B. M. Smith, A. E. Graham / Tetrahedron Letters 52 (2011) 6281–6283
6283
R
R
n
O
n = 0
87% yield
O
1 mol% In(OTf) , TMOF (1.5 equiv.)
3
O
n = 1, R = Me 91% yield
Ph
CH3
diol (1.1 equiv.), rt, neat
Ph
CH3
Scheme 2. Indium triflate mediated tandem acetalisation-acetal exchange reactions.
excellent isolated yields of cyclic acetal and ketal products. The
process is highly efficient, employing near-stoichiometric quanti-
ties of the diol and proceeds rapidly at room temperature. Further-
more, the reaction can be adapted to employ solvent-free
conditions, further improving the efficiency. We have extended
our studies in this area to develop a tandem acetalisation-acetal
exchange protocol, again employing solvent-free conditions, which
is applicable to the synthesis of cyclic ketals from unreactive ke-
tones. The reaction of acetophenone in the presence of TMOF and
M. W. C.; Timms, D. A.; Williams, S. M.; Graham, A. E. Tetrahedron Lett. 2007, 48,
249–6251.
(a) Smith, B. M.; Graham, A. E. Tetrahedron Lett. 2006, 47, 9317–9319; (b) Smith,
B. M.; Graham, A. E. Tetrahedron Lett. 2007, 48, 4891–4894.
6
5
.
6. (a) Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503–1531; (b) McPhail, D. R.;
Lee, J. R.; Fraser-Reid, B. J. Am. Chem. Soc. 1992, 112, 1905–1906; (c) Yoshimura,
Y.; Shimizu, H.; Hinoub, H.; Nishimura, S.-I. Tetrahedron Lett. 2005, 46, 4701–
4705.
7. (a) Crotti, C.; Farnetti, E.; Guidolin, N. Green Chem. 2010, 12, 2225–2231; (b)
Graham, A. E. Synth. Commun. 1999, 29, 697–703; (c) Maltais, R.; Bérubé, M.;
Marion, O.; Labrecque, R.; Poirier, D. Tetrahedron Lett. 2000, 41, 1691–1694.
8
.
Typical experimental procedure: In(OTf)
mixture of benzaldehyde dimethylacetal (152 mg, 1.00 mmol) and 2,2-
dimethyl-1,3-propanediol (111 mg, 1.10 mmol) in CH Cl (2 ml) and the
3
(5.6 mg, 1 mol %) was added to a
3
a diol proceeds under In(OTf) catalysis to produce the dimethyl
acetal in situ which then undergoes rapid exchange to give the cor-
responding cyclic ketal. The ketals are produced in high yields un-
der very mild reaction conditions without the requirement for high
temperatures or extended reaction times. We are currently inves-
tigating the scope and application of this novel tandem process.
2
2
reaction mixture stirred at room temperature for 30 min. At this time, the
solvent was removed and the reaction mixture was passed through a short plug
of silica which was then washed with hexane (2 Â 2 ml) and the solvent was
removed under reduced pressure to give the product, 5,5-dimethyl-2-phenyl-
[
1,3]-dioxane3g as a colourless oil (183 mg, 95%); 1H NMR (CDCl
3
; 400 MHz)
d = 0.75 (3H, s), 1.25 (3H, s), 3.60 (2H, d, J = 11 Hz), 3.80 (2H, d, J = 11 Hz), 5.45
(
1H, s), 7.25–7.35 (3H, m), 7.45–7.55 (2H, m); 13C NMR (CDCl
d = 138.4, 128.8, 128.2, 126.1, 101.7, 77.6, 30.2, 22.9, 21.8; mmax (film)/cm
3
; 100 MHz)
À1
Acknowledgments
(
neat) 2954, 2846, 1388, 1101, 1017, 745 and 696; MS (EI) m/z 192; HRMS (ES)
+
+
17 2
calcd for C12H O (M+H) 193.1223. Found (M+H) 193.1224.
The authors thank the Engineering and Physical Sciences Re-
search Council and the Royal Society of Chemistry for financial
support, and the EPSRC National Mass Spectrometry Service, Swan-
sea University.
9
.
(a) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Buriol, L.; Machado, P. Chem.
Rev. 2009, 109, 4140–4182; (b) Walsh, P. J.; Li, H. M.; de Parrodi, C. A. Chem. Rev.
2
009, 107, 2503–2545; (c) Cave, G. W. V.; Raston, C. L.; Scott, J. L. Chem.
Commun. 2001, 66, 2159–2169.
0. Typical experimental procedure under solvent-free conditions. In(OTf)
1
3
(5.6 mg,
mol %) was added to a mixture of cyclohexanone dimethyl acetal (144 mg,
.00 mmol) and finely ground 2,2-dimethyl-1,3-propanediol (111 mg,
.10 mmol) and the reaction mixture stirred at room temperature for 30 min.
1
1
1
References and notes
At this time, residual MeOH was removed under reduced pressure and the
crude residue was passed through a short plug of silica which was washed with
hexane (2 Â 2 ml). The solvent was removed under reduced pressure to give
1
2
.
.
Kocienski, P. J. Protecting Groups; Thieme: New York, 2003.
(a) Torok, D. S.; Figueroa, J. J.; Scott, W. J. J. Org. Chem. 1993, 58, 7274–7276; (b)
Lu, T.-J.; Yang, J.-F.; Sheu, L.-J. J. Org. Chem. 1995, 60, 2931–2934; (c) Yu, M.;
Pagenkopf, B. L. Tetrahedron 2003, 59, 2765–2771.
3f
the product, 3,3-dimethyl-1,5-dioxa-spiro[5.5]undecane as a colourless oil
1
(
3
2
170 mg, 92%); H NMR (CDCl
3
; 400 MHz) d = 0.90 (6H, s), 1.30–1.75 (10H, m),
3
.
(a) Sartori, G.; Ballini, R.; Bigi, F.; Bosica, G.; Maggi, R.; Righi, P. Chem. Rev. 2004,
13
.45 (4H, s); C NMR (CDCl
max (film)/cm (neat) 2936, 2858, 1104, 914, and 733; MS (EI) m/z 184;
HRMS (ES) calcd for C11
3
; 100 MHz) d = 97.7, 69.8, 32.6, 30.2, 25.8, 22.8,
104, 199–250; (b) Williams, D. B. G.; Lawton, M. C. Green Chem. 2008, 10, 914–
À1
2.6;
m
9
8
17; (c) Ishihara, K.; Karumi, Y.; Kubota, M.; Yamamoto, H. Synlett 1996, 839–
41; (d) Firouzabadi, H.; Iranpoor, N.; Karimi, B. Synlett 1999, 321–323; (e)
(M+H) 185.1536. Found (M+H)+ 185.1537.
+
H
21
O
2
1
1. (a) Tietze, L. F. Chem. Rev. 1996, 96, 115–136; (b) Taylor, R. J. K.; Reid, M.; Foot,
J.; Raw, S. A. Acc. Chem. Res. 2005, 38, 851–869; (c) Phillips, D. J.; Pillinger, K. S.;
Wei, L.; Taylor, A. E.; Graham, A. E. Chem. Commun. 2006, 21, 2280–2282; (d)
Phillips, D. J.; Pillinger, K. S.; Wei, L.; Taylor, A. E.; Graham, A. E. Tetrahedron
Leonard, N. M.; Oswald, M. C.; Freiberg, D. A.; Nattier, B. A.; Smith, R. C.; Mohan,
R. S. J. Org. Chem. 2002, 67, 5202–5207; (f) Srivastava, P.; Srivastava, R. Catal.
Commun. 2008, 9, 645–649; (g) Gregg, B. T.; Golden, K. C.; Quinn, J. F.
Tetrahedron 2008, 64, 3287–3295; (h) Wang, B.; Gu, Y.; Song, G.; Yang, T.; Yang,
L.; Suo, J. J. Mol. Catal. A 2005, 233, 121–126; (i) Robinson, M. W. C.; Graham, A.
E. Tetrahedron Lett. 2007, 48, 4727–4731.
(a) Kubczyk, T. M.; Williams, S. M.; Kean, J. R.; Davies, T. E.; Taylor, S. H.;
Graham, A. E. Green Chem. 2011, 13, 2320–2325; (b) Robinson, M. W. C.; Davies,
A. M.; Mabbett, I.; Davies, T. E.; Apperley, D. C.; Taylor, S. H.; Graham, A. E. J.
Mol. Catal. A 2010, 329, 57–63; (c) Robinson, M. W. C.; Davies, A. M.; Mabbett, I.;
Apperley, D. C.; Taylor, S. H.; Graham, A. E. J. Mol. Catal. A 2009, 314, 10–14; (d)
Robinson, M. W. C.; Davies, A. M.; Mabbett, I.; Taylor, S. H.; Graham, A. E. Org.
Biomol. Chem. 2009, 7, 2559–2564; (e) Smith, B. M.; Skellam, E. J.; Oxley, S. J.;
Graham, A. E. Org. Biomol. Chem. 2007, 5, 1979–1982; (f) Cott, D.; Owens, V.;
Zeigler, K. J.; Glennon, J. D.; Graham, A. E.; Holmes, J. D. Green Chem. 2005, 7,
2
(
007, 63, 10528–10533; (e) Phillips, D. J.; Graham, A. E. Synlett 2008, 649–652;
f) Harris, G. H.; Graham, A. E. Tetrahedron Lett. 2010, 51, 6890–6892; (g)
Bagley, M. C.; Lin, V.; Phillips, D. J.; Graham, A. E. Tetrahedron Lett. 2009, 50,
4
.
6
7
823–6825; (h) Page, P. C. B.; Graham, A. E.; Park, B. K. Tetrahedron 1992, 48,
265–7274.
1
2. Typical experimental procedure for tandem acetalisation-acetal exchange under
solvent-free conditions: In(OTf) (5.6 mg, 1 mol %) was added to a mixture of
acetophenone (120 mg, 1.00 mmol), trimethyl orthoformate (159 mg,
.50 mmol) and ethane-1,2-diol (68 mg, 1.10 mmol) and the reaction
3
1
mixture stirred at room temperature for 1 h. At this time, residual MeOH
was removed under reduced pressure and the crude product was passed
through a short plug of silica which was washed with hexane (2 Â 2 ml). The
1
05–110; (g) Robinson, M. W. C.; Pillinger, K. S.; Mabbett, I.; Timms, D. A.;
solvent was removed under reduced pressure to give the product 2-methyl-2-
Graham, A. E. Tetrahedron 2010, 66, 8377–8382; (h) Copley, M. P.; Graham, A.
E.; Holmes, J. D.; Morris, M. A.; Seraglia, R.; Spalding, T. R. Appl. Catal. A 2006,
phenyl-1,3-dioxolane as a light yellow oil (143 mg, 87%); 1H NMR (CDCl
3g
3
;
4
00 MHz) d = 1.65 (3H, s), 3.70–3.85 (2H, m), 3.95–4.05 (2H, m), 7.25–7.40 (3H,
304, 14–20; (i) Smith, B. M.; Kean, S. D.; Wyatt, M. F.; Graham, A. E. Synlett
13
3
m), 7.45–7.55 (2H, m); C NMR (CDCl ; 100 MHz) d = 143.5, 128.3, 127.9,
1
2
008, 1953–1956; (j) Robinson, M. W. C.; Pillinger, K. S.; Graham, A. E.
À1
25.3, 108.8, 64.2, 27.5;
mmax (film)/cm (neat) 2892, 1375, 1201, 1069, 733
Tetrahedron Lett. 2006, 47, 5919–5921; (k) Robinson, M. W. C.; Buckle, R.;
Mabbett, I.; Graham, A. E. Tetrahedron Lett. 2007, 48, 4723–4725; (l) Robinson,
and 650; MS (EI) m/z 164.