The selective preparation and Suzuki coupling reactivity of cyclic 1,3-dione derived mono- and ditriflates

Article abstract of DOI:10.1016/S0040-4039(01)00933-9

The combination of triflic anhydride and 2,6-di-tert-butyl-4-methylpyridine was found to be a selective reagent system for the conversion of cyclic 1,3-diones to the corresponding monotriflate derivatives. The use of N-(5-chloro-2-pyridyl)triflimide together with KHMDS was selective for the preparation of the corresponding ditriflates. The Suzuki coupling reactivity of both the mono- and ditriflates was also explored.

Full text of DOI:10.1016/S0040-4039(01)00933-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5105–5107
The selective preparation and Suzuki coupling reactivity of cyclic
1,3-dione derived mono- and ditriflates
Michael C. Willis* and Christelle K. Claverie
Department of Chemistry, University of Bath, Bath BA2 7AY, UK
Received 18 May 2001; accepted 31 May 2001
Abstract—The combination of triflic anhydride and 2,6-di-tert-butyl-4-methylpyridine was found to be a selective reagent system
for the conversion of cyclic 1,3-diones to the corresponding monotriflate derivatives. The use of N-(5-chloro-2-pyridyl)triflimide
together with KHMDS was selective for the preparation of the corresponding ditriflates. The Suzuki coupling reactivity of both
the mono- and ditriflates was also explored. © 2001 Elsevier Science Ltd. All rights reserved.
Vinyl and enol triflates are proving to be extremely
versatile coupling partners and have been shown to
participate in a variety of cross-coupling reactions
including variants of the Stille,1 Suzuki2 and Heck3
reactions.4 We proposed that the mono- and ditriflates,
such as 2 and 3, derived from cyclic 1,3-diones would
be useful building blocks for use in target syntheses or
as substrates for desymmetrisation studies.5 We there-
fore set out to determine reaction conditions to allow
the selective production of either the mono- or ditrifl-
ates. A concern at the outset of this study was the
stability of the required triflates, and in particular their
stability towards flash chromatography.
allowed the monotriflate 2 to be obtained in good yield
(Scheme 1).6 The use of N-phenyl triflimide as the
triflate source was similarly unsuccessful for the pro-
duction of 3.7 However, the combination of the more
reactive triflating reagent N-(5-chloro-pyridyl)triflimide
4 and KHMDS delivered the ditriflate 3 as the major
product.8 Optimised conditions involved treatment of
diketone 1 with 2 equiv. of KHMDS followed by 2.2
equiv. of 4 in THF at −78°C to furnish the required
ditriflate in 81% yield. Ditriflate 3 was isolated as an
amorphous white solid that could be readily purified by
crystallisation or flash chromatography upon silica
gel.
Initial attempts at the preparation of ditriflate 3 focused
on the use of triflic anhydride in combination with a
variety of bases, however, only low yields of ditriflate 3
were obtained with the monotriflate forming preferen-
tially. Optimisation of these conditions (2 equiv. Tf2O,
2.2 equiv. 2,6-di-t-Bu-4-Me-pyridine, DCE, 80°C)
These two sets of complimentary reaction conditions
were then successfully applied to two further diketone
substrates.9 Both the mono- and ditriflate derived from
the corresponding dimethylated 1,3-diketone were
obtained in excellent yields (5 90% and 6 92%, respec-
tively, Fig. 1) and again both were stable to purification
Me
Ph
Ph
Ph
Me
Me
Me
TfO
O
O
O
TfO
OTf
i. KHMDS, THF, -78 oC
tBu
N
tBu
Tf2O, DCE, 80 oC
ii.
Cl
2, 73%
1
3, 81%
N
N(Tf)2
4
Scheme 1.
Keywords: vinyl triflate preparation; triflic anhydride; N-(5-chloro-2-pyridyl)triflimide; Suzuki coupling.
* Corresponding author. Tel.: (+44)-01225-826568; fax: (+44)-01225-826231; e-mail: m.c.willis@bath.ac.uk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00933-9

5106
M. C. Willis, C. K. Cla6erie / Tetrahedron Letters 42 (2001) 5105–5107
Ph
Ph
Table 2.
Me
Me
Ph
TfO
OTf
O
OTf
Me
TfO
Ar
Ph
Me Me
6, 92%
Ph
Me Me
5, 90%
Me
X
11
+
9,
Pd(OAc)2 (10 mol%)
PPh3 (20 mol%)
TfO
OTf
Ph
Me
Ph
KOH, H2O, THF, rt
X
Ar
Ar
Me
Me
O
OTf
TfO
OTf
X
12
7, 69%
8, 73%
Substrate
X
Time (h)
Yield 11
Yield 12
(%)
(%)
Figure 1.
3
6
8
CH2
C(Me)2
–
24.0
4.0
1.0
7
31
71
8
17
0
by flash chromatography.10 The two triflates originating
from the cyclopenta-1,3-dione substrate were also
obtained in good yields (69% monotriflate, 73% ditrifl-
ate).11 Pleasingly, the potentially reactive conjugated
diene system present in ditriflate 8 proved to be simi-
larly stable to chromatography.
Of the ditriflate substrates the five-membered system 8
underwent facile coupling to provide the mono-coupled
material in excellent yield; none of the dicoupled mate-
rial was observed. The dimethylated six-membered sys-
tem 6 also performed well showing good reactivity,
although the desired mono-coupled material decom-
posed under the reaction conditions resulting in a low
isolated yield. The unsubstituted six-membered sub-
strate 3 performed poorly, yielding only low yields of
the two coupling products.
With the synthesis of the required mono- and ditriflates
achieved, we chose to explore their reactivity in Suzuki
cross-coupling reactions and these preliminary findings
are presented below in Tables 1 and 2.12 Gratifyingly,
the six-membered monotriflate 2 underwent reaction
with 4-methoxyphenylboronic acid 9 in the presence of
Pd(OAc)2 (10 mol%), PPh3 and KOH, to deliver the
coupled product in 91% yield (Table 1). Given the high
steric-crowding in the immediate environment of the
triflate functionality, the mild reaction conditions
(room temperature) and short reaction time (40 min)
for this transformation are particularly noteworthy.13
The dimethylated analogue 5 also performs well deliv-
ering the coupled product in 69% yield after 80 min.
Surprisingly, the five-membered monotriflate 7 showed
poor reactivity and after 18 h reaction, only 12% of the
coupled product was isolated.14
The reason for the poor reactivity of both the five-
membered monotriflate 7 and the six-membered ditrifl-
ate 3 is unclear at present. However, the allylic protons
in both 3 and 7 are more acidic than those present in
the other substrates, this combined with the use of
KOH as base may be responsible for the observed poor
reactivity.
In summary, we have described complementary condi-
tions for the selective production of either the mono- or
ditriflate derivatives from a range of cyclic 1,3-diones.
We have also demonstrated that several of these highly
functionalised substrates undergo facile Suzuki cou-
pling reactions under mild conditions. Further studies
on the coupling reactions of these substrates together
with details of their use in desymmetrisation reactions
will be reported in due course.
Table 1.
(HO)2B
OMe
Ph
Ph
9
Pd(OAc)2 (10 mol%)
PPh3 (20 mol%)
Me
Me
O
OTf
O
Ar
KOH, H2O, THF, rt
X
X
10
Acknowledgements
Substrate
X
Time
Yield 10 (%)
The University of Bath, the Nuffield Foundation, the
Royal Society, Pfizer and AstraZeneca (Strategic
Research Fund) are thanked for their support of this
study.
2
5
7
CH2
C(Me)2
–
40 min
80 min
18 h
91
69
12

M. C. Willis, C. K. Cla6erie / Tetrahedron Letters 42 (2001) 5105–5107
5107
References
C15H15O4SF3 requires C, 51.7; H, 4.31%. Ditriflate 3; lH
(400 MHz, CDCl3) 7.29–7.21 (3H, m), 7.10–7.06 (2H, m),
5.69 (2H, dd app. t, J 3.5, 4.1 Hz), 2.87 (2H, s), 2.76 (1H,
dt, J 4.1, 22.8 Hz), 2.33 (1H, dt, J 3.5, 22.8 Hz), 1.55 (3H,
s); lC (67.5 MHz, CDCl3) 147.7, 135.0, 130.1, 128.5,
127.4, 118.7, 114.2, 45.0, 42.1, 24.5, 23.1. Found C, 40.0;
H, 3.00, C16H14O6S2F6 requires C, 40.0; H, 2.92%.
Monotriflate 5: lH (400 MHz, CDCl3) 7.27–7.20 (3H, m),
7.09–7.05 (2H, m), 5.81 (1H, s), 3.09 (1H, d, J 13.4 Hz),
2.87 (1H, d, J 13.4 Hz), 2.26 (1H, d, J 14.7 Hz), 1.69 (1H,
d, J 14.7), 1.41 (3H, s), 1.02 (3H, s), 0.47 (3H, s); lC (100
MHz, CDCl3) 208.2, 147.8, 135.9, 130.1, 128.1, 127.4,
126.9, 118.3, 53.7, 51.4, 41.8, 32.5, 29.5, 28.5, 23.6; m/z
(EI). Found M+NH4+, 394.1306, C17H23SF3NO4 requires
394.1300. Ditriflate 6: lH (400 MHz, CDCl3) 7.29–7.18
(3H), 7.06–7.03 (2H, m), 5.48 (2H, s), 2.85 (2H, s), 1.52
(3H, s), 1.09 (3H, s), 0.34 (3H, s); lC (100 MHz, CDCl3)
1. For some recent examples, see: (a) Dominguez, B.; Pazos,
Y.; de Lera, A. R. J. Org. Chem. 2000, 65, 5817–5925; (b)
Luker, T.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem.
1997, 62, 8131–8140.
2. For some recent examples, see: (a) Occhiato, E. G.;
Trabacchi, A.; Guarna, A. J. Org. Chem. 2001, 66,
2459–2465; (b) Yao, M.-L.; Deng, M.-Z. Tetrahedron
Lett. 2000, 41, 9083–9087.
3. For some recent examples, see: (a) Gilbertson, S. R.; Fu,
Z. Org. Lett. 2001, 3, 161–164; (b) Hynes, Jr., J.; Over-
man, L. E.; Nasser, T.; Rucker, P. V. Tetrahedron Lett.
1998, 39, 4647–4650.
4. For a review on the uses and preparations of triflate
derivatives, see: Ritter, K. Synthesis 1993, 735–762.
5. For a review on enantioselective desymmetrisation, see:
Willis, M. C. J. Chem. Soc., Perkin Trans. 1 1999, 1765.
6. All new compounds reported in this paper were fully
characterised.
145.6, 135.7, 130.1, 128.3, 127.3, 124.3, 118.8, 46.1, 41.8,
35.5, 30.2, 28.7, 23.2 m/z (EI+). Found M+NH4
,
+
526.0796, C18H22NO6S2F6 requires 526.0793. Monotrifl-
ate 7: lH (270 MHz, CDCl3) 7.26–7.22 (3H, m), 7.06–7.03
(2H, m), 5.73 (1H, dd app. t, J 2.2, 2.6 Hz), 2.99 (1H, d,
J 13.4 Hz), 2.84 (1H, dd, J 22.5, 2.6 Hz), 2.79 (1H, d, J
13.4 Hz), 2.27 (1H, dd, J 22.5, 2.2 Hz), 1.31 (3H, s); lC
(100 MHz, CDCl3) 216.3, 150.3, 135.3, 129.4, 128.2,
127.0, 118.3, 110.8, 55.5, 42.2, 41.5, 20.6. Found C, 50.5;
H, 3.85, C14H13O4SF3 requires C, 50.3; H, 3.89%. Ditrifl-
ate 8: lH (400 MHz, CDCl3) 7.25–7.20 (3H, m), 7.07–7.06
(2H, m), 5.81 (2H, s), 2.97 (2H, s), 1.41 (3H, s); lC (100
MHz, CDCl3) 151.9, 134.0, 128.9, 128.0, 127.2, 118.3,
111.9, 54.2, 39.7, 18.5. Found C, 38.4; H, 2.65,
C15H12S2F6O6 requires C, 38.6; H, 2.6%.
7. McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24,
979–982.
8. Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33,
6299–6302.
9. Typical procedures for the preparation of the mono- and
ditriflates are given below. Monotriflate 2: A solution of
trifluoromethanesulfonic anhydride (2.5 ml, 14.7 mmol)
in dry DCE (5 ml) was added dropwise under nitrogen to
a stirred mixture of the diketone 1 (1.51 g, 7 mmol) and
2,6-di-tert-butyl-4-methylpyridine (3.24 g, 15 mmol) in
dry DCE (30 ml) at 0°C. The reaction was heated to 80°C
for 18 h after which time the mixture was cooled to room
temperature. Ether (150 ml) was added and the white
pyridinium triflate salt was filtered, washed with ether (30
ml) and the filtrate was concentrated under reduced
pressure to give a dark orange oil. The residue was
purified by flash chromatography (gradient elution, 2–
10% EtOAc/petrol) to give the monovinyltriflate as a
yellow oil (1.78 g, 73%). Ditriflate 3: A solution of
potassium hexamethyldisilazide (0.5 M in toluene, 9.7
mmol) was added dropwise over 1 h to a stirred mixture
of diketone 1 (1.00 g, 4.6 mmol) and N-(5-chloro-2-
pyridyl)triflimide (5.90 g, 10.1 mmol) in dry THF (40 ml)
at −78°C. The reaction mixture was stirred at this temper-
ature for 1 h then it was slowly warmed to room temper-
ature over 3 h. The mixture was diluted with hexane (90
ml), washed with water (50 ml), 10% NaOH (50 ml) and
brine (50 ml). The organic phase was dried (Na2SO4) and
concentrated under reduced pressure to give a dark oil
which was further purified by flash chromatography (gra-
dient elution, 5–10% ether/petrol) to give the ditriflate 3
as a white solid (1.79 g, 81%).
12. For reviews on Suzuki couplings, see: (a) Miyaura, N.;
Suzuki, A. Chem. Rev. 1995, 95, 2457–2483; (b) Suzuki,
A. J. Organomet. Chem. 1999, 576, 147–168.
13. For a recent study on the development of low tempera-
ture Suzuki couplings employing triflate substrates, see:
Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000,
122, 4020–4028.
14. Typical coupling procedure. Substrate 2: Dry THF (1 ml)
was added to a mixture of triflate 2 (35.0 mg, 0.1 mmol),
Pd(OAc)2 (2.2 mg, 0.01 mmol), triphenylphosphine (5.6
mg, 0.022 mmol) and 4-methoxyphenylboronic acid (19
mg, 0.125 mmol). The solution was stirred under nitrogen
for 10 min, KOH (10% aq, 0.2 ml, 0.1 mmol) was then
added via syringe and the reaction was stirred at room
temperature for 40 min. The mixture was partitioned
between water (5 ml) and EtOAc (5 ml). The aqueous
layer was extracted (2×2 ml EtOAc). The combined
organic phases were dried (Na2SO4), filtered and concen-
trated under reduced pressure. The residue was purified
by flash chromatography (10% DCM/petrol) to give the
coupled material as a bright yellow solid, mp 67−68°C
(from DCM/hexane); lH (400 MHz, CDCl3) 7.24–7.14
(5H, m), 7.09–7.04 (2H, m), 6.90–6.85 (2H, m), 5.81–5.79
(1H, dd app. t, J 4.7 and 3.9 Hz), 3.84 (3H, s), 3.14 (1H,
d, J 13.7 Hz), 2.97 (1H, d, J 13.7 Hz), 2.46–2.43 (2H, m),
2.33–2.24 (1H, m), 2.02–1.92 (1H, m), 1.22 (3H, s); lC
(100 MHz, CDCl3) 214.2, 158.4, 143.8, 137.4, 133.5,
130.2, 129.9, 127.9, 127.8, 126.3, 113.1, 55.3, 53.7, 44.6,
37.3, 24.2, 23.9; m/z (EI+) 306.2 (100%, M+). Found M,
306.1617, C21H22O2 requires 306.1620.
10. For the preparation of a dinonaflate compound similar to
ditriflate 5, see: Bra¨se, S. Synlett 1999, 1654–1656.
11. Representative data for compounds 2, 3 and 5“8.
Monotriflate 2: lH (400 MHz, CDCl3) 7.28–7.20 (3H, m),
7.08–7.02 (2H, m), 5.97 (1H, dd, app. t, J 4.7 Hz), 3.17
(1H, d, J 13.7 Hz), 2.83 (1H, d, J 13.7 Hz), 2.40–2.32
(1H, m), 2.21–2.12 (1H, m), 1.95 (1H, dt, J 15.2, 5.9 Hz),
1.74–1.65 (1H, m), 1.42 (3H, s); lC (67.5 MHz, CDCl3)
209.7, 149.9, 136.5, 130.3, 128.7, 127.4, 118.8, 118.1, 54.8,
43.1, 37.1, 23.4, 19.6. Found C, 51.5; H, 4.35;
.