Directed ortho-lithiation of unprotected diphenylphosphinic acids

Article abstract of DOI:10.1016/j.tet.2012.06.088

Directed ortho lithiation of diphenylphosphinic acid and subsequent electrophilic trapping provides mono ortho-functionalized derivatives including enantiopure γ-aminophosphinic acids in moderate yields. Copper catalyzed coupling of the ortho anion leads to biphenyl-2,2′- diylbis(phenylphosphinic acid), a phosphorus analogue of biphenyl-2,2′- dicarboxylic acid. Preliminary studies of the metal-binding abilities of this O,O-chelating ligand towards a series of metal cations are included.

Full text of DOI:10.1016/j.tet.2012.06.088

Tetrahedron 68 (2012) 7355e7362
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Directed ortho-lithiation of unprotected diphenylphosphinic acids
ꢀ
ꢀ
*
~
ꢀ
ꢀ
Víctor Yanez Rodríguez, Miguel Angel del Aguila, María Jose Iglesias, Fernando Lopez Ortiz
ꢀ
ꢀ
Area de Química Organica, Universidad de Almería, Carretera de Sacramento, 04120 Almería, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Directed ortho lithiation of diphenylphosphinic acid and subsequent electrophilic trapping provides
mono ortho-functionalized derivatives including enantiopure -aminophosphinic acids in moderate
yields. Copper catalyzed coupling of the ortho anion leads to biphenyl-2,20-diylbis(phenylphosphinic
acid), a phosphorus analogue of biphenyl-2,20-dicarboxylic acid. Preliminary studies of the metal-binding
abilities of this O,O-chelating ligand towards a series of metal cations are included.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 27 March 2012
Received in revised form 8 June 2012
Accepted 21 June 2012
g
Available online 28 June 2012
Keywords:
ortho-Lithiation
Phosphinic acid
ortho-Functionalization
g-Aminophosphinic acid
Bisphosphinic acid
1. Introduction
Directed ortho-lithiation (DoLi) has become a valuable method
for the regiospecific construction of polysubstituted aromatic sys-
tems in academe1,2 and industry.3 The method consists of a one-pot
process, in which an aromatic proton ortho to a polar functional
group (directing ortho-metallation group, DoM) is selectively ab-
stracted by a base and the anion formed is used in carbonecarbon
and carboneheteroatom bond forming reactions through in situ
trapping with a variety of electrophiles. The role of the DoM group
is threefold: increase the acidity of the ortho protons, facilitates the
approach of the lithium base to the deprotonation site and con-
tributes to the stabilization of the ortho lithiated species through
intramolecular coordination (Scheme 1).
A variety of functional groups based on phosphonic and phos-
phinic acid moieties have shown their ability to direct metallation to
the orthoposition ofa P-phenylring. Theyinclude esters, amides and
thioamides.4,5 Since these compounds are derivatives of the corre-
sponding acids, a more straightforward procedure would be the
ortho functionalization of the unprotected organophosphorus acids
themselves. The process would involve the initial deprotonation of
the OH linkage and the eP(]O)Oꢀ group formed may be too weak
for promoting a ring ortho-metallation that would lead to a dime-
tallated species. Ortho-lithiations directed by X(]O)YH functional
groups containing acidic protons, such as eCO2H,6 eCONHR,7
eCSNHR,8 eCONHOR,9 eNHCOR,10 eNHCOOR,11 eNRCOOLi,12
Scheme 1. Ortho-lithiation directed by X(]O)YH groups and electrophilic trapping.
Carbon/heteroatom-based refers to the atom connecting the functional group to the
aromatic ring.
eSONHR,13 eSO3H,14 eSO2NHR,15 SO2NHNR2,16 (tBu)S(]O)
(]NH),17 and ePONHR,5b have been reported (Scheme 1).
Unsymmetrical diarylphosphinic acids are commonly prepared
utilizing stepwise procedures involving mostly nucleophilic dis-
placement of P-halogen bonds18 or palladium-catalyzed cross-
coupling reactions of phosphinate19 and have attracted consider-
able attention in the last decades due to their applications.19c
Phosphinic acids are phosphorus analogues of carboxylic acids
showing a broad range of applications in areas as diverse as in-
dustrial,20 agricultural,21 medicinal,22 and synthetic organic and
ꢀ
* Corresponding author. E-mail address: flortiz@ual.es (F. Lopez Ortiz).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.088

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V. Yanez Rodríguez et al. / Tetrahedron 68 (2012) 7355e7362
organometallic chemistry.18b,23 In addition, the tetrahedral phos-
phinic acid moiety mimics the transition state of enzymatic amide
formation or hydrolysis.19b,24 These features make amino-
phosphinic acids particularly interesting compounds as useful en-
zyme inhibitors with potential therapeutic activity.25
Table 1
Ortho functionalization of diphenylphosphinic acid 1 through sequential ortho-
lithiation/electrophilic quench
Here we describe the direct synthesis of unsymmetrical
diarylphosphinic acids through ortho-lithiation of diphenylphos-
phinic acid followed by electrophilic trapping reactions. The pro-
cess provides access to a variety of derivatives containing new
ortho CeC and C-heteroatom bonds. In addition, oxidative coupling
of the ortho anion gives access to a new bis(phosphinic acid) that
behaves as an O,O-chelating ligand.
2. Results and discussion
Firstly, optimized conditions for the ortho deprotonation of
diphenylphosphinic acid26 1 were evaluated. The degree of ortho-
lithiation was determined through the reaction of dianion 2 with
MeI to give the ortho-methyl derivative 3. After some experimen-
tation, we found that the treatment of 1 with 4 equiv of t-BuLi at
ꢀ35 ꢁC in THF during 6 h and subsequent quench with MeI afforded
after 2 h of reaction phenyl(o-tolyl)phosphinic acid 3 in a conver-
sion of 80% (Scheme 2). Less than 8% of the di(ortho-tolyl) derivative
was detected. Similar results were obtained by using n-BuLi/
TMEDA as a base and performing the reaction at room temperature
during 2 h. The use of temperatures relatively high as compared
with other DoLi processes involving non metallated functional
groups, typically in the range of ꢀ90 to ꢀ70 ꢁC,1 indicates that the
lithium phosphinate is a rather poor activating group of P-phenyl
ortho-deprotonation. Purification of 3 through column chroma-
tography proved to be cumbersome due to strong interactions be-
tween the phosphinic acid moiety and the solid support. Using
CH2Cl2:methanol (10:1) as eluent the product was isolated in 36%
yield. Better results were achieved through pre-column de-
rivatization. The reaction of 3 with iodomethane and potassium
carbonate afforded the corresponding methyl phosphinate 3a that
could be isolated in good yield (68%).
Entry Comp.
Eþ
R1
R2
R3
Yield (%)
1
2
3
4
5
3(3a)a MeI
Me
Br
I
SnMe3
PhCHNHPh
36 (68)
36b
4
PhCH2Br
5(5a)a ICH2CH2I
38b (70)
68
6
7
Me3SnCl
PhCH]NPh
39
6
7
8
iPrCHNHS(O)tBu
19
9
iPrCHNHS(O)tBu
CH2OH
45c
8
9
10
11
12
13
10
11
12
13
14
15
DMFd
34e
DMFd
H
H
26 (55)e
67
Me2CO
CH3CHO
PhCHO
Me Me
H
H
H
CH3
Ph
50f
43g
HO(CH2O)nH
(CH2)2OH 37h
a
Derivatized as the methyl phosphinate.
Isolated as the triethylamonium salt.
Isolated as the methyl ester of the product of electrophilic quench. Mixture 1:1
b
c
of P-epimers.
d
10 equiv of electrophile were used.
Obtained by in situ reduction of the crude mixture with NaBH4. Yield given in
e
solvent
brackets corresponds to the reaction processed with 6 N HCl (see text).
f
Overall yield. Ratio of l:u stereoisomers formed of 1.1:1, isolated in two chro-
matographic fractions as mixtures of composition 4.1:1 and 1:3.9.
g
Ratio of l:u stereoisomers formed of 1.6:1, isolated as a mixture 3.6:1.
Small amounts of compounds 10 (8%) and 11 (10%) were also formed.
h
t
n
the reaction might proceed via a radical mechanism.27 Ortho io-
dination was achieved by treating anion 2 with ICH2CH2I to give 5
(conversion of 70%, entry 3) in acceptable yield (70% for the methyl
ester 5a). Stannylation with Me3SnCl takes place more efficiently.
The ortho-trimethylstannyl derivative 6 was isolated in 68% yield
(entry 4). Products 5 and 6 are valuable intermediates for further
derivatization via transition metal catalyzed cross-coupling re-
Mel,
Scheme 2. Optimization of the ortho-lithiation/methylation of 1. Conversions were
determined through 31P NMR of the crude reaction mixture.
Once suitable reaction conditions for ortho-lithiation of 1 were
established, the scope of the transformation was investigated by
allowing to react anion 2 with a variety of electrophiles. In all cases,
ortho deprotonation was achieved with the less hazardous and
cheaper base n-BuLi in the presence of the chelating diamine
TMEDA. The results obtained are shown in Table 1. The new prod-
ucts obtained were isolated through column chromatography using
mixtures of ethyl acetate/hexane and methylenedichloride/meth-
anol as eluent (see Supplementary data). Generally, conversions to
products above 60% were observed in the 31P NMR spectra of the
crude reaction mixtures. The performance of the purification im-
proved by transforming the unproctected phosphinic acid into the
corresponding methyl ester.
actions.28 The reaction with benzaldimine furnished
g-amino-
phosphinic acid 7 in a yield of 39% (conversion of 68%, entry 5).
Chirality was introduced by using the chiral sulfinamide
(R)-iPrCH]NS(O)tBu29 as electrophile. Compound 8 was isolated as
a single diastereoisomer, albeit in low yield (entry 6). The NMR
spectrum of the crude reaction mixture showed very broad signals
that prevented the identification of possible stereoisomers.
The degree of asymmetric induction of the process was estab-
lished indirectly. The g-aminophosphinic acid 8 was converted into
the corresponding methyl ester 9 by refluxing the crude reaction
mixture with MeI in acetone in the presence of K2CO3 during 3 h
(Scheme 3). The methyl phosphinate 9 was obtained as a 1:1
mixture of diastereoisomers epimers in the configuration of the
phosphorus atom (entry 7). Since the esterification step is expected
The reaction with benzyl bromide led to the product of bromine
transfer 4 (entry 2). Products of ortho-benzylation were not
detected through NMR analysis of the crude reaction mixture. This
unexpected halogen abstraction by the ortho anion 2 suggests that

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V. Yanez Rodríguez et al. / Tetrahedron 68 (2012) 7355e7362
7357
to proceed without stereocontrol, this result indicates that the
addition of 2 to the chiral imine takes place with very high dia-
stereroselectivity (dr>95:5). In addition, esterification of 8 fav-
oured the isolation of compound 9 in a yield of 45%. The
configuration of the carbon stereocenter remains unknown. Un-
fortunately, all attempts of obtaining crystals of either 8 or 9 suit-
able for X-ray diffraction failed.
from the NOEs observed by selective inversion of the respective
benzylic protons. This proton of isomer l-15 produced a strong NOE
with the ortho protons of the P-phenyl ring (Supplementary data).
Since phospholactones 15 apparently involve the unprecedented
participation of formaldehyde in the tandem creation of three
carbonecarbon bonds driven by an ortho anion,31 we performed
additional experiments to ascertain the origin of the 1,3-
propanediol moiety present in 15. It is well known that organo-
lithiums produce the fragmentation of THF32 via deprotonation
a to
oxygen to give a C-2 anion that undergo [3þ2] cycloreversion fur-
nishing ethylene and the lithium enolate of acetaldehyde (see
Scheme 4).33a The latter may function as a source of alkoxy frag-
ments that could participate in the formation of 15. To validate this
hypothesis we carried out the reaction of dianion 2 with para-
formaldehyde in THF-d8 under exactly the same reaction conditions
used in the synthesis of 15. The 31P NMR spectrum of the crude
reaction mixture showed two principal differences with respect to
the reaction in THF: a lower conversion to products with a chemical
shift characteristic of l-15 (dP 48.65 ppm) and u-15 (dP 48.87 ppm)
and a significant increase of the amount of 10 (30%) and 11 (14%)
obtained (Scheme 4). Most importantly, the multiplets for the
protons of the eCH(O)CH2e fragment were not present in the 1H
NMR spectrum.
Scheme 3. Synthesis of enantiopure
g-aminophosphinic acid derivatives via DoM
methodology.
Compounds 8 and 9 are phosphorus analogues of
g-amino-
butyric acid, the major inhibitory neurotransmitter in the mam-
malian central nervous system. They represent an important class
of compounds due to their properties as therapeutic agents.30 For
further applications in synthesis it is interesting to have access to
derivatives selectively protected in each functional group. Depro-
tonation of the OH of 8 with K2CO3 and subsequent methylation
with MeI gave the amino acid 9 (mixture 1:1 of P-epimers) with the
phosphinic acid moiety protected as a methyl ester (Scheme 3).
Removal of the sulfinyl moiety of 8 and 9 could be accomplished by
reaction with 12 M HCl in methanol during 3 days (Scheme 3). In
this way were obtained the N- and O-unprotected
g-amino-
phenylphosphinic acid 16 (25% yield) and the N-unprotected
methyl ester 17 (75% yield) (Scheme 3).
DMF reacted with anion 2 to yield a mixture of acyclic and cyclic
derivatives with a conversion of 85% that could not be separated.
Fortunately, in situ reduction of the adducts with NaBH4 lead to
a mixture of the ortho-hydroxymethylated phosphinic acid 10 and
the corresponding product of cyclocondensation 11 in a ratio of
56:44 that could be separated through column chromatography
(entries 8 and 9). Compound 10 was quantitatively converted into
11 by treating the crude reaction mixture with 6 N HCl during
workup. The use of acetone, acetaldehyde and benzaldehyde as
electrophiles produced alcoholate derivatives that undergo cyclo-
condensation to give oxaphospholones 12, 13 and 14, respectively
(entries 10e12). Compounds 13 and 14 consisted of mixtures of like
and unlike isomers. In both cases, the diastereoselectivity was low
and improved slightly through chromatographic purification (Table
1). The relative configuration of each isomer was assigned based on
1D gNOESY spectra.
Scheme 4. Mechanism proposed for the formation of 15 in the reaction of 2 with
paraformaldehyde.
Purification through column chromatography allowed to isolate
15-d3 (mixture of l/u diastereoisomers). The high resolution mass
spectrum confirmed the incorporation of 3 deuteriums ([Mþ1]þ
278.1018) as compared with 15. The positions deuterated were
identified as C-13 and C-14 based on the absence of the signals for
H-13 and H-14 in the 1H NMR spectrum and the multiplicity of
these carbons in the 13C NMR spectrum. Scheme 4 shows the two
Paraformaldehyde proved to be also a suitable electrophile for
functionalizing anion 2. However, the reaction proceeded in an
unexpected manner. The anticipated products 10 and 11 were
obtained in a very small conversion (<20%). They were identified in
the 31P NMR spectrum of the crude reaction mixture based on their
characteristic chemical shift. The major reaction products formed
triplets of relative intensity 1:1:1 observed for C-13 (dl/du 81.56/
were the diastereomeric g-phospholactones l-15 and u-15 in a ratio
81.45 ppm) due to the coupling with one deuterium of spin I¼1,
1JCD¼22.9 Hz. The signals of C-14 appear as unresolved multiplets
centred at dC 39.05 (u) and 39.35 (l) ppm (Supplementary data).
of 1.5:1 (entry 13). The structure of 15 was unequivocally assigned
through the analysis of the 1D (1H, 13C, DEPT135, 31P) and 2D NMR
spectra (COSY, HMQC, HMBC) and the stereochemistry deduced

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7358
These results establish that products of decomposition of THF by
standard. Assuming a coordination number of six for Y3þ, a first
sample was prepared by mixing the ligand and the yttrium salt in
a ratio 1:0.3. After sonication for 15 min, the 1H NMR spectrum of
the supernatant showed the presence of a 50% of free ligand 21.
When a 1:1 stoichiometry was used, the 1H NMR spectrum of the
solution consisted of the signals of the standard exclusively.
the base are involved in the pathway leading to compound 15. In
agreement with this conclusion, when the reaction was achieved
using toluene as solvent the only products observed were 10 and 11,
albeit in a very low conversion (17%). A reaction mechanism
explaining the formation of 15-d3/15 is shown in Scheme 4.The per-
deuterated lithium enolate 19 arising from the
a
lithiation of THF-
33a
d8
reacts with paraformadehyde to give the trideuterated aldol
3. Conclusions
adduct 20. Addition of the ortho anion 2 to the carbonyl group of 20
followed by cyclocondensation during acidic workup would yield
15-d3. The increase of the conversion of 10 and 11 observed in the
reaction in THF-d8 is assigned to a primary isotope effect.34 De-
composition of THF-d8 would proceed at a slower rate thanTHF, thus
increasing the probabilities of reaction of anion 2 with para-
formaldehyde. Clearly, decomposition of THF takes place in all re-
actions shown in Table 1. This explains the need for a large excess of
base to achieve the ortho lithiation of 1 in high yield. Compounds
analogue to 15 were observed in the reaction of 2 with acetaldehyde
in less than 10% of conversion.1D TOCSYexperiments performed on
the crudereaction mixturewith selectiveexcitationofH-13 revealed
the whole spin system arising from the aliphatic protons
(OeCH(Ar)eCH2CH(OH)CH3). These compounds were not detected
in the reaction with benzaldehyde. The high reactivity of para-
formaldehyde appears to favourthe indiscriminatereactionwith the
nucleophiles present in the reaction medium, the ortho anion 2 and
the acetaldehyde enolate provided by the THF fragmentation.
The utility of ortho-lithiation of diphenylphosphinic acid was
further extended to the synthesis of the biphenyl-2,20-diylbis-
(phenylphosphinic acid) 21 through Cu(I) catalysed oxidative cou-
pling following the method described by Spring et al. for the
preparation of 2,2-biarylcarboxylates.35 Thus, by allowing to react
anion 2 with 0.5 equiv of CuBr$SMe2 or CuCN in the presence of
2.5 equiv of 1,3-dinitrobenzeno at room temperature during 2 h the
biphenylic diacid 21 was obtained in a yield of 45% (Scheme 5).
In conclusion, we have developed a general method for the syn-
thesis of mono ortho-substituted diphenylphosphinic acids through
ortho lithiation of unprotected diphenylphosphinic acid followed by
electrophilic quench. Carbon- and heteroatom-centred electrophiles
can be used for the ortho functionalization of the parent compound. In
the particular case of paraformaldehyde and acetaldehyde as elec-
trophiles, the reaction includes a tandem process, in which the ortho
anion is quenched by the aldol adduct formed in the reaction of
formaldehyde with the acetaldehyde enolate generated in the de-
composition of the solvent by the base. Enantiopure
g-amino-
phosphinic acids were obtained by trapping the ortho anion with
a chiral sulfinylimine. The product was further elaborated to synthe-
size unproctected or selectively N- and O-protected derivatives. Oxi-
dative coupling of the ortho anion afforded biphenyl-2,20-
diylbis(phenylphosphinicacid) 21, anO,O-chelating ligand structurally
related with biphenic acid, inwhich the C]O group has been replaced
by a tetrahedral PhP]O moiety. Compound 21 showed promising
coordination properties. Even though the unsolubility of the com-
plexes formed prevented their characterization, this behaviour in-
dicates that diacid 21 may be a usefulagent for metal decontamination
of fluids. Further studies in this field are currently under investigation.
4. Experimental section
4.1. General experimental conditions
The reactions involving organolithium reagents were performed
under an inert atmosphere of nitrogen using Schlenk techniques.
The solvents were dried prior to use in a Pure Solv 400-4-MD
system, according to the procedure described by Pangborn and
Grubbs.38 Commercial reagents t-BuLi, n-BuLi, IMe, para-
formaldehyde were used as obtained from commercial sources
without further purification. TMEDA was dried over CaH2 and
distilled under reduce pressure. Benzaldehyde, aniline and chlor-
odiphenylphosphine were distilled before use. TLC was performed
on Merck plates with aluminium backing and silica gel 60 F254. For
Scheme 5. Synthesis of biphenyl-2,20-diylbis(phenylphosphinic acid) 21 by oxidative
coupling of 2.
column chromatography silica gel 60 (230e400 mesh
mm) was
Diacid 21 is a phosphorus analogue of diphenic acid (2,20-
biphenyldicarboxylic acid), an important chelating ligand that has
been extensively used in the preparation of coordination polymers
used. NMR spectra were recorded in CDCl3, CD3OD or DMSO-d6 on
a Bruker Avance DPX300 (1H, 300.13 MHz; 13C, 75.47 MHz; 31P,
121.47 MHz) equipped with a QNP 1H/13C/19F/31P probe and
a Bruker Avance 500 spectrometer (1H, 500 MHz; 13C, 125.7 MHz;
31P, 202.4 MHz) using a TBO 1H/31P/BB probe (only for compound
16). Chemical shifts are referred to internal tetramethylsilane for 1H
of a large number of metals showing a variety of applications.36
A
preliminary study of the complexation ability of 2137 showed the
quantitative formation of a precipitate in the presence of salts of
Cu(II), Zn(II), Eu(III) and Y(III). The solids obtained proved to be
insoluble in all solvents (H2O, methanol, ethanol, THF, toluene,
DMF, DMSO, diethyl ether, hexane, nitrobencene) and temperatures
(up to 210 ꢁC, refluxing nitrobencene) assayed. Although this be-
haviour supports the formation of coordination complexes no
structural information could be obtained. The equimolar mixture of
21 and Y(NO3)$6H2O in HNO3 as solvent afforded a homogeneous
solution, from which 1H and 31P NMR spectra were measured.
However, a solution of 21 in nitric acid devoid of the yttrium salt
provided the same spectra, i.e., the nitric acid displaced the metal
ion from the coordination sphere of the ligand. Indirect evidence
about the complexation ability of 21 was obtained through quan-
titative 1H NMR analysis of samples containing diacid 21 and
Y(NO3)3$6H2O in MeOH-d4 using cyclooctadiene as internal
and 13C and to external 85% H3PO4 for 31P. Chemical shifts (
d) are
quoted in parts per million (ppm) and coupling constants (J) are
measured in Hertz (Hz). Mass spectra were determined on an LC-
MS apparatus (APCI ionization mode). High resolution mass spec-
trometry (HRMS) spectra were measured using a LC/MSD-TOF
Agilent Technologies instrument. Infrared spectra were obtained
in KBr pellets or using ATR techniques. Elemental analyses were
registered on Carlo Erba Instruments EA 1108 CHNS-O.
4.2. General procedure for the synthesis of o-substituted
phosphinic acids 3e10 and phosphinates 11e15
Over
a solution of diphenylphosphinic acid 1 (150 mg,
0.69 mmol) and TMEDA (0.88 mL, 8.8 equiv) in THF (5 mL) at room

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V. Yanez Rodríguez et al. / Tetrahedron 68 (2012) 7355e7362
7359
temperature, was added a solution of n-BuLi (1.9 mL of a 1.6 M
(5%) (CH2Cl2:methanol, 20:1) 36% (101 mg); oil;
n
(KBr) 3426, 1188,
solution in hexane, 4.4 equiv). The lithiation was allowed to pro-
ceed during 2 h and then the corresponding electrophile was added
(4.4 except for DMF where 10 equiv were used). After 2 h of addi-
tional stirring, the reaction mixture was poured into a 1 N HCl
solution, extracted with CH2Cl2 and dried over Na2SO4. The organic
layers were concentrated in vacuo. 1H, 1H{31P}, and 31P{1H} NMR
spectra of the crude reaction mixture were measured in order to
establish the performance of the reaction. For the reaction with
DMF as electrophile 8 equiv of NaBH4 (0.21 g) in MeOH (2 mL) were
added prior to the quenching step. The reduction was allowed to
proceed during 1 h and then processed according to the procedure
described above. The products were purified by flash chromatog-
raphy using mixtures of AcOEt, hexane, CH2Cl2 and methanol
(Chart 1).
1129 cmꢀ1 dH (CD3OD) 1.28 (t, 9H, 3JHH 7.4 Hz, H14), 3.16 (q, 6H, 3JHH
;
5
3
4
7.4 Hz, H13), 7.30 (ddt, 1H, JPH 1.0, JHH 7.7, JHH 1.7 Hz, H6),
7.33e7.44 (m, 4H, H7, H11, H12), 7.55 (ddd, 1H, 4JPH 3.7, 3JHH 7.7, 4JHH
1.2 Hz, H5), 7.76 (ddd, 2H, 3JPH 12.3, 3JHH 7.7, 4JHH 1.7 Hz, H10), 8.12
(ddd, 1H, 3JPH 11.7, 3JHH 7.7, 4JHH 1.9 Hz, H8); dC (CD3OD) 7.67 (C14),
2
3
46.08 (C13), 125.41 (d, JPC 5.7 Hz, C4), 126.22 (d, JPC 10.2 Hz, C7),
127.20 (d, 3JPC 12.9 Hz, C11), 129.68 (d, 4JPC 2.9 Hz, C-12), 131.31 (d,
4
3
2JPC 9.9 Hz, C-10), 131.49 (d, JPC 2.3 Hz, C6), 133.52 (d, JPC 8.3 Hz,
C5),134.56 (d, 2JPC 7.2 Hz, C8),138.10 (d, 1JPC 138.0 Hz, C9),138.59 (d,
1JPC 129.9 Hz, C3); dP (CD3OD) 18.80; MS (m/z): 297 (Mþ1), 102 (M,
Et3NHþ).
4.2.4. Triethylammonium 2-iodophenyl(phenyl)phosphinate (5). Yield
after chromatography on silica gel impregnated with Et3N (5%)
(CH2Cl2:methanol, 20:1) 38% (118 mg); oil; n (KBr) 3395, 1190, 1131,
1098, 1053 cmꢀ1 dH (CD3OD) 1.26 (t, 9H, 3JHH 7.4 Hz, H14), 3.13 (q,
;
6H, 3JHH 7.4 Hz, H13), 7.08 (ddt, 1H, 5JPH 1.3, 3JHH 7.7, 4JHH3 1.8 Hz, H6),
4
4
7.33e7.40 (m, 3H, H11, H12), 7.44 (ddt, 1H, JPH 1.0, JHH 7.7, JHH
1.0 Hz, H7), 7.76 (ddd, 2H, 3JPH 12.2, 3JHH 7.7, 4JHH 1.7 Hz, H10), 7.91
4
4
3
(ddd, 1H, JPH 3.5, 3JHH 7.7, JHH 1.1 Hz, H5), 8.12 (ddd, 1H, JPH 11.7,
3JHH 7.7, 4JHH 1.9 Hz, H8); dC (CD3OD) 7.70 (C14), 45.95 (C13), 98.42
(d, 2JPC 7.4 Hz, C4), 126.88 (d, 3JPC 10.5 Hz, C7),127.23 (d, 3JPC 13.0 Hz,
C11), 129.65 (d, 4JPC 2.7 Hz, C12), 131.20 (d, 4JPC 2.6 Hz, C6),131.66 (d,
2JPC 9.9 Hz, C10), 134.28 (d, 2JPC 8.1 Hz, C8), 137.64 (d, 1JPC 136.8 Hz,
3
1
C9), 140.94 (d, JPC 9.8 Hz, C5), 141.90 (d, JPC 130.8 Hz, C3); dP
(CD3OD) 20.24; MS (m/z): 345 (Mþ2), 102 (M, Et3NHþ).
4.2.5. Methyl 2-iodophenyl(phenyl)phosphinate (5a). Yield after
chromatography (AcOEt:hexane, 1:1) 70% (110 mg); oil;
n
(ATR)
3
1225, 1034 cmꢀ1
; dH (CDCl3) 3.77 (d, 3H, JPH 11.4 Hz, H13), 7.30
4
3
4
(ddt, 1H, JPH 1.3, JHH 7.8, JHH 1.7 Hz, H7), 7.57 (m, 4H, H11, H12,
4
H6), 7.78 (m, 2H, H10), 8.03 (ddd, 1H, JPH 4.3, 3JHH 7.9, 4JHH 1.1 Hz,
3
3
4
H5), 8.07 (ddd, 1H, JPH 12.3, JHH 7.6, JHH 1.6 Hz, H8); dC (CDCl3)
2
2
3
51.01 (d, JPC 6.0 Hz, C13), 97.32 (d, JPC 9.1 Hz, C4), 127.74 (d, JPC
11.7 Hz, C7), 128.34 (d, JPC 13.5 Hz, C11), 128.91 (d, 1JPC 142.9 Hz,
3
Chart 1. Scheme numbering used for the NMR assignments of the new compounds
synthesized.
C9), 132.03 (d, 2JPC 10.8 Hz, C10), 132.52 (d, 4JPC 3.0 Hz, C12), 133.77
(d, 4JPC 3.0 Hz, C6) 133.45 (d, 1JPC 142.5 Hz, C3), 135.25 (d, 2JPC 8.4 Hz,
C8), 141.86 (d, 1JPC 10.8 Hz, C7); dP (CDCl3) 34.87; HRMS (ESI) calcd
for C13H13IO2P: 358.9698 (MHþ), found: 358.9691.
4.2.1. (2-Methylphenyl)phenylphosphinic acid (3). Yield after chro-
matography (CH2Cl2:methanol, 10:1) 36% (57 mg); oil;
n (KBr) 3397,
1156, 1138, 1127 cmꢀ1
;
dH (CD3OD) 2.37 (s, 1H, H13), 7.16 (dd, 1H,
4JPH 4.2, 3JHH 7.5 Hz, H5), 7.23 (bt, 1H, 3JHH 7.5 Hz, H7), 7.39 (m, 4H,
H6, H11, H12), 7.71 (ddd, 2H, 3JPH 12.1, 3JHH 7.7, 4JHH 1.5 Hz, H10), 7.95
(ddd,1H, 3JPH 12.5, 3JHH 7.5, 4JHH 1.2 Hz, H8); dC (CD3OD) 21.74 (d, 3JPC
4.0 Hz, C13), 126.04 (d, 3JPC 12.0 Hz, C7), 128.94 (d, 3JPC 12.5 Hz, C11),
131.45 (d, 4JPC 2.6 Hz, C12), 131.94 (d, 3JPC 11.7 Hz, C5), 131.89 (d, 4JPC
2.5 Hz, C6), 132.20 (d, 2JPC 10.1 Hz, C10), 133.75 (d, 2JPC 9.0 Hz, C8),
136.39 (d, 1JPC 131.3, Hz, C3), 139.20 (d, 1JPC 132.0, Hz, C9), 142.35 (d,
2JPC 10,4 Hz, C4); dP (CD3OD) 23.71; MS (m/z): 254.9 (MþNa), 277.0
(Mþ2Na-1).
4.2.6. Phenyl(2-(trimethylstannyl)phenyl)phosphinic acid (6). Yield
after chromatography on silica gel impregnated with Et3N (5%)
(CH2Cl2:methanol, 20:1) 68% (180 mg); white solid mp
260e261 ꢁC;
n
(KBr) 3395, 3052, 1126, 1104 cm
; dH (CD3OD) 0.61
ꢀ1
(s, 9H, H13), 7.40 (m, 4H, H7, H11, H12), 7.48 (bt, 1H, 3JHH 6.6 Hz, H6),
7.67 (dd, 1H, 2JPH 11.0, 3JHH 6.6 Hz, H8), 7.73 (ddd, 2H, 3JPH 11.2, 3JHH
4
7.6, JHH 1.6 Hz, H10), 7.97 (bd, 1H, H5); dC (CD3OD) -3.47 (C13),
127.59 (d, JPC 12.5 Hz, C11), 128.25 (d, 3JPC 12.3 Hz, C7), 129.48 (d,
3
4JPC 2.7 Hz, C6), 130.08 (d, JPC 2.1 Hz, C11), 130.85 (d, JPC 9.9 Hz,
4
2
C10), 130.95 (d, 2JPC 13.5 Hz, C8), 135.00 (d, 3JPC 14.9 Hz, C5), 138.00
1
1
2
4.2.2. Methyl (2-methylphenyl)phenylphosphinate (3a). Yield after
(d, JPC 132.5 Hz, C9), 143.52 (d, JPC 134.0 Hz, C3), 147.66 (d, JPC
chromatography (AcOEt:hexane, 1:1) 68% (77 mg); oil;
1224, 1034 cmꢀ1
dH (CDCl3) 2.43 (bs, 3H, H13), 3.76 (d, 3H, JPH
11.2 Hz, H14), 7.21 (m, 1H, H5), 7.28 (m, 1H, H7), 7.48 (m, 4H, H11,
n
(ATR),
15.3 Hz, C4); dP (CD3OD) 26.60; MS (m/z): 367 (Mꢀ15).
3
;
4.2.7. Phenyl(2-(phenyl(phenylamino)methyl)phenyl)phosphinic acid
(7). Yield after chromatography (AcOEt/AcOEt:MeOH 10:1) 39%
3
3
4
H12, H6), 7.75 (ddd, 2H, JPH 12.7, JHH 7.8, JHH 1.4 Hz, H10), 7.89
(ddd, 1H, 3JPH 12.9, 3JHH 7.8, 4JHH 1.4 Hz, H8); dC (CDCl3) 21.14 (d, 3JPC
(106.5 mg); oil;
n (KBr) 3397, 3053, 2924, 1665, 1598, 1179,
3
3
4.2 Hz, C13), 51.15 (d, 2JPC 5.4 Hz, C14), 125.45 (d, JPC 12.0 Hz, C7),
1131 cmꢀ1
; dH (CD3OD) 6.41 (d, 2H, JHH 7.8 Hz, H20), 6.52 (t, 1H,
128.43 (d, 3JPC 13.2 Hz, C11), 128.94 (d, 1JPC 135.2 Hz, C9), 131.42 (d,
3JPC 12.4 Hz, C5), 131.45 (d, 1JPC 134.8 Hz, C3), 131.57 (d, 2JPC 10.8 Hz,
C10), 132.01 (d, 4JPC 3.0 Hz, C12),132.36 (d, 4JPC 2.3 Hz, C6),133.17 (d,
2JPC 9.0 Hz, C8), 141.92 (d, 2JPC 11,4 Hz, C4); dP (CDCl3) 34.72; HRMS
(ESI) calcd for C14H15O2P: 247.0888 (MHþ), found: 248.0889.
3JHH 7.2 Hz, H22), 6.57 (s, 1H, H13), 6.92 (dd, 2H, JHH 7.8 Hz, JHH
7.8 Hz, H21), 7.06e7.35 (m, 11H, H5, H6, H7, H11, H12, H16, H17,
H18), 7.62 (ddd,, 3JPH 11.9, 3JHH 6.9, 4JHH 1.3 Hz, H10), 8.15 (ddd, 3JPH
11.8, 3JHH 6.6, 4JHH 1.8 Hz, H8); dC (CD3OD) 59.15 (d, 3JPC 3.6 Hz, C13),
115.24 (C20), 117.88 (C22), 127.28 (C18), 127.41 (d, 3JPC 11.1 Hz, C5),
3
3
3
128.59 (d, JPC 12.4 Hz, C11), 128.68 (C16), 128.95 (C17), 129.34
4.2.3. Triethylammonium 2-bromophenyl(phenyl)phosphinate (4).
Yield after chromatography on silica gel impregnated with Et3N
(C21), 130.53 (d, 3JPC 10.6 Hz, C7), 130.80 (d, 4JPC 2.5 Hz, C12), 131.81
(d, 4JPC 2.3 Hz, C6),132.19 (d, 2JPC 10.1 Hz, C10), 134.27 (d, 2JPC 8.4 Hz,

~
7360
V. Yanez Rodríguez et al. / Tetrahedron 68 (2012) 7355e7362
4
2
C8), 138.15 (d, 1JPC 127.2 Hz, C3), 140.60 (d, 1JPC 132.5 Hz, C9), 144.73
(C15), 147.08 (d, 2JPC 9.8 Hz, C4), 148.85 (C19); dP (CD3OD) 20.37; MS
(m/z): 444.0 (Mþ2Na-1).
C12), 132.81 (d, JPC 3.0 Hz, C6), 148.75 (d, JPC 18.62 Hz, C4); dP
(CDCl3) 47.29; HRMS (ESI) calcd for C14H14O2P: 245.0731 (MHþ),
found: 245.0720.
4.2.8. 2-(1-(1,1-Dimethylethylsulfinamido)-2-methylpropyl)phenyl
4.2.13. 1,3-Diphenyl-1,3-dihydro-2,1-benzoxaphosphole 1-oxide (u/l-
14). 1,3-Diphenyl-1,3-dihydro-2,1-benzoxaphosphole 1-oxide (u/l-
14)Yield after chromatography (CH2Cl2:MeOH, 10:1) 43% (57 mg),
(phenyl)phosphinic
acid
(8). Yield
after chromatography
(CH2Cl2/CH2Cl2:MeOH, 10:1) 19% (50 mg); oil; dH (DMSO-d6,
130 ꢁC) 0.09 (d, 3H, 3JHH 6.1 Hz, H18), 0.80 (d, 3H, 3JHH 6.3 Hz, H-19),
1.11 (s, 9H, H16), 1.88 (m, 1H, H17), 7.00e7.13 (m, 3H, ArH),
7.20e7.36 (m, 2H, ArH), 7.47 (m, 1H, ArH), 7.60 (m, 2H, 3JPH 11.4 Hz,
H10), 8.04 (m, 1H, 3JPH 11.6 Hz, H8); dP (DMSO-d6, 130 ꢁC) 12.02; MS
(m/z): 394.2 (Mþ1).
mixture of l:u isomers (3.6:1); oil;
n (KBr) 3059, 1231, 1143,
1122 cmꢀ1 dH (CD3OD) 6.77 (d,1H, 3JPH 10.1, H13, l), 6.88 (s,1H, H13,
;
u), 7.26e7.87 (m, 13H, ArH), 8.03 (m, 1H, H8); dC (CD3OD) 87.65 (d,
2
3
2JPC 0.6 Hz, C13, u), 88.10 (d, JPC 1.4 Hz, C13, l), 125.30 (d, JPC
11.6 Hz, C5, l), 125.40 (d, 2JPC 11.7 Hz, C5, u), 128.40 (d, 1JPC 126.3 Hz,
2
2
C3, l), 128.37 (C15, l), 128.74 (d, JPC 13.1 Hz, C7, l), 128.96 (d, JPC
12.7 Hz, C7, u), 129.26 (C17, l), 129.96 (C16, l), 130.04 (d, 3JPC 14.0 Hz,
C11, u), 130.08 (d, 3JPC 14.1 Hz, C11, l), 130.66 (d, 2JPC 12.4 Hz, C8, l),
131.45 (d, 1JPC 142.79 Hz, C9, l), 132.85 (d, 2JPC 11.7 Hz, C10, l), 133.04
4.2.9. 2-(Hydroxymethyl)phenyl(phenyl)phosphinic acid (10). Yield
after chromatography (CH2Cl2/CH2Cl2:MeOH, 10:1) 35% (61 mg);
oil; n ;
(KBr) 3403, 3203, 1153, 1019, cmꢀ1 dH (DMSO-d6, 110 ꢁC) 4.47
2
4
4
(s, 2H, H13), 7.14e7.28 (m, 6H, H5, H6, H7, H11, H12), 7.65 (ddd, 2H,
(d, JPC 11.7 Hz, C10, u), 134.44 (d, JPC 3.0 Hz, C6, l), 134.51 (d, JPC
3JPH 11.1, 3JHH 7.8 Hz, H10), 7.95 (ddd, 1H, 3JPH 11.6, 3JHH 7.3 Hz, H8);
3.0 Hz, C6, u), 134.66 (d, JPC 2.3 Hz, C12, u), 134.69 (d, JPC 2.7 Hz,
4
4
3
3
3
dC (DMSO-d6, rt) 63.21 (d, JPC 6.9 Hz, C13), 125.96 (d, JPC 11.6 Hz,
C5), 127.15 (d, 3JPC 11.6 Hz, C11), 127.85, 128.81, 129.47, 130.88 (d, 2JPC
8.5 Hz, C10), 133.82 (d, 2JPC 6.7 Hz, C8),144.44 (d, 2JPC 10.5 Hz, C4). dP
(DMSO-d6, 110 ꢁC) 13.75; MS (m/z): 249.1 (Mþ1).
C12, l), 139.41 (d, JPC 5.7 Hz, C14, u), 140.69 (d, 3JPC 1.2 Hz, C14, l),
2
2
148.51 (d, JPC 17.7 Hz, C4, u), 149.20 (d, JPC 19.8 Hz, C4, l); dP
(CD3OD) 50.12 (u), 50.28 (l); MS (m/z): 329.0 (MþNa).
4.2.14. 3-(2-Hydroxyethyl-1-phenyl-1,3-dihydrobenzo-[c][1,2]oxaphosp-
4.2.10. 1-Phenyl-1,3-dihydrobenzo[c][1,2]oxaphosphole 1-oxide
hole 1-oxide) (u/l-15). Yield after chromatography (CH2Cl2:MeOH,
(11). Yield after chromatography (CH2Cl2/CH2Cl2:MeOH, 10:1)
30:1) 37% (70 mg), mixture of l:u isomers (1.5:1); oil; n (KBr) 3376,
27% (42 mg); oil;
n
(KBr) 3060, 1200,1122 cmꢀ1
;
dH (CDCl3) 5.44 (dd,
1222 cmꢀ1
; dH (CDCl3) 1.90 (m, 1H, H14, u), 2.08 (m, 1H, H14, l), 2.35
1H, 3JPH 11.5, 2JHH 13.7, Hz, H13), 5.61 (dd, 1H, 3JPH 3.3, 2JHH 13.7 Hz,
(m, 1H, H140), 3.88 (m, 2H, H15), 5.82 (ddd, 1H, JPH 10.8, JHH 9.2,
3
3
H13), 7.39e7.48 (m, 4H, H5, H7, H11), 7.54 (dtt, 1H, 5JPH 1.5, 3JHH 7.5,
3JHH 2.9 Hz, H13, l), 5.94 (d, 1H, 3JHH 10.2 Hz, H13, u), 7.34e7.74 (m,
4JHH 1.4 Hz, H12), 7.61 (ddt, 1H, JPH 1.4, JHH 7.6, JHH 1.1 Hz, H6),
9H, ArH); dC (CDCl3) 39.60 (d, JPC 4.4 Hz, C14, u), 40.52 (C14, l),
5
3
4
3
3
7.66e7.76 (m, 3H, H8, H10); dC (CDCl3) 72.59 (C13), 122.18 (d, JPC
58.24 (C15, l), 58.60 (C15, u), 81.86 (d, 2JPC 0.8 Hz, C13, u), 82.36 (d,
11.2 Hz, C5),127.98 (d, 1JPC 126.7 Hz, C3),128.28 (d, 2JPC 13.3, Hz, C8),
2JPC 1.1 Hz, C13, l), 122.32 (d, JPC 11.7 Hz, C5, u), 122.61 (d, JPC
3
3
3
128.56 (d, JPC 14.0 Hz, C11), 128.95 (d, 3JPC 12.3 Hz, C7), 130.91 (d,
11.6 Hz, C5, l),127.99 (d, 1JPC 126.0 Hz, C3, u),128.05 (d, 1JPC 126.1 Hz,
1JPC 141.2 Hz, C9), 131.70 (d, 2JPC 11.4 Hz, C10), 132.69 (d, 4JPC 3.0 Hz,
C3, l), 128.22 (d, JPC 13.1 Hz, C7), 128.63 (d, JPC 13.8 Hz, C11, l),
128.68 (d, 3JPC 14.0 Hz, C11, u), 129.13 (d, 2JPC 12.4 Hz, C8), 130.53 (d,
3
3
4
2
C12), 132.76 (d, JPC 2.7 Hz, C6), 143.95 (d, JPC 20.8 Hz, C4); dP
(CDCl3) 50.30; MS (m/z): 231.1 (Mþ1).
1JPC 142.0 Hz, C9, u), 130.72 (d, 1JPC 141.6 Hz, C9, l), 131.75 (d, JPC
2
11.7 Hz, C10, l), 132.02 (d, 2JPC 11.6 Hz, C10, u), 132.76 (d, 4JPC 2.9 Hz,
C6/12, l), 132.79 (d, 4JPC 2.9 Hz, C6/12, u), 132.96 (d, 4JPC 2.8 Hz, C6/
12, l), 133.00 (d, 4JPC 2.7 Hz, C6/12, u), 147.77 (d, 2JPC 20.1 Hz, C4, l),
4.2.11. 3,3-Dimethyl-1-phenyl-1,3-dihydro-2,1-benzoxaphos-phole
1-oxide (12). Yield after chromatography (AcOEt:hexane, 1:1) 67%
2
(100 mg); oil;
n
(KBr) 1236,1225 cmꢀ1
;
dH (CD3OD) 1.81 (s, 3H, H14),
147.90 (d, JPC 19.0 Hz, C4, u); dP (CDCl3) 48.22, 48.23; MS (m/z):
1.84 (s, 3H, H140), 7.49e7.66 (m, 6H, H5, H7, H8, H11, H12),
7.70e7.80 (m, 3H, H6, H10); dC (CD3OD) 29.37 (d, 3JPC 5.0 Hz, C14),
297.0 (MþNa).
2
3
31.55 (C140), 91.35 (d, JPC 1.2 Hz, C13), 122.49 (d, JPC 12.2 Hz, C5),
4.2.15. 3-(1,1-Dideuterium-2-hydroxyethyl-3-deuterium-1-phenyl-
1,3-dihydrobenzo-[c][1,2]oxaphosphole 1-oxide) (u/l-15-d3). Yield
after chromatography (AcOEt:hexane, 1:1) 20% (25 mg), mixture of
127.97 (d, 1JPC 126.0 Hz, C3), 128.92 (d, 3JPC 12.9 Hz, C8), 129.99 (d,
3JPC 14.0 Hz, C11), 130.42 (d, JPC 12.6 Hz, C7), 131.46 (d, JPC
2
1
2
4
142.8 Hz, C9), 132.89 (d, JPC 11.6 Hz, C10), 134.24 (d, JPC 3.0 Hz,
C12), 134.79 (d, JPC 2.6 Hz, C6), 154.25 (d, JPC 18.2 Hz, C4); dP
(CD3OD) 46.79; MS (m/z): 281.0 (MþNa).
l:u isomers (1.6:1); oil; n ; dH
(ATR) 3379, 2880, 1264, 1219 cmꢀ1
4
2
(CDCl3) 3.92 (m, 2H, H15), 7.37e7.79 (m, 9H, ArH); dC (CDCl3) 39.05
(m, C14, u), 39.35 (C14, l), 58.33 (C15, l), 58.91 (C15, u), 81.45 (d, 1JCD
22.9 Hz, C13, u), 81.56 (t, 1JCD 22.9 Hz, C13, l), 122.13 (d, 3JPC 11.7 Hz,
C5, u), 122.44 (d, 3JPC 11.6 Hz, C5, l), 128.14 (d, 1JPC 126.1 Hz, C3, u),
128.23 (d, 1JPC 126.1 Hz, C3, l), 128.27 (d, 3JPC 12.9 Hz, C7, l), 128.28
(d, 3JPC 13.1 Hz, C7, u), 128.55 (d, 3JPC 14.3 Hz, C11, l), 128.61 (d, 3JPC
13.9 Hz, C11, u), 129.11 (d, 2JPC 12.1 Hz, C8), 130.55 (d, 1JPC 142.0 Hz,
C9, u), 130.68 (d, 1JPC 141.7 Hz, C9, l), 131.73 (d, 2JPC 11.4 Hz, C10, l),
131.98 (d, 2JPC 11.5 Hz, C10, u), 132.69 (d, 4JPC 2.9 Hz, C6/12, l), 132.70
(d, 4JPC 2.9 Hz, C6/12, u), 132.86 (d, 4JPC 2.8 Hz, C6/12, l), 132.91 (d,
4.2.12. 3-Methyl-1-phenyl-1,3-dihydro-2,1-benzoxaphos-phole
1-oxide (u/l-13). Yield after chromatography (AcOEt:hexane, 1:1)
41% (56 mg), mixture of l:u isomers (4.1:1 and 1:3.9); isomer l-13:
3
oil;
n
(ATR) 1264, 1232 cmꢀ1
;
dH (CDCl3) 1.81 (d, 3H, JHH 6.6 Hz,
3
3
H14) 5.70 (dq, 1H, JPH 10.0, JHH 6.6 Hz, H13), 7.35e7.69 (m, 6H),
7.70 (m, 2H, H10), 7.72 (m, 1H, H8); dC (CDCl3) 23.59 (C14), 81.11
(C13), 122.27 (d, JPC 11.8 Hz, C5), 128.06 (d, JPC 125.6 Hz, C9),
128.26 (d, 2JPC 12.6, Hz, C8), 128.51 (d, 3JPC 13.9 Hz, C11), 128.99 (d,
3JPC 12.0 Hz, C7), 131.21 (d, 1JPC 141.2 Hz, C3), 131.54 (d, 2JPC 11.4 Hz,
3
1
2
2
4JPC 2.7 Hz, C6/12, u), 147.51 (d, JPC 19.9 Hz, C4, l), 147.63 (d, JPC
19.1 Hz, C4, u); dP (CDCl3) 48.22, 48.23; HRMS (ESI) calcd for
C15H13D3O3P: 278.1022 (MHþ), found: 278.1018.
4
4
C10), 132.51 (d, JPC 3.0 Hz, C12), 132.81 (d, JPC 2.4 Hz, C6), 148.71
(d, JPC 20.0 Hz, C4); dP (CDCl3) 47.06; HRMS (ESI) calcd for
2
C14H14O2P: 245.0731 (MHþ), found: 245.0726. Isomer u-13: oil;
n
4.3. Synthesis of methyl (2-{1-[(tert-butylsulfinyl)amino]-2-
methylpropyl}phenyl)phenylphosphinate 9
(ATR) 1228, 1204 cmꢀ1
;
dH (CDCl3) 1.74 (d, 3H, 3JHH 6.6 Hz, 14), 5.89
(q, 1H, 3JHH 6.6 Hz, H13), 7.35e7.69 (7H, ArH), 7.77 (m, 2H, H10); dC
(CDCl3) 22.12 (d, 4JPC 4.8 Hz, C14), 80.40 (C13),121.94 (d, 3JPC 12.1 Hz,
C5), 128.18 (d, 2JPC 13.2, Hz, C8), 128.29 (d, 1JPC 125.6 Hz, C9) 128.51
To a solution of the crude reaction mixture of 8 (340 mg) in
acetone (10 mL), was added K2CO3 (0.95 g, 10 equiv) and MeI
(0.48 mL, 5 equiv). The reaction was stirred at reflux for 3 h. The
crude reaction was centrifuged at 4500 rpm for 5 min and the
3
3
1
(d, JPC 13.7 Hz, C11), 128.96 (d, JPC 12.6 Hz, C7),130.86 (d, JPC
2
4
141.8 Hz, C3), 132.04 (d, JPC 11.4 Hz, C10), 132.56 (d, JPC 3.0 Hz,

~
V. Yanez Rodríguez et al. / Tetrahedron 68 (2012) 7355e7362
7361
2
solvent was concentrated in vacuo. The product 9 was purified by
flash chromatography (CH2Cl2/CH2Cl2:MeOH, 10:1) 45% (128 mg),
(C17), 19.05 (C17), 33.49 (C15), 34.58 (C15), 50.74 (d, JPC 6.0 Hz,
C18), 50.86 (d, 2JPC 6.0 Hz, C18), 57.97 (d, 3JPC 5.0 Hz, C13), 58.43 (d,
3JPC 5.0 Hz, C13), 126.49 (d, 3JPC 12.8 Hz, C7), 126.60 (d, 3JPC 12.2 Hz,
C7),127.51 (d, 3JPC 12.4 Hz, C5),127.58 (d, 3JPC 12.6 Hz, C5),128.26 (d,
mixture 1:1 of P-epimers; oil; n (KBr) 3440, 2960, 2358, 2340, 1214,
1127, 1035 cmꢀ1 dH (CD3OD) 0.45 (d, 3H, 3JHH 6.7 Hz, H18), 0.74 (d,
;
3H, 3JHH 6.9 Hz, H19), 0.76 (s, 9H, H16), 1.05 (d, 3H, 3JHH 6.7 Hz, H18),
1JPC 137.3 Hz, C3), 128.64 (d, JPC 138.4 Hz, C3), 128.62 (d, JPC
13.2 Hz, C11), 128.62 (d, 3JPC 13.2 Hz, C11), 130.99 (d, 1JPC 133.7 Hz,
C9), 131.15 (d, 1JPC 134.7 Hz, C9), 131.38 (d, 2JPC 10.6 Hz, C10), 131.56
(d, 2JPC 10.8 Hz, C10),132.15 (d, 2JPC 8.7 Hz, ꢀ8),132.43 (d, 2JPC 9.7 Hz,
1
3
3
1.11 (d, 3H, JHH 6.6 Hz, H19), 1.04 (s, 9H, H16), 2.00 (m, 2H, H17),
3
3.72 (d, 3H, JPH 11.2 Hz, H20), 3.75 (d, 3H, 3JPH 11.4 Hz, H20), 4.95
(m, 2H, H13), 7.31e7.80 (m,16H,16ArH), 7.91 (ddd,1H, 3JPH 12.1, 3JHH
4
4
4
7.8, JHH 1.2 Hz, H8); dC (CD3OD) 19.89 (C18), 19.92 (C-19), 20.30
C8), 132.46 (d, JPC 2.9 Hz, C12), 132.54 (d, JPC 2.9 Hz, C12), 133.02
(d, 4JPC 2.7 Hz, C6), 133.09 (d, 4JPC 2.7 Hz, C6), 149.66 (d, 2JPC 12.2 Hz,
C4), 149.81 (d, 2JPC 11.9 Hz, C4); dP (CD3OD) 35.83, 36.26; MS (m/z):
304 (Mþ1).
(C18), 20.35 (C19), 22.69 (C16), 22.93 (C16), 35.21 (C17), 36.26 (C17),
2
2
52.10 (d, JPC 6.0 Hz, C20), 52.33 (d, JPC 6.0 Hz, C20), 56.74 (C15),
3
3
57.22 (C15), 64.67 (d, JPC 4.2 Hz, C13), 65.06 (d, JPC 4.8 Hz, C13),
127.96 (d, 3JPC 13.3 Hz, C5/7), 127.97 (d, 3JPC 11.5 Hz, C5/7), 129.00 (d,
1JPC 136.3 Hz, C3), 129.45 (d, JPC 137.5 Hz, C3), 129.84 (d, JPC
12.1 Hz, C7/5), 129.91 (d, 3JPC 12.6 Hz, C7/5), 130.00 (d, 3JPC 13.2 Hz,
C11), 130.11 (d, 3JPC 13.2 Hz, C11), 131.96 (d, 1JPC 134.5 Hz, C9), 132.56
1
3
4.6. Synthesisofbiphenyl-2,20-diylbis(phenylphosphinic acid) 21
Over
a solution of diphenylphosphinic acid 1 (150 mg,
1
2
2
(d, JPC 134.3 Hz, C9), 133.15 (d, JPC 10.3 Hz, C10), 133.21 (d, JPC
0.69 mmol) and TMEDA (0.88 mL, 8.8 equiv) in dry THF (5 mL) at rt,
was added a solution of n-BuLi (1.9 mL of a 1.6 M solution in hexane,
4.4 equiv). After 2 h of lithiation at rt it was added CuBr$SMe2
(70 mg, 0.5 equiv) and a solution of 1,3-dinitrobenzene (290 mg,
2.5 equiv) in dry THF (1.7 mL). The reaction was stirred for an ad-
ditional 1 h and then was filtered through a pad of silica, washed
firstly with CH2Cl2 to remove the 1,3-dinitrobenzene and sub-
sequently with MeOH to extract the product. The solvent was re-
moved under reduced pressure and the crude mixture obtained
was dissolved in CH2Cl2, washed with HCl (1 N) and water, dried
over Na2SO4 and concentrated in vacuo. The product was purified
by precipitation from AcOEt to give 24 in 45% yield (74 mg); brown
10.6 Hz, C10), 133.39 (d, 2JPC 8.5 Hz, C8), 133.67 (d, 2JPC 10.7 Hz, C8),
4
4
133.81 (d, JPC 2.8 Hz, C6/12), 134.04 (d, 2C, JPC 2.5 Hz, C6/12),
134.08 (d, 4JPC 2.9 Hz, C6/12), 149.42 (d, 2JPC 10.9 Hz, C4), 150.19 (d,
2JPC 12.6 Hz, C4); dP (CD3OD) 34.43, 36.85; MS (m/z): 408.2 (Mþ1).
4.4. Synthesis [2-(1-amino-2-methylpropyl)phenyl]
phenylphosphinic acid 16
To a solution of the crude reaction mixture of 8 (340 mg) in 8 mL
of MeOH was added 2 mL of 12 M HCl at room temperature and the
reaction was stirred for 3 days. Then, the pH was set to neutral by
adding 6 M NaOH and the solvent was evaporated in vacuo. To the
crude mixture was added water (10 mL) and CH2Cl2 (10 mL) and the
mixture was centrifuged at 4500 rpm for 5 min showing a white
solid interface. The water and the CH2Cl2 were eliminated and the
solid was dried in vacuo to give the amino acid 16 in 25% yield
solid mp 220 dec ꢁC;
n ; dH
(KBr) 3438, 3055, 1139, 962 cmꢀ1
(CD3OD) 6.23 (ddd, 1H, 4JPH 4.7, 3JHH 6.7, 4JHH 0.7 Hz, H5), 7.07 (ddt,
1H, 5JPH 1.3, 3JHH 7.6, 4JHH 1.2 Hz, H6), 7.22e7.34 (m, 4H, H10, H11),
7.45e7.52 (m, 2H, H7, H12), 8.15 (ddd, 3JPH 12.8, 3JHH 7.8, 4JHH 1.1 Hz,
H8); dC (CD3OD) 128.69 (d, 3JPC 11.8 Hz, C7), 129.35 (d, 3JPC 13.6 Hz,
(50 mg); white solid mp 289e290 ꢁC;
1125 cmꢀ1
n
(KBr) 3440, 3050, 1184,
1
4
C11), 132.07 (d, JPC 129.6 Hz, Hz, C3), 132.40 (d, JPC 2.6 Hz, C6),
3
2
3
4
;
dH (500.13 MHz, D2OþNaOD) 0.12 (d, 3H, JHH 6.4 Hz,
132.43 (d, JPC 10.7 Hz, C10), 132.85 (dd, JPC 11.6, JPC 0.6 Hz, C5),
133.05 (d, 4JPC 2.8 Hz, C12), 133.41 (d, 2JPC 8.2 Hz, C8), 134.17 (d, 1JPC
145.9 Hz, C9),144.38 (dd, 2JPC 11.7, 3JPC 4.1 Hz, C4); dP (CD3OD) 28.25.
MS (m/z): 435.0 (Mþ1).
H16), 0.77 (d, 3H, 3JHH 6.4 Hz, H17), 1.72 (dhp, 1H, 3JHH 9.8, 3JHH 6.4,
H15), 3.94 (d, 1H, 3JHH 9.8 Hz, H13), 4.71 (s, 2H, H14), 7.30e7.39 (m,
3H, H5, H7, H11, H12), 7.45 (t, 1H, 3JHH 7.6 Hz, H6), 7.52 (ddd, 2H, 3JPH
12.1, 3JHH 7.8, 3JHH 1.9 Hz, H10), 7.86 (ddd, 1H, 3JPH 12.1, 3JHH 7.7, 4JHH
1.9 Hz, H8); dC (D2OþNaOD) 18.60 (C16), 19.03 (C17), 33.25 (C15),
57.36 (d, 3JPC 4.8 Hz, C13), 126.29 (d, 3JPC 11.5 Hz, C5), 126.95 (d, 3JPC
Acknowledgements
3
2
11.0 Hz, C7), 128.26 (d, JPC 12.4 Hz, C11), 130.48 (d, JPC 10.3 Hz,
C10), 130.51 (d, 4JPC 2.7 Hz, C12),131.53 (d, 4JPC 2.5 Hz, C6),132.25 (d,
2JPC 9.1 Hz, C8), 135.49 (d, 1JPC 128.4 Hz, C3), 138.76 (d, 1JPC 131.0 Hz,
ꢀ
We thank the Ministerio de Ciencia e Innovacion, Ministerio de
Economía y Competitividad and FEDER program for financial sup-
port (projects: CTQ2008-117BQU, and CTQ2011-27705). V.Y.R.
thanks Ministerio de Ciencia e Innovacion for a pre-doctoral
2
C9), 147.95 (d, JPC 10.5 Hz, C4); dP (D2OþNaOD) 22.43; MS (m/z):
ꢀ
290.2 (Mþ1).
fellowship.
4.5. Synthesis methyl [2-(1-amino-2-methylpropyl)phenyl]
phenylphosphinate 17
Supplementary data
1H, 13C and 31P NMR spectra of the new products. Supplemen-
tary data associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tet.2012.06.088.
To a solution of methyl phosphinate 9 (0.23 mmol, 94 mg) in
8 mL of MeOH was added 2 mL of 12 M HCl at room temperature
and the reaction was stirred for 3 days. Then, the reaction was
extracted with CH2Cl2, the aqueous layers were alkalized with 1 M
NaOH and extracted with CH2Cl2. The organic layers were dried
over Na2SO4, filtered and concentrated in vacuo to give methyl
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n
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