Table 2 Diels–Alder reaction between cyclopentadiene and cinnamalde-
hyde using ethyl carbazate and benzoic hydrazide derived catalysts
Notes and references
‡
Typical experimental procedure for the preparation of 8: Benzoic
Entrya
Catalystb
exo+endo
% Yield
hydrazide (5.00 g, 36.7 mmol) was added to a mixture of acetone (22 ml)
and acetic acid (40 ml, 0.69 mmol) and stirring was continued at room
temperature for 48 h. The reaction mixture was diluted with water (30 ml)
and extracted with diethyl ether (3 3 30 ml). The extracts were washed with
brine, dried (MgSO4) and concentrated to give benzoic acid isopropylidine
hydrazide as a colourless solid (5.57 g, 31.6 mmol, 86%). mp 141–143 °C;
IR (Nujol mull) 3221, 1655 (CNO), 1638 (CNN), 1578, 1531, 1490, 718, 668
cm21; 1H NMR (400 MHz, CDCl3): d 8.70 (s, 1H, NH), 7.79 (d, 2H, J = 6.8
Hz, ArH), 7.52 (t, 1H, J = 7.2 Hz, ArH), 7.44 (dd, 2H, J = 7.6 and 7.3 Hz,
ArH), 2.15 (s, 3H, CH3), 1.97 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3),
d 164.6 (C), 156.9 (C), 134.1 (C), 132.1 (CH), 129.0 (CH), 127.6 (CH), 26.0
(CH3), 17.3 (CH3); m/z (GC-MS) 176 (M+, 8%), 161 (50), 105 (100), 77
(31); HRMS (found 176.0950; C10H12N2O requires 176.0950).
Ethanol (12 ml) and acetic acid (6 ml) were added to platinum oxide (0.68
g, 0.3 mmol) under an atmosphere of nitrogen. Benzoic acid isopropylidine
hydrazide (2.50 g, 14.2 mmol) was added and the flask charged with
hydrogen. The reaction mixture was stirred at room temperature for 48 h,
filtered through Celite® and the filtrate was neutralised with saturated
sodium bicarbonate solution. The organic phase was washed with brine,
dried (MgSO4) and concentrated to give 8 as a colourless powder (2.18 g,
12.2 mmol, 86%). mp 110–112 °C; IR (Nujol mull) 3289, 1640 (CNO),
1537, 725, 693 cm21; 1H NMR (400 MHz, CDCl3) d 7.69 (m, 3H, NH and
ArH), 7.46 (t, 1H, J = 7.3 Hz, ArH), 7.38 (dd, 2H, J = 7.7 and 7.1 Hz,
ArH), 4.81 (s, 1H, NH), 3.18 (hept, 1H, J = 6.2 Hz, CH(CH3)2) 1.05 (d, 6H,
J = 6.2 Hz, CH3); 13C NMR (100 MHz, CDCl3) d 167.5 (C), 132.9 (C),
131.9 (CH), 128.7 (CH), 126.9 (CH), 51.4 (CH), 20.9 (CH3); m/z (GC-MS)
178 (M+, 3%), 163 (9), 122 (13), 105 (100), 77 (34), 58 (20); HRMS (found
178.1105; C10H14N2O requires 178.1106).
1
2
3
6
7
8
65+35
67+33
67+33
94
97
93
a All reactions carried out for 48 h in methanol:water (19+1) at room
temperature with 10 mol% catalyst. b As HCl salt.
using the hydrazide 8 as the catalyst, with acrolein 9,
methacrolein 10 and crotonaldehyde 11 as the dienophiles and
cyclopentadiene 12 and 2,3-dimethyl butadiene 13 as the
dienes. The results obtained are shown in Table 3.
Table 3 Diels–Alder cycloaddition catalysed by 8a
Entry
Diene
Dienophile
Exo+Endob % Yield
1
2
3
4
5
6
12
12
12
13
13
13
9
10
11
9
10
11
41+59
83+17
54+46
—
—
—
98
98
98
97
98
89
a All reactions carried out for 48 h in methanol+water (19+1) at room
1
temperature with 10 mol% 8 as HCl salt. b Ratio determined by H NMR
analysis of the crude reaction mixtures.
1 P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2001, 40, 3726; H.
Groger and J. Wilken, Angew. Chem., Int. Ed., 2001, 40, 529.
2 A. B. Northrup and D. W. C. MacMillan, J. Am. Chem. Soc., 2002, 124,
2458; K. A. Ahrendt, C. J. Borths and D. W. C. MacMillan, J. Am.
Chem. Soc., 2000, 122, 4243.
The results show that once again the use of the a-effect
greatly accelerates the rates of reaction and this class of catalyst
appears to be general for the Diels–Alder reaction of a,b-
unsaturated aldehydes with both cyclic and acyclic dienes.
Finally, we investigated the optimal nature of the acid salt of
the catalyst. After scanning a number of systems we discovered,
in accordance with previous findings, that use of the perchlorate
salt was most effective for catalytic turnover. For example, the
use of 10 mol% of perchloric acid,13 in the presence of 10 mol%
of the amine catalyst 8 gave the Diels–Alder adduct between
cyclopentadiene and cinnamaldehyde in 86% yield in just 24 h.
The exo+endo ratios were 65+35, which is consistent with our
previous observations. Lowering the catalyst loading to just 1
mol% catalyst as its perchlorate salt gave the adduct in a very
pleasing 54% yield (exo+endo ratio 61+39) which greatly adds
to the usefulness of this procedure and bodes well for future
catalyst development.
In summary, we have shown that use of the a-effect as a
handle to promote iminium ion catalysed Diels–Alder reactions
between a variety of dienes and electron deficient dienophiles
provides an effective platform from which to approach catalyst
design. Of particular note is the fact that introduction of an
electon withdrawing group on the a-hetero atom greatly
enhances the catalytic activity whilst maintaining the ster-
eochemical outcome of these reactions. The ability to carry out
these reactions with acyclic catalysts will be of particular
significance in the design of asymmetric variants of this and
other OrganoCatalytic™ reactions. Our findings in these and
related areas will be reported shortly.
3 W. S. Jen, J. J. M. Wiener and D. W. C. MacMillan, J. Am. Chem. Soc.,
2000, 122, 9874.
4 N. A. Paras and D. W. C. MacMillan, J. Am. Chem. Soc., 2002, 124,
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123, 4370; N. A. Paras and D. W. C. MacMillan, J. Am. Chem. Soc.,
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Lerner and C. F. Barbas III, J. Am. Chem. Soc., 2000, 122, 2395; S.
Saito, M. Nakadai and H. Yamamoto, Synlett, 2001, 1245.
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The authors wish to thank The Royal Society and The
Nuffield Foundation for equipment grants, F. Hoffmann-La
Roche Ltd for a CASE award (JLC), the EPSRC for a Quota
award and Swansea HRMS service and Dr Andreas A.
Staempfli (F. Hoffmann-La Roche) for HRMS analyses.
13 Caution: Solutions of perchloric acid should be prepared and handled
with the utmost care.
CHEM. COMMUN., 2003, 728–729
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