Facile P,N-heterocycle synthesis via tandem aminomethylation-cyclization of H-phosphinate building blocks

Article abstract of DOI:10.1039/b917428a

Various heterocycles containing phosphorus and nitrogen are easily synthesized from readily available H-phosphinate building blocks. Aminomethylation of these H-phosphinates is followed by in situ cyclization through substitution or cross-coupling to prod

Full text of DOI:10.1039/b917428a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Facile P,N-heterocycle synthesis via tandem aminomethylation–cyclization of
H-phosphinate building blocks†
Cle´mence Queffe´lec and Jean-Luc Montchamp*
Received 24th August 2009, Accepted 25th September 2009
First published as an Advance Article on the web 5th November 2009
DOI: 10.1039/b917428a
Various heterocycles containing phosphorus and nitrogen are easily synthesized from readily available
H-phosphinate building blocks. Aminomethylation of these H-phosphinates is followed by in situ
cyclization through substitution or cross-coupling to produce novel heterocycles in moderate to good
yields.
Introduction
Results and discussion
Perhaps surprisingly, few phosphorus–nitrogen heterocycles have
been synthesized previously.1 In recent work, we reported
the formation of such heterocycles starting from w-amino-H-
phosphinates (eqn (1)) through condensation with carbonyl
compounds.2 The method was made possible by synthetic method-
ologies we developed to access the starting materials.3 Herein, we
shifted the focus to precursors which do not contain an amino
group, but instead possess a reactive halide.
Precursor synthesis
Several synthons were prepared through established reactions.3
Compounds 1, 2 and 5 were prepared via hydrophosphinylation,3d–j
compound 3 via Pd-catalyzed cross-coupling,3k and compound 4
via base-promoted alkylation.3r The detailed conditions are shown
in Schemes 2–4, and eqn (2) and (3). Synthon 1 (Scheme 2) was
synthesized through our radical hydrophosphinylation using Et3B
as the initiator, as reported previously.3h The resulting intermediate
6 was esterified5 directly to produce ester 1. The low yield of
compound 1 was attributed to difficulties during the purification
of this polar compound using chromatography on silica gel.
Nonetheless, the preparation of 1 was easily accomplished.
(1)
With the exception of our previous report (eqn (1)),2P,N-
containing phosphinic heterocycles are rare in the literature. Since
heterocycles have shown a variety of biological activities, and since
cyclic P,N-phosphinates can be considered analogs of amino acids,
we set out to expand the range of compounds accessible from sim-
ple building blocks. Below, we describe a general approach to P,N-
heterocycles based on the Kabachnick–Fields aminomethylation4
of precursors, followed by in situ cyclization of the resulting
amines (Scheme 1). Over the past several years, our laboratory
has reported several general methods to prepare functionalized
H-phosphinates.3 In the present work, such intermediates are
prepared and their use in the synthesis of P,N-heterocycles is
investigated.
Scheme 2 Synthesis of ethyl (3-chloropropyl)-H-phosphinate 1. (a)
NaH2PO2, Et3B, rt, 2 h, 71%; (b) (EtO)4Si, toluene, reflux, 24 h, 40%.
Scheme 1 Strategy for the synthesis of P,N-heterocycles
Homolog 2 was prepared in a single step through palladium-
catalyzed hydrophosphinylation3d of 4-bromo-1-butene (eqn (2)).
Synthon 2 was obtained in 67% yield. A similar reaction was used
to prepare 5 from commercially available 2-bromostyrene (eqn (3))
in 64% yield.
Department of Chemistry, TCU Box 298860, Texas Christian University,
Fort Worth, TX 76129, USA. E-mail: j.montchamp@tcu.edu; Fax: 1 817
257 5851; Tel: 1 817 257 6201
† Electronic supplementary information (ESI) available: Additional pro-
cedures and spectral data. See DOI: 10.1039/b917428a
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Table 1 P,N-heterocycle formation from 1 and 2
Entry Synthon Iminea
Product
Isolated yield (%)b
61
(2)
(3)
=
1
2
3
1
1
2
PhCH NPh
=
H2C NBn
58
76
Synthon 3 required the use of our palladium-catalyzed
cross-coupling of anilinium hypophosphite3k with 1-bromo-2-
iodobenzene. Esterification then proceeded in reasonable yield to
form 3 (Scheme 3).
=
PhCH NPh
=
4
2
H2C NBn
45
a Conditions: N-benzylideneaniline, toluene, reflux, 16 h; or 1,3,5-
tribenzylhexahydro-1,3,5-triazine, toluene, reflux, 16 h. b Yield of pure
compound after column chromatography.
and 2. Reaction of the H-phosphinates with imines proceeded
smoothly and cyclization then took place uneventfully.
Scheme 3 Synthesis of ethyl (2-bromophenyl)-H-phosphinate 3. (a)
1-bromo-2-iodobenzene, anilinium hypophosphite (3 equiv.), Pd(OAc)2
(2 mol%), dppp (2.2 mol%), CH3CN, reflux, 16 h, 65%; (b) (EtO)4Si,
toluene, reflux, 24 h, 64%.
The reactions of 2-bromophenyl-substituted H-phosphinate
esters were investigated next (Table 2). Compounds 3 and 4
were subjected to similar reaction conditions, except that a base
(Cs2CO3, 1.5 equiv.) and a palladium catalyst (Pd(PPh3)4, 2 mol%)
were also added to the reaction mixtures. As expected, the
aminomethylation took place easily, but, perhaps more surpris-
ingly, the simplest Pd-catalyst delivered C–N bond formation in
good yield, without the need for more sophisticated Buchwald–
Hartwig-type cross-coupling catalysts.7 Thus, 5- and 6-membered
P,N-heterocycles were obtained in a one-pot procedure (Table 2).
Compound 3 reacted with a variety of imines (Table 2, entries
1–6). Interestingly, a reaction (entry 3) conducted with in situ
formation of the imine (from paraformaldehyde and benzylamine)
gave the expected product in only slightly lower yield than with
the triazine precursor (entry 2). Compound 4 provided the 6-
membered heterocycle in comparable yields (entries 7 and 8).
Again, Pd(PPh3)4 successfully catalyzed the cross-coupling step.
However, with synthon 5, although the Kabachnik–Fields
reaction took place in good yield, the resulting intermediates did
not cyclize to give the 7-membered ring under otherwise identical
conditions. The aminomethylated products were obtained with N-
benzylideneaniline or 1,3,5-tribenzylhexahydro-1,3,5-triazine in
51 and 67% isolated yields, respectively.
Finally, synthon 4 was synthesized through the LiHMDS-
promoted alkylation3r of 2-bromobenzyl bromide followed by
deprotection of the acetal using TMSCl.6 The sequence produced
4 in 60% overall yield (Scheme 4).
Scheme 4 Synthesis of ethyl (2-bromobenzyl)-H-phosphinate 4. (a)
2-bromobenzyl bromide, LiHMDS, THF, -78 ◦C to rt, 3 h, 61%; (b)
TMSCl, CH2Cl2, EtOH, rt, 16 h, 99%.
In a different (but related) approach, the heterocyclization
of unsaturated ethyl cinnamyl-H-phosphinate was investigated
through a tandem aminomethylation–Heck cyclization process
Reactivity and cyclization
(Scheme 5). Readily available cinnamyl-H-phosphinic acid8
7
With the above precursors in hand, their reactions with imines were
was esterified5 to 8 using our typical conditions. Ester 8 was
investigated. Table 1 shows the results obtained with synthons 1
then reacted with 2-iodoaniline and paraformaldehyde to form
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Table 2 P,N-heterocycle formation from 3 and 4
Isolated
Entry Synthon
Iminea
Product
yield (%)b
=
1
2
3
4
5
3
3
3
3
3
PhCH NPh
61
63
53
74
44
c
=
H2C NBn
Scheme 5 Tandem aminomethylation–Heck cyclization. (a) (EtO)4Si,
toluene, reflux, 24 h, 92%; (b) 2-iodoaniline (1.2 equiv.), paraformaldehyde
(1.2 equiv.), toluene, reflux, 16 h, 46%; (c) Pd(OAc)2 (2 mol%), dppf
(2.2 mol%), i-Pr2NEt (2 equiv.), DMF, 110 ◦C, 35%.
(CH2O)n + BnNH2
=
PhCH NBn
=
PhCH N-tBu
Scheme 6 Attempted Pd(II)-catalyzed cyclization. (a) 1,3,5-tribenzylhex-
ahydro-1,3,5-triazine (0.4 equiv.), toluene, reflux, 16 h, 12a 57%; 12b 83%.
(b) Pd(OAc)2 (5 mol%), AcONa (2 equiv.), DMSO, O2, 80 ◦C, 60 h.
=
6
3
PhCH NMe
62
of ethyl cinnamyl-H-phosphinate 8 via sulfonamide 13 similarly
failed, although Liu and Stahl reported the successful cyclization
of the all-carbon analog 14.11c
=
7
8
4
4
PhCH NPh
76
41
c
=
H2C NBn
Admittedly, we have not fully investigated the palladium-
catalyzed heterocyclizations of precursors 9, 12 and 13. In spite
of the above failed experiments, tremendous flexibility remains
available to synthesize phosphorus heterocycles from simple
precursors. For example, Wolfe-type carboaminations12 could also
be tried on aminophosphinate precursors 12 and 13. Similarly,
the use of allyl amine in the place of 2-iodoaniline (Scheme 5)
could lead to a ring-closing metathesis precursor (the reaction of
8 with paraformaldehyde and allyl amine gives the corresponding
diene in 53% yield). Our methodologies have made available a
wide range of compounds through hydrophosphinylation, cross-
coupling (halides, carboxylates, alcohols), alkylation, etc.,3 so
that novel P-containing precursors could lead to facile syntheses
of heterocyclic products. The preparation of P,O-heterocycles
through the well-known addition of H-phosphinates to carbonyl
compounds, using the precursors described in the present work,
was not investigated because P,N-heterocycles are likely to be more
interesting as amino acid analogs.13
a Conditions: imine or triazine (1 equiv.), Cs2CO3 (1.5 equiv.), Pd(PPh3)4
(2 mol%), toluene, reflux, 24 h. b Yield of pure compound after column
chromatography. c 1,3,5-tribenzylhexahydro-1,3,5-triazine was used.
aminomethylated iodide 9 in moderate isolated yield. Compound
9 was subjected to Heck-type9 reaction conditions (Pd/dppf,
2 mol%) in DMF to produce the desired 7-membered ring
heterocycle 10 in 35% isolated yield. We have not optimized this
reaction, other than the use of dppf10 instead of PPh3. While more
work would be required to fully explore this strategy, Scheme 5
provides an interesting “proof of concept”, and the basis for future
experiments.
Along similar lines, we briefly attempted the Wacker-type
cyclization11 of unsaturated amino-H-phosphinate 12 (Scheme 6).
Unfortunately, attempts on 12a and 12b were unsuccessful. The use
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diluted in EtOAc (30 mL) and washed with brine (1 ¥ 10 mL). The
organic layer was dried and concentrated. The resulting oil was
purified by column chromatography (silica, EtOAc–hexanes 7 : 3,
v/v) to afford the desired product as a yellow oil (3.56 g, 64%): 1H
NMR (CDCl3, 300 MHz) d 7.53 (d, J = 8 Hz, 1H, aro CH), 7.20-
7.35 (m, 2H, aro CH), 7.14 (d, J = 532 Hz, 1H, H–P), 7.00-7.15
(m, 1H, aro CH), 4.00-4.25 (m, 2H, –CH2–O–), 2.90-3.10 (m, 2H,
–CH2–P), 2.00-2.20 (m, 2H, –C–CH2–), 1.37 (t, J = 14, 7 Hz, 3H,
CH3–); 13C NMR (CDCl3, 75.45 MHz) d 139.6 (d, JPCCC = 16 Hz),
133.2, 130.5, 128.6, 127.9, 124.3, 62.7 (d, JPOC = 7 Hz), 28.9 (d,
JPC = 92 Hz), 27.9, 16.5 (d, JPOCC = 6 Hz); 31P NMR (CDCl3,
121.47 MHz) d 37.4 (d, J = 532 Hz).
Conclusions
The facile synthesis of P,N-heterocycles (substituted 3-hydroxy-
1,3-azaphospholane and 3-hydroxy-1,3-azaphosphorinane-3-
oxides) is described. With aryl bromide precursors, the cyclization
proceeded well using Pd(PPh3)4 (2 mol%) as the cross-coupling
catalyst. The availability of simple H-phosphinate building blocks
opens up the possibility for the synthesis of various phosphorus
heterocycles. Catalytic methods for the cyclization of other
phosphinate precursors for the preparation of P,N- as well as
other P-heterocycles will be the object of future studies.
Experimental
Ethyl (2-bromobenzyl)-H-phosphinate (Scheme 4, compound 4)
For general chemistry information, and additional details on the
synthesis of precursors and intermediates, spectral data, and a
copy of the 31P, 1H and 13C NMR spectra, see the ESI.†
To ethyl (1,1-diethoxyethyl)-(2-bromobenzyl)phosphinate (3.03 g,
8 mmol) in 20 mL of 10% ethanol in dichloromethane was added
chlorotrimethylsilane (1.5 equiv., 12 mmol, 1.3 mL) under N2 and
the clear solution was stirred for 16 h at room temperature.6 The
solvent was removed in vacuo and the resulting oil was purified
by column chromatography (silica, EtOAc–hexanes 3 : 7, v/v) to
afford the desired product as a yellow oil (2.1 g, 99%): 1H NMR
(CDCl3, 300 MHz) d 7.58 (d, J = 8 Hz, 1H, aro CH), 7.20-7.40 (m,
2H, aro CH), 7.10-7.20 (m, 1H, aro CH), 7.16 (d, J = 544 Hz, 1H,
H–P), 4.00-4.25 (m, 2H, –CH2–O–), 3.35-3.55 (m, 2H, C–CH2–P),
1.32 (t, J = 14, 7 Hz, 3H, CH3–); 13C NMR (CDCl3, 75.45 MHz)
d 133.2 (d, J = 2 Hz), 132.1 (d, J = 6 Hz), 130.7 (d, J = 7 Hz),
129.2 (d, J = 4 Hz), 128.1 (d, J = 4 Hz), 124.8 (d, J = 7 Hz), 63.0
Ethyl (3-chloropropyl)-H-phosphinate (Scheme 2, compound 1)
To (3-chloropropyl)-H-phosphinic acid3g (2.56 g, 18 mmol) in
toluene (60 mL) was added tetraethyl orthosilicate (1.5 equiv.,
5.63 g) under N2, and the mixture was refluxed for 24 h. The
solvent was removed in vacuo and the resulting oil was purified
by column chromatography (silica, EtOAc 100%) to afford the
1
desired product as a yellow oil (1.22 g, 40%): H NMR (CDCl3,
300 MHz) d 7.17 (d, J = 533 Hz, 1H, H–P), 4.00-4.30 (m, 2H,
–CH2–O–), 3.64 (t, J = 5 Hz, 2H, –CH2–Cl), 1.85-2.10 (m, 4H,
2 x –CH2–), 1.39 (t, J = 7 Hz, 3H, CH3–); 13C NMR (CDCl3,
75.45 MHz) d 62.8 (d, JPOC = 6 Hz), 44.9 (d, JPCCCCl = 17 Hz), 26.3
(d, JPOC = 6 Hz), 37.3 (d, JPC = 89 Hz), 16.4 (d, JPOCC = 6 Hz); 31
P
NMR (CDCl3, 121.47 MHz) d 34.3 (d, J = 544 Hz); HRMS (EI+)
(d, JPC = 95 Hz), 24.2 (d, JPCC = 2 Hz), 16.4 (d, JPOCC = 6 Hz); 31
P
calc. for C9H12BrO2P 262.9837, found 262.9835.
NMR (CDCl3, 121.47 MHz) d 37.7 (d, J = 533 Hz); HRMS (EI+)
calc. for C5H12ClO2P 171.0342, found 171.0346.
General procedure for the cyclization from compound 1 or 2
Ethyl (3-bromobutyl)-H-phosphinate (eqn (2), compound 2)3e
To the compound 1 or 2 (1 mmol) in toluene (10 mL) was added N-
benzylideneaniline (1.2 equiv.) or 1,3,5-tribenzylhexahydro-1,3,5-
triazine (0.4 equiv) and the mixture was refluxed for 16 h. The
solvent was removed in vacuo, and the resulting oil was diluted in
EtOAc (30 mL) and washed with brine (1 ¥ 10 mL). The organic
layer was dried and concentrated. The resulting oil was purified
by column chromatography (silica, EtOAc–hexanes 3 : 7, v/v) to
afford the desired product.
To a solution of EtOP(O)H2 in CH3CN (2 equiv., 60 mmol,
120 mL) and 4-bromo-1-butene (30 mmol, 4.05 g, 3 mL) were
added Pd2dba3 (0.5 mol%, 137 mg) and xantphos (1.1 mol%,
191 mg). After 16 h of reflux, the mixture was concentrated and
the resulting oil was diluted in EtOAc (60 mL) and washed with
brine (1 ¥ 20 mL). The organic layer was dried and concentrated.
The resulting oil was purified by column chromatography (silica,
EtOAc 100%) to afford the desired product as a yellow oil (4.6 g,
1
1,2-Diphenyl-3-ethoxy-1,3-azaphosphorinane-3-oxide (Table 1,
67%): H NMR (CDCl3, 300 MHz) d 7.13 (d, J = 530 Hz, 1H,
1
entry 1). Yellow oil, yield: 61%. H NMR (CDCl3, 300 MHz)
H–P), 4.00-4.35 (m, 2H, –CH2–O), 3.43 (t, J = 7 Hz, 2H, –CH2–
Br), 1.95-2.10 (m, 2H, –CH2–), 1.65-1.90 (m, 4H, 2 x –CH2–), 1.37
(t, J = 7 Hz, 3H, CH3–); 13C NMR (CDCl3, 75.45 MHz) d 62.6 (d,
JPOC = 7 Hz), 33.1 (d, JPCC = 15 Hz), 32.7, 27.9 (d, JPC = 94 Hz),
19.6, 16.4 (d, JPOCC = 6 Hz); 31P NMR (CDCl3, 121.47 MHz) d
38.8 (d, J = 530 Hz); HRMS (EI+) calc. for C6H14BrO2P 228.9993,
found 228.9990.
d 7.00-7.50 (m, 7H, aro CH), 6.50-6.80 (m, 3H, aro CH), 4.80-
5.00 (m, 1H, –CH2–), 4.55-4.75 (m, 1H, –P–CH–N–), 4.00-4.25
(m, 2H, –CH2–O–)a, 3.20-3.40 and 3.65-3.85 (m, 2H, –CH2–O–)b,
3.55-3.60 (m, 1H, –CH2–), 3.40-3.50 (m, 1H, –CH2–), 2.00-2.20 (m,
1H, –CH2–), 1.60-2.00 (m, 2H, –CH2–), 1.20-1.40 (m, 3H, CH3–)a,
1.03 (t, J = 14, 7 Hz, 3H, CH3–)b; 13C NMR (CDCl3, 75.45 MHz)
d 146.4, 146.2, 135.9, 135.5, 129.5, 129.2, 128.9, 128.3, 128.2 (d,
J = 4 Hz), 127.8 (d, J = 4 Hz), 118.8, 114.3 (d, J = 6 Hz), 62.4 (d,
JPOC = 7 Hz)a, 62.1 (d, JPOC = 7 Hz)b, 57.9 (d, JPC = 93 Hz)b, 57.7
(d, JPC = 96 Hz)a, 45.4 (d, JPCC = 5 Hz)a, 45.1 (d, JPCC = 6 Hz)b,
Ethyl 2-(2-bromophenyl)ethyl-H-phosphinate (eqn (3), compound
5)
To a solution of EtOP(O)H2 in CH3CN (1.6 equiv., 32 mmol,
64 mL) and 2-bromostyrene (20 mmol, 3.66 g) were added Pd2dba3
(0.75 mol%, 137 mg) and xantphos (1.6 mol%, 185 mg). After 16 h
of reflux, the mixture was concentrated and the resulting oil was
25.4 (d, JPC = 92 Hz)a, 25.2, 24.3 (d, JPC = 95 Hz)b, 16.9 (d, JPOCC =
5 Hz)a, 16.6 (d, JPOCC = 6 Hz)b; 31P NMR (CDCl3, 121.47 MHz)
d 50.6 (s), 51.6 (s); HRMS (EI+) calc for C18H22NO2P 315.1388,
found 315.1388.
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1-Benzyl-3-ethoxy-1,3-azaphosphorinane-3-oxide (Table 1, entry
2). Yellow oil, yield: 58%. 1H NMR (CDCl3, 300 MHz) d 7.25-
7.35 (m, 5H, aro CH), 3.90-4.20 (m, 2H, –CH2–O–), 3.71 (dd, J =
12, 2 Hz, 1H, –CH2–), 3.49 (dd, J = 13, 2 Hz, 1H, –CH2–), 2.96
(t, J = 15 Hz, 1H, –CH2–), 2.79 (d, J = 12 Hz, 1H, –CH2–), 2.45
(d, J = 15 Hz, 1H, –CH2–), 2.20-2.35 (m, 1H, –CH2–), 1.85-2.10
(m, 3H, –CH2–CH2–), 1.60-1.80 (m, 1H, –CH2–), 1.33 (t, J = 14,
7 Hz, 3H, CH3–); 13C NMR (CDCl3, 75.45 MHz) d 137.4, 129.2
(m, 2H, –CH2–O–)a, 3.85-3.95 and 3.20-3.30 (m, 2H, –CH2–O–)b,
1.38 (t, J = 14, 7 Hz, 3H, CH3–)a, 0.95 (t, J = 14 Hz, 3H, CH3–)b;
13C NMR (CDCl3, 75.45 MHz) d 154.7 (d, J = 22 Hz)b, 152.9 (d,
J = 22 Hz)a, 143.2 (d, J = 8 Hz)a, 142.3 (d, J = 10 Hz)b, 134.8 (d,
J = 2 Hz)b, 134.6 (d, J = 2 Hz)a, 134.1 (d, J = 7 Hz), 129.8, 129.7,
129.5 (d, J = 6 Hz), 129.1 (d, J = 2 Hz), 128.9 (d, J = 6 Hz),
128.8 (d, J = 2 Hz), 128.2 (d, J = 3 Hz), 128.18, 128.12, 127.6
(d, J = 5 Hz), 126.1, 125.6 (d, J = 83 Hz), 123.2, 120.3, 120.1,
(2C), 128.5 (2C), 127.6, 64.4 (d, JPCNC = 15 Hz), 60.4 (d, JPOC
=
119.9, 112.8 (d, J = 10 Hz)a, 112.1 (d, J = 11 Hz)b, 65.6 (d, JPC =
7 Hz), 54.2 (d, JPCCC = 5 Hz), 52.2 (d, JPC = 98 Hz), 25.6 (d,
JPC = 89 Hz), 23.4 (d, JPCC = 6 Hz), 16.7 (d, JPOCC = 6 Hz); 31P
NMR (CDCl3, 121.47 MHz) d 44.2 (s); HRMS (EI+) calc. for
C13H20NO2P 253.1232, found 253.1230.
96 Hz)b, 64.8 (d, JPC = 99 Hz)a, 62.6 (d, JPOC = 7 Hz)b, 62.1 (d,
JPOC = 7 Hz)a, 16.9 (d, JPOCC = 6 Hz)a, 16.4 (d, JPOCC = 6 Hz)b;
31P NMR (CDCl3, 121.47 MHz) d 50.6 (s), 49.4 (s); HRMS (EI+)
calc. for C21H20NO2P 349.1232, found 349.1237.
1,2-Diphenyl-3-ethoxy-1,3-azaphosphepane-3-oxide (Table 1, en-
try 3). Yellow oil, yield: 76%. H NMR (CDCl3, 300 MHz) d
1-Benzyl-3-ethoxy-1,2-dihydro-benzo[1,3]azaphosphole-3-oxide
(Table 2, entry 2). Yellow oil, yield: 63%: H NMR (CDCl3,
1
1
6.50-7.60 (m, 10H, aro CH), 4.69 (d, J = 17 Hz, 1H, –P–CH–N–
)a, 4.61 (d, J = 16 Hz, 1H, –P–CH–N–)b, 3.70-3.85 and 4.00-4.30
(m, 2H, –CH2–O–), 3.39 (t, J = 13, 6 Hz, 1H, –CH2–), 3.29 (t, J =
13, 7 Hz, 1H, –CH2–), 1.70-2.00 (m, 4H, –CH2–CH2–), 1.50-1.65
(m, 2H, –CH2–), 1.28 (t, J = 14, 7 Hz, 3H, –CH3–)a, 1.02 (t, J = 14,
7 Hz, 3H, –CH3–)b; 13C NMR (CDCl3, 75.45 MHz) d 146.3, 136.1,
135.6, 133.2, 132.1, 129.4, 129.1 (d, J = 2 Hz), 128.9 (d, J = 2 Hz),
128.3 (d, J = 4 Hz)a, 127.8 (d, J = 4 Hz)b, 118.9, 114.4, 111.8, 62.3
(d, JPOC = 7 Hz)a, 61.9 (d, JPOC = 7 Hz)b, 57.9 (d, JPC = 91 Hz)a,
300 MHz) d 7.20-7.80 (m, 7H, aro CH), 6.75-6.85 (m, 2H, aro
CH), 4.52 (q, J = 16 Hz, 2H, –N–CH2–P–), 4.10-4.20 (m, 2H,
–CH2–O–), 3.37 (dd, J = 13, 5 Hz, 2H, –N–CH2–Ph), 1.34 (t, J =
14, 7 Hz, 3H, CH3–); 13C NMR (CDCl3, 75.45 MHz) d 155.3 (d,
J = 23 Hz), 136.8, 135.0 (d, J = 2 Hz), 132.3 (d, J = 16 Hz), 129.1,
128.8, 128.7 (d, J = 5 Hz), 127.9, 127.4, 117.9 (d, J = 12 Hz),
113.2 (d, J = 131 Hz), 109.9 (d, J = 12 Hz), 61.9 (d, JPOC = 6 Hz),
52.5 (d, JPCNC = 6 Hz), 47.6 (d, JPC = 102 Hz), 16.8 (d, JPOCC
=
6 Hz); 31P NMR (CDCl3, 121.47 MHz) d 52.4 (s); HRMS (EI+)
calc. for C16H18NO2P 287.1075, found 287.1080.
57.6 (d, JPC = 95 Hz)b, 33.6 (d, JPCC = 3 Hz)a, 33.4 (d, JPCC
=
3 Hz)b, 33.0, 32.9, 26.9 (d, JPC = 78 Hz)a, 25.7 (d, JPC = 80 Hz)b,
1-Benzyl-3-ethoxy-2-phenyl-1,2-dihydro-benzo[1,3]azapho-
sphole-3-oxide (Table 2, entry 4). Yellow oil, yield: 74%. 1H NMR
(CDCl3, 300 MHz) d 6.65-7.70 (m, 14H, aro CH), 4.75 (d, J =
16 Hz, 2H, –N–CH–Ph), 4.61 (d, J = 14 Hz, 1H, –N–CH–P–)b,
4.41 (d, J = 16 Hz, 1H, –N–CH2–P–)a, 4.00-4.25 (m, 2H, –CH2–
O–)a, 3.15-3.35 and 3.75-3.95 (m, 2H, –CH2–O–)b, 1.32 (t, J =
14, 7 Hz, 3H, CH3–)a, 0.91 (t, J = 14 Hz, 3H, CH3–)b; 13C NMR
(CDCl3, 75.45 MHz) d 155.2 (d, J = 23 Hz)b, 154.6 (d, J = 23 Hz)a,
137.0, 136.4, 135.21, 135.18, 133.87, 133.82, 133.74, 132.3 (d, J =
10 Hz), 129.5 (d, J = 5 Hz), 129.2 (d, J = 2 Hz)a, 129.1 (d, J =
2 Hz)b, 129.0, 128.5 (d, J = 2 Hz), 128.3 (d, J = 4 Hz), 127.73,
127.69, 127.63, 127.3, 118.7 (d, J = 12 Hz)b, 118.2 (d, J = 12 Hz)a,
113.5, 113.1, 111.7, 111.4, 110.7 (d, J = 11 Hz)a, 109.4 (d, J =
11 Hz)b, 63.4 (d, JPC = 98 Hz)b, 62.5 (d, JPOC = 7 Hz)b, 61.95 (d,
JPC = 101 Hz)a, 61.93 (d, JPOC = 7 Hz)a, 49.1 (d, JPCNC = 8 Hz)b,
20.7 (d, JPCCC = 5 Hz)a, 20.3 (d, JPCCC = 4 Hz)b, 16.9 (d, JPOCC
=
5 Hz)a, 16.7 (d, JPOCC = 5 Hz)b; 31P NMR (CDCl3, 121.47 MHz)
d 51.8 (s), 50.9 (s); HRMS (EI+) calc. for C19H24NO2P 329.1544,
found 329.1545.
1-Benzyl-3-ethoxy-1,3-azaphosphepane-3-oxide (Table 1, entry
4). Yellow oil, yield: 45%. 1H NMR (CDCl3, 300 MHz) d 7.25-
7.35 (m, 5H, aro CH), 3.90-4.00 (m, 1H, –N–CH2–P), 3.60-3.80
(m, 3H, –N–CH2–P and –CH2–O), 2.90-3.10 (m, 2H, –N–CH2–
P), 2.80-2.90 (m, 1H, –CH2–), 2.60-2.70 (m, 1H, –CH2–), 2.00-
2.20 (m, 3H, –CH2–CH2–), 1.55-1.90 (m, 3H, –CH2–CH2–), 1.23
(t, J = 14, 7 Hz, 3H, –CH3–); 13C NMR (CDCl3, 75.45 MHz)
d 138.7, 129.2 (2C), 128.5 (2C), 127.5, 64.2 (d, JPCNC = 16 Hz),
60.0 (d, JPOC = 7 Hz), 58.3, 54.5 (d, JPCC = 105 Hz), 30.2, 29.1
(d, JPC = 88 Hz), 19.9 (d, JPCC = 2 Hz), 16.7 (d, JPOCC = 6 Hz);
31P NMR (CDCl3, 121.47 MHz) d 63.1 (s); HRMS (EI+) calc. for
C14H22NO2P 267.1388, found 267.1389.
48.9 (d, JPCNC = 8 Hz)a, 17.0 (d, JPOCC = 6 Hz)a, 16.4 (d, JPOCC
=
6 Hz)b; 31P NMR (CDCl3, 121.47 MHz) d 51.1 (s), 49.8 (s); HRMS
(EI+) calc. for C22H22NO2P 363.1388, found 363.1395.
General procedure for the cyclization from compound 3 or 4
1-tert-Butyl-3-ethoxy-2-phenyl-1,2-dihydro-benzo[1,3]azapho-
sphole-3-oxide (Table 2, entry 5). Yellow oil, yield: 44%. 1H NMR
(CDCl3, 300 MHz) d 6.70-7.80 (m, 9H, aro CH), 4.84 (d, J = 20 Hz,
1H, –N–CH–P–)b, 4.66 (d, J = 20 Hz, 1H, –N–CH–P–)a, 4.00-4.25
(m, 2H, –CH2–O–)a, 3.15-3.35 and 3.75-3.95 (m, 2H, –CH2–O–)b,
1.43 (s, 9H, –N–C(CH3)3)a, 1.41 (s, 9H, –N–C(CH3)3)b, 1.33 (t,
J = 14, 7 Hz, 3H, CH3–)a, 0.80 (t, J = 14 Hz, 3H, CH3–)b; 13C
NMR (CDCl3, 75.45 MHz) d 154.7 (d, J = 25 Hz)b, 154.1 (d, J =
24 Hz)a, 139.1 (d, J = 4 Hz), 137.1, 134.18, 134.15, 134.13, 132.3
(d, J = 10 Hz), 130.1 (d, J = 6 Hz)a, 129.3 (d, J = 5 Hz)b, 129.04,
129.01, 128.97, 127.8 (d, J = 3 Hz)a, 127.6 (d, J = 3 Hz)b, 126.9 (d,
J = 4 Hz)a, 126.8 (d, J = 4 Hz)b, 118.1 (d, J = 12 Hz)b, 117.7 (d,
J = 12 Hz)a, 115.5, 114.8 (d, J = 11 Hz)b, 114.1 (d, J = 10 Hz)b,
113.8, 62.7 (d, JPOC = 7 Hz)b, 61.9 (d, JPC = 93 Hz)b, 61.6 (d,
To compound 3 or 4 (5 mmol) in toluene (50 mL) was added the
corresponding imine (1.2 equiv.) and the mixture was refluxed for
16 h. Then, caesium carbonate (1.2 equiv.) and Pd(PPh3)4 (2 mol%)
were added, and the mixture was refluxed for 24 h. The solvent
was removed in vacuo, and the resulting oil was diluted in EtOAc
(30 mL) and washed with brine (1 ¥ 10 mL). The organic layer was
dried and concentrated. The resulting oil was purified by column
chromatography (silica, EtOAc–hexanes 3 : 7, v/v) to afford the
desired product.
1,2-Diphenyl-3-ethoxy-1,2-dihydro-benzo[1,3]azaphosphole-3-
oxide (Table 2, entry 1). Yellow oil, yield: 61%. 1H NMR (CDCl3,
300 MHz) d 6.80-7.70 (m, 14H, aro CH), 5.13 (d, J = 15 Hz, 1H,
–N–CH–P–)b, 4.79 (d, J = 17 Hz, 1H, –N–CH–P–)a, 4.20-4.30
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JPOC = 7 Hz)a, 60.3 (d, JPC = 100 Hz)a, 57.7 (d, JPCNC = 6 Hz)b,
Formation in situ of the imine from an aldehyde (Table 2, entry 3)
56.8 (d, JPCNC = 6 Hz)a, 29.6 (3C)b, 29.5 (3C)a,16.9 (d, JPOCC
=
To the compound 3 (5 mmol) in toluene (50 mL) were added
benzylamine (1.2 equiv., 0.65 mL) and paraformaldehyde (1.2
equiv., 198 mg), and the mixture was refluxed for 16 h. Then,
caesium carbonate (1.2 equiv.) and Pd(PPh3)4 (2 mol%) were
added and the mixture was refluxed for 24 h. The solvent was
removed in vacuo, and the resulting oil was diluted in EtOAc
(30 mL) and washed with brine (1 ¥ 10 mL). The organic layer was
dried and concentrated. The resulting oil was purified by column
chromatography (silica, EtOAc–hexanes 3 : 7, v/v) to afford the
desired product as a yellow oil (760 mg, 53%).
6 Hz)a, 16.2 (d, JPOCC = 6 Hz)b; 31P NMR (CDCl3, 121.47 MHz)
d 52.3 (s), 51.3 (s); HRMS (EI+) calc. for C19H24NO2P 329.1545,
found 329.1546.
3-Ethoxy-1-methyl-2-phenyl-1,2-dihydro-benzo[1,3]azapho-
sphole-3-oxide (Table 2, entry 6). White solid mp 114–116 ◦C,
yield: 62%. 1H NMR (CDCl3, 300 MHz) d 6.70-7.70 (m, 9H, aro
CH), 4.45 (d, J = 15 Hz, 1H, –N–CH–P–)b, 4.32 (d, J = 15 Hz,
1H, –N–CH–P–)a, 4.15-4.25 (m, 2H, –CH2–O–)a, 3.10-3.30 and
3.75-3.95 (m, 2H, –CH2–O–)b, 2.84 (s, 3H, –N–CH3)b, 2.83 (s,
3H, –N–CH3)a, 1.37 (t, J = 14, 7 Hz, 3H, CH3–)a, 0.89 (t, J =
14 Hz, 3H, CH3–)b; 13C NMR (CDCl3, 75.45 MHz) d 156.2 (d,
J = 23 Hz)a, 155.4 (d, J = 23 Hz)b, 135.17, 135.15, 135.12, 135.09,
134.0 (d, J = 7 Hz), 133.9 (d, J = 4 Hz), 129.19, 129.17, 129.10,
129.07, 128.8 (d, J = 5 Hz), 128.47, 128.43, 128.39, 128.1 (d, J =
5 Hz), 127.8 (d, J = 4 Hz), 118.8 (d, J = 12 Hz)b, 117.9 (d, J =
12 Hz)a, 113.3 (d, J = 20 Hz), 111.7 (d, J = 17 Hz), 110.3 (d, J =
11 Hz)b, 109.1 (d, J = 11 Hz)a, 66.5 (d, JPC = 98 Hz)b, 64.8 (d,
JPC = 101 Hz)a, 62.4 (d, JPOC = 7 Hz)a, 61.9 (d, JPOC = 7 Hz)b,
Heck product (Scheme 5, compound 10)
To compound 9 (0.5 mmol, 221 mg) in DMF (2.5 mL) was
added N,N-diisopropylethylamine (2 equiv., 1 mmol, 0.2 mL),
1,1¢-bis(diphenylphosphino)ferrocene (2.2 mol%, 6.1 mg) and
Pd(OAc)2 (2 mol%, 2.2 mg). After 40 h of reflux, the solvent
was removed in vacuo, and the resulting oil was diluted in EtOAc
(10 mL) and washed with brine (1 ¥ 20 mL). The organic layer
was dried and concentrated. The resulting oil was purified by
column chromatography (silica, EtOAc 100%) to afford the desired
product as a pink oil (54.7 mg, 35%): 1H NMR (CDCl3, 300 MHz)
d 7.20-7.60 (m, 6H, aro CH), 7.13 (t, J = 15, 7 Hz, 1H, aro CH),
6.94 (d, J = 5 Hz, 1H, aro CH), 6.85 (t, J = 14, 7 Hz, 1H, aro CH),
34.2 (d, JPCNC = 11 Hz)a, 33.5 (d, JPCNC = 10 Hz)b, 16.9 (d, JPOCC
=
6 Hz)a, 16.4 (d, JPOCC = 6 Hz)b; 31P NMR (CDCl3, 121.47 MHz)
d 50.5 (s), 49.1 (s); HRMS (EI+) calc. for C16H18NO2P 287.1075,
found 287.1073.
=
6.67 (d, J = 8 Hz, 1H, –C CH–Ph), 4.00-4.25 (m, 1H, –NH–),
1,2-Diphenyl-3-ethoxy-1,2,3,4-tetrahydro-benzo[d][1,3]azapho-
sphinine (Table 2, entry 7). Yellow oil, yield: 76%: 1H NMR
(CDCl3, 300 MHz) d 6.80-7.60 (m, 14H, aro CH), 5.26 (d, J =
22 Hz, 1H, –N–CH–P–)b, 5.06 (d, J = 25 Hz, 1H, –N–CH–P–)a,
4.10-4.30 (m, 2H, –CH2–O–)a, 3.95-4.10 (m, 1H, –CH2–O–)b, 3.60-
3.75 (m, 1H, -CH2–O–)b, 3.00-3.30 (m, 2H, –C–CH2–P–), 1.28 (t,
J = 14, 7 Hz, 3H, CH3-)a, 0.76 (t, J = 14, 7 Hz, 1H, CH3–)b;
13C NMR (CDCl3, 75.45 MHz) d 149.2 (d, J = 4 Hz)a, 148.5 (d,
J = 4 Hz)b, 143.2 (d, J = 9 Hz)a, 142.8 (d, J = 9 Hz)b, 138.4,
136.6 (d, J = 6 Hz), 132.3 (d, J = 12 Hz)a, 130.9 (d, J = 7 Hz)b,
129.7, 129.2, 129.17, 129.15, 128.9 (d, J = 2 Hz), 128.5 (d, J =
2 Hz), 128.2, 127.87, 127.84, 127.3 (d, J = 4 Hz), 126.8 (d, J =
4 Hz), 126.6 (d, J = 10 Hz), 125.7 (d, J = 2 Hz), 125.1, 123.9,
122.2 (d, J = 9 Hz)a, 121.9, 121.6 (d, J = 7 Hz)b, 120.9, 117.3,
3.90-4.00 (m, 1H, –CH2–O–), 3.45-3.70 (m, 3H, P–CH2–N– and
P–CH2–C–), 3.35-3.45 (m, 1H, –CH2–O–), 3.15-3.25 (m, 1H, P–
CH2–C–), 1.09 (t, J = 14, 7 Hz, 3H, CH3–); 13C NMR (CDCl3,
75.45 MHz) d 145.5 (d, J = 2 Hz), 137.5 (d, J = 3 Hz), 133.0 (d,
J = 7 Hz), 131.9 (d, J = 11 Hz), 131.56, 131.54, 129.6, 128.9 (d,
J = 2 Hz), 128.88, 128.81, 128.5 (d, J = 2 Hz), 127.3, 119.9, 118.3,
60.9 (d, JPOC = 7 Hz), 44.3 (d, JPC = 119 Hz), 31.4 (d, JPC = 78 Hz),
16.6 (d, JPOCC = 6 Hz); 31P NMR (CDCl3, 121.47 MHz) d 54.2 (s);
HRMS (EI+) calc. for C18H20NO2P 313.1232, found 313.1230.
Acknowledgements
We thank the National Institute of General Medical Sci-
ences/NIH (1R01 GM067610) for the financial support of this
research.
63.2 (d, JPC = 95 Hz)b, 62.8 (d, JPC = 91 Hz)a, 61.7 (d, JPOC
=
7 Hz)b, 61.6 (d, JPOC = 7 Hz)a, 31.5 (d, JPC = 84 Hz)b, 28.6 (d,
JPC = 86 Hz)a, 16.7 (d, JPOCC = 6 Hz)a, 16.4 (d, JPOCC = 6 Hz)b;
31P NMR (CDCl3, 121.47 MHz) d 43.0 (s), 54.4 (s); HRMS (EI+)
calc. for C22H22NO2P 363.1388, found 363.1382.
Notes and references
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1-Benzyl-3-ethoxy-1,2,3,4-tetrahydro-benzo[d][1,3]azaphos-
phinine (Table 2, entry 8). Yellow oil, yield: 41%. 1H NMR
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