Catalytic asymmetric diarylphosphine addition to α-diazoesters for the synthesis of P-stereogenic phosphinates via P?-N bond formation

Article abstract of DOI:10.1021/acs.joc.0c00181

The asymmetric catalytic P.H addition of racemic secondary phosphines to electrophilic α-diazoesters via P?-N bond formation is disclosed for the first time. Interaction between the diazoester and the palladium catalyst resulted in the unusually enhanced electrophilic ability of the terminal nitrogen in the diazo functionality, as opposed to the commonly expected formation of a metal carbene by nitrogen elimination. Further derivatization of the generated phosphinic hydrazones provided access to enantioenriched P-stereogenic diarylphosphinates via a simple transformation.

Full text of DOI:10.1021/acs.joc.0c00181

Subscriber access provided by CARLETON UNIVERSITY
Note
Catalytic asymmetric diarylphosphine addition to #-diazoesters for
the synthesis of P-stereogenic phosphinates via P*-N bond formation.
Laszlo Bertalan Balazs, Yinhua Huang, Jasmina Begam
KHALIKUZZAMAN, Yongxin Li, Sumod A Pullarkat, and Pak-Hing Leung
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00181 • Publication Date (Web): 27 Mar 2020
Downloaded from pubs.acs.org on March 28, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 9
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Catalytic asymmetric diarylphosphine addition to α-diazoesters for the
synthesis of P-stereogenic phosphinates via P*-N bond formation.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
László B. Balázs,† Yinhua Huang,‡ Jasmina B. Khalikuzzaman,† Yongxin Li,† Sumod A. Pullarkat,*†
and Pak-Hing Leung*†
†Division of Chemistry & Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University, Singapore 637371. ‡College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University,
Hangzhou, China 311121. *E-mail for P.-H.L.: pakhing@ntu.edu.sg; *E-mail for S.A.P.: sumod@ntu.edu.sg.
Supporting Information Placeholder
ABSTRACT: A catalytic asymmetric P-H addition of racemic secondary phosphines to electrophilic α-diazoesters incorporating
P*-N bond formation is disclosed for the first time. Interaction between the diazoester and the palladium catalyst resulted in an
unusual enhanced electrophilic ability of the terminal nitrogen in the diazo functionality, instead of the commonly expected metal
carbene formation by nitrogen elimination. Further derivatization of the generated phosphinic hydrazones provided access to enan-
tioenriched P-stereogenic diarylphosphinates via a simple transformation.
Over the past decades, studies on transition metal-catalyzed
asymmetric transformations have revealed the significance of
chiral phosphine ligands.1 In general, phosphines bearing axi-
al, planar and carbon-centered chirality are more commonly
employed compared to their P-stereogenic counterparts in
asymmetric synthesis scenarios. The reason was the lack of
efficient synthetic methods to access the P-chiral derivatives,
despite their often observed enhanced efficiency in asymmet-
ric syntheses.2 Traditional methods to synthesize these com-
pounds include the usage of (-)-menthol,3 which later prompt-
ed the use of other chiral auxiliaries,2,4 as well as chiral metal
template-promoted methods.5 However, in recent years, sever-
al asymmetric catalytic methods have been developed to ac-
cess P-stereogenic phosphorus compounds, such as asymmet-
ric cross-coupling,6 desymmetrization7, enantioselective C-H
activation,8 alkylation of racemic secondary phosphines with
alkyl halides,9 ring closing metathesis,10 asymmetric deproto-
nation,11 Cu-catalyzed arylation of secondary phosphine ox-
ides12 and asymmetric allylation (Scheme 1a).13 Despite these
promising approaches, the generation of P-chiral phosphines is
still a highly demanding protocol in synthetic chemistry. Alt-
hough catalytic asymmetric P-H addition, as a route towards
synthesis of P-stereogenic phosphines, has been developed in
recent years, it is still considered a relatively unexplored area.
Dynamic kinetic resolution of racemic secondary phosphines
incorporating P*-C bond formation has been established via
asymmetric hydrophosphination of alkynes and olefins
(Scheme 1b).14 Recently, our group established a P-H addition
approach to access P-chiral phosphorus compounds via
asymmetric P*-O bond formation (Scheme 1c).15 To the best
of our knowledge, synthetic methods to generate P-stereogenic
compounds by catalytic asymmetric P-H addition of racemic
secondary phosphines via P*-N bond formation has never
been reported.
Diazo compounds have been employed widely in synthetic
chemistry as metal carbene precursors, 1,3-dipoles and
C-nucleophiles over the past decades.16 The nucleophilic na-
ture of the α-carbon and the terminal nitrogen is very well
known; however, the electrophilic capability of the latter is
much less explored.17 To exploit this nature, Feng and co-
workers reported the first asymmetric α-hydrazonation of ke-
tones resulting in scandium-catalyzed C*-N bond formation
(Scheme 1d).18 In this transformation, the chiral carbon at-
tached to the electrophilic terminal nitrogen of the diazoace-
tates. To further extend this area, herein we report a palladi-
um-catalyzed asymmetric phosphination strategy, which re-
sulted in P*-N bond formation between the P-stereogenic
phosphine fragment and the electrophilic α-diazoesters for the
first time (Scheme 1e). Derivatization of the generated phos-
phinic hydrazones provided direct access to enantioenriched
P-stereogenic diarylphosphinates.
We initially started to explore the transformation by using
ethyl 2-diazo-2-phenylacetate 1a and diarylphosphine 2a for
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Scheme 1. Formation of P-stereogenic compounds
Table 1. Optimization of the reaction conditionsa
Page 2 of 9
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Conver-
sion
[%]b
26d
3d
Catalyst
[mol%]
t
ee
[%]c
T
[°C]
Entry
Solvent
Base
[h]
1
2
3
5% Pd(MeCN)2Cl2
10% (R,R)-5
CHCl3
CHCl3
CHCl3
DBU
rt
24
72
48
-
-
-
-40
rt
N.D.
16
10% (R,R)-5
8d
CHCl3/
acetone
(8:1)
2.5% Pd2dba3
/
4
5
DBU
DBU
-80
-40
15
65
16d
n.r.
3
-
6% (R)-BINAP
5% Pd(OAc)2
/
CHCl3
6% (R)-BINAP
5% (R)-4
10% (R)-4
15% (R)-4
5% (R)-4
5% (R)-4
5% (R)-4
5% (R)-4
5% (R)-4
5% (R)-4
5% (R)-4
5% (R)-4
5% (R)-4
5% (R)-4
5% (R)-4
5% (R)-4
5% (R)-4
5% (R)-4
6
CHCl3
CHCl3
CHCl3
MeCN
toluene
DCM
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DMAe
DMAe
DBU
TBDf
DABCO
-40
-40
-40
-40
-40
-40
-80
-40
-40
-40
-40
-40
-40
rt
65
65
65
65
65
72
72
72
65
65
40
40
24
15
24
3
69
79
93
99
57
95
60
99
32
7
35
39
38
29
17
31
40
28
25
35
29
38
-
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
DCM
acetone
Et2O
the addition reaction to obtain 3aa (Table 1). We evaluated
various palladium catalyst systems (Table 1, entries 1-6).
Among these, the best result was achieved with complex (R)-4
and the screening revealed that despite the moderate conver-
sion (68.9%) and low ee (35%), the addition can occur in an
asymmetric fashion (for more examples of chiral catalyst and
chiral ligand screening, see SI). Higher catalyst loading was
also tested (Table 1, entries 7 and 8). For solvent screening,
we chose lower temperature (-40 and -80 ⁰C) and performed
several trials (Table 1, entries 9-17). The reaction could be
significantly accelerated by increasing the temperature, but the
stereoselectivity dropped in this case. Different external bases
were also tested (Table 1, entries 18-22). Among these results,
TBD (=1,5,7-triazabicyclo [4.4.0]dec-5-ene) and DBU (=1,8-
Diazabicyclo [5.4.0]undec-7-ene) were the most effective. We
achieved ee=34% for TBD within 3 hours and ee=36% for
DBU within 24 hours. Although TBD seemed to be a reasona-
ble choice of base, at -80 ⁰C temperature DBU provided better
selectivity. After optimization, our selected reaction condition
was 10 mol% (R)-4 catalyst, DBU as external base, -80 ⁰C
temperature and chloroform as a solvent mixed with a small
amount of acetone in order to prevent solvent freezing below
its melting point (Table 1, entry 24).19 Although the obtained
enantioselectivity (ee=55%) remained below our desired ex-
pectations, we recognized these results as an opportunity to
establish the asymmetric version of this challenging transfor-
mation which has hitherto not been achieved in an asymmetric
synthesis scenario. It is noteworthy, that there was a sole re-
port on the DBU-catalyzed achiral P-N bond formation be-
tween phosphonates and electrophilic diazoesters.17b In con-
trast to this earlier report, however, our substrates did not un-
dergo the P*-N bond formation in the absence of the pal-
ladacycle catalyst under the same reaction conditions (Table 1,
entry 25). The stereochemistry of the product was determined
by crystallizing the enantioenriched compound (3aa), then
THF
EtOH
DCE
75
28
n.r.
61
99
99
30
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
4
-40
-40
-40
36
34
39
65
CHCl3/
acetone
(8:1)
23
24
25
10% (R)-4
10% (R)-4
-
Et3N
DBU
DBU
-80
-80
-80
96
24
96
60
53
CHCl3/
acetone
(8:1)
94 (78)g 55
CHCl3/
acetone
(8:1)
n.r.
-
aReaction conditions: 1a (65.5 µmol, 1 eq.), 2a (78.6 µmol, 1.2
eq.), base (65.5 µmol, 1 eq.), catalyst (6.6 µmol, 10 mol%), sol-
b
vent (2.4 mL). See more details in ESI. Conversion was deter-
mined by 31P{1H} NMR measurement of the crude mixture.
d
cEnantiomeric excess was determined by chiral HPLC. Signifi-
cant amount of unidentified by-products were formed. eDMA:
f
g
dimethylaniline. TBD: 1,5,7-triazabicyclo[4.4.0]dec-5-ene. Iso-
lated yield in parentheses.
X-ray crystallographic structure determination was performed.
Based on the analysis, (R)-3aa was generated using (R)-4 cata-
lyst in the reaction.
By applying the optimized conditions, extension of the sub-
strate scope was conducted (Scheme 2). To demonstrate vari-
ous protection strategies, instead of using sulphur, the generat-
ed tertiary phosphines were oxidized by H2O2 for the substrate
scope. By modifying the aryl group of the phosphine and the
ester group of substrate 1, we were looking for a better
2
ACS Paragon Plus Environment

Page 3 of 9
The Journal of Organic Chemistry
for 6ca); however, the reaction became slower (48 hours). In
1
2
3
4
5
6
7
8
Scheme 2. Substrate scopea
the next trials, we introduced sterically demanding meta-
substituents on the aromatic ring of the phosphines. This mod-
ification caused significant improvement in the enantiomeric
excess (ee=78% for 6cb and ee=81% for 6cc). Benzhydryl-
and 2,6-dichlorobenzyl ester analogues were also tested, how-
ever, these modifications did not improve the selectivity sig-
nificantly (see examples 6ba, 6db and 6bc). Bearing in mind
that the enhanced steric character of the phosphines provided
better selectivities, we started to assess which specific substi-
tution positions of the aromatic ring we need to focus for in-
troduction of sterically demanding groups. Unfortunately, the
para-tert-butyl substituted analogue was formed only with low
enantioselectivity (ee=33% for 6cd), and all our attempts to
utilize the ortho-substituted phosphines failed (6af to 6ah).
One of the explanations for these findings must be that the
para-position is too far from the stereoprojecting groups of the
catalyst, thus the stereochemical induction is ineffective; and
in the case of the ortho-substituted counterparts, the diazo
compound is not able to coordinate to the catalyst due to steric
hinderance. Changing one of the aryl groups to alkyl chain
slowed down the reaction drastically and the observed selec-
tivity was low (ee=41% for 6ce). Lastly, we examined the
phosphination reaction of the (-)-menthyl ester diazosubstrate
analogue (1e). Because of the present chirality of the substrate,
we have examined the reaction applying both hand forms of
the catalyst. Using (R)-4 for the transformation, (R,S,R,R)-6eb
was obtained in 1 : 0.19 diastereomeric ratio and (S)-4 provid-
ed (R,S,R,S)-6eb with similar dr value (1 : 0.18). The isolated
yield for (R,S,R,S)-6eb was higher (61%) compared to its dia-
stereomeric counterpart (48%). It is important to mention, that
conversion was above 90% in almost every case (6aa to 6cd)
with the slight drop in isolated yield due to the acid-sensitivity
of the products.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To gain deeper insights into the reaction pathway, several
control experiments were performed (Scheme 3 and 4). In
these reactions, racemic secondary phosphines were replaced
by the achiral diphenylphospine and triphenylphosphine. By
these replacements, we were able to exclude any possible dia-
stereomer formation, thus the NMR studies provided a clearer
picture about the transformations. Firstly, the roles of the pal-
ladium catalyst and the base were examined (Scheme 3a-3c).
According to our findings, the presence of both palladium and
additional base are necessary for the addition reaction to oc-
cur. In this methodology, using only palladium without the
presence of any external base, the phosphination did not pro-
ceed satisfactorily (see SI). The next question which needed to
be tackled was whether there is any interaction between the
palladacycle and the diazo substrate, which would support the
intramolecular nature of this protocol and the origin of stere-
ocontrol.
aReaction conditions: 1 (65.5 µmol, 1 eq.), 2 (78.6 µmol, 1.2 eq.),
DBU (65.5 µmol, 1 eq.), catalyst (6.6 µmol, 10 mol%), solvent
(2.4 mL). For 6eb, de was determined by 31P{1H} NMR data.
Scheme 3. Control experiments
combination of the reactants, to achieve higher selectivity
within acceptable reaction time and yield. By introducing ste-
rically bulkier groups to the ester functionality of the
α-diazoacetate, the selectivity was slightly increased (ee=58%
To provide insights into this aspect, stoichiometric coordina-
tion studies were performed (Scheme 4). Based on previous
Scheme 4. Coordination experiments
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
According to the control experiments, we proposed a possi-
Page 4 of 9
Scheme 5. Proposed catalytic cycle
1
2
3
4
5
6
7
8
ble intramolecular mechanism (Scheme 5). In our proposal,
the terminal nitrogen of the diazo function is activated by co-
ordination of the α-carbon to the metal center (B) and the
product formation takes place via a 5-membered ring chelate
(D). During the catalytic cycle, the racemic secondary dia-
rylphosphines (A) are converted initially to the phosphido
intermediate (C), subsequently the elimination of the enanti-
oenriched phosphinic hydrazone (E to A) makes the dynamic
kinetic resolution plausible. The stereo determining step of the
reaction is the P*-N bond formation from stage C to D. The
demonstrated π-acceptance character of the aryl carbon in the
chiral auxiliary22 plays a critical role in stabilizing the diazo-
moiety at the trans position via the C(aryl)-Pd-C bond, there-
fore eliminating in this instance any possibility of N2 elimina-
tion.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Lastly, we investigated the possible derivatization of the
generated phosphinic hydrazones (Scheme 6a). Acidic meth-
anolysis of phosphinic amides is a well-known procedure in
the literature and a simple strategy to transform the P(O)-N
fragment to synthetically useful P(O)-OMe moiety.23 This
useful reaction allowed us to generate enantioenriched P-
stereogenic diarylphosphinates without any loss of enantiose-
lectivity and eliminating the need for chlorinated precursors,
such as PCl3 and intermediate alkyl‐ or ammonium-
phosphinates.2b As it was reported in several studies,23 this
reaction takes place via the inversion of the stereochemistry,
thus in our case, the phosphinic hydrazones (R)-6aa and (R)-
6cb were converted into enantioenriched diarylphosphinates
(R)-8a and (R)-8b respectively. To determine the absolute
stereochemistry of the P-stereogenic center in the 6eb prod-
ucts made separately by using (R)- and (S)-4 catalyst, the
phosphinic hydrazones were converted to the dia-
rylphosphinates using the acidic methanolysis strategy
(Scheme 6b). By comparing the chiral HPLC spectra of the
newly produced 6eb diarylphosphinates to that of obtained
after converting (R)-6cb to (R)-8b, we were able to determine,
that the (R)-4 catalyst produced the (R,S,R,R)-6eb product,
which was subsequently transformed to (R)-8b. On the same
basis, we determined that the usage of (S)-4 resulted in the
formation of (R,S,R,S)-6eb which was later derivatized to (S)-
8b (for HPLC spectra, see SI).
Scheme 6. Derivatization of the phosphinic hydrazones
In conclusion, we have established a novel synthetic strategy
in asymmetric catalysis to utilize α-diazoesters as electrophile
reaction partners via the terminal nitrogen. The asymmetric
P-H addition to this position is established for the first time in
literature resulting in P*-N bond formation. The obtained en-
antioenriched phosphinic hydrazones can be easily converted
to valuable P-stereogenic diarylphosphinates in a simple trans-
formation, without loss of the enantioselectivity. This new
synthetic method opens new areas not only in P-chiral phos-
phine chemistry, but also in the asymmetric transformations of
electrophilic diazoesters.
literature reports, diazo compounds can adopt various coordi-
nation modes to transition metals (Scheme 4a).20 Among these
structures, monodentate coordination to the metal center via
the α-carbon is well known, as the first step of metal carbene
synthesis from diazo compounds.17a,21 Upon coordination, the
α-carbon becomes highly electron-deficient in this species due
to the electron donation to the metal. In the crude 13C{1H}
(CDCl3) NMR spectrum of our experiments (Scheme 4b and
4c), a new singlet signal can be detected in the low field re-
gion at δ 186.4 ppm after the substrate addition, which indi-
cates the formation of an electron-deficient carbon (see SI).
This observation supports the possible mono-coordination of
the α-carbon to the palladium center. Other types of coordina-
tion modes may also happen in the reaction mixture; however,
those species (see Scheme 4) will disrupt any possible catalyt-
ic cycle occurring at the Pd center.
EXPERIMENTAL SECTION
General Information. All air sensitive manipulations were
carried out under positive pressure of nitrogen using Schlenk
techniques. All solvents were purchased from VWR and Avantor
and were degassed prior to use. All other reactants and reagents
were used as supplied without further purification. NMR spectra
were recorded on Bruker AV 300, AV 400, AV 500 and BBFO
400 spectrometers. Chemical shifts were reported in ppm and
referenced to an internal SiMe4 standard (0 ppm) in CDCl3 for 1H
NMR; chloroform-d (77.0 ppm) in CDCl3 for 13C{1H} NMR and
4
ACS Paragon Plus Environment

Page 5 of 9
The Journal of Organic Chemistry
an external 85% H3PO4 for 31P{1H} NMR. Low Temp Pairstirrer
General procedure for the synthesis of 1b and 1d. Diazoace-
tates 1b and 1d are new compounds and were synthesised based
on reported general procedure:30 the corresponding phenylacetate
1
2
3
4
5
6
7
8
PSL-1800 was used for low temperature reactions. Column chro-
matography was performed with Silica gel 60 (purchased from
Merck). Melting points were measured using SRS Optimelt Au-
tomated Point System SRS MPA100. HRMS using electrospray
ionization (ESI) method was performed on the Waters Q-Tof
Premier spectrometer. The enantioselectivities of the asymmetric
reactions were determined with an Agilent 1200 Series HPLC
machine fitted with the specified Daicel Chiralpak columns with
n-hexane/2-propanol mixture as eluent at 23 °C (for detailed con-
ditions, see SI). Optical rotations were examined with JASCO P-
1030 Polarimeter in DCM in a 0.1 dm cell at specified tempera-
tures. Catalysts (R)-424 and (R,R)-5,25 racemic secondary phos-
phine 2e26 and diazoacetates 1a,27 1c28 and 1e29 were synthesized
by following reported procedures.
General procedure for the synthesis of racemic secondary
diarylphosphines. Racemic secondary phosphines were synthe-
sized by following reported procedure with a slight modification.
To a solution of PhPCl2 (4.49 g, 25.1 mmol) in THF (50 mL),
ArMgBr (25.1 mmol in 50 mL of THF, prepared from ArBr (25.1
mmol) and Mg (0.72 g, 30.1 mmol) was added slowly in 50 mL
of THF at -80 °C under N2 atmosphere. The mixture was stirred
at -80 °C for 2 hours before it was warmed to room temperature
and stirred for overnight. The mixture was cooled to 0 °C and
LiAlH4 (1.14 g, 30.1 mmol) was added in small portions. The
mixture was kept stirring at room temperature for 2 hours. De-
gassed water (10 mL) was added dropwise at 0 °C and the mix-
ture was extracted with diethyl ether (3x). The organic layers
were combined and dried over MgSO4. The solvent was removed
by distillation and the residue was subjected to high vacuum mi-
crodistillation to give the corresponding secondary phosphines:
(3,5-dimethylphenyl)(phenyl)phosphane (2a): Appearance:
colorless oil (2.04 g, 9.52 mmol, 38%); 1H NMR (400 MHz,
CDCl3) δ 7.57 – 7.41 (m, 2H), 7.30 (d, J = 3.5 Hz, 3H), 7.10 (d, J
= 7.7 Hz, 2H), 6.94 (s, 1H), 5.18 (d, J = 218.9 Hz, 1H), 2.27 (s,
6H); 13C{1H} NMR (101 MHz, CDCl3) δ 138.1, 138.0, 135.1,
135.0, 134.1, 134.0, 133.9, 133.7, 131.9, 131.7, 130.3, 128.5,
128.5, 128.3, 21.2; 31P{1H} NMR (162 MHz, CDCl3) δ -40.12;
HRMS (ESI) m/z: [M+H]+ Calcd for C14H16P 215.0990; Found
215.0988.
(5 mmol) was introduced to
a stirred solution of 4-
acetamidobenzenesulfonyl azide (=p-ABSA, 1.44 g, 6 mmol) in 8
ml of acetonitrile. The mixture was cooled to 0 ⁰C, then
1,8-diazabicyclo[5.4.0]undec-7-ene (=DBU, 0.9 mL, 6 mmol)
was added dropwise. The reaction mixture was stirred at room
temperature for 24 h, followed by the addition of saturated aq.
NH4Cl (30 mL). The mixture was extracted with Et2O (3x), or-
ganic layers were combined, dried over MgSO4, filtered and the
solvent was evaporated under reduced pressure. Purification by
flash chromatography afforded the corresponding α-diazoester:
Benzhydryl 2-diazo-2-phenylacetate (1b): Appearance: orange
oil (1.12 g, 3.4 mmol, 68% yield after flash chromatography on
silica gel using Hexanes/ EtOAc 98:2 to 90:10 eluent system); 1H
NMR (400 MHz, CDCl3) δ 7.51 – 7.45 (m, 2H), 7.39 – 7.30 (m,
10H), 7.30 – 7.24 (m, 2H), 7.18 – 7.12 (m, 1H), 7.07 (s, 1H).
13C{1H} NMR (101 MHz, CDCl3) δ 164.1, 140.0, 128.9, 128.6,
128.0, 127.0, 125.9, 125.2, 124.0, 77.3. HRMS (ESI) m/z:
[M+H]+ Calcd for C21H17N2O2 329.1290; Found 329.1288.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2,6-dichlorobenzyl 2-diazo-2-phenylacetate (1d): Appearance:
orange oil (1.38 g, 4.3 mmol, 86% yield after flash chromatog-
raphy on silica gel using Hexanes/ EtOAc 98:2 to 90:10 eluent
1
system); H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.2 Hz, 2H),
7.40 – 7.31 (m, 4H), 7.28 – 7.13 (m, 2H), 5.59 (s, 1H); 13C{1H}
NMR (101 MHz, CDCl3) δ 164.9, 137.2, 131.4, 130.8, 129.1,
128.7, 126.0, 125.6, 124.1, 61.7; HRMS (ESI) m/z: [M+H]+
Calcd for C15H11Cl2N2O2 321.0198; Found 321.0185.
General procedure for the phosphination of α-diazoesters.
A nitrogen flushed 2-neck flask was charged with (R)-4 catalyst
(4.1 mg, 10 mol%), α-diazoester (65.5 μmol) and racemic second-
ary phosphine (78.6 μmol) in the mixture of de-gassed chloroform
(2 mL) and acetone (0.3 mL) at room temperature. Then the mix-
ture was cooled to -80 ⁰C, followed by the dropwise addition of
1,8-Diazabicyclo(5.4.0)undec-7-ene (=DBU, 10 mg, 65.5 μmol)
dissolved in 0.4 mL chloroform. The setup was stirred at -80 ⁰C
and monitored by TLC. After the α-diazoester was consumed in
the reaction based on TLC, sulfur (=S8, 33.6 mg, 131 μmol) or 0.1
mL hydrogen peroxide (30% solution) was added to the flask and
the mixture was warmed to room temperature, followed by stir-
ring for an additional 15 minutes. The mixture was washed with
water, dried over MgSO4, filtered, then the solvents were re-
moved by reduced pressure. The final product was obtained by
isolation on silica gel column chromatography:
(3,5-diethylphenyl)(phenyl)phosphane (2b): Appearance: color-
1
less oil (2.19 g, 9.04 mmol, 36%); H NMR (400 MHz, CDCl3) δ
7.53 – 7.44 (m, 2H), 7.30 (d, J = 3.6 Hz, 3H), 7.14 (d, J = 7.9 Hz,
2H), 6.99 (s, 1H), 5.22 (d, J = 210.2 Hz, 1H), 2.59 (dd, J = 15.2,
7.6 Hz, 4H), 1.20 (t, J = 7.6 Hz, 6H); 13C{1H} NMR (101 MHz,
CDCl3) δ 144.5, 144.5, 135.1, 135.0, 134.1, 134.0, 133.9, 133.7,
131.1, 130.9, 128.5, 128.4, 128.3, 127.9, 28.7, 15.5; 31P{1H}
NMR (162 MHz, CDCl3) δ -40.15; HRMS (ESI) m/z: [M+H]+
Calcd for C16H20P 243.1303; Found 243.1301.
(3,5-di-tert-butylphenyl)(phenyl)phosphane (2c): Appearance:
colorless oil (2.17 g, 7.28 mmol, 29%); 1H NMR (400 MHz,
CDCl3) δ 7.44 – 7.37 (m, 2H), 7.32 – 7.28 (m, 1H), 7.27 (d, J =
1.8 Hz, 1H), 7.26 – 7.22 (m, 3H), 7.19 (s, 1H), 1.22 (s, 18H). The
PhArPH proton is missing from the spectrum; 13C{1H} NMR (75
MHz, CDCl3) δ 150.9, 150.9, 135.2, 135.1, 133.9, 133.7, 133.0,
132.9, 128.5, 128.5, 128.4, 128.2, 122.8, 34.9, 31.4; 31P{1H}
NMR (162 MHz, CDCl3) δ -39.41; HRMS (ESI) m/z: [M+H]+
Calcd for C20H28P 299.1929; Found 299.1927.
(4-(tert-butyl)phenyl)(phenyl)phosphane (2d): Appearance:
colorless oil (2.8 g, 11.56 mmol, 46%); 1H NMR (400 MHz,
CDCl3) δ 7.43 – 7.37 (m, 2H), 7.37 – 7.30 (m, 2H), 7.30 – 7.20
(m, 5H), 5.10 (s, 1H), 1.23 (s, 9H); 13C{1H} NMR (101 MHz,
CDCl3) δ 151.7, 135.1 (d, J = 9.6 Hz), 134.0, 133.9, 133.8, 133.8,
130.8 (d, J = 8.6 Hz), 128.5 (d, J = 6.2 Hz), 128.3, 125.6 (d, J =
6.6 Hz), 34.6, 31.2; 31P{1H} NMR (162 MHz, CDCl3) δ -42.06;
HRMS (ESI) m/z: [M+H]+ Calcd for C16H20P 243.1303; Found
243.1299.
Ethyl (R,E)-2-(2-((3,5-dimethylphenyl)(phenyl) phosphorothi-
oyl)hydrazineylidene)-2-phenylacetate (3aa): Appearance:
yellow solid (22.3 mg, 51.1 μmol, 78% yield after flash chroma-
tography on silica gel using Hexanes/ EtOAc 95:5 to 80:20 eluent
21
system), ee=55%; Mp.: 127 – 129 ⁰C; [α]D -1.3 (c 0.5, CH2Cl2)
1
for ee=55%; H NMR (400 MHz, CDCl3) δ 7.98 – 7.88 (m, 2H),
7.58 – 7.42 (m, 8H), 7.32 – 7.26 (m, 2H), 7.17 (s, 1H), 7.10 (d, J
= 24.4 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 2.35 (s, 6H), 1.27 (t, J =
7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 163.8, 141.5 (d,
J = 13.6 Hz), 138.0 (d, J = 14.2 Hz), 133.9 (d, J = 3.2 Hz), 133.4,
132.6, 132.4, 132.1, 132.0, 131.9 (d, J = 3.0 Hz), 131.6, 130.1,
129.8, 129.7, 129.5, 128.5, 128.5, 128.3, 128.2, 61.4, 21.4, 14.2;
31P{1H} NMR (162 MHz, CDCl3) δ 59.39; HRMS (ESI) m/z:
[M+H]+ Calcd for C24H26N2O2PS 437.1453; Found 437.1453.
Ethyl
(R,E)-2-(2-((3,5-dimethylphenyl)(phenyl)phosphoryl)
hydrazineylidene)-2-phenylacetate (6aa): Appearance: color-
less oil (20.4 mg, 48.5 μmol, 74% yield after flash chromatog-
raphy on silica gel using Hexanes/ EtOAc 95:5 to 50:50 eluent
21
system), ee=55%; [α]D -1.8 (c 0.5, CH2Cl2) for ee=55%; 1H
NMR (400 MHz, CDCl3) δ 7.95 – 7.81 (m, 2H), 7.64 – 7.39 (m,
8H), 7.37 – 7.27 (m, 3H), 7.19 (s, 1H), 4.23 (q, J = 7.1 Hz, 2H),
2.34 (s, 6H), 1.27 (t, J = 5.7 Hz, 3H); 13C{1H} NMR (101 MHz,
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 9
CDCl3) δ 163.7, 142.6 (d, J = 13.9 Hz), 138.2 (d, J = 13.9 Hz),
ance: white solid (26.5 mg, 41.2 μmol, 63% yield after flash
1
2
3
4
5
6
7
8
134.3 (d, J = 2.9 Hz), 132.3 (d, J = 2.8 Hz), 132.1, 132.0, 131.7,
130.9, 130.5, 130.0, 129.7, 129.6, 129.5, 128.7, 128.6, 128.5,
128.3, 61.4, 21.3, 14.1; 31P{1H} NMR (162 MHz, CDCl3) δ
26.23; HRMS (ESI) m/z: [M+H]+ Calcd for C24H26N2O3P
421.1681; Found 421.1685.
chromatography on silica gel using Hexanes/ EtOAc 95:5 to
50:50 eluent system), ee=60%; Mp.: 77-79 ⁰C; [α]D -6.2 (c 1.0,
21
CH2Cl2) for ee=60%; 1H NMR (300 MHz, CDCl3) δ 7.95 (dd, J =
12.5, 7.1 Hz, 2H), 7.70 (d, J = 1.7 Hz, 1H), 7.66 (d, J = 1.6 Hz,
1H), 7.63 (s, 1H), 7.58 (d, J = 6.4 Hz, 1H), 7.54 – 7.40 (m, 6H),
7.40 – 7.12 (m, 12H), 6.88 (s, 1H), 1.27 (s, 18H); 13C{1H} NMR
(101 MHz, CDCl3) δ 162.7, 151.2 (d, J = 12.9 Hz), 141.9 (d, J =
14.1 Hz), 140.3 (d, J = 2.1 Hz), 132.4, 132.3, 132.2, 131.7, 130.4
(d, J = 3.4 Hz), 130.1, 129.5, 129.2, 128.7, 128.6, 128.4, 128.2,
127.7 (d, J = 2.3 Hz), 126.9, 126.9, 126.7 (d, J = 2.8 Hz), 126.2,
126.1, 77.6, 35.0, 31.3; 31P{1H} NMR (162 MHz, CDCl3) δ
27.67; HRMS (ESI) m/z: [M+H]+ Calcd for C41H44N2O3P
643.3090; Found 643.3087.
Benzhydryl (R,E)-2-(2-((3,5-dimethylphenyl)(phenyl) phos-
phoryl)hydrazineylidene)-2-phenylacetate (6ba): Appearance:
white solid (26.3 mg, 47.1 μmol, 72% yield after flash chromatog-
raphy on silica gel using Hexanes/ EtOAc 95:5 to 50:50 eluent
system), ee=54%; Mp.: 158 – 162 ⁰C; [α]D21 -2 (c 1.0, CH2Cl2) for
9
1
ee=54%; H NMR (500 MHz, CDCl3) δ 7.93 (dd, J = 12.5, 7.2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Hz, 2H), 7.62 – 7.56 (m, 1H), 7.53 (s, 1H), 7.51 – 7.38 (m, 7H),
7.32 – 7.27 (m, 2H), 7.26 – 7.24 (m, 5H), 7.24 – 7.23 (m, 5H),
7.21 (s, 1H), 6.90 (s, 1H), 2.31 (s, 6H); 13C{1H} NMR (101 MHz,
CDCl3) δ 162.7, 141.9, 141.7, 140.3 (d, J = 1.3 Hz), 138.4, 138.2,
134.3 (d, J = 3.2 Hz), 132.3 (d, J = 2.9 Hz), 132.2, 132.1, 131.7,
131.0, 130.4, 130.1, 129.8, 129.6, 129.5, 129.5, 128.7, 128.5,
128.4, 128.4, 128.2, 127.8 (d, J = 1.5 Hz), 126.8 (d, J = 4.6 Hz),
77.5, 29.7, 21.3; 31P{1H} NMR (162 MHz, CDCl3) δ 26.96;
HRMS (ESI) m/z: [M+H]+ Calcd for C35H32N2O3P 559.2151;
Found 559.2150.
Tert-butyl (R,E)-2-(2-((3,5-di-tert-butylphenyl)(phenyl) phos-
phoryl)hydrazineylidene)-2-phenylacetate (6cc): Appearance:
white solid (26.9 mg, 50.5 μmol, 77% yield after flash chroma-
tography on silica gel using Hexanes/ EtOAc 95:5 to 50:50 eluent
21
system), ee=81%; Mp.: 61 – 63 ⁰C; [α]D -7 (c 1.0, CH2Cl2) for
ee=81%; 1H NMR (400 MHz, CDCl3) δ 7.98 – 7.89 (m, 2H), 7.70
(dd, J = 13.3, 1.7 Hz, 2H), 7.61 (s, 1H), 7.58 – 7.36 (m, 7H), 7.31
– 7.20 (m, 2H), 1.45 (s, 9H), 1.32 (s, 18H); 13C{1H} NMR (101
MHz, CDCl3) δ 162.8, 151.1 (d, J = 12.8 Hz), 143.5 (d, J = 13.7
Hz), 132.3, 132.2, 132.1, 132.1, 131.9, 130.8, 130.7, 129.8, 129.5,
129.3, 129.1, 128.6, 128.2, 128.1, 126.5, 126.5, 126.4, 126.3,
126.1, 126.0, 81.7, 35.0, 31.3, 28.0; 31P{1H} NMR (162 MHz,
Tert-butyl (R,E)-2-(2-((3,5-dimethylphenyl)(phenyl) phos-
phoryl)hydrazineylidene)-2-phenylacetate (6ca): Appearance:
white solid (20.3 mg, 45.3 μmol, 69% yield after flash chromatog-
raphy on silica gel using Hexanes/ EtOAc 95:5 to 50:50 eluent
CDCl3)
δ
26.48; HRMS (ESI) m/z: [M+H]+ Calcd for
21
system), ee=58%; Mp.: 162 – 164.5 ⁰C; [α]D -2.6 (c 1.0,
CH2Cl2) for ee=58%; 1H NMR (400 MHz, CDCl3) δ 7.90 (dd, J =
12.4, 7.9 Hz, 2H), 7.60 – 7.37 (m, 8H), 7.31 – 7.27 (m, 2H), 7.22
(d, J = 20.5 Hz, 1H), 7.18 (s, 1H), 2.35 (s, 6H), 1.46 (s, 9H);
13C{1H} NMR (101 MHz, CDCl3) δ 162.9, 143.6 (d, J = 14.0
Hz), 138.1 (d, J = 13.8 Hz), 134.2 (d, J = 2.7 Hz), 132.2 (d, J =
2.9 Hz), 132.1, 132.0, 131.8, 131.1, 130.6, 129.9, 129.6, 129.5,
129.3, 128.9, 128.6, 128.4, 128.2, 81.7, 28.0, 21.3; 31P{1H} NMR
(162 MHz, CDCl3) δ 25.97; HRMS (ESI) m/z: [M+H]+ Calcd for
C26H30N2O3P 449.1994; Found 449.1997.
C32H42N2O3P 533.2933; Found 533.2934.
Tert-butyl (R,E)-2-(2-((4-(tert-butyl)phenyl)(phenyl) phos-
phoryl)hydrazineylidene)-2-phenylacetate (6cd): Appearance:
white solid (23.4 mg, 49.1 μmol, 75% yield after flash chromatog-
raphy on silica gel using Hexanes/ EtOAc 95:5 to 50:50 eluent
21
system), ee=33%; Mp.: 60-62 ⁰C; [α]D -8.1 (c 0.5, CH2Cl2) for
ee=33%; 1H NMR (400 MHz, CDCl3) δ 7.94 – 7.85 (m, 2H), 7.85
– 7.77 (m, 2H), 7.32 – 7.21 (m, 3H), 1.45 (s, 9H), 1.33 (s, 9H);
13C{1H} NMR (101 MHz, CDCl3) δ 162.8, 155.9, 143.5 (d, J =
14.0 Hz), 132.2, 132.2, 132.1, 132.0, 131.9, 131.8, 130.6, 129.8,
129.3, 128.9, 128.6, 128.4, 128.3, 128.1, 126.8, 125.4 (d, J = 13.4
Hz), 81.7, 35.0, 31.0, 28.0; 31P{1H} NMR (162 MHz, CDCl3) δ
25.94; HRMS (ESI) m/z: [M+H]+ Calcd for C28H34N2O3P
477.2307; Found 477.2308.
Tert-butyl (R,E)-2-(2-((3,5-diethylphenyl)(phenyl)phosphoryl)
hydrazineylidene)-2-phenylacetate (6cb): Appearance: color-
less oil (24 mg, 50.4 μmol, 77% yield after flash chromatography
on silica gel using Hexanes/ EtOAc 95:5 to 50:50 eluent system),
21
1
ee=78%; [α]D -5.2 (c 1.0, CH2Cl2) for ee=78%; H NMR (500
MHz, CDCl3) δ 7.91 (dd, J = 12.5, 7.2 Hz, 2H), 7.59 – 7.38 (m,
8H), 7.30 – 7.27 (m, 2H), 7.26 – 7.18 (m, 2H), 2.66 (q, J = 7.6 Hz,
4H), 1.46 (s, 9H), 1.23 (t, J = 7.6 Hz, 6H); 13C{1H} NMR (126
MHz, CDCl3) δ 162.9, 144.6 (d, J = 13.3 Hz), 143.6 (d, J = 13.8
Hz), 132.2, 132.1, 131.9 (d, J = 3.0 Hz), 131.7, 131.1, 130.7,
130.1, 129.9, 129.4, 129.0, 128.9, 128.8, 128.7, 128.6, 128.4,
128.3, 81.7, 28.8, 28.0, 15.5; 31P{1H} NMR (162 MHz, CDCl3) δ
26.08; HRMS (ESI) m/z: [M+H]+ Calcd for C28H34N2O3P
477.2307; Found 477.2311.
Tert-butyl (S,E)-2-(2-(ethyl(phenyl)phosphoryl) hydrazineyli-
dene)-2-phenylacetate (6ce): Appearance: white solid (4.6 mg,
12.4 μmol, 19% yield after flash chromatography on silica gel
using Hexanes/ EtOAc 95:5 to 50:50 eluent system), ee=41%;
Mp: 125-126 ⁰C; [α]D21 -3.5 (c 0.1, CH2Cl2) for ee=41%; 1H NMR
(500 MHz, CDCl3) δ 7.95 – 7.85 (m, 2H), 7.60 – 7.52 (m, 1H),
7.52 – 7.37 (m, 5H), 7.25 – 7.19 (m, 2H), 7.00 (d, J = 18.1 Hz,
1H), 2.50 – 2.35 (m, 1H), 2.29 – 2.16 (m, 1H), 1.52 (s, 9H), 1.19
(dt, J = 19.1, 7.6 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ
162.8, 143.1 (d, J = 13.5 Hz), 132.3 (d, J = 2.6 Hz), 131.3, 131.3,
131.2, 130.4, 129.8, 129.3, 128.9, 128.5, 128.5, 128.4, 81.8, 28.0,
22.0 (d, J = 90.6 Hz), 5.3 (d, J = 5.0 Hz); 31P{1H} NMR (162
MHz, CDCl3) δ 39.78; HRMS (ESI) m/z: [M+H]+ Calcd for
C20H26N2O3P 373.1681; Found 373.1677.
2,6-dichlorobenzyl
(R,E)-2-(2-((3,5-diethylphenyl)(phenyl)
phosphoryl)hydrazineylidene)-2-phenylacetate (6db): Appear-
ance: colorless oil (26.9 mg, 46.4 μmol, 71% yield after flash
chromatography on silica gel using Hexanes/ EtOAc 95:5 to
21
50:50 eluent system), ee=69%; [α]D -3.2 (c 0.5, CH2Cl2) for
1
ee=69%; H NMR (400 MHz, CDCl3) δ 7.85 (dd, J = 12.5, 7.2
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (E)-2-(2-((R)-(3,5-
diethylphenyl)(phenyl)phosphoryl)hydrazineylidene)-2-phenyl
acetate ((R,S,R,R)-6eb): Appearance: colorless oil (17.6 mg,
31.5 μmol, 48% yield after flash chromatography on silica gel
using Hexanes/ EtOAc 95:5 to 50:50 eluent system), de=68%
Hz, 2H), 7.54 – 7.46 (m, 4H), 7.46 – 7.27 (m, 9H), 7.26 – 7.20
(m, 1H), 7.18 (s, 1H), 5.49 (s, 2H), 2.57 (q, J = 7.6 Hz, 4H), 1.17
(t, J = 7.6 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 163.7,
144.7 (d, J = 13.3 Hz), 141.6 (d, J = 14.0 Hz), 137.3, 132.4 (d, J =
2.8 Hz), 132.3, 132.2, 132.0 (d, J = 3.0 Hz), 131.5, 131.4, 130.7,
130.7, 130.3, 130.1, 129.7, 128.9, 128.9, 128.8, 128.6, 128.5,
128.4, 62.3, 28.9, 15.6; 31P{1H} NMR (162 MHz, CDCl3) δ
26.39; HRMS (ESI) m/z: [M+H]+ Calcd for C31H30Cl2N2O3P
579.1371; Found 579.1374.
21
(based on 31P{1H} NMR (see SI)); Mp: 125-126 ⁰C; [α]D -38.1
1
(c 1.0, CH2Cl2) for de=68%; H NMR (400 MHz, CDCl3, mix-
ture) δ 8.00 – 7.80 (m, 2H), 7.74 – 7.38 (m, 8H), 7.36 – 7.28 (m,
3H), 7.24 – 7.18 (m, 1H), 4.70 (td, J = 10.8, 4.4 Hz, 1H), 2.76 –
2.56 (m, 4H), 2.04 (d, J = 11.6 Hz, 1H), 1.79 – 1.58 (m, 3H, H2O
peak is overlapping in the spectrum (see SI)), 1.53 – 1.42 (m, 1H),
1.39 – 1.28 (m, 1H), 1.27 – 1.16 (m, 6H), 1.11 – 0.93 (m, 2H),
Benzhydryl
(R,E)-2-(2-((3,5-di-tert-butylphenyl)(phenyl)
phosphoryl)hydrazineylidene)-2-phenyl acetate (6bc): Appear-
6
ACS Paragon Plus Environment

Page 7 of 9
The Journal of Organic Chemistry
0.93 – 0.82 (m, 4H), 0.79 – 0.72 (m, 3H), 0.71 – 0.61 (m, J = 5.9
Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3, mixture) δ 163.6,
144.9, 144.8, 144.7, 143.2, 143.0, 132.6, 132.5, 132.2, 132.1,
132.1, 131.7, 131.4, 131.2, 131.1, 130.4, 130.2, 130.2, 129.6,
129.1, 129.0, 128.9, 128.8, 128.8, 128.6, 128.4, 75.9, 47.2, 40.9,
34.4, 31.6, 29.0, 26.5, 23.9, 22.2, 20.8, 16.7, 15.6; 31P{1H} NMR
(162 MHz, CDCl3, mixture) δ 26.34 (major isomer); HRMS (ESI)
m/z: [M+H]+ Calcd for C34H44N2O3P 559.3090; Found 559.3086.
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (E)-2-(2-((S)-(3,5-
diethylphenyl)(phenyl)phosphoryl)hydrazineylidene)-2-phenyl
acetate ((R,S,R,S)-6eb): Appearance: colorless oil (22.3 mg,
39.9 μmol, 61% yield after flash chromatography on silica gel
using Hexanes/ EtOAc 95:5 to 50:50 eluent system), de=70%
NMR (400 MHz, CDCl3) δ 7.86 – 7.76 (m, 2H), 7.56 – 7.49 (m,
1
2
3
4
5
6
7
8
1H), 7.49 – 7.42 (m, 3H), 7.41 (s, 1H), 7.15 (s, 1H), 3.76 (d, J =
11.1 Hz, 3H), 2.33 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ
138.5 (d, J = 13.8 Hz), 134.2 (d, J = 3.0 Hz), 132.3 (d, J = 2.8
Hz), 131.9 (d, J = 10.1 Hz), 131.5, 130.9, 130.1, 129.5 (d, J = 10.1
Hz), 128.7 (d, J = 13.1 Hz), 51.7 (d, J = 6.0 Hz), 21.4; 31P{1H}
NMR (162 MHz, CDCl3) δ 33.96; HRMS (ESI) m/z: [M+H]+
Calcd for C15H18O2P 261.1044; Found 261.1045.
Methyl (R)-(3,5-diethylphenyl)(phenyl)phosphinate (8b): Ap-
pearance: colorless oil (10.7 mg, 37.1 μmol, 93% yield after flash
chromatography on silica gel using Hexanes/ EtOAc 80:20 to
9
21
1
20:80 eluent system), ee=77%; [α]D -3.6 for ee=77%; H NMR
(500 MHz, CDCl3) δ 7.87 – 7.77 (m, 2H), 7.55 – 7.49 (m, 1H),
7.49 – 7.42 (m, 4H), 7.19 (s, 1H), 3.76 (d, J = 11.1 Hz, 3H), 2.65
(q, J = 7.6 Hz, 4H), 1.22 (t, J = 7.6 Hz, 6H); 13C{1H} NMR (126
MHz, CDCl3) δ 144.7 (d, J = 13.4 Hz), 132.0 (d, J = 2.7 Hz),
131.9, 131.7, 131.6, 131.6, 131.6, 131.2, 130.9, 130.1, 128.5,
128.5, 128.4, 128.4, 51.5 (d, J = 6.1 Hz), 28.7, 15.4; 31P{1H}
NMR (162 MHz, CDCl3) δ 34.12; HRMS (ESI) m/z: [M+H]+
Calcd for C17H22O2P 289.1359; Found 289.1359.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
21
(based on 31P{1H} NMR (see SI)); Mp: 125-126 ⁰C; [α]D -31.4
1
(c 1.0, CH2Cl2) for de=70%; H NMR (500 MHz, CDCl3, mix-
ture) δ 7.95 – 7.80 (m, 2H), 7.72 – 7.36 (m, 8H), 7.35 – 7.27 (m,
3H), 7.25 – 7.17 (m, 1H), 4.71 (td, J = 10.8, 4.4 Hz, 1H), 2.72 –
2.61 (m, 4H), 2.12 – 2.02 (m, 1H), 1.83 – 1.72 (m, 1H), 1.71 –
1.57 (m, 2H, H2O peak is overlapping in the spectrum (see SI)),
1.53 – 1.43 (m, 1H), 1.40 – 1.31 (m, 1H), 1.28 – 1.16 (m, 6H),
1.11 – 0.91 (m, 2H), 0.91 – 0.80 (m, 4H), 0.80 – 0.72 (m, J =
11.6, 7.0 Hz, 3H), 0.71 – 0.64 (m, J = 6.7 Hz, 3H); 13C{1H} NMR
(126 MHz, CDCl3, mixture) δ 163.6, 144.8, 144.7, 142.7, 142.6,
132.6, 132.5, 132.4, 132.4, 132.3, 132.2, 132.1, 132.1, 131.3,
131.1, 130.2, 130.1, 129.6, 129.2, 129.1, 129.1, 129.0, 128.9,
128.9, 128.8, 128.8, 128.6, 128.6, 128.5, 128.5, 75.8, 47.3, 40.9,
34.5, 31.6, 29.0, 26.5, 23.9, 22.2, 20.9, 16.7, 15.8; 31P{1H} NMR
(202 MHz, CDCl3, mixture) δ 25.83 (major isomer). HRMS (ESI)
m/z: [M+H]+ Calcd for C34H44N2O3P 559.3090; Found 559.3086.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Ethyl
(E)-2-(2-(diphenylphosphoryl)hydrazineylidene)-2-
Details of optimization study; mechanistic investigations and
coordination studies with NMR spectroscopic data; 1H,
13C{1H} and 31P{1H} NMR spectra of isolated new com-
pounds; chiral HPLC chromatograms; X-ray diffraction data.
phenylacetate (6ai): Appearance: white solid (20.6 mg, 52.5
μmol, 80% yield after flash chromatography on silica gel using
Hexanes/ EtOAc 95:5 to 50:50 eluent system); Mp: 178-179 ⁰C;
1H NMR (400 MHz, CDCl3) δ 7.93 – 7.81 (m, 4H), 7.57 (td, J =
7.4, 1.4 Hz, 2H), 7.53 – 7.41 (m, 7H), 7.30 (dd, J = 11.9, 10.3 Hz,
3H), 4.22 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 163.7, 142.8 (d, J = 14.1 Hz), 132.5
(d, J = 2.8 Hz), 132.2, 132.1, 131.4, 130.2, 130.1, 129.5, 128.6,
128.6, 128.5, 128.4, 61.4, 14.1; 31P{1H} NMR (162 MHz, CDCl3)
δ 26.02; HRMS (ESI) m/z: [M+H]+ Calcd for C22H22N2O3P
393.1368; Found 393.1370.
Larger scale procedure for the synthesis of 6cb. The afore-
mentioned general phosphination procedure was carried out with
the following reagent quantities: α-diazoester 1c (240 mg, 1.1
mmol), racemic secondary phosphine 2b (320 mg, 1.32 mmol),
(R)-4 catalyst (69 mg, 10 mol%), DBU (168 mg, 1.1 mmol) in the
mixture of de-gassed chloroform (34 mL) and acetone (5.4 mL).
The reaction was stirred at -80 ⁰C for 48 hours. The phosphinic
hydrazone 6cb was obtained in 71% yield (372 mg, 0.78 mmol)
after flash chromatography on silica gel using Hexanes/ EtOAc
95:5 to 50:50 eluent system and the same level of enantioselectiv-
ity (ee=78%) was observed.
General procedure for the acidic methanolysis of the
phosphinic hydrazones. A round-bottom flask was charged
with phosphinic hydrazone (40 µmol) in methanol (2 mL), then
concentrated sulfuric acid was added to the mixture (0.1 mL). The
reaction was stirred at room temperature for 15 hours. After the
starting material was consumed based on TLC, the mixture was
treated with sat. NaHCO3 followed by extraction with DCM (4x).
The combined organic phases were washed with brine, dried over
MgSO4, filtrated and the solvents were evaporated under reduced
pressure. The diarylphosphinate products were obtained upon
isolation on silica gel column chromatography:
AUTHOR INFORMATION
Corresponding Authors
*E-mail for P.-H.L.: pakhing@ntu.edu.sg
*E-mail for S.A.P.: sumod@ntu.edu.sg.
Present Addresses
†Division of Chemistry & Biological Chemistry, School of Physi-
cal and Mathematical Sciences, Nanyang Technological Universi-
ty, Singapore 637371.
‡College of Material, Chemistry and Chemical Engineering,
Hangzhou Normal University, Hangzhou, China 311121.
ORCID
László B. Balázs: 0000-0002-2625-3423
Yinhua Huang: 0000-0002-5523-6286
Jasmina B. Khalikuzzaman: 0000-0002-1117-0158
Yongxin Li: 0000-0002-7860-3237
Sumod A. Pullarkat: 0000-0002-4150-2408
Pak-Hing Leung: 0000-0003-3588-1664
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank Nanyang Technological University for supporting this
research (grants M4080454 (NTU) and 2017-T1-001-175-02
(MOE)) and for a SINGA scholarship to L.B.B.
Methyl (R)-(3,5-dimethylphenyl)(phenyl)phosphinate (8a):
Appearance: colorless oil (9.5 mg, 36.5 μmol, 91% yield after
flash chromatography on silica gel using Hexanes/ EtOAc 80:20
REFERENCES
21
to 20:80 eluent system), ee=54%; [α]D -2.5 for ee=54%; 1H
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 9
(1) (a) Tang, W.; Zhang, X. New Chiral Phosphorus Ligands for
(13) Liu, X.-T.; Zhang, Y.-Q.; Han, X.-Y.; Sun, S.-P.; Zhang, Q.-
W. Ni-Catalyzed Asymmetric Allylation of Secondary Phosphine
Oxides. J. Am. Chem. Soc. 2019, 141, 16584-16589.
Enantioselective Hydrogenation. Chem. Rev. 2003, 103, 3029-3070;
(b) Leeuwen, P. W. N. M. v.; Kamer, P. C. J.; Claver, C.; Pàmies, O.;
Diéguez, M. Phosphite-Containing Ligands for Asymmetric
Catalysis. Chem. Rev. 2011, 111, 2077-2118.
(2) (a) Pietrusiewicz, K. M.; Zablocka, M. Preparation of Scalemic
P-Chiral Phosphines and Their Derivatives. Chem. Rev. 1994, 94,
1375-1411; (b) Grabulosa, A.; Granell, J.; Muller, G. Preparation of
optically pure P-stereogenic trivalent phosphorus compounds. Coord.
Chem. Rev. 2007, 251, 25-90.
(3) (a) Korpiun, O.; Lewis, R. A.; Chickos, J.; Mislow, K.
Synthesis and absolute configuration of optically active phosphine
oxides and phosphinates. J. Am. Chem. Soc. 1968, 90, 4842-4846; (b)
Berger, O.; Montchamp, J.-L. A General Strategy for the Synthesis of
P-Stereogenic Compounds. Angew. Chem., Int. Ed. 2013, 52, 11377-
11380.
(4) (a) Corey, E. J.; Chen, Z.; Tanoury, G. J. A new and highly
enantioselective synthetic route to P-chiral phosphines and
diphosphines. J. Am. Chem. Soc. 1993, 115, 11000-11001; (b) León,
T.; Riera, A.; Verdaguer, X. Stereoselective Synthesis of P-
Stereogenic Aminophosphines: Ring Opening of Bulky
Oxazaphospholidines. J. Am. Chem. Soc. 2011, 133, 5740-5743.
(5) (a) Leung, P.-H. Asymmetric Synthesis and Organometallic
Chemistry of Functionalized Phosphines Containing Stereogenic
Phosphorus Centers. Acc. Chem. Res. 2004, 37, 169-177; (b) Chew,
R. J.; Leung, P.-H. Our Odyssey with Functionalized Chiral
Phosphines: From Optical Resolution to Asymmetric Synthesis to
Catalysis. Chem. Rec. 2016, 16, 141-158.
(6) (a) Moncarz, J. R.; Laritcheva, N. F.; Glueck, D. S. Palladium-
Catalyzed Asymmetric Phosphination:ꢀ Enantioselective Synthesis of
a P-Chirogenic Phosphine. J. Am. Chem. Soc. 2002, 124, 13356-
13357; (b) Pican, S.; Gaumont, A.-C. Palladium catalysed
enantioselective phosphination reactions using secondary phosphine-
boranes and aryl iodide. Chem. Comm. 2005, 2393-2395; (c) Blank,
N. F.; Moncarz, J. R.; Brunker, T. J.; Scriban, C.; Anderson, B. J.;
Amir, O.; Glueck, D. S.; Zakharov, L. N.; Golen, J. A.; Incarvito, C.
D.; Rheingold, A. L. Palladium-Catalyzed Asymmetric
Phosphination. Scope, Mechanism, and Origin of Enantioselectivity.
J. Am. Chem. Soc. 2007, 129, 6847-6858.
(7) (a) Huang, Z.; Huang, X.; Li, B.; Mou, C.; Yang, S.; Song, B.-
A.; Chi, Y. R. Access to P-Stereogenic Phosphinates via N-
Heterocyclic Carbene-Catalyzed Desymmetrization of Bisphenols. J.
Am. Chem. Soc. 2016, 138, 7524-7527; (b) Trost, B. M.; Spohr, S.
M.; Rolka, A. B.; Kalnmals, C. A. Desymmetrization of Phosphinic
Acids via Pd-Catalyzed Asymmetric Allylic Alkylation: Rapid
Access to P-Chiral Phosphinates. J. Am. Chem. Soc. 2019, 141,
14098-14103; (c) Yang, G.-H.; Li, Y.; Li, X.; Cheng, J.-P. Access to
P-chiral phosphine oxides by enantioselective allylic alkylation of
bisphenols. Chem. Sci. 2019, 10, 4322-4327.
(8) Du, Z.-J.; Guan, J.; Wu, G.-J.; Xu, P.; Gao, L.-X.; Han, F.-S.
Pd(II)-Catalyzed Enantioselective Synthesis of P-Stereogenic
Phosphinamides via Desymmetric C–H Arylation. J. Am. Chem. Soc.
2015, 137, 632-635.
(9) (a) Scriban, C.; Glueck, D. S. Platinum-Catalyzed Asymmetric
Alkylation of Secondary Phosphines:ꢀ Enantioselective Synthesis of
P-Stereogenic Phosphines. J. Am. Chem. Soc. 2006, 128, 2788-2789;
(b) Chan, V. S.; Stewart, I. C.; Bergman, R. G.; Toste, F. D.
Asymmetric Catalytic Synthesis of P-Stereogenic Phosphines via a
Nucleophilic Ruthenium Phosphido Complex. J. Am. Chem. Soc.
2006, 128, 2786-2787.
1
2
3
4
5
6
7
8
(14) (a) Kovacik, I.; Wicht, D. K.; Grewal, N. S.; Glueck, D. S.;
Incarvito, C. D.; Guzei, I. A.; Rheingold, A. L. Pt(Me-Duphos)-
Catalyzed Asymmetric Hydrophosphination of Activated Olefins:ꢀ
Enantioselective Synthesis of Chiral Phosphines. Organometallics
2000, 19, 950-953; (b) Join, B.; Mimeau, D.; Delacroix, O.; Gaumont,
A.-C. Pallado-catalysed hydrophosphination of alkynes: access to
enantio-enriched P-stereogenic vinyl phosphine–boranes. Chem.
Comm. 2006, 3249-3251.
(15) Huang, Y.; Li, Y.; Leung, P.-H.; Hayashi, T. Asymmetric
Synthesis of P-Stereogenic Diarylphosphinites by Palladium-
Catalyzed Enantioselective Addition of Diarylphosphines to
Benzoquinones. J. Am. Chem. Soc. 2014, 136, 4865-4868.
(16) Doyle, M. P.; Mckervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds; Wiley: New
York, 1998.
(17) (a) Xia, Y.; Qiu, D.; Wang, J. Transition-Metal-Catalyzed
Cross-Couplings through Carbene Migratory Insertion. Chem. Rev.
2017, 117, 13810-13889; (b) Jiang, H.; Jin, H.; Abdukader, A.; Lin,
A.; Cheng, Y.; Zhu, C. Catalyst-controlled switchable phosphination
of α-diazoesters. Org. Biomol. Chem. 2013, 11, 3612-3615; (c) Huo,
J.; Xue, Y.; Wang, J. Regioselective copper-catalyzed
aminoborylation of styrenes with bis(pinacolato)diboron and diazo
compounds. Chem. Comm. 2018, 54, 12266-12269.
(18) Li, W.; Liu, X.; Hao, X.; Hu, X.; Chu, Y.; Cao, W.; Qin, S.;
Hu, C.; Lin, L.; Feng, X. New Electrophilic Addition of α-Diazoesters
with Ketones for Enantioselective C–N Bond Formation. J. Am.
Chem. Soc. 2011, 133, 15268-15271.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(19) For more details on the optimization see ESI.
(20) Rull, S. G.; Álvarez, E.; Fructos, M. R.; Belderrain, T. R.;
Pérez, P. J. The Elusive Palladium-Diazo Adduct Captured:
Synthesis, Isolation and Structural Characterization of [(ArNHC-
PPh2)Pd(η2-N2C(Ph)CO2Et)]. Chem. Eur. J. 2017, 23, 7667-7671.
(21) de Frémont, P.; Marion, N.; Nolan, S. P. Carbenes: Synthesis,
properties, and organometallic chemistry. Coord. Chem. Rev. 2009,
253, 862-892.
(22) Jia, Y.-X.; Li, B.-B.; Li, Y.; Pullarkat, S. A.; Xu, K.; Hirao,
H.; Leung, P.-H. Stereoelectronic and Catalytic Properties of Chiral
Cyclometalated Phospha-palladium and -platinum Complexes.
Organometallics 2014, 33, 6053-6058.
(23) del Águila-Sánchez, M. A.; Navarro, Y.; García López, J.;
Guedes, G. P.; López Ortiz, F. Synthesis of P-stereogenic
diarylphosphinic amides by directed lithiation: transformation into
tertiary phosphine oxides via methanolysis, aryne chemistry and
complexation behaviour toward zinc(ii). Dalton Trans. 2016, 45,
2008-2022.
(24) (a) Ng, J. K.-P.; Tan, G.-K.; Vittal, J. J.; Leung, P.-H. Optical
Resolution and the Study of Ligand Effects on the Ortho-Metalation
Reaction of Resolved (±)-Diphenyl[1-(1-naphthyl)ethyl]phosphine
and Its Arsenic Analogue. Inorg. Chem. 2003, 42, 7674-7682; (b)
Huang, Y.; Chew, R. J.; Li, Y.; Pullarkat, S. A.; Leung, P.-H. Direct
Synthesis of Chiral Tertiary Diphosphines via Pd(II)-Catalyzed
Asymmetric Hydrophosphination of Dienones. Org. Lett. 2011, 13,
5862-5865.
(25) (a) Yang, X.-Y.; Gan, J. H.; Li, Y.; Pullarkat, S. A.; Leung, P.-
H. Palladium catalyzed asymmetric hydrophosphination of α,β- and
α,β,γ,δ-unsaturated malonate esters – efficient control of reactivity,
stereo- and regio-selectivity. Dalton Trans. 2015, 44, 1258-1263; (b)
Yang, X.-Y.; Tay, W. S.; Li, Y.; Pullarkat, S. A.; Leung, P.-H.
Versatile Syntheses of Optically Pure PCE Pincer Ligands: Facile
Modifications of the Pendant Arms and Ligand Backbones.
Organometallics 2015, 34, 1582-1588.
(26) Petit, C.; Favre-Réguillon, A.; Mignani, G.; Lemaire, M. A
straightforward synthesis of unsymmetrical secondary phosphine
boranes. Green Chem. 2010, 12, 326-330.
(27) Keipour, H.; Jalba, A.; Delage-Laurin, L.; Ollevier, T.
Copper-Catalyzed Carbenoid Insertion Reactions of α-Diazoesters
and α-Diazoketones into Si–H and S–H Bonds. J. Org. Chem. 2017,
82, 3000-3010.
(10) Harvey, J. S.; Malcolmson, S. J.; Dunne, K. S.; Meek, S. J.;
Thompson, A. L.; Schrock, R. R.; Hoveyda, A. H.; Gouverneur, V.
Enantioselective Synthesis of P-Stereogenic Phosphinates and
Phosphine Oxides by Molybdenum-Catalyzed Asymmetric Ring-
Closing Metathesis. Angew. Chem., Int. Ed. 2009, 48, 762-766.
(11) Genet, C.; Canipa, S. J.; O'Brien, P.; Taylor, S. Catalytic
Asymmetric Synthesis of Ferrocenes and P-Stereogenic
Bisphosphines. J. Am. Chem. Soc. 2006, 128, 9336-9337.
(12) Beaud, R.; Phipps, R. J.; Gaunt, M. J. Enantioselective Cu-
Catalyzed Arylation of Secondary Phosphine Oxides with
Diaryliodonium Salts toward the Synthesis of P-Chiral Phosphines. J.
Am. Chem. Soc. 2016, 138, 13183-13186.
8
ACS Paragon Plus Environment

Page 9 of 9
The Journal of Organic Chemistry
(28) Keipour, H.; Ollevier, T. Iron-Catalyzed Carbene Insertion
Reactions of α-Diazoesters into Si–H Bonds. Org. Lett. 2017, 19,
5736-5739.
(30) Davis, O. A.; Croft, R. A.; Bull, J. A. Synthesis of diversely
functionalised 2,2-disubstituted oxetanes: fragment motifs in new
chemical space. Chem. Comm. 2015, 51, 15446-15449.
1
2
3
4
(29) Park, E. J.; Lee, S.; Chang, S. Acetone Cyanohydrin as a
Source of HCN in the Cu-Catalyzed Hydrocyanation of α-Aryl
Diazoacetates. J. Org. Chem. 2010, 75, 2760-2762.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9
ACS Paragon Plus Environment