Hydrolysis and hydrogenolysis of formamidines: N,N-dimethyl and N,N- dibenzyl formamidines as protective groups for primary amines

Full text of DOI:10.1021/jo980099g

J . Org. Chem. 1999, 64, 991-997
991
Notes
Hyd r olysis a n d Hyd r ogen olysis of
F or m a m id in es: N,N-Dim eth yl a n d
N,N-Diben zyl F or m a m id in es a s P r otective
Gr ou p s for P r im a r y Am in es
properties. There are a number of reports in the litera-
ture for the preparation of N′,N′-dialkyl amidines.
In the present work, the synthesis of N′,N′-dimethyl
1
4-16
formamidines was carried out using DMF dimethyl
acetal1
7-19
and the procedure described by Zemlicka.
12
St e´ phane Vincent, Charles Mioskowski, and
Luc Lebeau*
The synthesis of N′,N′-dibenzyl formamidines was carried
13
out according to our previously published procedure.
Laboratoire de Synth e` se Bioorganique associ e´ au CNRS,
Facult e´ de Pharmacie, Universit e´ Louis Pasteur de
Strasbourg, 74, route du Rhin - BP 24,
Hyd r olysis Rea ction s. The mechanism of amidine
hydrolysis has been studied in detail elsewhere.
15,20-24
The reaction proceeds via the formation of a hemiortho-
amide that can cleave in two different ways (Scheme 1).
Hydrolysis of N-alkyl N′,N′-dibenzyl formamidines in
neutral conditions proceeded in a way different from that
of N′,N′-dimethyl compounds (Table 1). The reaction
essentially goes through path a as N,N-dibenzyl forma-
mide 5a is formed during the reaction, whereas only a
trace amount of N-alkyl formamide 4b can be detected
6
7401 Illkirch Cedex, France
Received J anuary 21, 1998
In tr od u ction
Protective groups play a pivotal role in the synthesis
1
of complex organic substances. A number of reagents and
procedures have been described to specifically protect and
deprotect primary amines. N,N-Dialkyl formamidines
and especially N,N-dimethyl formamidines have been
1
by H NMR (entries 2, 3, 5, and 7). In the case of N-alkyl
N′,N′-dimethyl formamidines, the hydrolysis reaction is
much more rapid than with dibenzyl compounds and goes
through path b. This is clearly evidenced by the produc-
tion of N-alkyl formamide in almost quantitative yield
in a few hours at room temperature (entries 1, 4, and
widely used as protective groups for the exocyclic amino
function of nucleosides.2
-12
Recently, we described the use
of N,N-dibenzyl formamidine as a primary amine protec-
tive group.13 Our investigations originated from the need
to dispose of a protective group that is stable in moder-
ately acidic and basic experimental conditions and that
can be removed under neutral conditions. N,N-Dibenzyl
formamidines fulfill the performance and application
criteria, and the masking group can be removed by
catalytic hydrogenation with palladium-on-carbon cata-
lysts.
Herein, we describe the results of our investigations
concerning the reactivity of N,N-dimethyl and N,N-
dibenzyl formamidines toward hydrolysis and hydro-
genolysis reactions.
2
5
6
). The course of the reaction is assumed to be governed
by the respective pK value of each nitrogen atom in the
a
intermediate hemiorthoamide structure 2. In that com-
pound, the nitrogen atom bearing three alkyl substitu-
ents (N′) is more basic than the disubstituted one (N) as
a result of the electron-donating character of the alkyl
groups. Thus, the hemiorthoamide evolves toward species
3
b, further yielding the N-alkyl formamide 4b. In the
case of N′,N′-dibenzyl compounds, because of the small
electron-withdrawing character of the two benzyl moi-
2
6
eties, the N′ center appears less basic than the N center
and the hydrolysis reaction evolves through path a,
yielding the amine 4a .
Resu lts a n d Discu ssion
We prepared a series of N-alkyl and N-aryl N′,N′-
dimethyl and N′,N′-dibenzyl formamidines to study their
(14) M o¨ hrle, H.; Engelsing, R. Arch. Pharmaz. 1972, 306, 325-338.
(15) Granik, V. G. Russ. Chem. Rev. 1983, 52, 377-393.
*
Tel.: 33 (0)3 88 67 68 57. Fax: 33 (0)3 88 67 88 91. E-mail:
lebeau@aspirine.u-strasbg.fr.
1) Greene, T. W.; Wuts, P. G. M. Protective group in organic
synthesis, 2nd ed.; Wiley: New York, 1991.
(16) Boyd, G. V. In The chemistry of amidines and imidates; Patai,
S., Rappoport, Z., Eds.; J ohn Wiley & Sons: Chichester, 1991; Vol. 2,
pp 339-366.
(
(17) Abdulla, R. F.; Brinkmeyer, R. S. Tetrahedron 1979, 35, 1675-
1735.
(
2) Zemlicka, J . Collect. Czech. Chem. Commun. 1963, 28, 1060-
1
062.
(
(
(18) Meerwein, H.; Florian, W.; Sch o¨ n, N.; Stopp, G. Liebigs Ann.
Chem. 1961, 641, 1-39.
(19) Brederek, H.; Simchen, G.; Rebsdat, S.; Kantlehner, W.; Horn,
P.; Wahl, R.; Hoffmann, H.; Grieshaber, P. Chem. Ber. 1968, 101, 41-
50.
3) Beaucage, S. L.; Iyer, R. P. Tetrahedron 1992, 48, 2223-2311.
4) Seela, F.; Mertens, R.; Kazimierczuk, Z. Helv. Chim. Acta 1992,
7
5, 2298-2306.
5) Theisen, P.; McCollum, C.; Andrus, A. Nucleosides Nucleotides
993, 12, 1033-1046.
6) Arnold, L.; Tocik, Z.; Bradkova, E.; Hostomsky, Z.; Paces, V.;
Smrt, J . Collect. Czech. Chem. Commun. 1989, 54, 523-532.
7) Arnold, L.; Smrt, J .; Zajicek, J .; Ott, G.; Schiesswohl, M.; Sprinzl,
M. Collect. Czech. Chem. Commun. 1991, 56, 1948-1956.
8) Vu, H.; McCollum, C.; J acobson, K.; Theisen, P.; Vinayak, R.;
Spiess, E.; Andrus, A. Tetrahedron Lett. 1990, 31, 7269-7272.
9) McBride, L. J .; Kierzek, R.; Beaucage, S. L.; Caruthers, M. H.
J . Am. Chem. Soc. 1986, 108, 2040-2048.
10) Froehler, B. C.; Matteuci, M. D. Nucleic Acids Res. 1983, 11,
031-8036.
11) Holy, A.; Zemlicka, J . Collect. Czech. Chem. Commun. 1968,
4, 2449-2459.
12) Zemlicka, J .; Chladek, S.; Holy, A.; Smrt, J . Collect. Czech.
Chem. Commun. 1966, 31, 3198-3211.
13) Vincent, S.; Mons, S.; Lebeau, L.; Mioskowski, C. Tetrahedron
Lett. 1997, 38, 7527-7530.
(
1
(20) Patai, S. In The chemistry of functional groups: The chemistry
of amidines and imidates; Patai, S., Ed.; Wiley: London, 1975; Vol. 1.
(21) Fernandez, B.; Perillo, I.; Lamdan, S. J . Chem. Soc., Perkin
Trans. 2 1973, 1371-1374.
(
(
(22) Perillo, I.; Fernandez, B.; Lamdan, S. J . Chem. Soc., Perkin
Trans. 2 1977, 2068-2072.
(
(23) Halliday, J . D.; Symons, E. A. Can. J . Chem. 1978, 56, 1463-
(
1469.
(24) Perrin, C. L.; Arrhenius, G. M. L. J . Am. Chem. Soc. 1982, 104,
2839-2842.
(
8
(25) Interestingly, it was recently reported that hydrolysis of di-
methyl formamidines in absolute ethanol in the presence of 2 equiv of
zinc chloride required 24 h at room temperature to quantitatively afford
the corresponding N-alkyl formamide: Toste, D.; McNulty, J .; Still, I.
W. J . Synth. Commun. 1994, 24, 1617-1624.
(26) Christensen, J . J .; Izatt, R. M.; Wrathall, D. P.; Hansen, L. D.
J . Chem. Soc. A 1969, 1212-1223.
(
3
(
(
1
0.1021/jo980099g CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/20/1999

9
92 J . Org. Chem., Vol. 64, No. 3, 1999
Notes
Sch em e 1
hydrolysis reaction proceeds according to path a (Scheme
1
), except that the N center is not protonated.
Hyd r ogen olysis R ea ct ion s. There are very few
3
2-34
reports in the literature on hydrogenolysis of amidines,
and the reaction has not been investigated for primary
amine protection-deprotection purposes so far. We sub-
mitted a series of N-alkyl and N-aryl N′,N′-dimethyl or
N′,N′-dibenzyl formamidines to a set of different hydro-
genolysis conditions to study the scope of the deprotection
reaction (Table 2).
Hydrogenolysis of N-alkyl formamidines generally lead
to a mixture of compounds (entries 1-9). The N-alkyl-
amine is obtained together with the N-methyl alkylamine
and the N-alkyl formamide. The ratio between the
different constituents of the mixture varies depending
on the nature of the two N′ substituents (methyl or benzyl
2
groups), on the hydrogen source (H , ammonium formate,
or cyclohexene), and on the solvent and catalyst used. It
is likely that the formamide observed at entries 2 and 3
results from partial hydrolysis of the formamidine during
the course of the reaction. This is consistent with the
kinetics of the hydrolysis reaction reported in Table 1.
More intriguing is the obtaining of alkylamines and
N-methyl alkylamines. We found only one example in the
literature for the reduction of a N-alkyl formamide into
the corresponding N-methyl alkylamine by catalytic
hydrogenation.35 The transformation was described in
Hydrolysis of N-aryl N′,N′-disubstituted formamidines
is more difficult because of the conjugation between the
formamidine double bond and the aromatic cycle. As
previously reported, introduction of a phenyl ring on the
imino nitrogen of an amidine reduces its basicity by a
factor 1000.27 Consequently, the N-aryl formamidine
1
923 and requires very harsh experimental conditions
hydrolysis proceeds via path b (Scheme 1). The reaction
conditions are harsher, and unreacted starting material
is recovered in many cases (entries 8-13). In neutral
experimental conditions, N-aryl N′,N′-dimethyl form-
amidines afford the corresponding N-aryl formamides
(nickel catalyst, high pressure of hydrogen, 200-210 °C).
On the other hand, the obtaining of an alkylamine from
its formamide in hydrogenolysis condition has also been
reported.36 However, in that case, the amine probably
resulted from the acidic hydrolysis of the formamide.
Nevertheless, tentative hydrogenolysis of N-(4,4-diethoxy-
butyl)-formamide in the conditions described at entry 4
did fail, and starting material was quantitatively recov-
ered even after prolonged reaction time. This definitely
rules out the formation of the amine and/or methylamine
via the reduction or the hydrolysis of the formamide.
Though we have no direct experimental evidence of that,
it is supposed that the formation of amines results from
the preliminary reduction of the imino function in form-
amidines (Scheme 2). The orientation of the reaction
(
entries 8 and 11), whereas N′,N′-dibenzyl compounds
remain unreacted (entries 9 and 12). Hydrolysis of N-aryl
N′,N′-dibenzyl formamidines requires the use of a base
2
8
and higher temperature (entries 10, 12, and 13). When
triethylamine is used, N-aryl formamide is obtained
entry 10), whereas potassium hydroxide yields the
corresponding aniline without any trace of N-aryl form-
(
amide (entry 13). In both cases, the hydrolysis is expected
2
9
to yield the formanilide (Scheme 1, path b ) and it is
likely that, in the presence of potassium hydroxide, it is
rapidly hydrolyzed into the corresponding aniline. This
is consistent with the results in the literature related to
a
depends on the respective pK values of the two nitrogen
the rate of alkaline hydrolysis of formanilides.3
0,31
atoms in the aminal. Thus, the intermediate N-hy-
droxymethylamines 6a and 6b can evolve in two different
ways. They can eliminate either a formaldehyde molecule
to give the corresponding amine or a water molecule to
give the imine. That imine can be further hydrogenolyzed
and transformed into the N-methyl alkylamine.
The reactivity of formamidine derivatives of cytidine
toward hydrolysis was found to be intermediate between
those of N-alkyl and N-aryl formamidines. This is con-
sistent with the partial aromaticity of cytosine. Thus, the
4
N formamidine-protected cytosine nucleosides are quan-
titatively deprotected in neutral conditions at 50 °C
In the particular case of N-aryl formamidines (entries
10 to 19), N-methyl arylamines are not observed as side
products. This is in agreement with the results of Abrams
and Kallen on the formation of N-hydroxymethylamines
from aromatic exocyclic amines and formaldehyde. They
provided evidence that N-hydroxymethyl derivatives of
(entries 14 and 15). The N′,N′-dialkyl formamidine of
adenine and guanosine derivatives (entries 16-19) can-
not be deprotected in these conditions, and the recovery
of the exocyclic amino function requires the use of
potassium hydroxide. In all these cases, as a result of
the existence of mesomeric forms of the nucleosides, the
3
7
(
32) Breshears, S. R.; Wang, S. S.; Bechtolt, S. G.; Christensen, B.
(
(
27) Smith, J . A.; Taylor, H. J . Chem. Soc. B 1969, 66-67.
E. J . Am. Chem. Soc. 1959, 81, 3789-3792.
(33) J ones, R. C. F.; Turner, I.; Howard, K. J . Tetrahedron Lett. 1993,
28) Because of steric hindrance, 2,6-dimethylaniline derivatives
were very resistant to hydrolysis (Table 1, entries 11-13).
34, 6329-6332.
(
29) In the hydrolysis of N-aryl N′,N′-disubstituted formamidines
(34) J ones, R. C. F.; Hirst, S. C. Tetrahedron Lett. 1989, 30, 5365-
under basic conditions, the intermediate species 3b (Scheme 1) is
presumably not fully protonated at N′.
5368.
(35) Mailhe, M. A. C. R. Hebd. Sc e´ ances Acad. Sci. 1923, 176, 1159-
1161.
(
30) DeWolfe, R. H.; Newcomb, R. C. J . Org. Chem. 1971, 36, 3870-
3
1
878.
(36) Losse, G.; Nadolski, D. J . Prakt. Chem. 1964, 24, 118-124.
(37) Abrams, W. R.; Kallen, R. G. J . Am. Chem. Soc. 1976, 98, 7777-
7789.
(
31) Cunningham, I. D. J . Chem. Soc., Perkin Trans. 2 1988, 1485-
490.

Notes
J . Org. Chem., Vol. 64, No. 3, 1999 993
Ta ble 1
aniline and related compounds are in equilibrium with
the amine and formaldehyde and not with the imine.
Thus, the hydrogenolysis of a N-aryl formamidine is a
very clean reaction and affords the corresponding ary-

9
94 J . Org. Chem., Vol. 64, No. 3, 1999
Notes
Ta ble 2
lamine in almost quantitative yield. Cytidine derivatives
described in Table 1 were not submitted to hydrogenoly-
sis reaction conditions as the double bond in cytosine
would not be preserved. To complete our observations,

Notes
J . Org. Chem., Vol. 64, No. 3, 1999 995
Sch em e 2
showed one spot when checked by HPTLC (Merck 60F254 or RP-
1
8F254s). All the yields indicated refer to pure isolated com-
pounds.
Typ ica l P r oced u r e for th e P r ep a r a tion of Dim eth yl
F or m a m id in es. The primary amine (1 mmol) is stirred for 5 h
at room temperature in N,N-dimethyl formamide dimethyl
acetal (0.5 mL, 3.7 mmol).39 The reaction mixture is reduced in
vacuo, and the amino-protected compound is purified by chro-
matography on silica gel.
Typ ica l P r oced u r e for th e P r ep a r a tion of Diben zyl
F or m a m id in es. Dimethyl formamide dimethyl acetal (1 mmol)
and dibenzylamine (3 mmol) are refluxed in dry acetonitrile for
2
0 h. The reaction mixture is evaporated to dryness, and traces
of remaining DMF dimethyl acetal are removed by two succes-
sive addition/evaporation steps with toluene. The crude residue
is dissolved in anhydrous CH
3
CN and added to the primary
amine (0.4 mmol) in CH
3
CN.40 The resulting solution is stirred
at room temperature until the amine has completely disappeared
when checked by TLC. The solvent is removed in vacuo, and
the amino-protected compound is purified by chromatography
on silica gel.
N′-(4,4-Dieth oxy-bu tyl)-N,N-dim eth yl-for m am idin e (Table
1
1
2
, entry 1; yield: 99%). 1H NMR (CDCl
H); 4.51 (t, J ) 5.1, 1H); 3.75-3.36 (m, 4H); 3.27 (t, J ) 6.3,
3
, 200 MHz) δ 7.25 (s,
1
3
H); 2.81 (s, 6H); 1.70-1.62 (m, 4H); 1.25 (t, J ) 6.9, 6H).
, 50 MHz) δ 154.78; 102.84; 60.65; 55.83; 36.93;
1.15; 27.71; 15.19. IR (neat) ν 2974; 2926; 2873; 1655. MS
C
NMR (CDCl
3
3
+
(
CI/NH
N′-(4,4-Dieth oxy-bu tyl)-N,N-diben zyl-for m am idin e (Table
, entry 2; yield: 75%). 1H NMR (CDCl
, 200 MHz) δ 7.62 (s,
3
): 217 [M + H] .
1
1
3
3
H); 7.33-7.12 (m, 10H); 4.53 (t, J ) 5.1, 1H); 4.31 (s, 4H); 3.85-
.40 (m, 4H); 3.34 (t, J ) 5.9, 2H); 1.70-1.62 (m, 4H); 1.25 (t, J
)
6.9, 6H). 13C NMR (CDCl
28.32; 127.97; 127.68; 127.04; 102.82; 60.63; 55.77; 50.03; 31.14;
3
, 50 MHz) δ 154.54;137.61; 128.75;
1
2
3
7.56; 15.23. IR (neat) ν 2972; 2928; 2871; 1649. MS (CI/NH
3
):
+
69 [M + H] .
N′-(4,4-Dieth oxy-bu tyl)-N,N-d iben zyl-for m a m id in e h y-
d r och lor id e (Table 1, entry 3; this compound is obtained by
bubbling HCl gas in a solution of N′-(4,4-diethoxy-butyl)-N,N-
we have to mention that we did not find any significant
difference in the kinetics of the hydrogenolysis of N-aryl
N′,N′-dimethyl and N′,N′-dibenzyl formamidines.
dibenzyl-formamidine in ether; yield: 99%). 1H NMR (CDCl
,
3
2
00 MHz) δ 8.55 (s, 1H); 7.30-7.10 (m, 10H); 4.65-4.55 (m, 4H);
4.43 (t, J ) 5.1, 1H); 3.85-3.40 (m, 6H); 1.72 (m, 2H); 1.58 (m,
2
1
H); 1.16 (m, 6H). 13C NMR (CDCl
28.75; 128.26; 102.26; 61.15; 45.52; 29.99; 25.31; 15.09. IR (neat)
3
, 75 MHz) δ 155.60; 132.85;
Con clu sion
ν 3030; 2972; 2877; 1692.
We have investigated the properties of a series of
differently substituted formamidines in hydrolytic and
hydrogenolytic experimental conditions. We have out-
lined structural features related to the imino nitrogen
substituent and to the two amino substituents orienting
the course of the hydrolysis and hydrogenolysis reactions.
N-Alkyl N′,N′-dimethyl formamidines provide an easy
access to the corresponding formamide by neutral hy-
drolysis, whereas in the dibenzyl series, the same for-
mamidines are readily transformed into the primary
amine. Both types of compounds lead to a mixture of
alkylamine and N-methyl alkylamine when submitted to
hydrogenation. Aryl formamidines are more resistant to
hydrolysis and often require basic conditions to afford the
corresponding primary amine. On the other hand, their
hydrogenolysis quantitatively restores the aromatic exo-
cyclic primary amine. This definitely appears to be of
special interest in the field of oligonucleotide chemistry,
as it provides an alternative to the hydrolysis under basic
conditions that is incompatible with many substrates.
N′-(5-Hyd r oxy-p en tyl)-N,N-d im eth yl-for m a m id in e (Table
1, entry 4; yield: 98%). 1H NMR (CDCl
, 300 MHz) δ 7.18 (s,
H); 3.53 (t, J ) 6.2, 2H); 3.15 (t, J ) 6.6, 2H); 2.76 (s, 6H);
.60-1.38 (m, 4H); 1.29 (m, 2H). 13C NMR (CDCl
, 50 MHz) δ
54.91; 62.04; 55.86; 37.03; 32.35; 31.07; 23.23. IR (neat) ν 2930;
3
1
1
1
2
3
+
+
859; 1646. MS (CI/NH
3
): 159 [M + H] ; 176 [M + NH ] .
4
N′-(5-Hyd r oxy-p en tyl)-N,N-d iben zyl-for m a m id in e (Table
, entry 5; yield: 78%). 1H NMR (CDCl
1H); 7.42-7.20 (m, 10H); 4.38 (s, 4H); 3.65 (t, J ) 6.4, 2H); 3.38
(t, J ) 6.6, 2H); 1.67-1.62 (m, 4H); 1.25 (q, J ) 7.0, 2H).
1
3
, 200 MHz) δ 7.72 (s,
1
3
C
NMR (CDCl
3
, 50 MHz) δ 154.80; 137.12; 128.46; 127.74; 127.27;
1
2
26.90; 62.39; 55.20; 55.17; 32.30; 31.78; 23.14. IR (neat) ν 3028;
929; 2858; 1646. MS (CI/NH
+
4
): 328 [M + NH ] .
3
N′-Isobu tyl-N,N-d im eth yl-for m a m id in e (Table 1, entry 6;
1
yield: 99%). H NMR (CDCl
J ) 4.5, 2H); 2.83 (s, 6H); 1.73 (h, J ) 4.5, 1H); 0.89 (d, J ) 4.5,
6H). 13C NMR (CDCl
3
, 300 MHz) δ 7.21 (s, 1H); 3.03 (d,
3
, 75 MHz) δ 154.80; 64.29; 37.00, 30.36;
20.31. IR (neat) ν 2960; 2872; 1667. MS (CI/NH
3
): 129 [M +
+
H] .
N′-Isobu tyl-N,N-d iben zyl-for m a m id in e (Table 1, entry 7;
1
yield: 81%). H NMR (CDCl
3
, 200 MHz) δ 7.64 (s, 1H); 7.45-
7
6
1
.20 (m, 10H); 4.38 (s, 4H); 3.19 (d, J ) 6.8, 2H); 1.87 (h, J )
13
.8, 1H); 0.96 (d, J ) 6.8, 6H). C NMR (CDCl
3
, 50 MHz) δ
54.84; 137.70; 136.98; 129.03; 128.40; 127.99; 127.77; 127.13;
Exp er im en ta l Section
64.24; 56.35; 50.14; 30.42; 20.46. IR (neat) ν 2957; 2866; 1649.
+
MS (CI/NH
3
): 281 [M + H] .
General methods were previously reported elsewhere.38 All
compounds were purified to homogeneity, and analytical samples
(39) Hindered primary amines required prolonged reaction time at
higher temperature (50-60 °C).
(40) The reaction can be run in anhydrous DMF with a comparable
yield and without any formation of N, N-dimethyl formamidine.
(
38) Lebeau, L.; Oudet, P.; Mioskowski, C. Helv. Chim. Acta 1991,
7
4, 1697-1706.

9
96 J . Org. Chem., Vol. 64, No. 3, 1999
Notes
N′-(3-Meth oxy-ph en yl)-N,N-dim eth yl-for m am idin e (Table
1.55 (s, 3H); 1.29 (s, 3H). 13C NMR (CDCl
158.29; 151.88; 149.82; 141.25; 126.70; 113.93; 93.43; 85.78;
83.01; 81.36; 62.82; 41.13; 34.84; 27.19; 24.91. IR (neat) ν 2987;
3
, 50 MHz) δ 159.90;
1
1
(
1
2
, entry 8; yield: 99%). 1H NMR (CDCl
3
, 200 MHz) δ 7.85 (s,
H); 7.45-7.09 (m, 1H); 6.50-6.45 (m, 3H); 3.65 (s, 3H); 2.86
1
3
+
s, 6H). C NMR (CDCl
3
, 50 MHz) δ 159.80; 153.14; 152.81;
2935; 1633; 1566. MS (CI/NH
3
): 363 [M + H] .
29.02; 112.79; 107.70; 106.29; 54.48; 39.47; 34.02. IR (neat) ν
913; 1638; 1589. MS (CI/NH
6
2
′,3′-O-Isop r op ylid en e- N-d iben zyla m in om eth ylen e a d -
+
): 179 [M + H] .
1
3
en osin e (Table 1, entry 17; yield: 87%). H NMR (CDCl
MHz) δ 9.37 (s, 1H); 8.55 (s, 1H); 7.96 (s, 1H); 7.42-7.10 (m,
0H); 5.89 (d, J ) 5.0, 1H); 5.22 (dd, J ) 5.0, 5.6, 1H); 5.10 (d,
3
, 200
N′-(3-Meth oxy-ph en yl)-N,N-diben zyl-for m am idin e (Table
, entry 9; yield: 88%). 1H NMR (CDCl
, 200 MHz) δ 7.98 (s,
H); 7.82-7.20 (m, 14H); 6.80-6.62 (m, 3H); 4.74 (s, 2H); 4.35
1
1
(
1
1
3
1
J ) 5.6, 1H); 4.87 (s, 2H); 4.53 (m, 1H); 4.43 (s, 2H); 4.10-3.70
1
3
s, 2H); 3.67 (s, 3H). C NMR (CDCl
3
, 50 MHz) δ 161.37; 154.46;
13
3
(m, 2H); 1.63 (s, 3H); 1.36 (s, 3H). C NMR (CDCl , 50 MHz) δ
54.23; 137.90; 130.66; 129.65; 129.08; 128.59; 114.38; 109.54;
1
1
8
1
60.37; 158.97; 151.98; 150.17; 141.46; 135.36; 134.96; 128.84;
28.22; 127.99; 127.74; 127.65; 126.79; 113.82; 94.12; 85.90;
2.86; 81.59; 63.28; 54.54; 47.66; 27.53; 25.13. IR (neat) ν 2932;
08.05; 56.22; 54.57; 48.45. IR (neat) ν 3028; 2922; 1633; 1591.
+
+
MS (CI/NH
3
): 331 [M + H] ; 348 [M + NH ] .
4
N′-(2,6-Dim et h yl-p h en yl)-N,N-d im et h yl-for m a m id in e
Table 1, entry 11; yield: 73%). H NMR (CDCl
.19 (s, 1H); 7.05 (d, J ) 7.5, 2H); 6.84 (t, J ) 7.5, 1H); 3.01 (s,
H); 2.17 (s, 6H). C NMR (CDCl
+
+
4
554. MS (CI/NH
3
): 515 [M + H] , 532 [M + NH
] .
1
(
3
, 300 MHz) δ
2
2
′,3′-O-Ben zylid en e- N-d im eth yla m in om eth ylen e gu a -
7
6
1
1
1
n osin e (Table 2, entry 16; yield: 85%; 2 diastereomers). H NMR
CD OD, 200 MHz) δ 8.62 and 8.58 (2s, 1H); 8.07 and 8.05 (2s,
1
3
3
, 50 MHz) δ 153.12; 153.00;
(
3
49.94; 129.61; 127.65; 121.82; 37.01; 18.61. IR (neat) ν 2918;
1
0
1
3
H); 7.60-7.39 (m, 5H); 6.23 (d, J ) 2.9, 0.5H); 6.20 (d, J ) 3.3,
+
645. MS (CI/NH
3
): 177 [M + H] .
.5H); 6.19 and 6.03 (2s, 1H); 5.44-5.36 (m, 1H); 5.22-5.10 (m,
N ′-(2,6-Dim e t h yl-p h e n yl)-N ,N -d ib e n zyl-for m a m id in e
H); 4.47 (m, 0.5H); 4.35 (m, 0.5H); 3.82-3.74 (m, 2H); 3.14 and
1
(
7
Table 1, entry 12; yield: 93%). H NMR (CDCl
.60 (s, 1H); 7.46-7.30 (m, 10H); 7.10 (d, J ) 7.3, 2H); 6.92 (t,
J ) 7.3, 1H); 4.54 (s, 4H), 2.32 (s, 6H). C NMR (CDCl
δ 153.06; 149.74; 137.29; 129.53; 128.57; 127.79; 127.39; 122.05;
3.00; 48.45; 18.81. IR (neat) ν 3028; 2914; 1640; 1590. MS (CI/
3
, 300 MHz) δ
13
.13 (2s, 3H); 3.08 and 3.07 (2s, 3H). C NMR (CD
3
OD, 50 MHz)
δ 158.32; 157.08; 149.68; 138.05; 136.05; 135.91; 129.73-126.49
1
3
3
, 50 MHz)
(m); 120.37; 120.29; 107.38; 104.00; 91.01; 89.82; 85.69; 84.97;
8
1
3.87; 82.92; 80.35; 62.30; 62.07; 41.31; 34.98. IR (KBr) ν 2930;
5
+
+
4
679; 1632. MS (CI/NH
3
): 427 [M + H] , 444 [M + NH
] .
+
NH ): 329 [M + H] .
3
2
2
′,3′-O-Ben zylid en e- N-d ib en zyla m in om et h ylen e gu a -
4
N-Dim eth yla m in om eth ylen e cytid in e (Table 1, entry 14;
yield: 99%). H NMR (DMSO-d
s, 1H); 8.26 (d, J ) 7.1, 1H); 6.16 (d, J ) 7.1, 1H); 5.93 (d, J )
.5, 1H); 4.15 (m, 2H); 4.05 (m, 1H); 3.83 (AB part of ABX
1
n osin e (Table 2, entry 17; yield: 99%; 2 diastereomers). H NMR
CDCl , 200 MHz) δ 8.89 and 8.87 (2s, 1H); 7.81 and 7.76 (2s,
H); 7.60-7.25 (m, 15H); 6.02 (d, J ) 5.8, 1H); 6.22 and 6.04
2s, 1H); 5.37 (m, 1H); 5.17 (m, 1H); 4.75-4.40 (m, 5H); 3.91
m, 2H). 13C NMR (CDCl
, 50 MHz) δ 158.69; 157.76; 157.16;
49.24; 137.92 and 137.79; 136.11 and 135.83; 134.99 and 134.63;
1
6
/CD
3
OD 1/3, 300 MHz) δ 8.71
(
3
(
1
1
(
(
systtem, ∆ν ) 18.0, J AB ) 12.4, J AX ) 2.6, J BX ) 3.0, 2H); 3.25
1
3
3
(
s, 3H); 3.16 (s, 3H). C NMR (DMSO-d
δ 173.26; 159.92; 158.27; 144.09; 103.49; 92.20; 58.88; 76.29;
0.60; 61.76; 41.95; 35.69. IR (KBr) ν 2942; 1655; 1626; 1598.
6 3
/CD OD 1/3, 75 MHz)
1
1
1
29.67, 128.80, and 128.62; 128.37, 128.31, and 128.12; 127.73,
26.42 and 126.29; 121.37 and 121.29; 107.40 and 104.10; 91.61
7
+
MS (CI/NH
3
): 299 [M + H] .
N-Diben zyla m in om eth ylen e cytid in e (Table 1, entry 15;
and 90.28; 85.27 and 84.92; 83.78 and 83.55; 83.06 and 80.23;
2.48 and 62.16; 54.81; 47.77. IR (neat) ν 3029; 2926; 1685; 1615.
4
6
1
yield: 81%). H NMR (CDCl
3
/CD
H); 8.18 (d, J ) 7.3, 1H); 7.42-7.10 (m, 10H); 6.18 (d, J ) 7.3,
H); 5.76 (d, J ) 2.2, 1H); 4.72 (s, 2H); 4.58 (s, 2H); 4.35-4.05
3
OD 2/1, 200 MHz) δ 9.10 (s,
+
4
] .
MS (CI/NH
3
): 579 [M + NH
1
1
(
2
′,3′-O-Ben zylid en e-5′-O-(ben zyloxy-ben zyloxyca r bon yl-
1
2
m eth yl-p h osp h in oyl)- N-ben zyl- N-d iben zyla m in om eth yl-
m, 3H); 3.85 (AB part of ABX system, ∆ν ) 18.0, J AB ) 12.6,
1
1
3
en e gu a n osin e (Table 2, entry 18; 4 diastereomers). H NMR
J
3 3
AX ) 2.2, J BX ) 2.6, 2H). C NMR (CDCl /CD OD 2/1, 50 MHz)
(
7
2
CDCl
3
, 300 MHz) δ 8.80 and 8.53 (2s, 1H); 7.80, 7.78, 7.77 and
.74 (4s, 1H); 7.60-7.15 (m, 30H); 6.22, 6.19 and 6.12 (3d, J )
.6, 1H); 6.15, 6.14, 5.97 and 5.94 (4s, 1H); 5.55 (AB system, ∆ν
δ 172.04; 158.84; 156.81; 142.58; 134.58; 134.29; 128.63; 128.43;
1
6
(
28.08; 127.93; 127.62; 127.13; 102.96; 92.16; 84.31; 74.69; 68.54;
0.08; 54.61; 49.65. IR (CHCl ) ν 2928; 1651; 1573. MS
3
+
+
4
] .
) 9.0, J AB ) 14.7, 2H); 5.38, 5.30 and 5.21 (3dd, J ) 2.6, 6.4,
CI/NH
2
3
): 451 [M + H] ; 468 [M + NH
′,3′-O-Be n zylid e n e -5′-O-t er t -b u t yld im e t h ylsilyl- N -
ben zyl- N-d iben zyla m in o-m eth ylen e gu a n osin e (Table 1,
1
1H); 5.15-4.85 (m, 5H); 4.75-4.10 (m, 7H); 2.99, 2.98 and 2.95
(3d, J ) 21.4, 2H). 13C NMR (CDCl
, 50 MHz) δ 165.25 and
3
2
1
165.14; 158.05; 157.28; 147.52; 138.22; 136.75-135.01 (m);
3
entry 19; 2 diastereomers). H NMR (CDCl , 300 MHz) δ 8.87
1
8
6
29.86-126.50 (m); 120.47; 107.72 and 104.41; 89.14, 88.98 and
8.79; 85.09 and 84.93; 83.83, 83.71, and 82.64; 81.92 and 80.65;
8.51 and 67.52; 65.22; 54.69; 48.41; 45.50; 34.24 (d, J ) 135.8).
and 8.86 (2s, 1H); 7.89 and 7.83 (2s, 1H); 7.60-7.15 (m, 20H);
6
2
)
4
0
.28 and 6.21 (2d, J ) 4.1, 1H); 6.18 and 6.02 (2s, 1H); 5.57 (s,
H); 5.32 and 5.20 (2dd, J ) 4.1, 9.5, 1H); 5.08 and 4.99 (2dd, J
3
1
3
P NMR (CDCl , 121 MHz) δ 21.72; 21.70; 21.67; 21.64. IR (neat)
4.0, 9.5, 1H); 4.63 and 4.61 (2s, 2H); 4.54 and 4.39 (2m, 1H);
ν 3062; 3090; 2924; 1689; 1612; 1573.
.35 and 4.30 (2s, 2H); 3.85 (m, 2H); 0.88 and 0.86 (2s, 9H); 0.07,
.06, 0.04, and 0.02 (4s, 6H). 1 C NMR (DMSO-d
3
5′-O-(Ca r boxym eth yl-h yd r oxy-p h osp h in oyl) gu a n osin e
bistr ieth yla m m on iu m sa lt (Table 2, entry 18, product; yield:
/CDCl 1/2, 50
6 3
MHz) δ 158.12; 157.99; 157.05; 147.51 and 147.55; 138.55;
1
1
1
8
4
1
36.36-134.64 (m); 129.83-125.92 (m); 120.36 and 120.26;
07.49 and 104.25; 89.67 and 89.06; 85.96 and 85.73; 85.29 and
4.68; 82.69 and 81.77; 63.46 and 63.25; 54.76; 48.30 and 48.20;
5.33; 25.89; 18.35; -5.41 and -5.54. IR (neat) ν 3031; 2928;
94%). H NMR (D
2
O, 300 MHz) δ 8.00 (s, 1H); 5.74 (d, J ) 6.0,
1H); 4.32 (dd, J ) 3.0, 4.6, 1H); 4.15 (m, 1H); 3.99 (m, 2H); 2.96
(q, J ) 9.2, 12H); 2.73 (d, J ) 21.7, 2H); 1.02 (t, J ) 9.2, 18H).
1
3
2
C NMR (D O, 75 MHz) δ 174.27; 158.99; 154.03; 151.88; 137.70;
+
4
] .
116.22; 86.79; 84.13 (d, J ) 7.8); 73.81; 70.58; 64.04 (d, J ) 5.3);
688. MS (CI/NH
′,3′-O-Be n zylid e n e -5′-O-t er t -b u t yld im e t h ylsilyl- N -
ben zyl gu a n osin e (Table 1, entry 19, product; yield: 91%; 2
3
): 800 [M + NH
31
1
46.78; 37.01 (d, J ) 121.4); 8.34. P NMR (D O, 0.5 M Et N,
2
2
3
1
21 MHz) δ 18.20. IR (neat) ν 3422 (b); 3135; 2975; 2938.
1
HRMS: calcd for C12H15N O P 404.0607, found 404.0633 [M -
diastereomers). H NMR (CDCl
H); 7.60-7.15 (m, 5H); 6.12 and 5.98 (2s, 1H); 6.11 and 6.05
2d, J ) 2.5, 1H); 5.25 (m, 3H); 5.11 (m, 3H); 4.49 and 4.36 (2m,
3
, 200 MHz) δ 7.77 and 7.73 (2s,
5
9
-
H] .
2′,3′-O-Ben zylid en e-5′-O-(N-ben zyl-P ,P ′,P ′-tr iben zyl im i-
1
(
1
6
1
1
2
H); 3.81 (m, 2H); 0.91 and 0.88 (2s, 9H); 0.07, 0.06, 0.05 (3s,
d od ip h osp h a t e)- N-b en zyl- N-d ib en zyla m in om et h ylen e
1
3
1
H). C NMR (CDCl
3
, 75 MHz) δ 157.07; 153.32; 148.23; 136.05;
gu a n osin e (Table 2, entry 19; 4 diastereomers). H NMR
(CDCl , 300 MHz) δ 8.86 and 8.83 (2s, 1H); 7.80, 7.77, 7.74, and
3
35.80; 134.93; 129.92-126.56 (m); 117.98; 107.56; 104.24; 89.78
and 89.12; 86.37 and 85.26; 84.34; 82.49 and 80.82; 63.36 and
7.72 (4s, 1H); 7.60-7.15 (m, 40H); 6.16 and 6.15 (2d, J ) 1.9,
0.5H), 6.08 and 6.07 (2d, J ) 3.0, 0.5H); 6.09, 5.89, and 5.86
6
2
3.25; 44.87; 25.86; 18.31; -5.45 and -5.52. IR (neat) ν 2951;
+
927; 2854; 1690; 1630. MS (CI/NH
2
3
): 593 [M + NH
4
] .
(3s, 1H); 5.55 (AB system, ∆ν ) 10.5, J AB ) 13.9, 2H); 5.17 (m,
6
13
′,3′-O-Isop r op ylid en e- N-d im eth yla m in om eth ylen e a d -
3
1H); 5.05-4.31 (m, 14H); 4.25-3.95 (m, 2H). C NMR (CDCl ,
1
en osin e (Table 1, entry 16; yield: 99%). H NMR (CDCl
MHz) δ 8.81 (s, 1H); 8.37 (s, 1H); 7.98 (s, 1H); 5.87 (d, J ) 4.6,
H); 5.22 (dd, J ) 4.6, 5.8, 1H); 5.10 (dd, J ) 1.5, 5.8, 1H); 4.42
dd, J ) 1.5, 1.8, 1H); 3.75 (AB part of ABX system, ∆ν ) 19.0,
AX ) 1.8, J BX ) 2.6, J AB ) 12.4, 1H); 3.16 (s, 3H); 3.14 (s, 3H);
3
, 200
50 MHz) δ 158.07; 158.06; 157.20; 147.54; 138.25 and 137.84;
136.52, 135.67, 135.55, 135.41, 135.28, 135.03, 134.98, and
134.90; 129.86-126.49 (m); 120.50; 107.66, 104.36, and 104.31;
88.65 and 88.45; 84.87 and 84.72; 83.70, 83.42, and 82.24; 82.10,
81.98, and 80.61; 69.19; 69.07; 68.98 and 68.88; 66.13 and 66.04;
1
(
J

Notes
4.62; 50.81; 48.32; 45.46. 31P NMR (CDCl
J . Org. Chem., Vol. 64, No. 3, 1999 997
5
3
, 121 MHz) δ 4.71
) 3.6, 1P). HRMS: calcd for C10
441.0329 [M-H] .
H
15
N
6
O
10
P
2
441.0325, found
-
(
AB system, ∆ν ) 65.3, J AB ) 20.4); 4.67 (AB system, ∆ν ) 67.8,
AB ) 20.4); 4.66 (AB system, ∆ν ) 54.4, J AB ) 20.7); 4.56 (AB
system, ∆ν ) 59.9, J AB ) 20.4). IR (neat) ν 3031; 2926; 1691;
612; 1573.
′-O-Im id od ip h osp h a te gu a n osin e (Table 2, entry 19,
J
Ack n ow led gm en t. This work was supported by a
grant from MENRT (Minist e` re de l’ EÄ ducation Nationale,
de la Recherche et de la Technologie, France) to S.V.
1
5
1
product; yield: 91%). H NMR (D
2
O, 0.5 M Et
.00 (s, 1H); 5.83 (d, J ) 5.4, 1H); 4.60 (dd, J ) 5.1, 5.4, 1H);
.53 (dd, J ) 4.6, 5.1, 1H); 4.23 (m, 1H); 4.06 (m, 2H). 13C NMR
O, 0.5 M Et N, 75 MHz) δ 158.15; 154.38; 152.97; 137.35;
17.58; 87.66; 84.66; 74.15; 70.20; 64.06; 46.78; 10.64. P NMR
O, 0.5 M Et N, 121 MHz) δ 3.73 (d, J ) 3.6, 1P); -0.09 (d, J
3
N, 300 MHz) δ
1
Su p p or tin g In for m a tion Ava ila ble: Copies of the H and
C NMR spectra of all compounds described in the Experi-
mental Section. This material is available free of charge via
the Internet at http://pubs.acs.org.
8
4
13
(D
2
3
3
1
1
(D
2
3
J O980099G