Enol phosphinates and phosphonates: Practical electrophiles for cross-coupling strategies

Article abstract of DOI:10.1055/s-0029-1217067

Enol phosphinates and phosphonates can be readily prepared from simple lactams in high yields and are both stable and storable. Both these substrates can be employed successfully in homogeneous Suzuki-Miyaura and Stille cross-couplings protocols. Additionally, the phosphonate group can be immobilised on a phenol-on-polystyrene resin and utilised in a simple diversity linker strategy in which the coupled product is cleaved from the resin under Suzuki-Miyaura cross-coupling conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217067

PRACTICAL SYNTHETIC PROCEDURES
3897
Enol Phosphinates and Phosphonates: Practical Electrophiles for
Cross-Coupling Strategies
C
ross-Couplin
a
g Strategie
t
with
E
r
nol Pho
i
sphina
t
c
es and Pho
k
sphonates G. Steel,*a Tom M. Woodsa,b
a
Department of Chemistry, University of Durham, Science Laboratories, South Road Durham, DH1 3LE, UK
Fax +44(191)3844737; E-mail: p.g.steel@durham.ac.uk
b
Chemical Synthesis Laboratory, Swiss Federal Institute of Technology (EPFL), 1015 Lausanne,
Switzerland
PSP
E-mail: tom.m.woods@gmail.com
Received 18 June 2009; revised 7 July 2009
No172
Abstract: Enol phosphinates and phosphonates can be readily prepared from simple lactams in high yields and are both stable and storable.
Both these substrates can be employed successfully in homogeneous Suzuki–Miyaura and Stille cross-couplings protocols. Additionally,
the phosphonate group can be immobilised on a phenol-on-polystyrene resin and utilised in a simple diversity linker strategy in which the
coupled product is cleaved from the resin under Suzuki–Miyaura cross-coupling conditions.
Key words: lactams, arylboronic acids, stannanes, Suzuki–Miyaura coupling, Stille coupling, resin-bound enol phosphinate
Pd(PPh3)4, NaHCO3
DME–H2O
80 °C, 30 min
Pd(PPh3)4, LiCl
THF, 65 °C, 2 h
O
PPh2
O
N
N
N
O
(HO)2B
OMe
Bu3Sn
O
Boc
Boc
Boc
OMe
4a
6a-x
89%
6a-iii
99%
Pd(PPh3)4, Na2CO3
DME–H2O–EtOH
80 °C, 1 h
O
+
N
B(OH)2
P
Boc
O
O
N
Ph
57%
Boc
6a-i
11
Scheme 1 Cross-coupling reactions with enol phosphinates and phosphonates
triflimides. Of these two options, the former is corrosive,
produces triflic acid as a by-product and often gives poor
Introduction
Late transition metal (Pd, Ni) mediated cross-coupling re- yields whilst the latter reagents suffer from being relative-
actions represent one of the most common methods for ly expensive. As a result much effort has been focused on
forming C–C bonds, and whilst halides represent the most developing alternatives to the triflate group for activating
common electrophilic component, there are also a large oxygen functionalities towards cross-coupling protocols.
number of oxygen based leaving groups that have been re- The majority of these alternatives have explored different
ported.1 Of these, the vinyl and aryl triflates,2 by virtue of sulfonate groups including fluorosulfonates,3 alkyl sul-
their excellent leaving group ability and ease of prepara- fonates,4 arylsulfonates,5 and nonaflates.6 Although each
tion from phenols and enolates have become the most of these has its merits when compared to triflates, whether
widely used in the various cross-coupling strategies. it is similar or enhanced reactivity (fluorosulfonates and
However, despite its versatility and widespread use in or- nonaflates) or higher stability and ease of preparation
ganic chemistry, the triflate group often suffers from a (alkyl/aryl sulfonates), none has proven to be as useful as
lack of stability. Moreover, the preparation of triflates the triflate group as a general substrate for transition-
requires the use of either triflic anhydride or the bis- metal-catalysed cross-coupling protocols.
A more attractive alternative to the triflate group is the
SYNTHESIS 2009, No. 22, pp 3897–3904
Advanced online publication: 22.10.2009
DOI: 10.1055/s-0029-1217067; Art ID: Z12909SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
9
analogous phosphate group 1 (Figure 1). Not only are the
reagents needed for their preparation cheap and easily
stored and handled, phosphates are often found to be su-

3898
P. G. Steel, T. M. Wood
PRACTICAL SYNTHETIC PROCEDURES
perior substrates in cross-coupling reactions. Although nylphosphonic chloride afforded the desired phosphinate
previously reported in simple cuprate displacement reac- 4a in a 77% yield. The formation of the phosphinate is
tions,7 the first examples of palladium-mediated cross- characterised by a distinctive peak in the 31P NMR spec-
1
coupling of vinyl phosphates was reported in 1980 by trum at 29.7 ppm and in the H NMR spectrum at 5.36
Oshima et al. who coupled a series of vinyl phosphates ppm (1 H, dt, JP = 3 Hz, JH = 7 Hz) the latter being due to
with trialkylaluminum species in the presence of a the C-3 vinylic proton. LDA/TMEDA can be replaced by
Pd(PPh3)4 catalyst.8 More recently, amongst others, NaHMDS, which proved to be cleaner and more efficient
Nicolaou,9 Coudert,10 Occhiato,11 and Skrydstrup12 have providing phosphinate 4a in 90% yield.
successfully used enol phosphates in a variety of cross-
coupling reactions.
Using conditions identified through a parallel screen of
variables [1.0 equiv ArB(OH)2, 3.0 equiv NaHCO3,
0.1 equiv Pd(PPh3)4, DME–H2O (7:3), 85 °C, 1 h], which
R3
R2
R3
R2
R2
R1
explored the catalyst precursor, ligand, base, and solvent,
phosphinate 4a was combined with mesitylboronic acid
(5i) to afford the cross-coupled product 6a–i in an excel-
lent yield (83%, Scheme 2). This coupled product is char-
acterised by a distinctive shift of C-3 vinylic proton to
give two peaks in the 1H NMR spectrum at 5.85 and 6.11
ppm (1 H, t, J = 7 Hz) reflecting the formation of rotamer-
ic isomers (4:1 ratio). These coalesce to a single broad
peak on heating the sample in CDCl3 to 60 °C.
O
O
P
R
O
P
R1
P
OR
R
OR
O
O
O
OR
1 phosphate
2 phosphonate
3 phosphinate
Figure 1 Phosphates 1, phosphonates 2, and phosphinates 3
Despite these successful applications of the phosphate
group in cross-coupling strategies the parallel phospho-
nate and phosphinate groups, 2 and 3, respectively
(Figure 1), have remained unexplored. Differing, through
the oxygenation level at phosphorus, via the replacement
of one or two P–O bonds with a P–C bond, these groups
offer practical benefits in synthesis. In particular, since re-
placing P–O bonds with P–C bonds lowers the leaving
group ability, these groups are predicted to be more stable
than the equivalent triflates and phosphates. Additionally,
in comparison to triflates, the reagents required for the
synthesis of these substrates are cheap and noncorrosive,
further increasing their appeal in organic synthesis. Con-
sidering the lack of stability of many triflates9,10 and even
some phosphates,11a phosphonates, and phosphinates rep-
resent attractive alternatives to these electrophiles for the
use in cross-coupling reactions. Herein, we describe the
preparation and application of lactam-derived
phosphinates13 and phosphonates14 in homogeneous and
heterogeneous cross-coupling strategies (Scheme 1).
When using a seven-membered-ring lactam this proce-
dure can be applied successfully to a range of aryl and het-
eroarylboronic acids in conjunction with Boc, CO2Ph,
CO2Bn, and Ts protecting groups (Table 1, entries 1–18).
However, the use of the tosyl protecting group requires
NaHMDS for the metallation step as LDA/TMEDA lead
to the formation of a sultam as the major product via a di-
rected ortho-metallation procedure.15 Both electron-poor
(entries 7 and 8) and electron-rich boronic acids (entries 1
and 3) couple effectively. Of particular note is the cou-
pling of the highly hindered 2,4,6-trimethylphenylboronic
acid (5vi) giving the coupled product 6a-vi in 65% yield
(Table 1, entry 6). Unsurprisingly, however, employing
an electron-poor and sterically hindered boronic acid 5ix
results in a marked drop in yield giving 6a-ix in a moder-
ate 32% (entry 9). This situation can be rescued using the
corresponding trifluoroborate salt 7. Use of this in the
Suzuki coupling with 4c under identical conditions af-
fords the desired product in 58% yield (entry 17). The ap-
proach can be extended to other lactam rings including
five-, six-, and eight-membered, although the ring strain
found in smaller rings reduces the stability of the phosph-
inates and adversely effects their formation and/or cross-
coupling chemistry (entries 19–22). However, eight-
membered-ring lactams proved to be effective partners
(entry 23).
Scope and Limitations
A variety of enol phosphinates can be readily prepared
from commercially available lactams protected on nitro-
gen with simple electron-withdrawing protecting groups.
Simple N-alkylated lactams proved not to be effective
substrates. Treatment of a cold (–78 °C) solution of
N-Boc protected caprolactam in THF with LDA and
TMEDA and trapping of the resultant anion with diphe-
In a similar fashion, Stille cross-coupling of phosphinate
4a with aryl, heteroaryl, vinyl, and alkynyl tributylstan-
nanes are all viable using standard literature conditions
(HO)2B
Pd(PPh3)4, NaHCO3
O
+
PPh2
N
O
N
DME–H2O
80 °C, 30 min
Boc
Boc
4a (1 equiv)
6a-i 83%
5i (1 equiv)
Scheme 2
Synthesis 2009, No. 22, 3897–3904 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Cross-Coupling with Enol Phosphinates and Phosphonates
3899
Table 1 Suzuki–Miyaura Cross-Coupling Reactions of Phosphinates 4
O
P
ArB(OH)2 5 (1.1 equiv)
( )n
( )n
O
O
Pd(PPh3)4 (0.05 equiv)
NaHCO3 (3 equiv)
O
N
N
Ph
OPPh2
Boc
Boc
Ar
N
N
ArB(OH)2 (3 equiv)
Pd(PPh3)4, Na2CO3
8
ArSnBu3 (3 equiv)
DME–H2O (7:3)
85 °C, 0.5–1 h
R
R
Pd(PPh3)4
4
6
DME–EtOH–H2O, 80 °C
LiCl, THF, 65 °C
4a R = Boc, n = 3
4d R = Ts, n = 3
4g R = Ts, n = 4
4b R = CO2Ph, n = 3
4e R = Boc, n = 2
4c R = CO2Bn, n = 3
4f R = CO2Ph, n = 2
ArB(OH)2
5
N
N
iv
iii
i
ii
O
OMe
Boc
Boc
F
MeO
6a-ix 78%
6a-iii 36%
Scheme 3
F3C
MeO
v
viii
vi
vii
MeO2C
MeO
(Table 2, entries 1–4). Trimethylstannanes can also be
employed, although in the single example explored the re-
action proved to be less efficient than the analogous tribu-
tylstannane (Table 2, entries 4 and 5). Both thermal and
microwave protocols function equally efficiently. How-
ever, carrying out the reactions in a microwave has the ad-
vantage of drastically shortened reaction times and
dispensing with the need to degas solvents before the re-
action. A single example of a Kumada–Hayashi cross-
coupling reaction was also explored. Thus, treatment of a
solution of 4a and NiCl2(dppe) with isopropylmagnesium
bromide afforded the very hydrolytically labile alkyl
enamide 6a-xiv in a moderate 37% yield.
CF3
S
O
ix
x
xi
CO2Me
BF3–K+
CO2Me
7
Entry
Phosphinate 4 Boronic acid 5 Enamide 6
Yield (%)
1
2
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
5i
6a-i
83
81
99
89
75
65a
87
72
32
68a
5ii
6a-ii
6a-iii
6a-iv
6a-v
3
5iii
5iv
5v
Simply replacing diphenylphosphonic chloride with phe-
nylphosphonic dichloride [PhP(O)Cl2], PPDC) when
trapping the lactam enolate gives facile access to enol
phosphonates in high yields. These substrates have also
been demonstrated to be useful electrophiles for cross-
coupling chemistry. Enhanced atom economy can be rea-
lised through the use of a bis-enol phosphonate, for exam-
ple, 8. Addition of the lithium enolate of N-Boc
caprolactam to a solution of PPDC afforded bis-phospho-
nate 8. Reaction of this under classical Stille or Suzuki
cross-coupling conditions provides a general method for
the activation of two equivalents of an enol with a single
equivalent of the phosphorous reagent (Scheme 3).
4
5
6
5vi
5vii
5viii
5ix
5x
6a-vi
6a-vii
6a-viii
6a-ix
6a-x
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
4a
4b
4b
4b
4b
4c
4c
4d
4e
4e
4f
5xi
5iii
5i
6a-xi
6b-iii
6b-i
90
81
The use of a phosphonate permits this approach to be ex-
tended to solid-phase organic synthesis. Whilst alkyl enol
phosphinates do not have sufficient stability to represent
viable alternatives to the triflate group, the lower reactiv-
ity and enhanced stability of an aryl sp2C–OP bond allows
a phenol group to be employed as simple and easily intro-
duced linker unit. Generation of the enolate of N-Boc pro-
tected lactam 10 as described above, combining the
enolate with PPDC in THF at –78 °C and then transferring
this solution to a slurry of commercially available phenol
on polystyrene resin 9 in THF afforded the desired immo-
bilised enolate 11 (Scheme 4). Analysis by 31P NMR
spectra revealed a major broad peak at d = 12 for the de-
sired enol phosphonate 11 accompanied by a minor com-
ponent corresponding to a cross-linked bis-phenyl
phosphonate at d = 16. Importantly, this resin is stable,
giving identical analysis and performance in cross-cou-
75
5vi
5viii
5viii
7
6b-vi
6b-viii
6c-viii
6c-viii
6d-ii
6e-iii
6e-x
69
37
20
58
5ii
64
5iii
5x
41
29
5ii
6f-ii
~10
~10
86a
4f
5iii
5ii
6f-iii
6g-ii
4g
a Quoted yield based on recovered starting material.
Synthesis 2009, No. 22, 3897–3904 © Thieme Stuttgart · New York

3900
P. G. Steel, T. M. Wood
PRACTICAL SYNTHETIC PROCEDURES
Table 2 Further Cross-Coupling Reactions of Phosphinate 4a
OH
organometallic (RM), catalyst
solvent, base
O
9
i. PhP(O)Cl2
ii. combine
PPh2
N
N
O
R
Boc
Boc
[Li]O
N
iii. filter
4a
6
Boc
10
Entry RM
Product 5
Yield (%)
89,a 91b
ArB(OH)2
O
Pd(Ph3P)4, NaHCO3
P
O
R
O
O
1
2
3
N
O
N
N
SnBu3
Ph
DME–EtOH–H2O
80 °C, 1 h
Boc
Boc
Boc
11
6
6a-x
Scheme 4
82,a 85b
SnBu3
N
Similarly, the more electron-rich aryl derivatives hydro-
lyse in mild acidic conditions (CDCl3) to afford the corre-
sponding keto amine and this may account for some of the
lower yields for these derivatives under these standard re-
action conditions.
Boc
6a-xi
SnBu3
49,a 54b
N
Ph
Boc
Table 3 Suzuki Reaction Results with Resin 11
Ph
6a-xii
Entry ArB(OH)2 5
Product
Yield
(%)a
SnBu3
SnMe3
4
5
6
45,a 45b
N
Boc
Ph
Ph
B(OH)2
N
6a-xiii
1
49
46
Boc
MeO
iii
OMe
29a
N
Boc
6a-iii
6a-xiii
B(OH)2
N
2
3
Boc
37c
BrMg
ii
N
Boc
6a-ii
6a-xiv
B(OH)2
a Reaction conditions: R¢SnR3 (1.5 equiv), LiCl (2.5 equiv),
Pd(PPh3)4 (0 .05 equiv), THF, reflux, 2 h.
N
57
53
b Reaction conditions: R¢SnR3 (1.5 equiv), LiCl (2.5 equiv),
Pd(PPh3)4 (0.05 equiv), THF, microwave, 15 min.
c Reaction conditions: i-PrMgBr (1.5 equiv), Ni(dppe)Cl2
(0.05 equiv), Et2O–THF (1:1), r.t., 18 h.
Boc
i
6a-i
B(OH)2
pling reactions (vide infra) even after storage for several
N
months.
4
5
Boc
F
Treatment of a suspension of 11 in a mixture of DME–
H2O–EtOH with a range of boronic acids under standard
Suzuki reaction conditions [ArB(OH)2 (3.0 equiv),
Na2CO3 (4 equiv), Pd(PPh3)4 (0.1 equiv), DME–EtOH–
H2O (10:4:4), 80 °C, 1 h] afforded the desired 2-substitut-
ed enamides in moderate to good yields (Table 3).16 The
quoted yields refer to the overall process of resin activa-
tion, loading, and cross-coupling cleavage. Whilst the 2-
aryl and styryl products derived from caprolactam are sta-
ble compounds, attempts to isolate the vinyl derivative
derived from pent-1-enylboronic acid failed (entry 12).
iv
F
6a-iv
F3C
B(OH)2
N
CF3
48
Boc
CF3
F3C
vii
6a-vii
Synthesis 2009, No. 22, 3897–3904 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Cross-Coupling with Enol Phosphinates and Phosphonates
3901
Table 3 Suzuki Reaction Results with Resin 11 (continued)
All reactions were carried out under an argon atmosphere unless
otherwise stated. Solvents were purified following established pro-
tocols. PE refers to petroleum ether boiling in the 40–60 °C range.
Commercially available reagents were used as received unless oth-
erwise stated. Flash column chromatography was performed ac-
cording to the method of Still et al. using 200–400 mesh silica gel.17
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).
Entry ArB(OH)2 5
Product
Yield
(%)a
B(OH)2
6
35
N
NC
xv
Boc
Melting points were determined using Gallenkamp melting point
apparatus and are uncorrected. IR spectra were recorded as thin
films between KBr plates (liquids) or using an ATR attachment
(golden gate apparatus) on a PerkinElmer FT-IR 1600 spectrometer.
CN
6a-xv
B(OH)2
1
Unless otherwise stated H NMR spectra were recorded in CDCl3
N
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), assign-
ment]. Residual protic solvent CHCl3 (dH = 7.26) 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 ref-
erence. All chemical shifts are quoted in parts per million relative to
TMS (dH = 0.00) 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.
7
32
72
MeO
Boc
OMe
OMe
MeO
v
6a-v
O
B(OH)2
8
O
S
N
Boc
x
6a-x
S
B(OH)2
9
42
34
N
Boc
ix
NaHMDS Protocol for Phosphinate Formation; General Proce-
dure
6a-ix
To a cold solution (–78 °C) of the appropriate lactam (0.1 M,
1 equiv) in anhyd THF was added NaHMDS (2 M, 1.2 equiv) slow-
ly via syringe and the reaction mixture stirred at –78 °C for 1 h.
Diphenylphosphonic chloride (1.2 equiv) was added dropwise via
syringe and the mixture was stirred at –78 °C for an additional 2 h
before warming to r.t. and quenching with H2O (5.0 mL/mmol lac-
tam). The resulting mixture was concentrated and the aqueous layer
extracted with EtOAc (3 × 10.0 mL/mmol lactam). The combined
organics were washed with brine (3 × 5.0 mL/mmol lactam), dried
(MgSO4), and concentrated affording the crude product.
B(OH)2
N
10
Boc
xvi
6a-xvi
O
O
N
B(OH)2
11
12
21
Boc
xvii
LDA/TMEDA Protocol for Phosphinate Formation; General
Procedure
6a-xvii
To a cold solution (–78 °C) of the desired lactam (1 equiv) and
TMEDA (1.3 equiv) in anhyd THF (0.08–0.1 M) was added a cold
solution of LDA in anhyd THF (0.18 M, 1.3 equiv). The resulting
reaction mixture was stirred at –78 °C for 2 h after which time a
cold (–78 °C) solution of diphenylphosphonic chloride in anhyd
THF (0.2–0.4 M, 1.2 equiv) was added via cannula. The mixture
was stirred at –78 °C for 3 h, then warmed to r.t., and quenched with
aq NH4Cl (5.0 mL/mmol lactam). The THF was removed under re-
duced pressure and the aqueous layer extracted with EtOAc (3 ×
10.0 mL/mmol lactam). The combined organic phases were washed
with aq NaHCO3 (3 × 5.0 mL/mmol lactam) and brine (3 × 5.0 mL/
mmol lactam), dried (MgSO4), and concentrated under reduced
pressure to give the crude material.
C3H7
0
B(OH)2
N
C3H7
xviii
Boc
6a-xviii
a Yield of purified, isolated product based on initial resin 9 used.
In summary, enol phosphinates and phosphonates repre-
sent useful alternatives to the triflate and other carbonyl
activating groups for cross coupling reactions. They have
particular utility when enhanced stability of the enol form
is required. Additionally, enol phosphonates can be em-
ployed as a simple diversity linker unit for solid-phase or-
ganic synthesis, a method that has potential implications
in combinatorial chemistry.
Thermal Suzuki Coupling of Enol Phosphinates; General Pro-
cedure
A solution of the appropriate phosphinate 4 (1 equiv), NaHCO3
(3 equiv), and boronic acid (1 equiv) in DME–H2O (7:3) was de-
gassed via three freeze/pump/thaw cycles. Pd(PPh3)4 (0.05 equiv)
was added and the reaction mixture stirred at reflux (85 °C) for 0.5–
1 h. The mixture was cooled to r.t., concentrated, and extracted with
EtOAc (3 × 10.0 mL/mmol phosphinate). The combined organics
Synthesis 2009, No. 22, 3897–3904 © Thieme Stuttgart · New York

3902
P. G. Steel, T. M. Wood
PRACTICAL SYNTHETIC PROCEDURES
were washed with H2O (3 × 5.0 mL/mmol phosphinate) and brine
(3 × 5.0 mL/mmol phosphinate), dried (MgSO4), and concentrated
(Table 1).
N-(tert-Butyloxycarbonyl-2-(3¢,5¢-dimethylphenyl)-4,5,6,7-tet-
rahydroazepane (6a-i)
Via Thermal Suzuki Protocol: Flash chromatography on silica gel
(19:1 PE–EtOAc) afforded the title compound as a white solid (95
mg, 83%, 0.32 mmol); mp 113–115 °C; GC analysis: 1 peak, tR =
22.35 min.
Thermal Stille Coupling of Enol Phosphinates; General Proce-
dure
A solution of phosphinate 4a (1.0 equiv) and LiCl (2.5 equiv) in
THF was degassed via three freeze/pump/thaw cycles before
ArSnR3 (1.5 equiv) and Pd(PPh3)4 (0.05 equiv) were added. The
mixture was heated at reflux for 2 h and then cooled to r.t. The so-
lution was concentrated and extracted with EtOAc/1 M aq KF (10.0
mL/5.0 mL/mmol phosphinate), the organic phases were combined,
dried (MgSO4), filtered, and concentrated (Table 2).
IR (KBr): 2933, 1687 (C=O), 1391, 1357, 1161 cm–1.
1H NMR (500 MHz): d = 1.10 [9 H, s, C(CH3)3], 1.47 (2 H, m, 7-
H2), 1.79–1.89 (2 H, m, 6-H2), 2.21–2.33 (10 H, m, 3¢-CH3, 5¢-CH3,
4-H2, 5-H2), 5.85 (1 H, t, J = 7 Hz, 3-H), 6.88 (1 H, s, ArH), 6.92 (2
H, s, ArH).
13C NMR (125 MHz): d = 21.5 (C-5), 24.4 (C-3¢, C-5¢), 27.7 (C-4),
28.2 [(C(CH3)3], 28.7 (C-6), 48.2 (C-7), 79.9 [C(CH3)3], 122.8 (C-
3), 123.1 (C-2¢), 129.0 (C-4¢), 137.7 (C-3¢), 139.8 (C-2), 144.8 (C-
1¢), 153.9 (C=O).
Microwave Stille Coupling of Enol Phosphinates; General Pro-
cedure
A solution of phosphinate 4a (0.413 g, 1.0 mmol) and LiCl (2.5
equiv) in THF (10.0 mL; 0.1 M) was degassed via three freeze/
pump/thaw cycles before ArSnR3 (1.5 equiv) and Pd(PPh3)4
(0.05 equiv) were added. The reaction mixture was sealed in a stan-
dard 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 r.t. The solution
was extracted with EtOAc/1 M aq KF (10.0 mL/5.0 mL), the organ-
ic phases were combined, dried (MgSO4), filtered, and concentrated
(Table 2).
MS (ES+): m/z = 365 (M+ + NaMeCN), 302 (MH+), 246 (MH+ –
t-Bu).
HRMS (ES+): m/z calcd for C19H27NO2 + Na (M + Na+): 324.1932;
found: 324.1934.
1-Tosyl-4,5,6,7,8-quintahydro-1H-azepin-2-yl Diphenylphos-
phinate (4g)
Via NaHMDS Protocol for Phosphinate Formation: Purification on
a Horizon® column chromatography system (95:5 → 9:1 CHCl3–
EtOAc) afforded the title compound as a gummy oil, which solidi-
fied on standing (874 mg, 51%, 1.82 mmol); mp 199–200 °C;
HPLC: tR = 6.02 min, purity: 98.13%.
Suzuki Coupling of Enol Phosphonate Resin 11; General Proce-
dure
A suspension of resin 11 (1 g, 1.61 mmol), the desired boronic acid
(3 equiv), and Na2CO3 (4 equiv) in DME–H2O–EtOH (10:4:4) was
degassed via three freeze/pump/thaw cycles. Pd(PPh3)4 (0.05 equiv)
was added and the reaction mixture was refluxed for 1 h and then
cooled to r.t. The resin was filtered and washed with THF (3 × 5.0
mL) and Et2O (3 × 5.0 mL). The combined filtrates were concentrat-
ed and extracted with EtOAc/brine (3 × 10.0 mL/5.0 mL). The com-
bined organic phases were dried (MgSO4), filtered, and evaporated
(Table 3).
IR (KBr): 2928, 2851, 1671, 1593, 1440, 1348, 1235, 1156, 1126,
1076, 1006, 961, 874, 829, 730 cm–1.
1H NMR (400 MHz): d= 1.43–1.60 (6 H, m, 5-H2, 6-H2, 7-H2), 2.13
(2 H, m, 4-H2), 2.36 (3 H, s, 4¢¢-CH3), 3.31 (2 H, m, 8-H2), 5.54 (1
H, dt, 4JH,P = 2 Hz, J = 8 Hz, 3-H), 7.09 (2 H, d, J = 8 Hz, 3¢¢-H, 5¢¢-
H), 7.38–7.45 (4 H, m, ArH), 7.51–7.57 (2 H, m, 4¢-H), 7.63–7.70
(4 H, m, ArH), 7.73 (2 H, d, J = 8 Hz, 2¢¢-H, 6¢¢-H).
13C NMR (100 MHz): d = 21.9 (4¢¢-CH3), 26.2 (C-4), 26.9 (C-6),
27.2 (C-7), 28.8 (C-5), 50.3 (C-8), 119.3 (d, J = 4 Hz, C-3), 128.1
(C-2¢¢), 128.9 (d, J = 13 Hz, C-3¢), 129.8 (C-3¢¢), 130.5 and 131.89
(d, J = 136 Hz, C-1¢), 132.1 (d, J = 11 Hz, C-2¢), 132.8 (d, J = 3 Hz,
C-4¢), 137.7 (ArC), 138.5 (d, J = 10 Hz, C-2), 143.6 (ArC).
31P NMR (162 MHz): d = 32.4.
MS (ES+): m/z = 482.1 (MH+), 980.4 (2 M+ + H2O).
HRMS (ES+): m/z calcd for C26H29NO4SP (MH+): 482.1550; found:
482.1554; m/z calcd for C26H28NO4SP + Na (M+ + Na): 504.1369;
found: 504.1367.
N-(tert-Butyloxycarbonyl)-4,5,6,7-tetrahydro-1H-azepin-2-yl
Diphenylphosphinate (4a)
Via LDA/TMEDA Protocol for Phosphinate Formation: The crude
material was collected as a yellow-orange oil. Purification by flash
chromatography (4:1 PE–Et2O and recrystallisation from 5:1 PE–
Et2O) afforded the title compound as clear crystals (1.12 g, 77%,
2.71 mmol).
Via NaHMDS Protocol for Phosphinate Formation: The crude ma-
terial was collected as a yellow oil. Purification by flash chromatog-
raphy on silica gel (4:1 CH2Cl2–EtOAc) afforded a colourless oil,
which solidified on standing (1.80 g, 89%, 4.36 mmol); mp 81–
83 °C.
N-[(4¢¢-Methylphenyl)sulfonyl]-2-(4¢-methylphenyl)-4,5,6,7,8-
quintahydro-1H-azocine (6g-ii)
Via Thermal Suzuki Protocol: The reaction mixture was degassed
by passing a stream of N2 through it prior to adding the catalyst. Pu-
rification on a Horizon® column chromatography system (100:0 →
95:5 → 7:3 CHCl3–EtOAc) afforded the title compound as a white
solid (214 mg, 58%, 0.60 mmol). Starting material was also recov-
ered (164 mg, 33%, 0.34 mmol).
IR (KBr): 2932 (C–H), 1703 (C=O), 1681 (enol ether), 1440 (P–
Ph), 1356 (P=O), 1226 (P–O–Ar), 1159, 1131, 1059, 541, 524 cm–1.
1H NMR (400 MHz): d = 1.44 [13 H, m, (CH3)3C, 5-H2, 6-H2], 1.56
(2 H, m, 4-H2), 1.99 (2 H, m, 7-H2), 5.36 (1 H, dt, J = 3, 7 Hz, 3-H),
7.38–7.58 (6 H, m, ArH), 7.78–7.92 (4 H, m, ArH).
13C NMR (100 MHz): d = 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 (d,
J = 13 Hz, C-3¢), 130.9 and 132.3 (d, J = 137 Hz, C-1¢), 131.9 (d,
J = 10 Hz, C-2¢), 132.5 (C-4¢), 144.9 (C-2), 153.4 (C=O).
IR (KBr): 2924, 2855, 1691, 1447, 1340, 1155, 1118, 1086, 1010,
874, 815, 708 cm–1.
1H NMR (400 MHz): d = 1.60 (4 H, m, 5-H2, 6-H2), 1.72 (2 H, m,
7-H2), 2.31 (3 H, s, CH3), 2.36 (2 H, m, 4-H2), 2.40 (3 H, s, CH3),
3.63 (2 H, m, 8-H2), 6.39 (1 H, t, J = 8 Hz, 3-H), 6.97 (2 H, d,
J = 8 Hz, ArH), 7.07 (2 H, d, J = 8 Hz, ArH), 7.16 (2 H, d, J = 8 Hz,
ArH), 7.52 (2 H, d, J = 8 Hz, ArH).
13C NMR (100 MHz): d = 21.0 (CH3), 21.4 (CH3), 26.5 (C-4), 27.0
(C-5 or 6), 27.4 (C-7), 28.3 (C-5 or 6), 52.6 (C-8), 125.7 (ArCH),
31P NMR (162 MHz): d = 29.7.
MS (ES +): m/z = 436.2 (M+ + Na), 849.0 (2 M+ + Na).
Anal. Calcd for C23H28NO4P: C, 66.82; H, 6.83; N, 3.39. Found: C,
66.70; H, 6.82; N, 3.22.
Synthesis 2009, No. 22, 3897–3904 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Cross-Coupling with Enol Phosphinates and Phosphonates
3903
127.4 (ArCH), 128.8 (ArCH), 129.1 (ArCH), 132.4 (C-3), 134.1,
137.3, 138.0, 138.2 and 142.7 (tertiary-C).
MS (ES+): m/z = 356.3 (MH+), 373.2 (M+ + H2O), 728.4 (2 M+ +
resulting solution was concentrated and extracted with EtOAc/brine
(3 × 2.0 mL/1.0 mL), the organic phases were combined, dried
(MgSO4), filtered, and evaporated. Flash chromatography on silica
gel (19:1 to 9:1 PE–EtOAc) gave the coupled compound 6a-iii as a
white solid (22 mg, 36%, 0.07 mmol); mp 72–74 °C.
H2O).
HRMS (ES+): m/z calcd for C21H26NO2S [MH+]: 356.1679; found:
356.1680; m/z calcd for C21H25NO2S + Na [M + Na+]: 378.1498;
found: 378.1498.
IR (KBr): 2935 (C–H), 1687 (C=O), 1509, 1392, 1357, 1248, 1160
cm–1.
1H NMR (500 MHz): d = 1.11 [9 H, s, C(CH3)3], 1.46 (4 H, m, 5-
H2, 7-H2), 1.81 (2 H, m, 6-H2), 2.28 (2 H, m, 4-H2), 3.80 (3 H, s,
OCH3), 5.76 (1 H, t, J = 6 Hz, 3-H), 6.82 (2 H, d, J = 9 Hz, 2¢-H, 6¢-
H), 7.25 (2 H, d, J = 9 Hz, 3¢-H, 5¢-H).
13C NMR (125 MHz): d = 24.5 (C-5), 27.6 (C-4), 28.2 [(C(CH3)3],
30.0 (C-6), 48.1 (C-7), 55.6 (OCH3), 79.8 [C(CH3)3], 113.6 (C-2¢),
121.1 (C-3), 126.3 (C-3¢), 132.6 (C-2), 144.3 (C-1¢), 154.4 (C=O),
159.2 (C-4¢).
N-(tert-Butyloxycarbonyl-2-isobutyl-4,5,6,7-tetrahydro-
azepane (6a-xiv)
A suspension of 4a (0.413 g, 1.0 mmol) and 1,2-bis(diphenylphos-
phino)ethanenickel(II) chloride (26.4 mg, 0.05 mmol) in 1:1 Et2O–
THF (18 mL) was degassed by purging argon for 10 min before
isobutylmagnesium bromide (2.0 M solution in Et2O, 0.75 mL, 1.5
mmol) was added. The mixture was stirred for 18 h at r.t. The reac-
tion was quenched with H2O (5.0 mL) and the resulting solution was
extracted with EtOAc (3 × 10.0 mL). The organic phases were com-
bined, dried (MgSO4), filtered, and evaporated. Flash chromatogra-
phy on silica gel (19:1 to 9:1 PE–EtOAc) afforded the title
compound as a colourless oil (94 mg, 37%, 0.37 mmol); Rf = 0.50
(19:1 PE–EtOAc).
MS (ES+): m/z = 629 (2 M+ + Na).
Anal. Calcd for C18H23NO3: C, 71.26; H, 8.31; N, 4.62. Found: C,
71.22; H, 8.35; N, 4.64.
N-tert-Butyloxycarbonyl-2-furan-2-yl-4,5,6,7-tetrahydro-
azepane (6a-xi)
IR (film): 2931, 2807, 1703, 1654, 1388, 1162, 1012, 770 cm–1.
Via Stille Cross-Coupling Reaction from Bis-enol Phosphonate 8:
A solution of 8 (109.7 mg, 0.20 mmol) and LiCl (38.2 mg, 0.90
mmol) in THF (15 ml) was degassed by purging argon for 10 min
before 2-(tributylstannyl)furan (188.9 mL, 0.60 mmol) and
Pd(PPh3)4 (23.1 mg, 0.02 mmol) were added. The mixture was re-
fluxed for 2 h and then cooled to r.t. The resulting mixture was con-
centrated and extracted with EtOAc/1 M aq KF (3 × 2.0 mL/1.0
mL), the organic phases were combined, dried (MgSO4), filtered,
and evaporated. Flash chromatography on silica gel (19:1 to 9:1
PE–EtOAc) afforded the title compound as a pale yellow solid (82
mg, 78%, 0.16 mmol); Rf = 0.3 (19:1 PE–EtOAc); mp 89 °C (Lit.10c
mp 87 °C).
1H and 13C NMR: All signals in the NMR spectra were highly
broadened and could not be resolved.
MS (ES+): m/z = 276.1 (M + Na+).
Anal. Calcd for C15H27NO2: C, 71.10; H, 10.74; N, 5.53. Found: C,
70.76; H, 10.41; N, 5.64.
Phenylphosphonic Acid Bis-(4,5,6,7-tetrahydroazepine-1-car-
boxylic Acid tert-Butyl-2-yl) Ester (8)
To a cold (–78 °C) solution of N-Boc protected caprolactam (0.896
g, 4.20 mmol) and N,N,N¢,N¢-tetramethylenediamine (0.664 mL,
4.40 mmol) in anhyd THF (40 mL) was added a 2 M solution of
LDA in heptane–THF (2.20 mL, 4.40 mmol). The reaction mixture
was stirred at –78 °C for 1 h and phenylphosphonic dichloride
(0.284 mL, 2.00 mmol) was added dropwise. The mixture was
stirred at –78 °C for 1 h, then at r.t. for a further 18 h. The solution
was concentrated and extracted with EtOAc/brine (3 × 20 mL/10
mL), the organic phases were combined, dried (MgSO4), filtered,
and evaporated. Flash chromatography on silica gel (1:1 PE–
EtOAc) afforded the title compound as a yellow oil (0.540 g, 49%,
0.98 mmol); Rf = 0.8 (EtOAc).
IR (KBr): 2974, 2931, 2854, 1698, 1651, 1492, 1443, 1385, 1353,
1252, 1163, 1012, 966, 730 cm–1.
1H NMR (400 MHz): d = 1.26 [9 H, s, (CH3)3C], 1.49 (2 H, br, 5-
H2), 1.80 (2 H, m, 6-H2), 2.25 (2 H, m, 4-H2), 2.70–4.30 (2 H, br, 7-
H2), 6.03 (1 H, t, J = 7 Hz, 3-H), 6.17 (1 H, d, J = 4 Hz, 2¢-H), 6.34
(1 H, m, 3¢-H), 7.31 (1 H, m, 4¢-H).
13C NMR (100 MHz): d = 24.4 (C-4), 27.1 (C-5), 28.2 [(CH3)3C],
29.9 (C-6), 47.4 (C-7), 79.9 [(CH3)3C], 105.1 (C-3), 111.2 (C-2¢),
121.5 (C-3¢), 135.9 (C-2), 141.4 (C-4¢), 153.0 (OC=O), 154.1 (C-
1¢).
IR (film): 3061, 2975, 2931, 2854, 1767, 1720, 1687, 1643, 1442,
1377, 1253, 1161, 1050, 1008, 909, 777, 523 cm–1.
1H NMR (400 MHz): d = 1.33 [18 H, s, [CH3)3C], 1.47 (4 H, br, 5-
H2), 1.65 (4 H, m, 6-H2), 2.00 (4 H, m, 4-H2), 3.39 (4 H, br, 7-H2),
5.35 (2 H, t, J = 6.5 Hz, 3-H), 7.42 (2 H, m, 3¢-H) 7.52 (1 H, J = 7
Hz, 4¢-H), 7.82 (2 H, m, 2¢-H).
13C NMR (100 MHz): d = 24.2 (C-4), 24.6 (C-5), 28.2 [(CH3)3C],
29.4 (C-6), 46.5 (C-7), 80.8 [(CH3)3C], 109.4 (C-3), 128.3 (C-3¢),
128.5 (C-2¢), 131.9 (C-4¢), 132.8 (C-1¢), 145.0 (C-2), 153.1
(OC=O).
MS (ES+): m/z = 286.2 (M+ + Na).
Anal. Calcd for C15H21NO3: C, 68.42; H, 8.04; N, 5.32. Found: C,
68.60; H, 8.11; N, 5.28.
Enol Phosphonate Resin 11
To a cold (–78 °C) solution of N-Boc protected caprolactam (2.99
g, 14 mmol, 4 equiv) and TMEDA (1.95 g, 16.8 mmol, 4.8 equiv)
in anhyd THF (50 mL) was added a solution of LDA (1.8 g,
16.8 mmol, 4.8 equiv). This mixture was stirred at –78 °C for 40
min, then phenylphosphonic dichloride (2.46 g, 12.6 mmol,
3.6 equiv) was added dropwise. The reaction mixture was stirred for
0.5 h at –78 °C and then at r.t. for 1 h. It was then transferred via
cannula into a suspension of phenol on polystyrene resin 9
(3.5 mmol/g, 1.0 g, 3.5 mmol) and anhyd Et3N (0.71 g, 7 mmol,
2 equiv) in THF (10 mL). The suspension was stirred at r.t. for 18 h.
The mixture was then filtered. The beads were washed with MeOH
(3 × 20 mL), DMF (3 × 20 mL), THF (3 × 20 mL), and anhyd Et2O
(3 × 20 mL), and then dried to constant weight to afford the title res-
in which was used directly in subsequent transformations with an
31P NMR (64 MHz): d = 12.58.
MS (ES+): m/z = 571.2 (M+ + Na).
N-tert-Butyloxycarbonyl-2-(4¢-methoxyphenyl)-4,5,6,7-tetra-
hydroazepane (6a-iii)
Via Suzuki Cross-Coupling Reaction from Bisenol Phosphonate 8:
A suspension of 8 (109.7 mg, 0.20 mmol), 4-methoxyphenylboron-
ic acid (91.2 mg, 0.60 mmol), and Na2CO3 (84.8 mg, 0.80 mmol) in
DME (3 mL), H2O (2 mL), and EtOH (2 mL) was degassed by purg-
ing argon for 10 min. Then Pd(PPh3)4 (23.1 mg, 0.02 mmol) was
added. The mixture was refluxed for 30 min and cooled to r.t. The
Synthesis 2009, No. 22, 3897–3904 © Thieme Stuttgart · New York

3904
P. G. Steel, T. M. Wood
PRACTICAL SYNTHETIC PROCEDURES
assumed loading of 1.61 mmol/g calculated on the basis of quanti-
tative conversion of all reactive phenol groups.
(7) Blaszczak, L.; Winkler, J.; Kuhn, S. O. Tetrahedron Lett.
1976, 49, 4405.
(8) Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1980,
21, 2531.
31P NMR (121 MHz, CDCl3): d = 11.96, 15.93.
(9) (a) Nicolaou, K. C.; Shi, G.-Q.; Gunzer, J. L.; Gartner, P.;
Yang, Z. J. Am. Chem. Soc. 1997, 119, 5467. (b) Nicolaou,
K. C.; Shi, G.-Q.; Namoto, K.; Bernal, F. Chem. Commun.
1998, 1757.
Acknowledgment
We thank the EPSRC and GlaxoSmithKline 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 spec-
tra.
(10) (a) Lepifre, F.; Buon, C.; Rabot, R.; Bouyssou, P.; Coudert,
G. Tetrahedron. Lett. 1999, 40, 6373. (b) Chacun-Lefevre,
R.; Buon, C.; Rabot, R.; Bouyssou, P.; Coudert, G.
Tetrahedron 2000, 56, 605. (c) Lepifre, F.; Clavier, S.;
Bouyssou, P.; Coudert, G. Tetrahedron 2001, 57, 6969.
(11) (a) Galbo, F. L.; Occhiato, E. G.; Guarna, A.; Faggi, C.
J. Org. Chem. 2003, 68, 6360. (b) Galbo, F. L.; Occhiato, E.
G.; Guarna, A. J. Org. Chem. 2005, 70, 7324.
(12) (a) Hansen, A. L.; Ebran, J.-P.; Gogsig, T. M.; Skrydstrup,
T. Chem. Commun. 2006, 4137. (b) Hansen, A. L.;
Skrydstrup, T. J. Org. Chem. 2007, 72, 3392.
(13) Guo, J.; Harling, J. D.; Steel, P. G.; Woods, T. M. Org.
Biomol. Chem. 2008, 6, 4053; Article highlighted in Synfacts
2009, 89.
References
(1) For a review, see: Metal-Catalysed Cross-Coupling
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(2) (a) Ritter, K. Synthesis 1993, 735. (b) Luker, T.; Hiemstra,
H.; Speckamp, W. N. J. Org. Chem. 1997, 62, 8131.
(c) Occhiato, E. G.; Trabocchi, A.; Guarna, A. J. Org. Chem.
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Chem. Soc. 1969, 91, 4600.
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(4) (a) Perec, V.; Bae, J.-Y.; Hill, D. H. J. Org. Chem. 1995, 60,
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(15) Harling, J. D.; Steel, P. G.; Woods, T. M.; Yufit, D. M. Org.
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(16) In all cases, the 2-arylenamide products 6 are isolated as
rotameric mixtures interconvertable at 60 °C as ascertained
by simple VT NMR studies.
(17) Still, W. C.; Kahn, M.; Mitra, A. J. J. Org. Chem. 1978, 43,
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Synthesis 2009, No. 22, 3897–3904 © Thieme Stuttgart · New York