Manganese-Catalyzed and Mediated Synthesis of Arylphosphinates and Related Compounds

Article abstract of DOI:10.1021/acs.joc.9b01239

The free-radical arylation of H-phosphinates and related compounds was examined. A practical catalytic process with the air as the oxidant could not be found. However, an inexpensive and robust methodology was developed, using catalytic Mn(II) as the radi

Full text of DOI:10.1021/acs.joc.9b01239

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Article
Manganese-Catalyzed and Mediated Synthesis
of Arylphosphinates and Related Compounds
Olivier Berger, and Jean-Luc Montchamp
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01239 • Publication Date (Web): 27 Jun 2019
Downloaded from http://pubs.acs.org on June 28, 2019
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Manganese-Catalyzed and Mediated Synthesis of
Arylphosphinates and Related Compounds
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Olivier Berger, and Jean-Luc Montchamp*
Department of Chemistry, Box 298860, Texas Christian University, Fort Worth, Texas 76129 (USA). E-mail: j.montchamp@tcu.edu
Abstract: The free-radical arylation of H-phosphinates and related compounds was examined. A practical catalytic process
with air as the oxidant could not be found. However, an inexpensive and robust methodology was developed, using catalytic
Mn(II) as the radical initiator and excess Mn(IV) as the stoichiometric oxidant. Using these conditions the inter- and
intramolecular arylation of phosphinylidene compounds has a broad scope, including application to the synthesis of P-
heterocycles. A full account of this methodology is presented including a discussion of its limitations.
Introduction
Synthesizing organophosphorus compounds continues to be of interest because of their importance in various areas.
Particularly, arylphosphorus compounds have applications in medicinal chemistry, ligands for catalytic reactions, materials,
etc.1 Several methodologies (Scheme 1) have been reported for the synthesis of arylphosphonates (R1 = R2 = OAlk), fewer
for tertiary phosphine oxides (almost always R1 = R2 = Ph), and more rarely for phosphinates (R1 = Alk, Aryl, or H, R2 = OAlk).2
Of those methodologies, metal-catalyzed cross-couplings using palladium, nickel, and copper catalysts (Scheme 1a) are the
most common.3 More recently, metal-catalyzed C-H activation has been investigated for the preparation of arylphosphorus
compounds (Scheme 1b).4 Free-radical arylation (homolytic aromatic substitution, HAS; Scheme 1c) is a related class of
reaction, which also avoids the use of functionalized aromatics such as aryl halides necessary in metal-catalyzed cross-
couplings.5 Other processes that have been employed to prepare arylphosphorus compounds include deprotonation of aryl-
Csp2-H (or variations on this theme) followed by reaction with P-Cl reagents (Scheme 1d),6 and Friedel-Crafts electrophilic
aromatic substitution (Scheme 1e).7
Our laboratory has long been interested in the chemistry of phosphinates.8 As a result, we have reported several palladium-
catalyzed cross-coupling reactions for the synthesis of arylphosphinates. More recently we became interested in investigating
the free-radical arylation of H-phosphinates, which had been neglected as phosphorus partners.2 Even though the reactivity
of phosphinylidene compounds varies greatly,9 the published reactions with H-phosphonate diesters (or diphenylphosphine
oxide) could be used as a starting point. Herein we describe our full study of the free-radical arylation of H-phosphinates and
related compounds.
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Scheme 1. Various methodologies for the preparation of arylphosphorus compounds.
Results and Discussion
Arylation using catalytic oxidants. In reviewing the literature concerning the arylation of H-phosphonate diesters, we were
intrigued by Ishii's 2004 report concerning a Mn(II)/Co(II)-catalyzed process that uses oxygen as the terminal oxidant (Equation
1).10
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Reinvestigating this reaction was our starting point even though we immediately identified three significant issues: 1) the
reaction employs a large excess of H-phosphonate diesters; 2) the ratio of N2/O2 must be carefully controlled; and 3) not a
single yield was reported. We chose (EtO)2P(O)H and mesitylene as the model reagents, and under Ishii's conditions, we
obtained a 50% yield of diethyl mesitylphosphonate, undistinguishable from the 48% GC yield he reported.
Our main objective was to reduce the amount of (EtO)2P(O)H (so that ultimately H-phosphinates and other valuable
compounds could be used) and to find more practical conditions. In order to have a broader range of solvent and conditions,
we decided to employ lipophilic Mn(II)- and Co(II)-2-ethylhexanoates (5 mol % each) instead of the acetates, and the results
are shown in Table 1. Good results were obtained without any solvent, and in hexanes, ethyl acetate, and acetonitrile (entries
1-2) using compressed air instead of Ishii's 50:50 O2/N2 mixture. Unfortunately, decreasing the number of equivalents of the
H-phosphonate resulted in a drastic loss of yield (entries 2a-2d). Next, oxygen was used in the place of compressed air
(entries 3 and 4) and an oxygen balloon gave a yield similar to compressed air, whereas Ishii's 50:50 O2/N2 mixture was
satisfactory (entry 5), but not air (entry 6).
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Interestingly, switching from acetonitrile to ethyl acetate under a flow of oxygen was a significant improvement (entry 7a) and
amounts of Mn(II) and/or Co(II) could be lowered (entries 7b-7d) with only a slight drop in yield, but removing the cobalt
altogether gave no product at all. Once again but not as sharply as with CH3CN and compressed air (entry 2), reducing the
amount of (EtO)2P(O)H lowered the yield significantly (entries 8a-8c). Finally, using a balloon of oxygen was virtually identical
to the oxygen flow (entries 7a and 9).
Other results not shown in Table 1 are briefly summarized here. Other solvents tested were unsatisfactory (data not shown
in Table 1, yield %): DMSO (0), acetone (0), diisobutylketone (0), CHCl3 (0), THF (0), 1,4-dioxane (9), DMF (20), DME (37),
perfluorodecalin (41), t-AmOH (43).
Several conclusions could be drawn from this study. First, a more convenient terminal oxidant than 50:50 O2/N2 could be
identified (compressed air, oxygen flow, oxygen balloon). Second, using 2-ethylhexanoate salts allowed reaction in solvents
other than acetic or propanoic acids. Third, diethyl mesitylphosphonate could be synthesized in good yield (~70-80%) under
various catalytic conditions.
Table 1. Arylation of diethyl H-phosphonate with mesitylene
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n
Yield
(%)[a]
Entry
Solvent
Conditions
(Equiv)
8
9
1a
1b
1c
none
hexane(s)
EtOAc
60
55
57
90 oC,
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3
compressed air
2a
2b
2c
2d
3
2
71
37
21
12
90 oC,
CH3CN
1
compressed air
0.5
3
4
5
6
3
3
3
3
CH3CN
CH3CN
CH3CN
CH3CN
90 oC, O2 flow
90 oC, O2 balloon
90 oC, O2/N2 1:1
90 oC, air
57
73
61
33
7a
7b
7c
7d
78
73[b]
72[c]
65[d]
3
EtOAc
90 oC, O2 flow
8a
8b
8c
2
1
63
39
38
EtOAc
EtOAc
90 oC, O2 flow
0.2
9
3
90 oC, O2 balloon
77
[a] Yield after purification by chromatography on silica gel. [b] Only 1 mol % of
Co(II) 2-ethylhexanoate was employed. [c] Mn(II) and Co(II) 3 mol % each. [d]
Mn(II) and Co(II) 1 mol % each.…
A postulated mechanism for the free-radical arylation is shown in Scheme 2. Tautomerization9 of phosphinylidene 1 to less
stable 2 is followed by formation of a free-radical intermediate which adds to the aromatic ring to form resonance-stabilized
cyclohexadienyl radical 4. This radical intermediate is too stable to abstract the hydrogen atom from 1 or 2. Instead, oxidation
of free-radical 4 into cation 5 takes place and then loss of a proton rearomatizes the ring to produce arylphosphorus 6. A
major competing side reaction is the oxidation of 2 into acid 3.
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Scheme 2. Proposed mechanism for free-radical phosphinylidene arylation.
Unfortunately, the main goal of reducing the amount of H-phosphonate failed, as it leads to losses in yield that are too large.
This was a problem because H-phosphinates are much more valuable than (EtO)2P(O)H and sacrificing two equivalents as
"antioxidant" would be prohibitive. In fact, with butyl phenyl-H-phosphinate and conditions as in Table 1, entries 1a, 2a, and
7a; gave yields of 0 %,12 %, and 0 %, respectively. This once again illustrates the fact that phosphinylidene compounds
P(O)H have different reactivities that go back to their tautomeric equilibrium with the P-OH form. In our published study of this
equilibrium,9 we reported that the half-lives of deuteration with D2O for PhP(O)(OEt)H and (EtO)2P(O)H are 1.4 h and 21 h,
respectively. Because the direct oxidation of the phosphorus reactant takes place via the P-OH tautomer (2, Scheme 2), it
means that competing background oxidation to acid 3 will be more severe for the H-phosphinate than the H-phosphonate.
But as the mechanism shows, one must walk a tightrope between oxidizing radical 4 efficiently but not oxidizing 2! To some
extent, Ishii accomplished this by employing a 50:50 O2/N2 mixture: with air (21:78 O2/N2) the reaction did not proceed
efficiently (unreacted starting material) and with pure oxygen overoxidation of (EtO)2P(O)H took place.10
Arylation using excess oxidant. Since further studies failed to provide the desired catalytic process, we next turned our
attention to conditions that employ a stoichiometric (or excess) oxidant. Whereas Ishii's was the only report of a catalytic free-
radical arylation,10 the literature describing the free-radical arylation of H-phosphonate diesters with a stoichiometric excess
of oxidants is much more common and it dates back to Effenberger in 1985.5a Various oxidants were tested using butyl phenyl-
H-phosphinate and mesitylene as the model reactants. The results are shown in Table 2. In the literature, mesityl phosphorus
compounds have been synthesized through a variety of methods.5,11,12
Table 2. Arylation of butyl phenyl-H-phosphinate with mesitylene
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MesH
Yield[a]
(%)
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Entry
Solvent
Conditions
(equiv)
1a
1b
CH3CN/H2O
2:7
5
5
AgNO3 (10 mol %)
K2S2O8 (2 equiv)
9[b-e]
4[b,c,f]
Mn(OAc)3•2H2O
(3 equiv)
2
AcOH
AcOH
5
39
3
4
5
5
air
35[c,g]
CH3CN/H2O
3:1
AgNO3 (10 mol %)
MnO2 (3 equiv)
6
5
AcOH
5
AgNO3 (10 mol %)
78
6a
6b
6c
6d
5
2
1
5
Mn(OAc)2
(5 mol %)
81
72
AcOH
MnO2 (3 equiv)
70
71[e]
Mn(OAc)2 (5 mol %)
MnO2 (not activated,
3 equiv)
7
AcOH
5
29[c]
Mn(OAc)2 (5 mol %)
Fe2O3 (3 equiv)
8a
8b
AcOH
5
5
2[c]
0[h]
Fe3O4 (3 equiv)
Mn(OAc)2 (5 mol %)
MnO2 (3 equiv)
9
CH3CN
3[c]
[a] The H-phosphinate was slowly added to the reaction mixture under N2.
Yield after purification by chromatography on silica gel, unless otherwise
noted. [b] reaction conducted at rt for 48 h. [c] determined by 31P-NMR. [d]
80 % remaining starting material. [e] AcONa was not used. [f] 71 % remaining
starting material. [g] 50 % remaining starting material. [h] Unreacted starting
material.
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Effenberger's conditions5a were completely unsatisfactory (Table 2, entry 1). On the other hand using manganese(III) acetate
dihydrate, which has been used extensively with H-phosphonate diesters, was a significant improvement but still unsatisfactory
(entry 2). Replacing Mn(OAc)3 with Mn(acac)2 in air gave a similarly mediocre result (entry 3). When the superstoichiometric
oxidant in Effenberger's reaction was replaced with MnO2, the same result as in entry 1 was observed (entry 4). On the other
hand, switching the solvent to acetic acid gave a tremendous improvement to 78 % yield (entry 5). Substituting expensive
silver nitrate for manganese(II) acetate gave a similar result (81 %, entry 6a). From these conditions, decreasing the number
of equivalents of mesitylene lowered the yield to 72 % and 70 % (entries 6b and 6c, respectively). Omitting the base (AcONa,
3 equiv) gave a 10 % reduction in yield (entry 6d).
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If the manganese(IV) oxide was not the "activated" grade, then the yield dropped significantly (entry 7 versus entry 6a).
Replacing MnO2 with iron oxides was unsuccessful (entries 8a-b). Switching the solvent to acetonitrile also failed to deliver
the product in acceptable yield (entry 9). Other solvent tried in the place of acetic acid (data not shown in Table 2) were: DME
(0), MIBK (0), 1-butanol (0), 1,4-dioxane (0), NMP (0), DMSO (0), TFA (0), and perfluorodecalin (7).
As mentioned above, catalytic conditions were unsuccessful. The best conditions identified were PhP(O)(OBu)H (1.1 equiv)
slowly added into an acetic acid solution containing mesitylene (1 equiv), Mn(OAc)2 (5 mol %) and Co(OAc)2 (1 mol %), at 45
oC and under air/N2 (1:1), which produced a 45 % yield of product (Equation 2).
Additional experiments (Table 3) were conducted, this time using PhP(O)(OR)H with 5 equivalents of benzene, with 5 mol%
Mn(OAc)2, 2 equivalents of MnO2, 16 h, 70 oC, under N2 gave only 25 % yield under neat conditions (Table 3, entry 1). DMF
(entry 2) and other solvents like CH3CN or DMSO (not shown) were completely unsatisfactory. On the other hand, acetic acid
improved to 34 % (entry 3a) but increasing the temperature did not improve the yield (entry 3b). Running the reaction under
air gave results worse than under N2 (entry 4 versus 2). Next, the amount of MnO2 was increased to 3 equivalents, which
produced a significant improvement to 47 % (entry 5a versus 3a). Adding AcONa resulted in a modest improvement (entry
5b). On the other hand, the reaction time was important and adding PhP(O)(OR)H slowly over 2 h in order to minimize
background oxidation to acid 3, followed by an additional 2 h, gave the best result (entry 6a), while adding the reactant more
slowly was undistinguishable from the standard 16 h (entry 6b versus 5b). Removing AcONa lowered the yield significantly
(entry 7), as did removing the 5 mol% of Mn(OAc)2 (entry 8). Using excess Mn(OAc)2 without MnO2 similarly decreased the
yield (entry 9). Entry 10 shows the influence of the alkyl ester on the yield, with n-butyl (entry 6a) still being the best.
Concentration plays a role with the standard 0.2 M being the best (entry 6a versus 11). Finally, other oxidants were examined
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(entries 12-14), but none gave better results than catalytic Mn(II) with superstoichiometric Mn(IV), which was thus selected for
further investigations.
6
7
Table 3. Arylation of alkyl phenyl-H-phosphinate with benzene
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Yield[b]
Entry
1
Solvent
none
Conditions[a]
(%)
MnO2 (2 equiv); no base
25[c,d]
2a
2b
MnO2 (2 equiv); no base
0[c,e]
DMF
MnO2 (2 equiv); no base, 120 oC
14[c,f]
3a
3b
MnO2 (2 equiv); no base
34
27
AcOH
AcOH
AcOH
MnO2 (2 equiv); no base, 120 oC
4
MnO2 (2 equiv); no base, air
13
5a
5b
MnO2 (3 equiv); no base
47
52
MnO2 (3 equiv); AcONa (3 equiv)
MnO2 (3 equiv); AcONa (3 equiv)
2 h slow addition + 2 h
6a
64
AcOH
AcOH
AcOH
AcOH
6b
10 h slow addition + 2 h
49
MnO2 (3 equiv); no base
2 h slow addition + 2 h
7
8
9
50
40
36
MnO2 (3 equiv); AcONa (3 equiv)
no Mn(OAc)2, 2 h slow addition + 2 h
Mn(OAc)2 (3 equiv); AcONa (3 equiv)
no MnO2, 2 h slow addition + 2 h
10a
10b
10c
MnO2 (3 equiv)
AcONa (3 equiv)
R = Et
R = i-Bu
R = Cy
49
56
60
AcOH
AcOH
2 h slow addition + 2 h
MnO2 (3 equiv)
AcONa (3 equiv)
11a
11b
0.4 M
0.1 M
50
44
2 h slow addition + 2 h
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12a
12b
12c
KMnO4 (n equiv)
AcONa (3 equiv)
n = 2
30
32
29
AcOH
n = 1
2 h slow addition + 2 h
n = 0.5
7
8
9
13a
13b
MnO2 (3 equiv); AcONa (3 equiv)
2 h slow addition + 2 h
52[g]
53[h]
AcOH
AcOH
10
11
12
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BaMnO4 (1.5 equiv); AcONa (3 equiv)
2 h slow addition + 2 h
14
22
[a] Unless otherwise noted, the reactions were conducted with R = Bu, at 70 oC under N2, for 16 h at 0.2 M concentration. [b] Yield after purification by
chromatography on silica gel, unless otherwise noted. [c] 31P-NMR yield. [d] 69 % remaining starting material. [e] unreacted starting material. [f] 86 %
remaining starting material. [g] MnCO3 (5 mol %) instead of Mn(OAc)2. [h] Mn(OAc)2•4H2O (5 mol %) instead of Mn(OAc)2.
Intermolecular arylations. Our communication12 showed that the reaction has a relatively broad scope in terms of both the
phosphinylidene reagent and the aromatic substrate. Here we are presenting additional results to more fully delineate the
scope and limitations of our reaction.
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Mn(OAc)2 (5 mol %)
MnO2 (3 equiv)
O
P
O
P
R2
Ar
R2
R1
R1
+
ArH
AcONa (3 equiv)
AcOH, 70 oC, N2
H
yield[a]
(1 equiv)
(5 equiv)
7
8
9
O
O
O
OBu
OBu
OBu
Ph
P
Ph
P
Ph
P
N
10
11
12
13
14
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NH2
NO2
N
7: 0 %
8: 0 %
9: 11 %
O
O
P
O
P
OBu
OBu
OBu
Ph
P
Ph
Ph
NHAc
O
HN
O
NHBoc
NHAc
10: 21 %
11: 25 %[b]
12: 25 %
O
O
O
OBu
OBu
OBu
Ph
P
Ph
P
Ph P
OAc
NHAc
Me
N
CO2Me
14: 34 %
(mixture)
15: 37 %[b]
13: 29 % (44:56)
O
O
OBu
O
OBu
Ph
Ph
P
Ph
P
P
OAc
BuO
OR
16: R = H, 0 %
17: R = Ac, 18 %
18: R = Bz, 40 %
19: 36 %
20: 61 % (p:o = 97:3)
i-PrO
i-PrO
O
P
O
EtO
O
P
NHAc
HN
22: 42 %[b]
EtO
O
21: 35 % (p:o = 66:34)
EtO
O
P
EtO
O
Ph
Ph
P
O
23: 98 % (C6:C5 = 73:27)
24: 92 %[c]; 88 %[d]
Scheme 3. Intermolecular arylation with R1R2P(O)H. [a] Yield after purification by chromatography on silica gel. [b] Only 1 equivalent of ArH. [c] 10
equiv Ph2P(O)H, 1 equiv ArH. [d] 3 equiv Ph2P(O)H, 1 equiv ArH.
Scheme 3 shows some results not previously reported with various aromatics and heteroaromatics. The reaction does not
work on aniline, nitrobenzene, or phenol (7, 8, 16). It is also sluggish with aniline and phenol derivatives (10, 12, 13, 17),
although phenyl benzoate gave a moderate 40 % yield of 18. Chiral aminoacid derivatives were also tried but the yields of
11, and 15 were rather low, in part due to the fact that only 1 equivalent of the aromatic compound was used. Phosphotyrosine
analog 22 could still be prepared easily in acceptable yield.
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An attempt at making a precursor of the xantphos ligand14 was unsuccessful as only one Ph2P(O) group could be introduced
(compound 24), even when a very large excess of secondary phosphine oxide was employed. Other aromatics that were tried
unsuccessfully (not shown) were benzyl alcohol, phenethyl alcohol, phenethyl acetate, 1-phenylethyl acetate, anisole, phenyl
acetate, and phenyl benzoate.
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Figure 1. Phosphorus reagents that are unsuccessful (no desired product) in the arylation reaction.
Figure 1 shows phosphorus reagents that were tried unsuccessfully (defined as no product could be obtained from the
reaction). In the case of H-thiophosphonates 25 the oxidation P=S to P=O was observed. With phosphine-boranes 26 and
27 the free-radical apparently does not form under the manganese conditions, although free-radicals can certainly be obtained
using different initiators.15 Dicyclohexylphosphine oxide 28 also failed presumably because it does not tautomerize easily to
2 (Scheme 2). Di-tert-butyl H-phosphonate 29 and the Ciba-Geigy H-phosphinate 30 did not work because they are cleaved
under the acidic conditions. Compound 31 decomposes, but if the hydroxyl is acetylated, then the arylation takes place
uneventfully as reported previously.13 Phenyl-H-phosphinic acid 32 and phosphinates 33 do not work because they are rapidly
oxidized to acid 3 (Scheme 2).
Synthetic application. (4-Aminophenyl)diphenylphosphine oxide 38 has been synthesized for its second order non-linear
optical properties, or as a component of materials with interesting properties.16 Various literature syntheses of (4-
aminophenyl)diphenylphosphine oxide 38, and the reactions employed are representative of Scheme 1 and feature both cross-
couplings and aryl metal phosphorylations.16
Our straightforward multigram scale preparation of (4-aminophenyl)diphenylphosphine oxide 38 is shown in Scheme 4.
Arylation of diphenylphosphine oxide with acetanilide proceeded regiospecifically in reasonable yield. Deprotection gave the
insoluble aniline (which was converted to the hydrochloride salt for full characterization).
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Mn(OAc)2 (5 mol %)
MnO2 (3 equiv)
NHAc
O
O
Ph
Ph
Ph
Ph
P H
P
NHAc
AcONa (3 equiv)
AcOH, 70 oC, N2
37
54 %
(1 equiv) (5 equiv)
7
(16 mmol)
8
9
Ph
Ph
O
P
O
K2CO3 (0.1 equiv)
MeOH, rt, 16 h
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6 N aq. HCl
Ph
Ph
P
NH2•HCl
NH2
39
100 %
54 % overall
from Ph2P(O)H
38
100 %
(16 mmol)
4.63 g
Scheme 4. Multigram-scale preparation of (4-aminophenyl)diphenylphosphine oxide.
Of the literature methods,16 only the one using the nickel-catalyzed cross-coupling is competitive with ours in terms of cost
and simplicity, although the reported scale is small (twenty times smaller than ours) and no scale-up was demonstrated.16e,f
Phosphinate-Alkyne Cycloadditions. The reaction of H-phosphinates with alkynes under free-radical conditions gives a
high energy alkenyl radical intermediate, which can then be cyclized onto an aromatic ring, followed by oxidation and re-
aromatization.
Table 4. Literature H-Phosphinate-Alkyne Cycloaddition
Yield[a]
Entry
n
Conditions
(%)
1
2
3
2
2
AgOAc (4 equiv); DMF, 100 oC, N2, 4 h
Ag2O (2 equiv); DMF, 100 oC, N2, 8 h
AgOAc (2 equiv); DMSO, 120 oC, N2, 12 h
53[17a]
60[17b]
60[17c]
0.5
N-ethoxy-2-methylpyridinium tetrafluoroborate
4
2
43[17d]
(2 equiv)
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NaHCO3 (1.2 equiv); eosin Y (4 mol %), green
LED (525 nm), DMF, 35 oC, N2, 48 h
6
7
[a] Yield after purification by chromatography on silica gel.
8
9
Table 4 summarizes the results from other groups with ethyl phenyl-H-phosphinate.17 Miura and coworkers reported the
preparation of 40a using 4 equivalents of AgOAc (Table 4, entry 1).17a Chen and Duan also used 4 equivalents of silver(I)
(Ag2O 2 equivalents) in closely related conditions (entry 2).17b Ma and Ackerman also reported the silver-promoted synthesis
of 40a but this time using a two-fold excess of diphenylacetylene and silver (Table 4, entry 3).17c Finally, Lakhdar and
coworkers recently reported a photoredox process (entry 4).17d
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Scheme 5. Phosphinate-Alkyne Cycloaddition.
Scheme 5 summarizes the reactions using our manganese system.18 From H-phosphinate ester starting materials, both 5-
and 6-membered rings (Scheme 5, 40b-c and 41, respectively) could be obtained in acceptable to good yield. Increasing the
amount of H-phosphinate resulted in a higher yield of 40c. Again, Mn(II) was found to be the best catalyst for these reactions.
Interestingly, Chen and Duan reported making menthyl ester 40b under the same conditions as in Table 5, entry 2, in 40 %
yield but with very significant racemization, from 99 % de to 50 % de.17b In contrast, our method (Scheme 5) uses equimolar
amounts of phosphinate and alkyne and is completely stereospecific.13b Overall, the various literature methods deliver the
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benzo[b]phosphole oxide from the H-phosphinate in 43-60 % yield, whereas our all-manganese system is rather competitive
4
5
with 55-71 % yield.
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9
Intramolecular Arylations. The intramolecular reaction of aromatic H-phosphinate esters was investigated next. Table 5
shows the results for the preparation of 5-cyclohexyl-5H-benzo[b]phosphindole-5-oxide. Catalytic conditions were unsuccessful
(Table 5, entries 1 and 2). Palladium acetate was more successful but the reaction did not go to completion (entry 3), however,
adding MnO2 resulted in an excellent yield of cyclized product (entry 4). Nonetheless, our much cheaper all manganese
system gave the best result (entry 5).
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Table 5. Cyclization of cyclohexyl (2-phenyl)phenyl-H-phosphinate
Yield[a]
Entry
Conditions
(%)
Mn(OAc)2 (5 mol %)
1
2
3
4
0
Cyclohexane, 70 oC, air, 24 h
Mn(OAc)2 (5 mol %); Co(OAc)2•4H2O (1 mol %)
AcOH, 100 oC, air, 70 h
10[b]
48[c]
90
Pd(OAc)2 (5 mol %)
THF reflux, air, 20 h
Pd(OAc)2 (5 mol %); MnO2 (2 equiv)
THF, 70 oC, N2, 12 h
Mn(OAc)2 (5 mol %); MnO2 (3 equiv)
AcONa (3 equiv)
5
98
AcOH, 70 oC, N2, 2 h slow addition + 2 h
[a] Yield after purification by chromatography on silica gel, unless otherwise noted. [b] 31P-NMR yield. [c] 88 % based on recovered starting material,
ref. 16e.
The homologous reaction was investigated (Table 6). In this case the Mn(II)/Mn(IV) system was not tried, but standard Mn(III)
worked very well (Table 6, entry 3), whereas all catalytic reactions failed (entries 1 and 2).
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Table 6. Cyclization of alkyl (2-phenyl)benzyl-H-phosphinate
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Yield[a]
(%)
Entry
R
Bu
Bu
Cy
Conditions
Mn(OAc)2 5 mol %; Co(OAc)2•4H2O 1 mol %
AcOH, 100 oC, air, 70 h
1
2
3
20[b]
Pd(OAc)2 5 mol %
THF reflux, air, 20 h
0
Mn(OAc)3•2H2O 2 equiv; AcONa 2 equiv
AcOH, 70 oC, N2, 24 h
97
[a] Yield after purification by chromatography on silica gel, unless otherwise noted. [b] 31P-NMR yield.
The transformations shown in Scheme 6 are related to the reactions described in Tables 5 and 6. Once again, our
Mn(II)/Mn(IV) system gave good results with phosphine oxide 44 and phosphinates 45-47. The last example resulted in the
formation of a mixture of isomers favoring the 6-membered ring 46.
Scheme 6. More cyclizations using the Mn(II)/Mn(IV) system.
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More conditions were examined on compound 2-phenethyl phenyl-H-phosphinate 48a and the results are summarized in
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5
Table 7.
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8
Table 7. Cyclization of 2-phenethyl phenyl-H-phosphinate
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Yield[a]
Entry
Conditions
(%)
Mn(OAc)2 (5 mol %); Cu(OAc)2 (2 equiv)
AcOH, 70 oC, N2, 24 h
1
2
0
Mn(OAc)3•2H2O (2 equiv); AcONa (2 equiv)
DMSO, 100 oC, N2, 24 h
42
3a
Mn(OAc)3•2H2O (2 equiv); AcONa (2 equiv)
AcOH, 70 oC, N2, 24 h
78
3b
84[b]
Mn(OAc)2 (2 equiv); AcONa (2 equiv)
AcOH, 70 oC, air, 24 h
4
43
Mn(OAc)2 (5 mol %); MnO2 (2 equiv)
AcONa (2 equiv)
5
82
AcOH, 70 oC, N2, 2 h slow addition + 2 h
[a] Yield after purification by chromatography on silica gel. [b] After regenerating Mn(III) from entry 3a with KMnO4.
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Scheme 7. Comparison of the Mn(III) system with our Mn(II)/Mn(IV) system.
Scheme 7 show various examples of phosphonate, secondary phosphine oxides, and phosphinates under two different set of
conditions: the Mn(III) and the Mn(II)/Mn(IV) systems. When the same products are synthesized from the two methods, the
results can be virtually undistinguishable (Scheme 7, compounds 49a and 49d), although 7-membered ring 49f was formed
in significantly better yield using our Mn(II)/Mn(IV) method.
Scheme 8. Cyclization of para-substituted H-phosphinates.
Scheme 8 shows the results obtained with electron-rich para-substituted phenethyl esters. In general, good yields are
obtained although the acetamide derivative gave a somewhat lower yield. When the catalytic conditions (5 mol %
manganese(II) 2-ethylhexanoate, 5 mol % cobalt(II) 2-ethylhexanoate, EtOAc, O2, 90 oC; see also Table 1) were tried on 48a
and 48k, the yields were 37 % and 0 %, respectively.
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Conclusions
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The direct arylation of various phosphinylidene compounds (and particularly previously under-investigated H-phosphinates)
via homolytic aromatic substitution was studied. Unfortunately, a practical catalytic version using oxygen as the terminal
oxidant was not found. A main requirement imposed from the start was to use the phosphorus species as the limiting reagent
instead of using a large excess. This is because the phosphorus component is generally the most valuable, unless simple H-
phosphonate diesters are used. At the outset, the reaction of H-phosphinate was our main objective, especially because it
had not been established in the literature.
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The desired intra- and inter-molecular transformations could be accomplished using the inexpensive catalytic
Mn(II)/superstoichiometric Mn(IV) system. This system is similar or superior to the much more expensive Mn(III) system that
has been extensively used in the literature with H-phosphonate diesters. The scope and limitations of the arylation was
discussed. The reaction appears rather general when the aromatic ring is not electron-deficient, and even hindered
mesitylphosphorus compounds could be made more efficiently than via complicated or expensive cross-coupling reactions.
On the other hand, certain phosphinylidene compounds failed to undergo arylation and the reason may be specific to each,
for example: instability in acidic conditions, rapid oxidation of P-H to P-OH, etc. Overall, the Mn(II)/Mn(IV) system we
developed is inexpensive and easily scaled, and therefore it should be useful for the synthesis of various arylphosphorus
compounds.
Experimental Section
General Chemistry:
1H NMR spectra were recorded on a 300-MHz Varian INOVA spectrometer or 400-MHz Bruker Avance spectrometer. Chemical shifts for 1H
NMR spectra (in parts per million) relative to internal tetramethylsilane (Me4Si, δ = 0.00 ppm) with deuterated chloroform. 13C{1H} NMR spectra
were recorded at 75.5 or 101 MHz. Chemical shifts for 13C{1H} NMR spectra are reported (in parts per million) relative to CDCl3 (δ = 77.0
ppm). 31P NMR spectra were recorded at 121.5 or 162 MHz, and chemical shifts reported (in parts per million) relative to external 85%
phosphoric acid (δ = 0.0 ppm). Flash chromatography experiments were carried out on Silica Gel premium Rf grade (40−75 μm). Ethyl
acetate/hexane mixtures or dichloromethane/acetone were used as the eluent for chromatographic purifications. TLC plates were visualized
by UV or immersion in permanganate potassium (3 g KMnO4, 20 g K2CO3, 5 mL 5% aq. NaOH and 300 mL of water) followed by heating. High
resolution mass spectra (HRMS) were obtained either by direct probe (EI/CI) and analyzed by magnetic sector, or by electrospray using a TOF
analyzer.
Reagent and solvents:
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All starting materials were purchased from commercial sources and used as received. The solvents were distilled under N2 and dried according
to standard procedures (THF from Na/ benzophenone ketyl; DMF from MgSO4; CH3CN, toluene and dichloromethane from CaH2).
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7
Diethyl mesitylphosphonate (Table 1, Entry 7a):12
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9
To a solution of Mn(2-ethylhexanoate)2 (42.7 mg, 0.05 mmol, 5 mol%, 40% in mineral oil), Co(2-ethylhexanoate)2 (26.6 mg, 0.05 mmol, 5
mol%, 65% in mineral oil) and mesitylene (0.14 mL, 1 mmol, 1 equiv) in ethyl acetate (2 mL) was added diethylphosphite (414 mg, 3 mmol, 3
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0
equiv) and the reaction mixture was stirred for 16 hours at 90 C under a flow of O2. Ethyl acetate (30 mL) and a 0.2M aqueous solution of
Na2S2O4 saturated with NaHCO3 (40 mL) were added and stirred vigorously for 10 minutes. The two layers were separated and the organic
layer was washed with a 0.2M aqueous solution of Na2S2O4 saturated with NaHCO3 (40 mL), a saturated aqueous solution of NaHCO3 (40 mL)
and brine (40 mL), dried over MgSO4, filtered and concentrated under vacuum. The crude obtained was purified by column chromatography
(dichloromethane/acetone 97:3 to 96:4) to afford the product as a yellow oil (199 mg, 78%).
Butyl mesityl phenylphosphinate (Table 2, Entry 6a):12
To a suspension of Mn(OAc)2 (8.7 mg, 0.05 mmol, 5 mol%), MnO2 (261 mg, 3 mmol, 3 equiv), sodium acetate (246 mg, 3 mmol, 3 equiv) and
mesitylene (0.70 mL, 5 mmol, 5 equiv) in acetic acid (2.5 mL) at 70 0C under N2 was added a solution of butyl phenyl-H-phosphinate19 (198
mg, 1 mmol, 1 equiv) in acetic acid (2.5 mL) over 2 hours via a syringe pump. The reaction mixture was then stirred for an additional 2 hours
at 70 0C under N2. Ethyl acetate (30 mL) and a 0.2M aqueous solution of Na2S2O4 saturated with NaHCO3 (40 mL) were added. The suspension
was stirred vigorously for 5 minutes, filtered through celite and the two layers were separated. The organic layer was washed with a 0.2M
aqueous solution of Na2S2O4 saturated with NaHCO3 (40 mL), a saturated aqueous solution of NaHCO3 (40 mL) and brine (40 mL), dried over
MgSO4, filtered and concentrated under vacuum to afford the product as a colorless oil (257 mg, 81%).
Butyl mesityl phenylphosphinate (Equation 2):12
To a solution of butyl phenyl-H-phosphinate19 (220 mg, 1.1 mmol, 1.1 equiv) in acetic acid (1 mL) was added Mn(OAc)2 (8.7 mg, 0.05 mmol,
5 mol%), Co(OAc)2.4H2O (2.5 mg, 0.01 mmol, 1 mol%) and mesitylene (0.14 mL, 1 mmol, 1 equiv) and the reaction mixture was stirred for 16
hours at 45 0C under a mixture of O2 and N2 1:1. Ethyl acetate (30 mL) and a 0.2M aqueous solution of Na2S2O4 saturated with NaHCO3 (40
mL) were added and stirred vigorously for 10 minutes. The two layers were separated and the organic layer was washed with a 0.2M aqueous
solution of Na2S2O4 saturated with NaHCO3 (40 mL), a saturated aqueous solution of NaHCO3 (40 mL) and brine (40 mL), dried over MgSO4,
filtered and concentrated under vacuum. The crude obtained was purified by column chromatography (dichloromethane/acetone 100:0 to
90:10) to afford the product as a colorless oil (142 mg, 45%).
Butyl diphenylphosphinate (Table 3, Entry 6a):11e
To a suspension of Mn(OAc)2 (8.7 mg, 0.05 mmol, 5 mol%), MnO2 (261 mg, 3 mmol, 3 equiv), sodium acetate (246 mg, 3 mmol, 3 equiv) and
benzene (0.45 mL, 5 mmol, 5 equiv) in acetic acid (2.5 mL) at 70 0C under N2 was added a solution of butyl phenyl-H-phosphinate19 (198 mg,
1 mmol, 1 equiv) in acetic acid (2.5 mL) over 2 hours via a syringe pump. The reaction mixture was then stirred for an additional 2 hours at 70
0C under N2. Ethyl acetate (30 mL) and a 0.2M aqueous solution of Na2S2O4 saturated with NaHCO3 (40 mL) were added. The suspension
was stirred vigorously for 5 minutes, filtered through celite and the two layers were separated. The organic layer was washed with a 0.2M
aqueous solution of Na2S2O4 saturated with NaHCO3 (40 mL), a saturated aqueous solution of NaHCO3 (40 mL) and brine (40 mL), dried over
MgSO4, filtered and concentrated under vacuum to afford the product as a white solid (175 mg, 64%).
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General procedure for the arylation of H-phosphinates and related compounds:
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To a suspension of Mn(OAc)2 (8.7 mg, 0.05 mmol, 5 mol%), MnO2 (261 mg, 3 mmol, 3 equiv), sodium acetate (246 mg, 3 mmol, 3 equiv) and
the appropriate aryl (5 mmol, 5 equiv) in acetic acid (2.5 mL) at 70 0C via an oil bath and under N2 was added a solution of the appropriate H-
phosphinate (1 mmol, 1 equiv) in acetic acid (2.5 mL) over 2 hours via a syringe pump. The reaction mixture was then stirred for an additional
2 hours at 70 0C using an oil bath and under N2. Ethyl acetate (30 mL) and a 0.2M aqueous solution of Na2S2O4 saturated with NaHCO3 (40
mL) were added. The suspension was stirred vigorously for 5 minutes, filtered through celite and the two layers were separated. The organic
layer was washed with a 0.2M aqueous solution of Na2S2O4 saturated with NaHCO3 (40 mL), a saturated aqueous solution of NaHCO3 (40 mL)
and brine (40 mL), dried over MgSO4, filtered and concentrated under vacuum to afford the pure product without further purification or after a
column chromatography.
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Ethyl diphenylphosphinate (Table 3, Entry 10a):12
General procedure was used with benzene (0.45 mL, 5 mmol, 5 equiv) and ethyl phenyl-H-phosphinate20 (170 mg, 1 mmol, 1 equiv) to afford
the product as a colorless oil (121 mg, 49%).
Isobutyl diphenylphosphinate (Table 3, Entry 10b):12
General procedure was used with benzene (0.45 mL, 5 mmol, 5 equiv) and isobutyl phenyl-H-phosphinate12 (198 mg, 1 mmol, 1 equiv) to
afford the product as a white solid (153 mg, 56%).
Cyclohexyl diphenylphosphinate (Table 3, Entry 10c):11e
General procedure was used with benzene (0.45 mL, 5 mmol, 5 equiv) and cyclohexyl phenyl-H-phosphinate12 (224 mg, 1 mmol, 1 equiv) to
afford the product as a white solid (181 mg, 60%).
Butyl 2-pyrazyl phenylphosphinate 9:
General procedure was used with pyrazine (0.39 mL, 5 mmol, 5 equiv) and butyl phenyl-H-phosphinate19 (198 mg, 1 mmol, 1 equiv). The crude
obtained was purified by column chromatography (dichloromethane/acetone 95:5 to 80:20) to afford the product as an orange oil (30 mg, 11%).
31P NMR (162 MHz, CDCl3):  = 24.1 (s); 1H NMR (400 MHz, CDCl3):  = 9.24 (s, 1H), 8.72 (s, 1H), 8.64-8.69 (m, 1H), 7.92-8.02 (m, 2H), 7.54-
7.63 (m, 1H), 7.45-7.54 (m, 2H), 4.05-4.17 (m, 2H), 1.73 (quint., J = 7.1 Hz, 2H), 1.43 (sextuplet, J = 7.5 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3):  = 150.6 (d, JPC = 164 Hz), 148.1 (d, JPCNC = 23.0 Hz), 146.6 (d, JPCNCC = 3.0 Hz), 145.3 (d, JPCC = 16.1 Hz),
133.0 (d, JPCCCC = 2.7 Hz), 132.3 (d, JPCCC = 10.1 Hz, 2C), 129.1 (d, JPC = 141 Hz), 128.7 (d, JPCC = 13.4 Hz, 2C), 65.7 (d, JPOC = 6.3 Hz), 32.5
(d, JPOCC = 6.4 Hz), 18.8, 13.6; HRMS (EI+) m/z calcd for C14H17N2O2P ([M+H]+) 277.1100, found 277.1102.
Butyl p-(tert-butyl-N-phenylcarbamate) phenylphosphinate 10:
General procedure was used with tert-butylphenyl carbamate (966 mg, 5 mmol, 5 equiv) and butyl phenyl-H-phosphinate19 (198 mg, 1 mmol,
1 equiv). The crude obtained was purified by column chromatography (dichloromethane/acetone 100:0 to 90:10) to afford the product as a
colorless oil (83 mg, 21%). 31P NMR (162 MHz, CDCl3):  = 35.2 (s); 1H NMR (400 MHz, CDCl3):  = 10.14 (s, 1H), 8.31-8.38 (m, 1H), 7.75-
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7.84 (m, 2H), 7.39-7.56 (m, 5H), 6.96-7.03 (m, 1H), 4.09 (dm, J = 56.9 Hz, 2H), 1.74 (quint., J = 7.0 Hz, 2H), 1.52 (s, 9H), 1.46 (sextuplet, J =
7.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3):  = 153.1, 144.1 (d, JPCCC = 5.8 Hz), 133.6 (d, JPCCCC = 2.0 Hz), 132.4 (d,
JPCC = 12.1 Hz), 132.4, 131.7 (d, JPC = 138 Hz), 131.2 (d, JPCCC = 10.3 Hz, 2C), 128.6 (d, JPCC = 13.6 Hz, 2C), 121.7 (d, JPCC = 12.5 Hz), 119.6
(d, JPCCC = 9.1 Hz), 115.6 (d, JPC = 129 Hz), 80.3, 65.2 (d, JPOC = 6.0 Hz), 32.5 (d, JPOCC = 6.6 Hz), 28.3 (3C), 18.9, 13.6; HRMS (EI+) m/z calcd
for C21H28NO4P ([M]+) 389.1756, found 389.1757.
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Butyl [p-((S)-4-benzyl-2-oxazolidinone)] phenylphosphinate 11:
General procedure was used with (S)-4-benzyl-2-oxazolidinone (177 mg, 1 mmol, 1 equiv) and butyl phenyl-H-phosphinate19 (198 mg, 1 mmol,
1 equiv). The crude obtained was purified by column chromatography (dichloromethane/acetone 90:10 to 50:50) to afford the product as a
colorless oil (93 mg, 25%). 31P NMR (162 MHz, CDCl3):  = 30.9 (s); 1H NMR (400 MHz, CDCl3):  = 7.59-7.83 (m, 4H), 7.21-7.53 (m, 5H),
6.64 (s, 1H), 4.29-4.39 (m, 1H), 3.92-4.12 (m, 4H), 2.78-2.98 (m, 2H), 1.68 (quint., J = 6.5 Hz, 2H), 1.39 (sextuplet, J = 7.0 Hz, 2H), 0.89 (t, J
= 7.0 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3):  = 159.5, 140.5 (d, JPCCCC = 2.5 Hz), 133.0 (d, JPCCCC = 2.5 Hz), 132.3 (d, JPCCC = 10.4 Hz),
132.2 (d, JPCCC = 10.4 Hz, 2C), 131.6 (d, JPCCC = 10.1 Hz, 2C), 131.4 (d, JPC = 137 Hz), 130.5 (d, JPC = 139 Hz), 129.4 (d, JPCC = 13.4 Hz, 2C),
128.6 (d, JPCC = 13.1 Hz), 128.6 (d, JPCC = 13.1 Hz), 69.2 (0.5C), 69.2 (0.5C), 64.9 (d, JPOC = 6.1 Hz, 0.5C), 64.8 (d, JPOC = 6.0 Hz, 0.5C), 53.4,
41.2 (0.5C), 41.0 (0.5C), 32.5 (d, JPOCC = 6.6 Hz), 18.8, 13.6; HRMS (EI+) m/z calcd for C20H25NO4P ([M+H]+) 374.1516, found 374.1520.
Butyl (p-tolylacetate) phenylphosphinate (mixture of ortho and meta isomers) 13:
General procedure was used with p-tolylacetate (751 mg, 5 mmol, 5 equiv) and butyl phenyl-H-phosphinate19 (198 mg, 1 mmol, 1 equiv). The
crude obtained was purified by column chromatography (dichloromethane/acetone 100:0 to 90:10) to afford the product as a colorless oil (100
mg, 29%). 31P NMR (162 MHz, CDCl3):  = 30.0 (s, 46%, methyl in meta position) and 27.5 (s, 54%, methyl in ortho position); 1H NMR (400
MHz, CDCl3):  = 7.84-7.90 (m, 0.5H), 7.71-7.81 (m, 2H), 7.62-7.68 (m, 0.5H), 7.39-7.55 (m, 3H), 7.32-7.38 (m, 0.5H), 7.12-7.22 (m, 1H), 6.94-
7.01 (m, 0.5H), 3.89-4.12 (m, 2H), 2.39 (s, 1.5H), 2.36 (s, 1.5H), 2.28 (s, 1.5H), 2.07 (s, 1.5H), 1.71 (quint., J = 6.8 Hz, 2H), 1.42 (sextuplet, J
= 7.4 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3):  = 169.3 (0.5C), 169.0 (0.5C), 153.1, 149.9 (d, JPCCC = 3.4 Hz, 0.5C),
148.3 (d, JPCC = 16.5 Hz, 0.5C), 139.3 (d, JPCCC = 10.9 Hz, 0.5C), 135.8 (d, JPCC = 11.4 Hz, 0.5C), 134.6 (d, JPCCC = 6.0 Hz, 0.5C), 134.4 (d,
JPCCCC = 2.1 Hz, 0.5C), 132.5 (d, JPCC = 14.3 Hz, 0.5C), 132.4 (d, JPC = 98.8 Hz, 0.5C), 132.1 (d, JPCCC = 5.3 Hz, 0.5C), 132.1 (d, JPCCC = 5.4
Hz, 0.5C), 131.6 (d, JPCCC = 10.5 Hz), 131.6 (d, JPC = 136 Hz, 0.5C), 131.1 (d, JPCCC = 10.7 Hz), 130.9 (d, JPC = 113 Hz, 0.5C), 128.5 (d, JPCC
13.3 Hz), 128.4 (d, JPCC = 13.8 Hz), 126.1 (d, JPCCC = 9.4 Hz, 0.5C), 125.5 (d, JPCCCC = 2.6 Hz), 123.4 (d, JPCCC = 8.1 Hz, 0.5C), 123.2 (d, JPC
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133 Hz, 0.5C), 64.8 (d, JPOC = 5.9 Hz, 0.5C), 64.6 (d, JPOC = 5.9 Hz, 0.5C), 32.5 (d, JPOCC = 6.6 Hz), 21.0 (0.5H), 20.8 (0.5C), 20.8 (0.5C), 20.5
(d, JPCCC = 3.8 Hz, 0.5C), 18.9 (0.5C), 18.8 (0.5C), 13.6; HRMS (EI+) m/z calcd for C19H24O4P ([M+H]+) 347.1407, found 347.1402.
Butyl pyridyl phenylphosphinate (mixture of ortho and para derivatives) 14:
General procedure was used with pyridine (0.40 mL, 5 mmol, 5 equiv) and butyl phenyl-H-phosphinate19 (198 mg, 1 mmol, 1 equiv) to afford
the product as a colorless oil (93 mg, 34%). 31P NMR (162 MHz, CDCl3):  = 28.0 (s, 38%) and 25.4 (s, 54%); 1H NMR (400 MHz, CDCl3):  =
8.67-8.77 (m, 1H), 8.06-8.14 (m, 0.5H), 7.90-7.99 (m, 1H), 7.72-7.83 (m, 1.5H), 7.58-7.66 (m, 1H), 7.39-7.57 (m, 3H), 7.30-7.37 (m, 1H), 3.96-
4.09 (m, 2H), 1.63-1.74 (m, 2H), 1.33-1.46 (m, 2H), 0.89 and 0.86 (2t, J = 7.0 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3):  = 154.8 (d, JPC
=
168 Hz, 0.6C), 150.5 (d, JPCC = 20.5 Hz, 0.4C), 150.1 (d, JPCC = 10.8 Hz, 0.4C), 150.0 (d, JPCCC = 3.2 Hz, 0.4C), 140.9 (d, JPC = 132 Hz, 0.4C),
136.0 (d, JPCC = 10.1 Hz, 0.6C), 132.8 (d, JPCCCC = 2.6 Hz, 0.4C), 132.3 (d, JPCCCC = 2.6 Hz, 0.6C), 132.3 (d, JPCCCC = 5.0 Hz, 0.6C), 132.2 (d,
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JPCCC = 9.8 Hz, 1.2C), 131.7 (d, JPCCC = 10.2 Hz, 0.8C), 130.2 (d, JPC = 139 Hz, 0.4C), 129.9 (d, JPC = 139 Hz, 0.6C), 128.8 (d, JPCC = 13.3 Hz,
0.8C), 128.4 (d, JPCC = 13.2 Hz, 1.2C), 128.2 (d, JPCC = 20.6 Hz, 0.6C), 125.6 (d, JPCCCC = 3.0 Hz, 0.4C), 125.1 (d, JPCCC = 8.2 Hz, 0.6C), 65.3
(d, JPOC = 6.2 Hz), 32.5 (d, JPOCC = 6.6 Hz, 0.6C), 32.5 (d, JPOCC = 6.6 Hz, 0.4C), 18.8 (0.4C), 18.8 (0.6C), 13.6; HRMS (EI+) m/z calcd for
C15H18NO2P ([M+H]+) 276.1148, found 276.1155.
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Butyl [4-(D-phenylalanine)] phenylphosphinate 15:
General procedure was used with D-phenylalanine (443 mg, 2 mmol, 1 equiv) and butyl phenyl-H-phosphinate19 (396 mg, 2 mmol, 1 equiv).
The crude obtained was purified by column chromatography (dichloromethane/acetone 80:20 to 50:50) to afford the product as a yellow oil
(155 mg, 37%, mixture of 2 diastereoisomers 62 : 38). 31P NMR (162 MHz, CDCl3):  = 31.2 (s, 62%), 31.0 (s, 38%); 1H NMR (400 MHz,
CDCl3):  = 7.50-7.77 (m, 4H), 7.22-7.46 (m, 4H), 7.12-7.20 (m, 1H), 6.82-6.99 (m, 1H), 4.69-4.81 (m, 1H), 3.91 (s, 1H), 3.48-3.61 (m, 2H),
2.93-3.14 (m, 2H), 1.85 (s, 3H), 1.60 (quint., J = 6.5 Hz, 2H), 1.33 (sextuplet, J = 7.0 Hz, 2H), 0.82 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3, major diastereiosmer only):  = 171.9, 170.1, 140.9, 132.2, 131.7 (d, JPCCC = 12.4 Hz, 2C), 131.6 (d, JPCCC = 12.4 Hz, 2C), 131.4 (d, JPC
= 112 Hz), 130.0 (d, JPC = 114 Hz), 129.5 (d, JPCC = 13.3 Hz, 2C), 128.6 (d, JPCC = 13.0 Hz, 2C), 64.8 (d, JPOC = 6.0 Hz), 53.0, 52.4, 37.6, 32.5
(d, JPOCC = 6.4 Hz), 22.9, 18.8, 13.6; HRMS (EI+) m/z calcd for C21H27NO5P ([M+H]+) 404.1621, found 404.1614.
Butyl 4-(phenylbenzoate) phenylphosphinate 18:
General procedure was used with phenylbenzoate (991 mg, 5 mmol, 5 equiv) and butyl phenyl-H-phosphinate19 (198 mg, 1 mmol, 1 equiv).
The crude obtained was purified by column chromatography (dichloromethane/acetone 98:2 to 90:10) to afford the product as a colorless oil
(158 mg, 40%, mixture of 3 isomers 89 : 7 : 4). 31P NMR (162 MHz, CDCl3):  = 29.6 (s, 89%, para position); 1H NMR (400 MHz, CDCl3):  =
8.22-8.30 (m, 2H), 7.93-8.02 (m, 2H), 7.79-7.88 (m, 2H), 7.36-7.56 (m, 5H), 7.22-7.28 (m, 1H), 7.15-7.21 (m, 2H), 4.07 (dt, J = 7.1 Hz, 2H),
1.73 (quint., J = 7.0 Hz, 2H), 1.44 (sextuplet, J = 7.4 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3):  = 164.3, 150.7, 137.4
(d, JPC = 134 Hz), 132.7 (d, JPCCCC = 2.6 Hz), 132.5 (d, JPCCCC = 2.6 Hz), 131.8 (d, JPCCC = 10.2 Hz, 2C), 131.7 (d, JPCCC = 10.2 Hz, 2C), 130.8
(d, JPC = 138 Hz), 130.0 (d, JPCC = 13.0 Hz, 2C), 129.6 (2C), 128.7 (d, JPCC = 13.2 Hz, 2C), 126.1, 121.5 (2C), 65.1 (d, JPOC = 6.2 Hz), 32.5 (d,
JPOCC = 6.5 Hz), 18.9, 13.6; HRMS (EI+) m/z calcd for C23H24O4P ([M+H]+) 395.1407, found 395.1420.
Butyl 1-(pyrenyl) phenylphosphinate 19:
General procedure was used with pyrene (1011 mg, 5 mmol, 5 equiv) and butyl phenyl-H-phosphinate19 (198 mg, 1 mmol, 1 equiv). The crude
obtained was purified by column chromatography (dichloromethane/acetone 100:0 to 97:3) to afford the product as a colorless oil (175 mg,
44%, mixture of 2 isomers 83 : 17). 31P NMR (162 MHz, CDCl3):  = 32.6 (s, 83%, C-1 position), 31.8 (s, 17%, C-2 position); 1H NMR (400
MHz, CDCl3, major isomer only):  = 8.90-8.96 (m, 1H), 8.68-8.76 (m, 1H), 8.05-8.12 (m, 3H), 7.86-8.02 (m, 6H), 7.37-7.48 (m, 3H), 4.11-4.33
(m, 2H), 1.79 (quint., J = 7.0 Hz, 2H), 1.48 (sextuplet, J = 6.7 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3, major isomer
only):  = 138.2 (d, JPCCC = 7.8 Hz), 134.5 (d, JPCCCC = 2.8 Hz), 133.1 (d, JPCC = 11.4 Hz), 133.0 (d, JPC = 137 Hz), 132.0 (d, JPCCCC = 2.5 Hz),
131.6 (d, JPC = 125 Hz), 131.5 (2C), 131.4 (2C), 130.9, 130.2, 129.7, 129.1, 128.6 (d, JPCC = 13.3 Hz, 2C), 127.1, 126.3, 126.3 (d, JPCCC = 9.4
Hz, 2C), 127.3, 125.3 (d, JPCCC = 5.4 Hz), 124.1 (d, JPCC = 13.3 Hz), 64.9 (d, JPOC = 5.9 Hz), 32.7 (d, JPOCC = 6.7 Hz), 19.0, 13.7; HRMS (EI+)
m/z calcd for C26H24O2P ([M+H]+) 399.1508, found 399.1510.
Butyl [4-(2-acetoxyphenyl)phenyl] phenylphosphinate 20:
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General procedure was used with [1,1’-biphenyl]-2-yl acetate (1061 mg, 5 mmol, 5 equiv) and butyl phenyl-H-phosphinate19 (198 mg, 1 mmol,
1 equiv). The crude obtained (mixtures of 4 isomers, 61%) was purified by column chromatography (dichloromethane/acetone 100:0 to 90:10)
to afford the product as a colorless oil (249 mg, 61%). 31P NMR (162 MHz, CDCl3):  = 31.0 (s); 1H NMR (400 MHz, CDCl3):  = 7.82-7.95 (m,
4H), 7.46-7.61 (m, 5H), 7.38-7.45 (m, 2H), 7.31-7.37 (m, 1H), 7.13-7.19 (m, 1H), 4.02-4.14 (m, 2H), 2.09 (s, 3H), 1.75 (quint., J = 7.0 Hz, 2H),
1.47 (sextuplet, J = 7.0 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3):  = 169.3, 147.7, 141.5 (d, JPCCCC = 2.8 Hz), 133.8,
132.2 (d, JPCCCC = 2.5 Hz), 131.7 (d, JPCC = 12.9 Hz, 2C), 131.6 (d, JPCCC = 13.3 Hz, 2C), 131.5 (d, JPC = 140 Hz), 130.8 (d, JPC = 139 Hz), 130.7,
129.3, 129.0 (d, JPCC = 13.3 Hz, 2C), 128.6 (d, JPCCC = 13.0 Hz, 2C), 126.5, 123.0, 64.8 (d, JPOC = 6.0 Hz), 32.6 (d, JPOCC = 6.6 Hz), 20.9, 18.9,
13.7; HRMS (EI+) m/z calcd for C24H25O4P ([M]+) 408.1490, found 408.1502.
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Diethyl [4-(acetamido)phenyl]phosphonate 21:21
General procedure was used with acetanilide (676 mg, 5 mmol, 5 equiv) and diethyl phosphite (138 mg, 1 mmol, 1 equiv). The crude obtained
was purified by column chromatography (dichloromethane/acetone 90:10 to 70:30) to afford the product as a white solid (99 mg, 37%, mixture
of 2 isomers 66 : 34). Mp = 142-144 0C; 31P NMR (162 MHz, CDCl3):  = 19.0 (s, 66%) and 18.3 (s, 34%); 1H NMR (400 MHz, CDCl3):  = 9.79
(s, 0.34H), 9.70 (s, 0.66H), 7.97-8.06 (m, 0.66H), 7.61-7.79 (m, 2.64H), 7.32-7.47 (m, 0.66H), 3.96-4.13 (m, 4H), 2.17 (s, 1H), 2.16 (s, 2H),
1.27 (t, J = 7.0 Hz, 6H).
diisopropyl [p-((S)-4-benzyl-2-oxazolidinone)]phosphinate 22:
General procedure was used with (S)-4-benzyl-2-oxazolidinone (177 mg, 1 mmol, 1 equiv) and diisopropylphosphite (166 mg, 1 mmol, 1 equiv).
The crude obtained was purified by column chromatography (dichloromethane/acetone 85:15 to 50:50) to afford the product as a colorless oil
(143 mg, 42%, mixture of 2 isomers). 31P NMR (162 MHz, CDCl3):  = 16.3 (36%) and 16.2 (64%) (s, 89%, para position), 14.7 and 14.4 (s,
8%, ortho position); 1H NMR (400 MHz, CDCl3):  = 7.57-7.74 (m, 2H), 7.19-7.38 (m, 2H), 6.81 (s, 1H), 4.56-4.72 (m, 2H), 4.26-4.36 (m, 1H),
3.99-4.11 (m, 2H), 2.89-2.98 (m, 1H), 2.77-2.87 (m, 1H), 1.30 (t, J = 5.7 Hz, 6H), 1.16 (t, J = 6.1 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3):  =
159.6, 140.5 (d, JPCCCC = 3.0 Hz, 0.36C), 136.4 (d, JPCC = 15.1 Hz, 0.36C), 133.1 (d, JPCCCC = 3.0 Hz, 0.64C), 132.4 (d, JPCCC = 10.4 Hz, 0.64C),
132.2 (d, JPCCC = 10.2 Hz), 130.4 (d, JPC = 188 Hz, 0.64C), 130.2 (d, JPCCC = 9.3 Hz, 0.36C), 129.2 (d, JPCC = 15.2 Hz), 128.9 (d, JPCC = 15.4
Hz, 0.64C), 128.6 (d, JPC = 191 Hz, 0.36C), 71.0 (dd, JPOC = 5.8 and 1.1 Hz, 0.64C), 70.9 (d, JPOC = 5.7 Hz, 0.36C), 69.3 (0.36C), 69.1 (0.64C),
53.4 (0.64C), 53.4 (0.36C), 41.2 (0.36C), 40.9 (0.64C), 24.0 (d, JPOCC = 4.0 Hz, 2C), 23.8 (d, JPOCC = 4.6 Hz, 2C); HRMS (EI+) m/z calcd for
C16H25NO5P ([M+H]+) 342.1465, found 342.1464.
Diethyl tetrahydronaphthalene phosphonate (mixture of isomers C1 and C2 position) 23:5f
General procedure was used with tetrahydronaphthalene (0.70 mL, 5 mmol, 5 equiv) and diethyl phosphite (138 mg, 1 mmol, 1 equiv). The
crude obtained was purified by column chromatography (dichloromethane/acetone 96:4 to 90:10) to afford the product as an orange oil (262
mg, 98%, mixture of 2 isomers 73 : 27). 31P NMR (162 MHz, CDCl3):  = 19.9 (s, 73 %, C1-position) and 19.7 (s, 27%, C2-position); 1H NMR
(400 MHz, CDCl3, only the major isomer):  = 7.58-7.67 (m, 1H), 7.07-7.12 (m, 1H), 6.98-7.05 (m, 1H), 3.89-4.08 (m, 4H), 2.61-2.71 (m, 4H),
1.61-1.72 (m, 4H), 1.21 (t, J = 7.1 Hz, 6H).
Diphenyl 4-(2,7,9,9-tetramethyl-9H-xanthenyl) phosphine oxide 24:
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General procedure was used with 2,7,9,9-tetramethyl-9H-xanthene (120 mg, 0.5 mmol, 1 equiv) and diphenylphosphine oxide (303 mg, 1.5
mmol, 3 equiv). The crude obtained was purified by column chromatography (dichloromethane/acetone 100:0 to 95:5) to afford the product as
a colorless oil (192 mg, 88%). 31P NMR (162 MHz, CDCl3):  = 26.3 (s); 1H NMR (400 MHz, CDCl3):  = 7.78-7.86 (m, 4H), 7.68-7.74 (m, 1H),
7.48-7.54 (m, 2H), 7.39-7.46 (m, 5H), 7.12-7.16 (m, 1H), 6.76-6.81 (m, 1H), 5.96-6.01 (m, 1H), 2.38 (s, 3H), 2.29 (s, 3H), 1.59 (s, 6H); 13C{1H}
NMR (101 MHz, CDCl3):  = 149.6 (d, JPCCCC = 3.1 Hz), 147.6, 133.3 (d, JPC = 108 Hz, 2C), 133.0 (d, JPCCC = 6.0 Hz), 132.8, 132.6 (d, JPCC
=
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11.7 Hz), 131.8 (d, JPCCC = 10.4 Hz, 4C), 131.6 (d, JPCCCC = 2.0 Hz, 2C), 131.2, 131.0 (d, JPCCC = 6.3 Hz), 129.8, 128.3 (d, JPCC= 12.4 Hz, 4C),
127.8, 125.9, 118.8 (d, JPC = 102 Hz), 115.6, 34.3, 31.6 (2C), 29.3, 21.0; HRMS (EI+) m/z calcd for C29H28O2P ([M+H]+) 439.1821, found
439.1832.
Diphenyl-4-(aminophenyl) phosphine oxide hydrochloride salt 39:16e
General procedure was used with acetanilide (20.3 g, 150 mmol, 5 equiv) and diphenylphosphine oxide (6.1 g, 30 mmol, 1 equiv). The crude
obtained was purified by column chromatography (dichloromethane/acetone 80:20 to 40:60) to afford the product as a white solid (5.46 g,
54%).12 Mp = 150-152 0C; 31P NMR (162 MHz, CDCl3):  = 29.6 (s); 1H NMR (400 MHz, CDCl3):  = 9.16 (s, 1H), 7.62-7.70 (m, 6H), 7.44-7.59
(m, 8H), 2.19 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3):  = 169.4, 142.2 (d, JPCCCC = 3.0 Hz), 133.0 (d, JPCCC = 10.7 Hz, 2C), 132.3 (d, JPC = 105
Hz, 2C), 132.1 (d, JPCCCC = 2.5 Hz, 2C), 132.0 (d, JPCCC = 10.1 Hz, 4C), 128.6 (d, JPCC = 12.3 Hz, 4C), 126.3 (d, JPC = 109 Hz), 119.5 (d, JPCC
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12.6 Hz, 2C), 24.5.
To a solution of diphenyl-4-(acetamidophenyl) phosphine oxide (5.3 g, 15.8 mmol, 1 equiv) in methanol (80 mL) was added potassium
carbonate (0.22 g, 1.58 mmol, 10 mol %) and the mixture was stirred at rt for 16 hours under N2. The solvent was removed under vacuum. The
residue obtained was solubilized in chloroform and the organic layer was washed with brine. The aqueous layer was then extracted 5 times
with chloroform and the combined organic layers was dried over MgSO4, filtered and concentrated under vacuum to afford the product as a
white solid (4.63 g, 100%).16e Mp = 204-205 0C; 31P NMR (162 MHz, CDCl3):  = 32.3 (s).
To a solution of diphenyl-4-(aminophenyl) phosphine oxide (586 mg, 2 mmol, 1 equiv) in methanol (5 mL) was added a solution of HCl 6N (5
mL) and the mixture was stirred at rt for 12 hours under N2. The solvent was then concentrated under vacuum to afford the product as a yellow
solid (656 mg, 100%).16e Mp = 148-150 0C; 31P NMR (162 MHz, CDCl3):  = 29.8 (t, J = 10.8 Hz); 1H NMR (400 MHz, CDCl3):  = 7.63-7.71
(m, 4H), 7.50-7.56 (m, 2H), 7.36-7.48 (m, 6H), 6.66-6.72 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3):  = 149.9 (d, JPCCCC = 2.5 Hz), 133.8 (d,
JPCCC = 11.1 Hz, 2C), 133.3 (d, JPC = 103 Hz, 2C), 132.1 (d, JPCCC = 10.0 Hz, 4C), 131.7 (d, JPCCCC = 2.7 Hz, 2C), 128.4 (d, JPCC = 12.2 Hz, 4C),
119.7 (d, JPC = 114 Hz), 114.3 (d, JPCC = 13.3 Hz, 2C).
(Sp)-1-menthyl-2,3-diphenyl-1-phosphindole 40b:17b
To a suspension of Mn(OAc)2 (8.7 mg, 0.05 mmol, 5 mol%), MnO2 (261 mg, 3 mmol, 3 equiv), sodium acetate (246 mg, 3 mmol, 3 equiv) and
diphenylacetylene (178 mg, 1 mmol, 1 equiv) in acetic acid (2.5 mL) at 70 0C under N2 was added a solution of (Rp)-menthyl phenyl-H-
phosphinate13a (280 mg, 1 mmol, 1 equiv, >99% de) in acetic acid (2.5 mL) over 2 hours via a syringe pump. The reaction mixture was then
stirred for an additional 2 hours at 70 0C under N2. Ethyl acetate (~ 30 mL) and an aqueous solution of Na2S2O4 0.2M saturated with NaHCO3
(~40 mL) were added. The suspension was stirred vigorously for 5 minutes, filtered through celite and the two layers were separated. The
organic layer was washed with an aqueous solution of Na2S2O4 0.2M saturated with NaHCO3 (~40 mL), a saturated aqueous solution of
NaHCO3 (~ 40 mL) and brine (~ 40 mL), dried over MgSO4, filtered and concentrated under vacuum. The crude obtained was purified by
column chromatography (dichloromethane/acetone 100:0 to 98:2) to afford the product as a white solid (175 mg, 39%, > 99% de). Mp = 159-
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160 oC; 31P NMR (162 MHz, CDCl3):  = 44.8 (s); 1H NMR (400 MHz, CDCl3):  = 7.69-7.79 (m, 1H), 7.05-7.56 (m, 13H), 4.29-4.42 (m, 1H),
2.25-2.38 (s, 1H), 1.53-1.76 (m, 3H), 1.38-1.51 (m, 1H), 1.16-1.36 (m, 2H), 0.75-1.10 (m, 2H), 0.92 (d, J = 6.4 Hz, 3H), 0.66 (d, J = 7.0 Hz,
3H), 0.43 (d, J = 6.8 Hz, 3H); [α]D25 = -52.90 (chloroform).
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1-Butyl-2,3-diphenyl-1-phosphindole 40c:
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To a suspension of Mn(OAc)2 (8.7 mg, 0.05 mmol, 5 mol%), MnO2 (261 mg, 3 mmol, 3 equiv), sodium acetate (246 mg, 3 mmol, 3 equiv) and
diphenylacetylene (178 mg, 1 mmol, 1 equiv) in acetic acid (2.5 mL) at 70 0C under N2 was added a solution of butyl phenyl-H-phosphinate19
(198 mg, 1 mmol, 1 equiv) in acetic acid (2.5 mL) over 2 h via a syringe pump. The reaction mixture was then stirred for an additional 2 hours
at 70 0C under N2. Ethyl acetate (~ 50 mL) and an aqueous solution of Na2S2O4 0.2M saturated with NaHCO3 (~50 mL) were added. The
suspension was stirred vigorously for 5 minutes, filtered through celite and the two layers were separated. The organic layer was washed with
an aqueous solution of Na2S2O4 0.2M saturated with NaHCO3 (~50 mL), a saturated aqueous solution of NaHCO3 (~ 50 mL) and brine (~ 50
mL), dried over MgSO4, filtered and concentrated under vacuum. The crude obtained was purified by column chromatography
(dichloromethane/acetone 100:0 to 97:3) to afford the product as a yellow solid (205 mg, 55%). Mp = 96-97 oC; 31P NMR (162 MHz, CDCl3): 
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= 45.9 (s); 1H NMR (400 MHz, CDCl3):  = 7.69-7.76 (m, 1H), 7.32-7.43 (m, 7H), 7.20-7.26 (m, 2H), 7.13-7.20 (m, 3H), 7.06-7.11 (m, 1H), 3.92-
4.07 (m, 2H), 1.54 (quint., J = 7.0 Hz, 2H), 1.26 (sextuplet, J = 7.4 Hz, 2H), 0.78 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3):  = 148.6
(d, JPCC = 27.3 Hz), 141.9 (d, JPCC = 34.3 Hz), 133.9 (d, JPCC = 18.0 Hz), 133.1 (d, JPCCCC = 1.7 Hz), 132.5 (d, JPCCC = 9.0 Hz), 130.0 (d, JPC
=
125 Hz), 129.1, 129.0 (2C), 128.9 (4C), 128.7, 128.3 (2C), 128.0, 127.7 (d, JPCCC = 8.8 Hz), 127.2 (d, JPC = 134 Hz), 123.9 (d, JPCC = 13.4 Hz),
65.8 (d, JPOC = 6.6 Hz), 32.5 (d, JPOCC = 6.0 Hz), 18.6, 13.5; HRMS (EI+) m/z calcd for C24H23O2P ([M]+) 374.1436, found 374.1443.
1-Butyl-2,3-diphenyl-1-phosphindole 40c:
To a suspension of Pd(OAc)2 (11.2 mg, 0.05 mmol, 5 mol%), MnO2 (261 mg, 3 mmol, 3 equiv), sodium acetate (246 mg, 3 mmol, 3 equiv) and
diphenylacetylene (178 mg, 1 mmol, 1 equiv) in acetic acid (2.5 mL) at 70 0C under N2 was added a solution of butyl phenyl-H-phosphinate19
(198 mg, 1 mmol, 1 equiv) in acetic acid (2.5 mL) over 2 h via a syringe pump. The reaction mixture was then stirred for an additional 2 hours
at 70 0C under N2. Ethyl acetate (~ 50 mL) and an aqueous solution of Na2S2O4 0.2M saturated with NaHCO3 (~50 mL) were added. The
suspension was stirred vigorously for 5 minutes, filtered through celite and the two layers were separated. The organic layer was washed with
an aqueous solution of Na2S2O4 0.2M saturated with NaHCO3 (~50 mL), a saturated aqueous solution of NaHCO3 (~ 50 mL) and brine (~ 50
mL), dried over MgSO4, filtered and concentrated under vacuum. 31P NMR (162 MHz, CDCl3) of the crude:  = 46.0 (42%, s).
1-Butyl-2,3-diphenyl-1-phosphindole 40c:
To a suspension of Ru/C (202 mg, 0.05 mmol, 5 mol%, 2.5% wt in water), MnO2 (261 mg, 3 mmol, 3 equiv), sodium acetate (246 mg, 3 mmol,
3 equiv) and diphenylacetylene (178 mg, 1 mmol, 1 equiv) in acetic acid (2.5 mL) at 70 0C under N2 was added a solution of butyl phenyl-H-
phosphinate19 (198 mg, 1 mmol, 1 equiv) in acetic acid (2.5 mL) over 2 h via a syringe pump. The reaction mixture was then stirred for an
additional 2 hours at 70 0C under N2. Ethyl acetate (~ 50 mL) and an aqueous solution of Na2S2O4 0.2M saturated with NaHCO3 (~50 mL) were
added. The suspension was stirred vigorously for 5 minutes, filtered through celite and the two layers were separated. The organic layer was
washed with an aqueous solution of Na2S2O4 0.2M saturated with NaHCO3 (~50 mL), a saturated aqueous solution of NaHCO3 (~ 50 mL) and
brine (~ 50 mL), dried over MgSO4, filtered and concentrated under vacuum. The crude obtained was purified by column chromatography
(dichloromethane/acetone 100:0 to 96:4) to afford the product as a yellow solid (127 mg, 34%). Mp = 96-97 oC; 31P NMR (162 MHz, CDCl3): 
= 45.9 (s); 1H NMR (400 MHz, CDCl3):  = 7.69-7.76 (m, 1H), 7.32-7.43 (m, 7H), 7.20-7.26 (m, 2H), 7.13-7.20 (m, 3H), 7.06-7.11 (m, 1H), 3.92-
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4.07 (m, 2H), 1.54 (quint., J = 7.0 Hz, 2H), 1.26 (sextuplet, J = 7.4 Hz, 2H), 0.78 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3):  = 148.6
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(d, JPCC = 27.3 Hz), 141.9 (d, JPCC = 34.3 Hz), 133.9 (d, JPCC = 18.0 Hz), 133.1 (d, JPCCCC = 1.7 Hz), 132.5 (d, JPCCC = 9.0 Hz), 130.0 (d, JPC
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125 Hz), 129.1, 129.0 (2C), 128.9 (4C), 128.7, 128.3 (2C), 128.0, 127.7 (d, JPCCC = 8.8 Hz), 127.2 (d, JPC = 134 Hz), 123.9 (d, JPCC = 13.4 Hz),
65.8 (d, JPOC = 6.6 Hz), 32.5 (d, JPOCC = 6.0 Hz), 18.6, 13.5; HRMS (EI+) m/z calcd for C24H23O2P ([M]+) 374.1436, found 374.1443.
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2-butoxy-1,2-dihydro-3,4-dipropyl-2-isophosphinoline-2-oxide 41:18
To a solution of butyl benzyl-H-phosphinate18 (212 mg, 1 mmol, 2 equiv) and 4-octyne (55 mg, 0.5 mmol, 1 equiv) in acetic acid (2.5 mL) was
added Mn(OAc) (4.3 mg, 0.025 mmol, 5 mol %), MnO (85% activated, 154 mg, 1.5 mmol, 3 equiv). The suspension was stirred for 6 h at 70
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C under N . Ethyl acetate (40 mL) and 0.1 M aqueous solution of Na S O (saturated with NaCl, 20 mL) was added. The mixture was stirred
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for 5 min and the suspension was filtered over Celite®. The organic layer was washed with aqueous solutions of Na S O 0.1M, NaHCO
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and brine, dried over MgSO , filtered and concentrated under vacuum. The crude obtained was purified by column chromatography
4
(hexane/ethyl acetate 7:3 to 3:7) to afford the product as colorless oil (80 mg, 50%).
5-cyclohexyloxy-5H-benzo[b]phosphindole-5-oxide 42:11e
To a solution of cyclohexyl 2-(biphenyl)-H-phosphinate12 (150.2 mg, 0.5 mmol, 1 equiv) in tetrahydrofuran (2 ml) was added Pd(OAc)2 (5.6 mg,
0.025 mmol, 5.0 mol %) and the mixture was stirred for 20h at 70 °C. The solvent was removed under vacuum and the residue obtained was
purified by column chromatography (hexane/ethyl acetate 8:2 to 5:5) to afford the product as a white solid (72 mg, 48%, 88% based on
recovered SM).
5-cyclohexyloxy-5H-benzo[b]phosphindole-5-oxide 42:11e
To a solution of cyclohexyl 2-(biphenyl)-H-phosphinate12 (300 mg, 1 mmol, 1 equiv) in tetrahydrofuran (10 ml) was added Pd(OAc)2 (11.2 mg,
0.05 mmol, 5.0 mol %) and MnO2 (174 mg, 2 mmol, 2 equiv) and the mixture was stirred for 12h at 70 °C under N2. 50 mL of ethyl acetate was
added and the suspension was filtered to remove the manganese. The organic layer was washed with aqueous solutions of Na2S2O4 0.5M,
NaHCO3 and brine, dried over MgSO4, filtered and concentrated under vacuum. The crude obtained was purified by column chromatography
(dichloromethane/acetone 98:2 to 93:7) to afford the product as a white solid (267 mg, 90%).
5-cyclohexyloxy-5H-benzo[b]phosphindole-5-oxide 42:11e
To a suspension of Mn(OAc)2 (8.7 mg, 0.05 mmol, 5 mol%), MnO2 (261 mg, 3 mmol, 3 equiv) and sodium acetate (246 mg, 3 mmol, 3 equiv)
in acetic acid (2.5 mL) at 70 0C under N2 was added a solution of cyclohexyl 2-(biphenyl)-H-phosphinate12 (300 mg, 1 mmol, 1 equiv) in acetic
acid (2.5 mL) over 2 h via a syringe pump. The reaction mixture was then stirred for an additional 2h at 70 0C under N2. Ethyl acetate (50 mL)
and an aqueous solution of Na2S2O4 0.2M saturated with NaHCO3 (40 mL) were added. The suspension was stirred vigorously for 10 minutes,
filtered through celite and the two layers were separated. The organic layer was washed with an aqueous solution of Na2S2O4 0.2M saturated
with NaHCO3 (40 mL), a saturated aqueous solution of NaHCO3 (40 mL) and brine (40 mL), dried over MgSO4, filtered and concentrated under
vacuum to afford the product as a white solid (291 mg, 98%).
10-cyclohexyloxy-9,10-dihydro-10-phosphaphenanthrene-10-oxide 43:
To a solution of H3PO2 (1.32 g, 10 mmol, 2 equiv, concentrated under vacuum for 30 minutes) in tert-amylalcohol (25 mL) was added Pd2dba3
(23 mg, 0.025 mmol, 0.5 mol %), xantphos (32 mg, 0.055 mmol, 1.1 mol %) and 2-biphenylmethanol (921 mg, 5 mmol, 1 equiv). The mixture
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was stirred for 20 hours at reflux under N2 in a flask equipped with a Dean-Stark trap. After cooling down the reaction to rt, the solvent was
removed under vacuum to afford the crude as a brown oil.
The crude obtained was solubilized in toluene (20 mL) and then cyclohexanol (0.53 mL, 5 mmol, 2 equiv) was added. The reaction mixture
was stirred for 48 hours at reflux under N2 in a flask equipped with a Dean-Stark trap. After cooling down the reaction to rt, the solvent was
removed under vacuum and the crude obtained was purified by column chromatography (hexane/ethyl acetate 7:3 to 5:5) to afford the product
as a colorless oil (421 mg, 27% on two steps). 31P NMR (121.5 MHz, CDCl3):  = 33.0 (dm, J = 541 Hz); 1H NMR (300 MHz, CDCl3):  =
7.24-7.48 (m, 9H), 7.00 (dt, J = 1.9 and 541 Hz), 4.18-4.32 (m, 1H), 3.13-3.34 (m, 2H), 1.14-1.93 (m, 11H).
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To a solution of cyclohexyl-2-biphenylmethyl-H-phosphinate (400 mg, 1.27 mmol, 1 equiv) in acetic acid (5 mL) was added Mn(OAc)3.2H2O
(682 mg, 2.54 mmol, 2 equiv) and sodium acetate (208 mg, 2.54 mmol, 2 equiv). The suspension was stirred for 24 h at 100 oC under N2. 50
mL of ethyl acetate was added and the suspension was filtered to remove the manganese. The organic layer was washed with aqueous
solutions of Na2S2O4 0.5M, NaHCO3 and brine, dried over MgSO4, filtered and concentrated under vacuum to afford the product as a colorless
oil (386 mg, 97%). 31P NMR (121.5 MHz, CDCl3):  = 30.7 (s); 1H NMR (300 MHz, CDCl3):  = 7.99-8.10 (m, 1H), 7.74-7.86 (m, 2H), 7.62-7.71
(m, 1H), 7.43-7.52 (m, 1H), 7.34-7.43 (m, 1H), 7.22-7.34 (m, 2H), 4.22-4.36 (m, 1H), 3.15-3.43 (m, 2H), 1.75-1.86 (m, 1H), 1.54-1.67 (m, 1H),
1.32-1.50 (m, 4H), 1.02-1.31 (m, 4H); 13C{1H} NMR (75.5 MHz, CDCl3):  = 140.7 (d, JPCCC = 7.7 Hz), 133.6 (d, JPCC = 10.3 Hz), 133.1, 131.0
(d, JPCC = 8.4 Hz), 130.3 (d, JPC = 111 Hz), 130.0 (d, JPCCCC = 3.6 Hz), 128.6 (2C), 128.0, 127.7 (d, JPCC = 10.8 Hz), 126.5, 126.2 (d, JPCCC = 9.1
Hz), 74.8 (d, JPOC = 3.8 Hz), 33.8, 33.1, 32.4 (d, JPC = 96.7 Hz), 24.9, 23.3, 23.2; HRMS (EI+) m/z calcd for C19H21O2P ([M]+) 312.1279, found
312.1275.
5-phenyl-5H-benzo[b]phosphoindole-5-oxide 44:22
To a solution of cyclohexyl 2-(biphenyl)-H-phosphinate12 (600 mg, 2 mmol, 1 equiv) in tetrahydrofuran (10 mL) was added slowly at 0 oC under
N2 a solution of phenyl magnesium bromide 1M in tetrahydrofuran (3 mL, 3 mmol, 1.5 equiv). The mixture was stirred for 12 hours at rt under
N2. A saturated solution of NH4Cl was added to neutralize the excess of phenyl magnesium bromide. The two layers were separated and the
organic layer was washed with NaHCO3 and brine, dried over MgSO4, filtered and concentrated under vacuum.The crude obtained was purified
by column chromatography (dichloromethane/acetone 100:0 to 95:5) to afford the product as a colorless oil (460 mg, 83%).13 31P NMR
(162MHz, CDCl3):  = 18.8 (d, J = 493 Hz).
To a suspension of Mn(OAc)2 (10.2 mg, 0.059 mmol, 5 mol%), MnO2 (308 mg, 3.54 mmol, 3 equiv) and sodium acetate (290 mg, 3.54 mmol,
0
3 equiv) in acetic acid (2.5 mL) at 70 C under N2 was added a solution of phenyl 2-(biphenyl)-H-phosphine oxide (400 mg, 1.18 mmol, 1
equiv) in acetic acid (2.5 mL) over 2 hours via a syringe pump. The reaction mixture was then stirred for an additional 2 hours at 70 0C under
N2. Ethyl acetate (50 mL) and a 0.2M aqueous solution of Na2S2O4 saturated with NaHCO3 (40 mL) were added. The suspension was stirred
vigorously for 10 minutes, filtered through celite and the two layers were separated. The organic layer was washed with a 0.2M aqueous
solution of Na2S2O4 saturated with NaHCO3 (40 mL), a saturated aqueous solution of NaHCO3 (40 mL) and brine (40 mL), dried over MgSO4,
filtered and concentrated under vacuum. The crude obtained was purified by column chromatography (dichloromethane/acetone 98:2 to 94:6)
to afford the product as a white solid (222 mg, 80%). Mp: 151-153 °C; 31P NMR (162 MHz, CDCl3):  = 33.8 (s); 1H NMR (400 MHz, CDCl3): 
= 7.77-7.83 (m, 2H), 7.60-7.73 (m, 4H), 7.51-7.58 (m, 2H), 7.42-7.49 (m, 1H), 7.30-7.39 (m, 4H); 13C{1H} NMR (101 MHz, CDCl3):  = 141.8
(d, JPCC = 21.8 Hz, 2C), 133.4 (d, JPCCCC = 1.1 Hz, 2C), 132.8 (d, JPC = 112 Hz, 2C), 132.2 (d, JPCCCC = 2.3 Hz), 131.2 (d, JPCC = 24.6 Hz, 2C),
130.8 (d, JPC = 104 Hz), 129.9 (d, JPCCC = 9.5 Hz, 2C), 129.5 (d, JPCCC = 11.0 Hz, 2C), 128.7 (d, JPCC = 12.5 Hz, 2C), 121.3 (d, JPCC = 9.9 Hz,
2C).
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1-phenyl-2-oxy-3-hydro-[4,5]phenyl-1-phosphinoline-1-oxide 45:
In a flask equipped with a Dean-Stark trap was introduced phenylphosphinic acid (2.84 g, 20 mmol, 1 equiv), 1-naphthylmethanol (6.33 g, 40
mmol, 2 equiv) and toluene (40 ml). After 16 hours at reflux under N2, the reaction was cooled down to rt and the solvent was concentrated
under vacuum. The residue obtained was dissolved in ethyl acetate and the organic layer was washed with NaHCO3 and brine, dried over
MgSO4, filtered and concentrated under vacuum. The crude obtained was purified by column chromatography (hexane/ethyl acetate 9:1 to
5:5) to afford the product as a white solid (4.37 g, 77%). 31P NMR (162 MHz, CDCl3):  = 24.6 (d, J = 566 Hz); 1H NMR (400 MHz, CDCl3):  =
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8.02-8.10 (m, 1H), 7.65-7.88 (m, 4H), 7.59 (d, J = 566 Hz, 1H), 7.32-7.56 (m, 6H), 5.44-5.62 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3):  =
133.7, 133.1 (d, JPCCCC = 2.6 Hz), 131.4, 131.0 (d, JPOCC = 6.5 Hz), 130.9 (d, JPCCC = 12.1 Hz, 2C), 129.8, 129.6 (d, JPC = 132 Hz), 128.8, 128.7
(d, JPCC = 13.7 Hz, 2C), 127.5, 126.8, 126.2, 125.3, 123.5, 65.7 (d, JPOC = 5.9 Hz); HRMS (EI+) m/z calcd for C17H16O2P ([M+H]+) 283.0882,
found 283.0884.
To a solution of 1-naphthylmethyl phenyl-H-phosphinate (282 mg, 1 mmol, 1 equiv) in acetic acid (5 mL) was added Mn(OAc)2 (8.7 mg, 0.05
mmol, 5 mol%), MnO2 (261 mg, 3 mmol, 3 equiv) and sodium acetate (246 mg, 3 mmol, 3 equiv). The suspension was stirred for 24 hours at
70 oC under N2. 50 mL of ethyl acetate was added and the suspension was filtered to remove the manganese. The organic layer was washed
with aqueous solutions of Na2S2O4 0.5M, NaHCO3 and brine, dried over MgSO4, filtered and concentrated under vacuum. The crude obtained
was purified by column chromatography (dichloromethane/acetone 100:0 to 90:10) to afford the product as a colorless oil (174 mg, 62%). 31
P
NMR (162 MHz, CDCl3):  = 28.1 (s); 1H NMR (400 MHz, CDCl3):  = 7.94-8.01 (m, 1H), 7.64-7.85 (m, 4H), 7.42-7.51 (m, 3H), 7.30-7.39 (m,
3H), 5.83-5.92 (m, 1H), 5.32-5.44 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3):  = 132.8 (d, JPCCCC = 2.6 Hz), 132.7, 132.6 (d, JPCCCC = 3.1 Hz),
132.0 (d, JPCCC = 10.6 Hz, 2C), 130.8 (d, JPCCC = 11.3 Hz), 130.2 (d, JPCCC = 7.5 Hz), 130.1 (d, JPOCC = 6.1 Hz), 130.0 (d, JPC = 143 Hz), 128.5
(d, JPCC = 13.8 Hz, 2C), 128.3, 126.1, 125.8 (d, JPCC = 15.3 Hz), 124.9 (d, JPC = 128 Hz), 123.5, 66.9 (d, JPOC = 6.8 Hz); HRMS (EI+) m/z calcd
for C17H13O2P ([M]+) 280.0653, found 280.0655.
1-phenyl-3,4-dihydronaphtho-[1,2-c]-[1,2]-oxaphosphinine-1-oxide and 1-phenyl-3,4-dihydronaphtho-[1,8-cd]-[1,2]-oxaphosphepine
1-oxide 46 and 47:
In a flask equipped with a Dean-Stark trap was introduced phenylphosphinic acid (1.42 g, 10 mmol, 1 equiv), 1-naphthalene ethanol (3.44 g,
20 mmol, 2 equiv) and toluene (20 ml). After 16 hours at reflux under N2, the reaction was cooled down to rt and the solvent was concentrated
under vacuum. The residue obtained was dissolved in ethyl acetate and washed with NaHCO3 and brine, dried over MgSO4, filtered and
concentrated under vacuum. The crude obtained was purified by column chromatography (hexane/ethyl acetate 9:1 to 5:5) to afford the product
as a colorless oil (2.72 g, 92%). 31P NMR (162 MHz, CDCl3):  = 25.4 (dm, J = 566 Hz); 1H NMR (400 MHz, CDCl3):  = 7.97-8.05 (m, 1H),
7.86-7.93 (m, 1H), 7.77-7.83 (m, 1H), 7.63-7.73 (m, 2H), 7.53 (d, J = 566 Hz, 1H), 7.38-7.61 (m, 7H), 4.36-4.52 (m, 2H), 3.55 (t, J = 7.0 Hz,
2H); 13C{1H} NMR (75.46 MHz, CDCl3):  = 133.8, 133.0 (d, JPCCCC = 2.9 Hz), 132.9, 131.9, 130.8 (d, JPCCC = 11.8 Hz, 2C), 129.6 (d, JPC = 131
Hz), 128.8, 128.6 (d, JPCC = 13.8 Hz, 2C), 127.6, 127.3, 126.2, 125.7, 125.5, 123.4, 65.6 (d, JPOC = 6.6 Hz), 34.0 (d, JPOCC = 6.1 Hz); HRMS
(EI+) m/z calcd for C18H18O2P ([M+H]+) 297.1044, found 297.1036.
To a solution of 2-[(1-naphthyl)ethyl] phenyl-H-phosphinate (296 mg, 1 mmol, 1 equiv) in acetic acid (5 mL) was added Mn(OAc)2 (8.7 mg, 0.05
mmol, 5 mol%), MnO2 (261 mg, 3 mmol, 3 equiv) and sodium acetate (246 mg, 3 mmol, 3 equiv). The suspension was stirred for 24 hours at
70 oC under N2. 50 mL of ethyl acetate was added and the suspension was filtered to remove the manganese. The organic layer was washed
with aqueous solutions of Na2S2O4 0.5M, NaHCO3 and brine, dried over MgSO4, filtered and concentrated under vacuum. The crude obtained
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The Journal of Organic Chemistry
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was purified by column chromatography (dichloromethane/acetone 100:0 to 90:10) to afford product 46 as a white solid (204 mg, 70%) and
product 47 as a white solid (87 mg, 30%).
For product 46: Mp = 165-166 0C; 31P NMR (162 MHz, CDCl3):  = 26.3 (s); 1H NMR (400 MHz, CDCl3):  = 8.02-8.09 (m, 1H), 7.73-7.87 (m,
4H), 7.55-7.67 (m, 3H), 7.45-7.52 (m, 1H), 7.36-7.43 (m, 2H), 4.82-4.93 (m, 1H), 4.61-4.74 (m, 1H), 3.46-3.64 (m, 2H); 13C{1H} NMR (101 MHz,
CDCl3):  = 139.5 (d, JPCCC = 5.3 Hz), 134.6 (d, JPCCCC = 2.0 Hz), 132.5 (d, JPCCCC = 2.7 Hz), 131.9 (d, JPCCC = 10.6 Hz, 2C), 131.1 (d, JPC = 144
Hz), 130.8 (d, JPCCC = 11.8 Hz), 129.0, 128.5 (d, JPCC = 13.6 Hz, 2C), 128.1, 127.9 (d, JPCC = 13.4 Hz), 127.3, 126.4 (d, JPCCC = 11.6 Hz), 125.0
(d, JPC = 125 Hz), 123.7, 63.8 (d, JPOC = 5.9 Hz), 27.7 (d, JPOCC = 6.1 Hz); HRMS (EI+) m/z calcd for C18H15O2P ([M]+) 294.0810, found 294.0805.
For product 47: Mp = 141-142 0C; 31P NMR (162 MHz, CDCl3):  = 37.3 (s); 1H NMR (400 MHz, CDCl3):  = 7.93-7.98 (m, 1H), 7.81-7.90 (m,
3H), 7.57-7.64 (m, 1H), 7.46-7.56 (m, 4H), 7.30-7.42 (m, 2H), 4.85-4.93 (m, 1H), 4.73-4.84 (m, 1H), 4.43-4.56 (m, 1H), 3.21-3.31 (m, 1H);
13C{1H} NMR (101 MHz, CDCl3):  = 136.9 (d, JPCCCC = 3.1 Hz), 134.3 (d, JPCC = 10.3 Hz), 134.0 (d, JPCC = 14.8 Hz), 133.5 (d, JPCCC = 7.1 Hz),
132.7 (d, JPCCCC = 3.1 Hz), 132.4 (d, JPCCC = 4.7 Hz), 132.3 (d, JPCCC = 9.7 Hz, 2C), 131.9 (d, JPC = 148 Hz), 131.6 (d, JPC = 121 Hz), 129.7,
128.6 (d, JPCCCCC = 1.0 Hz), 128.3 (d, JPCC = 13.5 Hz, 2C), 126.3, 124.2 (d, JPCC = 16.9 Hz), 69.6 (d, JPOC = 5.9 Hz), 37.9 (d, JPOCC = 3.6 Hz);
HRMS (EI+) m/z calcd for C18H15O2P ([M]+) 294.0810, found 294.0810.
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1-phenyl-2-oxy-3,4-dihydro-1-phosphinoline-1-oxide 49a:18
In a flask equipped with a Dean-Stark trap was introduced phenylphosphinic acid (3.55 g, 25 mmol, 1 equiv), cyclohexanol (6.11 ml, 50 mmol,
2 equiv) and toluene (50 ml). After 16h at reflux under N2, the reaction was cooled down to rt and the solvent was concentrated under vacuum.
The residue obtained was dissolved in ethyl acetate and washed with NaHCO3 and brine, dried over MgSO4, filtered and concentrated under
vacuum. The crude obtained was purified by column chromatography (hexane/ethyl acetate 9:1 to 5:5) to afford product 48a as a colorless oil
(5.25 g, 85%).
To a solution of 2-phenylethyl phenyl-H-phosphinate (246 mg, 1 mmol, 1 equiv) in acetic acid (5 mL) was added Mn(OAc)3.2H2O (536 mg, 2
mmol, 2 equiv) and sodium acetate (164 mg, 2 mmol, 2 equiv). The suspension was stirred for 24 h at 100 oC under N2. 100 mL of ethyl acetate
was added and the suspension was filtered to remove the manganese. The organic layer was washed with aqueous solutions of Na2S2O4
0.5M, NaHCO3 and brine, dried over MgSO4, filtered and concentrated under vacuum. The crude obtained was purified by column
chromatography (hexane/ethyl acetate 8:2 to 5:5) to afford the product as a white solid (189 mg, 78%).
1-phenyl-2-oxy-3,4-dihydro-1-phosphinoline-1-oxide 49a:18
To a suspension of Mn(OAc)2 (43.3 mg, 0.25 mmol, 5 mol%), MnO2 (1.31 g, 15 mmol, 3 equiv) and sodium acetate (1.23 g, 15 mmol, 3 equiv)
in acetic acid (15 mL) at 70 0C under N2 was added a solution of 2-phenylethyl phenyl-H-phosphinate (1.23 g, 5 mmol, 1 equiv) in acetic acid
(10 mL) over 2 h via a syringe pump. The reaction mixture was then stirred for an additional 2h at 700C under N2. Ethyl acetate (100 mL) and
a 0.2M aqueous solution of Na2S2O4 saturated with NaHCO3 (100 mL) were added. The suspension was stirred vigorously for 10 minutes,
filtered through celite and the two layers were separated. The organic layer was washed with a 0.2M aqueous solution of Na2S2O4 saturated
with NaHCO3 (100 mL), a saturated aqueous solution of NaHCO3 (100 mL) and brine (100 mL), dried over MgSO4, filtered and concentrated
under vacuum. The crude obtained was purified by column chromatography (hexane/ethyl acetate 8:2 to 5:5) to afford the product as a white
solid (1.0 g, 82%).
1-(2-phenylethyl)-3,4-tetrahydro-1-phosphonoline-1-oxide 49b:18
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