Arylpyran Pseudoacid Racemization: Rate Estimation and Structural Influences

Article abstract of DOI:10.1007/s10870-020-00829-2

Abstract: Arylpyran pseudoacids showed slow ring-opening to the oxocarboxylic acids, and fast ring-closure to the lactols (pseudoacids) in a process that amounts to racemization. Compounds studied were patterned on “Cooper’s Pseudoacid” [3-hydroxy-4,4-dim

Full text of DOI:10.1007/s10870-020-00829-2

Journal of Chemical Crystallography
https://doi.org/10.1007/s10870-020-00829-2
ORIGINAL PAPER
Arylpyran Pseudoacid Racemization: Rate Estimation and Structural
Infuences
Jonathan Fung1 · Truc‑Vi Duong1 · Keean C. A. Braceros1 · Marilyn L. Brooks1 · Katie Schloesser‑Lingscheit1 ·
Tristen K. S. Tagawa1 · Johanna M. Wilson1 · Kevin K. Jones1 · Edward J. Valente1
Received: 25 February 2020 / Accepted: 7 April 2020
© Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
Arylpyran pseudoacids showed slow ring-opening to the oxocarboxylic acids, and fast ring-closure to the lactols (pseudoac-
ids) in a process that amounts to racemization. Compounds studied were patterned on “Cooper’s Pseudoacid” [3-hydroxy-
4,4-dimethylisobenzopyran-1-one, 1], to which modifcations were introduced to infuence racemization rates by steric
compression. Pseudoacid 1 in d6-DMSO had a barrier to racemization (ΔH‡) of +77.8(3) kJ/mol determined by dynamic
nuclear magnetic resonance line-broadening measured from 25 °C to 100 °C, and coalescence of its diastereotopic gem-
dimethyl signals at 78.5 °C. The solution half-life of 1 at room temperature is a few seconds. Introduction of various aryl
5-substituents lead to similar racemization barriers for the 5-fuoro-8-methyl derivative, and increasingly higher barriers for
5-methyl-8-methyl, 5-chloro-8-methyl, and 5-bromo-7-methyl derivatives. In 3-hydroxy-4,4,5,8-tetramethylisobenzopyran-
1-one, the barrier was + 104(6) kJ/mol, and the solution enantiomer t1/2 at room temperature was of the order of hours.
Chemical shift diferences (ΔνMe) between diastereotopic methyls of 8-methyl-5-substituted enantiomeric pseudoacids were
observed in the order F<CH3 <Cl, and generally decrease with increasing temperatures. The pseudoaxial and pseudoequato-
rial dispositions of the gem-dimethyl groups show smaller torsional diferences in the presence of adjacent aryl 5-substituents.
The crystal structures of 5-fuoro, 5-chloro and 5-methyl derivatives of 3-hydroxy-4,4,8-trimethylisobenzopyran-1-ones and
of 5-bromo-3-hydroxy-4,4,7-trimethylisobenzopyran-1-one are reported, along with several relevant secondary endocyclic
pseudoamide derivatives. Electronic energy computations (B3LYP/6-31 +(G(d,p) level of theory) generally support the
steric compression model. Equilibration between diastereomeric pseudoacids 3-hydroxy-4-ethyl-4-methylisobenzopyran-
1-one and 3-hydroxy-4,5,8-trimethyl-4-phenylisobenzopyran-1-one were rapid with trans isomers decreasingly favored as
temperature increases, and cis isomers less stable by +4.8(2) kJ/mol and +7.0(4) kJ/mol, respectively. The frst-order rate
of cis→trans conversion was measureable for 3-hydroxy-4,5,8-trimethyl-4-phenylisobenzopyran-1-one at 25 °C was found
to be 0.00403/min, t1/2 =2.87 h. Attempts to produce 5-isopropyl, 5-t-butyl and 4-phenyl-5-methyl pseudoacid derivatives
were frustrated by aryl substituent rearrangement upon ring closure to the intermediate indanones. Structures of rearranged
3-hydroxy-4-methyl-4-(2′-chloro-5′-methylphenyl)isobenzopyran-1-one (pseudoacid) and N-benzyl-6-isopropyl-4,4,8-tri-
methylisobenzopyrimidin-1-one (pseudoamide) are reported.
* Edward J. Valente
valentee@up.edu
1
Department of Chemistry, University of Portland, 5000
North Willamette Blvd, Portland, OR 97203, USA
Vol.:(0123456789)
1 3

Journal of Chemical Crystallography
Graphic Abstract
Arylpyran pseudoacids undergo slow ring opening and fast ring closing in solution amounting to racemization, rates of
which can be slowed considerably by steric compression between the 5-substituent and the adjacent gem-dimethyl groups.
Keywords Pseudoacids · Racemization · Dynamic NMR · Crystal structures · Steric compression
stability of the open intermediate forms that link the
equilibrating cyclic forms. Scheme 1 summarizes these
for d-glucose and d-fructose [4–7]. For these relevant and
representative hemiacetal and hemiketal systems, cyclic
forms are more stable than open forms, pyranoids form
more readily than furanoids, and aldehydes are more reac-
tive than ketones. In each of these systems, the intermedi-
ate open forms are observable.
Introduction
Open-cyclic systems are of interest for their dynamic
behavior and relevance to biological chemistry [1, 2].
Carbohydrates ofer many examples of open-cyclic equi-
libria with alcohol nucleophiles interacting with aldehyde
and ketone electrophiles [3]. Detailed kinetic and ther-
modynamic studies on sugars are enabled by the relative
Ko-c = 1.4 x 103
Ko-c = 2.5 x 103
3.4 x 104 / s
ko'-c'
4.7 x 10-4 / s
kc-o
O
OH
OH
O
O
OH
O
pH 7.25, 25oC
D-glucopyranose
kc'-o'
1.4 / s
ko-c
2.4 x 104 / s
Ko-c = 1.6 x 102
1.8 x 103 / s
Ko-c = 1.4 x 102
1.8 x 106 / s
ko'-c'
pH 8.4, 30oC
D-fructofuranose
O
OH
OH
O
OH
kc-o
kc'-o'
ko-c
1.26 x 104 / s
2.9 x 105 / s
Scheme 1 Kinetics and equilibria for carbohydrate (aldopyranose and ketofuranose) open-cyclic systems
1 3

Journal of Chemical Crystallography
Scheme 2 Kinetics and
equilibria in model furanoid
pseudoacid systems
Ko-c = 14.8
O
OH
O
OH
O
3.2 x 106 / M.s
O
ko-c
kc-o
pH 7.0, 25oC
H
o-formylbenzoic acid
2.2 x 105 / M.s
Ko-c = 6.9
O
OH
O
6.5 x 105 /M.s
ko-c
OH
O
pH 7.0, 25oC
O
2,2,3-trimethyl
levulinic acid
kc-o
9.3 x 104 / M.s
Scheme 3 Pyranoid enantiom-
ers of Cooper’s pseudoacid,
1, equilibrate through the
δ-oxoacid
O
O
O
OH
O
O
OH
OH
O
1
racemate is found [14, 15]. In solution, the cyclic system
is expected to undergo racemization through the interme-
diate open form, similar to other furan and pyran systems
(Scheme 3). The gem-dimethyl groups are diastereotopic,
and are used to gauge the interconversion.
H
O
O
O
R
H
H
O
O
S
O
H
In the crystal environment, system 1 forms complemen-
tary (but not cooperative) hydrogen-bonded dimers around a
crystallographic center-of-symmetry (Scheme 4) with motif
R2(12) [14, 16]. This motif has not been encountered very
fr2equently, but in β-hydroxyketones or γ- or δ-lactols, this
intermolecular contact is very likely to form according to a
study of cyclic organic Hydrogen-bonding motifs [17].
In the present study, the formation, structures and
dynamic (proton) nuclear magnetic resonance behavior
of 1 and several derivatives are presented. The racemi-
zation of 1 (Scheme 3) was examined through a variable
temperature dynamic nuclear magnetic resonance study,
and by similar investigation of the diastereomeric ana-
logs 4-ethyl-4-methyl-3-hydroxyisobenzopyran-1-one, 2,
3-hydroxy-4-methyl-4-phenylisobenzopyran-1-one, 3. The
crystal structure of 4-(2′-chloro-5′-methylphenyl)-4-methyl-
3-hydroxyisobenzopyran-1-one, 4, formed by rearrangement
of precursors afected by bulky substituents, is also reported
(Scheme 5).
Scheme 4 Arylpyran pseudoacid complementary inversion dimers
In γ- and δ-oxocarboxylic acid systems, the interacting
functions are in the next higher carbon oxidation states rela-
tive to sugars, with a carboxyl nucleophile interacting with
an aldehyde/ketone electrophile. Model furanoid systems
show similar open-cyclic tendencies as sugars though clearly
the equilibria favors cyclic forms rather less (Scheme 2) [8,
9]. From these studies, a plausible link between ortho aryl
disubstitution or adjacent alkyl steric efects on cycle forma-
tion can be inferred, and these infuences have been previ-
ously recognized [2]. Furanoid systems have received by far
the greater degree of attention [1, 10–13].
Pseudoacids are cyclic oxocarboxylic acids. As with sug-
ars, a chiral center is introduced into the cyclic structure on
ring closure. The pyranoid ring is of particular target in this
study, and the system employed incorporates several ring-
promoting features. In the molecule of interest, 3-hydroxy-
4,4-dimethylisobenzopyran-1-one (Cooper’s pseudoacid,
1), cyclization is promoted by ortho disubstitution of the
interacting groups (carboxylic acid and alkyl aldehyde) on
an aryl platform and an operative gem-dimethyl efect [14].
This system was briefy inspected so far as to note the sta-
bility of the cyclic forms, and in the solid state, the cyclic
Then, having established the open-cyclic solution chem-
istry of this arylpyran system, the structures and solution
behavior of several aryl substituted pseudoacid derivatives
allow exploration of structural features that can infuence the
dynamic behavior. Toward this end, pseudoacids 5–12 were
prepared (Scheme 6). Where possible, crystallographic stud-
ies were undertaken to correlate with the solution studies. The
1 3

Journal of Chemical Crystallography
Scheme 5 Diastereomeric pseu-
doacids in the arylpyran system
related to 1
O
O
O
O
O
O
OH
OH
OH
4
Cl
2
3
Scheme 6 Substituted
arylpyran pseudoacids with
modifed solution dynamic
behavior
R5
R6
R7
R8
R
R
O
5
CH3
F
H
H
H
H
H
H
H
CH3
H
CH3
H
H
CH3
CH3
CH3
H
CH3
H
CH3
CH3
8
6
R
7
7
Cl
Br
H
O
8
9
Br
H
R
OH
6
10
11
12
H
H
iPr
tBu
5
H
B
A
C
1
Scheme 7 Arylpyran pseudoacids through 3,3-dimethyl-1-inanone; a CF3SO3H, 25 °C; b Pb(OAc)4, HOAc, Ac2O, 75 °C, c H2O, K2CO3,
CH3OH, N2, 25 °C, then NaIO4, THF, H2O, 25 °C
O
O
H
O
O
O
O
c
a
b
d
O
O
O
O
O
O
O
O H
14
15
2
13
Scheme 8 Synthesis of the 3-ethyl-3-methyl-1-indanone 15, precursor to diastereomeric pseudoacids 2, beginning with Meldrum’s acid; a
NaOEt, EtOH; then butanone; b PhMgBr, then H3O+; c H2SO4 (2 M), 100 °C, 8 h; d polyphosphoric acid, 100 °C, 3 min
rearranged systems encountered with bulky aryl substituents
were characterized through nuclear magnetic resonance and
crystal and molecular structures of a few pseudoamide deriva-
tive (vide infra).
1 3

Journal of Chemical Crystallography
unsaturated ester is formed which is followed by saponi-
fcation to 3-phenyl-2-butenoic acid 19 in excellent yield
[19, 20]. Then, using the general method (A) of Scheme 7,
3-methyl-3-phenyl-1-indanone is obtained (Scheme 9).
In this study of the open-cyclic interconversion in com-
pounds like 1, the efects of fanking aryl substituents were
examined. Adaptation of the general method (Scheme 7) to
5,8-disubstituted derivatives of 1 and with varyingly bulky
groups next to the ultimate pyranone ring was met with lim-
ited success. For control of the acylation/alkylation, p-sub-
stituted toluenes were chosen [21, 22]. There is evidence
from analysis of intermediates occasionally seen in the trif-
luoromethane sulfonic acid promoted reaction of unsaturated
acids with arenes that acylation occurs frst with the acyl
group substituted ortho to the aryl methyl as expected. In
many cases, this was followed by alkylation to the indanone.
In some cases, an intermediate chalcone was formed in good
yield typically where the group para to the aryl methyl is
bulky. The chalcone could be cyclized using polyphosphoric
acid in a subsequent step (general method D, scheme 10)
[23]. In this step and depending on the bulk of the aryl sub-
stituents or at the unsaturated site of for alkylation, rear-
rangements became increasingly likely [24, 25]. Scheme 10
shows the two methods and the indanones formed with less
and more bulky p-substituted toluenes. Rearrangements
General Synthetic Methods
A useful method for formation of arylpyran pseudoacid 1
proceeds through suitably modifed indanones (Scheme 7).
Indanones are formed in superacid catalyzed acylation
and alkylation of an arene with 3-methyl-3-butenoic acid
(general method A). Then, the indanone is oxidized to the
2-acetoxyindanone (general method B). The ester is then
saponifed to the alcohol, which is then quickly subjected
to oxidative cleavage the δ-oxocarboxylic acid (general
method C). This process proves adaptable to a range of
arylpyran pseudoacids with diastereotopic or diastero-
meric aryl and pyran ring substituents [14].
To prepare diastereomeric analogs of 1, two strate-
gies were developed. Scheme 8 outlines a method toward
3,3-dialkyl-1-indanone beginning with Meldrum’s acid to
prepare 3-ethyl-3-phenylpentanoic acid, 14 [18]. The acid
is then cyclized to form the substituted 1-indanone, 15,
and pseudoacid 2 is then prepared by general methods B
and C as outlined in Scheme 7.
To introduce an aryl substituent on the indanone, as
in the synthesis of 3-methyl-3-phenyl-1-indanone, we
began with triethyl phosphonoacetate (Scheme 9). On
Wittig-Horner reaction of its enolate to acetophenone, the
O
O
O
O
EtO
O
P
O
O
P
O
P
O
EtO
a
c
b
_
OH
EtO
EtO
O
EtO
EtO
O
. .
d
_
O
Li+
Li+
19
20
Scheme 9 Formation of 3-aryl-1-indanones beginning with triethyl phosphonoacetate; a n-BuLi, heptane, 0 °C, 2 h; b acetophenone, 25 °C, 2 h;
c OH−(aq), then H3O+; d p-xylene, CF3SO3H, 25 °C
D
D
A
29
27
28
A
31 R5 = iPr
34 R5 =tBu
32 R6 = iPr
35 R6 =tBu
R = iPr, tBu
Scheme 10 Substituted indanones from p-substituted toluenes; a CF3SO3H, 25 °C; d polyphosphoric acid, 100 °C
1 3

Journal of Chemical Crystallography
frustrate placement of the bulky isopropyl and tert-butyl
substituents adjacent to the gem-dimethyl groups, and with
bromine, several rearranged products were formed.
In some cases, derivative endocyclic secondary pseu-
doamides were prepared to compare with the pseudoacids.
These were derived from the pseudoacyl chlorides as shown
in Scheme 12 [26, 27].
Since the aim was to place bulky substituents at the 4-
and 5- positions of the parent arylpyran pseudoacid (1),
two additional compounds were synthesized. In one case,
3-phenylbut-2-enoic acid (19) was reacted with p-xylene to
form 3,4,7-trimethyl-3-phenyl-1-indanone (20). In a second
case, 19 was reacted with p-chlorotoluene. In the latter case,
the adjacent bulky groups led to rearrangement during the
chalcone cyclization, forming to 3-methyl-3-(2′-methyl-
5′chlorophenyl)-1-indanone (48). The pseudoacids (3, 4)
from each of these indanones were then prepared follow-
ing the general method (Scheme 11). This family of com-
pounds was used to explore the open-cyclic equilibria of the
3-hydroxyisobenzopyran-1-one system.
Experimental
Materials were purchased from Sigma-Aldrich Chemical
Company, TCA America, VWR Scientifc Company and
used as received. Nuclear magnetic resonance spectroscopy
were recorded on a Varian Avance or Bruker 400 MHz
instrument with an upper limiting probe temperature of
130 °C; all spectra in 5 mm tubes, reference tetramethylsi-
lane. Correlation spectroscopy was used to confrm inter-
nuclear magnetic contacts, and calculated shieldings were
B,C
A,D
19
20
3
B,C
A
19
4
48
Scheme 11 3-Aryl isobenzopyrn-1-ones from arenes and 3-phenyl-2-butenoic acid (see Schemes 7, 10)
b
a
11
45
46
44
42
41
Scheme 12 Secondary pseudoamides from pseudoacids: a SOCl2, 55 °C, 12 h; b benzylamine, 55 °C, 2 days, and others prepared by this
method
1 3

Journal of Chemical Crystallography
Table 1 Proton chemical shifts for pseudoacids (26 °C, in CDCl3)
2 (67.3%)
2 (32.7%)
3 (75.9%)
3 (24.1%)
4 (72.0%)
4 (28.0%)
Ar–H
7.993 d
7.286 t
7.993 d
7.277 t
7.1–7.4
m 7H
7.1–7.4 m 7H
8.154 d
7.820 d
7.576 t
7.205 t
8.255 d
7.947 d
7.537 t
7.395 t
J
78 =J67 =7.6 Hz
J78 =J67 =7.6 Hz
7.499 t
7.238 d
7.504 t
7.238 d
J
56 =J67 =J78 =7.7 Hz
J
56 =J67 =J78
J
56 =J67 =7.6 Hz
J
56 =J67 =7.6 Hz
7.271 s
= 7.6 Hz
7.476 s
7.084 d
6.923 d
J=7.7 Hz
7.121 d
6.756 d
J=7.6 Hz
Ps-H
Ar-Me
5.573 s
n.a.
5.558 s
n.a.
5.664 s
5.350 s
5.300 s
2.360 s
5.212 s
2.408 s
2.673 s
2.701 s
1.800 s
1.901 s
Me (at C4)
CH2
1.360 s
1.66 dq
1.324 s
1.641 s
n.a.
1.836 s
n.a.
1.802 s
n.a.
1.569 s
n.a.
1.66 dq
J
gem =14 Hz
Jgem =14 Hz
CH3
OH
0.81 t
0.77 t
n.a.
n.a.
n.a.
n.a.
J=7.3 Hz
J=7.5 Hz
5.62 s(br)
5.33 s(br)
5.97 s(br)
4.80 s(br)
5.60 s(br)
5.58 s(br)
5
6
7
8
9
Ar–H
7.201, 7.065
7.06, 7.057
7.469, 7.123
7.868, 7.583
7.944 s
7.563 s
5.470 s
2.429 s
1.354 s
dd J67 =7.6 Hz
5.253 s
dd J67 =0.8 Hz
5.276 s
dd J67 =7.8 Hz
dd J57 =1.3 Hz
5.290 s
Ps-H
Ar-Me
Me,a
5.297 s
2.629 s
1.508 s
2.605 s, 2.459 s
1.429 s
2.541 s
2.272 s
1.414 s
1.369 d
5JHF =4.0 Hz
Me,b
(CH3)2CH
OH
1.494 s
n.a.
5.11 s(br)
1.429 d 5JHF =1.4 Hz
1.628 s
n.a.
7.77 s(br)
1.610 s
n.a.
4.94 s(br)
1.361 s
n.a.
4.14 s(br)
n.a.
5.4 s(br)
10
11
12
Ar–H
7.917 d
7.164 s
7.109 s
7.241 s
7.214 s
J
68 =1.0 Hz
7.418 dd
7.298 d
J
56 =7.9 Hz
Ps-H
Ar-Me
Me,a
Me,b
CH(CH3)2
5.466 s
2.396 s
1.377 s
1.392 s
n.a.
5.296 s
2.548 s
1.245 s
1.245 s
5.374 s
2.680 s
1.389 s
1.382 s
n.a.
2.916 septet
1.218 d J=6.8 Hz
(CH3)3C
OH
n.a.
3.8 s(br)
n.a.
3.32 s(br)
1.339 s
3.24 s(br)
n.a. not applicable, s singlet, d doublet, t triplet, q quartet; m multiplet(s), br broad
used to assist in assigning carbon resonances. Some spectra
reported in Tables 1, 2, and 3.
ethanol. To this solution, 3.40 g (50 mmol) sodium ethoxide
was added followed by 3.60 g (50 mmol) butanone. After
1 h at 25 °C, the mixture was warmed to 50 °C for 1 h, then
cooled and carefully acidifed with 2 M HCl, and extracted
with ether. The ether extract was washed with water,
then brine, and the ether removed by rotary evaporation.
The product oil was dissolved in 20 mL THF, and added
3-Hydroxy-4,4-dimethyisobenzopyran-1-one, 1. Cooper’s
pseudoacid was prepared as previously described [14].
2,2-Dimethyl-5-(2′-phenylbut-2′-yl)-1,3-dioxan-4,6-
dione, 13, [2-(2-Phenylbut-2-yl)Meldrum’s acid.] Mel-
drum’s acid, 7.20 g (50 mmol) was dissolved in 30 mL
1 3

Journal of Chemical Crystallography
Table 2 Proton chemical shifts
for pseudoamides (26 °C, in
CDCl3)
41
42
44
46
Ar–H
8.045 d
7.323 t
8.161 d
7.392, t
7.319 d
7.067 d
7.071 s
6.994 s
J
78 ≈J67 ≈7.6 Hz
J
78 ≈J67 ≈8 Hz
J67 =7.4 Hz
7.483 dd
7.510, dd
J
56 =7.2 Hz
J56 ≈4.8 Hz,
7.333 d
n.a.
7.275, d
Phenyl-H
Ps-H
7.2–7.5 m, 5H
n.a.
4.446 s
7.4–7.7 m, 5H
4.598 s
4.577 d
4.186 d
J=6.4 Hz
J=10.4 Hz
Me(s)
Ar–CH3
benzyl-CH2
1.504 s, 1.238 s
n.a.
n.a.
1.432 s, 1.024 s
n.a.
1.754 s,1.366 s
2.618 s
n.a.
1.399 s, 0.984 s
2.772 s
5.256, 4.477 dd
5.377, 4.169 dd
J=14.4 Hz
J=14.0 Hz
CH2–CH2–CH3
3.883 dt, 3.229 dt
J=8.1, 14.0 Hz
1.679 m
n. a.
n.a.
3.680 m, 3.388 m
1.688, m
n.a.
0.983 t J=7.6 Hz
0.966 t J=7.4 Hz
(CH3)3CH–
OH
n.a.
n.a.
1.267 d
2.90 septet
J=6.1 Hz
2.880 s(br)
4.382 d
5.501 s
6.145 d
J=6.4 Hz
J=10.4 Hz
n.a. not applicable, s singlet, d doublet, t triplet, q quartet; m multiplet(s), br broad
dropwise under dinitrogen gas to a stirred mixture of phenyl
magnesium bromide (32.5 mL, 2 M in THF, 65 mmol) to
which 1 mol % CuCl had been added. The mixture changed
color from green to brown, then to red, and fnally to orange
over 27 h. The mixture was poured into 250 mL of 5% HCl,
and extracted with ethyl acetate. The extract was washed
with water, then with brine and the solvent removed by
rotary evaporation leaving 13 as a pale yellow oil, 10.1 g
(73% yield); the oil crystallized at -10 °C. 1H-NMR (CDCl3,
26 °C) δH: 7.2–7.4, m, 5H, Ar–Hs; 3.84, s, 1H, methine;
2.08, s, 6H, methyls; 2.16, 1.89, m, 2H, CH2; 1.61, s, 3H,
CH3; 0.63, t J=7.2 Hz, CH3CH2. 13C-NMR, δC: 1631, 161.9,
diastereotopic C=O’s; 128,0, 129.3, 130.9, 142.0, aryl C’s;
105.2, ketal C; 57.3, CH(C=O)2; 46.0, quat-C; 32.3 30.1,
27.7, 8.0; alkyl C’s.
t, J=7.4 Hz, 3H, CH3CH2; 1.375, s, 3H, C–CH3; 1.612, q,
J=7.4 Hz, 1H, HCH; 1.772, q, J=7.4 Hz; 1H, HCH; 2.515,
2.615, doublets, Jgem =13.4 Hz, 2H, CH2; 7.015-7.283, m,
5H, Ar–Hs; 8.433, s(br), 1H, acid-H. 13C-NMR, δC: 176.7,
CO2H; 145.0, 127.1, 125.0, 124.9, Aryl-Cs; 45.5, CH2CO2H;
39.4, quat-C; 34.1, CH2; 22.9, CH3-CH2; 7.5, CH3.
3-Ethyl-3-methylindan-1-one, 15. 3-Methyl-3-phe-
nylpentanoic acid 14, 0.459 g (2.39 mmol) was placed in
a open large tube, and 20 g of polyphosphoric acid (PPA)
was added. The contents of the tube were stirred constantly
while heated to~100 °C (not exceeding 105 °C). After 2 min
above 90 °C, an additional 20 g PPA was added, and the
mixture was stirred at 85–100 °C for 5 min resulting in a
dark brown color. The mixture was cooled to room tempera-
ture and 50 mL water was added with stirring to thoroughly
dilute the viscous solution, resulting in a yellow suspension.
The mixture was extracted with portions of ether, and the
pooled ether extracts were washed with brine, and the sol-
vent removed by rotary evaporation. The resulting oil was
fash chromatographed (silica, CHCl3), and product 15 was
3-Methyl-3-phenylpentanoic acid, 14. Decomposition
of 2-(2′-phenylbut-2-yl)Meldrum’s acid. In a 100 mL fask
equipped with stir bar, 1.00 g of 13 (4.24 mmol) was com-
bined with 1 mL of acetic acid and 10 mL of 2 M sulfuric
acid. The mixture was heated to refux gently (about 100 °C)
for 17 h. After cooling, the aqueous and oily phases were
transferred to a separatory funnel and extracted with chlo-
roform. The organic phase was then extracted with 0.5 M
sodium hydroxide, and the alkaline phase was separated and
acidifed with 1.0 M hydrochloric acid, producing a cloudy
suspension. This suspension was extracted with ether and the
ether solution was dried over anhydrous sodium sulfate and
solvent removed by rotary evaporation leaving 14 as a yellow
oil, 0.308 g, 40% yield. 1H-NMR (CDCl3, 26 °C) δH: 0.589,
1
obtained as a yellow-orange oil, 0.291 g (70%). H-NMR
(CDCl3, 26 °C): δH 7.692-7.302, 4H, d, t, d, t, aryl H; 2.630,
d J=18 Hz, 1H, HCH; 2406, d J=18 Hz, 1H, HCH; 1.742-
1.656, m, 2H, CH2; 1.369, s, 3H, CH3; 0.709, t J=7.2 Hz,
3H, CH2CH3; 13C- NMR: δC 204.8, C=O; 161.5, 135.1,
133.8, 126.3, 122.8, 122.1, aryl C’s; 48.5, CH2; 41.2, quat-
C; 33.6, 26.8, 8.2 alkyl C’s.
2-Acetoxy-3-ethyl-3-methylindan-1-one, 16. To 0.465 g
(2.67 mmol) of 15 dissolved in 30 mL glacial acetic acid
1 3

Journal of Chemical Crystallography
Table 3 Carbon chemical shifts for pseudoacids and pseudoamides (26 °C, in CDCl3), ppm, reference TMS, rounded to nearest 0.1 ppm
8
8a
7
3
4
6
4a
5
2
2
3
3
5
6
7
8
(major)
(minor)
(major)
(minor)
C=O
C3 Pseudoacyl
C4 Quaternary
164.7
100.3
40.6
164.8
100.4
40.2
165.2
100.3
48.4
165.1
99.7
47.9
165.0
101.4
40.3
163.0
100.3
37.3
164.1
101.4
40.4
165.1
102.5
40.1
C8a
C4a
C5
C6
C7
122.7
144.0
125.0
133.0
126.0
129.1
31.4
122.8
145.1
126.0
133.2
126.0
129.2
25.8
124.0
145.7
126.8
134.5
128.6
131.1
22.7
124.3
144.5
127.2
134.4
128.4
131.0
22.8
123.6
144.1
133.7
137.4
130.7
140.6
122.7
131.9
158.0
120.4
130.9
137.9
24.2 21.4
125.3
142.8
130.7
136.0
131.8
141.9
126.2
141.7
121.1
138.5
130.6
140.6
C8
Methyl(s)
26.4
22.5
24.4
at C4
22.6
24.0
22.9
Aryl-Me(s)
Aryl at C4
n.a.
n.a.
n.a.
n.a.
21.3
16.2
137.4
128.6
128.1
127.4
21.7
16.2
137.3
128.7
127.4
127.3
24.6
23.0
n.a.
21.1
n.a.
22.7
n.a.
20.3
n.a.
CH2
CH3
17.9
7.4
20.8
6.9
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
9
10
11
12
41
42
44
46
C=O
C3 Pseudoacyl
C4 Quaternary
165.0
102.7
38.2
164.9
102.2
39.5
164.5
100.2
39.0
163.0
100.2
38.5
163.3
89.1
39.3
162.9
86.4
37.9
163.2
90.3
41.8
163.1
87.9
38.5
C8a
C4a
C5
C6
C7
C8
122.6
145.3
126.2
129.2
131.3
145.3
123.8
145.5
122.3
133.8
127.4
142.3
119.7
147.3
119.3
155.7
127.3
140.7
119.3
147.3
119.7
155.8
127.3
140.8
124.8
143.7
127.0
132.5
127.3
128.5
123.7
143.6
125.7
131.6
127.0
127.6
129.4
140.0
130.6
131.9
134.1
139.8
123.4
145.0
121.2
148.8
129.4
141.4
Methyl(s) at C4
25.0
26.9
26.5
26.1
29.7
26.7
25.1
29.5
22.5
22.6
22.5
21.9
21.7
21.6
21.7
23.6
Ar-Me
N-CH2(benzyl)
Aryl at N
23.7
n.a.
n.a.
22.5
n.a.
n.a.
23.0
n.a.
n.a.
22.2
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
63.8
136.4
127.8
127.4
126.5
22.6
n.a.
n.a
23.7
63.5
135.8
130.8
128.6
127.6
CH-(CH3)2
n.a.
n.a.
34.0
23.8
n.a.
n.a.
n.a.
n.a.
34.2
23.7
(CH3)3
N-CH2(propyl)
CH2-CH3
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
30.6
n.a.
n.a.
n.a.
47.8
n.a.
n.a.
n.a.
n.a.
48.3
n.a.
n.a.
n.a.
22.8
25.6
11.5
11.5
Notes: (1) CA–CF assigned from known shieldings [45]; mean deviations │(δoCbs −δCcalc)│: 0.7 (2, major), 0.7 (5), 0.0 (6), 0.3 (7), 0.3 (8), 0.3
(10), 1.2 (11), 1.0 (12)
1 3

Journal of Chemical Crystallography
and 8 mL of acetic anhydride, 1.78 g (4.01 mmol) of
lead(IV) acetate was added, and the mixture was heated
to 75 °C while stirring. A modestly exothermic reaction
sets in after about an hour raising the temperature to about
90 °C, and the reaction was then allowed to return to 75 °C
and maintained at that temperature for a day. The reaction
was complete as judged by the absence of the indanone
4-Fluoro-3,3,7-trimethyl-1-indanone, 17. (General
method A.) A mixture of 0.550 g (5.00 mmol) p-fuorotolu-
ene and 0.500 g (5.00 mmol) 3-methylcrotonic acid in 5 mL
dichloromethane was cooled to 0 °C while stirring. All at
once, 18 mL of trifuoromethanesulfonic acid was added as
the mixture was continually stirred at 0 °C. The reaction is
not exothermic. After 2 h, the mixture was allowed to warm
to room temperature, then poured into 100 mL of water
and extracted twice with diethyl ether. Ether extracts were
washed with saturated aqueous sodium bicarbonate solu-
tion, then water, then brine, and the ethereal solution was
evaporated slowly under an air stream. Colorless crystals
of 17 deposited, 0.680 g, yield 71%. NMR (CDCl3, 26 °C):
1H-NMR: (26 °C, CDCl3): δH 7.055, d, J=8.6 Hz, 1H, H6;
6.991, dd, JFH =5.2 Hz, 1H, H5; 2.507, s, 2H, C2H2; 2.500,
s, 3H, Ar–CH3; 1.430, s, 6H, (CH3)2.
1
methylene signal by H-NMR, the mixture was cooled,
poured into 200 mL ice-water, and the two-phase product
was extracted with diethyl ether. The ether extract was
washed with water (but not with sodium bicarbonate since
the ester was sensitive to base hydrolysis), and the ether
and excess acetic acid were removed in vacuo (several
1
days) leaving an orange oil, 0.568 g, (92%). H-NMR
(CDCl3, 26 °C): δ 7.438-7.762, m, 4H, aryl Hs; 5.606,
5.492, singlets, 1H, (trans, cis), C2–H; 2.417, 2.247,
3H, singlets, CH3CO2-, (trans, cis);1.909, 1.619, 2H, m,
(trans, cis), CH2CH3; 1.199, 1.549, 3H, singlets (trans,
cis), CH3; δ 0.888, 0.750, triplets, J = 7.2 Hz, 3H, (trans,
cis), CH2CH3; integrations 68% trans.
2-Acetoxy-4-fuoro-3,3,7-trimethyl-1-indanone, 18. (Gen-
eral method B.) To 2.500 g (13.0 mmol) of 17 dissolved in
30 mL glacial acetic acid and 8 mL of acetic anhydride,
6.00 g (13.5 mmol) of lead(IV) acetate was added, and the
mixture was heated to 75 °C while stirring. A modestly
exothermic reaction sets in after about an hour raising the
temperature to about 90 °C, and the reaction was allowed
to return to 75 °C and maintained at that temperature for
a day. An NMR sample was taken to assess the complete-
ness of the reaction, and an additional 1.0 g (2.2 mmol) of
lead(IV) acetate was added, if necessary. (This step may be
repeated.) When the reaction was complete (as judged by the
absence of the indanone methylene signal and appearance of
the downfeld ester methine signal) the reaction mixture was
cooled, poured into 200 mL ice-water, and the two-phase
product was extracted with diethyl ether. The ether extract
was washed with water (but not with sodium bicarbonate
since the ester is sensitive to base hydrolysis), and the ether
and acetic acid were removed in vacuo (several days) leaving
18 as a slowly crystallizing yellow oil, 2.75 g, yield 79%.
NMR (CDCl3, 26 °C): δH 7.2–7.4, m, 2H, Ar–Hs; 5.389, s,
1H, C2–H; 2.567, s, 3H, Ar–CH3; 1.649, s, 3H, CH3; 1.276,
s, 3H, CH3.
4-Ethyl-3-hydroxy-4-methylisobenzopyran-1-one, 2.
Acetoxyindanone 16 (0.568 g, 2.58 mmol) was dissolved
in 10 mL methanol and transferred to an addition funnel.
In a 50 mL reaction fask equipped with a stir bar, 10 mL
methanol, 0.373 g (3.52 mmol) sodium carbonate, and
10 mL water were combined, and dinitrogen gas was passed
through the solution for 10 min. The methanolic solution of
16 was then added dropwise under dinitrogen over a 10 min
period at room temperature to this solution. The mixture,
which changed color during the reaction from light yellow
to dark brown, was allowed to react for 2 h. The intermedi-
ate alcohol (Scheme 6, step c) was isolated by acidifying
the product methanolic solution with 2 M sulfuric acid and
extracting with four portions of ether. After the solvent was
removed, 0.428 g (87%) of the alcohol is recovered, and it
was carried to the pseudoacid with little delay to prevent
oxidation. To verify completeness of the reaction and pres-
1
ence of the alcohol, H-NMR (CDCl3, 26 °C) shows the
diasteereomeric methine-Hs at δ 4.307 and δ 4.210, singlets,
replacing the more downfeld methine signals of the ester
precursors (vide infra). The oily alcohol was dissolved in
5 mL tetrahydrofuran and water (~2 mL) was added to the
cloud point. Sodium periodate (0.446 g, 2.25 mmol) was
added and the reaction was allowed to stir at room tempera-
ture for 18 h. Sodium iodate precipitated from the reaction
mixture, which was then fltered, and the tetrahydrofuran
removed with a gentle stream of air. The oily product was
partitioned between 1 M NaOH and dichloromethane. The
aqueous phase was acidifed to pH 2.0 with 1.5 M HCl, and
the cloudy suspension was extracted with dichloromethane.
The organic phase was separated and evaporated under an air
stream, leaving 0.380 g (85%) 2, as a pale yellow oil. NMR,
see Tables 1 and 3.
5-Fluoro-3-hydroxy-4,4,8-trimethylisobenzopyran-
1-one, 6. (General method C.) To a solution of 20 mL
methanol, 5 mL water, and 1.00 g (7.2 mmol) potassium
carbonate under dinitrogen gas was slowly added a solu-
tion of 2.00 g (8.0 mmol) 18 in 5.0 mL methanol over a
30 min period. The suspension began to take on an increas-
ingly yellow color, giving way to a reddish and eventually
to a deep bluish color. After a total of 1 h, the suspension
was acidifed by addition of 20 mL of 3 M hydrochloric
acid, and the light yellow solution was treated with 6.0 g
sodium sulfate dodecahydrate, and extracted with diethyl
ether. The ether was removed by rotary evaporation leav-
ing the alcohol 4-fuoro-2-hydroxy-3,3,7-trimethyl-1-in-
danone a yellow oil. The entire indanol sample was then
1 3

Journal of Chemical Crystallography
dissolved in 5 mL tetrahydrofuran to which just enough
water was added to maintain solution. To this mixture,
1.584 g (8.0 mmol) sodium metaperiodate was added, and
the reaction mixture stirred at room temperature. Over a
few hours, the solution clouds, then precipitates a white
NaIO3. After a day, the solids were fltered by suction, and
the resulting solution was evaporated leaving a pale yellow
solid, 1.40 g, 78% yield. The product was recrystallized
from ethyl acetate to aford colorless crystals. NMR, see
Tables 1 and 3.
3,3,7-Trimethyl-1-indanone, 27, and 4-bromo-3,3,6-
trimethyl-1-indanone, 28, and 5-bromo-3,3,7-trimethyl-
1-indanone, 29. (General method D.) Polyphosphoric acid
(10.0 g) was heated while stirring manually to achieve
90–100 °C. To this, chalcone 26 1.00 g (3.96 mmol) was
added and the mixture was stirred continuously for 6 min.
Then, an additional 4.0 g of polyphosphoric acid was added,
and the temperature returned to 90–100 °C for 6 min while
continually stirring. After cooling to about 50 °C, the mix-
ture was quenched with 100 g ice-water, and thoroughly
mixed to produce an oily suspension. The mixture was
extracted with ether (2× 40 mL), and the combined ether
solutions were washed with water, then brine, and the ether
was removed by rotary evaporation to produce a yellow oil,
0.92 g, 92%. The product is a mixture of indanones 27–29
3,3,4,7-Tetramethylindan-1-one, 22. This compound was
prepared from p-xylene and 3-methylcrotonic acid using
general method A, and isolated as a colorless oil, yield 72%.
1H-NMR (CDCl3, 26 °C): δH 7.19, 7.00, dd, J=8.0 Hz, 2H,
Ar–H’s; 2.60, 2.47, singlets, 6H, Ar–CH3s; 2.58, s, 2H, CH2;
1.48, s, 6H, (CH3)2; 13C–NMR: δC: 207.0, ketone C=O;
160.50, 137.04, 136.25, 133.47, 132.30, 129.71, Aryl-Cs;
55.38, C2; 38.86, C3; 28.08, 19.41, 18.39, methyl Cs.
2-Acetoxy-3,3,4,7-tetramethylindan-1-one, 23. This com-
pound was prepared from indanone 22 following general
method B, and isolated as a yellow oil, yield 85%. 1H-NMR
(CDCl3, 26 °C): δH 7.26, 7.05, dd, J=6.0 Hz, 2H, Ar–Hs;
5.42, s, 1H, C2–H; 2.58, 2.48, singlets, 6H, Ar–CH3s; 2.25,
s, 3H, CH3C=O; 1.62, 1.24, singlets, 6H, (CH3)2; 13C–NMR:
δC 200.5, ketone C=O; 170.7, ester C=O; 132.3, 138.0,
130.5, 130.4, 156.4, 136.8, Aryl-Cs; 82.8, C2; 42.5, C3; 19.5,
20.8, 25.6, 23.6, 18.2, methyl Cs.
1
which were not separated at this stage. H-NMR (CDCl3,
26 °C): δH (28) 7.85, d J=2 Hz, 1H, Ar–H; 7.22, d, J=2 Hz,
1H, Ar–H; 2.644, s, 3H, Ar–CH3; 2.580, s, 2H, CH2; 1.589,
s, 6H, (CH3)2C; (29) 7.60, s, 1H, Ar–H; 7.35, s, 1H, Ar–H;
2.368, s, 3H, Ar–CH3; 2.496, s, 2H, CH2; 1.402, s, 6H,
CH3)2C. Indanone 27 was a minor component.
2-Acetoxy-4-bromo-3,3,6-trimethyl-1-indanone, 30, and
2-acetoxy-5-bromo-3,3,7-trimethyl-1-indanone, 31. These
compounds were prepared from the mixture of indanones
28 and 29 by general method B, and obtained as an oil, 40%
yield. 1H-NMR (CDCl3, 26 °C): δH (29) 7.376, 7.168, dou-
blets, J=8.0 Hz, 2H, Ar–Hs; 5.456, s, 1H, C2–H; 2.371, s,
3H, Ar-CH3; 2.247, s, 3H, CH3C=O; 1.535, s, 3H, CH3;
1.171, s, 3H, CH3; (30) 7.655, 7.527, singlets, 2H, Ar–Hs;
5.300, s, 1H, C2–H; 2.383, s, 3H, Ar–CH3; 2.258, s, 3H,
CH3C=O; 1.744, s, 3H, CH3; 1.311, s, 3H, CH3.
3-Hydroxy-4,4,5,8-tetramethylisobenzopyran-1-one, 5.
Compound 5 was prepared from the ester 23 by general
method C, and isolated as a colorless solid, 18% overall from
p-xylene. NMR, see Tables 1 and 3.
4-Chloro-3,3,7-trimethyl-1-indanone. 24. This compound
was prepared from p-chlorotoluene and 3-methylcrotonic
acid following general method A, and isolated as a colorless
oil, yield 60%. 1H-NMR (CDCl3, 26 °C): δH 7.381, 7.048,
dd, J=7.9 Hz, 2H, Ar–Hs; 2.609, s, 2H, CH2; 2.589, s, 3H,
Ar–CH3; 1.572, s, 6H, (CH3)2.
5-Bromo-3-hydroxy-4,4,7-trimethylisobenzopyran-1-one,
8, and 6-bromo-3-hydroxy-4,4,8-trimethylisobenzopyran-
1-one, 9. Compounds 8 and 9 were made from the mixture
of esters 30 and 31 following general method C, and isolated
as a slowly crystallizing oil, 30% overall from p-bromotolu-
ene. The crude reaction product was subjected to thick-layer
chromatography, 2 mm SiO2, CHCl3: ethyl acetate (10:1);
the band at Rf 0.5–0.6 contained the products. This fraction
was isolated and re-applied to thick-layer silica, and repeat-
edly eluted with CHCl3 (stabilized with amylene) until the
lead component of the mixture reached Rf 0.5. Compound
8 elutes at Rf 0.5, and compound 9 elutes at Rf 0.4, with a
small amount of 3-hydroxy-4,4,8-trimethylisobenzopyran-
1-one (10) also obtained at Rf 0.3. NMR, see Tables 1 and 3.
1-(5′-Isopropyl-2′-methylphenyl)-3-methylbut-2-en-1-one,
32. To a solution of 1.00 g (10.0 mmol) 3-methylcrotonic
acid and 1.342 g (10.0 mmol) p-cymene in 5 mL dichlo-
romethane was added 10 mL of CF3SO3H all at once. The
reaction was not exothermic, and after stirring at room
temperature for 2 h, the reaction mixture was poured into
100 mL ice-water. The suspension was extracted with ether
(2 × 40 mL) and the organic extracts were washed with
2-Acetoxy-4-chloro-3,3,7-trimethyl-1-indanone, 25. This
compound was prepared from indanone 24 following general
method B, and isolated as a yellow oil, yield 85%. 1H-NMR
(CDCl3, 26 °C): δH 7.457, 7.120, dd J = 8.0 Hz, Ar–Hs;
5.440, s, 1H, C2–H; 2.581, s, 3H, Ar–CH3; 2.267, s, 3H,
CH3C=O; 1.730, s, 3H, CH3; 1.319, s, 3H, CH3.
5-Chloro-3-hydroxy-4,4,8-trimethylisobenzopyran-1-one,
7. Compound 7 was prepared from the ester 25 following
general method C, and isolated as a colorless solid, 30%
overall from p-chlorotoluene. NMR, see Tables 1 and 3.
1-(5′-Bromo-2′-methylphenyl)-3-methylbut-2-en-1-one,
26. This chalcone was made from p-bromotoluene and
3-methylcrotonic acid following general method A, and was
obtained as a yellow oil, 80%. 1H-NMR (CDCl3, 26 °C): δH
7.0–7.5, m, 3H, Ar–Hs; 6.379, s, 1H, HC=; 2.633, s, 3H,
Ar–CH3; 2.170, 1.911, singlets, 6H, (CH3)2C=.
1 3

Journal of Chemical Crystallography
water, then brine, and the solvents removed by rotary evapo-
ration. Chalcone 32 was a pale yellow oil, 1.73 g, 80%. 1H-
NMR (CDCl3, 26 °C): δH 7.0–7.2, m, 3H, Aryl-Hs; 6.44, s,
1H, HC=; 2.35, s, 3H, =CCH3; 2.22, s, 3H, =CCH3; 2.09,
m, 1H, CH; 1.90, s, 3H, Ar–CH3; 1.23, d (J=7.2 Hz), 6H,
CMe2; 13C-NMR: δC 196.2, C=O; 156.3, 115.9, C=CH;
154.0, 138.3, 137.9, 129.9, 128.4, 122.3, Aryl-Cs; 34.1, CH;
28.2, 24.9, 24.2, 19.9, (CH3)s.
(CDCl3, 26 °C): δH 7.282, 7.184, singlets, 2H, Ar–Hs;
5.384, s, 1H, methine; 2.601, s, 3H, Ar–CH3; 2.240, s, 3H,
CH3C=O; 1.538, s, 3H, CH3; 1.323, s, 3H, CH3; 1.356, s,
9H, (CH3)3.
6-t-Butyl-3-hydroxy-4,4,8-trimethylisobenzopyran-1-one,
12. Compound 12 was prepared from ester 36 following gen-
eral method C, and the crude product was purifed by thick
layer chromatography (SiO2, 2 mm, CHCl3: ethyl acetate
10:1) and isolated as a colorless oil (Rf 0.4), 6% overall from
p-(t-butyl)toluene. NMR, see Tables 1 and 3.
5-Isopropyl-3,3,7-trimethylindan-1-one, 33. From chal-
cone 32 following general method D, the indanone was iso-
lated as a colorless oil, yield 40%. 1H-NMR (CDCl3, 26 °C):
δH: 7.21, d (J=1.2 Hz), Ar–H; 7.29, d, Ar–H; 2.38, m, 1H,
CH; 2.31, s, 3H, Ar–CH3; 1.705, s, 2H, CH2; 1.38, s, 6H,
(CH3)2C; 1.34, d J=6.9 Hz, 6H, (CH3)3CH; 13C-NMR: δC:
206, C=O; 165, 156, 138, 130, 128, 118, aryl-Cs; 54, CH2;
38, Cquat; 35, CH; 30, (CH3)2C; 24, CH3-Ar; 23, CH3-CH.
2-Acetoxy-5-isopropyl-3,3,7-trimethylindan-1-one, 34.
This compound was prepared from indanone 33 follow-
ing general method B and isolated as a yellow oil, yield
3-Phenylbut-2-enoic acid, 19. Step 1. Ethyl 3-phenyl-
2-butenoate. A two-necked fask equipped with a stirring
bar and rubber septa was purged with dinitrogen and all
operations were carried out under dinitrogen gas. Diisopro-
pylamine (6.68 g, 9.25 mL, 6.6 mmol) and 50 mL heptanes
were injected into the reaction fask, which was then cooled
in an ice bath to 0 °C. Then, 41.25 mL (6.6 mmol) of 1.6 M
n-butyllithium solution in hexane was added drop-wise
to the solution, and the mixture was stirred for 1 h. Then,
13.094 mL (14.80 g, 6.6 mmol) triethylphosphonoacetate
was added drop-wise after which the ice-bath was removed
leaving a bright yellow solution. After stirring for 90 min,
7.931 g (6.6 mmol) acetophenone was added slowly. Reac-
tion was stirred for 6 h then heated to refux gently at 75 °C
for 11 h. On cooling, diethylphosphoric acid precipitated as
a white solid. The mixture was fltered by suction, the pre-
cipitate was washed with pentane, and the combined organic
fltrates were reduced by rotatory evaporation leaving the
ester as an amber-brown oil with slightly fragrant odor,
8.40 g, 67% yield. 1H-NMR (CDCl3, 26 °C): δH 7.2–7.5, m,
5H, Ar–Hs; 6.13, s, 1H, =CH; 4.208, q J=7.2 Hz, 2H, CH2;
2.573, s, 3H, CH3–C=; 1.306, t, J=7.2 Hz, 3H, CH3–CH2.
Step 2. Two grams (0.0105 mmol) of the ester from Step 1
was combined with 40 mL of 0.5 M sodium hydroxide which
produced a cloudy yellow suspension. Ethanol was added
(about 5 mL) to efect solution, and the mixture was stirred
and heated to refux gently at 70 °C for 4 h. After cooling,
the mixture was acidifed with 0.5 M hydrochloric acid, and
the cloudy mixture was extracted with CH2Cl2. The CH2Cl2
layer was extracted again with 0.5 M sodium hydroxide,
and the aqueous phase was acidifed with 0.5 M HCl and
extracted a second time with CH2Cl2. Removal of the sol-
vent leaves a yellow solid, 1.53 g, 90% yield. Acid 19 was
recrystallized from hot water, leaving a white solid, which
proves to be the trans isomer. 1H-NMR (CDCl3, 26 °C): δH
8.47, s(br), acid OH; 7.512–7.382, aryl-Hs; 6.181, s, alkene-
H; 2.608, s, methyl. 13C-NMR: δC 158.383, =C3; 142.018,
phenyl ipso; 129.316, phenyl 4′; 128.557, aryl 2′; 126.396,
aryl 3′; 116.297,=C2H; 18.284, CH3.
1
65%. H-NMR (CDCl3, 26 °C): δH 7.323, 7.113, singlets,
2H, Ar–Hs; 5.457, s, 1H, C2-H; 2.900, m, 1H, CH(CH3)2;
2.482, s, 3H, Ar-CH3; 2.224, s, 3H, CH3C=O; 1.622, s, 3H,
CH3; 1.260, s, 3H, CH3; 1.239, d J=7.1 Hz, 6H, CH(CH3)2.
3-Hydroxy-6-isopropyl 4,4,8-trimethylisobenzopyran-
1-one, 11. Compound 11 was prepared from ester 34 fol-
lowing general method C, and the crude product was purifed
by thick layer chromatography (SiO2, 2 mm, CHCl3: ethyl
acetate 10:1) and isolated as a colorless oil (Rf 0.4), 15%
overall from p-cymene. NMR, see Tables 1 and 3.
1-(5′-t-Butyl-2′-methylphenyl)-3-methylbut-2-en-1-one,
35. To a solution of 1.00 g (10.0 mmol) 3-methylcrotonic
acid and 1.48 g (10.0 mmol) p-(t-butyl)toluene in 5 mL
dichloromethane was added 18 mL of CF3SO3H all at once.
The reaction was not exothermic, and after stirring at 25 °C
for 2 h, the reaction mixture was poured into 100 mL ice-
water. The suspension was extracted with ether (2×40 mL)
and the organic extracts were washed with water, then brine,
and the solvents removed by rotary evaporation. Chalcone 35
was a pale yellow oil, 1.84 g, 80%. 1H-NMR (CDCl3, 26 °C):
δH 7.488, d, J=7.2 Hz, 1H, Ar–H; 7.240, d, J=7.2 Hz, 1H,
Ar–H; 7.220, s, 1H, Ar–H; 6.463, s, 1H,=CH; 2.499, s, 3H,
Ar–CH3; 2.166, 1.956, singlets, 6H, (CH3)2C=; 1.313, s,
9H, (CH3)3.
5-t-Butyl-3,3,7-trimethylindan-1-one, 35. From chalcone
35 following general method D, the compound was isolated
as a yellow oil and purifed by fash chromatography (Rf
0.8; silica, CHCl3:ethyl acetate 10:1), yield 20%. 1H-NMR
(CDCl3, 26 °C): δH 7.277, s, 1H, Ar–H; 7.124, s, 1H, Ar–H;
2.618, s, 3H, Ar–CH3; 2.547, s, 2H, CH2; 1.395, s, 6H,
(CH3)2; 1.340, s, 9H, (CH3)3.
3,4,7-Trimethyl-3-phenyl-1-indanone, 20. This compound
was prepared from p-xylene and acid 19 by general method
A, and the product was obtained as a yellow oil, yield 90%.
1H-NMR (CDCl3, 26 °C): δH 7.4-7.0, m, 7H; 2.663, s, 3H,
2-Acetoxy-5-t-butyl-3,3,7-trimethylindan-1-one, 36. This
compound was prepared from indanone 35 following general
method B and isolated as a yellow oil, yield 65%. 1H-NMR
1 3

Journal of Chemical Crystallography
aryl-CH3; 1.851, s, 3H, aryl-CH3; 1.822, s, 3H, CH3; 2.833,
d, J=19.2 Hz, 1H, HCH; 2.863, d, J=19.2 Hz, 1H, HCH.
13C-NMR: δC 207.3, carbonyl; 160.6, 147.4, 137.2, 136.1,
133.7, 133.0, 130.2, 128.6, 126.2, 126.0, aryl-C’s; 58.1,
CH2; 45.632, quaternary-C; 25.6, 18.5, 18.4, (CH3)s.
2-Acetoxy-3,4,7-trimethyl-3-phenyl-1-indanone, 21. A
mixture of cis and trans isomers of 21 were prepared from
indanone 20 following general method B. The product was a
light yellow oil, yield 40%. 1H-NMR (CDCl3, 26 °C, major
trans form): δH 7.4-7.0, 2H, aryl Hs; 5.697, s, 1H methine-H;
2.643, s, 3H, ester Me; 2.185, 2.230, singlets, 6H, Ar–Me;
1.642, s, 3H, C3–Me.
for 1 d. Crystals of propylammonium chloride were fltered,
and the CHCl3 was allowed to evaporate. Colorless crystals
of 44 form, 0.051 g (95%). NMR, see Tables 2 and 3.
3-Chloro-4,4,8-trimethyl-6-isopropylisobenzopyran-
1-one, 45. To a solution of 11 (0.100 g, 0.402 mmol) in
2.0 mL CHCl3 was added 1.0 mL (1.6 g, 13.4 mmol) thionyl
chloride, and the mixture heated to 55 °C for 12 h. Excess
thionyl chloride was removed in vacuo leaving a pale yellow
oil, 0.102 g (95%). 1H-NMR (CDCl3, 26 °C): δH 7.03, s, 1H,
Ar–H; 6.97, s, 1H, Ar–H; 5.975, s, 1H, H–C3; 2.860, septet,
1H, (CH3)2CH–; 2.598, s, 3H, Ar–CH3; 1.426, s, 3H, CH3;
1.369, s, 3H, CH3; 1.204, d J=7.0 Hz, 6H, (CH3)2CH–.
3-Hydroxy-6-isopropyl-4,4,8-trimethyl-N-ben-
zyltetrahydrosoquinolin-1-one, 46. A solution of 0.050 g
(0.19 mmol) of chloride 45 in 4.0 mL CHCl3 was treated
with 1.00 g (9.3 mmol) benzylamine, and stirred at 55 °C
for 2 d. After cooling, the mixture was partitioned between
CHCl3 and 1 M HCl, and the organic phase was washed
with water, and the solvent removed in vacuo. The orange
oil was applied to thick-layer SiO2 plate (2 mm) and eluted
with CHCl3:ethyl acetate (10:1), and the material eluting at
Rf 0.4 is amide 46. Colorless crystals were obtained from
ethyl acetate solution by evaporation, 0.061 g (95%). NMR,
see Tables 2 and 3.
3-Hydroxy-4,5,8-trimethyl-4-phenylisobenzopyran-1-one,
3. A mixture of interconverting diastereomers of this com-
pound was prepared from ester 21 following general method
C. The product was purifed by thick-layer chromatography
(SiO2, CHCl3: ethyl acetate 10:1) with the product at Rf 0.45,
a colorless oil, yield 31%. NMR, see Table 1.
3-Chloro-4,4-dimethylisobenzopyran-1-one, 40. This
substance was prepared according to a literature method
[28]. 1H-NMR (CD3OD, 25 °C): δH 7.98, d, J=7.2 Hz, 1H,
C8-H; 7.51, t, J=7.5 Hz, 1H, C6-H; 7.33, d, 1H, C5-H; 7.26,
t, 1H, C7-H; 6.446, s, 1H, C3-H; 1.32, s, 3H, CH3; 1.27, s,
3H, CH3; 13C-NMR, δC: 165.8, C=O; 146.8, 134.6, 130.0,
127.1, 124.8, 123.3, aryl-C; 102.2, C3; 38.4, C4; 26.5, 21.9,
gem-dimethyl carbons.
3-Hydroxy-6-isopropyl-4,4,8-trimethyl-N-pro-
pylltetrahydrosoquinolin-1-one, 47. A solution of 0.050 g
(0.19 mmol) of chloride 45 in 4.0 mL CHCl3 was treated
with 1.00 g (17 mmol) n-propylamine, and stirred at 55 °C
for 2 d. After cooling, the mixture was partitioned between
CHCl3 and 1 M HCl, and the organic phase was washed with
water, and the solvent removed in vacuo. The yellow oil was
applied to thick-layer SiO2 plate (2 mm) and eluted with
CHCl3:ethyl acetate (10:1), and the material eluting at Rf
0.5 is amide 47. Colorless crystals were obtained from ethyl
3-Hydroxy-4,4-dimethyl-N-propyltetrahydrosoquinolin-
1-one, 41. A solution of 0.050 g (0.24 mmol) of chloride
40 in 4.0 mL CHCl3 was treated with 0.035 g (0.60 mmol)
1-propanamine, and stirred at 25 °C for 1 day. The mixture
was extracted with 5 mL 1 M HCl, and the organic layer
separated and allowed to evaporate. Colorless crystals of 41
deposit, 0.045 g (80%). NMR, see Tables 2 and 3.
3-Hydroxy-4,4-dimethyl-N-benzyltetrahydrosoquinolin-
1-one, 42. A solution of 0.050 g (0.24 mmol) of chloride
40 in 4.0 mL CHCl3 was treated with 0.064 g (0.60 mmol)
benzyl amine, and stirred at 25 °C for 1 day. The mixture
was extracted with 5 mL 1 M HCl, and the organic layer
separated and allowed to evaporate. Colorless crystals of 42
form, 0.040 g (80%). NMR, see Tables 2 and 3.
1
acetate solution by evaporation, 0.044 g (80%). H-NMR
(CDCl3, 26 °C): δH 7.014, s, 1H, Ar–H; 7.004, s, 1H, Ar–H;
4.538, d(br) J= 5.9 Hz, 1H, C3-H; 4.352, ddd J= 5.9, 7.8,
13.4 Hz, 1H, HC(–N)H; 4.338, ddd, 1H, HC(–N)H; 2.679,
s, 3H, Ar-CH3; 2.886, septet, J=5.9 Hz, (CH3)2CH; 2.06,
d(broad) J=5.9 Hz, 1H, OH;1.660, m, 2H, CH2; 1.4854, s,
3H, Me; 1.254, d J=5.9 Hz, 6H, (CH3)2CH; 1.2460, s, 3H,
Me; 0.981, t J=7.4 Hz, 3H, CH3. 13C: δC 163.6, C=O; 89.1,
C3; 123.5, C8a; 144.2, C4a; 121.2, C5; 152.5, C6; 129.4, C7;
141.2, C8; 39.8, C4; 29.6, Mea; 23.6, Meb; 23.5, Ar–Me;
34.2, CH; 23.7, (CH3)2CH; 48.1, CH2–N; 34.2, CH2; 11.5,
CH3.
3,5-Dichloro-4,4,8-trimethylisobenzopyran-1-one, 43.
To a solution of 7 (0.100 g, 0.44 mmol) in 2.0 mL CHCl3
was added 1.0 mL (1.00 g, 8.4 mmol) thionyl chloride,
and the mixture heated to 55 °C for 12 h. The solution was
evaporated in vacuo remove solvent and unreacted thionyl
chloride leaving a pale yellow oil, 0.108 g (95%). 1H-NMR
(CDCl3, 26 °C): δH 7.435, d J=8.4 Hz, 1H, Ar–H; 7.197,
d J=8.4 Hz, 1H, Ar–H; 5.914, s, 1H, C3–H; 2.650, s, 3H,
Ar–CH3; 1.743, 1.576, singlets, 6H, (CH3)2.
3-Methyl-3-(2′-chloro-5′-methylphenyl)-1-indanone, 48.
To a solution of 0.50 g (3.09 mmol) 3-phenylbut-2-enoic
acid (19) and 0.391 g (3.09 mmol) p-chlorotoluene in
5 mL dichloromethane were added 10 mL of CF3SO3H
all at once. The reaction was not exothermic, and after
stirring at room temperature for 2 h, the reaction mixture
was poured into 100 mL ice-water. The suspension was
5-Chloro-3-hydroxy-4,4,8-trimethyl-N-propyltet-
rahydrosoquinolin-1-one, 44. A solution of 0.050 g
(0.19 mmol) of chloride 43 in 4.0 mL CHCl3 was treated
with 1.00 g (16.9 mmol) 1-propanamine, and stirred at 25 °C
1 3

Journal of Chemical Crystallography
extracted with ether (2 × 20 mL) and the organic extracts
were washed with water, then brine, and the solvents
removed by rotary evaporation. Compound 48 was a pale
Dynamic Nuclear Magnetic Resonance
Spectroscopy
1
yellow oil, 0.281 g (30%). H-NMR (CDCl3, 26 °C): δH
Samples were dissolved in d6-DMSO, then degassed by
evacuation on cooling to − 96 °C, and sealed in 5.0 mm
NMR tubes. After setting probe temperatures, samples
were equilibrated for 20 min, shimmed and proton spec-
tra were collected. The chemical shifts and peak widths
for the gem-dimethyl peaks were analyzed by fitting
linewidths with WinDNMR [30–33]. Some variable tem-
perature data was similarly acquired in CDCl3 solutions,
but this limited the temperature to < 65 °C. The chemi-
cal shifts of the pseudoacyl-Hs display linear temperature
dependent changes suggesting the probe heater was operat-
ing within specifcations and producing a consistently lin-
ear range of temperatures. Probe design upper temperature
limit was 130 °C.
7.828, d, J = 7.5 Hz, 1H, C7–H; 7.572, t, J = 7.5 Hz, 1H,
C6–H; 7.42, t, 1H, C5–H; 7.031, d, J = 7.5 Hz, 1H, C4-H;
7.365, s, 1H, Ar–H; 7.193, d, J =7.5 Hz, 1H, Ar–H; 7.081,
d, 1H, Ar–H; 3.375, d, Jgem = 19.3 Hz, 1H, HCH; 2.794, d,
1H, HCH; 2.097, s, 3H, Ar–CH3; 2.225, s, 3H, C3–CH3.
2-Acetoxy-3-methyl-3-(2′-chloro-5′-methylphenyl)-1-
indanone, 49. This compound was prepared from indanone
48 following general method B and isolated as a yellow
oil, yield 58%. 1H-NMR (CDCl3, 26 °C, mostly trans Ph/
OAc): δH 7.825, d, J = 7.5 Hz, 1H, C7-H; 7.424, t, 1H,
C6–H; 7.571, t, 1H, C5–H; 7.028, d, J = 7.5 Hz, 1H, C4–H;
7.362, s, 1H, Ar–H; 7.208, d, J = 7.5 Hz, Ar–H; 7.081,
d, 1H, Ar–H; 4.600, s, 1H, C2–H; 2.401, s, 3H, Ar–CH3;
2.182, s, 3H, CH3CO2; 1.603, s, 3H, C3-H.
3-Hydroxy-4-methyl-4-(2′-chloro-5′-methylphenyl)
isobenzopyran-1-one, 4. This compound was prepared
from ester 49 by general method C. The crude product
was purifed by thick-layer (2 mm) chromatography (Rf
0.45, SiO2, CHCl3:ethyl acetate 10:1) and obtained as a
colorless solid, yield from p-chlorotoluene 15%. NMR see
Table 1.
6-tert-Butyl-3-hydroxy-4,4,8-trimethylisobenzopyran-
1-one, 12. This compound was prepared from ester 36 fol-
lowing general method C, and isolated as a pale yellow oil,
yield 8% based on p-(t-butyl)toluene. NMR see Table 1.
3-Hydroxy-4,4-dimethyl-7-nitroisobenzopyran-1-one,
50. This compound was prepared by a literature method
[14].
Fig. 2 Apparent chemical shifts diferences (ΔνMe) between dias-
tereotopic methyls of 1 decrease with increasing temperature (in
d6-DMSO)
7-Carboxy-3-hydroxy-4,4-dimethylisobenzopyran-
1-one, 51. This compound was prepared by a literature
method [29].
Fig. 1 Apparent diastereotopic methyl proton NMR chemical shifts
for 1 in d6-DMSO, with coalescence at 78.5 °C (trend-lines for com-
parison)
Fig. 3 Methyl chemical shifts for 1, 5–8, 11, 12 as a function of tem-
perature (d6-DMSO)
1 3

Journal of Chemical Crystallography
parameters for non-H atoms were refned by full-matrix
least-squares methods; H atoms were assigned locations
riding on their attached atoms, and assigned equivalent
isotropic librational parameters equal to 120% of the Ueq
of the attached atoms, 150% for methyl H’s. Hydroxy Hs
were located in diference density maps and allowed to
refne with a torsional parameter. Structures were refned
to convergence. Analytical absorption corrections were
applied to the data [37]. Drawings were prepared using
Mercury and ORTEP [38, 39]. Relevant metrics for the
molecular structures determined in the solid state are given
in Tables 6 and 7. Compound 8 was found to be very sol-
uble in most organic solvents, depositing crystals when
its concentrated solutions saturated. Invariably, retrieved
crystals of 8 were typically encrusted with a semi-opaque
veneer of microcrystallites. The structure reported here is
not in doubt though it is of inferior quality. The informa-
tion is relevant to the overall solution and solid state com-
parisons. Compound 10 is the frst arylpyran pseudoacid
observed to crystallize as a conglomerate; the specimen
absolute confguration could not be determined reliably
[Flack parameter -0.3(13)].
Cooper’s Pseudoacid (1)
Variable temperature NMR were collected between 26 °C
and 99 °C. Diastereotopic methyl chemical shifts for com-
pound 1 (d6-DMSO) show gradual increases with decreasing
diferences (ΔνMe) with increasing temperatures (Figs. 1 and
2). At 25 °C, ΔνMe was about 8 Hz and these signals broad-
ened approaching coalescence at 78.5 °C. The coalesced
signal sharpened above that. In CDCl3, ΔνMe declines from
18 Hz at 25 °C to 12 Hz at 65 °C, while in d4-acetic acid,
ΔνMe was about 11 Hz at 25 °C with coalescence at about
90 °C.
Other Pseudoacids
Among the enantiomeric pseudoacids (5–9, 11, 12), tem-
perature dependent studies were carried out in d6-DMSO
from 25 °C up to 100–125 °C. For compound 6, the gem-
dimethyls increase in chemical shift broadening into coales-
cence at 65 °C. For 7 and 8, methyl chemical shifts mostly
increased slightly with increasing temperature as ΔνMe
decreased (Fig. 3). For 11 and 12, ΔνMe modelstly increased
with temperature and eventually broadening, though coa-
lescence is above our experimental temperature capability.
Methyl signals for pseudoacid 5 show ΔνMe declining from
16 Hz at 25 °C to 6.5 Hz at 125 °C by which temperature,
signifcant line-broadening has occurred with coalescence
probably not far above 125 °C. Similar temperature depend-
ent studies were carried out in d6-DMSO on diastereomeric
pseudoacids 2 and 3.
Other structures were also determined from among
the synthetic targets of this study. Crystals of 17 were
orthorhombic, Pnma, a 8.3775(13)Å, b 6.9289(13)Å, c
17.9533(25)Å, molecules located on mirror planes. Crys-
tals of unsaturated acid 19 were triclinic, P-1, a 7.555(1)Å,
b 8.848(1) Å, c 13.830(2) Å, α 100.81(1)o, β 105.75(1)o, γ
97.72(1)˚, Z=6 (295 K). Poor quality and twinned crystals
of compound 9 were obtained from concentrated solutions,
and were monoclinic, P 21, a 14.194(2)Å, b 6.9676(10)Å,
c 20.339(3)Å, β 90.691(13)o, Z = 6 (101 K). This enan-
Computations
tiomeric phase showed (R) and (S) molecules in R2(12)
2
hydrogen-bonded pairs in general positions and an enan-
tiomer also in a general position forming C1(6) hydrogen-
bonded chains. The structure confrms the1spectroscopic
assignment 6-bromo-8-methyl substitution. Crystals of
47 were monoclinic, space group P21/c, a 16.106(6) Å,
b 10.036(2) Å, c 10.118(3) Å, β 96.25(3)o (110 K); low
resolution and shows 6-isopropyl-8-methyl rearranged
structure.
Ground state, gas-phase electronic energies were computed
at the B3LYP/6-31 + (G(d,p) level with SPARTAN-18 to
estimate a) the energy diferences between open and cyclic
1, and b) the ground-state (gas phase) molecular geometries
for 1, 5–8, 10 for comparison with the structural geometries
determined by difraction methods [34].
Crystallography
Crystallographic information for the structures (4,
1972595; 5, 1972592; 6, 1972594; 7, 1972593, 8,
1985346; 10, 1985345; 17, 1972591; 19, 1972599; 41,
1972598; 42, 1972597; 44, 1972596; 46, 1972590) have
been deposited with the Cambridge Crystallographic Data
Center. CCDC data can be obtained from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033, or by request at
https://www.ccdc.cam.ac.uk/structures/.
Crystals were obtained by slow evaporation of ethyl ace-
tate, or by vapor difusion (pentane into ethyl acetate), or
from the purifed oils on standing. Data were collected
on specimens of pseudoacids 4–8 and10, and pseudoam-
ides 41, 42, 44, 46 using a Rigaku-Oxford Gemini sin-
gle crystal X-ray difractometer ftted with a cryojet to
achieve lower specimen temperatures. Relevant experi-
mental details are given in Table 4 and 5. Molecular struc-
tures were determined with SHELXS, and refned with
SHELXL [35, 36]. Positions and anisotropic librational
1 3

Journal of Chemical Crystallography
Table 4 Crystal structure information for pseudoacid structures
Compound
4
5
6
7
Formula
C17H15ClO3
302.76
163(2)
Mo Kα
316
C13H16O3
220.27
150(2)
Mo Kα
472
C12H13FO3
224.23
100(2)
Mo Kα
236
C12H13ClO3
240.67
100(2)
Mo Kα
504
Formula Weight
Temperature, K
Radiation
F(000)
Crystal size
Crystal system
Space Group
Cell Constants
a (Å)
b (Å)
c (Å)
0.046×0.19×0.37
Triclinic
P−1
0.30×0.43×0.51
Monoclinic
P 21/n
0.18×0.55,×0.65
Triclinic
P−1
0.26×0.55×0.74
Monoclinic
P 21/c
8.3276(8)
9.020(2)
9.6848(13)
88.879(16)
82.249(10)
73.292(16)
689.6(2)
8.2540(3)
18.0912(5)
8.3216(3)
90
116.227(4)
90
1114.69(7)
4, 1.313
0.092
7.2042(8)
8.1585(8)
8.9914(6)
90.602(7)
94.510(7)
93.263(9)
525.92(9)
2, 1.416
7.4682(2)
8.0728(2)
18.6304(7)
90
99.401(3)
90
1108.13(6)
4, 1.443
0.333
α (°)
β (°)
γ (°)
Volume (Å3)
Z, density(Mg/m3)
2,1.458
0.284
μ (mm−1
)
0.112
Data, Rmerge
Unique data, I>2σI
4907, 0.0343
3076, 2271
99.4, 25.24
12,103, 0.0264
3730, 2987
99.8, 25.24
5509, 0.0249
3396, 2758
99.5, 25.24
7481, 0.0211
3597, 3109
99.5 25.24
Completeness
[%, full θ, (°)]
R, wR (unique data)
R (I>2σI)
Parameters, restraints
Goodness-of-ft
Δρ(fnal) (e−/Å3)
0.0942, 0.1621
0.0663
192, 0
1.068
+0.82, − 0.35
0.0613, 0.1112
0.0482
147, 0
1.042
+0.58, − 0.23
0.0628, 0.1189
0.0507
146, 0
1.039
+0.54 − 0.27
0.0490, 0.1017
0.0415
146, 0
1.039
+0.49, − 0.41
Compound
8
10
Formula
C12H13BrO3
285.14
102(2)
Mo Kα
576
C12H14O3
206.24
102(2)
Mo Kα
440
Formula Weight
Temperature, K
Radiation
F(000)
Crystal size
Crystal system
Space Group
Cell Constants
a (Å)
b (Å)
c (Å)
0.10×0.20×0.40
Monoclinic
P 21/c
0.18×0.28×0.31
Orthorhombic
P 212121
8.6384(9)
18.8567(18)
7.2572(7)
90
7.3917(2)
8.1635(3)
17.6951(7)
90
α (°)
β (°)
γ (°)
93.202(10)
90
1180.3(2)
4, 1.605
3.472
90
90
Volume (Å3)
Z, density(Mg/m3)
1067.76(6)
4, 1.283
0.092
μ (mm−1
)
Data, Rmerge
Unique data, I>2σI
16,410, 0.2048
3917, 1331
11,485, 0.0331
3532, 3024
1 3

Journal of Chemical Crystallography
Table 4 (continued)
Compound
8
10
Completeness
[%, full θ, (°)]
R, wR (unique data)
R (I>2σI)
98.5, 29.242
99.7, 30.44
0.2115, 0.2360
0.0939
0.0585, 0.1121
0.0474
Parameters, restraints
Goodness-of-ft
Δρ(fnal) (e−/Å3)
140, 7
1.161
+2.25, − 1.23
137, 0
1.014
+0.41, − 0.19
Estimated standard deviations in parentheses. For 10, Flack=−0.3(13)
Table 5 Crystal structure
Compound
41
42
44
46
information for pseudoamide
structures
Formula
C14H19NO2
233.31
103(2)
Mo Kα
504
0.14×0.36×0.50
Monoclinic
P21/n
C18H19NO2
281.36
298(2)
Mo Kα
600
0.10×0.15×0.35
Monoclinic
P 21/c
C15H20NO2Cl
281.78
102(2)
Mo Kα
600
0.25×0.48×0.52
Monoclinic
P 21/n
C22H27NO2
337.45
110(2)
Mo Kα
728
0.14×0.30×0.72
Monoclinic
P 21/c
Formula Weight
Temperature, K
Radiation
F(000)
Crystal size, mm3
Crystal system
Space Group
Cell Constants
a (Å)
10.3782(6)
10.8786(6)
11.2514(4)
90
9.4898(14)
22.957(3)
7.0759(10)
90
7.7386(2)
11.1854(4)
16.6725(6)
90
13.7813(3)
12.7769(2)
10.9815(3)
90
b (Å)
c (Å)
α (°)
β (°)
γ (°)
91.602(4)
90
1269.79(11)
4, 1.220
101.205(14)
90
1512.1(4)
4, 1.236
99.265(3)
90
1424.33(8)
4, 1.314
107.805(2)
90
1841.03(7)
4, 1.217
Volume (Å3)
Z, density
μ (mm−1
)
0.08
0.08
0.27
0.08
Data, Rmerge
Unique data, I>2σI
7859,0.0229
4091,3476
99.8, 25.242
6064, 0.0693*
3183, 1834
92.4, 25.242
16,388, 0.0282
4690, 4211
99.8, 25.242
21,419, 0.0193
6114, 5240
99.8, 25.242
Completeness
[%, max. θ, (°)]
R, wR (unique data)
R (I>2σI)
Parameters, restraints
Goodness-of-ft
Δρ(fnal) (e−/Å3)
0.0554, 0.1056
0.0450
155, 0
1.050
+0.41, − 0.21
0.0981, 0.1471
0.0602
192, 0
1.001
+0.23, − 0.18
0.0440, 0.1004
0.0392
192, 2**
1.043
+0.51, − 0.44
0.0496, 0.1056
0.0425
227, 0
1.029
+0.48, − 0.18
Estimated standard deviations in parentheses
*Non-merohedral twinned data, excludes overlapping refections
**Occupancy parameter for the major conformer (anti) of disordered n-propyl side chain 0.796(4)
spectroscopy. In d6-DMSO, ΔνMe is 8 Hz and in CDCl3
18 Hz at 25 °C. Methyl resonances usually increase very
modestly in chemical shift as the temperature increases,
ΔνMe decreases, and signals (eventually) broaden leading
Discussion
Racemization Rates
to coalescence at 78.5 °C in d6-DMSO at a rate constant
20 s−1, and t1/2 = 0.03 s (Figs. 1, 2). At and above this tem-
perature, the rate of interchange is too fast to distinguish
Diastereotopic methyl groups in Cooper’s pseudoacid
(1) are distinguishable by proton (and carbon) NMR
1 3

Journal of Chemical Crystallography
Table 6 Observed and calculated metrics for arylpyran pseudoacids and pseudoamides
R5
R6
R7
R8
1
5
6
7
8
H
H
H
H
H
H
H
H
H
CH3
H
CH3
H
H
CH3
F
CH3
8
8a
4a
1
4
CH3
CH3
H
CH3
H
7
6
2
3
Cl
Br
H
H
H
H
5
9
Br
H
Meb
Mea
10
11
12
iPr
tBu
CH3
CH3
H
H
R5
R6
R7
R8
Rn
41
42
44
46
H
H
Cl
H
H
H
H
H
H
H
H
H
Pr
Bz
H
CH3 Pr
CH3 Bz
iPr
A1 = < (plane C4a, C5, C6, C7, C8, C8a) (plane C8a, C1, O1, O2/N2)
T1 = R5-C5…C4-Mea T2 = R5-C5…C4-Meb
A2 = < C4a-C5-R5
| ΔT | = | T2 | - | T1 |
Compound
5-sub
A1
A2
T1
T2
|ΔT|
T1
T2
|ΔT|
calc. (°)
*
van der Waal radii
(pm) [46]
obs.
(°)
obs.
(°)
obs. (°)
obs. (°)
obs. (°)
calc. (°)
calc.
(°)
Pseudoacids
1*
H 120
F 147
CH3 200
Cl 175
Br 185
120
8.7
18.0
20.7
20.8
11.8
11.4
–
(120)
119.9
125.4
122.8
121.8
(120)
–
26.7
34.8
35.5
40.7
37.0
27.3
–
− 83.2
− 76.1
− 76.0
− 71.4
− 76.0
− 82.7
–
56.5
41.3
40.5
30.7
39.0
55.4
–
26.1
37.5
36.8
43.3
44.4
26.4
26.0
26.5
− 84.5
− 73.5
− 74.9
− 68.6
− 68.4
− 84.2
− 84.2
− 83.5
58.4
36.0
38.1
25.4
24.1
47.2
57.8
57.0
6
5
7
8
10
11
120
120
12
–
–
–
–
–
Pseudoamides
41
42
44
46
120
200
175
120
15.4
10.0
29.4
25.7
(120)
(120)
123.1
(120)
24.0
23.3
44.9
23.9
− 85.1
− 86.2
− 65.9
− 86.1
61.0
62.9
21.0
62.2
25.4
24.0
41.2
22.5
− 84.1
− 85.4
− 70.3
− 86.5
58.7
61.4
29.2
64.0
Pr propyl, iPr isopropyl, Bz benzyl; () enclose assigned values
*Average of six comparable structures (1, 10, 50, 51) see text; common (S) confguration; B3LYP/6–31+(G(d,p) level of theory
diastereotopic methyls. Eyring plot analysis of the inter-
conversion rates (estimated by line-width ftting) of the
racemization of 1 in d6-DMSO from 26 °C to 99 °C gives
an activation enthalpy of +77.8(3) kJ/mol (Fig. 4). Line-
width determinations are less certain in the 15 °C leading
to coalescence (just above 1/T = 0.00284), but the overall
correlation is satisfactory. Racemization of 1 is therefore
fast in solution at room temperature, with a rate of about
0.3 s−1 and t1/2 = 2.3 s at 25 °C (in d6-DMSO).
1 3

Journal of Chemical Crystallography
Table 7 Selected experimental metrics for pseudoacids and pseudoamides
O
1
4
R
R
O
R
8
8
8
R
R
Rn
OH
R
R
7
8a
4a
7
O
N
7
6
2
3
OH
6
6
5
R
5
5
Meb
Mea
A1 = < (plane C4a, C5, C6, C7, C8, C8a) (plane C8a, C1, O1, O2/N2)
T1 = R5-C5…C4-Mea T2 = R5-C5…C4-Meb/Ph
T3 O2/N2-C3-O3-H
Compound
A1
(°)
T1
T2
C–O(N)
endo
C–O
exo
T3
H-bond
O…O
(Å)
H-bond
motif
(°)
(°)
(°)
(Å)
(Å)
(5-Unsubstituted) pseudoacids
R2(12)
1a [14]
1b [14]
1c [14]
50 [14]
51 [29]
10
10.15
10.19
3.67
12.15
7.31
28.19
29.43
23.71
24.67
27.53
27.30
30.44
− 82.06
− 80.25
− 85.67
−85.94
−82.27
−82.66
−80.62(Ph)
1.455(2)
1.458(6)
1.470(5)
1.468(3)
1.4604(19)
1.471(2)
1.459(4)
1.386(2)
1.396(6)
1.389(5)
1.385(3)
1.3821(10)
1.384(2)
1.377(4)
− 64.43
− 69.25
− 67.92
−76.10
−62.04
−76.38
−63.92
2.809
2.759
2.839
2.746
2.782
2.732
2.764
2
R2(12)
2
R2(12)
2
C1(6)
1
R2(12)
2
C1(6)
11.36
13.05
1
R2(12)
4
2
5-Substituted pseudoacids
R2(12)
5
20.68
17.94
20.82
11.75
35.47
34.65
40.73
36.99
−75.99
−76.21
−71.42
−75.96
1.4486(14)
1.4522(16)
1.4472(16)
1.452(8)
1.3735(14)
1.3788(16)
1.3798(16)
1.367(8)
−64.12
−63.28
−64.01
−75.87
2.753(1)
2.749(1)
2.743(1)
2.764(6)
2
R2(12)
6
7
8
2
R2(12)
2
R2(12)
2
Pseudoamides
C1(6)
41
42
44
46
15.37
10.04
29.38
25.77
24.06
23.30
44.90
23.89
−85.12
−86.21
−65.89
−86.07
1.4694(12)
1.459(2)
1.4555(13)
1.4627(13)
1.4055(12)
1.3983(2)
1.4080(13)
1.4074(12)
−77.05
+32.84
−95.37
−86.78
2.740(1)
2.716(2)
2.734(1)
2.709(1)
1
C1(6)
1
C1(6)
1
C1(6)
1
Common pseudoacyl (S) confguration; angle esd’s less than 1°
The open intermediate aldehyde has a very short lifetime,
and NMR signals are not observed for this species. A modest
computational study of the open form of 1 from electronic
energies at the B3LYP/6-31 +(G(d,p) level of theory sug-
gests that the open aldehyde is less stable than the cyclic
forms by about +47 kJ/mol (gas phase). In conjunction with
the dynamic model of Fig. 5, the open intermediate probably
has a half-life of the order of milliseconds. This is consistent
with computations supporting Kopen-cyclic greater than 103
[15].
Support for this dynamic racemization model comes
1
from the temperature dependent H-NMR study of the
homolog 4-ethyl-4-methyl-3-hydroxyisobenzopvyran-
1-one (2), also conducted in d6-DMSO. Diastereomers of
2 are present in unequal amounts, with 32.1% minor form
(pseudoaxial methyl) at 25 °C increasing to 36.2% at 115 °C
determined by integrating the methine, methylene and both
methyl groups. An equilibrium constant analysis implies
a ΔGo (trans→cis) between diastereomers of +4.8(2) kJ/
mol favoring the trans ethyl/hydroxy confguration (3R,
4R)/(3S,4S) over the cis form (3S,4R)/(3R,4S), and which
1 3

Journal of Chemical Crystallography
and ΔνCH2 declines from 52.0 Hz to 47.2 Hz from 25 °C to
115 °C. A van’t Hof plot for 2 over the temperature range
stated gave ΔHo (trans→cis) of +4.8(2) kJ/mol (Fig. 6), and
therefore an estimate of ΔSo of +9.7 J/mol.K. The barrier
between diastereomers is probably similar to that determined
for 1. In CDCl3 (26–63 °C), a van’t Hof plot also gives ΔHo
(trans→cis) of +4.8(2) kJ/mol.
A third test of the racemization model comes from
analysis of the pseudoacid system 3-hydroxy-4,4,5,8-tetra-
methylisobenzopyran-1-one (5). (A general discussion of
aryl-substituted derivatives of 1 is given in the following
section.) A plot of the molecular structure is given in Fig. 8.
In d6-DMSO, the coalescence temperature of 5 is (not far)
above 125 °C, and the diastereotopic methyl separation
declines steadily from 15.8 Hz at 25 °C to 7.1 Hz at 125 °C
(Fig. 3). Measureable line broadening was observed above
85 °C, and analysis of this for rate information is given in
Fig. 9. From this, the activation enthalpy is estimated to be
+104(6) kJ/mol. This is a signifcant increase in the enthalpy
compared to 1, which lacks the fanking aryl substitutions,
and seems to be associated with the efects of steric com-
pression on the rate of ring opening. The rate of racemiza-
tion is still fast (0.031 s−1) at 85 °C, and enantiomer half-
life of 5 has been slowed to the order of seconds. At room
temperature, the half-life of the enantiomers is of the order
of hours.
Fig. 4 Eyring plot for the parent pseudoacid 1, in d6-DMSO
equilibrate through the (unobserved) open intermediate
enantiomeric aldehydes (Figs. 6 and 7). The axial methyl-
ene of the minor (cis) form has a higher chemical shift (δH
1.75 v. 1.62 ppm at 25 °C, and throughout the temperature
range studied) than for the major (trans) form, suggesting a
more crowded environment for the ethyl group of the minor
form (ethyl always gauche to hydroxy). In compound 2, the
ΔνH for the methyl and methylene groups in the two dias-
tereomers declines with increasing temperature (as it does
for the diastereotopic methyls in 1). For 2 in d6-DMSO,
ΔνMe declines from 6.8 Hz to 0.0 Hz (accidental overlap)
A fourth test of the racemization model comes from
analysis of the temperature dependent solution composition
of the diastereomers of 3-hydroxy-4,5,8-trimethyl-4-phe-
nylisobenzopyran-1-one (17). Based on the rates determined
for 3 (vide supra), equilibration between diastereomers
is expected to be established in the several hour variable
temperature experiments. In CDCl3 at 26 °C, 17 shows K
(trans → cis) = 0.318 (75.9% pseudoaxial phenyl, trans to
Fig. 5 Intermediate aldehyde
rapidly cyclizes in pseudoacid
racemization of 1
1 3

Journal of Chemical Crystallography
Fig. 6 Van’t Hof plot for diastereomeric pseudoacids for 2 (flled
triangle, in d6-DMSO) and 3 (flled circle, in CDCl3) and 3 (flled
square, in d6-DMSO)
Fig. 8 Thermal ellipsoid plot of pseudoacid 5
Fig. 9 Eyring plot for 5 in d6-DMSO
Fig. 7 Diastereomers of 2 equilibrate through the cyclic-open inter-
change (in d6-DMSO)
pseudoacids studied, is racemization. Open-form concentra-
tions in these rapidly equilibrating systems were negligible
and spectral evidence for the very-short lived and low con-
centration intermediate aldehydes was lacking.
hydroxy), and ΔGo +2.9 kJ/mol. In the range 26–63 °C, the
major diastereomer decreases to 72.5%, and a van’t Hof
plot shows an ΔHo (trans→cis) of +6.8(5) kJ/mol, and ΔSo
+13.4 J/mol.K (Fig. 6). In d6-DMSO, a more polar solvent,
the trans isomer of 17 comprises 84.2% at 25 °C, declin-
ing to 78.1% at 115 °C. In this solvent, ΔGo (trans → cis)
+4.1 kJ/mol, ΔHo =+7.0 kJ/mol, and ΔSo =+9.7 J/mol K
(Fig. 10). The larger diference in free energy between the
diastereomers and the higher activation enthalpy diference
are consistent with larger steric interactions in the diastere-
omers of 17 compared with 2. And for 17, the higher enthal-
pies of interconversion in a more polar solvent are consistent
with stronger associations between 17 and solvent. These
data support the general argument that the solution behav-
ior of Cooper’s pseudoacid (1), and for all the arylpyran
An attempt to synthesize an even more bulky pseudoacid
(5-chloro-3-hydroxy-4,8-dimethyl-4-phenylisobenzopyran-
1-one) led instead to diastereomers 4 by rearrangement in
the formation of the indanone. This compound no longer
has a 5-substituent, so its racemization was expected (and
found) to be fast at room temperature. At 25 °C, 4 was
observed to be 75% trans (phenyl to hydroxy), and thus K
(cis→trans)=3.0, ΔGo =+2.7 kJ/mol (d6-DMSO).
As a ffth test of the racemization model, the substitu-
ent efects on slowing the isomerization rate in 17 should
be at least as efective as for 5 (vide supra). It should be
possible to produce a dis-equilibrium in a solution of 17 by
1 3

Journal of Chemical Crystallography
methyls of 6 are pairs of doublets, J = 1.5 and 4.0 Hz,
separated by 9.2 Hz. These are assigned to 5JFH couplings
[40]. The larger splitting is observed for the upfeld methyl
at δH 1.345, and may be assigned to a pseudoaxial methyl
disposition, i.e. the methyl farther from fuorine and with
the larger dihedral angle (Fig. 3, Scheme 13). Thus, the
downfeld methyl is closer to the hydroxyl group. As the
temperature of the solution is increased, methyl signals
broaden and then coalesce at 65 °C into a broad (5JHF
-
coupled) doublet. At coalescence, the rate of racemization
is estimated at 21 s−1 (t1/2 = 0.03 s). The methyl doublet
sharpens on further temperature increase, and an averaged
5JFH coupling is observed (J = 2.8 Hz). The ΔH‡ for race-
mization was estimated to be +76(12) kJ/mol, similar to
that measured for 1. The crystal structure of 6 provided
information on the environment of the gem-dimethyls
(Table 7). In 1 and related compounds, the gem-dimethyl
torsions H5-C5···C4-CH3 (T1, T2) were distinguishable
with averages are 83.2°, − 26.7° (N = 5), an (absolute)
diference (│ΔT│) of 56.5°. For the fuoropseudoacid 6,
the F-C5···C4-Methyl torsions were 76.2°, − 34.6°, ΔT of
41.6° (Scheme 13). Computations supported this geom-
etry (│ΔT│ 47°), in which a modest steric compression
between the fuorine and the methyls reduced the (abso-
lute) diference between torsions T1 and T2. Additional
evidence for this increased contact was the slight down-
feld shifts of the methyl Hs relative to the unsubstituted
case (Fig. 3).
Fig. 10 Diastereomers of 17 equilibrate through the cyclic-open inter-
change (in d6-DMSO)
quenching a heated sample and monitoring the rate of return
to equilibrium concentrations. Compound 17 in d6-DMSO
was heated to 115 °C, at which temperature, 78.1% of the
compound is in the trans form. The sample was suddenly
quenched to 0 °C, then allowed to warm to 25 °C and the
well-separated pseudoacyl Hs integrated, and showing
78.4% trans-17 after the 5 min needed to warm, handle,
shim and collect a 1H-NMR spectrum. Over several hours,
the composition returned to 84.7% trans, and the frst-order
plot gave the cis-17 a half-life of 2.87 h (R=0.96, N=22,
observed for 6.28 h) at 25 °C, and a rate of 0.00403/min.
This rate of diastereomeric interconversion implies a barrier
of 99 kJ/mol, which agrees with that determined for 5 by line
broadening (vide supra).
Compound 6 also had 8-methyl substitution, which
should be considered to also infuence racemization rates.
From the structural studies summarized in Table 7, it can
be seen that the efect of 8-methyl substitution generally
induces a greater twist in the adjacent carboxyl group
relative to the aryl ring (angle A1) from an average of
8.7° (range 3.7–12.2°, N = 5) in the unsubstituted cases to
19.8° (range 17.9°–20.8°, average of 5–7). Calculation on
gas-phase models of these compounds largely agree with
a 10° increase in angle A1 (data not shown). The tempera-
ture dependent data collected on compound 11 and 12,
with 5-H-8-CH3 substitution show methyls still separated
at 100 °C with their ΔνMe amounting to only a few Hz
5‑Halogen 8‑Methyl Substituted Pseudoacids
Having established the model for pseudoacid racemization,
the efect of 5-halo-8-methyl substitutions was explored.
Compound 6 shows temperature dependent solution
behavior consistent with an open-cyclic equilibrium model
(Scheme 3). At 26 °C in d6-DMSO, the diastereotopic
O
-23.0o
O
O
O
O
O
OH
H
O
H
F
OH
76o
OH
O
F
calc 78o, 31o
(HF 6 311G**)
F
F
O
-35o
5JHF
4.0 Hz 1.5 Hz
H
5JHF 2.8 Hz
H
slow exchange
fast exchange; above coalescence
Scheme 13 Fluoropseudoacid 6 5JFH coupling before and after methyl coalescence
1 3

Journal of Chemical Crystallography
(Fig. 3). These systems apparently have racemization rates
slower than 1 or 6.
downfeld signal is assigned to the pseudoequatorial methyl
which is syn to the hydroxyl group and makes the smaller
torsion angle (T1) with the aryl 5-substituent (Table 7).
Some synthetic eforts were directed toward introducing
more bulky substituents at the 5-position. During the isola-
tion of the 5-bromo-8-methyl pseudoacid 8, its rearranged
6-bromo-8-methyl isomer (9) was also found along with a
trace of the debrominated 8-methyl derivative (10). In gen-
eral, the trifuoromethane sulfonic acid method applied to
p-bromotoluene, p-cymene and p-(t-butyl)toluene resulted
in acylation forming intermediate chalcones (Scheme 10).
Cyclization to the indanones with polyphosphoric acid then
led to aryl substituent rearrangements and formation of
6-isopropy-8-methyl pseudoacid 11 and 6-(t-butyl)-8-methyl
pseudoacid 12.
In compound 7, 5-chloro-8-methyl substitution, the gem-
dimethyl protons were observed further downfield, and
with a greater ΔνMe compared to 6 (Fig. 3). At 125 °C in
d6-DMSO, the rate of interconversion was still relatively
slow since line broadening was not observed. Methyl sep-
aration ΔνMe decreased from 35.4 Hz (26 °C) to 24.0 Hz
(125 °C). The implication is that the infuence of the 5-chlo-
rine is greater than that of the 5-methyl group in slowing
racemization rates. In both 5 and 7, the crystal structures
shows reduced │T│s compared to the 5,8-H examples as the
static crystalline gem-dimethyl dispositions have responded
to the bulk of the adjacent 5-substituents (Table 6). The
slower rate of racemization leads to greater discrimination
between the solution methyl resonances. Solid-state molecu-
lar conformations refect infuences by both intramolecular
steric forces as well as intermolecular packing forces.
In compound 8, with 5-bromo-7-methyl substitution, the
bromine is positioned adjacent to the gem-dimethyls and
ΔνMe were greater (57.2 Hz) than in 7 (35.4 Hz) in d6-DMSO
at 26 °C. Methyl line broadening was not observed in the
spectra of 8. Racemization in solution is slower for the
bromo derivative, consistent with a larger steric interaction
of the halogen with the adjacent gem-dimethyls and consist-
ent with its larger van der Waals radii (Table 6). Compound
8 lacks the 8-methyl group of the rest of the series 5–7. The
contribution of the 8-methyl (vide supra) toward showing
solution racemization rates would seem to be a lesser con-
tributor compared to the 5-halogen. The substituted series
5–8 all show reduced │ΔT│s consistent with the steric
interaction with the gem-dimethyls.
Pseudoacids 11 and 12 were oils. For 11, 1H-NMR spec-
tra at 26 °C (d6-DMSO) showed gem-dimethyl signals acci-
dentally isochronous at δH 1.246 ppm (similar chemical
shifts to 1). As temperature increased, the methyls moved
downfeld and separated until signal broadening began near
80 °C and ΔνMe 5 Hz. Coalescence was above 125 °C, and
racemization rates from analysis of line-broadening from
80 °C–125 °C gave ΔH‡ 78(5) kJ/mol (similar to 1). In
CDCl3, gem-dimethyls had ΔνMe 10 Hz at 26 °C, and coa-
lescence was observed at 55 °C. Broadening was estimated
with reference to the line-widths of the nearby isopropyl
doublet, ΔH‡ 85(5) kJ/mol. Racemization was fast at room
temperature for 11 in d6-DMSO solution.
For pseudoacid 12, a similar pattern similar to that for
the rearranged isopropyl pseudoacid 11 was observed. At
26 °C in d6-DMSO, gem-dimethyls were a pair of singlets
separated by only 1.0 Hz. On heating, these signals became
accidentally isochronous at about 35 °C, then separated to
about 6.0 Hz at 125 °C. Signal broadening was measurable
from about 90 °C, though coalescence is above 125 °C.
Line-width analysis, referenced to the t-butyl methyl signal,
again gave a ΔH‡ 80(5) kJ/mol (similar to 1 and 11).
In this group of pseudoacids, gem-dimethyl ΔνMe are
apparently inversely related to solution racemization
rates. Coalescence of the methyl signals rapidly increases
in the series studied, allowing measurement of rates only
for the parent 1 and the fuoro derivative 6. The trend in
ΔνMe follows F ≈ H < CH3 < Cl < Br with ΔνMe at 26 °C:
11≈8<15.6<36<57 Hz (d6-DMSO), respectively. In these
systems, ΔνMe diminished with increasing temperature, and
equilibrating NMR signals appeared to move toward each
well before the signals broadened approaching signal coa-
lescence. Broadening of the methyl signals was observed
for 1, 5 and 6, and became measurable where ΔνMe was less
than about about 9 Hz.
Pseudoamides
Reaction of a pseudoacyl chloride with a primary amine
leads to endocyclic secondary pseuodamides (Scheme 12).
These derivatives can form intermolecular hydrogen-bonds,
and many have crystallized. A few (41, 42, 44, 46) have been
synthesized and their structures determined for comparison
with the pseudoacids and to access structures which have
rearranged during indanone formation. Their NMR spectra
are also reported (Table 3). The pseudoamides have diaste-
reotopic gem-dimethyl groups, and the ΔνMe are much larger
than for corresponding pseudoacids. These are discussed
below.
In the pseudoacids 5–8, the efects of steric compression
appear evident in the chemical shifts of the diastereotopic
gem-dimethyl groups (Fig. 3). At 26 °C in d6-DMSO, for
the fuoropseuodacid 6, δH 1.346, 1.323, slightly downfeld
of the locations in Cooper’s pseudoacid (1). In the pseu-
doacid 5, methyl signals are at δH 1.435 and 1.499, in the
chloropseudoacid 7 they are at δH 1.503and 1.414, and in
the bromopseudoacid 8, at δH 1.530 and 1.387. The more
1 3

Journal of Chemical Crystallography
Fig. 11 Torsions angles for the parent pseudoacid, 1, and its 7-methyl
derivative, 10 (H-atoms omitted for clarity.)
Aryl Substitution, structural trends
Pseudoacids 5–11 were prepared to examine the infuence
on the racemization rate of fanking aryl substituents. Some
of these (Scheme 5, 5–8) have been crystallized and their
molecular structures determined in the solid-state. All
three show the hydrogen-bonded dimers around crystallo-
graphic inversion centers (Scheme 4) in their centrosym-
metric structures. Compared to the structures of the parent
pseudoacid (1), the 5,8-disubstituted aryl derivatives show
conformational diferences consistent with steric infuences
of the 5- and 8-substituents. Presence of the 8-methyl (in
5–7) twists the adjacent carboxyl group out of the mean aryl
plane (angle A1). The carboxyl forms part of the pyran ring,
and the exocyclic O is disposed on the opposite side of the
mean pyran ring plane from the pseudoacyl hydroxyl. In 1,
of which there are three literature structures, and two 7-sub-
stituted derivatives also in the literature, the average A1 is
8.7° (Table 3, range 3.7°–12.2°, N=5, Fig. 11) [14, 29]. As
noted above, presence of 8-methyl substitution induces a
further twist to A1 of about 10° (Table 6). The other metric
relevant to molecular conformation is the disposition of the
gem-dimethyl groups relative to the 5-substituent. The meth-
yls are pseudoeqautorial (angle T1) and pseudoaxial (angle
T2), and in 1a (Table 7, Fig. 11), the torsion angles are 28.2°,
82.1°, respectively. Similar values are found in 10, and for
the six comparable structures, the averages are 26.7° (range
23.7°–29.4°, N=5) and 83.2° (range 80.2°–85.7°, N=5), a
absolute diference │ΔT│of 56.5°.
Fig. 12 Torsion describing molecular conformations for pseudoacid
derivatives 5–8, (S) confguration
In structures 5–8, the gem-dimethyl angles respond to
the presence of the adjacent 5-substituent. Plots of these
are given in Fig. 12, which also shows the widened A1 from
the presence of the 8-methyl group in 5–7 compared to 8.
In the pseudoacid series 1, 5–8, some general observations
can be made from the combined crystallographic, spectro-
scopic and computational information. Relevant metrics for
the molecular structures determined in the solid state are
given in Tables 5 and 6.
(a) The presence of substituent groups on 5- position
infuence the pseudoaxial and pseudoequatorial gem-
dimethyl torsion angles, measured relative to the 5-sub-
stituent. In general for 5, 7, 8 (Tables 6), the torsions
angles A2 (C4a-C5-X) are larger than 120° and corre-
late with the size of the 5-substituent (CH3 >Cl~Br).
1 3

Journal of Chemical Crystallography
For the gem-dimethyls, the dispositions of these pseu-
doaxial and pseudoequatorial methyls in the crystals
structure 5–8 all show smaller │ΔT│ compared to
the parent (1). The average │ΔT│ is 37.9° (range:
30.7–41.3°), nearly 20° smaller than for 1 and its rela-
tives in their crystal environments. Computations sug-
gest that │ΔT│ should respond to steric bulk of the
5-substituents (for gas phase molecules) with the trend
Br < Cl < F < CH3 < H (Table 6). The molecular con-
formations in the crystals for 5–8 show │ΔT│ in the
order Cl<Br~CH3 <F. In the crystals, the dispositions
of the gem-dimethyl are infuenced by intermolecular
packing forces in addition to intramolecular steric com-
pressions.
Fig. 13 Torsions describing molecular conformation in pseudoamide
44 (major N-propyl conformer)
(b) The presence of 8-methyl group twists the carboxyl
group by about 10° (from near 10° to about 20°) in the
8-methyl pseudoacids (5–7) compared to the unsubsti-
tuted pseudoacid (1, 10). The carboxyl oxygen is in all
cases on the side opposite of the mean aryl ring from
the axial pseudoacyl hydroxy group, and on the same
side as the pseudoaxial methyl group.
observed with chemical shifts averaged for the mean
environment, and also for the open tautomer. Larger
ΔνMe suggest a greater degree of averaged diferentia-
tion. As temperatures rise and rates of interconversion
increase, the averaged methyl environments include
greater contributions from the open tautomer, and
become more similar while ΔνMe decreases.
(c) The combined 5,8-disubstitution supports a model in
which the approach of the nucleophile to the pseu-
doacyl carbon for ring-closure (carboxyl O becoming
pseudoacid pyran O) is geometrically better disposed.
The O-Cpseudoacyl-O angle widens from 108.5° (N=6)
in pseudoacids related to 1 (without 5- or 8- substitu-
ents) to 110.2 (8), 110.1° (6), 109.8° (7) and 110.4°
(5). If the nucleophilic reaction follows a typical Bürgi-
Dunitz trajectory, then the derivatives (5–8) are further
along the ring closure reaction path than 1 or 10, which
begins at a shallower attack angle [41, 42].
At several points, these fndings for pseudoacids (1, 5–8)
are supported by data generated for derivative endocyclic
secondary pseudoamides. Two N-propyl pseudoamides (41,
44) and two N-benzyl psedoamides (42, 46) were prepared.
One of these phases has 5-chloro-8-methyl disubstitution
(44), derived from pseudoacid 7, a second (46) is from rear-
ranged pseudoacid 11, and the others (41, 42) are derived
from 1. Predictions based on the pseudoacid model dis-
cussed above include the following, with a comparison to
the experimental evidence.
(d) This is consistent with shorter endocyclic C3-O2 dis-
tances (nC-O) in derivatives (5–8) compared to the
parent. In pseudoacid structures 1, 10, and close rela-
tives, nC-O averages 1.464(2) Å (N=6) respectively,
while nC-O lengths are 1.452(8)Å (8), 1.4522(16) Å
(6), 1.4486(14) Å (5), 1.4472(16) Å (7). The average
nC-O distance [1.450(2) Å] is signifcantly shorter in
the 5,8-disubstituted and the 8-Br structures. Between
these groups, nC-O lengths of the 5-substituted struc-
tures are shorter in all cases, and seven esds on average
shorter than for the 5,8-H structures. Exocyclic C3–O3
distances (xC–O) do not show a length trend. They are
infuenced by hydrogen-bonding in the crystal struc-
tures, and are generally shortened in pseudoacids to
about 1.38 Å.
a) Pseudoamides 41, 42, 44, 46 should show more pro-
nounced geometric trends among angles and torsions (A1
and│ΔT│) than observed in the related pseudoacids. Com-
pared to the pseudoacids without 8-substituents, │ΔT│s
are slightly larger in the pseudoamides: 62.9° (42) vs. 56.5°
(1), and angles A1 are about the same: 10.0° (42), 15.4 (41)
vs. 8.7° (1) (Table 6). With the 8-methyl groups, angles
A1 are larger: 25.8° (46) and 29.4° (44) compared to 19.8°
(average of 5-7). Diferences in gem-dimethyl torsions are
strongly dependent on the presence of the 5-substituent.
Without 5-substitutiion, │ΔT│s of 61.0° (41), 61.9° (42),
62.2° (46), closing to 21.0° in the 5-chloro pseudoamide (44)
(Fig. 13). In the pseuodacids, │ΔT│s without 5-substitution
average 56.5°, closing only to 30.7° for the 5-chloro case
(7) (Table 6). Deformation of angle A2 (C4a-C5-Cl) in 44 is
similar to that observed for 7, both larger than 120°.
(e) Solution NMR (d6-DMSO, 25 °C) ΔνMe follows a trend
which appears partly steric with 5-substituent size, with
Br>Cl>CH3 >F~H. These correlate with increased
pseudoacid half-lives in (polar) solution, and slower
racemization rates. On the NMR timescale, equili-
brating pseudoaxial and pseudoequatorial methyls are
b) The N-C3-O3 angles are larger than in the O2–C3–O3
angles in the pseudoacids. Amide nitrogen is a better
nucleophile than carboxylate oxygen, and similar geom-
etries should take the ring closure reaction farther along
1 3

Journal of Chemical Crystallography
O
O
O
O+
_
O –
O
n
x
OH
OH+
OH
C
B
A
Scheme 14 Resonance contributor: a lengthens nC–O and shortens xC–O distances in pseudoacids relative to the neutral ground state structure
(b)
its reaction trajectory. Also, a shorter and stronger N–C3
(nC–N) distance for the 5,8-disubstituted pseuodamide,
and a longer xC–O distance, compared to the unsubsti-
tuted case should be expected. The N–C3–O3 angles for
susceptible to modulation by the pyran geometry, tied to the
attack of the carboxyl nucleophile at the carbonyl carbon.
An extreme example has been described for a cyclic alkyl
δ-oxocarboxylic acid where molecular constraints produced
a very long nC–O distance (1.483 Å), a short xC–O distance
(1.364Å), and a shallow O–C–O angle of 108.6° [44]. In
the arylpyrans pseudoacids studied here (5–7), the increased
basicity of the carboxylate may be partially due to the efect
of the adjacent 8-methyl group which induces a rotation
of the carboxyl oxygen (=O) out of the aryl plane and the
other carboxyl oxygen (–O) toward the pseudoacyl carbon.
The 5-substituents rotate the pseudoacyl carbon (C3) so that
it approaches the endocyclic carboxyl oxygen (–O) more
nearly. The combination of these geometric factors makes
the (old aldehyde) carbonyl group more accessible to attack
by the carboxyl nucleophile.
o
o
pseuodamides are 111.2° (41), 111.6 (42), 110.6 (44)
and 111.4° (46), compared to an average of 109.1° for the
O2-C3-O3 angles of pseudoacids 1, 5-8, 10. The nC-N dis-
tances shorten from 1.469 Å (41), 1.459 Å (42) and 1.463
Å (46) for 5-H to 1.456 Å (44) for the 5-chloro case, with
the nC-N series [5,8-H] > [5-H, 8-CH3] > [5-Cl, 8-CH3],
again shortest in the 5,8-disubstituted case. Corresponding
xC-O bonds are observed lengthened: 1.405 Å (41), 1.398
Å (42), 1.407 Å (46), 1.408 Å (44), respectively in com-
parison with the pseudoacids (Table 7). Hydrogen-bonding
between pseudoamides follows the chain motif C1(6), with
slightly stronger and shorter O···O contacts th1an in the
pseudoacids with the R2(12) ring motif (Table 7). Stronger
As a group, the pseudoamides (41, 42, 44, 46) show
C3-N2 distances (1.455–1.470 Å) which are shorter than in
typical (3°) δ-lactams [1.479(7) Å, N=15 [47]. Since amide
N is a better nucleophile than carboxyl oxygen, contribu-
tions to the ground state (E) from resonance structure F are
more important in the pseudoamides (Scheme 15). A modest
lengthening of C3–O3 bonds relative to the pseudoacids is
also expected and observed.
2
hydrogen-bonding in the pseudoamides may contribute to
weaker and longer xC–O bonds.
c) To the degree that ΔνMe for pseudoamides difers
from the pseudoacids may be an indication of slower rates
of pseudoamide racemization. In CDCl3 (25 °C), ΔνMe
are observed as 106 Hz for 41, 178 Hz for 42, 155 Hz for
44, 164 Hz for 46. These are much larger than for pseu-
doacids, and suggest much more slowly racemizing sys-
tems. A similar downfeld shift in the chemical shift of the
gem-dimethyl groups is also observed where methyls are
adjacent to a 5-chloro substituent (44) compared to the 5-H
cases (Tables 1 and 2).
Conformations. Pseudoacids 1, 10, 50, 51, and 5–8 (and
pseudoamides 41, 42, 44, 46) are all α-anomers. The pseu-
doacids with dimeric R2(12) hydrogen-bonding have gauche,
synclinal T3 [N2/O2–C32–O3–H] torsions (62°–69°), consist-
ent with an exoanomeric efect [48]. These are weaker O..O
hydrogen-bonding contacts, with distances 2.74–2.83 Å
(Table 7). Exceptions among the pseudoacids include struc-
Other structural observations
tures 10 and 50, which form chain hydrogen-bonds with C1
1
In the pseudoacids, the C-O bond lengths at the pseudoa-
cyl carbon (C3) show disparities typical of the system [43].
Endocyclic nC-O distances are longer [1.464(2) Å, average
of 1, 10, 50, 51] than the exocyclic xC-O distances [1.387(2)
Å]. This can be attributed to diferences in resonance con-
tributions to the ground state structure (B) from structures
like A, rather than C (Scheme 14). The O2–C3–O3-H tor-
sions (~65°) have the conformation that allows nO →σ*C-O
hyperconjugation. As argued above, the nC–O is possibly
(6) motif. For these, the conformations show the hydroxy H
gauche and synclinal to the ring O, but with torsion T3 near
− 76° [14]. Pseudoamides 41, 42, 44, 46 also show the C1
1
(6) hydrogen-bonding motif, and the X2–C3–O3-H torsions
include a cluster near −85°, and an example at +33° (H over
the ring). These axial hydroxy orientations are consistent
with a weak negative hyperconjugation nO →σ*C-N efect,
serving to lengthen the nC–N bonds slightly.
1 3

Journal of Chemical Crystallography
O
O
O
R
_
+
R
R
N
N
N
_
n
x
OH
O H+
OH
F
E
D
Scheme 15 Resonance contributor F shortens nC–N and lengthens xC–O distances in pseudoamides relative to the neutral ground state struc-
ture E
less downfield
Scheme 16 Molecular con-
formations viewed down the
H3C
H3C
nC-O shortens
C4–C4a bond with 5-substitu-
ents modifying structure and
solution behavior in arylpyran
pseudoacids
T2 declines
T2
H
O
O
H
mean arene
plane
R
C
O
R
C
O
T1
H3C
T1 increases
O2-C3-O3 angle
widens
H3
C
HO
more downfield 5 - 8
rate faster
open form
rate slower
open form
o
OH
1, 10
OH
HO
H3
C
H3
R
C
O
O
C
R
C
H
O
H
O
H3C
H3
C
assistance, and to Dr. Buck Taylor for assistance with computations;
both are from the University of Portland. EJV expresses special appre-
ciation to the John Felice Rome Center of Loyola University of Chicago
and its Director Dr. Michael F. Andrews for a visiting lectureship and
provision of space and time for composition and data analysis.
Conclusions
In 3-hydroxy-4,4-dimethylisobenzopyran-1-one (Cooper’s
pseudoacid, 1), d6-DMSO solution racemization is fast
(enantiomer t1/2 in seconds at 25 °C). While its diastereo-
topic pseudoaxial and pseudoequatorial methyls are well dis-
criminated in the solid state, in solution their small chemi-
cal shift diferences suggest rapid equilibration through an
(unobserved) open intermediate. Aryl 8-methyl substitu-
tion promotes twisting the carboxyl C=O group out of the
mean aryl ring plane with the pyran oxygen on the opposite
side. Replacement of 5-H with a more bulky substitituents
signifcantly stabilizes the pseudoacid pyran ring, and the
geometry shows that this is accomplished probably by steric
crowding (Scheme 16) The 5-substituents tend to close the
ring, raise coalescence temperatures, and slow racemiza-
tion rates, in the order H ~ F > CH3 > Cl > Br. Molecular
conformations for 5-substituted derivatives show solid state
conformations with less discriminating gem-dimethyl orien-
tations (F>CH3 ~Br>Cl), and slower rates of racemization
contribute to more discriminating.
Compliance with ethical standards
Conflict of interest The authors declare no conficts of interest.
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