Concave reagents, 28. - Comparison of bimacrocyclic, monomacrocyclic, and nonmacrocyclic bis(amidomethyl)pyridines as catalysts in the base- catalyzed addition of alcohols to ketenes

Article abstract of DOI:10.1002/(SICI)1099-0690(199904)1999:4<847::AID-EJOC847>3.0.CO;2-3

Nineteen new bimacrocyclic, monomacrocyclic, and nonmacrocyclic pyridines 1-6 bearing amide functions have been synthesized and utilized in base-catalyzed additions of alcohols (ethanol, 2-propanol) and polyols [propane-1,2-diol (11a), butane-1,3-diol (12a), methyl 4,6-O-benzylidene-α- D-glucopyranoside (13a)] to diphenylketene. Compounds 4c, 4d and 1b proved to be efficient and selective catalysts; 4c and 4d exhibited better results with 11a and 12a, and 1b was the best catalyst for selective 2-O-acylation of 13a.

Full text of DOI:10.1002/(SICI)1099-0690(199904)1999:4<847::AID-EJOC847>3.0.CO;2-3

FULL PAPER
Concave Reagents, 28[°]
Comparison of Bimacrocyclic, Monomacrocyclic, and Nonmacrocyclic
Bis(amidomethyl)pyridines as Catalysts in the Base-Catalyzed Addition
of Alcohols to Ketenes
Sönke Petersen[a] and Ulrich Lüning*[a]
Keywords: Ketene / Homogeneous catalysis / Hydrogen bonds / Molecular recognition / General base / Macrocycles
Nineteen new bimacrocyclic, monomacrocyclic, and
nonmacrocyclic pyridines 1–6 bearing amide functions have
been synthesized and utilized in base-catalyzed additions of
glucopyranoside (13a)] to diphenylketene. Compounds 4c,
4d and 1b proved to be efficient and selective catalysts; 4c
and 4d exhibited better results with 11a and 12a, and 1b was
alcohols (ethanol, 2-propanol) and polyols [propane-1,2-diol the best catalyst for selective 2-O-acylation of 13a.
(11a), butane-1,3-diol (12a), methyl 4,6-O-benzylidene-α-
D
-
The esterification of hydroxy groups is a very important the use of PFL (Pseudomonas fluorescens lipase) leads to
reaction, which is widely used for the protection of alcohol the 2-O-acylated model compound in 94% yield.[8] Despite
functions.[1] Three factors are important in choosing a suit- these good results, there is still a need for new and improved
able protecting group: (i) selective introduction, (ii) suf- selective acylation reagents as the applicability of enzymes
ficient stability to allow various transformations of the pro- is often limited by the solvents that can be used.[9] Gener-
tected molecule, and (iii) selective deprotection. Require- ally speaking, the substrates have to be hydrophilic.
ments (ii) and (iii) are fulfilled by the ester group. In natural
Steric control seems to be a major factor in determining
products such as carbohydrates, however, more than one the aforementioned selectivities. Consequently, the acy-
hydroxy group is likely to be present. Here, the key require- lation of alcohols and polyols by ketenes, as catalyzed by
ment is the selective introduction of protecting groups.
various sterically demanding bases, including the concave
Butane-1,3-diol (12a) has been widely used as a model bases 1 and 2, has been investigated, and selectivities have
compound in studies of the selective acylation of primary been measured for a number of model compounds.[10] The
and secondary hydroxy groups. Selective acylation of the ketenes used in these studies were diarylketenes.[11]
primary alcohol function has been accomplished in yields
of 80Ϫ99% with varying primary/secondary selectivities.[2]
Good results have been achieved by variation of the leaving
group of the acylating reagent and by employing sterically
hindered bases.[3]
With carbohydrates, differentiation between various sec-
ondary hydroxy groups is often important. These secondary
alcohol functions can be oriented axially or equatorially.
Many reagents have been tested with the model compound
methyl 4,6-O-benzylidene-α--glucopyranoside (13a), in
The mechanism of the base-catalyzed addition of al-
cohols to ketenes has been well investigated.[12] Two princi-
pal reaction pathways can be envisaged: activation of the
alcohol by the base through formation of a hydrogen
bond,[12b] or addition of the base to the ketene to form a
betaine as a reactive intermediate.[12c] Although keteneϪ
pyridine ylides have been observed in matrices,[13] in the
case of sterically shielded pyridines, such as the concave
pyridines 1 or 2, the base cannot react as a nucleophile due
to steric hindrance.[10a] Thus, with these bases, the catalysis
takes place by formation of a hydrogen bond between the
alcohol and the base. This increases the nucleophilicity of
the oxygen atom and facilitates nucleophilic attack on the
sp-hybridized carbon atom of the ketene. This reaction of
the alcohol oxygen atom with the ketene represents the sel-
which two secondary equatorial hydroxy groups are pre-
sent. While acyl chlorides in pyridine offer little selectivity
and lead to mixtures of 13b, 13c and 13d,[4] other reagents
favor acylation at the 2-position and thus selectively furnish
13b.[5] Using carboxylic acid imidazolides in combination
with dibutyltin oxide, a selectivity of 92:1 in favor of 13b
was found.[6] Excellent selectivities have also been realized
in enzyme-catalyzed acylations and deacylations.[7] Thus,
[°]
Part 27: U. Lüning, H. Ross, I. Thondorf, J. Chem. Soc., Perkin
Trans. 2 1998, 1313Ϫ1317.
[a]
Institut für Organische Chemie der Christian-Albrechts-
Universität zu Kiel,
Olshausenstraße 40, D-24098 Kiel, Germany
Fax: (internat.) ϩ 49(0)431/880-1558
E-mail: luening@oc.uni-kiel.de
Eur. J. Org. Chem. 1999, 847Ϫ854
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0404Ϫ0847 $ 17.50ϩ.50/0
847

S. Petersen, U. Lüning
FULL PAPER
Scheme 2. Synthesis of bis(amidomethyl)pyridines, as exemplified
by the case of the nonmacrocyclic pyridines 5 and 6; bimacrocyclic
or monomacrocyclic analogues 1Ϫ4 were obtained by using diva-
lent amines or acid chlorides[14]
ZZ). The yields, basicities, and conformer distributions are
listed in Table 1.
Compared to the bimacrocyclic pyridinebis(lactams) 1
and 2, the monomacrocycles 3 and 4 were obtained in bet-
ter yields as no second macrocycle had to be built-up and
thus high-dilution conditions were unnecessary. Com-
pounds 3 and 4 exhibit simpler NMR spectra than 1 and
2, despite the fact that they also exist as mixtures of con-
formers. In fact, the monomacrocycles 3 and 4 possess
higher symmetry than the bimacrocycles 1 and 2 (time aver-
aged, the molecules are planar). Diphenylketene was syn-
thesized as described previously.[18]
Scheme 1
ectivity-determining step. Steric shielding at both the ketene
and the baseϪalcohol complex changes the activation pa-
rameters for the addition and thus has an influence on the
selectivity. The outcome of the acylation can thus be influ-
enced by judicious choice of the pyridine catalyst.
Selectivity Measurements
The various catalysts 1Ϫ6 were subsequently tested in the
acylation of hydroxy groups with diphenylketene. Table 2
lists the selectivities achieved with these pyridine catalysts in
Syntheses of the Catalysts 1؊6
The syntheses of the catalysts 1Ϫ6 were carried out in anal- four model reactions using diphenylketene as the acylating
ogy to literature procedures.[10b,14] Nineteen new com- agent. The four model reactions[10] were (i) an intermolecu-
pounds have been fully characterized. All syntheses started lar competition between the primary alcohol ethanol and
from pyridine-2,6-dicarbaldehydes.[10b,14] In the first step, the secondary alcohol 2-propanol, (ii) and (iii) two intra-
Schiff bases were formed by reaction with primary mono- molecular competitions between primary and secondary
or diamines. The resulting diimides were then reduced with hydroxy groups in propane-1,2-diol (11a) and butane-1,3-
sodium tetrahydroborate to give monomacrocyclic second- diol (12a), and (iv) an intramolecular competition between
ary diamines[10b,14] and nonmacrocyclic secondary diamines two secondary equatorial hydroxy groups in the glucose de-
8 and 9. In the second reaction step, these secondary di- rivative 13a.
amines were acylated using mono- or diacid chlorides to
The reaction mixtures were analyzed by GC in the case
give bimacrocyclic (1 and 2), monomacrocyclic (3 and 4), of the ethyl and isopropyl esters 10a and 10b, as were the
and nonmacrocyclic (5 and 6) pyridinebis(lactams) (1 and product mixtures 11b/11c and 12b/12c, after derivatization
2) and -diamides (3Ϫ6, see Scheme 2). The basicities of the of the remaining alcohol functions with trimethylsilyl chlo-
products in ethanol solution were measured using an estab- ride. The carbohydrate mixtures 13aϪ13d were analyzed by
lished photometric titration against thymol blue,[15] which 1H-NMR spectroscopy.
gives relative basicities lg K. Due to the amide functions, all
Besides the concave pyridines 1 and 2, some of the mono-
pyridines 1Ϫ6 exist as mixtures of conformers (EE, EZ, and nonmacrocyclic pyridines 3Ϫ6 also selectively catalyzed
848
Eur. J. Org. Chem. 1999, 847Ϫ854

Concave Reagents, 28
Table 1. Yields, basicities (listed as lg K values[15]), and conformer distributions of the pyridinebis(lactams) 1Ϫ6
FULL PAPER
R
polyether chain or X
Y
yield (%)
lg K
ZZ/EZ/EE
1a
1b
1c
1d
1e
2a
2b
2d
2e
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
5a
5b
5d
6a
6b
6c
6d
6e
H
CH2[CH2OCH2]3CH2
CH2[CH2OCH2]3CH2
CH2[CH2OCH2]3CH2
CH2[CH2OCH2]3CH2
CH2[CH2OCH2]3CH2
CH2[CH2OCH2]2CH2
CH2[CH2OCH2]2CH2
CH2[CH2OCH2]2CH2
CH2[CH2OCH2]2CH2
CH2[CH2OCH2]3CH2
CH2[CH2OCH2]3CH2
CH2[CH2OCH2]3CH2
CH2[CH2OCH2]3CH2
CH2[CH2OCH2]3CH2
CH2[CH2OCH2]2CH2
CH2[CH2OCH2]2CH2
CH2[CH2OCH2]2CH2
CH2[CH2OCH2]2CH2
CH2[CH2OCH2]2CH2
Ph
[CH2]10
[CH2]10
[CH2]10
[CH2]10
[CH2]8
[CH2]10
[CH2]10
[CH2]10
[CH2]8
Me
48[14]
45[14]
20[16]
46[10b]
44
Ϫ0.30[14]
1.00[14]
ca. 4.0[16]
1.30
75:ca. 23:< 5[14]
68:27:5[14]
71:23:6[16]
68:27:5[10b]
60:34:6
63:25:12[14]
54:28:18[14]
34:46:20
18:69:13
18:60:22
Ϫ[a]
OMe
NEt2
OEt
OEt
1.10
H
56[17]
44[14]
46[10b]
24
0.60[14]
> 1.40[14]
2.20
OMe
OEt
OEt
ca. 2.5
0.60
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
86
tBu
76
1.10
Ph
Bzl
49
0.40
Ϫ[a]
39
0.45
20:60:20
20:60:20
25:50:25
Ϫ[a]
CH2Bzl
Me
42
0.75
60
1.30
tBu
61[10b]
66
1.70
Ph
1.20
Ϫ[a]
Bzl
44
1.40
25:50:25
25:50:25
Ϫ[a]
CH2Bzl
Me
75
1.50
22
ca. Ϫ0.45
ca. 0.45
ca. 1.10
Ϫ0.40
Ϫ0.20
Ϫ0.70
Ϫ0.60
Ϫ0.50
Ph
tBu
17
Ϫ[a]
Ph
Bzl
28
Ϫ[a]
Bzl
Me
52
25:50:25
Bzl
tBu
67
Ϫ[a]
Bzl
Ph
61
50:00:50
20:60:20
20:60:20
Bzl
Bzl
55
Bzl
CH2Bzl
50
[a]
Conformer distributions could not be determined (broad signals).
Scheme 3
Scheme 5
dines 5 and 6 produced comparable or lower selectivities
than the bimacrocycles 1 and 2.
In the intramolecular competitions (acylation of the diols
11a and 12a), the monomacrocycles 3 and 4 again proved
to be selective catalysts. The 15-membered ring systems 3
gave rise to 11b/11c selectivities of 20 to 28, while the larger
Scheme 4
acylation of the primary hydroxy groups in the ethanol/2- macrocycles 4 led to favored formation of the primary ester
propanol mixture (intermolecular competition) and in the by factors of 11.5 to 14.
diols 11a and 12a (intramolecular competition). The most
promising catalysts 1Ϫ6 were then employed in the acyl- to favored formation of the 2-O derivative 13b over the 3-
ation of the sugar derivative 13a with diphenylketene. O derivative 13c with selectivities comparable to those
With the carbohydrate 13a, some monomacrocycles led
Compared to the bimacrocycles 1 and 2 as well as to achieved with the most effective bimacrocycle 1b. A com-
regular pyridines, the results in Table 2 show that in the parison of catalysts 1b, 4c and 4d reveals a better conversion
intermolecular competition between ethanol and 2-propa- with the monomacrocycles 4c and 4d (100% and 93%) than
nol, the monomacrocycles 3 are the most selective catalysts with 1b (85%), but the monomacrocycles allow the forma-
of all the pyridines investigated. The nonmacrocyclic pyri- tion of some 3-O-acyl derivative 13c. While the starting ma-
Eur. J. Org. Chem. 1999, 847Ϫ854
849

S. Petersen, U. Lüning
FULL PAPER
Table 2. Selectivities achieved in base-catalyzed acylations of different hydroxy groups with diphenylketene in four sets of experiments:
intermolecular competition: EtOH/iPrOH; intramolecular competition: 11a, 12a and 13a (reaction time 15 h)
catalyst
product ratios
product ratio
13a/13b/13c/13d
10a/10b
11b/11c
12b/12c
without catalyst
3.4
4.7
4.9
7.1
9.1
7.9
10.0
12.0
10.5
6.3
3.5
4.1
4.0
3.5
14
2.7
6.3
9.7
Ϫ
24.0
10.3
13.0
Ϫ
2.5
8.7
Ϫ
22.0
40.0
Ϫ
23.0
Ϫ
Ϫ
Ϫ
Ϫ
4.2
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
74
18
8
Ϫ
7
pyridine
36
45
12
Ϫ
32
31
Ϫ
Ϫ
Ϫ
Ϫ
trace
Ϫ
8
2-picoline
Ϫ
Ϫ
Ϫ
14
19
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
2,6-lutidine
34
20
24
Ϫ
85
Ϫ
57
22
Ϫ
24
Ϫ
2,4,6-collidine
26[a]
Ϫ
1a
1b
1c
1d
1e
2a
2b
2d
2e
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
5a
5b
5d
6a
6b
6c
6d
6e
15[b]
Ϫ
13.2
7.5
4.0
4.5
5.0
4.0
13
43
78
Ϫ
68
Ϫ
Ϫ
Ϫ
Ϫ
4
15
10
9
Ϫ
56[c]
52[c]
35[c]
17[c]
33[c]
42[c]
36[c]
Ϫ[c]
7[c]
18[c]
Ϫ
40
33
55
74
63
51
53
93
89
76
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
15
11.5
12
13
13
12
Ϫ
Ϫ
13
14
4
11.2
12.8
8.6
11.2
13.9
9.9
12.9
8.5
6.3
6.3
4.4
4.6
5.2
23
16
21
16
21
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
7
24
11
7
20
24
4
6
28
9.1
10.2
11.5
12.5
14.5
14.2
10.5
13.3
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
[a]
[b]
[c]
10 equiv. of base. Ϫ 0.02 equiv. of base. Ϫ 1.50 equiv. of diphenylketene.
Syntheses of Pyridinediamines 8 and 9. ؊ General Procedure: One
equivalent of 4-methoxypyridine-2,6-dicarbaldehyde (7)[14]
(3.0Ϫ9.1 mmol) was dissolved in 150 mL of dry methanol. Under
nitrogen, 2.2 equivalents of aniline or benzylamine, dissolved in 30
mL of dry methanol, were added over a period of ca. 30 min. The
reddish-brown mixture was stirred for 1 h at room temperature and
was then heated under reflux for several hours until no further
reaction could be detected by TLC (reaction time 2.5Ϫ4 h). After
cooling to 0°C, sodium tetrahydroborate (18.2Ϫ54.6 mmol) was
added in small portions. The resulting mixture was stirred for 15 h
at room temperature, 50 mL of water was added, and stirring was
continued for a further 6 h. The mixture was then concentrated to
a volume of 100 mL, whereupon it became very turbid owing to
terial 13a can easily be removed from the 2-O-acyl deriva-
tive 13b by chromatography, the separation of 13b and 13c
is tedious. Therefore, it is advisable to aim for selectivity
rather than for maximum conversion. Formation of the di-
acyl derivative 13d was not observed with any of the bi- or
monomacrocycles 1Ϫ4.
Conclusions
Three different types of 2,6-disubstituted pyridines bear-
ing amidomethyl substituents have been investigated as
catalysts. For the acylation of polyols, efficient and selective the precipitation of borates. After filtration, the dark-brown solu-
tion was extracted four times with 100 mL of dichloromethane. The
combined organic extracts were dried with MgSO4 and filtered.
The solvents were evaporated and the residue was dried in vacuo.
catalysts have only been found among the monomacro-
cycles and bimacrocycles (4c, 4d and 1b). Among the mono-
macrocycles, a 15-membered ring (4 in contrast to 3) is es-
sential for selectivity, while the bimacrocycles require one
4-Methoxy-2,6-bis(phenylaminomethyl)pyridine (8): Starting materi-
additional ethylene oxide moiety between the two amide ni- als: 1.00 g (3.6 mmol) of 4-methoxypyridine-2,6-dicarbaldehyde[14]
(7), 0.62 g (6.7 mmol) of aniline, 0.69 g (18.2 mmol) of sodium
trogen atoms (1). As with enzymes, there is no single opti-
mal catalyst for all substrates; the best catalyst for each sub-
strate may vary and has to be found in each specific case.
1
tetrahydroborate. Yield: 0.84 g (87%), brown oil. Ϫ H NMR (200
MHz, CDCl3): δ ϭ 3.77 (s, 3 H), 4.41 (s, 4 H), 4.67 (br. s, ca. 2 H,
exchangeable with D2O), 6.6Ϫ6.8 (m, ca. 8 H), 7.1Ϫ7.3 (m, ca. 4
H). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ 53.5 (t), 54.6 (t), 55.1
(q), 106.5 (d), 127.0 (d), 128.3 (d), 128.4 (d), 140.2 (s), 161.0 (s),
166.7 (s). Ϫ IR (KBr): ν˜ ϭ 3400 cmϪ1 (br., NH), 1603 (arom.),
1573 (arom.). Ϫ MS (EI, 70 eV); m/z (%): 319 (100) [Mϩ], 318 (31),
226 (44). Ϫ MS (CI, isobutane); m/z (%): 320 (100) [Mϩ ϩ H], 319
Experimental Section
General Remarks: See refs.[10b,10c] The selectivity measurements
were carried out as described in ref.[10c]
850
Eur. J. Org. Chem. 1999, 847Ϫ854

Concave Reagents, 28
FULL PAPER
(15) [Mϩ]. Ϫ HR MS: C20H21N3O: calcd. 319.1685; found ca. 0.9 H), 4.72 (s, ca. 0.7 H), 4.76 (s, 1.2 H), 6.53 (d, J ϭ 2.2 Hz,
319.1684. C1913CH21N3O: calcd. 320.1718; found 320.1718.
0.6 H, PyHEZ), 6.58 (s, 0.36 H, PyHZZ), 6.76 (s, 0.44 H, PyHEE),
6.80 (d, J ϭ 2.2 Hz, 0.6 H, PyHEZ). Ϫ 1H NMR (200 MHz, CDCl3,
7.8 equiv. of picric acid): δ ϭ 2.11 (br. s, ca. 1.3 H), 2.22 (br. s, ca.
1.3 H), 2.24 (br. s, ca. 3.4 H), 3.3Ϫ3.8 (m, ca. 16 H), 4.08 (s, ca. 1
H), 4.09 (s, ca. 2 H), 4.91 (s, ca. 2.72 H), 4.93 (s, ca. 0.64 H), 5.07
(s, ca. 0.64 H), 6.96 (d, J ϭ 2.0 Hz, 0.35 H, PyHEZ), 7.06 (d, J ϭ
2.0 Hz, 0.35 H, PyHEZ), 7.15 (s, 1.30 H), 9.13 (br. s, ca. 15.6 H,
picric acid). Ϫ IR (KBr): ν˜ ϭ 1624 cmϪ1 (CϭO), 1576 (arom.). Ϫ
MS (EI, 70 eV); m/z (%): 409 (55) [Mϩ], 366 (86) [Mϩ Ϫ COCH3],
320 (35), 291 (39), 281 (48), 248 (60), 220 (97), 137 (100). Ϫ MS
(CI, isobutane); m/z (%): 410 (100) [Mϩ ϩ H], 409 (4) [Mϩ]. Ϫ
C20H31N3O6 (409.2): calcd. C 58.67, H 7.63, N 10.26; found C
58.48, H 7.57, N 10.19.
4-Methoxy-2,6-bis(benzylaminomethyl)pyridine (9): Starting materi-
als: 1.50 g (3.6 mmol) of 4-methoxypyridine-2,6-dicarbaldehyde[14]
(7), 2.14 g (20.0 mmol) of benzylamine, 2.06 g (54.6 mmol) of so-
dium tetrahydroborate. Yield: 2.34 g (73%), brown oil. Ϫ 1H NMR
(200 MHz, CDCl3): δ ϭ 2.50 (br. s, ca. 2 H, exchangeable with
D2O), 3.83 (s, 8 H), 3.86 (s, 3 H), 6.75 (s, 2 H), 7.2Ϫ7.4 (m, 10 H).
Ϫ IR (KBr): ν˜ ϭ 3300 cmϪ1 (br., NH), 1598 (arom.), 1574 (arom.).
Ϫ MS (EI, 70 eV); m/z (%): 347 (1) [Mϩ], 242 (100). Ϫ MS (CI,
isobutane); m/z (%): 348 (100) [Mϩ ϩ H], 242 (11).
27-Ethoxy-4,7,10-trioxa-1,13,31-triazatricyclo[11.10.7.125,29]hentri-
aconta-25(31),26,28-triene-14,23-dione (1e): Synthetic procedure see
ref.[14]; amounts used: 2.10 g (6.2 mmol) of 19-ethoxy-6,9,12-trioxa-
3,15,21-triazabicyclo[15.3.1]heneicosa-1(20),17(21),18-triene,[10c]
1.48 g (6.2 mmol) of sebacoyl dichloride, 3.76 g (37.2 mmol) of
NEt3. Yield: 1.37 g (44%), colorless needles, m.p. 118Ϫ119°C. Ϫ
1H NMR (500 MHz, CDCl3): δ ϭ 1.0Ϫ1.7 (m, ca. 19 H), 2.1Ϫ2.6
(m, ca. 4 H), 3.1Ϫ4.3 (m, ca. 14 H), 4.4Ϫ5.3 (m, ca. 4 H), 6.52 (s,
1.2 H, PyHZZ), 6.52 (d, J ϭ 2.2 Hz, ca. 0.34 H, PyHEZ), 6.76 (d,
J ϭ 2.2 Hz, ca. 0.34 H, PyHEZ), 6.90 (s, 0.12 H, PyHEE). Ϫ IR
(KBr): ν˜ ϭ 1649 cmϪ1 (CϭO), 1600 (arom.), 1572 (arom.). Ϫ MS
(EI, 70 eV); m/z (%): 505 (100) [Mϩ], 475 (32), 416 (38). Ϫ MS
(CI, isobutane); m/z (%): 506 (100) [Mϩ ϩ H], 505 (6) [Mϩ]. Ϫ
C27H43N3O6 (505.3): calcd. C 64.13, H 8.57, N 8.31; found C 64.42,
H 8.78, N 7.80.
3,15-Bis(2,2-dimethylpropionyl)-19-methoxy-6,9,12-trioxa-3,15,21-
triazabicyclo[15.3.1]heneicosa-1(20),17(21),18-triene (3b): Starting
materials: 1.08 g (3.3 mmol) of 19-methoxy-6,9,12-trioxa-3,15,21-
triazabicyclo[15.3.1]heneicosa-1(20),17(21),18-triene,[14] 0.88 g (7.3
mmol) of pivaloyl chloride, 2.02 g (20.0 mmol) of NEt3. Yield: 1.25
g (76%), pale-yellow oil. Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 1.32
(s, ca. 18 H), 3.5Ϫ3.8 (m, ca. 16 H), 3.79 (s, 3 H), 4.88 (br. s, 4 H),
6.61 (s, 2 H). Ϫ IR (KBr): ν˜ ϭ 1633 cmϪ1 (CϭO), 1574 (arom.).
Ϫ MS (EI, 70 eV); m/z (%): 493 (23) [Mϩ], 436 (54) [Mϩ Ϫ C4H9],
408 (100) [Mϩ Ϫ COC(CH3)3], 367 (30), 137 (60). Ϫ MS (CI, isobu-
tane); m/z (%): 493 (100) [Mϩ ϩ H], 492 (6) [Mϩ]. Ϫ HR MS:
C26H43N3O6: calcd. 493.3152; found 493.3152. C2513CH43N3O6:
calcd. 494.3185; found 494.3184. Ϫ C26H43N3O6 (493.2): calcd. C
63.26, H 8.78, N 8.51; found C 63.92, H 8.97, N 8.53.
24-Ethoxy-15,18-dioxa-1,12,28-triazatricyclo[10.8.7.122,26]octacosa-
22(28),23,25-triene-2,11-dione (2e): Synthetic procedure see ref.[14]
;
3,15-Dibenzoyl-19-methoxy-6,9,12-trioxa-3,15,21-triazabicyclo-
[15.3.1]heneicosa-1(20),17(21),18-triene (3c): Starting materials:
1.30 g (4.0 mmol) of 19-methoxy-6,9,12-trioxa-3,15,21-triazabicy-
clo[15.3.1]heneicosa-1(20),17(21),18-triene,[14] 1.24 g (8.8 mmol) of
benzoyl chloride, 2.42 g (24.0 mmol) of NEt3. Yield: 1.04 g (49%),
amounts used: 1.74 g (5.9 mmol) of 16-ethoxy-6,9-dioxa-3,12,18-
triazabicyclo[12.3.1]octadeca-1(17),14(18),15-triene,[10c] 1.26 g (5.9
mmol) of sebacoyl dichloride, 3.58 g (35.4 mmol) of NEt3. Yield:
0.65 g (24%), colorless oil, slowly crystallizing, m.p. 104Ϫ107°C.
Ϫ
1H NMR (200 MHz, CDCl3): δ ϭ 0.8Ϫ1.8 (m, ca. 19 H),
1
pale-yellow oil. Ϫ H NMR (200 MHz, CDCl3): δ ϭ 3.4Ϫ3.9 (m,
1.8Ϫ2.5 (m, ca. 4 H), 3.0Ϫ4.4 (m, ca. 10 H), 4.7Ϫ5.4 (m, ca. 4 H),
6.57 (s, 0.36 H, PyHZZ), 6.59 (d, J ϭ 2.0 Hz, 0.69 H, PyHZE), 6.81
(d, J ϭ 2.0 Hz, 0.69 H, PyHZE), 6.87 (s, 0.26 H, PyHEE). Ϫ IR
(KBr): ν˜ ϭ 1636 cmϪ1 (CϭO), 1596 (arom.), 1571 (arom.). Ϫ MS
(EI, 70 eV); m/z (%): 461 (88) [Mϩ], 431 (64), 416 (50), 151 (100).
Ϫ C25H39N3O6 (461.3): calcd. C 65.05, H 8.52, N 9.10; found C
65.22, H 8.56, N 8.86.
ca. 19 H), 4.7Ϫ5.1 (m, ca. 4 H), 6.5Ϫ6.7 (m, ca. 1 H), 6.8Ϫ7.0 (m,
ca. 1 H), 7.40 (mc, ca. 10 H). Ϫ IR (KBr): ν˜ ϭ 1636 cmϪ1 (CϭO),
1599 (arom.), 1575 (arom.). Ϫ MS (EI, 70 eV); m/z (%): 533 (16)
[Mϩ], 428 (23) [Mϩ Ϫ COPh], 105 (100) [C7H5Oϩ]. Ϫ MS (CI,
isobutane); m/z (%): 534 (100) [Mϩ ϩ H], 533 (5) [Mϩ]. Ϫ HR MS:
C30H35N3O6: calcd. 533.2526; found 533.2523. C2913CH35N3O6:
calcd. 534.2559; found 534.2558. Ϫ C30H35N3O6 (533.3): calcd. C
67.53, H 6.61, N 7.87; found C 66.26, H 6.47, N 7.61.
Syntheses of Pyridinebis(lactams) 3, 4, 5 and 6. ؊ General Pro-
cedure: One equivalent of the appropriate pyridinediamine[14]
(1.6Ϫ5.6 mmol) and six equivalents of triethylamine were dissolved
in 100 mL of dry dichloromethane. To this, 2.1 equivalents of the
appropriate acid chloride, dissolved in 25 mL of dry dichlorometh-
ane, were added over a period of 1 h. The resulting mixture was
stirred for 15 h at room temperature, then concentrated to a volume
of 50 mL, and washed with 50 mL of 2  NaOH solution. The
aqueous layer was extracted three times with 100 mL of dichloro-
methane. The combined organic phases were dried with MgSO4
and filtered. After evaporation of the solvent, the remaining oil was
purified by column chromatography (silica gel, 100 g, diameter 4
cm, dichloromethane/ethanol, 10:1) and radial chromatography
(Chromatotron, dichloromethane).
19-Methoxy-3,15-bis(phenylacetyl)-6,9,12-trioxa-3,15,21-triaza-
bicyclo[15.3.1]heneicosa-1(20),17(21),18-triene (3d): Starting materi-
als: 1.82 g (5.6 mmol) of 19-methoxy-6,9,12-trioxa-3,15,21-triazab-
icyclo[15.3.1]heneicosa-1(20),17(21),18-triene,[14] 1.90
g
(12.3
mmol) of phenylacetyl chloride, 3.39 g (33.6 mmol) of NEt3. Yield:
1.21 g (39%), pale-yellow oil. Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ
1.50 (br. s, 1 H, H2O), 3.4Ϫ3.8 (m, ca. 19 H), 4.65 (s, 1.2 H), 4.71
(s, 0.8 H), 4.74 (s, 0.8 H), 4.80 (s, 1.2 H), 6.35 (d, J ϭ 2.4 Hz, 0.6
H, PyHEZ), 6.37 (s, 0.4 H, PyHZZ), 6.67 (s, 0.4 H, PyHEE), 6.72 (d,
J ϭ 2.4 Hz, 0.6 H, PyHEZ), 7.2Ϫ7.4 (m, 10 H). Ϫ IR (KBr): ν˜ ϭ
1644 cmϪ1 (CϭO), 1599 (arom.), 1574 (arom.). Ϫ MS (EI, 70 eV);
m/z (%): 561 (32) [Mϩ], 470 (19) [Mϩ Ϫ C7H7], 442 (28) [Mϩ
Ϫ
COCH2Ph], 324 (17), 137 (48), 91 (100) [C7H7ϩ]. Ϫ MS (CI, isobu-
tane); m/z (%): 562 (100) [Mϩ ϩ H], 561 (5) [Mϩ]. Ϫ HR MS:
C32H39N3O6: calcd. 561.2839; found 561.2836. C3113CH39N3O6:
calcd. 562.2872; found 562.2870. Ϫ C32H39N3O6 · 0.5 H2O (561.3
ϩ 9.0): calcd. C 67.35, H 7.07, N 7.36; found C 67.59, H 7.12,
N 7.19.
3,15-Diacetyl-19-methoxy-6,9,12-trioxa-3,15,21-triazabicyclo-
[15.3.1]heneicosa-1(20),17(21),18-triene (3a): Starting materials:
0.82 g (2.5 mmol) of 19-methoxy-6,9,12-trioxa-3,15,21-triazabicy-
clo[15.3.1]heneicosa-1(20),17(21),18-triene,[14] 0.42 g (5.3 mmol) of
acetyl chloride, 1.54 g (15.3 mmol) of NEt3. Yield: 0.90 g (86%),
1
m.p. 72Ϫ74°C. Ϫ H NMR (200 MHz, CDCl3): δ ϭ 2.13 (s, ca. 3
H), 2.17 (s, ca. 3 H), 3.4Ϫ3.8 (m, ca. 16 H), 3.81 (s, ca. 0.75 H), 19-Methoxy-3,15-bis(3-phenylpropionyl)-6,9,12-trioxa-3,15,21-tri-
3.83 (s, ca. 1.65 H), 3.84 (s, ca. 0.6 H), 4.62 (s, ca. 1.2 H), 4.70 (s,
azabicyclo[15.3.1]heneicosa-1(20),17(21),18-triene (3e): Starting ma-
Eur. J. Org. Chem. 1999, 847Ϫ854
851

S. Petersen, U. Lüning
FULL PAPER
terials: 1.44 g (4.4 mmol) of 19-methoxy-6,9,12-trioxa-3,15,21-tri-
3.1Ϫ3.9 (m, ca. 19 H), 4.7Ϫ4.8 (m, 4 H), 6.22 (d, J ϭ 2.2 Hz, 0.5
azabicyclo[15.3.1]heneicosa-1(20),17(21),18-triene,[14] 1.64 g (9.8 H, PyHEZ), 6.28 (s, 0.5 H, PyHZZ), 6.62 (s, 0.5 H, PyHEE), 6.67 (d,
mmol) of 3-phenylpropionyl chloride, 2.68 g (26.6 mmol) of NEt3.
J ϭ 2.2 Hz, 0.5 H, PyHEZ), 7.2Ϫ7.4 (m, ca. 10 H). Ϫ 1H NMR
Yield: 1.11 g (42%), yellow oil. Ϫ 1H NMR (200 MHz, CDCl3): (200 MHz, CDCl3, 9.1 equiv. of picric acid): δ ϭ 3.15 (s, 4 H),
δ ϭ 2.6Ϫ2.8 (m, 4 H), 2.9Ϫ3.1 (m, 4 H), 3.4Ϫ3.8 (m, ca. 19 H), 3.3Ϫ3.9 (m, 12 H), 4.03 (s, 3 H), 4.89 (s, 4 H), 7.1Ϫ7.4 (m, ca. 12
4.59 (s, 1.2 H), 4.64 (s, 0.8 H), 4.69 (s, 0.8 H), 4.74 (s, 1.2 H), 6.43
H), 9.15 (br. s, ca. 18.2 H, picric acid). Ϫ IR (KBr): ν˜ ϭ 1644 cmϪ1
(d, J ϭ 2.2 Hz, 0.6 H, PyHEZ), 6.45 (s, 0.4 H, PyHZZ), 6.73 (s, 0.4 (CϭO), 1599 (arom.), 1574 (arom.). Ϫ MS (EI, 70 eV); m/z (%):
H, PyHEE), 6.76 (d, J ϭ 2.2 Hz, 0.6 H, PyHEZ), 7.1Ϫ7.3 (m, ca.
517 (48) [Mϩ], 426 (32) [Mϩ Ϫ C7H7], 398 (38) [Mϩ Ϫ COCH2Ph],
91 (100) [C7H7ϩ]. Ϫ MS (CI, isobutane); m/z (%): 518 (100) [Mϩ
10 H). Ϫ IR (KBr): ν˜ ϭ 1644 cmϪ1 (CϭO), 1599 (arom.), 1574
(arom.). Ϫ MS (EI, 70 eV); m/z (%): 589 (35) [Mϩ], 484 (5) [Mϩ ϩ H], 517 (7) [Mϩ]. Ϫ HR MS: C30H35N3O5: calcd. 517.2577;
Ϫ C8H9], 456 (28) [Mϩ Ϫ COCH2CH2Ph], 105 (62) [C8H9ϩ], 91 found 517.2575. C2913CH35N3O5: calcd. 518.2611; found 518.2609.
(100) [C7H7ϩ]. Ϫ MS (CI, isobutane); m/z (%): 590 (100) [Mϩ
ϩ
Ϫ C30H35N3O5 (517.3): calcd. C 69.61, H 6.82, N 8.12; found C
H], 589 (6) [Mϩ]. Ϫ HR MS: C34H43N3O6: calcd. 589.3152; found
589.3152. C3313CH43N3O6: calcd. 590.3185; found 590.3185. Ϫ
C34H43N3O6 (589.3): calcd. C 69.25, H 7.35, N 7.13; found C 68.70,
H 7.36, N 6.86.
69.14, H 6.78, N 8.04.
16-Methoxy-3,12-bis(3-phenylpropionyl)-6,9-dioxa-3,12,18-triaza-
bicyclo[12.3.1]octadeca-1(17),14(18),15-triene (4e): Starting materi-
als: 1.00 g (3.6 mmol) of 16-methoxy-6,9-dioxa-3,12,18-triazabicy-
clo[12.3.1]octadeca-1(17),14(18),15-triene,[14] 1.32 g (7.8 mmol) of
3-phenylpropionyl chloride, 2.16 g (21.4 mmol) of NEt3. Yield: 1.48
g (75%), pale-yellow oil. Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ
3,12-Diacetyl-16-methoxy-6,9-dioxa-3,12,18-triazabicyclo-
[12.3.1]octadeca-1(17),14(18),15-triene (4a): Starting materials: 1.25
g
(4.5 mmol) of 16-methoxy-6,9-dioxa-3,12,18-triazabicy-
clo[12.3.1]octadeca-1(17),14(18),15-triene,[14] 0.77 g (9.8 mmol) of 2.6Ϫ2.9 (m, ca. 4 H), 2.9Ϫ3.1 (m, ca. 4 H), 3.1Ϫ3.8 (m, ca. 15 H),
acetyl chloride, 2.70 g (26.7 mmol) of NEt3. Yield: 0.97 g (60%), 4.51 (s, 1 H), 4.59 (s, 1 H), 4.66 (s, 1 H), 4.69 (s, 1 H), 6.47 (s, 0.5
yellow oil, slowly crystallizing, m.p. 70Ϫ74°C. Ϫ 1H NMR (300 H, PyHZZ), 6.50 (d, J ϭ 2.2 Hz, 0.5 H, PyHEZ), 6.81 (s, 0.5 H,
MHz, CDCl3): δ ϭ 2.17 (s, ca. 3.0 H), 2.25 (s, ca. 1.50 H), 2.27 (s,
ca. 1.75 H), 3.0Ϫ3.8 (m, 12 H), 4.60 (s, 1 H), 4.65 (s, 1 H), 4.68 (s,
PyHEE), 6.86 (d, J ϭ 2.2 Hz, 0.5 H, PyHZZ), 7.1Ϫ7.4 (m, ca. 10
H). Ϫ H NMR (200 MHz, CDCl3, 9.1 equiv. of picric acid): δ ϭ
1
2 H), 6.58 (s, 0.5 H, PyHZZ), 6.59 (d, J ϭ 2.3 Hz, 0.5 H, PyHEZ), 2.6Ϫ2.8 (m, ca. 4 H), 2.9Ϫ3.1 (m, ca. 4 H), 3.1Ϫ3.2 (m, ca. 4 H),
1
6.82 (s, 0.5 H, PyHEE), 6.88 (d, J ϭ 2.3 Hz, 0.5 H, PyHEZ). Ϫ H 3.3Ϫ3.5 (m, ca. 4 H), 3.6Ϫ3.8 (m, ca. 4 H), 3.92 (s, 0.60 H), 4.03
NMR (200 MHz, CDCl3, 6.1 equiv. of picric acid): δ ϭ 2.18 (br. (s, 2.40 H), 4.80 (s, 0.60 H), 4.88 (s, 3.40 H), 7.1Ϫ7.4 (m, ca. 12
s, ca. 1.5 H), 2.25 (br. s, ca. 4.5 H), 3.20 (br. s, 4 H), 3.4Ϫ3.9 (m,
H), 9.15 (br. s, ca. 18.2 H, picric acid). Ϫ IR (KBr): ν˜ ϭ 1644 cmϪ1
(CϭO), 1600 (arom.), 1574 (arom.). Ϫ MS (EI, 70 eV); m/z (%):
ca. 8 H), 4.08 (s, ca. 0.75 H), 4.10 (s, ca. 2.25 H), 4.90 (br. s, ca. 4
H), 6.91 (d, J ϭ 2.3 Hz, 0.10 H, PyHEZ), 7.30 (s, 1.8 H), 7.34 (d, 545 (100) [Mϩ], 440 (8) [Mϩ
Ϫ Ϫ
C8H9], 412 (83) [Mϩ
J ϭ 2.3 Hz, 0.10 H, PyHEZ), 9.13 (br. s, ca. 12.2 H, picric acid). Ϫ COCH2CH2Ph], 137 (94). Ϫ MS (CI, isobutane); m/z (%): 546
IR (KBr): ν˜ ϭ 1633 cmϪ1 (CϭO), 1598 (arom.), 1571 (arom.). Ϫ
MS (EI, 70 eV); m/z (%): 365 (70) [Mϩ], 335 (29), 322 (77) [Mϩ
(100) [Mϩ ϩ H], 545 (11) [Mϩ]. Ϫ HR MS: C32H39N3O5: calcd.
Ϫ
545.2890; found 545.2887. C3113CH39N3O5: calcd. 546.2923; found
COCH3]. Ϫ MS (CI, isobutane); m/z (%): 366 (100) [Mϩ ϩ H], 365 546.2920. Ϫ C32H39N3O5 (545.3): calcd. C 70.44, H 7.20, N 7.70;
(4) [Mϩ].
Ϫ
HR MS: C18H27N3O5: calcd. 365.1951; found
found C 70.28, H 7.31, N 7.60.
365.1947. C1713CH27N3O5: calcd. 366.1984; found 366.1983. Ϫ
C18H27N3O5 (365.2): calcd. C 59.16, H 7.45, N 11.50; found C
59.15, H 7.50, N 11.42.
2,6-Bis[(N-acetyl-N-phenylamino)methyl]-4-methoxypyridine (5a):
Starting materials: 0.94 g (2.9 mmol) of 4-methoxy-2,6-bis(phenyla-
minomethyl)pyridine (8), 0.94 g (2.9 mmol) of acetyl chloride, 1.79
1
3,12-Dibenzoyl-16-methoxy-6,9-dioxa-3,12,18-triazabicyclo[12.3.1]-
octadeca-1(17),14(18),15-triene (4c): Starting materials: 1.00 g (3.6
mmol) of 16-methoxy-6,9-dioxa-3,12,18-triazabicyclo[12.3.1]octa-
g (17.7 mmol) of NEt3. Yield: 0.35 g (22%), pale-yellow oil. Ϫ H
NMR (200 MHz, CDCl3): δ ϭ 1.92 (s, ca. 5.27 H), 2.06 (s, ca. 0.73
H), 3.82 (s, ca. 2.3 H), 3.90 (s, ca. 0.7 H), 4.89 (mc, ca. 4 H), 6.75
deca-1(17),14(18),15-triene,[14] 1.10 g (7.8 mmol) of benzoyl chlo- (br. s, 2 H), 7.0Ϫ7.4 (m, ca. 10 H). Ϫ 1H NMR (200 MHz, CDCl3,
ride, 2.16 g (21.4 mmol) of NEt3. Yield: 1.16 g (66%), m.p.
9.7 equiv. of picric acid): δ ϭ 1.89 (s, ca. 4.5 H), 2.04 (s, ca. 1.5 H),
55Ϫ58°C. Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 3.1Ϫ3.9 (m, ca. 15 4.11 (s, 2.25 H), 4.26 (s, 0.75 H), 5.1Ϫ5.3 (m, ca. 4 H), 7.0Ϫ7.4 (m,
H), 4.64 (br. s, 1.8 H), 4.91 (br. s, 2.2 H), 6.55 (br. s, 0.9 H), 6.9Ϫ7.0
(m, 1.1 H), 7.3Ϫ7.7 (m, ca. 10 H). Ϫ 1H NMR (200 MHz, CDCl3,
ca. 12 H), 9.14 (br. s, ca. 19.4 H, picric acid). Ϫ IR (KBr): ν˜ ϭ
1660 cmϪ1 (CϭO), 1596 (arom.). Ϫ MS (EI, 70 eV); m/z (%): 403
5.5 equiv. of picric acid): δ ϭ 3.19 (br. s, ca. 4 H), 3.40 (br. s, 4 H), (10) [Mϩ], 360 (63) [Mϩ Ϫ COCH3], 317 (75) [Mϩ Ϫ COCH3 Ϫ
3.76 (br. s, 4 H), 4.15 (br. s, 3 H), 5.11 (br. s, 4 H), 7.3Ϫ7.5 (m, ca.
COCH3], 225 (100). Ϫ MS (CI, isobutane); m/z (%): 404 (100) [Mϩ
12 H), 9.11 (br. s, ca. 11.0 H, picric acid). Ϫ IR (KBr): ν˜ ϭ 1629 ϩ H], 403 (6) [Mϩ], 361 (17) [Mϩ ϩ H Ϫ COCH3]. Ϫ C24H25N3O3
cmϪ1 (CϭO), 1600 (arom.), 1576 (arom.). Ϫ MS (EI, 70 eV); m/z
(403.2): calcd. C 71.45, H 6.25, N 10.41; found. C 70.83, H 6.45,
(%): 489 (13) [Mϩ], 384 (23) [Mϩ Ϫ COPh], 105 (100) [C7H5Oϩ]. N 9.81.
Ϫ MS (CI, isobutane); m/z (%): 490 (100) [Mϩ ϩ H], 489 (5) [Mϩ].
2,6-Bis{[N-(2,2-dimethylpropionyl)-N-phenylamino]methyl}-4-meth-
oxypyridine (5b): Starting materials: 1.20 g (3.8 mmol) of 4-meth-
oxy-2,6-bis(phenylaminomethyl)pyridine (8), 1.00 g (8.4 mmol) of
pivaloyl chloride, 2.30 g (22.8 mmol) of NEt3. Yield: 0.32 g (17%),
pale-yellow oil. Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 1.04 (s, 18
H), 3.83 (s, ca. 3 H), 4.81 (s, ca. 4 H), 6.77 (s, 2 H), 7.1Ϫ7.4 (m,
10 H). Ϫ IR (KBr): ν˜ ϭ 1634 cmϪ1 (CϭO), 1595 (arom.). Ϫ MS
(EI, 70 eV); m/z (%): 487 (3) [Mϩ], 430 (100) [Mϩ Ϫ C(CH3)3], 402
Ϫ
HR MS: C28H31N3O5: calcd. 489.2264; found 489.2259.
C2713CH31N3O5: calcd. 490.2297; found 490.2297. Ϫ C28H31N3O5
(489.2): calcd. C 68.70, H 6.38, N 8.58; found C 67.98, H 6.30,
N 8.46.
16-Methoxy-3,12-bis(phenylacetyl)-6,9-dioxa-3,12,18-triazabicyclo-
[12.3.1]octadeca-1(17),14(18),15-triene (4d): Starting materials: 1.00
g
(3.6 mmol) of 16-methoxy-6,9-dioxa-3,12,18-triazabicy-
clo[12.3.1]octadeca-1(17),14(18),15-triene,[14] 1.21 g (7.9 mmol) of (97) [Mϩ Ϫ COC(CH3)3]. Ϫ MS (CI, isobutane); m/z (%): 488 (100)
phenylacetyl chloride, 2.16 g (21.4 mmol) of NEt3. Yield: 0.81 g
[Mϩ ϩ H]. Ϫ C30H37N3O3 (487.3): calcd. C 73.89, H 7.65, N 8.62;
found C 72.67, H 7.57, N 8.90.
(44%), m.p. 103Ϫ105°C. Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ
852
Eur. J. Org. Chem. 1999, 847Ϫ854

Concave Reagents, 28
FULL PAPER
2,6-Bis[(N-benzoyl-N-phenylamino)methyl]-4-methoxypyridine (5d):
Starting materials: 1.20 g (3.8 mmol) of 4-methoxy-2,6-bis(phenyla-
minomethyl)pyridine (8), 1.30 g (8.4 mmol) of phenylacetyl chlo-
ride, 2.30 g (22.8 mmol) of NEt3. Yield: 0.58 g (28%), yellow oil.
(6) [Mϩ]. Ϫ C38H37N3O3 (583.3): calcd. C 78.19, H 6.38, N 7.20;
found C 78.15, H 6.46, N 7.13.
2,6-Bis{[N-benzyl-N-(3-phenylpropionyl)amino]methyl}-4-methoxy-
pyridine (6e): Starting materials: 1.23 g (3.5 mmol) of 2,6-bis(ben-
zylaminomethyl)-4-methoxypyridine (9), 1.19 g (7.1 mmol) of 3-
phenylpropionyl chloride, 2.15 g (21.3 mmol) of NEt3. Yield: 1.08
Ϫ
1H NMR (200 MHz, CDCl3): δ ϭ 3.5Ϫ3.7 (m, ca. 4 H), 3.83
(s, ca. 3 H), 4.7Ϫ4.9 (m, ca. 4 H), 6.6Ϫ6.8 (m, ca. 2 H), 7.1Ϫ7.4
(m, 10 H). Ϫ IR (KBr): ν˜ ϭ 1654 cmϪ1 (CϭO), 1602 (arom.). Ϫ
MS (EI, 70 eV); m/z (%): 555 (9) [Mϩ], 478 (32) [Mϩ Ϫ C6H5], 319
(81), 145 (100). Ϫ MS (CI, isobutane); m/z (%): 556 (4) [Mϩ ϩ H],
320 (100).
1
g (50%), yellow oil. Ϫ H NMR (200 MHz, CDCl3): δ ϭ 2.6Ϫ2.8
(m, ca. 4 H), 2.9Ϫ3.1 (m, ca. 4 H), 3.65 (s, ca. 0.7 H), 3.74 (s, ca.
1.7 H), 3.79 (s, ca. 0.6 H), 4.3Ϫ4.7 (m, ca. 8 H), 6.38 (s, 0.5 H,
PyHZZ), 6.40 (d, J ϭ 2.2 Hz, 0.5 H, PyHEZ), 6.69 (s, 0.5 H, PyHEE),
6.70 (d, J ϭ 2.2 Hz, 0.5 H, PyHEZ), 7.0Ϫ7.4 (m, ca. 20 H). Ϫ IR
(KBr): ν˜ ϭ 1650 cmϪ1 (CϭO), 1599 (arom.), 1574 (arom.). Ϫ MS
(EI, 70 eV); m/z (%): 611 (5) [Mϩ], 520 (3) [Mϩ Ϫ C7H7], 478 (4)
[Mϩ Ϫ C9H9O], 374 (100). Ϫ MS (CI, isobutane); m/z (%): 612
(100) [Mϩ ϩ H], 611 (8) [Mϩ]. Ϫ C40H41N3O3 (611.3): calcd. C
78.53, H 6.75, N 6.87; found C 77.81, H 6.87, N 6.58.
2,6-Bis[(N-acetyl-N-benzylamino)methyl]-4-methoxypyridine (6a):
Starting materials: 1.17 g (3.4 mmol) of 2,6-bis(benzylaminometh-
yl)-4-methoxypyridine (9), 0.58 g (7.4 mmol) of acetyl chloride, 2.02
1
g (20.0 mmol) of NEt3. Yield: 0.76 g (52%), pale-yellow oil. Ϫ H
NMR (200 MHz, CDCl3): δ ϭ 2.19 (s, 1.5 H), 2.21 (s, 4.5 H), 3.75
(s, 0.75 H), 3.79 (s, 1.5 H), 3.81 (s, 0.75 H), 4.42 (d, J ϭ 4.2 Hz, 2
H), 4.60 (s, 4 H), 4.6Ϫ4.7 (m, 2 H), 6.47 (d, J ϭ 2.2 Hz, 0.5 H,
PyHEZ), 6.48 (s, 0.5 H, PyHZZ), 6.71 (s, 0.5 H, PyHEE), 6.72 (d,
1
J ϭ 2.2 Hz, 0.5 H, PyHEZ), 7.1Ϫ7.4 (m, 10 H, ArH). Ϫ H NMR
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG Lu 378/12) and the Fonds der Chemischen Industrie.
(200 MHz, CDCl3, 7.5 equiv. of picric acid): δ ϭ 2.12 (br. s, 1 H),
2.22 (br. s, 5 H), 3.96 (s, 0.5 H), 4.02 (s, 2.5 H), 4.60 (br. s, 4 H),
4.77 (br. s, 4 H), 6.7Ϫ7.3 (m, ca. 12 H), 9.10 (br. s, ca. 15 H, picric
acid). Ϫ IR (KBr): ν˜ ϭ 1650 cmϪ1 (CϭO), 1599 (arom.), 1574
(arom.). Ϫ MS (EI, 70 eV); m/z (%): 431 (1) [Mϩ], 388 (2) [Mϩ
Ϫ
[1] [1a]
COCH3], 284 (100). Ϫ MS (CI, isobutane); m/z (%): 432 (100) [Mϩ
ϩ H]. Ϫ C26H29N3O3 (431.2): calcd. C 72.37, H 6.77, N 9.74; found
C 71.62, H 6.92, N 9.49.
T. W. Green, Protective Groups in Organic Synthesis, John
Wiley and Sons, New York, Chichester, Brisbane, Toronto, Sin-
[1b]
gapore, 1981. Ϫ
P. J. Kocienski, Protecting Groups, Georg
Thieme Verlag, Stuttgart, New York, 1994.
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E. Hungerbühler, D. Seebach, D. Wasmuth, Helv. Chim.
Acta 1981, 64, 1467Ϫ1487. Ϫ [2b] B. M. Trost, T. R. Verhoeven,
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2,6-Bis{[N-benzyl-N-(2,2-dimethylpropionyl)amino]methyl}-4-meth-
oxypyridine (6b): Starting materials: 1.20 g (3.5 mmol) of 2,6-
bis(benzylaminomethyl)-4-methoxypyridine (9), 0.92 g (7.6 mmol)
of pivaloyl chloride, 2.12 g (21.0 mmol) of NEt3. Yield: 1.24 g
1985, 50, 1751Ϫ1752. Ϫ [2e] S. Yamada, J. Org. Chem. 1992, 57,
1
(67%), pale-yellow oil. Ϫ H NMR (500 MHz, CDCl3): δ ϭ 1.33
[2f]
1591Ϫ1592. Ϫ
M. Allainmat, P. LЈHaridon, L. Toupet, D.
(s, 18 H), 3.80 (s, 3 H), 4.4Ϫ5.0 (m, ca. 8 H), 6.57 (s, 2 H), 7.1Ϫ7.4
Plusquellec, Synthesis 1990, 27Ϫ32.
(m, ca. 10 H). Ϫ IR (KBr): ν˜ ϭ 1632 cmϪ1 (CϭO), 1600 (arom.),
[3] [3a]
M. Sekine, A. Kume, T. Hata, Tetrahedron Lett. 1981, 22,
[3b]
1574 (arom.). Ϫ MS (EI, 70 eV); m/z (%): 430 (3) [Mϩ
Ϫ
3617Ϫ3620. Ϫ
Org. Chem. 1993, 58, 3791Ϫ3793.
K. Ishihara, H. Kurihara, H. Yamamoto, J.
COC(CH3)3], 326 (100). Ϫ MS (CI, isobutane); m/z (%): 516 (100)
[Mϩ ϩ H]. Ϫ C32H41N3O3 (515.3): calcd. C 74.53, H 8.01, N 8.15;
found C 74.44, H 8.21, N 7.95.
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R. W. Jeanloz, D. A. Jeanloz, J. Am. Chem. Soc. 1957, 79,
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1223Ϫ1230.
2,6-Bis[(N-benzoyl-N-benzylamino)methyl]-4-methoxypyridine (6c):
Starting materials: 1.23 g (3.5 mmol) of 2,6-bis(benzylaminometh-
yl)-4-methoxypyridine (9), 1.09 g (7.1 mmol) of benzoyl chloride,
2.15 g (21.3 mmol) of NEt3. Yield: 0.98 g (61%), colorless oil,
slowly crystallizing, m.p. 101Ϫ109°C. Ϫ 1H NMR (200 MHz,
CDCl3): δ ϭ 1.52 (br. s, 1 H, H2O), 3.82 (br. s, ca. 3 H), 4.3Ϫ4.9
(m, ca. 8 H), 6.49 (br. s, ca. 1 H), 6.81 (br. s, ca. 1 H), 7.1Ϫ7.6 (m,
ca. 20 H). Ϫ IR (KBr): ν˜ ϭ 1633 cmϪ1 (CϭO), 1600 (arom.), 1574
(arom.). Ϫ MS (EI, 70 eV); m/z (%): 450 (3) [Mϩ Ϫ COPh], 347
(39) [Mϩ Ϫ COPh Ϫ COPh], 346 (100). Ϫ MS (CI, isobutane); m/z
(%): 556 (100) [Mϩ ϩ H], 346 (23) [Mϩ Ϫ COPh Ϫ COPh]. Ϫ
C36H33N3O3 · 0.5 H2O (555.3 ϩ 9.0): calcd. C 76.57, H 6.07, N
7.44; found C 76.77, H 6.13, N 7.30.
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R. M. Munavu, H. H. Szmant, J. Org. Chem. 1976, 41,
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1832Ϫ1836. Ϫ
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12), Elsevier, Oxford, 1994. Ϫ
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B. De Jeso, S. Drouillard, M. Degueil-Castaing, A. Saux,
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B. Maillard, Synth. Commun. 1988, 18, 1691Ϫ1697. Ϫ
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[8c]
M. J.
2,6-Bis[(N-benzyl-N-phenylacetylamino)methyl]-4-methoxypyridine
(6d): Starting materials: 1.23 g (3.5 mmol) of 2,6-bis(benzylamino-
methyl)-4-methoxypyridine (9), 1.09 g (7.1 mmol) of phenylacetyl
chloride, 2.15 g (21.3 mmol) of NEt3. Yield: 1.14 g (55%), colorless
oil. Ϫ 1H NMR (200 MHz, CDCl3): δ ϭ 3.6Ϫ3.9 (m, ca. 8 H),
4.3Ϫ4.7 (m, ca. 8 H), 6.35 (s, 0.40 H, PyHZZ), 6.37 (d, J ϭ 2.2 Hz,
0.60 H, PyHEZ), 6.56 (s, 0.40 H, PyHEE), 6.61 (d, J ϭ 2.2 Hz, 0.60
H, PyHEZ), 7.0Ϫ7.4 (m, ca. 20 H). Ϫ IR (KBr): ν˜ ϭ 1644 cmϪ1
(CϭO), 1599 (arom.), 1573 (arom.). Ϫ MS (EI, 70 eV); m/z (%):
583 (5) [Mϩ], 492 (6) [Mϩ Ϫ C7H7], 464 (5) [Mϩ Ϫ C8H7O], 360
(100). Ϫ MS (CI, isobutane); m/z (%): 584 (100) [Mϩ ϩ H], 583
Chinn, G. Iacazio, D. G. Spackman, N. J. Turner, S. M. Roberts,
J. Chem. Soc., Perkin Trans. 1 1992, 661Ϫ662.
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Received September 22, 1998
[O98429]
854
Eur. J. Org. Chem. 1999, 847Ϫ854