Planar chiral PHANOLs as double hydrogen bonding donor organocatalysts: Synthesis and catalysis

Article abstract of DOI:10.1002/adsc.200404065

4,12-Dihydroxy[2.2]paracyclophanediol (PHANOL; 1), and its para-substituted derivatives 2, 5 and 7, were found to catalyse Diels-Alder cyclo-additions of α,β-unsaturated aldehydes or ketones with dienes and/or epoxide ring opening reactions with amines. The mode of catalysis by the PHANOLs is via double hydrogen bonding to the two sp² lone pairs of a carbonyl group or the two lone pairs of the epoxide. The order of activity of the PHANOLs for catalysis of the Diels-Alder reaction essentially correlates with the expected hydrogen-bond donor strength based on the degree of electron-withdrawing capability of the group(s) in the para position. In contrast, ortho-substituted PHANOLs 10, 11 and 14 were not active as catalysts due to steric interference with the double hydrogen bonding mode. ¹H NMR and IR spectral data for the various PHANOLs are discussed in support of the proposed double hydrogen bond mode.

Full text of DOI:10.1002/adsc.200404065

FULL PAPERS
Planar Chiral PHANOLs as Double Hydrogen Bonding Donor
Organocatalysts: Synthesis and Catalysis
D. Christopher Braddock,a,* Iain D. MacGilp,b Benjamin G. Perrya
a
Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK
Fax: (þ44)-207-594-5805, e-mail: c.braddock@imperial.ac.uk
b
GlaxoSmithKline, Synthetic Chemistry, Chemical Development Division, Gunnels Wood Road, Stevenage, Hertfordshire,
SG1 2NY, UK
Received: March 3, 2004; Accepted: July 2, 2004
Abstract:
4,12-Dihydroxy[2.2]paracyclophanediol capability of the group(s) in the para position. In con-
(PHANOL; 1), and its para-substituted derivatives trast, ortho-substituted PHANOLs 10, 11 and 14 were
2, 5 and 7, were found to catalyse Diels–Alder cyclo- not active as catalysts due to steric interference with
1
additions of a,b-unsaturated aldehydes or ketones the double hydrogen bonding mode. H NMR and
with dienes and/or epoxide ring opening reactions IR spectral data for the various PHANOLs are dis-
with amines. The mode of catalysis by the PHANOLs cussed in support of the proposed double hydrogen
is via double hydrogen bonding to the two sp2 lone bond mode.
pairs of a carbonyl group or the two lone pairs of
the epoxide. The order of activity of the PHANOLs
for catalysis of the Diels–Alder reaction essentially Keywords: Diels–Alder; double hydrogen bonding;
correlates with the expected hydrogen-bond donor epoxides; organic catalysis; [2.2]paracyclophane;
strength based on the degree of electron-withdrawing PHANOL
Introduction
ble of activating 1,2-diketones (complex III, Figure 1)
for Diels–Alder reactions,[6] and a sulfonamide has
The use of hydrogen bonding to create and stabilise been used to accelerate the addition of pyrrolidine to
ground state architectures is ubiquitous in supramolecu- 2(5H)-furanone, presumably via complex IV (Fig-
lar chemistry.[1] Arguably, the ultimate example of the ure 1).[7] A second category aims for a more generic sol-
utility of hydrogen bonding to assemble extended struc- ution by forming multiple hydrogen bonds to a single ac-
tures is the case of the base-paired DNA double helix.[2] ceptor atom.[8] Specifically, the aim is to use a double hy-
However, the activation of substrates by the formation drogen bond donor with the correct spatial orientation
of temporary hydrogen bonds (i.e., catalytically) be- to be able to form two hydrogen bonds to the two sp2
tween a hydrogen bond donor and a hydrogen bond ac- lone pairs of a carbonyl group (complex V, Figure 1).
ceptor – in particular, the explicit activation of a carbon- Such an arrangement was first demonstrated crystallo-
yl group by a “designer” hydrogen bond donor – has graphically by Hine, who showed that 1,8-biphenylene-
been much less explored. Clearly, this approach has par- diol forms two strong hydrogen bonds to an electron-
allels with the activation of a carbonyl group by a Lewis rich carbonyl group (complex VI, Figure 1).[9] In this ad-
acid and their relative merits have been excellently sum- duct the two components are essentially co-planar, the
marised in a recent review.[3] Progress in the field[3–14] has two O H···O bond lengths and angles are essentially
À
focused on the use of multiple hydrogen bonding for the identical at 2.545 (3) Š and 2.548 (3) Š, and 177 (3)8
obvious reason of increased activation and two distinct and 174 (3)8, respectively. The first X-ray crystallo-
categories are emerging. In one category, the use of graphic evidence for a 1:1 adduct with two intermolec-
matched hydrogen bond donors and acceptors creates ular hydrogen bonds to a simple ketone was reported
an activated assembly for further reaction. For example, later by Saied (complex VII, Figure 1).[10] However, un-
Schreiner has employed a thiourea (25 mol % loading) til recently there had been only one report of such dou-
to activate oxazolidinones (complex I, Figure 1) for ble hydrogen bonding to a carbonyl group in order to
Diels–Alder reactions.[4] Philp has shown that a diami- promote catalysis.[11] Kelly showed that a derivative of
dopyridine (100 mol %) activates maleimide (complex biphenylenediol (40–50 mol %) could activate a,b-un-
II, Figure 1) for 1,3-dipolar cycloadditions.[5] Göbel re- saturated aldehydes and ketones for Diels–Alder reac-
ported that amidinium ions (25–100 mol %) were capa- tions, presumably via a complex of the type V (Figure 1)
Adv. Synth. Catal. 2004, 346, 1117–1130
DOI: 10.1002/adsc.200404065
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1117

D. Christopher Braddock et al.
FULL PAPERS
by analogy with Hineꢁs work. Schreiner has also recently
reported the use of thioureas for the catalysis of Diels–
Alder reactions where such a double hydrogen bonding
mode is proposed.[12] From an asymmetrical catalysis
perspective the use of a double hydrogen bonding inter-
action to the oxygen of a carbonyl group as in complex V
(Figure 1) is attractive since it removes the conforma-
tional ambiguities associated with the single point bind-
ing of traditional Lewis acid-activated carbonyls (com-
plex VIII, Figure 1). The first two examples using chiral
double hydrogen bonding catalysts were reported inde-
pendently by our group[13] and Rawalꢁs group.[14] Rawal
et al. demonstrated excellent enantioselectivities and
activities in the asymmetric hetero-Diels–Alder reac-
tion between aldehydes and electron-rich dienes using
TADDOLs as double hydrogen bonding catalysts. We
chose to study the Diels–Alder reaction of a,b-unsatu-
rated aldehydes and ketones with various dienes using
planar chiral 4,12-dihydroxy[2.2]paracyclophanes
(PHANOLs)[15] as double hydrogen bonding catalysts.
Herein we report these studies in full. We also report
on the ability of PHANOLs to activate epoxides to nu-
cleophilic ring opening by double hydrogen bonding to
the two lone pairs of an epoxide (complex IX, Fig-
ure 1).[16]
Results and Discussion
Catalyst Design
The selection of PHANOLs as potential double hydro-
gen bonding catalysts was driven by the inherent planar
chirality of 4,12-disubstituted [2.2]paracyclophanes, and
an estimated phenolic separation of ca. 4.1 Š based on
in-house molecular modelling. This compares with a
phenolic separation of ca. 4.0 Š in the biphenylenediol
Figure 1. Hydrogen bonded complexes.
systems where X-ray crystallographic evidence for dou- bond donors. para-Substituted (“rear-face” functional-
ble hydrogen bonding has been secured.[9] Additionally, ised) PHANOLs should maximise this effect without
we considered it possible to introduce other substitu- perturbing the sterics of the binding site. ortho-Substitu-
tents variously at the ortho and para positions of the tion (“front-face” functionalisation) would allow us to
PHANOL to modulate activity, enantioselectivity and/ explore the steric effects and was expected to create a
or solubility as necessary (vide infra). The synthesis of “chiral pocket”. Substitution in either position should
the parent PHANOL, 4,12-dihydroxy[2.2]paracyclo- allow for the tuning of solubility. Accordingly, we target-
phane, as a racemate, had previously been reported by ed the synthesis of several PHANOLs with electron-
Cram in 1969[17] (although it was characterised as its di- withdrawing groups in the para position, and also or-
methyl ether) and the above factors were deemed suffi- tho-alkyl substituted PHANOLS.
cient precedents to instigate our studies in this area.
It was considered that there are three major param-
eters that would influence the catalytic prowess of sub- Synthesis
stituted PHANOLs: solubility, hydrogen bonding abili-
ty and “expression of chirality” around the binding site. Both hands of enantiopure PHANOL 1[15] and racemic
The degree of hydrogen bonding – within a given series 7,15-dinitroPHANOL 2[13] are available through our
of PHANOLs – was expected to mirror pKa values, and previously published procedures (Scheme 1).
hence electron-withdrawing groups on the aromatic ring
should increase their capability to be good hydrogen droxy[2.2]paracyclophane 5 and (Æ)-4,12-dihydroxy-
“Rear-face” functionalised (Æ)-7-Bromo-4,12-dihy-
1118
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1117–1130

Planar Chiral PHANOLs as Organocatalysts
FULL PAPERS
Scheme 1. Synthesis of PHANOLs 1 and 2.
Scheme 3. Synthesis of PHANOLs 10, 11 and 14.
Rozenberg has demonstrated the ortho-selective Fries
rearrangement of O-acyl-4-hydroxy[2.2]paracyclo-
phanes to give 5-acyl-4-hydroxy[2.2]paracyclophanes
with TiCl4, or by direct acylation of the phenol with
the corresponding acid chloride also mediated by
TiCl4.[18] Treatment of PHANOL 1 with valeroyl chlor-
ide (a representative acyl grouping) and TiCl4 in reflux-
ing dichloromethane was found to give monoacyl ester
8, presumably via double O-acylation and subsequent
ortho-selective mono-Fries rearrangement (Scheme 3).
Evidently, the desired second rearrangement is disfav-
oured by the transannular electron-withdrawing effect
of the newly installed acyl grouping. The resulting hy-
Scheme 2. Synthesis of PHANOLs 5 and 7.
7,15-di(N,N-diethyl)sulfonyl[2.2]paracyclophane 7 were droxyacyl motif in 8 may also act to chelate titanium:
synthesised as follows (Scheme 2). heightening the electron-withdrawing effect. Double
Attempted double aromatic electrophilic bromina- acylation was achieved by direct treatment of PHANOL
tion of (Æ)-diacetate 3[15] with wet tetrabromocyclohexa- with valeroyl chloride and TiCl4 in refluxing 1,2-di-
dienone (TBCO) gave instead bromodienone 4 in good chloroethane to give diacylPHANOL 9. With these pro-
yield. This can be considered as a “trapped Wheland in- cedures in hand a small library of potential double hy-
termediate” where the loss of the evidently sterically drogen bonding catalysts can be generated: Double
shielded proton to a base is slow compared with compet- Clemmensen reduction of diketone 9 provided “front-
itive deacylation with H2O acting as the nucleophile. To face” functionalised 4,12-dihydroxy-5,13-dipentyl[2.2]-
the best of our knowledge this is the first example of a 4- paracyclophane 10. Sodium borohydride reduction of
bromodienone where the other group in the 4-position is diketone 9 gave monoolefin 11 as the major product,
a hydrogen atom. The dienone could be rearomatised to where a curious aromatic deacylation has also oc-
the corresponding monobromoacetate by treatment curred.[19] 4,12-Dihydroxy-5-ethyl[2.2]paracyclophane
with DBU, and subsequent acetate cleavage with meth- 14 was synthesised via the application of mono-Fries
anolic NaOH delivered 7-bromoPHANOL 5. Bissulfon- rearrangement conditions to PHANOL 1 with acetyl
amide 7 was prepared by double chlorosulfonation of di- chloride giving ketoester 12. Ester hydrolysis to ketone
acetate 3 to give bissulfonyl chloride 6, followed by heat- 13 and subsequent Clemmensen reduction furnished 14.
ing with diethylamine in DMF solution. PHANOLs 5 4,16-Dihydroxy[2.2]paracylophane 15[17] was prepared
and 7 were prepared as racemates, but the single enan- by treatment of commercially available [2.2]paracylo-
tiomers should be available by application of the above phane with lead tetraacetate in TFA[20] followed by basic
procedures to the bisacetates derived from either (R)- or hydrolysis (Scheme 4).[13] This compound represents a
(S)-PHANOL[15] separately.
control PHANOL where the two hydroxy groups have
Adv. Synth. Catal. 2004, 346, 1117–1130
asc.wiley-vch.de
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1119

D. Christopher Braddock et al.
FULL PAPERS
Scheme 4. Synthesis of PHANOL 15.
Scheme 6. Diels–Alder reactions catalysed by PHANOL 1.
ation of Diels–Alder reactions of a,b-unsaturated alde-
hydes with a representative diene (cyclopentadiene 18).
We propose that this occurs by double hydrogen bond-
ing of PHANOL to the carbonyl group of the dienophile
thus lowering the energy of thedienophile LUMO as per
classical Lewis acids. The observation that the endo:exo
ratios are enhanced is also consistent with this analysis.
However, attempts to directly measure the extent of in-
teraction of PHANOL 1 with a given carbonyl group
were thwarted by its sparingly soluble nature in solvents
Scheme 5. Synthesis of polymer-supported PHANOL 17.
a pseudo-para relationship and should not be able to such as dichloromethane, chloroform and hexane.[23]
bind to carbonyl groups in a double hydrogen bonding Thus in the experiments described above, PHANOL 1
mode.
was only partially solubilised in the reaction mixture.
A polymer-bound PHANOL 17 was also prepared by Further, it was found that dinitroPHANOL 2 was com-
diazo coupling of an excess of the dilithio salt of PHA- pletely insoluble under these conditions and no signifi-
NOL 1 with the solid-supported diazonium salt 16, the cant increase in formation of cycloadduct 20 (11%,
latter recently reported by Brase et al. (Scheme 5).[21] 0.5 h) was observed in its attempted use in the Diels–Al-
The loading of the resulting dark-red resin 17 was calcu- der reaction of cyclopentadiene 18 with acrolein 19. Sul-
lated as 0.92Æ0.9 mmol/g.
fonamide 7 was found to be sparingly soluble in chloro-
form, and when used at a nominal 10 mol % loading was
found to give a 25% conversion to the cycloadduct 20 in
the benchmark Diels–Alder reaction (7:1; endo:exo).
Compared to the 20% conversion obtained with PHA-
Diels–Alder Catalysis
Initial catalyst testing utilised 10 mol % PHANOL 1 as NOL 1, this result is consistent with increased hydrogen
a catalyst in the Diels–Alder reaction between a 1:1 bonding capability of the PHANOL 7 due to the strong-
mixture of cyclopentadiene 18 and acrolein 19 in chloro- ly electron-withdrawing nature of the two para-sulfon-
form solution at room temperature (Scheme 6). Com- amide substituents. However, the increase in conversion
pared to the control experiment where a 10% conver- is only modest. This may be attributed to the relative in-
sion to the desired cycloadduct 20 had occurred in solubility of sulfonamide 7 (i.e., the true – homogeneous
0.5 h without catalyst, it was found that the presence of – catalyst loading may be much reduced than the nomi-
10 mol % PHANOL 1 resulted in a 20% conversion. nal 10 mol % added). Alternatively, it may indicate that
The endo:exo ratio of 20 was found to increase from the sulfonamide groups are not fully conjugated to the
4:1 in the control experiment to 5.5:1 in the presence aromatic ring where steric repulsion with either the ben-
of PHANOL 1. Further Diels–Alder reactions were car- zylic position or the other sulfonamide moiety forces the
ried out under comparable conditions with crotonalde- groups to twist out of plane (i.e., steric inhibition of res-
hyde 21 and methacrolein 23 as dienophiles in the onance).
Diels–Alder reactions with cyclopentadiene. The lower
It is evident that solubility issues are particularly im-
reactivity of these electrophiles, however, necessitated portant in this system. We were therefore pleased to
longer reaction times (70 h).[22] In both cases the extent find that all three of the ortho-alkyl PHANOLs 10, 11
of formation of the corresponding cycloadducts 22 and and 14 displayed complete solubility in chloroform at
24 was found to increase from 4% to 10% and 24% to a 10 mol % loading. However, within the limits of exper-
37%, respectively, compared to the control reaction in imental error it was found that they displayed no catalyt-
the presence of 10 mol % PHANOL. The endo:exo ra- ic activity for the benchmark Diels–Alder reaction of cy-
tios of cycloadducts 22 and 24 were also found to in- clopentadiene 18 with acrolein 19 giving 13%, 11% and
crease from 2:1 to 3.5:1 and 1:6 to 1:5, respectively.
10% conversions to cycloadduct 20, respectively. We
The above experiments demonstrate that catalytic propose that these PHANOLs are unable to form dou-
quantities of PHANOL 1 are capable of modest acceler- ble hydrogen bonds to a carbonyl group due to steric in-
1120
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1117–1130

Planar Chiral PHANOLs as Organocatalysts
FULL PAPERS
essentially unchanged compared to the control experi-
ment.
Further Diels–Alder reactions are shown in Table 1.
The use of either a,b-unsaturated aldehydes (entries
1–6) or ketone (entry 7) as dienophiles resulted in the
increased formation of the respective cycloadducts in
the presence of catalytic quantities of PHANOLs 1 or
2, but PHANOL 1apparently did not activate an a,b-un-
saturated ester (entry 8). These results are consistent
with those of Kelly who found that while a,b-unsaturat-
ed aldehydes and ketones could be activated by 1,8-bi-
phenylenediol for Diels–Alder reactions, a,b-unsaturat-
ed esters were not.[11a] As seen for the Diels–Alder reac-
Scheme 7. Diels–Alder reaction catalysed by PHANOLs.
terference by the ortho-alkyl substituent and therefore tion of cyclopentadiene with acrolein (Table 1, entry 1)
do not catalyse the reaction. This suggestion is support- using PHANOL 1, the endo:exo ratio of a given cycload-
ed by a comparison of IR and 1H NMR data of various duct increases compared to the control reaction (Ta-
members of the PHANOL family (vide infra).
ble 1, entries 2, 5, 6 and 7), but with dinitroPHANOL
In light of the above results it was considered that suc- 2 the observed endo:exo ratios are somewhat less pre-
cessful catalysis of Diels–Alder reactions could instead dictable.
be carried out in neat diene-dienophile mixtures. The re-
(R)-PHANOL[15] was examined with respect to its
action betweenneat cyclopentadiene 18 and crotonalde- ability to catalyse the Diels–Alder reaction of crotonal-
hyde 21 was chosen as the Diels–Alder reaction to study dehdye 21 with cyclopentadiene 18 enantioselectively.
initially since the background rate of reaction is very However, after analysis of the resulting cycloadducts
slow at room temperature (<1%, 15 h) (Scheme 7). by diastereomeric imine formation with a-methylben-
PHANOL 1 was indeed found to be soluble in this zylamine, the diastereomeric excesses, and hence the
neat Diels–Alder reaction mixture, and dinitroPHA- enantioselection in the Diels–Alder reaction were
NOL 2 displayed an improved solubility profile. The found to be minimal (<5%). It is reasonable to assume
use of 10 mol % PHANOL 1 gave a 17% conversion that the preferred conformation of a given PHANOL-
(15 h) to the desired cycloadduct 22, and the use of bound a,b-unsaturated aldehyde or ketone is s-trans
10 mol % dinitroPHANOL 2 resulted in a 37% conver- by analogy with complexes formed with Lewis acids
sion in the same time period. PHANOL 7 proved to be (which generally bind anti to the double bond).[27]
insoluble in this reaction mixture, and therefore an in- With this in mind, the minimal enantioselectivities ob-
crease in conversion was not observed. The use of served are presumably a reflection of poor “expression
4,16-dihydroxy[2.2]paracyclophane 15, which displayed of chirality” by the planar-chiral PHANOL backbone
good solubility in the reaction mixture, showed no sig- to the region of space where the dienophile is bound
nificant increase in the quantity of cycloadduct 22 gener- for reaction in the s-trans conformation. In marked con-
ated, reinforcing the argument that the catalytic effect of trast to a,b-unsaturated aldehydes, a,b-unsaturated es-
PHANOL and its derivatives is due to a double hydro- ters are known to bind Lewis acids syn to the double
gen bonding effect. Interestingly, we note that the use bond so as to preserve the preferred s-cis geometry of
of BINOL 25 as a potential catalyst gave a 9% conver- the ester unit.[27] It follows that if PHANOL 1 can only
sion to the desired cycloadduct, implying that the double make one hydrogen bond to the syn lone pair of the es-
hydrogen bonding mode is in operation here too.
The relative difference in reactivity between 4,16-di-
ter, then little activation will be observed.
Recycling of PHANOLs from a given Diels–Alder re-
hydroxy-substituted PHANOL 15 and the 4,12-dihy- action was considered possible via basic work-up to se-
droxy-substituted PHANOLs 1 and 2 is consistent quester the catalyst as a salt in the aqueous phase, fol-
with a double hydrogen bonding mode to the carbonyl lowed by re-acidification and extraction. Representa-
group possible in 1 and 2 but not in 15, and with the in- tive results of such recycling are shown in Table 2 for
creased acidity (and hence hydrogen bonding ability) the Diels–Alder reaction of cyclopentadiene with croto-
of dintroPHANOL 2compared toPHANOL 1. Further, naldehdye using 10 mol % dinitroPHANOL 2.
in line with our proposal that carbonyl activation occurs
Inspection of the results in Table 2 shows that recycle
via double hydrogen bonding tothe carbonyl group, thus is indeed possible and that catalytic activity holds-up
lowering the LUMO of the dienophile as per classical from run to run although the mass of catalyst recovered
1
Lewis acids, the endo:exo ratio of the cycloadduct in- diminishes. Pleasingly, H NMR analysis of the recov-
creased from 1.9:1 in the control experiment to 3.8:1 ered catalyst between runs showed no decomposition
when employing catalytic quantities of 1. However, de- or contaminating impurities.
spite the significant rate acceleration with 2 (>30-fold)
The use of solid-phase derivative 17 (Scheme 5) was
as the catalyst, the endo:exo ratio in this case remained explored as a catalyst for Diels–Alder reactions. Under
Adv. Synth. Catal. 2004, 346, 1117–1130
asc.wiley-vch.de
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1121

D. Christopher Braddock et al.
FULL PAPERS
Table 1. Catalytic Diels–Alder reactions using PHANOLs 1 and 2.
Entry[a]
1[c]
Diene
Dienophile
Cycloadduct
Time
15 h
Control[b]
1[b]
2[b]
<1 (1.9: 1)
17 (3.8: 1); 17
37 (1.9: 1); 37
2[c]
3[c]
4[d]
10 min
15 h
35 (4.3: 1)
79 (5.6: 1); 2.3
36; 3.0
74 (6.2: 1); 2.1
40; 3.3
12
15 h
3[e]
8[e]; 2.7
13[e]; 4.3
5[c]
15 h
15 h
34 (1: 4.7)
2 (1.1: 1)
74 (1: 4.5); 2.2
5 (1.8: 1); 2.5
77 (1: 6.5); 2.2
7 (1.5: 1); 3.5
6[c]
7[f]
10 min
16 h
26 (6.6: 1)
70[g]
72 (14: 1); 2.8
73[g]; 1.0
–
–
8
[a]
All reactions carried out with 10 mol % catalyst and a 1: 1 ratio of diene:dienophile at room temperature
[b]
Percentage conversion as determined by integration of the relevant signals in the 1H NMR spectrum (CDCl3 solvent). The
figures in parentheses give the endo:exo ratio respectively. The italicised figure after the semi-colon gives the acceleration
factor.
[c]
[d]
[e]
[f]
[g]
For characterization of this cycloadduct see Ref.[24]
For characterization of this cycloadduct see Ref.[25]
endo only.
For characterization of this cycloadduct see Ref.[26]
endo:exo ratio not determined.
Table 2. Recycling of dinitroPHANOL 2.
characteristic change in the endo:exo ratio. However,
because of the need to swell the resin using excess diene
the extent of the background Diels–Alder reactions in-
creased.
Run[a]
Conversion[a]
Recovery [%]
1
2
3
50
58
45
100
90
81
Epoxide Ring-Opening Catalysis
[a]
All reactions carried out with 10 mol% PHANOL 2 and a
1: 1 ratio of cyclopentadiene:crotonaldehyde at room tem-
perature for 96 h.
Percentage conversion as determined by integration of the
relevant signals in the 1H NMR spectrum (CDCl3 sol-
vent).
On the basis of Hineꢁs report that biphenylenediol was
significantly able to accelerate the nucleophilic ring-
opening of phenyl glycidyl ether with diethylamine,[16b]
we also investigated the ability of various PHANOLs
to activate epoxides to nucleophilic attack by amines.
Here, we postulate a model invoking double hydrogen
[b]
neat conditions, it was found that an excess of diene (typ- bonding to the two lone pairs of the epoxides (Complex
ically 10-fold) was required in order to swell the resin. IX, Figure 1). Using an enantiopure catalyst raises the
The results are tabulated below (Table 3).
The results demonstrate that solid-supported PHA- give 1,2-amino alcohols as single enantiomers.
NOL 17 is also capable of catalysing Diels–Alder reac- Initial experiments proved promising. The neat reac-
tions of a,b-unsaturated aldehydes with dienes, with a tion of diethylamine 26 with (Æ)-styrene oxide 27 in
possibility of asymmetric meso-epoxide openings to
1122
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1117–1130

Planar Chiral PHANOLs as Organocatalysts
FULL PAPERS
Table 3. Diels–Alder reactions with solid-phase catalyst 17.
Entry[a]
Diene
Dienophile
Cycloadduct
Time
Control[b]
48 (3.2: 1)
17[b]
1
10 min
73 (5.1: 1); 1.5
2
3
15 h
18 h
5 (1.7: 1)
3[c]
19 (3.8: 1); 3.8
5[c]; 1.7
5
18 h
48 (1: 4.6)
73 (1: 5.2); 1.5
[a]
All reactions carried out with 10 mol % solid-supported PHANOL 17 and a 10: 1 ratio of diene:dienophile at room tem-
perature for 96 h.
[b]
[c]
Percentage conversion as determined by integration of the relevant signals in the 1H NMR spectrum (CDCl3 solvent). The
figures in parentheses give the endo:exo ratio respectively. The italicised figure after the semi-colon gives the acceleration
factor relative to the control experiment.
endo only.
Scheme 8. Epoxide ring-opening catalysed by PHANOL 1.
Scheme 9. Epoxide ring-opening catalysed by PHANOLs.
the presence of 10 mol % PHANOL 1 at room temper- ide (Table 4, entry 3) and cyclohexene oxide (Table 4,
ature for 24 h resulted in 50% conversion to the desired entry 4). It is evident that morpholine is not sufficiently
ring-opened products 28 and 29 (3:1) (Scheme 8). With nucleophilic to attack anyof the selected epoxides under
no catalyst present no ring-opening was observed under these conditions, and no ring opening was observed in
the same conditions. Further, the use of phenol the control experiments either. These results can be
(10 mol %) as a potential monodentate activator of the readily rationalised on the basis of relative nucleophilic-
epoxide resulted in less than 1% conversion to the ity where the order is piperidine>diethylamine>mor-
ring-opened products. These experiments are consistent pholine. An interesting feature of these PHANOL-cat-
with activation of the epoxides by a double hydrogen alysed reactions of styrene oxide is that the epoxide is
bonding mode.
preferentially attacked at the terminus of the epoxide.
To further explore the ability of PHANOL 1 to cata- This suggests that the use of PHANOL for epoxide
lyse epoxide ring openings with amines, we elected to openings is analogous to activation by a relatively non-
screen some representative epoxides and amines. Styr- powerful Lewis acid and the lack of a strongly carboca-
ene oxide, cis-stilbene oxide and cyclohexene oxide tionic centre in the transition state.[31] The success of
were selected as representative epoxides and diethyl- opening cyclohexene oxide with piperidine as catalysed
amine, piperidine and morpholine were selected as rep- by PHANOL 1 where there is no background reaction
resentative amines. The reactions were run neat with without catalyst, proffered itself as an ideal test system
10 mol % PHANOL 1 and 1.5 equivalents of amine (Ta- for any enantioselectivity using enantiopure catalyst.
ble 4).
Accordingly, the reaction was allowed to proceed to
Inspection of the results immediately reveals that ter- completion as catalysed by 10 mol % (R)-PHANOL.
minal epoxides are more reactive to ring opening than Chiral HPLC analysis of the product revealed it to be es-
1,2-disubstituted meso-epoxides. While diethylamine sentially a racemate, however.
and piperidine both attack styrene oxide (Table 4, en-
The use of catalytic quantities of PHANOLs 2, 5 and 7
tries 1 and 2), only piperidine reacts with cis-stilbene ox- was explored for the ring opening of cyclohexene oxide
Adv. Synth. Catal. 2004, 346, 1117–1130
asc.wiley-vch.de
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1123

D. Christopher Braddock et al.
FULL PAPERS
Table 4. Ring opening of epoxides with amines catalysed by PHANOL 1.
Run[a]
1[c]
Epoxide
Amine
Product
Time
24 h
Control[b]
0
1[b]
50 (3.4: 1)
2[c]
19 h
49 (14: 1)
>95 (4: 1)
3[d]
7 days
32 h
14
0
36
50
4[e]
[a]
All reactions carried out neat with 10 mol % PHANOL 1 and a 1.5: 1 ratio of amine:epoxide at room temperature.
Percentage conversion as determined by integration of the relevant signals in the 1H NMR spectrum (CDCl3 solvent). The
figures in parentheses give the ratio of “terminus” to “internal” attack, respectively;
For characterization of this amino alcohol see Ref.[28]
[b]
[c]
[d]
[e]
For characterization of this amino alcohol see Ref.[29]
For characterization of this amino alcohol see Ref.[30]
with piperidine for comparison with PHANOL 1 Table 5. NMR and IR spectral data for PHANOLs.
(Scheme 9).
[b]
PHANOL
d [ppm][a]
IR [cmÀ1
]
On the basis of potential hydrogen-bonding ability, it
might be predicted that the “rear-face” functionalised
PHANOLs 2, 5 and 7 bearing electron-withdrawing
groups should be better catalysts than PHANOL, and
that PHANOLs with two electron-withdrawing groups
(i.e., 2 and 7) should be better catalysts than those with
just one (i.e., 5). In fact, the complete opposite of this
is observed in the attempted ring opening of cyclohex-
ene oxide with piperidine, where PHANOL 1 is more ef-
fective than bromoPHANOL 5 which is more effective
than dinitroPHANOL 2 (it transpired that sulfonamide
7 was completely insoluble under these conditions and
this fact accounts for the zero conversion observed).
The results can be rationalised by noting that across
the series 1 to 5 to 7, the PHANOLs are expected to be-
1
2
5
8.48[c]
3500–3100
3500–3100
3500–3100
3500–3000
3477
10.83[c]
8.61 and 8.87[d]
8.66[e]
7
10
11
14
4.34[d]
5.38 and 4.35[d]
5.84 and 5.38[d]
3600–3100
3600–3100
[a]
1
Chemical shift of OH resonance(s) in the H NMR spec-
trum.
[b]
[c]
[d]
[e]
Wavenumber of OH stretch(es) in the IR spectrum.
DMSO-d6 solution.
CDCl3 solution.
Acetone-d6 solution.
come more acidic. It seems reasonable to assume that pi- that hydrogen bonding leads to deshielding of a given
peridine is increasingly capable of deprotonating the proton that participates.[32] Similarly, hydrogen bonding
PHANOLs of increasing acidity. This would increasing- is readily determined by inspection of the IR spectrum
ly reduce the amount of PHANOLs available for catal- in the region of 3000þwavenumbers.[32]
ysis in line with the observed results.
Typically, a “strong” hydrogen bond is defined in
which the total length is shorter than the sum of the
Van der Waalꢁs radii of the two substituents by at least
0.3 Š.[33] This works out to be 2.50 Š for an O-H···O sys-
tem. Double-well (“weak”) hydrogen bonds typically
IR and NMR Features of PHANOLs
The 1H NMR chemical shifts and IR stretching frequen- have O···O separations of 2.8 Š.[1] In this respect, where
cies for the OH group of various PHANOLs are collect- the PHANOLs are expected to have a phenolic O···O
1
ed in Table 5. For H NMR data, it is well understood separation of ca. 4.0 Š (vide supra) it seems likely that
1124
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1117–1130

Planar Chiral PHANOLs as Organocatalysts
FULL PAPERS
1
neither “strong” nor “weak” intramolecular hydrogen Critically, however, the H NMR chemical shift value
bonds between the phenolic groups can be formed. of 4.35 ppm for PHANOL 11 by comparison to the value
Therefore, the experimental data gathered in Table 5 obtained for PHANOL 10 shows that at least one of the
can be used to indicate which PHANOLs are capable phenolic groups is unable to participate in intermolecu-
of intermolecular hydrogen bonding as required for cat- lar hydrogen bonding (assigned as the OH at the 4-posi-
alysis. Moreover, these data also corroborate our pro- tion). The intermolecular hydrogen bonding is therefore
posal that the PHANOLs act as catalysts by double hy- due to the sterically unencumbered phenolic group res-
drogen bonding (vide infra).
onating at 5.38 ppm in the NMR spectrum (presumably
The parent PHANOL 1 displays a sharp singlet with the broad band at 3600–3100 cmÀ1 in the IR spectrum is
chemical shift of 8.48 ppm for the two OH protons in obscuring the expected sharp signal for the non-hydro-
its 1H NMR spectrum, and a broad stretching frequency gen bonded phenol in the IR spectrum at ca. 3475 cmÀ
at 3500–3100 cmÀ1 in the IR spectrum (Table 5, entry 1). Since PHANOL 11 is not active for catalysis, but is ca-
1). On the basis of the analysis above, the characteristic pable of making one intermolecular hydrogen bond, this
broad signal in the IR spectrum requires that PHANOL clearly shows that PHANOLs 1, 2, 5 and 7 are catalysing
1 is participating in intermolecular hydrogen bonding. reactions via a double hydrogen bonding mode. The re-
In comparison, dintroPHANOL 2 shows a singlet at sults for monoalkylPHANOL 14 (Table 5, entry 7) are
10.83 ppm in the 1H NMR spectrum (Table 5, entry 2), less clear-cut however. It is not an active catalyst, but it
indicating that it is a better hydrogen bond donor by vir- does display intermolecular hydrogen bonding as evi-
tue of the electron-withdrawing nitro groups – as wit- denced by the IR spectrum. Like PHANOL 11, two res-
nessed by the experimental results for catalysis of onances are observed in the 1H NMR spectrum, but the
Diels–Alder reactions (vide supra). The relative melting chemical shifts are 5.84 and 5.38 ppm. This discrepancy
points of (Æ)-PHANOL 1 compared to dinitroPHA- may arise from the different steric shielding effects of
NOL 2 of 229–2318C and 2808C (dec.), respectively, a C2-alkyl chain (14) versus a C5-alkyl chain (10, 11).
also testify to the increased hydrogen bonding ability
of the latter. The monosubstituted bromide 5 shows
two OH resonances in its NMR spectrum at 8.61 and Conclusion
8.87 ppm (Table 5, entry 3) where presumably the high-
er chemical shift value represents the resonance for the In conclusion, we have demonstrated catalysis of Diels–
phenol of the ring also bearing the para-bromine atom. Alder and epoxide opening reactions via double hydro-
1
PHANOL 7 shows a H NMR resonance at 8.66 ppm gen bonding interactions using catalysts based on the
(Table 5, entry 4). All these compounds also show broad 4,12-dihydroxy[2.2]paracylophane (PHANOL) frame-
IR signals showing intermolecular hydrogen bonding.
work. The double hydrogen bonding mode is supported
1
In direct contrast, di-ortho-alkylPHANOL 10 shows by an analysis of H NMR and IR data for the various
an extremely sharp OH stretch in its IR spectrum at PHANOLs. For Diels–Alder reactions the order of ac-
3477 cmÀ1 (Table 5, entry 5) unambiguously showing tivity of a given PHANOL catalyst is in-line with in-
that it cannot make intermolecular hydrogen bonds. creased electron-withdrawing groups at the para-posi-
The 1H NMR spectrum shows a resonance at 4.34 ppm tions. However, substitution at the ortho-position of a
– a much reduced magnitude of chemical shift compared PHANOL sterically prevents double hydrogen bonding
to PHANOL 1 – entirely consistent with the above. The and kills catalysis. In contrast to Diels–Alder reaction
change in chemical shift from 8.48 ppm in PHANOL 1 catalysis, the more electron-deficient PHANOLs were
to 4.34 ppm in PHANOL 10 is therefore diagnostic for found to display essentially the reverse order of activity
a phenolic OH unable to participate in intermolecular for catalysis of epoxide opening with an amine. This was
hydrogen bonding in these systems. It also follows that attributed to the increasing capability of the amine to
if intermolecular hydrogen bonding cannot occur, then deprotonate the increasingly acidic PHANOLs, reduc-
it should not be active for catalysis – as observed exper- ing the amount of active catalyst. Attempts to use enan-
imentally. Further, incremental evidence for the non-hy- tiopure catalyst (R)-PHANOL to effect asymmetric in-
drogen bonding capability of 10 comes from the ob- duction in either Diels–Alder reactions or epoxide
served melting point of 135–1408C (cf. PHANOL 1: openings failed, presumably due to poor “expression
229–2318C) and from its improved solubility in non-po- of chirality” by the planar chiral PHANOL at the react-
lar solvents. We attribute the inability of PHANOL 10 to ing centre. Although the rate accelerations in the Diels–
make intermolecular hydrogen-bonds simply to steric Alder reactions are in general modest, and could have
shielding by the ortho-alkyl groups.
been induced instead by, e.g., the application of pressure
In further contrast, monoalkylPHANOL 11, shows or heating, these results demonstrate that double hydro-
1
two resonances in the H NMR at 5.38 and 4.35 ppm, gen bonding to a carbonyl group can be achieved with a
but shows a broad signal in its IR spectrum (Table 5, en- chiral catalyst and the potential for asymmetric (orga-
try 6). The latter spectrum is consistent with the ability of no)catalysis is clear. Indeed, the recent work of Rawal[14]
PHANOL 11 to make intermolecular hydrogen bonds. for the highly enantioselective catalysis of hetero-Diels–
Adv. Synth. Catal. 2004, 346, 1117–1130
asc.wiley-vch.de
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1125

D. Christopher Braddock et al.
FULL PAPERS
hours, concentrated and chromatographed (CH2Cl2) to give
bromide 4 as a white solid; yield: 871 mg (78%); mp 1508C
(dec.); Rf ¼0.25 (CH2Cl2); IR (thin film): n¼3241, 2996, 2929,
Alder reactions via double hydrogen bonding with
TADDOL shows the promise of this area, and this
work should prove useful in further identifying enantio-
selective catalysts that operate via a multiple hydrogen
bonding donor mode.[34]
1766, 1658, 1623 cmÀ1
;
1H NMR (CDCl3, 270 MHz): d¼
2.10–2.21 (1H, m), 2.29 (3H, s), 2.61–2.67 (2H, m), 2.75–
2.99 (3H, m), 3.14–3.25 (2H, m), 4.52 (1H, dd, J¼5.6,
0.9 Hz), 5.83 (1H, s), 6.07 (1H, d, J¼5.6 Hz), 6.44 (1H, d, J¼
1.8 Hz), 6.64 (1H, dd, J¼8.0, 1.8 Hz), 6.95 (1H, d, J¼8.0 Hz);
13C NMR (CDCl3, 68 MHz): d¼21.1, 30.0, 31.0, 32.1, 32.8,
40.0, 126.8, 129.0, 129.9, 131.9, 133.6, 140.7, 142.2, 142.4,
150.7, 158.1, 168.6, 184.9; MS(EI): m/z¼362, 360, 320, 318,
282, 240, 200, 198, 162, 120; HR-MS(EI): m/z¼360.0357
(M)þ, 362.0335 (M)þ; calcd. for C18H17O379Br: 360.0361,
C18H17O381Br: 362.0341.
Experimental Section
General
[2.2]Paracyclophane was purchased from Speciality Coating
Systems. 4,12-Dihydroxy[2.2]paracyclophane (1),[17] 4,12-dihy-
droxy-7,15-dinitro[2.2]paracyclophane (2),[15] 4,12-diacetoxy-
[2.2]paracyclophane (3),[17] 4,16-dihydroxy[2.2]paracyclo-
phane (15)[15,19,22] and 2,4,4,6-tetrabromocyclohexa-2,5-dien-
one[35] were prepared according to published procedures. Ace-
tyl chloride, valeryl chloride and titanium tetrachloride were
distilledimmediately before use. Cyclopentadiene was cracked
from dicyclopentadiene (bath temperature 1508C) immediate-
ly before use. CH2Cl2 was distilled from CaH2. All other re-
agents and solvents were used as received. All reactions were
performed under an atmosphere of nitrogen unless otherwise
specified.
Analytical thin-layer chromatography (TLC) was carried
out on silica gel F254/366 60 Š plates with visualisation using
UV light (254 nm) or potassium permanganate as appropriate.
Chromatography refers to flash column chromatography per-
formed using BDH 33–70 mm grade silica gel using the method
of Still.[36] Eluents are given in parentheses. Solvents for flash
chromatography, i.e., EtOAc, Et2O, petroleum ether, CH2Cl2,
MeOH were ACSreagent grade or GPR grade and were
used as received. Concentrated refers to concentrated under
vacuum.
Melting points were recorded on a Reichart-Thermovar
melting point apparatus and are uncorrected. Fourier trans-
form infra-red (IR) spectra were recorded through Diffuse
Reference Infra-red Fourier Transform Spectroscopy
(DRIFTS) or a thin film on NaCl plates using a Mattson 500
FTIR spectrometer. Solid phase infra-red (IR) spectra were re-
corded using a Mattson Infinity Series FTIR spectrometer.
1H NMR were recorded at270 MHz on a JEOL GSX-270spec-
trometer or at 300 MHz on a Bruker DRX spectrometer.
13C NMR were recorded at 68 MHz and 75 MHz on a JEOL
GSX-270 spectrometer or on a 300 MHz Bruker DRX spec-
trometer, respectively. NMR samples were run in the indicated
solvents and were referenced internally. Low resolution mass
spectroscopy (LR-MS) [EI and CI] and high resolution mass
spectrometry (HR-MS) [EI] were recorded by the Imperial
College Department of Chemistry Mass Spectroscopy Service.
Elemental analyses were carried out by Mr. Stephen Bowyer at
the University of North London.
7-Bromo-4,12-dihydroxy[2.2]paracyclophane (5)
To stirred solution of bromide 4 (950 mg, 2.7 mmol) in CH2Cl2
(23 mL) at 08C was added DBU in one portion (0.4 mL,
2.7 mmol). The resulting mixture was warmed to room temper-
ature and stirred for 4 hours. The mixture was poured into
aqueous HCl (30 mL, 2.5 M) and the layers were separated.
The aqueous layer was extracted with CH2Cl2 (2ꢀ20 mL),
and the combined organics were washed with aqueous HCl
(30 mL) and brine (30 mL), dried over MgSO4, filtered, con-
centrated and chromatographed (1:99 MeOH:CH2Cl2) to
give 12-acetoxy-7-bromo-4-hydroxy[2.2]paracyclophane as a
white solid; yield: 650 mg (68%); mp 145–1508C; Rf ¼0.25
(1% MeOH in CH2Cl2); IR (DRIFTS, KBr): n¼3600–3100,
1
2934, 1715 cmÀ1; H NMR (CDCl3, 270 MHz): d¼2.32 (3H,
s), 2.46–2.57 (1H, m), 2.65–2.77 (1H, m), 2.88–3.12 (4H, m),
3.22–3.39 (2H, m), 5.62 (1H, s), 5.94 (1H, s), 6.33 (1H, dd,
J¼8.0, 1.8 Hz), 6.50 (1H, s), 6.80 (1H, d, J¼1.8 Hz), 7.08
(1H, d, J¼8.0 Hz); 13C NMR (CDCl3, 68 MHz): d¼21.6,
29.0, 30.7, 33.1, 34.0, 117.6, 121.2, 122.0, 128.5, 129.6, 130.6,
131.9, 138.8, 140.6, 141.7, 149.5, 153.8, 170.0; MS(EI): m/z¼
362, 360, 320, 318, 282, 239, 200, 198, 162, 120; HR-MS(EI):
m/z¼360.0364 (M)þ, 362.0344 (M)þ; calcd. for C18H1779BrO3:
360.0361, C18H1781BrO3: 362.0341.
To a stirred solution of 12-acetoxy-7-bromo-4-hydroxy[2.2]-
paracyclophane (177 mg, 0.49 mmol) in MeOH (10 mL) was
added powdered NaOH (500 mg, 8.9 mmol) in one portion.
The resulting mixture was heated to reflux for 10 minutes,
cooled to room temperature, poured into aqueous HCl
(20 mL, 2.5 M) and extracted with EtOAc (3ꢀ10 mL). The or-
ganic layers were combined, washed consecutively with satu-
rated aqueous sodium bicarbonate solution (2ꢀ20 mL) and
brine (2ꢀ20 mL), dried over MgSO4, filtered, concentrated
and chromatographed (1:1 EtOAc:petroleum ether) to give
5 as a pale yellow oil; yield: 147 mg (95%); Rf ¼0.50 (1:1
EtOAc:petroleum ether); IR (thin film): n¼3600–3100,
1
2984, 2855 cmÀ1; H NMR (CDCl3, 270 MHz): d¼2.31–2.53
13-Bromo-11-oxo-tricyclo[8.2.2.24,7]hexadeca-
4(5),6,10(14),1(12)-pentaen-5-yl Acetate (4)
(1H, m), 2.62–2.86 (4H, m), 2.95–3.04 (1H, m), 3.10–3.25
(2H, m), 5.99 (1H, dd, J¼7.7, 1.6 Hz), 6.15 (1H, d, J¼
1.6 Hz), 6.26 (1H, s), 6.38 (1H, s), 6.84 (1H, d, J¼7.7 Hz),
8.61 (1H, s), 8.87 (1H, s); 13C NMR (CDCl3, 67.5 MHz): d¼
29.3, 30.6, 33.8, 34.0, 115.8, 119.0, 119.8, 123.3, 124.4, 127.5,
131.5, 138.2, 140.6, 142.2, 155.7, 156.4.
To a stirred solution of 2,4,4,6-tetrabromohexadieneone
(3.15 g, 7.7 mmol) in CH2Cl2 (30 mL) at À208C was added a
solution of diacetate 3 (1.00 g, 3.1 mmol) in CH2Cl2 (20 mL).
The mixture was warmed to room temperature, stirred for 24
1126
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1117–1130

Planar Chiral PHANOLs as Organocatalysts
FULL PAPERS
4,12-Dihydroxy-7,15-di(N,N-
diethyl)sulfonyl[2.2]paracyclophane (7)
4,12-Dihydroxy-5,13-dipentanoyl[2.2]paracyclophane
(9)
Neat chlorosulfonic acid (8 mL, 120 mmol) was added cau-
tiously to a vessel containing diacetate 3 (612 mg, 1.9 mmol).
The resulting dark red mixture was stirred at room tempera-
ture for 3 days, and poured carefully onto ice (50 g). The mix-
ture was further diluted with water (150 mL), extracted with
EtOAc (3ꢀ100 mL), and the combined organics were washed
with brine (2ꢀ50 mL), dried over MgSO4, filtered and concen-
trated to give crude disulfonyl chloride 6 (>90% purity by 1H
NMR) as a black solid. DMF (10 mL) was added, followed by
diethylamine (5 mL). The mixture was heated to 608C for 16
hours, allowed to cool to room temperature, diluted with water
(30 mL), and extracted with EtOAc (3ꢀ20 mL). The com-
bined organics were washed consecutively with aqueous HCl
(2ꢀ20 mL) and brine (2ꢀ20 mL), dried over MgSO4, filtered,
concentrated and chromatographed (1:1 petroleum ether:
EtOAc to 100% EtOAc) to give bissulfonamide 7 as an off-
white powder; yield: 150 mg (16%); mp 2408C (dec.);
Rf ¼0.45 (EtOAc); IR (DRIFTS): n¼3600–3100, 2955, 2937,
To a stirred solution of PHANOL 1 (200 mg, 0.83 mmol) in
(ClCH2)2 (16 mL) at room temperature under nitrogen was
added dropwise TiCl4 (0.37 mL, 3.3 mmol), followed by valeryl
chloride (1.0 mL, 8.8 mmol). The resulting cherry red mixture
was heated to 858C for 13 hours, allowed to cool to room tem-
perature and aqueous HCl (10 mL, 2.5 M) was added cautious-
ly. After stirring for 15 minutes the organic layer was removed,
and the aqueous layer extracted with CH2Cl2 (2ꢀ20 mL). The
combined organics were washed consecutively with saturated
aqueous sodium bicarbonate solution (2ꢀ30 mL) and brine
(1ꢀ25 mL), dried over MgSO4, filtered, concentrated and
chromatographed (2:1 petroleum ether:CH2Cl2) to give dike-
tone 9 as a yellow oil; yield: 200 mg (60%); Rf ¼0.35 (1:1 petro-
leum ether:CH2Cl2); IR (thin film): n¼2957, 2930, 2871, 1619,
cmÀ1; 1H NMR (CDCl3, 270 MHz): d¼0.90 (6H, t, J¼7.3 Hz),
1.34 (4H, sextet, J¼7.3 Hz), 1.70 (4H, ddt, J¼6.5, 7.3, 8.9 Hz),
2.53 (2H, m), 2.80 (2H, ddd, J¼6.5, 8.9, 15.3 Hz), 2.99 (2H, ddd,
J¼6.5, 8.9, 15.3 Hz), 3.07 (2H, m), 3.39 (2H, m), 3.61 (2H, m),
6.34 (2H, d, J¼7.6 Hz), 6.62 (2H, d, J¼7.6 Hz), 12.91 (2H, s);
13C NMR (CDCl3, 68 MHz): d¼14.0, 22.2, 27.8, 30.3, 34.8,
43.2, 121.7, 125.8, 126.9, 138.8, 143.9, 162.2, 208.2; MS(EI):
m/z¼408 (M)þ, 379, 295, 203; HR-MS(EI): m/z¼408.2320
(M)þ; calcd. for C26H32O4: 408.2301; anal. calcd. for C26H32O4:
H 7.90, C 76.44; found: H 8.04, C 76.55.
1569, 1164 cmÀ1
;
1H NMR (270 MHz, acetone-d6): d¼1.00
(12H, t, J¼7.6 Hz), 2.82–3.14 (4H, m), 3.10 (4H, q,
J¼7.6 Hz), 3.12 (4H, q, J¼7.6 Hz), 3.15–3.28 (2H, m), 3.59
(2H, m), 6.51 (2H, s), 7.18 (2H, s), 8.66 (2H, s); 13C NMR
(68 MHz, acetone-d6): d¼13.8, 30.2, 33.2, 41.7, 120.8, 124.8,
129.6, 134.0, 141.5, 158.7; MS(EI): m/z¼510, 446, 349; HR-
MS(EI): m/z¼510.1858 (M)þ; calcd. for C24H34O6N2S2:
510.1861.
4,12-Dihydroxy-5,13-dipentyl[2.2]paracyclophane (10)
Mossy zinc (9.21 g, 141 mmol) and mercuric chloride (1.14 g,
4.2 mmol) were combined in a round-bottomed flask, and wa-
ter (25 mL) and HCl (3 mL, 12 M) were added. After stirring
for 1 hour at room temperature, the aqueous layer was de-
canted and the amalgam washed thoroughly with water. A sol-
ution of diketone 9 (374 mg, 0.92 mmol) in EtOH (18 mL) was
added to the amalgam along with HCl (3 mL, 10 M). The mix-
ture was refluxed for 20 hours, with portions of HCl (4ꢀ
1.5 mL, 12 M) added at regular intervals. Once all traces of yel-
low colour had disappeared (ca. 16 h) the mixture was cooled
to room temperature and the aqueous layer extracted with
EtOAc (3ꢀ25 mL). The organic layers were combined, wash-
ed with brine (2ꢀ20 mL), dried over MgSO4, filtered, concen-
trated and recrystallised from petroleum ether:Et2O (5:1), giv-
ing 10 as a white solid; yield: 242 mg (69%); mp 135–1408C; IR
(thin film): n¼3477, 3109, 2923, 2856 cmÀ1; 1H NMR (CDCl3;
270 MHz): d¼0.83 (6H, t, J¼6.9 Hz), 1.23 (12H, m), 2.56–2.69
(4H, m), 2.73–2.84 (4H, m), 3.22–3.36 (4H, m), 4.34 (2H, s),
6.13 (2H, d, J¼7.8 Hz), 6.33 (2H, d, J¼7.8 Hz); 13C NMR
(CDCl3; 67.5 MHz): d¼14.1, 22.7, 27.2, 28.7, 31.1, 31.8, 32.4,
124.2, 127.3, 128.3, 132.3, 139.3, 152.3.
4-Hydroxy-5-pentanoyl[2.2]paracyclophan-12-yl
Pentanoate (8)
To a stirred solution of PHANOL 1 (72 mg, 0.30 mmol) in dry
CH2Cl2 (2 mL) was added a solution of TiCl4 in CH2Cl2
(1.8 mL, 0.7 M, 1.26 mmol) and valeryl chloride (76 mL,
0.63 mmol) at 08C. The resulting dark red solution was heated
to reflux, and maintained at this temperature for 8 hours. Water
was added (2 mL), followed by aqueous HCl (2 mL, 2.5 M) and
CH2Cl2 (4 mL), and the resultant mixture stirred for 0.5 hours.
The organic layer was removed, and the aqueous layer was ex-
tracted with CH2Cl2 (5 mL). The combined organics were
washed consecutively with water (1ꢀ10 mL) and brine (1ꢀ
10 mL), dried over MgSO4, filtered and concentrated to give
8 as a yellow oil; yield: 118 mg (95%); Rf ¼0.32 (1:1 petroleum
ether:CH2Cl2); IR (thin film): n¼2931, 2861, 1757, 1612 cmÀ1
;
1H NMR (CDCl3, 270 MHz): d¼0.94 (3H, t, J¼7.4 Hz), 1.01
(3H, t, J¼7.5 Hz), 1.37 (2H, sextet, J¼7.5 Hz), 1.48 (2H, sex-
tet, J¼7.4 Hz), 1.73 (4H, m), 2.47 (2H, dt, J¼4.7, 7.4 Hz),
2.53–2.60 (1H, m), 2.68–2.77 (1H, m), 2.91 (2H, t, J¼
7.2 Hz), 3.02–3.17 (4H, m), 3.38–3.48 (2H, m), 6.18 (1H, d,
J¼7.6 Hz), 6.51 (1H, dd, J¼7.9, 1.3 Hz), 6.53 (1H, d, J¼
1.3 Hz), 6.58 (1H, d, J¼7.6 Hz), 6.66 (1H, d, J¼7.9 Hz),
13.10 (1H, s, Ar-OH); 13C NMR (CDCl3, 68 MHz): d¼13.8,
14.0, 22.3, 22.6, 27.1, 28.1, 30.4, 31.0, 33.5, 34.2, 35.1, 43.3,
121.3, 123.5, 126.8, 128.6, 129.0, 129.4, 135.0, 139.6, 142.6,
142.7, 149.4, 162.1, 171.5, 207.5.
(E)-4,12-Dihydroxy-5-pent-1-enyl[2.2]paracyclophane
(11)
To a stirred solution of diketone 9 (100 mg, 0.25 mmol) in
MeOH (5 mL), was added sodium borohydride (232 mg,
6.1 mmol) in one portion. The mixture was heated to reflux
for 14 hours, cooled to room temperature, poured into aqueous
HCl (30 mL, 2.5 M) and extracted with EtOAc (3ꢀ25 mL).
The organic layers were combined, washed with saturated
Adv. Synth. Catal. 2004, 346, 1117–1130
asc.wiley-vch.de
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1127

D. Christopher Braddock et al.
FULL PAPERS
aqueous sodium bicarbonate solution (1ꢀ25 mL) and brine
(1ꢀ25 mL), dried over MgSO4, filtered, concentrated and
chromatographed (1:1 petroleum ether:CH2Cl2) to give al-
kene 11 as a pale yellow oil; yield: 50 mg (65%); Rf ¼0.25
(CH2Cl2); IR (thin film): n¼3600–3100, 2958, 2931,
206.4; MS(CI, NH þ): m/z¼282 (M)þ, 161, 120; HR-MS
4
(EI): m/z¼282.1266 (M)þ; calcd. for C18H18O3: 282.1256.
1
2870 cmÀ1; H NMR (CDCl3, 270 MHz): d¼0.96 (3H, t, J¼
7.4 Hz), 1.48 (2H, sextet, J¼7.4 Hz), 2.19 (2H, ddt, J¼7.4,
6.9, 1.3 Hz), 2.54–2.88 (3H, m), 2.94 (2H, m), 3.34 (3H, m), 4,12-Dihydroxy-5-ethyl[2.2]paracyclophane (14)
¼
4.35 (1H, s), 5.39 (1H, s), 5.66 (1H, dt, J 16.4, 6.9 Hz), 6.14
Water (10 mL) and HCl (1 mL, 12 M) were added to a solid
mixture of mossy zinc (3.58 g, 59 mmol) and mercuric chloride
(432 mg, 1.6 mmol). After stirring for 1 hour at room tempera-
ture, the aqueous layer was decanted and the amalgam washed
thoroughly with water. A solution of ketone 13 (100 mg,
0.42 mmol) in EtOH (6 mL) was added to the amalgam along
with HCl (1 mL, 12 M). The mixture was refluxed at 788C for
20 hours, with portions of HCl (4ꢀ0.5 mL) added over regular
intervals. Once all traces of yellow colour had disappeared the
(1H, d, J¼7.7 Hz), 6.15 (1H, dd, J¼7.7, 1.7 Hz), 6.19 (1H, d,
J¼1.7 Hz), 6.33 (1H, d, J¼7.7 Hz), 6.49 (1H, d, J¼7.7 Hz),
6.65 (1H, dt, J¼16.4, 1.3 Hz); 13C NMR (CDCl3, 68 MHz):
d¼13.8, 22.6, 29.2, 30.6, 31.6, 33.6, 35.6, 116.2, 124.2, 124.7,
124.9, 125.6, 126.1, 134.1, 135.2, 136.1, 140.0, 142.4, 151.3,
154.3; MS(CI, NH 4þ): m/z¼356, 339, 321, 307, 269, 189, 120.
mixture was cooled to room temperature, diluted with water,
and the aqueous layer extracted with EtOAc (3ꢀ25 mL).
The combined organics were washed with brine (2ꢀ20 mL),
dried over MgSO4, filtered, concentrated and chromatograph-
ed (4:1 petroleum ether:EtOAc) giving ethylPHANOL 14 as
a white solid; yield: 100 mg (88%); mp 148–1498C; IR
4-Hydroxy-5-ethanoyl[2.2]paracyclophan-12-yl
Acetate (12)
To a stirred solution of PHANOL 1 (200 mg, 0.83 mmol) in
(ClCH2)2 (8.3 mL) at room temperature under nitrogen was
added dropwise TiCl4 (0.07 mL, 3.5 mmol), followed by acetyl
chloride (137 mL, 2.1 mmol). The resulting cherry red mixture
was heated to 408C for 4 hours, allowedto cool toroom temper-
ature, and HCl (4 mL, 2.5 M) was added cautiously. After stir-
ring for 0.25 h the organic layer was removed, and the aqueous
layer diluted with water (10 mL) and extracted with CH2Cl2
(2ꢀ5 mL). The organic layers were combined, washed consec-
utively with saturated aqueous sodium bicarbonate solution
(10 mL) and brine (10 mL), dried over MgSO4, filtered, con-
centrated and the crude material chromatographed (1:3
EtOAc:petroleum ether) to give ketoacetate 12 as a yellow sol-
id; yield: 47 mg (58%); mp 175–1808C; IR (thin film): n¼2937,
1753, 1609 cmÀ1; 1H NMR (CDCl3, 270 MHz): d¼2.21 (3H, s),
2.48–2.77 (2H, m), 2.63 (3H, s), 2.93–3.19 (4H, m), 3.40 (1H,
m), 3.59 (1H, m), 6.15 (1H, d, J¼8.0 Hz), 6.47 (1H, dd, J¼
7.8, 1.8 Hz), 6.54 (1H, d, J¼1.8 Hz), 6.56 (1H, d, J¼7.8 Hz),
6.63 (1H, d, J¼8.0 Hz), 13.29 (1H, s); 13C NMR (CDCl3,
68 MHz): dC ¼21.0, 30.2, 30.6, 31.4, 33.5, 35.0, 120.9, 123.5,
126.9, 128.7, 129.0, 129.5, 135.0, 139.8, 142.8, 143.0, 149.3,
162.8, 166.9; MS(CI, NH 4þ): m/z¼342 (MþNH4)þ, 324, 282.
(DRIFTS)
n¼3600–3100 cmÀ1
;
1H NMR
(CDCl3,
270 MHz): d¼0.95 (3H, t, J¼7.4 Hz), 2.60–2.89 (5H, m),
2.95 (2H, m), 3.20–3.43 (3H, m), 5.38 (1H, br s), 5.84 (1H, br
s), 6.12 (1H, dd, J¼7.6, 1.4 Hz), 6.21 (1H, d, J¼7.8 Hz), 6.27
(1H, d, J¼1.4 Hz), 6.32 (1H, d, J¼7.8 Hz), 6.47 (1H, d, J¼
7.6 Hz); 13C NMR (CDCl3, 68 MHz): d¼16.1, 20.5, 28.8, 30.5,
32.1, 33.8, 116.0, 124.6, 125.2, 126.1, 127.2, 131.2, 132.3, 135.1,
139.8, 141.6, 151.3, 154.7; MS(CI, NH þ): m/z¼269 (Mþ
4
H)þ, 148, 120.
Solid-Supported PHANOL 17
To a stirred solution of PHANOL 1 (1.54 g, 6.43 mmol) in
EtOH (60 mL) was added finely ground lithium hydroxide
monohydrate (540 mg, 12.86 mmol). The suspension was ho-
mogenised through sonication and heated to reflux for 5 mi-
nutes. The EtOH was removed under vacuum to give the dili-
thio salt of PHANOL (yield: 1.58 g, 97%) as a dark brown solid,
which was used immediately without further purification.
To a nitrogen-agitated suspension of resin 16[23] (0.70 mmol,
loading 1.4 mmol/g) in CH2Cl2 (5 mL) at room temperature
was added the dilithio salt in DMF (8 mL). The suspension
was maintained under nitrogen for 2 hours, diluted with
MeOH, filtered and washed with a solution of AcOH in CH2
Cl2 (3ꢀ5 mL, 20%). The mother liquor was concentrated, di-
luted with water (20 mL), extracted with ethyl acetate (2ꢀ
20 mL), the organic layers combined, washed consecutively
with saturated aqueous sodium bicarbonate solution (2ꢀ
20 mL) and brine (20 mL), dried over MgSO4, filtered and
evaporated to give diol 1 (1.24 g, 5.2 mmol recovery). The re-
maining resin was washed consecutively with CH2Cl2, DMF
and MeOH, then dried under vacuum to give 17 (yield:
1.260 g, 0.92 mmol/g based on mass gain and recovered diol
1) as a dark red resin. IR (solid phase): n¼3444, 3024, 2924,
4,12-Dihydroxy-5-ethanoyl[2.2]paracyclophane (13)
To a stirred solution of ketoacetate 12 (100 mg, 0.31 mmol) in
MeOH (10 mL) was added powdered KOH (500 mg,
8.9 mmol). The resulting mixture was maintained at reflux
for 5 minutes, cooled, acidified with HCl (10 mL, 2.5 M) and
extracted with EtOAc (2ꢀ25 mL). The organic layers were
combined, washed with saturated aqueous sodium bicarbonate
solution (1ꢀ25 mL) and brine (1ꢀ25 mL), dried over MgSO4,
filtered and concentrated to give hydroxyketone 13 as a white
solid; yield: 80 mg (91%); IR (DRIFTS): n¼3500–3100, 2929,
1
2852 cmÀ1; H NMR (CDCl3, 270 MHz): d¼2.47–2.75 (2H,
m), 2.69 (3H, s), 2.87–3.11 (3H, m), 3.34–3.49 (2H, m),
3.60–3.72 (1H, m), 6.13 (1H, d, J¼7.6 Hz), 6.17 (1H, d, J¼
1.6 Hz), 6.24 (1H, dd, J¼7.7, 1.6 Hz), 6.50 (1H, d, J¼7.6 Hz),
6.61 (1H, d, J¼7.7 Hz), 13.23 (1H, s); 13C NMR (CDCl3,
68 MHz): d¼30.3, 30.4, 31.4, 33.6, 34.6, 117.5, 120.8, 123.6,
124.3, 127.2, 128.1, 135.5, 139.8, 143.0, 144.3, 155.2, 162.6,
1724, 1585, 1493, 1451, 1330, 1226, 1147 cmÀ1
.
1128
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1117–1130

Planar Chiral PHANOLs as Organocatalysts
FULL PAPERS
[4] P. R. Schreiner, A. Wittkopp, Org. Lett. 2002, 4, 217–220.
[5] H. L. Rowe, N. Spencer, D. Philp, Tetrahedron Lett. 2000,
41, 4475–4479.
[6] a) T. Schuster, M. Kurz, M. W. Göbel, J. Org. Chem.
2000, 65, 1697–1701; b) for the use of an axially chiral
amidinium ion, see: T. Schuster, M. Bauch, G. Dürner,
M. W. Göbel, Org. Lett. 2000, 2, 179–181; c) for the
use of a C2-symmetrical chiral bisamidinium salt as a cat-
alyst, see: S. B. Tsogoeva, G. Dürner, M. Bolte, M. W.
Göbel, Eur. J. Org. Chem. 2003, 1661–1664.
General Procedure for the Diels–Alder Reaction
Catalysed by PHANOLs
The appropriate PHANOL (0.1 equiv., 0.042 mmol, 10 mol %)
was loaded into one of two identical reaction tubes. The appro-
priate dieneophile (1 equiv.) and diene (1 equiv.) were added
sequentially to each tube, and the resulting reaction mixtures
were stirred for the appropriate length of time before being di-
luted with CDCl3 (0.7 mL). This resulted in the PHANOL cat-
alysts precipitating, thereby “quenching” the reaction and si-
multaneously solubilising the Diels–Alder products and any
remaining unreacted dienophile and diene (and cyclopenta-
diene dimer). The mixture was then directly analysed by
1H NMR. The results are shown in Table 1. The percentage
conversions were determined by integrating selected resonan-
ces for the desired cycloadducts and unreacted dienophile. En-
try 1 (CpHþcrotonaldehyde): endo adduct,[24] dH (CHO)¼
9.35 ppm, exo adduct, dH (CHO)¼9.77 ppm, unreacted croto-
naldehyde, dH (CHO)¼9.48 ppm [contains ca. 2.5% Z-olefin,
dH (CHO)¼10.12 ppm]. Entry 2 (CpHþacrolein): endo ad-
duct,[24] dH (CHO)¼9.39 ppm, exo adduct, dH (CHO)¼
9.77 ppm, unreacted acrolein, dH (CHO)¼9.55 ppm. Entry 3
(2,3-dimethyl-1,3-butadieneþacrolein): cycloadduct,[24] dH
(CHO)¼9.65 ppm, unreacted acrolein, dH (CHO)¼
9.55 ppm. Entry 4 (cyclohexa-1,3-dieneþacrolein): cycload-
duct (endo only),[25] dH (CHO)¼9.44 ppm, unreacted acrolein,
dH (CHO)¼9.55 ppm. Entry 5 (CpHþmethacrolein): endo
adduct, dH (CHO)¼9.39 ppm, exo adduct,[24] dH (CHO)¼
9.68 ppm, unreacted methacrolein, dH (CHO)¼9.54 ppm. En-
try 6 (CpHþcinnamaldehyde): endo adduct,[24] dH (CHO)¼
9.59 ppm, exo adduct, dH (CHO)¼9.90 ppm, unreacted cinna-
maldehyde, dH (CHO)¼9.70 ppm. Entry 7 (CpHþmethyl vi-
nyl ketone): endo adduct,[26] dH (COCH3)¼2.12 ppm, exo ad-
duct,[26] dH (COCH3)¼2.20 ppm, unreacted methyl vinyl ke-
tone, dH (COCH3)¼2.28 ppm.
[7] C. Raposo, M. Almaraz, M. Crego, M. L. Mussons, N.
´
´
Perez, M. C. Caballero, J. R. Moran, Tetrahedron Lett.
1994, 35, 7065–7068.
[8] M. Oestreich, Nachr. Chem. 2004, 52, 35–38.
[9] a) J. Hine, K. Ahn, J. C. Gallucci, S.-M. Linden, J. Am.
Chem. Soc. 1984, 106, 7980–7981; b) a 1:1 crystalline ad-
duct of 4,5-dinitro-1,8-biphenylenediol with 2,6-dimeth-
yl-g-pyrone with double hydrogen bonding to the car-
bonyl, shows the two nitro groups twisted out of the
plane with dihedral angles of 208 and 438: J. Hine, K.
Ahn, J. Org. Chem. 1987, 52, 2089–2091.
[10] O. Saied, M. Simard, J. D. Wuest, J. Org. Chem. 1998, 63,
3756–3757.
[11] a) T. R. Kelly, P. Meghani, V. S. Ekkundi, Tetrahedron
Lett. 1990, 31, 3381–3384; b) for a urea doubly hydrogen
binding to the ether oxygen of 6-methoxyallyl vinyl ether
to promote a Claisen rearrangement, see: D. P. Curran,
L. H. Kuo, Tetrahedron Lett. 1995, 36, 6647–6650; c)
for the activation of nitrones with thioureas, see: T. Oki-
no, Y. Hoashi, Y. Takemoto, Tetrahedron Lett. 2003, 44,
2817–2821.
[12] A. Wittkopp, P. R. Schreiner, Chem. Eur. J. 2003, 9, 407–
414.
[13] a) D. C. Braddock, I. D. MacGilp, B. G. Perry, Synlett
2003, 1121–1124; b) B. G. Perry, PhD thesis, Imperial
College London (UK), 2002.
[14] Y. Huang, A. K. Unni, A. N. Thadani, V. H. Rawal, Na-
ture 2003, 424, 146–146.
General Procedure for the Nucleophilic Ring Opening
with Amines Catalysed by PHANOLs
The appropriate PHANOL (0.1 equiv., 0.042 mmol) was load-
ed into one of two identical reaction tubes. The appropriate ep-
oxide (1 equiv.) and nucleophile (1.5 equiv.) were added se-
quentially to each tube. The resulting reaction mixtures were
stirred for the appropriate length of time before being diluted
with CDCl3 (0.7 mL) and analysed by 1H NMR. The results are
shown in Table 4 and Scheme 9.
[15] a) D. C. Braddock, I. D. MacGilp, B. G. Perry, J. Org.
Chem. 2002, 67, 8679–8681; b) for a resolution method
via diastereomeric biscamphanic esters of PHANOL,
see: B. Jiang, X.-L. Zhao, Tetrahedron: Asymmetry
2004, 15, 1141–1143.
[16] a) For a theoretical study of the activation of oxirane by
1,8-biphenylenediol see: K. Omoto, H. Fujimoto, J. Org.
Chem. 2000, 65, 2464–2471; b) for the double hydrogen
bonding biphenylenediol-catalysed nucleophilic ring
opening of phenyl glycidyl ether with diethylamine,
see: J. Hine, S.-M. Linden, V. M. Kanagasabapathy, J.
Org. Chem. 1985, 50, 5096–5099; c) J. Hine, S.-M. Lin-
den, V. M. Kanagasabapathy J. Am. Chem. Soc. 1985,
107, 1082–1083.
Acknowledgements
We thank the EPSRC for a CNAA award (to D. C. B.) and
GlaxoSmithKline Ltd for a CASE award (to B. G. P.)
[17] H. J. Reich, D. J. Cram, J. Am. Chem. Soc. 1969, 91,
3527–3533.
References and Notes
[18] V. Rozenberg, T. Danilova, E. Sergeeva, E. Vorontsov, Z.
Starikova, K. Lysenko, Y. Belokon, Eur. J. Org. Chem.
2000, 3295–3303.
[1] L. J. Prins, D. N. Reinhoudt, P. Timmerman, Angew.
Chem. Int. Ed. 2001, 40, 2382–2426, and references cited
therein.
[19] D. C. Braddock, I. D. MacGilp, B. G. Perry, Tetrahedron
Lett. 2001, 42, 7527–7529.
[2] J. D. Watson, F. H. C. Crick, Nature 1953, 171, 737–738.
[3] P. R. Schreiner Chem. Soc. Rev. 2003, 32, 289–296.
Adv. Synth. Catal. 2004, 346, 1117–1130
asc.wiley-vch.de
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1129

D. Christopher Braddock et al.
FULL PAPERS
[20] T. Sato, K. Torizuka, M. Shimizu, Y. Kurihara, N. Yoda,
Bull. Chem. Soc. Jpn. 1979, 52, 2420–2423.
[26] A. S. Caselli, D. J. Collins, G. M. Stone, Aust. J. Chem.
1982, 35, 799–808.
[21] The solid-supported diazonium salt is obtained from
Merrifield resin following the protocol given in: S. Brꢂse,
J. Köbberling, D. Enders, R. Lazny, M. Wang, S. Brandt-
ner, Tetrahedron Lett. 1999, 40, 2105–2108.
[27] For an excellent discussion on Lewis acid complexation
of carbonyl groups, see: S. Shambayati, W. E. Crowe,
S. L. Schreiber, Angew. Chem. Int. Ed. 1990, 29, 256–
272.
[22] As a consequence of such long reaction times, a signifi-
cant competing reaction pathway was the dimerisation
of cyclopentadiene 18 to dicyclopentadiene. Had a slight
excess of diene 18 been employed for these reactions in
order to compensate for this loss of reactant, slightly
greater conversions may have been observed, but for
the sake of comparative analysis, a 1:1 ratio of diene
to dieneophile was maintained throughout all catalytic
analyses presented here.
[28] M. Chini, P. Crotti, F. Macchia, J. Org. Chem. 1991, 56,
5939–5942.
[29] Y. S. Wang, K. S. Schanze,J. Phys. Chem. 1995, 99, 6876–
6888.
[30] C. E. Harris, G. B. Fisher, D. Beardsley, L. Lee, C. T.
Goralski, L. W. Nicholson, B. Singaram, J. Org. Chem.
1994, 59, 7746–7751.
[31] M. Chini, P. Crotti, F. Macchia, Tetrahedron Lett. 1990,
31, 4661–4664.
[23] PHANOL 1 was found to be fully soluble in EtOAc,
DMSO and DMF, where presumably it is able to form
strong hydrogen bonds to the solvents. However, at-
tempted Diels–Alder catalysis in these solvents did not
result in rate acceleration. Presumably PHANOL 1
forms stronger hydrogen bonds to the solvent molecules
than to the dienophile. Its lack of solubility in non-hydro-
gen bonding solvents precluded the direct examination
(without solvent interference) of dienophile-PHANOL
interactions by H NMR.
[24] K. Ishihara, H. Kurihara, M. Matsumoto, H. Yamamoto,
J. Am. Chem. Soc. 1998, 120, 6920–6930.
[25] D. J. Burnell, H. B. Goodbrand, S. M. Kaiser, Z. Valenta,
Can. J. Chem. 1987, 65, 154–165.
[32] See, for example: D. H. Williams, I. Fleming, Spectro-
scopic Methods in Organic Chemistry, McGraw-Hill,
Cambridge, 1995, 5th edn., pp. 41–42 (hydrogen bonding)
and p. 76 (1H NMR).
[33] J. Emsley, Chem. Soc. Rev. 1980, 9, 91–124.
[34] For a recent highlight article entitled “Activation of Car-
bonyl Groups by Double Hydrogen Bonding: An
Emerging Tool in Asymmetric Catalysis” see: P. M. Pih-
ko, Angew. Chem. Int. Ed. 2004, 43, 2062–2064.
[35] G. J. Fox, G. Hallas, J. D. Hepworth, K. N. Paskins, Org.
Synth. Coll. Vol. VI, pp. 181–183, 1988.
1
[36] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43,
2923–2925.
1130
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1117–1130