N,N′-transphthaloylation in a monoprotected diamine

Article abstract of DOI:10.1055/s-2006-926362

A convenient and simple method is described for formally transferring a phthaloyl protecting group from one amino group to another in an unsymmetrical diamine. The NMR spectra of some of the amido intermediates reveal that, at room temperature, there is restricted rotation around N-C=O and, in some cases, C-C=O bonds in these molecules. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926362

PAPER
983
N,N¢-Transphthaloylation in a Monoprotected Diamine
N
, N
¢
-Tran
o
sphthaloylati
a
on ina Mo
n
noprotectedDiami
E
ne . McCormick, R. Stanley McElhinney,† T. Brian H. McMurry,* John E. O’Brien
University Chemical Laboratory, Trinity College, Dublin 2, Ireland
Fax +353(1)6712826; E-mail: tmcmurry@tcd.ie
Received 20 September 2005
† Dedicated to the memory of our co-author, Stanley McElhinney, who initiated this work, but who died October 10, 2005, after this paper
was submitted.
On standing in DMSO-d6, the free base 3 gives a complex
equilibrium mixture whose H NMR spectrum suggests
that it contains two bicyclic compounds 9 and 10
(Scheme 2) involving the dihydrofluorouracil system
Abstract: A convenient and simple method is described for formal-
ly transferring a phthaloyl protecting group from one amino group
to another in an unsymmetrical diamine. The NMR spectra of some
of the amido intermediates reveal that, at room temperature, there is
1
restricted rotation around N–C=O and, in some cases, C–C=O (one enantiomer shown), a small amount of 3, and also the
bonds in these molecules.
base 1. The formation of the bicyclic compounds mirrors
the reactions of similar 1-(3-aminopropyl)-5-
fluorouracils12 and related compounds.13 The presence of
the bicyclic compounds is shown by the appearance of
two 1H NMR double doublet peaks at 4.98 ppm (J = 46.7
and 8.0 Hz) and 5.15 ppm (J = 45.7 and 5.0 Hz), which
are characteristic of the CHF proton. The assigned struc-
tures are based on a mechanism that involves attack by the
amino group on the 6-position of the uracil so that the
original H-1 and the newly formed bridgehead proton are
cis. The major bicyclic isomer 9 is formed if the amino
group delivers a proton to the 5,4-enolate anion interme-
diate from the side from which it approaches the a,b-
enone system. In 9, the 5-fluoro substituent is equatorial
and the hydrogen axial, giving rise to an axial–axial cou-
pling constant for the 5,6-protons. The presence of the iso-
mer 1 is more surprising, and its formation must involve a
twelve-membered ring intermediate (11). When the free
base 1 is liberated from its hydrochloride, its NMR spectra
(sample freshly prepared) fit the structure, but when the
sample is allowed to stand, then the NMR spectra show
the presence of traces of the isomeric amine 3.
Key words: N-phthaloyl protecting groups, transphthaloylation,
NMR spectra, restricted rotation, hindered amines
The availability of the mono-protected diamine 1, defined
as a seco-nucleoside,1 (readily prepared2 from the chloride
23 and ethanolamine hydrochloride) and the synthesis of
potential biologically active derivatives based on manipu-
lation of its free amino group2 suggested that we should
prepare the isomer 3 and convert this into the correspond-
ing compounds 9 and 10. We now describe a simple two-
step method whereby 1 can be converted into 3
(Scheme 1). This amounts to an effective transphthaloyla-
tion and avoids a lengthy process of selective protection
and deprotection. While we demonstrated this formal
transfer of a protecting phthaloyl entity from one amino
group to another in a single system, it may be of use in
others involving selective modification of unsymmetrical
a,w-diamines such as lysine esters4 or spermidine,5 and in
purpurosamine6a and other diaminosugars.6b–d
o-(1-Pyrrolidinylcarbonyl)benzoic acid (4)7–9 was con-
verted into the mixed anhydride 57, which on reaction
with the amine 1 afforded the diamidophthalimide 6
(Scheme 1). Treatment of this with hydrazine hydrate at
–15 °C gave the amidohydrazide 7, which was not isolat-
ed but reacted with aqueous methanolic hydrochloric acid
at 20 °C to afford the amine salt (3·HCl). This process in-
volves ring closure of the o-(1-pyrrolidinylcarbonyl)ben-
zamide unit10 to give the N-substituted phthalimide, and
cleavage of the (N-aminocarbamoyl)benzamide unit to
liberate the amine as the salt (3·HCl) with elimination of
phthalohydrazide11. The amine 3 was further character-
ised as the picrate and as the N-trifluoroacetyl derivative.
The latter was quite different from the trifluoroacetyl de-
rivative prepared from 1. As expected, when the diami-
dophthalimide 6 was treated with aqueous methanolic
hydrochloric acid at 20 °C, it was converted into the
bisphthalimide 8.
o-(N,N-Diisopropylcarbamoyl)benzoic acid,7–9 in a simi-
lar series of reactions, was converted into the mixed anhy-
dride 12 and thence into the diamidophthalimide 13
(Scheme 3). Unlike 6, 13 did not cyclise to the bisphthal-
imide 8 with aqueous methanolic hydrochloric acid, but
did when toluene-p-sulfonic acid in refluxing acetic acid
was used. The diamidophthalimide 13 reacted with hydra-
zine hydrate to give the amine 14.
We established the conditions for the reactions in the
above schemes by using a model system based on o-ami-
dobenzoic acids. The mixed anhydride 5 reacted with ben-
zylamine to give the diamide 15, which could also be
formed from N-benzylphthalimide (16) and pyrrolidine
(Scheme 4). Compound 15 did not react with hydrazine
hydrate, but underwent ring closure with aqueous metha-
nolic hydrochloric acid to give 16 and pyrrolidine. The di-
amide 17 was also formed from the corresponding mixed
anhydride 12 and benzylamine, but could not be formed
from N-benzylphthalimide (16) and diisopropylamine.
SYNTHESIS 2006, No. 6, pp 0983–0988
x
x
.
x
x
.2
0
0
6
Advanced online publication: 27.02.2006
DOI: 10.1055/s-2006-926362; Art ID: P14905SS
© Georg Thieme Verlag Stuttgart · New York
The structures of the starting materials and the new com-
pounds described above were confirmed by IR and H,
1

984
J. E. McCormick et al.
PAPER
O
N
2
F
H
N
N
N
O
O
O
ii
O
O
O
Cl
N
F
OH
O
O
O
OEt
4
5
O
N
i
O
N
H
N
F
H
O
N
O
O
5'
O
4'
O
1'
NH2
NH2
O
2'
N
3'
N
1
1a
O
O
iii
O
N
O
N
F
H
H
F
N
N
N
N
O
O
iv
O
O
NHNH2
O
O
NH
NH
O
NH
O
N
O
O
6
O
7
O
v
v
O
O
N
O
F
F
H
N
H
N
H
N
O
O
+
O
N
O
O
N
H
N
N
O
N
O
NH2
O
O
O
8
3
O
Scheme 1 Reagents: (i) HOCH2CH2NH2·HCl; (ii) EtOCOCl, Et3N; (iii) 5, acetone; (iv) NH2NH2·H2O; (v) HCl, MeOH–H2O.
13C, and 19F NMR measurements. We used a combination and 14 reveal further complications. These are best illus-
of DEPT, TOCSY, NOE, HMQC, and HMBC techniques trated by signals due to the uracil residue in compound 14;
to establish the structures. The NMR spectra of the o-(1- the H-6 signal in the 1H and the F-5 signal in the 19F NMR
pyrrolidinylcarbonyl)benzoic acid (4) were complicated spectra both appear doubled at room temperature. These
by the fact that the partial double-bond character of the collapse as the temperature is raised, and at 50 °C, they
amide N–C=O bond means that there is restricted rotation become singlets (see experimental section for details).
around this bond at room temperature, and the four CH2 This phenomenon can be explained if there is restricted
groups of the pyrrolidinyl residue give separate signals. rotation around the aromatic C–C=O bond, giving rise to
These merge into two signals at higher temperatures. The two rotamers at 20 °C, and thus two diastereoisomers.
same behaviour occurs in all the compounds containing a
pyrrolidinyl residue. The diisopropylamido acid gives
Melting points are uncorrected. IR spectra were measured on a Per-
kin Elmer Spectrum 1 FT IR instrument. H, 13C, and 19F NMR
spectra were measured on a Bruker DPX400 machine at 400, 100,
and 376.5 MHz respectively. 1H and 13C NMR values are given in
ppm from tetramethylsilane, and 19F values based on trifluorotolu-
ene as standard (dF = –63.9). Peaks marked with an asterisk (*) may
be interchanged.
1
even more complex spectra, since not only are there two
sets of signals each for the methyls and hydrogens com-
prising the isopropyl groups, due to restricted rotation
around the N–C=O bond, but also the methyls in each iso-
propyl group are non-equivalent as they are prochiral. In-
terestingly, the prochirality of the methylene hydrogens in
the benzyl residue in 17 is demonstrated by the two sepa-
rate signals observed for them. The NMR spectra of 13
o-(1-Pyrrolidinylcarbonyl)benzoic Acid (4)7–9
IR (nujol): 1714 cm–1.
Synthesis 2006, No. 6, 983–988 © Thieme Stuttgart · New York

PAPER
N,N¢-Transphthaloylation in a Monoprotected Diamine
985
F
CH3 CH3
CH3 CH3
O
O
O
CH3
CH3
CH3
CH3
N
N
O
H
N
N
N
3
1
H
i
O
O
O
N
O
O
OEt
H
OH
11
O
O
O
O
H
H
F
12
F
H
H
H
N
N
O
O
H
H
+
O
N
H
N
O
N
H
N
ii
H
N
N
O
O
CH3 CH3
O
N
O
O
9
10
F
CH3
CH3
N
HN
O
Scheme 2
O
O
O
NH
1H NMR (400 MHz, DMSO-d6): d = 1.77 (quin, J = 6.2 Hz, 2 H,
CH2-4), 1.84 (quin, J = 6.8 Hz, 2 H, CH2-3), 3.01 (t, J = 6.2 Hz, 2
H, CH2-5), 3.43 (t, J = 6.8 Hz, 2 H, CH2-2),7.32 (d, J = 7.5 Hz, 1
H, Ar-H-3), 7.50 (t, J = 7.5 Hz, 1 H, Ar-H-5), 7.63 (t, J = 7.5 Hz, 1
H, Ar-H-4), 7.89 (d, J = 7.5 Hz, 1 H, Ar-H-6), 13.20 (br s, 1 H, OH).
N
O
O
iv
13
13C NMR (100 MHz, DMSO-d6): d = 24.1 (C-3), 25.4 (C-4), 45.1
(C-2), 47.8 (C-5), 126.7 (Ar-C-3), 127.9 (q, Ar-C-1), 128.5 (Ar-C-
5), 129.9 (Ar-C-6), 132.5 (Ar-C-4), 139.7 (q, Ar-C-2), 167.0 (car-
boxyl C=O), 168.2 (carbamoyl C=O).
CH3 CH3
O
N
iii
F
CH3
CH3
HN
N
O
O
O
F
NH
N-[3-(2-Aminoethoxy)-3-(5-fluorouracil-1-yl)propyl]phthal-
imide Hydrochloride (1·HCl)2,3
HN
O
NH2
O
O
14
IR (nujol): 1702 cm–1.
O
N
O
N
1H NMR (400 MHz, DMSO-d6): d = 2.04 (m, 1 H, H-2), 2.25 (m, 1
H, H-2), 2.93 (m, 2 H, CH2CH2O), 3.60 (m, 2 H, H-3), 3.65 (t,
J = 6.5 Hz, 2 H, CH2CH2O), 5.70 (t, 1 H, J = 6.0 Hz, H-1), 7.85 (m,
4 H, phthalimido H), 8.03 (d, J = 7.0 Hz, 1 H, uracil H-6), 8.09 (br
O
N
O
8
O
+
Scheme 3 Reagents: (i) EtOCOCl, Et3N; (ii) 5, acetone; (iii) TsOH,
AcOH; (iv) NH2NH2·H2O.
s, 3 H, NH3 ), 11.80 (s, 1 H, uracil NH-3).
13C NMR (100 MHz, DMSO-d6): d = 32.1(C-2), 33.5 (C-3), 38.1
(CH2CH2O), 64.5 (CH2CH2O), 82.5 (C-1), 123.1 (phthalimido C-
3), 124.0 (d, J = 31.1 Hz, uracil C-6), 131.6 (q, phthalimido C-1),
134.5 (phthalimido C-4), 140.8 (d, J = 230.0 Hz, uracil C-5), 149.7
(uracil O=C-2), 157.1 (d, J = 25.4 Hz, uracil O=C-4), 167.8
(phthalimido C=O).
N-{3-[2-(o-(1-Pyrrolidinylcarbony)lbenzamido)ethoxy]-3-(5-
fluorouracil-1-yl)propyl}phthalimide (6)
Ethyl chloroformate (0.095 mL, 1.00 mmol) in acetone (1 mL) was
added slowly to o-(1-pyrrolidinylcarbonyl)benzoic acid (219 mg,
19F NMR (376.5 MHz, DMSO-d6): d = –166.7.
N
N
O
ii
O
O
O
O
i
NCH2Ph
NHCH2Ph
O
OEt
iii
O
O
O
O
16
15
5
iv
CH3 CH3
CH3 CH3
CH3
N
CH3
CH3
N
CH3
i
O
O
O
O
NHCH2Ph
O
OEt
O
O
O
17
12
Scheme 4 Reagents: (i) PhCH2NH2; (ii) HCl, MeOH–H2O; (iii) pyrrolidine; (iv) HN(CHMe2)2.
Synthesis 2006, No. 6, 983–988 © Thieme Stuttgart · New York

986
J. E. McCormick et al.
PAPER
1.00 mmol) and Et3N (0.28 mL, 2.0 mmol) in acetone (6 mL) at –
15 °C. The mixture was stirred for 10 min at this temperature to give
the mixed anhydride 5, which was used without purification. It was
added to the amine 1 as its hydrochloride (413 mg, 1.00 mmol) in
acetone (24 mL), and the reaction was set aside overnight. The sol-
vent was removed and the residue triturated with H2O to give the
phthalimide 6 (356 mg, 60%); mp 141.5–143.5 °C.
Anal. Calcd for C17H17FN4O5·HCl·0.5H2O: C, 48.39; H, 4.54; N,
13.29. Found: C, 49.02; H, 4.54; N, 13.05.
Free Base:
Mp 143–146 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.67 (m, 1 H, H-2), 1.84 (m, 1
H, H-2), 3.67 m, (3 H, CH2CH2O, CH2CH2O), 3.79 (m, 1 H,
CH2CH2O), 5.73 (t, J = 6.0 Hz, 1 H, H-1), 7.73 (d, J = 6.5 Hz, 1 H,
uracil H-6), 7.85 (s, 4 H, phthalimido H-3–6).
IR (nujol): 1718, 1612 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.75 (m, 2 H, pyrrolidinyl H-
4), 1.83 (m, 2 H, 3-pyrrolidinyl H-3), 2.03 (m, 1 H, H-2), 2.24 (m,
1 H, H-2), 3.06 (t, J = 6.8 Hz, 2 H, pyrrolidinyl H-5), 3.31 (m, 2 H,
CH2CH2O), 3.36 (m, 2 H, pyrrolidinyl H-2), 3.50 (m, 2 H,
CH2CH2O), 3.36 (t, J = 6.8 Hz, 2 H, H-3), 5.66 (t, J = 6.2 Hz, 1 H,
H-1), 7.29 (d, J = 7.5 Hz, 1 H, phthalamido H-3), 7.41 (t, J = 7.5
Hz, 1 H, phthalamido H-5), 7.50 (t, J = 7.5 Hz, 1 H, phthalamido H-
4), 7.56 (d, J = 7.5 Hz, 1 H, phthalamido H-6), 7.85 (m, 2 H, phthal-
imido H-3–6), 7.86 (m, 2 H, phthalimido H-3–6), 8.04 (d, J = 6.2
Hz, 1 H, uracil H-6), 8.62 (br s, 1 H, amido NH), 11.80 (s, 1 H,
uracil NH-3).
19F NMR (376.5 MHz, DMSO-d6): d = –166.7
The hydrochloride and picric acid in aq MeOH afforded the picrate;
mp 205–206 °C.
Anal. Calcd for C23H20FN7O12: C, 45.57; H, 3.35; N, 16.05. Found:
C, 45.35; H, 3.35; N, 16.05.
The N-trifluoroacetyl derivative was prepared from the hydrochlo-
ride (55 mg, 0.13 mmol) in EtOAc (1.3 mL) and TFA anhydride
(0.19 mL, 1.3 mmol) at –10 °C. The mixture was allowed to warm
to r.t. and after 2 h the solvent was removed and the residue triturat-
ed with H2O to give the derivative (54 mg, 84%); mp 155–157 °C.
13C NMR (100 MHz, DMSO-d6): d = 24.1 (pyrrolidinyl C-3), 25.4
(pyrrolidinyl C-4), 32.3 (C-2), 33.6 (C-3), 38.5 (CH2CH2O), 45.0
(pyrrolidinyl C-2), 47.9 (pyrrolidinyl C-5), 65.0 (CH2CH2O), 82.8
(C-1), 123.1 (phthalimido C-3), 124.2 (d, J = 31.1 Hz, uracil C-6),
126.5 (phthalamido C-3), 127.4 (phthalamido C-6), 128.2 (phthal-
amido C-5), 130.4 (phthalamido C-4), 131.6 (q, phthalimido C-1),
133.2 (q, phthalamido C-1), 134.5 (phthalimido C-4), 138.1 (q, ph-
thalamido C-2), 140.6 (d, J = 231.2 Hz, uracil C-5), 149.7 (uracil
O=C-2), 157.1 (d, J = 26.2 Hz, uracil C-4), 167.1 (alkoxyethylami-
do C=O), 167.8 (phthalimido C=O), 168.5 (pyrrolidinylcarbonyl
C=O).
Anal. Calcd for C19H16F4N4O6: C, 48.29; H, 3.42; N, 11.86. Found:
C, 48.14; H, 3.35; N, 11.75.
Derivatives of the Phthalimidoamine 1
The picrate prepared from the hydrochloride of 1 and picric acid had
mp 143–145 °C (from MeOH).
Anal. Calcd for C23H20FN7O12·H2O: C, 44.3; H, 3.55; N, 15.75.
Found: C, 44.73; H, 3.75; N, 15.75.
The trifluoroacetamide prepared as above had mp 207–210 °C and
was identical with a sample prepared3 from 2-trifluoroacetamido-
ethanol and 2 which had mp 211.5–213.5 °C.
19F NMR (376.5 MHz, DMSO-d6): d = –167.1.
Anal. Calcd for C29H28FN5O7·0.5H2O: C, 59.36; H, 4.99; N, 11.94.
Found: C, 59.15; H, 5.02; N, 11.83.
N-[3-(2-Phthalimidoethoxy)-3-(5-fluorouracil-1-yl)propyl]ph-
thalimide (8)
The diamidophthalimide 6 (117 mg, 0.200 mmol) was dissolved in
aq methanolic HCl soln (1 N; 1.2 mL) [made by adding concd HCl
soln (1 mL) to MeOH (10.6 mL)] and the mixture was set aside for
18 h at 20 °C. The precipitate was collected to afford the bisphthal-
imide 8 (73 mg, 65%) as needles; mp 215–216 °C.
1H NMR (400 MHz, DMSO-d6): d = 1.93 (m, 1 H, H-2), 2.18 (m, 1
H, H-2), 3.57 (t, J = 6.5 Hz, 2 H, H-3), 3.66 (m, 3 H, CH2CH2O,
CH2CH2O), 3.74 (m, 1 H, CH2CH2O), 5.62 (t, J = 6.0 Hz, 1 H, H-
1), 7.82 (s, 9 H, phthalimido H, uracil H-6), 11.79 (br s, 1 H, uracil
NH-3).
13C NMR (100 MHz, DMSO-d6): d = 32.0 (C-2), 33.4 (C-3), 37.4
(CH2CH2O), 65.3 (CH2CH2O), 82.6 (C-1), 123.0 (phthalimido C-
3), 124.0 (d, J = 34.0 Hz, uracil C-6), 131.47 (q, phthalimido C-1),
131.52 (q, phthalimido C-1), 134.38 (phthalimido C-4), 134.41 (ph-
thalimido C-4), 140.4 (d, J = 232.3 Hz, uracil C-5), 149.7 (uracil
O=C-2), 156.8 (d, J = 27.3 Hz, uracil O=C-4), 167.7 (phthalimido
C=O), 167.8 (phthalimido C=O).
3-(2-Phthalimidoethoxy)-3-(5-fluorouracil-1-yl)propylamine
(3)
The diamidophthalimide 6 (866 mg, 1.48 mmol) in DMF (3.5 mL)
was treated with hydrazine hydrate (0.15 mL, 3.0 mmol) at –15 °C
overnight. HCl soln (2 N; 2.4 mL) was added, the solvent was com-
pletely removed, and H2O (7.5 mL) was added. After 6 h, concd
HCl soln was added until pH 2 had been reached, and the reaction
mixture was set aside at 0 °C overnight. Phthalohydrazide (194 mg,
80%) was collected and the filtrate concentrated to 4.5 mL. Benzal-
dehyde (0.365 mL, 0.358 mmol) in MeOH (4.5 mL) was added and
the formed benzalazine (326 mg) was collected. MeOH was evapo-
rated, and the residual aqueous solution was extracted with Et2O.
The Et2O layer was dried, and the solvent removed. MeCN (7 mL)
was added and the mixture was set aside for 4 d to afford the amine
3 as the hydrochloride (547 mg, 88%); mp 203–203.5 °C (from
EtOH).
IR (nujol): 1713 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.90 (sept, J = 7.5 Hz, 1 H, H-
2), 2.06 (sept, J = 7.5 Hz, 1 H, H-2), 2.79 (t, J = 6.5 Hz, 2 H, H-3),
3.68 (m, 3 H, CH2CH2O, CH2CH2O), 3.79 (dt, J = 16.1, 6.5 Hz, 1
H, CH2CH2O), 5.76 (t, J = 6.5 Hz, 1 H, CH-1), 7.79 (dd, J = 6.5,
1.5 Hz, 1 H, uracil H-6), 7.85 (AB q, 4 H, phthalimido H-3–4), 8.05
19F NMR (376.5 MHz, DMSO-d6): d = –166.9.
o-(N,N-Diisopropylcarbamoyl)benzoic Acid7–9
IR (nujol): 1720, 1584 cm–1.
+
(v br s, NH3 ).
1H NMR (400 MHz, DMSO-d6): d = 1.05 (m, 6 H, s-anti-isopropyl
CH3), 1.44 (d, J = 6.8 Hz, 6 H, s-syn-isopropyl CH3), 3.46 (sept,
J = 6.8 Hz, 1 H, s-anti-isopropyl H), 3.55 (sept, J = 6.2 Hz, 1 H, s-
syn-isopropyl H), 7.22 (d, J = 7.8 Hz, 1 H, Ar-H-3), 7.46 (t, J = 7.8
Hz, 1 H, Ar-H-5), 7.59 (dt, J = 7.8, 1.4 Hz, 1 H, Ar-H-4), 7.89 (d,
J = 7.8 Hz, 1 H, Ar-H-6), 13.10 (br s, 1 H, COOH).
13C NMR (100 MHz, DMSO-d6): d = 31.5 (C-2), 34.7 (C-3), 37.2
(CH2CH2O), 65.4 (CH2CH2O), 82.2 (C-1), 123.0 (phthalimido C-
3), 123.6 (d, J = 34.0 Hz, uracil C-6), 131.5 (q, phthalimido C-1),
134.5 (phthalimido C-4), 140.7 (d, J = 230.2 Hz, uracil C-5), 149.6
(uracil O=C-2), 157.0 (d, J = 26.2 Hz, uracil O=C-4), 167.9 (ph-
thalimido C=O).
13C NMR (100 MHz, DMSO-d6): d = 19.3 (s-syn-isopropyl CH3),
20.6 (s-syn-isopropyl CH3), 19.6 (s-anti-isopropyl CH3), 20.0 (s-
19F NMR (376.5 MHz, DMSO-d6): d = –166.5.
Synthesis 2006, No. 6, 983–988 © Thieme Stuttgart · New York

PAPER
N,N¢-Transphthaloylation in a Monoprotected Diamine
987
anti-isopropyl CH3), 44.4 (s-syn-isopropyl CH), 50.5 (s-anti-iso-
propyl CH), 125.8 (Ar-C-3), 127.6 (q, Ar-C-1), 128.0 (Ar-C-5),
130.0 (Ar-C-6), 132.4 (Ar-C-4), 140.4 (q, Ar-C-2), 167.0 (q, acid
C=O), 168.8 (q, amido C=O).
13C NMR (100 MHz, DMSO-d6): d = 19.4 (s-anti-isopropyl CH3),
19.9 (s-anti-isopropyl CH3), 19.9 (s-syn-isopropyl CH3), 20.5 (s-
syn-isopropyl CH3), 31.8 (C-2), 34.8 (C-3), 38.8 (CH2CH2O), 44.4
(s-syn-isopropyl CH), 50.7 (s-anti-isopropyl CH), 66.7
(CH2CH2O), 82.4 (C-1), 123.8 (d, J = 33.0 Hz, uracil C-6), 125.5
(phthalamido C-3), 127.6 (phthalamido C-6), 127.8 (phthalamido
C-5), 130.3 (phthalamido C-4), 132.9 (phthalamido C-1), 138.6
(phthalamido C-2), 140.8 (d, J = 233.2 Hz, uracil C-5), 149.6
(uracil O=C-2), 157.2 (d, J = 26.2 Hz, uracil O=C-4), 167.1
(alkoxyethylamido C=O), 169.3 (diisopropylamido C=O).
N-{3-[2-(Diisopropylamidocarbonylbenzamido)ethoxy]-3-(5-
fluorouracil-1-yl)propyl}phthalimide (13)
The mixed anhydride 12 made from o-(N,N-diisopropylcarbam-
oyl)benzoic acid (623 mg, 2.50 mmol), Et3N, and ethyl chlorofor-
mate as described above was added to the amine 1 as its
hydrochloride (1.03g, 2.50 mmol) in acetone (30 ml) and the mix-
ture was set aside overnight. The solvent was removed, and the res-
idue triturated with H2O to give the diamidophthalimide 13 (1.38 g,
91%). No suitable solvent was found for crystallisation.
19F NMR (376.5 MHz, DMSO-d6): d = – 166.6, –166.8.
Anal. Calcd for C23H32FN5O5·HCl: C, 53.75; H, 6.45; N, 13.63.
Found: C, 53.45: H, 6.55; N, 13.52.
1
IR (nujol): 1713 cm–1.
At 50 °C, in the H spectrum the s-anti-CH3 doublets become a
broad singlet, the s-syn-CH3 a doublet (J = 5.8 Hz), the multiplet at
3.48 ppm separates into a multiplet at 3.52 ppm (2 × isopropyl CH
and 2 × CH2CH2O) and a broad signal at 3.42 ppm (CH2CH2O), the
two doublets at 7.95 ppm and 8.01 ppm merge to one doublet at 7.88
ppm, and the 8.38 ppm broad singlet sharpens to a possible triplet.
In the 19F spectrum, the two peaks merge to a single peak at –165.6
ppm.
1H NMR (400 MHz, DMSO-d6): d = 1.01 (m, 3 H, s-anti-isopropyl
CH3), 1.07 (m, 3 H, s-anti-isopropyl CH3), 1.39 (m, 6 H, s-syn-iso-
propyl CH3), 2.02 (m, 1 H, H-2), 2.23 (m, 1 H, H-2), 3.20 (m, 1 H,
CH2CH2O), 3.48 (m, 5 H, CH2CH2O, s-syn- and s-anti-isopropyl
CH, CH2-3), 3.68 (t, J = 6.8 Hz, 2 H, CH2CH2O), 5.65 (t, J = 6.0
Hz, 1 H, H-1), 7.17 (d, J = 7.5 Hz, 1 H, phthalamido H-3), 7.37 (t,
J = 7.5 Hz, 1 H, phthalamido H-5), 7.48 (t, J = 7.5 Hz, 1 H, phthal-
amido H-4), 7.55 (d, J = 7.5 Hz, 1 H, phthalamido H-6), 8.26 (d,
J = 6.1 Hz, 1 H, uracil H-6), 11.82 (br s, 1 H, uracil NH-3).
13C NMR (100 MHz, DMSO-d6): d = 19.5 (s-anti-isopropyl CH3),
20.0 (s-anti-isopropyl CH3), 20.0 (s-syn-isopropyl CH3), 20.5 (s-
syn-isopropyl CH3), 32.4 (C-2), 33.6 (C-3), 38.9 (CH2CH2O), 44.4
(s-syn-isopropyl CH), 44.6 (s-syn-isopropyl CH), 50.6 (s-anti-iso-
propyl CH), 50.7 (s-anti-isopropyl CH), 66.8 (CH2CH2O), 82.9 (C-
1), 123.1 (phthalimido C-3), 124.2 (d, J = 32.5 Hz, uracil C-6),
125.5 (phthalamido C-3), 127.6 (phthalamido C-5–6), 130.3 (ph-
thalamido C-4), 131.6 (phthalimido C-1), 132.8 (phthalamido C-1),
134.5 (phthalimido C-4), 138.6 (phthalamido C-2), 140.5 (d,
J = 236.1 Hz, uracil C-5), 149.6 (uracil O=C-2), 157.1 (d, J = 26.2
Hz, uracil O=C-4), 167.0 (alkoxyethylamido C=O), 167.8 (phthal-
imido C=O), 169.2 (diisopropylamido C=O).
N-Benzyl-o-(1-pyrrolidinylcarbonyl)benzamide (15)
(a) Ethyl chloroformate (0.095 mL, 1.00 mmol) in acetone (1 mL)
was added to a solution of o-(1-pyrrolidinylcarbonyl)benzoic acid
(219 mg, 1.00 mmol) and Et3N (0.28 mL, 2.0 mmol) in acetone (6
mL) at –15 °C. The mixture was set aside for 10 min, benzylamine
hydrochloride (144 mg, 1.00 mmol) was added, and the reaction
mixture was allowed to warm to r.t. After 3 h, the solvent was re-
moved, H2O (2 mL) was added, and the mixture was extracted with
CH2Cl2. The organic layer was dried over MgSO4 and the solvent
was removed to give the diamide 15 (223 mg, 72%); mp 124.5–
126 °C (from aq MeOH).
IR (nujol): 3268, 1662, 1620 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 1.72 (m, 2 H, CH2-4), 1.79 (m,
2 H, CH2-3), 3.06 (t, J = 6.2 Hz, 2 H, CH2-5), 3.37 (t, J = 6.2 Hz, 2
H, CH2-2), 4.42 (dd, J = 15.0, 6.0 Hz, 2 H, benzyl CH2), 7.24 (m, 1
H, p-Ar-H), 7.31 (m, 5 H, o- and m-Ar-H, phthalamido-H-3), 7.46
(m, 1 H, phthalamido H-5), 7.52 (m, 1 H, phthalamido H-4), 7.68
(d, J = 6.8 Hz, 1 H, phthalamido H-6), 8.91 (NH).
19F NMR (376.5 MHz, DMSO-d6): d = –167.0, –167.2.
Anal. Calcd for C31H34FN5O7·H2O: C, 59.59; H, 5.65; N, 11.22.
Found: C, 60.35; H, 6.05; N, 10.71.
The Bisphthalimide 8 from the Diamidophthalimide 13
The diamidophthalimide 13 (121 mg, 0.201 mmol), TsOH·H2O (42
mg, 0.22 mmol) and AcOH (1 mL) were refluxed for 16 h, and the
solvent was removed. After addition of H2O (1.5 mL) and extraction
of the mixture with CH2Cl2, the organic layer was dried over
MgSO4 and gave the bisphthalimide 8, identical with the compound
prepared from 6.
13C NMR (100 MHz, DMSO-d6): d = 24.0 (C-3), 25.1 (C-4), 42.5
(ArCH2), 45.0 (C-2), 47.9 (C-5), 126.6* (p-Ar-C), 126.7* (phthal-
amido C-3), 127.2 (o-Ar-C), 127.5 (phthalamido C-6), 128.2 (m-
Ar-C), 128.3 (phthalamido C-5), 130.4 (phthalamido C-4), 133.4
(phthalamido C-1), 138.0 (phthalamido C-2), 139.5 (ipso-Ar-C),
167.0 (benzylamido C=O), 168.5 (pyrrolidinyl C=O).
Anal. Calcd for C19H20N2O2: C, 74.0; H 6.55; N, 9.1. Found: C,
74.13; H, 6.55; N, 9.05.
N-{2-[3-Amino-1-(5-fluorouracil-1-yl)propoxy]ethyl}-N¢,N¢-di-
isopropylphthalamide (14)
The diamidophthalimide 13 (152 mg, 0.253 mmol) was dephthaloy-
lated as described for the analogue 6. The crude product (141 mg)
was recrystallised from EtOH to afford the aminophthalamide 14 as
its hydrochloride (64 mg, 50%); mp 210–210.5 °C.
(b) Pyrrolidine (0.05 mL, 0.60 mmol) was added to a solution of N-
benzylphthalimide (119 mg, 0.502 mmol) in THF. The mixture was
set aside for 24 h, the solvent was removed, and the residue was re-
crystallised from aq MeOH to afford the diamide 15 (126 mg, 82%),
identical with the sample prepared as descibed above.
1H NMR (400 MHz, DMSO-d6): d = 1.03 (d, J = 6.0 Hz, 3 H, s-
anti-isopropyl CH3), 1.06 (d, J = 6.0 Hz, 3 H, s-anti-isopropyl
CH3), 1.40 (d, J = 6.0 Hz, 6 H, s-syn-isopropyl CH3), 1.95 (m, 1 H,
H-2), 2.10 (m, 1 H, H-2), 2.89 (t, J = 7.3 Hz, 2 H, H-3), 3.49 (m,
CH2CH2O, CH2CH2O, 6 H, s-syn- and s-anti-isopropyl CH), 5.75
(br s, 1 H, H-1), 7.19 (d, J = 7.6 Hz, 1 H, phthalamido H-3), 7.41 (t,
J = 7.6 Hz, 1 H, phthalamido H-5), 7.50 (t, J = 7.6 Hz, 1 H, phthala-
mido H-4), 7.58 (br d, 1 H, phthalamido H-6), 7.98 and 8.02 (2 × d,
J = 5.9 Hz, 1 H, two rotamers of uracil H-6), 8.05 (br s, 3 H, NH3+),
8.38 (d, 1 H, amido NH), 11.79 (br s, 1 H, uracil NH-3).
This compound did not react with hydrazine hydrate.
N-Benzyl-N¢,N¢-diisopropylphthalamide (17)
The mixed anhydride from N,N-diisopropylphthalamic acid (498
mg, 2.00 mmol), Et3N (0.56 mL, 4.0 mmol), and benzylamine hy-
drochloride (288 mg, 2.00 mmol) in acetone were set aside for 16 h.
The solvent was removed and H2O was added. The solid was col-
lected, and recrystallised from aq MeOH to give the phthalamide
17; mp 118–120 °C.
Synthesis 2006, No. 6, 983–988 © Thieme Stuttgart · New York

988
J. E. McCormick et al.
PAPER
(2) Lucey, N. M.; McCormick, J. E.; McElhinney, R. S. J.
1H NMR (400 MHz, DMSO-d6): d = 1.04 (d, J = 6.3 Hz, 3 H, s-
anti-isopropyl CH3), 1.10 (d, J = 6.3 Hz, 3 H, s-anti-isopropyl
CH3), 1.42 (d, J = 7.0 Hz, 6 H, s-syn-isopropyl CH3), 3.49 (sept,
J = 7.0 Hz, 1 H, s-syn-isopropyl H), 3.55 (sept, J = 6.3 Hz, 1 H, s-
anti-isopropyl CH), 4.44 (dAB q, J = 15.0, 6.0 Hz, 2 H, benzyl
CH2), 7.22 (m and d, J = 8.0 Hz, 2 H, p-Ar-H and phthalamido H-
3), 7.33 (m, 4 H, o- and m-Ar-H), 7.43 (t, J = 7.5 Hz, 1 H, phthala-
mido H-5), 7.50 (t, J = 7.5 Hz, 1 H, phthalamido H-4), 7.65 (d,
J = 7.5 Hz, 1 H, phthalamido H-6), 8.80 (t, J = 5.8 Hz, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 19.4 (s-anti CH3), 19.9 (2 C,
s-anti CH3 and s-syn CH3), 20.5 (s-syn CH3), 42.5 (benzyl CH2),
44.5 (s-syn CH), 50.7 (s-anti CH), 125.5 (phthalamido C-3), 126.7
(p-Ar-C), 127.2 (o-Ar-C), 127.6* (phthalamido C-5), 127.7* (ph-
thalamido C-6), 128.2 (m-Ar-C), 130.2 (phthalamido C-4), 133.3
(phthalamido C-1), 138.8 (phthalamido C-2), 139.4 (ipso-Ar-C),
167.1 (benzylamido C=O), 169.3 (diisopropylamido C=O).
Chem. Soc., Perkin Trans. 1 1990, 795.
(3) McCormick, J. E.; McElhinney, R. S. J. Chem. Res., Synop.
1983, 176; J. Chem. Res., Miniprint 1983, 736.
(4) (a) Freidinger, R. M.; Hinkle, J. S.; Perlow, D. S.; Arison, B.
H. J. Org. Chem. 1983, 48, 77. (b) Sakaitani, M.; Ohfune,
Y. J. Org. Chem. 1990, 55, 870.
(5) (a) Bergeron, R. J. Acc. Chem. Res. 1986, 19, 105.
(b) Kuksa, V.; Buchan, R.; Lin, P. K. T. Synthesis 2000,
1189. (c) Theodoridis, G. Tetrahedron 2000, 56, 2339.
(6) (a) Erbeck, S.; Liang, X.; Krieger, R.; Prinzbach, H. Eur. J.
Org. Chem. 1998, 481. (b) Debenham, J.; Rodebaugh, R.;
Fraser-Reid, B. Liebigs Ann./Recl. 1997, 791. (c) Nilsson,
M.; Norberg, T. Carbohydr. Res. 2000, 327, 261.
(d) Hermann, T. Angew .Chem. Int. Ed. 2000, 39, 1890.
(7) Perron, Y. G.; Minor, W. F.; Crast, L. B.; Gourevitch, A.;
Lein, J.; Cheney, L. C. J. Med. Pharm. Chem. 1962, 5, 1016.
(8) Metha, N. B.; Brooks, R. E.; Strelitz, J. Z.; Horodniak, J. W.
J. Org. Chem. 1963, 28, 2843.
Anal. Calcd for C21H26N2O2: C, 74.51; H, 7.75; N, 8.28. Found: C,
74.71; H, 7.74; N, 8.23.
(9) Sterk, L.; Hasko, J.; Nador, K. Arzneim. Forsch. 1968, 18,
798.
(10) Astleford, B.; Weigel, L. O. Tetrahedron Lett. 1991, 32,
3301.
This compound could not be formed by reaction of N-benzylphthal-
imide with diisopropylamine.
Acknowledgment
(11) Curley, O. M. S.; McCormick, J. E.; McElhinney, R. S.;
McMurry, T. B. H. Arkivoc 2003, (vii), 180.
(12) (a) McCormick, J. E.; McElhinney, R. S. Proc. R. Ir. Acad.,
Sect. B: Biol. Geol. Chem. Sci. 1989, 89, 213.
We are grateful to Conor Noonan for help in the measurement of the
NMR spectra, to Neil Lucey for the preparation of intermediates,
and to the Irish Cancer Society and the Screening and Pharmacolo-
gy Group of the EORTC for financial support.
(b) McCormick, J. E.; McElhinney, R. S.; McMurry, T. B.
H. J. Chem. Res., Synop. 1991, 138; J. Chem. Res., Miniprint
1991, 1216.
(13) McCormick, J. E.; McElhinney, R. S. J. Chem. Res., Synop.
1981, 310; J. Chem. Res., Miniprint 1981, 3601.
References
(1) (a) McCormick, J. E.; McElhinney, R. S. J. Chem. Res.,
Synop. 1981, 12; J. Chem. Res., Miniprint 1981, 256.
(b) McElhinney, R. S.; McCormick, J. E.; Lucey, N. M.
Canc. Treat. Rev. 1988, 15, 73.
Synthesis 2006, No. 6, 983–988 © Thieme Stuttgart · New York