Preparation of glycoluril monomers for expanded cucurbit[n]uril synthesis

Article abstract of DOI:10.1016/S0040-4020(03)00150-9

Glycoluril derivatives bearing free ureidyl groups (1) and bis(cyclic ethers) (2) are the fundamental building blocks for the synthesis of cucurbituril, its derivatives, and its congeners. The known derivatives of 1 and 2 fall into two main classes - those bearing alkyl or aryl functional groups on their convex face. In this paper we present a third class of glycolurils, namely those bearing substituents that are electron withdrawing in character. This class of compounds carries carboxylic acid derived functional groups on their convex face and are derived from diesters 1e and 2e. An improved synthesis of 1e and 2e is reported and their modification described. For example, 1e and 2e are converted into secondary amides (10-15) by heating in solutions of the neat primary amines. The secondary amides can be transformed into imides (19-22, 24, 25) by heating with PTSA in ClCH₂CH₂Cl. The isolation of these compounds in pure form in high yields is accomplished by simple and scalable washing or recrystallization procedures. We also present the X-ray crystallographic characterization of bis(cyclic ethers) 2e, 8, and 22. We anticipate that the ready availability of ester, carboxylate, acid, secondary amide, imide, and tertiary amide derivatives of 1 and 2 will expand the scope of the synthesis of cucurbituril derivatives by providing a new class of building blocks with electron withdrawing substituents.

Full text of DOI:10.1016/S0040-4020(03)00150-9

Tetrahedron 59 (2003) 1961–1970
Preparation of glycoluril monomers for expanded
cucurbit[n]uril synthesis
Christopher A. Burnett,a Jason Lagona,a Anxin Wu,a Jennifer A. Shaw,a Daniel Coady,a
James C. Fettinger,a Anthony I. Dayb and Lyle Isaacsa
,
*
aDepartment of Chemistry and Biochemistry, University of Maryland, College Park, College Park, MD 20742, USA
bSchool of Chemistry, University College, University of New South Wales, Australian Defence Force Academy,
Canberra, ACT 2600, Australia
Received 16 December 2002; revised 22 January 2003; accepted 22 January 2003
Abstract—Glycoluril derivatives bearing free ureidyl groups (1) and bis(cyclic ethers) (2) are the fundamental building blocks for the
synthesis of cucurbituril, its derivatives, and its congeners. The known derivatives of 1 and 2 fall into two main classes—those bearing alkyl
or aryl functional groups on their convex face. In this paper we present a third class of glycolurils, namely those bearing substituents that are
electron withdrawing in character. This class of compounds carries carboxylic acid derived functional groups on their convex face and are
derived from diesters 1e and 2e. An improved synthesis of 1e and 2e is reported and their modification described. For example, 1e and 2e are
converted into secondary amides (10–15) by heating in solutions of the neat primary amines. The secondary amides can be transformed into
imides (19–22, 24, 25) by heating with PTSA in ClCH2CH2Cl. The isolation of these compounds in pure form in high yields is accomplished
by simple and scalable washing or recrystallization procedures. We also present the X-ray crystallographic characterization of bis(cyclic
ethers) 2e, 8, and 22. We anticipate that the ready availability of ester, carboxylate, acid, secondary amide, imide, and tertiary amide
derivatives of 1 and 2 will expand the scope of the synthesis of cucurbituril derivatives by providing a new class of building blocks with
electron withdrawing substituents. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
molecular complexation studies,4–6,14 and the catalysis of
dipolar cycloadditions.15–17
In 1905, Behrend reported that the condensation of
glycoluril and formaldehyde in dilute HCl yielded an
insoluble polymeric material now known as Behrend’s
polymer. By heating Behrend’s polymer in H2SO4, a
substance was obtained that formed crystalline complexes
with a variety of salts.1 The molecular structure of this
substance was disclosed by Mock and co-workers in 1981
who named it cucurbituril.1b Cucurbituril, Q[6],2 is
composed of six glycoluril rings and 12 methylene bridges.
Q[6] has two carbonyl lined portals that allow access to its
˚
hydrophobic cavity. The diameter of these portals is 3.9 A,
3
˚
the cavity is 5.8 A in diameter with a volume of 164 A , and
˚
3
˚
the overall depth of Q[6] is 9.1 A. The geometry of Q[6]
Despite the range of useful properties of Q[6], several
drawbacks prevent its more widespread use. These draw-
backs include: (1) the small cavity volume of Q[6] which
limits the range of molecular guests that can be bound, (2)
the poor solubility of Q[6] in water and common organic
solvents, and (3) a lack of easily manipulated functional
groups that would allow derivatization. Several groups have
been involved in efforts to alleviate each of these problems.
For example, the groups of Day and co-workers and Kim
and co-workers have reported the synthesis and isolation
of Q[5], Q[7], and Q[8].2,3,18,19 More recently, Day and
co-workers reported the isolation and crystallographic
and its structural rigidity leads to outstanding molecular
recognition properties. In particular, Q[6] binds tightly to
alkylammonium species by a combination of ion–dipole
interactions and the hydrophobic effect.4–6 Q[6] has also
been demonstrated to perform well in a variety of
applications including the preparation of molecular neck-
laces,7,8 bowls,9 DNA complexes,10 molecular switches,11,12
non-covalent modification of dendrimers,13 ion and
Keywords: glycoluril; cucurbituril; synthesis; crystal structures.
*
Corresponding author. Tel.: þ1-301-405-1884; fax: þ1-301-314-9121;
e-mail: LI8@umail.umd.edu
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00150-9

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C. A. Burnett et al. / Tetrahedron 59 (2003) 1961–1970
properties of methylene bridged glycoluril dimers.36–41 The
methylene bridged glycoluril dimer substructure (bold in
Q[6]) constitutes the fundamental substructure of the
cucurbit[n]uril family. We have found that glycoluril
derivatives bearing electron withdrawing functional groups
(ex: ester, carboxylate, amide, and imide) on their convex
face are more efficient substrates for the formation of the
methylene bridged glycoluril dimer substructure than are
those bearing substituents capable of stabilizing an adjacent
carbocation (ex: cyclohexyl and phenyl).39 The implication
is that glycoluril derivatives 1 and 2 bearing electron
withdrawing functional groups should participate in Q[n]
forming reactions. Glycoluril derivatives bearing ester,
amide, and imide functional groups have a high degree of
organic solubility unlike most other known glycolurils. This
paper presents practical syntheses of glycoluril derivatives
bearing free ureidyl groups and cyclic ethers carrying a
range of electron withdrawing functional groups (ester,
carboxylate, amide, and imide). These compounds are novel
monomers which have the potential for the synthesis of
substituted Q[n].
Scheme 1. Chemical structures of 1 and 2 and synthesis of known Q[n]
derivatives. (a) Homomeric Q[n] and Q[s,u] forming reactions of 1.
(b) Homomeric Q[n] forming reactions of 2b. (c) Heteromeric Q[s,u]
forming reaction of 1a with 2b.
characterization of Q[5]@Q[10].20 These studies partially
address the first two drawbacks by increasing the volume of
the cavity and by improving the solubility in salt-free water.
These advances have already resulted in the preparation of
molecular Russian dolls,21 gyroscopes,20 ball bearings,22
molecular sieves,23,24 ionophores with pronounced Pb2þ
selectivity,25 the recognition of charge transfer complexes26
and viologens,27,28 the catalysis of a 2þ2 photoreaction,29
and studies of molecular polarizability.30
2. Results and discussion
For the synthesis of glycoluril derivatives bearing a range of
electron withdrawing functional groups on their convex
face, we viewed the ethoxycarbonyl groups of 1e as an ideal
common intermediate (Scheme 2). The synthesis of 1e from
disodium dihydroxytartrate 3 has been known for over
100 years.42–45 Until recent years, compound 3 was an
inexpensive commercial precursor to the manufacture of the
commonly known dye tartrazine. With the phasing out of
the use of tartrazine, however, 3 has become prohibitively
expensive for use in the synthesis of 1e. We prepare 3 by the
oxidation of 4 with Br2 in glacial acetic acid.46,47 This
reaction is scalable and delivers 3 in high yield and purity.
The conversion of 3 into 1e using the procedure reported by
Rebek45 reliably delivers 1e in the reported yield (47%). We
have discovered a modification of this procedure that leads
to more straightforward product isolation and higher yields
(58–64%). With large quantities of 1e in hand, we turned
our attention to functional group modification including
transformations to corresponding cyclic ethers.
Efforts to improve the solubility of the cucurbiturils in
organic media have focused on the use of glycoluril
derivatives bearing functional groups on their convex face
(e.g. 1 and 2) in Q[n] and Q[s,u] forming reactions.18 To
date, the synthesis, purification, and full characterization
of Me10Q[5],2,31 Cy5Q[5] and Cy6Q[6],32 Ph2Q[1,5],33 and
Me6Q[3,3]34 have been reported in the literature.35 The
synthesis of these substituted Q[n] have taken place by three
distinct routes involving the reaction of glycoluril and its
derivatives (1) and bis(cyclic ethers) 2 (Scheme 1). For
example, the synthesis of Me10Q[5] is accomplished either
by the reaction of 1b with formaldehyde or by the reaction
of bis(cyclic ether) 2b under acidic conditions (Scheme 1a
and b). Both reactions are examples of homomeric
cyclization reactions. Day recently demonstrated that
heteromeric cyclization reactions are also possible (Scheme
1c). For example, the reaction of 1a and 2b yields D3h
symmetrical Me6Q[3,3] whose substituents alternate.34,36
These fully substituted Q[n] (Me10Q[5], Cy5Q[5], and
Cy6Q[6]) and partially substituted Q[s,u] (Ph2Q[1,5] and
Me6Q[3,3]) impart solubility in organic solvents and have
already begun to expand the range of applications to include
the preparation of ion-selective electrodes.32
For the transformation of 1e into 2e,48 we considered the
two step procedure developed by Nolte and co-workers for
the synthesis 2c.49 To avoid the aqueous conditions used by
Nolte we developed a one step procedure that proceeds
under anhydrous acidic conditions where the CO2Et groups
are stable (Scheme 3). We used anhydrous TFA in this
reaction as it is sufficiently acidic, easy to remove, and an
excellent solvent for 1e. This reaction delivers 2e in modest
yield (46%) along with acetal 5 (20%). We hypothesized
that 5 was a kinetic product that might be converted to 2e
under more highly acidic conditions. Accordingly, treat-
ment of the crude reaction mixture with anhydrous PTSA in
ClCH2CH2Cl at reflux for 2 h allows the isolation of 2e in
92% yield from 1e.
Our group has been engaged in the synthesis and recognition
With good methods in hand for the synthesis of 1e and 2e—
the two building blocks for potential use in the synthesis of
substituted Q[n]—we explored the transformations of their
Scheme 2. Synthesis of glycoluril ethyl ester 1e.45 Conditions:
(a) CH3CO2H, Br2, H2O; (b) EtOH, HCl; (c) PhH, H2NCONH2, TFA, reflux.

C. A. Burnett et al. / Tetrahedron 59 (2003) 1961–1970
1963
Scheme 3. Transformations of 1e and 2e. Conditions: (a) TFA, (CH2O)n,
reflux; (b) PTSA, ClCH2CH2Cl; (c) H2O, NaOH, 808C, 90%; (d) PTSA,
46%; (e) CH3OH, H2O, LiOH, 708C, 80%; (f) CH3OH, H2O, LiOH, then
TFA, 76%.
CO2Et groups. We first investigated the formation of
carboxylate salts and the corresponding carboxylic acids
(Scheme 3). Compound 6 was first reported by Anschutz in
1891, but the experimental details and spectroscopic data
are scant.44 We repeated this reaction and isolated 6 in 90%
yield as an insoluble powder. Conversion of 6 into the
carboxylic acid 742,43 was possible by treatment with an
excess of PTSA. Hydrolysis of 2e occurs in 80% yield by
treatment with excess LiOH. Diacid 9 was isolated after
acidification with TFA. The good solubility of 6–9 suggests
that these compounds as water soluble monomers have the
potential for improved aqueous solubility of a similarly
substituted Q[n].
Scheme 5. Synthesis of tertiary amide 18. Conditions: (a) HN(CH2CH2)2O,
1288C; (b) THF, NaH, MeI, reflux, 75%.
verted into 10–12 by treatment with N,N-dimethylamino-
propylamine, n-butylamine, and ethanolamine, respectively.
Similar reactions were used to transform 2e into 13–15.
Purification can be achieved by simply removing the excess
amine by distillation followed by washing of the resulting
solid with solvents in which 10–15 are insoluble.
Potential limitations of secondary amides 10–15 in Q[n]
synthesis include their ability to react with formaldehyde
and their propensity to form the corresponding imides
which, if incomplete, could lead to complex reaction
mixtures. Tertiary amides would not suffer from these
limitations and should be stable to the strongly acidic
aqueous conditions (ex: 9 M HCl, 758C) used in Q[n]
synthesis. We attempted the direct amidation of 1e and 2e
by heating in neat morpholine at 1288C (Scheme 5). The
products of these reactions were ammonium salts 16 and 17
rather than the desired tertiary amides. Alkylation of 14 with
MeI in THF delivered tertiary amide 18 in 75% yield.
In previous work we have found that 3-dimethylamino-
propyl amide derivatives of glycoluril impart outstanding
solubility characteristics in both organic and aqueous
media.48 Direct amidation reactions of 1e and 2e in neat
primary amines (75–908C) converts the esters into amide
functional groups (Scheme 4). For example, 1e was con-
We next considered the conversion of diamides 10–15 into
the corresponding imides by treatment with PTSA in
ClCH2CH2Cl (Scheme 6). The conversion of 10 and 11
into imides 19 and 20 occurred smoothly in high yield
(.85%). The conversion of 13 and 14 into imides 21 and 22
occurred without incident in comparatively lower yield
(.66%). In these cases it was necessary to work at low
concentration (<10 mM) to minimize polymerization reac-
tions analogous to the formation of Behrend’s polymer.
Heating 12 under similar conditions did not result in the
formation of the expected imide; an N- to O-acyl transfer
reaction50 occurred instead delivering 23 as its PTSA salt.
To prevent the N- to O-acyl transfer reaction, we acetylated
diol 14 and induced ring closure to the imide in a single step
delivering 24 in 73% yield. Similarly, 15 was converted into
25 in 73% yield. We believe that these imide substituted
glycoluril derivatives hold excellent promise in the
synthesis of Q[n] derivatives. For example, the ester (1e
and 2e) and amide (10–15) derived glycolurils might be
expected to undergo hydrolysis and imide forming reactions
Scheme 4. Amidation reactions of 1e and 2e. Conditions: (a) H2N(CH2)3-
NMe2, 908C, 86%; (b) CH3(CH2)3NH2, 758C, 87%; (c) H2NCH2CH2OH,
808C, 85%; (d) H2N(CH2)3NMe2, 788C, 88%; (e) CH3(CH2)3NH2, 788C,
90%; (f) H2NCH2CH2OH, 858C, 93%.

1964
C. A. Burnett et al. / Tetrahedron 59 (2003) 1961–1970
cis-fused five-membered rings with both functional groups
displayed on one face of the molecule. The dihedral angles
between the substituents at C3a and C6a are small. The
angles between the mean planes defined by the two five-
membered rings are between 103.98 and 112.18. These
values are similar to that measured for 2b which has been
successfully converted into Me10Q[5], but as expected is
smaller than those observed for glycolurils bearing free
ureidyl groups (1a,b, and f) and cucurbiturils (Q[6] and
Me10Q[5]). The distance between the two carbonyl oxygen
atoms (O7–O8) defines the cavity depth of the hypothetical
Q[n]. For the five cyclic ethers given in Table 1, this
˚
distance increases from 4.979 to 5.271 A in the following
order (2b,17,2e,8,22). This suggests that lithium
carboxylate 8 and imide 22 are the sterically least
demanding in this series and might be expected to best
form the larger Q[n] homologs most efficiently. As expected
these O–O distances are considerably smaller than those
˚
observed for 1a,b, and f (5.754–5.997 A) and Me10Q[5] and
˚
Q[6] (5.98–6.06 A) since they increase as the ring size
of the laterally fused n-membered rings increases.51,52
These structural details suggest the potential utility of ester,
carboxylate, and imide based glycolurils in Q[n] forming
reactions.
3. Conclusions
Scheme 6. Synthesis of glycoluril imides. Conditions: (a) ClCH2CH2Cl,
PTSA, 25–32 mM, reflux; (b) ClCH2CH2Cl, PTSA, <10 mM, reflux;
(c) Ac2O, AcOH, then PTSA, (d) ClCH2CH2Cl, Ac2O, then PTSA.
In previous work, we have determined that glycoluril
derivatives bearing electron withdrawing ethyl ester groups
on their convex face are highly proficient at forming the
protected methylene bridged glycoluril dimers. Sub-
structures of this type in the unprotected form are basic
building blocks of Q[n] and its derivatives.36,37,39 This
observation implies that the synthesis of Q[n] derivatives
might be best performed using glycoluril building blocks 1
and 2 bearing carboxylic acid derived functional groups on
their convex face. We have presented an improved synthesis
of 1e which serves as a common synthetic intermediate for
the preparation of glycoluril derivatives with unfunctional-
ized ureidyl N-atoms. Compound 1e can also be converted
to bis(cyclic ether) 2e which serves as a similar common
intermediate. Compounds 1e and 2e can be converted into
carboxylate salts (6 and 8) by basic hydrolysis reactions and
under the aqueous acidic reaction conditions typically used
for Q[n] synthesis. In contrast, imides 19–22 are expected
to be stable to these reaction conditions.
2.1. X-Ray crystallographic characterization
We were able to obtain crystals of 2e, 5, 8, 17, and 22 that
were suitable for X-ray structural determination. Figure 1
shows ORTEP plots of the structures of 2e, 8, and 22 in the
crystal. The structural details of these molecules are similar
to those determined previously for glycoluril derivatives
and Q[n] (Table 1). We briefly discuss here the structural
details that are most relevant to their potential use as
monomers for Q[n] synthesis. All five compounds have
Figure 1. ORTEP plots of the molecular structures of: (a) 2e, (b) 8, and (c) 22 in the crystal. The lithium counterions have been removed from the structure of 8.
Thermal ellipsoids are drawn at the 50% probability level.

C. A. Burnett et al. / Tetrahedron 59 (2003) 1961–1970
1965
Table 1. Selected details from X-ray structures
Mean plane angle (8)a
Dihedral R–C3a–C6a–R0 (8)
˚
O7–O8 (A)
˚
O9–O10 (A)
Compound
2e
5
8
17
106.9
112.1
106.5
103.9
110.7
11.2
1.3
8.2
7.5
5.120
5.505
5.174
4.995
5.271
5.004
5.100
5.152
4.925
22
0.9
Me10Q[5]31
Q[6]1b
1a53
1b54
1f55
116.7–120.0
118.1–121.5
120.3
1.2–3.5
1.0–7.5
0
0
9.5
6.02–6.06
5.98–6.04
5.997
5.754
5.935
4.979
115.1
118.4
103.9
2b56
2.6
5.062
a
Defined as the angle between the best mean planes through N1, C2, N3, C3a, and C6a and N4, C5, N6, C6a, and C3a.
into secondary amides (10–15) by heating in solutions of
neat primary amines. The workup and purification is simple
and the yields are high. The amide derived glycolurils can
be converted into the imides (19–22) by heating with PTSA
in ClCH2CH2Cl. We have obtained structural information
for the ester, carboxylate, and imide derived bis(cyclic
ethers) 2e, 8, 17, and 22 by single crystal X-ray diffraction
studies. The efficient production of these fundamental
monomeric building blocks will allow an investigation of
their incorporation in Q[n] derivatives and may expand the
scope of Q[n] synthesis.
slurry of 3 (35.0 g, 133.5 mmol) in absolute EtOH (350 mL)
is cooled to 08C in an ice-water bath. The reaction mixture is
slowly saturated with HCl over a period of 45 min at 08C
and then stirred at rt for 24 h. The reaction mixture is again
cooled to 08C, saturated with HCl over 30 min at 08C and
stirred for an additional 24 h. The reaction mixture is filtered
through a medium porosity frit to remove NaCl, and the
NaCl washed with EtOH (50 mL). To this clear solution was
added urea (20.0 g, 337.6 mmol). The resulting solution was
concentrated by rotary evaporation (T<40–458C). Benzene
(50 mL) was added and then removed by rotary evaporation.
To the resulting oil was added benzene (200 mL) and TFA
(24 mL). The flask was equipped with a Dean-Stark trap and
immersed in an oil bath that had been preheated to 1408C.
The initial EtOH containing distillate (50 mL) was siphoned
off and the reaction mixture was maintained at reflux for 6 h.
The reaction mixture was cooled to rt and the solvent
thoroughly decanted. EtOH (100 mL) was added to the solid
product and the mixture was stirred overnight at rt. The
white solid was collected by filtration, washed with
CH3COCH3, and dried on the frit at atmospheric pressure
giving 1e (22.0–24.5 g, 58–64%).
4. Experimental
4.1. General
Starting materials and were purchased from commercial
suppliers and were used without further purification. THF
and toluene were distilled from sodium benzophenone ketyl
and methylene chloride was distilled from CaH2 immedi-
ately before use. TLC analysis was performed using pre-
coated glass plates. Column chromatography was performed
using silica gel (230–400 mesh, 0.040–0.063 mm) from
E. Merck using eluents in the indicated v:v ratio. Melting
points were measured on a Meltemp apparatus in open
capillary tubes and are uncorrected. IR spectra were
recorded as KBr pellets or thin films on NaCl plates and
are reported in cm21. NMR spectra were measured on
instruments operating at 400 MHz for 1H and 100 MHz for
13C. Mass spectrometry was performed using a magnetic
sector instrument by electron impact (EI) or by fast atom
bombardment (FAB) using the indicated matrix. The matrix
‘magic bullet’ is a 5:1 (w:w) mixture of dithiothreitol:
dithioerythritol. Elemental analyses were performed by
Midwest MicroLab (Indianapolis, IN).
4.2.2. Compound 2e and 5. Method 1. Compound 1e
(1.00 g, 3.50 mmol) was dissolved in TFA (4 mL) and
paraformaldehyde (1.05 g, 35.0 mmol of CH2O) was added
in one portion. The reaction mixture was stirred and heated
at 728C for 6 h. After removal of TFA by rotary evaporation,
the residue was dissolved in EtOAc (250 mL), washed with
sat. Na2CO3, dried over anh. MgSO4, and concentrated.
Flash chromatography (SiO2, CHCl3/hexanes/EtOAc 2:1:1)
gave 2e (0.592 g, 1.62 mmol, 46%) and 5 as white solids.
Compound 5 was recrystallized from EtOAc (0.270 g,
0.682 mmol, 20%).
Method 2. Compound 1e (1.00 g, 3.50 mmol) was dissolved
in TFA (4 mL) and paraformaldehyde (1.05 g, 35.0 mmol)
was added in one portion. The mixture was heated at reflux
for 16 h, concentrated, and dried under high vacuum. A
mixture of the crude material, PTSA (3.90 g, 20.5 mmol)
and ClCH2CH2Cl (100 mL) was heated under N2 at reflux
4.2. Synthetic procedures
4.2.1. Compound 1e. This modification of the known
procedures42–45 delivers 1e in the highest yield to date. A

1966
C. A. Burnett et al. / Tetrahedron 59 (2003) 1961–1970
under an addition funnel filled with molecular sieves (4 A)
for 2 h. The reaction mixture was diluted with EtOAc
(250 mL), washed with sat. Na2CO3 and brine, dried over
anh. MgSO4, concentrated and dried under high vacuum to
yield 1 as a white solid (1.17 g, 3.19 mmol, 92%).
4.2.5. Compound 7.42,43 A solution of PTSA·H2O (0.914 g,
4.80 mmol) in H2O (10 mL) was added to 6. The excess
H2O was removed by rotary evaporation and the resulting
residue was dried under high vacuum. The residue was
washed with MeOH (5£5 mL) and dried under high vacuum
to give 7 (0.256 g, 1.11 mmol, 46%) as a white solid. Mp
195–1988C. IR (KBr, cm21): 3418s, 3322s, 2920w, 1747m,
1685w, 1653s, 1506m, 1275m, 1167s. 1H NMR (400 MHz,
DMSO-d6): 7.76 (s, 4H). 13C NMR (100 MHz, DMSO-d6):
169.0, 159.8, 77.9. MS (FAB, Magic Bullet): m/z 231 (100,
[MþH]þ). HR-MS (FAB, Magic Bullet): m/z 231.0360
([MþH]þ, C6H7N4O6, calcd 231.0366). Anal. calcd for
C6H6N4O6·H2O (248.15): C, 29.04; H, 3.25. Found: C,
29.06; H, 3.07.
˚
Compound 2e. Mp 189–1908C. TLC (CHCl3/hexanes/
EtOAc 2:1:1) Rf 0.38. IR (CHCl3, cm21): 2940w, 2911w,
2873w, 1755s, 1735s, 1474s, 1403s, 1380s, 1294s, 1170,
1027s. 1H NMR (400 MHz, CDCl3): d 5.53 (d, J¼11.3 Hz,
4H), 4.82 (d, J¼11.3 Hz, 4H), 4.31 (q, J¼7.2 Hz, 4H), 1.32
(t, J¼7.2 Hz, 6H). 13C NMR (100 MHz, CDCl3): d 164.4,
156.7, 74.4, 72.2, 63.6, 13.7. MS (FAB, Magic Bullet): m/z
371 (27, [MþH]þ); 341 (100, [MþH2CH2O]þ). HR-MS
(FAB, Magic Bullet): m/z 371.1197 ([MþH]þ,
C14H19O8N4, calcd 371.1203). X-Ray crystal structure.
4.2.6. Compound 8.
A
mixture of 2e (0.205 g,
0.554 mmol), LiOH (0.173 g, 7.24 mmol), deionized H2O
(150 mL), and MeOH (150 mL) was heated at 708C for 1
week. The reaction mixture was filtered, excess H2O/MeOH
was removed by rotary evaporation, and the residue was
dried under high vacuum. The solid was crystallized from
MeOH (120 mL), filtered, and dried under high vacuum to
give 8 (0.144 g, 0.443 mmol, 80%) as a white crystalline
solid. Mp.3008C (dec.). IR (KBr, cm21): 3542s, 2965w,
1719s, 1674s, 1476s, 1382m, 1305m, 1247m, 1178m,
1010s. 1H NMR (400 MHz, buffered D2O, pD¼7.41):
5.29 (d, J¼11.6 Hz, 4H), 4.71 (d, J¼11.6 Hz, 4H). 13C
NMR (100 MHz, buffered D2O, pD¼7.41): 168.9, 159.5,
77.4, 72.3. ES-MS: m/z 645 (100, [2M2Li]2), 319 (8,
[M2Li]2). X-Ray crystal structure.
Compound 5. Mp 204–2068C. TLC (CHCl3/hexanes/
EtOAc 2:1:1) Rf 0.14. IR (KBr, cm21): 2979w, 2940w,
2909w, 1744s, 1754s, 1724s, 1474s, 1443s, 1425m, 1403m,
1393m, 1369m, 1323m, 1286s, 1237s, 1216s, 1188m,
1
1125s, 1095s, 1072m, 1044m, 1022m, 1006m. H NMR
(400 MHz, CDCl3): 5.51 (d, J¼11.2 Hz, 2H), 5.45–5.35
(br. s, 3H), 4.90–4.80 (br. s, 3H), 4.72 (d, J¼11.2 Hz, 2H),
4.35–4.20 (m, 4H), 1.30 (t, J¼7.2 Hz, 6H). 13C NMR
(100 MHz, CDCl3): 164.8, 164.4, 155.4, 78.5, 74.2, 73.7,
72.4, 63.7, 63.6, 13.9, 13.8. (only 11 of the 12 expected
resonances were observed). MS (EI): m/z 400 (10, [M]þ),
370 (40, [M2CH2O]þ), 327 (100, [M2C3H5O2]þ). HR-MS
(EI): m/z 400.1239 ([M]þ, C15H20N4O9, calcd 400.1230).
X-Ray crystal structure (from EtOAc).
4.2.7. Compound 9. A mixture of 2e (0.503 g, 1.35 mmol),
LiOH (0.324 g, 13.51 mmol), H2O (125 mL), and MeOH
(125 mL) was heated at 708C for 24 h. The reaction mixture
was concentrated and dried under high vacuum. The residue
was dissolved in H2O (20 mL) and neutralized with TFA
(1.56 g, 13.65 mmol). The solution was concentrated and
dried under high vacuum. The resulting solid was washed
with CH3CN (4£5 mL), dried under high vacuum, and
redissolved in H2O (2.5 mL). Addition of conc. HCl (2 mL)
provided a precipitate that was filtered then dried under high
vacuum to give 9 (0.322 g, 1.03 mmol, 76%) as a white
solid. Mp.3008C (dec.). IR (KBr, cm21): 3532s, 2960m,
1757s, 1700s, 1478m, 1379m, 1228w, 1174m, 1012s, 930s.
1H NMR (400 MHz, DMSO-d6): 5.32 (d, J¼11.1 Hz, 4H),
4.87 (d, J¼11.1 Hz, 4H). 13C NMR (100 MHz, DMSO-d6):
165.8, 157.2, 74.5, 72.1. MS (FAB, glycerol): m/z 313 (100,
[M2H]2). HR-MS (FAB, glycerol): m/z 313.0413
([M2H]2, C10H9N4O8, calcd 313.0420).
4.2.3. Compound 3. The procedure described by Fenton for
oxidation of dihydroxymaleic acid was adapted for use with
dihydroxyfumaric acid.46,47 To a suspension of 4 (25.0 g,
150 mmol) in AcOH (70 mL) was added dropwise a solu-
tion of Br2 (8.8 mL, 27.3 g, 171 mmol) in AcOH (10 mL).
Occasionally during the addition, small quantities of H2O
(1 mL) were added to aid in decolorization. After the
addition was complete and the solution was homogenous,
the solvent was removed by rotary evaporation. The resul-
ting oil was dissolved in water (500 mL) and transferred to a
2 L beaker equipped with an efficient stir bar. The solution
was treated with solid Na2CO3 until bubbling ceased and
the solution was basic. The heavy white precipitate was
collected by filtration, resuspended in water, filtered,
suspended in CH3COCH3, and filtered. The resulting
white solid was dried at atmospheric pressure on the frit
yielding 3 (33.8–35.3 g, 86–90%).
4.2.4. Compound 6.44
A
mixture of 1e (1.010 g,
4.2.8. Compound 10. A mixture of 1e (1.035 g, 3.62 mmol)
and 3-(dimethylamino)propylamine (25 mL) was heated at
908C for 24 h. The excess amine was removed by rotary
evaporation and the residue was dried under high vacuum.
The solid was crystallized from MeOH (50 mL), filtered,
and dried under high vacuum to give 10 (1.243 g,
3.12 mmol, 86%) as an off-white crystalline solid. Mp
231–2338C. IR (KBr, cm21): 3324m, 3246m, 2947m,
2862m, 2780m, 1734m, 1685s, 1533s, 1466s. 1H NMR
(400 MHz, DMSO-d6): 7.88 (t, J¼5.5 Hz, 2H), 7.48 (s, 4H),
3.03 (m, 4H), 2.19 (t, J¼6.8 Hz, 4H), 2.10 (s, 12H), 1.50 (m,
4H). 13C NMR (100 MHz, DMSO-d6): 166.5, 160.9, 79.1,
57.0, 45.1, 38.3, 26.3. MS (FAB, PEG): m/z 399 (30,
3.53 mmol), NaOH (0.286 g, 7.15 mmol), and deionized
H2O (7 mL), was heated at 808C for 3 h. After cooling to
room temperature, the reaction mixture was filtered, and the
residue was dried under high vacuum to give 6 (0.872 g,
3.18 mmol, 90%) as a white powder. Mp.3408C (dec.). IR
(KBr, cm21): 3473w, 3282s, 2819m, 1709s, 1638s, 1396w,
1382w, 1168m, 1029m. 1H NMR (400 MHz, D2O/H2O
(1:1) selective excitation): 7.34 (br., 4H). 13C NMR
(100 MHz, D2O): 171.4, 162.6, 80.6. MS (FAB, glycerol):
m/z 275 (10, [MþH]þ), 115 (100, [C3H3N2O3]þ). HR-MS
(FAB2, glycerol): m/z 229.0210 ([MþH22Na]2)
C6H5N4O6, calcd 229.0209.

C. A. Burnett et al. / Tetrahedron 59 (2003) 1961–1970
1967
[MþH]þ), 45 (100, [C2H7N]þ). HR-MS (FAB, PEG): m/z
Rf 0.19. IR (KBr, cm21): 3286s, 2954m, 2932m, 2874m,
1766s, 1743s, 1688s, 1469m, 1410s, 1303m, 1243m,
399.2482 ([MþH]þ, C16H31N8O4, calcd 399.2468).
1
1180m. H NMR (400 MHz, CDCl3): 6.64 (t, J¼5.3 Hz,
4.2.9. Compound 11. A mixture of 1e (1.084 g, 3.79 mmol)
and n-butylamine (50 mL) was heated at 758C for 20 h. The
excess amine was removed by rotary evaporation and the
resulting residue was dried under high vacuum. The
resulting solid was crystallized from MeOH (50 mL),
filtered, and dried under high vacuum to give 11 (1.122 g,
3.30 mmol, 87%) as a white crystalline solid. Mp.2838C
(dec.). IR (KBr, cm21): 3303s, 2960s, 2874s, 1714s, 1541s,
1465s, 1378m, 1312w, 1277w, 1163s. 1H NMR (400 MHz,
DMSO-d6): 7.61 (t, J¼5.7 Hz, 2H), 7.48 (s, 4H), 2.98 (m,
4H), 1.36 (m, 4H), 1.25 (m, 4H), 0.85 (t, J¼7.2 Hz, 6H). 13C
NMR (100 MHz, DMSO-d6): 166.5, 160.8, 79.1, 39.2, 30.8,
19.5, 13.7. MS (FAB, Magic Bullet): m/z 341 (38,
[MþH]þ), 225 (100, [C9H13N4O3]þ). HR-MS (FAB,
Magic Bullet): m/z 341.1944 ([MþH]þ, C14H25N6O4,
calcd 341.1937). Anal. calcd for C14H24N6O4 (340.38): C,
49.40; H, 7.11. Found: C, 49.12; H, 7.14.
2H), 5.53 (d, J¼11.3 Hz, 4H), 4.59 (d, J¼11.3 Hz, 4H), 3.28
(m, 4H), 1.50 (m, 4H), 1.33 (m, 4H), 0.92 (t, J¼7.3 Hz, 6H).
13C NMR (100 MHz, CDCl3): 162.5, 157.2, 75.5, 72.5,
40.4, 31.1, 20.0, 13.6. MS (FAB, Magic Bullet): m/z 425
(100, [MþH]þ). HR-MS (FAB, Magic Bullet): m/z
425.2166 ([MþH]þ, C18H29N6O6, calcd 425.2149). Anal.
calcd for C18H28N6O6 (424.45): C, 50.93; H, 6.65. Found:
C, 50.85; H, 6.71.
4.2.13. Compound 15. A mixture of 2e (0.236 g,
0.637 mmol) and ethanolamine (20 mL) was heated at
858C for 20 h. The excess amine was removed by vacuum
distillation and the resulting residue was washed with EtOH
(3£10 mL), and then dried under high vacuum to give 15
(0.238 g, 0.595 mmol, 93%) as a white powder. Mp 276–
2798C. IR (KBr, cm21): 3422s, 3335s, 2948m, 1758m,
1
1736s, 1692s, 1486m, 1419m, 1040m, 1028m. H NMR
(400 MHz, DMSO-d6): 8.53 (t, J¼5.8 Hz, 2H), 5.29 (d,
J¼11.3 Hz, 4H), 4.69 (d, J¼11.3 Hz, 4H), 4.59 (t, J¼
5.9 Hz, 2H), 3.41 (m, 4H), 3.16 (m, 4H). 13C NMR
(100 MHz, DMSO-d6): 162.6, 157.5, 75.4, 72.0, 59.0,
42.5. MS (FAB, Magic Bullet): m/z 401 (100, [MþH]þ).
HR-MS (FAB, Magic Bullet): m/z 401.1418 ([MþH]þ,
C14H21N6O8, calcd 401.1421). Anal. calcd for C14H20N6O8
(400.34): C, 42.00; H, 5.04. Found: C, 41.99; H, 5.05.
4.2.10. Compound 12. A mixture of 1e (0.521 g,
1.82 mmol) and ethanolamine (25 mL) was heated at 808C
for 24 h. The excess amine was removed by vacuum
distillation and the resulting residue was washed with H2O
(3£10 mL), and then dried under high vacuum to give 12
(0.491 g, 1.55 mmol, 85%) as a white powder. Mp 2788C.
IR (KBr, cm21): 3483s, 3403m, 2950w, 2932m, 2889m,
1742s, 1706s, 1545s, 1420m, 1253m, 1170m. 1H NMR
(400 MHz, DMSO-d6): 7.72 (t, J¼5.5 Hz, 2H), 7.56 (s, 4H),
4.60 (t, J¼5.6 Hz, 2H), 3.37 (m, 4H), 3.08 (m, 4H). 13C
NMR (100 MHz, DMSO-d6): 166.9, 160.6, 79.0, 59.2, 42.1.
MS (FAB, glycerol): m/z 317 (100, [MþH]þ). HR-MS
(FAB, glycerol): m/z 317.1212 ([MþH]þ, C10H17N6O6,
calcd 317.1210). Anal. calcd for C10H16N6O6 (316.27): C,
37.98; H, 5.10. Found: C, 37.55; H, 5.10.
4.2.14. Compound 16. A mixture of 1e (2.010 g,
7.02 mmol) and morpholine (150 mL) was heated at
1288C for 96 h. The excess amine was removed by rotary
evaporation and the residue was dried under high vacuum.
The solid was washed with hot MeOH (50 mL), filtered, and
dried under high vacuum to give 16 (1.599 g, 3.95 mmol,
56%) as a white solid. Mp 211–2148C. IR (KBr, cm21):
3417m, 3256s, 2867m, 1675s, 1638s, 1382m, 1364w,
1162m, 1104m, 1044m, 1025m. 1H NMR (400 MHz,
DMSO-d6): 6.92 (s, 4H), 3.72 (t, J¼4.6 Hz, 8H), 3.00 (t,
J¼4.6 Hz, 8H). 13C NMR (100 MHz, DMSO-d6): 170.9,
161.2, 79.6, 63.9, 43.2. ES-MS: m/z 483 (100, [2Mþ4Hþ
Na22C4H10NO]þ), 405 (2, [MþH]þ). ES-MS: m/z 229
(100, [MþH22C4H10NO]2).
4.2.11. Compound 13. A mixture of 2e (0.539 g,
1.46 mmol) and 3-(dimethylamino)propylamine (12 mL)
was heated at 788C for 20 h. The amine was removed by
rotary evaporation and the residue was dried under high
vacuum. The residue was suspended in Et2O, filtered, and
dried under high vacuum to give 13 (0.618 g, 1.28 mmol,
88%) as a yellow powder. Mp 168–1708C. TLC (CHCl3/
MeOH, 9:1, 2% NH4OH) Rf 0.12. IR (KBr, cm21): 3295s,
2942m, 2872m, 2766s, 1767s, 1738s, 1690s, 1538s, 1469s,
4.2.15. Compound 17. A mixture of 2e (0.506 g,
1.37 mmol) and morpholine (50 mL) was heated at 1288C
for 72 h. The amine was removed by rotary evaporation and
the residue was dried under high vacuum. The residue was
suspended in MeOH (2£5 mL), decanted, and dried under
high vacuum to give 17 (0.550 g, 1.13 mmol, 82%) as an
off-white powder. Mp 214–2188C. IR (KBr, cm21): 3036m,
2874m, 1715s, 1654s, 1473m, 1435m, 1379s, 1308m,
1
1242s, 1180s. H NMR (400 MHz, CDCl3): 9.62 (br., 2H),
5.52 (d, J¼11.2 Hz, 4H), 4.63 (d, J¼11.2 Hz, 4H), 3.36 (m,
4H), 2.45 (t, J¼5.6 Hz, 4H), 2.19 (s, 12H) 1.65 (m, 4H). 13C
NMR (100 MHz, CDCl3): 162.6, 157.6, 75.7, 72.3, 59.0,
44.8, 41.7, 23.9. MS (FAB, Magic Bullet): m/z 483 (100,
[MþH]þ). HR-MS (FAB, Magic Bullet): m/z 483.2693
([MþH]þ, C20H35N8O6, calcd 483.2680). Anal. calcd for
C20H34N8O6 (482.53): C, 49.78; H, 7.10. Found: C, 49.96;
H, 6.97.
1
1105m, 1015s. H NMR (400 MHz, DMSO-d6): 5.21 (d,
J¼10.7 Hz, 4H), 4.79 (d, J¼10.7 Hz, 4H), 3.72 (t, J¼
4.8 Hz, 8H), 3.00 (t, J¼4.8 Hz, 8H). 13C NMR (100 MHz,
DMSO-d6): 167.7, 158.2, 76.1, 71.7, 63.4, 42.8. MS (FAB,
Magic Bullet): m/z 489 (4, [MþH]þ), 88 (100,
[C4H10NO]þ). X-Ray crystal stucture (from MeOH).
4.2.12. Compound 14. A mixture of 2e (0.205 g,
0.554 mmol) and n-butylamine (10 mL) was heated at
788C for 20 h. The amine was removed by rotary
evaporation and the residue was dried under high vacuum.
The residue was suspended in Et2O, filtered, and dried under
high vacuum to give 14 (0.211 g, 0.499 mmol, 90%) as a
white powder. Mp 238–2428C. TLC (CHCl3/MeOH, 25:1)
4.2.16. Compound 18. A solution of 14 (0.502 g,
1.23 mmol) in anh. THF (20 mL) was treated with NaH
(0.123 g, 5.13 mmol) and heated at 408C for 5 min. Methyl
iodide (1.739 g, 12.26 mmol) was added and the reaction

1968
C. A. Burnett et al. / Tetrahedron 59 (2003) 1961–1970
mixture was heated at reflux for 5 h. An additional portion
of CH3I (1.140 g, 8.03 mmol) was added and reflux
continued for 2 h. The reaction mixture was concentrated
and dried under high vacuum. The residue was suspended in
H2O (500 mL) and extracted with EtOAc (3£100 mL). The
combined extracts were dried over MgSO4, filtered, and
concentrated. The residue was purified by flash chroma-
tography (SiO2, CHCl3/MeOH, 50:1) to give 18 (0.415 g,
0.918 mmol, 75%) as a foam. TLC (CHCl3/MeOH, 25:1) Rf
0.47. IR (KBr, cm21): 2959s, 2874m, 1756s, 1736s, 1664s,
1470m, 1410s, 1301m, 1179s, 1030s, 1008s. 1H NMR
(400 MHz, CDCl3): 5.57 (d, J¼7.8 Hz, 2H), 5.52 (d, J¼
11.1 Hz, 2H), 4.9 (m, 2H) 4.56 (m, 2H), 3.57 (m, 0.5H), 3.43
(m, 1.5H), 3.27 (m, 1H), 3.13 (m, 0.5H), 2.96 (s, 2H), 2.82
(s, 2.5H), 2.80 (s, 1.5H), 2.60 (m, 0.5H), 1.47 (m, 3H), 1.30
(m, 3H), 1.17 (m, 2H), 0.94 (t, J¼7.3 Hz, 4H), 0.83 (t,
J¼7.3 Hz, 2H). 13C NMR (100 MHz, CDCl3): 162.0, 161.9,
161.6, 161.5, 155.9, 155.8, 138.0, 75.7, 75.5, 73.0, 71.8,
71.6, 51.0, 50.9, 50.8, 36.6, 36.0, 30.6, 30.5, 29.0, 28.8,
20.0, 19.7, 14.2, 13.8, 13.6, 10.9. MS (FAB, Magic Bullet):
m/z 453 (46, [MþH]þ), 100 (100, [C5H10NO]þ). HR-MS
(FAB, Magic Bullet): m/z 453.2469 ([MþH]þ,
C20H33N6O6, calcd 453.2462.
solvent was removed by rotary evaporation and the residue
was dried under high vacuum. The residue was washed with
EtOH, filtered, and dried under high vacuum to give 21
(0.389 g, 0.704 mmol, 66%) as a white solid. Mp 210–
2158C. IR (KBr, cm21): 3443s, 2960w, 2727w, 1725s,
1
1653w, 1647w, 1436m, 1375m, 1218s, 1182s, 1011m. H
NMR (400 MHz, DMSO-d6): 9.23 (br., 1H), 7.47 (d, J¼
7.9 Hz, 2H), 7.10 (d, J¼7.9 Hz, 2H), 5.43 (d, J¼11.3 Hz,
4H), 5.09 (d, J¼11.3 Hz, 4H), 3.54 (t, J¼7.1 Hz, 2H), 3.07
(m, 2H), 2.75 (d, J¼4.8 Hz, 6H), 2.28 (s, 3H), 1.91 (m, 2H).
13C NMR (100 MHz, DMSO-d6): 167.0, 157.8, 145.4,
137.8, 128.1, 125.5, 72.3, 70.2, 54.1, 42.3, 36.5, 22.0,
20.7. MS (FAB, Magic Bullet): m/z 381 (29, [MþH2
CH3C6H4SO3]þ) 58 (100, [C3H8N]þ). HR-MS (FAB,
Magic
C15H21N6O6, calcd 381.1523).
Bullet):
m/z
381.1530
([C15H21N6O6]þ,
4.2.20. Compound 22. Method 1. A mixture of 14 (0.050 g,
0.118 mmol), ClCH2CH2Cl (20 mL), and PTSA·H2O
(0.114 g, 0.589 mmol) was heated at reflux for 20 h. The
solvent was removed by rotary evaporation and the residue
was dried under high vacuum. The residue was washed with
H2O (3£8 mL) and dried under high vacuum to give 22
(0.034 g, 0.096 mmol, 82%) as an off-white solid.
4.2.17. Compound 19. A mixture of 10 (0.254 g,
0.637 mmol), ClCH2CH2Cl (25 mL), and PTSA·H2O
(0.607 g, 3.19 mmol) was heated at reflux for 20 h. After
rotary evaporation, the residue was dried under high
vacuum. The residue was washed with EtOH, filtered, and
dried under high vacuum to give 19 (0.270 g, 0.576 mmol,
91%) as a white solid. Mp 132–1388C. IR (KBr, cm21):
3443s, 2946w, 2919w, 1718s, 1700s, 1653w, 1635w,
Method 2. A mixture of 20 (0.199 g, 0.749 mmol), TFA
(0.5 mL), and paraformaldehyde (0.091 g, 3.00 mmol) was
heated at 758C for 12 h. TFA was removed by rotary
evaporation, the residue dissolved in EtOAc (50 mL),
washed with sat. aq. Na2CO3 (3£50 mL), and dried over
anh. MgSO4. After filtration and rotary evaporation, the
residue was purified by flash chromatography (SiO2,
CHCl3/EtOAc/hexanes, 2:1:1) to give 22 (0.079 g,
0.225 mmol, 30%) as a white crystalline solid. Mp 182–
1848C. TLC (CHCl3/EtOAc/hexanes, 2:1:1) Rf 0.43. IR
(KBr, cm21): 2959w, 1778s, 1732s, 1478m, 1465m, 1371m,
1307m, 1230m, 1200m, 1035m, 1013m. 1H NMR
(400 MHz, CDCl3): 5.51 (d, J¼11.1 Hz, 4H), 5.09 (d, J¼
11.1 Hz, 4H), 3.59 (t, J¼7.3 Hz, 2H), 1.59 (m, 2H), 1.30 (m,
2H), 0.92 (t, J¼7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3):
167.3, 157.6, 72.4, 70.4, 39.1, 29.1, 19.7, 13.4. MS (FAB,
Magic Bullet): m/z 352 (89, [MþH]þ), 322 (100). HR-MS
(FAB, Magic Bullet): m/z 352.1268 ([MþH]þ,
C14H18N5O6, calcd 352.1257). X-Ray crystal structure.
Anal. calcd for C14H17N5O6 (351.32): C, 47.86; H, 4.88.
Found: C, 48.01; H, 5.07.
1
1457m, 1191s, 1125m. H NMR (400 MHz, DMSO-d6):
9.25 (br., 1H), 8.70 (s, 4H), 7.46 (d, J¼7.9 Hz, 2H), 7.10 (d,
J¼7.9 Hz, 2H), 3.48 (t, J¼7.4 Hz, 2H), 3.05 (m, 2H), 2.75
(d, J¼4.6 Hz, 6H), 2.28 (s, 3H), 1.84 (m, 2H). 13C NMR
(100 MHz, DMSO-d6): 170.5, 158.9, 145.5, 137.8, 128.2,
125.5, 73.8, 54.1, 52.3, 35.8, 22.4, 20.8. MS (FAB, Magic
Bullet): m/z 297 (100, [MþH2CH3C6H4SO3]þ). HR-MS
(FAB, Magic Bullet): m/z 297.1313 ([C11H17N6O4]þ,
C11H17N6O4, calcd 297.1311).
4.2.18. Compound 20. A mixture of 11 (0.508 g,
1.49 mmol), ClCH2CH2Cl (50 mL), and PTSA·H2O
(1.40 g, 7.35 mmol) was heated at reflux for 20 h. The
solvent was removed by rotary evaporation and the resulting
residue was dried under high vacuum. The residue was
suspended in H2O, filtered, and dried under high vacuum to
give 20 (0.336 g, 1.26 mmol, 85%) as a white solid.
Mp.3458C (dec.). IR (KBr, cm21): 3297m, 3229m,
4.2.21. Compound 23. A mixture of 12 (0.505 g,
1.60 mmol), ClCH2CH2Cl (50 mL), and PTSA·H2O
(3.09 g, 16.24 mmol) was heated at reflux for 24 h. The
solvent was removed by rotary evaporation and the resulting
residue was dried under high vacuum. The residue was
washed with EtOH (3£8 mL), then with EtOAc (1£5 mL),
and dried under high vacuum to give 23 (0.114 g,
0.173 mmol, 11%) as an off-white solid. Mp 240–2448C.
IR (KBr, cm21): 3438s, 3186s, 2929w, 1752s, 1724m,
1
2934w, 2858w, 1723s, 1468m, 1446m, 1386m, 1158m. H
NMR (400 MHz, DMSO-d6): 8.69 (s, 4H), 3.45 (t, J¼
7.0 Hz, 2H), 1.47 (m, 2H), 1.19 (m, 2H), 0.85 (t, J¼7.3 Hz,
3H). 13C NMR (100 MHz, DMSO-d6): 170.8, 159.0, 73.8,
38.0, 28.8, 19.3, 13.5. MS (FAB, Magic Bullet): m/z 268
(100, [MþH]þ). HR-MS (FAB, Magic Bullet): m/z
268.1040 ([MþH]þ, C10H14N5O4, calcd 268.1046). Anal.
calcd for C10H13N5O4 (267.24): C, 44.94; H, 4.90. Found:
C, 44.75; H, 4.91.
1
1694s, 1496s, 1279s, 1186m, 1126s. H NMR (400 MHz,
DMSO-d6): 8.11 (s, 4H), 7.79 (br., 6H), 7.46 (d, J¼7.8 Hz,
4H), 7.11 (d, J¼7.8 Hz, 4H), 4.25 (t, J¼4.8 Hz, 4H), 3.12
(m, 4H), 2.28 (s, 6H). 13C NMR (100 MHz, DMSO-d6):
166.7, 159.1, 145.2, 138.0, 128.2, 125.5, 77.8, 62.4, 37.9,
20.8. MS (FAB, Magic Bullet): m/z 317 (15, [MþH2
2C7H8O3S]þ), 44 (100, [C2H6N]þ). HR-MS (FAB, Magic
4.2.19. Compound 21. A mixture of 13 (0.515 g,
1.07 mmol), ClCH2CH2Cl (100 mL), and PTSA·H2O
(1.05 g, 5.52 mmol) was heated at reflux for 20 h. The

C. A. Burnett et al. / Tetrahedron 59 (2003) 1961–1970
1969
Bullet): m/z 317.1223 ([MþH22C7H8O3S]þ, C10H17N6O6,
193(2) K; R(F)¼0.0352; GOF on F 2¼1.084. Crystal data
for 8: [C10H12Li2N4O10] (362.12); monoclinic, space group
calcd 317.1210).
˚
˚
P2(1)/n; colorless rod, a¼7.8069(3) A, b¼12.1012(5) A,
˚
4.2.22. Compound 24. A mixture of 12 (0.502 g,
1.59 mmol), acetic anhydride (0.490 g, 4.76 mmol), and
acetic acid (50 mL) was heated at reflux for 24 h. To this
solution, PTSA·H2O (1.51 g, 7.94 mmol) was added and
reflux continued for 24 h. The reaction mixture was
concentrated and dried under high vacuum. The residue
was washed with EtOH (4£4 mL) and dried under high
vacuum to give 24 (0.338 g, 1.14 mmol, 72%) as a white
solid. Mp 329–3328C. IR (KBr, cm21): 3245s, 2961m,
1762m, 1735s, 1698s, 1399m, 1374m, 1334m, 1229s,
1165m. 1H NMR (400 MHz, DMSO-d6): 8.68 (s, 4H),
4.16 (t, J¼5.2 Hz, 2H), 3.71 (t, J¼5.2 Hz, 2H), 1.90 (s, 3H).
13C NMR (100 MHz, DMSO-d6): 170.5, 170.2, 158.9, 73.7,
59.6, 37.7, 20.3. MS (EI): m/z 297 (45, [M]þ), 254 (100,
[C8H8N5O5]þ). HR-MS (EI): m/z 297.0717 ([M]þ,
C10H11N5O6, calcd 297.0709). Anal. calcd for
C10H11N5O6 (297.22): C, 40.41; H, 3.73. Found: C, 40.29;
H, 3.66.
c¼15.2717(6) A; a¼908, b¼94.6540(10)8, g¼908, V¼
3
˚
1438.00(10) A ; Z¼4; T¼293(2) K; R(F)¼0.0344; GOF
on F2¼1.077. Crystal data for 17: [C19H32N6O11] (520.51);
˚
triclinic, space group P-1; colorless block, a¼10.5703(4) A,
˚
˚
b¼10.9034(4) A, c¼10.9550(4) A; a¼75.6780(10)8, b¼
3
˚
80.0040(10)8, g¼74.3000(10)8, V¼1169.99(8) A ; Z¼2;
T¼193(2) K; R(F)¼0.0337; GOF on F 2¼1.044. Crystal
data for 22: [C14H17N5O6] (351.33); monoclinic, space
˚
group P2(1)/n; colorless plate, a¼8.2888(7) A, b¼
˚
˚
12.5119(11) A, c¼15.6990(14) A; a¼908, b¼91.706(2)8,
3
˚
g¼908, V¼1627.4(2) A ; Z¼4; T¼193(2) K; R(F)¼0.0380;
GOF on F 2¼1.087.
Acknowledgements
We thank the National Institutes of Health (GM61854) and
the University of Maryland for partial support of this work.
L. I. is a Cottrell Scholar of Research Corporation.
4.2.23. Compound 25. A mixture of 15 (0.435 g,
1.09 mmol), acetic anhydride (0.336 g, 3.26 mmol), and
ClCH2CH2Cl (160 mL) was heated at reflux for 1 h. To this
solution, PTSA·H2O (1.034 g, 5.44 mmol) was added and
reflux continued for 24 h. The excess ClCH2CH2Cl was
removed by rotary evaporation and the resulting residue
was dried under high vacuum. The residue was washed with
H2O (4£10 mL) and dried under high vacuum to give 25
(0.301 g, 0.790 mmol, 73%) as a white solid. Mp 251–
2548C. TLC (CHCl3/EtOAc, 2:1) Rf 0.35. IR (KBr, cm21):
2935w, 2885w, 1780m, 1757s, 1730m, 1385s, 1235s,
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