Catalytic and stoichiometric Lewis acid participation in aldehyde ene cyclisations

Article abstract of DOI:10.1135/cccc20000741

Racemic 2-isopropyl-2-methylhex-5-enal has been synthesised in order to probe ene cyclisations leading to menthol analogues. The objective was first to discover catalytic conditions for preferential cyclisation to the menthol rather than the neomenthol series and then to develop (dynamic) kinetic resolution procedures which afforded a single enantiomer of product. It was found that catalytic quantities of both Me₂AlCl and a bulky methyl-aluminium bis(phenoxide) reagent gave products attributed to a Meerwein-Pondorff-Verley reaction. In this the aldehyde is reduced to a primary alcohol and the ene product oxidised to the corresponding α,β-unsaturated ketone. By contrast, a related bulky chloroaluminium reagent catalysed the ene cyclisation cleanly, but preferentially to the undesired neomenthyl stereoisomer.

Full text of DOI:10.1135/cccc20000741

Aldehyde Ene Cyclisations
741
CATALYTIC AND STOICHIOMETRIC LEWIS ACID PARTICIPATION
IN ALDEHYDE ENE CYCLISATIONS
1
2,
D. Christopher BRADDOCK and John M. BROWN *
Dyson Perrins Laboratory, South Parks Rd., Oxford OX1 3QY, U.K.;
1
2
e-mail: c.braddock@ic.ac.uk, bjm@ermine.ox.ac.uk
Received February 16, 2000
Accepted March 31, 2000
Dedicated to Professor Otakar Červinka on the occasion of his 75th birthday, in appreciation of his
contributions to organic stereochemistry.
Racem ic 2-isopropyl-2-m eth ylh ex-5-en al h as been syn th esised in order to probe en e
cyclisation s leadin g to m en th ol an alogues. Th e objective was first to discover catalytic con -
dition s for preferen tial cyclisation to th e m en th ol rath er th an th e n eom en th ol series an d
th en to develop (dyn am ic) kin etic resolution procedures wh ich afforded a sin gle en an tiom er
of product. It was foun d th at catalytic quan tities of both Me2AlCl an d a bulky m eth yl-
alum in ium bis(ph en oxide) reagen t gave products attributed to a Meerwein –Pon dorff–Verley
reaction . In th is th e aldeh yde is reduced to a prim ary alcoh ol an d th e en e product oxidised
to th e correspon din g α,β-un saturated keton e. By con trast, a related bulky ch loroalum in ium
reagen t catalysed th e en e cyclisation clean ly, but preferen tially to th e un desired n eom en th yl
stereoisom er.
Key w ord s: En e reaction s; Aldeh ydes; Alum in ium catalysts; Lewis acids; Terpen oids;
Stereoselective cyclisation s.
On e of th e m ost successful m eth ods for th e catalytic asym m etric syn th esis
of C–C bon ds is th e carbon yl en e reaction of alken es1 in wh ich Mikam i′s
con tribution h as been at th e forefron t2. In th e m ain , successful exam ples
in volve an activated carbon yl com poun d such as a glyoxylate ester3,
fluoral4 or form aldeh yde5. Th e glyoxylate ester en e reaction h as been ap-
plied with success by oth er auth ors6, an d tran sition -state m odels h ave been
proposed7. Yam am oto′s outstan din g con tribution s to th e developm en t of
in tram olecular cases do n ot in clude a prescription for catalytic asym m etric
syn th esis8, an d th ere are rath er few successful con tribution s to th is prob-
lem 9. In a related reaction wh ere an en an tiom erically pure reactan t cyclises
un der th e in fluen ce of an en an tiom erically pure catalyst, on ly m odest
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

742
Braddock, Brown:
m atch in g is observed10. Th e lim itation s en courage th e search for n ew en e
cyclisation catalysts11.
Th e in cen tive for our work was th e poten tial ease of access to m en th ol
an d its stereoisom eric relatives th rough an in tram olecular en e reaction , al-
ready dem on strated by Yam am oto an d co-workers. Th e aim was to provide
a basis for an asym m etric syn th esis th rough detailed an alysis of th e reactiv-
ity an d stereoselectivity of en e cyclisation of a sin gle reactan t. In th e first
part of th is work, we described a broad m ech an istic fram ework for defin in g
th e stereoch em ical course of Type II en e cyclisation s of com poun d 1, an d
h ow variation s in m ech an ism with ch an ge of Lewis acid provide routes to
differen t products an d also to distin ct stereoisom ers12. Th e form ation of th e
various products 2–5 m ay be ration alised accordin g to a com m on m ech a-
n istic fram ework (Sch em e 1). A furth er paper will provide in form ation on
th e syn th esis an d cyclisation of en an tiom erically pure aldeh yde 1 (ref.13).
Here we describe an evaluation of differen t alum in ium com poun ds as Lewis
acids an d progress from stoich iom etric prom otion of th e en e reaction to-
wards catalysis.
9
10
6
8
Br
2
9
1
4
X
7
3
1
X
2
5
5
3
Me
O
6
4
O
Al
8
10
7
Br
Numbering scheme
18
HO
HO
HO
Me
Me
Me
Me
Me
CH2
(i)
(iii)
O
H
4
2
CH2
Me
Me
(iii)
Me
(ii)
HO
Me
Me
Me
Me
Me
CH2
1
5
3
R-enantiomer of racemate shown
(i) Me2AlCl; (ii) MABR 18; (iii) Sc(OTf)3 or Cp2Ti(OTf)2
SCHEME 1
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Aldehyde Ene Cyclisations
743
EXPERIMENTAL
Gen eral
Boilin g poin t values recorded for sh ort-path distillation s were obtain ed usin g a Büch i
GKR-51 Kugelroh r oven . Th e value quoted is th e un corrected pot tem perature. Elem en tal
m icroan alyses were perform ed by Mrs V. Lam burn in th e Dyson Perrin s Laboratory usin g a
Carlo Erba 1106 elem en tal an alyser. In frared spectra (waven um bers in cm –1) were recorded
on a Perkin –Elm er 1750 Fourier Tran sform spectrom eter. Sam ples were prepared as th in
film s on sodium ch loride plates or as potassium brom ide disks. Abbreviation s used in th e
description of spectra are: w weak, m m edium , s stron g, br broad, def. deform ation . 1H NMR
spectra were recorded on a Varian Gem in i 200 (200 MHz), Bruker WH 300 (300 MHz) or
Bruker AM 500 (500 MHz) spectrom eter. Ch em ical sh ifts (δH) are quoted in ppm an d are
referenced to the residual solvent of chloroform (7.27 ppm ), coupling constants J are given in Hz.
13C NMR spectra were recorded on a Varian Gem in i 200 (50.3 MHz) or Bruker AM 500
(125.6 Hz) spectrom eter usin g DEPT editin g on th e form er. Quatern ary carbon s were as-
sign ed from a broad-ban d-decoupled an alysis used in con jun ction with th e DEPT program .
Ch em ical sh ifts (δC) are quoted in ppm an d are in tern ally referen ced to th e solven t (CDCl3,
δC 77.0). Mass spectra were recorded on a Trio-1 GCMS (Hewlett–Packard GC) spectrom eter
by ch em ical ion isation with am m on ia gas. Solven ts were purch ased from Rh ôn e–Poulen c,
Fison s, Rath burn s or th e Aldrich Ch em ical Com pan y, an d were dried prior to use by distilla-
tion from stan dard dryin g agen ts accordin g to th e procedures of Perrin et al.14. Com m ercial
sam ples of butyllith ium were titrated again st fresh ly recrystallised diph en ylacetic acid im m e-
diately before use15. NMR solven ts were stored un der argon in th e presen ce of activated 4Å
m olecular sieves an d distilled wh ere n ecessary from stan dard dryin g agen ts im m ediately
before use. All other reagents were purified according to the procedures described by Perrin et al.
or used as obtain ed from com m ercial sources.
3-Meth ylbut-3-en -1-yl Tosylate (8)
3-Meth ylbut-3-en -1-yl tosylate was prepared usin g a m odified syn th esis of Maitlin et al.16
Tosyl ch loride (42.0 g, 220 m m ol) was added in portion s to stirred solution of
.
a
3-m eth ylbut-3-en -1-ol (20.0 m l, 200 m m ol) in pyridin e (200 m l) at 0 °C . Th e m ixture was
allowed to stan d for 16 h at 0 °C an d th en diluted with water (200 m l). Th e organ ics were
extracted with dieth yl eth er (3 × 300 m l), wash ed with ice-cold 1 M HCl (3 × 500 m l), water
(200 m l) an d brin e. Th e organ ic layer was dried (MgSO4), filtered an d th e solven t evaporated
to afford th e title com poun d as a th erm ally sen sitive pale yellow oil (40.3 g, 85%). IR (th in
film ): 3 078 w (sp2 CH), 2 971 m (sp3 CH), 2 955 m (sp3 CH), 2 925 m (sp3 CH), 1 653
(C=C), 1 599 m (Ar C=C), 1 496 m (Ar C=C), 1 450 m (CH def.), 1 359 s (SO2–O–), 1 176 s
(SO2–O–). 1H NMR (200 MHz, CDCl3): 7.81 (2 H, d, J = 8.4, 2′-H); 7.36 (2 H, d, J = 8.4, 3′-H);
4.80 (1 H, br s, 4-H); 4.69 (1 H, br s, 4-H); 4.14 (2 H, t, J = 6.8, 1-H); 2.47 (3 H, s, 5′-H); 2.36
(2 H, br t, J = 6.8, 2-H); 1.67 (3 H, s, 5-H). 13C NMR (50.3 MHz, CDCl3): 145.0 (C3), 140.3
(C1′), 133.2 (C4′), 130.0 (C2′), 128.1 (C3′), 113.2 (C4), 68.5 (C1), 36.6 (C2), 22.2 (C5′), 21.5
(C5). MS (CI+, NH3), m/z (rel.%): 258 (M + 18+, 100), 241 (M + 1+, 13), 136 (5), 108 (5), 68 (3).
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744
Braddock, Brown:
4-Brom o-2-m eth ylbut-1-en e (9)
3-Meth ylbut-3-en -1-yl tosylate (24.0 g, 100 m m ol) was added dropwise via a double en ded
n eedle to a solution of vacuum dried LiBr (17.4 g, 200 m m ol) in dry DMF (50 m l) un der ar-
gon at room tem perature. Th e solution was stirred for 24 h , water (200 m l) was added an d
th en extracted with pen tan e (3 × 100 m l). Th e organ ics were wash ed with water (3 × 100 m l),
dried (MgSO4), filtered an d th e solven t evaporated to give a pale yellow oil. Sh ort-path dis-
tillation un der reduced pressure yielded th e title com poun d as a sweet-sm ellin g colourless
oil (11.4 g, 76%), b.p. 100 °C (0.1 m m Hg). IR (th in film ): 3 079 m (sp2 CH), 2 971 s (sp3
CH), 2 938 s (sp3 CH), 1 651 m (C=C), 1 450 s (CH def.). 1H NMR (200 MHz, CDCl3): 4.87
(1 H, br s, 4-H); 4.79 (1 H, br s, 4-H); 3.49 (2 H, t, J = 7.4, 1-H); 2.63 (2 H, br t, J = 7.4, 2-H);
1.76 (3 H, s, 5-H). 13C NMR (50.3 MHz, CDCl3): 142.6 (C3), 112.8 (C4), 40.8 (C1), 30.7 (C2),
21.8 (C5). MS (EI+), m/z (rel.%): 150 (M+, 10), 148 (M+, 9), 137 (6), 109 (11), 69 (C5H+9 , 100),
58 (70).
4-Iodo-2-m eth ylbut-1-en e (10)
3-Meth ylbut-3-en -1-yl tosylate (38.4 g, 160 m m ol) was added dropwise to a solution of so-
dium iodide (48.0 g, 320 m m ol) in aceton e (400 m l) at reflux. A pale yellow precipitate was
form ed im m ediately. Th e m ixture was refluxed for a furth er 2 h an d th en cooled to room
tem perature. Th e in organ ics were solubilised by th e addition of water (500 m l) an d th e
organ ics extracted with pen tan e (2 × 250 m l). Th e com bin ed extracts were wash ed with
brin e, dried (an h ydrous MgSO4), filtered an d evaporated to give a brigh t red oil. Sh ort-path
distillation un der reduced pressure yielded th e title com poun d as a colourless oil (22.5 g,
72%), b.p. 45 °C (0.01 m m Hg). IR (th in film ): 3 077 s (sp2 CH), 2 969 s (sp3 CH), 2 936 s
(sp3 CH), 2 915 s (sp3 CH), 1 651 s (C=C), 1 446 s (CH def.). 1H NMR (200 MHz, CDCl3):
4.88 (1 H, br s, 4-H); 4.77 (1 H, br s, 4-H); 3.28 (2 H, t, J = 7.4, 1-H); 2.60 (2 H, br t, J = 7.4,
2-H); 1.75 (3 H, s, 5-H). 13C NMR (50.3 MHz, CDCl3): 144.1 (C3), 112.5 (C4), 41.8 (C2), 21.6
(C5), 3.4 (C1). MS (EI+), m/z (rel.%): 196 (M+, 3), 127 (55), 69 (C5H+9 , 100).
N-(3-Meth ylbutyliden e)cycloh exylam in e (6)
3-Meth ylbutan al (17.2 g, 200 m m ol) was added dropwise to cycloh exylam in e (19.8 g, 200
m m ol) with stirrin g at 0 °C. Th e m ixture im m ediately turn ed m ilky. Sodium h ydroxide pel-
lets (8.8 g, 220 m m ol) were added, th e h om ogen eous liquid filtered an d distilled to yield th e
title com poun d as a colourless liquid (21.2 g, 63%), b.p. 212–213 °C. For C11H21N (167.3)
calculated: 78.98% C, 12.65% H, 8.37% N; foun d: 78.96% C, 12.46% H, 8.58% N. IR (th in
film ): 2 956 s (sp3 CH), 2 929 s (sp3 CH), 2 855 s (sp3 CH), 2 577 s (sp3 CH), 1 667 m (C=N).
1H NMR (500 MHz, CDCl3): 7.63 (1 H, t, J = 5.4, 1-H); 2.89 (1 H, tt, J = 10.7, 4.2, 1′-H); 2.10
(2 H, dd, J = 7.0, 5.4, 2-H); 1.86 (1 H, tqq, J = 7.0, 6.8, 6.8, 3-H); 1.76 (2 H, br dt, J = 13.2,
3.3, 3′eq-H); 1.63 (3 H, m , 2′eq-H, 4′eq-H); 1.47 (2 H, dq, J = 12.1, 3.1, 2′ax-H); 1.29 (2 H, tq, J =
12.7, 3.3, 3′ax-H); 1.18 (1 H, tq, J = 12.4, 3.2, 4′ax-H); 0.93 (6 H, d, J = 6.8, 4-H, 5-H).
13C NMR (50.3 MHz, CDCl3): 162.4 (C1), 69.8 (C1′), 44.5 (C2), 34.3 (C2′), 26.3 (C3), 25.5
(C3′), 24.7 (C4′), 22.2 (C4, C5). MS (CI+, NH3), m/z (rel.%): 168 (M + 1+, 100), 152 (5), 125
(10), 110 (5).
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Aldehyde Ene Cyclisations
745
(±)-N-(2-Isopropyl-5-m eth ylh ex-5-en yliden e)cycloh exylam in e (11)
Method A: Butyllith ium (2.3 m l, 1.6 m ol l–1 in h exan es) was added to a stirred solution of
diisopropylam in e (0.51 m l, 3.6 m m ol) in dry THF (5 m l) un der argon at –78 °C. Th e pale
straw yellow solution was stirred for 1 h at –78 °C an d th en added via a double en ded n ee-
dle to a stirred solution of N-(3-m eth ylbutyliden e)cycloh exylam in e (6) (0.55 g, 3.3 m m ol) in
THF (10 m l) un der argon at –20 °C. Th e brigh t yellow solution was stirred at –20 °C for 1 h .
A solution of 4-brom o-2-m eth ylbut-1-en e (9) (0.54 g, 3.6 m m ol) in dry THF (5 m l) was
added wh ereupon th e brigh t yellow colour was disch arged. Th e m ixture was allowed to
warm to room tem perature over a period of 2 h , an d th en quen ch ed with water (2 m l). THF
was rem oved un der reduced pressure, an d th e residue partition ed between pen tan e (20 m l)
an d water (20 m l). Th e water layer was extracted with pen tan e (2 × 20 m l), th e com bin ed
organ ics dried (MgSO4), filtered an d th e solven t evaporated to give a dark yellow oil.
1H NMR an alysis of th e crude m ixture sh owed 25% con version to th e title com poun d (11).
Method B: Alkylation of N-(3-m eth ylbutyliden e)cycloh exylam in e (6) with 4-iodo-2-m eth yl-
but-1-en e in place of brom ide. Th e followin g quan tities of reagen ts were used: Butyllith ium
(118 m l, 1.6 m ol l–1 in h exan es); diisopropylam in e (31 m l, 222 m m ol) in THF (120 m l);
N-(3-m eth ylbutyliden e)cycloh exylam in e (6) (28.6 g, 171 m m ol) in THF (100 m l);
4-iodo-2-m eth ylbut-1-en e (10) (47 g, 256 m m ol) in THF (30 m l). Fraction al distillation un -
der reduced pressure afforded th e title com poun d (11) as a colourless liquid (25.0 g, 62%)
b.p. 90-92 °C (0.01 m m Hg). For C16H29N (235.4) calculated: 81.63% C, 12.42% H, 5.95% N;
foun d: 81.27% C, 12.99%H, 5.76% N. IR (th in film ): 3 074 m (sp2 CH), 2 927 s (sp3 CH),
2 856 s (sp3 CH), 1 666 s (C=N), 1 650 m (C=C), 1 450 s (CH def.). 1H NMR (500 MHz,
CDCl3): 7.42 (1 H, d, J = 7.5, 1-H); 4.68 (1 H, br s, 6-H); 4.66 (1 H, br s, 6-H); 2.92 (1 H , tt, J =
10.6, 4.2, 1′-H); 1.95 (3 H, m , 2-H, 4α-H, 4β-H); 1.75 (2 H, br dt, J = 13.2, 3.3, 3′eq-H); 1.74
(1 H, dqq, J = 7.0, 6.9, 6.9, 9-H); 1.69 (3 H, br s, 7-H); 1.64 (4 H, m , 2′eq-H, 4′eq-H, 3β-H);
1.52 (3 H, m , 2′ax-H, 3α-H); 1.30 (2 H, tq, J = 12.7, 3.3, 3′ax-H); 1.24 (1 H, tq, J = 12.4, 3.2,
4′ax-H); 0.93 (3 H, d, J = 6.9, 8-H); 0.90 (3 H, d, J = 6.9, 10-H). 13C NMR (50.3 MHz, CDCl3):
165.3 (C1), 145.7 (C5), 110.0 (C6), 70.0 (C1′), 50.6 (C2), 35.2 (C4), 34.4 (C2′), 30.3 (C9),
27.5 (C3), 25.4 (C3′), 24.6 (C4′), 22.2 (C7), 19.5 (C8), 20.1 (C10). MS (CI+, NH3), m/z (rel.%):
236 (M + 1+, 100), 167 (13).
(±)-2-Isopropyl-2-m eth ylh ex-5-en al (1)
(±)-2-Isopropyl-2-m eth ylh ex-5-en al was prepared usin g th e gen eral procedure of House et
al.19. A two-ph ase m ixture of (±)-N-(2-isopropyl-5-m eth ylh ex-5-en yliden e)cycloh exylam in e
(11) (3.82 g, 16 m m ol) in h exan e (16 m l) an d acetic acid (2.9 g, 48 m m ol) in water (48 m l)
was stirred vigorously at room tem perature for 2 h . Th e water layer was saturated with solid
sodium ch loride an d th e organ ics extracted with dieth yl eth er (3 × 50 m l). Th e com bin ed
organ ics were wash ed with saturated aqueous sodium h ydrogen carbon ate (3 × 100 m l), brin e
an d water. Th e organ ic layer was dried (an h ydrous MgSO4), filtered an d th e solven t evapo-
rated. Purification by flash ch rom atograph y on silica gel (3% eth yl acetate in pen tan e) gave
th e title com poun d as a colourless liquid (1.82 g, 74%). For C10H18O (154.3) calculated:
77.87% C, 11.76% H; foun d: 77.60% C, 12.06% H. IR (th in film ): 3 075 m (sp2 CH), 2 963 s
(sp3 CH), 2 921 s (sp3 CH), 2 837 s (sp3 CH), 2 707 m (O=C–H), 1 724 s (C=O), 1 650 m
(C=C), 1 456 s (CH def.). 1H NMR (500 MHz, CDCl3): 9.66 (1 H, d, J = 3.2, 1-H); 4.74 (1 H,
br s, 6-H); 4.69 (1 H, br s, 6-H); 2.10 (1 H, dddd, J = 9.4, 6.2, 3.6, 3.2, 2-H); 2.03 (1 H, dqq, J =
6.8, 6.8, 6.2, 9-H); 2.02 (1 H, br ddd, J = 14.8, 10.1, 5.5, 4β-H); 1.95 (1 H, br ddd J = 14.8,
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

746
Braddock, Brown:
9.4, 6.6, 4α-H); 1.81 (1 H, dddd, J = 13.6, 9.4, 9.4, 5.5, 3β-H); 1.72 (3 H, br s, 7-H); 1.61 (1 H,
dddd, J = 13.6, 10.1, 6.6, 3.6, 3α-H); 0.99 (3 H, d, J = 6.8, 8-H); 0.98 (3 H, d, J = 6.8, 10-H).
13C NMR (50.3 MHz, CDCl3): 206.1 (C1), 145.3 (C5), 110.7 (C6), 57.5 (C2), 35.5 (C4), 28.2
(C9), 23.6 (C3), 22.2 (C7), 20.1 (C8), 19.5 (C10). MS (CI+, NH3), m/z (rel.%): 172 (M + 18+,
23), 155 (M + 1+, 10), 137 (100), 121 (15), 111 (23), 93 (18), 81 (33), 69 (31).
(±)-2-Isopropyl-5-m eth ylh ex-5-en -1-ol (12)
Sodium boroh ydride (27 m g, 0.6 m m ol) was added in on e portion to
a solution of
(±)-2-isopropyl-2-m eth ylh ex-5-en al (1) (77 m g, 0.5 m m ol) in eth an ol (10 m l). Water (10 m l)
was added after 10 m in followed by careful addition of dilute 1 M HCl (10 m l). Th e organ ics
were extracted with dieth yl eth er (3 × 10 m l), th e extracts com bin ed, dried (an h ydrous
MgSO4), filtered an d th e solven t evaporated to give th e title com poun d as a colourless oil
(78 m g, 100%). IR (th in film ): 3 600–3 100 br s (OH), 3 074 w (sp2 CH), 2 959 s (sp3 CH),
2 943 s (sp3 CH), 2 874 s (sp3 CH), 1 650 m (C=C), 1 454 m (sp3 CH def.), 1 387 m , 1 370 m ,
1 037 m , 886 m . 1H NMR (500 MHz, CDCl3): 4.72 (1 H, br s, 6-H); 4.70 (1 H, br s, 6-H); 3.61
(2 H, m , H-1), 2.09 (1 H, ddd, J = 14.7, 10.9, 5.9, 4α-H); 2.03 (1 H, ddd, J = 14.7, 9.3, 6.1,
4β-H); 1.83 (1 H, dqq, J = 6.9, 6.9, 4.7, 9-H); 1.74 (3 H, br s, 7-H); 1.50 (1 H, dddd, J = 13.8,
10.9, 6.1, 5.0, 4α-H); 1.40 (1 H, dddd, J = 3.8, 9.3, 7.8, 5.9, 4β-H); 1.34 (1 H, ddddd, J = 7.8,
5.0, 5.0, 5.0, 4.7, 2-H); 0.92 (3 H, d, J = 6.9, 8-H); 0.91 (3 H, d, J = 6.9, 10-H). 13C NMR (50.3 MHz,
CDCl3): 146.5 (C5), 110.0 (C6), 63.4 (C1), 46.0 (C2), 35.8 (C4), 27.7 (C9), 25.6 (C3), 22.3
(C7), 19.6 (C8), 19.0 (C10). MS (CI+, NH3), m/z (rel.%): 174 (M + 18+, 7), 157 (M + 1+, 100),
138 (13), 123 (47), 109 (10), 95 (83), 82 (94), 69 (67), 55 (38).
Effect of a Substoich iom etric Am oun t of Dim eth ylalum in ium Ch loride
on (±)-2-Isopropyl-2-m eth ylh ex-5-en al (1)
A solution of dim eth ylalum in ium ch loride in h exan e (0.2 m l, 1 m ol l–1, 20 m ole %) was
added to a stirred solution of (±)-2-isopropyl-2-m eth ylh ex-5-en al (1) (154 m g, 1 m m ol) in
dich lorom eth an e (2 m l) at room tem perature un der argon . Th e colourless solution was
stirred for 16 h an d th en quen ch ed with 1 M sulfuric acid (2 m l). Th e organ ics were ex-
tracted with dich lorom eth an e (3 × 10 m l), com bin ed, dried (an h ydrous MgSO4), filtered an d
th e solven t evaporated to give a pale yellow oil (148 m g). Th e crude m aterial was an alysed
by 1H NMR an d was foun d to con sist of a 1 : 2 : 2 m ixture of un reacted aldeh yde 1, iden tical
with previously prepared m aterial, (±)-2-isopropyl-5-m eth ylh ex-5-en -1-ol (12) an d
(±)-6-isopropyl-3-m eth ylcycloh ex-2-en -1-on e (13) (piperiton e)17 1H NMR (300 MHz, CDCl3):
.
5.83 (1 H, s, 6-H); 2.2–1.2 (6 H, m , 2-H, 3-H, 4-H, 8-H); 1.90 (3 H, s, 7-H); 0.95 (3 H, d, J =
6.7, 9-H); 0.93 (3 H, d, J = 6.7, 10-H).
Effect of th e Alkoxides 14a an d 14c Gen erated Directly from Two Equivalen ts
of (1R*,2R*)-(2) an d (1S*,2R*)-(2-Isopropyl-5-m eth yliden e)cycloh exan -1-ol (3)
on (±)-2-Isopropyl-2-m eth ylh ex-5-en al (1)
A solution of dim eth ylalum in ium in h exan e (0.2 m l, 1 m ol l–1, 0.2 m m ol) was added sepa-
rately to stirred solution s of (1R*,2R*)- an d (1S*,2R*)-(2-isopropyl-5-m eth yliden e)-
cycloh exan -1-ol (2) an d (3) (62 m g, 0.4 m m ol) in dich lorom eth an e (2 m l) at room tem pera-
ture un der argon . Vigorous effervescen ce occurred an d after
1
h
(±)-2-isopropyl-
2-m eth ylh ex-5-en al (1) (154 m g, 1.0 m m ol) was added to th e colourless solution s. After 16 h
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Aldehyde Ene Cyclisations
747
th e m ixtures were quen ch ed with 1 M sulfuric acid (5 m l) an d th e organ ics were extracted
with dich lorom eth an e (3 × 10 m l). Th e com bin ed organ ics were dried (an h ydrous MgSO4),
filtered an d th e solven t evaporated to give yellow oils (203 an d 211 m g respectively). Th e
crude m aterials were an alysed by 1H NMR. Both system s sh owed th e sam e product distribu-
tion : a 3 : 2 : 2 ratio of un reacted aldeh yde 1, (±)-2-isopropyl-5-m eth ylh ex-5-en -1-ol (12) an d
(±)-6-isopropyl-3-m eth ylcycloh ex-2-en -1-on e (13).
Effect of a Substoich iom etric Am oun t of MABR (18)
on (±)-2-Isopropyl-2-m eth ylh ex-5-en al (1)
A solution of trim eth ylalum in ium in toluen e (0.1 m l, 2 m ol l–1, 0.2 m m ol) was added
dropwise to a solution of 4-brom o-2,6-di-tert-butylph en ol (114 m g, 0.4 m m ol) in dich loro-
m eth an e (2 m l) with vigorous effervescen ce at 0 °C un der argon . After 1 h th e red solution
was cooled to –78 °C an d added dropwise to a solution of (±)-2-isopropyl-2-m eth ylh ex-
5-en al (1) (154 m g, 1 m m ol) in dich lorom eth an e (2 m l). Th e solution was stirred for 1 h
an d th en allowed to warm to room tem perature. After 5 days th e m ixture was quen ch ed
with 1 M sulfuric acid (5 m l), th e organ ics were extracted with dich lorom eth an e (3 × 10 m l),
dried (an h ydrous MgSO4), filtered an d th e solven t evaporated to give a dark brown residue.
1H NMR an alysis sh owed th at n o aldeh yde 1 rem ain ed an d a 1 : 1 m ixture of (±)-2-iso-
propyl-5-m eth ylh ex-5-en -1-ol (12) an d (±)-6-isopropyl-3-m eth ylcycloh ex-2-en -1-on e (13) was
obtain ed.
Effect of Ch loroalum in ium Bis(4-brom o-2,6-di-tert-butylph en oxide) (21) (CABR)
on (±)-2-Isopropyl-2-m eth ylh ex-5-en al (1)
Method A: A solu tion of dim eth ylalu m in iu m ch loride in h exan es (1.0 m l, 1 m ol l–1
,
1.0 m m ol) was added dropwise to a solution of 4-brom o-2,6-di-tert-butylph en ol (627 m g,
2.2 m m ol) in dich lorom eth an e (2 m l) at room tem perature un der argon . Effervescen ce oc-
curred an d after 1 h (±)-2-isopropyl-2-m eth ylh ex-5-en al (1) (77 m g, 0.5 m m ol) was added to
th e deep red solution at 0 °C. Th e m ixture was stirred for 0.5 h an d th en worked-up in th e
usual m an n er. Th e crude m aterial was an alysed by 1H NMR.
Method B: As for m eth od A but with a catalytic am oun t (20 m ole %) of CABR. Th e followin g
am oun t of m aterials were used: Dim eth ylalum in ium ch loride (0.2 m l, 1 m ol l–1, 0.2 m m ol),
4-brom o-2,6-di-tert-butylph en ol (125 m g, 0.44 m m ol) an d (±)-2-isopropyl-2-m eth yl-
h ex-5-en al (1) (77 m g, 0.5 m m ol).
RESULTS AND DISCUSSION
Synthesis of (±)-2-Isopropyl-2-methylhex-5-enal (1)
(±)-2-Isopropyl-2-m eth ylh ex-5-en al (1) was syn th esised via alkylation of
N-(3-m eth ylbutyliden e)cycloh exylam in e (6), itself prepared by con den sa-
tion of n eat 3-m eth ylbuten al an d cycloh exylam in e in th e presen ce of so-
dium h ydroxide. Previous work h ad sh own 4-brom o-2-m eth ylbut-1-en e (9)
to be an effective electroph ile for alkylation of th e dian ion of isovaleric
acid18. Brom ide 9 was readily prepared from 3-m eth ylbut-3-en -1-ol (7) via
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

748
Braddock, Brown:
tosylate 8. Attem pted alkylation of im in e 6 with brom ide 7 in THF usin g
lith ium diisopropylam ide (LDA) at –20 °C gave approxim ately 25% of th e
desired product as judged by 1H NMR. Th e rem ain der of th e m aterial was
recovered im in e 6. Ch an gin g th e solven t to 1,2-dim eth oxyeth an e or em -
ployin g N,N′-propylen eurea as a co-solven t gave n o im provem en t in yield.
Deuterium quen ch experim en ts (m eth an ol-d4) sh owed th at essen tially com -
plete deproton ation of im in e 6 h ad occurred at –40 °C. Moreover,
alkylation with 1-brom obutan e, a saturated electroph ile, in THF at –20 °C
gave 83% of alkylated adduct. Th ese experim en ts sh ow th at alkylation an d
elim in ation are com petin g processes, with elim in ation of h ydrogen bro-
m ide m ade m ore facile by th e presen ce of a h om oallylic double bon d.
As an altern ative alkylatin g agen t, 4-iodo-2-m eth ylbut-1-en e (10), also
prepared from 3-m eth ylbut-3-en -1-ol (7), was em ployed. Alkylation of
im in e 6 with 1.3 equivalen ts of LDA an d 1.5 equivalen ts of iodide 10 in
THF resulted in 75% con version to (±)-N-(2-isopropyl-5-m eth yl h ex-5-en y-
liden e)cycloh exylam in e (11) as a m ixture of Z an d E geom etrical isom ers.
Im in e 11 was purified by fraction al distillation un der reduced pressure (b.p.
90–92 °C) an d th e th erm odyn am ically favoured E isom er was obtain ed ex-
clusively as a colourless liquid. Th e aldeh yde fun ction ality was un m asked
by vigorous stirrin g of im in e 11 in a h exan e–aqueous acetic acid m ixture19
for 2 h to give (±)-2-isopropyl-2-m eth ylh ex-5-en al (1) as an an alytically
pure oil after ch rom atograph y. Alcoh ol 12 was obtain ed as a colourless oil
on NaBH4 reduction (Sch em e 2).
H
CH2
O
CH2
N
(iv)
(v)
N
H
H
6
11
1
(vi)
CH2
7; X = OH
8; X = OTs
9; X = Br
10; X = I
CH2
(i)
OH
(ii)
(iii)
X
12
(i) TsCl, Py, 85%; (ii) LiBr, DMF, 76%; (iii) NaI, acetone, reflux, 72%; (iv) LDA, THF, 9 or 10, 62%;
(v) AcOH, H2O, hexane, 74%; (vi) NaBH4, EtOH, 100%
SCHEME 2
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Aldehyde Ene Cyclisations
749
Lewis Acid Catalysed Cyclisations
Man y of th e successful application s of Lewis acid prom otion to en e reac-
tion ch em istry in volve alum in ium com plexes. Th e gen eration of stron g ac-
ids in som e Lewis ch loro-acid-m ediated en e reaction s (e.g. BCl3, TiCl4)
creates side reaction s wh ich are circum ven ted by th e stoich iom etric use of
alkylalum in ium s. Th ey act n ot on ly as Lewis acids but as Brøn sted bases20.
Alcoh ol–alkylalum in ium com plexes form ed in carbon yl en e reaction s de-
com pose rapidly an d irreversibly to gen erate alkan es (m eth an e in th e case
of dim eth ylalum in ium ch loride) an d n on -basic alum in ium alkoxides th at
are stable un til work-up.
Th e sam e feature th at allows alkylalum in ium reagen ts to be used so suc-
cessfully in en e reaction s lim its th eir use to stoich iom etric am oun ts, h ow-
ever. Wh en (±)-1 was treated with 20 m ole % of dim eth ylalum in ium
ch loride at –78 °C, th e reaction proceeded to approxim ately 40% com ple-
tion . An alysis of th e crude reaction m ixture by 1H NMR after acidic
work-up sh owed th at th e cis an d trans cycloadducts 2 an d 3 were form ed in
th e sam e diastereom eric ratio (33 : 1) as wh en a stoich iom etric am oun t of
Lewis acid was used. If th e m ixture was allowed to warm from –78 °C to
room tem perature for 24 h a 1 : 1 m ixture of (±)-12 (38%) an d (±)-6-isopro-
pyl-3-m eth ylcycloh ex-2-en -1-on e (13) (38%) was obtain ed alon g with a
substan tial quan tity of un reacted (±)-1 (22%) an d a trace of cis cycloadduct
2 (2%) (Sch em e 3). Here an d elsewh ere, dilute sulfuric acid was used as th e
proton source in th e work-up procedures described h ere, resultin g in wa-
ter-soluble alum in ium com plexes, an im provem en t on th e oft-described
use of dilute h ydroch loric acid.
O
(ii)
(i)
CHO
1 (60%) + (2 +3) (40%)
1 (22%) + 12 (38%) +
dr: 33 : 1
1
13
(38%)
(i) 20 mole % Me2AlCl, -78ºC; (ii) 20 mole % Me2AlCl, -78ºC r.t.
SCHEME 3
Alcoh ol 12 an d α,β-un saturated keton e 13 result from a Meerwein –
Pon dorff–Verley (MPV) type reaction 21 wh ereby th e m etal cen tre in th e alu-
m in ium bis(alkoxides) 14a–14c gen erated from th e en e cyclisation are suffi-
cien tly deactivated by th e reson an ce stabilisation con ferred from th e
oxygen atom s to preven t furth er en e cyclisation at –78 °C. At elevated tem -
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

750
Braddock, Brown:
peratures aldeh yde 1 is in stead preferen tially reduced to alcoh ol 12 with
con com itan t oxidation of th e boun d alkoxides via tetrah edral alum in ium
com plexes 15 an d 16. Non e of th e expected β,γ-un saturated keton e 17 was
observed an d th e double bon d presum ably sh ifts in to con jugation with th e
keton e un der th e reaction con dition s (Sch em e 4).
O
AlCl
14a; cis,cis
20 mol% Me2AlCl
-78ºC
CHO
1 (60%)
+
2
14b; cis, trans
14c; trans, trans
20% total, major 14a
1
1 , r.t
OCH2R
AlCl
O
OR'
O
1
O
H
1
AlCl
O
(RCH2O)2AlCl
H
H
R
H
R
16
15
H+ w/u
O
R' =
R =
12
1 : 1 ratio
+
13
17
SCHEME 4
Th e relative ratios of th e products in dicate th at little or n o en e
cyclisation occurs on ce th e ch loroalum in ium bis(alkoxide) species 14a–14c
h ave been form ed an d th at th e cycloh exen ol adducts 2 an d 3 act as MPV
reductan ts. MPV type processes are reversible an d do n ot usually proceed to
com pletion with out selective rem oval of on e of th e products or by th e use
of a large excess of reductan t (or both ). In th is case, th e drivin g force wh ere
th e MPV equilibrium essen tially lies com pletely to on e side is th e form ation
of an α,β-un saturated keton e 13 an d a prim ary alcoh ol 12 from secon dary
alcoh ols 2 or 3 an d aldeh yde 1 respectively.
Con firm ation th at th e alum in ium alkoxide 14a was beh avin g as an in
situ MPV reductan t was dem on strated by its direct form ation from two
equivalen ts of cis-cycloh exen ol 2 an d dim eth ylalum in ium ch loride (with
con com itan t m eth an e gen eration ) an d allowin g it to react with 5 equiva-
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Aldehyde Ene Cyclisations
751
len ts of (±)-aldeh yde 1 at room tem perature for 16 h . A sim ilar experim en t
was perform ed with th e alum in ium alkoxide 14c gen erated from
trans-cycloadduct 3. In both cases a 1 : 1 m ixture of alcoh ol 12 (29%) an d
α,β-un saturated keton e 13 (29%) was produced alon g with th e correspon d-
in g am oun t of un reduced aldeh yde 1 (42%). On ly traces of un reacted
1
cycloh exen ols 2 an d 3 were observed in th e H NMR spectra.
Wh en aldeh yde 1 was treated with a catalytic quan tity (20 m ole %) of
m eth ylalum in ium bis(4-brom o-2,6-di-tert-butylph en oxide) (18) (MABR) an
an alogous MPV process occurred an d th e usual 1 : 1 m ixture of alcoh ol 12
an d α,β-un saturated keton e 13 was obtain ed (Sch em e 5). After five days n o
aldeh yde 1 rem ain ed in th e reaction m ixture in dicatin g th at th e
alkoxyalum in ium diph en oxide 19 so produced acts as a fast MPV reductan t
for un reacted aldeh yde 1 gen eratin g alkoxide 20 wh ich in turn is capable of
catalysin g th e en e cyclisation in a rate lim itin g sequen ce. Th e electron -
with drawin g n ature of th e two 4-brom o-2,6-di-tert-butylph en oxide ligan ds
O
O
O
Al(OAr)2
20 mole % MABR 18
+
-40 ºC
20%
80%
19
1
1
12
RCH2O
Al(OAr)2
Al(OAr)2
O
O
H
H
H
O
O
=
ArO
Br
H
R
Ene
slow
MPV
fast
13
RCH2O Al(OAr)2
O
RCH2O Al(OAr)2
20
H
R
SCHEME 5
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

752
Braddock, Brown:
in alkoxide 20 is apparen tly sufficien t to allow furth er, albeit slow, en e
cyclisation .
Hen ce MPV type reaction s occur wh en an alum in ium reagen t can n ot
catalyse th e en e cyclisation of (±)-1 with out th e in terven tion of alkoxide in -
term ediates. Th is perm its a useful probe for th e catalytic effectiven ess of
alum in ium com plexes. If an alum in ium based Lewis acid m ain tain s its
structural in tegrity, th en MPV-type products will n ot be observed an d th e
Lewis acid can be assum ed to be a true catalyst.
Lackin g α-h ydrogen atom s, 4-brom o-2,6-di-tert-butylph en oxide is effec-
tively a spectator ligan d in th e proposed MPV processes occurrin g wh en al-
deh yde 1 is treated with a catalytic am oun t of MABR 18. Th e various
arom atic an d aliph atic alcoh ols in solution com pete for th e alum in ium
bin din g sites via fast proton exch an ge an d dissociation of th e proton ated
species from th e m etal cen tre (Sch em e 6).
ligand
ROH
+
+
R'OH
R'O AlX2
RO AlX2
exchange
proton
R'O AlX2
HOR
R'O AlX2
exchange
H
OR
SCHEME 6
Th e relative pKa values of ph en ols (≈10) an d aliph atic alcoh ols (≈17)
sh ould en sure th at th e two arom atic ligan ds in MABR rem ain boun d to th e
alum in ium m etal cen tre th rough out th e reaction regardless of th e ch em is-
try occurrin g at th e oth er co-ordin ation sites. Th is would en able ph en ols to
act as ligan ds on alum in ium for catalytic turn over of th e en e cyclisation
provided th at alkoxide in term ediates like 19 are preven ted from form in g. If
th e m eth yl group in MABR was exch an ged for a group th at does n ot act as a
Brøn sted base (e.g., ch loride) th en a catalytic reagen t could be en visaged.
Th us dim eth ylalum in ium ch loride was treated with 2 equivalen ts of
4-brom o-2,6-di-tert-butylph en ol at room tem perature in an attem pt to gen -
erate a catalytic version of MABR. Th e resultin g Lewis acid ch loroalu-
m in ium bis(4-brom o-2,6-di-tert-butylph en oxide) (21) (CABR) was treated
with 5 equivalen ts of (±)-1 in dich lorom eth an e at 0 °C.
Th e CABR reagen t 21 was foun d to act as a catalyst: aldeh yde 1 was rap-
idly (<0.5 h ) con verted in to cycloadducts 2 an d 3 with on ly trace am oun ts
of MPV products (<5%) an d sm all am oun ts of un iden tified side products
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Aldehyde Ene Cyclisations
753
(<5%). However, th e diastereom eric ratio of cycloadducts 2 an d 3 resultin g
from th e catalytic use of CABR was foun d to be differen t from th at of MABR
(at a stoich iom etric level) an d th e cis-cycloadduct 2 was produced as th e
m ajor diastereom er in 70% de. Th is was un expected an d several con trol ex-
perim en ts were perform ed in an attem pt to provide a ration ale (Table I).
Th e experim en ts perform ed with MABR at catalytic an d stoich iom etric lev-
els are in cluded in th e table for com parative purposes.
It was foun d th at th e use of CABR at a stoich iom etric level resulted in th e
sam e diastereoselectivity as at a catalytic level. Wh en th e catalytic (en try 6,
Table I) an d stoich iom etric (en try 7, Table I) reaction s with CABR were per-
form ed at –40 °C (see th e literature con dition s for MABR, en try 1, Table I),
th e reaction rates were slower (as expected) but little effect on th e
diastereoselectivities was observed. In deed it was foun d th at MABR could be
used with little loss in diastereoselectivity in stoich iom etric am oun ts at 0 °C
an d th e reaction was com plete with in 0.5 h (en try 3, Table I).
Th ese experim en ts do n ot provide an y clear in sigh t in to th e dram atic loss
of trans-cycloadduct 3 diastereoselectivity wh en CABR m ediates th e en e
cyclisation of aldeh yde 1 rath er th an MABR. Th e lack of sign ifican t quan ti-
ties of MPV products suggests th at alcoh olysis of th e alum in ium –ch lorin e
bon d is n ot a m ajor process. However, it seem s un likely th at th e catalyti-
TABLE I
Diastereom eric ratios (2 : 3) of products of cyclisation of aldeh yde 1 depen din g on th e Lewis
acid used
En try
Lewis acid
Mole %
T, °Ca
Reaction tim e, h
2 : 3b
1
2
3
4
5
6
7
18
18
18
21
21
21
21
200
20
–40
–40–0
0
2
5:95
96
MPV
200
20
<0.5
<0.5
<0.5
6d
7:93
0
81:19c
82:18c
77:23c
79:21c
200
20
0
–40
–40
200
1
a
b
All experim en ts perform ed in dich lorom eth an e with 0.5 m m ol aldeh yde 1. As judged by
in tegration of th e 1H NMR reson an ces at δH 4.12 an d 3.51 ppm for th e cycloadducts 2 an d 3
respectively in th e 1H NMR spectrum of th e crude reaction m ixture. Traces of MPV-type
c
d
products were observed. Approxim ately 85% com plete after th is tim e.
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

754
Braddock, Brown:
cally active species h as a related structure to th at of MABR. On th is basis it
is ten tatively suggested th at a disproportion ation process via a dim eric
species of the type 22 occurs to som e extent generating the relatively powerful
but m uch less bulky Lewis acid dichloroalum inium 4-brom o-2,6-di-tert-butyl-
phenoxide (23) th at is respon sible for catalysis. Th e oth er product of th is
disproportion ation reaction , alum in ium tris(4-brom o-2,6-di-tert-butyl-
ph en oxide) (24) would n ot be expected to act readily as a catalyst both on
steric an d electron ic groun ds (Sch em e 7).
Ar
O
ArO
Al Cl
ArO
ArO
Al
ArO
Cl
(ArO)3Al
+
ArOAlCl2
2
Al
Cl
24
23
OAr
21
22
ArO = 4-bromo-2,6-di-tert-butylphenoxide
SCHEME 7
SUMMARY AND CONCLUSIONS
Th e application of en e cyclisation ch em istry to un saturated aldeh ydes, fol-
lowin g Yam am oto’s work, is successful at th e stoich iom etric level wh en alu-
m in ium -based Lewis acids are em ployed. In earlier work we h ad em ployed
deuterium labelled reactan ts in order to defin e th e stereoch em ical course of
cyclisation , an d proposed a gen eral m odel to accoun t for results described
in th e literature. Here th e attem pts m ade to m ove from stoich iom etric
ch em istry to catalysis are described; th ese proved to be successful, with on e
im portan t proviso. Part of th e value of th e Yam am oto procedure is th at th e
product can be form ed with eith er relative con figuration at th e two adja-
cen t stereogen ic cen tres. Th is is a con sequen ce of th e fact th at th e
six-m em bered rin g tran sition -state for cyclisation can be ch air-like, with a
sm all Lewis acid givin g 2 or boat-like with a bulky on e (MABR) givin g 3. In
turn th is provides a sen sitive test for th e n ature of th e catalyst, wh ich is re-
vealin g h ere. Alth ough sign ifican t turn over is observed in several cases, it is
associated with low steric dem an ds in th e catalyst. Th is is even true in th e
case wh ere CABR is th e ligan d, an d in dicates th at th e true catalyst is
part-dissociated. Th is will clearly provide a lim itation in attem pts to de-
velop alum in ium -based Lewis acids for asym m etric catalysis of th e en e reac-
tion .
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Aldehyde Ene Cyclisations
755
We thank EPSRC and Quest International for joint support of a Studentship to D. C. B. under the
CASE Scheme, and Dr Ch. S. Sell for his interest and support. Mrs E. McGuinness made excellent con-
tributions to NMR.
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