Temporary protection of H-phosphinic acids as a synthetic strategy

Article abstract of DOI:10.1002/ejoc.200900694

H-Phosphinates obtained through, various methodologies are protected directly by the reaction with triethyl orthoacetate. The resulting products can be manipulated easily, and various synthetic reactions are presented. For example, application to the synt

Full text of DOI:10.1002/ejoc.200900694

FULL PAPER
DOI: 10.1002/ejoc.200900694
Temporary Protection of H-Phosphinic Acids as a Synthetic Strategy
Laëtitia Coudray[a] and Jean-Luc Montchamp*[a]
Keywords: Phosphorus / Palladium / Metathesis / Cross-coupling / Synthetic methods
H-Phosphinates obtained through various methodologies are
protected directly by the reaction with triethyl orthoacetate.
The resulting products can be manipulated easily, and
various synthetic reactions are presented. For example, ap-
plication to the synthesis of aspartate transcarbamoylase
(ATCase) or kynureninase inhibitors are illustrated. Other re-
actions, such as Sharpless’ asymmetric dihydroxylation, or
Grubbs’ olefin cross-metathesis are also demonstrated.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
ceed with low loadings of transition-metal catalysts or with
a radical initiator, and either no by-product is created (ad-
dition/hydrophosphinylation) or water is formed (condensa-
tion/cross-coupling). As a result, many H-phosphinates are
now accessible directly, through routes unavailable to the
Ciba-Geigy reagents. However, H-phosphinates are often
not compatible with many reactions (oxidation/reduction,
etc.) that would modify the carbon chain, so a temporary
protection scheme is sometimes necessary. We recently re-
ported one solution to this problem, based on borane com-
plexes.[4] Because our methodologies provide compounds
which cannot be made easily (or efficiently) from reagents
2 or 3, we decided to investigate a protection strategy based
on acetals. Perhaps surprisingly, few reports have described
the reaction of H-phosphinates with orthoesters. There is
only one reference that describes the reaction of a single H-
phosphinic acid with triethyl orthoformate,[5] and none with
triethyl orthoacetate (Table 1).
Introduction
Gallagher, and soon afterwards chemists at Ciba-Geigy
(formerly) have introduced and developed an ingenious
family of reagents in which one P–H bond of hypophos-
phorous acid (HPA, H3PO2, 1) is masked temporarily and
then re-introduced in a later step.[1] This allows selective
reactions and solves the problem of disubstitution of the
two reactive P–H bonds in HPA. We have been referring to
these reagents as “Ciba-Geigy reagents” [ethyl 1,1-(di-
ethoxyethyl)- and 1,1-(diethoxymethyl)-H-phosphinates,
RC(OEt)2P(O)(OEt)H, R = Me, H; 2 and 3, respectively],
in keeping with their historical origins. Reagents 2 and 3
have permitted the synthesis of many phosphinic acid deriv-
atives through alkylation, and they have been used rather
extensively.[2] Reagent 2 is often superior to reagent 3 be-
cause cleavage of the acetal functionality takes place under
milder conditions and without cleavage of the P(O)OEt
ester group.[1d]
Table 1. Literature references to access protected phosphinates.[a]
H3PO2
R2PCl
RPO2H2
RP(O)(OR1)H
[1]
[1]
[6]
[4]
[7]
[5]
[1a,1b,8]
[1g,9]
[10]
(EtO)3CH
[7]
(EtO)3CMe
H2C=C(OEt)2
TIPSCl/BH3
this work
–
–
–
Over the past ten years, we have developed several reac-
tions for the synthesis of H-phosphinates, directly from hy-
pophosphorous precursors (HPA, anilinium and sodium
hypophosphites, alkyl phosphinates, etc.).[3] Many of these
reactions provide an environmentally benign access to H-
phosphinates, because halogenated compounds and/or
stoichiometric strong bases are avoided, the reactions pro-
[4]
[4]
[a] See references.
During the synthesis of an aspartate transcarbamoylase
(ATCase) inhibitor, we recently were confronted with the
need to protect cinnamyl-H-phosphinic acid before an
ozonolysis step, and we successfully employed triethyl or-
thoacetate to prepare 4 in excellent yield [Equation (1)].[11]
We realized that this strategy would be synthetically useful,
and this prompted the present study on the direct synthesis
of various ethyl (1,1-diethoxyethyl)phosphinates from H-
phosphinic acids, and some of their reactivity.
[a] Department of Chemistry, Box 298860, Texas Christian Univer-
sity,
Fort Worth, Texas 76129, USA
Fax: +1-817-257-5851,
E-mail: j.montchamp@tcu.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900694.
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Temporary Protection of P–H Acids as a Synthetic Strategy
using a strong base and an electrophile, they can be silylated
and alkylated, and some cross-coupling chemistry has been
reported (with high loadings of palladium catalyst).
Even our protecting strategy based on phosphonite–
borane complexes
7 obtained either from 5 or 9
(1)
(Scheme 1),[4] is not competitive because, for example, the
simple hydrogenation of an alkene is sluggish [Equation
(2)], and if the same reaction is conducted in methanol, de-
complexation of the borane takes place exclusively.
Herein, we report on the reaction of H-phosphinic acids
with triethyl orthoacetate, as well as some subsequent trans-
formations not previously exploited in the literature. The
synthetic transformations illustrated include oxidations
(ozonolysis, epoxidation, Sharpless’ asymmetric dihydrox-
ylation), reductions (hydrogenation, hydroboration), Buch-
wald–Hartwig amination, and olefin cross-metathesis. All
these reactions are not compatible with free P–H bonds, at
least in our hands.
(2)
The protection of dichlorophosphanes 8 (Scheme 1 and
Table 1) has been used, especially with ClCH2PCl2, but the
lack of availability of these compounds is a significant
limitation (in fact, 8 can be made from 5, R2 = H).
Results and Discussion
The advantages of our strategy (Scheme 1), over the use
of the Ciba-Geigy reagents, stems from the much wider
availability of H-phosphinates 5 using our methodologies,
as well as the more practical nature of using triethyl ortho-
acetate on H-phosphinates 5 instead of HPA 1, or the sim-
pler purification of the products 5 as opposed to purifying
2 and 3. Thus, although the two strategies are only differing
in the order of the steps, the limited transformations avail-
able from 2 (or 3) to compounds 6 are narrowing the scope
of these reagents. For example, 2 and 3 can be alkylated
1. Synthesis of Phosphinate Acetals 6 from H-Phosphinates
5
Because the reaction of H-phosphinic acids with triethyl
orthoacetate has not been described previously,[12] we de-
cided to investigate its scope. Table 2 shows the results of
this study. All the substrates are readily available through
various methodologies we have developed. Isolated yields
of protected acetals range from moderate to good (41–80%)
for a wide range of functionalized substrates.
As described for other phosphinylidene-containing com-
pounds, BF3·Et2O in a sub-stoichiometric amount was sat-
isfactory in general (Method A, Table 1). In some cases, a
small amount of ytterbium triflate also gave good results,
especially in hydroxy-containing substrates. In this case,
some acetate is directly obtained as a mixture with the
alcohol, so acetylation was conducted on the crude reaction
mixture. With alcohol-containing substrates, partial esterifi-
cation was observed, and acetylation was conducted to
drive the reaction to completion (Method E). With
BF3·Et2O, a full equivalent was used for alcohols (Method
D).
Triethyl orthoformate is less satisfactory (Method B), but
only useful in cases where the H-phosphinic acid intermedi-
ate is ultimately desired because selective deprotection is
problematic.[2] Attempts at using the literature condition
(pTosOH),[5] or BF3·Et2O, did not give good results.
2. Synthetic Applications with Compounds 6
Several reactions were tried on protected ethyl H-phos-
phinates 6 (Schemes 2 and 3).
Dihydroxylation of allyl-H-phosphinate 10 (Scheme 2)
proceeds in good yield to afford diol 11. Compound 11 can
be used to prepare phospholipid analogs, and this will be
investigated in future work. Hydrolysis of 11 afforded H-
phosphinate 12 in quantitative yield. Diol 12 was also oxid-
ized using our catalytic process[3h] to afford phosphonic
Scheme 1. Strategies for the synthesis of protected phosphinates.
R1 = H, Me; R2 = H, Et; R3 = TIPS, Et. [a] (i) TIPSCl/Et3N
(1.5/1.6 equiv.), CH3CN, 0 °C to room temp., 14 h; (ii) BH3·Me2S
(2.0 equiv.), CH3CN, room temp., 5 h.
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L. Coudray, J.-L. Montchamp
FULL PAPER
Table 2. Protection of H-phosphinates.
Scheme 2. Dihydroxylation, hydroboration, and Buchwald–Hart-
wig amination.
[a] Method A: BF3·Et2O (0.2 or 0.5 equiv.), CH3C(OEt)3
(6.0 equiv.), room temp., N2, 16–24 h; Method B: HC(OEt)3
(60 equiv.), reflux, N2, 24 h; Method C: Yb(OTf)3 (3 mol-%),
CH3C(OEt)3 (6.0 equiv.), THF (0.4 ), room temp., N2, 22 h;
Method D: BF3·Et2O (1.0 equiv.), CH3C(OEt)3 (6.0 equiv.), room
temp., N2, 4 h then at 0 °C, pyridine (10.0 equiv.) and Ac2O
(5.0 equiv.), room temp., N2, 4 h; Method E: Yb(OTf)3 (3 mol-%),
CH3C(OEt)3 (6.0 equiv.), room temp., N2, 3 h then at 0 °C, pyridine
(10.0 equiv.) and Ac2O (5.0 equiv.), room temp., N2, 4 h. [b] Iso-
lated yields (unless otherwise noted). [c] NMR yield. [d] Acetate.
acid 13. Hydroboration/oxidation of 10 proceeded unevent-
fully to afford alcohol 14 in 71% yield. Another important
reaction (Scheme 2) is the palladium-catalyzed cross-cou-
pling of chloride 15. Buchwald–Hartwig amination took
place in moderate yield to afford aniline derivative 16. Be-
cause H-phosphinates can undergo oxidation or cross-cou-
pling, protection of the P–H functionality is necessary to
perform these reactions.
Scheme 3. Reactions of compound 4.
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Temporary Protection of P–H Acids as a Synthetic Strategy
A series of reactions was performed on ethyl cinnamyl-
1,1-(diethoxy)ethylphosphinate (4) (Scheme 3). Unlike the
sluggish hydrogenation of borane complexes [Equation (2)],
hydrogenation of 4 under standard conditions takes place in
quantitative yield to produce 17. The presence of a phos-
phinylidene functionality P(O)H seems to be incompatible
with hydrogenation as we have never been able to conduct
the heterogeneous hydrogenation of H-phosphinic acids or
esters, most likely because of complexation to Pd and poi-
soning of the catalyst. Hydroboration of 4 gave a mixture
of regioisomers 18 (97% NMR yield) in low yield after chro-
matographic separation of each isomer (18a and 18b). On
the other hand, epoxidation gave racemic 19 in moderate
yield. Finally, Sharpless’ asymmetric dihydroxylation[13] gave
the corresponding diol 20 in good yield. Interestingly, no
kinetic resolution was observed in the formation of 20. As
in Scheme 2, acidic hydrolysis delivered the diol 21 in quan-
titative yield and 59% ee. The absolute configuration was
assigned based on the Sharpless–Corey models.[14] Enantio-
meric excess determination was based on the formation of a
diastereomeric salt with quinine and 31P NMR analysis.
Another illustration of our strategy is an improved syn-
thesis of a potent ATCase inhibitor (Ki = 0.42 µ, 27,
Scheme 4).[11] Initially, we used the temporary protection
strategy with cinnamyl-H-phosphinic acid [Equation (1)],
but because no purification was conducted, the benzoic
acid side product required an adjustment in stoichiometry
for the amidation step. Instead, we realized that isoprenyl-
ation would give volatile acetone after ozonolysis/reduction
and so the reaction product would be cleaner and the subse-
quent yield higher. We have previously described the hydro-
phosphinylation of isoprene,[3n] and low catalyst loading
can be employed. In spite of this, selection of our reusable
polystyrene-supported catalyst[3l] for the hydrophosphin-
ylation of isoprene was superior, resulting in a quantitative
yield of product 22 after 5 runs of nixantphos-polymer 23
recycling (Scheme 4).
Scheme 4. Improved synthesis of ATCase inhibitor 27.
Isoprenyl-H-phosphinic acid (22) was protected accord-
ing to method A (Table 1, Entry 3) to produce 24. The syn-
thesis of 22 and subsequently 24 is much more efficient and
environmentally friendly than the alternative alkylation of
2 with isoprenyl halides (either through deprotonation or
silylation of 2) would be (Scheme 1). Ozonolysis and oxi-
dation of 24 with sodium chlorite[15] gave the corresponding
carboxylic acid 25, which was used without intermediate
isolation. Deprotection of the resulting amide 26 through
hydrogenolysis of the benzyl groups, and acid hydrolysis of
the acetal provided inhibitor 27 in good yield after ion-ex-
change chromatography.
Another application of building block 24, this time
through an ozonolysis/Strecker sequence is shown in
Scheme 5. Compound 28 could be hydrolyzed to the phos-
phinyl analog 29 of aspartic acid,[16] or it could be N-pro-
tected to 30, P-deprotected selectively, then cross-coupled
to an aryl halide to form 32[17] after deprotection of inter-
mediate 31.[18] This strategy could be applied to the combi-
natorial synthesis of other kynureninase inhibitors 32 by
selecting other aryl halides for coupling.
Scheme 5. Syntheses of phosphinylaspartate analog 29 and kynur-
eninase inhibitor 32.
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L. Coudray, J.-L. Montchamp
FULL PAPER
Kynureninase inhibitors have potential for the blockage cessible. Future work from our laboratory will investigate
of quinolinic acid biosynthesis. Quinolinic acid has been the synthesis of phospholipid analogs and additional asym-
implicated in various neurological disorders, such as epi- metric reactions on protected phosphinates 6, as well as
lepsy, Huntington’s disease, and AIDS-related dementia.[17] Tsuji–Trost-type allylation reactions on unsaturated ace-
Thus, our method offers a flexible entry to prepare various tates.
analogs of 33 which could have useful biological activities.
The last example of a reaction on protected phosphinic
acid 10 is shown in Equation (3). Olefin metathesis of phos-
phorus-containing compounds,[19] as well as cross-metathe-
sis of phosphonates[20] are known, but no example related
to the cross-metathesis of phosphinic acids has ever been
reported. Phosphinylidene-containing compounds are not
reactive partners in this reaction, but temporary protection
clearly solves this problem. Cross-metathesis of 10 using the
“second generation Grubbs’ catalyst” 34 afforded acrylate
33 in good yield.
Experimental Section
General Procedure for the Protection of H-Phosphinates: (Table 2,
Method A). To H-phosphinic acid or H-phosphinic acid ethyl ester
(5.0 mmol, 1.0 equiv.) were added triethyl orthoacetate (5.5 mL,
30.0 mmol, 6.0 equiv.) and boron trifluoride–diethyl ether (0.13 or
0.31 mL, 1.0 or 2.5 mmol, 0.2 or 0.5 equiv.) at room temp. The
reaction mixture was vigorously stirred for 16–24 h under N2 at
room temp. to afford a yellow solution. The reaction mixture was
diluted with ethyl acetate (50 mL) and washed with 0.5  aqueous
NaHCO3 (1ϫ15 mL) then brine (2ϫ15 mL). The organic layer
was dried with MgSO4 and concentrated in vacuo. The resulting
oil was purified by chromatography over silica to afford the clean
product.
Ethyl (1,1-Diethoxyethyl)cinnamylphosphinate (4): [Equation (1),
Table 2, Entries 1a and 2a]. Method A, 0.2 equiv. BF3·OEt2, 24 h,
using cinnamyl-H-phosphinic acid.[21] Chromatography over silica
gel (hexanes/ethyl acetate, 6:4, v/v) afforded 4 as a light yellow oil
(1.3 g, 80% yield). 1H NMR (300 MHz, CDCl3): δ = 7.20–7.38 (m,
3
4
5 H, CHarom.), 6.53 (dd, JH,H = 16.0, JHCCCP = 4.0 Hz, 1 H,
-CH=), 6.19–6.31 (m, 1 H, -CH=), 4.15–4.28 (m, 2 H, -CH2-O),
3.60–3.83 (m, 4 H, -CH2-O), 2.71–2.92 (m, 2 H, -CH2-P), 1.54 (d,
3JHCCP = 11.0 Hz, 3 H, CH3-C-P), 1.31 (t, J = 7.0 Hz, 3 H,
(3)
3
CH3-), 1.22 (t, J = 7.0 Hz, 3 H, CH3-), 1.21 (t, JH,H = 7.0 Hz, 3
H, CH3-) ppm. 13C NMR (75.45 MHz, CDCl3): δ = 137.3, 134.8 (d,
JPCCC = 12.0 Hz), 128.8 (2 C), 127.7, 126.4 (d, JPCCCCC = 1.5 Hz, 2
C), 119.1 (d, JPCC = 10.5 Hz), 101.5 (d, JPC = 139.0 Hz), 62.1 (d,
JPOC = 7.0 Hz), 58.5 (d, JPCOC = 5.0 Hz), 57.0 (d, JPCOC = 7.0 Hz),
Conclusions
31.7 (d, JPC = 82.5 Hz), 20.8 (d, JPCC = 12.0 Hz), 17.0 (d, JPOCC
=
The temporary protection of H-phosphinic acids has not
been described previously. In spite of 20 years of successful
use of the Ciba-Geigy reagents, a more efficient approach
to useful synthetic intermediates has been developed. This
manuscript describes the synthesis of various temporarily
protected H-phosphinic acids for the synthesis of more
complex intermediates. Because numerous H-phosphinic
acids are now readily available using various environmen-
tally benign methodologies we have developed, the present
strategy offers an attractive alternative to others previously
described in the literature. For certain H-phosphinic acids
that can be difficult to purify, this method also allows puri-
fication and esterification, so the purified ethyl H-phos-
5.0 Hz), 15.7, 15.5 ppm. 31P NMR (121.47 MHz, CDCl3): δ = 45.96
(s) ppm. HR-MS (EI+): calcd. for C15H22O3P, [M – OEt]+
281.1307; found 281.1302.
Ethyl (1,1-Diethoxyethyl)[4-(phenylamino)phenyl]phosphinate (16):
(Scheme 2) In a sealed tube, K3PO4 (0.297 g, 1.4 mmol, 1.4 equiv.),
Pd2dba3 (0.0092 g, 0.01 mmol, 4.0 mol-%) and 2-(dicyclohexyl-
phosphanyl)-2Ј-(dimethylamino)biphenyl (0.017 g, 0.044 mmol,
4.4 mol-%) were added to the ester 15 (0.32 g, 1.0 mmol) in DME
(2.0 mL) at room temp. After 24 h at 100 °C, the reaction mixture
was cooled and filtered through Celite®. The solution was concen-
trated in vacuo and the resulting oil was purified by chromatog-
raphy over silica gel (hexanes/ethyl acetate, 4:6, v/v) to afford the
amine 16 as a colorless oil (0.197 g, 52%). 1H NMR (300 MHz,
3
phinate ester can be obtained easily after treatment with CDCl3): δ = 7.70 (dd, JH,H = 10.5, 3JH,H = 8.5 Hz, 2 H, CHarom.),
7.30–7.36 (m, 2 H, CHarom.), 7.18 (d, 3JH,H = 8.5 Hz, 2 H, CHarom.),
TMSCl/CHCl3. Even if P-diastereoselective reactions were
not observed and kinetic resolution could not be ac-
complished for the preparation of P-chiral compounds, the
present approach should be useful to phosphorus chemists
in general. From dihydroxylation to cross-coupling to cross-
metathesis, the temporary protection of H-phosphinic acids
as the corresponding acetals offers a new and efficient ap-
proach toward functional intermediates. Because deprotec-
tion of the 1,1-(diethoxy)ethyl group can deliver H-phos-
7.02–7.08 (m, 3 H, CHarom.), 4.02–4.26 (m, 2 H, -CH2-O), 3.56–
3.80 (m, 4 H, -CH2-O), 1.45 (d, 3JHCCP = 12.0 Hz, 3 H, CH3-C-P),
3
3
1.34 (t, JH,H = 7.0 Hz, 3 H, CH3-), 1.19 (t, JH,H = 7.0 Hz, 3 H,
CH3-), 1.18 (t, JH,H = 7.0 Hz, 3 H, CH3-) ppm. 13C NMR
3
(75.45 MHz, CDCl3): δ = 148.1 (d, JPCCCC = 2.5 Hz), 141.4, 134.7
(d, JPCC = 10.5 Hz, 2 C), 129.5 (2 C), 122.8, 120.5 (2 C), 118.1 (d,
JPC = 128.5 Hz), 114.9 (d, JPCCC = 13.0 Hz, 2 C), 101.6 (d, JPC
153.5 Hz), 61.4 (d, JPOC = 7.0 Hz), 58.4 (d, JPCOC = 5.5 Hz), 58.0
(d, JPCOC = 7.0 Hz), 20.5 (d, JPCC = 13.0 Hz), 16.9 (d, JPOCC
=
=
phinate esters or acids, a wide range of intermediates is ac- 5.5 Hz), 15.8, 15.6 ppm. 31P NMR (121.47 MHz, CDCl3): δ = 36.74
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Temporary Protection of P–H Acids as a Synthetic Strategy
(s) ppm. HR-MS (EI+): calcd. for C20H28NO4P, [M]+ 377.1756;
found 377.1754.
(50 mL) and washed with 0.5  aqueous HCl (1ϫ10 mL) and brine
(2ϫ20 mL). The organic layer was dried with MgSO4 and concen-
trated in vacuo. The resulting oil was purified by chromatography
over silica gel (hexanes/ethyl acetate, 6:4, v/v to ethyl acetate 100%)
to afford amide 26 as a lightly yellow oil (1.81 g, 66% yield). 1H
Isoprenyl-H-Phosphinic Acid 22. Synthesis with the Polymer Cata-
lyst:[3n] (Scheme 4, Table 2, phosphinate, Entry 3). In a sealed tube,
isoprene (0.5 mL, 5.0 mmol, 1.0 equiv.) was added to concentrated
H3PO2 (0.495 g, 7.5 mmol, 1.5 equiv.) in acetonitrile (10.0 mL,
0.5 ), followed by Pd2dba3 (0.023 g, 0.025 mmol, 0.5 mol-%) and
nixantphos-polystyrene catalyst 23[3l] (0.06 mmol, 1.2 mol-%). Af-
ter the tube was sealed, the reaction was heated at 85 °C for 12–
16 h. After cooling, the reaction was filtered and the polymer reco-
vered and used directly in another run. The combined filtrate from
5 reaction runs was concentrated in vacuo. The resulting crude was
diluted with ethyl acetate (75 mL) and washed with brine
(3ϫ20 mL). The organic layer was dried with MgSO4 and concen-
trated in vacuo to afford 22 as a light yellow oil (3.34 g, 100%). 1H
NMR (CDCl3, 300 MHz): δ = 10.91 (br. s, 1 H, OH), 6.94 (d, 1JHP
= 550 Hz, 1 H, H-P), 5.13 (m, 1 H, -CH=), 2.57 (dd, 2JHCP = 19.0,
3
NMR (300 MHz, CDCl3): δ = 7.88 & 7.75 (2d, JH,H = 8.0 Hz, 1
2
H, NH), 7.29–7.37 (m, 10 H, CHarom.), 5.10 & 5.09 (2d, JH,H
=
12.0 Hz, 4 H, Bn -CH2-), 4.90–4.98 (m, 1 H, -CH-N), 4.13–4.5 (m,
2 H, -CH2-O), 3.59–3.81 (m, 4 H, -CH2-O), 2.74–3.08 (m, 4 H,
-CH2- & -CH2-P), 1.49 (d, 3JHCCP = 12.0 Hz, 3 H, CH3-C-P), 1.17–
1.37 (m, 9 H) ppm. 13C NMR (75.45 MHz, CDCl3): δ = 170.3,
170.1, 164.6 (2d, JPCC = 8.5 Hz), 135.4, 135.2, 128.5 (2 C), 128.4
(2 C), 128.3, 101.0 (d, JPC = 150.5 Hz), 67.4, 66.8, 62.6 (2d, JPOC
= 8.0 Hz), 58.5 (2d, JPCOC = 5.0 Hz), 57.9 (2d, JPCOC = 8.0 Hz),
49.1 (d, JPCCNC = 10.5 Hz), 36.4 (d, JPCCNCC = 6.0 Hz), 34.6 &
34.5 (2d, JPC = 72.0 Hz), 20.0 (d, JPCC = 13.0 Hz), 16.5 (2d, JPOCC
= 4.5 Hz), 15.3, 15.6 ppm. 31P NMR (121.47 MHz, CDCl3): δ =
42.77 & 42.70 (2s) ppm. HRMS (CI, NH3): calcd. for C28H38NO9P,
([M + H]+) 564.2362; found 564.2355.
4
3JH,H = 8.0 Hz, 2 H, -CH2-P), 1.77 (d, JH,H = 4.0 Hz, 3 H, CH3-
4
C=), 1.66 (d, JH,H = 4.0 Hz, 3 H, CH3-C=) ppm. 13C NMR
H-Phosphinic Acid 27: (Scheme 4) To a solution of amide 26 (1.0 g,
1.78 mmol) in a mixture THF/H2O (2:1, v/v, 5.1 mL) was added
Pd/C (0.24 g, 10 wt.-%). The reaction was placed in a hydrogenator
at 50 psi H2 and room temp. After 17 h, the reaction mixture was
filtered through Celite® and concentrated in vacuo. The resulting
oil was dissolved in water (30 mL) and washed with CH2Cl2
(3ϫ10 mL). The aqueous layer was concentrated then dissolved
in a mixture THF/H2O (2:1, v/v, 12 mL) and treated with washed
Amberlite IR-120 plus (0.83 g). The suspension was heated at 80 °C
for 15 h under N2. After filtration, the reaction mixture was con-
centrated in vacuo. The resulting oil was dissolved in water, neutral-
ized at pH 7.0 and purified by ion exchange over AG-1 X8 anion
exchange resin (70 mL) which had been equilibrated with 100 m
(CDCl3, 75.45 MHz): δ = 138.4 (d, JPCCC = 14 Hz), 110.6 (d, JPCC
= 9 Hz), 30.1 (d, JPC = 92 Hz), 25.8 (d, JPCCCC = 3 Hz), 18.2 (d,
JPCCCC = 3 Hz) ppm. 31P NMR (CDCl3, 121.47 MHz): δ = 35.86
(dm, JPH = 550 Hz) ppm. HR-MS (EI+): calcd. for C5H11O2P,
[M]+ 134.0497; found 134.0494.
Ethyl (1,1-Diethoxyethyl)(3-methylbut-2-enyl)phosphinate (24):
(Scheme 4, Table 2, Entry 3). Method A, 0.2 equiv. BF3·OEt2, 24 h.
Chromatography over silica gel (hexanes/ethyl acetate, 7:3, v/v) af-
forded 24 as a light yellow oil (0.89 g, 64% yield). 1H NMR
(300 MHz, CDCl3): δ = 5.22–5.29 (m, 1 H, -CH=), 4.12–4.26 (m,
2 H, -CH2-O), 3.62–3.83 (m, 4 H, -CH2-O), 2.59 (dd, 2JHCP = 15.5,
4
3JH,H = 8.0 Hz, 2 H, -CH2-P), 1.77 (d, JH,H = 4.0 Hz, 3 H, CH3-
4
3
C=), 1.67 (d, JH,H = 4.0 Hz, 3 H, CH3-C=), 1.51 (d, JHCCP
=
–
Et3NH+HCO3 (pH 7.3). The column was washed with water
3
11.0 Hz, 3 H, CH3-C-P), 1.30 (t, JH,H = 7.0 Hz, 3 H, CH3-), 1.22
(60 mL) then eluted with a linear gradient (200 mL + 200 mL, 100–
(t, JH,H = 7.0 Hz, 6 H, CH3-) ppm. 13C NMR (75.45 MHz,
3
500 m) of Et3NH+HCO3 (pH 7.3). Fractions containing phos-
–
CDCl3): δ = 136.5 (d, JPCCC = 12.0 Hz), 112.6 (d, JPCC = 9.5 Hz),
101.4 (d, JPC = 137.0 Hz), 61.7 (d, JPOC = 7.0 Hz), 58.2 (d, JPCOC
= 4.5 Hz), 57.7 (d, JPCOC = 7.0 Hz), 26.2 (d, JPC = 84.5 Hz), 25.9
(d, JPCCCC = 2.5 Hz), 20.6 (d, JPCC = 12.0 Hz), 18.1 (d, JPCCCC
= 2.0 Hz), 16.7 (d, JPOCC = 5.5 Hz), 15.3, 15.6 ppm. 31P NMR
(121.47 MHz, CDCl3): δ = 47.30 (s) ppm. HRMS (CI, NH3): calcd.
for C13H28O4P, [M + H]+ 279.1725; found 279.1727.
phorus compounds were identified by using the Pi assay developed
by Ames[22] and concentrated. The resulting white residue was dis-
solved in water, the solution passed through a Dowex H+ column,
neutralized to pH 7 and then concentrated to afford H-phosphinic
acid 27 as a light yellow oil (0.243 g, 57% yield). 1H NMR
1
(300 MHz, D2O): δ = 6.95 (d, JHP = 540.0 Hz, 1 H, H-P), 4.22
3
3
(dd, JH,H = 9.0, JH,H = 4.0 Hz, 1 H, -CH-N), 2.47–2.58 (m, 3
2
3
Phosphinate 26: (Scheme 4): After saturation of a solution of the
ester 24 (1.37 g, 4.93 mmol, 1.0 equiv.) in CH2Cl2 (0.2 , 26.0 mL)
at –78 °C with ozone, Me2S (2.5 mL, 33.5 mmol, 6.8 equiv.) was
added under N2 at –78 °C. The reaction mixture was warmed up
to room temp. overnight, then the solution was concentrated in
vacuo. The resulting oil was dissolved in a mixture tBuOH/H2O
(2:1, v/v, 20 mL) and treated successively with 2-methylbutene
(0.5  in THF, 9.8 mL, 9.8 mmol, 2.0 equiv.), NaH2PO4·H2O
(1.0 g, 7.4 mmol, 1.5 equiv.) and NaClO2 (0.67 g, 3.4 mmol,
1.5 equiv.) at 0 °C. After 3 h at room temp., the reaction mixture
was diluted with ethyl acetate (50 mL) and washed with 10% aque-
ous tartaric acid (2ϫ15 mL). The aqueous layer was reextracted
with ethyl acetate (1ϫ20 mL). The combined organic layers were
dried with MgSO4 and concentrated in vacuo to afford compound
25 which was used without further purification.
H, -CH2-P, -CH2-), 2.35 (dd, JH,H = 16.0, JH,H = 9.0 Hz, 1 H,
-CH2-) ppm. 13C NMR (75.45 MHz, D2O): δ = 179.0, 178.8, 168.9,
53.6, 41.5 (d, JPC = 78.5 Hz), 39.8 ppm. 31P NMR (121.47 MHz,
D2O): δ = 20.76 (dt, JPH = 539.5, JPCH = 17.0 Hz) ppm. HRMS
(ESI+): calcd. for C6H10O7NP, ([M + Na]+) 262.0093; found
262.0096.
Ethyl (1,1-Diethoxyethyl)(2-amino-2-cyanoethyl)phosphinate (28):
(Scheme 5) After saturation of a solution of the ester 24 (0.834 g,
3.0 mmol, 1.0 equiv.) in CH2Cl2 (0.2 , 15.0 mL) at –78 °C with
ozone, Me2S (1.5 mL, 20.4 mmol, 6.8 equiv.) was added under N2
at –78 °C. The reaction mixture was warmed up to room temp.
overnight then the solution was concentrated in vacuo. The re-
sulting oil was dissolved in methanol (0.8 , 4.0 mL) then added
dropwise to a solution of sodium cyanide (0.25 g, 5.1 mmol,
1.7 equiv.), ammonium chloride (0.284 g, 5.4 mmol, 1.8 equiv.) in
25% aqueous ammonium hydroxide (1.0 , 4.5 mL) at 0 °C. The
-Aspartic acid dibenzyl ester p-toluenesulfonate (2.38 g, 4.9 mmol,
1.0 equiv.), Et3N (0.76 mL, 5.4 mmol, 1.1 equiv.), EDC·HCl (2.8 g, reaction mixture was kept at 0 °C for 1 h then at room temp. for
14.7 mmol, 3.0 equiv.) and DMAP (2.38 g, 4.9 mmol, 3.0 equiv.) 17 h. The reaction mixture was extracted with diethyl ether
was added to a solution of the compound 25 (4.93 mmol,
1.0 equiv.) in distilled THF (0.2 , 26 mL). After 16 h at room
temp. under N2, the reaction mixture was diluted with ethyl acetate
(3ϫ50 mL) and the combined organic layers were washed with
brine (2ϫ20 mL). The organic layer was dried with MgSO4 and
concentrated in vacuo to afford amine 28 as a colorless oil (0.566 g,
Eur. J. Org. Chem. 2009, 4646–4654
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4651

L. Coudray, J.-L. Montchamp
FULL PAPER
68%). 2 diastereoisomers 54/46. H NMR (300 MHz, CDCl3): δ =
4.19–4.35 (m, 2 H & 1 H, -CH2-O & -CH-N), 3.63–3.84 (m, 4 H,
2 H, CHarom.); 7.32–7.36 (m, 5 H, CHarom.), 6.84 (d, 3JH,H = 6.5 Hz,
0.5 H, NH), 6.71 (d, JH,H = 6.5 Hz, 0.5 H, NH), 4.85–5.13 (m, 3
1
3
-CH2-O), 1.94–2.49 (m, 2 H & 2 H, -CH2-P & NH2), 1.53 (2d, H, Cbz -CH2- & -CH-N), 3.83–4.19 (m, 2 H, -CH2-O), 2.22–2.66
3
3
3JHCCP = 11.5 Hz, 3 H, CH3-C-P), 1.37 (t, JH,H = 7.0 Hz, 3 H, (m, 2 H, -CH2-P), 1.32 & 1.29 (2d, JH,H = 7.0 Hz, 3 H, CH3-)
CH3-), 1.24 & 1.23 (2t, 3JH,H = 7.0 Hz, 6 H, CH3-) ppm. 13C NMR ppm. 13C NMR (75.45 MHz, CDCl3): δ = 155.4 & 155.3, 136.0 &
(75.45 MHz, CDCl3): δ = 121.4 (d, JPCCC = 14.0 Hz), 121.3 (d, 135.9, 133.5 (2d, JPCCCC = 6.5 Hz), 132.0 & 131.7 (2d, JPCC
JPCCC = 12.0 Hz), 101.3 (d, JPC = 147.0 Hz), 101.2 (d, JPC 10.5 Hz, 2 C), 129.5 (d, JPC = 128.5 Hz), 129.3 & 129.2 (2d, JPCCC
146.0 Hz), 62.6 (d, JPOC = 6.5 Hz), 62.4 (d, JPOC = 7.0 Hz), 58.8 = 13.0 Hz, 2 C), 128.8 (2 C), 128.6, 128.5 (2 C), 117.8 (d, JPCCC
(2d, JPCOC = 5.5 Hz), 58.2 (d, JPCOC = 7.0 Hz), 58.1 (d, JPCOC 12.0 Hz), 117.6 (d, JPCCC = 14.0 Hz), 67.7 (d, JPOC = 7.0 Hz),
8.0 Hz), 38.9 (d, JPCC = 4.0 Hz), 38.5 (d, JPCC = 3.5 Hz), 32.1 & 62.0 & 61.8 (d, JPCC = 5.5 Hz), 38.3 & 38.2, 32.6 (d, JPC
=
=
=
=
=
31.7 (2d, JPC = 83.0 Hz), 20.1 (d, JPCC = 14.0 Hz), 19.9 (d, JPCC
=
99.0 Hz) & 32.4 (d, JPC = 100.0 Hz), 16.6 (d, JPOCC = 6.0 Hz) ppm.
31P NMR (11.47 MHz, CDCl3): δ = 40.55 (s, 50%), 39.79 (s, 50%)
ppm. HRMS (EI+): calcd. for C19H21N2O4P, [M]+ 372.1239; found
372.1241.
12.5 Hz), 16.8 (d, JPOCC = 5.5 Hz), 15.7, 15.5 & 15.4 ppm. 31P
NMR (11.47 MHz, CDCl3): δ = 44.87 (s, 54%), 44.68 (s, 46%)
ppm.
Ethyl (2-Benzyloxycarbonylamino-2-cyanoethyl)(1,1-diethoxyethyl)-
phosphinate (30): (Scheme 5) To amine 28 (1.2 g, 4.3 mmol) in THF
(0.2 , 22.0 mL) was added pyridine (0.42 mL, 5.18 mmol,
1.2 equiv.) followed by benzyl chloroformate (0.61 mL, 4.13 mmol,
1.0 equiv.) at 0 °C under N2. After 3 h at room temp., the reaction
mixture was diluted with ethyl acetate (75 mL) and washed with
brine (3ϫ20 mL). The organic layer was dried with MgSO4 and
concentrated in vacuo. The resulting oil was purified by chromatog-
raphy over silica gel (hexanes/ethyl acetate, 7:3, v/v) to afford pro-
2-Amino-3-(hydroxyphenylphosphinoyl)propionic Acid Hydrochlo-
ride (32):[17] (Scheme 5). A solution of phosphinate 31 (0.072 g,
0.19 mmol) in concentrated aqueous HCl (5.0 mL) was refluxed
under nitrogen. After 20 h, the reaction mixture was cooled and
concentrated. The resulting oil was dissolved with water (30 mL)
and washed with dichloromethane (3ϫ10 mL). The aqueous layer
was concentrated to afford phosphinic acid 32 (0.046 mg, 90%). 1H
NMR (300 MHz, D2O): δ = 7.56–7.63 (m, 2 H, CHarom.), 7.34–
3
7.48 (m, 3 H, CHarom.), 3.98 (ddd, JHCCP = 15.0 Hz, 1 H, -CH-
tected amine 30 as a colorless oil (1.58 g, 89%). 1H NMR
2
2
3
N), 2.36 (ddd, JHCP = 14.0, JH,H = 13.5, JH,H = 5.0 Hz, 1 H,
3
(300 MHz, CDCl3): δ = 7.35 (s, 5 H, CHarom.), 6.83 (d, JH,H
=
2
2
3
-CH2-P), 2.13 (ddd, JHCP = 14.0, JH,H = 13.5, JH,H = 8.5 Hz, 1
H, -CH2-P) ppm. 13C NMR (75.45 MHz, D2O): δ = 171.1 (d, JPCCC
= 11.0 Hz), 133.4 (d, JPC = 131.0 Hz),132.3 (d, JPCCCC = 2.5 Hz),
131.0 (d, JPCC = 10.0 Hz, 2 C), 128.9 (d, JPCCC = 12.5 Hz, 2 C),
49.0, 30.7 (d, JPC = 92.0 Hz) ppm. 31P NMR (121.47 MHz,
CDCl3): δ = 31.09 (s) ppm.
3
8.0 Hz, 0.54 H, NH), 6.49 (d, JH,H = 6.5 Hz, 0.46 H, NH), 5.14
(s, 2 H, Cbz -CH2-), 4.90–5.10 (m, 1 H, -CH-N), 4.08–4.35 (m, 2
H, -CH2-O), 3.55–3.82 (m, 4 H, -CH2-O), 2.23–2.52 (m, 2 H, -CH2-
P), 1.51 & 1.48 (2d, 3JHCCP = 11.5 Hz, 3 H, CH3-C-P), 1.34 & 1.30
3
(2t, JH,H = 7.0 Hz, 3 H, CH3-), 1.17–1.23 (m, 6 H, CH3-) ppm.
13C NMR (75.45 MHz, CDCl3): δ = 155.2, 135.7, 128.5 (2 C),
128.3, 128.2 (2 C), 118.0 & 117.8 (2d, JPCCC = 10.0 Hz), 100.9 (d,
JPC = 148.5 Hz) & 100.8 (d, JPC = 148.0 Hz), 67.5, 62.7 & 62.6 (2d,
JPOC = 7.0 Hz), 58.8 & 58.7 (2d, JPCOC = 5.5 Hz), 58.2 & 58.1 (2d,
Phosphinate 33: See Equation (3); tert-butyl acrylate (0.44 mL,
3.0 mmol, 3.0 equiv.) and 2nd generation Grubbs catalyst 34
(0.042 g, 0.05 mmol, 5 mol-%) was added to alkene 10 (0.25 g,
1.0 mmol) in dichloromethane (0.02 , 20.0 mL) at room temp. Af-
ter 22 h, at reflux under N2, the reaction mixture was cooled. Char-
coal (2 g) was added and the suspension was filtered through Ce-
lite®. The solution was concentrated in vacuo. The resulting oil was
purified by chromatography over silica gel (hexanes/ethyl acetate,
6:4, v/v) to afford ester 33 as a colorless oil (0.257 g, 73%). 1H
NMR (300 MHz, CDCl3): δ = 6.80–6.92 (m, 1 H, -CH=), 5.85–
JPCOC = 7.5 Hz), 38.0 (d, JPCC = 4.0 Hz), 28.9 & 27.9 (2d, JPC
82.0 Hz), 19.6 & 19.5 (2d, JPCC = 12.0 Hz), 16.5 (2d, JPOCC
=
=
5.5 Hz), 15.4, 15.2 & 15.1 ppm. 31P NMR (11.47 MHz, CDCl3): δ
= 45.75 (s, 54%), 43.82 (s, 46%) ppm. HRMS (CI, NH3): calcd.
for C19H30N2O6P, [M + H]+ 413.1842; found 413.1839.
Ethyl (2-Benzyloxycarbonylamino-2-cyanoethyl)phenylphosphinate
(31): (Scheme 5) Chlorotrimethylsilane (0.25 mL, 2.0 mmol,
2.0 equiv.) was added to the acetal 30 (0.412 g, 1.0 mmol) in chloro-
form (0.1 , 10.0 mL) at room temp. under N2. After 4 h, the reac-
tion mixture was diluted with chloroform (50 mL) and washed with
0.5  aqueous NaHCO3 (1ϫ20 mL) and brine (2ϫ20 mL). The
organic layer was dried with MgSO4 and concentrated in vacuo to
afford the H-phosphinic ethyl ester as a colorless oil, which was
used without further purification. To the H-phosphinic ethyl ester
in acetonitrile (0.1 , 10.0 mL) was added diisopropylethylamine
(0.23 mL, 1.3 mmol, 1.3 equiv.), iodobenzene (0.11 mL, 1.0 mmol,
1.0 equiv.) followed by Pd(OAc)2 (0.0045 mg, 0.02 mmol, 2.0 mol-
%) and dppf (0.0122 mg, 0.022 mmol, 2.2 mol-%). After 2 h at re-
flux under N2, the reaction mixture was cooled and another por-
tion of Pd(OAc)2 (0.0045 mg, 0.02 mmol, 2.0 mol-%) and dppf
(0.0122 mg, 0.022 mmol, 2.2 mol-%) was added. After a total of
16 h at reflux under N2, the reaction mixture was cooled and con-
centrated in vacuo. The resulting oil was dissolved with ethyl ace-
tate (50 mL) and washed with brine (3ϫ20 mL). The organic layer
was dried with MgSO4 and concentrated in vacuo. The resulting
oil was purified by chromatography over silica gel (hexanes/ethyl
acetate, 1:1, v/v) to afford the phosphinic acid ethyl ester 31 as a
colorless oil (0.16 g, 43%). 1H NMR (300 MHz, CDCl3): δ = 7.72–
7.82 (m, 2 H, CHarom.), 7.57–7.64 (m, 1 H, CHarom.), 7.50–7.52 (m,
5.92 (m, 1 H, -CH=), 4.10–4.32 (m, 2 H, -CH2-O), 3.60–3.81 (m,
3
4 H, -CH2-O), 2.67–2.87 (m, 2 H, -CH2-P), 1.53 (d, JHCCP
=
=
3
12.0 Hz, 3 H, CH3-C-P), 1.49 [s, 9 H, C(CH3)3], 1.34 (t, JH,H
3
7.0 Hz, 3 H, CH3-), 1.23 (t, JH,H = 7.0 Hz, 3 H, CH3-), 1.22 (t,
3JH,H = 7.0 Hz, 3 H, CH3-) ppm. 13C NMR (75.45 MHz, CDCl3):
δ = 165.2, 136.6 (d, JPCC = 9.0 Hz), 127.6 (d, JPCCC = 11.0 Hz),
101.5 (d, JPC = 143.0 Hz), 80.6, 62.2 (d, JPOC = 7.0 Hz), 58.5 (d,
JPCOC = 4.5 Hz), 58.0 (d, JPCOC = 7.0 Hz), 31.1 (d, JPC = 80.0 Hz),
28.3, 20.5 (d, JPCC = 12.5 Hz), 16.8 (d, JPOCC = 5.0 Hz), 15.7, 15.4
ppm. 31P NMR (121.47 MHz, CDCl3): δ = 44.57 (s) ppm. HRMS
(CI, NH3): calcd. for C16H32O6P, [M + H]+ 351.1937; found
351.1941.
Supporting Information (see also the footnote on the first page of
this article): General chemistry (1 page), procedures and spectro-
1
scopic data, H, 13C and 31P NMR spectra.
Acknowledgments
We thank the National Institute of General Medical Sciences/NIH
(1R01 GM067610) for the financial support of this research.
4652
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4646–4654

Temporary Protection of P–H Acids as a Synthetic Strategy
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FULL PAPER
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Received: June 22, 2009
Published Online: August 11, 2009
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4654
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4646–4654