Aminoalkyl-phosphine (P,N) ligands with pentane-2,4-diyl backbone in asymmetric allylic substitution reactions

Article abstract of DOI:10.1007/s00706-017-2029-2

Abstract: The asymmetric allylic substitution reaction of rac-1,3-diaryl-2-propenyl acetates with several C- and N-nucleophiles catalyzed by the palladium-complexes of eleven structurally analogous aminoalkyl-phosphines (P,N) with pentane-2,4-diyl backbone is reported. The role of the N-substituents and the influence of the ligand/palladium molar ratio on the activity and enantioselectivity of the catalytic system are studied. The solvent and the temperature dependence of the catalytic reaction were also assessed yielding enantioselectivities up to 95% in alkylation and 90% in amination processes under optimized reaction conditions.

Full text of DOI:10.1007/s00706-017-2029-2

Monatsh Chem (2017) 148:2069–2077
DOI 10.1007/s00706-017-2029-2
ORIGINAL PAPER
Aminoalkyl-phosphine (P,N) ligands with pentane-2,4-diyl
backbone in asymmetric allylic substitution reactions
1
3
•
Zsofia Csaszar Patrik Imre1 Szabolcs Balogh2 Attila Benyei
•
•
•
´
´
´
´
Gergely Farkas1 Jozsef Bakos
1
•
´
Received: 28 March 2017 / Accepted: 27 June 2017 / Published online: 20 October 2017
Ó Springer-Verlag GmbH Austria 2017
Keywords Homogeneous catalysis Á Alkylations Á
Abstract The asymmetric allylic substitution reaction of
rac-1,3-diaryl-2-propenyl acetates with several C- and
N-nucleophiles catalyzed by the palladium-complexes of
eleven structurally analogous aminoalkyl-phosphines (P,N)
with pentane-2,4-diyl backbone is reported. The role of the
N-substituents and the influence of the ligand/palladium
molar ratio on the activity and enantioselectivity of the
catalytic system are studied. The solvent and the temper-
ature dependence of the catalytic reaction were also
assessed yielding enantioselectivities up to 95% in alky-
lation and 90% in amination processes under optimized
reaction conditions.
Chiral auxiliaries Á Phosphorus compounds Á
Transition metals compounds
Introduction
Asymmetric allylic substitution provides an efficient route
for the enantioselective formation of C,C- and C-heteroa-
tom bonds [1–6]. From another point of view, the
palladium-catalyzed asymmetric substitution of allylic
substrates is a typical benchmark reaction for the com-
parison of new ligands. Consequently, there is
a
remarkable interest in this area, and a large number of new
chiral ligands have been developed in the last few years
[7–12]. Enantiomerically enriched alkylation and amina-
tion products are formed from racemic substrates by
different reactivities of the two allyl termini in the inter-
mediate p-allyl systems. Desymmetrization of the allyl
system can be performed by electronic and steric effects
induced by the ligand(s) bound to the metal center [13]. For
C2-symmetric systems, asymmetry arises only from steric
interactions between the ligand and the substrate [14–17].
In the case of C1-symmetric ligands non-steric factors may
become dominant as, for example, in those containing two
distinct donor groups that differ in their coordination to the
metal center. Consequently, asymmetric induction may
chiefly occur as a result of the different trans influences of
the donor atoms [18–23]. In transition metal complexes
modified by heterobidentate aminoalkyl-phosphine (P,N)
ligands the difference in the trans influence between the P
and N donor atoms distinguishes the two binding sites
mainly, making the substituent trans to the phosphorus
more labile. Besides the extensively applied libraries of
chiral P,N ligands like phosphino-oxazolines (a) [24–26],
Graphical abstract
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-017-2029-2) contains supplementary
material, which is available to authorized users.
´
& Jozsef Bakos
bakos@almos.uni-pannon.hu
1
Department of Organic Chemistry, University of Pannonia,
´
Egyetem u. 10, Veszprem 8200, Hungary
2
3
NMR Laboratory, University of Pannonia, Egyetem u. 10,
´
Veszprem 8200, Hungary
Department of Pharmaceutical Chemistry, University of
´
Debrecen, Egyetem ter 1, Debrecen 4032, Hungary
123

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Z. Csaszar et al.
2070
Scheme 1
a
b
c
Fig. 1 Widely utilized P,N-type ligands for asymmetric catalytic
synthesis
Scheme 2
Quinap (b) and its congeners [27–29], or aminoalkyl-fer-
rocenes (c) [30, 31], alkane-diyl based aminoalkyl-
phosphines emerged as a powerful class of P,N-type
compounds with exceptional catalytic properties (Fig. 1)
[32].
A systematic stereochemical fine-tuning of the coordi-
nating subunits of this type of compounds can be
implemented due to their structural modularity and to the
versatility of the synthetic methodologies available for
their preparation [33–35]. Additionally, aminoalkyl-phos-
phines with stereogenic nitrogen and chiral backbone may
induce higher optical yields compared to achiral N-donors
of similar ligand systems [36]. The coordination chemistry
and catalytic properties of P,N ligands with stereogenic
nitrogen, which are capable of forming five-membered
chelates, have been previously investigated by several
workgroups [37–47]. Six-membered chelate analogues of
such systems having phosphinite [48] or aminophosphine
[49, 50] functionalities are also known. However, in the
case of six-membered aminoalkyl-phosphine chelate com-
plexes containing stereogenic nitrogens there are still many
important issues to be addressed concerning catalytic
behaviour.
Results and discussion
The aminoalkyl-phosphines 3a–3k were prepared in two
simple steps according to Scheme 1. The family of ligands
3a–3f and 3i–3k, which were synthesized previously
[34, 35], has been extended by the synthesis of two new
compounds (3g and 3h) with sterically unique 2-tolyl and
1-adamantyl N-groups. The low cost, ready availability,
stereoelectronic properties, and relative ease of function-
alisation of adamantane makes it an ideal candidate for
incorporation into catalyst design [52]. The first step of the
synthesis is the reaction of enantiomerically pure cyclic
sulfate 1 and the corresponding primary amine mixed in
THF leading to the corresponding aminoalkyl sulfates 2.
The addition of three equivalents of LiPPh2 in THF pro-
vided the aminoalkyl-phosphines 3g and 3h in moderate
yields, 56 and 51%, respectively. Both the ring-opening
reaction of the cyclic sulfate with the amine and the second
substitution reaction take place with complete inversion at
the stereogenic centers.
In previous studies we introduced a new methodology
for the synthesis of modular P,N ligands 3a–3f and 3i–3k
with pentane-2,4-diyl backbone associated with different
nitrogen substituents (Scheme 1) [34, 35]. Recently, we
have demonstrated, on a structural basis, the importance of
the steric demand of N-substituent (3a, 3b) in stereose-
lective coordination [51]. These two ligands were screened
in asymmetric allylic substitution. It was found that beside
the chiral backbone and the electronic differences in the
donor atoms of the chelate, the stereoselective coordination
of the nitrogen can also play an important role in efficient
asymmetric catalysis. This allowed the establishment of a
new stereocenter coordinated to the metal in one facile
step. Based on these observations the careful stereoelec-
tronic fine-tuning of the stereogenic nitrogen donor plays a
crucial role in efficient catalyst design. Herein, we disclose
a detailed account of the palladium-catalyzed asymmetric
allylic substitution reaction of 1,3-diaryl-2-propenyl acetates
with several C- and N-nucleophiles using a series of pentane-
2,4-diyl based P,N ligands.
First, the ligands were investigated in the palladium-
catalyzed asymmetric allylic alkylation of the benchmark
substrate 1,3-diphenyl-2-propenyl acetate with dimethyl
malonate (Scheme 2, substrate 4 and HNu = CH2
(COOCH3)2). The substrate reacted with the nucleophile
prepared in situ from dimethyl malonate (3 eq.) and N,O-
bis(trimethylsilyl)acetamide (BSA, 3 eq.) in the presence
of 1 mol% catalyst and 5 mol% KOAc in CH2Cl2. The
catalyst was synthesized in situ by the reaction of [Pd(g3-
C3H3)Cl]2 and the chiral ligand in the same solvent.
Initially, we intended to optimize the reaction conditions
by studying the role of the temperature and solvent on the
activity and selectivity of the catalytic process using ligand
3b. According to the results achieved in different solvents
and at different temperatures it is reasonable to assume that
123

Aminoalkyl-phosphine (P,N) ligands with pentane-2,4-diyl backbone in asymmetric allylic…
2071
Table 1 Optimization of reaction conditions: the effect of the solvent and temperature using ligand 3b
Entry
Temp/°C
Solvent
Conversiona/%
eea/%
1
-20
0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
48
82
61
88
92
91
94
87
92
92
2
3
25
40
25
25
25
25
[99
[99
[99
28
4
5b,c
6b
7b
8b
Toluene
CHCl3
[99
[99
Reaction conditions: catalyst prepared in situ from 0.5 mol % of [(g3-C3H5)PdCl]2 and 1.5 mol % of ligand 3b; substrate 4 1.25 mmol; dimethyl
malonate 3.75 mmol; solvent 10 cm3; BSA 3.75 mmol; KOAc 7 mg; temperature RT; reaction time 1 h. Prevailing configuration of the product:
(R)
a
Conversion and enantiomeric excess were determined by chiral HPLC
b
The L/Pd molar ratio was 1
c
Ref. [51]
non-polar reaction media and ambient temperature have a
positive effect on both the activity and the ee (Table 1).
After having promising results in hand for the model
systems, we applied the optimised protocol for the alky-
lation reaction using our ligand library (3a–3k). The effect
of the N-substituent was examined at 25 °C using CH2Cl2
as solvent and a metal-to-ligand molar ratio of 1 (Table 2).
The enantioselectivity was strongly dependent on the
nitrogen substituent. Ligands having alkyl or aralkyl sub-
stituted secondary amino functionality provided high
activity and a trend in the variation of enantioselectivity
can be observed. Increasing the steric demand of the
N-substituent generally resulted in an increase in the pro-
duct’s optical purity (Table 2, entries 1–5 and 8), up to
94% ee with ligand 3b. This might originate from the
ligands capability for the stereoselective coordination [51].
Moreover, according to this trend the ee can roughly be
considered as a function of branching at the first carbon
center of the N-substituent [51].
malonate nucleophile have a minor effect on the enan-
tioselectivity of the reaction.
Variation of the ligand/palladium molar ratio had a
profound effect on the enantioselectivity. The relationship
between L/Pd and ee was thoroughly screened by using
ligands 3a–3c having N-substituents of different steric
properties. When the ligand-to-metal ratio was increased
above 1, the enantioselectivity falls dramatically with
ligand 3b and especially with ligand 3c (Fig. 2). In this
latter case, the ee changes from 95 to 58% when varying
the value of L/Pd from 0.25 to 2. The same trend was
observed using ligand 3h; the ee improved from 90 to 94%
when the ligand-to-metal ratio was reduced from 1 to 0.5.
In addition, we performed catalytic experiments at L/Pd
molar ratio of 10 with ligands 3a–3c, 3g, and 3k to shed
light on the limits of selectivity change. In each case the
reactions completed within 1 h yielding selectivities up to
36% (Table 2, entries 1–3, 7, and 11). The explanation for
the pronounced effect can be the fact that at ligand-to-
metal ratios less than or equal to 1:1 chelated allyl inter-
mediates predominate. The attack of the nucleophile
preferentially occurs trans to the phosphorus due to its
better p-acceptor ability compared to that of N. At higher
L/Pd ratios non-chelate species (e.g. bisphosphorous
complexes) can form in appreciable amount that provide
less enantiodiscrimination in contrast to the chelate com-
plex [39, 53]. These species, however, might provide
higher catalytic activities as in the case of ligands 3g and
3k, where increasing the L/Pd ratio from 1 to 10 results in
completing the reaction in 1 h (Table 2, entries 7 and 11).
Furthermore, the extent of change in the ee as a function of
L/Pd ratio shows a high dependence on the nitrogen sub-
stituent. The higher sensitivity of the catalyst containing 3c
on the variation of L/Pd suggests that the chelate formed in
Interestingly, palladium catalysts modified by ligands 3f
and 3g with aryl substituents yielded only poor activities
and selectivities (Table 2, entries 6 and 7). Ligands pos-
sessing endocyclic and non-stereogenic nitrogen atoms (3i–
3k) afforded ees up to 86% (Table 2, entries 9–11).
However, a comparison of selectivities achieved with
ligands 3b–3d, 3h, and 3i (Table 2, entries 2–4, 8, and 9)
emphasizes that high enantioselectivities can also be
obtained by using ligands containing non-stereogenic
nitrogen donor.
Ligand 3c was also tested in the allylation of substrate 4
with dibenzyl and diethyl malonate and in the reaction of
substrates 5 and 6 (Scheme 2) with dimethyl malonate
(Table 2, entries 12–15). The results suggest that the p-
substituents of the substrate and the structure of the
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Z. Csaszar et al.
2072
Table 2 Allylic alkylation reactions: screening of ligands, substrates and nucleophiles
Entry
Ligand
Substrate
HNu
Conversiona,b/%
eea,b/%
1c
2c
3
R1 = H, R2 = Me (3a)
R1 = H, R2 = iPr (3b)
R1 = H, R2 = tBu (3c)
R1 = H, R2 = Cy (3d)
R1 = H, R2 = Bn (3e)
R1 = H, R2 = Ph (3f)
R1 = H, R2 = 2-Me-C6H4 (3g)
R1 = H, R2 = 1-Ad (3h)
R1, R2 = –(CH2)4– (3i)
R1, R2 = –(CH2)5– (3j)
R1, R2 = –(CH2)2O(CH2)2– (3k)
R1 = H, R2 = tBu (3c)
R1 = H, R2 = tBu (3c)
R1 = H, R2 = tBu (3c)
R1 = H, R2 = tBu (3c)
4
4
4
4
4
4
4
4
4
4
4
4
4
5
6
CH2(COOCH3)2
CH2(COOCH3)2
CH2(COOCH3)2
CH2(COOCH3)2
CH2(COOCH3)2
CH2(COOCH3)2
CH2(COOCH3)2
CH2(COOCH3)2
CH2(COOCH3)2
CH2(COOCH3)2
CH2(COOCH3)2
CH2(COOCH2CH3)2
CH2(COOCH2Ph)2
CH2(COOCH3)2
CH2(COOCH3)2
[99 ([99)
[99 ([99)
[99 ([99)
[99
24 (24)
94 (36)
89 (28)
88
4
5
[99
30
22
6
13
7
21 ([99)
[99
8 (10)
90
8
9
[99
23
86
10
11
12
13
14
15
76
31 ([99)
[99
94
62 (18)
88
86
80
89
45
92
Reaction conditions: catalyst prepared in situ from 0.5 mol % of [(g3-C3H5)PdCl]2 and 1 mol % of chiral ligand; substrate 1.25 mmol; dimethyl
malonate 3.75 mmol; solvent 10 cm3 of CH2Cl2; BSA 3.75 mmol; KOAc 7 mg; temperature RT; reaction time 1 h. Prevailing configuration of
the product: (R)
a
Conversion and enantiomeric excess were determined by chiral HPLC
b
Values in brackets were determined at an L/Pd molar ratio of 10
c
Ref. [53]
Scheme 3
the molar ratio when hemilabile P,N-ligands are used for
the modification of the catalyst.
Fig. 2 The effect of ligand/palladium molar ratio (reaction condi-
tions: catalyst prepared in situ from 0.5 mol% of [(g3-C3H5)PdCl]2
and calculated amount of chiral ligand according to the L/Pd ratio;
In the next set of experiments, we evaluated the efficiency
of the catalytic system in asymmetric allylic amination
substrate 1.25 mmol; dimethyl malonate 3.75 mmol; solvent 10 cm3;
BSA 3.75 mmol; KOAc 7 mg; temperature RT; reaction time 1 h.
reactions (Scheme 3). Using 1 mol% Pd2(dba)3Á(CHCl3)
and 2 mol% of chiral ligand 3b as catalyst, the reaction was
performed in CH2Cl2 as solvent (Table 3). The catalytic
Prevailing configuration of the product: (R). In each case, the reaction
proceeded with full conversion. Conversion and enantiomeric excess
were determined by chiral HPLC)
process was particularly sensitive to the nature of the
nucleophile. The use of heterocyclic amines as nucleophiles
resulted in high activities and ees up to 86% (Table 3, entries
this case is less stable. This can be interpreted by the
3, 6 and 9).
stronger destabilizing effect of the sterically more
One of the key principles of green chemistry is the
demanding tBu substituent compared to the iPr group.
elimination of solvents in chemical processes. When the
According to this hypothesis, less strained chelates are less
amount of solvent was decreased the reaction proceeded
inclined to open that might result in the enhancement of
significantly faster (entries 1–3, 4–6, and 7–9). Under
enantioselectivity. These results reflect the importance of
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Aminoalkyl-phosphine (P,N) ligands with pentane-2,4-diyl backbone in asymmetric allylic…
Table 3 Asymmetric allylic amination: scope of N-nucleophiles using ligand 3b
2073
Entry HNu
Reacꢀon ꢀme/h Solvent
Conversiona/% eea/%
1b
2
0.5 min
Neat
>99
24
72
80
40
84
86
34
74
82
74
90
64
0.5
2 cm3 CH2Cl2 >99
4 cm3 CH2Cl2 >99
3
1
4b
5
0.5 min
0.5
Neat
>99
2 cm3 CH2Cl2 >99
4 cm3 CH2Cl2 >99
6
1
7b
8
0.5 min
0.5
Neat
>99
2 cm3 CH2Cl2 >99
4 cm3 CH2Cl2 >99
2 cm3 CH2Cl2 53
2 cm3 CH2Cl2 >99
2 cm3 CH2Cl2 >99
9
1
10
11c
12
48
18
24
13c
14c
24
24
2 cm3 CH2Cl2 >99
2 cm3 CH2Cl2 >99
78
70
15c
24
2 cm3 CH2Cl2 >99
61
Reaction conditions: catalyst prepared in situ from 1 mol% of Pd2(dba)3.(CHCl3) and 2 mol% of ligand 3b; substrate 0.625 mmol; amine
1.88 mmol; solvent 2 cm3 of CH2Cl2; temperature RT
a
Conversion and enantiomeric excess were determined by chiral HPLC
[Pd(g3-Ph2-C3H3)(3b)]BF4 complex is used as catalyst and no solvent was applied
b
c
1.25 mmol Cs2CO3 was added as base
solvent-free conditions using preformed complex [Pd(g3-
Ph2-C3H3)(3b)]BF4 [51] as catalyst (entries 1, 4, and 7)
moderate ees (up to 40%) and complete conversions in
0.5 min was obtained resulting in a remarkably high
turnover frequency of [12,000 1/h. The exact reason for
such dramatic positive effect of the nucleophile
concentration on catalytic activity remains unclear. How-
ever, this finding provides highly useful information for the
development of catalytic systems.
Contrarily to the heterocyclic nucleophiles, reactions
with non-cyclic amines took place with lower activity and
selectivity (Table 3, entries 10 and 12). Recently, Bunt and
123

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Z. Csaszar et al.
2074
Table 4 Asymmetric allylic amination with different P,N-ligands
Entry
Ligand
Reaction time/h
Conversiona/%
eea/%
1
2
3
4
5
R1 = H, R2 = Me (3a)
R1 = H, R2 = iPr (3b)
R1 = H, R2 = tBu (3c)
R1 = H, R2 = Cy (3d)
R1 = H, R2 = 1-Ad (3h)
0.5
0.5
1
[99
[99
[99
97
20
84
54
88
62
1
0.5
[99
Reaction conditions: catalyst prepared in situ from 1 mol% of Pd2(dba)3.(CHCl3) and 2 mol% of ligand 3b; substrate 0.625 mmol; piperidine
1.88 mmol; solvent 2 cm3 of CH2Cl2; temperature RT
a
Conversion and enantiomeric excess were determined by chiral HPLC
coworkers reported on the reversible nucleophilic addition
in allylic amination reactions that might lower the enan-
tioselectivity of the catalytic process [54]. However, the
addition of a strong base (e.g. DBU or Cs2CO3) suppressed
the proton driven reversibility and resulted in higher ee’s.
Motivated by these findings, we decided to add Cs2CO3 to
the catalytic reactions. This method clearly improved the
performance of the catalytic system (entries 10–13), 90 and
78% ee could be obtained with diethylamine and benzy-
lamine nucleophiles, respectively. For aniline and
cyclohexylamine (entries 14 and 15) the reaction com-
pleted after 24 h with up to 70% ee. It is a noteworthy
result since aromatic amines have not been used commonly
in allylic amination, presumably because they are less
nucleophilic than the more commonly used benzylamine or
stabilized anionic nitrogen nucleophiles [55, 56]. However,
recent studies proved the successful application of P,N
ligands in the allylic aminations using aromatic amines
[57]. The results achieved unambiguously prove that P,N-
ligands with aliphatic backbone are capable of forming
active and selective catalysts for allylic amination
reactions.
Conclusion
In summary, we have determined the beneficial features
of pentane-2,4-diyl based aminoalkyl-phosphine (P,N)
ligands in the palladium-catalyzed asymmetric allylic
alkylation and amination of rac-1,3-diphenyl-2-prope-
nyl acetate with several C- and N-nucleophiles giving
high activities and enantioselectivities (up to 95% ee in
alkylation and 90% ee in amination processes). The
enantioselectivity of the asymmetric allylic alkylation
with a series of analogous P,N ligands is strongly
sensitive to the steric properties of the N-substituent. A
general increase in enantioselectivity with the steric
bulk of the substituents could be observed. The ligand-
to-metal molar ratio has a profound effect on the
enantioselectivity that was attributed to the possibility
of the formation of less selective non-chelated species.
It was observed that the catalyst with bulkier N-sub-
stituent (e.g. tBu vs. iPr) gives a more sensitive respond
to the variation of L/Pd ratio. In amination reactions
heterocyclic nucleophiles reacted smoothly with very
high activities and good selectivities (up to 88%).
Furthermore, under solvent-free conditions extremely
high activities (TOF [ 12,000/h) could be obtained
with up to 40% enantioselectivity. The activity and
selectivity of the reaction with non-heterocyclic amines
could readily be enhanced by the addition of Cs2CO3,
with diethylamine 90% ee was obtained. However,
ligands with sterically more demanding N-sidechain
provided lower selectivities. These results allowed us to
conclude that chelates carrying sterically more
demanding nitrogen substituents are more inclined to
open. Consequently, the strategy, i.e. the variation of
(1) the steric bulk of the substituent connected to the
stereogenic nitrogen donor and of (2) the ligand-to-
metal molar ratio in the Pd-complexes of pentane-2,4-
diyl based ligands proved to be efficient means to
enhance the catalyst activity/enantioselectivity.
Next, we studied the asymmetric allylic amination of
1,3-diphenyl-2-propenyl acetate with piperidine as nucle-
ophile in the presence of palladium-catalysts modified by
different P,N-compounds (Table 4). Ligands with bulky,
tertiary N-groups (3c and 3h, entries 3 and 5) gave only
moderate selectivity compared to the catalysts having
secondary nitrogen side chains (3b and 3d, entries 2 and 4,
Table 4). Similar to the effect of L/Pd ratio on the enan-
tioselectivity, this phenomenon also emphasizes the
significance of the substituent steric bulk in determining
catalytic performance. However, it is important to note that
the catalysts provided good enantioselectivities (up to
88%) and very high activities. Full conversions were
achieved less than in 1 h under optimized conditions
emphasizing the catalytic potential of P,N-type compounds
with aliphatic backbone.
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Aminoalkyl-phosphine (P,N) ligands with pentane-2,4-diyl backbone in asymmetric allylic…
2075
of ether. After drying with MgSO4 the solvent was evap-
orated to give 3g as a transparent oil. The crude product
was then chromatographed on silica using n-hexane/EtOAc
15/1 as eluent to yield the product as a white powder.
Yield: 3.2 g, 56%; m.p.: 87 °C; [a]2D2 = -54° (c = 0.985,
Experimental
All manipulations were carried out under argon using
Schlenk techniques. Solvents were purified, dried and
deoxygenated by standard methods. Cyclic sulfate 1 was
prepared according to the literature method [58]. All other
starting materials were purchased from Sigma-Aldrich.
1
CHCl3); H NMR (400 MHz, CDCl3): d = 7.57–6.57 (m,
14H, aromatic), 3.68 (m, 1H, NCH), 2.53 (m, 1H, PCH),
31P{1H}, 13C{1H}, and H NMR spectra were recorded on
1
2.11 (s, 3H, CH3), 1.74 (m, 1H, CH2, diast.), 1.53 (m, 1H,
3
CH2, diast.), 1.21 (d, J(H,H) = 6.2 Hz, 3H, CH3), 1.16
a Bruker Avance 400 spectrometer (NMR Laboratory,
University of Pannonia) operating at 161.98, 100.61, and
400.13 MHz, respectively. EI mass spectra were recorded
on a Shimadzu GCMS QP2010 SE spectrometer.
(dd, 3J(P,H) = 14.8 Hz, 3J(H,H) = 6.9 Hz, 3H, CH3)
ppm; 13C{1H} NMR (100 MHz, CDCl3): d = 145.71
(broad s, 1C), 137.66 (d, J(P,C) = 14.0 Hz, 1C), 137.57 (d,
J(P,C) = 15.0 Hz, 1C), 134.43 (d, J(P,C) = 19.5 Hz, 2C),
134.20 (d, J(P,C) = 19.1 Hz, 2C), 130.94 (s, 1C), 129.49
(s, 1C), 129.44 (s, 1C), 129.08 (d, J(P,C) = 6.9 Hz, 2C),
128.98 (d, J(P,C) = 7.2 Hz, 2C), 127.74 (s, 1C), 122.42
(broad s, 1C), 117.14 (broad s, 1C), 110.83 (broad s, 1C),
47.18 (broad s, 1C), 41.65 (d, J(P,C) = 17.3 Hz, 1C),
28.12 (d, J(P,C) = 10.3 Hz, 1C), 21.11 (broad s, 1C),
18.31 (s, 1C), 17.21 (d, J(P,C) = 15.4 Hz) ppm; 31P {1H}
NMR (162 MHz, CDCl3): d = 0.47 (s) ppm; EI-MS:
m/z = 361 (M?, calculated 361.2).
(2S,4S)-4-(Diphenylphosphino)-N-(2-methylphenyl)-2-pen-
tanamine (3g, C24H28NP)
At first (2S,4R)-2-(2-methylphenyl)amino-4-sulfatopentane
was synthesized that was used without further purification
in the next step. o-Toluidine (2.46 g, 23.02 mmol) was
added to a solution of 3 g 1 (18.06 mmol) in 6 cm3 THF
and the mixture was stirred for 48 h at room temperature.
After that 60 cm3 ether was added to the mixture. The
suspension formed was stirred for 30 min and then filtered.
The solid was washed two times with ether, and dried by
azeotropic distillation with toluene. The residual solvent
was evaporated by vacuum to give (2S,4R)-2-(2-methyl-
phenyl)amino-4-sulfatopentane as a white powder. Yield:
4.3 g, 87%; m.p.: 220 °C, [a]2D2 = ? 24° (c = 1.105,
DMSO); 1H NMR (400 MHz, DMSO-d6): d = 8.70 (s,
2H, NH2?), 7.59–7.38 (m, 4H, aromatic), 4.27 (m, 1H,
NCH), 2.98 (m, 1H, PCH), 1.85 (m, 1H, CH2, diast.), 1.63
(m, 1H, CH2, diast.), 1.51 (d, 3H, CH3), 1.18 (d,
3J(H,H) = 5.7 Hz, 3H, CH3, overlapped), 1.17 (d,
3J(H,H) = 6.1 Hz, 3H, CH3, overlapped) ppm; 13C{1H}
NMR (100 MHz, DMSO-d6): d = 133.92 (broad s, 1C),
132.87 (s, 1C), 131.77 (broad s, 1C), 128.82 (broad s, 1C),
127.65 (s, 1C), 124.25 (broad s, 1C), 70.48 (s), 55.14 (s),
41.06 (s), 22.50 (s), 17.52 (s), 17.01 (s) ppm.
(2S,4S)-4-(Diphenylphosphino)-N-(1-adamantyl)-2-pen-
tanamine (3h, C27H36NP)
At first (2S,4R)-2-(1-adamantyl)amino-4-sulfatopentane
was synthesized that was used without further purification
in the next step. 1-Adamantylamine (3.5 g, 23.02 mmol)
was added to a solution of 3 g 1 (18.06 mmol) in 6 cm3
THF and the mixture was stirred for 24 h at room
temperature. After that 20 cm3 ether was added to the
mixture. The suspension formed was stirred for 30 min and
then filtered. The solid was washed two times with ether,
dried by azeotropic distillation with toluene. The residual
solvent was evaporated by vacuum to give (2S,4R)-2-(1-
adamantyl)amino-4-sulfatopentane as a white powder.
Yield: 3.2 g, 56%; m.p.: 230–234 °C; [a]2D2 = ? 4°
(c = 1.00, DMSO); 1H NMR (400 MHz, DMSO-d6):
d = 6.46 (broad s, 2H, NH2?), 4.22 (m, 1H, NCH), 3.55
(m, 1H, PCH), 2.08 (m, 3H, adamantyl CH), 1.84–1.56
(broad m, 12H, CH2), 1.22 (d, 3J(H,H) = 6.4 Hz, 3H,
CH3), 1.19 (d, 3J(H,H) = 6.2 Hz, 3H, CH3) ppm; 13C{1H}
NMR (100 MHz, DMSO-d6): d = 70.76 (s, 1C), 56.99 (s,
1C), 45.64 (s, 1C), 44.65 (s, 1C), 39.82 (s, 3C) 35.91 (s,
3C), 29.20 (s, 3C), 22.41 (s, 1C), 21.25 (s, 1C) ppm.
LiPPh2Á1,4-dioxane adduct (26.4 g, 94.2 mmol) was
dissolved in 80 cm3 THF under argon and the red solution
was cooled to -10 °C. 2g (4.3 g, 15.7 mmol) was added
dropwise to this solution in small portions. The reaction
mixture was stirred at room temperature for 24 h. The color
of the reaction mixture remained red. After evaporation of
the solvent, 80 cm3 deoxygenated water and 60 cm3 ether
were added to the residue and the mixture was stirred until
the two phases became clear solutions. The pH of the
mixture was then adjusted to 1 with 10% deoxygenated
aqueous HCl solution. The two phases were then separated
and the aqueous phase was washed three times with 30 cm3
portions of ether. The pH was then adjusted to about 9–10
with dropwise addition of a solution of Na2CO3. The
product was then extracted four times with 30 cm3 portions
LiPPh2Á1,4-dioxane adduct (6 g, 21.4 mmol) was dis-
solved in 30 cm3 THF under argon and the red solution was
cooled to -10 °C. 2 h (2.3 g, 7.1 mmol) was added dropwise
to the red solution in small portions. The reaction mixture was
stirred at room temperature for 24 h. The color of the reaction
mixture remained red. After evaporation of the solvent,
80 cm3 deoxygenated water and 60 cm3 ether were added to
123

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Z. Csaszar et al.
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the residue and the mixture was stirred until the two phases
became clear solutions. The pH of the mixture was then
adjusted to 1 with 10% deoxygenated aqueous HCl solution.
The two phases were then separated and the aqueous phase
was washed three times with 30 cm3 portions of ether. The pH
was then adjusted to about 9–10 with dropwise addition of a
solution of Na2CO3. The product was then extracted four
times with 30 cm3 portions of ether. After drying with MgSO4
the solvent was evaporated to give 3h as a transparent oil. The
crude product was then chromatographed on silica using
CHCl3/MeOH 6/1 as eluent to yield the product as a white
powder. Yield: 1.5 g, 51%; m.p.: 72–74 °C; [a]2D2 = -104°
(c = 1.265, CHCl3); 1H NMR (400 MHz, CDCl3):
d = 7.51–7.27 (m, 10H, aromatic), 3.06 (m, 1H, NCH), 2.37
(m, 1H, PCH), 2.01 (m, 3H, adamantyl CH), 1.59 (m, 12H,
adamantyl CH2), 1.39 (m, 2H, CH2), 1.05 (dd,
´
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3J(P,H) = 14.8 Hz, J(H,H) = 6.8 Hz, 3H, CH3), 1.03 (d,
3J(H,H) = 6.8 Hz, 3H, CH3) ppm; 13C{1H} NMR
(100 MHz, CDCl3): d = 137.25 (d, J(P,C) = 15.0 Hz, 1C),
137.15 (d, J(P,C) = 13.9 Hz, 1C), 133.94 (d,
J(P,C) = 19.1 Hz, 2C), 133.75 (d, J(P,C) = 18.5 Hz, 2C),
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Acknowledgements We thank Mr. Bela Edes for skilful assistance in
´
analytical measurements and synthetic experiments and Dr. Imre Toth
´
for his useful comments on the manuscript. The research was sup-
ported by the ‘National Excellence Program’ in the framework of the
´
Project TAMOP-4.2.4.A/2-11/1-2012-0001 and by the National
Research, Development and Innovation Office—NKFIH, K 115539.
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