First example of quinine-squaramide catalyzed enantioselective addition of diphenyl phosphite to ketimines derived from isatins

Article abstract of DOI:10.1039/c3ob42026d

A highly enantioselective addition of diphenyl phosphite to ketimines derived from isatins has been achieved using a bifunctional organocatalyst, quinine-derived squaramide catalyst. This method works efficiently with several ketimines to produce the corresponding 3-amino-2-oxoindolin-3-yl-phosphonates in excellent yields with high enantioselectivity (up to 98% ee). This journal is The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3ob42026d

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
First example of quinine-squaramide catalyzed
enantioselective addition of diphenyl phosphite to
ketimines derived from isatins†
Cite this: Org. Biomol. Chem., 2014,
12, 1595
Jimil George,a B. Sridharb and B. V. Subba Reddy*a
Received 10th October 2013,
Accepted 3rd December 2013
A highly enantioselective addition of diphenyl phosphite to ketimines derived from isatins has been
achieved using a bifunctional organocatalyst, quinine-derived squaramide catalyst. This method works
efficiently with several ketimines to produce the corresponding 3-amino-2-oxoindolin-3-yl-phospho-
nates in excellent yields with high enantioselectivity (up to 98% ee).
DOI: 10.1039/c3ob42026d
www.rsc.org/obc
ketimines12 have been developed for the synthesis of 3-amino-
oxindoles. Although a large number of oxindoles are known in
Introduction
Phosphonic esters are common structural units in natural the literature, an efficient asymmetric synthesis of oxindoles
nucleotides, which play an important role as metabolic inter- with two heteroatoms at the 3-position is still rare.13
mediates, regulatory switches for proteins, and backbones for
Following our interest in asymmetric catalysis and also reac-
genetic information.1 In particular, α-aminophosphonic acid tions of ketimines,14 we wish to report a highly enantio-
derivatives are known to exhibit a broad spectrum of biological selective approach for the addition of diphenyl phosphite to
activities such as peptide mimetics,2 antibacterial,3 antiviral ketimines derived from isatins using quinine-squaramide
agents,4 and enzyme inhibitors.5 The biological activity of organocatalyst.15
α-aminophosphonates are connected with their absolute
As a model reaction, we attempted the addition of diphenyl
stereochemistry. Therefore, the synthesis of chiral α-amino- phosphite to ketimine 2a derived from N-methylisatin using
phosphonates through asymmetric addition of phosphite cinchona derived organocatalysts. The catalysts used in this
nucleophiles to imines is of prime importance.6 Though a study are shown in Fig. 1. As shown in Table 1, the reaction
variety of metal catalysts and organocatalysts have been de- was quite slow with quinine (1a) and the desired α-aminopho-
veloped for the enantioselective addition of phosphite to al- sphonate 4a was obtained in 34% ee (Table 1, entry 1). In
dimines,7 there are only a few reports on asymmetric addition order to improve the ee, the next reaction was performed with
of phosphite to simple ketimines.8 Thus, an asymmetric 6′-hydroxyquinine catalyst 1b. Unfortunately, 1b also gave the
addition of phosphite to functionalized ketimines still product 4a with low yield and enantioselectivity. Therefore, the
remains a challenging task because of their lower reactivity
and difficulty in enantiofacial discrimination.
On the other hand, the 3-aminooxindole core with a qua-
ternary carbon center is frequently found in various natural
products, which are known to exhibit a broad spectrum of bio-
logical activities.9 Due to their prominent importance in med-
icinal chemistry,10 numerous catalytic methods such as
α-amination of oxindoles11 and nucleophilic addition of
aNatural Product Chemistry, CSIR-Indian Institute of Chemical Technology,
Hyderabad, India. E-mail: basireddy@iict.res.in; Fax: +91-40-27160512;
Tel: +91-40-27193535
bLaboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology,
Hyderabad, India
†Electronic supplementary information (ESI) available: Experimental proce-
dures, spectral data, HPLC chromatogram of all products; X-ray crystal co-ordi-
nate and CIF file format of 4b. CCDC 960126. For ESI and crystallographic data
Fig. 1 Screening of various organocatalysts in asymmetric addition of
in CIF or other electronic format see DOI: 10.1039/c3ob42026d
phosphite to ketimines.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 1595–1602 | 1595

View Article Online
Paper
Organic & Biomolecular Chemistry
but with improved enantiomeric excess (90% ee). In addition,
the presence of a 4 Å molecular sieve was found to enhance
the rate of reaction.
Table 1 Screening of organocatalysts for asymmetric addition of
diphenyl phosphite to isatin-derived ketiminesa
Therefore, all the reactions were carried out in the presence
of 10 mol% of 1f at −20 °C in dichloromethane to achieve the
best results. From the above results, we found that quinine
based organocatalysts are so effective than quinidine derived
ones.
Our next attempt was to demonstrate the scope of the reac-
tion. The ketimine derived from N-unsubstituted isatin, was
also found to be effective in producing the corresponding
phosphonate 4b with good enantiomeric excess (91% ee,
Table 2, entry 2). Also we performed the reaction with various
ketimines derived from N-substituted isatins.
The N-substituted isatin imines had shown excellent reac-
tivity and enantioselectivity in presence of 10 mol% of 1f. Sur-
prisingly, the reaction of N-benzylisatin imine with diphenyl
phosphite was sluggish at −20 °C. Therefore, this reaction was
carried out at −10 °C. Among various N-protected isatin
imines, the best enantiomeric excess was obtained with keti-
mine derived from N-benzylisatin (97% ee, Table 2, entry 3).
Next, we turned our attention to the reactivity of 5-substi-
tuted-N-benzylisatin imines. Remarkably, 5-substituted-N-ben-
zylisatin imines showed excellent enantioselectivity (68–98%
ee, Table 2, entries 6–10). Of these, 5-bromo-N-benzylisatin
imine 2g furnished the product with 98% ee (Table 2, entry 7).
Similarly, 5-methyl- and 5-methoxy-N-benzylisatin imines 2h
and 2i gave the products in good yields and enantioselectivity.
Temp
(°C)
Time
(h)
Yieldb
(%)
eec
(%)
_Entry
Catalyst
Solvent
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1d
1d
1d
1d
1d
1d
1d
1f
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
25
25
25
25
25
24
24
2
0.25
0.5
2.0
2.0
48
5
78
66
91
98
98
96
94
48
95
90
92
85
96
91
87
92
95
34
43
0
65
60
75
78
76
68
74
72
65
88
84
90
91
91
0
−10
−30
−10
−10
−10
−10
−10
−10
−20
−20
−20
9
10
11
12
13
14
13
13d
14d,e
5
DCE
12
24
24
48
70
48
40
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1g
1f
1f
1f
a All reactions were carried out in 0.25 mmol scale in 2.0 mL solvent
under nitrogen. b Yield refers to pure products after chromatography.
c ee was determined by HPLC analysis on Chiralpak IC column.
d Reaction was performed in presence of 100 mg of 4 Å MS. e 2.0 equiv.
of 3 was used.
Table 2 Organocatalytic addition of diphenyl phosphite to ketimines
reaction was performed with another catalyst 1c (i.e.
6′-hydroxy-O-benzyl quinine catalyst). Though the product 4a
was obtained in 91% yield, the ee was 0%. Further experiments
were conducted with cinchona derived thiourea catalysts to
improve the ee. Using 10 mol% of quinine derived thiourea
1d, the product 4a was obtained in 98% yield with 65% ee. Fur-
thermore, quinidine based thiourea catalyst 1e was found to
be less effective as compared to quinine thiourea 1d. There-
fore, we decided to optimize the reaction with 1d so as to
improve the ee by changing the reaction parameters. At
−10 °C, the catalyst 1d gave the desired product 4a in 94%
yield with 78% ee. Further lowering the temperature resulted
in the reverse effect on yield and enantiomeric excess. Thus
the maximum ee was obtained at −10 °C using 10 mol% of 1d.
Next we tested the efficiency of different solvents such as
dichloromethane, toluene, THF and DCE. Of these, dichloro-
methane was found to be the best for this transformation. The
above results clearly indicate that quinine–thiourea can give
the product only with moderate enantioselectivity (up to 78%
ee). Therefore, we further decided to examine the efficiency of
squaramide catalysts at −10 °C. Interestingly, squaramide cata-
lysts gave the product in good to high enantiomeric excess (up
to 88% ee). However, quinidine derived squaramide catalyst 1g
afforded the product with slightly lower enantiomeric excess
(84% ee) compared to quinine-squaramide 1f. At −20 °C,
derived from isatinsa
Temp
(°C)
t
(h)
Yieldb
(%)
eec
(%)
Entry
2a–r(R,R1)
1
2
3
4
5
6
7
8
2a (R = Me, R1 = H)
2b (R = H, R1 = H)
−20
−20
−10
−20
−10
−10
−10
−10
−10
−10
25
−10
−10
−10
−20
−20
−20
40
24
36
48
24
24
24
12
24
12
60
30
24
36
40
40
40
95
90
94
92
92
90
95
93
93
96
80
90
90
85
91
92
94
91
91
97
90
89
92
98
95
90
68
52
83
91
91
86
92
86
2c (R = Bn, R1 = H)
2d (R = Allyl, R1 = H)
2e (R = PMB, R1 = H)
2f (R = Bn, R1 = 5-Cl)
2g (R = Bn, R1 = 5-Br)
2h (R = Bn, R1 = 5-Me)
2i (R = Bn, R1 = 5-OMe)
2j (R = Bn, R1 = 5-NO2)
2k (R = Bn, R1 = 4-Br)
2l (R = Bn, R1 = 6-Br)
2m (R = Bn, R1 = 7-Me)
2n (R = Bn, R1 = 7-Cl)
2o (R = H, R1 = 5-Br)
2p (R = H, R1 = 5-Me)
2q (R = H, R1 = 5-OMe)
9
10
11
12
13
14
15
16
17
a All reactions were carried out in 0.25 mmol scale using 2.0 equiv. of
diphenyl phosphite in 2.0 mL solvent in presence of 100 mg molecular
sieves. b Yield refers to pure products after chromatography. c ee was
quinine-squaramide 1f gave the product slightly in lower yield determined by HPLC analysis on AD-H or IC column.
1596 | Org. Biomol. Chem., 2014, 12, 1595–1602
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
Scheme 1 Organocatalytic addition of diphenyl phosphite to N-benzyl
isatin.
Surprisingly, 5-nitro-N-benzylisatin imine 2j afforded the
product with low enantioselectivity.
Fig. 3 A plausible ternary complex model.
In contrast with 5-substituted variants, the 4-substituted
isatin imine was less reactive in quinine-squaramide catalyzed
asymmetric addition. For example, treatment of 4-substituted
ketimine 2k derived from 4-bromoisatin with diphenyl phos-
phite at room temperature furnished the corresponding phos-
phonate 4k in 80% yield with 52% ee (Table 2, entry 11).
Whereas the ketimine 2l derived from 6-bromoisatin afforded
the α-aminophosphonate 4l in 90% yield with 83% ee. In a
similar fashion, 7-methyl- and 7-chloroisatin imines gave the
corresponding α-aminophosphonates 4m and 4n with 91% ee
each (Table 2, entries 12 and 13).
Additionally, we examined the reactivity of a few more isatin
imines derived from 5-substituted isatins without N-protec-
tion. These substrates also provided good to high enantio-
meric excess under optimized conditions. Notably, the
ketimine 2p derived from 5-methylisatin afforded the respect-
ive α-aminophosphonate 4p in 92% yield with 92% ee
(Table 2, entry 16).
outcome of the reaction, we proposed a ternary complex model
to understand how the catalyst controls the stereochemistry.
As in the usual way, squaramide binds with isatin imine
whereas quinuclidine moiety abstracts the acidic proton from
phosphite to facilitate the reaction. A preferential Re-face
attack of phosphite nucleophile to ketimine affords the
(R)-isomer (Fig. 3).
Conclusions
In conclusion, we have developed a highly efficient organocata-
lytic approach for the enantioselective addition of diphenyl
phosphite to ketimines derived from isatins using 10 mol%
of quinine-derived squaramide as the catalyst. A variety of
chiral 3-amino-2-oxoindolin-3-ylphosphonates were prepared
in excellent yields with high enantiomeric excess (up to 98%
ee). Further application and biological evaluation of these
chiral α-aminophosphonates are in progress in our laboratory.
The asymmetric addition of diphenyl phosphite on simple
isatin was unsuccessful. Though, the reaction proceeded
smoothly to afford the 3-hydroxy-2-oxindolyl-3-phosphonate in
95% yield but the ee was 0%. The above experiment clearly
indicates that the asymmetric addition was successful only Experimental
with ketimines not with ketones (Scheme 1).
General remarks
Furthermore, the reaction was unsuccessful with dialkyl
All the solvents were dried according to standard procedures.
phosphites such as diethyl- and dimethyl phosphites, due to
their lower reactivity under optimized reaction conditions
(Fig. 2).
A single crystal X-ray analysis shows that the configuration
of the product 4b was (R)-isomer.17 Based on the stereochemical
The reactions were carried out under a nitrogen atmosphere.
The isatin derivatives were purchased from commercial
sources and used as such. The isatin derived ketimines were
prepared according to previously reported procedure.12c Diphe-
nyl phosphite was purchased from Sigma Aldrich and used
without any purification. The enantiomeric excess was deter-
mined by HPLC analysis on chiral stationary phase (Chiralpak
AD-H and IC column) using a mixture of hexane–isopropyl
alcohol as eluent. Racemic samples were prepared by perform-
ing the reaction in the presence of triethylamine as catalyst. All
the compounds were purified by column chromatography on
100–200 mesh silica gel using hexanes–ethyl acetate as eluent.
All the reactions were monitored by TLC analysis. 1H NMR
spectra were recorded on 500 MHz or 300 MHz instruments
using CDCl3 as solvent and TMS as an internal standard.
13C NMR spectra were recorded at 75 MHz or 125 MHz using
CDCl3 as solvent and reference. Optical rotation was recorded
on a Perkin Elmer-343 Polarimeter. Absolute configuration of
the product was determined by single crystal X-ray analysis.
Fig. 2 ORTEP diagram of 4b.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 1595–1602 | 1597

View Article Online
Paper
Organic & Biomolecular Chemistry
Based on the stereochemistry of 4b, the relative configuration calculated mass for C25H25N2NaO6P [M + Na]+ = 503.1342;
of all the products were determined.
found 503.1329.
Quinine and quinidine were purchased from Sigma Aldrich.
(R)-tert-Butyl 1-benzyl-3-(diphenoxyphosphoryl)-2-oxoindolin-
Catalysts 1b and 1c were prepared according to the literature 3-yl carbamate (4c). Purified by column chromatography on
procedure.16a The catalysts 1d and 1e were prepared according silica gel using 30% EtOAc in hexane as eluent; 94% yield and
to the previously reported procedures.16b The catalysts 1f and 97% ee; solid mp. 196–198 °C; αD25 = +2.8 (c = 1.0, CHCl3);
1g were also prepared based on previous procedures.15a
1H NMR (CDCl3, 500 MHz) δ: 1.29 (s, 9H), 4.76 (s, 1H), 5.27 (d,
J = 15.6 Hz, 1H), 5.96 (d, J = 11.4 Hz, 1H), 6.60 (d, J = 8.0 Hz,
2H), 6.70 (d, J = 8.0 Hz, 1H), 7.02–7.16 (m, 2H), 7.16–7.28 (m,
6H), 7.30 (t, J = 8.0 Hz, 1H), 7.36–7.40 (m, 2H), 7.52 (dd, J =
General procedure for the asymmetric addition of phosphite
to isatin derived ketimines
To a stirred mixture of isatin derived ketimine (0.25 mmol), 1.0, 7.3 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ: 28.0, 44.6, 81.4,
squaramide catalyst 1f (16.6 mg, 10 mol%) and 100 mg of 4 Å 109.4, 120.1 (d, J = 3.6 Hz), 120.9 (d, J = 3.6 Hz), 122.9 (d, J =
MS was charged in a flame dried Schlenk tube under a 2.7 Hz), 125.2 (d, J = 4.5 Hz), 125.5, 125.8, 127.2, 128.6, 129.5,
nitrogen atmosphere. Dry DCM (2.0 mL) was added and 129.8, 129.9, 135.3, 143.6 (d, J = 6.3 Hz), 149.9 (dd, J = 9.9,
the suspension was cooled to a prescribed temperature 26.3 Hz), 153.6 (d, J = 18.1 Hz), 171.1; IR (KBr): 3268, 3061,
(−10 °C or −20 °C). After stirring for 15 min, diphenyl phos- 2975, 2926, 2854, 1733, 1610, 1591, 1488, 1364, 1281,
phite (117 mg, 0.50 mmol) was added to the reaction mixture 1207, 1182, 1159, 956, 753 cm−1; HPLC on Ic column
through a syringe and then allowed to stir at the same temp- (70 : 30 hexane–IPA, 1.0 mL min−1, 254 nm); tR = 8.55 min
erature until completion of the reaction (as indicated by TLC (minor) and tR = 11.57 min (major); HRMS (ESI) m/z: calcu-
analysis). The solvent was removed under reduced pressure lated mass C32H31N2NaO6P [M + Na]+ = 593.1812; found
and the resulting residue was purified by column chromato- 593.1794.
graphy on silica gel (100–200 mesh) using hexane–ethyl acetate
as eluent.
(R)-tert-Butyl 1-allyl-3-(diphenoxyphosphoryl)-2-oxoindolin-
3-yl carbamate (4d). Purified by column chromatography on
(R)-tert-Butyl 3-(diphenoxyphosphoryl)-1-methyl-2-oxoindo- silica gel using 30% EtOAc in hexane as eluent; 92% yield and
lin-3-yl carbamate (4a). Purified by column chromatography 90% ee; solid mp. 134–136 °C; α2D5 = −14.3 (c = 0.4, CHCl3);
on silica gel using 30% EtOAc in hexane as eluent; 95% yield 1H NMR (CDCl3, 500 MHz) δ: 1.28 (s, 9H), 4.22 (d, J = 11.8 Hz,
and 91% ee; viscous liquid; α2D5 = −16.5 (c = 0.5, CHCl3); 1H), 4.62 (d, J = 15.3 Hz, 1H), 5.16 (d, J = 10.4 Hz, 1H), 5.36 (d,
1H NMR (CDCl3, 500 MHz) δ: 1.26 (s, 9H), 3.29 (s, 3H), 5.87 (d, J = 17.2 Hz, 1H), 5.78–5.96 (m, 2H), 6.68 (d, J = 7.9 Hz, 2H),
J = 11.1 Hz, 1H), 6.70 (d, J = 7.9 Hz, 2H), 6.85 (d, J = 7.9 Hz, 6.86 (d, J = 7.8 Hz, 1H), 7.06 (t, J = 7.0 Hz, 2H), 7.12–7.26 (m,
1H), 7.05 (dd, J = 7.3, 14.3 Hz, 2H), 7.14–7.26 (m, 5H), 5H), 7.28–7.38 (m, 3H), 7.52 (dd, J = 6.7 Hz, 1H); 13C NMR
7.30–7.40 (m, 3H), 7.52 (dd, J = 1.32, 7.3 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ: 27.9, 43.0, 81.3, 109.3, 117.6, 120.2 (d, J =
(CDCl3, 75 MHz) δ: 27.0, 27.9, 81.3, 108.4, 120.1 (d, J = 3.6 Hz), 4.5 Hz), 120.8 (d, J = 4.5 Hz), 122.8 (d, J = 3.6 Hz), 125.1 (d, J =
120.8 (d, J = 3.6 Hz), 122.9 (d, J = 2.7 Hz), 125.1 (d, J = 3.6 Hz), 3.6 Hz), 125.5, 125.8, 129.5, 129.7, 129.9 (d, J = 2.7 Hz), 130.8,
125.5, 125.8, 129.5, 129.8, 130.1 (d, J = 2.7 Hz), 144.4 (d, J = 143.6 (d, J = 6.3 Hz), 149.8 (dd, J = 9.9, 24.5 Hz), 153.4 (d, J =
7.3 Hz), 150.0 (dd, J = 9.9, 16.3 Hz), 153.6 (d, J = 18.2 Hz), 17.3 Hz), 170.6; IR (KBr): 3260, 3023, 2984, 2928, 1740, 1706,
170.9; IR (KBr): 3431, 3272, 3061, 2925, 2853, 1729, 1611, 1591, 1609, 1592, 1531, 1488, 1358, 1284, 1265, 1207, 1185, 1163,
1489, 1369, 1346, 1280, 1208, 1182, 1161, 956, 754 cm−1; HPLC 957, 933, 769, 751 cm−1; HPLC on Ic column (70 : 30 hexane–
on Ic column (70 : 30 hexane–IPA, 1.0 mL min−1, 254 nm); tR = IPA, 1.0 mL min−1, 254 nm); tR = 7.93 min (minor) and
11.79 min (minor) and tR = 17.18 min (major); HRMS (ESI) tR = 10.93 min (major); HRMS (ESI) m/z: calculated mass
m/z: calculated mass for C26H27N2NaO6P [M + Na]+ = 517.1499; C28H29N2NaO6P [M + Na]+ = 543.1655; found 543.1631.
found 517.1484.
(R)-tert-Butyl 3-(diphenoxyphosphoryl)-1-(4-methoxybenzyl)-
(R)-tert-Butyl 3-(diphenoxyphosphoryl)-2-oxoindolin-3-yl car- 2-oxoindolin-3-yl carbamate (4e). Purified by column chrom-
bamate (4b). Purified by column chromatography on silica gel atography on silica gel using 30% EtOAc in hexane as eluent;
using 40% EtOAc in hexane as eluent; 90% yield and 91% ee; 92% yield and 89% ee; solid mp. 188–190 °C; α2D5 = +6.5 (c =
1
solid mp. 158–160 °C; α2D5 = −12.7 (c = 0.6, CHCl3); 1H NMR (CDCl3, 1.0, CHCl3); H NMR (CDCl3, 500 MHz) δ: 1.29 (s, 9H), 3.70 (s,
300 MHz) δ: 1.31 (s, 9H), 5.94 (d, J = 11.7 Hz, 1H), 6.66 (d, J = 3H), 4.70 (s, 1H), 5.20 (d, J = 15.1 Hz, 1H), 5.94 (d, J = 11.3 Hz,
7.7 Hz, 2H), 6.84 (d, J = 7.7 Hz, 1H), 7.02–7.38 (m, 10H), 1H), 6.58 (d, J = 7.9 Hz, 2H), 6.72 (dd, J = 8.8, 18.2 Hz, 3H),
7.30–7.48 (d, J = 5.9 Hz, 1H), 8.08 (s, 1H); 13C NMR (CDCl3, 7.06 (dd ∼ q, J = 7.5, 7.3 Hz, 2H), 7.12 (dd, J = 7.4 Hz, 15.6 Hz,
75 MHz) δ: 27.9, 81.7, 110.4, 120.2 (d, J = 3.6 Hz), 120.9 (d, J = 2H), 7.18–7.26 (m, 4H), 7.30–7.34 (m, 4H), 7.52 (td, J = 1.3, 2.3,
3.6 Hz), 122.8 (d, J = 1.8 Hz), 125.4 (d, J = 3.6 Hz), 125.5, 125.8, 8.9 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ: 27.9, 44.0, 81.3,
129.5, 129.8, 130.1 (d, J = 2.7 Hz), 141.6 (d, J = 7.3 Hz), 149.6 109.4, 114.0, 120.1 (d, J = 3.8 Hz), 120.9 (d, J = 3.8 Hz), 122.8
(dd, J = 9.9, 16.3 Hz), 153.6 (d, J = 18.2 Hz), 172.4; IR (KBr): (d, J = 2.7 Hz), 125.2 (d, J = 3.8 Hz), 125.4, 125.8, 127.4, 128.6,
3244, 2977, 1739, 1708, 1618, 1591, 1489, 1366, 1259, 1208, 129.5, 129.8, 129.9 (d, J = 2.7 Hz), 143.6 (d, J = 7.1 Hz),
1186, 1163, 959, 756 cm−1
; HPLC on AD-H column 150.1 (q, J = 9.9 Hz), 153.4(d, J = 18.1 Hz), 171.9; IR (KBr):
(70 : 30 hexane–IPA, 1.0 mL min−1, 254 nm); tR = 13.07 min 3270, 2976, 2931, 1739, 1709, 1611, 1590, 1515, 1488, 1356,
(major) and tR = 19.96 min (minor); HRMS (ESI) m/z: 1284, 1249, 1183, 958, 760 cm−1; HPLC on Ic column
1598 | Org. Biomol. Chem., 2014, 12, 1595–1602
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
(70 : 30 hexane–IPA, 1.0 mL min−1, 254 nm); tR = 11.26 min
(R)-tert-Butyl 1-benzyl-3-(diphenoxyphosphoryl)-5-methoxy-
(minor) and tR = 13.41 min (major); HRMS (ESI) m/z: calcu- 2-oxoindolin-3-yl carbamate (4i). Purified by column chromato-
lated mass C33H34N2O7P [M + H]+ = 601.2098; found 601.2103.
graphy on silica gel using 30% EtOAc in hexane as eluent; 93%
(R)-tert-Butyl
1-benzyl-5-chloro-3-(diphenoxyphosphoryl)- yield and 90% ee; solid mp. 188–190 °C; α2D5 = +14.3 (c = 0.9,
2-oxoindolin-3-yl carbamate (4f). Purified by column chrom- CHCl3); 1H NMR (CDCl3, 500 MHz) δ: 1.32 (s, 9 H), 3.70 (s,
atography on silica gel using 30% EtOAc in hexane as eluent; 3H), 4.75 (s, 1H), 5.24 (d, J = 13.6 Hz, 1H), 5.92 (d, J = 10.7 Hz,
90% yield and 92% ee; solid mp. 220–222 °C; α2D5 = +22.5 (c = 1H), 6.60 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 7.8 Hz, 2H), 6.74 (d, J =
0.9, CHCl3); 1H NMR (CDCl3, 500 MHz) δ: 1.34 (s, 9 H), 4.76 (d, 8.2 Hz, 2H), 7.04–7.40 (m, 14H), 13C NMR (CDCl3, 75 MHz) δ:
J = 15.3 Hz, 1H), 5.20 (d, J = 15.8 Hz, 1H), 5.92 (d, J = 11.5 Hz, 28.0, 44.6, 55.8, 81.4, 109.1, 111.9, 115.0, 120.1 (d, J = 4.5 Hz),
1H), 6.60 (d, J = 8.3 Hz, 1H), 6.72 (d, J = 8.1 Hz, 2H), 7.02–7.26 120.9 (d, J = 3.6 Hz, 125.5, 125.8, 127.2, 127.5, 128.6, 129.5,
(m, 10H), 7.28–7.42 (m, 4H), 7.48 (t, J = 2.1 Hz, 1H); 13C NMR 129.8, 135.4, 136.9 (d, J = 6.4 Hz), 150.1 (q, J = 9.9 Hz), 153.6
(CDCl3, 75 MHz) δ: 28.1, 44.7, 81.7, 110.4, 120.1 (d, J = 3.1 Hz), (d, J = 17.2 Hz), 156.0 (d, J = 2.7 Hz, 170.8; IR (KBr): 3263,
120.8 (d, J = 3.6 Hz), 125.4 (d, J = 4.5 Hz), 125.7, 125.9, 127.2, 2976, 1734, 1709, 1595, 1528, 1492, 1457, 1360, 1272, 1183,
127.6, 128.3 (d, J = 3.6 Hz), 128.7, 129.6, 129.8, 134.9, 142.1 (d, 957, 767 cm−1; HPLC on AD-H column (70 : 30 hexane–IPA,
J = 7.2 Hz), 149.9 (dd, J = 9.9, 16.3 Hz), 153.6 (d, J = 18.6 Hz), 1.0 mL min−1, 254 nm); tR = 12.27 min (minor) and tR
=
170.7; IR (KBr): 3259, 3028, 2974, 2925, 1744, 1711, 1642, 1606, 17.71 min (major); HRMS (ESI) m/z: calculated mass for
1531, 1488, 1285, 1266, 1207, 1184, 1162, 964 cm−1; HPLC on C33H33N2NaO7P [M + Na]+ = 623.1917; found 623.1900.
Ic column (70 : 30 hexane–IPA, 1.0 mL min−1, 254 nm); tR
=
(R)-tert-Butyl 1-benzyl-3-(diphenoxyphosphoryl)-5-nitro-
5.93 min (minor) and tR = 7.33 min (major); HRMS (ESI) m/z: 2-oxoindolin-3-yl carbamate (4j). Purified by column chromato-
calculated mass C32H30ClN2NaO6P [M + Na]+ = 527.1422; graphy on silica gel using 40% EtOAc in hexane as eluent;
found 527.1404.
(R)-tert-Butyl
96% yield and 68% ee; solid mp. 198–200 °C; α2D5 = +16.2 (c =
1-benzyl-5-bromo-3-(diphenoxyphosphoryl)- 1.00, CHCl3); H NMR (CDCl3, 500 MHz) δ: 1.36 (s, 9 H), 4.88
1
2-oxoindolin-3-yl carbamate (4g). Purified by column chromato- (d, J = 15.7 Hz, 1H), 5.22 (d, J = 15.8 Hz, 1H), 6.08 (d, J =
graphy on silica gel using 30% EtOAc in hexane as eluent; 95% 11.3 Hz, 1H), 6.80 (d, J = 8.5 Hz, 1H), 6.82 (d, J = 8.3 Hz, 2H),
yield and 98% ee; solid mp. 216–218 °C; α2D5 = +19.3 (c = 1.0, 7.10–7.40 (m, 13H), 8.16 (d, J = 8.7 Hz. 1H), 8.40 (t, J = 2.3 Hz,
1
CHCl3); H NMR (CDCl3, 500 MHz) δ: 1.34 (s, 9 H), 4.78 (d, J = 1H); 13C NMR (CDCl3, 75 MHz) δ: 28.1, 44.9, 82.2, 109.2, 119.9
7.6 Hz, 1H), 5.20 (d, J = 16.1 Hz, 1H), 5.90 (d, J = 11.5 Hz, 1H), (d, J = 4.5 Hz), 120.5 (d, J = 4.5 Hz), 120.8 (d, J = 3.6 Hz), 125.9,
6.56 (d, J = 8.3 Hz, 1H), 6.74 (d, J = 8.3 Hz, 2H), 7.02–7.36 (m, 126.1, 126.8 (d, J = 2.7 Hz), 127.2, 127.9, 128.9, 129.8, 129.9,
16H), 7.62 (t, J = 1.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ: 134.2, 143.2, 148.9 (d, J = 6.3 Hz, 149.8 (d, J = 9.0 Hz), 171.5
28.1, 44.7, 81.7, 110.9, 115.5, 120.1, 120.7, 125.7, 125.9, 127.2, (dd, J = 2.7, 3.6 Hz); IR (KBr): 3251, 3064, 3026, 2976, 2934,
127.7, 128.1, 128.7, 129.6, 129.9, 132.7, 134.9, 142.6, 149.9 1753, 1706, 1613, 1527, 1489, 1450, 1390, 1337, 1288, 1267,
(q, J = 8.2 Hz), 153.6 (d, J = 18.6 Hz), 170.7; IR (KBr): 3259, 1181, 1160, 1070, 964, 932, 761 cm−1; HPLC on Ic column
3025, 2974, 2925, 1743, 1711, 1608, 1585, 1530, 1487, 1284, (70 : 30 hexane–IPA, 1.0 mL min−1, 254 nm); tR = 7.68 min
1206, 1184, 1161, 963, 764 cm−1; HPLC on Ic column (minor) and tR = 8.790 min (major); HRMS (ESI) m/z: calcu-
(70 : 30 hexane–IPA, 1.0 mL min−1, 254 nm); tR = 6.07 min lated mass for C32H303N3NaO8P [M + Na]+ = 638.1662; found
(minor) and tR = 7.58 min (major); HRMS (ESI) m/z: calculated 638.1670.
mass C32H30BrN2NaO6P [M + Na]+ = 671.0917; found 671.0905.
(R)-tert-Butyl 1-benzyl-3-(diphenoxyphosphoryl)-5-methyl- 2-oxoindolin-3-yl carbamate (4k). Purified by column chromato-
(R)-tert-Butyl
1-benzyl-4-bromo-3-(diphenoxyphosphoryl)-
2-oxoindolin-3-yl carbamate (4h). Purified by column chromato- graphy on silica gel using 30% EtOAc in hexane as eluent;
graphy on silica gel using 30% EtOAc in hexane as eluent; 93% 80% yield and 52% ee; solid mp. 170–172 °C; α2D5 = +18.8 (c =
1
yield and 95% ee; solid mp. 204–206 °C; α2D5 = +10.9 (c = 0.6, 1.15, CHCl3); H NMR (CDCl3, 500 MHz) δ: 1.41 (s, 9 H), 4.78
CHCl3); 1H NMR (CDCl3, 500 MHz) δ: 1.30 (s, 9 H), 2.25 (s, (d, J = 15.9 Hz, 1H), 5.26 (d, J = 15.4 Hz, 1H), 6.16 (d, J =
3H), 4.76 (s, 1H), 5.24 (d, J = 14.9 Hz, 1H), 5.92 (d, J = 11.1 Hz, 9.7 Hz, 1H), 6.66 (d, J = 7.1 Hz, 1H), 6.70–6.78 (m, 2H),
1H), 6.58 (d, J = 7.9 Hz, 1H), 6.62 (d, J = 8.2 Hz, 2H), 7.0 (d, J = 7.02–7.26 (m, 10H), 7.30 (dd ∼ t, J = 8.2, 7.6 Hz, 3H)), 7.36–7.42
8.0 Hz, 1H), 7.06 (t, J = 7.2 Hz, 1H), 7.12 (t, J = 7.6 Hz, 2H), (m, 2H); 13C NMR (CDCl3, 75 MHz) δ: 28.1, 44.8, 81.3, 108.6,
7.16–7.22 (m, 4H), 7.24–7.28 (m, 2H), 7.30–7.42 (m, 5H); 13C 120.1 (d, J = 3.6 Hz), 120.8, 125.5, 125.7, 127.2, 127.6 (d, J =
NMR (CDCl3, 125 MHz) δ: 20.9, 27.9, 44.5, 81.4, 109.2, 115.3, 11.8 Hz), 128.7, 129.5, 129.7, 130.8, 135.0, 145.3 (d, J = 6.4 Hz),
119.7, 120.0 (d, J = 4.5 Hz), 120.8 (d, J = 3.6 Hz), 125.4, 125.7, 150.0 (dd, J = 8.2, 30.8 Hz), 170.6; IR (KBr): 3445, 3288,
127.1, 127.4, 128.6, 129.3, 129.4, 129.7, 130.3, 132.5, 135.4, 3032, 2975, 2925, 1736, 1697, 1597, 1520, 1488, 1450, 1364,
141.1 (d, J = 7.3 Hz), 150.1 (dd, J = 9.9 Hz), 153.7 (d, J = 1289, 1209, 1179, 964, 765 cm−1; HPLC on Ic column
18.2 Hz), 170.9; IR (KBr): 3279, 2977, 2927, 1735, 1625, 1590, (70 : 30 hexane–IPA, 1.0 mL min−1, 254 nm); tR = 8.38 min
1532, 1490, 1368, 1263, 1203, 1185, 958, 765 cm−1; HPLC on Ic (minor) and tR = 13.07 min (major); HRMS (ESI) m/z: calcu-
column (70 : 30 hexane–IPA, 1.0 mL min−1, 254 nm); tR
=
lated mass for C32H30BrN2NaO6P [M + Na]+ = 671.0917; found
8.47 min (minor) and tR = 10.29 min (major); HRMS (ESI) m/z: 671.0923.
calculated mass for C33H33N2NaO6P [M + Na]+ = 607.1968;
found 607.1951.
(R)-tert-Butyl
1-benzyl-6-bromo-3-(diphenoxyphosphoryl)-
2-oxoindolin-3-yl carbamate (4l). Purified by column
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 1595–1602 | 1599

View Article Online
Paper
Organic & Biomolecular Chemistry
chromatography on silica gel using 30% EtOAc in hexane as and 86% ee; solid mp 110–112 °C; α2D5 = +25 (c = 0.45, CHCl3);
eluent; 90% yield and 83% ee; solid mp. 198–200 °C; α2D5 1H NMR (CDCl3, 500 MHz) δ: 1.34 (s, 9H), 5.98 (d, J = 11.4 Hz,
=
−7.2 (c = 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz) δ: 1.33 (s, 1H), 6.64 (d, J = 8.2 Hz, 1H), 6.83 (d, J = 8.2 Hz, 2H), 7.12 (t, J =
9 H), 4.76 (s, 1H), 5.22 (dd ∼ t, J = 6.7, 16.2 Hz, 1H), 5.94 (d, J = 7.3 Hz, 1H), 7.16–7.24 (m, 5H), 7.34 (t, J = 8.0 Hz, 3H), 7.58 (t,
11.1 Hz, 1H), 6.68 (d, J = 8.1 Hz, 2H), 6.86 (s, 1H), 7.10 (dd ∼ t, J = 2.1 Hz, 1H), 8.46 (s, 1H); 13C NMR (CDCl3 + DMSO-d6,
J = 7.1, 14.6 Hz, 1H), 7.18 (dd ∼ t, J = 7.9, 16.2 Hz, 3H), 75 MHz) δ: 27.2, 80.3, 110.4, 119.4, 119.9, 124.8, 124.9, 125.0,
7.20–7.26 (m, 5H), 7.30–740 (m, 6H); 13C NMR (CDCl3, 127.2, 128.9 (d, J = 15.9 Hz), 131.8 (d, J = 8.8 Hz), 141.4 (d, J =
75 MHz) δ: 28.0, 44.7, 81.7, 112.8 (d, J = 2.72 Hz), 120.0 (d, J = 9.3 Hz), 149.0 (d, J = 10.5 Hz), 152.8 (d, J = 17.1 Hz), 173; IR
4.5 Hz), 120.8 (d, J = 4.5 Hz), 125.6, 125.8 (d, J = 3.6 Hz), 125.9, (KBr): 3262, 2976, 1736, 1616, 1591, 1484, 1367, 1262, 1187,
126.2 (d, J = 3.6 Hz), 127.2, 127.7, 128.8, 128.9, 129.6, 129.8, 1159, 960, 762 cm−1; HPLC on AD-H column (70 : 30 hexane–
134.7, 144.8, 149.8 (q, J = 10.0 Hz), 153.6 (d, J = 4.5 Hz), 170.9; IPA, 1.0 mL min−1, 254 nm); tR = 9.51 min (major) and tR
=
IR (KBr): 3431, 3246, 3065, 3011, 2976, 2926, 1733, 1698, 1597, 22.79 min (minor); HRMS (ESI) m/z: calculated mass for
1526, 1488, 1288, 1275, 1204, 1180, 1163, 960, 770 cm−1; HPLC C25H25BrN2O6P [M + H]+ = 559.0628; found 559.0633.
on Ic column (70 : 30 hexane–IPA, 1.0 mL min−1, 254 nm); tR =
(R)-tert-Butyl 3-(diphenoxyphosphoryl)-5-methyl-2-oxoindo-
6.12 min (minor) and tR = 8.51 min (major); HRMS (ESI) m/z: lin-3-yl carbamate (4p). Purified by column chromatography
calculated mass for C32H30BrN2NaO6P [M + Na]+ = 673.0902; on silica gel using 40% EtOAc in hexane as eluent; 92% yield
found 673.0907.
(R)-tert-Butyl
and 92% ee; solid mp 96–98 °C; α2D5 = +8.5 (c = 1.00, CHCl3);
1-benzyl-3-(diphenoxyphosphoryl)-7-methyl- 1H NMR (CDCl3 + DMSO-d6, 500 MHz) δ: 1.30 (s, 9 H), 2.26 (s,
2-oxoindolin-3-yl carbamate (4m). Purified by column chromato- 3H), 6.06 (d, J = 11.7 Hz, 1H), 6.70 (d, J = 7.9 Hz, 2H), 6.78 (d,
graphy on silica gel using 30% EtOAc in hexane as eluent; J = 7.9 Hz, 1H), 7.07 (t, J = 7.2 Hz, 2H), 7.12–7.40 (m, 8H), 7.34
90% yield and 91% ee; solid mp. 170–172 °C; α2D5 = −8.2 (c = (t, J = 8.0 Hz, 3H), 9.95 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ:
1
0.75, CHCl3); H NMR (CDCl3, 500 MHz) δ: 1.33 (s, 9 H), 2.24 21.0, 27.9, 81.6, 110.2, 120.2 (d, J = 4.5 Hz), 120.8 (d, J = 4.5 Hz),
(s, 3H), 5.02 (m, 1H), 5.40 (d, J = 14.5 Hz, 1H), 5.96 (d, J = 125.4, 125.7, 125.8 (d, J = 3.6 Hz), 129.4, 129.7, 130.4 (d, J =
10.7 Hz, 1H), 6.71 (d, J = 8.1 Hz, 2H), 6.96–7.02 (m, 2H), 7.08 1.8 Hz), 132.3 (d, J = 2.7 Hz), 139.3 (d, J = 8.1 Hz), 150.0 (d, J =
(dd ∼ t, J = 7.6, 7.8 Hz, 1H), 7.14–7.24 (m, 8H), 7.28–7.36 (m, 9.9 Hz), 153.8 (d, J = 17.2 Hz), 172.5; IR (KBr): 3279, 2977,
4H), 7.42 (d, J = 7.2 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ: 18.7, 2926, 1734, 1693, 1624, 1591, 1532, 1490, 1368, 1262, 1186,
28.1, 45.9, 81.4, 119.9 (d, J = 2.7 Hz), 120.2 (d, J = 3.6 Hz), 120.9 1160, 960, 766 cm−1; HPLC on AD-H column (70 : 30 hexane–
(d, J = 4.5, 122.9 (d, J = 3.6 Hz), 123.1 (d, J = 4.5 Hz), 125.5, IPA, 1.0 mL min−1, 254 nm); tR = 12.18 min (major) and tR
=
125.8, 125.9, 127.0, 128.7, 129.6, 129.8, 134.0 (d, J = 2.7 Hz), 21.93 min (minor); HRMS (ESI) m/z: calculated mass for
137.5, 141.7 (d, J = 7.3 Hz), 150.1 (dd, J = 10.9, 23.6 Hz), 153.6 C26H27N2NaO6P [M + Na]+ = 517.1499; found 517.1505.
(d, J = 18.2 Hz), 171.9; IR (KBr): 3270, 3061, 3024, 2932, 1738,
(R)-tert-Butyl 3-(diphenoxyphosphoryl)-5-methoxy-2-oxoin-
1712, 1599, 1528, 1490, 1446, 1354, 1282, 1261, 1202, 1164, dolin-3-yl carbamate (4q). Purified by column chromatography
953, 767 cm−1; HPLC on Ic column (70 : 30 hexane–IPA, 1.0 mL on silica gel using 40% EtOAc in hexane as eluent; 94% yield
min−1, 254 nm); tR = 8.14 min (minor) and tR = 12.13 min and 86% ee; solid mp 86–88 °C; αD25 = +13.9 (c = 0.55, CHCl3);
(major); HRMS (ESI) m/z: calculated mass for C33H33N2NaO6P 1H NMR (CDCl3, 500 MHz) δ: 1.32 (s, 9 H), 3.72 (s, 3H), 5.94 (d,
[M + Na]+ = 607.1968; found 607.1971.
(R)-tert-Butyl
J = 11.5 Hz, 1H), 6.70–6.84 (m, 4H), 7.02–7.25 (m, 7H), 7.32
1-benzyl-7-chloro-3-(diphenoxyphosphoryl)- (dd, J = 7.9, 7.4 Hz, 2H), 8.30 (s, 1H); 13C NMR (CDCl3,
2-oxoindolin-3-yl carbamate (4n). Purified by column chrom- 75 MHz) δ: 27.9, 55.8, 81.7, 111.7 (d, J = 2.2 Hz), 115.5 (d, J =
atography on silica gel using 30% EtOAc in hexane as eluent; 1.6 Hz), 120.2 (d, J = 3.8 Hz), 120.8 (d, J = 3.8 Hz), 125.5, 125.8,
85% yield and 91% ee; solid mp. 178–180 °C; α2D5 = −10.6 (c = 129.5, 129.8, 135.1 (d, J = 7.1 Hz), 150.0 (dd, J = 2.7, 9.3 Hz),
1.0, CHCl3); 1H NMR (CDCl3, 300 MHz) δ: 1.33 (s, 9 H), 5.40 (s, 153.8 (d, J = 18.1 Hz), 155.9 (d, J = 2.7 Hz), 172.5; IR (KBr):
2H), 5.94 (d, J = 11.1 Hz, 1H), 6.68 (d, J = 8.1 Hz, 2H), 7.0 (t, J = 3263, 2976, 2974, 2928, 2231, 1727, 1645, 1593, 1491,
7.4 Hz, 1H), 7.06–7.40 (m, 14H), 7.46 (d, J = 1.5, 7.4 Hz, 1H); 1268, 1203, 1159, 1027, 955 cm−1; HPLC on Ic column
13C NMR (CDCl3, 75 MHz) δ: 28.0, 45.7, 81.7, 115.6, 120.0 (d, (70 : 30 hexane–IPA, 1.0 mL min−1, 254 nm); tR = 15.18 min
J = 3.8 Hz), 120.8 (d, J = 3.8 Hz), 123.6, 125.6, 125.9, 126.6, (major) and tR = 22.22 min (minor); HRMS (ESI) m/z: calcu-
126.9, 128.4, 129.6, 129.8, 132.5 (d, J = 2.2 Hz), 137.3, 139.7 (d, lated mass for C26H27N2NaO7P [M + Na]+ = 533.1448, found
J = 6.5 Hz), 150.0 (dd, J = 4.9, 10.0 Hz), 153.3 (d, J = 17.6 Hz), 533.1452.
171.5; IR (KBr): 3238, 3013, 2929, 1739, 1708, 1593, 1525, 1482,
Diphenyl 1-benzyl-3-hydroxy-2-oxoindolin-3-yl phosphonate
1357, 1260, 1175, 964 cm−1
;
HPLC on Ic column (5). Purified by column chromatography on silica gel using
(70 : 30 hexane–IPA, 1.0 mL min−1, 254 nm); tR = 6.39 min 30% EtOAc in hexane as eluent; 94% yield and 0% ee; semi-
1
(minor) and tR = 8.82 min (major); HRMS (ESI) m/z: calculated solid; H NMR (CDCl3, 500 MHz) δ: 2.54 (brs, 1H), 4.86 (d, J =
mass for C32H30ClN2NaO6P [M + Na]+ = 627.1422; found 15.7 Hz, 1H), 4.90 (d, J = 15.7 Hz, 1H), 5.88 (d, J = 11.8 Hz, 2H),
627.1428.
6.68 (d, J = 7.9 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 7.18–7.34 (m,
(R)-tert-Butyl 5-bromo-3-(diphenoxyphosphoryl)-2-oxoindo- 12H), 7.36 (d, J = 4.2 Hz, 4H); 13C NMR (CDCl3, 75 MHz) δ:
lin-3-yl carbamate (4o). Purified by column chromatography 43.9, 73.5 (d, J = 6.1 Hz), 109.6, 120.4 (t, J = 5.5 Hz), 123.2,
on silica gel using 40% EtOAc in hexane as eluent; 91% yield 125.6, 126.1, 127.3, 127.8, 128.8, 129.7, 130.8, 134.9, 143.4,
1600 | Org. Biomol. Chem., 2014, 12, 1595–1602
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
150.5 (q, J = 7.7 Hz), 171.1 (d, J = 7.1 Hz); IR (KBr): 3451, 3062,
2926, 1734, 1615, 1590, 1489, 1469, 1289, 1187, 1101, 1076,
1024, 959 cm−1; HPLC on AD-H column (70 : 30 hexane–IPA,
1.0 mL min−1, 254 nm); tR = 16.53 min and tR = 21.75 min;
HRMS (ESI) m/z: calculated mass for C27H22NNaO5P
[M + Na]+ = 494.1128, found 494.1135.
(d) T. Akiyama, H. Morita, J. Itoh and K. Fuchibe, Org. Lett.,
2005, 7, 2583; (e) J. P. Abell and H. Yamamoto, J. Am. Chem.
Soc., 2008, 130, 10521; (f) S. Nakamura, H. Nakashima,
A. Yamamura, N. Shibata and T. Toru, Adv. Synth. Catal.,
2008, 350, 1209; (g) X. Cheng, R. Goddard, G. Buth and
B. List, Angew. Chem., Int. Ed., 2008, 47, 5079; (h) D. Zhao,
Y. Wang, L. Mao and R. Wang, Chem.–Eur. J., 2009, 15, 10983.
8 For hydrophosphonylation of ketimines, see: (a) S. Nakamura,
M. Hayashi, Y. Hiramatsu, N. Shibata, Y. Funahashi and
T. Toru, J. Am. Chem. Soc., 2009, 131, 18240; (b) L. Yin,
Y. Bao, N. Kumagai and M. Shibasaki, J. Am. Chem. Soc.,
2013, 135, 10338; For cyclic imines, see: (c) H. Xie, A. Song,
X. Zhang, X. Chen, H. Li, C. Sheng and W. Wang, Chem.
Commun., 2013, 49, 928.
Acknowledgements
J. G. is thankful to CSIR, Govt. of India for award of scholar-
ship. B.V.S. thanks CSIR, New Delhi for financial support as
part of XII five year plan program under title ORIGIN
(CSC-0108).
9 For reviews, see: (a) A. B. Dounay and L. E. Overman, Chem.
Rev., 2003, 103, 2945; (b) C. V. Galliford and K. A. Scheidt,
Angew. Chem., Int. Ed., 2007, 46, 8748; (c) F. Zhou, Y. L. Liu
and J. Zhou, Adv. Synth. Catal., 2010, 352, 1381;
(d) K. Shen, X. Liu, L. Lin and X. Feng, Chem. Sci., 2012, 3,
327; (e) J. E. M. Klein and R. J. K. Taylor, Eur. J. Org. Chem.,
2011, 6821; For selected examples, see: (f) H. Takayama,
I. Mori and M. Kitajima, Org. Lett., 2004, 6, 2945;
(g) A. K. Ghosh, G. Schiltz, R. S. Perali, S. Leshchenko,
S. Kay, D. E. Walters, Y. Koh, K. Maeda and H. Mitsuya,
Bioorg. Med. Chem. Lett., 2006, 16, 1869; (h) V. V. Vintonyak,
K. Warburg, H. Kruse, S. Grimme, K. Hübel, D. Rauh and
H. Waldmann, Angew. Chem., Int. Ed., 2010, 49, 5902;
(i) A. Czarna, B. Beck, S. Srivastava, G. M. Popowicz,
S. Wolf, Y. Huang, M. Bista, T. A. Holak and A. Dömling,
Angew. Chem., Int. Ed., 2010, 49, 5352; ( j) S. Mohamadi,
R. Heiran, R. P. Herrera and E. Marquès-Lòpez, Chem-
CatChem, 2013, 5, 2131.
Notes and references
1 (a) F. H. Westheimer, Science, 1987, 235, 1173;
(b) J. Hiratake and J. Oda, Biosci., Biotechnol., Biochem.,
1997, 61, 211; (c) B. Dhawan and D. Redmore, Phosphorus
Sulfur Relat. Elem., 1987, 32, 119; (d) V. P. Kukhar,
V. A. Soloshonok and V. A. Solodenko, Phosphorus, Sulfur
Silicon Relat. Elem., 1994, 92, 239; (e) V. D. Romanenko and
V. P. Kukhar, Chem. Rev., 2006, 106, 3868; (f) R. Enge,
Chem. Rev., 1977, 77, 349.
2 (a) Aminophosphonic and Aminophosphinic Acids, ed.
V. P. Kukhar and H. R. Hudson, Wiley, New York, 2000;
(b) P. Kafarski and B. Lejczak, Phosphorus, Sulfur Silicon
Relat. Elem., 1991, 63, 193; (c) P. Kafarski and B. Lejczak,
Curr. Med. Chem.: Anti-Cancer Agents, 2001, 1, 301;
(d) Z. H. Kudzin, M. H. Kudzin, J. Drabowicz and
C. V. Stevens, Curr. Org. Synth., 2011, 15, 2015; 10 For reviews, see: (a) P. Chauhan and S. S. Chimni, Tetrahe-
(e) A. B. Smith III, K. M. Yager and C. M. Taylor, J. Am.
Chem. Soc., 1995, 117, 10879.
dron: Asymmetry, 2013, 24, 343; (b) F. Zhou, Y.-L. Liu and
J. Zhou, Adv. Synth. Catal., 2010, 352, 1381.
3 J. Huang and R. Chen, Heteroat. Chem., 2000, 11, 480.
4 (a) M. C. Allen, W. Fuhrer, B. Tuck, R. Wade and
J. M. Wood, J. Med. Chem., 1989, 32, 1652; (b) J. Bird,
R. E. De Mello, A. J. Miles-Williams, S. S. Rahman and
R. W. Ward, J. Med. Chem., 1994, 37, 158; (c) W. M. Smith
and P. A. Bartlett, J. Am. Chem. Soc., 1998, 120, 4622.
5 D. V. Patel, K. Rielly-Gauvin, D. E. Ryono, A. F. Charles,
W. L. Rogers, S. A. Smith, J. M. Deforrest, R. S. Oehl and
E. W. Petrillo Jr., J. Med. Chem., 1995, 38, 4557.
11 (a) S. Mouri, Z. Chen, H. Mitsunuma, M. Furutachi,
S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2010,
132, 1255; (b) L. Cheng, L. Liu, D. Wang and Y.-J. Chen,
Org. Lett., 2009, 11, 3874; (c) Z.-Q. Qian, F. Zhou, T.-P. Du,
B.-L. Wang, M. Ding, X.-L. Zhao and J. Zhou, Chem.
Commun., 2009, 6753; (d) K. Shen, X. Liu, G. Wang, L. Lin
and X. Feng, Angew. Chem., Int. Ed., 2011, 50, 4684;
(e) T. Bui, G. Hernández-Torres, C. Milite and C. F. Barbas
III., Org. Lett., 2010, 12, 5696.
6 For review, see: (a) P. Merino, E. Marques-Lopez and 12 (a) Y.-L. Liu, F. Zhou, J.-J. Cao, C.-B. Ji, M. Ding and
R. P. Herrera, Adv. Synth. Catal., 2008, 350, 1195;
(b) M. Ordóñez, H. Rojas-cabrera and C. Cativiela, Tetra-
hedron, 2009, 65, 17; (c) P. S. Bhadury and H. Li, Synlett,
2012, 23, 1108; (d) D. Zhao and R. Wang, Chem. Soc. Rev.,
2012, 41, 2095; (e) M. Ordóñez, J. L. Viveros-Ceballos,
C. Cativiela and A. Arizpe, Curr. Org. Synth., 2012, 9, 310.
7 For selected examples: (a) H. Gröger, Y. Saida, H. Sasai,
K. Yamaguchi, J. Martens and M. Shibasaki, J. Am. Chem.
Soc., 1998, 120, 3089; (b) H. Sasai, S. Arai, Y. Tahara and
M. Shibasaki, J. Org. Chem., 1995, 60, 6656; (c) G. D. Joly
and E. N. Jacobsen, J. Am. Chem. Soc., 2004, 126, 4102;
J. Zhou, Org. Biomol. Chem., 2010, 8, 3847; (b) A. Sacchetti,
A. Silvani, F. G. Gatti, G. Lesma, T. Pilati and B. Trucchi,
Org. Biomol. Chem., 2011, 9, 5515; (c) W. Yan, D. Wang,
J. Feng, P. Li, D. Zhao and R. Wang, Org. Lett., 2012, 14,
2512; (d) Q.-X. Guo, Y.-W. Liu, X.-C. Li, L.-Z. Zhong and
Y.-G. Peng, J. Org. Chem., 2012, 77, 3589; (e) J. Feng,
W. Yan, D. Wang, P. Li, Q. Sun and R. Wang, Chem.
Commun., 2012, 48, 8003; (f) N. Hara, S. Nakamura,
M. Sano, R. Tamura, Y. Funahashi and N. Shibata, Chem.–
Eur. J., 2012, 18, 9276; (g) D. Chen and M.-H. Xu, Chem.
Commun., 2013, 49, 1327; For racemic version of
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 1595–1602 | 1601

View Article Online
Paper
Organic & Biomolecular Chemistry
hydrophosphonylation
(h) G. I. Shakibaei, S. Samadi, R. Ghahremanzadeh and
A. Bazgir, J. Comput. Chem., 2010, 12, 295.
of
isatin
imines,
see:
selected examples of squaramide organocatalysis, see:
(b) J. P. Malerich, K. Hagihara and V. H. Rawal, J. Am.
Chem. Soc., 2008, 130, 14416; (c) H. Konishi, T. Y. Lam,
J. P. Malerich and V. H. Rawal, Org. Lett., 2010, 12, 2028;
(d) W. Yang and D.-M. Du, Org. Lett., 2010, 12, 2350;
(e) L. Albrecht, G. Dickmeiss, F. C. Acosta, C. Rodríguez-
Escrich, R. L. Davis and K. A. Jørgensen, J. Am. Chem. Soc.,
2012, 134, 2543.
13 F. Zhou, X.-P. Zeng, C. Wang, X.-L. Zhao and J. Zhou, Chem.
Commun., 2013, 49, 2022.
14 (a) B. V. S. Reddy and J. George, Tetrahedron: Asymmetry,
2011, 22, 1169; (b) J. George and B. V. S. Reddy, Org. Biomol.
Chem., 2012, 10, 4731; (c) J. George and B. V. S. Reddy, Adv.
Synth. Catal., 2013, 355, 383; (d) T. Rajasekaran, G. Karthik, 16 (a) H. Li, Y. Wang, L. Tang and L. Deng, J. Am. Chem. Soc.,
B. Sridhar and B. V. S. Reddy, Org. Lett., 2013, 15, 1512;
(e) B. V. S. Reddy, G. Karthik, T. Rajasekaran, A. Antony and
B. Sridhar, Tetrahedron Lett., 2012, 53, 2396.
2004, 126, 9906; (b) B. Vakulya, S. Varga, A. Csámpai and
T. Soós, Org. Lett., 2005, 7, 1967.
17 The CCDC no. 960126 for X-ray crystallography of 4b was
deposited on Cambridge Crystallographic Data Base (for
CIF file, see: ESI†).
15 For review, see: (a) J. Alemán, A. Parra, H. Jiang and
K. A. Jørgensen, Chem.–Eur. J., 2011, 17, 6890; For
1602 | Org. Biomol. Chem., 2014, 12, 1595–1602
This journal is © The Royal Society of Chemistry 2014