Palladium-catalyzed allylation/benzylation of H-phosphinate esters with alcohols

Article abstract of DOI:10.3390/molecules21101295

The Pd-catalyzed direct alkylation of H-phosphinic acids and hypophosphorous acid with allylic/benzylic alcohols has been described previously. Here, the extension of this methodology to H-phosphinate esters is presented. The new reaction appears general,

Full text of DOI:10.3390/molecules21101295

molecules
Article
Palladium-Catalyzed Allylation/Benzylation of
H-Phosphinate Esters with Alcohols
Anthony Fers-Lidou, Olivier Berger and Jean-Luc Montchamp *
Department of Chemistry and Biochemistry, TCU Box 298860, Texas Christian University, Fort Worth,
TX 76129, USA; a.fers-lidou@outlook.fr (A.F.-L.); o.berger@tcu.edu (O.B.)
* Correspondence: j.montchamp@tcu.edu; Tel.: +1-817-257-5851
Academic Editor: György Keglevich
Received: 10 September 2016; Accepted: 19 September 2016; Published: 28 September 2016
Abstract: The Pd-catalyzed direct alkylation of H-phosphinic acids and hypophosphorous acid with
allylic/benzylic alcohols has been described previously. Here, the extension of this methodology to
H-phosphinate esters is presented. The new reaction appears general, although its scope is narrower
than with the acids, and its mechanism is likely different. Various alcohols are examined in their
reaction with phosphinylidene compounds R1R2P(O)H.
Keywords: palladium; cross-coupling; alcohols; H-phosphinate esters; allylation; benzylation
1. Introduction
In the classic Pd-catalyzed Tsuji-Trost reaction, the allylic electrophile is an alcohol derivative
(most often the acetate) and numerous nucleophiles can be employed easily [
1]. More recently,
the use of allylic alcohols has emerged [ ]. Using alcohols for the direct allylation of nucleophiles is
1,2
desirable because water is the only byproduct. In the context of carbon-phosphorus bond-formation,
we disclosed 10 years ago the reaction between hypophosphorous acid (HPA) and allylic alcohols
catalyzed by Pd to directly afford the corresponding allylic H-phosphinic acids (Scheme 1a) [
The reaction was subsequently extended to include H-phosphinic acids instead of HPA to form
disubstituted phosphinic acids under slightly more forcing conditions (Scheme 1b) [ ]. Around the
same time, we also described the benzylation of HPA and H-phosphinic acids with benzylic alcohols
under similar conditions (Scheme 1c) [ ]. These reactions were discovered based on mechanistic
reasoning that was supported by model studies [ ]. It was thought that the reaction required a PO2H
3].
4
5
6
motif for Fisher esterification and tautomerization. More recently, we decided to reexamine this type
of reaction, but using H-phosphinic esters as starting materials, and were surprised to observe a
successful allylation, suggesting that a different mechanism could be operative. This manuscript
describes these findings (Scheme 1d).
2. Results and Discussion
Based on our prior work in this area, we selected cinnamyl alcohol and butyl
phenyl-H-phosphinate in equimolar amounts as the reacting partners for the initial investigation
(Table 1). Cinnamyl alcohol was identified previously as a very reactive partner in our Pd-catalyzed
allylation [3–6]. Additionally, based on our prior findings, t-amyl alcohol was selected as
the solvent for the azeotropic removal of the water byproduct (reflux, Dean-Stark trap) [4,5]
.
Using palladium acetate as the catalyst, and without added ligand, the reaction failed to
produce any detectable amount of product (entry 1). As we had found in our other couplings,
Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) performed superbly affording the
desired product in nearly quantitative isolated yield (entry 2). Switching the solvent to toluene (still
with a Dean-Stark trap) gave a satisfactory yield, albeit lower (entry 3). This was not entirely unexpected
Molecules 2016, 21, 1295; doi:10.3390/molecules21101295
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as t-amyl alcohol was initially identified for its ability to promote P(V) to P(III) tautomerization through
hydrogen-bonding. Changing the salt from palladium acetate to palladium chloride resulted in a
slightly lower yield (entry 4 vs. 2). On the other hand, tris(dibenzylideneacetone)dipalladium(0)
(Pd2(dba)3) (as we had done in most of our prior work on allylation/benzylation) also gave a nearly
quantitative yield of product (entry 5). Using 1,1’-bis(diphenylphosphino)ferrocene (Dppf) as the
ligand did afford the desired product, but in significantly lower yield (entry 6). Thus, the results
shown in Table 1 confirmed the catalyst system we had identified earlier for the cross-coupling of
phosphinic acids.
Scheme 1. Carbon-phosphorus bond formation by allylation/benzylation with alcohols. Xantphos,
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; MS, molecular sieves; t-AmOH, t-amyl alcohol.
Table 1. Test reaction between butyl phenyl-H-phosphinate and cinnamyl alcohol.
◦
Yield (%) b
Entry
Solvent a
Temp. ( C) a
Pd Salt (mol %)
Ligand (mol %)
1
2
3
4
5
6
t-AmOH
t-AmOH
toluene
t-AmOH
t-AmOH
t-AmOH
102
102
111
102
102
102
Pd(OAc)2 (2)
Pd(OAc)2 (2)
Pd(OAc)2 (2)
PdCl2 (2)
None (-)
0 c
99
88
90
99
67
Xantphos (2) d
Xantphos (2) d
Xantphos (2) d
Xantphos (2) d
Dppf (2) f
Pd2(dba)3 (1) e
Pd2(dba)3 (1) e
a
Reflux, Dean-Stark trap; b Isolated yield after column chromatography over silica gel (Note: the 31P-NMR
yield of the crude before purification is comparable); No product in the 31P-NMR spectrum; Xantphos,
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; e Pd2(dba)3, tris(dibenzylideneacetone)dipalladium(0); dba,
dibenzylideneacetone; f Dppf, 1,1’-bis(diphenylphosphino)ferrocene.
c
d

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Next, the scope of the allylation with cinnamyl alcohol was investigated with a variety of
phosphinylidene compounds (Table 2). Not surprisingly, changing the ester group from n-butyl
to cyclohexyl gave a good result (entry 2), while a benzyl ester gave a lower yield (entry 3), presumably
because of competing transesterification. The less reactive cyclohexyl-octyl-H-phosphinate [7]
reacted uneventfully (entry 4), while butyl cinnamyl-H-phosphinate afforded a quantitative yield
of butyl bis(cinnamyl)phosphinate (entry 5). Other functionalized H-phosphinate esters were
tested (entries 6–9) giving generally good results. However, the Ciba-Geigy reagent (entry 10)
was unsatisfactory. The acetal moiety is acid sensitive and this result may point out to the
presence of acidic species along the reaction coordinates. The rather special H-phosphinate DOPO
5]oxaphosphinine 6-oxide) [
(6H-dibenzo[c,e][1,2λ 7] gave an excellent yield of product (entry 11).
Other types of phosphinylidene were tested: diethyl H-phosphonate and diphenyl phosphine oxide
both afforded the desired products in excellent yields (entries 12–13).
Table 2. Allylation of various phosphinylidene compounds with cinnamyl alcohol.
Entry
R1
R2
Isolated Yield (%) a
1
2
3
Ph
Ph
Ph
OBu
OCy
OBn
99
91
77
4
Oct
OCy
87
5
6
7
8
PhCH=CHCH2 (Cin)
4-MeOC6H4CH2CH2
PhtNCH2CH2
AcOCH2
HOCH2
OBu
OBu
OBu
100
70
100
77
OBu
OMen b,c
OEt
9
91
47 d,e
96
10
11
12
13
MeC(OEt)2
DOPO f
OEt
OEt
Ph
94
92
Ph
a
Isolated yield after column chromatography over silica gel. Unless otherwise noted, the palladium salt is
Pd2(dba)3 (1 mol %); b Men, ( )-menthyl; c 50:50 diastereoisomeric mixture; d Pd(OAc)2 (2 mol %) was used;
−
e 31P-NMR yield; f DOPO, 6H-dibenzo[c,e][1,2λ5]oxaphosphinine 6-oxide.
Whereas the cinnamyl moiety is a versatile functional group and its introduction appears quite
general (Table 2), we next examined other allylic alcohols as well as benzylic alcohols. The results are
gathered in Table 3.

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Table 3. Allylation and benzylation of various phosphinylidene compounds.
Entry
Phosphorus P(O)H Compound
Alcohol
Product
Isolated Yield (%) a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
PhP(O)(OBu)H
PhP(O)(OCy)H
CinP(O)(OBu)H
PhP(O)(OCy)H
CinP(O)(OBu)H
CinP(O)(OBu)H
PhP(O)(OBu)H
OctP(O)(OCy)H
CinP(O)(OBu)H
PhP(O)(OCy)H
CinP(O)(OBu)H
OctP(O)(OCy)H
OctP(O)(OBn)H
(EtO)2P(O)H
H2C=CHCH2OH (2 equiv.)
H2C=CHCH2OH (2 equiv.)
H2C=CHCH2OH (2 equiv.)
PhP(O)(OBu)CH2CH=CH2
PhP(O)(OCy)CH2CH=CH2
CinP(O)(OBu)CH2CH=CH2
98
94
91
93
77
51
74
65
57
2-Methyl-3-phenyl-2-propen-1-ol (1 equiv.) PhP(O)(OCy)CH2C(Me)=CHPh
2-Methyl-3-phenyl-2-propen-1-ol (1 equiv.) CinP(O)(OBu)CH2C(Me)=CHPh
Methallyl alcohol (1 equiv.)
Myrtenol (1 equiv.)
CinP(O)(OBu)CH2C(Me)=CH2
PhP(O)(OBu)C10H15
PhCH2OH (1 equiv.)
PhCH2OH (1 equiv.)
1-NpCH2OH (5 equiv.)
1-NpCH2OH (1 equiv.)
Furfuryl alcohol (2 equiv.)
PhCH2OH (1 equiv.)
PhCH2OH (2 equiv.)
OctP(O)(OCy)CH2Ph
CinP(O)(OBu)CH2Ph
PhP(O)(OCy)CH2-1-Np
CinP(O)(OBu)CH2-1-Np
OctP(O)(OCy)CH2(OC4H3)
OctP(O)(OBn)CH2Ph
(EtO)2P(O)CH2Ph
73
49
24 b
18 b
23 b
a
Isolated yield after column chromatography over silica gel. The palladium salt is Pd2(dba)3 (1 mol %); b 31P-NMR yield.

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Reactions with the simple allyl alcohol (2 equiv.) gave excellent results (>90% isolated
yield) as shown in entries 1–3. The 2-methyl substituted version of cinnamyl alcohol,
2-methyl-3-phenyl-2-propen-1-ol (1 equiv.) also gave satisfactory results (entries 4–5). Methallyl
alcohol, on the other hand, gave only a moderate yield of product (entry 6), but this result was
not unexpected, as this alcohol also had given poor results with HPA [3]. Myrtenol also reacted
successfully (entry 7). Next, the benzylation was investigated (entries 8–11) and products were
obtained in moderate to good yields. Unfortunately, some other combinations of reactants did not
afford the desired product in acceptable yields (for example: entries 12–14), thereby showing some
limitations in scope. Electron-rich furfuryl alcohol (entry 12) may lead to slow oxidative-addition
and an overall inefficient transformation. Acid sensitivity may become an issue: while this alcohol
was successful with hypophosphorous acid [5], the more difficult the desired reaction, the more side
reactions will be competing. Perhaps for a similar reason, none of the secondary allylic alcohols we
tried reacted successfully. In entry 13, transesterification of the benzyl ester is a greater problem than it
was in entry 8 because the reaction is slower than with cinnamyl alcohol (Table 2, entry 4). Similarly,
diethyl H-phosphonate, which reacted satisfactorily with cinnamyl alcohol (Table 2, entry 12) also gave
little product with benzyl alcohol (entry 14). Thus, marginal results are obtained when the reaction
is slowed due to any of the following parameters (or combinations): less reactive allylic/benzylic
electrophile (aromatics, of course, being much less reactive than alkenes), unfavorable tautomerization
profile [7], transesterification of the phosphorus ester, or acid sensitivity of a reactant.
Although the scope of this reaction seems more limited than the corresponding reaction
of phosphinic acids, it can offer significant synthetic advantages. Since disubstituted phosphinic
acids cannot be esterified easily through Fischer-like reactions with azeotropic water-removal [8,9],
formation of their esters requires prior activation of the acid (P(O)OH to P(O)LVG + ROH, P(O)OH to
P(O)(OAg) + RX, where LVG is a leaving group and RX an alkyl halide) or a diazoalkane. Therefore,
the intermediacy of disubstituted phosphinic acids implies atom-wasteful procedures (Scheme 2).
On the other hand, H-phosphinic acids can be esterified easily with an alcohol and, therefore,
the resulting synthetic sequence is more convenient and environmentally friendly (Scheme 2).
Scheme 2. H-phosphinic acids versus H-phosphinic esters.1 SOCl2 then ROH; carbodiimide + ROH;
RCHN2; R1COCl then ROH; Ag2O then alkyl halide (RX), etc.
An illustrative example is shown in Scheme 3 for the preparation of 3-phospholenic esters.
The “classic” approach is illustrated by Miokowski’s work (Scheme 3a) [10]. The double allylation of
bis-(trimethylsiloxy)phosphine afforded the symmetrical phosphinic acid. Subsequent esterification via
P(O)Cl then provided the benzyl ester, which was converted to the phospholene ester by ring-closing
metathesis (RCM). It should be noted that the attempted RCM reaction of diallylphosphinic acid failed
completely. The overall sequence produced the phospholene in 31% isolated yield.

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Scheme 3. Comparison of methods for the synthesis of 3-phospholenic esters. HMDS:
hexamethyldisilazane; IMes: 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene.
Next, our allylation methodology was used to produce bis(cinnamyl)phosphinic acid in
quantitative yield [4]. Silver-promoted esterification gave the corresponding benzyl ester in 77%
yield. Ring-closing metathesis afforded the desired heterocycle in 51% isolated yield. The moderate
yield of this reaction may be attributed to the fact that both alkenes are substituted. In spite of this,
the overall sequence gave the phospholene derivative in 39% yield.
Cinnamyl-H-phosphinic acid is easily synthesized, as we reported [11]. Low loading of Pd
(0.5 mol %) can be employed to still deliver a very high 95% yield (Scheme 2c) [3]. Esterification with
n-butanol under Dean-Stark conditions proceeded in 96% yield. The present allylation reaction (Table 3,
entry 3) gave the disubstituted ester in 91% yield (Scheme 2c, in box). Subsequent RCM afforded the
phospholene in 85% yield. Overall, the sequence in Scheme 3c produced the phospholene derivative
in four steps and 70% overall yield, through catalytic reactions and with only water as the byproduct.
An alternative using our silicate esterification [9] directly gives butyl cinnamyl-H-phosphinate from
cinnamyl alcohol in 98% isolated yield [ ]. Using this sequence, the phospholenic acid is still produced
6
inexpensively in an outstanding 76% overall yield.
In addition to the advantages of Dean-Stark processes over the use of wasteful stoichiometric
reagents, the present allylation of H-phosphinate esters can offer unique opportunities. For example
(Scheme 4), the cinnamylation of optically-active menthyl hydroxymethyl-H-phosphinate proceeds
with complete stereoselectivity in a nearly quantitative isolated yield [12].
Scheme 4. Stereospecific cinnamylation. Men: (−)-menthyl.

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Mechanistically, the present reaction must proceed through a pathway different from the one we
have proposed for the allylation of phosphinic acids [ ]. Scheme 5 shows a proposed mechanism for
6
the Pd-catalyzed allylation/benzylation of H-phosphinate esters.
Scheme 5. Proposed Mechanisms for the allylation of H-phosphinate esters (top) and phosphinic
acids (bottom).
The key difference between the two mechanisms (Scheme 5) is in the order of tautomerization
and esterification. H-phosphinic esters are not esterified to the P(III) phosphonite under Dean-Stark
conditions. Furthermore, while transesterification is possible in principle, this reaction is inefficient
(in the absence of catalysts, particularly bases) and very difficult on esters like cyclohexyl. This would
also result in the formation of disubstituted phosphinic acids. The fact that the reaction takes place
with Pd(0) complexes but not with Pd(II) (Table 1) also points to a mechanism in which Lewis acidity
is not key. Given those facts and some of the limitations in the scope discussed earlier, we propose the
following (Scheme 5, top): the H-phosphinate ester must tautomerize to the P(III) form, which can then
act as a ligand to the Pd(0) catalyst. The resulting putative intermediate would be sufficiently acidic to
undergo Fischer-like esterification (with water being removed azeotropically). The esterification of the
phosphinite-Pd complex would be a key step. The resulting Pd complex of the mixed phosphonite
ester would then undergo oxidative addition (allylO to allylPd migration) to produce the classic Pd(II)
intermediate in the Tsuji-Trost reaction. Subsequent formation of a π-allyl complex and attack of the
phosphorus nucleophile would afford the allylated product with concomitant reductive elimination to
regenerate the Pd(0) catalyst.
In the case of phosphinic acids (HPA or H-phosphinic, Scheme 5, bottom), first esterification
to produce the allyl ester takes place in a well-established process. Tautomerization of the
allyl-H-phosphinate ester leads to a phosphonite, which then complexes the Pd(0). Oxidative addition
in this complex produces the same type of Pd(II) intermediate (R = H). The mechanism of phosphinic
acid allylation (Scheme 5, bottom) is fully consistent with all our prior results [6]. Overall, the success
or failure of the allylation depends on various parameters, like the tautomeric equilibrium of the
phosphinylidene species, the nucleophilicity of the P(III) tautomer to complex the Pd, and the reactivity
of the allylic/benzylic moiety towards oxidative addition.

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3. Materials and Methods
3.1. General Procedure for the Allylation/Benzylation of H-Phosphinates and Related Compounds
To a solution of the appropriate H-phosphinate ester (1 equiv.) in t-amyl alcohol (10 mL),
tris(dibenzylideneacetone)dipalladium(0) Pd2(dba)3 (1 mol %), Xantphos (2 mol %), and the
corresponding alcohol (1 equiv.) were added. The reaction mixture was stirred at reflux for 24 h
under N2 in a flask equipped with a Dean-Stark trap. After cooling down the reaction to room
temperature (rt), the solvent was removed under vacuum and the residue obtained was purified by
column chromatography on silica gel using a mixture of hexane/ethyl acetate to afford the different
products. The NMR spectra of the products can be found in the Supplementary Materials.
Butyl cinnamyl phenylphosphinate (Table 2, Entry 1) [13]. General procedure was used with cinnamyl
alcohol (0.13 mL, 1 mmol, 1 equiv.) and butyl phenyl-H-phosphinate (198 mg, 1 mmol, 1 equiv.).
The crude obtained was purified by column chromatography (hexane/ethyl acetate 100:0 to 0:100) to
afford the product as a yellow oil (310 mg, 99%). 31P-NMR (CDCl3, 162 MHz)
δ
= 39.1 (s); 1H-NMR
= 7.73–7.80 (m, 2H), 7.47–7.54 (m, 1H), 7.40–7.46 (m, 2H), 7.21–7.27 (m, 4H),
(CDCl3, 400 MHz)
δ
7.14–7.20 (m, 1H), 6.33 (dd, J = 5.0 and 15.8 Hz, 1H), 6.04–6.15 (m, 1H), 3.93 (dm, J = 95 Hz, 2H), 2.89
(dd, J = 7.6 and 18.5 Hz, 2H), 1.63 (quint., J = 6.8 Hz, 2H), 1.37 (dsextuplet, J = 1.7 and 7.5 Hz, 2H), 0.87
(t, J = 7.4 Hz, 3H).
Cyclohexyl cinnamyl phenylphosphinate (Table 2, Entry 2). General procedure was used with cinnamyl
alcohol (0.13 mL, 1 mmol, 1 equiv.) and cyclohexyl phenyl-H-phosphinate (224 mg, 1 mmol, 1 equiv.).
The crude obtained was purified by column chromatography (hexane/ethyl acetate 100:0 to 0:100) to
afford the product as a yellow oil (311 mg, 91%). 31P-NMR (CDCl3, 162 MHz)
δ
= 37.7 (s); 1H-NMR
= 7.76–7.84 (m, 2H), 7.49–7.55 (m, 1H), 7.41–7.47 (m, 2H), 7.23–7.30 (m, 4H),
(CDCl3, 400 MHz)
δ
7.16–7.22 (m, 1H), 6.35 (dd, J = 5.0 and 15.8 Hz, 1H), 6.06–6.17 (m, 1H), 4.30–4.41 (m, 1H), 2.89
(ddd, J = 1.0, 7.6 and 18.4 Hz, 2H), 1.97–2.07 (m, 1H), 1.57–1.79 (m, 4H), 1.39–1.52 (m, 2H), 1.15–1.36
(m, 3H); 13C-NMR (101 MHz, CDCl3):
132.2 (d,
δ
= 137.0 (d, JPCCCC = 3.3 Hz), 134.9 (d, JPCC = 13.2 Hz),
J
PCCCC = 2.7 Hz), 131.7 (d, JPCCC = 9.6 Hz, 2C), 131.5 (d, JPC = 128 Hz), 128.5 (2C), 128.4
(d, JPCC = 12.5 Hz, 2C), 127.4, 126.1, 126.1, 118.9 (d, JPCCC = 10.3 Hz), 74.7 (d, JPOC = 6.9 Hz), 35.9
(d, JPC = 97.3 Hz), 34.2 (d, JPOCC = 2.9 Hz), 33.7 (d, JPOC = 4.1 Hz), 25.1, 23.6, 23.6; HRMS (EI+) m/z
calcd for C21H26O2P ([M + H]+) 341.1665, found 341.1675.
Benzyl cinnamyl phenylphosphinate (Table 2, Entry 3). General procedure was used with cinnamyl alcohol
(0.13 mL, 1 mmol, 1 equiv.) and benzyl phenyl-H-phosphinate (232 mg, 1 mmol, 1 equiv.). The crude
obtained was purified by column chromatography (hexane/ethyl acetate 100:0 to 0:100) to afford the
product as an orange oil (248 mg, 71%). 31P-NMR (CDCl3, 162 MHz)
400 MHz)
δ
= 41.4 (s); 1H-NMR (CDCl3,
= 7.80–7.87 (m, 2H), 7.54–7.60 (m, 1H), 7.45–7.52 (m, 2H), 7.31–7.40 (m, 5H), 7.26–7.31
δ
(m, 4H), 7.20–7.25 (m, 1H), 6.38 (dd, J = 5.2 and 15.9 Hz, 1H), 6.08–6.19 (m, 1H), 5.18 (dd, J = 7.3 and
11.8 Hz, 1H), 4.88 (dd, J = 7.2 and 11.8 Hz, 1H), 2.99 (dd, J = 7.6 and 18.7 Hz, 2H); 13C-NMR (101 MHz,
CDCl3):
(d, PCCCC = 2.5 Hz), 131.9 (d, JPCCC = 9.7 Hz, 2C), 130.1 (d,
2C), 128.6 (2C), 128.5 (2C), 128.4, 127.9 (2C), 127.6, 126.3, 126.2, 118.4 (d, JPCCC = 10.4 Hz), 66.3
(d,
POC = 6.4 Hz), 35.3 (d, JPC = 96.3 Hz); HRMS (EI+) m/z calcd for C22H22O2P ([M + H]+) 349.1357,
δ
= 136.9 (d, JPCCCC = 3.5 Hz), 136.4 (d, JPOCC = 6.8 Hz), 135.3 (d, JPCC = 13.3 Hz), 132.6
J
J
PC = 125 Hz), 128.7 (d, JPCC = 12.3 Hz
,
J
found 349.1379.
Cyclohexyl cinnamyl octylphosphinate (Table 2, Entry 4). General procedure was used with cinnamyl
alcohol (0.13 mL, 1 mmol, 1 equiv.) and cyclohexyl octyl-H-phosphinate (260 mg, 1 mmol, 1 equiv.).
The crude obtained was purified by column chromatography (hexane/ethyl acetate 50:50 to 0:100) to
afford the product as an orange oil (328 mg, 87%). 31P-NMR (CDCl3, 162 MHz)
δ
= 51.6 (s); 1H-NMR
= 7.24–7.35 (m, 4H), 7.16–7.22 (m, 1H), 6.47 (dd, J = 4.5 and 15.8 Hz, 1H), 6.10–6.22
(CDCl3, 400 MHz)
δ

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(m, 1H), 4.34–4.46 (m, 1H), 2.71 (dd, J = 7.7 and 17.3 Hz, 2H), 1.83–1.94 (m, 2H), 1.42–1.75 (m, 8H),
1.15–1.37 (m, 14 H), 0.84 (t, J = 6.8 Hz, 3 H); 13C-NMR (101 MHz, CDCl3):
= 136.8 (d, PCCCC = 3.0 Hz),
δ
J
134.4 (d, JPCC = 12.6 Hz), 128.5 (2C), 127.5, 126.1, 126.1, 119.7 (d, JPCCC = 9.4 Hz), 73.7 (d, JPOC = 7.0 Hz),
34.6 (d, JPC = 82.2 Hz), 34.2 (d, JPOCC = 5.6 Hz), 34.1, 31.8, 30.8 (d, JPCC = 15.1 Hz), 29.0, 29.0, 28.3 (d,
J
PC = 93.1 Hz), 25.2, 23.7 (2C), 22.6, 21.6 (d, JPCCC = 4.2 Hz), 14.1; HRMS (EI+) m/z calcd for C23H38O2P
([M + H]+) 377.2609, found 377.2531.
Butyl bis cinnamylphosphinate (Table 2, Entry 5). General procedure was used with cinnamyl alcohol
(0.13 mL, 1 mmol, 1 equiv.) and butyl cinnamyl-H-phosphinate (238 mg, 1 mmol, 1 equiv.). The crude
obtained was purified by column chromatography (hexane/ethyl acetate 50:50 to 0:100) to afford the
product as an orange oil (354 mg, 100%). 31P-NMR (CDCl3, 162 MHz)
400 MHz)
2H), 4.02 (dt, J = 6.8 and 7.0 Hz, 2H), 2.73 (dd, J = 7.6 and 17.5 Hz, 4H), 1.61 (quint., J = 7.2 Hz, 2H),
1.36 (sextuplet, J = 7.5 Hz, 2H), 0.88 (t, J = 7.4 Hz, 3H); 13C-NMR (101 MHz, CDCl3):
= 136.7 (d,
PCCCC = 3.0 Hz, 2C), 135.0 (d, JPCC = 13.1 Hz, 2C), 128.6 (4C), 127.7 (2C), 126.2 (2C), 126.2 (2C), 118.9
δ
= 49.9 (s); 1H-NMR (CDCl3,
δ
= 7.21–7.33 (m, 8H), 7.14–7.20 (m, 2H), 6.45 (dd, J = 4.6 and 15.8 Hz, 2H), 6.11–6.22 (m,
δ
J
(d, JPCCC = 9.6 Hz, 2C), 64.6 (d, JPOC = 7.2 Hz), 33.3 (d, JPC = 88.7 Hz, 2C), 32.8 (d, JPOCC = 5.6 Hz), 18.8,
13.7; HRMS (EI+) m/z calcd for C22H28O2P ([M + H]+) 355.1827, found 355.1831.
Butyl 2-[(4-methoxyphenyl)ethyl] cinnamylphosphinate (Table 2, Entry 6). General procedure was used with
cinnamyl alcohol (0.13 mL, 1 mmol, 1 equiv.) and butyl 2-[4-methoxyphenyl)ethyl]-H-phosphinate
(256 mg, 1 mmol, 1 equiv.). The crude obtained was purified by column chromatography (hexane/ethyl
acetate 100:0 to 0:100) to afford the product as an orange oil (261 mg, 70%). 31P-NMR (CDCl3, 162 MHz)
δ
= 52.3 (s); 1H-NMR (CDCl3, 400 MHz)
δ = 7.29–7.38 (m, 4H), 7.22–7.28 (m, 1H), 7.10–7.15 (m, 2H),
6.81–6.87 (m, 2H), 6.45 (dd, J = 4.6 and 15.8 Hz, 1H), 6.11–6.22 (m, 1H), 4.06 (dt, J = 6.6 and 6.7 Hz, 2H),
3.78 (s, 3H), 2.83–2.99 (m, 2H), 2.73 (ddd, J = 0.7, 7.2 and 16.8 Hz, 2H), 2.01–2.12 (m, 2H), 1.68 (quint.,
J = 7.5 Hz, 2H), 1.43 (sextuplet, J = 7.5 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H); 13C-NMR (101 MHz, CDCl3):
δ
= 158.2, 136.7 (d, JPCCCC = 3.2 Hz), 134.8 (d, JPCCC = 12.9 Hz), 133.0 (d, JPCC = 14.6 Hz), 129.1 (2C),
128.6 (2C), 127.7, 126.2, 126.2, 119.1 (d, JPCCC = 9.4 Hz, 2C), 114.0 (2C), 64.4 (d, JPOC = 7.0 Hz), 55.3, 34.0
(d, JPC = 86.0 Hz), 32.8 (d, JPOCC = 5.7 Hz), 29.7 (d, JPC = 90.4 Hz), 27.0 (d, JPCC = 3.5 Hz), 18.9, 13.7;
HRMS (EI+) m/z calcd for C22H29O3P ([M + H]+) 373.1933, found 373.1855.
Butyl (2-ethylphthalimide) cinnamylphosphinate (Table 2, Entry 7). General procedure was used with
cinnamyl alcohol (1.7 mL, 12.94 mmol, 1 equiv.) and butyl (2-ethylphthalimide)-H-phosphinate
(3.3 g, 12.94 mmol, 1 equiv.). The crude obtained was purified by column chromatography
(dichloromethane/acetone 100:0 to 90:10) to afford the product as an orange oil (4.87 g, 100%).
31P-NMR (CDCl3, 162 MHz) δ = 49.1 (s); 1H-NMR (CDCl3, 400 MHz) δ = 7.82–7.90 (m, 2H), 7.68–7.75
(m, 2H), 7.20–7.44 (m, 5H), 6.62 (dd, J = 4.7 and 15.8 Hz, 1H), 6.16–6.27 (m, 1H), 3.95–4.12 (m, 4H),
2.88 (dd, J = 7.5 and 17.5 Hz, 2H), 2.17–2.34 (m, 2H), 1.58 (quint., J = 7.1 Hz, 2H), 1.35 (sextuplet,
J = 7.4 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H); 13C-NMR (101 MHz, CDCl3):
JPCCCC 3.2 Hz), 135.3 (d, PCC = 13.1 Hz), 134.1 (2C), 132.0 (2C), 128.6 (2C), 127.7, 126.3, 126.3, 123.4
δ = 167.8 (2C), 136.6 (d,
=
J
(2C), 118.5 (d, JPCCC = 9.6 Hz), 64.6 (d, JPOC = 7.0 Hz), 33.7 (d, JPC = 88.4 Hz), 32.6 (d, JPCC = 5.9 Hz),
31.7, 26.5 (d, JPC = 89.7 Hz), 18.8, 13.6; HRMS (EI+) m/z calcd for C23H27NO4P ([M + H]+) 412.1678,
found 412.1676.
Butyl (acetoxymethyl) cinnamylphosphinate (Table 2, Entry 8). General procedure was used with cinnamyl
alcohol (0.13 mL, 1 mmol, 1 equiv.) and butyl (acetoxymethyl)-H-phosphinate (194 mg, 1 mmol,
1 equiv.). The crude obtained was purified by column chromatography (hexane/ethyl acetate 100:0 to
0:100) to afford the product as an orange oil (239 mg, 77%). 31P-NMR (CDCl3, 162 MHz) δ = 43.6 (s)
;
1H-NMR (CDCl3, 400 MHz)
δ = 7.27–7.32 (m, 2H), 7.21–7.27 (m, 2H), 7.14–7.20 (m, 1H), 6.50 (dd, J = 5.0
and 15.9 Hz, 1H), 6.06–6.17 (m, 1H), 4.43 (dd, J = 7.8 and 14.5 Hz, 1H), 4.27 (dd, J = 4.2 and 14.5 Hz, 1H),
4.03 (dm, J = 39.6 Hz, 2H), 2.79 (ddd, J = 1.0, 7.7 and 18.5 Hz, 2H), 2.03 (s, 3H), 1.60 (quint., J = 7.5 Hz,

Molecules 2016, 21, 1295
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2H), 1.34 (sextuplet, J = 7.5 Hz, 2H), 0.86 (t, J = 7.4 Hz, 3H); 13C-NMR (101 MHz, CDCl3):
δ
= 170.0
(d, JPCOC = 6.8 Hz), 136.5 (d, JPCCCC = 3.5 Hz), 135.5 (d, JPCC = 13.3 Hz), 128.6 (2C), 127.8, 126.3, 126.2,
117.5 (d, JPCCC = 10.2 Hz), 65.2 (d, JPOC = 6.9 Hz), 57.9 (d, JPC = 108 Hz), 32.6 (d, JPOCC = 5.8 Hz), 32.5 (d,
J
PC = 93.1 Hz), 20.5 (d, JPOCCC = 8.8 Hz), 18.7, 13.6; HRMS (EI+) m/z calcd for C16H24O4P ([M + H]+)
311.1407, found 311.1401.
(Rp)/(Sp)-Menthyl cinnamyl(hydroxymethyl)phosphinate (Table 2, Entry 9) [14]. To a solution of
(Rp)/(Sp)-menthyl (hydroxymethyl)-H-phosphinate (2.34 g, 10 mmol, 1 equiv, 56:44 diastereoisomeric
ratio) in t-amyl alcohol (30 mL), Pd2(dba)3 (92 mg, 0.1 mmol, 1 mol %), Xantphos (116 mg, 0.2 mmol,
2 mol %), and cinnamyl alcohol (1.3 mL, 10 mmol, 1 equiv.) were added. The reaction mixture was
stirred at reflux for 20 h 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 residue obtained was purified by
column chromatography (dichloromethane/acetone 100:0 to 90:10) to afford the product as a white
solid (3.19 g, 91%, 56:44 diastereoisomeric ratio). 31P-NMR (162 MHz, CDCl3):
48.1 (s, 44%).
δ = 48.4 (s, 56%) and
6-(Cinnamyl)-6H-dibenzo[c,e][1,2λ
5]oxaphosphinine-6-oxide (Table 2, Entry 11). General procedure was
used with cinnamyl alcohol (0.13 mL, 1 mmol, 1 equiv.) and DOPO (216 mg, 1 mmol, 1 equiv.).
The crude obtained was purified by column chromatography (hexane/ethyl acetate 50:50 to 0:100) to
afford the product as a yellow solid (318 mg, 96%). 31P-NMR (CDCl3, 162 MHz)
δ
= 27.4 (s); 1H-NMR
(CDCl3, 400 MHz)
7.22–7.30 (m, 6H), 7.16–7.21 (m, 2H), 6.35 (dd, J = 5.3 and 15.8 Hz, 1H), 6.02–6.13 (m, 1H), 3.08 (ddt,
J = 1.3, 7.6 and 18.2 Hz, 2H); 13C-NMR (101 MHz, CDCl3):
= 149.6 (d, JPOC = 8.2 Hz), 136.5 (d,
PCCCC = 3.6 Hz), 135.9 (d, JPCCC = 6.1 Hz), 135.8 (d, JPCC = 13.8 Hz), 133.4 (d, JPCCCC = 2.3 Hz), 130.7,
δ = 7.89–7.99 (m, 2H), 7.68–7.74 (m, 1H), 7.49–7.55 (m, 1H), 7.36–7.42 (m, 1H),
δ
J
130.5 (d, JPCCC = 10.2 Hz), 128.5 (2C), 128.4 (d, JPCC = 13.0 Hz), 127.7 (d, JPCCCC = 2.2 Hz), 126.2, 126.2,
125.2, 124.6, 124.2 (d, JPC = 120 Hz), 123.8 (d, JPCCC = 9.6 Hz), 122.3 (d, JPCCC = 10.5 Hz), 120.4 (d,
JPCCC = 6.3 Hz), 117.2 (d, JPCC = 11.0 Hz), 34.5 (d, JPC = 93.8 Hz); HRMS (EI+) m/z calcd for C21H18O2P
([M + H]+) 333.1039, found 333.1048.
Diethyl cinnamylphosphonate (Table 2, Entry 12) [15]. General procedure was used with cinnamyl alcohol
(0.13 mL, 1 mmol, 1 equiv.) and diethylphosphite (138 mg, 1 mmol, 1 equiv.). The crude obtained
was purified by column chromatography (hexane/ethyl acetate 50:50 to 0:100) to afford the product
as an orange oil (240 mg, 94%). 31P-NMR (CDCl3, 162 MHz) δ = 34.8 (s); 1H-NMR (CDCl3, 400 MHz)
δ = 7.34–7.40 (m, 2H), 7.28–7.34 (m, 2H), 7.21–7.26 (m, 1H), 6.53 (dd, J = 5.1 and 15.8 Hz, 1H), 6.12–6.23
(m, 1H), 4.08–4.18 (m, 4H), 2.76 (dd, J = 7.6 and 22.2 Hz, 2H), 1.32 (t, J = 6.1 Hz, 6H).
Cinnamyl diphenylphosphine oxide (Table 2, Entry 13) [16]. General procedure was used with cinnamyl
alcohol (0.13 mL, 1 mmol, 1 equiv.) and diphenyl phosphine oxide (202 mg, 1 mmol, 1 equiv.).
The crude obtained was purified by column chromatography (hexane/ethyl acetate 100:0 to 0:100) to
afford the product as a yellow oil (292 mg, 92%). 31P-NMR (CDCl3, 162 MHz)
δ
= 28.9 (s); 1H-NMR
= 7.75–7.82 (m, 4H), 7.46–7.58 (m, 6H), 7.18–7.29 (m, 5H), 6.44 (dd, J = 4.5 and
(CDCl3, 400 MHz)
δ
15.8 Hz, 1H), 6.14–6.25 (m, 1H), 3.31 (ddd, J = 1.2, 7.5 and 15.0 Hz, 2H).
Butyl allyl phenylphosphinate (Table 3, Entry 1) [17]. General procedure was used with allyl alcohol
(0.13 mL, 2 mmol, 2 equiv.) and butyl phenyl-H-phosphinate (198 mg, 1 mmol, 1 equiv.). The crude
obtained was purified by column chromatography (hexane/ethyl acetate 100:0 to 0:100) to afford the
1
product as a yellow oil (234 mg, 98%). 31P-NMR (CDCl3, 162 MHz)
δ
= 35.1 (s); H-NMR (CDCl3,
400 MHz)
δ = 7.66–7.75 (m, 2H), 7.45–7.51 (m, 1H), 7.36–7.43 (m, 2H), 5.61–5.75 (m, 1H), 4.95–5.09 (m,
1H), 3.93–4.03 (m, 1H), 3.69–3.80 (m, 1H), 3.31 (dd, J = 7.0 and 18.5 Hz, 2H), 1.58 (quint., J = 7.1 Hz, 2H),
1.32 (sextuplet, J = 1.9 and 7.4 Hz, 2H), 0.83 (t, J = 7.4 Hz, 3H).

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Cyclohexyl allyl phenylphosphinate (Table 3, Entry 2). General procedure was used with allyl alcohol
(0.13 mL, 2 mmol, 2 equiv.) and cyclohexyl phenyl-H-phosphinate (224 mg, 1 mmol, 1 equiv.). The crude
obtained was purified by column chromatography (hexane/ethyl acetate 100:0 to 0:100) to afford
1
the product as an orange oil (247 mg, 94%). 31P-NMR (CDCl3, 162 MHz)
δ
= 37.7 (s); H-NMR
(CDCl3, 400 MHz)
4.97–5.11 (m, 2H), 4.22–4.33 (m, 1H), 2.65–2.76 (m, 2H), 1.92–2.02 (m, 1H), 1.51–1.75 (m, 4H), 1.34–1.47
(m, 2H), 1.12–1.32 (m, 3H); 13C-NMR (101 MHz, CDCl3):
= 132.1 (d, JPCCCC = 2.7 Hz), 131.7 (d,
δ = 7.70–7.79 (m, 2H), 7.46–7.52 (m, 1H), 7.38–7.45 (m, 2H), 5.64–5.78 (m, 1H),
δ
JPCCC = 9.6 Hz, 2C), 131.4 (d, JPC = 126 Hz), 128.3 (d, JPCC = 12.5 Hz, 2C), 127.4 (d, JPCCC = 9.2 Hz),
120.1 (d, JPCC = 13.0 Hz), 74.6 (d, JPOC = 6.9 Hz), 36.6 (d, JPC = 97.5 Hz), 34.2 (d, JPOCC = 3.1 Hz),
33.7 (d, JPOCC = 4.3 Hz), 25.1, 23.6, 23.6; HRMS (EI+) m/z calcd for C15H22O2P ([M + H]+) 265.1352,
found 265.1359.
Butyl allyl cinnamylphosphinate (Table 3, Entry 3) [6]. General procedure was used with allyl alcohol
(0.15 mL, 2 mmol, 2 equiv.) and butyl cinnamyl-H-phosphinate (238 mg, 1 mmol, 1 equiv.). The crude
obtained was purified by column chromatography (hexane/ethyl acetate 100:0 to 0:100) to afford the
product as an orange oil (254 mg, 91%). 31P-NMR (CDCl3, 162 MHz)
δ
= 48.0 (s); 1H-NMR (CDCl3,
400 MHz)
1H), 5.72–5.86 (m, 1H), 5.14–5.23 (m, 2H), 4.00 (dt, J = 6.8 and 6.9 Hz, 2H), 2.72 (ddd, J = 0.7, 7.6 and
17.6 Hz, 2H), 2.60 (dd, J = 7.5 and 17.2 Hz, 2H), 1.60 (quint., J = 7.1 Hz, 2H), 1.35 (sextuplet, J = 7.5 Hz
2H), 0.88 (t, J = 7.4 Hz, 3H); 13C-NMR (101 MHz, CDCl3):
= 136.7 (d, JPCCCC = 3.3 Hz), 135.0 (d,
PCC = 12.9 Hz), 128.6 (2C), 127.7 (d, JPCCC = 8.0 Hz), 127.6, 126.2, 126.1, 120.3 (d, JPCC = 12.6 Hz), 118.8
δ = 7.23–7.34 (m, 4H), 7.15–7.21 (m, 1H), 6.46 (dd, J = 4.7 and 15.8 Hz, 1H), 6.08–6.19 (m,
,
δ
J
(d, JPCCC = 9.6 Hz), 64.5 (d, JPOC = 7.2 Hz), 33.8 (d, JPC = 88.7 Hz), 32.9 (d, JPC = 89.0 Hz), 32.7 (d,
JPOCC = 5.7 Hz), 18.8, 13.6.
Cyclohexyl 3-[(2-methyl-2-propene)phenyl] phenylphosphinate (Table 3, Entry 4). General procedure
was used with trans-2-methyl-3-phenyl-2-propen-1-ol (0.15 mL, 1 mmol, 1 equiv.) and cyclohexyl
phenyl-H-phosphinate (224 mg, 1 mmol, 1 equiv.). The crude obtained was purified by column
chromatography (hexane/ethyl acetate 100:0 to 0:100) to afford the product as an orange oil (330 mg,
1
93%). 31P-NMR (CDCl3, 162 MHz)
δ
= 39.5 (s); H-NMR (CDCl3, 400 MHz)
δ
= 7.77–7.85 (m, 2H),
7.48–7.54 (m, 1H), 7.40–7.47 (m, 2H), 7.22–7.29 (m, 2H), 7.11–7.17 (m, 1H), 7.03–7.09 (m, 2H), 6.09 (d,
J = 5.5 Hz, 1H), 4.29–4.40 (m, 1H), 2.76–2.91 (m, 2H), 1.98–2.07 (m, 1H), 1.92 (dd, J = 1.3 and 3.5 Hz,
3H), 1.59–1.79 (m, 4H), 1.39–1.49 (m, 2H), 1.17–1.36 (m, 3H); 13C-NMR (101 MHz, CDCl3):
δ
= 137.8 (d,
JPCCCC = 3.7 Hz), 132.1 (d, JPCCCC = 2.7 Hz), 131.9 (d, JPCCC = 9.5 Hz, 2C), 131.6 (d, JPC = 125 Hz), 130.0
(d, JPCC = 11.5 Hz), 129.3 (d, JPCCC = 10.3 Hz), 128.7 (d, JPCCCCC = 2.9 Hz, 2C), 128.3 (d, PCC = 12.4 Hz
J
,
2C), 128.0 (2C), 126.3, 74.7 (d, JPOC = 7.0 Hz), 42.8 (d, JPC = 95.2 Hz), 34.3 (d, JPOCC = 2.9 Hz), 33.7
(d, JPOCC = 4.3 Hz), 25.2, 23.6 (2C), 19.5 (d, JCCC = 2.1 Hz); HRMS (EI+) m/z calcd for C22H28O2P
([M + H]+) 355.1827, found 355.1849.
Butyl 3-[(2-methyl-2-propene)phenyl] cinnamylphosphinate (Table 3, Entry 5). General procedure
was used with trans-2-methyl-3-phenyl-2-propen-1-ol (0.15 mL, 1 mmol, 1 equiv.) and butyl
cinnamyl-H-phosphinate (238 mg, 1 mmol, 1 equiv.). The crude obtained was purified by column
chromatography (hexane/ethyl acetate 50:50 to 0:100) to afford the product as an orange oil (283 mg,
77%). 31P-NMR (CDCl3, 162 MHz)
δ δ = 7.19–7.38 (m, 10H),
= 48.2 (s); 1H-NMR (CDCl3, 400 MHz)
6.54 (dd, J = 4.4 and 15.8 Hz, 1H), 6.43 (d, J = 4.8 Hz, 1H), 6.19–6.30 (m, 1H), 4.10 (dt, J = 6.7 and
6.8 Hz, 2H), 2.84 (dd, J = 7.6 and 17.1 Hz, 2H), 2.77 (d, J = 17.3 Hz, 2H), 2.07 (d, J = 3.1 Hz, 3H), 1.68
(quint., J = 7.4 Hz, 2H), 1.42 (sextuplet, J = 7.5 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13C-NMR (101 MHz,
CDCl3): δ = 137.5 (d, JPCCCC = 3.5 Hz), 136.8 (d, JPCCCC = 3.1 Hz), 135.0 (d, JPCC = 12.7 Hz), 129.9 (d,
JPCCC = 11.7 Hz), 129.8 (d, JPCC = 10.0 Hz), 128.9, 128.8, 128.6 (2C), 128.2 (2C), 127.7, 126.6, 126.2, 126.2,
119.2 (d, JPCCC = 9.9 Hz), 64.6 (d, JPOC = 7.2 Hz), 40.6 (d, JPC = 86.7 Hz), 33.5 (d, JPC = 88.0 Hz), 32.9 (d,
J
POCC = 5.7 Hz), 19.6 (d, JPCCC = 1.9 Hz), 18.9, 13.7; HRMS (EI+) m/z calcd for C23H30O2P ([M + H]+)
369.1983, found 369.1906.

Molecules 2016, 21, 1295
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Butyl (2-methylprop-2-ene) cinnamylphosphinate (Table 3, Entry 6). General procedure was used with
methylallyl alcohol (0.154 mL, 1 mmol, 1 equiv.) and butyl cinnamyl-H-phosphinate (238 mg, 1 mmol,
1 equiv.). The crude obtained was purified by column chromatography (hexane/ethyl acetate 100:0
to 0:100) to afford the product as an orange oil (148 mg, 51%). 31P-NMR (CDCl3, 162 MHz)
δ
= 47.4
(s); 1H-NMR (CDCl3, 400 MHz)
δ = 7.30–7.39 (m, 4H), 7.22–7.28 (m, 1H), 6.52 (dd, J = 4.6 and 15.8 Hz,
1H), 6.14–6.25 (m, 1H), 4.97–5.01 (m, 1H), 4.95 (d, J = 4.5 Hz, 1H), 4.06 (dt, J = 6.8 Hz, 2H), 2.81 (dd,
J = 7.6 and 17.3 Hz, 2H), 2.62 (d, J = 17.4 Hz, 2H), 1.92 (t, J = 1.2 Hz, 3H), 1.66 (quint., J = 7.5 Hz, 2H),
1.41 (sextuplet, J = 7.6 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13C-NMR (101 MHz, CDCl3):
δ
= 136.8 (d,
J
PCCCC = 3.3 Hz), 136.7 (d, JPCCC = 9.0 Hz), 134.9 (d, JPCC = 13.1 Hz), 128.6 (2C), 127.6, 126.2, 126.2,
119.2 (d, JPCCC = 9.7 Hz), 115.7 (d, JPCC = 10.9 Hz), 64.6 (d, JPOC = 7.2 Hz), 37.6 (d, JPC = 87.4 Hz), 33.1
(d, JPC = 88.3 Hz), 32.8 (d, JPOCC = 5.8 Hz), 24.1 (d, JPCCC = 2.2 Hz), 18.8, 13.7; HRMS (EI+) m/z calcd
for C17H26O2P ([M + H]+) 293.1670, found 293.1693.
Butyl myrtenyl phenylphosphinate (Table 3, Entry 7). General procedure was used with myrtenol (0.17 mL,
1 mmol, 1 equiv.) and butyl phenyl-H-phosphinate (198 mg, 1 mmol, 1 equiv.). The crude obtained
was purified by column chromatography (hexane/ethyl acetate 100:0 to 0:100) to afford the product
δ
as an orange oil (246 mg, 74%). 31P-NMR (CDCl3, 162 MHz) = 40.3 (s); 1H-NMR (CDCl3, 400 MHz)
δ = 7.64–7.72 (m, 2H), 7.41–7.47 (m, 1H), 7.33–7.40 (m, 2H), 5.15–5.21 (m, 1H), 3.88–3.97 (m, 1H),
3.61–3.71 (m, 1H), 2.52–2.76 (m, 2H), 2.17–2.26 (m, 1H), 2.00–2.12 (m, 3H), 1.87–1.96 (m, 1H), 1.53
(quint., J = 7.2 Hz, 2H), 1.30 (sextuplet, J = 7.5 Hz, 2H), 1.14 (d, J = 10.4 Hz, 3H), 0.99 (dd, J = 8.7
and 20.1 Hz, 1H), 0.81 (t, J = 7.6 Hz, 3H), 0.72 (d, J = 4.0 Hz, 3H); 13C-NMR (101 MHz, CDCl3):
δ = 137.8 (d, JPCC = 10.4 Hz), 132.0 (d, JPCCCC = 2.8 Hz, 0.5C), 132.0 (d,
(d, JPCCC = 9.7 Hz), 131.8 (d, JPCCC = 9.8 Hz), 131.0 (d, JPC = 123 Hz), 131.0 (d,
(d, PCC = 12.3 Hz, 2C), 122.2 (d, JPCCC = 12.6 Hz, 0.5C), 122.2 (d, JPCCC = 12.6 Hz, 0.5C), 64.1 (d,
POC = 7.0 Hz, 0.5C), 64.0 (d, POC = 7.0 Hz, 0.5C), 46.9 (d, JPOCC = 2.8 Hz, 0.5C), 46.7 (d, JPOCC = 2.4 Hz
0.5C), 40.1 (0.5C), 40.1 (0.5C), 38.7 (d, JPC = 97.6 Hz), 37.9 (d, JPCCCC = 2.2 Hz, 0.5C), 37.9 (d,
JPOCC = 2.2 Hz, 0.5C), 32.5 (0.5C), 32.5 (0.5C), 31.6 (d, PCCCC = 2.4 Hz, 0.5C), 31.5 (d, PCCCC = 2.0 Hz,
J
PCCCC = 2.8 Hz, 0.5C), 131.8
J
PC = 123 Hz), 128.2
J
J
J
,
J
J
0.5C), 26.1 (0.5C), 26.1 (0.5C), 21.0 (0.5C), 20.9 (0.5C), 18.7, 13.6; HRMS (EI+) m/z calcd for C20H30O2P
([M + H]+) 333.1983, found 333.1906.
Cyclohexyl benzyl octylphosphinate (Table 3, Entry 8) [1]. General procedure was used with benzyl alcohol
(0.11 mL, 1 mmol, 1 equiv.) and cyclohexyl octyl-H-phosphinate (260 mg, 1 mmol, 1 equiv.). The crude
obtained was purified by column chromatography (hexane/ethyl acetate 50:50 to 0:100) to afford the
product as an orange oil (226 mg, 65%). 31P-NMR (CDCl3, 162 MHz)
δ
= 52.1 (s); 1H-NMR (CDCl3,
400 MHz)
δ = 7.22–7.37 (m, 5H), 4.30–4.42 (m, 1H), 3.13 (d, J = 16.7 Hz, 2H), 1.86–1.95 (m, 2H), 1.40–1.84
(m, 10H), 1.17–1.37 (m, 12H), 0.89 (t, J = 6.9 Hz, 3H).
Butyl benzyl cinnamylphosphinate (Table 3, Entry 9). General procedure was used with benzyl alcohol
(0.11 mL, 1 mmol, 1 equiv.) and butyl cinnamyl-H-phosphinate (238 mg, 1 mmol, 1 equiv.). The crude
obtained was purified by column chromatography (hexane/ethyl acetate 100:0 to 0:100) to afford the
product as an orange oil (187 mg, 57%). 31P-NMR (CDCl3, 162 MHz)
400 MHz)
3.20 (d, J = 16.8 Hz, 2H), 2.70 (dd, J = 7.6 and 17.2 Hz, 2H), 2.01–2.12 (m, 2H), 1.62 (quint., J = 7.3 Hz
2H), 1.37 (sextuplet, J = 7.5 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H); 13C-NMR (101 MHz, CDCl3): δ = 136.8
δ
= 48.5 (s); 1H-NMR (CDCl3,
δ
= 7.21–7.39 (m, 10H), 6.45 (dd, J = 4.2 and 15.8 Hz, 1H), 6.08–6.20 (m, 1H), 3.93–4.07 (m, 2H),
,
(d, JPCCCC = 3.1 Hz), 135.1 (d, JPCCC = 13.0 Hz), 131.6 (d, JPCC = 7.3 Hz), 129.9 (d, JPCCC = 5.8 Hz
2C), 128.7 (d, JPCCCC = 2.6 Hz, 2C), 128.6 (2C), 127.7, 127.0 (d, JPCCCCC = 3.0 Hz), 126.2, 126.2, 118.9
(d, JPCCC = 9.8 Hz), 64.8 (d, JPOC = 7.0 Hz), 36.0 (d, JPC = 87.1 Hz), 33.2 (d, JPC = 88.0 Hz), 32.8 (d,
JPOCC = 5.9 Hz), 27.0 (d, JPCC = 3.5 Hz), 18.8, 13.7; HRMS (EI+) m/z calcd for C20H26O2P ([M + H]+)
329.1665, found 329.1671.
,
Cyclohexyl 1-(naphthylmethyl) phenylphosphinate (Table 3, Entry 10). General procedure was used with
1-naphthalenemethanol (158 mg, 1 mmol, 1 equiv.) and cyclohexyl phenyl-H-phosphinate (224 mg,

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1 mmol, 1 equiv.). The crude obtained was purified by column chromatography (hexane/ethyl acetate
100:0 to 0:100) to afford the product as an orange oil (266 mg, 73%). 31P-NMR (CDCl3, 162 MHz)
δ = 35.5 (s); 1H-NMR (CDCl3, 400 MHz)
δ = 7.95–8.02 (m, 1H), 7.77–7.84 (m, 1H), 7.69–7.75 (m, 1H),
7.56–7.65 (m, 2H), 7.39–7.48 (m, 3H), 7.29–7.37 (m, 3H), 7.22–7.28 (m, 1H), 4.22–4.33 (m, 1H), 3.76
(d, J = 17.8 Hz, 2H), 1.77–1.86 (m, 1H), 1.45–1.67 (m, 4H), 1.09–1.44 (m, 5H); 13C-NMR (101 MHz,
CDCl3):
δ = 133.8 (d, JPCCCC = 2.1 Hz), 132.2 (d, JPCCCC = 4.3 Hz), 132.1 (d, JPCCCC = 2.2 Hz), 132.0 (d,
JPCCC = 9.5 Hz, 2C), 131.4 (d, JPC = 124 Hz), 128.6 (d, JPCCC = 6.7 Hz), 128.4, 128.4 (d, JPCC = 8.0 Hz),
128.2 (d, JPCC = 12.4 Hz, 2C), 127.5 (d, JPCCCC = 3.8 Hz), 125.7, 125.5, 125.2 (d, JPCCCC = 3.6 Hz), 124.6,
74.9 (d, JPOC = 6.8 Hz), 35.9 (d, JPC = 96.1 Hz), 34.0 (d, JPOCC = 2.6 Hz), 33.5 (d, JPOCC = 4.0 Hz), 25.1,
23.4 (2C); HRMS (EI+) m/z calcd for C22H28O2P ([M + H]+) 355.1827, found 355.1849.
Butyl (1-methylnaphthalene) cinnamylphosphinate (Table 3, Entry 11). General procedure was used with
1-naphthalenemethanol (316 mg, 2 mmol, 2 equiv.) and butyl cinnamyl-H-phosphinate (238 mg,
1 mmol, 1 equiv.). The crude obtained was purified by column chromatography (hexane/ethyl acetate
100:0 to 0:100) to afford the product as an orange oil (186 mg, 49%). 31P-NMR (CDCl3, 162 MHz)
δ = 47.5 (s); 1H-NMR (CDCl3, 400 MHz)
δ = 8.09–8.14 (m, 1H), 7.85–7.90 (m, 1H), 7.76–7.82 (m, 1H),
7.49–7.58 (m, 2H), 7.42–7.48 (m, 1H), 7.29–7.36 (m, 5H), 7.23–7.29 (m, 1H), 6.40 (dd, J = 4.5 and 15.8 Hz,
1H), 6.09–6.20 (m, 1H), 3.83–4.01 (m, 2H), 3.62–3.78 (m, 2H), 2.75 (dd, J = 7.6 and 16.8 Hz, 2H), 1.51
(quint., J = 7.4 Hz, 2H), 1.27 (sextuplet, J = 7.6 Hz, 2H), 0.85 (t, J = 7.4 Hz, 3H); 13C-NMR (101 MHz,
CDCl3):
(d, JPCCC = 4.6 Hz), 128.8, 128.6 (2C), 128.5 (d, JPCCCC = 6.7 Hz), 128.1 (d, JPCC = 8.2 Hz), 127.9 (d,
PCCCC = 3.8 Hz), 127.7, 126.2 (3C), 125.9, 125.4 (d, JPCCCC = 3.6 Hz), 124.4 (d, JPCCCCC = 1.2 Hz), 118.9
δ = 136.7 (d, JPCCCC = 3.1 Hz), 135.0 (d, JPCC = 12.8 Hz), 134.0 (d, JPCCCC = 2.4 Hz), 132.1
J
(d, JPCCC = 9.9 Hz), 64.9 (d, JPOC = 7.3 Hz), 33.7 (d, JPC = 88.2 Hz), 33.2 (d, JPC = 87.7 Hz), 32.7 (d,
JPOCC = 5.9 Hz), 18.7, 13.6; HRMS (EI+) m/z calcd for C24H28O2P ([M + H]+) 379.1827, found 379.1750.
3.2. 1-Butoxy-3-Phospholene 1-Oxide (Scheme 3c) [6]
To a solution of cinnamyl phosphinic acid [13] (3.64 g, 20 mmol, 1 equiv.) in toluene (40 mL),
1-butanol (3.7 mL, 40 mmol, 2 equiv.) was added and the reaction was stirred for 16 h at reflux
in a flask equipped with a Dean-Stark trap. After cooling down the reaction to room temperature,
the solvent was removed under vacuum. The residue obtained was dissolved in ethyl acetate and
the organic layer was washed with an aqueous saturated solution of NaHCO3 and brine, dried over
MgSO4, filtered, and concentrated under vacuum. The residue obtained was purified by column
chromatography (hexane/ethyl acetate 80:0 to 20:80) to afford butyl cinnamyl-H-phosphinate as a
]. 31P-NMR (CDCl3, 162 MHz) = 36.2 (dm, J = 543 Hz); 1H-NMR (CDCl3,
yellow oil (4.59 g, 96%) [1 δ
400 MHz) δ = 7.31–7.41 (m, 4H), 7.23–7.29 (m, 1H), 7.07 (dt, J = 1.9 and 543 Hz, 1H), 6.57 (dd, J = 6.0
and 15.9 Hz, 1H), 6.06–6.18 (m, 1H), 4.12–4.21 (m, 1H), 4.00–4.09 (m, 1H), 2.83 (dd, J = 7.6 and 16.8 Hz,
2H), 1.71 (quint., J = 7.1 Hz, 2H), 1.43 (sextuplet, J = 7.5 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H).
General procedure was used with allyl alcohol (0.15 mL, 2 mmol, 2 equiv.) and butyl
cinnamyl-H-phosphinate (238 mg, 1 mmol, 1 equiv.). The crude obtained was purified by column
chromatography (hexane/ethyl acetate 100:0 to 0:100) to afford butyl allyl cinnamylphosphinate
1
as an orange oil (254 mg, 91%) [
6
]. 31P-NMR (CDCl3, 162 MHz)
δ
= 48.0 (s); H-NMR (CDCl3,
400 MHz) δ = 7.23–7.34 (m, 4H), 7.15–7.21 (m, 1H), 6.46 (dd, J = 4.7 and 15.8 Hz, 1H), 6.08–6.19 (m,
1H), 5.72–5.86 (m, 1H), 5.14–5.23 (m, 2H), 4.00 (dt, J = 6.8 and 6.9 Hz, 2H), 2.72 (ddd, J = 0.7, 7.6 and
17.6 Hz, 2H), 2.60 (dd, J = 7.5 and 17.2 Hz, 2H), 1.60 (quint., J = 7.1 Hz, 2H), 1.35 (sextuplet, J = 7.5 Hz
2H), 0.88 (t, J = 7.4 Hz, 3H); 13C-NMR (101 MHz, CDCl3):
= 136.7 (d, JPCCCC = 3.3 Hz), 135.0
(d, JPCC = 12.9 Hz), 128.6 (2C), 127.7 (d, JPCCC = 8.0 Hz), 127.6, 126.2, 126.1, 120.3 (d, JPCC = 12.6 Hz),
118.8 (d, PCCC = 9.6 Hz), 64.5 (d, JPOC = 7.2 Hz), 33.8 (d, JPC = 88.7 Hz), 32.9 (d, JPC = 89.0 Hz), 32.7
,
δ
J
(d, JPOCC = 5.7 Hz), 18.8, 13.6.
To a solution of butyl allyl cinnamylphosphinate (92 mg, 0.33 mmol, 1 equiv.) in dichloromethane
(50 mL), [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene] dichloro(phenylmethylene)-

Molecules 2016, 21, 1295
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(tricyclohexylphosphine)ruthenium (5.6 mg, 0.0066 mmol, 0.02 equiv.) was added and the mixture was
placed under N2. The reaction was heated at reflux for 12 h and then allowed to cool down to rt and
treated with activated charcoal (0.1 g). The resulting suspension was stirred for 12 h at rt, suction-filtered
through a Celite pad in a Buchner funnel, and concentrated under vacuum. The crude obtained was
purified by column chromatography (hexane/ethyl acetate 100:0 to 0:100) to afford an orange oil (48 mg,
1
85%). 31P-NMR (CDCl3, 162 MHz)
δ
= 74.2 (s); H-NMR (CDCl3, 400 MHz) δ = 5.91 (d, J = 33.0 Hz,
2H), 4.04 (dt, J = 6.9 and 7.0 Hz, 2H), 2.35–2.50 (m, 4H), 1.67 (quint., J = 7.1 Hz, 2H), 1.40 (sextuplet,
J = 7.5 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13C-NMR (101 MHz, CDCl3):
δ
= 127.0 (d, PCC = 15.4 Hz, 2C), 64.7
J
(d, JPOC = 6.7 Hz), 32.6 (d, JPOCC = 6.0 Hz), 29.2 (d, JPC = 91.2 Hz, 2C), 18.8, 13.6.
3.3. (Rp)-Menthyl Cinnamyl(hydroxymethyl)phosphinate (Scheme 4) [14]
To a solution of (Rp)-menthyl (hydroxymethyl)-H-phosphinate (468 mg, 2 mmol, 1 equiv., >99%
diastereoisomeric excess) in t-amyl alcohol (10 mL), Pd2(dba)3 (18.3 mg, 0.02 mmol, 1 mol %), Xantphos
(23.2 mg, 0.04 mmol, 2 mol %) and cinnamyl alcohol (0.26 mL, 2 mmol, 1 equiv.) were added.
The reaction mixture was stirred at reflux for 20 h 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 residue
obtained was purified by column chromatography (dichloromethane/acetone 100:0 to 90:10) to afford
◦
the product as a white solid (681 mg, 97%, >99% diastereoisomeric excess). Mp = 145–146 C; 31P-NMR
(162 MHz, CDCl3): = 7.19–7.39 (m, 5H), 6.55 (dd, J = 4.7
δ
= 48.8 (s); 1H-NMR (400 MHz, CDCl3):
δ
and 15.8 Hz, 1H), 6.12–6.27 (m, 1H), 4.20–4.34 (m, 1H), 3.87 (s, 2H), 3.64 (s, 1H), 2.85 (dd, J = 7.6
and 17.6 Hz, 2H), 2.06–2.22 (m, 2H), 1.60–1.71 (m, 2H), 1.28–1.54 (m, 2H), 1.15 (q, J = 11.7 Hz, 1H),
0.74–1.07 (m, 2H), 0.91 (d, J = 6.4 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H), 0.77 (d, J = 7.0 Hz, 3H); 13C-NMR
(101 MHz, CDCl3): δ = 136.8 (d, JPCCCC = 3.3 Hz), 135.0 (d, JPCC = 12.2 Hz), 128.5 (2C), 127.5, 126.2 (d,
J
PCCCCC = 1.7 Hz, 2C), 118.4 (d, JPCCC = 10.5 Hz), 76.7 (d, JPOC = 8.3 Hz), 59.5 (d, JPC = 106 Hz), 48.6 (d,
JPOCC = 5.6 Hz, 2C), 43.5, 34.0, 31.6 (d, JPC = 87.3 Hz), 31.5, 25.5, 22.7, 22.1, 21.0, 15.5; HRMS (EI+) m/z
calcd for C20H31O3P ([M]+) 350.2011, found 350.2012; [α]2D4 −51.6◦ (c 1 g/100 mL, chloroform).
4. Conclusions
We have described the Pd-catalyzed allylation/benzylation of H-phosphinate esters using alcohols
as the electrophilic partner. While the scope of this reaction is somewhat narrower than when
phosphinic acids are used, it still constitutes a useful synthetic methodology for the synthesis of
disubstituted phosphinic acid derivatives. In addition, because H-phosphinate esters can be produced
easily by Dean-Stark esterification of the corresponding acids, it avoids the need for cumbersome
esterification procedures on disubstituted phosphinic acids. Therefore, when the present reaction
is successful, the sequence esterification-allylation/benzylation is superior to the reverse sequence
allylation/benzylation-esterification. A possible mechanism is also proposed.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/21/
10/1295/s1.
Acknowledgments: This material is based in part upon work supported by the National Science Foundation
under grant CHE-1262254.
Author Contributions: Jean-Luc Montchamp conceived and designed the experiments. Anthony Fers-Lidou
conducted the majority of the experiments and Olivier Berger performed some of the experiments and wrote the
experimental procedures. Jean-Luc Montchamp prepared the manuscript.
Conflicts of Interest: The authors declare no conflict of interest. The funding sponsors had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the
decision to publish the results.
Abbreviations
The following abbreviations are used in this manuscript:
HPA
hypophosphorous acid (H3PO2)
molecular sieves
t-amyl alcohol
MS
t-AmOH

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Pd2(dba)3
Dba
Dppf
Xantphos
Cin
Cy
Np
Men
tris(dibenzylideneacetone)dipalladium(0)
dibenzylideneacetone
1,1’-bis(diphenylphosphino)ferrocene
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
cinnamyl
cyclohexyl
naphthyl
(-)-menthyl
6H-dibenzo[c,e][1,2λ5]oxaphosphinine 6-oxide
hexamethyldisilazane
DOPO
HMDS
IMes
1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene
ring closing metathesis
RCM
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Sample Availability: Not available.
©
2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC-BY) license (http://creativecommons.org/licenses/by/4.0/).