A divergent strategy to the withasomnines

Article abstract of DOI:10.1039/b910632d

A concise synthesis of three members of the withasomnine family of natural products is reported. The synthesis features a regioselective sydnone-alkynylboronate cycloaddition followed by Suzuki cross coupling and silyl group removal, and marks the first d

Full text of DOI:10.1039/b910632d

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A divergent strategy to the withasomnines†
Robert S. Foster, Jianhui Huang, Je´roˆme F. Vivat, Duncan L. Browne and Joseph P. A. Harrity*
Received 29th May 2009, Accepted 22nd June 2009
First published as an Advance Article on the web 27th July 2009
DOI: 10.1039/b910632d
A concise synthesis of three members of the withasomnine family of natural products is reported. The
synthesis features a regioselective sydnone–alkynylboronate cycloaddition followed by Suzuki cross
coupling and silyl group removal, and marks the first divergent approach to this family of pyrazole
based natural products.
Introduction
The withasomnine alkaloids are a rare class of pyrazole based
natural products isolated from the roots of Withania somnifer
(Solanaceae),1 Newbouldia laevis,2 the shrub Elytraria acaulis,3
and recently from the stem bark of Discopodium penninervium.4
Withasomnine 1 displays both CNS and circulatory system
depressant properties as well as being a mild analgesic.2
Fig. 1 Divergent synthetic strategy to the withasomnines.
Owing to these attributes, these natural products are ideal
candidates for the demonstration of new pyrazole based synthetic
of this particular mesoionic heterocycle have shown that the
trimethylsilyl substituted alkynylboronate 5 would deliver the
desired regiochemistry.10k Moreover, the employment of this
alkyne would append a removable group at the 3-position of the
pyrazole product.
methodologies. Indeed, several syntheses of the parent molecule
(1) have been reported. Some examples include, tin mediated
radical cyclisations of selenium containing substrates,5 conversion
of functionalised cyclopropanols to pyrazoles,6 intramolecular
alkylation,7 oxidative coupling of diamines8 and cycloadditions
of sydnones with alkynes.9 In general, all of the approaches thus
far reported are not amenable for efficient and rapid divergency
to all three of the natural withasomnine congeners (1, 2 and
3). We envisaged that such a strategy could serve as a basis
for the discovery of more potent unnatural analogues. Herein
we report the realisation of this goal as demonstrated by a
short, regioselective and divergent approach to withasomnine 1,
4¢ hydroxywithasomnine 2 and 4¢ methoxywithasomnine 3.
In general, we have found that C-4 substituted sydnone sub-
strates typically require more forcing conditions f◦or cycloaddition
with alkynylboronates (typically 48 hours at 180 C).10k However,
Nikitenko et al. have demonstrated that sydnone 4 is thermally
unstable, showing a large exotherm at 180 ◦C, presumed to be due
to the loss of carbon dioxide.11 Indeed, our previously reported
studies on this particular regioselective cycloaddition support this
data, yielding only 21% of decarboxylated cycloadduct (6) after
72 hours at 160 ◦C.10k Accordingly, preliminary investigations were
geared towards promoting cycloaddition over degradation of the
sydnone; our results are shown in Table 1. Increasing the reaction
temperature to 210 ◦C (Table 1, entry 4) gave only trace amounts
of product and confirmed our suspicions of the thermal instability
of sydnone 4. Changing the solvent to ortho-dichlorobenzene
(o-DCB) and reducing the reaction temperature to 180 ◦C (Table 1,
entry 5) demonstrated that a 19% yield of the cycloadduct was
attainable within a quarter of the reaction time. Interestingly,
analysis of the 1H NMR spectrum of the crude reaction mixture
revealed that the alkynylboronate had undergone degradation.
With this in mind, addition of a further 2 equivalents of alkyne and
further heating for another 24 hours gave the product in greatly
increased yield (Table 1, entry 6). Finally, it was discovered that
starting the reaction with 4 equivalents of alkynylboronate and
heating for 24 hours at 180 ◦C delivers the desired pyrazole boronic
ester in 66% yield as a single regioisomer (Table 1, entry 7).12
Results and discussion
Within the last decade we have developed a series of alkynyl-
boronate cycloadditions10 to access a range of (hetero)aromatic
boronic esters. Specifically relevant to this case is the cycload-
dition of alkynylboronates with sydnones for the synthesis of
functionalisable pyrazoles.10i–k With this methodology in mind,
retrosynthetic analysis of the withasomnines hinged upon the
regioselective cycloaddition of the known proline derived sydnone
4 with alkyne 5 (Fig. 1).11 Previous studies on the cycloaddition
Department of Chemistry, University of Sheffield, Sheffield, UK S3 7HF.
E-mail: j.harrity@shef.ac.uk; Fax: +44 (0) 1142 229346; Tel: +44 (0) 1142
229496
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of compounds 1–3, 6–9; 1H spectrum of pyrazole isolates from
cycloaddition of sydnone 4 and alkyne 10. See DOI: 10.1039/b910632d
4052 | Org. Biomol. Chem., 2009, 7, 4052–4056
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Table 1 Optimisation of the cycloaddition reaction
Table 3 Couplings towards the other natural product precursors
Entry Solventa
Equiv. 5
Time (h)
Yield (%)
Entry
X
Yield (%)a
1
2
3
4
5
6
7
Xylenes (140)
Mesitylene (160)
Mesitylene (160)
Nitrobenzene (210)
o-Dichlorobenzene (180)
o-Dichlorobenzene (180)
o-Dichlorobenzene (180)
2
2
2
2
2
4b
4
64
48
72
18
18
42b
24
9
14
21
Trace
19
52
66
1
2
3
H (7)
OH (8)
OMe (9)
78 (76)
65 (50)
74 (54)
a Numbers in parentheses represent yields when reaction conducted in a
microwave reactor at 130 ◦C for 1 h
a Reaction temperature (◦C) in parentheses. b Reaction started with 2 equiv.
of 5, with a further 2 equiv. added after 18 h.
Table 4 Desilylation to the withasomnines
Table 2 Optimisation of the coupling reaction
Entry
Ar
Yield (%)
1
2
3
Ph (1)
4-HO-Ph (2)
4-MeO-Ph (3)
70
55
83
Entry Pd cat.
Solvent
Time (hrs) Yield (%)
1
2
3
4
Pd(dppf)Cl2
1,4-dioxanea
1,4-dioxane
20
24
72
0
Finally we turned our attention to the desilylation step. In-
terestingly, previous studies from our laboratory have found the
pyrazolyl-3-trimethylsilyl group to be surprisingly resistant to
removal. For example, K2CO3 in MeOH, 1M HCl(aq) in refluxing
ether and trifluoroacetic acid in DCM (1:1) all failed to produce
even a trace of desilylated pyrazole. Pleasingly however, switching
to TBAF and heating the reaction mixture for 24 hours at reflux
in THF facilitated the required desilylation, furnishing the three
natural withasomine congeners in good yields (Table 4).
Pd(dppf)Cl2
Trace
81
78
Pd2dba3, tBu3P·HBF4 MeCN
PdCl2(PPh3)2
DME/H2O (1:1) 18
a Reaction conducted at 85 ◦C.
With the required boronic ester in hand, the Suzuki–Miyaura
cross coupling reaction was assessed. Preliminary studies were
conducted towards withasomnine 1, by employing iodobenzene
as the coupling partner.
Having confirmed that the alkynylboronate cycloaddition ap-
proach could be exploited in the synthesis of the withasomnines,
we felt that it was important to compare this approach with
the potentially simpler aryl-substituted alkyne cycloaddition reac-
tions. In this context, Ranganathan and Bamezai have previously
reported the synthesis of withasomnine through a cycloaddition
of phenylacetylene and the proline derived sydnone 4.9 Unfor-
tunately, this cycloaddition delivers the reverse isomer as the
major product (approximately 3:1 in favour of the 3-phenyl-4H-
pyrazole analogue, 12) giving the natural product in just 18%
yield. Employing our optimal cycloaddition conditions we were
able to verify that indeed iso-withasomnine 12 is obtained as the
major product from this cycloaddition. Nonetheless, it could be
argued that phenyl trimethylsilyl acetylene 10 could potentially
offer improved regiocontrol (Fig. 2). Accordingly, we conducted
the cycloaddition of alkyne 10 with sydnone 4 and found it
to be non-selective and significantly slower than the reaction
of the alkynylboronate, delivering a 1:1 mixture of the 3- and
4- trimethylsilyl substituted pyrazole isomers 7 and 11 in modest
yield. Moreover, this sample was contaminated by a significant
amount of iso-withasomnine.
Attempts to make use of some previously successful conditions
for the coupling of pyrazolyl-4-boronic esters failed to yield any
biaryl compound 7 (Table 2, entry 1).10i Increasing the reaction
temperature to the solvent boiling point appeared to deliver
minimal amounts of the product (Table 2, entry 2). Switching to an
alternative set of catalyst conditions, Pd2dba3, tBu3P·HBF4 devel-
oped by Fu and Netherton13 was found to furnish 3-trimethylsilyl-
withasomnine 7 in 81% yield. Disappointingly however, this
reaction required 72 hours for complete consumption of the
boronic ester (Table 2, entry 3). In order to circumvent this
prolonged reaction time we opted to assess alternative conditions.
Pleasingly, switching to a DME/H2O solvent system allowed us to
generate the product in 78% yield using a relatively simple Pd(II)
pre-catalyst (Table 2, entry 4).
Using these optimal conditions, the palladium mediated cou-
plings towards the other natural analogues were studied. Within
18 hours both the para-iodophenol (65%) and the para-iodoanisole
(74%) had successfully coupled in good yield (Table 3, entries 2
and 3). Moreover, these reactions could also be conducted in a
microwave reactor and were complete within 1 hour.
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broad, m = multiplet), coupling constants (J) in Hz. 13C NMR
spectra were recorded on a Bruker AC-250 (62.9 MHz), AMX-
400 (100.6 MHz) or DRX-500 (500 MHz) with complete proton
decoupling. Chemical shifts are reported in ppm with the solvent
resonance as the internal standard (CDCl3: d 77.0 ppm) unless oth-
erwise stated. Infrared (FTIR) spectra were recorded on a Perkin
Elmer Paragon 100 FTIR spectrophotometer, nmax in cm-1. Bands
are characterized as broad (br), strong (s), medium (m) and weak
(w). Samples were recorded as thin films using sodium chloride
plates, as a DCM solution. Low resolution mass spectra were
recorded on Micromass Autospec, operating in E.I., C.I. or FAB
mode; or a Perkin-Elmer Turbomass Benchtop GC-MS operating
in either E.I. or C.I mode. High-resolution mass spectroscopy
recorded for accurate mass analysis, were performed on either a
MicroMass LCT operating in Electrospray mode (TOF ES+) or a
MicroMass Prospec operating in either FAB (FAB+), EI (EI+) or
CI (CI+) mode. Melting points were recorded on a Gallenkamp
melting point apparatus and are uncorrected. Microwave reactions
were performed on a Biotage Initiator Sixty supplied with built in
temperature/pressure probes and associated software.
Fig. 2 Cycloaddition of phenyl trimethylsilyl acetylene.
Lastly, we investigated the possibility of the combined removal
of the silyl group and cross coupling of the boronate (i.e. 6→1).
We have previously reported a tactic for isoxazole desilylation in
the presence of a boronic ester employing caesium fluoride.10d
However, a CsF promoted Suzuki coupling reaction on sim-
ilar pyrazole structures has proven unsuccessful for silyl group
removal.14 Palladium catalysed cross-coupling reactions in the
presence of TBAF are known in the literature.15 We were pleased
to find that on heating our optimal coupling reaction in the
presence of 2 equivalents of TBAF we could successfully isolate
withasomnine 1 in 50% yield after 72 hours. We have also
demonstrated that this process can be carried out in a sealed tube
giving an improved 68% yield at 140 ◦C for 20 hours.16
Synthesis of 5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]oxadiazol-3-ol
411. To L-proline (5.00 g, 43.4 mmol) and sodium nitrite (4.10 g,
59.5 mmol) in water (50 mL) was added concentrated hydrochloric
acid (3.70 mL) at 0 ◦C. The resulting slurry was stirred for
16 hours at room temperature. The crude reaction mixture was
extracted with ethyl acetate (3 ¥ 50 mL) and the organic layer
was dried over MgSO4. The solvent was removed in vacuo to give
the crude nitrosamine as a white solid (3.65 g, 25.3 mmol). This
solid (caution: this material is a suspected carcinogen) was taken
to the next step without further purification. To the nitrosamine
(3.65 g, 25.3 mmol) in THF (50 mL) was added TFAA (3.60 mL,
50.7 mmol) at 0 ◦C. The resulting reaction mixture was stirred
under nitrogen for 16 hours at room temperature. The solvent was
removed in vacuo to give the crude product. Further purification
by flash chromatography on silica gel (25% EtOAc in PE) gave
product 4 (1.71 g, 54%) as a yellow solid. M.p. 31–33 ◦C. (Lit.
Conclusions
In conclusion we have developed an efficient, regioselective and
divergent strategy for the synthesis of all three withasomnine
natural products from the key intermediate 6. We have also
highlighted the potential of alkynylboronates to offer improved
regioselectivity and reactivity over alternative 1,2-disubstituted
alkynes. Finally, we envisage that the discovery of a tandem
regioselective cycloaddition/one pot desilylative Suzuki reaction
protocol provides the opportunity to rapidly generate a series of
novel pyrazole libraries.
◦
1
m.p. 33–38 C11). H NMR (250 MHz, CDCl3): dH 4.40 (2H, t,
J = 7.5 Hz, CH2), 2.92–2.71 (4H, m, CH2); 13C NMR (100.6 MHz,
CDCl3): dC 165.3, 110.6, 50.5, 26.0, 21.0; FTIR (CH2Cl2): 2970 (w),
2878 (w), 1727 (s), 1507 (m), 1452 (m) cm-1.
Synthesis of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-
(trimethylsilyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 6. A solu-
tion of sydnone 4 (530 mg, 4.21 mmol) and alkyne 5 (3.77 g,
16.83 mmol) in o-DCB (10 mL) was stirred under nitrogen at
reflux for 24 hours. The solvent was removed in vacuo to give the
crude product. Further purification by flash chromatography on
silica gel (20% EtOAc in PE) gave product 6 (850 mg, 66%) as a
Experimental
General methods
All cycloaddition reactions were conducted in oven or flame-
dried glassware under an inert atmosphere of dry nitrogen. Flash
chromatography was performed on silicagel(Fluorochem Silicagel
LC60A4–63 micron). Thin layer chromatography (TLC) was
performed on aluminium backed plates pre-coated with silica
(0.2 mm, Merck DC-alufolien Kieselgel 60 F254) which were
developed using standard visualizing agents: Ultra Violet light
or potassium permanganate. 1H NMR spectra were recorded
on a Bruker AC-250 (250 MHz) or AMX-400 (400 MHz)
supported by an Aspect 3000 data system, unless otherwise stated.
Chemical shifts are reported in ppm with the solvent resonance
as the internal standard (CDCl3: d 7.27 ppm) unless otherwise
stated. Data are reported as follows: chemical shift, integration,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br =
◦
1
yellow solid. M.p. 110–112 C. H NMR (250 MHz, CDCl3): dH
4.15 (2H, t, J = 7.0 Hz, CH2), 2.96 (2H, t, J = 7.0 Hz, CH2),
2.67–2.55 (2H, m, CH2), 1.29 (12H, s, CH3), 0.33 (9H, s, CH3); 13
C
NMR (100.6 MHz, CDCl3): dC 156.3, 154.1, 83.1, 47.6, 27.2, 25.4,
23.6, 0.4; FTIR (CH2Cl2): 2973 (s), 1541 (s), 1406 (s), 1370 (m)
1311 (m), 1243 (s), 1149 (s), 1044 (s), 842 (s) cm-1; HRMS (EI):
m/z [M]+ calcd for C15H27BN2O2Si: 306.1935, found: 306.1927.
General method A: Suzuki cross-coupling of 3-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)-2-(trimethylsilyl)-5,6-dihydro-
4H-pyrrolo[1,2-b]pyrazole 4 with aryliodides. To 6 (1 eq.),
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aryliodide (2 eq.) and tripotassium phosphate (2 eq.) in
50% DME in water (0.1–0.2 M) was added dichloro-
bis(triphenylphosphine)palladium(II) (5 mol%). The resulting
reaction mixture was stirred at reflux for 18 hours. The crude
reaction mixture was extracted with EtOAc (3 ¥ 10 mL) and dried
over Na2SO4. Further purification by flash chromatography on
silica gel (20% EtOAc in PE) gave products 7–9.
(m), 1199 (w), 994 (w), 841 (m), 750 (w) cm-1; HRMS (ES): m/z
[MH]+ calcd. for C15H20ON2Si 272.1345, found 272.1334.
Using general method B: boronic ester 4 (50 mg, 0.16 mmol), 4-
iodophenol (72 mg, 0.33 mmol), tripotassium phosphate (70 mg,
0.33 mmol), dichlorobis(triphenylphosphine)palladium(II) (6 mg,
0.01 mmol) and 50% DME in water (2 mL), gave product 8 (22 mg,
50%) as a yellow solid.
Synthesis
of
3-(4-methoxy-phenyl)-2-trimethylsilanyl-5,6-
General method B: Microwave assisted Suzuki cross-coupling of
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trimethylsilyl)-
5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 4 with aryliodide. To 6
(1 eq.), aryliodide (2 eq.) and tripotassium phosphate (2 eq.)
in 50% DME in water (0.1–0.2 M) was added dichloro-
bis(triphenylphosphine)palladium(II) (5 mol%). The resulting
reaction mixture was heated at 130 ◦C for 1 hour in a sealed
microwave vessel in a microwave reactor. The crude reaction
mixture was extracted with EtOAc (3 ¥ 10 mL) and dried over
Na2SO4. Further purification by flash chromatography on silica
gel (20% EtOAc in PE) gave products 7–9.
dihydro-4H-pyrrolo[1,2-b]pyrazole 9. Using general method
A: Boronic ester 6 (50 mg, 0.16 mmol), 4-iodoanisole (75 mg,
0.33 mmol), tripotassium phosphate (70 mg, 0.33 mmol),
dichlorobis(triphenylphosphine)palladium(II) (6 mg, 0.01 mmol)
and 50% DME in water (2 mL), gave product 9 (35 mg, 74%)
as a yellow solid. M.p. 86–88 C; H NMR (250 MHz, CDCl3):
dH 7.25–7.22 (2H, m, Ar), 6.93–6.89 (2H, m, Ar), 4.22 (2H, t,
J = 7.0 Hz, CH2), 3.84 (3H, s, CH3), 2.88 (2H, t, J = 7.0 Hz,
CH2), 2.71–2.60 (2H, m, CH2), 0.21 (9H, s, CH3); 13C NMR
(100.6 MHz, CDCl3): dC 158.5, 156.1, 144.8, 130.4, 127.9, 122.7,
113.9, 55.7, 48.0, 27.3, 22.6, 0.2; FTIR (CH2Cl2): 2955 (w), 1556
(w), 1506 (m), 1246 (s), 1175 (w), 990 (w), 838 (s), 758 (w) cm-1;
HRMS (ES): m/z [MH]+ calcd. for C16H22ON2Si 286.1501, found
286.1504.
◦
1
General method C: Synthesis of withasomnine natural products 1–
3. A solution of pyrazole 7, 8 or 9 (1 eq.) in TBAF (1M in THF)
(10 eq.) was heated at reflux for 24 hours. The crude reaction
mixture was extracted with EtOAc (3 ¥ 10 mL) and dried over
Na2SO4. Further purification by flash chromatography on silica
gel (100% Et2O) gave products 1–3.
Using general method B: boronic ester 6 (50 mg, 0.16 mmol), 4-
iodoanisole (75 mg, 0.33 mmol), tripotassium phosphate (70 mg,
0.33 mmol), dichlorobis(triphenylphosphine)palladium(II) (6 mg,
0.01 mmol) and 50% DME in water (2 mL), gave product 9 (25 mg,
54%) as a yellow solid.
Synthesis
pyrrolo[1,2-b]pyrazole 7. Using general method A: Boronic
ester (100 mg, 0.33 mmol), iodobenzene (13 mg,
of
3-phenyl-2-trimethylsilanyl-5,6-dihydro-4H-
Synthesis of withasomnine 1. Using general method C: Pyra-
zole 7 (30 mg, 0.12 mmol) and TBAF (1 M in THF) (1.2 mL,
1.17 mmol), gave product 1 (15 mg, 70%) as a colourless solid. M.p.
114–116 ◦C. This sample of withasomnine 1 showed identical
analytical data (1H, 13C, HRMS) to that reported.2a,c 1H NMR
(250 MHz, CDCl3): dH 7.82 (1H, s, Ar), 7.47–7.16 (5H, m, Ar)
4.18 (2H, t, J = 7.0 Hz, CH2), 3.10 (2H, t, J = 7.0 Hz, CH2) 2.69
(2H, m, CH2); 13C NMR (100.6 MHz, CDCl3): dC 142.6, 140.9,
133.4, 128.8, 125.6, 125.0, 115.3, 47.5, 26.4, 23.8; HRMS (ES):
m/z [MH]+ calcd. for C12H12N2 184.1006, found 184.1000.
6
0.65 mmol), tripotassium phosphate (140 mg, 0.65 mmol),
dichlorobis(triphenylphosphine)palladium(II) (12 mg, 0.02 mmol)
and 50% DME in water (2 mL), gave product 7 (65 mg, 78%) as a
yellow solid. M.p. 118–120 ◦C; 1H NMR (250 MHz, CDCl3): dH
7.33–7.16 (5H, m, Ar), 4.16 (2H, t, J = 7.0 Hz, CH2), 2.84 (2H, t,
J = 7.0 Hz, CH2), 2.65–2.54 (2H, m, CH2), 0.15 (9H, s, CH3); 13
C
NMR (100.6 MHz, CDCl3): dC 156.1, 145.0, 135.6, 129.2, 128.5,
126.6, 123.1, 48.0, 27.3, 22.7, 0.2; FTIR (CH2Cl2): 2966 (w), 1602
(m), 1540 (w), 1498 (w), 1434 (w), 1247 (s), 987 (m), 842 (s), 756
(s) cm-1; HRMS (ES): m/z [MH]+ calcd. for C15H20N2Si 256.1396,
found 256.1384.
Synthesis of 4¢-hydroxywithasomnine 2. Using general method
C: Pyrazole 8 (28 mg, 0.10 mmol) and TBAF (1 M in THF)
(1.0 mL, 1.00 mmol), gave product 2 (11 mg, 55%) as a colourless
Using general method B: boronic ester 6 (50 mg, 0.16 mmol),
iodobenzene (3.6 mg, 0.33 mmol), tripotassium phosphate (70 mg,
0.33 mmol), dichlorobis(triphenylphosphine)palladium(II) (6 mg,
0.01 mmol) and 50% DME in water (2 mL), gave product 7 (32 mg,
76%) as a yellow solid.
◦
solid. M.p. 232–234 C. This sample of 4¢-hydroxywithasomnine
2 showed identical analytical data (1H, 13C, HRMS) to that
reported.2a,b
,
1H NMR (250 MHz, CDCl3:CD3OD (1:1)): dH 7.51
3
(1H, s, Ar), 7.10 (2H, d, J = 8.0 Hz, Ar), 6.66 (2H, d, J =
8.0 Hz, Ar), 3.96 (2H, t, J = 7.0 Hz, CH2), 3.17 (1H, s, OH),
2.89 (2H, t, J = 7.5 Hz, CH2) 2.52 (2H, m, CH2); 13C NMR
(125.8 MHz, CDCl3:CD3OD (1:1)): dC 154.9, 142.1, 139.7, 126.0,
124.2, 115.3, 115.3, 47.0, 26.0, 23.2. HRMS (ES): m/z [MH]+
calcd. for C12H12N2O 200.0956, found 200.0950.
Synthesis of 4-(2-trimethylsilanyl-5,6-dihydro-4H-pyrrolo[1,2-
b]pyrazol-3-yl)-phenol 8. Using general method A: Boronic ester
6 (50 mg, 0.16 mmol), 4-iodophenol (72 mg, 0.33 mmol),
tripotassium phosphate (70 mg, 0.33 mmol), dichloro-
bis(triphenylphosphine)palladium(II) (6 mg, 0.01 mmol) and 50%
DME in water (2 mL◦), gave product 8 (29 mg, 65%) as a yellow
Synthesis of 4¢ methoxywithasomnine 3. Using general method
C: pyrazole 9 (40 mg, 0.14 mmol) and TBAF (1 M in THF)
(1.4 mL, 1.40 mmol), gave product 3 (25 mg, 83%) as a colourless
solid. M.p. 123–125 ◦C. This sample of 4¢-methoxywithasomnine
3 showed identical analytical data (1H, 13C, HRMS) to that
reported.2b 1H NMR (250 MHz, CDCl3): dH 7.74 (1H, s, Ar),
7.37 (2H, d, J = 8.0 Hz, Ar), 6.91 (2H, d, J = 8.0 Hz, Ar),
4.16 (2H, t, J = 7.0 Hz, CH2), 3.82 (3H, s, CH3), 3.06 (2H, t,
1
solid. M.p. 198–202 C; H NMR (250 MHz, CDCl3:CD3OD
(1:1)): dH 6.83 (2H, d, J = 8.0 Hz, Ar), 6.53 (2H, d, J = 8.0 Hz,
Ar), 3.88 (2H, t, J = 7.0 Hz, CH2), 3.05 (1H, s, OH), 2.57 (2H, t,
J = 7.0 Hz, CH2), 2.41–2.37 (2H, m, CH2), 0.13 (9H, s, CH3); 13
C
NMR (100.6 MHz, CDCl3:CD3OD (1:1)): dC 155.5 (2 C), 144.8,
130.0, 125.9, 122.8, 114.8, 47.2, 26.7, 21.8, 0.8; FTIR (CH2Cl2):
3117 (s), 2923 (w), 1610 (w), 1541 (m), 1506 (w), 1428 (w), 1269
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J = 7.0 Hz, CH2) 2.67 (2H, m, CH2); 13C NMR (125.8 MHz,
CDCl3): dC 157.8, 142.1, 140.7, 126.2, 125.1, 115.2, 114.3, 55.3,
47.6, 26.5, 23.7. HRMS (ES): m/z [MH]+ calcd. for C13H14N2O
214.1113, found 214.1106.
We thank Johnson-Matthey for the generous loan of palladium
salts.
Notes and references
General procedure for a desilylative Suzuki cross-coupling syn-
thesis of withasomnine derivatives demonstrated by the synthesis of
withasomnine 1. To 4 (50 mg, 0.16 mmol), iodobenzene (3.6 mg,
0.33 mmol), dichlorobis(triphenylphosphine)palladium(II) (6 mg,
0.01 mmol) and tripotassium phosphate (70 mg, 0.33 mmol) in
50% DME in water (2 mL) was added TBAF in THF (1 M in
THF) (0.33 mL, 0.33 mmol). The resulting solution was heated at
reflux for 72 hours. The crude reaction mixture was extracted with
EtOAc (3 ¥ 10 mL) and dried over Na2SO4. Further purification
by flash chromatography on silica gel (100% Et2O) gave product 1
(15 mg, 50%) as a yellow solid.
1 H.-B. Schro¨ter, D. Neumann, A. R. Katritzky and F. J. Swinbourne,
Tetrahedron, 1966, 22, 2895.
2 (a) S. A. Adesanya, R. Nia, C. Fontaine and M. Pais, Phytochem.,
1994, 35, 1053; (b) A. J. Aladesanmi, R. Nia and A. Nahrstedt, Planta
Med., 1998, 64, 90; (c) P. J. Houghton, R. Pandey and J. E. Hawkes,
Phytochem., 1994, 35, 1602. The latter report assign their isolated
natural product as a new molecule called newbouldine but the proposed
structure and physical data match that of withasomnine.
3 V. Ravikanth, P. Ramesh, P. V. Diwan and Y. Venkateswarlu, Biochem.
Syst. Ecol., 2001, 29, 753.
4 A. A. Wube, E.-M. Wenzig, S. Gibbons, K. Asres, R. Bauer and F.
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5 (a) S. M. Allin, W. R. S. Barton, W. R. Bowman and T. McInally,
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W. R. Bowman, E. Bridge, M. R. J. Elsegood, T. McInally and V.
McKee, Tetrahedron, 2008, 64, 7745.
Desilylative Suzuki cross-coupling synthesis of withasomnine 1.
To 4 (100 mg, 0.33 mmol), iodobenzene (13 mg, 0.65 mmol),
dichlorobis(triphenylphosphine)palladium(II) (12 mg, 0.02 mmol)
and tripotassium phosphate (140 mg, 0.66 mmol) in 50% DME
in water (2 mL) was added TBAF hydrate (853 mg, 3.27 mmol).
The reaction mixture was heated in a sealed microwave vessel in
a silicone oil bath at reflux for 20 hours. The crude reaction was
transferred to a round bottom flask and sodium periodate (210 mg,
0.980 mmol) and 2 M HCl (0.2 mL) were added. The resulting
solution was stirred at room temperature for 24 hours. The crude
reaction mixture was extracted with EtOAc (3 ¥ 10 mL) and dried
over Na2SO4. Further purification by flash chromatography on
silica gel (10% acetone in DCM) gave product 1 (41 mg, 68%) as
a yellow solid.
6 O. Kulinkovich, N. Masalov, V. Tyvorskii, N. De Kimpe and M.
Keppens, Tetrahedron Lett., 1996, 37, 1095.
7 A. Marimoto, K. Noda, T. Watanabe and H. Takasugi, Tetrahedron.
Lett., 1968, 9, 5707.
8 T. Onaka, Tetrahedron Lett., 1968, 9, 5711.
9 D. Ranganathan and S. Bamezai, Synth. Commun., 1985, 15,
259.
10 For boronic esters of benzenes see: (a) P. M. Delaney, J. E. Moore and
J. P. A. Harrity, Chem. Commun., 2006, 3323; (b) P. M. Delaney, D. L.
Browne, H. Adams, A. Plant and J. P. A. Harrity, Tetrahedron, 2007,
64, 866; Isoxazoles: (c) M. W. Davies, R. A. J. Wybrow, J. P. A. Harrity
and C. N. Johnson, Chem. Commun., 2001, 1558; (d) J. E. Moore, M. W.
Davies, K. M. Goodenough, R. A. J. Wybrow, M. York, C. N. Johnson
and J. P. A. Harrity, Tetrahedron, 2005, 61, 6707; Pyridazines: (e) M. D.
Helm, J. E. Moore, A. Plant and J. P. A. Harrity, Angew. Chem., Int. Ed.,
2005, 44, 3889; (f) E. Gomez-Bengoa, M. D. Helm, A. Plant and J. P. A.
Harrity, J. Am. Chem. Soc., 2007, 129, 2691; Pyridines and 2-pyridones:
(g) P. M. Delaney, J. Huang, S. J. F. Macdonald and J. P. A. Harrity,
Org. Lett., 2008, 10, 781; (h) Triazoles: J. Huang, S. J. F. Macdonald
and J. P. A. Harrity, Chem. Commun., 2009, 436; Pyrazoles: (i) D. L.
Browne, M. D. Helm, A. Plant and J. P. A. Harrity, Angew. Chem., Int.
Ed., 2007, 46, 8656; (j) D. L. Browne, J. B. Taylor, A. Plant and J. P. A.
Harrity, J. Org. Chem., 2009, 74, 396; (k) D. L. Browne, J. F. Vivat, A.
Plant, E. Gomez-Bengoa and J. P. A. Harrity, J. Am. Chem. Soc., 2009,
131, 7762.
11 Sydnone 4 can be synthesized on 2.5 kg scale, see: A. A. Nikitenko,
M. W. Winkley, J. Zeldis, K. Kremer, A. W. -Y. Chan, H. Strong, M.
Jennings, I. Jirkovsky, D. Blum, G. Khafizova, G. T. Grosu and A. M.
Venkatesan, Org. Proc. Res. Dev., 2006, 10, 712.
12 It is noteworthy that 2 equivalents of the alkynylboronate can be
recovered from this reaction (after column chromatography).
13 M. R. Netherton and G. C. Fu, Org. Lett., 2001, 3,
4295.
Experiment to explore the reactivity and regioselectivity of other
disubstituted alkynes. A solution of sydnone 4 (63 mg, 0.5 mmol)
and alkyne 10 (350 mg, 2.0 mmol) in o-DCB (1.25 mL) was stirred
under nitrogen at reflux for 72 hours. The crude reaction mixture
was partially resolved by flash chromatography on silica gel (35%
EtOAc in PE) to give a mixture of the pyrazole products 7, 11
and 12 (65 mg, 51%, approximate yield estimated on the basis
1
of the molecular weight of 7 and 11) as a yellow oil. Crude H
NMR (prior to chromatography) gives the same peak ratio as
that of the isolated pyrazole products. The peak at 6.30 ppm
has been assigned as the pyrazole CH of 12 (as observed by the
cycloaddition of phenylacetylene and sydnone 4). The TMS peaks
(at ~ 0.2 ppm) have been assigned to the isomers 7 and 11 in a
1.1:1 ratio. The multiplets at ~ 2.6, 2.95 and 4.15 ppm are ascribed
to all three compounds.
14 Attempts to cross couple and desilylate 1-phenyl-4-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)-3-(trimethylsilyl)-1H-pyrazole using
standard CsF mediated Suzuki conditions delivered the cross coupled
product with the silyl group intact.
Acknowledgements
15 For a Hiyama coupling in the presence of TBAF, see: Z. Wu, M. Yang,
H. Li and Y. Qi, Synthesis, 2008, 1415.
We are grateful to GlaxoSmithKline (JH), Syngenta (DLB), the
EPSRC and the University of Sheffield for financial support.
16 The reaction mixture was sealed in a microwave vial and heated at
140 ◦C in a silicone oil bath.
4056 | Org. Biomol. Chem., 2009, 7, 4052–4056
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The Royal Society of Chemistry 2009
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