Bulky p*-chirogenic diazaphospholidines as monodentate ligands for asymmetric catalysis

Article abstract of DOI:10.1002/ejoc.200900058

A series of easily prepared bulky P*-chiral diamidophosphites based, on (2R,5S)-3-phenyl-1,3-diaza-2-phosphabicyclo[3.3.0]octane and (2R,5S)-3-(p-bromophenyl)-l,3-diaza-2phosphabicyclo[3.3.0]octane backbones have been designed and developed. Ligands of th

Full text of DOI:10.1002/ejoc.200900058

FULL PAPER
DOI: 10.1002/ejoc.200900058
Bulky P*-Chirogenic Diazaphospholidines as Monodentate Ligands for
Asymmetric Catalysis
Konstantin N. Gavrilov,*[a] Eduard B. Benetskiy,[b] Tatiana B. Grishina,[a]
Eugenie A. Rastorguev,[a] Marina G. Maksimova,[a] Sergey V. Zheglov,[a]
Vadim A. Davankov,[b] Benjamin Schäffner,[c] Armin Börner,[c] Stephane Rosset,[d]
Gaelle Bailat,[d] and Alexandre Alexakis[d]
Keywords: Asymmetric catalysis / P ligands / Hydrogenation / Allylation / Conjugate addition
A series of easily prepared bulky P*-chiral diamidophos-
phites based on (2R,5S)-3-phenyl-1,3-diaza-2-phosphabicy-
clo[3.3.0]octane and (2R,5S)-3-(p-bromophenyl)-1,3-diaza-2-
phosphabicyclo[3.3.0]octane backbones have been designed
and developed. Ligands of this type exhibited high enantio-
selectivities in Pd-catalysed allylic substitution reactions of
(E)-1,3-diphenylallyl acetate with NaSO2pTol (up to 87% ee),
CH2(CO2Me)2 (up to 92% ee), (C3H7)2NH (up to 93% ee)
and (CH2)4NH (up to 99% ee). These novel stereoselectors
have also been successfully employed in Rh-catalysed asym-
metric hydrogenations of dimethyl itaconate (up to 76% ee),
methyl (Z)-2-acetamido-3-phenylacrylate (up to 73% ee) and
methyl 2-acetamidoacrylate (up to 98% ee). Cu-catalysed
conjugate addition of diethylzinc to cyclohexenone leads to
a maximum of 70% ee with quantitative conversion.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
intensely investigated. Besides a high level of asymmetric
induction, the advantages of this method include its toler-
ance of a wide range of functional groups and a great flexi-
bility in the type of bonds that can be formed. For example,
H-, C-, N-, O-, and S-centred nucleophiles can be em-
ployed.[3] Enantioselective Cu-catalysed conjugate addition
represents another powerful carbon–carbon bond-forming
method. Significant advantages of this process are its high
compatibility with many functional groups, the low cost of
the copper salts and the often high regio- and enantio-
selectivities.[4] Because the design of chiral ligands plays a
key role in the development of these metal-catalysed reac-
tions, many recent studies have addressed the tuning of exi-
sting ligands and/or the development of novel chiral li-
gands. Optically active phosphite-type compounds play im-
portant roles here, because of their intrinsic electronic prop-
erties and steric variability. Indeed, various P–O and/or P–
N bond containing phosphorus ligands may be constructed
in large quantities through the use of relatively simple con-
densation processes, and from inexpensive starting materi-
als. In addition, they are characterized by pronounced π-
acidity and high oxidative stability.[5]
Introduction
Asymmetric catalysis now provides one of the most cost-
effective and environmentally responsible methods for the
production of a truly vast array of structurally diverse, en-
antiomerically pure compounds. In addition to well-known
pharmaceutical applications, asymmetric catalytic methods
are being employed to great effect in the flavour and fra-
grance, agrochemical, animal health, polymer and liquid-
crystal industries.[1] Rh-catalysed enantioselective hydro-
genation, Pd-catalysed allylic substitution and Cu-catalysed
conjugate addition represent a number of the major cata-
lytic processes. Asymmetric catalytic hydrogenation of un-
saturated bonds, employing dihydrogen and small amounts
of transition-metal complexes modified intrinsically by chi-
ral ligands, is now recognized as the most promising strat-
egy for the synthesis of large amounts of optically pure
products, and enormous progress has been achieved in this
area.[2] Asymmetric allylic substitution has also been very
[a] Department of Chemistry, Ryazan State University,
46 Svoboda Street, 390000 Ryazan, Russian Federation
Fax: +7-4912-775498
E-mail: k.gavrilov@rsu.edu.ru
[b] Institute of Organoelement Compounds, Russian Academy of
Sciences,
28 Vavilov Street, 119991 Moscow, Russian Federation
[c] Leibniz-Institut für Katalyse an der Universität Rostock e.V.,
Albert-Einstein-Straße 29a, 18059 Rostock, Germany
[d] Departement de Chimie Organique Universite de Geneve,
30 quai Ernest Ansermet, 1211 Geneva 4, Switzerland
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900058.
Phosphite-type ligands, in which the chiral centre exists
at the phosphorus atom itself, are very promising. In their
complexes, the chirogenic phosphorus atoms bind directly
to the metal atom. This factor eliminates potentially inef-
ficient secondary transfer of chirality from the ligand back-
bone and thus provides more efficient chiral environments
at the sites where the enantioselection takes place.[2] Excel-
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K. N. Gavrilov et al.
FULL PAPER
lent results have thus been achieved in the Rh-catalysed hy- examine whether the presence of bulky organic groups and/
drogenation of functionalized olefins with P*-stereogenic or chiral axes in the exocyclic substituents may be useful
phosphoramidites derived from ortho-substituted BINOL for improving catalytic outcomes in asymmetric reactions.
and (S)-diphenylprolinol.[6]
Note that P*-chiral diazaphospholidines are one of the
most attractive groups of optically active diamidophosphite
ligands. In general, diazaphospholidines are good π-ac-
ceptor ligands, thanks to the availability of low-lying π*PN
orbitals, and good σ-donor ligands. The inclusion of the
phosphorus atom in a cyclic structure, in particular a five-
membered ring, is a key feature, because it increases sta-
Figure 1. Examples of P*,N-bidentate and P*-monodentate diaza-
phospholidine ligands.
bility towards air and moisture. In addition, these ligands
are modular in nature because the substituents at the nitro-
gen and the phosphorus atom can be varied.[7] Buono and
co-workers, and more recently Gavrilov et al., have reported
QUIPHOS-type ligands LA and some other P*,N-bidentate
compounds (such as the iminophosphites LB in Figure 1)
derived from C1-symmetric (2-anilinomethyl)pyrrolidine,
Results and Discussion
Novel P*-monodentate diamidophosphites can be read-
which induced excellent enantioselectivities in Pd-catalysed ily obtained in two steps from (S)-2-(anilinomethyl)pyrroli-
allylic substitution.[8] At the same time, it was shown that dine or (S)-2-(p-bromoanilinomethyl)pyrrolidine. In turn,
mixed donor ligands containing heterodonor atoms with ni- these optically active diamines are easily accessible (in two
trogen and phosphorus functional moieties are not neces- and three steps, respectively) from -glutamic acid.[11] The
sary for achieving high enantioselectivity, and that the P*- pyrrolidine compounds react with PCl3 in benzene to yield
monodentate diazaphospholidine stereoselectors LC could the phosphorylating reagents 1a and 1b.[9a] Subsequent
also provide very good ees in asymmetric allylation.[9] Nev- treatment of chlorodiamidophosphites 1a or 1b with appro-
ertheless, such ligands with small exocyclic OR substituents priate alcohols in benzene leads to the desired compound
(R = Me, iPr) provide only disappointing stereodiscrimin- 2a–f (Scheme 1). The reactions require the presence of Et3N
ation (no more than 20% ees) in the Cu-catalysed conjugate as a base because of the concomitant formation of HCl.
addition of diethylzinc to cyclohexenone and the Rh-cata- The starting alcohols are commercially available, with the
lysed hydrogenation of dimethyl itaconate.[10] Accordingly, exception of (S)- and (R)-1-(2-hydroxynaphthalen-1-yl)-
careful selection and design of the novel LC-type mono- naphthalen-2-yl pivalates, which are conveniently obtained
dentate ligands is currently a very relevant task. Here we by direct interaction between the appropriate enantiomer of
Scheme 1. Synthesis of P*-chiral diazaphospholidines 2a–f.
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Diazaphospholidines as Monodentate Ligands for Asymmetric Catalysis
BINOL and pivaloyl chloride.[12] The novel ligands are pounds.[17] We first tested the new diazaphospholidines in
stable enough to allow manipulation in open air and can the asymmetric allylic amination of 3 with dipropylamine
be stored under dry conditions at room temperature over as N-nucleophile, under standard conditions and in CH2Cl2
several months without any degradation. In addition, they as solvent (Table 2). The catalysts were generated in situ
are fairly stable in solutions in common organic solvents. from [Pd(allyl)Cl]2 and the ligands at 1:1 and 2:1 ligand/
1
For instance, the H and 31P NMR spectra of compound palladium ratios. Compounds 2b and 2c displayed mediocre
2d, recorded two months after its dissolution in CDCl3, efficiency (no more than 67% ee and 41% conversion),
showed no signals of any decomposition products.
whereas 2a produced higher levels of reactivity and asym-
During the phosphorylation process, exclusive formation
of the stereoindividual diamidophosphites 2c and 2d takes
place, although the other ligands contain 16–33% of the
second P* epimers (Table 1). According to the literature
data, compounds 2c and 2d and the major epimers of 2a,
2b, 2e and 2f each have the pseudoequatorial orientation of
the exocyclic substituent at the phosphorus atom and a cis
orientation between the lone pair of the phosphorus atom
and C(8) [i.e., (R) configuration at the P* stereocenter].
Table 2. Pd-catalysed allylic amination of (E)-1,3-diphenylallyl ace-
tate (3).[a]
2
This was concluded from the large JC(8),P values (32.7–
Entry Ligand
L/Pd
Solvent
Conv. [%]
ee [%]
38.2 Hz) in their 13C NMR spectra (see Experimental Sec-
tion).[9a,11a,13] The minor (SP) epimers of compounds 2a,
2b, 2e and 2f (Table 1) are each characterized by a trans
orientation of the phosphorus lone pair to C(8) and, in con-
Allylic amination with dipropylamine[b]
1
2
3
4
5
6
7
8
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
2f
1:1
2:1
1:1
2:1
1:1
2:1
1:1
2:1
1:1
2:1
1:1
2:1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
100
100
29
41
14
21
99
100
57
68
76 (+)
74 (+)
47 (+)
67 (+)
45 (+)
46 (+)
93 (+)
90 (+)
91 (+)
90 (+)
26 (+)
59 (+)
2
sequence, minimal values of JC(8),P (3.4–4.4 Hz for 2a, 2e
and 2f; see ref.[9a] and Experimental Section).
Table 1. 31P NMR chemical shifts (CDCl3) and cone angles θ of
ligands 2a–f.
9
10
11
12
Ligand
δP [ppm]
θ [°]
73
93
(RP)-2a (74%)[a]
(SP)-2a (26%)
(RP)-2b (84%)
(SP)-2b (16%)
(RP)-2c
126.7
112.3
125.7
111.6
121.9
124.1
125.9
117.9
129.7
119.6
168[b]
2f
Allylic amination with pyrrolidine[c]
170
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
2a
2a
2a
2a
2b
2b
2b
2b
2c
2c
2c
2c
2d
2d
2d
2d
2e
2e
2e
2e
2f
1:1
2:1
1:1
2:1
1:1
2:1
1:1
2:1
1:1
2:1
1:1
2:1
1:1
2:1
1:1
2:1
1:1
2:1
1:1
2:1
1:1
2:1
1:1
2:1
CH2Cl2
CH2Cl2
THF
100
100
64
92
70
88
25
40
100
100
53
100
100
100
35
63
73
97
22
85 (R)
87 (R)
86 (R)
90 (R)
74 (R)
79 (R)
43 (R)
85 (R)
75 (R)
74 (R)
67 (R)
70 (R)
94 (R)
91 (R)
69 (R)
90 (R)
74 (R)
76 (R)
39 (R)
67 (R)
99 (R)
73 (R)
89 (R)
88 (R)
165
174
177
(RP)-2d
(RP)-2e (67%)
(SP)-2e (33%)
(RP)-2f (73%)
(SP)-2f (27%)
THF
CH2Cl2
CH2Cl2
THF
197
[a] Percentage of P* epimers. [b] Published data.[9a]
THF
CH2Cl2
CH2Cl2
THF
With a view to an estimation of the steric demands of
2a–f, we calculated their Tolman cone angles[14] by the re-
ported method using a semiempirical quantum-mechanical
AM1 method with full optimization of geometrical param-
eters.[15] The obtained results show that 2a–e are very bulky
diazaphospholidines and that their steric parameters (θ)
vary within the rather narrow interval of 165°–177°
(Table 1). It is interesting that 2f is an extremely bulky li-
gand (θ = 197°). For comparison, the Tolman angle for
P(C6F5)3 is 184° and that for P(o-Tol)3 is 194°.[15,16]
THF
CH2Cl2
CH2Cl2
THF
THF
CH2Cl2
CH2Cl2
THF
THF
88
96
100
98
32
CH2Cl2
CH2Cl2
THF
2f
With these sterically congested ligands to hand, we first
chose to explore their reactivities and enantioselectivities in
the Pd-catalysed allylic amination of (E)-1,3-diphenylallyl
acetate (3, Table 2). On the one hand, this is a common
benchmark test for novel groups of stereoselectors. On the
other, it is also a highly efficient procedure for the prepara-
tion of optically active aromatic amines with stereocentres
α to their nitrogen atoms. Such amines are important struc-
2f
2f
THF
[a] All reactions were carried out with 2 mol-% of [Pd(allyl)Cl]2 at
room temperature over 48 h. [b] The conversion of the substrate 3
and the enantiomeric excess of 4a were determined by HPLC
[Daicel Chiralcel OD-H, C6H14/iPrOH/HN(Et)2, 1000:1:1,
0.4 mLmin–1, 254 nm, t(+) = 8.2 min, t(–) = 9.1 min]. [c] The con-
version of the substrate 3 and the enantiomeric excess of 4b were
determined by HPLC [Daicel Chiralcel OD-H, OD-H, C6H14/
tural motifs in a number of biologically active com- iPrOH/HN(Et)2, 200:1:0.1, 0.9 mLmin–1, 254 nm].
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K. N. Gavrilov et al.
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metric induction (up to 76% ee). The best stereoselector ate to good enantioselectivities (63–87%). As stated above,
was diamidophosphite 2d, bearing a fluorous ponytail. It the fluorous diamidophosphite 2d is a powerful stereoin-
provided up to 93% ee and quantitative conversion ductor in allylic amination, but in allylic sulfonylation, like
(Table 2, Entries 7, 8). Similar enantioselectivity, but lower the similar LC-type ligand with strong π-acidity [R =
activity was demonstrated by 2e (Table 2, Entries 9, 10). CH(CF3)2],[9a] 2d provided rather moderate optical and me-
Note that its epimer 2f is a significantly poorer stereoinduc- diocre chemical yields of product (S)-4c (Table 3, Entries 5
tor (only up to 59% ee) as a result of the mismatched and 6). Diazaphospholidine 2e, containing the (Ra)-Piv-BI-
(2R,5S) phosphorus centre/(Sa)-Piv-BINOL combination. NOL unit, was found to be a good stereoselector, whereas
The use of pyrrolidine as N-nucleophile allows higher stere- its epimer 2f was much less efficient (up to 87 and 24% ees,
oselectivity to be achieved. In this case, diazaphospholid- respectively, Table 3, Entries 7–10).
ines 2a–e provide up to 90, 85, 75, 94 and 76% ees, respec-
Previously we had established that in the allylic alky-
tively (Table 2, Entries 16, 20, 21, 25 and 30). As a rule, lation of 3 with dimethyl malonate as C-nucleophile, cata-
CH2Cl2 is the optimum solvent, and in this medium the lytic systems based on the P*-chirogenic diamidophosphite
enantioselectivity is almost independent of the ligand/palla- 2a and [Pd(allyl)Cl]2 or [Pd2(dba)3]·xCHCl3 allowed up to
dium ratio. It should be noted that the fluorous diamidoph- 87% optical yields of product (S)-4d to be achieved.[9a] The
osphite 2d produced more than 90% optical yields of prod- use of Pd(CF3CO2)2 as a precatalyst led to an increase in
ucts 4a and 4b in both allylic amination reactions. It is enantioselectivity up to 92% (Table 3, Entries 11–14). The
interesting that, in contrast with the allylic amination in the enantiomeric excess depended on the solvent used: CH2Cl2
presence of dipropylamine, in the pair of epimers 2e and 2f, is the optimal solvent (Table 3, Entry 12).
2f is more efficient [up to 99% ee, (Table 2, Entry 33)]. It is
In the second set of experiments, the new P*-chiral di-
possible to assume that this is the consequence of a matched azaphospholidines were applied in Rh-catalysed hydrogena-
(2R,5S) phosphorus centre/(Sa)-Piv-BINOL combination tions of common benchmark substrates: namely dimethyl
and the much greater value of the Tolman cone angle for itaconate (5a), methyl (Z)-2-acetamido-3-phenylacrylate
2f (Table 1).
(5b) and methyl 2-acetamidoacrylate (5c). In all cases the
We have also tested novel P*-stereogenic diazaphosphol- cationic rhodium catalysts were prepared in situ by treating
idines in the enantioselective Pd-catalysed allylic sulfo- [Rh(cod)2]BF4 with 2 equiv. of the corresponding mono-
nylation of 3 with NaSO2pTol as S-nucleophile (Table 3). dentate ligand; the results are summarized in Table 4. For
As well as in allylic aminations, these processes are also substrates 5a–c, the low or moderate enantioselectivity
powerful tools in the total synthesis of natural products.[3b] varied within rather similar ranges between 33–76, 13–73
Earlier we reported that ligand 2a provided up to 90% ee and 31–68% ee, respectively. The exception is the excellent
in this reaction.[9a] Compounds 2b–e also displayed moder- result achieved in the hydrogenation of methyl 2-acet-
Table 3. Pd-catalysed allylic sulfonylation and alkylation of (E)-1,3-diphenylallyl acetate (3).[a]
Entry
Ligand
Precatalyst
L/Pd
Solvent
Time [h]
Conv. [%][b]
ee [%]
Allylic sulfonylation with sodium p-toluenesulfinate[c]
1
2
3
4
5
6
7
8
9
2b
2b
2c
2c
2d
2d
2e
2e
2f
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
1:1
2:1
1:1
2:1
1:1
2:1
1:1
2:1
1:1
2:1
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
48
48
48
48
48
48
48
48
48
48
46
95
54
66
33
26
48
51
38
27
66 (S)
77 (S)
74 (S)
81 (S)
63 (S)
74 (S)
75 (S)
87 (S)
21 (S)
24 (S)
10
2f
Allylic alkylation with dimethyl malonate (BSA, KOAc)[d]
11
12
13
14
2a
2a
2a
2a
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
1:1
1:1
1:1
1:1
PC[e]
CH2Cl2
THF
14
14
14
14
79
87
92
82
91 (S)
92 (S)
80 (S)
84 (S)
toluene
[a] All reactions were carried out with 2 mol-% of [Pd(allyl)Cl]2 (allylic sulfonylation) and with 1 mol-% of Pd(CF3CO2)2 (allylic alkylation)
at room temperature. [b] Isolated yield of 4c in allylic sulfonylation. [c] Enantiomeric excess of 4c was determined by HPLC (Daicel
Chiralcel OJ, C6H14/iPrOH, 4:1, 0.5 mLmin–1, 254 nm). [d] The conversion of substrate 3 and enantiomeric excess of 4d were determined
by HPLC (Daicel Chiralcel OD-H, C6H14/iPrOH, 99:1, 0.6 mLmin–1, 254 nm). [e] Propylene carbonate.
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Diazaphospholidines as Monodentate Ligands for Asymmetric Catalysis
amidoacrylate (5c) with the participation of ligand 2a: a diethylzinc to cyclohexenone 7 (Table 5). Copper catalysts
98% optical yield of the product (R)-6c and quantitative were prepared by treatment of copper(I) thiophenecarbox-
conversion of the starting substrate (Table 4, Entry 14). ylate (CuTC) with 2 equiv. of the ligand in Et2O. With par-
This stereoselector also provided the best enantioselectivi- ticipation of diamidophosphite 2a, 2e and 2f, nearly quanti-
ties (up to 73–75%) in the cases of substrates 5a and 5b tative conversion of 7 (Ͼ99%) was achieved, but with disap-
(Table 4, Entries 2 and 9). For dimethyl itaconate (5a), anal- pointing enantioselectivities (16–21%). In contrast, diaza-
ogous asymmetric induction (76% ee) was also observed phospholidine 2d with the fluorous ponytail was quite ef-
with the participation of the fluorous diamidophosphite 2d ficient and gave a 70% optical yield of product 8 with com-
(Table 4, Entry 5). Optical yields strongly depended on the
nature of the solvent: they increased dramatically on re-
placement of propylene carbonate with CH2Cl2 (Table 4,
Entries 1, 2 and 8, 9). In contrast with the allylic substitu-
Table 5. Cu-catalysed conjugate addition of Et2Zn to cyclohex-
enone.[a]
tion, in all hydrogenation experiments the epimeric ligands
2e and 2f caused the formation of products 6a–c with oppo-
site absolute configurations, as a consequence of the de-
termining influence of the Piv-BINOL fragment. For com-
parison it should be noted that catalytic systems based on
Entry
Ligand
Conv. [%]
ee [%][b]
the known P*,N-bidentate diazaphospholidines LB (R1, R2
= Me and R1 = sBu, R2 = H)[8g] and [Rh(cod)2]BF4 (L/Rh
molar ratio = 1:1 and 2:1) provided only low enantio-
selectivities (13–26%) in the hydrogenation of 5a and no
more than 50% conversions. In the case of substrate 5c its
conversion has not exceeded 4%.
1
2
3
4
2a
2d
2e
2f
Ͼ99
Ͼ99
99
21 (S)
70 (S)
16 (S)
18 (S)
Ͼ99
[a] All reactions were carried out with 2 mol-% of CuTC at –30 °C
over 3 h. [b] The conversion of substrate 7 and the enantiomeric
excess of 8 were determined by GC (Lipodex E, 25 mϫ0.25 mm,
In the third step, we screened several P*-chiral diaza-
phospholidines in the Cu-catalysed conjugate addition of 60 °C, 1 mL min–1).
Table 4. Rh-catalysed hydrogenation of α-dehydrocarboxylic acid esters.[a]
Entry
Substrate
Ligand
Solvent
Time [min]
Conv. [%]
ee [%][b–d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
5a
5a
5a
5a
5a
5a
5a
5b
5b
5b
5b
5b
5b
5c
5c
5c
5c
5c
5c
2a
2a
2b
2c
2d
2e
2f
2a
2a
2b
2d
2e
2f
2a
2b
2c
2d
2e
2f
PC[e]
35
30
100
100
100
35
100
100
100
100
100
75
100
100
100
100
85
45 (S)
75 (S)
67 (S)
33 (S)
76 (S)
55 (S)
47 (R)
13 (R)
73 (R)
50 (R)
34 (R)
45 (R)
27 (S)
98 (R)
68 (R)
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PC[e]
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1440
1440
1200
1440
1440
80
1200
1440
1440
1440
1440
1200
1440
1440
1200
1440
1440
0
62
100
100
46 (R)
40 (R)
31 (S)
[a] All reactions were carried out with 1 mol-% of [Rh(cod)2]BF4 at 25 °C and 1 bar H2. [b] The conversion of substrate 5a and the
enantiomeric excess of 6a were determined by GC (Lipodex E, 25 mϫ0.25 mm, 80 °C, 1 mL min–1) or HPLC (Daicel Chiralcel OD-H,
C6H14/iPrOH, 98:2, 0.8 mLmin–1, 220 nm, t(R) = 9.1 min, t(S) = 16.1 min). [c] The conversion of the substrate 5b and the enantiomeric
excess of 6b were determined by GC (Lipodex E, 25 mϫ0.25 mm, 145 °C, 1 mL min–1). [d] The conversion of substrate 5c and the
enantiomeric excess of 6c were determined by GC [XE-valin(tert-butylamide) 4ϫ0.25 mm, 85 °C, 1 mL min–1]. [e] Propylene carbonate.
Eur. J. Org. Chem. 2009, 3923–3929
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3927

K. N. Gavrilov et al.
FULL PAPER
cording to a known procedure.[24] Starting substrates 3 and 5b were
synthesised as published.[18,25] Adamantan-1-ol, ferrocenemeth-
anol, 2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-nonadecafluorodecan-
1-ol, (R)- and (S)-2,2Ј-dihydroxy-1,1Ј-binaphthyl [(R)- and (S)-BI-
NOL], dimethyl malonate, BSA [N,O-bis(trimethylsilyl)acetamide],
sodium p-toluenesulfinate, dimethyl itaconate, methyl 2-acet-
amidoacrylate, cyclohexenone, Et2Zn solution in hexane (1 ) and
CuTC [copper(I) thiophenecarboxylate] were purchased from Ald-
rich and Acros Organics and used without further purification.
plete conversion of the starting substrate. As in the case of
Rh-catalysed hydrogenation, the P*,N-bidentate diazaphos-
pholidines LB (R1, R2 = Me and R1 = sBu, R2 = H) pro-
vided only low asymmetric induction (13–15% ee) under
the same conditions. Note that the monodentate ligand 2d
as stereoselector also surpasses QUIPHOS-type P*,N-bi-
dentate ligands LA, which in this reaction allow no more
than 55% ees to be achieved.[8e]
General Procedure for Preparation of the Ligands 2b–f: A solution
of Et3N (0.27 mL, 1.9 mmol) and the appropriate alcohol
(1.8 mmol) in benzene (8 mL) were added dropwise to a vigorously
stirred solution of phosphorylating reagent 1a or 1b (1.8 mmol) in
benzene (8 mL). The mixture was heated to the boiling point with
stirring and was then allowed to cool to 20 °C. Solid Et3N·HCl was
filtered off; benzene was removed under reduced pressure (40 Torr).
Products 2d, 2e and 2f were extracted with hexane. The residue was
Conclusions
We have described the successful application of various
easily accessible sterically congested (θ = 165–197°) mono-
dentate P*-chirogenic diazaphospholidines in Pd-catalysed
asymmetric allylic substitution and Rh-catalysed asymmet-
ric hydrogenation reactions of several substrate types, as dissolved in hexane (3ϫ15 mL; boiling hexane in the case of 2e
and 2f) and the mixture filtered, concentrated and dried in vacuo
(1 Torr) for 2 h. Compounds 2b and 2c were purified by flash
chromatography on silica gel with use of non-degassed eluents
(ethyl acetate/hexane, 1:10 and 1:6, respectively).
well as in the Cu-catalysed conjugate addition of diethylzinc
to cyclohexenone. It has been shown that in the two last
catalytic processes such ligands can afford enantioselectivi-
ties superior to those of their chelating LA and small mono-
dentate LC (OR = OMe, OiPr) analogues, whereas in the
Pd-catalysed allylation all three groups of stereoselectors
show comparable efficiencies. Novel diazaphospholidines
can be considered modular, and because the bulky exocyclic
moieties can be varied, a large library of these ligands is
readily available. Accordingly, our ongoing experiments are
focused on the fine-tuning of the structures of P*-chiral di-
azaphospholidines to improve the optical yields in various
asymmetric transformations and will be reported in due
course.
(2R,5S)-2-(Tricyclo[3.3.1.1.3Ј,7Ј]dec-1Ј-yloxy)-3-(p-bromophenyl)-
1,3-diaza-2-phosphabicyclo[3.3.0]octane (2b): White amorphous so-
lid (0.60 g, 76%), 13C NMR (100.6 MHz, CDCl3, 25 °C): δC = 26.0
3
[d, J = 4.4 Hz, C(7)], 30.8 [s, C(3Ј,5Ј,7Ј)], 31.5 [s, C(6)], 35.9 [s, C
2
2
(4Ј,6Ј,10Ј)], 44.7 [d, J = 8.8 Hz, C(2Ј,8Ј,9Ј)], 47.7 [d, J = 35.0 Hz,
2
2
C(8)], 52.9 [d, J = 5.9 Hz, C(4)], 62.4 [d, J = 8.1 Hz, C(5)], 74.2
[d, 2J = 6.6 Hz, C(1Ј)], 110.4 (s, CAr), 117.0 (d, 3J = 12.5 Hz, CHAr),
131.4 (s, CHAr), 144.9 (d, 2J = 14.7 Hz, CAr) ppm. MS (EI, 70 eV):
m/z (%) = 435 (12) [M]+, 251 (93), 205 (32), 135 (84), 95 (100).
C21H28BrN2OP (434.1): calcd. C 57.94, H 6.48, N 6.43; found C
58.22, H 6.62, N 6.32.
(2R,5S)-2-(Ferrocenylmethoxy)-3-phenyl-1,3-diaza-2-phosphabicyclo-
[3.3.0]octane (2c): Yellow powder (0.50 g, 66%), m.p. 65–66 °C. 13
C
NMR (100.6 MHz, CDCl3, 25 °C): δC = 26.0 [d, 3J = 3.9 Hz, C(7)],
31.8 [s, C(6)], 48.6 [d, 2J = 38.2 Hz, C(8)], 54.9 [d, 2J = 7.1 Hz,
C(4)], 60.1 (d, 2J = 2.9 Hz, CH2O), 63.0 [d, 2J = 8.7 Hz, C(5)], 68.2
(s, CCp), 68.0, 68.1, 68.4, 68.6 (4 s, CFc), 84.6 [d, 3J = 1.5 Hz,
Experimental Section
General: IR spectra were recorded with a Specord M-80 spectro-
photometer in CHCl3 (KBr cuvette). 31P, 13C, 1H and 19F NMR
spectra were recorded with
a
Bruker AMX 400 instrument
3
CFc(ipso)], 114.6 (d, J = 11.6 Hz, CHAr), 118.7 (s, CHAr), 128.9 (s,
(162.0 MHz for 31P, 100.6 MHz for 13C, 400.13 MHz for 1H and
282.4 MHz for 19F). Complete assignment of all the 13C NMR res-
onances was achieved by the use of DEPT techniques. Chemical
shifts (ppm) are given relative to Me4Si (1H and 13C), 85% H3PO4
(31P NMR) and CCl3F (19F). Mass spectra were recorded with a
Varian MAT 311 spectrometer (EI). Elemental analyses were per-
formed at the Laboratory of Microanalysis (Institute of Organo-
element Compounds, Moscow). All reactions were carried out un-
der dry argon in freshly dried and distilled solvents; triethylamine,
pyrrolidine and dipropylamine were distilled from KOH and then
from a small amount of LiAlH4 before use. Phosphorylating rea-
gents, (2R,5S)-2-chloro-3-phenyl-1,3-diaza-2-phosphabicyclo[3.3.0]-
octane (1a) and (2R,5S)-2-chloro-3-para-bromophenyl-1,3-diaza-2-
phosphabicyclo[3.3.0]octane (1b), were prepared analogously to a
known procedure.[9a] The synthesis of ligand 2a was described by us
2
CHAr), 145.6 (d, J = 16.1 Hz, CAr) ppm. MS (EI, 70 eV): m/z (%)
= 420 (92) [M]+, 355 (100), 199 (75). C22H25FeN2OP (420.1): calcd.
C 62.87, H 6.00, N 6.67; found C 63.0, H 5.95, N 6.58.
(2R,5S)-2-(2Ј,2Ј,3Ј,3Ј,4Ј,4Ј,5Ј,5Ј,6Ј,6Ј,7Ј,7Ј,8Ј,8Ј,9Ј,9Ј,10Ј,10Ј,10Ј-
Nonadecafluorodecyloxy)-3-phenyl-1,3-diaza-2-phosphabicyclo-
[3.3.0]octane (2d): Colourless, viscous oil solidifying on storage
(1.03 g, 81 %), m.p. 62–63 °C. 13C NMR (100.6 MHz, CDCl3,
3
2
25 °C): δC = 26.4 [d, J = 3.7 Hz, C(7)], 31.8 [s, C(6)], 48.3 [d, J =
37.2 Hz, C(8)], 54.9 [d, 2J = 6.6 Hz, C(4)], 58.6 (m, 2J = 5.3 Hz,
CH2O), 63.2 [d, 2J = 8.8 Hz, C(5)], 109.4 [br. m, C(2Ј)–C(10Ј)],
115.0 (d, 3J = 11.7 Hz, CHAr), 119.7 (s, CHAr), 129.2 (s, CHAr),
2
145.1 (d, J = 16.8 Hz, CAr) ppm. 19F NMR (282.4 MHz, CDCl3,
25 °C): δF = –79.1 to –79.35 (m, 3 F), –117.92 (s, 2 F), –120.25 (s,
8 F), –121.15 (s, 2 F), –121.4 (s, 2 F), –124.55 (s, 2 F) ppm. MS
(EI, 70 eV): m/z (%) = 704 (10) [M]+, 484 (8), 222 (100), 205 (82).
C21H16F19N2OP (704.3): calcd. C 35.81, H 2.29, N 3.98; found C
36.04, H 2.37, N 3.79.
[19]
[20]
earlier.[9a] [Pd(allyl)Cl]2,[18] Pd(CF3CO2)2
and [Rh(cod)2]BF4
were prepared as described earlier. Pd-catalysed allylic substitution:
amination of substrate 3 with dipropylamine and pyrrolidine, sulfo-
nylation with sodium p-toluenesulfinate and alkylation with di-
methyl malonate were performed according to the appropriate pro-
cedures.[9a,9b,21] Rh-catalysed hydrogenation of α-dehydrocarbox-
ylic acid esters 5a–c was performed as published.[22,23] Cu-catalysed
1,4-addition of diethylzinc to cyclohexenone 7 was performed ac-
(2R,5S,Ra)-2-[1-(2-Pivaloxynaphthalen-1-yl)naphthalen-2-yloxy]-3-
phenyl-1,3-diaza-2-phosphabicyclo[3.3.0]octane (2e): White powder
(0.72 g, 70 %), m.p. 63–64 °C. 13C NMR (100.6 MHz, CDCl3,
25 °C): δC = 25.7 [d, 3J = 4.4 Hz, C(7)], 26.1, 26.4 (s, CH3), 31.2 [s,
C(6)], 38.5 (s, 1 C), 46.9 [d, 2J = 35.7 Hz, C(8)], 53.3 [d, 2J = 7.3 Hz,
3928
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3923–3929

Diazaphospholidines as Monodentate Ligands for Asymmetric Catalysis
2
3
K. N. Gavrilov, O. G. Bondarev, A. I. Polosukhin, Russ. Chem.
Rev. 2004, 73, 671–699.
a) M. T. Reetz, J.-A. Ma, R. Goddard, Angew. Chem. Int. Ed.
2005, 44, 412–415; b) O. G. Bondarev, R. Goddard, Tetrahe-
dron Lett. 2006, 47, 9013–9015.
a) G. Buono, N. Toselli, D. Martin, in Phosphorus Ligands in
Asymmetric Catalysis (Ed.: A. Börner), Wiley-VCH,
Weinheim, 2008, vol. II, pp. 529–546; b) M. T. Reetz, H. Oka,
R. Goddard, Synthesis 2003, 1809–1814.
C(4)], 62.3 [d, J = 8.8 Hz, C(5)], 114.8 (d, JC,P = 13.1 Hz), 118.6,
119.5, 122.8, 122.9, 123.2, 123.9, 124.1, 125.5, 125.7, 125.8, 125.9,
127.4, 127.7, 128.5, 128.7, 128.9, 129.2, 130.2, 133.7, 133.9, 147.0
[6]
[7]
(d, 2J = 20.4 Hz), 150.0 (d, JC,P = 5.8 Hz), 155.2 (all CHAr and
Ar), 176.1 (s, C=O, major epimer); 26.2, 26.3 (s, CH3), 27.4 [s,
C(7)], 31.5 [s, C(6)], 38.3 (s, 1 C), 42.5 [d, J = 4.4 Hz, C(8)], 50.9
2
C
2
2
2
3
[d, J = 5.8 Hz, C(4)], 65.3 [d, J = 10.2 Hz, C(5)], 117.0 (d, JC,P
= 13.1 Hz), 118.4, 119.8, 122.8, 123.0, 123.5, 123.9, 124.1, 125.1,
125.6, 125.8, 126.2, 127.5, 127.7, 128.3, 128.7, 128.9, 129.0, 130.5,
[8]
a) J. M. Brunel, T. Constantieux, A. Labande, F. Lubatti, G.
Buono, Tetrahedron Lett. 1997, 38, 5971–5974; b) T. Con-
stantieux, J. M. Brunel, A. Labande, G. Buono, Synlett 1998,
49–50; c) G. Muchow, J. M. Brunel, M. Maffei, O. Pardigon,
G. Buono, Tetrahedron 1998, 54, 10435–10448; d) J. M. Brunel,
A. Tenaglia, G. Buono, Tetrahedron: Asymmetry 2000, 11,
3585–3586; e) G. Delapierre, J. M. Brunel, T. Constantieux, G.
Buono, Tetrahedron: Asymmetry 2001, 12, 1345–1352; f) K. N.
Gavrilov, V. N. Tsarev, A. A. Shiryaev, O. G. Bondarev, S. E.
Lyubimov, E. B. Benetsky, A. A. Korlyukov, M. Yu. Antipin,
V. A. Davankov, H.-J. Gais, Eur. J. Inorg. Chem. 2004, 629–
634; g) V. N. Tsarev, S. E. Lyubimov, O. G. Bondarev, A. A.
Korlyukov, M. Yu. Antipin, P. V. Petrovskii, V. A. Davankov,
A. A. Shiryaev, E. B. Benetsky, P. A. Vologzhanin, K. N. Gavri-
lov, Eur. J. Org. Chem. 2005, 2097–2105.
a) V. N. Tsarev, S. E. Lyubimov, A. A. Shiryaev, S. V. Zheglov,
O. G. Bondarev, V. A. Davankov, A. A. Kabro, S. K. Moiseev,
V. N. Kalinin, K. N. Gavrilov, Eur. J. Org. Chem. 2004, 2214–
2222; b) S. E. Lyubimov, V. A. Davankov, K. N. Gavrilov, Tet-
rahedron Lett. 2006, 47, 2721–2723.
a) T. Pfretzschner, L. Kleemann, B. Janza, K. Harms, T.
Schrader, Chem. Eur. J. 2004, 10, 6048–6057; b) S. E. Lyubi-
mov, V. A. Davankov, P. V. Petrovskii, N. M. Loim, Russ.
Chem. Bull. Int. Ed. 2007, 56, 2094–2096.
132.6, 134.2, 144.9 (d, 2J = 15.3 Hz), 150.6 (d, JC,P = 2.8 Hz),
2
155.0 (all CHAr and CAr), 175.9 (s, C=O, minor epimer) ppm. IR
(CHCl ): ν = 1744 (C=O) cm–1. MS (EI, 70 eV): m/z (%) = 575 (4)
˜
3
[M]+, 473 (25), 370 (40), 286 (81), 205 (100). C36H35N2O3P (574.2):
calcd. C 75.24, H 6.14, N 4.87; found C 75.40, H 6.21, N 4.79.
(2R,5S,Sa)-2-[1-(2-Pivaloxynaphthalen-1-yl)naphthalen-2-yloxy]-3-
phenyl-1,3-diaza-2-phosphabicyclo[3.3.0]octane (2f): White powder
(0.78 g, 75%), m.p. 59–60 °C. 13C NMR (100.6 MHz, CDCl3,
25 °C): δC = 26.0 [d, 3J = 3.8 Hz, C(7)], 26.2, 26.3 (s, CH3), 31.0 [s,
C(6)], 38.5 (s, 1 C), 47.1 [d, 2J = 32.7 Hz, C(8)], 53.1 [d, 2J = 6.8 Hz,
2
3
C(4)], 62.0 [d, J = 8.0 Hz, C(5)], 115.0 (d, JC,P = 12.4 Hz), 118.2,
120.5, 122.7, 122.9, 123.6, 123.9, 124.0, 124.9, 125.7, 125.8, 126.2,
127.4, 127.7, 128.3, 128.7, 128.9, 129.2, 130.9, 133.5, 133.9, 146.0
[9]
(d, 2J = 17.7 Hz), 151.0 (d, JC,P = 5.1 Hz), 154.6 (all CHAr and
2
CAr), 176.1 (s, C=O, major epimer); 26.4, 26.5 (s, CH3), 27.3 [s,
C(7)], 31.6 [s, C(6)], 38.3 (s, 1 C), 43.0 [d, J = 3.8 Hz, C(8)], 51.0
2
2
2
3
[d, J = 6.5 Hz, C(4)], 65.2 [d, J = 10.7 Hz, C(5)], 117.2 (d, JC,P
= 13.1 Hz), 118.0, 120.6, 122.7, 122.9, 123.3, 123.9, 124.7, 124.9,
125.1, 125.9, 126.0, 127.5, 127.7, 128.4, 128.6, 128.9, 129.5, 130.8,
[10]
133.7, 133.9, 146.8 (d, 2J = 16.7 Hz), 151.5 (d, JC,P = 3.1 Hz),
2
155.6 (all CHAr and CAr), 176.0 (s, C=O, minor epimer) ppm. IR
(CHCl ): ν = 1742 (C=O) cm–1. MS (EI, 70 eV): m/z (%) = 575 (5) [11]
˜
a) J. M. Brunel, T. Constantieux, G. Buono, J. Org. Chem.
1999, 64, 8940–8942; b) C. W. Edwards, M. R. Shipton, N. W.
Alcock, H. Clase, M. Wills, Tetrahedron 2003, 59, 6473–6480.
3
[M]+, 473 (28), 370 (34), 286 (92), 205 (100). C36H35N2O3P (574.2):
calcd. C 75.24, H 6.14, N 4.87; found C 75.50, H 6.04, N 5.01.
[12]
[13]
H. Hocke, Y. Uozumi, Tetrahedron 2003, 59, 619–630.
Supporting Information (see footnote on the first page of this arti-
cle): General experimental procedures for asymmetric catalytic re-
actions and H NMR spectroscopic data for ligands 2b–f.
a) H. Arzoumanian, G. Buono, M. Choukrad, J.-F. Petrignani,
Organometallics 1988, 7, 59–62; b) S. Reymond, J. M. Brunel,
G. Buono, Tetrahedron: Asymmetry 2000, 11, 1273–1278; c)
C. J. Ngono, T. Constantieux, G. Buono, Eur. J. Org. Chem.
2006, 1499–1507; d) M. Kimura, Y. Uozumi, J. Org. Chem.
2007, 72, 707–714.
1
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Received: January 20, 2009
Published Online: July 1, 2009
Eur. J. Org. Chem. 2009, 3923–3929
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3929