A versatile synthesis of poly- and diversely substituted isoindolin-1- ones

Article abstract of DOI:10.1055/s-2000-6385

A variety of diversely substituted isoindolin-1-ones have been prepared by alkaline cleavage of the C-P bond in the corresponding phosphorylated lactams obtained by base-induced aryne-mediated cyclization of o-halogeno-N- (phosphinylmethyl)benzamide derivatives.

Full text of DOI:10.1055/s-2000-6385

PAPER
655
A Versatile Synthesis of Poly- and Diversely Substituted Isoindolin-1-ones
Christophe Hoarau, Axel Couture,* Eric Deniau, Pierre Grandclaudon
Laboratoire de Chimie Organique Physique, ESA CNRS N° 8009, Université des Sciences et Technologies de Lille, F-59655 Villeneuve
d’Ascq Cédex, France
Fax +33(0)320336309; E-mail: Axel.Couture@univ-lille1.fr
Received 24 January 2000
O
O
R1
R3
Abstract: A variety of diversely substituted isoindolin-1-ones have
been prepared by alkaline cleavage of the C-P bond in the corre-
sponding phosphorylated lactams obtained by base-induced aryne-
mediated cyclization of o-halogeno-N-(phosphinylmethyl)benza-
mide derivatives.
R2
N
R
N
COOH
1
2
Key words: isoindolinones, arynes, carbanions, cyclizations, de-
phosphorylation, heterocycles, cleavage, phosphorus
O
O
N
O
N
NH
The chemistry of isoindolin-1-ones (phthalimidines 1) has
been the focus of new synthetic methodologies in many
research groups during the last few years.1 The interest
demonstrated by the scientific community for these heter-
obicyclic compounds stems mainly from their diverse bi-
ological activities.2 Indeed, bioactive compounds such as
indoprofen3 (2, anti-inflammatory agent), deoxythali-
domide4 (3, reductor of tumour necrosis factor produc-
tion), batracyclin5 (4, neoplasm inhibitor) as well as archi-
tecturally more sophisticated compounds known for their
activity as non-nucleosidic HIV-reverse transcriptase
inhibitors2b and vasodilatators6 are based on the isoindoli-
none structure. In addition the isoindolinone skeleton con-
stitutes the framework of many naturally occurring
substances as exemplified by lennoxamine 5 and aristoy-
agonine 6.
N
O
3
O
4
OMe
O
O
MeO
N
N Me
MeO
O
MeO
MeO
O
O
6
5
Almost all the new synthetic routes to these (fused)poly-
cyclic isoindolinones have been secured by exploring the
reactivity and selective functionalization of the parent ph-
thalimidines. Unfortunately despite the fact that syntheses
of phthalimidine derivatives have been investigated previ-
ously, the applicability of past methods is generally unsat-
isfactory because of drastic reaction conditions,
difficulties in purification and above all restrictions in the
choice of substituents namely in their nature, their number
and their position on the aromatic nucleus.7-11 The most
convenient routes to these bicyclic lactams involve (i) the
free radical bromination of 2-methylbenzoyl ester deriva-
tives followed by addition of an appropriate primary
amine,7 (ii) the condensation of a primary amine with the
corresponding 1(3H)-isobenzofuranones,8 (iii) the reduc-
tion of phthalimides under various conditions9 via their
aminals or more recently their thioaminals10 and finally
(iv) the reaction of o-phthalaldehyde with a primary
amine.11 All these synthetic approaches are of procedural
simplicity and generally proceed in satisfactory yields.
However, these methods suffer from several drawbacks
and are notably inadequate for the synthesis of models
carrying specific substituents in particular positions on the
basic benzene nucleus. Thus the first method does not tol-
erate the presence in the parent models of substituents that
will not survive the bromination step (e.g. simply a methyl
group). Issues raised by elaboration of diversely substitut-
ed isoindolinones by applying the second method may not
be simply addressed from their corresponding oxo ana-
logs. Finally, the last two synthetic approaches genuinely
lack selectivity since the presence of one or several differ-
ent substituents on the aromatic nucleus of the parent
compounds would invariably induce the formation of dif-
ficultly separable regioisomers. Consequently, we under-
stand why these routes have been mainly confined to the
synthesis of bare models.
We therefore considered that for the convenient synthesis
of a range of contiguously or uncontiguously and differ-
entially substituted isoindolin-1-ones a more versatile
procedure would be necessary. The present work originat-
ed with the following premises (i) the isoindolinone tem-
plate, variously equipped with one or several groups,
namely phenolic methyl and benzyl protected hydroxy
groups present in a wide range of alkaloids and drugs,
should be readily accessible by taking advantage of a re-
Synthesis 2000, No. 5, 655–660 ISSN 0039-7881 © Thieme Stuttgart · New York

656
C. Hoarau et al.
PAPER
Table 1 Compounds 1, 8, 11 and 16 Prepared
cently developed aryne-mediated cyclization metho-
dolgy applied to o-halogeno-N-(phosphinylmethyl)benza-
mide derivatives 812 (Scheme 1), (ii) once prepared the
phosphorylated appendage of the initial annulated product
7 should be easily removed by alkaline cleavage owing to
the sensitivity of the phosphoryl group with respect to nu-
cleophilic attack, a rarely exploited property13 and (iii) the
formation of the transient carbanion 9 should be strongly
facilitated since such a species can be represented as
o-quinodimethane resonance structure 10 owing to elec-
tronic delocalization (Scheme 2).
1, 8,
R1
R2
R3
R4
R5
X
11, 16
a
b
c
d
e
f
g
h
i
-
OMe
OBn
OBn
-
OMe
-
-
Me
OMe
OMe
-
PMBa
PMBa
PMBa
Me
Me
Me
-
Br
Br
Br
F
F
Cl
F
F
-
-
-
-
-
-
OMe
-
-
OBn
OMe
-
-
OMe
OMe
-
-
-
-
OMe
-
-
OMe
Me
-
Me
-
-
-
PMBa
Me
Me
Bn
j
O
N
O
N
P
R1
R3
R1
R3
a PMB = p-methoxybenzyl.
R2
R4
R2
R4
O
mediacy of the carbanionic phosphorylated lactam 15
arising from the metal counterion shift from the initially
formed aromatic anionic species 14. Protonation and sub-
sequent alkaline cleavage of the P-C bond of the resulting
phosphane oxides then complete the synthesis of the de-
sired isoindolinones. The progress of these reactions has
some obvious implications and thus electrophile introduc-
tion prior to dephosphorylation gives rise to models
equipped with various substituents at the 3-position of the
heterocyclic nucleus as illustrated by the straightforward
one-pot synthesis of the 2,3-dialkylisoindolinones 16i and
16j from the opened models 8a and 8e (Scheme 4, Table
3).
Ph Ph
1
7
O
R1
R3
R2
N
R4
X
O
P
Ph
Ph
8
Scheme 1
1. SOCl2, DMF
O
N
O
N
R1
2. R4NHCH2P(O)Ph2
R1
R3
R1
R1
12 (R4 = Me),
13 (R4 = PMB)
O
N
R2
R4
R2
R4
R2
R3
COOH
X
R2
R3
R4
R3
71-96%
X
O
P
9
10
Ph
Ph
11a-h
8a-h
Scheme 2
R1
R1
KHMDS (2 equiv)
THF
-78 °C to rt, 2h
The first facet of this synthesis, the elaboration of the re-
quired o-halogeno-N-(phosphinylmethyl)benzamide de-
rivatives 8a-h, was readily accomplished by coupling the
N-[(diphenylphosphinyl)methyl]-N-alkylamines 12 and
13 with the acid chlorides derived from the diversely sub-
stituted o-halogenobenzoic acid derivatives 11a-h
(Scheme 3, Tables 1 and 2). The resulting phosphorylated
halogenobenzamide derivatives were then exposed to po-
tassium bis(trimethylsilyl)amide (KHMDS, 2 equiv) at
-78°C in THF. The reaction mixture was then warmed to
room temperature and subsequently refluxed over a short
period in the presence of aqueous NaOH solution (2.5 M,
2 equiv) to generate the target isoindolinones 1a-h. A
representative series of annulated products which have
been prepared by this method are presented in the Tables
1 and 3 where it may be seen that this protocol affords ex-
cellent yields of the polysubstituted isoindolin-1-ones
1a-h. It is likely that these reactions proceed via the inter-
O
O
R2
R3
R2
R3
R4
N
R4
O
N
O
P
P
Ph Ph
14a-h
Ph Ph
15a-h
R1
O
OH- / H2O
reflux, 3h
R2
R3
N
R4
63-77%
1a-h
Scheme 3
Synthesis 2000, No. 5, 655–660 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Versatile Synthesis of Poly- and Diversely Substituted Isoindolin-1-ones
657
Table 2 Spectroscopic and Physical Data of the Phosphorylated Amides 8a-h
Prod- Yield
mp
(°C)
IR (KBr)
1H NMR (CDCl3/TMS)
d, J (Hz)
13C NMR (CDCl3/TMS)
d, J (Hz)
31P NMR
d
ucta
(%)
n (cm-1)
8a
96
165−166 1639 (C=O),
3.65 (3 H, s, CH3O), 3.76 (3 H, s, CH3O), C: 109.5, 127.0, 130.7 (d, JCP = 98), 30.7
4.44 (2 H, ddd, J = 5.6, 6.1, 15.1, CH2P), 131.7, 137.7, 158.8, 159.3, 168.6
4.53 (1 H, d, J = 15.1, NCH2Ar), 4.77 (1 (C=O), CH: 113.3, 113.9, 116.9,
H, d, J = 15.1, NCH2Ar), 6.27 (1 H, d, J 128.7 (d, JCP = 11), 130.0, 131.3 (d,
= 3.0, Harom), 6.71 (1 H, dd, J = 3.0, 8.8, JCP = 9), 132.3, 133.9, CH2: 41.9 (d,
Harom), 6.83 (2 H, d, J = 8.8, Harom), 7.24 JCP = 76), 52.6, CH3: 55.3, 55.6
(2 H, d, J = 8.8, Harom), 7.35 (1 H, d, J =
1242 (P=O)
8.8, Harom), 7.48−7.63 (6 H, m, Harom),
7.87−8.00 (4 H, m, Harom
)
8b
73
179−180 1635 (C=O),
3.78 (3 H, s, CH3O), 4.45 (2 H, ddd, J = C: 109.9, 127.0, 131.1 (d, JCP = 98), 30.7
5.4, 6.3, 15.3, CH2P), 4.51 (1 H, d, J = 136.0, 137.7, 157.9, 159.3, 168.6
15.2, NCH2Ar), 4.74 (1 H, d, J = 15.2, (C=O), CH: 114.1, 114.3, 118.0,
1241 (P=O)
NCH2Ar), 4.84 (1 H, d, J = 11.7,
OCH2Ar), 4.91 (1 H, d, J = 11.7,
127.4, 128.2, 128.7 (d, JCP = 11),
128.8, 130.0, 131.3 (d, JCP = 9),
OCH2Ar), 6.36 (1 H, d, J = 3.0, Harom), 132.3 (d, JCP = 3), 134.0, CH2: 42.0
6.70 (1 H, dd, J = 3.0, 8.5, Harom), 6.82 (2 (d, JCP = 76), 52.6, 70.4, CH3: 55.3
H, d, J = 8.7, Harom), 7.22 (2 H, d, J = 8.7,
Harom), 7.25 (1 H, d, J = 8.5, Harom), 7.32−
7.41 (5 H, m, Harom), 7.45−7.56 (6 H, m,
Harom), 7.88−8.01 (4 H, m, Harom
)
8c
91
184−185 1649 (C=O),
3.78 (3 H, s, CH3O), 3.84 (3 H, s, CH3O), C: 110.7, 127.2, 128.7, 136.0, 147.2, 30.8
1258 (P=O)
4.29-4.57 (2 H, m, CH2P), 4.47 (1 H, d, 150.8, 159.3, 168.8 (C=O), CH:
J = 15.0, NCH2Ar), 4.61 (1 H, d, J =
113.5, 114.1, 116.0, 127.4, 128.2,
15.0, NCH2Ar), 4.82 (1 H, d, J = 12.1, 128.6 (d, JCP = 11), 128.7, 129.8,
OCH2Ar), 4.97 (1 H, d, J = 12.1, 131.3 (d, JCP = 8), 131.3 (d, JCP = 8),
OCH2Ar), 6.25 (1 H, s, Harom), 6.80 (2 H, 132.3 (d, JCP = 3), CH2: 42.0 (d, JCP
d, J = 8.6, Harom), 7.05 (1 H, s, Harom),
7.15 (2 H, d, J = 8.6, Harom), 7.31−7.59
(11 H, m, Harom), 7.85−8.00 (4 H, m,
= 76), 52.6, 71.1, CH3: 55.3, 56.2
Harom
)
8d
8e
8f
81
85
96
108−109 1639 (C=O),
3.05 (3 H, s, CH3N), 3.51 (3 H, s, CH3O), C: 113.3 (d, JCF = 22), 130.9 (d, JCP 31.1
4.49−4.64 (2 H, ddd, J = 5.9, 6.0, 15.5, = 99), 156.7 (d, JCF = 8), 158.9 (d,
CH2P), 6.51−6.52 (2 H, m, Harom), 7.18 JCF = 248), 164.6 (C=O), CH: 106.6
(1 H, ddd, J = 6.6, 8.4, 8.5, Harom), 7.41− (d, JCP = 2.5), 108.0 (d, JCF = 21),
1273 (P=O)
7.49 (6 H, m, Harom), 7.82−7.95 (4 H, m, 128.5 (d, JCP = 12), 128.7 (d, JCP
=
Harom 12), 130.9 (d, JCF = 10), 131.1 (d, JCP
)
= 10), 131.3 (d, JCP = 10), 132.1 (d,
JCP = 3), 132.2 (d, JCP = 3), CH2: 46.6
(d, JCP = 77), CH3: 37.2, 55.9
126−127 1637 (C=O),
3.09 (3 H, s, CH3N), 3.55 (3 H, s, CH3O), C: 119.0 (d, JCF = 22), 131.6 (d, JCP 31.0
3.76 (3 H, s, CH3O), 4.51−4.66 (2 H, = 97), 145.7 (d, JCF = 6), 149.0 (d,
ddd, J = 5.8, 6.1, 15.0, CH2P), 6.67 (1 H, JCF = 3), 153.8 (d, JCF = 266), 164.4
dd, J = 8.0, 9.1, Harom), 6.77 (1 H, dd, J = (C=O), CH: 110.3 (d, JCF = 22),
1281 (P=O)
5.2, 9.1, Harom), 7.43−7.50 (6 H, m,
Harom), 7.82−7.95 (4 H, m, Harom
113.3 (d, JCF = 9), 128.6 (d, JCP =
)
12), 128.7 (d, JCP = 12), 131.1 (d, JCP
= 9), 131.3 (d, JCP = 9.5), 132.1,
132.2, CH2: 46.6 (d, JCP = 77), CH3:
37.4, 56.3, 61.3
143−144 1629 (C=O),
3.08 (3 H, s, CH3N), 4.34−4.81 (2 H, br. C: 127.7, 130.9 (d, JCP = 98), 131.1, 31.7
d, J = 5.2, CH2P), 5.00 (2 H, s, OCH2Ar), 135.9, 159.7, 168.4 (C=O), CH:
6.64 (1 H, d, J = 8.6, Harom), 6.77 (1 H, 113.9, 115.8, 127.4, 128.3, 128.6,
dd, J = 2.4, 8.6, Harom), 6.89 (1 H, d, J = 128.7 (d, JCP = 12), 128.8, 131.3 (d,
1289 (P=O)
2.4, Harom), 7.29−7.41 (5 H, m, Harom),
7.46−7.59 (6 H, m, Harom), 7.88−7.89 (4 77), 70.3, CH3: 38.0
H, m, Harom
JCP = 9), 132.3, CH2: 42.0 (d, JCP =
)
Synthesis 2000, No. 5, 655–660 ISSN 0039-7881 © Thieme Stuttgart · New York

658
C. Hoarau et al.
PAPER
Table 2 (continued)
Prod- Yield
mp
(°C)
IR (KBr)
1H NMR (CDCl3/TMS)
d, J (Hz)
13C NMR (CDCl3/TMS)
d, J (Hz)
31P NMR
d
ucta
(%)
n (cm-1)
8g
81
139-140 1630 (C=O),
3.07 (3 H, s, CH3N), 3.60 (3 H, s, CH3O), C: 130.8 (d, JCP = 95), 131.0 (d, JCP 31.2
3.69 (3 H, s, CH3O), 4.57 (2 H, ddd, J = = 98), 157.5 (d, JCF = 11), 159.8 (d,
6.1, 6.3, 14.0, CH2P), 6.11 (1 H, s, Harom), JCF = 245), 162.0 (d, JCF = 13), 164.7
6.13 (1 H, d, JCF = 7.4, Harom), 7.35−7.48 (C=O), CH: 93.2 (d, JCF = 26), 94.5,
1291 (P=O)
(6 H, m, Harom), 7.81−7.93 (4 H, m, Harom) 128.5 (d, JCP = 12), 128.6 (d, JCP
=
12), 131.1 (d, JCP = 10), 131.3 (d, JCP
= 10), 131.9 (d, JCP = 2.5), 132.1 (d,
JCP = 2.5), CH2: 46.7 (d, JCP = 77),
CH3: 37.3, 55.6, 55.7
8h
71
120-121 1629 (C=O),
2.19 (3 H, s, CH3Ar), 3.08 (3 H, s,
C: 123.1 (d, JCF = 18), 130.7 (d, JCP 32.0
1275 (P=O)
CH3N), 4.56 (2 H, br d, J = 4.8, CH2P), = 98), 134.1, 156.1 (d, JCF = 246),
6.57 (1 H, m, Harom), 6.84 (1 H, t, J = 8.8, 167.0 (C=O), CH: 115.4 (d, JCF
Harom), 7.05 (1 H, s, Harom), 7.47−7.50 (6 21), 128.6 (d, JCP = 12), 128.7 (d, JCF
=
H, m, Harom), 7.86−7.92 (4 H, m, Harom
)
= 8), 131.2 (d, JCP = 10), 131.8 (d,
JCF = 8), 132.3 (d, JCP = 4.5), CH2:
48.9 (d, JCP = 76), CH3: 20.4, 38.0
a Satisfactory microanalyses obtained: C 0.26, H 0.29, N 0.25.
centre. For flash chromatography, Merck silica gel 60 (230-400
mesh ASTM) was used. All solvents were dried and distilled ac-
cording to standard procedures. Dry glassware for moisture-sensi-
tive reactions was obtained by oven drying and assembly under Ar.
An inert atmosphere was obtained with a stream of Ar and glass-
ware equipped with rubber septa; reagent transfer was performed by
syringe.
The o-halogenobenzoic acid derivatives 11a,14 11c,15 11d,16 11e,17
11f,18 11g,16 were prepared according to already reported proce-
dures. 11b was prepared by oxidation (CrO3/H2SO4/ H2O/acetone)
of 5-benzyloxy-2-bromobenzaldehyde.19 Compound 11h is com-
mercially available. The phosphorylated amines 12,20 13,12a were
synthesized according to the literature. The o-halogenobenzoic acid
derivatives 11a-h were converted by the conventional method
(SOCl2, DMF cat., CH2Cl2) into their corresponding acid chlorides
which were used directly for the next step without further purifica-
tion. The coupling reaction between the appropriately substituted
o-halogenobenzoyl chlorides and the phosphorylated amines 12, 13
was performed by following an already reported procedure.12a
1. KHMDS (2 equiv)
THF
-78 °C to rt, 2h
R1
R1
2. R5X, 5 min
3. OH- / H2O
reflux 3h
O
O
N
R2
R3
R2
R3
R4
R4
N
X
O
52-58%
R5
P
Ph
Ph
16i,j
8a,e
Scheme 4
Examination of the Table 1 deserves some comment. The
method is tolerant to a variety of substituents on the aro-
matic moiety and particularly with methyl, methoxy and
also benzyloxy groups, which can be regarded as protect-
ed phenolic functions. The reaction can be indifferently
performed with fluoro, chloro or the more easily accessi-
ble bromo derivatives. This new conceptual approach al-
lows access to poly- and diversely substituted models at
Isoindolin-1-ones 1a-h and 16i,j; General Procedure
A solution of KHMDS (4 mL, 0.5 M in toluene, 2 mmol) was added
dropwise to a stirred solution of the appropriate phosphorylated ha-
logenobenzamides 8a-h (1 mmol) in THF (25 mL) at -78 °C under
Ar. The solution was stirred for 30 min at this temperature and then
the 2, 3, 5, 6, 7 positions of the bicyclic framework and allowed to warm to r.t. over a period of 2 h. A solution of an elec-
trophile (1 mmol) in THF (2 mL) was added by syringe at this stage.
due to initial aryne formation only the 4-substituted ana-
An aq NaOH solution (2.5 M, 0.8 mL) was slowly added to the re-
logues remain unobtainable by this method. The simplic-
action mixture which was subsequently refluxed for 3 h. H2O
(10 mL) was added and the mixture was extracted with Et2O
(3 × 10 mL). The organic layer was washed with water and brine,
dried (MgSO4), concentrated in vacuo to a residue which was puri-
fied by flash column chromatography with acetone/hexanes (40:60
for 1a-c and 16i; 80:20 for 1d; 60:40 for 1f-h and 16j).
ity and versatility of this new synthetic route should be
rewarded by giving easy access to a wide array of natural
and biologically active compounds. Further exploitation
along these lines is underway in our laboratories.
Melting point determinations were carried out on a Reichert-Ther-
1
mopan apparatus and were recorded uncorrected. H, 13C and 31P
Acknowledgement
NMR spectra were measured at 300 MHz, 75 MHz and 121 MHz
respectively on a Bruker AM 300 spectrometer as solutions in
CDCl3 with TMS as internal standard or H3PO4 as external standard.
Elemental analyses were determined by the CNRS microanalysis
We thank Dr. T. G. C. Bird (Zeneca Pharma) for helpful comments
on the manuscript. This research was supported by the Centre Na-
tional de la Recherche Scientifique and MENESR (grant to C. H.).
Synthesis 2000, No. 5, 655–660 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Versatile Synthesis of Poly- and Diversely Substituted Isoindolin-1-ones
659
Table 3 Spectroscopic and Physical Data of the Isoindol-1-ones 1a-h and 16i,j
Prod-
ucta
Yield
(%)
mp
(°C)
IR (KBr)
n (cm-1
1H NMR (CDCl3/TMS)
d, J (Hz)
13C NMR (CDCl3/TMS)
d, J (Hz)
)
1a
1b
1c
77
73
67
oil
1679 (C=O) 3.75 (3 H, s, CH3O), 3.83 (3 H, s, CH3O), 4.14 (2 H, s, C: 129.1, 134.0, 136.0, 159.1, 159.9,
NCH2Ar), 4.69 (2 H, s, NCH2Ar), 6.83 (2 H, d, J = 8.6, 168.4 (C=O), CH: 106.6, 114.1,
Harom), 7.04 (1 H, dd, J = 2.5, 8.0, Harom), 7.20 (2 H, d, 119.7, 123.5, 129.5, CH2: 45.9, 48.9,
J = 8.6, Harom), 7.22 (2 H, d, J = 8.0, Harom), 7.34 (1 H, CH3: 55.3, 55.6
d, J = 2.5, Harom
)
oil
1674 (C=O) 3.78 (3 H, s, CH3O), 4.16 (2 H, s, NCH2Ar), 4.71 (2 H, C: 128.6, 129.1, 133.6, 136.5, 159.1,
s, NCH2Ar), 5.11 (2 H, s, OCH2Ar), 6.85 (2 H, d, J = 168.3 (C=O), CH: 107.7, 114.1,
8.7, Harom), 7.14 (1 H, dd, J = 2.4, 8.3, Harom), 7.22 (2 H, 120.4, 123.6, 127.5, 128.1, 128.6,
d, J = 8.7, Harom), 7.28-7.44 (7 H, m, Harom
)
129.5, CH2: 45.9, 48.9, 70.3, CH3:
55.3
oil
1661 (C=O) 3.79 (3 H, s, CH3O), 3.88 (3 H, s, CH3O), 4.05 (2 H, s, C: 125.5, 127.9, 129.7, 141.9, 147.5,
NCH2Ar), 4.55 (2 H, s, NCH2Ar), 5.11 (2 H, s,
OCH2Ar), 6.87 (2 H, d, J = 8.7, Harom), 7.00 (1 H, s,
151.5, 166.5 (C=O), CH: 114.1,
115.1, 116.2, 127.5, 128.1, 128.6,
129.3, CH2: 43.8, 45.8, 71.1, CH3:
55.3, 56.3
Harom), 7.25-7.42 (8 H, m, Harom
)
1d
1e
1f
71
68
63
84-85
1669 (C=O) 3.10 (3 H, s, CH3N), 3.92 (3 H, s, CH3O), 4.27 (2 H, s, C: 120.1, 134.8, 157.2, 167.4 (C=O),
NCH2Ar), 6.84 (1 H, dd, J = 0.6, 8.3, Harom), 6.95 (1 H, CH: 110.1, 114.7, 132.7, CH2: 51.5,
dd, J = 0.6, 7.5, Harom), 7.42 (6 H, dd, J = 7.5, 8.3, Harom) CH3: 29.2, 55.8
107-108b 1683 (C=O) 3.10 (3 H, s, CH3N), 3.85 (3 H, s, CH3O), 4.03 (3 H, s, C: 125.0, 134.3, 152.2, 166.8 (C=O),
CH3O), 4.29 (2 H, s, NCH2Ar), 7.02 (2 H, m, Harom
)
CH: 116.1, 117.6, CH2: 51.0, CH3:
29.3, 56.7, 62.5
151-152 1671 (C=O) 3.13 (3 H, s, CH3N), 4.27 (2 H, s, NCH2Ar), 5.09 (2 H, C: 125.8, 136.3, 143.2, 161.6, 168.5
s, OCH2Ar), 6.96 (1 H, d, J = 2.0, Harom), 7.02 (1 H, dd, (C=O), CH: 107.7, 108.6, 115.2,
J = 2.0, 8.4, Harom), 7.32-7.43 (5 H, m, Harom), 7.72 (1 124.8, 127.4, 128.2, 128.6, CH2: 51.8,
H, d, J = 8.4, Harom
)
70.3, CH3: 29.4
1g
1h
72
69
139-140 1665 (C=O) 3.01 (3 H, s, CH3N), 3.77 (3 H, s, CH3O), 3.84 (3 H, s, C: 113.4, 145.6, 158.1, 164.0, 167.4
CH3O), 4.16 (2 H, s, NCH2Ar), 6.33 (2 H, s, Harom),
6.41 (1 H, s, Harom
(C=O), CH: 98.1, 98.9, CH2: 51.6,
CH3: 29.1, 55.6, 55.8
)
75-76
1685 (C=O) 2.38 (3 H, s, ArCH3), 3.13 (3 H, s, CH3N), 4.27 (2 H, s, C: 125.8, 136.3, 143.2, 161.6, 168.5
NCH2Ar), 7.26 (2 H, s, Harom), 7.58 (1 H, s, Harom
)
(C=O), CH: 107.7, 108.6, 115.2,
124.8, 127.4, 128.2, 128.6, CH2: 51.8,
70.3, CH3: 29.4
16i
16j
52
58
oil
1680 (C=O) 1.37 (3 H, d, J = 6.7, CH3), 3.75 (3 H, s, CH3O), 3.85 C: 129.3, 133.1, 136.3, 159.0, 156.0,
(3 H, s, CH3O), 4.16 (1 H, d, J = 15.0, NCH2Ar), 4.28 167.9 (C=O), CH: 53.9, 106.5, 114.1,
(1 H, q, J = 6.7, CHMe), 5.25 (1 H, d, J = 15.0,
119.7, 122.8, 129.3, CH2: 55.2, 43.2,
NCH2Ar), 6.82 (2 H, d, J = 8.7, Harom), 7.05 (1 H, dd, J CH3: 18.1
= 2.5, 7.7, Harom), 7.19 (2 H, d, J = 8.7, Harom), 7.22 (1
H, d, J = 7.7, Harom), 7.35 (1 H, d, J = 2.5, Harom
)
86-87
1674 (C=O) 2.84 (1 H, dd, J = 7.5, 13.8, CH2Ph), 3.07 (3 H, s,
C: 136.0, 138.7, 152.3, 166.6 (C=O),
CH3N), 3.28 (1 H, dd, J = 4.9, 13.8, CH2Ph), 3.85 (3 H, CH: 61.6, 115.6, 117.8, 126.9, 128.4,
s, CH3O), 3.98 (3 H, s, CH3O), 4.54 (1 H, dd, J = 4.9, 129.5 CH2: 39.0, CH3: 28.1, 56.6, 62.5
7.5, CHBn), 6.59 (1 H, d, J = 8.2, Harom), 6.93 (1 H, d,
J = 8.2, Harom), 7.02-7.07 (2 H, m, Harom), 7.18-7.27 (3
H, m, Harom
)
a Satisfactory microanalyses obtained: C 0.25, H 0.24, N 0.36.
b Lit.21 107–108 °C.
53, 2495.
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Synthesis 2000, No. 5, 655–660 ISSN 0039-7881 © Thieme Stuttgart · New York