Synopsis
SYNOPSIS
The thesis entitled “Studies towards the stereoselective synthesis of (+)sordidin and oximidine II” has been divided into three chapters.
Chapter I: This chapter describes the introduction of pheromones, earlier synthetic
approaches and stereoselective synthesis of (+)-sordidin.
Chapter II: This chapter describes the brief introduction to cancer, benzolactone
enamides, earlier synthetic approaches and studies towards the stereoselective synthesis
of oximidine II.
Chapter III: This chapter describes the ZrCl4 catalyzed synthesis of α-amino
phosphonates.
Chapter I. Stereoselective synthesis of (+)-sordidin
The banana weevil Cosmopolites sordidus (Germar) is the most devastating insect
pest on banana plants and spread world over. These are long lived weevils and lay their
eggs in the rhizome of the plant. The larvae hatch, feed and tunnel in the rhizome of the
plant, weakening it and leading to snapping of the rhizome at ground level before the
bunch is ripe. The release of a volatile aggregation pheromone by male Cosmopolites
sordidus was first reported by Budenberg et al. in 1993. Subsequently, in 1995 Ducrot
and his coworkers isolated 100 µg of the major component of the pheromone and thus
proved its bioactivity, named it sordidin, proposed its structure and relative
stereochemistry to be (1S,3R,5R,7S)-1-ethyl-3,5,7-trimethyl-2,8-dioxabicyclo-[3.2.1]
octane 1a.
H3 C
O
O
CH3
H3 C
H3 C
Fig. 1. (1S,3R,5R,7S)-1a
I
Synopsis
O
CH3
O
CH3
O
O
S
O
+
S
OBn
O
1a
26a
17
15
CH3
BnO
O
BnO
HO
2
(+/-)
O
OH
OEt
10
8
16
Scheme 1
Retrosynthetic analysis of (1S,3R,5R,7S)-(+)-sordidin 1a was depicted in Scheme
1. The ketone 26a was assumed as the key intermediate, which after intramolecular
acetalisation would lead to the target pheromone. The ketone 26a could be prepared by
alkylative cleavage of (R)-propylene oxide 17 with the organo lithium reagent obtained
from the dithiane 15. The dithiane 15 could be prepared from cyclic acetal 10. Cyclic
acetal 10 would be easily synthesized from 8 which in turn was synthesized from
commercially available 3-butyn-1-ol 2.
Synthesis of sordidin 1a was starting from commercially available 3-butyn-1-ol 2.
Substrate 2 was protected as benzyl ether in presence of NaH and benzyl bromide in dry
EtMgBr, (HCHO)n
NaH, BnBr
HO
BnO
THF, 0 oC-r.t., 91%
2
3
4
D-(-)-DIPT, Ti(OiPr)4
LiAlH4, THF
0 oC-r.t., 88%
OBn
THF, 0 oC-r.t., 89%
BnO
OH
TBHP, CH2Cl2
-20 oC, 91%
5
TPP, imidazole, I2
Et2O:CH3CN (3:1)
0 oC, 90%
Zn, NaI, MeOH
O
BnO
I
O
BnO
OH
6
BnO
reflux, 87%
7
OH
8
Scheme 2
II
OH
Synopsis
THF to afford 3 in 91% yield. Treatment of benzyl ether 3 with EtMgBr (prepared from
EtBr and Mg) and (HCHO)n in dry THF resulted a propargylic alcohol derivative 4. The
propargylic alcohol 4 was converted to trans allylic alcohol 5 with LiAlH4 and was
subjected to Sharpless asymmetric epoxidation with D-(-)-DIPT, Ti(OiPr)4 and tert-butyl
hydroperoxide (3.2 M in toluene) in CH2Cl2 under anhydrous conditions to yield epoxy
alcohol 6 in 91% yield. Epoxy alcohol 6 was converted to epoxy iodide 7 using PPh3,
imidazole and I2 in Et2O:CH3CN (3:1) at 0 oC and was further treated with Zn and NaI in
refluxing methanol furnished allylic alcohol 8 in 87% yield.
Compound 8 on reaction with NBS and ethyl vinyl ether in dry CH2Cl2 at 0 oC
gave bromo acetal 9, which on radical cyclization using n-Bu3SnH and catalytic amount
of 2,2-azobisisobutyronitrile (AIBN) as a radical initiator in refluxing toluene afforded
trans cyclic ethylacetal 10 as a major isomer (trans:cis in 96:4 ratio). Cleavage of benzyl
ether in 10 with lithium in liquid ammonia at –33 ˚C resulted the alcohol 11 in 91% yield.
Tosylation of alcohol 11 with para-toluenesulfonyl chloride, triethylamine and DMAP in
CH2Cl2 furnished the tosylate 12, which on reduction with LiAlH4 in dry THF afforded
the cyclic ethylacetal 13 in 89% yield.
BnO
n-Bu3SnH, AIBN
NBS, EVE
BnO
O
CH2Cl2, 0 oC, 88%
OH
EtO
8
Br
toluene, reflux, 89%
9
CH3
CH3
Li, liq. NH3
BnO
p-TsCl, Et3N, DMAP
HO
THF, -33 oC, 91%
O
OEt
11
10
CH3
CH3
LiAlH4, THF
TsO
0 oC-r.t., 89%
O
CH2Cl2, 0 oC-r.t., 90%
O
O
OEt
OEt
12
13
Scheme 3
III
OEt
Synopsis
Kinetic resolution of ()-propylene oxide 14 using (R,R')-(-)-N,N'-Bis (3,5-ditert-butylsalicylidene)-1,2-cyclohexanediaminocobalt (II) (Jacobsen’s catalyst) to afford
the (R)-propylene oxide 15 in 42% yield with 98% ee along with the chiral diol 16
(Scheme 4).
(R,R)- Jacobsen's catalyst
O
OH
O
0.05 mol%
+
HO
0.55 eq. water
14
16
15
Scheme 4
Hydrolysis of the cyclicacetal and in situ protection of resulting aldehyde was
achieved by treating the acetal 13 with 1,3-propanedithiol and BF3.OEt2 in CH2Cl2 to
result 17 in 87% yield. Alcohol 17 was protected as benzyl ether 18 using NaH, TBAI
and benzyl bromide in THF under refluxing conditions. Treatment of benzyl ether 18
CH3
1,3-propanedithiol
BF3.OEt2, CH2Cl2
CH3
S
-10 oC-r.t., 87%
O
OEt
BF3.OEt2, THF
15, -78 oC, 88%
CH3
NaH, BnBr, TBAI
OBn
18
17
H3C
S
S
OH
S
S
THF, reflux, 89%
OH
13
n-BuLi, TMEDA
THF, -40 oC
S
TBDPSCl, DMAP
imidazole, CH2Cl2
H3C
S
S
OTBDPS
0 oC-r.t., 90%
OBn
OBn
20
19
Scheme 5
with n-BuLi and TMEDA in dry THF at -40 oC, with BF3.OEt2 and (R)-propylene oxide
15 at -78 oC furnished the alcohol 19 in 88% yield. Alcohol 19 was protected with tertbutyldiphenylsilyl chloride, DMAP and imidazole in CH2Cl2 to yield TBDPS ether 20,
which on hydrolysis with Dess-Martin periodinane furnished ketone 21 in 85% yield.
IV
Synopsis
Treatment of ketone 21 with freshly prepared methyllithium in anhydrous diethyl ether
afforded the diastereomeric mixture of alcohols 22a and 22b in 65:35 ratio (Scheme 6).
H3C
S
S
Dess-Martin periodinane
CH3CN:CH2Cl2:H2O (8:1:1)
OTBDPS
CH3
O
OTBDPS
r.t., 85%
OBn
OBn
21
20
MeLi
diethyl ether
CH3
CH3
OH OTBDPS
OH OTBDPS
+
0 oC-r.t., 87%
OBn
OBn
22b
22a
Scheme 6
Both the isomers 22a and 22b were subjected to a standard reaction sequence to
reach the final target as well as to know the stereochemistry of the isomers. Thus, slow
running isomer 22a on thin layer chromatography was subjected to deprotection of silyl
ether with TBAF in THF resulting in diol 23a, in 89% yield which on further protection
CH3
OH OTBDPS
CH3
TBAF, THF
r.t., 89%
OBn
23a
O
O
CH3
Li, Liq.NH3
O
OH
OBn
25a
24a
O
O
sat.aq. oxalic acid
n-pentane
0
oC,
O
TEMPO, NaOCl, NaBr
EtOAc:toluene (1:1), H2O
0 oC-r.t., 92%
THF, -33 oC, 90%
CH3
2,2-DMP, pTSA
CH2Cl2, 0 oC-r.t., 87%
OBn
22a
CH3
OH OH
O
O
62%
O
1a
26a
Scheme 7
V
Synopsis
with 2,2-dimethoxypropane and pTSA in CH2Cl2 afforded the 1,3-acetonide 24a in 87%
yield. Debenzylation of 24a with lithium in liq.NH3 at -33 oC afforded the alcohol 25a,
which on oxidation with TEMPO free radical furnished ketone 26a in 92% yield. The
ketone 26a with saturated aqueous oxalic acid in n-pentane at 0
o
C underwent
intramolecular acetalisation without epimerization to afford target pheromone
(1S,3R,5R,7S)-(+)-sordidin 1a in 62% yield (Scheme 7).
In the same manner as described in Scheme 7, the fast running isomer 22b on thin
layer chromatography was subjected to deprotection of silyl ether with TBAF in THF
furnished the diol 23b in 90% yield, which on further protection with 2,2dimethoxypropane and pTSA in CH2Cl2 afforded 1,3-acetonide 24b in 88% yield. The
compound 24b on debenzylation using lithium in liq.NH3 at -33 oC afforded alcohol 25b,
which was subjected to oxidation with TEMPO free radical furnished the ketone 26b in
91% yield. The ketone 26b with saturated aqueous oxalic acid in n-pentane at 0 oC
underwent intramolecular acetalisation to resulted the (1S,3R,5S,7R/S)- sordidin 1b as a
mixture of isomers (70:30) in 60% yield. May be the isomers are due to epimerization at
C-7 position (Scheme 8).
CH3
OH OTBDPS
CH3
TBAF, THF
OBn
23b
22b
CH3
O
O
CH3
Li, liq. NH3
O
OBn
OH
25b
24b
O
O
sat.aq. oxalic acid
n-pentane
0
oC,
O
TEMPO, NaOCl, NaBr
EtOAc:toluene (1:1), H2O
0 oC-r.t., 91%
THF, -33 oC, 88%
CH3
2,2-DMP, pTSA
CH2Cl2, 0 oC-r.t., 89%
r.t., 90%
OBn
OH OH
O
O
60%
O
1b
26b
Scheme 8
VI
Synopsis
Chapter 2. This Chapter describes the brief introduction to cancer, benzolactone
enamides, earlier synthetic approaches and studies towards the stereoselective synthesis
of oximidine II.
The oximidines feature a rigid 12-membered macrocyclic lactone bearing an Nmethoxy enamide side chain and are among a family of natural products known as
benzolactone enamides. Almost all the compounds in this class exhibit strong biological
potency, including inhibition of tumor cell proliferation. In 1999, oximidine II was
isolated from Pseudomonas sp.Q52002 by Hayakawa and co-workers, which display
potent antitumor activity and inhibits mammalian vacuolar type (H+) ATPases (vATPases) with unprecedented selectivity suggesting that these proton translocating may
constitute a novel molecular targets for cancer therapeutic agents. The promising biologi-
Retrosynthesis:
H
N
18
OH
3
OBn
O
17
O
OH
N
OH
OMOM
O
H2 N
OMe
1 O
9
27
O
13
12
+
O
N
OMe
11
29
28
OBn
OMe
CO2 Et
OMOM
+
HO
40
54
AcO
HO
I
O
AcO
OAc
41
30
Scheme 9
VII
Synopsis
cal property of oximidine II makes a genuine target for total synthesis. Its unusual
structural features provide an excellent challenge for validation of new methods.
Accordingly, retrosynthetic analysis revealed two key fragments macrolactone
core 28 and enamide sidechain 29. Due to the unstability of enamide sidechain, we aimed
first at the synthesis of macrolactone core 28, which could be obtained from derivative of
ethyl salicylate 40 and chiral aliphatic chain 54 (Scheme 9).
Synthesis of C1-C9 fragment:
Synthesis of C1-C9 fragment 40 started with 3-butyn-1-ol 30 which on protection
as PMB ether 31 using 4-methoxy benzyl bromide and NaH in dry THF. Treatment of 31
with n-BuLi and ethylchloroformate in dry THF at -78 oC resulted in substituted ethyl
propionate 32 in 93% yield. Anisole 33 on Birch reduction with lithium in liq.NH3 at -33
o
C afforded 1-methoxy-1,4-cyclohexadiene 34. Diels-Alder reaction between 32 and 34
in the presence of catalytic dichloromaleic anhydride (DCMA) at 280 oC in a sealed tube
afforded compound 35 (Scheme 10).
CO2 Et
NaH, PMBBr
THF
HO
0 oC-r.t., 90%
n-BuLi, THF
ClCOOEt
PMBO
-78 oC, 93%
30
OMe
32
31
Li, liq.NH3
Et2O, EtOH
OMe
OMe
CO2 Et
32, DCMA, neat
280 oC, 83%
-33 oC, 82%
33
OPMB
34
OPMB
35
Scheme 10
The compound 35 on PMB ether deprotection using DDQ in CH2Cl2:H2O (19:1)
resulted in alcohol 36, which on oxidation under Dess-Martin conditions afforded
aldehyde 37 in 92% yield. Treatment of Aldehyde 37 with n-BuLi and
ethynyltrimethylsilane at -78 oC afforded propargyl alcohol derivative 38. Mesylation of
VIII
Synopsis
OMe
CO2 Et
OPMB
CO2 Et
0 oC-r.t., 85%
35
ethynyltrimethylsilane
n-BuLi, THF
OMe
OMe
DDQ
CH2Cl2:H2O
CO2 Et
Dess-Martin periodinane
OH
CH2Cl2, 0 oC-r.t., 92%
CHO
37
36
OMe
1. MsCl, Et3N, DMAP
CH2Cl2, 0 oC-r.t.
COOEt
OH
OMe
CO2 Et
2. DBU, toluene
reflux, 75% (2 steps)
-78 oC, 79%
38
TMS
39
TMS
OMe
K2CO3, MeOH
CO2 Et
r.t., 87%
40
Scheme 11
38 by using methanesulfonyl chloride, triethylamine and DMAP in CH2Cl2 followed by
elimination with DBU in toluene under refluxing temperature furnished compound 39,
which on further treatment with K2CO3 in MeOH at room temperature afforded enyne 40
in 87% yield (Scheme 11).
Synthesis of C10-C17 fragment:
Chiral aliphatic C10-C17 fragment 54 was prepared from commercially available
D-Galactose. Utilizing a standard literature procedure, D-Galactose was transformed into
tri-O-acetyl-D-Galactal 41. Acetyl deprotection of 41 with 1M NaOMe in MeOH
furnished D-Galactal 42. Selective protection of the primary alcohol in 42 with pivaloyl
chloride and pyridine in dry CH2Cl2 resulted pivaloyl ether 43, which on hydrogenation
with 5% Pd/C in EtOAc furnished pyran derivative 44. The diol in 44 was protected as
acetonide 45 with 2,2-dimethoxypropane and catalytic amount of pTSA in CH2Cl2
followed by deprotection of pivaloyl ether 45 with K2CO3 in MeOH furnished alcohol 46.
Chlorination of 46 with catalytic amount of NaHCO3 and PPh3 in CCl4 under refluxing
conditions resulted in pyranyl chloride 47. Ring opening of 47 with LDA in dry THF at
-78 oC afforded propargylic alcohol 48 in 82% yield (Scheme 12).
IX
Synopsis
O
AcO
r.t., 92%
AcO
OH
43
42
2,2-dimethoxy propane
pTSA, CH2Cl2
O
PivO
r.t., 94%
O
PPh3, CCl4
NaHCO3
K2CO3, MeOH
r.t., 85%
0 oC-r.t., 82%
HO
O
PivO
O
OH
44
O
45
O
Cl
LDA, THF
reflux, 80%
O
HO
OH
41
HO
O
PivO
0 oC-r.t., 87%
HO
OAc
Pd/C, H2
EtOAc
Pivaloyl chloride
Pyridine, CH2Cl2
O
HO
1 M NaOMe
O
O
46
-78
oC,
O
82%
O
OH
O
48
47
Scheme 12
Ph
O
OH
pTSA, MeOH
OH
PhCH(OMe)2
pTSA, CH2Cl2
O
OH 0 oC-r.t., 86%
r.t., 85%
O
48
OH
49
OH
50
Ph
i-Pr2NEt
MOMCl, CH2Cl2
O
O
0 oC-r.t., 78%
0 oC-r.t., 87%
OH
DIBAL-H
CH2Cl2
OBn
OMOM
OMOM
52
51
BnO
NIS, AgNO3
acetone
I
TsNHNH2
NaOAc
OH
OBn
0 oC, 62%
OMOM
THF:H2O (1:1)
60 oC, 61%
OMOM
HO
I
54
53
Scheme 13
X
O
Synopsis
Acetonide deprotection of compound 48 with catalytic amount of pTSA in MeOH
afforded the triol 49, which on selective 1,3-diol protection with benzaldehyde dimethyl
acetal and catalytic pTSA in CH2Cl2 resulted in alcohol 50 in 86% yield. Protection of 50
with methoxymethyl chloride and N,N-diisopropylethylamine in CH2Cl2 furnished MOM
ether 51. Regioselective reductive cleavage of compound 51 with DIBAL-H in dry
CH2Cl2 gave alcohol 52, which on iodination with N-iodosuccinimide and catalytic
amount of silver nitrate in acetone afforded 1-iodo-1-alkyne 53 followed by diimide
reduction with TsNHNH2 and NaOAc in THF:H2O (1:1) at 60 oC furnished cis-1-iodo-1alkene 54 in 61% yield (Scheme 13).
Construction of the C1-C17 frame work:
The Sonogashira coupling of cis-1-iodo-1-alkene 54 with enyne 40 in the
presence of Pd(PPh3)4, CuI and diethylamine in dry ether resulted in the alkyne 55
followed by ester hydrolysis of 55 with LiOH in MeOH:H2O (4:1) at refluxing conditions
afforded acid 56. Intramolecular Mitsunobu lactonization of acid 56 using DEAD and
PPh3 in dry THF at room temperature and later at refluxing conditions did not yield the
BnO
OMe
Pd(PPh3)4, CuI
OMOM
(C2H5)2NH, ether
CO2 Et
+
HO
OMe
CO2 Et
OMOM
r.t., 87%
OBn
I
40
55
54
OH
BnO
OMe
LiOH
MeOH:H2O (4:1)
OMOM
OMe O
CO2 H
DEAD, PPh3
OMOM
reflux, 90%
OBn
56
O
THF, reflux
57
OH
Zn, Cu(OAc)2
AgNO3
MeOH:H2O (1:1), r.t.
Scheme 14
XI
unseparable mixture of isomers
Synopsis
macrolactone 57. Reduction of 56 with Zn (Cu, Ag) complex in MeOH:H2O (1:1)
resulted in an unseparable mixture of isomers (Scheme 14).
BnO
MsCl, Et3N, DMAP
CH2Cl2, -10 oC
OMe
OMOM
OMe O
CO2 H
O
OMOM
OBn
OH
56
2,4,6-Cl3(C6H2)COCl
Et3N, DMAP, toluene
reflux
58
Scheme 15
Intramolecular lactonization of 56 with methanesulfonyl chloride, DMAP and
triethylamine in dry CH2Cl2 at -10 oC and Yamaguchi lactonization using 2,4,6-trichloro
benzoyl chloride, triethyl amine and DMAP in toluene at refluxing conditions were un
successful to get the 12 membered macrolactone ring 58 (scheme 15). Due to the 10
continuous sp2 or sp atoms in the ring system macrolactonization was unsuccessful.
Revised Retrosynthesis:
BnO
OH
BnO
OMOM
O
BnO
OMOM
OMe O
O
O
28
OMe
OMOM
CO2 H
HO
OPMB
59
CHO
64
BnO
+
O
OH
65
61
Scheme 16
XII
OMOM
OMe O
Synopsis
Revised retrosynthetic analysis is shown in Scheme 16, which targetted to
achieve the macrolactone core 28 by mesylation followed by elimination of alcohol 65.
Alcohol 65 could be synthesized from intramolecular alkynylation of 64. Aldehyde 64
inturn could be obtained from Mitsunobu lactonization of acid 59 and alcohol 61.
OMe
LiOH
MeOH:H2O (4:1)
CO2 Et
OPMB
OMe
CO2 H
reflux, 89%
OPMB
35
59
Scheme 17
Ester hydrolysis of compound 35 using LiOH in MeOH:H2O (4:1) at refluxing
temperature afforded acid 59 in 89% yield (Scheme 17). Sonogashira coupling of 54 with
ethynyltrimethylsilane using Pd(PPh3)4, CuI and diethylamine resulted in 60, which on
TMS deprotection with K2CO3 in MeOH furnished enyne 61 (Scheme 18).
BnO
BnO
BnO
OMOM
OMOM
ethynyltrimethylsilane
Pd(PPh3)4, CuI
HO
HO
OMOM
K2CO3, MeOH
r.t., 87%
diethylamine
0 oC-r.t., 90%
HO
I
54
TMS 60
61
Scheme 18
Mitsunobu lactonization of acid 59 with alcohol 61 using DEAD and PPh3 in dry
THF furnished enyne 62 in 90% yield. PMB deprotection of 62 with DDQ in
CH2Cl2:H2O resulted in alcohol 63, which on oxidation under Dess-Martin conditions
afforded aldehyde 64 in 90% yield (Scheme 19).
XIII
Synopsis
BnO
BnO
OMe
OMOM
CO2 H
+
DEAD, PPh3
THF
OMOM
OMe O
O
HO
0 oC-r.t., 86%
OPMB
59
OR
62
61
R= PMB
BnO
BnO
OMOM
Dess-Martin periodinane
CH2Cl2
OMe O
DDQ
CH2Cl2:H2O
O
r.t., 84%
OH
OMOM
OMe O
O
CHO
r.t., 90 %
64
63
Scheme 19
Intramolecular alkynylation of aldehyde 64 using catalytic amount of InBr3 and iPr2NEt at 40 oC did not yield macrolactone derivative 65. Further trials with InBr3, Et3N
in diethyl ether at 40 oC and with LiHMDS in dry THF at -78 oC were unsuccessful to
give macrolactone core 65. May be, due to the triple bond in the 12-membered ring
system, macrolactonization was unsuccessful.
cat. InBr3
cat. i-Pr2NEt
neat, 40 oC
BnO
OMOM
OMe O
LiHMDS, THF
-78 oC
BnO
O
CHO
OMOM
OMe O
O
InBr3, Et3N
Et2O, 40 oC
65
64
Scheme 20
XIV
OH
Synopsis
Chapter III: This chapter describes the ZrCl4 catalyzed synthesis of α-amino
phosphonates.
In recent years, the synthesis of -amino phosphonates has received an
increasing amount of attention because they can be considered as structural analogues to
the corresponding -amino acids and transition state mimics of peptide hydrolysis. In this
connection the utility of the -amino phosphonates as peptide mimics, enzyme inhibitors,
haptens of catalytic antibodies, antibiotics, herbicides and pharmacological agents are
well documented. A variety of synthetic approaches to -amino phosphonates are
available. Of these methods, the nucleophilic addition of the phosphates to imines is one
of the most convenient methods, which is usually promoted by an alkali metal oxide or an
acid. NaOEt has been mainly used for this purpose. Since the pioneering work of Pudovik
et al., Lewis acids such as SnCl4, SnCl2 and BF3.OEt2 have also been found to be
effective. A later work by Zon et al., demonstrated that the reaction can be strongly
promoted by ZnCl2 or MgBr2 in high yields. However, these reactions cannot be carried
out in one pot operation with a carbonyl compound, amine and phosphate because the
amines and water that exist during the imine formation can decompose or deactivate the
Lewis acid. However, many of these procedures involve stoichiometric amount of
catalysts, expensive reagents, longer reaction times and low yields of products in the case
of aliphatic aldehydes and amines. Therefore, there is a need to develop a convenient and
practically potential method for the synthesis of α-amino phosphonates.
Herein, a new methodology is demonstrated for Aldimines to undergo
nucleophilic addition with diethyl phosphate in the presence of a catalytic amount of
zirconium tetrachloride at ambient temperature to afford the corresponding α-amino
phosphonates in high yields with high selectivity (Scheme 21). This method describes a
general procedure for producing biologically important -amino phosphonates.
R'
ZrCl4
N
R
H
+
HOP(OEt)2
CH3CN, r.t.
HN
R'
OEt
R
P
O
Scheme 21
XV
OEt
Synopsis
Table 1: ZrCl4-Catalyzed synthesis of -amino phosphonatesa
Entry
Aldehyde
1
Amine
2
CHO
a
Reaction
Ti me (h)
NH2
Yieldb
4 (%)
3.5
87
5.0
90
5.5
85
2b
5.0
90
2b
4.5
92
7.0
81
5.5
85
4.5
82
8.0
78
6.0
87
NH2
CHO
b
OH
c
NH2
1b
Cl
CHO
d
MeO
CHO
e
Me
f
NH2
1a
CHO
g
2b
NH2
CHO
h
Me
()
i
j
4
NH2
CHO
NH2
1e
Me
Br
a
Products were characterized by 1H NMR, IR and mass spectroscopy
b
isolated yields of products.
XVI