-phenylene), 128.7 (s, C-3 and C-5 of
phenyl), 124.5 (s, C-4 of phenyl), 123.6 (s, C-5 of 1,2-phenylene),

A. Yagodkin et al. / Tetrahedron 66 (2010) 2210–2221
2221
(125 MHz, DMSO-d6):
d
164.2 (s, C-4 of pyrimidine), 154.4 (s,
Supplementary data
NHCOO), 151.4 (s, C-1 of O-phenyl), 150.9 (s, C-2 of pyrimidine),
136.7 (s, C-6 of pyrimidine), 129.7 (s, C-3 and C-5 of O-phenyl),
125.5 (s, C-4 of O-phenyl), 122.2 (s, C-2 and C-6 of O-phenyl), 109.9
(s, C-5 of pyrimidine), 85.1 (s, C-1 of tetrahydrofuran), 83.9 (s, C-4
of tetrahydrofuran), 61.7 (s, C-5 of tetrahydrofuran), 51.4 (s, C-3 of
tetrahydrofuran), 37.6 (s, C-2 of tetrahydrofuran), 12.7 (s, CH3).
HRMS ESI (m/z): [(MþH)þ] calcd for C17H20N3O6, 362.1352; found,
362.1335.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2010.01.017.
References and notes
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4.26. 1-((2S,3S,5R)-2-(Hydroxymethyl)-5-(5-methyl-2,4-dioxo-
3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl)-3-
phenylurea (31)
Purified by crystallization from acetonitrile to give white
crystals. Mp 218–221 ꢀC. 1H NMR (500 MHz, CD3CN–DMSO-d6,
7. Matsuda, K. Med. Res. Rev. 1994, 14, 271–305.
4:1):
d 10.74 (1H, s, NH-3 of pyrimidine), 8.15 (1H, s, NHCONH–
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Bryant, M. L.; Clare, M.; Houseman, K. A.; Marr, J. J.; Mueller, R. A.; Vazquez,
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phenyl), 7.72 (1H, d, J¼0.9 Hz, H-5 of pyrimidine), 7.40 (2H, m, H-
2, H-6 of phenyl), 7.24 (2H, m, H-3, H-5 of phenyl), 6.94 (1H, m,
H-4 of phenyl), 6.44 (1H, d, J¼7.2 Hz, NHCONHCH2–phenyl), 6.21
(1H, t, J¼6.2 Hz, H-1 of tetrahydrofuran), 4.59 (1H, m, 5-OH of
tetrahydrofuran), 4.34 (1H, m, H-3 of tetrahydrofuran), 3.82 (1H,
m, H-4 of tetrahydrofuran), 3.76 (1H, m, H-5a of tetrahydrofu-
ran), 3.68 (1H, m, H-5b of tetrahydrofuran), 2.30 (1H, m, H-2a of
tetrahydrofuran), 2.22 (1H, m, H-2b of tetrahydrofuran), 1.83 (3H,
d, J¼0.9 Hz, CH3). 13C NMR (125 MHz, CD3CN–DMSO-d6, 4:1):
d
164.2 (s, C-4 of pyrimidine), 155.5 (s, NHCONHC6H5), 150.9 (s,
C-2 of pyrimidine), 140.3 (s, C-1 of phenyl), 136.1 (s, C-6 of py-
rimidine), 128.8 (s, C-3 and C-5 of phenyl), 121.7 (s, C-4 of
phenyl), 118.3 (s, C-2 and C-6 of phenyl), 110.0 (s, C-5 of py-
rimidine), 85.8 (s, C-1 of tetrahydrofuran), 83.9 (s, C-4 of tetra-
hydrofuran), 61.4 (s, C-5 of tetrahydrofuran), 49.7 (s, C-3 of
tetrahydrofuran), 37.9 (s, C-2 of tetrahydrofuran), 11.9 (s, CH3).
HRMS ESI (m/z): [(MþH)þ] calcd for C17H21N4O5, 361.1512; found,
361.1505.
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Acknowledgements
Financial support by the Finnish Funding Agency for Technology
and Innovation (TEKES), Metkinen Chemistry (www.metkinen-
chemistry.com) and University of Eastern Finland is gratefully
acknowledged. We thank Prof. Jouko Vepsa¨la¨inen for fruitful dis-
cussions and Dr. Ewen Macdonald and Dr. James Callaway for
reading the manuscript.
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