A practical method for N-alkylation of phosphinic (thio)amides with alcohols via transfer hydrogenation

Article abstract of DOI:10.1016/j.tet.2019.04.029

This manuscript describes a modular method for preparing N-alkyl phosphinic amides from primary or secondary alcohols and primary phosphinic amide (R¹R²P = ONH₂) nucleophiles via transfer hydrogenation. The transformation typically proceeds in excellent yields, employs conveniently available reagents, and produces water as the only byproduct.

Full text of DOI:10.1016/j.tet.2019.04.029

Accepted Manuscript
A practical method for N-alkylation of phosphinic (thio)amides with alcohols via
transfer hydrogenation
Tanner C. Jankins, Ziyang Qin, Keary M. Engle
PII:
S0040-4020(19)30431-4
https://doi.org/10.1016/j.tet.2019.04.029
TET 30274
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 February 2019
Revised Date: 3 April 2019
Accepted Date: 11 April 2019
Please cite this article as: Jankins TC, Qin Z, Engle KM, A practical method for N-alkylation of
phosphinic (thio)amides with alcohols via transfer hydrogenation, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2019.04.029.
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A Practical Method for N-Alkylation of Phosphinic (Thio)amides with Alcohols via Transfer
Hydrogenation
Tanner C. Jankins, Ziyang Qin and Keary M. Engle

1
Jankins, Qin, and Engle / Tetrahedron
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com/locate/jestch
A practical method for N-alkylation of phosphinic (thio)amides with alcohols via transfer
hydrogenation
a
a
a
†
†
Tanner C. Jankins , Ziyang Qin and Keary M. Engle*
a Departmentof Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
†
Authors contributed equally.
AB ST R ACT
AR T ICL E INFO
Article history:
Received
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
This manuscript describes a modular method for preparing N-alkyl phosphinic amides from
primary or secondary alcohols and primary phosphinic amide (R1R2P=ONH2) nucleophiles via
transfer hydrogenation. The transformation typically proceeds in excellent yields, employs
conveniently available reagents, and produces water as the only byproduct.
Available online
Keywords:
Transfer Hydrogenation
Ruthenium
Phosphorous
Phosphinic Amide
Amination
addition[2] or via an SN2 reaction between an alkyl halide and
an P(V)–NH2 phosphinic amide nucleophile under phase-
transfer conditions.[10] Given the widespread availability of
1. Introduction
Phosphinic amides are a unique class of P(V)
compounds that have been explored for diverse applications
as medicines, agrochemicals, and materials, among others
uses. (Fig. 1A).[1] Additionally N-alkyl phosphinic amides are
commonly employed in organic synthesis as amine precursors
by taking advantage of methods for reliable cleavage of the
N–P bond.[2,3] These multifarious uses have motivated the
development of several different methods for accessing
structurally diverse phosphinic amides, including N-alkyl and
N,N-dialkyl variants (Fig. 1B).[4] Strategies employing both
P(III) and P(V) precursors have been pursued. P(III)-based
methods inherently require an oxidation event at phosphorous,
typically as a discrete step before or after P–N bond
formation. In one example, a diorganophosphine chloride is
coupled with an amine, followed by oxidation.[5]
Alternatively, nucleophilic secondary phosphine oxides are
first treated with an electrophilic halogenating reagent (or an
electrophilic oxygenating agent followed activation with a
reagent such as SOCl2)
to form the corresponding
diorganophosphinic halide, which is then allowed to react
with an amine.[6,7] While useful in their own right, P(III)-
based methods have the disadvantage of generally employing
air- or moisture-sensitive reagents and typically require two
steps. Direct N-aryl/alkyation of P(V)–NH2 phosphinic
amides is an attractive alternative, as the starting materials in
this case are air- and moisture-stable and the reaction requires
only a single step.[8] N-Arylation of P(V)–NH2 phosphinic
amides has been described via Chan–Lam[9a] or Ullman
coupling.[9b] Complementary N-alkylation can be achieved by
several methods, including condensation with an aldehyde to
form
a (diorganophosphinoyl)imine, followed by 1,2-

2
Jankins, Qin, and Engle / Tetrahedron
ACCEPTED MANUSCRIPT
1 mol% Ru-MACHO
15 mol% KOH
structurally diverse primary and secondary alcohols, direct
coupling between a phosphinic amide nucleophile and an
alcohol would represent an attractive alternative to the
approaches described above. Seminal work during the past
R1
O
P
R1
O
P
Ph
Ph
Ph
Ph
+
R2
N
PhMe, 110–140 °C
(– H2O)
R2
NH2
HO
H
two
decades
has
established
that
weak
N–H
primary alcohols
nucleophiles,[11,12a] undergo N-alkylation with alcohols under
transfer hydrogenation conditions. Additionally, electron rich
primary aliphatic and aryl amines are known to give exclusive
mono-methylation with methanol and Ru-MACHO (CAS no.
1295649-40-9; [RuHCl(CO)(HN(CH2CH2PPh2)2)]).[12b,12c] To
our knowledge, the strategy has been applied with P(V)–NH2
phosphinic amides in two previous publications. In one case,
Rámon and coworkers employed a copper catalyst at 150 °C
for 10 days to couple benzyl alcohol and 1-hexanol with P,P-
diphenylphosphinic amide, affording 35% and 17% of the
desired products, respectively.[11a] In more recent work,
Williams enlisted catalytic [Ru(p-cymene)Cl2]2 with PPh3 as
ligand to couple benzyl alcohol with P,P-diphenylphosphonic
amide in 71% yield after 24 h at 150 °C.[11b] As part of our
ongoing program in catalytic alkene functionalization via
directed nucleometalation, we previously described Pd(II)-
catalyzed hydrofunctionalization and difunctionalization
reactions that employ weakly nucleophile nitrogen coupling
partners, such as imides, amides, and sulfonamides.[13] We
thus became interested in employing phosphinic amides to
this type of reaction.[14] To this end, we sought access to a
diverse collection of N-alkyl phosphinic amides, and thus
required a robust and functional-group-tolerant method for
their synthesis, which motivated the present study.
O
O
Me
Me
Me
O
P
Me
Ph
P
Ph
Ph
Ph
P
N
R
Ph
N
H
N
Ph
H
H
1c, 80%
Me
1a, 95%
1b, 98%
1d, 93%
(from (–)-β-citronellol)
O
P
O
O
Ph
Ph
Ph
Ph
P
P
S
N
N
N
N
Ph
Ph
H
H
H
1e, 92%
1f, 99%
1g, 98%
O
O
P
O
P
Ph
Ph
Ph
Ph
P
N
N
N
N
Ph
Ph
H
H
H
N
N
N
1h, 70%
1i, 99%
1j, 72%
O
O
P
O
X
Ph
Ph
Ph
P
Ph
Ph
X
P
N
H
Ph
N
H
N
H
X
1r (X = Cl), 85%
1s (X = Br), 90%
1o (X = OMe), 80%
1p (X = F), 86%
1q (X = Me), 98%
1k (X = Cl), 92%
1l (X = Me), 79%
1m (X = F), 81%
1n (X = H), 99%
1t (X = OMe), 99%
1u (X = Ph), 78%
1v (X = t-Bu), 76%
1w (X = CF3), 89%
1x (X = CO2Me), 22%a
secondary alcohols
O
P
Me
O
P
Me
O
P
Me
Ph
Ph
Ph
Ph
Ph
Ph
N
N
N
H
H
H
OMe
F
2a, 88%
2c, 65%
Me
2b, 48%
Me
2. Results and Discussion
O
Me
O
Ph
O
P
Ph
N
H
Ph
P
Ph
P
2.1. Reaction Design and Optimization
N
Ph
N
Ph
H
H
Cl
N
2e, 22%
2d, 44%
2f, 65%
Based on the precedents above, we were attracted to the idea
of preparing phosphinic amides via Ru(II)-catalyzed transfer
hydrogenation[15], which we surmised would allow for atom-
economical and modular coupling of P(V) N–H nucleophiles
with alcohols. In terms of the proposed mechanism, we
envisioned the following sequence of events. First,
dehydrogenation of the alcohol would form the corresponding
aldehyde or ketone, which would then be attacked by the
weakly nucleophilic primary phosphinic amide. Loss of water
would form the imine, and subsequent imine hydrogenation
by the Ru(II) catalyst would turn over the catalyst and form
the N-alkylated product. The commercial availability of a vast
library of structurally diverse alcohols offered a convenient
and inexpensive platform for building molecular complexity
in a direct manner. After screening known (de)hydrogenative
catalysts and bases, we identified Ru-MACHO[12,16] and KOH
to give near quantitative yields for most primary alcohols and
good yields for secondary alcohols, albeit at slightly higher
temperatures. We also found a convenient base-free protocol
using Ru-MACHO-BH[16b] (cas no. 1295649-41-0; [RuH(H-
BH3)(CO)(HN(CH2CH2PPh2)2)]) for substrates with base-
sensitive functional groups (1x). Ru-MACHO-BH was also a
viable catalyst for the other substrates, but typically gave
slightly lower yields (~5–10%) compared with Ru-MACHO
in combination with KOH. We attribute the higher efficiency of
the basic conditions to the ability of the base to deprotonate the
alcohol and make coordination to the catalyst more favorable.
H
Me
Me
Me
Me
Me
H
Me
H
O
O
P
Ph
P
N
H
H
H
Ph
Ph
Ph
N
Me
H
2g, 56% (1:1 d.r.)
(from (–)-carveol)
2h, 65% (>20:1 d.r.)
(from chlostereol)
[X-ray]
Table 1: Reaction condtions: phosphinic amide (0.2 mmol), alcohol (0.24 mmol), Ru-
MACHO (0.002 mmol), KOH (0.030 mmol), toluene (0.7 mL), 110 °C (primary
alcohols) or 140 °C (secondary alcohols), 16 h. Per centages represent isolated yields.
a Ru-MACHO-BH used as catalyst without addition of base.
Having identified an efficient catalyst system, we next moved
on to examine the substrate scope (Table 1). The reaction was
found to tolerate most common functional groups, giving
excellent (in many cases quantitative) yields, provided that the
alcohol is sterically unencumbered. Remarkably, disubstituted
Z-alkenes (1a) were compatible, and no hydrogenation or
isomerization of the alkene was observed—despite the fact
that the reaction involves formation of a metal hydride
intermediate at high temperature—showcasing the exquisite
chemoselectivity of this catalyst. Additionally, a methyl ester
(1x) was not hydrogenated under the reaction conditions,
despite the fact that Ru-MACHO can be used as an ester
hydrogenation catalyst under similar reaction conditions.[16a]
The reaction also gave quantitative yields with heteroaryl-
substituted alcohols that could coordinate in a bidentate
fashion with the metal (1d, 1f, 1h). Other heterocycles
similarly gave high yields (1g, 1i, 2f). A variety of electron-
rich and neutral benzylic alcohols were superb electrophiles.
In contrast the presence of strongly electron-withdrawing
2.2. Transfer Hydrogenation Substrates

3
Jankins, Qin, and Engle / Tetrahedron
ACCEPTED MANUSCRIPT
1 mol% Ru-MACHO
15 mol% KOH
X
X
P
HO
+
R1
P
R1
R2
P-chiral starting materials was accomplished by using phenyl
tert-butylphosphine chloride and a commercially available
enantiopure secondary benzyl amine, followed by mild
oxidation to provide the P(V) intermediate. Separation of the
two diastereomers by HPLC, followed by deprotection of the
benzyl group afforded both enantiomers of P-tert-butyl,P-
phenyl phosphinic amide (4b). When subjected to the
catalytic N-alkylation conditions, (R)-(4b) gave similar yields
to 3a and 3f, which have a similar steric environment about
phosphorus, and the ee of the product was >99%, indicating
that the P-stereocenter was configurationally stable under the
reactions conditions.
N
R2
NH2
H
OMe
PhMe (1 M), 130 °C
(– H2O)
OMe
phosphinic (thio)amides
O
P
O
O
Cy
Cy
t-Bu
t-Bu
i-Pr
P
P
N
N
N
i-Pr
H
H
H
OMe
OMe
OMe
OMe
OMe
3a, 52%
3b, 80%
3c, 73%
S
P
S
P
Ph
Ph
t-Bu
t-Bu
N
N
H
H
3e, 44%
3f, 62%
[X-ray]
Although the use of Ru-MACHO is typically limited to
handling in a glovebox,[12] we found that our procedure can be
carried out outside of the glovebox with nearly identical
yields to those set up under strictly inert glovebox conditions.
This finding simplifies the reaction operationally by allowing
for alcohols to be used directly from the bottle without any
degassing or drying.
Table 2: Reaction condtions: phosphinic (thio)amide (0.2 mmol), alcohol (0.24 mmol),
Ru-MACHO (0.002 mmol), KOH (0.030 mmol), toluene (0.7 mL), 130 °C, 16 h.
Percentages represent isolated yields.
groups or ortho-substituents led to diminished yields (1k, 1l,
1x). Aryl halides gave excellent yields and showed no
evidence of decomposition under the reaction conditions (1k,
1m, 1p, 1r, 1s). Trifluoroethanol and methanol were both
low-yielding (<5 %) under the standard reaction conditions.
With methanol, slightly higher yield (13 %) could be obtained
when 10 equiv MeOH was used. Some secondary alcohols
were also amenable to this reaction, giving moderate to good
yields depending on the properties of the alcohol coupling
partner (2a-2h). In low-yielding cases, we attribute the
decreased efficiency to the increased steric hindrance of these
substrates and to the attenuated electrophilicity of the
corresponding ketone intermediates compared to their
aldehyde counterparts. We found that a number of naturally
occurring terpenes such as cholesterol (2h), β-citronellol (1b)
and carveol (2g) were viable substrates under the standard
reaction conditions. Cholesterol reacted in good yield with
high d.r. The major diastereomer was assigned by X-ray
crystallography, and the stereochemical configuration of the
C–N bond indicates that hydrogenation took place
predominantly from the less hindered face. (–)-Carveol (used
as a mixture of alcohol stereoisomers) was also reactive but
generated a mixture of diastereomers, presumably due to the
fact that the two faces of the putative imine intermediate were
not significantly sterically differentiated. Given that the
alcohol stereocenter is ablated during the initial
dehydrogenation, the stereochemistry of the starting alcohol is
not expected to affect the final d.r.
2.3. Proposed Mechanism
The mechanism of this transformation likely follows a similar
pathway to what has previously been described in the
literature (Scheme 2).[12,17] Evidence for
a
stepwise
dehydrogenation/hydrogenation pathway rather a concerted
attack of the amine on a ruthenium bound alcohol/aldehyde is
supported by the detection of the imine intermediate by
LCMS when using 4-nitrobenzyl alcohol as the electrophile.
Additionally, when synthesizing substrate 2e, some unreacted
ketone was also detected by LCMS. Based on these
observations, it seems that the imine intermediate is highly
reactive and cannot be trapped unless another suitable
hydrogen acceptor such as a nitro group is present. Olefins
(1a, 1b, 2g, 2h) do not appear to be competitive hydrogen
acceptors in the presence of the imine intermediate. Although
an acceptorless dehydrogenation of the alcohol where gaseous
H2 is generated followed by reactivation of H2 by intermediate
C is possible, the loss of H2 from B is considered to be the
rate limiting step with similar catalysts.[17] Therefore it is
likely to be only a minor pathway, if operative at all. This
reaction also appears to be completely selective for mono-N-
alkylation; N,N-dialkylated products were never detected,
even when using sterically unencumbered alcohols, such as
ethanol, in large excess (10 equiv).
We next investigated the nucleophile scope and found
different primary phosphinic amides performed well under the
optimal reaction conditions (3a–3f, Table 2). Interestingly,
benzamide (the carbon analog of P,P-diphenylphosphinic
amide) was completely unreactive under standard conditions,
illustrating that the presence of a heteroatom connected to the
nucleophilic –NH2 site is essential for reactivity. We also
found that the much less explored sulfur analogs,
thiophosphinic amides, were highly effective, providing
similar yields.
Next we sought to demonstrate that chiral-at-P phosphinic
amides could be employed in this chemistry without erosion
of optical purity (Scheme 1). The synthesis of optically pure

4
Jankins, Qin, and Engle / Tetrahedron
ACCEPTED MANUSCRIPT
3. Conclusion
4.2. Characterization of new compounds
We have developed an efficient, high-yielding, and
functional-group-tolerant route to access N-alkyl phosphinic
amides from the corresponding P(V)–NH2 nucleophiles and
alcohols. This method allows rapid access to structurally
diverse phosphinic amides from simple starting materials, and
circumvents limitations associated with the use of P(III)
precursors. We demonstrated enantioretentive N-alkylation
with enantioenriched chiral-at-P phosphinic amides, allowing
this family of bench-stable starting materials to serve as an
entry point to more highly substituted chiral-at-P target
molecules.
(Z)-N-(hex-4-en-1-yl)-P,P-diphenylphosphinic amide (1a):
The title compound was prepared from Ru•MACHO (1.2 mg,
0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
diphenylphosphinic amide (43.4 mg, 0.20 mmol) and (Z)-hex-
4-en-1-ol (24 mg, 0.24 mmol) according to General Procedure
1. Purification by reverse phase HPLC gave the product as a
white solid (57 mg, 95% yield). 1H NMR (600 MHz, DMSO-
d6) δ 8.15–8.07 (m, 1H), 7.96–7.89 (m, 1H), 7.88–7.78 (m,
5H), 7.67 (d, J = 7.1 Hz, 1H), 7.57–7.41 (m, 9H), 5.94 (dt, J =
9.6, 7.2 Hz, 1H), 4.45 (dd, J = 9.4, 7.2 Hz, 2H). 13C NMR
(150 MHz, DMSO-d6) δ 134.06 (d, J = 126.0 Hz), 131.65 (dd,
J = 9.2, 2.8 Hz), 131.31, 129.95, 128.37 (d, J = 12.0
Hz),123.82, 31.45 (d, J = 6.3 Hz) 23.84, 17.70, 12.61.31P
NMR (162 MHz, DMSO) δ 22.82. HRMS (FAB+) m/z Calcd
for C18H23NOP [M]+ 300.1512, found 300.1511.
4. Experimental
4.1. General Procedures
Glovebox Procedure (General Procedure 1): Inside an argon-
filled glovebox (O2 levels between 35.0–55.0 ppm, H2O levels
unknown), to an oven dried 10-mL screw cap vial equipped
with a Teflon-coated magnetic stir bar were added Ru-
MACHO (1.2 mg, 2.00 ꢀmol), KOH (1.7 mg, 30.0 ꢀmol), and
the appropriate phosphinic amide (0.200 mmol) in that order.
Subsequently, toluene (0.7 mL) was added via micropipette,
with care taken to ensure that solids on the wall were washed
to the bottom of the vial. Next, the appropriate alcohol (0.240
mmol) was added either as a solid or via micropipette for
liquid substrates. The reaction was sealed tightly with a non-
puncturable cap and was further sealed by placing a piece of
electrical tape around the cap and top of vial.
(S)-N-(3,7-dimethyloct-6-en-1-yl)-P,P-diphenylphosphinic
amide (1b): The title compound was prepared from Ru-
MACHO (1.2 mg, 0.002 mmol), KOH (1.7 mg, 0.030 mmol),
P,P-diphenylphosphinic amide (43.4 mg, 0.20 mmol) and (–)-
β-citronellol (34 mg, 0.22 mmol) according to General
Procedure 1. Purification by reverse phase HPLC gave the
1
product as a white solid (57 mg, 98% yield). H NMR (600
MHz, DMSO-d6) δ 7.78 (dd, J = 11.6, 7.5 Hz, 4H), 7.59–7.41
(m, 6H), 5.22 (q, J = 7.3 Hz, 1H), 5.04 (t, J = 7.3 Hz, 1H),
2.74 (ddddt, J = 28.2, 12.3, 9.1, 6.0, 3.0 Hz, 2H), 1.89 (dq, J =
14.5, 7.2 Hz, 2H), 1.62 (s, 3H), 1.53 (s, 3H), 1.47 (m, 2H),
1.30 (ddt, J = 13.0, 7.8, 4.1 Hz, 1H), 1.19 (ddt, J = 12.3, 9.5,
6.0 Hz, 1H), 1.05 (ddt, J = 13.5, 9.1, 6.6 Hz, 1H), 0.75 (d, J =
6.5 Hz, 3H). 13C NMR (150 MHz, DMSO-d6) δ 134.06 (d, J
= 125.2 Hz), 131.64 (d, J = 9.2 Hz), 131.29, 130.40, 128.34
(d, J = 12.0 Hz) 124.61, δ 38.57 (d, J = 6.5 Hz) 37.98, 36.52,
29.31, 25.48, 24.81, 19.32, 17.49. 31P NMR (162 MHz,
DMSO) δ 21.64. HRMS (FAB+) m/z Calcd for C22H31NOP
[M]+ 356.2138, found 356.2139.
Schlenk Line Procedure (General Procedure 2): To a flame-
dried vial were quickly added Ru-MACHO (1.2 mg, 2.00
ꢀmol) and KOH (1.7 mg, 30.0 ꢀmol) (stored under Ar)
(addition time <1 min), and the reaction vial was left open
under a steady flow of nitrogen (applied via a needle placed at
the top of the vial). Next, the appropriate phosphinic amide
(0.200 mmol) was added, followed by the addition of toluene
(0.7 mL) from a standard Solvent Purification System (SPS).
Lastly, the appropriate alcohol (0.240 mmol) was added either
as a solid or via micropipette for liquid substrates. The
nitrogen line was removed and the vial was then quickly and
tightly sealed with a non-puncturable cap and further sealed
by placing a piece of electrical tape around the cap and top of
the vial. After the differing series of operations described
above, General Procedures 1 and 2 then followed then same
protocol. The reaction vessel was placed in a preheated oil
bath at 110–140 °C with a stirring rate of 500 rpm. As the
reaction was proceeding, the vessel was periodically visually
monitored. If large amounts of solid were found to have
accumulated on the wall, the vial was briefly removed from
the oil bath and shaken to wash the solids back to the bottom
of the vial. After 16 h, the vial was removed from the oil bath
and allowed to cool to room temperature. Methanol (1 mL)
was added to dissolve all solids, and the solvent removed in
vacuo. The solid was redissolved in methanol (1 mL), and the
solution was filtered through a 40-micron syringe filter.
Samples were then purified by reverse-phase HPLC or
recrystallized from hot benzene. In the case of HPLC
purification, the fractions were combined, frozen in liquid N2,
and lyophilized to sublime the solvent.
N-ethyl-P,P-diphenylphosphinic amide (1c): The title
compound was prepared from Ru-MACHO (1.2 mg, 0.002
mmol), KOH (1.7 mg, 0.030 mmol), P,P-diphenylphosphinic
amide (43.4 mg, 0.20 mmol) and ethanol (58 µL, 1.0 mmol)
according to General Procedure 1. Purification by reverse
phase HPLC gave the product as a white solid (39 mg, 80%
1
yield). H NMR (600 MHz, DMSO-d6) δ 7.79 (ddt, J = 11.7,
6.8, 1.5 Hz, 4H), 7.58 – 7.40 (m, 6H), 5.30 (q, J = 7.3 Hz,
1H), 2.90 – 2.66 (m, 2H), 1.09 (t, J = 7.1 Hz, 3H). 13C NMR
(151 MHz, DMSO-d6) δ 134.05 (d, J = 126.1 Hz), 131.64 (d,
J = 9.3 Hz), 131.33 (d, J = 2.6 Hz), 128.39 (d, J = 12.0 Hz),
34.87 (d, J = 1.4 Hz), 17.42 (d, J = 6.9 Hz). 31P NMR (162
MHz, DMSO) δ 21.61. HRMS (FAB+) m/z Calcd for
C14H16NOP [M+H]+ 246.1042, found 246.1042.
N-(cyclopropylmethyl)-P,P-diphenylphosphinic
amide
(1d): The title compound was prepared from Ru-MACHO
(1.2 mg, 0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
diphenylphosphinic amide (43.4 mg, 0.20 mmol) and
cyclopropylmethanol (19 µL, 0.24 mmol) according to
General Procedure 1. Purification by reverse phase HPLC
1
gave the product as a white solid (58 mg, 93% yield). H
The primary phosphinic amides used in the synthesis of
compounds 3a–3f were purchased from commercial sources
or synthesized according to a known procedure.[19] Additional
details can be found in the Supporting Information (page S-4).
NMR (600 MHz, DMSO-d6) δ 7.84–7.77 (m, 4H), 7.55–7.49
(m, 2H), 7.48 (tdd, J = 6.5, 3.1, 1.7 Hz, 3H), 7.26 (dq, J = 4.5,
2.3 Hz, 1H), 5.41 (dt, J = 9.0, 7.0 Hz, 1H), 2.64 (dt, J = 10.5,
6.8 Hz, 2H), 0.93 (dddd, J = 11.5, 6.6, 4.0, 1.6 Hz, 1H), 0.40–
0.32 (m, 2H), 0.12 (dt, J = 6.1, 4.3 Hz, 2H). 13C NMR (150

5
Jankins, Qin, and Engle / Tetrahedron
ACCEPTED MANUSCRIPT
δ 22.31. HRMS (FAB+) m/z Calcd for C17H17NOPS [M+H]+
314.0763, found 377.0764.
MHz, DMSO-d6) δ 134.13 (d, J = 126.0 Hz), 131.67 (d, J =
9.3 Hz), 131.31, 128.34 (d, J = 12.1 Hz) 44.74, 12.80, 3.51.
31P NMR (162 MHz, DMSO) δ 21.57. HRMS (FAB+) m/z
Calcd for C24H24ClNOP [M+H]+ 272.1199, found 272.1200.
P,P-diphenyl-N-(pyridin-4-ylmethyl)phosphinic
amide
(1h): The title compound was prepared from Ru-MACHO
(1.2 mg, 0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
diphenylphosphinic amide (43.4 mg, 0.20 mmol) and pyridin-
4-ylmethanol (26.2 mg, 0.24 mmol) according to General
Procedure 1. Purification by reverse phase HPLC gave the
product as a white solid (43 mg, 70% yield). 1H NMR (600
MHz, DMSO-d6) δ 8.49 (d, J = 4.5 Hz, 2H), 7.83 (dd, J =
11.1, 7.8 Hz, 4H), 7.53 (d, J = 6.9 Hz, 2H), 7.51–7.45 (m,
4H), 7.42 (d, J = 4.5 Hz, 2H), 6.08 (q, J = 7.6 Hz, 1H), 4.07–
3.96 (m, 2H). 13C NMR (150 MHz, DMSO-d6) δ 149.73 (d, J
= 5.8 Hz), 149.32, 133.46 (d, J = 126.6 Hz), 131.71 (d, J = 9.4
Hz), 131.64 (d, J = 2.7 Hz), 128.53 (d, J = 12.1 Hz), 122.35,
42.63. 31P NMR (162 MHz, DMSO) δ 22.85. HRMS (FAB+)
m/z Calcd for C18H18N2OP [M+H]+ 309.1151, found
309.1151.
P,P-diphenyl-N-(3-(piperidin-1-yl)propyl)phosphinic
amide (1e): The title compound was prepared from Ru-
MACHO (1.2 mg, 0.002 mmol), KOH (1.7 mg, 0.030 mmol),
P,P-diphenylphosphinic amide (43.4 mg, 0.20 mmol) and 3-
(piperidin-1-yl)propan-1-ol (37 µL, 0.24 mmol) according to
General Procedure 1. Purification by reverse phase HPLC
gave the product as a viscous colorless oil (58 mg, 93%
yield). This material was sparingly soluble in DMSO-d6,
MeOH-d4, Acetone-d6 or CDCl3. The 13C NMR spectrum
showed extremely complex splitting in the aliphatic region, so
peaks are listed without attempting to accurately calculate
1
splitting values. H NMR (600 MHz, Acetone-d6) δ 8.35 (s,
1H), 7.83 (ddd, J = 11.1, 7.3, 1.9 Hz, 5H), 7.30 (dt, J = 6.7,
3.7 Hz, 5H), 3.28 (dt, J = 22.2, 6.6 Hz, 1H), 2.98 (dt, J = 17.8,
6.7 Hz, 1H), 2.90–2.58 (m, 6H), 2.00–1.88 (m, 2H), 1.80–
1.35 (m, 8H). 13C NMR (150 MHz, Acetone-d6) δ 140.77 (d,
J = 130.6 Hz), 130.86 (d, J = 9.2 Hz), 128.84 (d, J = 2.3 Hz),
127.14 (d, J = 11.6 Hz) 55.14, 52.82, 52.58, 52.47, 52.39,
52.33, 47.26, 37.54, 36.62, 25.15, 24.85, 23.81, 23.55, 23.41,
22.97, 22.45, 22.26, 22.10, 21.98..31P NMR (162 MHz,
Acetone) δ 16.51. HRMS (FAB+) m/z Calcd for C20H28N2OP
[M+H]+ 345.1934, found 345.1936.
P,P-diphenyl-N-(pyridin-2-ylmethyl)phosphinic
amide
(1l): The title compound was prepared from Ru-MACHO (1.2
mg, 0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
diphenylphosphinic amide (43.4 mg, 0.20 mmol) and pyridin-
2-ylmethanol (23 µL, 0.24 mmol) according to General
Procedure 1. Purification by reverse phase HPLC gave the
1
product as a white solid (61 mg, 99% yield). H NMR (600
MHz, DMSO-d6) δ 8.49–8.42 (m, 1H), 7.88–7.82 (m, 4H),
7.80 (td, J = 7.7, 1.9 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.54
(td, J = 7.3, 1.5 Hz, 2H), 7.49 (td, J = 7.4, 3.1 Hz, 4H), 7.25
(dd, J = 7.5, 4.8 Hz, 1H), 5.99 (dt, J = 9.4, 7.4 Hz, 1H), 4.08
(dd, J = 10.9, 7.3 Hz, 2H). 13C NMR (150 MHz, DMSO-d6) δ
159.82 (d, J = 6.7 Hz), 148.47, 136.64, 133.56 (d, J = 126.5
Hz), 131.71 (d, J = 9.4 Hz), 131.58 (d, J = 2.6 Hz), 128.51 (d,
J = 12.1 Hz), 122.02, 121.36, 45.43. 31P NMR (162 MHz,
DMSO) δ 22.67. HRMS (FAB+) m/z Calcd for C18H18N2OP
[M+H]+ 309.1151, found 309.1152.
N-(naphthalen-2-ylmethyl)-P,P-diphenylphosphinic amide
(1f): The title compound was prepared from Ru-MACHO (1.2
mg, 0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
diphenylphosphinic amide (43.4 mg, 0.20 mmol) and
naphthalen-2-ylmethanol (38.0 mg, 0.24 mmol) according to
General Procedure 1. Purification by reverse phase HPLC
1
gave the product as a white solid (72 mg, 99% yield). H
NMR (600 MHz, DMSO-d6) δ 8.13–8.08 (m, 1H), 7.95–7.90
(m, 1H), 7.87–7.79 (m, 5H), 7.67 (d, J = 7.1 Hz, 1H), 7.55–
7.43 (m, 9H), 5.94 (dt, J = 9.6, 7.2 Hz, 1H), 4.45 (dd, J = 9.4,
7.2 Hz, 2H). 13C NMR (150 MHz, DMSO-d6) δ 135.71 (d, J
= 7.3 Hz), 134.24, 133.40, 133.12, 131.60 (d, J = 9.4 Hz),
131.48 (d, J = 2.4 Hz), 130.67, 128.59–128.24 (m), 127.33,
126.02, 125.63, 125.38, 125.23, 123.36, 41.12. 31P NMR (162
MHz, DMSO) δ 22.82. HRMS (FAB+) m/z Calcd for
C23H21NOP [M+H]+ 358.1355, found 358.1356.
P,P-diphenyl-N-(pyrimidin-5-ylmethyl)phosphinic amide
(1i):
The title compound was prepared from Ru-MACHO (1.2 mg,
0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
diphenylphosphinic amide (43.4 mg, 0.20 mmol) and
pyrimid-5-ylmethanol (26 mg, 0.24 mmol) according to
General Procedure 1. Purification by reverse phase HPLC
1
gave the product as a white solid (45 mg, 72% yield). H
NMR (600 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.78 (s, 2H), 7.82
(ddd, J = 11.8, 8.3, 1.5 Hz, 4H), 7.54 (td, J = 7.3, 1.5 Hz, 2H),
7.49 (ddd, J = 9.6, 5.3, 2.1 Hz, 4H), 6.12–6.00 (m, 1H), 4.03
(dd, J = 11.6, 7.3 Hz, 2H). 1H NMR (600 MHz, Methanol-d4)
δ 9.02 (s, 1H), 8.77 (s, 2H), 7.86 (dd, J = 12.3, 7.5 Hz, 5H),
7.57 (t, J = 7.5 Hz, 2H), 7.51 (td, J = 7.7, 3.2 Hz, 5H), 4.17 (d,
J = 11.6 Hz, 2H). 13C NMR (151 MHz, Methanol-d4) δ
157.90, 157.69133.55 (d, J = 2.8 Hz), 133.05 (d, J = 10.0 Hz),
132.74 (d, J = 9.9 Hz), 129.90 (d, J = 12.7 Hz), 129.56 (d, J =
12.7 Hz). 40.61. 31P NMR (162 MHz, MeOD) δ 28.03.
HRMS (FAB+) m/z Calcd for C17H17N3OP [M+H]+
310.1105, found 310.1104.
P,P-diphenyl-N-(thiophen-2-ylmethyl)phosphinic
amide
(1g): The title compound was prepared from Ru-MACHO
(1.2 mg, 0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
diphenylphosphinic amide (43.4 mg, 0.20 mmol) and
thiophen-2-ylmethanol (23 µL, 0.24 mmol) according to
General Procedure 1. Purification by reverse phase HPLC
1
gave the product as a white solid (77 mg, 98% yield). H
NMR (600 MHz, DMSO-d6) δ 7.83 (dd, J = 11.7, 7.4 Hz,
4H), 7.55 (t, J = 7.3 Hz, 2H), 7.50 (td, J = 7.6, 2.9 Hz, 4H),
7.40 (d, J = 5.0 Hz, 1H), 6.99 (d, J = 3.5 Hz, 1H), 6.95 (t, J =
4.3 Hz, 1H), 6.09 (q, J = 7.8 Hz, 1H), 4.14 (dd, J = 9.4, 7.3
Hz, 2H). 13C NMR (150 MHz, DMSO-d6) δ 144.61 (d, J =
8.3 Hz), 133.60 (d, J = 126.3 Hz), 131.66 (d, J = 9.4 Hz),
131.56 (d, J = 2.6 Hz), 128.47 (d, J = 12.1 Hz), 126.72,
124.73 (d, J = 11.7 Hz), 38.78. 31P NMR (162 MHz, DMSO)
N-(2-chlorobenzyl)-P,P-diphenylphosphinic amide (1k):
The title compound was prepared from Ru-MACHO (1.2 mg,
0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-

6
Jankins, Qin, and Engle / Tetrahedron
ACCEPTED MANUSCRIPT
diphenylphosphinic amide (43.4 mg, 0.20 mmol) and (2-
chlorophenyl)methanol (34.3 mg, 0.24 mmol) according to
General Procedures 1 or 2. Both yields are reported below.
Purification by reverse phase HPLC gave the product as a
white solid (GP1: 63 mg, 92% yield; GP2: 61 mg, 89%
methoxyphenyl)methanol (30 µL, 0.24 mmol) according to
General Procedure 1. Purification by reverse phase HPLC
gave the product as a white solid (54 mg, 80% yield). H
1
NMR (600 MHz, DMSO-d6) δ 7.88–7.77 (m, 4H), 7.56–7.51
(m, 2H), 7.48 (td, J = 7.5, 2.8 Hz, 4H), 7.21 (t, J = 7.8 Hz,
1H), 7.03–6.88 (m, 2H), 6.79 (dd, J = 8.1, 2.7 Hz, 1H), 5.91
(q, J = 7.9 Hz, 1H), 3.94 (dt, J = 11.3, 5.7 Hz, 2H), 3.72 (s,
3H). 13C NMR (150 MHz, DMSO) δ 159.19, 142.34, 133.78
(d, J = 126.5 Hz). 131.69 (d, J = 9.3 Hz), 131.47, 129.11,
128.44 (d, J = 12.1 Hz). 119.43, 112.93, 112.10, 54.93, 43.52.
31P NMR (162 MHz, DMSO) δ 22.48. HRMS (FAB+) m/z
Calcd for C20H21NO2P [M+H]+ 338.1304, found 338.1304.
1
yield;). H NMR (600 MHz, DMSO-d6) δ 7.84 (ddt, J = 11.8,
6.9, 1.5 Hz, 4H), 7.78 (dd, J = 7.7, 1.6 Hz, 1H), 7.58–7.51 (m,
2H), 7.48 (ddd, J = 8.5, 6.6, 3.1 Hz, 4H), 7.42–7.34 (m, 2H),
7.27 (td, J = 7.7, 1.7 Hz, 1H), 6.00 (dt, J = 9.3, 7.5 Hz, 1H),
4.06 (dd, J = 10.6, 7.5 Hz, 2H). 13C NMR (150 MHz, DMSO-
d6) δ 137.60 (d, J = 6.6 Hz), 133.89, 133.05, 131.65 (d, J =
9.4 Hz), 131.59 (d, J = 2.8 Hz), 131.49, 128.90 (d, J = 51.2
Hz), 128.49 (d, J = 12.1 Hz)., 128.35, 127.09, 41.04. 31P
NMR (162 MHz, Acetone) δ 22.94. HRMS (FAB+) m/z
Calcd for C19H18ClNOP [M+H]+ 342.0809, found 342.0809.
N-(3-fluorobenzyl)-P,P-diphenylphosphinic amide (1p):
The title compound was prepared from Ru-MACHO (1.2 mg,
0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
diphenylphosphinic amide (43.4 mg, 0.20 mmol) and (3-
fluorophenyl)methanol (30.3 mg, 0.24 mmol) according to
General Procedure 1. Purification by reverse phase HPLC
N-(2-methylbenzyl)-P,P-diphenylphosphinic amide (1j):
The title compound was prepared from Ru-MACHO (1.2 mg,
0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
diphenylphosphinic amide (43.4 mg, 0.20 mmol) and o-
tolylmethanol (29 µL, 0.24 mmol) according to General
Procedure 1. Purification by reverse phase HPLC gave the
product as a white solid (58 mg, 79% yield). 1H NMR (600
MHz, DMSO-d6) δ 7.88–7.75 (m, 3H), 7.58–7.42 (m, 7H),
7.22–7.03 (m, 3H), 5.79–5.65 (m, 1H), 3.94 (dd, J = 9.5, 7.2
1
gave the product as a white solid (56 mg, 86% yield). H
NMR (600 MHz, DMSO-d6) δ 7.82 (dd, J = 11.8, 7.4 Hz,
4H), 7.58–7.43 (m, 6H), 7.33 (td, J = 7.9, 6.0 Hz, 1H), 7.30–
7.23 (m, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.04 (td, J = 8.6, 2.7
Hz, 1H), 6.01 (dt, J = 9.8, 7.4 Hz, 1H), 3.99 (dd, J = 11.1, 7.5
Hz, 2H). 13C NMR (150 MHz, DMSO-d6) δ 162.20 (d, J =
243.0 Hz), 143.92 (t, J = 6.5 Hz), 133.62 (d, J = 126.5 Hz),
131.70 (d, J = 9.4 Hz), 131.56 (d, J = 2.6 Hz), 129.96 (d, J =
8.2 Hz), 128.49 (d, J = 12.1 Hz), 123.22 (d, J = 2.7 Hz),
114.00 (d, J = 21.7 Hz), 113.36 (d, J = 21.1 Hz) 43.14. 31P
NMR (162 MHz, DMSO) δ 22.64. 19F NMR (376 MHz,
Hz, 2H), 2.16 (s, 3H).
13C NMR (150 MHz, DMSO-d6) δ
138.32 (d, J = 7.2 Hz), 135.11, 133.84 (d, J = 126.0 Hz),
131.63 (d, J = 9.4 Hz), 131.45 (d, J = 2.7 Hz), 129.62, 128.42
(d, J = 12.1 Hz) δ, 127.55, 126.58, 125.69, 40.95, 18.55. 31P
NMR (162 MHz, DMSO) δ 22.66. HRMS (FAB+) m/z Calcd
for C20H21NOP [M+H]+ 322.1355, found 322.1355.
DMSO)
δ -114.14. HRMS (FAB+) m/z Calcd for
C19H18FNOP [M+H]+ 326.1105, found 326.1104.
N-(2-fluorobenzyl)-P,P-diphenylphosphinic amide (1m):
The title compound was prepared from Ru-MACHO (1.2 mg,
0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
diphenylphosphinic amide (43.4 mg, 0.20 mmol) and (2-
fluorophenyl)methanol (30.3 mg , 0.24 mmol) according to
General Procedure 1. Purification by reverse phase HPLC
N-(3-methylbenzyl)-P,P-diphenylphosphinic amide (1q):
The title compound was prepared from Ru-MACHO (1.2 mg,
0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
diphenylphosphinic amide (43.4 mg, 0.20 mmol) and m-
tolylmethanol (29 µL, 0.24 mmol) according to General
Procedure 1. Purification by reverse phase HPLC gave the
product as a white solid (57 mg, 78% yield). 1H NMR (600
MHz, DMSO-d6) δ 7.82 (dd, J = 11.6, 7.2 Hz, 4H), 7.52 (t, J
= 7.2 Hz, 2H), 7.48 (td, J = 7.5, 2.8 Hz, 4H), 7.19 (d, J = 5.2
Hz, 2H), 7.15 (s, 1H), 5.87 (q, J = 7.9 Hz, 1H), 3.93 (dd, J =
10.3, 7.4 Hz, 2H), 2.27 (s, 3H). 13C NMR (150 MHz, DMSO-
d6) δ 140.58 (d, J = 6.6 Hz), 131.71 (d, J = 9.3 Hz), 137.06,
134.26, 133.43, 131.46 (d, J = 2.7 Hz), 128.44 (d, J = 11.9
1
gave the product as a white solid (53 mg, 81% yield). H
NMR (600 MHz, DMSO-d6) δ 7.88–7.78 (m, 4H), 7.59–7.45
(m, 6H), 7.21–7.13 (m, 3H), 7.03 (dt, J = 5.7, 2.3 Hz, 1H),
5.87 (dt, J = 9.5, 7.4 Hz, 1H), 3.93 (dd, J = 10.3, 7.4 Hz, 2H).
13C NMR (150 MHz, DMSO-d6) δ 140.56 (d, J = 6.9 Hz),
131.69 (d, J = 9.3 Hz), 131.44 (d, J = 2.7 Hz), 128.42 (d, J =
12.1 Hz), 127.98 (d, J = 5.9 Hz). 19F NMR (376 MHz,
DMSO) δ -119.85. 31P NMR (162 MHz, DMSO) δ 22.49.
HRMS (FAB+) m/z Calcd for C19H18FNOP [M+H]+
326.1105, found 326.1107.
Hz), 128.00 (d, J = 5.9 Hz), 127.28, 124.45, 43.52, 21.07. 31
P
NMR (162 MHz, DMSO) δ 22.45. HRMS (FAB+) m/z Calcd
for C20H21NOP [M+H]+ 322.1355, found 322.1356.
N-(4-chlorobenzyl)-P,P-diphenylphosphinic amide (1r):
The title compound was prepared from Ru-MACHO (1.2 mg,
0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
diphenylphosphinic amide (43.4 mg, 0.20 mmol) and (4-
chlorophenyl)methanol (34.3 mg, 0.24 mmol) according to
General Procedure 1. Purification by reverse phase HPLC
gave the product as a white solid (58 mg, 85% yield). 1H
NMR (600 MHz, DMSO-d6) δ 7.86–7.77 (m, 4H), 7.55–7.50
(m, 2H), 7.48 (td, J = 7.5, 3.0 Hz, 4H), 7.42 (d, J = 8.3 Hz,
2H), 7.36 (d, J = 8.5 Hz, 2H), 5.98 (dt, J = 9.8, 7.4 Hz, 1H),
3.96 (dd, J = 10.8, 7.4 Hz, 2H). 13C NMR (150 MHz, DMSO-
d6) δ 139.83 (d, J = 6.1 Hz), 133.66 (d, J = 126.4 Hz), 131.70
(d, J = 9.3 Hz), 131.54 (d, J = 2.6 Hz), 131.19, 129.19, 128.48
(d, J = 12.1 Hz), 128.00, 42.93. 31P NMR (162 MHz, DMSO)
N-benzyl-P,P-diphenylphosphinic amide (1n): The title
compound was prepared from Ru-MACHO (1.2 mg, 0.002
mmol), KOH (1.7 mg, 0.030 mmol), P,P-diphenylphosphinic
amide (43.4 mg, 0.20 mmol) and benzyl alcohol (24 µL, 0.24
mmol) according to General Procedures 1 or 2, both giving
identical yields. Purification by reverse phase HPLC gave the
product as a colorless oil (61 mg, 99% yield). The NMR
spectra match with reported spectra9.
N-(3-methoxybenzyl)-P,P-diphenylphosphinic amide (1o):
The title compound was prepared from Ru-MACHO (1.2 mg,
0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
diphenylphosphinic amide (43.4 mg, 0.20 mmol) and (3-

7
Jankins, Qin, and Engle / Tetrahedron
ACCEPTED MANUSCRIPT
δ 22.58. HRMS (FAB+) m/z Calcd for C19H18ClNOP [M+H]+
342.0809, found 342.0810.
gave the product as a white solid (55 mg, 76% yield). 1H
NMR (600 MHz, DMSO-d6) δ 7.84–7.79 (m, 3H), 7.52 (dt, J
= 7.4, 3.7 Hz, 2H), 7.47 (d, J = 2.9 Hz, 2H), 7.34–7.28 (m,
4H), 5.82 (q, J = 7.9 Hz, 1H), 3.92 (dd, J = 10.1, 7.3 Hz, 2H),
1.26 (s, 10H). 13C NMR (150 MHz, DMSO-d6) δ 149.00,
137.61 (d, J = 6.9 Hz), 133.81 (d, J = 126.1 Hz), 131.69 (d, J
= 9.3 Hz), 131.42 (d, J = 2.6 Hz), 128.41 (d, J = 12.1 Hz),
127.12, 124.80, 43.25, 34.13, 31.19. 31P NMR (162 MHz,
DMSO) δ 22.30. HRMS (FAB+) m/z Calcd for C20H21NOP
[M+H]+ 364.1825, found 364.1825.
N-(4-bromobenzyl)-P,P-diphenylphosphinic amide (1s):
The title compound was prepared from Ru-MACHO (1.2 mg,
0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
diphenylphosphinic amide (43.4 mg, 0.20 mmol) and (4-
bromophenyl) methanol (45 mg, 0.24 mmol) according to
General Procedure 1. Purification by reverse phase HPLC
1
gave the product as a white solid (57 mg, 90% yield). H
NMR (500 MHz, CDCl3) δ 7.69–7.64 (m, 2H), 7.42–7.38 (m,
2H), 7.31 (t, J = 7.9 Hz, 2H), 7.27–7.17 (m, 4H), 7.01 (s, 1H),
6.93 (d, J = 8.1 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 4.85 (s,
1H), 2.23 (s, 3H), 0.91 (s, 9H); 13C NMR (125 MHz, CDCl3)
δ 156.36, 143.89, 140.38, 132.42, 130.52, 129.52, 129.20,
128.13, 127.62, 127.40, 127.32, 126.97, 125.73, 110.14,
95.95, 63.66, 51.00, 30.44, 21.06; HRMS (FAB+) m/z Calcd
for C19H18BrNOP [M]+ 386.0304, found 386.0305.
P,P-diphenyl-N-(4-(trifluoromethyl)benzyl)phosphinic
amide (1w): The title compound was prepared from Ru-
MACHO (1.2 mg, 0.002 mmol), KOH (1.7 mg, 0.030 mmol),
P,P-diphenylphosphinic amide (43.4 mg, 0.20 mmol) and (4-
(trifluoromethyl)phenyl)methanol (33 µL, 0.24 mmol)
according to the General Procedure 1. Purification by reverse
phase HPLC gave the product as a white solid (67 mg, 89%
yield). 1H NMR (600 MHz, DMSO-d6) δ 7.82 (ddt, J = 11.7,
6.9, 1.5 Hz, 4H), 7.67 (d, J = 8.2 Hz, 2H), 7.62 (d, J = 8.1 Hz,
2H), 7.56–7.51 (m, 2H), 7.48 (tdd, J = 6.5, 3.1, 1.5 Hz, 4H),
6.05 (dt, J = 9.6, 7.5 Hz, 1H), 4.06 (dd, J = 11.0, 7.4 Hz, 2H).
. 13C NMR (150 MHz, DMSO-d6) δ 159.66 (d, J = 243.8 Hz),
133.54 (d, J = 126.3 Hz), 131.67 (d, J = 9.3 Hz), 131.55 (d, J
= 2.4 Hz), 129.83 (d, J = 4.3 Hz), 128.64 (d, J = 8.2 Hz),
128.46 (d, J = 12.0 Hz), 124.23 (d, J = 3.5 Hz), 114.73 (d, J =
21.1 Hz), 36.85 (d, J = 4.8 Hz).31P NMR (162 MHz, DMSO)
δ 22.65. 19F NMR (376 MHz, DMSO) δ -61.67. HRMS
(FAB+) m/z Calcd for C20H18F3NOP [M+H]+ 376.1073, found
376.1073.
N-(4-methoxybenzyl)-P,P-diphenylphosphinic amide (1t):
The title compound was prepared from Ru-MACHO (1.2 mg,
0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
diphenylphosphinic amide (43.4 mg, 0.20 mmol) and (4-
methoxyphenyl)methanol (30 µL, 0.24 mmol) according to
General Procedure 1. Purification by reverse phase HPLC
1
gave the product as a white solid (67 mg, 99% yield). H
NMR (600 MHz, DMSO-d6) δ 7.87–7.76 (m, 4H), 7.56–7.51
(m, 2H), 7.48 (td, J = 7.7, 2.5 Hz, 4H), 7.29 (d, J = 8.3 Hz,
2H), 6.89–6.84 (m, 2H), 5.82 (d, J = 8.5 Hz, 1H), 3.90 (dd, J
= 10.1, 7.2 Hz, 2H), 3.73 (s, 3H). 13C NMR (150 MHz,
DMSO-d6) δ 158.13, 133.88 (d, J = 126.2 Hz), 132.66 (d, J =
6.9 Hz), 131.71 (d, J = 9.3 Hz), 131.44 (d, J = 2.6 Hz),
128.54, 128.43 (d, J = 12.0 Hz), 113.50, 55.05, 42.99. 31P
NMR (162 MHz, DMSO) δ 22.33. HRMS (FAB+) m/z Calcd
for C20H21NO2P [M+H]+ 338.1304, found 338.1302.
methyl 4-(((diphenylphosphoryl)amino)methyl)benzoate
(1x): The title compound was prepared from Ru-MACHO-BH
(1.2 mg, 0.002 mmol), P,P-diphenylphosphinic amide (43.4
mg, 0.20 mmol) and methyl 4-(hydroxymethyl)benzoate (29
µL, 0.24 mmol) according to General Procedure 1.
Purification by reverse phase HPLC gave the product as a
white solid (16 mg, 22% yield). 1H NMR (600 MHz, DMSO-
d6) δ 7.90 (d, J = 7.9 Hz, 2H), 7.82 (dd, J = 11.7, 7.5 Hz, 4H),
7.53 (t, J = 7.8 Hz, 4H), 7.48 (td, J = 7.6, 3.0 Hz, 4H), 6.02 (q,
J = 8.1 Hz, 1H), 4.04 (dd, J = 10.8, 7.4 Hz, 2H), 3.84 (s, 3H).
13C NMR (150 MHz, DMSO-d6) δ 166.16, 134.01, 133.18,
131.68 (d, J = 9.4 Hz), 131.56 (d, J = 2.7 Hz), 129.01, 128.49
(d, J = 12.1 Hz). 128.01, 127.51, 52.05, 43.33. 31P NMR (162
MHz, DMSO) δ 22.78. HRMS (FAB+) m/z Calcd for
C21H21NO3P [M+H]+ 366.1254, found 366.1253.
N-([1,1'-biphenyl]-4-ylmethyl)-P,P-diphenylphosphinic
amide (1u): The title compound was prepared from Ru-
MACHO (1.2 mg, 0.002 mmol), KOH (1.7 mg, 0.030 mmol),
P,P-diphenylphosphinic amide (43.4 mg, 0.20 mmol) and
[1,1'-biphenyl]-4-ylmethanol (44 mg, 0.24 mmol) according
to General Procedure 1. Purification by reverse phase HPLC
gave the product as a white solid (60 mg, 78% yield). 1H
NMR (600 MHz, DMSO-d6) δ 7.85 (dd, J = 11.7, 7.3 Hz,
4H), 7.65 (d, J = 7.7 Hz, 2H), 7.61 (d, J = 7.9 Hz, 2H), 7.53
(t, J = 7.2 Hz, 2H), 7.49 (t, J = 8.5 Hz, 6H), 7.45 (d, J = 7.6
Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 5.96 (q, J = 7.5 Hz, 1H),
4.06–3.97 (m, 2H). 13C NMR (150 MHz, DMSO-d6) δ
140.05, 140.00 (d, J = 6.6 Hz), 138.61, 134.22, 133.39,
131.74 (d, J = 9.3 Hz), 131.50 (d, J = 2.6 Hz), 128.92, 128.48
(d, J = 12.0 Hz), 127.96, 127.29, 126.50 (d, J = 23.0 Hz),
43.31. 31P NMR (162 MHz, DMSO) δ 22.52. HRMS (FAB+)
m/z Calcd for C25H23NOP [M+H]+ 384.1512, found 384.1512.
P,P-diphenyl-N-(1-phenylethyl)phosphinic amide (2a): The
title compound was prepared from Ru-MACHO (1.2 mg,
0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
diphenylphosphinic amide (43.4 mg, 0.20 mmol) and 1-
phenylethan-1-ol (29 µL, 0.24 mmol) according to General
Procedure 1. Purification by reverse phase HPLC gave the
1
product as a white solid (57 mg, 88% yield). H NMR (600
MHz, DMSO-d6) δ 7.87–7.79 (m, 2H), 7.74–7.68 (m, 2H),
7.57–7.45 (m, 4H), 7.40 (td, J = 7.7, 2.9 Hz, 2H), 7.37 (d, J =
7.6 Hz, 2H), 7.29 (t, J = 7.5 Hz, 2H), 7.20 (t, J = 7.3 Hz, 1H),
5.90 (t, J = 9.9 Hz, 1H), 4.15 (td, J = 10.7, 6.7 Hz, 1H), 1.44
(d, J = 6.8 Hz, 3H). 13C NMR (150 MHz, DMSO-d6) δ
146.11 (d, J = 5.6 Hz), 134.09 (dd, J = 126.8, 42.7 Hz),
131.77 (dd, J = 9.3, 2.0 Hz), 131.38 (dd, J = 14.2, 2.6 Hz),
128.33 (dd, J = 23.0, 12.1 Hz), 128.04, 126.36, 126.01, 50.22,
N-(4-(tert-butyl)benzyl)-P,P-diphenylphosphinic
amide
(r): The title compound was prepared from Ru-MACHO (1.2
mg, 0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
diphenylphosphinic amide (43.4 mg, 0.20 mmol) and (4-(tert-
butyl)phenyl)methanol (39.4 mg, 0.24 mmol) according to
General Procedure 1. Purification by reverse phase HPLC

8
Jankins, Qin, and Engle / Tetrahedron
ACCEPTED MANUSCRIPT
25.93. 31P NMR (162 MHz, DMSO) δ 20.60. HRMS (FAB+)
m/z Calcd for C20H21NOP [M+H]+ 322.1355, found 322.1353.
P,P-diphenyl-N-(1-phenylpropyl)phosphinic amide (2e):
The title compound was prepared from Ru-MACHO (1.2 mg,
0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
diphenylphosphinic amide (43.4 mg, 0.20 mmol) and 1-
phenylpropan-1-ol (33 µL, 0.24 mmol) according to General
Procedure 1. Purification by reverse phase HPLC gave the
product as a white solid (15 mg, 22% yield). 1H NMR (600
MHz, DMSO-d6) δ 7.81–7.74 (m, 2H), 7.63 (ddt, J = 11.7,
6.8, 1.4 Hz, 2H), 7.55–7.51 (m, 1H), 7.51–7.43 (m, 3H), 7.36
(td, J = 7.7, 3.2 Hz, 2H), 7.29–7.23 (m, 4H), 7.19 (ddt, J =
7.4, 5.9, 1.9 Hz, 1H), 5.87–5.81 (m, 1H), 3.84 (tt, J = 10.6, 7.1
Hz, 1H), 1.81 (dt, J = 13.5, 7.3 Hz, 1H), 1.68 (dp, J = 14.3,
7.2 Hz, 1H), 0.78 (t, J = 7.3 Hz, 3H). 13C NMR (150 MHz,
DMSO-d6) δ 145.01 (d, J = 4.5 Hz), 134.82–133.49 (m),
131.80 (dd, J = 26.6, 9.3 Hz), 131.30 (dd, J = 18.6, 2.7 Hz),
128.33 (d, J = 12.1 Hz), 128.13 (d, J = 12.1 Hz), 127.96,
126.44 (d, J = 16.3 Hz), 56.61, 32.12 (d, J = 5.0 Hz), 11.10.
31P NMR (162 MHz, DMSO) δ 20.44. HRMS (FAB+) m/z
Calcd for C21H23NOP [M+H]+ 336.1512, found 336.1512.
N-(1-(4-methoxyphenyl)ethyl)-P,P-diphenylphosphinic
amide (2b): The title compound was prepared from Ru-
MACHO (1.2 mg, 0.002 mmol), KOH (1.7 mg, 0.030 mmol),
P,P-diphenylphosphinic amide (43.4 mg, 0.20 mmol) and 1-
(4-methoxyphenyl)ethan-1-ol (34 µL, 0.24 mmol) according
to General Procedure 1. Purification by reverse phase HPLC
gave the product as a white solid (34 mg, 48% yield). 1H
NMR (600 MHz, DMSO-d6) δ 7.81 (ddd, J = 11.6, 8.2, 1.5
Hz, 2H), 7.74–7.63 (m, 2H), 7.56–7.42 (m, 4H), 7.40 (td, J =
7.7, 3.0 Hz, 2H), 7.26 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz,
2H), 5.79 (t, J = 9.9 Hz, 1H), 4.08 (td, J = 10.6, 5.8 Hz, 1H),
3.72 (s, 3H), 1.40 (d, J = 6.8 Hz, 3H). 13C NMR (150 MHz,
DMSO-d6) δ 157.80, 138.20 (d, J = 5.9 Hz), 135.01–133.22
(m), 131.77 (dd, J = 9.3, 6.9 Hz), 131.35 (dd, J = 12.2, 2.7
Hz), 128.32 (dd, J = 19.9, 12.0 Hz), 127.10, 113.38, 55.02,
49.66, 25.98. 31P NMR (162 MHz, DMSO) δ 20.47. HRMS
(FAB+) m/z Calcd for C21H23NO2P [M+H]+ 352.1461, found
352.1462.
P,P-diphenyl-N-(1-(pyridin-3-yl)ethyl)phosphinic amide
(2f): The title compound was prepared from Ru-MACHO (1.2
mg, 0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
diphenylphosphinic amide (43.4 mg, 0.20 mmol) and 1-
(pyridin-3-yl)ethan-1-ol (29.6 mg, 0.24 mmol) according to
General Procedure 1. Purification by reverse phase HPLC
gave the product as a white solid (42 mg, 65% yield). 1H
NMR (600 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.45 (d, J = 4.8
Hz, 1H), 7.89 (dt, J = 7.9, 2.0 Hz, 1H), 7.70 (ddd, J = 11.7,
8.2, 1.4 Hz, 2H), 7.55 (td, J = 7.3, 1.5 Hz, 1H), 7.50 (dddd, J
= 13.2, 11.6, 6.6, 2.2 Hz, 3H), 7.40 (ddd, J = 15.7, 7.8, 3.9
Hz, 3H), 6.04 (t, J = 10.0 Hz, 1H), 4.23 (tq, J = 10.4, 6.8 Hz,
1H), 1.47 (d, J = 6.8 Hz, 3H). 13C NMR (150 MHz, DMSO-
d6) δ 146.94 (d, J = 7.0 Hz), 141.69 (d, J = 4.7 Hz), 134.79,
133.70 (dd, J = 126.9, 11.1 Hz), 131.74 (dd, J = 17.7, 9.4 Hz),
131.54 (dd, J = 16.4, 2.6 Hz), 128.51 (d, J = 12.0 Hz), 128.34
(d, J = 12.1 Hz), 123.62, 48.15, 25.35. 31P NMR (162 MHz,
DMSO) δ 20.84. HRMS (FAB+) m/z Calcd for C19H20N2OP
[M+H]+ 323.1308, found 340.1310.
N-(1-(4-fluorophenyl)ethyl)-P,P-diphenylphosphinic
amide (2c): The title compound was prepared from Ru-
MACHO (1.2 mg, 0.002 mmol), KOH (1.7 mg, 0.030 mmol),
P,P-diphenylphosphinic amide (43.4 mg, 0.20 mmol) and 1-
(4-fluorophenyl)ethan-1-ol (30 µL, 0.24 mmol) according to
General Procedure 1. Purification by reverse phase HPLC
1
gave the product as a white solid (44 mg, 65% yield). H
NMR (500 MHz, DMSO-d6) δ 7.82 (dd, J = 11.6, 7.4 Hz,
2H), 7.68 (dd, J = 11.7, 7.5 Hz, 2H), 7.50 (ddd, J = 18.5, 14.3,
7.4 Hz, 4H), 7.39 (td, J = 8.6, 4.1 Hz, 4H), 7.09 (t, J = 8.7 Hz,
2H), 5.90 (t, J = 10.0 Hz, 1H), 4.14 (td, J = 10.3, 5.6 Hz, 1H),
1.41 (d, J = 6.8 Hz, 3H). 13C NMR (150 MHz, DMSO-d6) δ
160.85 (d, J = 241.6 Hz), 142.33 (dd, J = 5.5, 2.8 Hz), 133.98
(dd, J = 126.8, 32.6 Hz), 131.75 (d, J = 8.9 Hz), 131.41 (dd, J
= 16.3, 2.6 Hz), 128.35 (dd, J = 25.1, 12.1 Hz), 127.95 (d, J =
7.9 Hz), 114.63 (d, J = 21.0 Hz), 49.59, 25.85. 31P NMR (162
MHz, DMSO) δ 20.58. 19F NMR (376 MHz, DMSO) δ -
117.40. HRMS (FAB+) m/z Calcd for C20H20FNOP [M+H]+
340.1261, found 340.1263.
N-((j,5R)-2-methyl-5-(prop-1-en-2-yl)cyclohex-2-en-1-yl)-
P,P-diphenylphosphinic amide (2g): The title compound
was prepared from Ru-MACHO (1.2 mg, 0.002 mmol), KOH
(1.7 mg, 0.030 mmol), P,P-diphenylphosphinic amide (43.4
mg, 0.20 mmol) and carveol (38 uL, 0.24 mmol) according to
General Procedure 1. Purification by reverse phase HPLC
gave the product as a white solid (39 mg, 56% yield). NMR
assignments are given for the mixture of diastereomers.
Attempts to assign the major and minor diastereomers were
not made as the ratio was close to 1:1. The 13C splitting
combined with the mixture of the diastereomers made
determining coupling very complicated, so peaks are reported
without assigning multiplets and major/minor diastereomers.
The ratio of diastereomers was determined by the integration
of the 31P NMR. 1H NMR (600 MHz, CDCl3) δ 8.11–7.79 (m,
4H), 7.50 (dtd, J = 28.9, 8.2, 7.5, 3.6 Hz, 6H), 5.59–5.49 (m,
1H), 4.86–4.58 (m, 3H), 4.04 (dt, J = 9.6, 5.0 Hz, 0H), 3.67 (s,
1H), 3.58 (s, 1H), 2.98 (dd, J = 10.5, 7.1 Hz, 1H), 2.79 (dd, J
= 11.7, 6.3 Hz, 1H), 2.59 (t, J = 9.6 Hz, 1H), 2.47 (dd, J = 3.2,
1.6 Hz, 1H), 2.43–2.34 (m, 1H), 2.29 (q, J = 12.4, 12.0 Hz,
1H), 2.22–1.99 (m, 2H), 1.86 (d, J = 5.7 Hz, 3H), 1.78–1.62
(m, 7H), 1.61–1.34 (m, 1H), 1.09 (d, J = 7.3 Hz, 1H), 0.96 (d,
J = 6.8 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 148.98,
148.95, 148.14, 147.33, 135.34, 135.29, 134.71, 134.67,
N-(1-(4-chlorophenyl)ethyl)-P,P-diphenylphosphinic
amide (2d): The title compound was prepared from Ru-
MACHO (1.2 mg, 0.002 mmol), KOH (1.7 mg, 0.030 mmol),
P,P-diphenylphosphinic amide (43.4 mg, 0.20 mmol) and 1-
(4-chlorophenyl)ethan-1-ol (32 µL, 0.24 mmol) according to
General Procedure 1. Purification by reverse phase HPLC
gave the product as a white solid (31 mg, 44% yield). 1H
NMR (600 MHz, DMSO-d6) δ 7.82 (ddt, J = 11.7, 6.8, 1.5
Hz, 2H), 7.69 (ddt, J = 11.7, 6.8, 1.4 Hz, 2H), 7.58–7.46 (m,
4H), 7.44–7.36 (m, 4H), 7.35–7.32 (m, 2H), 5.93 (t, J = 9.9
Hz, 1H), 4.14 (tq, J = 10.7, 6.8 Hz, 1H), 1.42 (d, J = 6.8 Hz,
3H). 13C NMR (150 MHz, DMSO-d6) δ 145.14, 131.76 (d, J
= 6.2 Hz), 131.70 (d, J = 6.4 Hz), 131.43 (d, J = 13.1 Hz),
130.88, 128.44 (d, J = 12.2 Hz), 128.28 (d, J = 12.1 Hz),
127.96 (d, J = 8.4 Hz). 49.65, 25.67.31P NMR (162 MHz,
DMSO) δ 20.62. HRMS (FAB+) m/z Calcd for C20H20ClNOP
[M+H]+ 356.0966, found 356.0968.

9
Jankins, Qin, and Engle / Tetrahedron
ACCEPTED MANUSCRIPT
1.02 (ddd, J = 15.3, 7.1, 2.0 Hz, 12H). 13C NMR (150 MHz,
DMSO-d6) δ 157.92, 128.36, 134.30 (d, J = 4.1 Hz), 113.41,
55.00, 42.25.25.43 (d, J = 82.4 Hz), 15.67 (dd, J = 47.3, 3.1
Hz). 31P NMR (162 MHz, DMSO) δ 51.94. HRMS
C14H25NO2P [M+H]+ 270.1617, found 270.1615.
132.57, 132.51, 132.39, 132.33, 132.24, 132.18, 131.95,
131.93, 128.65, 128.57, 128.54, 125.40, 125.29, 112.19,
109.97, 109.34, 109.31, 70.43, 52.35, 50.02, 49.69, 44.64,
41.89, 40.96, 39.95, 39.62, 39.38, 37.76, 37.34, 36.62, 36.61,
36.21, 35.47, 34.35, 30.94, 30.83, 28.01, 22.04, 21.44, 21.09,
21.01, 20.83, 18.73, 13.62, 12.94. 31P NMR (162 MHz,
Acetone) δ 22.60 (minor), 22.23 (major).
P,P-dicyclohexyl-N-(4-methoxybenzyl)phosphinic amide
(3c): The title compound was prepared from Ru-MACHO
(1.2 mg, 0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
dicyclohexylphosphinic amide (45.9 mg, 0.20 mmol) and (4-
methoxyphenyl)methanol (30 µL, 0.24 mmol) according to
General Procedure 1. Purification by reverse phase HPLC
gave the product as a white solid (51 mg, 73% yield). 1H
NMR (600 MHz, DMSO-d6) δ 7.27–7.23 (m, 2H), 6.89–6.85
(m, 2H), 4.31 (dt, J = 14.5, 7.2 Hz, 1H), 3.93 (t, J = 7.8 Hz,
2H), 3.72 (s, 3H), 1.85–1.55 (m, 12H), 1.31–1.07 (m, 10H).
13C NMR (150 MHz, DMSO-d6) δ 157.95, 134.32 (d, J = 4.4
Hz), 128.41, 113.42, 55.04, 42.26, 36.04, 35.49, 26.00 (dd, J
= 13.0, 9.7 Hz), 25.80, 25.10 (dd, J = 31.8, 2.9 Hz). 31P NMR
(162 MHz, DMSO) δ 46.66. HRMS C20H32NO2P [M+H]+
350.2243, found 350.2243.
N-((3R,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-((R)-6-
methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-
tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-P,P-
diphenylphosphinic amide (2h): The title compound was
prepared from Ru-MACHO (1.2 mg, 0.002 mmol), KOH (1.7
mg, 0.030 mmol), P,P-diphenylphosphinic amide (38.7 mg,
0.20 mmol) and cholesterol (93 mg, 0.24 mmol) according to
General Procedure 1. After 16 hr the reaction was allowed to
cool to room temperature, diluted with EtOAc and washed
with aq. NaHCO3. The aq. layer was then extracted with
EtOAc (×3) and the combined organic layers were dried with
MgSO4 then concentrated to dryness by rotary evaporation.
The crude white solid could easily be recrystallized from hot
benzene to give crystals suitable for X-ray crystallography
and afford the pure product as a white solid (76 mg, 65%
yield). 1H NMR (600 MHz, CDCl3) δ 7.92 (dd, J = 11.9, 7.6
Hz, 4H), 7.56–7.38 (m, 6H), 5.37 (q, J = 1.7 Hz, 1H), 3.57
(ddq, J = 10.9, 5.3, 2.7 Hz, 1H), 2.81 (dd, J = 11.4, 6.1 Hz,
1H), 2.18–1.87 (m, 6H), 1.86–1.74 (m, 1H), 1.72–1.60 (m,
3H), 1.59–1.49 (m, 3H), 1.42–1.26 (m, 5H), 1.26–1.01 (m,
7H), 0.99 (s, 3H), 0.91–0.82 (m, 12H), 0.65 (s, 3H). 13C NMR
(150 MHz, CDCl3) δ 147.32, 132.45 (dd, J = 129.7, 27.0 Hz),
131.71 (dd, J = 12.4, 9.2 Hz), 131.24, 128.01 (dd, J = 12.6,
9.9 Hz), 123.04 (d, J = 6.6 Hz),55.63, 53.92, 48.47, 41.98,
39.36, 39.05, 36.45, 32.54, 31.78, 29.92, 27.73, 27.54, 23.75,
23.35, 22.36, 22.10, 20.53, 18.56, 18.18, 11.50. 31P NMR
(162 MHz, CDCl3) δ 23.22. HRMS C39H56NOP [M+H]+
586.4172, found 586.4172. X-ray (single-crystal) Single
crystals suitable for X-ray diffraction were grown using the
procedure described above (CCDC 1893911).17
N-(4-methoxybenzyl)-P,P-diphenylphosphinothioic amide
(3e): The title compound was prepared from Ru-MACHO
(1.2 mg, 0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
diphenylthiophosphinic amide (46.7 mg, 0.20 mmol) and (4-
methoxyphenyl)methanol (30 µL, 0.24 mmol) according to
General Procedure 1. Purification by reverse phase HPLC
1
gave the product as a white solid (31 mg, 44% yield). H
NMR (600 MHz, DMSO-d6) δ 7.96–7.82 (m, 4H), 7.51 (dtd,
J = 14.7, 7.2, 2.6 Hz, 6H), 7.33–7.24 (m, 2H), 6.92–6.84 (m,
2H), 5.74 (q, J = 7.0 Hz, 1H), 3.97 (dd, J = 10.6, 7.0 Hz, 2H),
2.51 (p, J = 1.9 Hz, 2H). 13C NMR (150 MHz, DMSO-d6) δ
158.19, 135.15 (d, J = 100.8 Hz), 132.25 (d, J = 9.4 Hz),
131.39 (d, J = 2.8 Hz), 131.12 (d, J = 11.0 Hz), 128.87,
128.35 (d, J = 12.5 Hz), 113.53, 55.06, 43.27. 31P NMR (162
MHz, DMSO) δ 58.90. HRMS C20H20NOPS [M+H]+
354.1076, found 354.1078.
P,P-di-tert-butyl-N-(4-methoxybenzyl)phosphinothioic
amide (3f): The title compound was prepared from Ru-
MACHO (1.2 mg, 0.002 mmol), KOH (1.7 mg, 0.030 mmol),
P,P-tert-butylthiophosphinic amide (38.7 mg, 0.20 mmol) and
(4-methoxyphenyl)methanol (30 µL, 0.24 mmol) according to
General Procedure 1. Purification by reverse phase HPLC
gave the product as a white solid (39 mg, 62% yield).
Recrystalization from hot benzene gave single crystals
suitable for x-ray diffraction 1H NMR (600 MHz, DMSO-d6)
δ 7.26 (d, J = 8.3 Hz, 2H), 6.86 (d, J = 8.2 Hz, 2H), 4.59 (dt, J
= 12.9, 6.8 Hz, 1H), 4.16 (dd, J = 9.8, 6.8 Hz, 2H), 3.72 (s,
3H), 1.23 (d, J = 15.1 Hz, 18H). 13C NMR (150 MHz,
DMSO-d6) δ 157.91, 134.44 (d, J = 5.4 Hz), 128.67, 113.37,
55.01, 44.38, 27.07, 27.06. 31P NMR (162 MHz, DMSO) δ
97.83. HRMS (FAB+) m/z Calcd for C16H29NOPS [M+H]+
314.1702, found 314.1700. X-ray (single-crystal) Single
crystals suitable for X-ray diffraction were grown using the
procedure described above (CCDC 1893909).17
P,P-ditertbutyl-N-(4-methoxybenzyl)phosphinic
amide
(3a): The title compound was prepared from Ru-MACHO
(1.2 mg, 0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
ditertbutylphosphinic amide (35.4 mg, 0.20 mmol) and (4-
methoxyphenyl)methanol (30 µL, 0.24 mmol) according to
General Procedure 1. Purification by reverse phase HPLC
1
gave the product as a white solid (31 mg, 52% yield). H
NMR (600 MHz, DMSO-d6) δ 7.33–7.19 (m, 2H), 6.93–6.77
(m, 2H), 4.34 (dt, J = 16.5, 7.2 Hz, 1H), 4.00 (t, J = 7.4 Hz,
2H), 3.73 (s, 3H), 1.13 (d, J = 13.4 Hz, 18H). 13C NMR (150
MHz, DMSO-d6) δ 157.83, 134.60, 128.50, 113.36, 54.98,
42.93 (d, J = 2.1 Hz), 36.01 (d, J = 76.4 Hz), 26.37. 31P NMR
(162 MHz, DMSO) δ 55.63. HRMS C16H26NO2P [M+H]+
298.1930, found 298.1932.
P,P-diisopropyl-N-(4-methoxybenzyl)phosphinic
amide
(3b) The title compound was prepared from Ru-MACHO (1.2
mg, 0.002 mmol), KOH (1.7 mg, 0.030 mmol), P,P-
diisopropylphosphinic amide (30.0 mg, 0.20 mmol) and (4-
methoxyphenyl)methanol (30 µL, 0.24 mmol) according to
General Procedure 1. Purification by reverse phase HPLC
4.3. Preparation of Enantioenriched Chiral-at-P Starting
Material
1
gave the product as a white solid (43 mg, 80% yield) H
P-(tert-butyl)-P-phenyl-N-((S)-1-phenylethyl)phosphinic
amide (4a): A solution of phenyl tertbutylphosphine chloride
(2.00 g, 9.97 mmol) in dichloromethane (20 mL) was added
dropwise with stirring to a solution of triethylamine (1.51g,
NMR (600 MHz, DMSO-d6) δ 7.26 (d, J = 8.3 Hz, 2H), 6.87
(d, J = 8.5 Hz, 2H), 4.38 (dt, J = 14.6, 7.3 Hz, 1H), 3.96 (t, J =
7.8 Hz, 2H), 3.72 (s, 3H), 1.86 (dhept, J = 10.0, 7.1 Hz, 2H),

10
Jankins, Qin, and Engle / Tetrahedron
ACCEPTED MANUSCRIPT
15.0 mmol) and (S)-1-phenylethan-1-amine (1.81g, 15.0
mmol) in dichloromethane (30 mL) held at a temperature of –
45 °C. The mixture was allowed to warm to room temperature
and stir for 1 h, at which point it was filtered. The resulting
filtrate was cooled to 0 °C and 30% hydrogen peroxide (3.4
mL) was added in a dropwise manner over a period of 1 h.
Stirring was continued at room temperature for 1 h. Then, the
organic layer was separated, washed with water (20 mL), and
dried over MgSO4. The solvent was removed in vacuo to give
the crude product as a solid. This material was recrystallized
from hot benzene to afford the product as a 1:1 mixture of
diastereomers. The diastereomers were separated by reverse
phase HPLC. Below analytical data is provided for both
compounds. The two diastereomers are referred to by their P-
stereochemistry, which was assigned based on X-ray
crystallography of one of the final products.
chiral SFC on a Daicel IG column (3 ꢀm, 4.6Å×250 mm),
20% MeOH/CO2, 4.0 mL/min, λ = 212 nm, t (R enantiomer) =
2.225 min, t (S enantiomer) = 1.654 min.
(R)-P-(tert-butyl)-N-(4-methoxybenzyl)-P-
phenylphosphinic amide (4c): The title compound was
prepared from Ru-MACHO (0.1 mg, 0.002 mmol), KOH (0.2
mg, 0.030 mmol), (R)-P-(tert-butyl)-P-phenylphosphinic
amide (4.0 mg, 0.020 mmol) and (4-methoxyphenyl)methanol
(3 µL, 0.024 mmol) according to General Procedure 1.
Purification by reverse phase HPLC gave the product as a
white solid (4 mg, 62% yield). Single crystals suitable for X-
Ray diffraction could be grown by slow evaporation over one
week of a dilute solution of the product in hot benzene. 1H
NMR (600 MHz, Methanol-d4) δ 7.84–7.76 (m, 2H), 7.63–
7.57 (m, 1H), 7.52 (td, J = 7.7, 3.0 Hz, 2H), 7.28 (d, J = 8.3
Hz, 2H), 6.86 (d, J = 8.3 Hz, 2H), 5.12 (dt, J = 14.4, 7.2 Hz,
1H), 4.05–3.86 (m, 2H), 3.78 (s, 3H), 1.15 (d, J = 15.1 Hz,
9H). 13C NMR (150 MHz, Methanol-d4) δ 158.87, 133.44 (d,
J = 8.9 Hz), 132.41 (d, J = 5.6 Hz), 131.74 (d, J = 2.8 Hz),
129.27, 128.43, 127.96 (d, J = 11.7 Hz), 113.30, 54.26, 43.15
(d, J = 2.4 Hz), 31.49 (d, J = 90.3 Hz), 23.47. 31P NMR (162
1
(R-at-P)-diastereomer: H NMR (600 MHz, DMSO-d6) δ
7.81–7.73 (m, 2H), 7.61–7.47 (m, 3H), 7.45–7.42 (m, 2H),
7.30 (t, J = 7.7 Hz, 2H), 7.21–7.14 (m, 1H), 5.17 (dd, J =
16.0, 10.6 Hz, 1H), 4.15 (dq, J = 15.8, 7.1 Hz, 1H), 1.32 (d, J
= 6.9 Hz, 3H), 0.98 (d, J = 14.6 Hz, 9H). 13C NMR (150
MHz, DMSO-d6) δ 146.86, 133.05 (d, J = 8.3 Hz), 132.12 (d,
J = 111.1 Hz), 131.07, 127.83 (d, J = 11.0 Hz),127.82,
126.12, 126.07, 48.98, 31.69 (d, J = 90.8 Hz), 25.25 (d, J =
5.3 Hz), 24.29. 31P NMR (162 MHz, DMSO) δ 40.01. HRMS
C18H25NOP [M+H]+ 302.1668, found 302.1669.
MHz, MeOD)
δ
47.17. HRMS C18H24NO2P [M+H]+
318.1617, found 318.1616. SFC (chiral column). The
enantiomeric excess was determined by chiral SFC on a
Daicel IG column (3 ꢀm, 4.6Å×250 mm), 30% MeOH/CO2,
4.0 mL/min, λ = 217 nm, t (R enantiomer) = 2.282 min, t (S
enantiomer) = 1.921 min. X-ray (single-crystal) Single
crystals suitable for X-ray diffraction were grown using the
procedure described above (CCDC 1893910).17
(S-at-P)-isomer: 1H NMR (600 MHz, DMSO-d6) δ 7.53 (ddd,
J = 10.3, 8.1, 1.4 Hz, 2H), 7.46–7.41 (m, 1H), 7.35–7.28 (m,
4H), 7.27–7.22 (m, 2H), 7.18–7.13 (m, 1H), 5.05 (dd, J =
12.6, 10.6 Hz, 1H), 4.11 (td, J = 10.1, 6.5 Hz, 1H), 1.43 (d, J
= 6.9 Hz, 3H), 1.03 (d, J = 14.6 Hz, 9H). 13C NMR (150
MHz, DMSO-d6) δ 146.27 (d, J = 6.2 Hz), 133.11 (d, J = 8.6
Hz), 130.96 (d, J = 2.7 Hz), 127.91, 127.56, 127.49, 126.19,
125.94, 49.75, 31.66 (d, J = 90.1 Hz). 26.26, 24.37. 31P NMR
(162 MHz, DMSO) δ 41.15.
5. References
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1
compound as a white solid (5 mg, 20% yield; >99% ee). H
NMR (600 MHz, Acetone-d6) δ 7.87 (ddd, J = 10.0, 8.0, 1.4
Hz, 2H), 7.55 (td, J = 7.4, 1.5 Hz, 1H), 7.49 (td, J = 7.6, 2.3
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(150 MHz, Acetone-d6) δ 134.09, 128.60, 128.53 (d, J = 8.2
Hz), 131.98 (d, J = 2.7 Hz), 32.84 (d, J = 93.0 Hz), 25.09. 31
P
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Acknowledgments
This work was financially supported by The Scripps Research
Institute and the National Institutes of Health
(5R35GM125052-02). We graciously acknowledge USTC for
sponsoring Z.-Y.Q. with a summer exchange scholarship and
Takasago for the generous donation of Ru-MACHO and Ru-
MACHO-BH. We thank Brittney Sanchez and Dr. Jason Chen
for their assistance with reaction analysis and purification. We
thank Dr. Milan Gembicky, Dr. Curtis Moore, and Prof.
Arnold Rheingold (UCSD) for collection and assignment of
the X-ray crystallography data.
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Group by Using Ruthenium Carbonyl Complex Having

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