Rapid and Efficient Microwave-Assisted Hydrophosphinylation of Unactivated Alkenes with H -Phosphinic Acids without Added Metal or Radical Initiator

Article abstract of DOI:10.1055/s-0035-1560209

A microwave-assisted hydrophosphinylation of unactivated alkenes with phosphinic acid and its derivatives under metal-free and initiator-free conditions is reported. Such hydrophosphinylations are operationally simple, use aqueous hypophosphorus acid, H-phenylphosphinic acid, and H-alkylphosphinic acids, and seem to proceed by a radical mechanism. Good isolated yields were obtained using a reasonable excess of the appropriate reagent.

Full text of DOI:10.1055/s-0035-1560209

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2714–2719
letter
2714
P. Troupa et al.
Letter
Synlett
Rapid and Efficient Microwave-Assisted Hydrophosphinylation
of Unactivated Alkenes with H-Phosphinic Acids without Added
Metal or Radical Initiator
Panagiota Troupa
R
MW
O
Georgia Katsiouleri
Stamatia Vassiliou*
R
R
aq H3PO2
+
P
dioxane
180 °C, 1 h
H
R
OH
R1
Laboratory of Organic Chemistry, Department of Chemistry,
University of Athens, Panepistimiopolis, Zografou,
15701 Athens, Greece
O
O
MW
R1
(Ph) R2
P
R1
(Ph) R2 PH
+
svassiliou@chem.uoa.gr
dioxane
160–180 °C, 1 h
R1
OH
OH
32 examples
20–92% yield
no metal, no radical initiator
Received: 22.07.2015
Accepted after revision: 09.08.2015
Published online: 01.09.2015
DOI: 10.1055/s-0035-1560209; Art ID: st-2015-d0571-l
Abstract A microwave-assisted hydrophosphinylation of unactivated
alkenes with phosphinic acid and its derivatives under metal-free and
initiator-free conditions is reported. Such hydrophosphinylations are
operationally simple, use aqueous hypophosphorus acid, H-phenyl-
phosphinic acid, and H-alkylphosphinic acids, and seem to proceed by a
radical mechanism. Good isolated yields were obtained using a reason-
able excess of the appropriate reagent.
Key words phosphinic acid, organophosphorus compounds, micro-
waves, unactivated alkenes, hydrophosphinylation
Stamatia Vassiliou obtained her undergraduate degree in chemistry
from the University of Athens (Greece). She received her PhD in organic
chemistry from the University of Athens (Greece) and then completed
postdoctoral training at Lyon University (France). She joined the De-
partment of Chemistry in Athens as a lecturer in 2010. Her research
group is interested in the synthetic and medicinal chemistry of organo-
phosphorus compounds.
Organophosphorus compounds constitute a large class
of important and valuable building blocks with applications
in pharmaceutical, agrochemical, and materials sciences.1
Constructing the C–P bond has received a considerable
amount of attention during recent decades,2 with direct hy-
drophosphinylation of alkenes being an attractive and
atom-economical approach.3 The free-radical addition of
P–H bonds to alkenes using peroxides,4 azobisisobutyroni-
trile (AIBN),5 Et3B/O2,6 organic dye/photoirradiation,7 silver,8
or air9 as radical initiators have been reported. All these
methodologies give the anti-Markovnikov adduct I as the
main product, and variable amounts of the branched Mar-
kovnikov product II are also obtained (Scheme 1). In several
cases, the double addition product III is detected.
Since the first report on the use of microwave energy in
organic chemistry,10 the technique has become well estab-
lished. It may lead to increased yield, enhanced product pu-
rity, drastic decrease of reaction time, and even feasibility
of transformations impossible under thermal conditions.11
Stockland reported a microwave-assisted hydrophosphi-
nylation of activated alkenes, leading to the synthesis of
phosphine oxide phophinates.12,13 Taking into consideration
the nature of hydrophosphinylation reagents, we proposed
that microwave heating should also be perfectly suitable for
the coupling of hypophosphorous acid and its derivatives
O
radical initiator
R2
P
+
(R1,Ph) H
H
OH
O
P
R2
O
(R1,Ph) H
R2
(R1,Ph) H
+
P
+
R2
R2
P
OH
OH
OH
O
I
II
III
Scheme 1
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2714–2719

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P. Troupa et al.
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since, due to their ionic nature, they should absorb micro-
wave energy very efficiently by a conduction mechanism.14
With this in mind, and following recent literature reports,15
we decided to investigate the microwave-assisted radical
hydrophosphinylation of unactivated alkenes with hypo-
phosphorous acid using conventional initiators, such as
AIBN, in an attempt to diminish the reaction time and to
avoid the need for repetitive addition of the initiator during
prolonged reaction.
Initially, we examined the microwave-assisted hydro-
phosphinylation of 1-decene (2a) with 50% aqueous hypo-
phosphorous acid (HPA, 1) using AIBN as a radical initiator
in MeOH, which is the solvent of choice under thermal con-
ditions. The desired H-phosphinic acid 3a was formed in
69% yield along with methyl decylphosphinate (4a) in 27%
yield, as judged by 31P NMR spectroscopy and mass spec-
trometry (Scheme 2). Formation of the ester side-product
was not unexpected, because Keglevich had reported the
microwave-assisted direct esterification of phosphinic acids
with alcohols.16 However, when the reaction was per-
formed without AIBN, we also isolated the desired product
3a in 67% yield along with by-product 4a in 24% yield.
and selective GABAB agonist (IC50 = 5 nM) introduced by No-
vartis.18 While H-phosphinic acids bearing a hydroxyl
group (3g) or a carboxylic acid moiety (3h,i) are easily pre-
pared, their isolation was not possible due to their water
solubility.
O
O
H
N
P
P
H
H
Ph
Cbz
OH
OH
3f
3j
O
4-phenyl-1-butene
P
H
aq H3PO2
Ph
OH
dioxane, MW, 180 °C
aq workup
91% yield
3f
O
O
P
Ph
N
O
O
NaO2C
Monopril
O
Scheme 3 (4-Phenylbutyl)phosphinic acid (3f) and Cbz-aminopropyl
phosphinic acid (3j)
Having established the microwave-assisted C–P forma-
tion protocol with hypophosphorous acid, we became in-
terested to see if a second C–P bond could be formed equal-
ly. To verify this, we initially used phenyl phosphinic acid
(5), an activated H-phosphinic acid,3 as a substrate for the
AIBN
+
aq H3PO2
C8H17
MeOH, MW
O
1
2a
O
P
P
H
H
+
H17C8
H17C8
OMe
OH
3a
4a
Scheme 2 Initial experiments on the addition of HPA (1) to alkene 2a
Table 1 Microwave-Promoted Hydrophophinylation of Unactivated
Terminal Alkenes Using Hypophosphorous Acida
With this result in hand, we undertook a thorough in-
vestigation to find the optimal conditions leading solely to
3a (see Table 1 of the Supporting Information). From these
data, a 5:1 molar ratio of H3PO2–alkene and an alkene con-
centration of 0.1 M in dioxane was adopted as the standard
conditions for the formation of the corresponding H-phos-
phinic acid.
O
P
H
R
R
aq H3PO2
+
OH
dioxane
MW
1
2
3
Entry
Alkene R
Product 3
31P NMR yield Isolated yield
(%)b
(%)c
We then explored the scope of the reaction with respect
to olefinic substrates (Table 1). Consistently high yields
were obtained with terminal alkenes ranging from 8–16
carbon atoms. Some limitations were observed when the
reaction was attempted with alkenes that are water soluble
to a certain degree (entries 5, 7–9). Although the desired
products were formed as judged by 31P NMR analysis of the
crude reaction mixture, they were isolated in low yield, or
not at all, upon aqueous workup. Of special interest is the
synthesis of (4-phenylbutyl)phosphinic acid (3f), an inter-
mediate in the synthesis of the heart drug Monopril
(Scheme 3). The current Bristol–Myers Squibb synthesis in-
volves a modified Nifant’ev thermal radical addition.17 With
our protocol, the desired product was obtained in excellent
yield and purity, without the need for chromatography. Ad-
ditionally, Cbz-aminopropyl phosphinic acid (3j) is the pre-
cursor to 3-aminopropylphosphinic acid (APPA), a potent
1
2
C8H17
C6H13
C10H21
C14H29
C4H9
3a
3b
3c
3d
3e
3f
100
93
85
87
83
32
91
0
91
100
97
3
4
5
78
6
C2H4Ph
96
7
C3H6OH
3g
3h
3i
92
8
C2H4CO2H
C8H16CO2H
CH2NHCbz
91
0
9
78
45
72
10
3j
93
a Reaction conditions: alkene (0.4 mmol), aq H3PO2 (2 mmol), dioxane (4 mL,
0.1 M alkene concentration), 100 W initial microwave power level, 180 °C, 60
min.
b Determined by integration of all signals. The yields are assessed to be within
10% of the value indicated.
c After work-up and column chromatography when necessary.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2714–2719

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hydrophosphinylation of several unactivated alkenes (Table
2). Increasing the alkene ratio resulted in increased yield
(entry 1), but also involved laborious purification of the
product by column chromatography. Therefore, for the rest
of the experiments the alkene/phenylphosphinic acid ratio
was set to two. The presence of a phenyl ring conferred de-
creased water solubility to the products, therefore making
them readily isolable after aqueous workup (entries 5 and
8). Again, a variety of functionalities such as hydroxyl (en-
try 5), carboxyl (entry 8), Cbz amine (entry 6) was well tol-
erated in the final products, rendering further modifica-
tions.
Table 3 Microwave-Promoted Hydrophosphinylation between
H-Phosphinic Acids 3 and Unactivated Terminal Alkenesa
O
O
R2
R1
P
R2
R1 PH
+
dioxane
MW
OH
OH
3
2
7
Entry
1
3
Alkene R2
C10H21
Product 7 Isolated yield (%)b
3c
7a
64
60c
72d
2
3
3f
3f
CH2NCbz
7b
7c
50
53
C8H16CO2H
Table 2 Microwave-Promoted Hydrophosphinylation of Unactivated
a Reaction conditions: alkene (1.2 mmol), H-phosphinic acid 3 (0.4 mmol),
dioxane (4 mL, 0.1 M H-phosphinic acid concentration), 100 W initial micro-
wave power level, 180 °C, 60 min.
Terminal Alkenes and Phenylphosphinic Acida
b After column chromatography.
O
P
O
R
c Alkene (0.8 mmol).
R
PH
OH
+
d Alkene (2 mmol).
dioxane
MW
OH
5
2
6
Keeping in mind the general order of reactivity of ole-
fins19 in hydrofunctionalization reactions (Figure 1), we be-
came interested in testing our methodology on less reactive
nonterminal unactivated alkenes and heteroatom-contain-
ing cyclic analogues that have been rarely used.6a,20
Entry
1
Alkene R
C8H17
Product 6
Isolated yield (%)b
6a
75
78c
84d
Initially, we used cyclohexene and aqueous H3PO2 to
find the optimal conditions. All experiments were per-
formed in dioxane, and the yield was calculated based on
31P NMR spectroscopic analysis. Varying the amount of
aqueous H3PO2 did not substantially affect the yield, and no
disubstitution product was observed when equimolar ra-
tios of aqueous H3PO2/alkene were used. This trend can be
attributed to the diminished reactivity of internal alkenes
compared to their terminal counterparts; therefore, the
molar ratio of aqueous H3PO2/alkene was set to 2:1 for the
rest of the experiments (Table 4, entries 2, 4, and 5).
Phenylphosphinic acid also reacted with these adducts,
giving the corresponding phosphinic acids in moderate
yields (Table 5).
2
3
4
5
6
7
8
9
C6H13
6b
6c
6d
6e
6f
70
72
79
80
69
71
70
74
C10H21
C14H29
C3H6OH
CH2NHCbz
C2H4Ph
6g
6h
6i
CH2CH2CO2H
(CH2)8CO2H
a Reaction conditions: alkene (0.4 mmol), phenylphosphinic acid (0.2
mmol), dioxane (4 mL, 0.1 M alkene concentration), 100 W initial micro-
wave power level, 160 °C, 60 min.
b After column chromatography.
c Alkene (0.6 mmol).
d Alkene (0.8 mmol).
Reactions attempted with electron-deficient alkenes
(methyl acrylate, styrene, acrylic acid, and cinnamic acid)
proceeded in very low yield, thus making this methodology
inappropriate for the preparation of the corresponding
phosphinic acids. However, these materials can be satisfac-
torily prepared using the well-established silyl-mediated
phospha-Michael reaction.21
To verify the driving force of this reaction, several ex-
periments were conducted. When hydrophosphinylation
was attempted under thermal conditions, no desired prod-
uct was detected by 31P NMR analysis (Table 6, entries 1 and
H-Phosphinic acids 3 were the next substrates tested for
the microwave-assisted hydrophosphinylation reaction (Ta-
ble 3). The reaction did proceed, albeit in lower yield com-
pared to hypophosphorous acid and phenyl phosphinic ac-
id. Therefore, symmetrical di-n-dodecylphosphinic acid
(7a) was prepared along with nonsymmetrical dialkyl
phosphinic acids bearing a carboxyl group (Table 3, entry 3)
and Cbz amine (entry 2) in moderate yields using an
alkene/H-phosphinic acid ratio of 3:1.
>
>
>
&
>
>
Figure 1 Order of reactivity of olefins in hydrofunctionalizsation reactions
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2714–2719

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Table 4 Microwave-Assisted Reaction of Hypophosphorous Acid with
Table 5 Microwave-Assisted Reaction of Phenylphosphinic Acid with
Internal Alkenesa
Internal Alkenesa
O
H
R
O
O
P
dioxane
MW
R
R
R
R
aq H3PO2
+
P
+
PH
OH
dioxane
MW
OH
Ph
R
R
R
OH
10
5
8
1
8
9
Entry Alkene
Product 9
31P NMR Isolated
yield (%)b yield (%)c
Entry
Alkene
Product
Isolated
yield (%)b
O
O
O
H
Ph
P
P
P
P
68
1
52d
64e
65
1
54
94
OH
OH
9a
10a
10b
O
H
Ph
OH
2
3
4
95
50
53
90
41
47
2
3
OH
9b
9c
O
O
Ph
OH
P
H
P
C3H7
H7C3
32
39
OH
10c
O
H
O
P
Ph
P
OH
OH
4
9d
O
H
10d
P
OH
O
5
6
31
37
28
30
P
5
6
33
20
N
N
HO Ph
Cbz
Cbz
10e
9e
O
O
P
P
H
Ph
N
N
OH
OH
Cbz
9f
Cbz
10f
a Reaction conditions: alkene (0.4 mmol), aq H3PO2 (0.8 mmol), dioxane 4
mL (0.1 M alkene concentration), 100 W initial microwave power level,
180 °C, 60 min.
a Reaction conditions: alkene (0.4 mmol), phenylphosphinic acid (0.2
mmol), dioxane (4 mL, 0.1 M alkene concentration), 100 W initial micro-
wave power level, 160 °C, 60 min.
b Determined by integration of all signals. The yields are accurate within
10% of the value indicated.
b After column chromatography.
c After workup and column chromatography when necessary.
d H3PO2 aq (0.4 mmol).
e H3PO2 aq (2.0 mmol).
A plausible pathway for the hydrophosphinylation is
shown in Scheme 4. Upon microwave irradiation in the
presence of oxygen, the H-phosphinic acid is converted into
a phosphoryl radical, a well-known reactive species in
phosphorus chemistry.22 This radical attacks the terminal
carbon of the alkene 2 selectively in an anti-Markovnikov
manner to form a carbon-centered phosphoroalkyl radical.
This intermediate abstracts hydrogen from the unreacted
H-phosphinic acid, affording the final alkyl phosphinic acid
and a new radical, thus propagating the radical chain.
2). When a radical scavenger (TEMPO) was added, the reac-
tion was completely suppressed (entry 3), which suggests
that the reaction proceeds via radicals. When a degassed re-
action mixture was subjected to microwave irradiation, no
product was formed (entry 4), suggesting that oxygen is re-
quired for the production of the phosphoryl radicals, which
is in accordance with previous findings.6a,9
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Table 6 Thermal, Degassing, and Radical Trapping Experiments
Entry
Conditions
Yield (%)a
1
2
3
4
50% aq H3PO2 (2.0 mmol), 1-decene (0.4 mmol), dioxane (4 mL), reflux, 2 h
0
0
0
0
Phenyphosphinic acid (0.2 mmol), 1-decene (0.4 mmol), dioxane (4 mL), reflux, 2 h
Phenyphosphinic acid (0.2 mmol), 1-decene (0.4 mmol), dioxane (4 mL), TEMPO (0.2 mmol), 160 °C, 100 W, 1 h
50% aq H3PO2 (2.0 mmol), 1-decene (0.4 mmol), dioxane (4 mL), degassing, 180 °C, 100 W, 1 h
a Yields were determined by 31P NMR spectroscopy.
OH
P
R2
O
P
(4) (a) Dubert, O.; Gautier, A.; Condamine, E.; Piettre, S. R. Org. Lett.
2002, 4, 359. (b) Gautier, A.; Garipova, G.; Salcedo, C.; Balieu, S.;
Piettre, S. R. Angew. Chem. Int. Ed. 2004, 43, 5963.
(5) (a) Nifant'ev, E. E.; Magdeeva, R. K.; Shchepet'eva, N. P. J. Gen.
Chem. USSR 1980, 50, 1416. (b) Karanewsky, D. S.; Badia, M. C.;
Cushman, D. W.; DeForrest, J. M.; Dejneka, T.; Loots, M. J.; Perri,
M. G.; Petrillo, E. W.; Powell, J. R. J. Med. Chem. 1988, 31, 204.
(c) Jessop, C. M.; Parsons, A. F.; Routledge, A.; Irvine, D. Tetrahe-
dron Lett. 2003, 44, 479. (d) Antczak, M. I.; Montchamp, J.-L. Syn-
thesis 2006, 3080. (e) Jessop, C. M.; Parsons, A. F.; Routledge, A.;
Irvine, D. J. Eur. J. Org. Chem. 2006, 1547.
(6) (a) Deprèle, S.; Montchamp, J.-L. J. Org. Chem. 2001, 66, 6745.
(b) Feng, Y.; Coward, J. K. J. Med. Chem. 2006, 49, 770.
(7) (a) Yoo, W.-J.; Kobayashi, S. Green Chem. 2013, 15, 1844.
(b) Kawaguchi, S.-I.; Nomoto, A.; Sonoda, M.; Ogawa, A. Tetrahe-
dron Lett. 2009, 50, 624.
R1
R1
R2
H
O2
R3
O
O
P
R2
P
R2
R1
R1
R3
O
O
P
R1
R2
P
R2
R1
R3
H
Scheme 4 Proposed reaction mechanism
(8) Li, Z.; Fan, F.; Zhang, Z.; Xiao, Y.; Liu, D.; Liu, Z.-Q. RSC Adv. 2015,
5, 27853.
(9) Hirai, T.; Han, L.-B. Org. Lett. 2007, 9, 53.
(10) Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L.; Laberge,
L.; Rousell, J. Tetrahedron Lett. 1986, 27, 279.
(11) de la Hoz, A.; Diaz-Ortiz, A.; Moreno, A. Chem. Soc. Rev. 2005, 34,
164.
(12) Guenin, E.; Meziane, D. Curr. Org. Chem. 2011, 15, 3465.
(13) Stockland, R. A. Jr.; Taylor, R. I.; Thompson, L. E.; Patel, P. B. Org.
Lett. 2005, 7, 851.
In summary, a rapid and efficient microwave-assisted
hydrophosphinylation of unactivated alkenes and H-phos-
phinic acid and its derivatives has been established.23 The
advantages of this methodology lie in the absence of added
metal or radical initiator and the direct use of aqueous
H3PO2. This protocol has been applied using aqueous hypo-
phosphorous acid, phenyl phosphinic acid, and H-alkyl
phosphinic acid usually with good to excellent yields.
(14) Gabriel, C.; Gabriel, S.; Grant, E. H.; Halstead, B. S. J.; Mingos, D.
M. P. Chem. Soc. Rev. 1998, 27, 213.
(15) Markoulides, M. S.; Regan, A. C. Org. Biomol. Chem. 2013, 11,
119.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560210.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(16) Keglevich, G.; Kiss, N. Z.; Mucsi, Z.; Körtvélyesi, T. Org. Biomol.
Chem. 2012, 10, 2011.
(17) Anderson, N. G.; Coradetti, M. L.; Cronin, J. A.; Davies, M. L.;
Gardineer, M. B.; Kotnis, A. S.; Lust, D. A.; Palaniswamy, V. A.
Org. Process Res. Dev. 1997, 1, 315.
(18) Ong, J.; Harrison, N. L.; Hall, R. G.; Barker, J. L.; Johnston, G.; Kerr,
D. Brain Res. 1990, 526, 138.
(19) (a) Olah, G. A.; Molnár, Á. In Hydrocarbon Chemistry; John Wiley
and Sons: Hoboken, NJ, 2003, 2nd ed. (b) Hydrofunctionalization,
In Topics in Organometallic Chemistry; Vol 43; Ananikov, V. P.;
Tanaka, M., Eds.; Springer: Berlin, 2013.
(20) Ortial, S.; Fisher, H. C.; Montchamp, J.-L. J. Org. Chem. 2013, 78,
6599.
References and Notes
(1) (a) Corbridge, D. E. C. In Phosphorus: Chemistry, Biochemistry
and Technology; CRC Press: London, 2013, 6th ed. (b) Quin, L. D.
In A Guide to Organophosphorus Chemistry; Wiley-Interscience:
Hoboken, NJ, 2000. (c) Hartley, F. R. The Chemistry of Organo-
phosphorus Compounds; Vol. 4; Wiley: New York, 1996.
(2) For selected reviews on C–P bond formation, see: (a) Engel, R.;
Cohen, J. I. Synthesis of Carbon–Phosphorus Bonds; CRC Press:
Boca Raton, 2003, 2nd ed. (b) Wicht, D. K.; Glueck, D. S. In Cata-
lytic Heterofunctionalization; Togni, A.; Grützmacher, H., Eds.;
Wiley-VCH: Weinheim, 2001. (c) Delacroix, O.; Gaumont, A.-C.
Curr. Org. Chem. 2005, 9, 1851. (d) Schwan, A. L. Chem. Soc. Rev.
2004, 33, 218. (e) Tanaka, M. Top. Curr. Chem. 2004, 232, 25.
(f) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104,
3079. (g) Baillie, C.; Xiao, J. Curr. Org. Chem. 2003, 7, 477.
(21) Enders, D.; Saint-Dizier, A.; Lannou, M.-I.; Lenzen, A. Eur. J. Org.
Chem. 2006, 29.
(22) Demmer, C. S.; Krogsgaard-Larsen, N.; Bunch, L. Chem. Rev.
2011, 111, 7981.
(23) Typical Procedures
Procedure A
(3) Coudray, L.; Montchamp, J.-L. Eur. J. Org. Chem. 2008, 3601.
H3PO2 (50% aq, 0.21 mL, 2 mmol), 10-undecenoic acid (74 mg,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2714–2719

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0.4 mmol), and dioxane (4 mL) were added to a 10 mL micro-
wave vial containing a Teflon-coated stirrer bar and a septum.
The vial was sealed and heated under microwave irradiation at
180 °C (100 W) for 1 h. After cooling to r.t. the reaction mixture
was partitioned between CH2Cl2 (15 mL) and H2O (10 mL), the
organic phase was dried over Na2SO4, filtered, and concentrated
under reduced pressure. Chromatographic purification on silica
gel using CH2Cl2–MeOH–AcOH = 9:1:0.5 as eluent afforded 11-
(hydroxyhydrophosphoryl)undecanoic acid (3i) as a white solid
(40 mg, 45%); mp 82–84 °C.Rf = 0.41 (CHCl3–MeOH–AcOH =
7:1:0.5). 1H NMR (200 MHz, DMSO): δ = 8.23 (br s, 1 H), 5.64 (s,
1 H), 2.18 (t, J = 7.2 Hz, 2 H), 1.51–1.18 (m, 18 H). 13C NMR (50
MHz, DMSO): δ = 174.6, 33.7, 29.9 (d, JPCC = 15.1 Hz), 28.9, 28.9,
5.05 (s, 2 H), 3.21 (s, 2 H), 2.58 (s, 2 H), 1.64 (s, 10 H). 13C NMR
(50 MHz, CDCl3): δ = 156.5, 141.8, 136.4, 128.5, 128.3, 128.0,
125.8, 66.6, 41.2, 35.4, 32.5 (d, JPCC = 4.0 Hz), 30.9 (d, JPC = 140.6
Hz), 30.6 (d, JPC = 128.8 Hz), 29.6 (d, JPCC = 4.0 Hz), 22.6, 22.1,
21.3, 14.1. 31P NMR (81 MHz, CDCl3): δ = 59.66. ES-MS (TOF):
m/z calcd for C21H28NO4P [M – H]–: 388.17; found: 388.22.
HRMS: m/z calcd for C21H28NO4P [M – H]–: 388.1683; found:
388.1688.
Procedure D
H3PO2 (50% aq, 84 μL, 0.8 mmol), cyclododecene (66 mg, 0.4
mmol), and dioxane (4 mL) were added to a 10 mL microwave
vial containing a Teflon-coated stirrer bar and a septum. The
vial was sealed and heated under microwave irradiation at
180 °C (100 W) for 1 h. After cooling to r.t. the reaction mixture
was partitioned between CH2Cl2 (15 mL) and H2O (4 mL), the
organic phase was dried over Na2SO4, filtered, and concentrated
under reduced pressure. Chromatographic purification on silica
gel using CH2Cl2–MeOH–AcOH = 9:1:0.5 as eluent afforded
cyclododecylphosphinic acid (9e) as a viscous oil (26 mg,
28%).Rf = 0.35 (CHCl3–MeOH–AcOH = 9:1:0.5). 1H NMR (200
MHz, CDCl3): δ = 9.98 (s, 1 H), 6.91 (d, J = 527.5 Hz, 1 H), 1.45–
1.30 (m, 23 H). 13C NMR (50 MHz, CDCl3): δ = 33.7 (d, JPC = 90.7
Hz), 25.5 (d, JPCC = 13.1 Hz), 23.6, 23.2, 22.4. 31P NMR (81 MHz,
CDCl3): δ = 44.80. MS (ES): m/z calcd for C12H24O2P [M – H]–:
231.15; found: 231.27. HRMS (TOF): m/z calcd for C12H24O2P [M
– H]–: 231.1519; found: 231.1512.
28.8, 29.7 (d, JPC = 95.6 Hz), 28.6, 24.57, 20.8 (d, JPCC = 2.7 Hz). 31
NMR (81 MHz, DMSO): δ = 31.74. MS (ES): m/z calcd for
P
C
11H23O4P [M – H]–: 249.13; found: 249.25. HRMS (TOF): m/z
calcd for C11H23O4P [M – H]–: 249.1261; found: 249.1259.
Procedure B
Phenyphosphinic acid (28 mg, 0.2 mmol), benzyl allyl carba-
mate (76 mg, 0.4 mmol), and dioxane (4 mL) were added to a 10
mL microwave vial containing a Teflon-coated stirrer bar and a
septum. The vial was sealed and heated under microwave irra-
diation at 160 °C (100 W) for 1 h. After cooling to r.t. the reac-
tion mixture was purified by column chromatography on silica
gel using CH2Cl2–MeOH–AcOH = 9:0.5:0.5 as eluent to give (3-
{[(benzyloxy)carbonyl]amino}propyl)(phenyl)phosphinic acid
(6f) as an oil (46 mg, 69%).Rf = 0.50 (CHCl3–MeOH–AcOH =
7:1:0.5). 1H NMR (200 MHz, CDCl3): δ = 7.84–7.01 (m, Ar, 10 H),
5.04 (s, 2 H), 3.13 (s, 2 H), 1.95–1.48 (m, 4 H). 13C NMR (50 MHz,
CDCl3): δ = 156.4, 136.5, 132.1, 131.0, 128.4, 128.0, 66.5, 41.1,
27.5 (d, JPC = 92.8 Hz), 22.5. 31P NMR (81 MHz, CDCl3): δ = 45.25.
MS (ES): m/z calcd for C17H20NO4P [M – H]–: 332.11; found:
332.14. HRMS (TOF): m/z calcd for C17H20NO4P [M – H]–:
332.1057; found: 332.1068.
Procedure E
Phenyphosphinic acid (28 mg, 0.2 mmol), N-carbobenzoxy-3-
pyrroline (81 mg, 0.4 mmol), and dioxane (4 mL) were added to
a 10 mL microwave vial containing a Teflon-coated stirrer bar
and a septum. The vial was sealed and heated under microwave
irradiation at 160 °C (100 W) for 1 h. After cooling to r.t. the
reaction mixture was purified by column chromatography on
silica gel using CH2Cl2–MeOH–AcOH = 9:0.5:0.5 as eluent to give
{1-[(benzyloxy)carbonyl]pyrrolidin-3-yl}(phenyl)phosphinic
acid (10e) as a white solid (23 mg, 33%); mp 121–123 °C
Procedure C
(4-Phenylbutyl)phosphinic acid (3f, 79 mg, 0.4 mmol), benzyl
allylcarbamate (229 mg, 1.2 mmol), and dioxane (4 mL) were
added to a 10 mL microwave vial containing a Teflon-coated
stirrer bar and a septum. The vial was sealed and was heated
under microwave irradiation at 180 °C (100 W) for 1 h. After
cooling to r.t. the reaction mixture was purified by column
chromatography on silica gel using CH2Cl2–MeOH–AcOH =
9:0.5:0.5 as eluent to (3-{[(benzyloxy)carbonyl]amino}pro-
pyl)(4-phenylbutyl)phosphinic acid (7b) as a white solid (78
1
Rf = 0.60 (CH2Cl2–MeOH–AcOH = 9:0.5:0.5). H NMR (200 MHz,
CDCl3): δ = 7.64–7.29 (m, 10 H), 5.04 (s, 2 H), 3.33–3.12 (m, 4 H),
2.33 (s, 1 H), 1.86 (s, 2 H). 13C NMR (150 MHz, CDCl3): δ = 154.4,
136.8, 132.0, 131.4, 130.8 (d,JPCC = 4.3 Hz), 128.4, 127.8
(d,JPCCC = 9.7 Hz), 66.7, 46.3 (d,JPCCC = 32.8 Hz), 45.7, 39.3
(d,JPCC = 93.8 Hz), 25.7 (d,JPC = 103.2 Hz). 31P NMR (81 MHz,
CDCl3): δ = 40.14. MS (ES): m/z calcd for C18H19NO4P [M – H]–:
344.11; found: 344.16. HRMS (TOF): m/z calcd C18H19NO4P [M –
H]–: 344.1057; found: 344.1061.
mg, 50%); mp 137–139 °C.Rf = 0.44 (CHCl3–MeOH–AcOH
9:0.5:0.5). H NMR (200 MHz, CDCl3): δ = 7.45–7.06 (m, 10 H),
=
1
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2714–2719