Reaction prospecting by 31P NMR: enantioselective rhodium-DuPhos catalysed addition of ZnMe2 to diphenylphosphinoylimines

Article abstract of DOI:10.1016/j.tetasy.2009.09.020

Chiral shift ³¹P NMR spectroscopy allows the identification of ligand leads in asymmetric catalyst systems for ZnMe₂ addition to ArCH{double bond, long}NP(O)Ph₂. Subsequent GC-based optimisation shows [RhCl(CH₂{double bond, long}CH₂)₂]₂ and (R,R)-MeDuPhos to be the optimal pre-catalyst combination (product in 78-93% ee). Transmetallation of [(MeDuPhos)Rh{N(P(O)Ph₂-CHMeAr}] with ZnMe₂ appears to be the rate limiting step of the catalytic cycle as competing coordination by the imine starting material leads to Ph₂P(O)NHCH₂Ar via MVP hydrogen-transfer. This limitation can largely be overcome by the slow addition of the imine.

Full text of DOI:10.1016/j.tetasy.2009.09.020

Tetrahedron: Asymmetry 20 (2009) 2497–2503
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Reaction prospecting by 31P NMR: enantioselective rhodium-DuPhos
catalysed addition of ZnMe2 to diphenylphosphinoylimines
Rosemary H. Crampton a, Samir El Hajjaji a, Martin E. Fox b, Simon Woodward a,
*
a School of Chemistry, The University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom
b Chirotech Technology Ltd, Dr. Reddy’s Laboratories, Unit 162 Cambridge Science Park, Milton Road, Cambridge, CB4 0GH, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Chiral shift 31P NMR spectroscopy allows the identification of ligand leads in asymmetric catalyst systems
for ZnMe2 addition to ArCH@NP(O)Ph2. Subsequent GC-based optimisation shows [RhCl(CH2@CH2)2]2
and (R,R)-MeDuPhos to be the optimal pre-catalyst combination (product in 78–93% ee). Transmetalla-
tion of [(MeDuPhos)Rh{N(P(O)Ph2–CHMeAr}] with ZnMe2 appears to be the rate limiting step of the cat-
alytic cycle as competing coordination by the imine starting material leads to Ph2P(O)NHCH2Ar via MVP
hydrogen-transfer. This limitation can largely be overcome by the slow addition of the imine.
Ó 2009 Elsevier Ltd. All rights reserved.
Article history:
Received 11 August 2009
Accepted 23 September 2009
Available online 24 November 2009
1. Introduction
Ts
Ts
HN
N
Convenience and technical simplicity are defining goals in con-
temporary organic methodology. Recently, we experienced a need
for chiral 2-arylethylamines 1 (Scheme 1) for use in ligand syn-
thesis1 and sought to attain a straightforward method for their
production from precursor aldimines 3 via protected 2. Our crite-
ria for such a preparation were: (i) that the N-protecting group
must engender crystallinity in the products, but be easily re-
moved (ii) that any chiral ligand and metal additives used in pre-
paring 2 be readily commercially available (iii) that the reaction
proceed rapidly and (iv) that any screening procedures leading
to the enantioselective catalyst for production of 2 should be
readily applicable to high throughput screening and not compli-
cated by the presence of impurities. Recently several excellent
processes for the preparation of precursors to 1 have appeared
in the literature,2,3 but these often raise issues when compared
against harsh criteria (i)–(iv) above. Hayashi3b has described ac-
tive and selective diene-ligated rhodium catalysts. However in
this case, the use of aldimine 3a (PG = Ts) is required. The re-
moval of such tosyl protecting groups sometimes can be problem-
atic. Charette3c has described Cu(OTf)2/DuPhos-monooxide
approaches using 3b [PG = P(O)Ph2] in up to 97% ee but the reac-
tion is relatively slow (48 h). In our hands, alkylations employing
3b were also prone to producing significant amounts (ꢀ10%) of
fluorescent co-eluting by-products in initial trials that invalidated
or slowed down chiral HPLC high throughput screenings when
using 3b. We thought that we might be able to utilize the power
of 31P NMR spectroscopy to overcome these issues in catalyst
discovery.
Ar
Ar
Ar
NH2
2a
3a
or....
or....
+ "Me"
Ar
O
O
1
PPh2
PPh2
HN
N
Ar
2b
3b
Scheme 1. Typical approaches to 2-arylethylamines.
2. Results and discussion
2.1. Synthesis of aldimines 3b and catalyst discovery by 31P
NMR spectroscopy
In our hands the starting aryl imines 3b were best prepared
using the detailed Ph2P(O)NH2/TiCl4/ArCHO procedure provided
by Scheidt.4 We were only able to improve on this procedure in
two ways. Firstly, the isolated yields of the somewhat hydrolyti-
cally labile imines 3b are improved by prompt chromatography
in EtOAc/CH2Cl2 compared to just EtOAc, as recommended, due
to solubility issues with 3b. Secondly, the relatively commercially
expensive Ph2P(O)NH2 was prepared from inexpensive Ph2P(O)Cl
and aqueous ammonia avoiding the need for liquid NH3 use.5 Race-
mic 2ba (Ar = Ph) was easily prepared by the reaction of 3ba with
MeMgBr. Preliminary investigations indicated that group 8 metal
salts in the presence of phosphines led to active systems for the
* Corresponding author. Fax: +44 115 9513564.
E-mail address: simon.woodward@nottingham.ac.uk (S. Woodward).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.09.020

2498
R. H. Crampton et al. / Tetrahedron: Asymmetry 20 (2009) 2497–2503
addition of AlMe3 or ZnMe2 in refluxing THF in under 3 h. To avoid
fluorescent by-product issues when screening crude catalytic mix-
tures of 2ba we have developed an alternative procedure for the
catalyst assay using 31P NMR spectroscopy. Conveniently, in the
presence of camphorsulfonic acid (CSA), two resolved diastereo-
meric 31P NMR signals can be attained on in situ formed 2baÁCSA
(Ar = Ph) using material directly attained from the reaction mix-
ture. Optimal separations were attained with ca. 10 mg samples
of crude 2ba in CDCl3 (0.6 ml) with CSA (4 equiv) added as a solid.
Phosphorus spectra were collected under standard conditions.6
The two diastereomeric 31P signals were reproducibly separated
by 0.2 ppm. Typical spectra are shown in Figure 1. Control experi-
ments indicated that this 31P NMR approach is accurate enough
(error range 2–6%, average 4% ee) to allow the discovery of selec-
tive metal–ligand combinations (Fig. 2). Rapid (5 min/sample)
matrices of the type shown in Figure 3 could be built up from sam-
ples collected on an autosampler equipped NMR spectrometer.
From the range tested (>60 combinations,7 not all shown in
Fig. 3), it was clear that the use of methyl-DuPhos LA and a rho-
dium(I) source, in the presence of ZnMe2, afforded an optimal cat-
alyst for 2ba production (typically at 86–93% ee). Deviation from
this choice led to much poorer behavior. For example, the use of
the convenient, commercially available precursor [Rh(CO-
D)(LA)]BF4 (Rh(1)) with AlMe3 provided 2ba in only 32% ee. The
use of the air-stable analogue of trimethylaluminium DABAL-
100
80
60
40
20
0
0
20
40
60
80
100
ee of authentic 2ba (Ar=Ph) from prepared sample
Figure 2. Comparison of ee values (%) determined by 31P NMR spectroscopy6 on
2baÁCSA (Ar = Ph) against independently prepared authentic scalemic samples (0–
100% ee in 10% steps).
Ir(1) Ir(2)
Ir(3) Rh(1)
Ir(1) = [IrCl(COE)2]2 + ligand using AlMe3
Ir(2) = [IrCl(COD)]2 + ligand using AlMe3
Ir(3) = [Ir(L)(COD)]BF4 using AlMe3
8
Me3 unfortunately also led to very poor conversions and
selectivities.
LA
LB
LC
LD
LE
LF
Rh(1) = [Rh(L)(COD)]BF4 using ZnMe2
-
-
-
= negligible ee (0-20%)
= low ee (21-50%)
= significant ee (51-85%)
= high ee (86+%)
-
-
-
R
R
P
R
P
R
R
R
P
R
P
R
LD R = Me
L
E R = Ph
LA R = Me
LB R = Et
LC R = Pri
R
P
R
R
Fe
PPh2
PPh2
P
R
Figure 1. 31P NMR assay of 2ba (Ar = Ph) 0.05 M in CDCl3 in the presence of
camphorsulfonic acid (4.0 equiv).6 Sample (a) is from racemic 2ba; sample (b) from
a reaction using [RhCl(CH2@CH2)2]2/LG showing 47 4% ee (R)-2ba, based on the
integrals of the signals at 33.6 (major) and 33.4 (minor) ppm respectively
(determined as 49% ee by chiral GC).
LG R = Me
LH R = Et
LF
Figure 3. Selected discovery data for active catalyst combinations using 31P NMR
assay6 of 2ba (Ar = Ph) from reactions of imine 3ba with various methyl sources
(AlMe3, ZnMe2) in the presence of a range of metal complexes with (or without)
added chiral ligands. Reaction conditions: refluxing THF, 3 h, 5.8 mol % metal–
ligand. Ligand LG gave 49% ee while LH led to inactive systems.
2.2. Catalyst system optimisation
Two issues remained to be resolved with the discovered Rh(I)–
MeDuPhos system. Firstly, as anticipated, problems were encoun-
tered with the co-elution of a minor by-product in the HPLC assays
of the reaction mixture. Secondly, reactions catalysed by the iso-
lated complex [Rh(COD)(LA)]BF4 occasionally led to non-reproduc-
ible runs where the enantioselectivity fell to unacceptable levels
(down to 77%). We turned our attention to the chemoselectivity is-
sue first. The final optimisation of the Rh(I)–MeDuPhos system was
carried out by chiral GC analysis (error 1% ee) to avoid any poten-
tial issues with HPLC (co-eluting impurities) or 31P NMR (less accu-
O
(CF3CO)2O
O
or
PPh2
AcCl, DMAP
HN
CY3
HN
no solvent
then H2O
Ar
Ar
2c (Y = F)
2d (Y = H)
2b
Scheme 2. Derivatisation of the phosphoramides 2b by in situ trans-acetylation.

R. H. Crampton et al. / Tetrahedron: Asymmetry 20 (2009) 2497–2503
2499
racy) assay. Direct exchange of the P(O)Ph2 group to suitable ace-
P(O)Ph2
MeZn
Ph2(O)P
N
tates without the need to isolate the free amine 1 was developed
(Scheme 2). The addition of water promotes the reaction, presum-
ably by hydrolysis of the acylated intermediates. While efficient,
this derivatisation was not as quick as the 31P NMR ee measure-
ment process described earlier (overnight sample preparation
and >20 min run vs 10 min sample preparation + 5 min run).
The absolute stereochemistry of the product 2ba (Ar = Ph) could
confirmed by its independent synthesis from authentic (R)-1
(Ar = Ph) using TFAA. This confirmed that (R,R)-MeDuPhos LA
causes the addition to the re-face of the imine 2ba. The other imi-
nes are assumed to undergo the same sense of asymmetric addi-
tion. The use of the 4-tolyl imine 3bb allowed us to confirm the
formation of 4-TolCH2NHP(O)Ph2 11bb as the minor (reduction)
impurity (4–5%) in the methylation product 2bb. Due to the simi-
larity of both their chromatographic properties and crystallinity,
the identity of 4-TolCH2NHP(O)Ph2 was confirmed by its indepen-
dent synthesis. Such reductive behaviour appears to not have been
noted before in methylation reactions of diphenylphosphinoyl or
tosyl protected imines. As no b-hydrogens are available in the sup-
posed Rh–Me intermediates, we believe that this product arises
out of MVP hydrogen transfer reactions at rhodium (Scheme 3).
Thus, an initial rhodium methyl species coordinates to the
imine leading to 5 which after enantioselective methyl transfer af-
fords key unsaturated intermediate 6. If transmetallation with
ZnMe2 is rapid then the cycle closes leading to 2 after protolytic
workup. However if transmetallation is slow, then 6 can coordinate
a second equivalent of 3 leading to 8, which is predisposed to MVP
hydrogen transfer. Although the catalytic cycle still closes, a 1:1
mixture of 10:11 is generated on workup. Consistent with this pic-
ture, the presence of both 11 and 10 (and/or its acetophenone
hydrolysis product) could be detected in the proton NMR spectra
of crude samples of 2bb (Ar = 4-Tol). The spectra of both were
identical to authentic independently prepared samples of 10–11.
As expected, 11 also became the sole product if ZnEt2 was used
due to efficient b-elimination at rhodium. The key involvement
of 6 in determining methylation versus reduction was probed by
the following reactions. Refluxing equimolar mixtures of 2 and 3
in the presence of ZnMe2 alone did not give any 11. Similarly,
the deliberate formation of 7 (by the addition of ZnMe2 to 2) fol-
lowed by the addition of an equivalent of 3 and ZnMe2 activated
[Rh(COD)(LA)]BF4 (5.8 mol %) did not lead to increased levels of
11, even after extended reflux. This implies that there is no equilib-
rium cross-over between the two reaction pathways and the che-
moselectivity of the reaction depends only on the kinetic fate of
6 as a function of reaction conditions. As the physical separation
of 2 and 11 is hindered by their similar properties we sought reac-
tion conditions to maximise the efficiency of the upper methyla-
tion cycle of Scheme 3. Lowering the reaction temperature to
25 °C or changing the solvent to 2-methyltetrahydrofuran, DME
or 1,4-dioxane had no positive effect. Changing the reaction’s con-
centration in the range 0.05–0.15 M had no beneficial effect, nor
did increasing the number of equivalents of ZnMe2 used from 2
to 3. The most effective strategy we could identify was the slow
addition of imine 3 (over 2.6 h). Clearly this helps us to minimise
the concentration of 8 maximising the reaction’s chemoselectivity.
While the use of the commercial hydrogenation catalyst
[Rh(COD)(LA)]BF4 had its advantages (purity, good ‘shelf life’, ease
of use), the use of this catalyst gave non-reproducible results and
wide ee fluctuations often occurred. Re-subjecting the isolated
product 2ba to the reaction conditions led to no racemisation.
We proposed that the non-reproducibility is due to the generation
of achiral [MeRh(COD)] during the genesis of the active catalyst
(Scheme 4).
N
7
Me
LnRh
3
Ar
4
Ar
ZnMe2
Me
LnRh
Ph2(O)P
LnRh
Ph2(O)P
N
Ar
Ar
N
6
5
Ar
N
Ph2(O)P
+
Ph2(O)P
NH
N
LnRh
N
H
Ar
Ar
10
11
Ar
Ph2(O)P
1:1
[on workup]
8
Scheme 3. Competing transfer hydrogenation in methylation of 3b.
P
Rh
BF4
P
MAJOR
ZnMe2
Activation
minor
P
P
Rh Me AND Me Rh
13
Fast - achiral
12
Slow - enantioselective
Scheme 4. Competing activation paths for [Rh(COD)(LA)]BF4.
(diphosphine).9 Rhodium diphosphine complexes show ligand
retardation rather than acceleration effects.10 Under the conditions
of Scheme 4, the generation of any 13 (and to a lesser extent any
other achiral ‘naked’ RhI species) results in a serious erosion of
the selective reaction engendered by 12. Support for this idea
comes from studies using a [RhCl(CH2@CH2)2]2 pre-catalyst in the
presence of increasing amounts of (R,R)-Me-DuPhos LA and imine
3bd (Ar = 4-ClPh) Table 1.
At Rh:LA ratios of 1:1, poor reproducibility in the ee value (66–
82%) derived for product 2bd was noted. Up to Rh:LA ratios of
1:1.8, the ee of 2bd increased smoothly to 86% (run 3) before fall-
ing again at higher ligand concentrations (runs 4–5). We attribute
this poor performance to the formation of significant populations
of inactive [Rh(LA)2]+ in the reaction mixture. Consistent with the
picture of Scheme 4 the species [RhCl(COD)]2 was found to be an
active catalyst for the addition of ZnMe2 to 3ba leading to racemic
3ba. Attempts to maximise the profitable cleavage to 12 by using
It is known that the relative catalytic activity of rhodium-based
systems in C–C coupling is: MeRhI(diene) >> MeRhI > MeRhI

2500
R. H. Crampton et al. / Tetrahedron: Asymmetry 20 (2009) 2497–2503
Table 1
Rh:LA effects in 1,2-addition of ZnMe2 to imine 3bda
Ph2(O)P
Ph2(O)P
Me
Cl
N
N
ZnMe2
ZnMe2 (2 Equiv.)
P(O)Ph2
P(O)Ph2
P(O)Ph2
+
Cat.
LnRh-Me
[RhCl(CH2=CH2)2]2
N
HN
HN
2.9 mol%
LA
8.1-17.4 mol%
4-ClPh
4-ClPh
4-ClPh
3bi in situ
3bk
3bd
2bd
11bd
ZnMe2
1,2-Addition on mixture
Cat. Rh(Me)(LA)
2bk
Run
Rh:LA
Conv.a (%)
2bd:11bdb
ee (2bd)b (%)
2bi
(65% ee)
(84% ee)
1
2
3
4
5
1:1
100
100
100
86
90:10
92:8
95:5
94:6
72:28
66–82 (R)
82 (R)
86 (R)
80 (R)
78 (R)
1:1.4
1:1.8
1:2.2
1:3.0
Scheme 5. In situ methylation of 2-chloroimine 3bk.
11
methylation at 79% ee, we have observed strong solvent and addi-
tive effects in this chemistry, and the reduction of the ee to 65% in
the presence of a mixture of 3bi/3bk was expected.
a
Ratio of 3bd:Rh (5.8 mol %):ZnMe2 0.6:0.035:1.2 mmol; 10 ml THF, reflux, 3 h.
Conversion based on 1H NMR spectroscopy.
Chemoselectivity determined by 1H NMR on crude sample; ee by GC (CP-
b
ChiraSil-Dex CB on trifluoroacetate derivative).
3. Conclusion
various dienes and counter anions in the [Rh(LA)(diene)]X pre-cat-
alyst (diene = COD, nbd; X = BF4, OTf) were not successful so we
continued to use a strategy involving 2.9 mol % [RhCl(CH2@CH2)2]2
in the presence of excess LA (10.4 mol %). The results for a range of
substrates are given in Table 2.
The use of 31P NMR enabled us to realise our goal of identifying
a useful system for the preparation of 2-arylethyl amines 1 through
the addition of methyl organometallics to imines 3b. Complica-
tions were observed due to competing chemoselectivity (reduc-
tion) issues and the apparent complex dependency of the
enantiofacial selectivity as a function the substituent pattern with-
in the aryl group. Fortunately, the phosphamides 2b are all crystal-
line compounds and enantioselective enrichment to >99% ee can
be affected via simple recrystallisation, at least in the case of com-
pound 2ba (Ar = Ph).
Table 2
1,2-Addition of ZnMe2 to a range of imines 3a
ZnMe2 (2 Equiv.)
[RhCl(CH2=CH2)2]2
P(O)Ph2
P(O)Ph2
P(O)Ph2
+
N
HN
HN
2.9 mol%
LA
10.4 mol%
4. Experimental
4.1. General
Ar
Ar
Ar
3b
2b
11b
All experiments were carried out under an argon atmosphere
using standard Schlenk techniques. Solvents were dried prior to
use: THF and diethyl ether were distilled from sodium-benzophe-
none ketyl and dichloromethane from calcium hydride. Proton, 13C
and 31P NMR spectra were recorded on Bruker DPX400, Bruker
AV400 and Bruker AV(III)400 spectrometers using Me4Si or resid-
ual CHCl3 as an internal reference. Infrared spectra were recorded
on a Bruker Tensor 27 machine. Mass spectra were recorded using
electrospray (ES) or electron impact (EI) techniques using a Bruker
ApexIV FT-ICR machine. Optical rotations were measured using a
Bellingham Stanley ADP440 digital polarimeter at ambient tem-
perature in units of 10À1 deg cm2 gÀ1 (c in g/100 cm3). Enantiose-
lectivities were determined by chiral GC. GC analyses were
performed on a Varian 430 gas chromatograph using chiral col-
umns under the conditions given (Table 3). Thin layer chromatog-
raphy (TLC) was performed on Merck Silica Gel 60 F254+366 pre-
coated plates (0.25 mm) silica. The plates were visualised by the
use of a combination of ultraviolet light (254 and 366 nm) and/or
aqueous potassium permanganate with heating. Liquid chroma-
tography was by forced flow (flash chromatography) with the sol-
vent systems indicated using Silica Gel 60 (220–240 mesh)
supplied by Fluka. The starting imines and product amides were
compared against genuine samples prepared by literature proce-
dures except where noted as new compounds herein.
Run
Ar (3b)
Yieldb (%)
2b:11bc
ee (2b)c (%)
1
2
3
4
5
6
7
8
9
Ph (3ba)
4-MePh (3bb)
4-FPh (3bc)
4-ClPh (3bd)
4-BrPh (3be)
4-CF3Ph (3bf)
3-MePh (3bg)
3-ClPh (3bh)
2-MePh (3bi)
2-Naphthyl (3bj)
63
59
49
60
65
70
60
44
34
73
96:4
97:3
94:6
93:7
93:7
95:5
95:5
89:11
91:9
96:4
93 (>99)d
92
84
86
75
78
89
78
79
10
84
a
Ratio of 3b:Rh (5.8 mol %):LA:ZnMe2 0.6:0.035:0.07:1.2 mmol; 10 ml THF, slow
addition of 3b (2.6 h), then reflux (3 h).
b
Isolated combined yield of 2b and 11b.
Chemoselectivity determined by 1H NMR on crude sample; ee by GC (columns
c
of Table 3 on trifluoroacetate or acetate derivative).
d
After recrystallisation from CH2Cl2–hexane.
A range of aromatic diphenylphosphinoylimines gave (R):(S)
selectivities in the 10–20:1 range although in all cases, some minor
competing reduction was also seen. The enantioselectivity is
clearly determined by both steric (compare runs 2 and 9) and elec-
tronic (runs 7 and 8) effects in the substrate imine. The ketimine
10bb (Ar = 4-Tol, Scheme 3) was inactive in the attempted methyl-
ation using this system. The use of the 2-chloroimine 3bk led to an
approximate 1:1 mixture of the 2-Cl and 2-Me functionalised
amides 2bk (84% ee) and 2bi (65% ee) (Scheme 5). Given that the
enantioselectivities are different, it is likely that methylation takes
place prior to 1,2-methyl addition. Although pure 3bi undergoes
4.2. Diphenylphosphinic amide
This compound is commercially available (Aldrich) but is rela-
tively expensive. It is best prepared by treatment of Ph2P(O)Cl

R. H. Crampton et al. / Tetrahedron: Asymmetry 20 (2009) 2497–2503
2501
Table 3
GC conditions for measurement of the enantioselectivities
Comp.
Ar
Ph
PG
Column
CBa
Program
Ret. times (min)
2ca
COCF3
100 °C
(isothermal)
165 °C
(isothermal)
100 °C
(isothermal)
120 °C
(isothermal)
(R) 17.7
(S) 18.2
(S) 9.0
2db
2cc
2cd
2ce
2cf
4-MePh
4-FPh
Ac
CB
(R) 9.3
COCF3
COCF3
COCF3
COCF3
COCF3
COCF3
COCF3
Ac
CB
(R) 22.6
(S) 23.6
(R) 22.0
(S) 22.7
(R) 43.1
(S) 43.8
(R) 35.1
(S) 35.9
(S) 134.0
(R) 134.1
(R) 25.6
(S) 27.7
(S) 22.5
(R) 23.0
(S) 47.5
(R) 49.6
(R) 12.1
(S) 13.3
4-ClPh
4-BrPh
4-CF3Ph
3-MePh
3-ClPh
2-MePh
2-Naph
2-ClPh
CB
CB
115–125 °C at 0.2 °C/min +15 min at 125 °C
CB
100 °C
(isothermal)
70 °C
(isothermal)
115 °C
(isothermal)
100 °C
(isothermal)
160 °C
(isothermal)
2cg
2ch
2ci
2,6-cb
CB
CB
2dj
2ck
CB
COCF3
CB
120 °C
(isothermal)
a
Column: CP-ChiraSil-Dex CB: 0.25 mm  0.25
l
m  25 m.
b
Column: Octakis(2,6-di-O-methyl-3-O-pentyl)-
c
-cyclodextrin 0.25 lm id (60% in OV 1701 w/w).
(5.0 cm3, 26.2 mmol) in THF (70 cm3) with saturated aqueous
ammonia (3.6 cm3 of ca. 35% w/w solution, 65.5 mmol, Stench!).
The resulting suspension was filtered, and the filtrate was washed
with water and extracted with dichloromethane. The solution was
evaporated to dryness and the product was allowed to dry under
vacuum (100 °C, 1 h) to give Ph2P(O)(NH2) (5.57 g, 98%). An op-
tional recrystallisation step in hot toluene afforded the product
(4.32 g, 76%) as a white powder with literature properties.5
a homogeneous solution. The 31P NMR were acquired under stan-
dard conditions and the relative enantiomeric composition deter-
mined by integration of the signals at +33.4 and +33.6 ppm.
4.6. (R)-N-(1-(3-Chlorophenyl)ethyl)-P,P-diphenylphosphinic
amide 2bh
Prepared from 3bh. Rf 0.19 (EtOAc); mp 168–170 °C; [
a]D = +15.5
(c 1.06, MeOH, for 78% ee material); IR (CHCl3)
m
max/cmÀ1 3377,
4.3. Preparation of imines 3b
2986, 1439, 1189, 1124, 1108, 963; 1H NMR (400 MHz, CDCl3) dH
7.93–7.87 (m, 2H), 7.82–7.77 (m, 2H), 7.53–7.42 (m, 4H), 7.39–
7.34 (m, 2H), 7.24–7.14 (m, 4H), 4.42–4.32 (m, 1H), 3.22 (dd, 1H,
J = 9.6, 5.6 Hz), 1.55 (d, 3H, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3)
dC 147.1, 134.3, 132.3 (d, J = 9.6 Hz), 132.0, 131.8 (d, J = 9.5 Hz),
131.9 (d, J = 2.8 Hz), 129.8, 128.5 (t, J = 12.9 Hz), 127.2, 126.1,
124.3, 50.6, 25.8 (d, J = 3.5 Hz); 31P NMR (162 MHz, CDCl3) dP
22.7; HRMS (ESI positive) calcd for C20H19ClNOP, [M+H]
356.0966, found 356.0974.
Titanium tetrachloride (0.5 equiv, 5.0 mmol) in CH2Cl2 (4 cm3)
was added dropwise to a stirred solution of the aldehyde (1 equiv,
10.0 mmol), diphenylphosphinic amide (1 equiv, 10.0 mmol) and
triethylamine (3.5 equiv, 35.0 mmol) in CH2Cl2 (50 cm3) at 0 °C.
The solution was stirred at 0 °C for 1 h and room temperature for
1 h. The suspension was filtered through a silica pad, washed with
1:1 CH2Cl2/EtOAc. The filtrate was concentrated to a cream solid
and purified by prompt flash chromatography (1:1 CH2Cl2/EtOAc).
4.7. (R)-P,P-Diphenyl-N-(1-o-tolylethyl)phosphinic amide 2bi
4.4. Enantioselective preparation of phosphoramides 2b
Prepared from 3bi. Rf 0.13 (EtOAc); mp 201–204 °C; [
a]D = +7.1
A flame-dried Schlenk tube was charged with [RhCl(C2H4)2]2
(6.8 mg, 5.8 mol % Rh), (R,R)-MeDuPhos (LA) (19.1 mg, 10.4 mol %)
and THF (6 cm3). The solution was stirred at room temperature
for 30 min before ZnMe2 (2.0 M in toluene, 0.6 cm3, 1.2 mmol)
was added. The imine (0.6 mmol) in THF (4 cm3) was added slowly
by syringe pump (2.6 h). The reaction mixture was stirred at reflux
for 3 h, then cooled and quenched with saturated NH4Cl solution
(20 cm3), extracted with CH2Cl2 (3 Â 20 cm3). The organics were
dried (Na2SO4) and concentrated in vacuo to an oil, which was puri-
fied using flash chromatography (100% EtOAc).
(c 1.02, MeOH, for 79% ee material); IR (CHCl3)
m
max/cmÀ1 3382,
2984, 1439, 1183, 1125, 1086, 958; 1H NMR (400 MHz, CDCl3) dH
7.93–7.87 (m, 2H), 7.76–7.71 (m, 2H), 7.51–7.40 (m, 6H), 7.33–
7.28 (m, 1H), 7.25 (t, J = 6.8 Hz, 1H), 7.14 (td, J = 7.4, 1.2 Hz, 1H),
7.05 (d, J = 7.6 Hz, 1H), 4.65–4.55 (m, 1H), 3.28 (dd, J = 8.8, 5.6 Hz,
1H), 2.00 (s, 3H), 1.50 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
dC 143.7 (d, J = 7.0 Hz), 133.3 (d, J = 150 Hz), 132.4 (d, J = 9.7 Hz),
131.8 (d, J = 9.4 Hz), 131.8 (d, J = 2.4 Hz), 131.7 (d, J = 2.7 Hz),
130.3, 128.4 (d, J = 12.5 Hz), 128.2 (d, J = 12.7 Hz), 126.8, 126.5,
124.7, 47.1, 26.0 (d, J = 3.0 Hz), 18.8; 31P NMR (162 MHz, CDCl3)
dP 22.7; HRMS (ESI positive) calcd for C21H22NOP, [M+H]
336.1512, found 336.1499.
4.5. Enantiomeric excess determination by 31P NMR
spectroscopy
4.8. N-(1-(2-Chlorophenyl)ethyl)-P,P-diphenylphosphinic
A sample of crude 2b attained from the quench of an aliquot of
the reaction (typically ca. 10.0 mg) was dissolved in CDCl3 and
placed in a 5 mm NMR tube. Solid (1S)-10-camphorsulfonic acid
(4.0 equiv) was added and the tube capped and shaken to produce
amide 2bk
Prepared from 3bk. Rf 0.17 (EtOAc); mp 209–211 °C; IR (CHCl3)
m
max/cmÀ1 3379, 2984, 1602, 1439, 1186, 1124, 1107, 958; 1H

2502
R. H. Crampton et al. / Tetrahedron: Asymmetry 20 (2009) 2497–2503
NMR (400 MHz, CDCl3) dH 7.91–7.86 (m, 2H), 7.79–7.73 (m, 2H),
7.52–7.40 (m, 4H), 7.38–7.30 (m, 2H), 7.28–7.23 (m, 2H), 7.16
(td, J = 7.6, 2.0 Hz, 2H), 4.79–4.69 (m, 1H), 3.49 (dd, J = 9.6,
6.0 Hz, 1H), 1.57 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) dC
142.3 (d, J = 5.6 Hz), 132.9 (d, J = 127 Hz), 132.3 (d, J = 9.6 Hz),
131.9, 131.8 (d, J = 9.4 Hz), 131.7 (d, J = 2.8 Hz), 131.1, 129.8,
128.4 (d, J = 12.4 Hz), 128.2 (d, J = 12.5 Hz), 128.1, 127.4, 127.1,
49.1, 25.0 (d, J = 3.7 Hz); 31P NMR (162 MHz, CDCl3) dP 22.8; HRMS
(ESI positive) calcd for C20H18ClNOP, [M+Na] 378.0785, found
378.0781.
19F NMR (376 MHz, CDCl3) dF À62.7, À75.8; HRMS (ESI negative)
calcd for C11H9F6NO, [MÀH] 284.0516, found 284.0515.
4.13. (R)-2,2,2-Trifluoro-N-(1-m-tolylethyl)acetamide 2cg
Prepared from 2bg. Rf 0.85 (CH2Cl2); mp 65–66 °C; IR (CHCl3)
m
max/cmÀ1 3429, 1722, 1529, 1171; 1H NMR (400 MHz, CDCl3) dH
7.28–7.25 (td, J = 7.2, 1.2 Hz, 1H), 7.14–7.10 (m, 3H), 6.52 (br s,
1H), 5.10 (quintet, J = 6.8 Hz, 1H), 2.36 (s, 3H), 1.57 (d, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) dC 156.2 (q, J = 36.6 Hz), 140.8,
138.8, 128.9, 128.9, 127.0, 123.1, 115.8 (q, J = 287 Hz), 49.9, 21.4,
21.1; 19F NMR (376 MHz, CDCl3) dF À75.9; HRMS (ESI negative)
calcd for C11H12F3NO, [MÀH] 230.0798, found 230.0810.
4.9. Protecting group exchange—conversion of 2b into
trifluoroacyl or acyl derivatives 2c/d
A 10 cm3 vial equipped with a magnetic stirrer was charged
with the pure protected secondary amine 2b (30 mg) and trifluoro-
acetic anhydride (50 equiv) or acetyl chloride (50 equiv) with
DMAP (7 mol %). The suspension was stirred for 30 min before
the cautious addition of two drops of water. The resulting solution
was stirred overnight and the reaction mixture was transferred in a
larger container before quenching it cautiously with a saturated
NaHCO3 solution (30 cm3). The mixture was extracted with CH2Cl2
(3 Â 20 cm3), dried (Na2SO4) and concentrated. The residue was
purified by filtration over a pad of silica (CH2Cl2) or by flash chro-
matography (pet. ether/EtOAc 1:1). Samples of 2c/d, assessed pure
by 1H NMR spectroscopy, were used directly for ee determination
by GC. Assays were carried out on an autosampler equipped Varian
430 using the conditions and columns described in Table 3.
4.14. (R)-N-(1-(3-Chlorophenyl)ethyl)-2,2,2-trifluoroacetamide
2ch
Prepared from 2bh. Rf 0.67 (CH2Cl2); mp 52–54 °C; IR (CHCl3)
m
max/cmÀ1 3428, 2984, 1724, 1530, 1169, 879; 1H NMR
(400 MHz, CDCl3) dH 7.33–7.28 (m, 3H), 7.21–7.19 (m, 1H), 6.59
(br s, 1H), 5.10 (quintet, J = 7.2 Hz, 1H), 1.57 (d, J = 7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3) dC 156.5 (q, J = 37.1 Hz), 143.0, 134.9,
130.4, 128.4, 126.4, 124.5, 115.8 (q, J = 286 Hz), 49.4, 21.1; 19F
NMR (376 MHz, CDCl3) dF À75.8; HRMS (ESI negative) calcd for
C10H9ClF3NO, [MÀH] 250.0252, found 250.0252.
4.15. (R)-2,2,2-Trifluoro-N-(1-o-tolylethyl)acetamide 2ci
Prepared from 2bi. Rf 0.55 (CH2Cl2); mp 65–67 °C; [
a]D = +39.0 (c
4.10. (R)-2,2,2-Trifluoro-N-(1-(4-fluorophenyl)ethyl)acetamide
2cc
1.15, MeOH, for 79% ee material); IR (CHCl3)
m
max/cmÀ1 3428, 3012,
1723, 1528, 1171; 1H NMR (400 MHz, CDCl3) dH 7.31–7.19 (m, 4H),
6.37 (br s, 1H), 5.34 (quintet, J = 7.2 Hz, 1H), 2.37 (s, 3H), 1.58 (d,
J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) dC 156.1 (q, J = 36.8 Hz),
138.8, 136.0, 131.1, 128.1, 126.6, 124.6, 115.8 (q, J = 286.3 Hz),
46.3, 20.5, 19.0; 19F NMR (376 MHz, CDCl3) dF À75.8; HRMS (ESI
negative) calcd for C11H12F3NO, [MÀH] 230.0798, found 230.0801.
Prepared from 2bc. Rf 0.53 (CH2Cl2); mp 55–57 °C; [
a]D = +75.1
(c 1.23, MeOH, for 84% ee material); IR (CHCl3)
m
max/cmÀ1 3429,
1723, 1607, 1513, 1170, 837; 1H NMR (400 MHz, CDCl3) dH 7.31–
7.26 (m, 2H), 7.07–7.03 (m, 2H), 6.48 (br s, 1H), 5.12 (quintet,
J = 7.2 Hz, 1H), 1.58 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
dC 162.4 (d, J = 245 Hz), 156.3 (d, J = 37.1 Hz), 136.7 (d,
J = 10.6 Hz), 127.9 (d, J = 8.2 Hz), 115.9 (d, J = 21.5 Hz), 115.7 (d,
J = 286 Hz), 49.1, 21.1; 19F NMR (377 MHz, CDCl3) dF À75.9,
À113.8; HRMS (ESI negative) calcd for C10H9F4NO, [MÀH]
234.0548, found 234.0543.
4.16. N-(1-(2-Chlorophenyl)ethyl)-2,2,2-trifluoroacetamide 2ck
Prepared from racemic 2bk. Rf 0.75 (CH2Cl2); mp 101–103 °C; IR
(CHCl3)
m
max/cmÀ1 3432, 1726, 1530, 1171, 1041; 1H NMR
(400 MHz, CDCl3) dH 7.42–7.39 (m, 1H), 7.34–7.31 (m, 1H), 7.30–
7.25 (m, 2H), 6.78 (br s, 1H), 5.42 (quintet, J = 7.2 Hz, 1H), 1.61
(d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) dC 156.1 (q,
J = 37.1 Hz), 138.0, 133.0, 130.5, 129.3, 127.4, 127.4, 115.8 (q,
J = 286 Hz), 48.2, 20.2; 19F NMR (376 MHz, CDCl3) dF À75.9; HRMS
(ESI negative) calcd for C10H9ClF3NO, [MÀH] 250.0252, found
250.0255.
4.11. (R)-N-(1-(4-Chlorophenyl)ethyl)-2,2,2-trifluoroacetamide
2cd
Prepared from 2bd. Rf 0.67 (CH2Cl2); mp 106–107 °C;
[a]D = +44.8 (c 1.10, MeOH, for 86% ee material); IR (CHCl3) mmax/
cmÀ1 3429, 1725, 1530, 1495, 1170, 828; 1H NMR (400 MHz,
CDCl3) dH 7.36–7.33 (m, 2H), 7.27–7.24 (m, 2H), 6.47 (br s, 1H),
5.11 (quintet, J = 7.2 Hz, 1H), 1.57 (d, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) dC 156.4 (q, J = 37.1 Hz), 139.5, 134.1, 129.2,
127.7, 114.4, 49.3, 21.1; 19F NMR (376 MHz, CDCl3) dF À75.9; HRMS
(ESI negative) calcd for C10H9ClF3NO, [MÀH] 250.0252, found
250.0242.
Acknowledgements
Two of us (R.C., S.E.H.) are grateful to ChiroTech Technology Ltd
for support of Ph.D. studentships. We also thank this organisation
for generous gifts of chiral ligands and complexes. Helpful input
from the COST D40 Programme on ‘Innovative Catalysis’ and from
the UK Government (EPSRC grant EP/F033478/1) is acknowledged
by S.W.
4.12. (R)-2,2,2-Trifluoro-N-(1-(4-
(trifluoromethyl)phenyl)ethyl)acetamide 2cf
References
Prepared from 2bf. Rf 0.66 (CH2Cl2); mp 78–80 °C; [
a]D = +106.7
(c 1.16, MeOH, for 78% ee material); IR (CHCl3)
m
max/cmÀ1 3429,
1. For example, use as amine ligands directly or as part of phosphoramidites:
Reviews: (a) Goldsmith, P.; Woodward, S. Angew. Chem., Int. Ed. 2005, 44, 2235–
2237; (b) Alexakis, A.; Albrow, V.; Biswas, K.; d’Augustin, M.; Prieto, O.;
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2. Reviews of RM addition to imines: (a) Petrini, M.; Torregiani, E. Synthesis 2007,
159–186; (b) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895–
1946.
1726, 1531, 1327, 1171, 1132, 1070, 841; 1H NMR (400 MHz,
CDCl3) dH 7.64 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 6.48 (br
s, 1H), 5.19 (quintet, J = 7.2 Hz, 1H), 1.61 (d, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) dC 156.7, 156.3, 145.0, 130.6, 130.3, 126.5,
126.1, 126.1, 126.0, 126.0, 122.6, 117.2, 114.3, 111.5, 49.5, 21.2;

R. H. Crampton et al. / Tetrahedron: Asymmetry 20 (2009) 2497–2503
2503
3. Development of this field. Use of N-Ts aldimines (94–98% ee): (a) Soeta,
T.; Nagai, K.; Fujihara, H.; Kuriyama, M.; Tomioka, K. J. Org. Chem. 2003,
68, 9723–9727; (b) Nishimura, T.; Yasuhara, Y.; Hayashi, T. Org. Lett. 2006,
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Charette, A. B.; Boezio, A. A.; Cote, A.; Moreau, E.; Pytkowicz, J.;
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162.0 MHz at 298 K using 30° pulses (zypg30 pulse programme), an acquisition
time 448 ms and a relaxation delay of 2 s. A total of 128 scans with 2 dummy
scans were collected giving 64 k complex data points that were zero filled to
give 64 k data points. The final FT conversion was subjected to
a 1 Hz
exponential line broadening. A standard capillary of 85% H3PO4 in D2O was
used to calibrate the chemical shift.
7. El Hajjaji, S. Ph.D. Thesis, University of Nottingham, 2009.
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