Synthesis of Enantioenriched Aryl-tert-Butylphenylphosphine Oxides via Cross-Coupling Reactions of tert-Butylphenylphosphine Oxide with Aryl Halides

Article abstract of DOI:10.1002/ejoc.201800698

A series of enantiomerically enriched tertiary phosphine oxides have been prepared via the Pd-catalyzed cross-coupling reactions of enantiomerically pure tert-butylphenylphosphine oxide, with a variety of aryl iodides and bromides. This new protocol under optimized reaction conditions [toluene, 110 ⁰C, Pd(PPh₃)₄, K₂CO₃ (or Et₃N)] afforded highly functionalized P-chiral phosphine oxides with a yield of 78% to 95% and with enantiomeric excesses above 98%. The stereoretentive outcome of the cross-coupling reactions was proved by X-ray crystallography of selected phosphine oxides: (S)-(2-aminophenyl)(tert-butyl)(phenyl)phosphine oxide (3a) and (S)-anthracen-9-yl(tert-butyl)(phenyl)phosphine oxide (3i). When attempting to convert the enantiomerically pure phosphine oxide 3a to the corresponding borane by the treatment with the borane dimethyl sulfide complex partial stereoerosion at a stereogenic phosphorus atom was observed. Racemic tert-butyl (2-(dimethylamino)phenyl)(phenyl)phosphine (7a) was isolated in a quantitative yield upon deprotection of the corresponding borane (8a) and converted to a palladium crystalline complex (9), the structure of which has been proved by X-ray crystallography.

Full text of DOI:10.1002/ejoc.201800698

A Journal of
Accepted Article
Title: SYNTHESIS OF ENANTIOENRICHED ARYL-tert-
BUTYLPHENYLPHOSPHINE OXIDES via the CROSS-
COUPLING REACTIONS OF tert-BUTYLPHENYLPHOSPHINE
OXIDE WITH ARYL HALIDES
Authors: Jacek Chrzanowski, Dorota Krasowska, Malgorzata Urbaniak,
Leslaw Sieron, Patrycja Pokora- Sobczak, Oleg M. Demchuk,
and Jozef Drabowicz
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800698
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800698
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10.1002/ejoc.201800698
European Journal of Organic Chemistry
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SYNTHESIS OF ENANTIOENRICHED ARYL-tert-BUTYLPHENYLPHOSPHINE
OXIDES via the CROSS-COUPLING REACTIONS OF tert-
BUTYLPHENYLPHOSPHINE OXIDE WITH ARYL HALIDES
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Jacek Chrzanowskia*, Dorota Krasowskaa, Małgorzata Urbaniaka, Lesław Sierońc, Patrycja
Pokora-Sobczaka, Oleg M. Demchukd, Józef Drabowicza,b*
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a Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz,
Poland; * , Fax: (+48)-42-680-32-61; phone: (+48)-42-680-32-17; e-mail: jacekchrzanowski1@gmail.com, ORCID
ID: https://orcid.org/0000-0003-1254-0242
b
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Department of Chemistry, Environmental Protection and Biotechnology, Jan Dlugosz University in
Czestochowa, Armii Krajowej Ave. 13/15, 42-200 Czestochowa, Poland; phone: (+48)-42-680-32-34; e-mail:
draj@cbmm.lodz.pl
c
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Institute of General and Ecological Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz,
Poland
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d Department of Organic Chemistry, Maria Curie-Sklodowska University, 33 Gliniana St., Lublin 20-614
This paper is dedicated to Professor Janusz Zakrzewski on the occasion of his 70th birthday.
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Introduction
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P-chiral organophosphorus compounds are of great importance in biological
chemistry, agrochemistry, organic synthesis, and particularly in the field of organometallic
asymmetric catalysis [1]. Considerable attention is continuously devoted to non racemic
tertiary phosphine oxides (TPO). This result from the fact that their reduction is one of the
most useful methods for the preparation of optically active tertiary phosphines. They can
serve as versatile organocatalysts and ligands in transition metal-mediated asymmetric
synthesis [2]. The preparation of P-stereogenic phosphine oxides still constitutes a synthetic
challenge in spite of the recent number of achievements in this field.
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The classical and oldest method for the preparation of P-chiral tertiary phosphine
oxides, described by Mislow (Figure 1) [3a], is based on the nucleophilic displacement of the
menthoxy group in diastereomerically pure menthyl alkylaryl(diaryl, dialkyl)phosphinates
(usually isolated by a time-consuming recrystallization), by an organometallic nucleophile
(Grignard reagent or an organolithium compound). In later years, this approach was
extended by the use of diastereomerically pure phosphinates obtained from other chiral
alcohols: D-glucofuranose [3b], (-)-cholesterol [3c], (-)-borneol [3d] as well as cinchonine or
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cinchonidine [3e]. This stereospecific reaction, which proceeds with the inversion of the
configuration at a stereogenic phosphorus center, suffers from limitations related to the
reactivity of functional groups present in the starting phosphinates towards organometallic
reagents or from a series of restrictions in the preparation of Grignard or organolithium
reagents.
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Figure 1. Selected examples of the previous attempts at TPOs synthesis
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Highly stereoselective reductive removal of the menthoxy group in
diastereoisomerically pure O-menthyl phosphinates after reaction with lithium 4,4-di-tert-
butylbiphenyl amide (LDBB) and subsequent reaction of the generated phosphinyl anion
with an alkyl halide is also an easy way to synthesize enantiopure phosphine oxides. This
transformation proceeds with retention of the configuration at a stereogenic phosphorus
atom [4]. An alternative and more convenient approach to enantiomerically pure phosphine
oxides is a Michaelis-Becker type reaction which is based on the alkylation of the metallated
secondary phosphine oxides (SPO) with primary alkyl halides [5].
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Considerable progress has recently been made on the synthesis of P-stereogenic
organophosphorus compounds due to development of new and efficient methods for the
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stereoselective formation of C-P bonds in cross-coupling reactions catalysed by transition
metals [2d].
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It should be noted that the formation of a phosphorus-carbon bond in the reaction
of dialkyl phosphites with sp2 carbon electrophiles catalysed by palladium has been
described by Hirao et al. as early as 1981 [6]. Since then, it has been a simple way to make P-
2
Csp bonds, starting from secondary phosphites (H-phosphonates), H-phosphinates or SPO.
This approach was also used to synthesize chiral organophosphorus derivatives. Therefore,
the palladium catalysed coupling of enantioenriched alkyl alkylphosphonites with
bromoarenes led to alkyl alkylarylphosphinates with full retention of configuration, as
proven by Xu in 1988 [7]. Similarly, copper salts, as the less expensive transition metal
catalysts were found to be a good substitute for palladium [8] for the coupling of haloarenes
with H-phosphinates [9], and with secondary phosphine oxides [10]. In the latter case the
catalytic system based on copper(I) iodide and (S)-α-phenylethylamine as a ligand exhibits a
high activity that allows for the convenient synthesis of racemic tertiary aryl-phosphine
oxides by coupling of the readily available SPO with aryl bromides or iodides. Furthermore,
aminoarylphosphono-derivatives were prepared via coupling of sodium dialkyl phosphites
with iodoaminoarenes in the presence of CuI in HMPA [11]. In this context, it is worth noting
that attempts to couple unsymmetrical alkyl phosphites with iodo- or- bromoanilines in the
presence of palladium (0) and triethylamine were unsuccessful [12].
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A limited number of reports concern the stereochemical aspects of the catalytic
coupling of secondary phosphine oxides, leading to the formation of P-chiral tertiary oxides.
Recently, Gaunt et al. described the enantioselective synthesis of TPOs by the copper(I)-
catalyzed arylation of secondary phosphine oxides with diaryl-iodonium salts [13a]. On the
other hand, a dynamic kinetic resolution (DKR) strategy was applied to isolate a series of
enantiomerically enriched triaryl phosphine oxides [13b]. The iridium(III)-catalyzed, highly
enantioselective C-H amidation reaction of prochiral TPOs was found to afford a series of
chiral, aminoarylated TPOs [13c]. A series of P-stereogenic alkynylphosphine oxides were
isolated in the rhodium-catalyzed [2+2+2] cycloaddition reaction of dialkynyl phosphine
oxides with 1,6-diynes [13d].
Considering previously studied procedures, palladium-catalysed coupling reactions
of H-phosphonates diesters with benzyl halides [14] and isopropyl methyl–H-phosphinate
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with bromobenzene [7] should be noted. It was found that for both reactions the
stereochemical integrity of the stereogenic phosphorus is preserved. Very recently, Herzon
et al. have shown that the room temperature coupling of (S)-methylphenylphosphine oxide
with 2-iodothiophene, in the presence of a bidentate phosphine ligand (Xantphos) in
combination with tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3] as a catalyst,
proceeds with complete integrity at phosphorus. It is important to remember that when
sterically hindered tert-butylphenylphosphine oxide 1 was used, no coupling product was
observed [15]. Conversely, nickel-catalysed arylation of enantiomerically pure secondary
phosphine oxides led to the final product in the form of racemates or partially racemized
samples [16].
With respect to our continuous interest in chiral non racemic heteroorganic
compounds, we have aimed to develop an efficient synthetic procedure for the synthesis of
a series of enantioenriched aryl-tert-butyl-phenyl phosphine oxides variously functionalised
in the aryl groups. Knowing that enantiomerically pure tert-butylphenylphosphine oxide is
relatively easily available [17], we decided to check whether its cross-coupling reaction with
functionalized aryl halides catalysed by transition metals would be a useful route for their
preparation. Herein we disclose the results of our preliminary studies aimed at developing
an efficient procedure for the preparation of aryl-tert-butylphenylphosphine oxides by the
stereospecific arylation of enantiomerically pure, secondary tert-butylphenylphosphine
oxide 1.
Results and discussion
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Firstly, the reaction of 2-iodoaniline 2a with enantiomerically pure tert-
butylphenylphosphine oxide 1 was investigated to identify suitable transition metal catalysts
and reaction conditions. This enantiomerically pure phosphine oxide 1 was obtained via the
optical resolution of its racemic mixture with mandelic acid as a complexing agent within a
single complexation process [17]. Its coupling with 2-iodoaniline 2a in the presence of 5
mol% of CuI and 30 mol% of DMEDA and K2CO3 proceeded smoothly to afford product 3a in
81% yield (entry 1, Table 1). However, the reaction was found to proceed with stereoerosion
at the phosphorus atom. Next, we attempted to use, instead of DMEDA, (S)-1-
phenylethylamine (30 mol%) as a mono-chelating ligand. This protocol provided the
expected coupling product in 62% yield (entry 2) but again with full racemization.
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Considering the experiments mentioned above, one should note a recent protocol of
Stankevic et al. in which the use of CuI/DMEDA catalytic system for the coupling of
diphenylphosphine oxide with 2-iodotoluene afforded diphenyl–o-tolylphosphine oxide in
only 29% yield [10]. Attempts to apply the Zhang procedure [18] for the C-P bond formation
using an inexpensive Ni-Zn catalytic system in a water medium proved to be unsuccessful
(entry 3). Dissatisfied with these results, we decided to examine other protocols for the
synthesis of tertiary phosphine oxides based on palladium catalysts. Using [1,2-
bis(diphenylphosphino)ethane]dichloropalladium(II) [Pd(dppe)Cl2], K2CO3 in toluene, we
isolated the product 3a in 65% yield and with 68% ee (entry 4). Furthermore, in the presence
of 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) [Pd(dppf)Cl2], the reaction
gave the desired product 3a in 87% yield and with almost full retention of configuration
(entry 5). When the reaction was conducted with Pd(PPh3)4 and triethylamine in acetonitrile
at 50 °C the yield decreased to 75% and we observed partial loss of optical purity (entry 6).
In order to improve the chemical yield, Pd(PPh3)4 -catalysed coupling reactions were
examined in the presence of K2CO3 instead of tertiary amine in MeCN at 50 °C. Under these
conditions, the reaction delivered the desired product with a very good yield of 90% and
with 85.8% ee.(entry 7). The best results were observed when we performed the reaction of
(S)-tert-butylphenylphosphine oxide 1 with 2-iodoaniline 2a in toluene at 110 °C in the
presence of Pd(PPh3)4 as catalyst and triethylamine or K2CO3 (entries 8-9). Screening
experiments showed the sufficiency of only 0.5 mol% of a palladium catalyst in the cross-
coupling reactions of aryl iodides with the phosphine oxide 1 (entry 11). The additional
experiment showed that ortho-bromoaniline exhibited a lowered reactivity and at least 5
mol% of a metal catalyst was required.
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Table 1. Screening experiments for the transition metal-catalysed coupling of enantiopure
phosphine oxide 1 with 2-iodoaniline 2a
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Product 3a
Abs. Conf.
[%-mol]
of cat.
Solvent/time
[h]/temp.[°C]
Entry
Catalyst
Base
of 1
Yield
[%]
ee
[%]
b
[α]D
a
c
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(R)
(S)
(R)
(S)
(S)
(R)
(S)
(R)
(S)
(S)
(S)
CuI/DMEDA
CuI/PEA
5/30
K2CO3
K2CO3
2,2’-By
K2CO3
Cs2CO3
Et3N
toluene/24/110
toluene/24/110
water/24/70
toluene/8/110
MeCN/8/60
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62
0
0
0
10/30
0
0
3
NiCl2•6H2O/Zn
Pd(dppe)Cl2
Pd(dppf)Cl2
Pd(PPh3)4
10/2eq
-
-
4
5
5
65
87
75
90
88
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95
93
+67.7
+97.4
-86
68.0
98.0
85.4
85,8
>99
>99
>99
>99
5
6
5
MeCN/4/50
7
Pd(PPh3)4
5
K2CO3
Et3N
MeCN/4/50
+87.5
-102.4
+101.3
+102.3
+101.1
8
Pd(PPh3)4
5
toluene/5/110
toluene/3/110
toluene/3/110
toluene/2/110
9
Pd(PPh3)4
5
K2CO3
K2CO3
K2CO3
10
11
Pd(PPh3)4
2
Pd(PPh3)4
0.5
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a isolated yield
b c = 1 in CHCl3
c Determined using chiral HPLC
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These results prompted us to carry out, under the optimized conditions, a series of
Pd-catalysed coupling reactions of enantiopure phosphine oxide 1 with differently
substituted haloarenes 2a-s, including condensed aryl halides or heteroaromatic halides
(Table 2). According to the general protocol, tertiary phosphine oxides 3a-s were obtained in
high yields and, in most cases, with excellent enantiomeric excess [ee was confirmed by
NMR spectroscopy using chiral solvating agent (CSA) or chiral HPLC - see SI]. The data listed
in Table 2 clearly indicate that the coupling reaction proceeded smoothly, independently of
the substitution in the aryl ring of substrates 2, either with electron-withdrawing groups
[such as trifluoromethyl (2g) and nitro (2h)] or electron-donating (EDG) groups (such as 2a-f
and 2j). Only (anthracen-9-yl)-tert-butylphenylphosphine oxide – 3i was obtained in a slightly
reduced yield and enantiomeric excess (70.9%, ee = 78.7%). However, heterocyclic 2- or 3-
bromothiophenes (2l and 2m) were coupled in a very good yield (91%), although in these
cases 10%-mol palladium catalyst and longer reaction time (72h) were required to achieve
full conversion of 1. We also obtained phosphine oxides which contain a tertiary amine
group 3n or a pyridine ring 3o. They should be able to coordinate with transition metals. It
should be noted that phosphine oxide 3s containing the cyclopropyl moiety is an analogue of
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sulfoxide which has been used as a chiral auxiliary in asymmetric C(sp3)-H activation in
cyclopropane ring[19].
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Table 2. Scope of the arylation of tert-butylphenylphosphine oxide 1 with aryl halides 2
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Enantiomeric excess (ee) was determined by HPLC analysis or by NMR using CSA (Chiral Solvating Agent) (see Experimental Section)
a) X= I, Pd(PPh3)4 [0.5%mol] was used, b) X= Br and Pd(PPh3)4 [5%mol] was used, c) Pd(PPh3)4 [10%mol] was used
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By this same protocol we synthesized amino-phosphine oxide ligands 6a-e. The needed aryl
bromides 5a-e were prepared starting from 2-bromobenzyl alcohol 2f which was converted
to the corresponding methanesulfonic ester 4, and next it was subjected to a nucleophilic
substitution reaction with the appropriate amine (or aminoalcohol), resulting in the desired
aryl bromides 5a-e. (Scheme 1)
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Scheme 1
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In the next stage, the palladium-catalysed coupling of the obtained 2-bromobenzylamines
5a-e and enantiomerically pure tert-butylphenylphosphine oxide 1, led to the desired
phosphine oxides 6a-e, functionalized with an amino group (Scheme 2).
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Scheme 2
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Having access to enantioenriched compounds we attempted to check whether it
would be possible to observe the stereospecific reduction of the P=O bond in these
phosphine oxides. The preliminary experiments were carried out with (S)-(2-N,N-
dimethylaniline)-tert-butylphenylphosphine oxide – 3n and (S)-tert-butyl(phenyl)(pyridin-2-
yl)phosphine oxide – 3o using phenylsilane as the reducing agent. The expected phosphines
7a and 7b were detected in the reaction mixture. Then, they were converted into the
corresponding phosphine boranes 8a and 8b. Unfortunately, full racemization at the
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phosphorus atom has been observed, probably due to the thermal racemization at 120 C.
(Scheme 3)
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Scheme 3
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In our attempts to reduce phosphine oxides 3a, 3o, 3s by the procedure reported in [13a] we
have not observed the expected phospine. Instead, only methylation or quaternization of the
amino group was observed. We have also tried to reduce the phosphine oxide 3a with the
complex of borane and dimethyl sulfide (this reagent has recently been used to reduce
phosphine oxides that contain an aminomethyl or hydroxymethyl group [20a-b] The
expected product, phosphine borane 8c was obtained, but in a low yield (50%) and with a
low enantiomeric excess (ee= 35.2%).
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Scheme 4
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Having phosphine boranes on hand, we attempted to check whether it would be possible to
achieve their conversion into parent phosphines, which should constitute a new and
interesting family of metal ligands based on functionalized phosphines. The model
experiment was carried out with the phosphine borane 8a as a model substrate using our
newest protocol, in which the trimethylphosphine was used as the deprotection agent [25].
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The expected phosphine 7a was prepared quantitatively and then converted to the
corresponding palladium complex 9. (Scheme 5)
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Scheme 5
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Crystallographic Studies
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Since all the tert-butylarylphenylphosphine oxides 3 obtained are P-chiral, it was interesting
to determine the stereochemical result of the studied coupling reactions leading from
substrate 1 to tertiary products. Therefore, we decided to perform X-ray crystallographic
studies for selected TPOs. Single crystals of enantiomerically pure 3a [26a] and 3i [26b] and
3l [26c] suitable for X-ray analysis were isolated by diffusion crystallization from
CH2Cl2/hexane and their absolute configuration at phosphorus was unambiguously
determined by using the Bijvoet method. These determinations clearly indicated that the
palladium-catalyzed formation of carbon-phosphorus bonds took place with retention of
configuration and this is consistent with the studies reported up to now, concerning the
details of the stereochemistry of arylation of various phosphoryl compounds. Accordingly,
stereoretention has previously been demonstrated for the palladium-catalysed coupling of
alkyl aryl(alkyl)phosphinate with aryl halides [7], [21] (S)-menthyloxyphenylphosphine
borane with 2-iodoanisole in MeCN [22], likewise for Pd(0)-Cu(I)-co-catalysed coupling of
methylphenylphosphine borane with aryl halides and aryl nonaflates [23].
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In the crystal structure the amine and phosphoryl groups are involved in an intra- and
intermolecular NHO hydrogen bonds. This results in an infinite chains along the b axis,
corresponding to C1 (4)[S(6)] graph-set motif [24]. The structures are further stabilized by
2
CH···π interactions connecting these chains (Figure 2).
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Figure 2. The intra- and intermolecular NH···O hydrogen bonds and CH···π contacts in 3a,
shown as dashed green lines. Hydrogen atoms not involved in the hydrogen-bonding scheme
are omitted for clarity.
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In the structure 3i, similarly to 3a, a position of anthracene ring seems determined by the
presence in the molecule a strong intramolecular contact of CH···O type with the distance
of 2.14 Å. The same as in 3a the tert-butyl group is involved in intermolecular CH···π
contacts with adjacent aromatic ring system and its shortest perpendicular distance to the
anthracene ring plane is 2.64 Å. The most noticeable difference in molecular geometry of 3i
is a dihedral angle between benzene and anthracene ring planes of 79° since in 3a the
corresponding dihedral angle between benzene and aniline ring planes is 121° (Figure 3).
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Figure 3. A view of 3i with the atomic numbering scheme. Displacement ellipsoids are drawn
at the 50% probability level.
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Figure 4. The intermolecular CH···O and CH···S contacts in 3l running along a axis, shown
as dashed green lines. Hydrogen atoms not involved in the hydrogen-bonding scheme are
omitted for clarity.
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Interestingly, in the crystal of 3l the intermolecular contacts are defined by bifurcated
unsymmetrical hydrogen bonds CH···O(P)···HC linking molecules together with CH···S
contacts into chains running along a axis (Figure 4).
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We also performed a X-ray crystallographic analysis for the compound 8a. A presence of
inversion center causes that the crystal is a racemic mixture of two enantiomers. A dihedral
angle between two benzene ring planes is about 76°. (Figure 5).
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Figure 5. A view of independent molecule of 8a with the atomic numbering scheme.
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Displacement ellipsoids are drawn at the 50% probability level.
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The X-ray crystal structure 9 contains a crystallographic center of inversion. In the crystal net
there are two types of molecule of 9 (A and B, Figure 6). Both molecules A and B have
essentially the same geometries except for a different benzene ring position with a rotation
of 46° (Figure 6).
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Figure 6. An overlay of two symmetry-independent molecules (A – red, B – green) of 9,
showing a different benzene ring location. Hydrogen atoms are omitted for clarity.
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Conclusions:
In summary, this work demonstrates an useful route to the synthesis of new, enantiopure
tertiary phosphine oxides via the palladium-catalyzed cross-coupling reactions of tert-butyl
phenylphosphine oxide with aryl halides. This protocol was found to be versatile and
efficient as the products were obtained generally in good yields and in most cases with
enantiomeric excesses from 98 to 99%. The stereoretention of the reaction was confirmed
by means of X-Ray analysis of the model tertiary phosphine oxides 3a and 3i. In preliminary
experiments to convert the model phosphine oxide to the corresponding phosphine
stereoerosion at a stereogenic phosphorus atom was observed. Racemic tert-butyl(2-
(dimethylamino)phenyl)(phenyl)phosphine (7a) was isolated in a quantitative yield upon
deprotection of the corresponding borane (8a) and converted to a crystalline complex with
palladium chloride (9a) the structure of which has been
proved by X-ray
crystallography.The results presented in this paper may open new possibilities in the
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application of functionalized tertiary phosphine oxides i.e. as chiral ligands for transition
metal catalysis or auxiliaries in asymmetric synthesis and new material chemistry.
273 Experimental Section
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Materials and methods
All reactions were carried out under argon atmosphere using standard Schlenk techniques
(in heating gun vacuum dried glassware). Dry solvents were degassed before the use. All
commercial reagents were purchased from Acros Organics, Aldrich, TCI, FluoroChem or abcr
GmbH. Dry solvents were prepared according to standard procedures. Synthesis and
resolution for enantiomers of tert-butylphenyl phosphine oxide 1 was carried out according
to literature procedure [17]. Reactions were followed using thin layer chromatography (TLC)
31
on silica gel-coated plates (Merck 60 F254) with the indicated solvent mixture or P NMR.
Optical rotations were measured on a Perkin–Elmer 241 MC polarimeter (c 1). Column
1
chromatography was carried out using Merck 60 (40-63 or 230-400mesh) silica gel. H NMR
13
spectra were recorded at 200 or 500 MHz and C NMR spectra at 126 MHz in CDCl3 as
solvent. 1H NMR chemical shifts are given in ppm with respect to tetramethylsilane (TMS) as
an internal standard. As an external reference for 31P NMR spectra, 85% phosphoric acid was
used. Coupling constants are reported as J values in Hz. Mass spectra (MS) were recorded
using chemical ionization technique on a Finningan MAT 95 spectrometer. Solvents for chiral
HPLC (hexane, i-PrOH) were distilled prior to use. The enantiomeric excess (ee) values were
determined by chiral HPLC (Chiralpak-AS-H). The ee with CSA (Chiral Solvating Agent) was
determined by addition of (+)-(R)-tert-butylphenylphosphinothioic acid (2 eq.) to the NMR
probe of the analyzed compound (1 eq.). Cross-coupling reactions, using copper and nickel
catalysts, were performed using literature procedures [10] [18].
Crystal Structure Determination
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X-ray diffraction data were collected for 3a [26a], 3i [26b], 3l [26c], 8a [26d], 9 [26e] at 100 K
by the ω-scan technique using a Bruker AXS Smart APEX-II CCD [Bruker (2008). APEX2, SAINT
and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.] diffractometer with MonoCap
capillary and 30W Incoatec Microfocus Source IµS with Montel optics and Cu-Kα radiation (λ
= 1.54178 Å). The crystal structure was solved by direct methods with the SHELXS-2013
program and refined by full-matrix least-squares techniques against F2 (SHELXL-2014/7) [27].
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Atomic scattering factors were taken from the International Tables for X-ray Crystallography.
Data were corrected for Lorentz and polarization effects. Data were corrected for absorption
effects using the multi-scan method (SADABS, Bruker (2008) APEX2, SAINT and SADABS.
Bruker AXS Inc., Madison, Wisconsin, USA). All non-hydrogen atoms were refined
anisotropically. The hydrogen atoms were located in a Fourier difference map and fully
refined. Figures were drawn using the Mercury CSD program [28].
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Synthesis and Characterization
General optimized procedure for the cross-coupling reaction using palladium catalyst
Dry Schlenk tube containing aryl halide (1.05 equiv), anhydrous K2CO3 (2 equiv) and
Pd(PPh3)4 (0.5-5%-mol) was evacuated and backfilled with argon (3x) and dry (degassed)
toluene was added next. The mixture was stirred at room temperature under argon for 30
minutes. Enantiomerically pure (R or S) tert-Butylphenyl phosphine oxide (1 equiv) was
dissolved in dry toluene and dropped slowly to the reaction mixture. It was then heated at
110°C until phosphine oxide disappeared as judged by TLC or 31P NMR. After cooling to room
temperature reaction mixture was filtered through a short plug of Celite, washed with ethyl
acetate (3x) and the filtrate was evaporated under reduced pressure. The residue was
purified by column chromatography.
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(S)-(2-Aminophenyl)(tert-butyl)(phenyl)phosphine oxide (S)-(3a): According to the general
procedure, (S)-3a was prepared from 2-Iodoaniline 2a (1.5374 g, 7.02 mmol), anhydrous
K2CO3 (1.9375 g), Pd(PPh3)4 (0.5%-mol, 38.7 mg) and (S)-tert-Butylphenyl phosphine oxide 1
(1.2095 g, 6.7 mmol). The crude product was purified by column chromatography (silica,
EtOAc 100%) to yield the product (S)-3a as a white solid (1.7102 g, 93.5%, ee= 99.6%).
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(R)-(2-Aminophenyl)(tert-butyl)(phenyl)phosphine oxide (R)-3a was obtained in the same
way, starting from (R)-tert-Butylphenyl phosphine oxide 1 (0.4637 g, 2.56 mmol) and 2-
1
iodoaniline 2a (0.5611 g, 2.56 mmol). 0.6165 g (88.1%, ee= 99%). H NMR (500 MHz, CDCl3)
δ= 1.32 (d, 9H, J= 14.4 Hz), 5.70 (bs, 2H), 6.59-6.62 (m, 2H), 7.19 (t, 1H, J= 7.6 Hz), 7.28-7.30
13
(m, 1H), 7.45-7.52 (m, 3H), 7.92 (t, 2H, J= 8.7 Hz); C NMR (126 MHz, CDCl3) δ= 25.45
(C(CH3)3), 35.38 (d, JC-P= 68.5 Hz, C(CH3)3), 109.40 (d, JC-P= 93.9 Hz), 115.74 (d, JC-P= 13.4 Hz),
117.33 (d, JC-P= 6.7 Hz), 128.28 (d, JC-P= 8.9 Hz), 131.41, 131.82, 132.16 (d, JC-P= 8.0 Hz),
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132.36, 132.45, 132.53, 132.59 (d, JC-P= 2.2 Hz), 153.69; P NMR (CDCl3) δ= 46.99; Chiral
HPLC: Chiralpack AS-H, 4.6 x 250 mm; Hexane:iPrOH (95:5), 1.0 mL/min, 254 nm, (S) rt(S)=
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13.20 min. (R), rt(R)= 15.17 min; (R); [α]D=-102,4 (c= 1 in CHCl3); (S) [α]D= +101.3 (c= 1 in
CHCl3); m.p. 145-147 °C; MS (EI): 273.0; Elemental analysis calcd (%) for C16H20PON (273.0): C
70.31; H 7.38; N 5.12. Found: C 70.43; H 7.29; N 5.17. Single crystal suitable for X-ray analysis
(CCDC 1562094) was isolated by diffusion crystallization from CH2Cl2/hexane.
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(S)-(4-Aminophenyl)(tert-butyl)(phenyl)phosphine oxide (3b): According to the general
procedure, (S)-3b was prepared from 4-Iodoaniline 2b (4.0907 g, 18.6 mmol), anhydrous
K2CO3 (5.1336 g), Pd(PPh3)4 (0.5%-mol, 107.5 mg) and (S)-tert-Butylphenyl phosphine oxide 1
(3.0905 g, 17.0 mmol). The crude product was purified by column chromatography (silica,
1
EtOAc:MeOH 20:1) to yield the product as a white solid (2.9496 g, 63.6 %, ee= 83.6%). H
NMR (500 MHz, CDCl3) δ 1.19 (d, 9H, J= 14.5 Hz), 4.07 (bs, 2H), 6.69 (d, 2H, J= 10.0 Hz), 7.41-
7.48 (m, 3H), 7.67 (t, 2H, J= 10.0 Hz), 7.89 (t, 2H, J= 10 Hz); 13C NMR (126 MHz, CDCl3) δ 25.25
(C(CH3)3), 33.95 (d, JC-P= 71.8 Hz), 114.21, 114.30, 118.20 (d, JC-P= 99.5 Hz), 128.09, 128.18,
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131.19, 131.85 (d, JC-P=69.3 Hz), 132.19, 132.29, 133.71, 133.78, 149.64; P NMR (CDCl3) δ
39.58; Elemental analysis calcd (%) for C16H20PON (273.0): C 70.31; H 7.38; N 5.12. Found: C
70.14; H 7.35; N 5.19; Chiral HPLC: Chiralpack AS-H, 4.6 x 250 mm; IPA: Hexane (10:90), 0.5
mL/min, 254 nm, (S) rt(S)= 39.79 min.; (R), rt(R)= 46.17 min.; (S) [α]D= -12.4 (c= 1 in MeOH).
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(S)-(3-Aminophenyl)(tert-butyl)(phenyl)phosphine oxide (3c): According to the general
procedure, (S)-3c was prepared from 3-Iodoaniline 2c (1.3675 g, 6.24 mmol), anhydrous
K2CO3 (1.7222 g), Pd(PPh3)4 (0.5%-mol, 325 mg) and (S)-tert-butylphenyl phosphine oxide 1
(1.0228 g, 5.62 mmol). The crude product was purified by column chromatography (silica,
EtOAc 100% -EtOAc:MeOH 20:1) to yield the product as a white solid (1.3961 g, 91.0 %,
ee>98%). 1H NMR (500 MHz, CD3OD) δ= 1.21 (d, 9H, J= 14.4 Hz), 6.87-6.90 (m, 1H), 7.13-7.18
(m, 1H), 7.21-7.27 (m, 2H), 7.51-7.56 (m, 2H), 7..57-7.61 (m, 1H), 7.89-7.95 (m, 2H); 13C NMR
(126 MHz, CD3OD) δ= 25.92 (C(CH3)3), 35.19 (d, JC-P= 70.2 Hz, C(CH3)3), 119.58 (d, JC-P= 9.5
Hz), 120.04, 122.29, 122.36, 130.07 (d, JC-P= 11.2 Hz), 130.85 (d, JC-P= 12.8 Hz), 131.55 (d, JC-P=
19.0 Hz), 132.29 (d, JC-P= 18.0 Hz), 133.63, 133.73, 133.80, 150.18 (d, JC-P= 13.2 Hz); 31P NMR
(CD3OD) δ= 43.4; Elemental analysis calcd (%) for C16H20PON (273.0): C 70.31; H 7.38; N 5.12.
Found: C 70.22; H 7.43; N 5.21; (S) [α]D= +28.3 (c= 1 in CHCl3).
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(S)-tert-Butyl(4-methoxyphenyl)(phenyl)phosphine oxide (3d): According to the general
procedure, (S)-3d was prepared from 1-Bromo-4-methoxybenzene 2d (0.2094 g, 1.12 mmol),
anhydrous K2CO3 (0.3091 g), Pd(PPh3)4 (5%-mol, 64.7 mg) and (S)-tert-Butylphenyl phosphine
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oxide 1 (0.2038 g, 1.12 mmol). The crude product was purified by column chromatography
(silica, EtOAc100%-EtOAc:MeOH 20:1) to yield the product as a white solid (0.3097 g, 96.0%,
ee>98%). 1H NMR (500 MHz, CDCl3) δ= 1.19 (d, 9H, J= 15 Hz), 3.81 (s, 3H), 6.95-6.97 (m, 2H),
7.43-7.47 (m, 3H), 7.84-7.92 (m, 4H); 13C NMR (126 MHz, CDCl3) δ= 25.21 (C(CH3)3), 34.01 (d,
JC-P= 71.7 Hz), 55.31, 113.84, 113.93, 121.72, 122.49, 128.18, 128.26, 131.23,131.94, 132.10,
132.16, 133.93, 134.01, 162.10; 31P NMR (CDCl3) δ= 38.9; MS (EI): 288.2; HRMS: m/z calcd for
C17H21O2P: 288.1279; found: 288.1275. (S) [α]D= -11.3 (c= 1 in CHCl3).
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(S)-tert-Butyl(4-(tert-butyl)phenyl)(phenyl)phosphine oxide (3e): According to the general
procedure, (S)-3e was prepared from 4-tert-Butyliodobenzene 2e (0.2362 g, 0.163 mL, 0.91
mmol), anhydrous K2CO3 (0.2511 g), Pd(PPh3)4 (0.5%-mol, 5.3 mg) and (S)-tert-Butylphenyl
phosphine oxide 1 (0.1653 g, 0.91 mmol). The crude product was purified by column
chromatography (silica, EtOAc 100%) to yield the product as a white solid (0.2681 g, 94.0%,
ee>98%). 1H NMR (200 MHz, CDCl3) δ= 1.25 (d, 9H, J= 14 Hz), 1.32 (s, 9H), 7.45-7.49 (m, 5H),
7.83-7.99 (m, 4H); 13C NMR (126 MHz, CDCl3) δ= 25.17 (C(CH3)3), 31.06 (C(CH3)3), 33.90 (d, JC-
= 70.8 Hz), 34.85, 125.24 (d, JC-P= 10.85), 128.13 (d, JC-P= 11.0 Hz), 128.46 (d, JC-P=
12.02),131.27, 131.78, 131.90, 131.98, 132.01, 132.05, 132.12, 132.19, 154.73; 31P NMR
(CDCl3) δ= 38.7; HRMS: m/z calcd. for C20H27OP: 314.1799 ; found: 314.1803. (S) [α]D= -12.04
(c= 1 in CHCl3).
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(S)-tert-Butyl(2-(hydroxymethyl)phenyl)(phenyl)phosphine oxide (3f): According to the
general procedure, (S)-3f was prepared from 2-Bromobenzyl alcohol 2f (0.1870 g, 1.0 mmol),
anhydrous K2CO3 (0.207g), Pd(PPh3)4 (5%-mol, 57.8 mg) and (S)-tert-Butylphenyl phosphine
oxide 1 (0.1712 g, 1.0 mmol). The crude product was purified by column chromatography
(silica, EtOAc:MeOH 50:1) to yield the product as a white solid (0.2432 g, 84.4 %, ee>98%). 1H
NMR (500 MHz, CDCl3) δ= 1.36 (d, 9H, J= 15.0 Hz), 4.50 (d, 1H, J= 12.9 Hz), 4.62 (d, 1H, J=
13
12.9 Hz), 7.34-7.37 (m, 1H), 7.40-7.54 (m, 5H), 7.72-7.81 (m, 3H); C NMR (126 MHz, CDCl3)
δ= 25.58 (C(CH3)3), 34.53 (d, JC-P= 69.8 Hz), 65.44, 126.65 (d, JC-P= 12.2 Hz), 128.29 (d, JC-P=
12.2 Hz), 129.42, 130.12, 131.23, 131.63, 131.95, 132.02 (d, JC-P= 8.8 Hz), 132.12 (d, JC-P= 2.2
Hz), 132.29 (d, JC-P= 7.8 Hz), 132.36 (d, JC-P= 6.2 Hz), 147.50 (d, JC-P= 6.5 Hz); 31P NMR (CDCl3)
δ= 45.53; MS (EI): 288.1; HRMS: m/z calcd. for C17H21O2P: 288.1279; found: 288.1281; (S)
[α]D< 1 (c= 1 in CHCl3).
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(S)-tert-Butyl(phenyl)(4-(trifluoromethyl)phenyl)phosphine oxide (3g): According to the
general procedure, (S)-3g was prepared from 4-Iodobenzotrifluoride 2g (0.2627 g, 0.97
mmol), anhydrous K2CO3 (0.2666g), Pd(PPh3)4 (0.5%-mol, 5.6 mg) and (S)-tert-Butylphenyl
phosphine oxide 1 (0.1758 g, 0.96 mmol). The crude product was purified by column
chromatography (silica, EtOAc 100%) to yield the product as a white solid (0.2976 g, 94.5 %,
1
ee>98%). H NMR (500 MHz, CDCl3) δ= 1.24 (d, 9H, J= 15.2 Hz), 7.47-7.55 (m, 3H), 7.72 (d,
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2H, J= 7.8 Hz), 7.93 (t, 2H, J= 8.8 Hz), 8.08 (t, 2H, J= 8.8 Hz); C NMR (126 MHz, CDCl3) δ=
25.05 (C(CH3)3), 34.00 (d, JC-P= 69.9 Hz), 122.48, 124.94 (d, J= 3.1 Hz), 125.03 (d, J= 3.1 Hz),
128.45 (d, J= 11.3 Hz), 129.96, 130.69, 131.82 (d, J= 1.8 Hz), 132.02 (d, J= 8.1 Hz), 132.63 (d,
31
J= 8.1 Hz), 133.06, 133.34, 135.52, 136.21; P NMR (CDCl3) δ= 38.04; MS (EI): 326.1; HRMS:
m/z calcd. for C17H18OPF3: 326.1047; found: 326.1043. (S) [α]D= +2.95 (c= 1 in CHCl3).
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(S)-tert-Butyl(2-nitrophenyl)(phenyl)phosphine oxide (3h): According to the general
procedure, (S)-3h was prepared from 1-Bromo-2-nitrobenzene 2h (0.1091 g, 0.54 mmol),
anhydrous K2CO3 (0.1499 g), Pd(PPh3)4 (5%-mol, 31.2 mg) and (S)-tert-Butylphenyl phosphine
oxide 1 (0.0934 g, 0.513 mmol). The crude product was purified by column chromatography
(silica, EtOAc:Hex 70:30) to yield the product as a light-brown solid (0.1322 g, 85.0 %, ee=
99%). 1H NMR (500 MHz, CDCl3) δ= 1.26 (d, 9H, J= 15.4 Hz), 5.83 (d, 1H, J= 12.1 Hz), 6.79 (td,
1H, J= 7.7 Hz, 1.5 Hz), 6.94 (td, 1H, J= 7.7 Hz, 1.4 Hz), 7.16 (d, 1H, J= 8.0 Hz), 7.30 (d, 1H, J=
13
8.0 Hz), 7.42-7.45 (m, 2H), 7.50-7.53 (m, 1H), 7.74-7.78 (m, 2H); C NMR (126 MHz, CDCl3)
δ= 24.69 (C(CH3)3), 32.75 (d, JC-P= 86.9 Hz, C(CH3)3, 118.92 (d, JC-P= 2.5 Hz), 122.08, 122.21 (d,
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JC-P= 8.0 Hz), 127.56, 127.83, 128.48, 128.58, 129.04, 132.21, 133.53, 133.61, 137.31; P
NMR (CDCl3) δ= 37.78; MS (EI): 303.1; Elemental analysis calcd (%) for C16H18PON3: C 63.36;
H 5.98; N 4.62. Found: C 63.29; H 6.05; N 4.51; Chiral HPLC: Chiralpack AS-H, 4.6 x 250 mm;
Hexane:iPrOH (95:5), mL/min, 254 nm, (S) rt(S)= 10.25 min. (R) rt(R)= 14.51 min; (S) [α]D=
+115.9 (c= 1 in CHCl3).
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(S)-Anthracen-9-yl(tert-butyl)(phenyl)phosphine oxide (3i): According to the general
procedure, (S)-3i was prepared from 9-Bromoanthracene 2i (0.3595 g, 1.41 mmol),
anhydrous K2CO3 (0.3864 g), Pd(PPh3)4 (5%-mol, 80.9 mg) and (S)-tert-Butylphenyl phosphine
oxide 1 (0.2545 g, 1.4 mmol). The crude product was purified by column chromatography
(silica, EtOAc100%-EtOAc:MeOH 10:1) to yield the product as a colorless solid (0.3549 g, 70.9
1
%, ee= 78.7%). H NMR (500 MHz, CDCl3) δ= 1.54 (d, 9H, J= 15 Hz), 7.33-7.41 (m, 7H), 7.78-
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7.98 (m, 2H), 7.97 (d, 2H, J= 10 Hz), 8.63 (s, 1H), 9.08 (d, 2H, J= 5 Hz); C NMR (126 MHz,
CDCl3) δ= 27.24 (C(CH3)3), 37.70 (d, JC-P= 69,2 Hz), 121.44, 122.09, 124.66, 125.98126.55,
128.21, 128.25, 128.72, 128.81, 129.16, 129,94, 130.11, 130.18, 130.68, 131.10, 131.18,
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134.35, 134.38, 135.90, 135.96, 138.03, 138.75; P NMR (CDCl3) δ= 49.5; MS (EI): 358.2;
HRMS: m/z calcd. for C24H23OP: 358.1486; found: 358.1479. (S) [α]D= +161.9 (c= 1 in CHCl3).
Single crystal suitable for X-ray analysis (CCDC 1562095) was isolated by diffusion
crystallization from CH2Cl2/hexane.
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(S)-(2,6-bis((p-Tolyloxy)methyl)phenyl)(tert-butyl)(phenyl)phosphine oxide (3j): According to
the general procedure, (S)-3j was prepared from 2,6-bis(4-Methylphenoxymethyl)
bromobenzene 2j (0.2527 g, 0.64 mmol), anhydrous K2CO3 (0.1766 g), Pd(PPh3)4 (5%-mol,
32.9 mg) and (S)-tert-Butylphenyl phosphine oxide 1 (0.1037 g, 0.57 mmol). The crude
product was purified by column chromatography (silica, EtOAc:Hex 50:50) to yield the
product as a greenish oil (0.2442 g, 86.0%, ee= 68.4%). 1H NMR (500 MHz, CDCl3) δ= 1.51 (d,
9H, J= 15.2 Hz), 2.30 (s, 6H), 5.02 (d, 2H, J= 12.4 Hz), 5.40 (d, 2H, J= 12.4 Hz), 6.74 (d, 4H, J=
8.5 Hz), 7.07 (d, 4H, J= 8.5 Hz), 7.43-7.45 (m, 3H), 7.62 (dt, 1H, J1= 1.2 Hz, J2= 7.8 Hz), 7.83-
13
7.88 (m, 4H); C NMR (126 MHz, CDCl3) δ= 20.31 (CH3), 25.91 (C(CH3)3), 36.20 (d, JC-P= 69.7
Hz), 68.49, 68.51, 114.21, 125.07, 125.72, 128.43, 128.50, 128.70, 128.78, 129.64, 129.80,
31
130.16, 130.23, 131.12, 131.74, 136.43, 137.13, 142.80, 152.26; P NMR (81 MHz, CDCl3) δ=
48.4; MS (EI): 498.2; HRMS: m/z calcd. for C32H35O3P: 498.2324 ; found: 498.2326. (S) [α]D=
+19.1 (c= 1 in CHCl3)
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(S)-tert-Butyl(naphthalen-1-yl)(phenyl)phosphine oxide (3k): According to the general
procedure, (S)-3k was prepared from 1-Bromonaphthalene 2k (0.1216 g, 0.59 mmol),
anhydrous K2CO3 (0.1629 g), Pd(PPh3)4 (5%-mol, 34.1 mg) and (S)-tert-Butylphenyl phosphine
oxide 1 (0.1021 g, 0.56 mmol). The crude product was purified by column chromatography
(silica, EtOAc:Hex 50:50) to yield the product as a white solid (0.1536 g, 89.0 %, ee> 98%). 1H
NMR (500 MHz, CDCl3) δ= 1.39 (d, 9H, J= 14.7 Hz), 7.42-7.51 (m, 6H), 7.82-7.89 (m, 3H), 7.92-
7.98 (m, 2H), 8.97-8.99 (m, 1H); 13C NMR (126 MHz, CDCl3) δ= 26.14 (C(CH3)3), 34.91 (d, JC-P=
70.6 Hz, C(CH3)3, 123.53 (d, JC-P= 13.9 Hz), 126.19, 126.93, 127.61, 128.13, 128.22, 128.61,
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131.25, 132.21, 132.28, 132.32, 132.50, 132.75, 133.21, 134.15 (d, JC-P= 7.6 Hz , 135.81); P
NMR (CDCl3) δ= 44.45; (S) [α]D= +69.1 (c= 1.73 in CHCl3); mp: 130-132 °C; MS (EI): 308.1;
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Elemental analysis calcd (%) for C20H21PO: C 77.90; H 6.86; Found: C 77.72; H 6.97; HRMS:
m/z calcd. for C20H21OP: 308.1323; found: 308.1330.
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(S)-tert-Butyl(phenyl)(thiophen-2-yl)phosphine oxide (3l): According to the general
procedure, (S)-3l was prepared from 2-Bromothiophene 2l (0.4579 g, 2.81 mmol), anhydrous
K2CO3 (0.7756 g), Pd(PPh3)4 (10%-mol, 294 mg) and (S)-tert-Butylphenyl phosphine oxide 1
(0.4601 g, 2.54 mmol). The crude product was purified by column chromatography (silica,
1
EtOAc 100%) to yield the product as a light-brown solid (0.6075 g, 91.0%, ee= 88.6%). H
NMR (500 MHz, CDCl3) δ= 1.18 (d, 9H, J= 15.4 Hz), 7.15-7.19 (m, 1H), 7.41-7.49 (m, 3H), 7.66-
13
7.69 (m, 1H), 7.70-7.73 (m, 1H), 7.85-7.91 (m, 2H); C NMR (126 MHz, CDCl3) δ= 24.51
(C(CH3)3), 33.98 (d, JC-P= 75.5 Hz), 128.00 (d, JC-P= 12.2 Hz), 128.16 (d, JC-P= 11.5 Hz), 128.52
(d, JC-P= 11.6 Hz), 130.36 (d, JC-P= 20.4 Hz), 131.12 (d, JC-P= 18.2 Hz), 131.69, 132.02 (d, JC-P=
8.2 Hz),132.93, 132.95, 136.90 (d, JC-P= 7.4 Hz);31P NMR (CDCl3) δ= 38.11; MS (EI): 264.1;
HRMS: m/z calcd. for C14H17OPS: 264.0738; found: 264.0740. (S) [α]D= +3.8 (c= 1.42 in CHCl3).
Single crystal for X-ray analysis (CCDC 1562096) was isolated by diffusion crystallization from
CH2Cl2/hexane.
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(S)-tert-Butyl(phenyl)(thiophen-3-yl)phosphine oxide (3m): According to the general
procedure, (S)-3m was prepared from 3-Bromothiophene 2m (0.1591 g, 0.98 mmol),
anhydrous K2CO3 (0.2760 g), Pd(PPh3)4 (10%-mol, 102 mg) and (S)-tert-Butylphenyl
phosphine oxide 1 (0.1599 g, 0.88 mmol). The crude product was purified by column
chromatography (silica, EtOAc100% - EtOAc:MeOH 50:1) to yield the product as a light-
1
brown solid (0.1926 g, 83.1%, ee= 79.8%). H NMR (500 MHz, CDCl3) δ= 1.21 (d, 9H, J= 15.6
13
Hz), 7.46-7.52 (m, 5H), 7.88 (t, 2H, J= 8.8 Hz), 8.09 (d, 1H, J= 6.3 Hz); C NMR (126 MHz,
CDCl3) δ= 24.66 (C(CH3)3), 33.78 (d, JC-P= 73.7 Hz), 127.15 (d, JC-P= 13.6 Hz), 128.22 (d, JC-P=
11.7 Hz), 129.19 (d, JC-P= 12.6 Hz), 130.30, 131.05, 131.62, 131.79, 131.88, 131.95, 135.61 (d,
31
JC-P= 10.9 Hz); P NMR (CDCl3) δ= 37.04; MS (EI): 264.1; Elemental analysis calcd (%) for
C14H17POS: C 63.62; H 6.48; Found: C 63.71; H 6.50;. (S) [α]D= + 1.61 (c= 2.0 in CHCl3).
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(S)-tert-Butyl(2-(dimethylamino)phenyl)(phenyl)phosphine oxide (3n): According to the
general procedure, 3n was prepared from 2-Bromo-N,N-dimethylaniline 2n (0.6950 g, 3.47
mmol), anhydrous K2CO3 (0.9577 g), Pd(PPh3)4 (5%-mol, 190.7 mg) and (S)-tert-Butylphenyl
phosphine oxide 1 (0.5913 g, 3.3 mmol). Crude reaction mixture was washed with 1M HCl
(3x30 mL). Aquerous layers were alkalyzed with solid NaOH and extracted with EtOAc (3x50
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10.1002/ejoc.201800698
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mL). Organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4, filtered
and concentrated in vacuo. Crude product was purified by column chromatography (silica,
EtOAc 100% -> EtOAc:MeOH 20:1) to yield the product 3n as a white solid (0.8070 g, 81.2 %,
1
78.8% ee). H NMR (500 MHz, CDCl3) δ= 1.30 (d, 9H, J= 14.0 Hz), 2.26 (s, 6H), 7.16-7.23 (m,
1H), 7.24-7.29 (m, 1H), 7.32-7.44 (m, 3H), 7.44-7.51 (m, 1H), 7.70-7.79 (m, 2H), 7.93-8.01 (m,
13
1H); C NMR (126 MHz, CDCl3) δ= 26.14 (C(CH3)3), 34.14 (d, JC-P= 71.0 Hz), 45.79 (N(CH3)2),
123.50, 124.16, 127.31 (d, JC-P= 10.8 Hz), 128.45 (d, JC-P= 10.8 Hz), 130.16, 131.63 (d, JC-P= 8.6
31
Hz)), 131.87, 132.05 (d, JC-P= 9.8 Hz), 132.82, 133.92, 134.53, 158.82; P NMR (CDCl3) δ=
40.48; MS (EI): 301; Elemental analysis calcd (%) for C18H24PON (301): C 71.74; H 8.03; N
4.65. Found: C 71.45; H 8.29; N 4.71; Chiral HPLC: Chiralpack OD-H, 4.6 x 250 mm;
Hexane:iPrOH (96:4), 0.8 mL/min, 254 nm, (S) rt(S)= 9.70 min. (R) rt(R)= 11.99 min; (S) [α]D= -
28.2 (c= 1.49 in CHCl3).
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(S)-tert-Butyl(phenyl)(pyridin-2-yl)phosphine oxide (3o): According to the general procedure,
3o was prepared from 2-Iodopyridine 2o (0.7258 g, 3.54 mmol), anhydrous K2CO3 (0.9770
g), Pd(PPh3)4 (0.5%-mol, 19.5 mg) and (S)-tert-Butylphenyl phosphine oxide 1 (0.6105 g, 3.37
mmol). The crude product was purified by column chromatography (silica, EtOAc 100%) to
1
yield the product as a white solid (0.7632 g, 87.4%, ee>98%). H NMR (500 MHz, CDCl3) δ=
1.21 (d, 9H, J= 15.4 Hz), 7.37-7.39 (m, 1H), 7.42-7.46 (m, 2H), 7.46-7.51 (m, 1H), 7.78-7.84
13
(m, 1H), 8.17-8.27 (m, 3H), 8.80 (d, 1H, J= 4.8 Hz); C NMR (126 MHz, CDCl3) δ= 24.61
(C(CH3)3), 33.88 (C(CH3)3, d, JC-P= 67.5 Hz), 125.12 (d, JC-P= 2.9 Hz), 127.91 (d, JC-P= 11.0 Hz),
129.28, 129.29 (d, JC-P= 17.4 Hz), 129.99, 131.55 (d, JC-P= 1.7 Hz), 132.83 (d, JC-P= 7.6 Hz),
31
136.16 (d, JC-P= 8.1 Hz), 149.34 (d, JC-P= 17.4 Hz), 155.97, 156.90; P NMR (CDCl3) δ= 32.96;
Elemental analysis calcd (%) for C15H18PON: C 69.48; H 7.00; N 5.40; Found: C 69.53; H 7.08;
N 5.47; (S) [α]D= -73.6 (c= 1.97 in CHCl3); Chiral HPLC: Chiralpack AS-H, 4.6 x 250 mm;
Hexane:iPrOH (98:2), 0.5 mL/min, 254 nm, (R) rt(R)= 40.865 min. (S) rt(S)= 46.01 min.
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(S)-tert-Butyl(phenyl)(2-vinylphenyl)phosphine oxide (3p): According to the general
procedure, (S)-3p was prepared from 2-Bromostyrene 2p (0.6638 g, 3.45 mmol), anhydrous
K2CO3 (0.9660 g), Pd(PPh3)4 (5%-mol, 179 mg) and (S)-tert-Butylphenyl phosphine oxide 1
(0.5651 g, 3.1 mmol). The crude product was purified by column chromatography (silica,
EtOAc 100%- EtOA:MeOH 20:1) to yield the product as a white solid (0.7171 g, 81.3%, ee
N/D). 1H NMR (500 MHz, CDCl3) δ= 1.34 (d, 9H, J= 14.7 Hz), 5.14 (dd, 1H, J= 10.8 Hz, 1.2 Hz),
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5.51 (dd, 1H, J= 17.4 Hz, 1.3 Hz), 7.25-7.29 (m, 1H), 7.40-7.51 (m, 4H), 7.63-7.67 (m, 1H),
13
7.68-7.76 (m, 2H), 7.77-7.82 (m, 2H); C NMR (126 MHz, CDCl3) δ= 26.51 (C(CH3)3), 35.27
(C(CH3)3, d, JC-P= 70.2 Hz), 116.70, 126.74 (d, JC-P= 11.8 Hz), 128.22, 128.30, 128.62, 128.71,
31
129.38, 131.79, 132.05, 132.90, 133.82, 136.98 (d, JC-P= 3.8 Hz), 144.57 (d, JC-P= 6.0 Hz); P
NMR (CDCl3) δ= 43.89; MS (EI): 284; Elemental analysis calcd (%) for C18H21PO: C 76.04; H
7.44; Found: C 75.81; H 7.68; (S) [α]D= +35.9 (c= 1.1 in CHCl3).
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(S)-tert-Butyl(4-isopropoxy-3-vinylphenyl)(phenyl)phosphine
oxide
(3r):
5-Bromo-2-
isoproxystyrene 2r was prepared from commercially available 5-Bromo-2-
hydroxybenzaldehyde in two steps. 5-Bromo-2-hydroxybenzaldehyde (10.5042 g, 52.25
mmol), anhydrous K2CO3 (21.64 g, 156.75 mmol) and anhydrous Cs2CO3 (1.7024 g, 5.23
mmol) were placed in round-bottom flask and anhydrous DMF (50 mL) was added. Isopropyl
bromide (9.81 mL, 104.5 mmol) was dropped to the reaction mixture and it was heated
(40°C) for 48 hours. Starting material disappeared (judged by TLC Hex:Et2O 10:1) and DMF
was evaporated. Residue was dissolved in Et2O (100mL). Solution was transferred to the
separatory funnel and water was added (100mL). Aquerous layer was extracted (3x50 mL)
with Et2O. Combinated organic layers were washed with water (50 mL), 5% NaOH (50mL),
brine (50 mL) and dried over anhydrous Na2SO4, filtered and evaporated. Crude product was
washed with cold hexane provided to pure product (10.2420 g, 81%). Spectroscopic data of
5-bromo-2-isopropoxybenzaldehyde in agreement with literature [29].
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Methyltriphenylphosphonium bromide (8.0846 g, 22.63 mmol) was placed in dry THF (30
mL) and solution of tBuOK (2.5281 g, 22.63 mmol) in THF (15 mL) was dropped slowly at 0°C.
The reacion mixture was stirred for 3h at rt. Next, the reaction mixture was cooled to -78°C
and a solution of 5-bromo-2-isopropoxybenzaldehyde (2.3824 g, 9.84 mmol) in THF (10 mL)
was dropped slowly. It was stirred for 24h at rt. Starting material disappeared (judged by TLC
Hex:Et2O 10:1) and saturated solution of NH4Cl (40 mL) was added. Aquerous layer was
extracted with Et2O (3x50 mL). Combinated organic layers were washed with water (2x20
mL), brine (1x20 mL), dried over anhydrous Na2SO4, filtered and evaporated. Crude product
was purified by column chromatography (silica, Hex:Et2O 10:1) to yield the product as a
colorless oil (2.0137 g, 85.2%). Spectroscopic data of 5-Bromo-2-isopropoxystyrene in
agreement with literature [29].
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According to the general procedure, (S)-3r was prepared from 5-Bromo-2-isoproxystyrene 2r
(0.5015 g, 2.09 mmol), anhydrous K2CO3 (0.5767 g), Pd(PPh3)4 (5%-mol, 113 mg) and (S)-tert-
Butylphenyl phosphine oxide 1 (0.3549 g, 1.95 mmol). The crude product was purified by
column chromatography (silica, EtOAc:MeOH 50:1 -> 20:1) to yield the product as a white
solid (0.5612 g, 84.1%, ee N/D). 1H NMR (500 MHz, CDCl3) δ= 1.25 (d, 9H, J= 15.2 Hz), 1.37 (d,
6H, J= 6.1 Hz), 4.63 (m, 1H), 5.29 (dd, 1H, J= 11.1 Hz, 0.9 Hz), 5.79 (dd, 1H, J= 17.7 Hz, 0.9 Hz),
6.95 (dd, 1H, J= 8.6 Hz, 1.8 Hz), 6.98-7.06 (m, 1H), 7.45-7.54 (m, 3H), 7.77 (td, 1H, J= 9.1 Hz,
1.7 Hz), 7.93 (t, 2H, J= 8.4 Hz), 8.02 (dd, 1H, J= 10.5 Hz, 1.6 Hz); 13C NMR (126 MHz, CDCl3) δ=
22.08 (CH(CH3)2), 25.24 (C(CH3)3), 34.07 (C(CH3)3, d, JC-P= 70.5 Hz), 70.65 (CH(CH3)2, 112.69,
112.79, 115.58, 127.54, 127.63, 128.31 (d, JC-P= 11.0 Hz), 130.96, 131.04, 131.34, 131.54,
132.16, 132.23, 132.95, 133.03; 31P NMR (CDCl3) δ= 39.56; MS (EI): 342.2; Elemental analysis
calcd (%) for C21H27PO2: C 73.66; H 7.95; Found: C 73.41; H 8.08; (S) [α]D= -17.6 (c= 1.1 in
CHCl3).
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(S)-N-(2-(tert-Butyl(phenyl)phosphoryl)phenyl)cyclopropanecarboxamide (3s): 2-Iodoaniline
2a (1.0530 g, 4.81 mmol), K2CO3 (0.7302 g, 5.29 mmol, 1.1 eq.) were placed in round-botom
flask and dry MeCN (50 mL) were added. pivaloyl chloride (1.05 eq., 0.62 mL, 5.05 mmol)
was added dropwise, under an argon atmosphere, at 0°C. After 1h TLC analysis (Hex:Et20
10:1) showed full consumption of the substrate. The reaction mixture was filtered through
short plug of celite and washed with EtOAc (2x50 mL). Filtrate was evaporated and crude
product was purified by column chromatography (Hex 100% -> Hex:Et20 10:1) to afford the
product 2s as white solid (1.3390 g, 97%). Spectroscopic data of N-(2-
Iodophenyl)cyclopropanecarboxamide – 2s in agreement with literature [30].
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According to the general procedure, (S)-3s was prepared from N-(2-
Iodophenyl)cyclopropanecarboxamide 2s (0.0987 g, 0.34 mmol), anhydrous K2CO3 (0.0938 g,
0.68 mmol), Pd(PPh3)4 (0.5%-mol, 19.6 mg) and (S)-tert-Butylphenyl phosphine oxide 1
(0.0601 g, 0.33 mmol). The crude product was purified by column chromatography to yield
1
the product as a colorless oil (0.0909 g, 80.7 %, ee= 99.6%). H NMR (500 MHz, CDCl3) δ=
0.73-0.83 (m, 2H), 0.94-1.03 (m, 2H), 1.29 (d, 9H, J= 15.3 Hz), 1.61-1.67 (m, 1H), 6.95-7.00
(m, 1H), 7.34-7.43 (m, 2H), 7.45-7.49 (m, 2H), 7.50-7.54 (m, 1H), 7.90-7.95 (m, 2H), 8.53-8.57
13
(m, 1H), 11.89 (bs, 1H); C NMR (126 MHz, CDCl3) δ= 7.81, 7.84, 16.31, 25.14 (C(CH3)3),
35.33 (C(CH3)3, d, JC-P= 70.2 Hz), 114.15, 114.85, 121.67 (d, JC-P= 11.6 Hz), 121.82 (d, JC-P= 7.1
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Hz), 128.55 (d, JC-P= 10.7 Hz), 130.24, 130.97, 131.86, 131.99, 132.05, 132.77, 145.20, 172.54;
31P NMR (CDCl3) δ= 49.38; MS (EI): 341; Elemental analysis calcd (%) for C20H24PO2N: C:
70.37; H: 7.09; N: 4.10; Found: C: 70.52; H: 7.21; N: 4.23; Chiral HPLC: Chiralpack AS-H, 4.6 x
250 mm; Hexane:iPrOH (95:5), 1 mL/min, 254 nm, (S) rt= 8.88 min. (R) rt= 10.23 min, (S)
[α]D= +84.6 (c= 1.1 in CHCl3).
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(2-N,N-Dimethylaniline)-tert-butylphenylphosphine-P-borane (8a): To an oven-dried Schlenk
tube, (S)-tert-Butyl(2-(dimethylamino)phenyl)(phenyl)phosphine oxide 3n (0.2304 g, 0.77
mmol, 78% ee) and phenylsilane (5.0 mL, 40.7 mmol) were added and the reaction mixture
31
was evacuated and refilled with argon three times. It was then heated at 120°C until the P
NMR (7.36 ppm – phosphine 7a) showed full consuption of the substrate (72h). The reaction
mixture was cooled to room temperature and excess of the PhSiH3 was removed on vaccum
pump. The residue was dissolved in dry and degassed toluene (10 mL) and 1M BH3*THF
(3.85 mL, 5eq.) was added at 0°C. After stirring for 3h at room temperature deionised water
(20 mL) was added. Layers were separated and the water phase was extracted with EtOAc
(3x25 mL). Combined organic layers were dried over Na2SO4, filtered and evaporated. Crude
product was purified via column chromatography (Hex 100% -> Hex:EtOAc 10:1) to afford
1
the desired product as white solid (0.1576 g, 68.4 %, ee= 0%). H NMR (500 MHz, CDCl3) δ=
1.33 (d, 9H, J= 13.7 Hz), 2.14 (bs, 6H), 7.21-7.25 (m, 1H), 7.27-7.33 (m, 1H), 7.33-7.41 (m,
13
3H), 7.44-7.49 (m, 1H), 7.72-7.77 (m, 2H), 7.84-7.89); C NMR (126 MHz, CDCl3) δ= 27.32
(C(CH3)3), 31.33 (d, JP-C= 31.4 Hz, C(CH3)3), 46.08 (N(CH3)2), 124.45, 124.49, 125.04, 127.36,
31
127.44, 129.86, 132.01, 133.47, 133.53, 134.49, 134.55, 159.02; P NMR (CDCl3) δ= 33.25;
Elemental analysis calcd (%) for C20H24PO2N: C: 72.26; H: 9.10; N: 4.68; Found: C: 72.09; H:
9.11; N: 4.73; MS (CI) [M-1]= 298; Chiral HPLC: Chiralpack OD-H, 4.6 x 250 mm;
Hexane:iPrOH (99.5:0.5), 0.3 mL/min, 254 nm, rt1= 30.88 min., rt2= 38.33 min. Single crystal
suitable for X-ray analysis (CCDC 1562097) was isolated by diffusion crystallization from
CH2Cl2/hexane.
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tert-Butylphenyl(pyridin2-yl)-phosphine-P-borane (8b): To an oven-dried Schlenk tube, (S)-
tert-Butyl(phenyl)(pyridin-2-yl)phosphine oxide 3o (0.1328 g, 0.51 mmol) and phenylsilane
(3.14 mL, 25.5 mmol) were added and the reaction mixture was evacuated and refilled with
31
argon three times. It was then heated at 120°C until the P NMR (16.14 ppm – phosphine
7b) showed full consuption of the substrate (72h). The reaction mixture was cooled to room
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temperature and excess of the PhSiH3 was removed on vaccum pump. The residue was
dissolved in dry and degassed toluene (5 mL) and 1M BH3*THF (2.5mL, 5eq) was added at
0°C. After stirring for 3h at room temperature deionised water (10 mL) was added. Layers
were separated and the water phase was extracted with EtOAc (3x20 mL). Combined organic
layers were dried over Na2SO4, filtered and evaporated. Crude product was purified via
column chromatography (Cyclohexane 100% -> Cyclohexane:Et2O 10:1) to afford the desired
product as white solid (0.1120 g, 85.4%, ee= 0%). 1H NMR (500 MHz, CDCl3) δ= 1.26 (d, 9H, J=
14.5 Hz), 7.35-7.39 (m, 1H), 7.40-7.44 (m, 2H), 7.45-7.50 (m, 1H), 7.71-7.75 (m, 1H), 8.11-
8.17 (m, 3H), 8.82-8.84 (m, 1H); 13C NMR (126 MHz, CDCl3) δ= 28.15 (C(CH3)3), 33.30 (d, JC-P=
33.1 Hz, (C(CH3)3), 126.60, 128.43, 128.84, 129.90 (d, JC-P= 9.5 Hz), 132.98, 132.99, 133.14,
31
133.34, 136.63 (d, JC-P= 8.6 Hz), 137.92 (d, JC-P= 10.4 Hz), 151.35 (d, J= 12.1 Hz); P NMR
(CDCl3) δ= 27.40 (d, JB-P= 66.0 Hz); Elemental analysis calcd (%) for C15H21BNP: C: 70.07; H:
8.23; N: 5.45; Found: C: 69.93; H: 8.41; N: 5.28. [α]D= 0 (c= 1.0 in CHCl3).
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(2-Aminophenyl)(tert-butyl)(phenyl)phosphine-P-borane (8c): To an oven-dried Schlenk tube,
(S)-(2-Aminophenyl)(tert-butyl)(phenyl)phosphine oxide (S)-(3a) (0.1845 g, 0.68 mmol) was
added and it was cooled to 0°C. 2M BH3*Me2S (2.1 mL, 4.1 mmol, 6.0 eq.) was added
dropwise and the reaction mixture was heated at 80°C for 72h. The reaction mixture was
cooled to room temperature and water (10 mL) was added. Layers were separated and the
water phase was extracted with Et2O (3x20 mL). Combined organic layers were dried over
Na2SO4, filtered and concentrated. The residue was purified via column chromatography
(Hex 100% -> Hex:Et2O 2:1) to afford the desired product as colorless oil (0.0959g, 52%, ee=
1
35.2%). H NMR (200 MHz, CDCl3); δ= 1.41 (d, 9H, J= 14.3 Hz), 6.74-7.04 (bs, 2H), 7.15-7.37
13
(m, 3H), 7.40-7.54 (m, 3H), 7.66-7.79 (m, 2H); C NMR (126 MHz, CDCl3) δ= 28.22 (C(CH3)3),
33.36 (d, JC-P= 32.4 Hz) (C(CH3)3), 126.71, 128.53, 128.91, 129.94 (d, JC-P= 10.5 Hz), 133.11,
133.23, 133.41, 136.71, 136.82, 137.91, 138.05, 151.42 (d, JC-P= 11.8 Hz); 31P NMR (CDCl3) δ=
30.53 (d, JB-P= 42.9 Hz); Elemental analysis calcd (%) for C16H23BNP: C: 70.87; H: 8.55; N: 5.17;
Found: C: C: 70.59; H: 8.68; N: 4.98. Chiral HPLC: Chiralpack AS-H, 4.6 x 250 mm;
Hexane:iPrOH (95:5), 1.0 mL/min, 254 nm, rt(minor)= 18.65 min., rt(major)= 26.24 min.
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tert-Butyl(2-(dimethylamino)phenyl)(phenyl)phosphine (7a): The (2-N,N-Dimethylaniline)-
tert-butylphenylphosphine-P-borane 8a (0.0838 g, 0.28 mmol) and 2 mL of CPME
(cyclopenthyl methyl ether) were placed in a Schlenk tube. Then an amount of
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chromatographic silica gel 60 equal to borane mass was added, and the reactor was
evacuated and refilled with argon. The 1.0 M solution of trimethylphosphine in toluene (0.9
o
mL) was added under an argon atmosphere, and the mixture was heated at 100 C for 12 h.
The mixture was cooled down to r. t. After that, the 31P NMR analysis of the reaction mixture
indicated the complete conversion of the starting complex. The solvents were removed by a
rotary evaporator. The trace amounts of volatile impurities were removed during an
additional 16 h evacuation of the obtained crude product under 5 torr pressure. The
1
resulting product (0.0800 g, 100%) didn’t need further purification. H NMR (500 MHz, C6D6)
δ= 1.24 (d, J = 12.0 Hz, 9H), 2.49 (s, 6H), 6.97-6.92 (m, 2H), 7.11-7.06 (m, 3H), 7.15-7.12 (m,
1H), 7.59-7.55 (m, 2H), 7.62 (dt, J= 7.6, 1.9 Hz, 1H); 13C NMR (126 MHz, C6D6) δ= 28.63 (d, J=
15.4 Hz), 44.88 (d, J= 4.5 Hz), 120.66 (d, J = 2.7 Hz), 123.46, 127.97, 128.19, 129.36, 134.03
(d, J= 20 Hz), 134.61, 134.75, 139.82 (d, J= 20.9 Hz), 159.05 (d, J= 19.1 Hz); 31P NMR (C6D6) δ=
6.91.
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{2-[tert-Butyl(phenyl)phosphanyl-P]-N,N-dimethylaniline-N}(dichloro)palladium (9):
A
solution of racemic (2-N,N-Dimethylaniline)-tert-butylphenylphosphine 7a (80 mg, 0.28
mmol) in 1 mL of C6D6 was slowly added to a stirred solution of Dichloro[bis(2,2-
dimethylpropanenitrile)]palladium (100 mg, 0.29 mmol) in 3 mL of C6D6. After the 48h of
stirring the precipitate was filtered off and dry under the reduced pressure to furnish 120 mg
1
(92%) of yellow amorphous complex 7. H NMR (500 MHz, CD3CN) δ= 1.51 (d, J = 16.7 Hz,
9H), 3.47 (d, J = 3.2 Hz, 6H), 7.56-7.47 (m, 4H), 7.62-7.59 (m, 1H), 7.76-7.72 (m, 1H), 7.83 (dd,
13
J = 8.5, 3.8 Hz, 1H), 7.98 (ddd, J = 11.7, 8.5, 1.3 Hz, 2H); C NMR (DEPT 135, 125.75 MHz,
CD3CN) δ= 29.2 (d, J = 3.7 Hz), 54.51, 57.25, 124.02 (d, J = 11.7 Hz), 129.73 (d, J = 11.7 Hz),
31
130.35 (d, J = 6.8 Hz), 132.66, 134.62 (d, J = 9.8 Hz), 135.04, 135.53; P NMR (CD3CN) δ=
- +
61.99; HRMS (ESI): m/z = 436.0668 [C18H24NPPd+CHO2 ] , m/z (theor.) = 436.0652, diff. = 3.67
ppm. Single crystal suitable for X-ray analysis (CCDC 1562098) was isolated by dissolution of
7 in 10 mL of hot dry CH3CN. Solution was filtered through syringe PTFE filter and left in
covered by plastic cap test tube for the crystallisation upon slow solvent evaporation for 7
days.
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General procedure for the synthesis of aryl bromides 5a-e from 2-bromobenzyl alcohol:
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Methanesulfonic anhydride (1.5 eq.) was added portionwise to a solution of 2-Bromobenzyl
alcohol 2f (1.0 eq.) and Et3N (2.0 eq.) in DCM at 0°C. After 5 minutes reaction was completed
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and quenched with water. The aquerous layer was extracted with DCM (3x). Combined
organic layers were washed with 1M HCl, brine, dried over MgSO4, filtered and evaporated.
The residue was purified via column chromatography (Hex:EtOAc 10:1) to afford product as
colorless oil (quantitatively). Spectroscopic data of 2-Bromobenzyl methanesulfonate 4 are
in agreement with literature [31].
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To a solution of 2-Bromobenzyl methanesulfonate 4 (1.0 eq.) in DCM, Et3N (2.0 eq.) and the
appropriate amine (1.1 eq.) were added. The reaction mixture was stirred at rt for 72h and
concentrated. The residue was dissolved in Et2O and washed with 1M HCl (3x). Water phase
was alkalyzed with solid NaHCO3 to pH 8-9 and extracted with Et2O (3x). Combined organic
layers were washed with water (1x), brine (1x), dried over Na2SO4, filtered and concentrated.
The residue was purified via column chromatography.
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(S)-N-(2-Bromobenzyl)-1-(naphthalen-1-yl)ethan-1-amine (5a): According to the general
procedure, (S)-5a was prepared from 2-Bromobenzyl methanesulfonate 4 (0.9194 g, 3.48
mmol), Et3N (0.97 mL, 6.96 mmol) and (S)-1-Naphthylethanamine (0.6550 g, 3.83 mmol). The
crude product was purified by column chromatography (DCM:MeOH 40:1 -> 20:1) to yield
1
(S)-5a as a yellow oil (0.8903 g, 68.9%). H NMR (500 MHz, CDCl3) δ= 1.59 (d, 3H, J= 6.6 Hz),
1.98 (bs, 1H). 3.89 (AB, 2H, J= 13.5 Hz), 4.73 (q, 1H, J= 6.6 Hz), 7.18 (dt, 1H, J= 1.7 Hz, 7.6 Hz),
7.27-7.33 (m, 1H), 7.34-7.37 (m, 1H), 7.52-7.63 (m, 4H), 7.81-7.89 (m, 2H), 7.93-7.97 (m, 1H),
8.17-8.23 (m, 1H); 13C NMR (126 MHz, CDCl3) δ= 24.80, 52.90, 53.81, 124.04, 124.15, 125.13,
126.35, 126.77, 126.84, 128.34, 128.45, 129.65, 130.00, 131.70, 132.36, 133.85, 135.05,
140.52, 141.70; (S) [α]D= -11.3 (c= 2.2 in CH2Cl2); MS (CI): 340; Elemental analysis calcd (%)
for C19H18BrN: C: 67.07; H: 5.33; N: 4.12. Found: C: 67.12; H: 5.19; N: 4.17.
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(S)-N-(2-Bromobenzyl)-1-phenylethan-1-amine (5b): According to the general procedure, (S)-5b
was prepared from 2-Bromobenzyl methanesulfonate 4 (0.6046 g, 2.29 mmol), Et3N (0.64
mL, 4.58 mmol) and (S)-1-Phenylethanamine (0.3048 g, 2.52 mmol). The crude product was
purified by column chromatography (DCM:MeOH 30:1 -> 15:1) to yield (S)-5b as a colorless
oil (0.5537g, 83.6%). Spectroscopic data are in agreement with literature [32].
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(1R,2R)-2-(Benzyloxy)-N-(2-bromobenzyl)cyclopentan-1-amine (5c): According to the general
procedure, (1R,2R)-5c was prepared from 2-Bromobenzyl methanesulfonate 4 (0.8213 g,
3.11 mmol), Et3N (0.87 mL, 6.22 mmol) and (1R,2R)-1-Amino-2-benzyloxycyclopentane
(0.6534 g, 3.42 mmol). The crude product was purified by column chromatography
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10.1002/ejoc.201800698
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(DCM:MeOH 50:1 -> 25:1) to yield (1R,2R)-5c as a colorless oil (0.8636 g, 77.3 %). H NMR
(500 MHz, CDCl3) δ= 1.37-1.47 (m, 1H), 1.67-1.79 (m, 4H), 1.95-2.07 (m, 2H), 3.13 (q, 1H, J=
4.6 Hz), 3.76-3.87 (m, 1H), 3.88 (AB, 2H, J= 14.0 Hz), 4.53 (AB, 2H, J= 11.8 Hz), 7.12 (dt, 1H, J=
13
1.6 Hz, 7.8 Hz), 7.25-7.31 (m, 2H), 7.33-7.40 (m, 5H), 7.55 (dd, 1H, J= 1.1 Hz); C NMR (126
MHz, CDCl3) δ= 21.56, 30.35, 30.89, 52.46, 63.86, 71.35, 85.80, 124.06, 127.50, 127.58,
127.77, 128.44, 128.65, 130.49, 132.87, 138.75, 139.42; (1R,2R) [α]D= - 27.5 (c= 1.7 in
CH2Cl2); MS (CI): 360; Elemental analysis calcd (%) for C19H22BrNO: C: 63.34; H: 6.15; N: 3.89.
Found: C: 63.42; H: 6.17; N: 3.95.
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(R)-2-((2-Bromobenzyl)amino)-4-methylpentan-1-ol (5d): According to the general
procedure, (R)-5d was prepared from 2-Bromobenzyl methanesulfonate 4 (0.6810 g, 2.58
mmol), Et3N (0.72 mL, 5.16 mmol) and (R)-(-)-Leucinol (0.3326 g, 2.84 mmol). The crude
product was purified by column chromatography (DCM:MeOH 50:1 -> 20:1) to yield (R)-5d as
a colorless oil (0.4358 g, 59.2 %). 1H NMR (500 MHz, CDCl3) δ= 0.84 (d, 3H, J= 4.5 Hz), 0.89 (d,
3H, J= 6.5 Hz), 1.21-1.27 (m, 1H), 1.38-1.45 (m, 1H), 1.58-1.67 (m, 1H), 2.71-2.77 (m, 1H),
3.29 (dd, 1H, J= 5.8 Hz), 3.70 (dd, 1H, J= 3.9 Hz), 3.86 (AB, 1H, J= 13.3 Hz), 7.13 (dt, 1H, J= 1.7
Hz, 7.8 Hz), 7.28 (dt, 1H, J= 1.1 Hz, 7.5 Hz), 7.36 (dd, 1H, J= 1.6 Hz, 7.5 Hz), 7.55 (dd, 1H, J=
13
1.1 Hz, 8.0 Hz); C NMR (126 MHz, CDCl3) δ= 22.84, 24.92, 41.36, 51.18, 55.98, 63.20,
124.21, 127.58, 128.89, 130.60, 132.97, 139.22; (R) [α]D= - 5.4 (c= 1.4 in CH2Cl2); MS (CI):
286; Elemental analysis calcd (%) for C13H20BrNO: C: 54.55; H: 7.04; N: 4.89. Found: C: 54.61;
H: 7.10; N: 4.92.
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(R)-(1-(2-Bromobenzyl)pyrrolidin-2-yl)methanol (5e): According to the general procedure,
(R)-5e was prepared from 2-Bromobenzyl methanesulfonate 4 (1.0637 g, 4.03 mmol), Et3N
(1.12 mL, 8.06 mmol) and (R)-(-)-Prolinol (0.4481 g, 4.43 mmol). The crude product was
purified by column chromatography (DCM:MeOH 30:1-> 5:1) to yield (R)-5e as a colorless oil
1
(1.0319 g, 86.6 %). H NMR (500 MHz, CDCl3) δ= 1.65-1.76 (m, 2H), 1.82-1.90 (m, 1H), 1.91-
2.00 (m, 1H), 2.28-2.37 (m, 1H), 2.74-2.81 (m, 1H), 2.92-2.99 (m, 1H), 3.42 (dd, 1H, J= 2.1 Hz,
10.9 Hz), 3.48 (d, 1H, J= 13.3 Hz), 3.72 (dd, 1H, J= 3.2 Hz, 10.9 Hz), 4.04 (d, 1H, J= 13.3 Hz),
7.12 (dt, 1H, J= 1.65 Hz, 7.64 Hz), 7.27 (dt, 1H, J= 1.16 Hz, 7.45 Hz), 7.37 (dd, 1H, J= 1.45 Hz,
13
7.5 Hz), 7.54 (dd, 1H, J= 1.1 Hz, 8.0 Hz); C NMR (126 MHz, CDCl3) δ= 23.73, 27.70, 54.67,
58.53, 61.88, 64.73, 124.54, 127.36, 128.74, 131.04, 132.95, 138.39; (R) [α]D= + 36.8 (c= 1.94
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in CH2Cl2); MS (CI): 270; Elemental analysis calcd (%) for C12H16BrNO: C: 53.35; H: 5.97; N:
5.18. Found: C: 53.17; H: 6.04; N: 5.22.
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(S)-tert-Butyl(2-((((S)-1-(naphthalen-1-yl)ethyl)amino)methyl)phenyl)(phenyl)phosphine oxide
(6a): According to the general procedure, (SC, SP)-6a was prepared from 5a (0.6883 g, 2.03
mmol), anhydrous K2CO3 (0.5051 g), Pd(PPh3)4 (5%-mol, 105.8 mg) and (S)-tert-Butylphenyl
phosphine oxide 1 (0.3325 g, 1.83 mmol). The crude product was purified by column
chromatography (silica, EtOAc100% - EtOAc:MeOH 20:1) to yield the product 6a as a white
1
solid (0.7103 g, 83.1%). H NMR (500 MHz, CDCl3) δ= 1.36 (d, 9H, J= 14.4 Hz), 1.39 (d, 3H, J=
6.6 Hz), 2.81 (bs, 1H), 3.72 (AB, 2H, J= 12.8 Hz), 4.47 (q, 1H, J= 6.6 Hz), 7.27-7.32 (m, 2H),
13
7.33-7.49 (m, 7H), 7.68-7.73 (m, 3H), 7.79-7.86 (m, 3H), 8.08-8.13 (m, 1H); C NMR (126
MHz, CDCl3) δ= 24.16, 25.92 (C(CH3)3), 34.48 (C(CH3)3, d, JC-P= 69.5 Hz), 51.15, 66.90, 123.35
(d, JC-P= 18.0 Hz), 125.12, 125.45, 125.84, 126.88, 128.12 (d, JC-P= 12.0 Hz), 128.82, 129.74,
130.45, 131.28, 131.43, 131.68, 131.84, 131.93, 131.99, 132.71, 133.12, 133.20, 133.42,
133.96, 141.45, 146.76 (d, JC-P= 6.3 Hz); 31P NMR (CDCl3) δ= 42.99; (SC, SP) [α]D= +69.7 (c 1.75,
CHCl3); MS (CI): 442; Elemental analysis calcd (%) for C29H32NOP: C: 78.88; H: 7.31; N: 3.17.
Found: C: 78.59; H: 7.47; N: 3.21.
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(S)-tert-Butyl(phenyl)(2-((S)-1-phenylethyl)amino)methyl)phenyl)phosphine
oxide
(6b):
According to the general procedure, (SC, SP)-6b was prepared from 5b (0.5537g, 1.92 mmol),
anhydrous K2CO3 (0.5299 g), Pd(PPh3)4 (5%-mol, 111.0 mg) and (S)-tert-Butylphenyl
phosphine oxide 1 (0.3145 g, 1.73 mmol). The crude product was purified by column
chromatography (silica, EtOAc:MeOH 30:1 - EtOAc:MeOH 10:1) to yield the product 6b as a
1
colorless oil (0.7103 g, 81.5%). H NMR (500 MHz, CDCl3) δ= 1.25 (d, 3H, J= 6.4 Hz), 1.35 (d,
9H, J= 14.6 Hz), 3.49 (d, 1H, J= 12.8 Hz), 3.67 (q, 1H, J= 6.4 Hz), 3.75 (d, 1H, J= 12.8 Hz), 7.19-
7.24 (m, 1H), 7.28-7.41 (m, 8H), 7.42-7.48 (m, 2H), 7.66 (t, 2H, J= 8.8 Hz), 7.75-7.80 (m, 1H);
13C NMR (126 MHz, CDCl3) δ= 24.69, 25.76 (C(CH3)3), 34.28 (C(CH3)3, d, JC-P= 71.9 Hz), 50.69,
57.70, 125.80 (d, JC-P= 11.8 Hz), 126.66, 127.05, 127.98, 128.07, 128.25, 129.74, 130.44,
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131.23, 131.61, 131.72, 131.81, 132.00, 132.07, 133.04, 133.11, 133.33, 133.38; P NMR
(CDCl3) δ= 43.15; (SC, SP) [α]D= +45.1 (c= 1 in CHCl3); HRMS: m/z calcd. for C25H30NOP:
392.2143 ; found: 392.2141. Elemental analysis calcd (%) for C25H30NOP: C: 76.70; H: 7.72; N:
3.58. Found: C: 76.52; H: 7.81; N: 3.57.
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