Phosphinates as new electrophilic partners for cross-coupling reactions

Article abstract of DOI:10.1039/b809577a

The use of enol phosphinates as electrophiles for cross-coupling reactions has been explored. Both boronic acids (Suzuki-Miyaura reaction) and stannanes (Stille reaction) couple efficiently with lactam derived phosphinates. The 2008 Royal Society of Chemi

Full text of DOI:10.1039/b809577a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Phosphinates as new electrophilic partners for cross-coupling reactions†
Jun Guo,a John D. Harling,b Patrick G. Steel*a and Tom M. Woodsa
Received 5th June 2008, Accepted 22nd August 2008
First published as an Advance Article on the web 15th September 2008
DOI: 10.1039/b809577a
The use of enol phosphinates as electrophiles for cross-coupling reactions has been explored. Both
boronic acids (Suzuki–Miyaura reaction) and stannanes (Stille reaction) couple efficiently with lactam
derived phosphinates.
Introduction
Late transition metal (Pd, Ni) mediated cross-coupling reactions
represent one of the most common methods for forming C–C
bonds.1 Whilst halides represent the most common electrophilic
component, there are a large number of oxygen based leaving
groups that have been described.2 Of these, vinyl and aryl
triflates,2a–c,3 by virtue of their excellent leaving group ability and
ease of preparation from phenols and enolates, have become the
most widely used in the various cross-coupling strategies. However,
these versatile intermediates often suffer from drawbacks, such as
a lack of stability and the need to use expensive triflating reagents,
which can be difficult to handle and store. An attractive alternative
to the triflate group is the analogous phosphate group. Not only
are the reagents needed for their preparation cheap and easily
stored, phosphates are often found to be superior substrates in
cross-coupling reactions. Although previously reported in simple
cuprate displacement reactions (Fig. 1a),4 the first examples
of palladium mediated cross-coupling of vinyl phosphates was
reported in 1980 by Oshima et al., who coupled a series of vinyl
phosphates with trialkyl aluminium species in the presence of
a Pd(PPh3)4 catalyst (Fig. 1b).5 More recently, amongst others,
Nicolaou et al.6 and Coudert et al.7 have successfully used enol-
phosphates in a variety of cross-coupling reactions (Fig. 1c
and 1d).
Fig. 1 Phosphate electrophiles in cross-coupling reactions.
Despite these successful applications of the phosphate group in
cross-coupling chemistry, the parallel phosphonate and phosphi-
nate groups, Fig. 2, remain unexplored.
Since replacing P–O bonds with P–C bonds lowers the leaving
group ability, these groups are predicted to be more stable and
thus potentially more suitable for more labile functionality. In
this respect, we have begun to explore applications of these
other phosphorus groups as electrophiles in synthesis. We have
previously shown that both solution and solid phase phosphonates
are viable partners in Suzuki and Stille cross-coupling strategies,
Fig. 3,8 and in this paper, we describe the application of lactam
Fig. 2
Results and discussion
As a simple system to explore phosphinate based electrophiles in
derived phosphinates in simple transition metal catalysed cross-
cross-coupling chemistry, we chose to build on our earlier work
coupling strategies.
and use simple N-Boc caprolactam enolates as test substrates.
Although reaction with Boc2O in DCM was unsuccessful, simple
treatment of commercially available caprolactam 1 with DMAP
and Boc anhydride in THF smoothly furnished 2 in an excellent
aDepartment of Chemistry, University of Durham, Science Laboratories,
yield of 92%. Subsequent treatment of a cold THF solution of 2
South Road, Durham, UK, DH1 3LE. E-mail: p.g.steel@durham.ac.uk
with LDA and TMEDA and trapping of the resultant anion with
diphenylphosphonic chloride afforded the desired phosphinate 3a
in a 77% yield. The formation of the phosphinate was characterised
bGlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts, UK, SG1 2NY
† Electronic supplementary information (ESI) available: Experimental. See
DOI: 10.1039/b809577a
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Scheme 1 Initial Suzuki cross-coupling studies with phosphinate 3a.
Fig. 3
salts, 7 ligands 10 bases and 8 solvents.‡ Using the Suzuki reaction
between phosphinate 3a and 3,5-dimethylphenyl boronic acid 4i
as the test transformation, an array of reactions were carried
out in parallel on a 0.1 mmol scale in a Radley Technologies
Greenhouse Parallel SynthesiserTM. The reactions were carried out
on a 0.1 mmol scale with analysis via GC using dodecane as an
internal standard to enable conversion levels and chemical yields
to be calculated for each run.
This simple screen revealed that, regardless of the choice of
solvent, the use of an organic base (NEt3) resulted in poor yields of
the desired product, ≤11%, indicating that an inorganic/aqueous
base is essential to the success of the reaction. Of the seven
conditions that fulfilled this requirement and gave yields that
merit discussion (Table 1), six employed a protic solvent (EtOH
or H2O) and the five highest yielding entries all employed water
as a co-solvent in tandem with an organic solvent with which it is
miscible. It is suspected that such an aqueous–organic solvent
combination provides greater solubility of all the reagents in
the reaction leading to better results. Using the most promising
conditions identified from the array (Table 1, A4) the Suzuki cross-
coupling of phosphinate 3a was then carried out on a preparative
(0.4 mmol) scale The reaction was followed by TLC analysis and
no starting material remained after 1 h. Following a standard
work-up, the coupled product 5a-i was isolated in an excellent
83% yield (Scheme 2, Table 2, entry 1).
by a single peak in the 31P NMR spectrum at 29.7 ppm and a
distinctive signal at 5.36 ppm (1H, dt, JP = 3 Hz, JH = 7 Hz) in the
1H NMR spectrum due to the C-3 vinylic proton. Subsequently
replacing LDA–TMEDA by NaHMDS proved to be cleaner and
more efficient, providing phosphinate 3a in 90% yield.
With the phosphinate now readily available, attention then
turned to cross-coupling reactions. Reflecting its widespread
use, and the low toxicity of the reagents involved, we opted
to commence these studies using the Suzuki–Miyaura reaction.
Following the protocol successfully applied in the coupling of enol
phosphonates (1.5 eq ArB(OH)2, 2 eq Na2CO3, 0.05 eq Pd(PPh3)4,
DME–EtOH–H2O, 80 ◦C, 1 h), the reaction of phosphinate
3a with three boronic acids (3,5-dimethylphenyl 4i, p-tolyl 4ii,
and thiophene boronic acid 4iii) was attempted. Whilst with
3,5-dimethylphenyl boronic acid, the desired product could be
isolated, as evidenced by a shift in the resonance for the C-3 vinylic
proton to 5.85 ppm (1H, t, J = 7 Hz) and a molecular ion at MNa+
of m/z = 324.1934 in the ESI mass spectrum, the yield was low
(30%). Moreover, as with the majority of the coupled products vide
infra, 5a-i was isolated as a mixture of rotameric isomers (4 : 1 ratio)
1
as characterised by two sets of peaks in the H NMR spectrum.
Notably, two peaks due to the C-3 vinyl proton can be seen at
6.11 ppm (t, J = 7 Hz). These coalesce to a single broad peak
◦
on heating the sample in CDCl3 to 60 C (see ESI for spectra†).
Importantly, these optimised conditions proved to be relatively
general across a range of boronic acids affording cross coupled
products 5a-i to 5a-ix in generally excellent yields (Table 2, entries
1–11). Of particular note is the coupling of the highly hindered
2,4,6-trimethylphenyl boronic acid 4vi giving coupled product
However, reactions with the other boronic acids selected failed to
afford any of the desired coupled products (Scheme 1).
Consequently, we initiated asimple screeningstrategy to identify
conditions to effect the coupling of phosphinate 3a with a range
of boronic acids in good yields. Since the number and range of
variables render a complete and systematic screen impractical, we
simply selected combinations drawn from a total of 4 palladium
‡ A full listing of all combinations explored can be found in the ESI.†
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Table 1 Selected results from the array optimisation of Suzuki cross-
coupling protocol using phosphinate 3 and 3,5-dimethylphenyl boronic
acid.a
Table 2 Suzuki–Miyaura cross-coupling reactions of phosphinates 3
Entry Catalyst
Ligand
Base
Solvent
DMF
GC yield
A2
A4
A5
C5
D1
D4
D6
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
Pd2(dba)3
PdCl2(Binap)
PdCl2(Binap)
K3PO4
NaHCO3 DME–H2O
Ba(OH)2 DME–H2O
23%
98%
72%
44%
tBu2P(BiPh) K3PO4
KOAc
EtOH–H2O
Toluene–EtOH 31%
NaHCO3 DME–H2O
CsF
46%
63%
THF–H2O
Reaction conditions: carried out on a 0.1 mmol scale. ArB(OH)2 (1.0 eq),
phosphinate 3 (1 eq), dodecane (1 eq), Pd source (0.05 eq), phosphine
(0.05 eq), base (3 eq), solvent (1 ml total), 80 ◦C, 18 h.a A full listing of all
combinations explored can be found in the ESI.†
Entry
Phosphinate 3
Boronic acid 4
Enamide 5
Yield
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3c
3c
3d
3e
3e
3f
4i
5a-i
83%
81%
99%
89%
75%
65%a
87%
72%
32%
68%a
90%
81%
75%
69%
37%
20%
58%
64%
41%
29%
~10%
~10%
86%a
4ii
5a-ii
5a-iii
5a-iv
5a-v
4iii
4iv
4v
4vi
4vii
4viii
4ix
4x
4xi
4iii
4i
4vi
4viii
4viii
6
4ii
4iii
4x
4ii
4iii
4ii
5a-vi
5a-vii
5a-viii
5a-ix
5a-x
5a-xi
5b-iii
5b-i
5b-vi
5b-viii
5c-viii
5c-viii
5d-ii
5e-iii
5e-x
Scheme 2
5a-vi in a 65% yield (Table 2, entry 6) as well as electron poor
boronic acids yielding coupled products 5a-vii and 5a-viii in 87%
and 72% respectively (entries 7 and 8). Unsurprisingly, however,
employing an electron poor and sterically hindered boronic acid
4ix resulted in a marked drop in yield giving 5a-ix in a moderate
32% (entry 9). Significantly, in contrast to our preliminary studies,
the electron rich heterocyclic boronic acids 4x and 4xi could also
be successfully employed in the Suzuki reaction, furnishing the
corresponding coupled products in 68% and 90% yield respectively
(entries 10 and 11).
Having established the viability of N-Boc caprolactam phosphi-
nate 3a as the electrophilic component in cross-coupling reactions,
the scope and limitations of the process were investigated by
varying the protecting group and the lactam ring.
Initial attempts to use simple alkyl protecting groups (Me
and Bn) were unsuccessful, owing to an inability to form the
5f-ii
5f-iii
5g-ii
3f
3g
a Quoted yield based on recovered starting material.
enol phosphinate. However, preparation of, and subsequent
phosphinate formation with the more electron withdrawing N-
phenyl carbamate, N-benzyl carbamate and N-tosyl protected
caprolactams proceeded smoothly, following analogous proce-
dures to that employed for Boc protected phosphinate 3a. In each
case, the phosphinates (3b–d) were isolated in good to excellent
yields, 90%, 58% and 73% respectively. All three phosphinates
were then investigated in the thermal Suzuki reaction. Using the
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Table 3 Further cross-coupling reactions of phosphinate 3
standard conditions identified for the N-Boc derivative 3a, coupled
products 5 were isolated in moderate to good yields (Table 2,
entries 12–18). Again, electron rich and electron poor boronic
acids both perform well, although coupling of the sterically
demanding and deactivated 2-carboxymethylphenyl boronic acid
4viii with both 3b and 3d under thermal conditions afforded the
corresponding coupled product 5b-viii and 5c-viii in poor yields
of 37% and 20% respectively (Table 2, entries 15 and 16). Given
that similar observations had been made with phosphinate 3a
(Table 2, entry 9), we then explored the use of the corresponding
potassium trifluoroborate salts, which are often more reactive in
Suzuki coupling reactions than their boronic acid equivalents.9
Consequently, 2-carboxymethylphenyl boronic acid was treated
with KHF2 in a MeOH–H2O mixture; recrystallisation from
acetonitrile afforded the trifluoroborate salt 6 in a 75% yield.
Pleasingly, use of this in a Suzuki coupling with 3d under identical
conditions resulted in a threefold increase in yield, affording the
desired product in a now reasonable 58% yield (Table 2, entry 17).
We then turned to consider the effect of lactam ring size. Whilst
attempts to generate the five-membered ring enol phosphinates
appeared successful by LCMS analysis of the crude material,
all attempts to purify these proved unsuccessful, leading only
to recovered lactams. Similar results were obtained on using
the phosphinates directly in cross-coupling experiments and we
surmise that the 5-membered enol phosphinate is highly strained,
making it very prone to hydrolysis. Although the six-membered
ring analogue protected as the N-Ts also exhibited some degree of
hydrolytic instability, both the N-Boc and N-CO2Ph derivatives
3e and 3f were stable to flash column chromatography and
could be isolated in excellent yields, 89% and 95% respectively,
but proved to be unstable with respect to prolonged storage or
acidic media. Similar problems complicated applications in cross-
coupling reactions, which provided modest yields of the desired
arylenamides (Table 2, entries 19–22). This instability persisted in
the products, which, although stable in the solid state, as solutions
in CDCl3 were found to gradually convert to the corresponding
acyclic amino ketones over a period of days.
In contrast, ring strain appears to be much reduced in the eight
membered phosphinate 3g, which could be prepared in a moderate
51% yield from the corresponding N-Ts protected 8-membered
ring lactam and was successfully coupled with p-tolylboronic acid
4ii (Table 2, entry 23). Notably, this substrate performed better
in the Suzuki reaction than the analogous N-Ts 7-membered ring
phosphinate 3d (Table 2, entry 18).
Having demonstrated the viability of phosphinate electrophiles
in the Suzuki–Miyaura reaction, we then considered other com-
mon cross-coupling methods. Initially exploring the Stille cross-
coupling, aryl, heteroaryl, vinyl and alkynyl tributylstannanes
were all coupled in moderate to good yields using standard
literature conditions (Table 3, entries 1–4). Trimethylstannanes
can also be employed, although in the single example explored,
the reaction proved to be less efficient than the analogous tributyl-
stannane (Table 3, entries 4 and 5). Both thermal and microwave
protocols performed equally well, however, carrying out the
reactions in a microwave has the advantage of drastically shortened
reaction times and dispensing with the need to degas solvents
before the reaction. Whilst Kumada–Hayashi type coupling with
isopropylmagnesium bromide in the presence of a Ni salt and
phosphine ligand afforded the very hydrolytically labile alkyl
Entry
1
RM
Product 5
Yield
89%a 91%b
2
3
82%a 85%b
49%a 54%b
4
5
6
45%a 45%b
29%a
37%c
Reaction conditions:a 1.5 eq R¢SnR3, 2.5 eq LiCl, 0.05 eq Pd(PPh3)4,
THF, reflux, 2 h. b 1.5 eq R¢SnR3, 2.5 eq LiCl, 0.05 eq Pd(PPh3)4, THF,
i
microwave, 15 min. c 1.5 eq PrMgBr, 0.05 eq Ni(dppe)Cl2, Et2O–THF
(1 : 1), r.t., 18 h.
enamide 5aq in a moderate 37% yield (Table 3, entry 6), all attempts
to utilise 3 in Heck and Sonogashira coupling protocols have, to
date, been unsuccessful.
In conclusion, lactam derived enol phosphinates with electron
withdrawing groups on the nitrogen atom have been shown to
be excellent partners for both Suzuki and Stille cross-coupling
protocols and also show some activity in nickel catalysed Kumada
type coupling reactions. Both electron rich and electron poor
boronic acids couple equally efficiently, with the only restriction
being those combining deficiency with steric hindrance. However,
this problem may be circumvented by use of the corresponding
aryltrifluoroborate salt. Whilst six- to eight-membered rings are
tolerated, a limitation appears to be ring strain, which results
in hydrolysis being competitive for smaller rings. Overall, these
results suggest that phosphinates represent a viable alternative to
the more commonly used triflate group.
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syringe and the reaction mixture was stirred at -78 ◦C for 1 h.
Diphenylphosphonic chloride (1.2 eq) was added dropwise via
syringe and the reaction mixture was stirred at -78 ◦C for an
additional 2 h before warming to room temperature and quenching
with H2O. The resulting mixture was concentrated and the
aqueous layer extracted into EtOAc (3 ¥). The combined organics
were washed with brine, dried over MgSO4 and concentrated,
affording the crude product as a yellow oil. Purification by flash
chromatography ([1 : 1] dichloromethane–ethyl acetate) afforded
the title compound as a white solid (90%). Mp 81–83 ◦C. Found;
C, 66.70; H, 6.82; N, 3.22%; Calc. for C23H28NO4P; C, 66.82; H,
Experimental section
All reactions were carried out under an argon atmosphere unless
otherwise stated. Solvents were purified following established
protocols. Petrol refers to petroleum spirit boiling in the 40–
60 ◦C range. Ether refers to diethyl ether. Commercially available
reagents were used as received unless otherwise stated. Flash
column chromatography was performed according to the method
of Still et al. using 200–400 mesh silica gel. Yields refer to isolated
yields of products of greater than 95% purity as determined by
1H + 13C NMR spectroscopy or elemental analysis (Durham
University Microanalytical Laboratory).
=
6.83; N, 3.39%. nmax (KBr) 2932 (C–H), 1703 (C O), 1681 (enol
Melting points were determined using Gallenkamp melting
point apparatus and are uncorrected. Infrared spectra were
recorded as thin films between KBr plates (liquids) or using an
ATR attachment (golden gate apparatus) on a Perkin-Elmer FT-
IR 1600 spectrometer. Unless otherwise stated, 1H NMR spectra
were recorded in CDCl3 on Varian Mercury 200, Varian Unity-
300, Mercury-400 or Varian Inova-500 and are reported as follows:
chemical shift d (ppm) (number of protons, multiplicity, coupling
constant J (Hz), assignment). Residual protic solvent CHCl3
(dH = 7.26 ppm) was used as the internal reference. 13C NMR
spectra were recorded at 101 MHz or 126 MHz on Mercury-400
or Varian Inova-500 respectively, using the central resonance of
CDCl3 (dc = 77.0 ppm) as the internal reference. All chemical shifts
=
ether), 1440 (P–Ph), 1356 (P O), 1226 (P-O–Ar), 1159, 1131, 1059,
541, 524 cm-1. dH (400 MHz, CDCl3) 1.44 (13H, m, (CH3)3C, 5-
H2, 6-H2), 1.56 (2H, m, 4-H2), 1.99 (2H, m, 7-H2), 5.36 (1H, dt,
JP = 3 Hz, JH = 7 Hz, 3-H), 7.38–7.58 (6H, m, Ar–H), 7.78–
7.92 (4H, m, Ar–H). dC (100 MHz, CDCl3) 24.3 (C-5), 24.8 (C-6),
28.5 (C(CH3)3), 29.4 (C-4), 46.4 (C-7), 81.0 (C(CH3)3), 110.1 (C-
3), 128.6, 128.7 (ArC–H), 130.9, 131.9 and 132.0 (ArC–H), 132.3
=
and 132.5 (ArC), 144.9 (C-2), 153.4 (C O). dP (162 MHz, CDCl3)
29.7. m/z (ES+) 436.2 (MNa+), 849.0 (2MNa+).
Typical Suzuki cross-coupling protocols.
N-[(4¢-Methylphenyl)sulfonyl]-2-(4¢-methylphenyl)-
4,5,6,7-tetrahydro-azepane 5d-ii
are quoted in parts per million relative to tetramethylsilane (dH
=
Method A. A solution of phosphonite 3d (1 eq), NaHCO3
(3 eq), and 3¢,5¢-dimethylphenylboronic acid (1 eq) in DME–
H2O (7 : 3) was degassed via the freeze–pump–thaw method.
Pd(PPh3)4 (0.05 eq) was added and the reaction mixture stirred
at reflux (85 ◦C) for 1 h. The reaction mixture was cooled to
room temperature, concentrated and extracted into EtOAc (3 ¥).
The combined organics were washed with H2O (3 ¥) then brine
(3 ¥), dried over MgSO4 and concentrated. Purification on a
0.00 ppm) and coupling constants are given in Hertz to the nearest
0.3 Hz. All 13C spectra were proton decoupled. Assignment of
spectra was carried out using DEPT, COSY, HSQC and NOESY
experiments. Low-resolution electrospray mass spectra (ES) were
obtained on a Micromass LCT Mass Spectrometer or a Thermo-
Finnigan LTQ. High-resolution mass spectra (ES) were obtained
on a Thermo-Finnigan LTQFT Mass Spectrometer in Durham.
Procedures for the reaction screen and characterisation data for
compounds 3b–3e, 5a-i to 5a-xv can be found in the ESI.†
R
Horizonꢀ column chromatography system (1.5% ethyl acetate–
DCM) afforded recovered starting material (33%) and the title
compound as a white solid (43%).
N-(tert-Butyloxycarbonyl)-2-oxo-azepane 2
Method B. The desired phosphinate (1 eq), boronic acid
(1.1 eq), Na2CO3 (3 eq) and catalyst (0.05 eq) were placed in a
standard 2 ml microwave vial, the solvent (DME–H2O–EtOH,
[7 : 3 : 1]) was added and the vial sealed. Reaction parameters;
Prestir = 10 s, reaction time = 300 s, temperature = 100 ◦C. The
reaction was allowed to cool to room temperature, concentrated
and extracted into EtOAc (3 ¥). The combined organics were
washed with H2O (3 ¥) then brine (3 ¥), dried over MgSO4
and concentrated, affording the crude product. Purification on
To a solution of caprolactam (11.47 g, 0.10 mol) and DMAP
(13.62 g, 0.11 mol) in dry THF (120 ml) was added a solution
of di-tert-butyldicarbonate (24.33 g, 0.11 mol) in dry THF
(60 ml). The reaction mixture was stirred at RT for 3 h. The
mixture was concentrated and extracted with EtOAc (150 ml).
The organic phase was washed with 5% HCl (3 ¥ 25 ml), brine
(3 ¥ 25 ml) and NaHCO3 (3 ¥ 25 ml), dried over MgSO4 and
concentrated. Kugelrohr distillation (50 ◦C, 0.4 mbar) afforded
the title compound as a yellow oil (19.87 g, 93.17 mmol, 92%).
R
a Horizonꢀ column chromatography system (1. 5% ethyl acetate–
=
=
nmax (NaCl) 1768 (CH2C O), 1716 (O C-O), 1457, 1367, 1299,
1152 cm-1. dH (500 MHz, CDCl3) 1.50 (9H, s, C(CH3)3), 1.72 (6H,
m, 4-H2, 5-H2, 6-H2), 2.62 (2H, m, 7-H2), 3.75 (2H, m, 3-H2).
dC (125 MHz, CDCl3) 23.7 (CH3)3), 28.3 (C-5), 28.9 (C-6), 29.5
(C-4), 39.7 (C-3), 46.4 (C-7), 83.0 (C(CH3)3), 153.1 (C-2), 176.0
DCM) afforded recovered starting material (32%) and the title
compound as a white solid (35%). nmax (ATR) 2938, 2918, 1440,
1334, 1150, 1087, 1058, 950, 814, 763, 704 cm-1. dH (400 MHz,
CDCl3) 1.43 (2H, m, 5-H2), 1.83 (2H, quint, J = 6 Hz, 6-H2),
2.06 (2H, q, J = 7 Hz, 4-H2), 2.34 (3H, s, CH3), 2.41 (3H, s,
CH3), 6.04 (1H, t, J = 7 Hz, 3-H), 7.04 (2H, d, J = 8 Hz, Ar–
H), 7.18 (4H, d, J = 8 Hz, Ar–H), 7.55 (2H. d, J = 8 Hz, Ar–
H). dC (100 MHz, CDCl3) 19.8 (CH3), 20.2 (CH3), 22.3 (C-5),
25.3 (C-4), 28.6 (C-6), 49.3 (C-7), 124.7 (Ar–CH), 126.1 (Ar–
CH), 126.9 (C-3), 127.4 (Ar–CH), 127.9 (Ar–CH), 134.4 (Ar–
C), 136.2 (C-2), 137.4 (Ar–C), 141.6 (Ar–C), 141.7 (Ar–C). m/z
(ES+) 342.3 (MH+), 359.4 (MH2O+), 700.6 (2MH2O+). HRMS
+
+
=
(OC O). m/z (ES+) 236.1 (MNa ), 449.1 (2MNa ).
Typical procedure for the formation of enol phosphinates.
N-(tert-Butyloxycarbonyl)-4,5,6,7-tetrahydro-1H-azepin-2-yl
diphenylphosphinate 3a
◦
To a cold solution (-78 C) of the N-protected lactam 2 (0.1 M,
1 eq) in dry THF was added NaHMDS (2 M 1.2 eq) slowly via
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(ES) found MH+ 342.1523, C20H24NO2S requires 342.1522, found
MNa+ 364.1342, C20H23NO2SNa requires 364.1342.
24.5 (C-4), 27.1 (C-5), 28.3 ((CH3)3C), 29.8 (C-6), 46.7 (C-7), 80.0
=
=
((CH3)3C), 111.9 (CH2 CH), 127.8 (C-3), 134.3 (CH2 CH), 144.3
+
=
(C-2), 154.1 (O-C O). mlz (ES+) 246.0 MNa .
Stille protocols. N-tert-Butyloxycarbonyl-2-vinyl-4,5,6,7-
tetrahydro-azepane 5a-xii
Acknowledgements
Method A. A solution of 3a (0.413 g, 1.0 mmol) and LiCl
We thank the EPSRC (GR/M75990/01 - JG), and Glaxo-
SmithKline for financial support of this work (CASE award to
TMW); the EPSRC Mass Spectrometry Service for accurate mass
determinations, Dr A. M. Kenwright for assistance with NMR
experiments and Dr M. Jones for mass spectra.
(0.106 g, 2.50 mmol) in THF (15 ml) was degassed by purging Ar
=
for 10 minutes before CH2 CHSnBu3 (1.5 mmol) and Pd(PPh3)4
(0.058 g, 0.05 mmol) were added. The mixture was refluxed for
2 h before cooling to room temperature. The solution was concen-
trated and extracted with EtOAc–(1 M aqueous KF), the organic
phase was combined, dried (MgSO4), filtered and evaporated.
Flash chromatography on silica (19 : 1 to 9 : 1 petroleum ether–
EtOAc) gave the coupled compound as a colourless oil (82%).
References
1 For
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Method B. A solution of 3 (0.413 g, 1.0 mmol) and LiCl
(0.106 g, 2.50 mmol) in THF (7 ml) was degassed by purging
with Ar for 10 minutes before ArSnR3 (1.5 mmol) and Pd(PPh3)4
(0.058 g, 0.05 mmol) was added. The reaction mixture was
sealed in a standard 10 ml microwave vial and was heated in a
Biotage microwave oven with stirring (irradiation power; 50 W;
temperature ramped to 150 ◦C in 2 min and held for 15 min),
then cooled to rt. The solution was extracted with EtOAc–(1 M
aqueous KF), the organic phase was combined, dried (MgSO4),
filtered and evaporated. Flash chromatography on silica (19 : 1 to
9 : 1 petroleum ether–EtOAc) gave the title compound (85%). Rf
(19 : 1 petroleum ether–EtOAc): 0.30. Found; C, 69.11; H, 9.31;
N, 6.09%: Calc. for C13H21NO2; C, 69.92; H, 9.48; N, 6.27%. nmax
(NaCl film) 3092, 2926, 2933, 2853, 1703, 1698, 1645, 1445, 1391,
1253, 1166, 985, 896 and 779 cm-1. dH (400 MHz, CDCl3) 1.37
(9H, s, (CH3)3C), 1.47 (2H, br, 5-H2), 1.78 (2H, quintet, J = 6 Hz,
6-H2), 2.15 (2H, m, 4-H2), 2.90–3.70 (2H, br, 7-H2), 4.95 (1H, d,
J = 10 Hz), 5.07 (1H, d, J = 17 Hz), 5.67 (t, 1H, J = 7 Hz, 3-H),
6.18 (1H, dd, J1 = 17 Hz, J2 = 10 Hz). dC (100 MHz, CDCl3)
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4058 | Org. Biomol. Chem., 2008, 6, 4053–4058
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