Enantioselective hydrophosphonylation of N- benzyl imines, isatin derived ketimines and isatins catalyzed by in-situ generated Ti(IV) macrocyclic salen complexes

Article abstract of DOI:10.1016/j.apcata.2015.12.037

Ti-salen complexes were generated by using a series of chiral macrocyclic salen ligands and were used as catalysts for enantioselective hydrophosphonylation (EHP) reaction of benzylimines, isatin derived ketimines and isatins. The corresponding phosphonyl

Full text of DOI:10.1016/j.apcata.2015.12.037

Accepted Manuscript
Title: Enantioselective hydrophosphonylation of N-benzyl
imines, isatin derived ketimines and isatins catalyzed by
in-situ generated Ti(IV) macrocyclic salen complexes
Author: Mohd Nazish Ajay Jakhar Noor-ul H. Khan Shailesh
Verma Rukhsana I. Kureshy Sayed H.R. Abdi Hari C. Bajaj
PII:
S0926-860X(15)30314-8
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.apcata.2015.12.037
APCATA 15713
To appear in:
Applied Catalysis A: General
Received date:
Revised date:
Accepted date:
9-10-2015
25-12-2015
28-12-2015
Please cite this article as: Mohd Nazish, Ajay Jakhar, Noor-ul H.Khan, Shailesh
Verma, Rukhsana I.Kureshy, Sayed H.R.Abdi, Hari C.Bajaj, Enantioselective
hydrophosphonylation of N-benzyl imines, isatin derived ketimines and isatins
catalyzed by in-situ generated Ti(IV) macrocyclic salen complexes, Applied Catalysis
A, General http://dx.doi.org/10.1016/j.apcata.2015.12.037
This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.

s
Enantioselective hydrophosphonylation of N-benzyl imines, isatin derived ketimines
and isatins catalyzed by in-situ generated Ti(IV) macrocyclic salen complexes
Mohd Nazish,a,b Ajay Jakhar,a,b Noor-ul H. Khan,*a,b Shailesh Verma,a,b Rukhsana I. Kureshy,a,b Sayed H.
R. Abdia,b and Hari C. Bajaja,b
aDiscipline of Inorganic Materials and Catalysis, bAcademy of Scientific and Innovative Research, CSIR-Central Salt and Marine
Chemicals Research Institute (CSIR-CSMCRI), G. B. Marg, Bhavnagar- 364 002, Gujarat, India. Fax: (+91) 0278-2566970. E-
mail: khan251293@yahoo.in
Highlights
 macrocyclic salen-titanium complex
 catalyst recyclable five times
 Asymmetric hydrophosphonylation reaction with 21 examples
 Simple, ideal and efficient catlytic protocol
 Proposed a mechanism based on NMR spectroscopic study
Abstract:

Ti-salen complexes were generated in situ by using a series of chiral macrocyclic salen ligands and were
used as catalysts hytfor enantioselective hydrophosphonylation (EHP) reaction of benzylimines, isatin
derived ketimines and isatins. The corresponding phosphonylated products were obtained with excellent
yield (up to 92%) and enantioselectivity (ee up to 99%) with low catalyst loading at room temperature using
dimethyl phosphite as nucleophile (IIa) for isatins and benzylimines, whereas for ketimines diphenyl
phosphite (IIb) gave best results with very good yield (up to 88%) and ee (up to 99%). The Ti(IV) complex
was recoverable and recyclable with retention of its catalytic performance at gram scale level. To
understand the reaction mechanism NMR studies have been carried out using benzylimine as a model
substrate and dimethyl phosphite as a nucleophile.
Keywords: Hydrophosphonylation, isatin imine, ketone, titanium, phosphite
1. Introduction:
Chiral α-amino-1 and α-hydroxy-2 phosphonates are important class of synthetic intermediates used for
pharmaceutical compounds. These potentially bioactive compounds are having anti-fungal,3 anti-bacterial,4
anti-HIV5 and anti-protease6 properties. Enantioselective hydrophosphonylation of aldimines/ketimines and
ketones are straightforward methods for the synthesis of α-amino- and α-hydroxy-phosphonates
respectively, however, for achieving high enantioselectivity and yield in the desired product under mild
reaction conditions is still a challenge. Nevertheless, since last two decades there are several reports on
metal catalysts and organo-catalysts mediated enantioselective addition of phosphite to aldehydes7,8 and
aldimines,9,10,7k but the substrates like ketones11,12 and ketimines.13are less explored. Furthermore, reports
on hydrophosphonylation of less reactive ketones like isatins (4a)11(c,d) and isatin derived ketimines
(6a)13(b,c) are fewer in number. Notwithstanding the above, there is no report for hydrophosphonylation
reaction that can effectively handle these less-reactive substrates as well as benzylimine (Ia). Hence,
development of an efficient catalytic protocol is desirable from commercials and practical point of view.
With our ongoing interest in developing chiral catalysts for various asymmetric organic transformations,14
herein, we report the use of macrocyclic Ti(IV)-salen complexes as catalysts for EHP of benzylimine, isatin
derived ketimines and isatins. We have found that macrocylic ligand 1d (having pentagol linker) in
combination with Ti(OiPr)4 is the best catalyst among others (1a-1d, 2d and 3d) for all the three types of
substrates stated above using dimethyl phosphite (DMP)/diphenyl phosphite (DPP) as nucleophile under
mild reaction condition to get enantioenriched phosphonylated products in good to excellent yield. To the
best of our knowledge, this is the most efficient Ti complex based catalytic system for the enantioselective
hydrophosphonylation reaction with an advantage of handling varied substrates.
2. Results and Discussion:

Chiral macrocyclic ligands 1a-1d, 2d and 3d were synthesised and characterized according to the reported
procedure (Scheme 1).14a To evaluate their efficacy in EHP reaction, these ligands were allowed to react
with Ti(OiPr)4 in 1:1 L:M molar ratio in order to in situ generate the corresponding complex. To begin
with, benzylimine Ia was used as a model substrate for the EHP using in situ generated Ti(IV) macrocyclic
salen complexes as catalyst (5 mol%) and 1.5 equivalent of IIa (with respect to substrate) as nucleophile
at room temperature (RT) under N2 atmosphere using toluene as a solvent for 30 h and the data are shown
in Figure 1. In all the cases the desired product (IIIa) was obtained in moderate to good yield (48-76%)
with low to moderate enantioselectivity (35-72%). It is evident from the results that the nature of the linker
played a significant role in yield and enantioselectivity of the desired product IIIa. Lower yield and
enantioselectivity (Figure 1) was achieved with ligand 1a which had a short and rigid linker as compared
to the ligand 1b and 1c. Among them (1a-1d, 2d and 3d), the ligand 1d having (1R,2R)-(-)-1,2-
diaminocyclohexane and pentagol as a linker in combination of Ti(OiPr)4 turned out to be a better catalyst
to give phosphonylated products in better yield. This shows that a more flexible linker is beneficial to
provide favourable environment for the enantioselective catalytic process (Figure 1). For further improve
the catalytic protocol, we have screened the effect of different titanium sources (Figure 2) using the ligand
1d to generate active catalyst in situ and found that Ti(OiPr)4 (yield 76%, ee 72%) is the best metal source
as compared to other titanium sources like Ti(OtBu)4 (yield 45%, ee 42%), TiCl4 (yield 18%, ee 20%) and
TiBr4 (yield 16%, ee 15%). The high reactivity of Ti(OiPr)4 is probably due to the presence of isopropoxide
ion, which is relatively better for activating the nucleophile via abstracting the proton.15 Having identified
the suitable metal source, we froze Ti(OiPr)4 as the right choice of metal source (5 mol%) in combination
with 5 mol% of 1d to optimize other reaction parameters.
Since there are two salen units in the macrocyclic ligand (1d), it was prudent to vary metal to ligand ratio.
Accordingly, experiments were carried out with different amounts of Ti(OiPr)4 with respect to 1d (ratios
ranged over 1:0.5 to 1:1.5) using 5 mol% of Ti(OiPr)4 in all the cases. On decreasing the amount of ligand
from metal:ligand ratio 1:1 (Table 1, entry 1) to 1:0.5 there was a significant improvement in the product
yield (92%) and enantioselectivity (77%, Table 1, entry 2). While on increasing the ligand amount (M:L
ratio 1:1.5, entry 3) there was no substantial change in the reaction outcome. On the other hand lowering
of the catalyst loading using M:L ratio 1:0.5 from 5 mol% (as per entry 2) to 2.5 mol%, resulted in slight
increase in ee (82% ee, entry 4) of the product but the yield was decreased. However, on increasing the
catalyst loading to 10 mol% and 15 mol% (entries 5 and 6) product yield (96% and 97% respectively) was
increased, but the ee (72% and 60%) decreased significantly. So based on the above observations we
concluded that a metal to ligand ratio of 1:0.5 with 2.5 mol% catalyst loading is optimum to get product in
high yield and ee (entry 4). Next, the solvent screening study showed that toluene is the best solvent as
compare to other solvents such as CH2Cl2, CHCl3 and THF which gave lower product yield and

enantioselectivity (Figure 3). Variation in reaction temperature is known to affect both yield and
enantioselectivity of the product significantly; therefore we investigated the outcomes of EHP reaction at
lower temperatures like 0°C and -10°C. Unfortunately, we observed a drastic drop in the yield and minor
decrease in enantioselectivity at lower temperatures (Figure 3). Besides DMP, we have also tried other
commercially available phosphonylating reagents in order to explore the possibility of getting better
product yield and enantioselectivity. Accordingly, we took 1.5 equivalents of diphenyl phosphite (DPP),
diethyl phosphite (DEP) and dibenzyl phosphite (DBP) to study the influence of these nucleophiles under
the above optimized reaction condition (Figure 3). Among all the phosphite sources used here, DMP was
found to be the best (yield 89% and ee 82%) for this reaction (Table 2, entry 1). Ideally substrate and
phosphite should be taken in equimolar quantities, often variation in nucleophile concentration leads to
variation in reaction outcome. Accordingly, the reaction was carried out with 0.8 to 2.0 equivalent of
phosphite (DMP) with respect to substrate and found that only a slight excess i.e., 1.1 equivalent of DMP
is sufficient enough to achieve highest enantioselectivity (92%) with good yield (84%) (Table 2, entry 7).
To get a deeper insight into the matter, we have tested the nonlinear effect (NLE) of the present bimetallic
titanium system (Figure 4) and observed a positive NLE of this catalytic system. At this point of time, the
specific reason for this effect on reactivity and enantioselectivity is unknown but based on Figure 4 a
possible cooperative effect in bimetallic complex cannot be ruled out. Further, with the optimized reaction
condition (as per Table 2, entry 7), this protocol was extended to various substituted imines Ia-Ih bearing
electron donating as well as withdrawing groups at various positions of aromatic ring (of aromatic aldehyde
origin) and got the products in high yield (82-92%) and excellent enantioselectivity (92-98%, Table 3). As
such we have not got any trend in the results on varying substituents, but in general higher ee in the products
were achieved with substituted imines as substrates, except for 4-trifluromethyl substituted imine Ih (Table
3, entry 8 ) where the results were at par with unsubstituted imine Ia (Table 3, entry 1 ).
3. Asymmetric hydrophosphonylation reaction of isatins derived ketimines (IVa)
The catalytic protocol that was used above for imines Ia-Ih, was explored for its effectiveness in the EHP
of isatin derived ketimine IVa where we got the corresponding product Va in high yield (85%) but with
lower ee (40%) (Table 4, entry 1). In order to improve the results we first varied several reaction conditions
e.g., temperature, solvent and catalyst loading but with little or no success (data not included). However,
when we used phosphonylating agents namely, DEP, DBP and DPP there was significant improvement in
the enantioselectivities (Table 4, entries 2-4). Highest enantioinduction was obtained in the case of
phosphonylating agent DPP (ee, 88%; Table 4, entry 4). To take these results forward we explored the
role of additives in EHP of IVa using DPP as phosphonylating agent under the above optimized
conditions. Accordingly methanol, water, 4Å molecular sieve (MS), benzoic acid and lutidine were

used as additives for this reaction (Table 4, entries 5-9). Clearly, the use of 4Å-MS significantly
improved the enantioselectivity of the desired product Va (Table 4, entry 7) with marginal
improvement in the product yield.
The above optimized conditions were further extended to other related substrates IVa
-IVf to get
the products Va Vf in very good yields (up to 84-88%, Table 5, entries 1-6). However, excellent
-
enantioselectivities were obtained with substrates IVa and IVb (ee’s >99 and 98%) having no
substituent or with electron donating methyl group respectively. Presence of an electron-
withdrawing groups (Cl and F) adversely effected enantioselectivty (Table 5; entries 3 and 4; ee’s
68 and 63% respectively) whereas yields remained same. A substrate with
N
-methyl isatin derived
ketimine IVe gave results (Table 5, entry 5; yield, 86%; ee, >99%) at par with
N-benzyl isatin derived
ketimine IVa. On the other hand substrate isatin having no substituent at N- (IVf) provided the product
with significantly lower ee (46%; entry, 6) but with good yield (88%).
4. Asymmetric Hydrophosphonylation reaction of isatins (VIa)
In order to further expand the scope of the above-developed hydrophosphonylation protocol, we used isatins
(VIa-VIg) as substrates to get biologically important target compounds (VIIa-VIIg). The catalytic system
that was explored for the substrates Ia-Ig, was also used for EHP of isatin derivatives (VIa-VIg) to get
the corresponding products VIIa-g (Table 6) in high yield (up to 88%) as well as high enantioselectivity
(up to 99%) except for the N-protected isatins VId and VIg, which gave racemic products VIId and VIIg.
These results are in contrast to those obtained for the EHP reaction of isatin imines (Table 5) where N-
protected isatins gave products with better ee’s.
5. Mechanism
To understand the reaction mechanism during hydrophosphonylation reaction we carried out a series of
NMR experiments using N-benzylimine as representative substrate. The formation of Ti(IV) complex was
1
evident from the H NMR spectra of ligand 1d alone (Figure 5a) and 1d + Ti(Oipr)4 (Figure 5b) where
phenolic proton of 1d disappears on complexation with a significant upfield shift (0.25 ppm) in the imine
proton. To the complex thus formed, the imine Ia was added. We observed a downfield (0.05 ppm, Figure
5d) shift in the imine proton suggesting a weak interaction between imine nitrogen of Ia with titanium
(bearing Lewis acidity) (Scheme-2, intermediate-A). Consequently the substrate was activated and makes
it available for the attack by P of phosphonylating agent IIa. We also carried out 31PNMR experiments to
see the involvement of IIa (Figure 6a) in the catalytic cycle and found a 0.10 ppm downfield shift in its
peak when added to the reaction mixture containing titanium complex and substrate Ia (Figure 6b)

(Scheme 2, intermediate-B). Based on the above observation we have proposed a probable mechanism as
given in Scheme 2.
6. Recycling of catalyst
In an oven dried sample vial, ligand 1d (2.5 mol%) and titanium tetra isopropoxide (5 mol%) were taken
in dry toluene (1 mL). The mixture thus obtained was stirred at room temperature under N2 for 2 h.
Subsequently, Substrate Ib (10 mmol) was added to the above stirring yellow solution followed by the
addition of DMP. After the completion of the reaction (20-30 h) the solvent and the volatile compounds
were evaporated under reduced pressure. The residue was extracted and washed with hexane to remove
excess DMP, unreacted substrate and product were dried under reduced pressure for 12 h and was used as
catalyst Ti-1d for the next cycle of asymmetric hydrophosphonylation reaction. This process was repeated
over five consecutive cycles with retention of catalyst activity and enantioselectivity (Figure 7).
7. Conclusions
In conclusion, we have developed a chiral Ti(IV)-salen complex as an efficient catalyst for enantioselective
hydrophosphonylation reaction of N-benzylimines, isatin derived ketimines and isatins. In most of the
cases, the corresponding phosphonylated products were obtained in very good yield and excellent ee at RT.
The catalyst was recycled five times with retention of its catalytic activity and enantioselectivity. A
probable mechanism for this reaction was proposed based on a series of NMR experiments by using N-
benzylimine as a representative substrate.
8. Experimental
8.1 Materials and methods;
All the solvents were dried using standard procedures, distilled and stored under nitrogen. NMR spectra
were obtained by using Bruker Avance DPX200 and Bruker Avance II 500 spectrometers and were
referenced internally to trimethylsilane (TMS). Enantiomeric excess (ee) values were determined by HPLC
(Shimadzu SCL-10AVP) using Daicel Chiralpak AD-H, IC, IA and OJ chiral columns with 2-
propanol/hexanes as eluent. For the product purification, flash chromatography was performed using
230−400 mesh silica gel.
8.2 Typical experimental procedure for the enantioselective hydrophosphonyation reaction Uusing
catalyst 1d.

In an oven dried reaction vial, ligand 1d (2.5 mol %) was dissolved in dry toluene (1 mL), and to the
resulting solution Ti(OiPr)4 (5 mol%) was added and the resulting solution was stirred for 2 h under N2 at
RT. To the above stirred solution (Ia)/isatin (0.17 mmol) was added and the stirring was further continued
for another 30 min. After that, DMP (0.19 mmol) was added drop-wise to the above solution over 30 min.
While in the case of isatin derived ketimines, initially ligand 1d (2.5 mol%) was dissolved in dry toluene
(1 mL), and Ti(OiPr)4 (5 mol%) was added to it and the resulting solution was stirred for 2 h at RT. Then
4Å MS (20 mg) and isatin derived ketimines (IVa) were added under stirring condition. After 30 min, DPP
(IIb) was added over a period of 30 min. The reaction was monitored by TLC using hexane/ethyl acetate
(70/30) as eluent. After the completion of the reaction, the solvent was removed on a rotary evaporator, and
the product was purified by flash column chromatography on a silica gel column (eluted with hexane/ethyl
acetate=70/30). The purified products were characterized by LCMS and NMR.
Acknowledgements
CSIR-CSMCRI Communication No. DIMC-107/2015 Authors are thankful to CSIR Indus magic project
CSC 0123, M. Nazish UGC JRF for financial assistance, also AcSIR for Ph.D. registration and Analytical
Discipline for providing instrumental facilities.
Supplementary data
For additional characterization data of hydrophosphonylated products (see the supporting information).
References and Notes
1 a) F. Shi and B. Song, Org. Biomol. Chem. 7 (2009) 1292-1298; b) Y. Zhao, X. Li, F. Mo, L. Li
and X. Lin, RSC Adv. 29 (2013) 11895-11901.
2 a) T. Deng, H. Wang and C. Cai, Org. Biomol Chem. 12 (2014) 5843; b) L. Peng, L. Wang, J. Bai,
L. Jia, Q. Yang, Q. Huang, X. Xu and L. Wang, Tetrahedron Lett. 52 (2011) 1157-1160.
3 For reviews of the biological activity of R-amino phosphonic acids, see: a) V. P. Kukhar and H. R.
Hudson, Eds. John Wiley & Sons New York, 2000; b) L. J. Christopher and B. Sanmitra, Abstracts
of Papers, 244th ACS National Meeting & Exposition, Philadelphia, PA, United States 2012 (2012)
19-23; ORGN-149. c) F. H. Westheimer, Science 235
(1987) 1173; d) J. Hiratake and J. Oda,
Biosci. Biotechnol. Biochem., 61 1997) 211; e) B. Dhawan and D. Redmore, Phosphorus Sulfur
(

Relat. Elem. 32 (1987) 119; f) V. P. Kukhar, V. A. Soloshonok and V. A. Solodenko, Phosphorus
Sulfur Silicon Relat. Elem. 92 1994) 239; g) V. D. Romanenko and V. P. Kukhar, Chem Rev. 106
2006) 3868; h) R. Enge, Chem. Rev. 77 1977) 349.
4 a) P. Kafarski and B. Lejczak, Phosphorus, Sulfur Silicon Relat. Elem. 63
and B. Lejczak, Curr. Med. Chem. Anti-Cancer Agents 1 2001) 301; c) Z. H. Kudzin, M. H.
Kudzin, J. Drabowicz and C. V. Stevens, Curr. Org. Synth. 15 2011) 2015; d) A. B. Smith III, K.
M. Yager and C. M. Taylor J. Am. Chem. Soc. 117 1995) 10879.
5 a) F. R. Atherton, C.H. Hassall and R.W. Lambert, J. Med. Chem. 29
Atherton, M. J. Hall, C. H. Hassal, S. W. Holmes, R.W. Lambert, L. J. Nisbet and P.S. Ringrose,
Nature, 272 1978) 56.
6 E. Alonso, A. Solis and C. del Pozo, Synlett
7 a) S. Gou, X. Zhou, J. Wang, X. Liu and X. Feng, Tetrahedron 64
Y. Hui, X. Zhou, J. Jiang, Y. Cai, X. Liu, L. Lin and X. Feng, Tetraheron Lett. 51
4178; c) S. R. Davies, M. C. Mitchell, P C. Christopher, P. G Devitt, R. J Taylor and T. P Kee, J.
Organomet. Chem. 550 1998) 29-57; d) T. Yokomatsu, T. Yamagishi and S. Shibuya, Tetraheron
Asymmetry 4 1993) 1779-1782; e) B. Saito, H. Egami and T. Katsuki, J. Am. Chem. Soc. 129
(2007) 1978-1986; f) W. Li, S. Qin, Z. Su, H. Yang, and C. Hu, Organomet 30 2011) , 2095-2104;
g) B. Ramalingam and C. Chinpiao, Adv. Synth. Catal 355 2013) 3443-3450; h) ) A.-Requena, V.
Juan; M.-Lopez, Eugenia, S. Miguel and J. Pablo., Org. Biomol. Chem. 12 (2014) 1258-1264; i) D.
Tao. and C. Chun, RSC Adv 53 2014) 27853-27856; j) P. Merino, E. M.-Lopez, and R. P. Herrera,
Adv. Synth. Catal. 350 2008) 1195-1208; k) M. Nazish, S. Saravanan, N. H. Khan, P. Kumari, R.
I. Kureshy, S. H. R. Abdi and H. C. Bajaj, ChemPlusChem, 79 2014) 1753-1760.
8 X. Zhou, X. Liu, X. Yang, D. Shang, J. Xin, and X. Feng, Angew. Chem. Int. Ed. 47
9 a) F. Shi, B. Song., Org. Biomol. Chem. 7, (2009) 1292-1298; b) G. D. Joly and E. N. Jacobsen, J.
Am. Chem. Soc. 126 2004) 4102-4103; c) T. Akiyama, H. Morita, J. Itoh and K. Fuchibe, Org.
(
.
(
(
(
1991) 193; b) P. Kafarski
(
(
,
(
(1986) 29; b) J. G. Allen, F.R.
(
,
2000, 698-700.
(2008) 2864-2870; b) W. Chen,
(2010) 4175-
(
(
,
(
.
(
.
(
(
(
(2008) 392.
(

Lett. 7 (2005) 2583-2585; d) T. Yamaguchi, K. Matsumoto, B. Saito and T. katsuki, Angew. Chem.
Int. Ed. 117 (2005) 4676-4678; e) B. Saito and T. Katsuki, Angew. Chem. Int. Ed 44, (2005) 4600-
4602; f) B. Saito, H. Egami and T. Katsuki, J. Am. Chem. Soc. 129 2007) 1978-1986; g) H. Sasai,
S. Arai, Y. Tahara and M. Shivasaki, J. Org. Chem. 60 1995) 6656-6657.
10X. Zhou, D. Shang, Q. Zang, L. Lin, X. Liu and X. Feng, Org. Lett. 11 2009) 1401.
11 a) X. Zhou, Y. Liu, L. Chang, J. Zhao, D. Shang, X. Liu, L. Lin and X. Feng, Adv. Synth. Catal
351 (2009) 2567-2572; b) L. Wang, J. Bai, L. Jia, Q. Yang, Q. Huang, X. Xu and L. Wang,
Tetrahedron Lett. 52 2011) 1157-1160.
12X. Z., Q. Zhang, Y. Hui, W. Chen, J. Jiang, L. Lin, X. Liu, and X. Feng, Org. Lett. 12
.
(
(
(
.
(
(2010) 4296.
13 For reviews of enantioselective reactions of ketimines, see: a) M. Shibasaki and M. Kanai, Chem.
Rev. 108 2008) 2853; b) A. Kumar, V. Sharma, J. Kaur, V. Kumar, S. Mahajan, N. Kumar and S.
S. Chimni, Tetrahedron, 70 2014) 7044-7049; c) G. Jimil, B. Sridhar and R. B. V. Subba, Org.
Biomol. Chem. 12 2014) 1595-1602;
14 a) S. Saravanan, N. H. Khan, P. K. Bera, R. I. Kureshy, S. H. R. Abdi, P. Kumari, and H. C. Bajaj,
ChemCatChem, 5 2013) 1374-1385; b) N. H. Khan, S. Saravanan, R. I. Kureshy, S. H. R. Abdi,
A. Sadhukhan and H. C. Bajaj, J. Organomet. Chem. 695 2010) 1133; c) S. Saravanan, A.
Sadhukhan, N. H. Khan, R. I. Kureshy, S. H. R. Abdi and H. C. Bajaj, J. Org. Chem. 77 2012)
4375-4384; d) A. Sadhukhan, S. Saravanan, N. H. Khan, R. I. Kureshy, S. H. R. Abdi and H. C.
Bajaj, J. Org. Chem. 77 2012) 7076-7080.
15 T. Yokomatsu, T. Yamagishi and S. Shibuya, J. Chem. Soc., Perkin Trans. 1
(
(
(
(
(
(
(
(1997) 1527.

Linker
OH
O
OH
O
(a)
OH (b)
OH
OH
t-Bu
t-Bu
t-Bu
N
N
OH
OH
N
N
OH
OH
O
O
O
OH (c)
OH
O
O
(d)
t-Bu
O
O
OH
Cl
a-d
Linkers
Linker
(R)
(R)
NH2
NH2
t
r
1a-1d
,
t-Bu
Linker
5a-5d
F
H
OH O
T
,
H
a
N
t-Bu
t-Bu
(R)
NH2
NH2
Ph
(R)
OH
O
NH2
O
OH
Ph
(R)
NH2
( R)
Linker
Linker
t-Bu t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
N
Ph
Ph
OH
OH
OH HO
N
OH
OH
Ph
Ph
N
N
N
N
3d
Linker
2d
Scheme 1: Synthesis of chiral ligands with different type of chiral sources (1a-1d) (R,R)-cyclohexane-1,2-diamine, Dry THF,
RT. (2d) (R,R)-1,2-diphenylethane-1,2-diamine, Dry THF, RT. (3d) (R,R)-cyclohexane-1,2-diamine, MeOH, RT.
O
O
P O
OiPr
N
H
Ti
N
OiPr
Ia
OiPr
OiPr
Ti
OiPr
Ti
Catalytic
cycle
N
P
N
A
OMe
OH
MeO
B
OH
P
OMe
MeO
O
P
H
OMe
MeO
Scheme 2. Proposed Reaction Mechanism with N-benzylimine substrate.
Figure 1. Screening of ligands for asymmetric HP reaction. Isolated yield after flash chromatography. ee’s were determined by
chiral HPLC using chiralpak IA column.

Figure 2. Reaction condition: ligand 1d (5 mol%), Ti(Oipr)4 (5 mol%), N-benzylimine (1 mmol), DMP (1.5 mmol) at RT Isolated
yield after flash chromatography. ee’s were Determined by chiral HPLC using an chiralpak IA column.
Figure 3. Reaction condition: ligand 1d (2.5 mol %), Ti(OiPr)4 (5 mol%), N-benzylimine (1 mmol), DMP (1.5 mmol) at RT.
Isolated yield after flash chromatography. ee’s were Determined by chiral HPLC using an chiralpak IA column.
B
100
80
60
40
20
0
0
20
40
60
80
100
ee of 1R, 2R -1d ligand
Figure 4. Positive NLE in the HP of N-benzylimine with in situ generated bimetallic Ti-complex from dimeric ligand 1d.
Figure 4. Positive NLE in the HP of N-benzylimine with in situ generated bimetallic Ti-complex from dimeric ligand 1d.

Figure 5. (a)1H NMR of Ligand in CDCl3, (b)Ti-Complex, (c)Substrate N-benzylimine, (d)Ti-Complex + Substrate N-
benzylimine.
Figure 6. 31P NMR in CDCl3 (a) DMP (b) Ti-Complex + Substrate N-benzylimine + DMP.

Table 1 Optimization catalyst loading and metal/ligand ratioa
Ph
Ti(OiPr)4
NH
O
O
1d
H
P
N
Ph
P
O
O
O
O
Toluene, RT, 30 h
Ia
IIa
IIIa
Entry
Cat. loading (mol%)
Ti(OiPr)4/1d
1:1
Yieldb (%)
eec (%)
72
1
2
3
4
5
6
5
5
76
92
74
89
96
97
1:0.5
77
5
1:1.5
75
2.5
10
15
1:0.5
82
1:0.5
72
1:0.5
60
aReaction condition: ligand 1d, Ti(OiPr)4, N-benzylimine (1 mmol), DMP (1.5 mmol) at RT
c
bIsolated yield after flash chromatography. ee’s were determined by chiral HPLC using
chiralpak IA column.

Table 2 Screening of phosphorous sources for asymmetric HP of N-benzyliminea
Loading
(equivalent)
Entry
Phosphite sources
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
DMP(IIa)
DEP(IIb)
DPP(IIc)
DBP(IId)
DMP
1.5
1.5
89
44
60
15
90
87
84
72
66
82
63
58
89
54
88
92
87
87
1.5
1.5
2
DMP
1.2
1.1
1
DMP
DMP
DMP
0.8
aReaction condition: ligand 1d (2.5 mol%), Ti(OiPr)4 (5 mol%), N-benzylimine (1 mmol),
DMP at RT bIsolated yield after flash chromatography. cee’s were determined by chiral HPLC
using chiralpak IA column.
Table 3 Asymmetric HP reaction of various N-benzylimines (Ia-Ih) under optimized reaction conditiona
Entry
Substrates
Product
Yieldb (%)
eec (%)

84
92
1
2
90
82
92
98
97
98
3
4
5
6
92
97
90
83
97
97
7
8
N
Ph
84
92
F3C
Ih
aReaction condition: ligand 1d (2.5 mol%), Ti(OiPr)4 (5 mol%), N-benzylimine (1 mmol),
DMP (1.1 mmol) at RT bIsolated yield after flash chromatography. cee’s were Determined by
chiral HPLC using an chiralpak AD-H column.
Table 4 Screening of phosphorous sources in asymmetric hydrophosphonylation reaction of isatin
derived ketimine IVa a

Entry
1
Phosphite source
DMP
Additives
-
Yieldb (%)
85
eec (%)
40
2
3
4
5
6
7
8
DEP
DPP
DBP
DPP
DPP
DPP
DPP
-
-
-
36
78
15
90
90
84
80
53
88
72
88
89
CH3OH (1mol%)
H2O (1mol%)
MS(4Å) (20mg)
Benzoic acid
(1mol%)
>99
86
9
DPP
Lutidine (1mol%)
90
72
aReaction condition: ligand 1d (2.5 mol%), Ti(OiPr)4 (5 mol%), IVa (1 mmol),
c
IIa/IIb/IIc/IId (1.1 mmol) at RT bIsolated yield after flash chromatography. ee’s were
Determined by chiral HPLC using an chiralpak IC column.
Table 5. Substrates scope for the EHP reaction of isatin iminesa
Entry
Substrates
Product
Yieldb (%)
eec (%)
1
84
>99
2
88
98

3
84
68
4
5
6
88
86
88
63
>99
46
aReaction condition: ligand 1d (2.5 mol%), Ti(OiPr)4 (5 mol%), IV (1 mmol), DPP (1.1 mmol), MS
(20mg) at RT bIsolated yield after flash chromatography. cee’s were Determined by chiral HPLC using an
chiralpak IC and ADH column.
Table 6. Asymmetric hydrophosphonylation reaction of various isatinsa
Yieldb (%)
eec (%)
92
Entry
Substrates
Products
1
84

2
3
80
88
>99
91
4
5
6
90
80
74
Racemic
84
92
7
90
Racemic
aReaction condition: ligand 1d (2.5 mol%), Ti(OiPr)4 (5 mol%), VI (1 mmol), DMP (1.1 mmol) at
b
c
RT Isolated yield after flash chromatography. ee’s were determined by chiral HPLC using an
chiralpak IC column.