An unexpected one step domino conversion of TMS-alkynes to protected ketones in 4-chromenone system

Article abstract of DOI:10.1016/j.tetlet.2013.07.082

An unexpected metal-free high yielding one step domino procedure for TMS-deprotection and simultaneous conversion of resulting alkynes to protected carbonyls (ketals) in 4-chromenone systems is reported. A mechanistic rationale involving an allene intermediate is also proposed based on dynamic NMR and mass spectra.

Full text of DOI:10.1016/j.tetlet.2013.07.082

Tetrahedron Letters 54 (2013) 5137–5139
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Tetrahedron Letters
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An unexpected one step domino conversion of TMS-alkynes
to protected ketones in 4-chromenone system
⇑
Prabuddha Bhattacharya, Amit Basak
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An unexpected metal-free high yielding one step domino procedure for TMS-deprotection and
simultaneous conversion of resulting alkynes to protected carbonyls (ketals) in 4-chromenone systems
is reported. A mechanistic rationale involving an allene intermediate is also proposed based on dynamic
NMR and mass spectra.
Received 24 May 2013
Revised 11 July 2013
Accepted 12 July 2013
Available online 20 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Chromenone
Deprotection
Domino reaction
Ketal
Alkyne
Silyl-deprotection of TMS-acetylenes, subsequent hydration of
resulting terminal alkynes and ketalization of the carbonyl are
three simple but important transformations in synthetic organic
chemistry. Although fluorides1 are the usual reagents for silyl
deprotection, the process may also be carried out under basic,2
acidic conditions3 or Ag(I) catalysis.4 The hydration of alkynes5
requires the use of toxic mercury(II) salts or expensive transition
metal catalysts (Ru, Rh, Pt, Au etc.).5 Other alternatives require
the presence of acids7 (H2SO4, HCOOH, TfOH or p-TsOH),5 which
may not be compatible in terms of selectivity in the case of
functionalized substrates. Ketalization is done with alcohols under
anhydrous acidic conditions (Scheme 1).
by the absence of ethynyl hydrogen in the 1H NMR spectrum
(Fig. 1) of the crude reaction mixture. It also indicated the forma-
tion of predominantly one major (singlets at d 8.3, 3.2 and 1.8)
Ist step
R
SiMe3
R
H
(F- )
3rd step
R1OH/H+
(H+/M+)
2nd step
??
Me
R
Me
R
OR1
OR1
O
It will be of great importance if all the three steps can be
combined to convert a TMS-acetylene to a ketal in a single step
(domino reaction). In this Letter we report a single step conversion
of 3-trimethylsilyl alkynyl 4-chromenones to fully protected
3-keto methyl 4-chromones in high yields. A mechanistic rationale
is also proposed.
Our initial intention was to synthesize chromenonyl xanthones
via GB cyclization6 of bis chromonyl propargyl sulfones (Scheme
2). For that we required 3-ethynyl 4-chromenone7 which are
accessible from the corresponding trimethylsilyl ethynyl deriva-
tive. With this intention, the latter was prepared via Sonogashira8
coupling of 3-iodo 4-chromenone derivative9 with TMS-acetylene.
Attempted desilylation of 1a with potassium fluoride (KF) in
methanol, however, did not afford the expected alkyne as revealed
Scheme 1. 3-Step protocol for the conversion of TMS-acetylene to ketals.
O
O
O
X
R
X
GB cyclization
R
O
R
A
O
R
O
O
B
O
O
O
R1
O
OH
R
R
O
C
D
R1 = H
R
1 = TMS
⇑
Corresponding author.
E-mail address: absk@chem.iitkgp.ernet.in (A. Basak).
Scheme 2. Proposed synthesis of xanthones based on GB cyclization.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.082

5138
P. Bhattacharya, A. Basak / Tetrahedron Letters 54 (2013) 5137–5139
O
O
OMe
OMe
CH3
O
Si
O
O
O
CH3
Ethylene glycol,
MeOH (5:1)
KF
O
1a
O
2a
9
ii
iii
i
MeOH
..
a
H
H
O
O
O
b
O
OMe
H
C
-H+
a
H
+H+
(Solvent)
O lone pair
participation
O
O
MeOH
4a
5
6
-H+
+H+
b
(Solvent)
Me.O.H
MeOH
..
O
O
O
OMe
C
+H+
CH3
(Solvent)
O
OMe
O
OMe
O
Figure 1. 1H NMR of crude reaction and chromatographically isolated product.
10
11
7
-H+
-
O
MeOH
Me.O.H
O
O
OMe
OMe
Table 1
-
MeOH
CH3
H
Results of one step conversion of TMS-acetylene to cyclic ketals
9
9
H
OMe 1, 4-addition
of MeOH
O
12
6
O
O
O
O
O
Si
I
i
ii
R
R
R
O
O
Si
i KF/CH3CN ii Ethylene glycol, MeOH (5:1)
iii MeOH
O
2a-e
O
1a-e
KF/ MeOH
O
3a-e
15
16
i = Pd(PPh3)2Cl2, CuI, TMS-acetylene; ii = KF, ethylene glycol-MeOH (5:1 mL),
45 oC, 16-18 h
Scheme 3. Proposed mechanism.
Substrate
Product
Time (h)
Yield (%)
ketone 8. The same product was obtained after chromatography
when the reaction was done in ethanol or by replacing KF with
CsF or TBAF. The reaction was then repeated with super dry meth-
anol in the presence of dry CsF/KF. The chromatographic purifica-
tion was done quickly and the NMR was taken in acid-free CDCl3
which was now same as the crude and the product was character-
ized as dimethyl ketal 9. Realizing the origin of the methyl ketone
via hydrolysis of the unstable dimethyl ketal, we thought of pre-
paring a more stable cyclic ketal. Thus, the reaction was carried
out in a mixture of ethylene glycol and methanol10 (5:1) in the
presence of KF or CsF. The reaction now furnished a stable cyclic
ketal 2a in excellent yields.
The reaction was repeated with various substituted chromones
and in all cases, excellent yields of ketals 2a–e were obtained in a
single step. The results are shown in Table 1. Interestingly, our ori-
ginal target acetylene could be obtained in high yields using KF in a
non-protic solvent like CH3CN (Scheme 3).
Two possible mechanisms (pathways a and b) have been pro-
posed as shown in Scheme 3, both of which involved intermediacy
of the free alkyne 4a. This was supported by the conversion of free
alkyne to the ketal when a solution of the alkyne in ethylene gly-
col-methanol (5:1) was stirred at rt for 14 h. To gain further in-
sight, the 1H NMR (Fig. 2) of a d4-MeOH solution of alkyne 4a
was recorded at different time intervals which indicated initial for-
mation of the enol ether (appearance of signals in the region of d
7.1 for aryl-hydrogens and a singlet at d 6.2 for the vinylic-H) for
the proposed intermediate 6 or 11. These signals slowly disap-
peared and the formation of a new product was indicated by a
new set of signals in the aromatic region. ESI mass analysis indi-
cated the presence of two compounds: a major nona-deuteriated
ketal 13 and a minor trideuteriated methyl ketone 14 ( Fig. 3).
The latter was presumably formed by hydrolysis of the ketal. It also
indicated the exchange of alkyne hydrogen with deuterium during
the reaction.
O
O
O
O
Si
18
82
O
O
1a
2a
O
O
O
O
O
O
Si
16
16
83
85
2b
1b
O
O
O
O
Si
O
O
O
O
O
O
2c
1c
O
O
O
O
O
O
Si
16
17
84
85
2d
1d
O
O
O
O
Si
O
O
2e
1e
and a minor product (singlets at d 8.6 and 2.7). Interestingly, upon
chromatographic purification, the 1H NMR resembled only that of
the minor product, indicating complete conversion of the major
product to the minor one during chromatography. The product iso-
lated after chromatography was characterized as the methyl

P. Bhattacharya, A. Basak / Tetrahedron Letters 54 (2013) 5137–5139
5139
References and notes
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Tetrahedron Lett. 1996, 37, 8455; (c) Corey, E. J.; Fleet, G. W. J.; Kato, M.
Tetrahedron Lett. 1973, 14, 3963; (d) Clive, D. L. J.; Tao, Y.; Bo, Y.; Hu, Y.-Z.;
Selvakumar, N.; Sun, S.; Daigneault, S.; Wu, Y.-J. Chem. Commun. 2000, 1341; (e)
Kraus, G. A.; Bae, J. Tetrahedron Lett. 2003, 44, 5505; (f) Mukai, C.; Nomura, I.;
Kitagaki, S. J. Org. Chem. 2003, 68, 1376; (g) Gueugnot, S.; Alami, M.;
Linstrumelle, G.; Mambu, L.; Petit, Y.; Larchevêque, M. Tetrahedron 1996, 52,
6635.
2. (a) Garcia, J.; López, M.; Romeu, J. Synlett 1999, 429; (b) Austin, W. B.; Bilow, N.;
Kelleghan, W. J.; Lau, K. S. Y. J. Org. Chem. 1981, 46, 2280; (c) Taylor, E. C.; Ray, P.
S. J. Org. Chem. 1988, 53, 35; (d) Wong, W.-Y.; Lee, A. W.-M.; Wong, C.-K.; Lu, G.-
L.; Zhang, H.; Mo, T.; Lam, K.-T. New J. Chem. 2002, 26, 354; (e) Nishinaga, T.;
Miyata, Y.; Nodera, N.; Komatsu, K. Tetrahedron 2004, 60, 3375; (f) Nakanishi,
H.; Sumi, N.; Aso, Y.; Otsubo, T. J. Org. Chem. 1998, 63, 8632; (g) Miller, R. B.
Synth. Commun. 1972, 2, 267; (h) Perlman, M. E.; Watanabe, K. A.; Schinazi, R.
F.; Fox, J. J. J. Med. Chem. 1985, 28, 741; (i) Casara, P.; Danzin, C.; Metcalf, B.;
Jung, M. J. Chem. Soc., Perkin Trans. 1 1985, 2201.
3. (a) Daly, M. S.; Armstrong, R. W. Tetrahedron Lett. 1989, 30, 5713; (b) Smith, A.
B., III; Condon, S. M.; McCauley, J. A.; Leazer, J. L.; Leahy, J. W., Jr.; Maleczka, R.
E., Jr. J. Am. Chem. Soc. 1995, 117, 5407; (c) Acevedo, O. L.; Andrews, R. S.;
Dunkel, M.; Cook, P. D. J. Heterocycl. Chem. 1994, 31, 989; (d) Gao, L.-X.; Murai,
A. Heterocycles 1996, 42, 745.
Figure 2. 1H NMR of a d4-MeOH solution of the alkyne taken at different time
points.
4. Carpita, A.; Mannocci, L.; Rossi, R. Eur. J. Org. Chem. 1859, 2005.
5. Hintermann, L.; Labonne, A. Synthesis 2007, 1121. and references therein.
6. (a) Braverman, S.; Segev, D. J. Am. Chem. Soc. 1974, 96, 1245; (b) Garratt, P. J.;
Neoh, S. B. J. Org. Chem. 1979, 44, 2667; (c) Cheng, Y. S. P.; Garratt, P. J.; Neoh, S.
B.; Rumjanek, V. H. Isr. J. Chem. 1985, 26, 101; (d) Braverman, S.; Duar, Y.; Segev,
D. Tetrahedron Lett. 1976, 17, 3181; (e) Zafrani, Y.; Gottlieb, H. E.; Sprecher, M.;
Braverman, S. J. Org. Chem. 2005, 70, 10166; (f) Maji, M.; Mallick, D.; Mondal, S.;
Anoop, A.; Bag, S.; Basak, A.; Jemmis, E. D. Org. Lett. 2011, 13, 888; (g) Basak, A.;
Das, S.; Mallick, D.; Jemmis, E. D. J. Am. Chem. Soc. 2009, 131, 15695; (h) Mondal,
S.; Mitra, T.; Mukherjee, R.; Addy, P. S.; Basak, A. SynLett. 2012, 2582.
7. Wentrup, C. Angew. Chem. 1978, 60, 643.
8. (a) Gammill, R. B. Synthesis 1979, 901; (b) Eisnor, C. R.; Gossage, R. A.; Paras, N.;
Yadav, P. N. Tetrahedron 2006, 62, 3395.
9. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467; (b)
Takahashi, K.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1980, 8,
627.
OCD3
O
O
O
O
CD3
CD3
OCD3
O
C11H5D3O3
C13H5D9O4
14
13
Calculated mass MH+: 192.0740
Found: 192.0781
Calculated mass MNa+ : 266.1355
Obtained mass: 266.1396
Figure 3. Structures of deuteriated products formed in d4-MeOH.
10. Controlled amount of methanol was added for solubility reasons.
11. Hydroxyl amine addition to 3-alkynyl 4-chromones leading to isoxazole
derivatives via a similar allenic intermediate has been reported: Yu, X.; Du, B.;
Wang, K.; Zhang, J. Org. Lett. 1876, 2010, 12.
Although it is difficult to distinguish between the two mecha-
nisms, path b may appear to be more favoured in view of the re-
ported facile 1, 4-addition in 4-chromenone systems.11 The
nucleophile in this case is probably the alcohol which is activated
via the strong H-bond by the fluoride anion, a well known activator
of the Michael reaction.12 On the other hand, in a further experi-
ment, it has been shown that the fluoride-mediated deprotection
of 2-trimethylsilylethynyl 2-cyclehexenone 15 followed the ex-
pected route producing the corresponding 2-ethynylcyclohexe-
none 16 (Scheme 3). Thus, the participation of ring oxygen lone
pair is necessary for this unexpected conversion. This result seems
to favour the mechanism as depicted in path a.
In conclusion, we have developed an unexpected one-pot
domino conversion of TMS-acetylene to ketal13 in excellent yields
in 4-chromenone systems. Currently we are exploring other het-
erocyclic systems for carrying out similar conversion to explore
the generality of such conversions.
12. Clark, J. H. Chem. Rev. 1980, 80, 429.
13. General procedure for one-step conversion of TMS-acetylene to ketal.
To the solution of the TMS-acetylenes (0.12 mmol) in MeOH (3 mL) and
ethylene glycol (15 mL), KF (11 mg) was added and stirred at 45 °C for 16–18 h.
The progress of the reaction was monitored by TLC. The reaction was finally
quenched with water. The organic layer was extracted with DCM (20 mL) and
washed with brine. The mixture was concentrated in vacuo and the pure cyclic
ketal was isolated by flash column chromatography of the crude residue over Si
gel, using petroleum ether–ethyl acetate (ratio ranging from 7:1 to 3:1) as
eluent.
All compounds were characterized by NMR (400 MHz for 1H and 100 MHz for
13C) and mass spectral analysis. Spectral data of some selected compounds are
mentioned:
Compound 2a: State: solid; mp 85 °C; yield: 82%; dH 8.25 (1H, d, J = 8.0 Hz), 8.12
(1H, s), 7.67–7.63 (1H, m), 7.44–7.37 (2H, m), 4.10–4.06 (2H, m), 3.93–3.89
(2H, m), 1.84 (3H, s); dC 176.4, 156.4, 153.6, 133.7, 126.3, 125.3, 125.0, 124.4,
118.1, 106.9, 64.9, 25.1; Calculated for C13H12O4+H+ 233.0814 found 233.0851.
Compound 2b: State: solid; mp 87 °C; yield: 83%; dH 8.09 (1H, s), 8.02 (1H, br s),
7.46 (1H, dd, J = 8.5, 1.8 Hz), 7.33 (1H, d, J = 8.5 Hz), 4.09–4.06 (2H, m), 3.92–
3.89 (2H, m), 2.44 (3H, s), 1.84 (3H, s); dC 176.4, 154.7, 153.5, 135.3, 135.0,
125.6, 124.7, 124.1, 117.9, 107.0, 64.9, 25.1, 21.1; Calculated for C14H14O4+H+
247.0970 found 247.0960.
Compound 2c: State: solid; mp 86 °C; yield: 85%; dH 8.14 (1H, d, J = 8.9 Hz), 8.03
(1H, s), 6.95 (1H, dd, J = 8.9, 2.1 Hz), 6.80 (1H, d, J = 2.1 Hz), 4.08–4.05 (2H, m),
3.91–3.89 (5H, m), 1.82 (3H, s); dC 175.7, 164.2, 158.2, 153.1, 127.7, 124.2,
118.9, 114.6, 107.0, 100.2, 64.9, 56.0, 25.2; Calculated for
263.0919 found 263.0958.
Acknowledgements
C
14H14O5+H+
P.B. is grateful to CSIR, Government of India for a research fel-
lowship (to PB). DST is thanked for providing funds for the project
and for the JC Bose Fellowship awarded to AB.
Compound 2d: State: solid; mp 146 °C; yield: 84%; dH 8.16 (1H, d, J = 9.0 Hz),
8.03 (1H, s), 7.45–7.35 (5H, m), 7.04 (1H, dd, J = 9.0 Hz, 2.3 Hz), 6.88 (1H, d,
J = 2.3 Hz), 4.08–4.05 (2H, m), 3.91–3.88 (2H, m), 1.83 (3H, s); dC 175.7, 163.2,
158.1, 153.2, 135.8, 128.9, 128.6, 127.8, 127.7, 124.2, 119.1, 115.1, 107.0, 101.4,
70.7, 64.9, 25.2; Calculated for C20H18O5+H+ 339.1232 found 339.1270.
Compound 2e: State: solid; mp 89 °C; yield: 85%; dH 8.48 (1H, dd, J = 8.0 Hz,
0.4 Hz), 8.32 (1H, s), 8.19 (1H, d, J = 8.6 Hz), 7.93 (1H, dd, J = 8.2 Hz, 1.0 Hz),
7.76 (1H, d, J = 8.6 Hz), 7.30–7.65 (2H, m), 4.13–4.09 (2H, m), 3.97–3.93 (2H,
m), 1.89 (3H, s); dC 176.2, 153.9, 152.8, 136.0, 129.5, 128.3, 127.3, 125.7, 125.5,
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.07.
082.
124.1, 122.4, 121.4, 121.2, 107.0, 65.0, 25.1; Calculated for
283.0970 found 283.1009.
C
17H14O4+H+