Novel enamine derivatives of 5,6-dihydro-2′-deoxyuridine formed in reductive amination of 5-formyl-2′-deoxyuridine

Article abstract of DOI:10.1080/15257770802271789

Reductive amination of 5-formyl-3′,5′-di-O-acetyl-2′- deoxyuridine with primary amines and sodium triacetoxyborohydride (NaBH(OAc)3) afforded novel enamine derivatives of 5,6-dihydro-2′-deoxyuridine as a result of unexpected 1,4-conjugate reduction of intermediate Schiff bases in addition to the secondary amine derivatives of 2′-deoxyuridine, typical 1,2-reduction products. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770802271789

Nucleosides, Nucleotides and Nucleic Acids, 27:1045–1060, 2008
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770802271789
NOVEL ENAMINE DERIVATIVES OF 5,6-DIHYDRO-2ꢀ-DEOXYURIDINE
FORMED IN REDUCTIVE AMINATION OF
5-FORMYL-2ꢀ-DEOXYURIDINE
Elzbieta Sochacka and Damian Smuga
Institute of Organic Chemistry, Technical University of Lodz, Lodz, Poland
Reductive amination of 5-formyl-3ꢁ,5ꢁ-di-O-acetyl-2ꢁ-deoxyuridine with primary amines and
2
sodium triacetoxyborohydride (NaBH(OAc)3) afforded novel enamine derivatives of 5,6-dihydro-
2ꢁ-deoxyuridine as a result of unexpected 1,4-conjugate reduction of intermediate Schiff bases in
addition to the secondary amine derivatives of 2ꢁ-deoxyuridine, typical 1,2-reduction products.
Keywords Modified nucleosides; 5-formyl-2ꢁ-deoxyuridine; reductive amination; nucle-
oside Schiff bases; sodium triacetoxyborohydride
INTRODUCTION
Reductive amination of aldehydes and ketones is widely used in organic
synthesis[1] and provides expedient access to structurally diverse amines.
In general, the reductive amination is a two-step transformation which
proceeds via imine intermediate, further reduced to the corresponding
amine by a variety of reducing agents, including NaBH4,[2] NaBH3CN,[3]
and NaBH(OAc)3.[4–6]
Recently, reductive amination has found wide application in the synthe-
sis of various modified nucleosides and nucleic acid conjugates.[7] In partic-
ular, reductive amination of 5-formyl-2ꢁ-deoxyuridine (f5dU) has been used
in the synthesis of 5-alkylamino derivatives of pyrimidine nucleosides.[8–11]
These types of amino-modified nucleosides are useful units for nucleic acids
labeling, stabilization of nucleic acids structures and for introduction of
additional functionality to nucleic acid fragments designed as aptamers,
Received 31 March 2008; accepted 22 May 2008.
This work was supported by the State Committee for Scientific Research (Project PBZ-MNiSW-
07/I/2007) and by European Social Fund and Polish State (“Mechanism WIDDOK” project, contract
number Z/2.10/II/2.6/04/05/ U/2/06).
Address correspondence to Elzbieta Sochacka, Institute of Organic Chemistry, Technical University
of Lodz, Zeromskiego 116, 90-924, Lodz, Poland. E-mail: ejsochac@p.lodz.pl
1045

1046
E. Sochacka and D. Smuga
biosensors or catalysts.[12,13] In all previously reported reductive aminations
of 5-formyl-2ꢁ-deoxyuridine,[8–11] NaBH4, and NaBH3CN were used as the
reducing agents.
In this article, we present the first application of a very mild and
nontoxic sodium triacetoxyborohydride for the reductive amination of
5-formyl-3ꢁ,5ꢁ-di-O-acetyl-2ꢁ-deoxyuridine. A direct reductive amination was
applied for the reactions carried out in the presence of reactive primary
alkyl amines and a stepwise protocol was used for the less nucleophilic
aromatic amines, according to recently described protocol for the formation
of Schiff bases derived from 5-formyl-2ꢁ-deoxyuridine.[14]
RESULTS AND DISCUSSION
We started experiments using 5-formyl-3ꢁ,5ꢁ-di-O-acetyl-2ꢁ-deoxyuridine
(1)[15] and n-butylamine as a model primary amine of high nucleophilicity
(pKa = 10.7). The reaction was carried out by mixing of aldehyde 1 with 1.2
equivalents of n-butylamine in anhydrous CH2Cl2 followed by addition of
NaBH(OAc)3 (1.2 equivalent) and additional portion (0.5 equivalent) after
2 hours (Scheme 1).
After 4 hours at room temperature, TLC analysis (silica gel,
CHCl3/MeOH, 9:1 v/v) showed complete disappearance of starting nucle-
oside 1, with no detectable reduction of 5-formyl group as compared with
H
O
O
R
O
N
NH
NH
RNH2, CH2Cl2, r.t.
i or ii
NaBH(OAc)3
iii or iv
N
N
O
O
O
1
O
AcO
AcO
AcO
AcO
2a - i
R
NH
O
O
O
N
R
R
NH
N
H
N
NH
NH
H
+
+
N
O
N
O
O
O
O
O
AcO
AcO
AcO
AcO
AcO
AcO
Z-4a-i
3a - i
E-4a-i
mixture of isomers
Aliphatic RNH2 : a) n-butylamine, b) methylamine, c) histamine monomethoxytritylated at imidazole ring, d) benzylamine, e) t-butylamine
Aromatic RNH2 f) aniline, g) p-toluidine, h) p-nitroaniline
:
SCHEME 1 Reductive amination of 5-formyl-5ꢁ,3ꢁ-di-O-acetyl-2ꢁ-deoxyuridine (1) with RNH2 a–h and
NaBH(OAc)3. Reagents and conditions: (i) 1.2 equivalent of RNH2 a–d or (ii) 1.5 equivalent of RNH2 e-h,
and 2 hours for imine formation; (iii) for RNH2 a–d—1.2 equivalent of NaBH(OAc)3 and additional 0.5
equivalent after 2 hours, overall reaction time 4h or (iv) for RNH2 e–h—1.2 equivalent of NaBH(OAc)3
and additional 0.5 equivalent added after 2 hours and 4 hours, overall reaction time 16 hours.

Reductive Amination of 5-Formyl-2ꢁ-deoxyuridine
1047
authentic sample of 5-hydroxymethyl-3ꢁ,5ꢁ-di-O-acetyl-2ꢁ-deoxyuridine.[15]
We observed formation of one product of low chromatographic mobility (Rf
= 0.16, strong spot, UV lamp detection at 254 nm) and two more lipophilic
compounds producing very weak TLC spots (Rf = 0.44 and Rf = 0.55).
The latter products were better visualized with a ninhydrin test. The polar
product was easily isolated by silica gel column chromatography in 44% yield
and its spectral analysis (FAB MS, 1H and 13C NMR data) fully confirmed the
structure of expected secondary amine derivative 3a.
However, several attempts at chromatographic separation of two more
lipophilic compounds were unsuccessful and they were isolated as a mix-
1
ture in 48% yield. Spectral analysis of this mixture (FAB MS, H, and
13C NMR) revealed that these compounds are Z and E isomers of the
5-butylaminomethylidene-5,6-dihydro-3ꢁ,5ꢁ-di-O-acetyl-2ꢁ-deoxyuridine Z-4a
and E-4a (Scheme 1).
In the FAB MS, the measured m/z values for [M+H]+ and [M-H]− were
consistent with the MW calculated for 4a. The UV spectrum of isomers 4a
(Figure 1) confirmed substantial changes in the structure of heterobase
FIGURE 1 UV spectra of 1 and 2a–4a in CHCl3, c = 5.0 × 10−5 mol/dm3.

1048
E. Sochacka and D. Smuga
moiety as compared to 3a. The values λmax = 308.5 nm and λmin = 257.0
nm explain poor visualization of TLC spots of 4a under UV detection at 254
nm.
In a 1H NMR spectrum recorded for the mixture of 4a in the CDCl3 solu-
tion, the shape of signals of H-1ꢁ anomeric protons revealed predominance
of one isomer. The ratio of the isomers (80:20) and their Z/E configuration
were determined by the analysis of the proton signals for characteristic
C=CH-NH fragment of the enamine 4a. A doublet of higher intensity of
a vinyl proton at 6.70 ppm compared to less intensive doublet of the more
deshielded vinyl proton at 7.49 ppm indicated the Z configuration of the
major isomer of 4a. Additionally, a high chemical shift (8.37 ppm) of NH
proton of major Z isomer may be explained in terms of intramolecular
H-bonding between NH proton and oxygen atom of C-4 carbonyl group.
Analogous NH signal of the minor E isomer was observed at 5.36 ppm. Both
isomers showed a characteristic trans-vicinal coupling 13–14 Hz between the
olefinic and the amino proton.
The formation of almost equal amounts of 3a and 4a can be explained
by nonselective reduction of conjugated double bonds of Schiff base 2a with
NaBH(OAc)3. The secondary amine derivative 3a is a 1,2-reduction product
of 2a, while isomers Z/E-4a result from unexpected 1,4-reduction of the
imine derivative. It is worth to emphasize that the 5,6-dihydrouridines 4a are
non-aromatic compounds and therefore the process of 1,4-reduction should
be rather not favorable. In particular, the 1,4-reductive amination products
are not observed for various aromatic aldehydes under similar reductive
amination conditions with NaBH(OAc)3.[4–6] In the case of 5-formyl-2ꢁ-
deoxyuridine 1, the formation of 1,4-conjugated product is probably possi-
ble due to the stabilization of dihydrouridine derivative by intramolecular
hydrogen bonding. Similar effect of the intramolecular H-bonding was
observed for many compounds with analogous enaminone functionality,
for example, in the products derived from reactions of 3-formylchromones
with amino compounds[16] and for 6-aminomethylene derivatives of 5-oxo-
2-phenyl-5,6,7,8-tetrahydroquinazoline.[17]
Although the reduction with NaBH(OAc)3 is not selective toward
conjugated double bond system of 2a, it is worth to mention that the
transformation of aldehyde 1 to amino-modified nucleosides 3 and 4 is
almost quantitative. To the best of our knowledge, the dihydrouridine
derivative of 4a structure has not been described in the literature to date.
In all the reported reactions of the reductive amination of f5dU, employ-
ing various amine components and NaBH4 or NaBH3CN, the secondary
amine derivatives of 2ꢁ-deoxyuridines were the only isolated amino-modified
products.[6–10,14]
The scope of f5dU reductive amination carried out with NaBH(OAc)3
was investigated with a series of primary amines of different nucleophilicity

Reductive Amination of 5-Formyl-2ꢁ-deoxyuridine
1049
TABLE 1 Yields of secondary amine 2ꢁ-deoxyuridine derivatives 3 and
5,6-dihydro-2ꢁ-deoxyuridine derivatives 4 (Z and E isomers) in reductive amination
of 1 with NaBH(OAc)3
Entry
Amine
% of 3
% of 4 (Z/E ratio)a
a
b
c
d
e
f
n-butylamine
methylamine
histamineb
44
39
55
58
7
63
68
71
48 (80:20)
56 (90:10)
41 (85:15)
39 (55:45)
85 (80:20)
11 (70:30)
15 (90:10)
6 (90:10)
benzylamine
t-butylamine
anilinec
g
h
p-toluidinec
p-nitroanilined
aIsomers ratio was determined from the 1H NMR spectra (CDCl3) of isolated 4.
bThe histamine derivative with MMTr on the imidazole ring was used as the amine
component.
cUnreacted aldehyde 1 was isolated in 13% and 10% from the reaction mixture
with aniline and p-toluidine, respectively.
d5-hydroxymethyl-3ꢁ,5ꢁ-di-O-acetyl-2ꢁ-deoxyuridine was isolated in 17% yield (prod-
uct of aldehyde 1 reduction).
(aliphatic and aromatic amines), steric hindrance (t-butylamine) and with
additional functionality present (histamine; Table 1).
The reactions of f5dU 1 with reactive primary amines (Table 1, entries
a through d) were performed following direct procedure with 1.2 molar
excess of amine over aldehyde 1 and 1.7 molar equivalents of NaBH(OAc)3
(1.2 equivalent of NaBH(OAc)3 added directly after substrates mixing and
additional 0.5 equivalent after 2 hours, Scheme 1). After 4 hours the
substrate 1 was fully converted to the mixture of the corresponding products
3 and 4, with no detectable aldehyde reduction. In experiments with n-
butylamine and methylamine (entries a, b) the corresponding 5,6-dihydro-
2ꢁ-deoxyuridine derivatives 4a and 4b were isolated in a slight excess over
derivatives 3a and 3b, while for histamine and benzylamine (entries c, d)
the yields of 3c and 3d were slightly higher than for 4c and 4d.
However, the predominant formation of dihydrouridine 4e for bulky
t-butylamine (entry e, 85% isolated yield of 4e compared to 7% for 3e)
suggests the influence of steric factors associated with intermediate imine
2e on the outcome of the reaction.
The reductive amination with weakly nucleophilic aromatic amines
(Table 1, entries f through h) was performed according to a two-step
preparative procedure with 1.5 molar excess of amine and 2 hours for-
mation of intermediate imine. To each of the corresponding pre-formed
Schiff bases 2f−h, the 2.2 equivalents of NaBH(OAc)3 were added in three
portions (Scheme 1) and the reactions were continued for 16 hours. In
the experiments with aniline and p-toluidine (entries f, g) the reduction

1050
E. Sochacka and D. Smuga
of intermediate imines with NaBH(OAc)3 was not completed and the
unreacted 1 was isolated in ca. 10%. No competing aldehyde reduction
was observed. In the case of the least basic p-nitroaniline the formation
of imine 2h was not quantitative and the product of aldehyde 1 reduction
(5-hydroxymethyl-2ꢁ-deoxyuridine derivative) was isolated in 17% yield. In
all experiments with aromatic amines, corresponding 5-arylaminomethyl-2ꢁ-
deoxyuridines 3f-h were isolated as the major products.
CONCLUSION
We have found that NaBH(OAc)3 is an efficient reducing agent towards
the unique conjugate bond system of intermediate Schiff bases derived
from 5-formyl-2ꢁ-deoxyuridine and various amines. In direct reductive am-
ination of f5dU with strong nucleophilic primary alkyl amines a quantita-
tive conversion to amino-modified nucleosides was observed without any
detectable amount of substrate aldehyde 1 reduction. For the non-hindered
amine components, the reductive amination of 1 afforded nearly the same
amounts of 1,2-reduction product 3 (2ꢁ-deoxyuridine derivatives) and of 1,4-
reduction (4, 5,6-dihydro-2ꢁ-deoxyuridine analogs). For bulky t-butylamine,
the predominant formation of the 5,6-dihydrouridine derivative (isolated
yield 85%) indicates the influence of steric factors on the reduction
process. In the reductive amination of aldehyde 1 with aromatic amines the
corresponding secondary amine derivatives of 2ꢁ-deoxyuridine were isolated
in good yields as the main reaction products. The new enamine analogs
4 are in fact nucleosides with vinylogous amide functionality which can
explain their relatively high stability.
Our results expand the knowledge about reductive amination of f5dU
and may be useful in designing and synthesis of novel 5-amino-modified
nucleosides for structural and biological activity studies.
EXPERIMENTAL
Representative Procedure for the Direct Reductive Amination
of 1; Reaction with n-Butylamine
5-Formyl-5ꢁ,3ꢁ-di-O-acetyl-2ꢁ-deoxyuridine (1) (340 mg, 1 mmol) was
dried by repeated co-evaporation with anhydrous CH2Cl2 (2 × 10 mL)
and finally dissolved in the same solvent (7 mL). To this stirred solution,
n−butylamine (118 µL 1.2 mmol) was added followed by immediate addi-
tion of NaBH(OAc)3 (254 mg, 1.2 mmol). After 2 hours at room temper-
ature, when TLC analysis (CHCl3/MeOH–9:1, v/v system) revealed some
remaining aldehyde 1, the second portion of NaBH(OAc)3 (106 mg, 0.5
mmol) was added. After stirring for an additional 2 hours, the reaction was
quenched with NaHCO3 (10 mL, 5% aq. solution) and then extracted with

Reductive Amination of 5-Formyl-2ꢁ-deoxyuridine
1051
CH2Cl2 (3 × 20 mL). The combined organic phases were dried (MgSO4),
filtered and concentrated in vacuo. The oily residue was chromatographed
on a silica gel column with increasing amounts (from 0 to 25%) of CH3OH
in CHCl3. The corresponding fractions (checked on TLC with ninhydrine
test) were collected and evaporated to give 5-n-butylaminomethylidene-
5,6-dihydro-5ꢁ,3ꢁ-di-O-acetyl-2ꢁ-deoxyuridine (4a) as a mixture of Z and E
isomers (190 mg, yield 48%) and 5-n-butylaminomethyl-5ꢁ,3ꢁ-di-O-acetyl-2ꢁ-
deoxyuridine (3a) (175 mg, yield 44%).
TLC (silica gel plates): 3a Rf 0.16 and 4a Rf 0.44, 0.55 (CHCl3/MeOH
90:10); 3a Rf 0.10 and 4a Rf 0.37, 0.48 (AcOEt/MeOH 95:5).
Spectral Data for 3a and 4a Z and E Isomers
3a: m/z (HRMS, FAB) 398.1919 ([M+H]+ C18H28N3O7 requires
398.1927); 1H NMR (250 MHz, CDCl3) δ 0.95 (t, 3H, J = 7.3 Hz, CH3CH2),
1.32–1.50 (m, 2H, CH3CH2CH2), 1.58–1.80 (m, 2H, CH2 CH2 CH2), 2.11
ꢁ
ꢁ
(s, 3H, CH3COO), 2.15 (s, 3H, CH3COO), 2.39 (ddd, 1H, J H2 ,H3 = 6.4 Hz,
J H2 ,H1v = 8.4 Hz, J gem = 14.6 Hz, H2ꢁ), 2.51 (ddd, 1H, J H2 ,H3 = 2.0 Hz,
ꢁ
ꢁꢁ
ꢁ
J H2 ,H1 = 5.9 Hz, J gem = 14.4 Hz, H2ꢁꢁ), 2.75–2.97 (m, 2H, CH2CH2NH),
ꢁꢁ
ꢁ
3.67 (d, 1H, J gem = 13.1 Hz, one of CH2–7), 3.74 (d, 1H, J gem = 13.1
Hz, one of CH2–7), 4.22 (m, 1H, H4ꢁ), 4.30 (dd, 1H, J H5 ,H4 = 3.7 Hz,
ꢁꢁ
ꢁ
J gem = 11.9 Hz, H5ꢁꢁ), 4.45 (dd, 1H, J H5 ,H4 = 5.4 Hz, J gem = 12.0 Hz,
ꢁ
ꢁ
H5ꢁ), 5.23 (dt, 1H, J H3 ,H2 = J H3 ,H4 = 2.1 Hz, J H3 ,H2 = 6.5 Hz, H3ꢁ),
ꢁ
ꢁꢁ
ꢁ
ꢁ
ꢁ
ꢁ
6.28 (dd, 1H, J H1 ,H2 = 5.8 Hz, J H1 ,H2 = 8.3 Hz, H1ꢁ), 7.83 (s, 1H,
H6); 13C NMR (63 MHz, CDCl3) δ 13.68 (CH3CH2), 20.03(CH3CH2CH2),
20.89 (2xCH3COO), 29.15 (CH2CH2CH2), 36.91 (C2ꢁ), 44.31 (C7), 47.79
(CH2CH2NH), 63.85 (C5ꢁ), 74.29 (C3ꢁ), 82.49 (C4ꢁ), 85.42 (C1ꢁ), 107.57
(C5), 141.26 (C6), 150.54 (C2), 164.54 (C4), 170.31 (CH3COO), 170.60
(CH3COO);); UV (CHCl3) λmax = 265.5 nm (ε = 8600).
ꢁ
ꢁꢁ
ꢁ
ꢁ
4a Z and E isomers; m/z (HRMS, FAB) 398.1938 ([M+H]+ C18H28N3O7
1
requires 398.1927); H NMR (250 MHz, CDCl3) δ 0.94 (t, J = 7.2 Hz,
6H, CH3CH2 of Z and E), 1.24–1.47 (m, 4H, CH3CH2CH2 of Z and
E), 1.47–1.63 (m, 4H, CH2 CH2 CH2 of Z and E), 1.98–2.26 (m, 16H,
2xCH3COO, H2ꢁ, H2ꢁꢁ of Z and E), 3.20 (q, J = 6.6 Hz, 2H, CH2CH2NH
4
of Z), 3.28 (m, 1H, CH2CH2NH of E), 3.53 (dd, J H6,H7 = 1.4 Hz, J gem
=
13.2 Hz, 1H, one of CH2 -6 of E), 3.75 (d, J gem = 12.6 Hz, 1H, one of CH2–6
of Z), 3.98 (d, J gem = 12.7 Hz, 1H, one of CH2–6 of Z), 4.00 (m, 1H, one
of CH2–6 of E), 4.11 (m, 1H, H4ꢁ of Z), 4.15–4.38 (m, 4H, H5ꢁ, H5ꢁꢁ of Z,
H4ꢁ, H5ꢁꢁ of E), 4.52 (dd, J H5 ,H4 = 8.8 Hz, J gem = 12.2 Hz, 1H, H5ꢁ of E),
ꢁ
ꢁ
5.02–5.18 (m, 2H, H3ꢁ of Z and E), 5.36 (m, 1H, CH2NHCH of E), 6.32 (dd,
J H1 ,H2 = 6.1 Hz, J H1 ,H2 = 8.7 Hz, 1H, H1ꢁ of Z), 6.41 (dd, J H1 ,H2 = 5.6 Hz,
ꢁ
ꢁꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
J H1 ,H2 = 8.6 Hz, 1H, H1ꢁ of E), 6.70 (d, J H7,NH = 12.9 Hz, 1H, H7 of Z), 7.10
(bs, 1H, NH-3 of Z), 7.14 (bs, 1H, NH-3 of E), 7.49 (d, J H7,NH = 13.1 Hz, 1H,
H7 of E), 8.37 (m, 1H, CH2NHCH of Z); 13C NMR (63 MHz, CDCl3) δ 13.74
ꢁ
ꢁ

1052
E. Sochacka and D. Smuga
(CH3CH2 of Z and E), 19.70 (CH3CH2CH2 of E), 19.76 (CH3CH2CH2 of
E), 20.98 (CH3COO of Z), 21.05 (CH3COO of Z and E) 21.22 (CH3COO
of E), 32.70 (C2ꢁof E), 33.27 (CH2CH2CH2 of Z and E, C2ꢁ of Z), 36.40 (C6
of E), 40.27 (C6 of Z), 48.88 (CH2CH2NH of Z), 49.04 (CH2CH2NH of E),
64.05 (C5ꢁ of E), 64.15 (C5ꢁ of Z), 74.36 (C3ꢁ of Z and E), 80.35 (C4ꢁ of Z),
81.14 (C4ꢁ of E), 84.18 (C1ꢁ of Z), 85.00 (C1ꢁ of E), 85.08 (C5 of Z), 87.34
(C5 of E), 146.70 (C7 of E), 149.95 (C7 of Z), 152.85 (C2 of E), 153.74 (C2
of Z), 165.05 (C4 of E), 166.98 (C4 of Z), 170.68 (2xCH3COO of Z), 170.77
(CH3COO- C3ꢁof E), 171.62 (CH3COO-C5ꢁof E); UV (CHCl3) λmax = 308.5
nm (ε = 16500).
Direct Reductive Amination with Methylamine Hydrochloride
The same conditions were applied as for n-butylamine besides that
methylamine hydrochloride was used and the free amine was obtained by
the addition of equimolar amount of triethylamine.
Isolated products: 3b, 138 mg, yield 39%; 4b, 199 mg, yield 56%
TLC: 3b Rf 0.06 and 4b Rf 0.42, 0.58 (CHCl3/MeOH 90:10); 3b Rf 0.02
and 4b Rf 0.29, 0.58 (AcOEt/MeOH 95:5).
Spectral Data for 3b and 4b Z and E Isomers
3b: m/z (HRMS, FAB) 356.1469 ([M+H]+ C15H22N3O7 requires
1
356.1458); H NMR (250 MHz, CDCl3) δ 2.11 (s, 3H, CH3COO), 2.15 (s,
ꢁ
ꢁ
ꢁ
ꢁ
3H, CH3COO), 2.27 (ddd, J H2 ,H3 = 6.6 Hz, J H2 ,H1 = 8.5 Hz, J gem = 14.5
Hz, 1H, H2ꢁ), 2.43 (ddd, J H2 ,H3 = 1.9 Hz, J H2 ,H1 = 5.6 Hz, J gem = 14.3
Hz, 1H, H2ꢁꢁ), 2.52 (s, 3H, CH3NH), 3.56 (d, J gem = 13.6 Hz, 1H, one of
CH2–7), 3.63 (d, J gem = 13.8 Hz, 1H, one of CH2–7), 4.23 (m, 1H, H4ꢁ),
ꢁꢁ
ꢁ
ꢁꢁ
ꢁ
4.31 (dd, J H5 ,H4 = 3.4 Hz, J gem = 12.0 Hz, 1H, H5ꢁꢁ), 4.41 (dd, J H5 ,H4
ꢁꢁ
ꢁ
ꢁ
ꢁ
= 4.8 Hz, J gem = 12.0 Hz, 1H, H5ꢁ), 5.22 (dt, J H3 ,H2 = J H3 ,H4 = 2.0 Hz,
ꢁ
ꢁꢁ
ꢁ
ꢁ
J H3 ,H2 = 6.7 Hz, 1H, H3ꢁ), 6.31 (dd, J H1 ,H2 = 5.6 Hz, J H1 ,H2 = 8.5 Hz,
1H, H1ꢁ), 7.66 (s, 1H, H6); 13C NMR (63 MHz, CDCl3) δ 20.95 (CH3COO),
21.05 (CH3COO), 34.55 (CH3NH), 37.34 (C2ꢁ), 47.13 (C7), 63.99 (C5ꢁ),
74.41(C3ꢁ), 82.49 (C4ꢁ), 85.26 (C1ꢁ), 110.40 (C5ꢁ), 138.96 (C6), 150.75 (C2),
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁ
ꢁ
164.50 (C4), 170.52 (CH3COO), 170.68 (CH3COO); UV (CHCl3) λmax
265 nm (ε = 8100).
=
4b Z and E isomers; m/z (HRMS, FAB) 356.1474 ([M+H]+ C15H22N3O7
requires 356.1458); 1H NMR (250 MHz, CDCl3) δ 2.10 (s, 3H, CH3COO of
Z), 2.11 (s, 3H, CH3COO of Z), 2.11 (s, 3H, CH3COO of E), 2.12 (s, 3H,
CH3COO of E), 2.00–2.28 (m, 4H, H2ꢁ, H2ꢁꢁ of Z and E), 3.01 (d, J = 5.0
Hz, 3H, CH3NH of Z), 3.07 (d, J = 4.7 Hz, 3H, CH3NH of E), 3.66 (dd,
4J H6,H7 = 1.5 Hz, J gem = 13.2 Hz, 1H, one of CH2 -6 of E), 3.79 (d, J gem
= 12.6 Hz, 1H, one of CH2–6 of Z), 3.94 (d, J gem = 12.5 Hz, 1H, one of
4
CH2–6 of Z), 3.98 (dd, J H6,H7 = 1.3 Hz, 1H, J gem = 13.0 Hz, one of CH2
-6 of E), 4.06–4.28 (m, 5H, H4ꢁ of Z and E, H5ꢁ, H5ꢁꢁ of Z, H5ꢁꢁ of E), 4.51

Reductive Amination of 5-Formyl-2ꢁ-deoxyuridine
1053
(dd, J H5 ,H4 = 8.8 Hz, J gem = 12.2 Hz, 1H, H5ꢁ of E), 5.05–5.14 (m, 2H, H3ꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁ
ꢁ
of Z and E), 5.25 (m, 1H, CH3NH of E), 6.32 (dd, J H1 ,H2 = 6.1 Hz, J H1 ,H2
= 8.7 Hz, 1H, H1ꢁ of Z), 6.40 (dd, J H1 ,H2 = 5.7 Hz, J H1 ,H2 = 9.1 Hz, 1H,
ꢁ
ꢁꢁ
ꢁ
ꢁ
H1ꢁ of E), 6.68 (d, J H7,NH = 13.1 Hz, 1H, H7 of Z), 7.31 (s, 1H, NH-3 of Z),
4
7.34 (s, 1H, NH-3 of E), 7.45 (dt, J H7,H6 = 1.3 Hz, 1H, J H7,NH = 14.4 Hz,
H7 of E), 8.22 (m, 1H, CH3NH of Z); 13C NMR (63 MHz, CDCl3) δ 21.04
(CH3COO of Z and E), 21.10 (CH3COO of Z and E), 33.40 (CH3NH of
Z and E), 35.37 (C2ꢁ of Z and E), 36.25 (C6 of E), 40.30 (C6 of Z), 64.10
(C5ꢁ of E), 64.21 (C5ꢁ of Z), 74.40 (C3ꢁ of Z and E), 80.43 (C4ꢁ of Z), 81.19
(C4ꢁ of E), 84.23 (C1ꢁ of Z), 85.05 (C1ꢁ of E), 85.59 (C5 of Z), 87.94 (C5 of
E), 147.62 (C7 of E), 151.07 (C7 of Z), 152.80 (C2 of E), 153.64 (C2 of Z),
164.99 (C4 of E), 167.03 (C4 of Z), 170.71 (CH3COO of Z and E), 170.79
(CH3COO of Z and E); UV (CHCl3) λmax = 305 nm (ε = 13000).
Direct Reductive Amination with Histamine Derivative
The histamine derivative with MMTr on the imidazole ring was prepared
according to the procedure described by Verbeure, B., at al.[18]
Isolated products: 3c, 390 mg, yield 55%; 4c, 290 mg, yield 41%.
TLC: 3c Rf 0.32 and 4c Rf 0.48, 0.63 (CHCl3/MeOH 90:10); 3c Rf 0.11
and 4c Rf 0.23, 0.41 (AcOEt/MeOH 90:10).
Spectral Data for 3c and 4c Z and E Isomers
3c: m/z (HRMS, FAB) 708.3052 ([M+H]+ C39H42N5O8 requires
1
708.3033); H NMR (250 MHz, CDCl3) δ 2.10 (s, 3H, CH3COO), 2.11
ꢁ
ꢁ
ꢁ
ꢁ
(s, 3H, CH3COO), 2.30 (ddd, J H2 ,H3 = 6.4 Hz, J H2 ,H1 = 8.4 Hz, J gem
=
14.5 Hz, 1H, H2ꢁ), 2.43 (ddd, J H2 ,H3 = 1.8 Hz, J H2 ,H1 = 5.7 Hz, J gem
= 14.3 Hz, 1H, H2ꢁꢁ), 2.80 (t, J =ꢁꢁ7.0 Hz, 2H, ImCH2), 2.99 (t, J = 7.0
Hz, 2H, CH2NH), 3.57 (d, J gem = 13.7 Hz, 1H, one of CH2–7), 3.66 (d,
J gem = 13.8 Hz, 1H, one of CH2–7), 3.81 (s, 3H, OCH3), 4.21 (m, 1H,
ꢁ
ꢁꢁ
ꢁ
H4ꢁ), 4.28 (dd, J H5 ,H4 = 3.5 Hz, J gem = 12.0 Hz, 1H, H5ꢁꢁ), 4.39 (dd,
ꢁꢁ
ꢁ
J H5 ,H4 = 4.7 Hz, J gem = 12.0 Hz, 1H, H5ꢁ), 5.22 (dt, J H3 ,H2 = J H3 ,H4
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁ
ꢁ
= 2.0 Hz, J H3 ,H2 = 6.3 Hz, 1H, H3ꢁ), 6.30 (dd, J H1 ,H2 = 5.7 Hz, J H1 ,H2
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁ
ꢁ
= 8.6 Hz, 1H, H1ꢁ), 6.59 (d, J H5,H2 = 1.2 Hz, 1H, Im-CH-5), 6.77–7.37
4
4
(m, 14H, MMTr), 7.38 (d, J H2,H5 = 1.4 Hz, 1H, Im-CH-2), 7.66 (s, 1H,
H6); 13C NMR (63 MHz, CDCl3) δ 21.08 (2xCH3COO), 27.56 (ImCH2),
37.34 (C2ꢁ), 45.52 (C7), 48.85 (CH2NH), 55.47 (OCH3), 64.03 (C5ꢁ),
74.58 (MMTr-CPh3), 75.05 (C3ꢁ), 82.52 (C4ꢁ), 85.30 (C1ꢁ), 111.73 (C5),
113.45(MMTr-oꢁ), 118.74(Im-CH-5), 128.19 (MMTr-o,p), 129.82 (MMTr-m),
131.30 (MMTr-mꢁ), 134.64 (Im-CH-4), 138.13 (MMTr-iꢁ), 138.64 (C6),138.71
(Im-CH-2), 142.88 (MMTr-i), 150.43 (C2), 159.25 (MMTr-pꢁ), 163.47 (C4),
170.51 (CH3COO), 170.65 (CH3COO); UV (CHCl3) λmax = 266 nm (ε =
7700).

1054
E. Sochacka and D. Smuga
4c Z and E isomers; m/z (HRMS, FAB) 708.3048 ([M+H]+ C39H42N5O8
1
requires 708.3033 H NMR (250 MHz, CDCl3) δ 2.08 (s, 3H, CH3COO of
Z), 2.09 (s, 3H, CH3COO of Z), 2.03–2.19 (m, 10H, 2xCH3COO of E, H2ꢁ,
H2ꢁꢁ of Z and E), 2.77 (t, J = 6.7 Hz, 2H, ImCH2 of Z), 2.79–2.88 (m, 2H,
ImCH2 of E), 3.48–3.60 (m, 4H, CH2NH of Z and E), 3.81 (s, 3H, OCH3
of Z), 3.82 (s, 3H, OCH3 of E), 3.68–3.98 (m, 4H, CH2–6 of Z and E),
3.99–4.39 (m, 6H, H4ꢁ, H5ꢁ, H5ꢁꢁ of Z and E), 5.06–5.19 (m, 3H, H3ꢁ of Z
ꢁ
ꢁꢁ
ꢁ
ꢁ
and E, CH2NHCH of E), 6.30 (dd, J H1 ,H2 = 5.9 Hz, J H1 ,H2 = 8.9 Hz, 1H,
H1ꢁ of Z), 6.41 (dd, J H1 ,H2 = 5.9 Hz, J H1 ,H2 = 8.8 Hz, 1H, H1ꢁ of E), 6.60
ꢁ
ꢁꢁ
ꢁ
ꢁ
4
4
(d, J H5,H2 = 1.0 Hz, 1H, Im-CH-5 of Z), 6.61 (d, J H5,H2 = 1.0 Hz, 1H,
Im-CH-5 of E), 6.70 (d, J H7,NH = 13.1 Hz, 1H, H7 of Z), 6.79–7.41 (m, 31H,
4
MMTr, NH-3 of Z and E, Im-CH-2 of E), 7.43 (d, J H2,H5 = 1.3 Hz, 1H,
Im-CH-2 of Z), 7.46 (m, 1H, H7 of E), 8.43 (m, 1H, CH2NHCH of Z); 13
C
NMR (63 MHz, CDCl3) δ 21.00 (CH3COO of E and Z), 21.06 (CH3COO
of E and Z), 28.90 (ImCH2 of E), 30.09 (ImCH2 of Z), 32.69 (C2ꢁof E),
33.30 (C2ꢁ of Z), 36.84 (C6 of E), 40.32 (C6 of Z), 48.75 (CH2NH of Z),
49.34 (CH2NH of E), 55.42 (OCH3 of Z and E), 63.94 (C5ꢁ of E), 64.16 (C5ꢁ
of Z), 74.34 (C3ꢁ of E), 74.46 (C3ꢁ of Z), 75.10 (MMTr-CPh3 of Z), 75.22
(MMTr-CPh3 of E), 80.44 (C4ꢁof Z), 80.66 (C4ꢁ of E), 84.20 (C1ꢁ of Z), 84.59
(C1ꢁ of E), 85.00 (C5 of Z), 87.43 (C5 of Z), 113.44 (MMtr-oꢁ of Z and E),
118.91 (Im-CH-5 of E), 119.60 (Im-CH-5 of Z), 128.17 (MMTr-o of Z and E,
MMTr-p of Z), 128.44 (MMTr-p of E), 129.74 (MMTr-m of Z and E), 131.23
131.30 (MMTr-mꢁof Z and E), 134.31 (Im-CH-4 of E), 134.43 (Im-CH-4 of
Z), 137.18 (MMTr-iꢁ of Z), 137.75 (MMTr-iꢁ of E), 138.57 (Im-CH-2 of E),
138.83 (Im-CH-2 of Z), 142.61 (MMTr-i of E), 142.70 (MMTr-i of Z), 146.72
(C7 of E), 150.15 (C7 of Z), 153.09 (C2 of E), 153.81 (C2 of Z), 159.25
(MMTr-pꢁ of Z and E), 164.91 (C4 of E), 166.71 (C4 of Z), 170.63 (CH3COO
of Z and E), 171.09 (CH3COO of Z and E); UV (CHCl3) λmax = 305 nm (ε
= 12600).
Direct Reductive Amination with Benzylamine
Isolated products: 3d, 250 mg, yield 58%; 4d, 168 mg, yield 39%.
TLC: 3d Rf 0.23 and 4d Rf 0.30, 0.49 (CHCl3/MeOH 95:5); 3d Rf 0.25
and 4d Rf 0.30, 0.56 (AcOEt/MeOH 95:5).
Spectral Data for 3d and 4d Z and E Isomers
3d: m/z (HRMS, FAB) 432.1764 ([M+H]+ C21H26N3O7 requires
1
432.1771); H NMR (250 MHz, CDCl3) δ 1.98 (s, 3H, CH3COO), 2.11 (s,
3H, CH3COO), 2.17 (m, 1H, H2ꢁ), 2.45 (ddd, J H2 ,H3 = 1.8 Hz, J H2 ,H1
=
ꢁꢁ
ꢁ
ꢁꢁ
ꢁ
5.6 Hz, J gem = 14.1 Hz, 1H, H2ꢁꢁ), 3.52 (s, 2H, CH2–7), 3.80 (s, 2H, PhCH2),
4.20–4.32 (m, 2H, H4ꢁ, H5ꢁꢁ), 4.38 (dd, J H5 ,H4 = 4.0 Hz, J gem = 11.8 Hz,
ꢁ
ꢁ
1H, H5ꢁ), 5.20 (dt, J H3 ,H2 = J H3 ,H4 = 1.8 Hz, J H3 ,H2 = 6.5 Hz, 1H, H3ꢁ),
ꢁ
ꢁꢁ
ꢁ
ꢁ
ꢁ
ꢁ
6.33 (dd, J H1 ,H2 = 5.5 Hz, J H1 ,H2 = 8.6 Hz, 1H, H1ꢁ), 7.18–7.38 (m, 6H,
ꢁ
ꢁꢁ
ꢁ
ꢁ

Reductive Amination of 5-Formyl-2ꢁ-deoxyuridine
1055
Ph), 7.46 (s, 1H, H6); 13C NMR (63 MHz, CDCl3) δ 20.82 (CH3COO),
21.05 (CH3COO), 37.62 (C2ꢁ), 45.62 (C7), 53.21 (PhCH2), 64.01 (C5ꢁ),
74.37 (C3ꢁ), 82.36 (C4ꢁ), 85.04 (C1ꢁ), 113.61 (C5), 127.33 (Ph-p), 128.35
(Ph-m), 128.65 (Ph-o), 136.42 (C6), 139.61 (Ph-i), 150.51 (C2), 163.52
(C4), 170.46 (CH3COO), 170.54 (CH3COO); UV (CHCl3) λmax = 264 nm
(ε = 8200).
4d Z and E isomers; m/z (HRMS, FAB) 432.1755 ([M+H]+ C21H26N3O7
requires 432.1771); 1H NMR (250 MHz, CDCl3) δ 2.05 (s, 3H, CH3COO of
Z), 2.09 (s, 3H, CH3COO of Z), 1.94–2.39 (m, 10H, 2xCH3COO of E, H2ꢁ,
H2ꢁꢁ of Z and E), 3.67 (dd, 4J H6,H7 = 1.8 Hz, J gem = 13.2 Hz, 1H, one of CH2
-6 of E), 3.79 (d, J gem = 12.8 Hz, 1H, one of CH2–6 of Z), 3.95 (d, J gem
=
12.8 Hz, 1H, one of CH2–6 of Z), 4.01 (m, 1H, one of CH2 -6 of E), 4.10
(m, 1H, H4ꢁ of Z), 4.21–4.56 (m, 5H, H5ꢁ, H5ꢁꢁ of Z and E, H4ꢁ of E), 4.39
(d, J = 5.9 Hz, 2H, PhCH2NH of Z), 4.44 (d, J = 5.8 Hz, 1H, PhCH2NH
of E), 5.03–5.14 (m, 2H, H3ꢁ of Z and E), 5.75 (m, 1H, CH2NHCH of E),
6.32 (dd, J H1 ,H2 = 6.1 Hz, J H1 ,H2 = 8.7 Hz, 1H, H1ꢁ of Z), 6.40 (dd, J H1 ,H2
ꢁ
ꢁꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
= 5.6 Hz, J H1 ,H2 = 9.5 Hz, 1H, H1ꢁ of E), 6.76 (d, J H7,NH = 12.9 Hz, 1H,
H7 of Z), 7.11–7.46 (m, 12H, Ph, NH-3 of Z and E), 7.60 (dt, 4J H7,H6 = 1.4
Hz, J H7,NH = 14.3 Hz, 1H, H7 of E), 8.68 (m, 1H, CH2NHCH of Z); 13C
NMR (63 MHz, CDCl3) δ 20.99 (2xCH3COO of E), 21.10 (2xCH3COO of
Z), 32.71(C2ꢁof E), 33.37 (C2ꢁ of Z), 36.42 (C6 of E), 40.32 (C6 of Z), 52.48
(PhCH2 of Z), 53.19 (PhCH2 of E), 64.05 (C5ꢁ of E), 64.16 (C5ꢁ of Z), 74.37
(C3ꢁ of Z and E), 80.45 (C4ꢁof Z), 81.32 (C4ꢁ of E), 84.24 (C1ꢁ of Z), 85.13
(C1ꢁ of E), 86.54 (C5 of Z), 88.48 (C5 of E), 127.41 (Ph-o of Z), 127.73
(Ph-o of E), 128.02 (Ph-p of E), 128.12 (Ph-p of E), 129.03 (Ph-m of Z and
E), 137.87 (Ph-i of E), 138.07 (Ph-i of Z), 146.35 (C7 of E), 149.54 (C7 of
Z), 152.67 (C2 of E), 153.55 (C2 of Z), 165.00 (C4 of E), 166.96 (C4 of Z),
170.69 (CH3COO of Z and E), 170.77 (CH3COO of Z and E); UV (CHCl3)
λmax = 304.5 nm (ε = 14600).
ꢁ
ꢁ
Representative Procedure for the Undirect Reductive Amination
of 1; Reaction with t-Butylamine
5-Formyl-5ꢁ,3ꢁ-di-O-acetyl-2ꢁ-deoxyuridine (1) (340 mg, 1 mmol),
predried by repeated evaporation with anhydrous CH2Cl2 (2 × 10 mL), was
dissolved in the same solvent (7 mL) and t-butylamine (158 µL 1.5 mmol)
was added. The reaction mixture was stirred for 2 hours at room tempera-
ture and then treated with NaBH(OAc)3 (254 mg, 1.2 mmol). After 2 and 4
hours, when TLC analysis (CHCl3/MeOH–95:5, v/v system) revealed some
remaining aldehyde 1, two additional portions of NaBH(OAc)3 (each 106
mg, 0.5 mmol) were added. After stirring for the next 12 hours, the reaction
was quenched with NaHCO3 (10 mL, 5% aq. solution) and then extracted
with CH2Cl2 (3 × 20 mL). The combined organic phases were dried over
MgSO4, filtered and concentrated in vacuo. The oily residue was purified on

1056
E. Sochacka and D. Smuga
a silica gel column using increasing amounts of CH3OH in CHCl3 (from 0
to 25%). The corresponding fractions (checked on TLC with ninhydrine
test) were collected and evaporated to give 5-t-butylaminomethylidene-5,
6-dihydro-5ꢁ,3ꢁ-di-O-acetyl-2ꢁ-deoxyuridine (4e) as a mixture of Z and E
isomers (337 mg, yield 85%) and 5-t-butylaminomethyl-5ꢁ,3ꢁ-di-O-acetyl-2ꢁ-
deoxyuridine (3e) (28 mg, yield 7%).
TLC: 3e Rf 0.09 and 4e Rf 0.20, 0.28 in (CHCl3/MeOH 95:5); 3e Rf 0.03
and 4e Rf 0.28, 0.58 (AcOEt/MeOH 95:5).
Spectral Data for 3e and 4e Z and E Isomers
3e: m/z (HRMS, FAB) 398.1909 ([M+H]+ C18H28N3O7 requires
1
398.1927); H NMR (250 MHz, CDCl3) δ 1.43 (s, 9H, (CH3)3C), 2.11 (s,
3H, CH3COO), 2.20 (s, 3H, CH3COO), 2.50–2.73 (m, 2H, H2ꢁ, H2ꢁꢁ), 3.63
(d, J gem = 12.5 Hz, 1H, one of CH2–7), 3.82 (d, J gem = 12.3 Hz, 1H, one of
ꢁ
ꢁ
ꢁ
ꢁꢁ
ꢁ
ꢁ
CH2–7), 4.20 (ddd, J H4 ,H3 = 2.0 Hz, J H4 ,H5 = 3.3 Hz, J H4 ,H5 = 5.5 Hz, 1H,
H4ꢁ), 4.29 (dd, J H5 ,H4 = 3.4 Hz, J gem = 12.0 Hz, 1H, H5ꢁꢁ), 4.55 (dd, J H5 ,H4
ꢁꢁ
ꢁ
ꢁ
ꢁ
= 5.5 Hz, J gem = 11.9 Hz, 1H, H5ꢁ), 5.26 (m, 1H, H3ꢁ), 6.31 (m, 1H, H1ꢁ),
7.98 (s, 1H, H6);
13C NMR (63 MHz, CDCl3) δ 21.12 (CH3COO), 21.30 (CH3COO),
26.76 ((CH3)3C), 37.04 (C2ꢁ), 38.57 (C7), 55.87 ((CH3)3C), 64.19 (C5ꢁ),
74.85 (C3ꢁ), 83.36 (C4ꢁ), 85.88 (C1ꢁ), 105.11 (C5), 144.06 (C6), 149.70 (C2),
164.82 (C4), 170.57(CH3COO), 170.98 (CH3COO); UV (CHCl3) λmax
266 nm (ε = 7900).
=
4e Z and E isomers; m/z (HRMS, FAB) 398.1919 ([M+H]+ C18H28N3O7
requires 398.1927); 1H NMR (250 MHz, CDCl3) δ 1.31 (s, 18H, (CH3)3C of
Z), 1.34 (s, 3H, (CH3)3C of E), 2.10 (s, 3H, CH3COO of Z), 2.11 (m, 3H,
CH3COO of Z), 2.12 (m, 3H, CH3COO of E), 2.13 (s, 3H, CH3COO of E),
2.01–2.31 (m, 4H, H2ꢁ, H2ꢁꢁ of Z and E), 3.64 (dd, 4J H6,H7 = 1.6 Hz, J gem
=
4
13.2 Hz, 1H, one of CH2 -6 of E), 3.80 (dd, J H6,H7 = 0.8 Hz, J gem = 12.6
4
Hz, 1H, one of CH2–6 of Z), 3.96 (dd, J H6,H7 = 0.8 Hz, J gem = 12.6 Hz,
1H, one of CH2–6 of Z), 4.00 (dd, 4J H6 H7
.
= 1.4 Hz, Jgem = 13.3 Hz, 1H, one
of CH2 -6 of E), 4.11 (m, 1H, H4ꢁ of Z), 4.16–4.44 (m, 4H, H5ꢁ, H5ꢁꢁ of Z,
H4ꢁ, H5ꢁꢁ of E), 4.53 (dd, J H5 ,H4 = 1.8 Hz, J gem = 9.1 Hz, 1H, H5ꢁ of E),
5.02–5.18 (m, 2H, H3ꢁ of Z and E), 5.45 (d, J NH,H7 = 15.0 Hz, 1H, CNHCH
ꢁ
ꢁ
of E), 6.34 (dd, J H1 ,H2 = 6.0 Hz, J H1 ,H2 = 8.8 Hz, 1H, H1ꢁ of Z), 6.41 (dd,
ꢁ
ꢁꢁ
ꢁ
ꢁ
J H1 ,H2 = 5.6 Hz, J H1 ,H2 = 9.2 Hz, 1H, H1ꢁ of E), 6.88 (d, J H7,NH = 13.6
Hz, 1H, H7 of Z), 7.16 (bs, 1H, NH-3 of Z), 7.20 (s, 1H, NH-3 of E), 7.68
(dt, J H7,H6 = 1.5 Hz, J H7,NH = 15.0 Hz, 1H, H7 of E), 8.65 (d, J NH,H7 = 13.6
Hz, 1H, CNHCH of Z); 13C NMR (63 MHz, CDCl3) δ 21.02 (2xCH3COO of
Z), 21.10 (2xCH3COO of E), 30.27 ((CH3)3C of Z and E), 32.72 (C2ꢁof E),
33.28 (C2ꢁ of Z), 36.44 (C6 of E), 40.58 (C6 of Z), 52.32 ((CH3)3C of Z),
53.22((CH3)3C of E), 64.00 (C5ꢁ of E), 64.14 (C5ꢁ of Z), 74.36 (C3ꢁ of Z),
74.47 (C3ꢁ of E), 80.40 (C4ꢁ of Z), 81.44 (C4ꢁ of E), 84.25 (C1ꢁ of Z), 84.98
ꢁ
ꢁꢁ
ꢁ
ꢁ

Reductive Amination of 5-Formyl-2ꢁ-deoxyuridine
1057
(C5 of Z), 85.19 (C1ꢁ of E), 87.55 (C5 of E), 142.31 (C7 of E), 145.65 (C7 of
Z), 152.69 (C2 of E), 153.73 (C2 of Z), 164.80 (C4 of E), 166.72 (C4 of Z),
170.71, 170.80, 171.45 (2xCH3COO of Z and E); UV (CHCl3) λmax = 305
nm (ε = 16200).
Undirect Reductive Amination with Aniline
Isolated products: 3f, 263 mg, yield 63%; 4f, 46 mg, yield 11%.
TLC: 3f Rf 0.20 and 4f Rf 0.41, 0.49 (CHCl3/MeOH 95:5); 3f Rf 0.60
and 4f Rf 0.55, 0.72 (AcOEt/MeOH 95:5).
Spectral Data for 3f and 4f Z and E Isomers
3f: m/z (HRMS, FAB) 418.1624 ([M+H]+ C20H24N3O7 requires
1
418.1614) H NMR (250 MHz, CDCl3) δ 2.02 (m, 1H, H2ꢁ), 2.05 (s, 3H,
ꢁꢁ
ꢁ
ꢁꢁ
ꢁ
CH3COO), 2.10 (s, 3H, CH3COO), 2.43 (ddd, J H2 ,H3 = 1.8 Hz, J H2 ,H1
=
5.6 Hz, J gem = 14.3 Hz, 1H, H2ꢁꢁ), 4.04–4.16 (m, 3H, CH2–7, H5ꢁꢁ), 4.19 (m,
1H, H4ꢁ), 4.27 (dd, J H5 ,H4 = 4.9 Hz, J gem = 11.2 Hz, 1H, H5ꢁ), 5.11 (dt,
ꢁ
ꢁ
J H3 ,H2 = J H3 ,H4 = 1.9 Hz, J H3 ,H2 = 6.4 Hz, 1H, H3ꢁ), 6.28 (dd, J H1 ,H2
=
ꢁ
ꢁꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁꢁ
5.5 Hz, J H1 ,H2 = 8.6 Hz, 1H, H1ꢁ), 6.58–6.65 (m, 2H, Ph-o), 6.73 (m, 1H,
Ph-p), 7.12–7.22 (m, 2H, Ph-m), 7.44 (t, 4J H6,H7 = 1.2 Hz, 1H, H6);
13C NMR (63 MHz, CDCl3) δ 20.83 (CH3COO), 20.97 (CH3COO),
37.48 (C2ꢁ), 41.03 (C7), 63.80 (C5ꢁ), 74.25 (C3ꢁ), 82.40 (C4ꢁ), 85.31
(C1ꢁ), 112.51 (C5), 113.52 (Ph-o), 118.36 (Ph-p), 129.42 (Ph-m), 136.19
(C6), 147.39 (Ph-i), 150.44 (C2), 163.50 (C4), 170.48 (CH3COO), 170.67
(CH3COO); UV(MeOH) λmax = 248 nm (ε = 11000).
ꢁ
ꢁ
4f Z and E isomers; m/z (HRMS, FAB) 418.1629 ([M+H]+ C20H24N3O7
1
requires 418.1614) H NMR (250 MHz, CDCl3) δ 2.10 (s, 3H, CH3COO of
Z), 2.12 (s, 3H, CH3COO of Z), 2.03–2.31 (m, 10H, 2xCH3COO of E, H2ꢁ,
H2ꢁꢁ of Z and E), 3.81 (dd, J H6,H7 = 1.9 Hz, J gem = 13.9 Hz, 1H, one of
4
CH2 -6 of E), 3.92 (dd, 4J H6,H7 = 0.7 Hz, J gem = 13.1 Hz, 1H, one of CH2–6
of Z), 4.04–4.40 (m, 7H, one of CH2–6, H4ꢁ of Z and E, H5ꢁ, H5ꢁꢁ of Z, H5ꢁꢁ
of E), 4.69 (dd, J H5 ,H4 = 9.5 Hz, J gem = 12.1 Hz, 1H, H5ꢁ of E), 5.08–5.18
(m, 2H, H3ꢁ of Z and E), 5.21 (m, 1H, PhNHCH of E), 6.34 (dd, J = 6.1
ꢁ
ꢁ
Hz, J = 8.6 Hz, 1H, H1ꢁ of Z), 6.42 (dd, J H1 ,H2 = 5.2 Hz, J H1 ,H2 = 9.6 Hz,
1H, H1ꢁ of E), 6.54–7.48 (m, 13H, Ph, NH-3 of Z and E, H7 of Z), 8.06 (dt,
4J H7,H6 = 1.7 Hz, J H7,NH = 13.8 Hz, 1H, H7 of E), 10.29 (d, J NH,H7 = 12.6
Hz, 1H, PhNHCH of Z); 13C NMR (63 MHz, CDCl3) δ, 20.93 (CH3COO of
E and Z), 21.09 (CH3COO of E and Z), 32.90 (C2ꢁof E), 33.45 (C2ꢁ of Z),
36.38 (C6 of E), 40.35 (C6 of Z), 64.10 (C5ꢁ of Z and E), 74.38 (C3ꢁ of Z
and E), 80.70 (C4ꢁof Z), 81.73 (C4ꢁ of E), 84.42 (C1ꢁ of Z), 85.38 (C1ꢁ of
E), 89.92 (C5 of Z), 92.50 (C5 of E), 115.85 (Ph-o of E), 115.98 (Ph-o of Z),
130.27 (Ph-m of E), 130.35 (Ph-m of Z), 131.68 (Ph-p of E), 132.01 (Ph-p of
Z), 137.65 (C7 of E), 138.53 (Ph-i of Z), 139.41 (Ph-i of E), 141.02 (C7 of
Z), 152.44 (C2 of E), 153.25 (C2 of Z), 165.03 (C4 of E), 166.99 (C4 of Z),
ꢁ
ꢁꢁ
ꢁ
ꢁ

1058
E. Sochacka and D. Smuga
170.66 (CH3COO of Z and E), 170.74, (CH3COO of Z and E); UV(MeOH)
λmax = 340.5 nm (ε = 20600).
Undirect Reductive Amination with p-Toluidine
Isolated products: 3g, 293 mg, yield 68%; 4g, 65 mg, yield 15%.
TLC: 3g Rf 0.24 and 4g Rf 0.28, 0.47 in (CHCl3/MeOH 95:5); 3g Rf 0.15
and 4g Rf 0.23, 0.46 (AcOEt/MeOH 98:2).
Spectral Data for 3g and 4g Z and E Isomers
3g: m/z (HRMS, FAB) 432.1784 ([M+H]+ C21H26N3O7 requires
1
432.1771); H NMR (250 MHz, CDCl3) δ 2.03 (m, 1H, H2ꢁ), 2.05 (s, 3H,
ꢁꢁ
ꢁ
CH3COO), 2.10 (s, 3H, CH3COO), 2.22 (s, 3H, CH3Ph), 2.43 (ddd, J H2 ,H3
= 1.8 Hz, J H2 ,H1 = 5.6 Hz, J gem = 14.2 Hz, 1H, H2ꢁꢁ), 4.00–4.17 (m, 3H,
ꢁꢁ
ꢁ
CH2–7, H5ꢁꢁ), 4.19 (m, 1H, H4ꢁ), 4.27 (dd, J H5 ,H4 = 4.6 Hz, J gem = 11.2
ꢁ
ꢁ
Hz, 1H, H5ꢁ), 5.11 (dt, J H3 ,H2 = J H3 ,H4 = 1.6 Hz, J H3 ,H2 = 6.3 Hz, 1H,
ꢁ
ꢁꢁ
ꢁ
ꢁ
ꢁ
ꢁ
H3ꢁ), 6.27 (dd, J H1 ,H2 = 5.6 Hz, J H1 ,H2 = 8.6 Hz, 1H, H1ꢁ), 6.44–6.64 (m,
ꢁ
ꢁꢁ
ꢁ
ꢁ
4
2H, Ph-o), 6.83–7.07 (m, 2H, Ph-m), 7.43 (t, J H6,H7 = 1.1 Hz, 1H, H6);
13C NMR (63 MHz, CDCl3) δ 20.43 (CH3COO), 20.79 (CH3COO), 20.94
(CH3Ph), 37.45 (C2ꢁ), 41.46 (C7), 63.79 (C5ꢁ), 74.26 (C3ꢁ), 82.35 (C4ꢁ),
85.26 (C1ꢁ), 112.64 (C5), 113.80 (Ph-o), 127.65 (Ph-p), 129.88 (Ph-m),
136.18 (C6), 145.00 (Ph-i), 150.45 (C2), 163.48 (C4), 170.46 (CH3COO),
170.48 (CH3COO); UV(MeOH) λmax = 247 nm (ε = 12300).
4g Z and E isomers; m/z (HRMS, FAB) 432.1765 ([M+H]+ C21H26N3O7
requires 432.1771); 1H NMR (250 MHz, CDCl3) δ 2.11 (s, 3H, CH3COO of
Z), 2.12 (s, 3H, CH3COO of Z), 2.06–2.41 (m, 13H, 2xCH3COO, CH3Ph
4
of E, H2ꢁ, H2” of Z and E), 2.31 (s, 3H, CH3Ph of Z), 3.81 (dd, J H6,H7
=
1.8 Hz, J gem = 13.9 Hz, 1H, one of CH2 -6 of E), 3.92 (d, J gem = 13.6 Hz,
1H, one of CH2–6 of Z), 4.04–4.18 (m, 3H, one of CH2–6 of Z and E, H4ꢁ
of Z), 4.19–4.41 (m, 4H, H5ꢁ, H5ꢁꢁ of Z, H4ꢁ, H5ꢁꢁ of E), 4.70 (dd, J H5 ,H4
=
ꢁ
ꢁ
9.4 Hz, J gem = 12.1 Hz, 1H, H5ꢁ of E), 5.09–5.17 (m, 2H, H3ꢁ of Z and E),
ꢁ
ꢁꢁ
ꢁ
ꢁ
5.21 (m, 1H, PhNHCH of E), 6.34 (dd, J H1 ,H2 = 6.1 Hz, J H1 ,H2 = 8.7 Hz,
1H, H1ꢁ of Z), 6.41 (dd, J H1 ,H2 = 5.0 Hz, J H1 ,H2 = 9.3 Hz, 1H, H1ꢁ of E),
6.86–7.47 (m, 10H, Ph, NH-3 of Z and E), 7.31 (d, J H7,NH = 12.7 Hz, 1H,
H7 of Z), 8.03 (m, 1H, H7 of E), 10.24 (d, J NH,H7 = 12.6 Hz, 1H, PhNHCH
of Z); 13C NMR (63 MHz, CDCl3) δ, 20.81 (CH3Ph), 21.07 (2xCH3COO of
E and Z), 32.85 (C2ꢁof E), 33.43 (C2ꢁ of Z), 36.44 (C6 of E), 40.40 (C6 of
Z), 64.11(C5ꢁ of Z and E), 74.34 (C3ꢁ of Z), 74.45(C3ꢁ of E), 80.62 (C4ꢁof
Z), 81.60 (C4ꢁ of E), 84.33 (C1ꢁ of Z), 85.35 (C1ꢁ of E), 89.86 (C5 of Z),
92.47 (C5 of E), 115.89 (Ph-o of E), 116.05 (Ph-o of Z), 130.31 (Ph-m of E),
130.39 (Ph-m of Z), 132.89 (Ph-p of E), 133.22 (Ph-p of Z), 137.81 (C7 of
E), 137.96 (Ph-i of Z), 138.52 (Ph-i of E), 141.22 (C7 of Z), 152.47 (C2 of
E), 153.27 (C2 of Z), 164.99 (C4 of E), 166.96 (C4 of Z), 170.68 (CH3COO
ꢁ
ꢁꢁ
ꢁ
ꢁ

Reductive Amination of 5-Formyl-2ꢁ-deoxyuridine
1059
of Z and E), 170.76, (CH3COO of Z and E); UV(MeOH) λmax = 340 nm (ε
= 21000).
Undirect Reductive Amination with p-Nitroaniline
Isolated products: 3h, 254 mg, yield 55%; 4h, 28 mg, yield 6%
TLC : 3h Rf 0.23 and 4h Rf 0.43, 0.53 in (CHCl3/MeOH 95:5); 3h Rf 0.10
and 4h Rf 0.23, 0.44 (AcOEt/MeOH 98:2).
Spectral Data for 3h and 4h Z and E Isomers
3h: m/z (HRMS, FAB) 463.1452 ([M+H]+ C20H23N4O9 requires
1
463.1465 H NMR (250 MHz, CDCl3) δ 2.04 (m, 1H, H2ꢁ), 2.10 (s, 3H,
ꢁꢁ
ꢁ
ꢁꢁ
ꢁ
CH3COO), 2.12 (s, 3H, CH3COO), 2.53 (ddd, J H2 ,H3 = 1.8 Hz, J H2 ,H1
= 5.5 Hz, J gem = 14.3 Hz, 1H, H2ꢁꢁ), 4.16–4.52 (m, 5H, CH2–7, H4ꢁ, H5ꢁ,
H5ꢁꢁ), 5.13 (dt, J H3 ,H2 = J H3 ,H4 = 2.0 Hz, J H3 ,H2 = 6.6 Hz, 1H, H3ꢁ), 6.24
ꢁ
ꢁꢁ
ꢁ
ꢁ
ꢁ
ꢁ
(dd, J H1 ,H2 = 5.4 Hz, J H1 ,H2 = 8.4 Hz, 1H, H1ꢁ), 6.60–6.74 (m, 2H, Ph-o),
7.59 (s, 1H, H6), 8.03–8.14 (m, 2H, Ph-m); 13C NMR (63 MHz, CDCl3) δ
20.97 (2xCH3COO), 37.69 (C2ꢁ), 40.16 (C7), 63.78 (C5ꢁ), 74.07 (C3ꢁ), 82.78
(C4ꢁ), 85.90 (C1ꢁ), 111.12 (C5), 111.60 (Ph-o), 126.42 (Ph-m), 137.18 (C6),
138.29 (Ph-i), 150.22 (C-2), 153.06 (Ph-p), 163.58 (C4), 170.53 (CH3COO),
170.85 (CH3COO); UV(MeOH) λmax = 260 nm (ε = 8200), λmax = 380 nm
(ε = 16500).
ꢁ
ꢁꢁ
ꢁ
ꢁ
4h Z and E isomers; m/z (HRMS, FAB) 463.1447 ([M+H]+ C20H23N4O9
requires 463.1465) 1H NMR (250 MHz, CDCl3) δ 2.12 (s, 3H, CH3COO of
Z), 2.13 (s, 3H, CH3COO of Z), 2.09–2.23 (m, 10H, 2xCH3COO of E, H2ꢁ,
H2ꢁꢁ of Z and E), 3.86 (dd, 4J H6,H7 = 1.9 Hz, J gem = 14.6 Hz, 1H, one of CH2
-6 of E), 3.98 (dd, 4J H6,H7 = 0.9 Hz, J gem = 13.5 Hz, 1H, one of CH2–6 of Z),
4.12–4.46 (m, 7H, one of CH2–6, H4ꢁ of Z and E, H5ꢁ, H5ꢁꢁ of Z, H5ꢁꢁ of E),
4.75 (dd, J H5 ,H4 = 9.9 Hz, J gem = 12.1 Hz, 1H, H5ꢁ of E), 5.07–5.16 (m, 1H,
ꢁ
ꢁ
H3ꢁ of Z and E), 5.24 (m, 1H, PhNHCH of E), 6.35 (dd, J H1 ,H2 = 6.6 Hz,
ꢁ
ꢁꢁ
J H1 ,H2 = 8.1 Hz, 1H, H1ꢁ of Z), 6.40 (m, 1H, H1ꢁ of E), 7.05–7.16 (m, 2H,
Ph-o of Z), 7.21–7.27 (m, 2H, Ph-o of E), 7.44 (d, J = 12.1 Hz, 1H,H7 of Z),
7.56 (s, 1H, NH-3 of E), 7.74 (s, 1H, NH-3 of Z), 8.18–8.29 (m, 5H, Ph-m
ꢁ
ꢁ
of Z and E, H7 of E), 10.56 (d, J NH,H7 = 12.0 Hz, 1H, PhNHCH of Z); 13
C
NMR (63 MHz, CDCl3) δ 20.99 (CH3COO of E and Z), 21.10 (CH3COO of
E and Z), 33.04 (C2ꢁof E), 33.55 (C2ꢁ of Z), 36.26 (C6 of E), 40.29 (C6 of
Z), 64.03 (C5ꢁ of Z and E), 74.26 (C3ꢁ of Z and E), 80.96 (C4ꢁof Z), 81.96
(C4ꢁ of E), 84.51 (C1ꢁ of Z), 85.54 (C1ꢁ of E), 95.06 (C5 of Z), 98.99 (C5 of
E), 115.01(Ph-o of Z and E), 126.25 (Ph-m of Z and E), 135.25 (C7 of E),
138.45 (C7 of Z), 142.75 (Ph-i of E), 142.85 (Ph-i of E), 145.58 (Ph-p of E),
145.71 (Ph-p of Z), 151.40 (C2 of E), 152.67 (C2 of Z), 164.55 (C4 of E),
166.94 (C4 of Z), 170.64 (CH3COO of Z and E), 170.72, (CH3COO of Z
and E); UV(MeOH) λmax = 372.5 nm (ε = 21500).

1060
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