Stereochemical control of reductions. 9. Haptophilicity studies with 1,1-disubstituted 2-methyleneacenaphthenes

Article abstract of DOI:10.1021/jo010633b

A series of 1-methyl-2-methyleneacenaphthenes has been synthesized, bearing an additional variable substituent (R) at the 1-position. These compounds have been hydrogenated in ethanol over a 5% Pd/C catalyst under standardized conditions in order to assess the haptophilicity of R, its ability to enforce addition of hydrogen from its own face of the molecule by coordination to the catalyst surface. The order of decreasing haptophilicity, assessed as the product epimer ratio, for the groups studied was R = CH₂NH₂, CH₂NMe₂, CH₂OH, CHNOH, CH₂OMe CHO, CONH₂, CH₂NHCOMe, COOK, COMe, CN, CONHOH, COOH, COOMe, COONa, COOLi. Because knowledge of group haptophilicities offers potential for stereochemical control in such reductions, comparisons are provided with haptophilic orders found in other molecular systems. It is shown that absolute haptophilicities can be manipulated by varying the dielectric constant of the solvent employed.

Full text of DOI:10.1021/jo010633b

J . Org. Chem. 2002, 67, 2813-2825
2813
Ster eoch em ica l Con tr ol of Red u ction s. 9. Ha p top h ilicity Stu d ies
w ith 1,1-Disu bstitu ted 2-Meth ylen ea cen a p h th en es
Hugh W. Thompson* and Shaker Y. Rashid
Carl A. Olson Memorial Laboratories, Department of Chemistry, Rutgers University,
Newark, New J ersey 07102
hwt@andromeda.rutgers.edu
Received J une 21, 2001
A series of 1-methyl-2-methyleneacenaphthenes has been synthesized, bearing an additional variable
substituent (R) at the 1-position. These compounds have been hydrogenated in ethanol over a 5%
Pd/C catalyst under standardized conditions in order to assess the haptophilicity of R, its ability to
enforce addition of hydrogen from its own face of the molecule by coordination to the catalyst surface.
The order of decreasing haptophilicity, assessed as the product epimer ratio, for the groups studied
was R ) CH2NH2, CH2NMe2, CH2OH, CHNOH, CH2OMe, CHO, CONH2, CH2NHCOMe, COOK,
COMe, CN, CONHOH, COOH, COOMe, COONa, COOLi. Because knowledge of group hapto-
philicities offers potential for stereochemical control in such reductions, comparisons are provided
with haptophilic orders found in other molecular systems. It is shown that absolute haptophilicities
can be manipulated by varying the dielectric constant of the solvent employed.
In tr od u ction
results bear little relationship to the usual measures of
group size, basicity or polarity alone but apparently
represent complex combinations of such properties, tem-
pered by the shape and accessibility of the influencing
group.3 We term the net ability of such a group to enforce
addition of hydrogen from its own face of the molecule
“haptophilicity,” and have established a haptophilic order
for a dozen of the most common functional groups.3,9
Knowledge of group haptophilicities offers promise of
stereochemical control in such reductions, but for a
haptophilic order to be generally useful, it must be shown
to apply to a variety of substrate systems.
When reduction of unsaturation creates new stereo-
centers, the presence of other groups within the substrate
offers the potential to control product stereochemistry.
Beyond the more familiar steric hindrance effects, use
of functional groups as reagent hinges or leashes is now
common. Our own studies of the latter phenomenon have
focused on the heterogeneous catalytic hydrogenation of
alkenes,1-9 where profound changes in product stereo-
chemistry may be generated by simple changes in such
“spectator” functional groups.10-20 These stereochemical
(1) Thompson, H. W. J . Org. Chem. 1971, 36, 2577.
(2) Thompson, H. W.; Naipawer, R. E. J . Org. Chem. 1972, 37, 1307.
(3) Thompson, H. W.; Naipawer, R. E. J . Am. Chem. Soc. 1973, 95,
6379.
(4) Thompson, H. W.; McPherson, E. J . Am. Chem. Soc. 1974, 96,
6232.
(5) Thompson, H. W.; McPherson, E.; Lences, B. L. J . Org. Chem.
1976, 41, 2903.
(6) Thompson, H. W.; McPherson, E. J . Org. Chem. 1977, 42, 3350.
(7) Thompson, H. W.; Shah, N. V. J . Org. Chem. 1983, 48, 1325.
(8) Thompson, H. W.; Wong, J . K.; Lalancette, R. A.; Boyko, J . A.;
Robertiello, A. M. J . Org. Chem. 1985, 50, 2115.
(9) Thompson, H. W.; Wong, J . K. J . Org. Chem. 1985, 50, 4270.
(10) Minckler, L. S.; Hussey, A. S.; Baker, R. H. J . Am. Chem. Soc.
1956, 78, 1009.
(11) (a) Howard, T. J . Chem. Ind. (London) 1963, 1899. (b) Howard,
T. J . Recl. Trav. Chim. Pays-Bas 1964, 83, 992. (c) Mitsui, S.; Senda,
Y.; Saito, H. Bull. Chem. Soc. J pn. 1966, 39, 694. (d) Howard, T. J .;
Morley, B. Chem. Ind. (London) 1967, 73.
(12) (a) Dart, M. C.; Henbest, H. B. J . Chem. Soc. 1960, 3563. (b)
Nishimura, S.; Mori, K. Bull. Chem. Soc. J pn. 1963, 36, 318.
(13) Mori, K.; Abe, K.; Washida, M.; Nishimura, S.; Shiota, M. J .
Org. Chem. 1971, 36, 6, 231.
(14) (a) Heathcock, C. H.; Badger, R. A.; Patterson, J . W., J r. J . Am.
Chem. Soc. 1967, 89, 4133. (b) McMurry, J . E. Tetrahedron Lett. 1970,
3731.
(15) Brieger, G.; Hachey, D. L.; Ciaramitaro, D. J . Org. Chem. 1969,
34, 220.
(16) Powell, R. G.; Madrigal, R. V.; Smith, C. R., J r.; Mikolajczak,
K. L. J . Org. Chem. 1974, 39, 676.
(17) Warawa, E. J .; Campbell, J . R. J . Org. Chem. 1974, 39, 3511.
(18) Gula, M. J .; Spencer, T. A. J . Org. Chem. 1980, 45, 805.
(19) Stork, G.; Kahne, D. E. J . Am. Chem. Soc. 1983, 105, 1072.
(20) MaGee, D. I.; Lee, M. L.; Decken, A. J . Org. Chem. 1999, 64,
2549.
Our previous studies of these effects utilized systems
1-3,1,6,8 bearing several features in common. Each is a
racemate without diastereomers and is reducible from
either of two molecular faces, yielding only two epimers.
Along with ease of construction, we have sought systems
amenable to GC but large enough to make crystal-
linity likely. As our studies have evolved, we have
also tried to choose systems with alkenes incapable of
isomerizing, a potential complication with palladium
catalysts,3 and having uncluttered 1H NMR spectra,
since NMR is a principal tool for assessing product ratios.
The subject of the present study is the system repre-
sented by 8, which we have synthesized as shown in
Scheme 1. Both this system and 38,9 incorporate quater-
1
nary methyls to fix stereochemistry and act as H NMR
markers.
10.1021/jo010633b CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/02/2002

2814 J . Org. Chem., Vol. 67, No. 9, 2002
Thompson and Rashid
Sch em e 1
Sch em e 2
Resu lts a n d Discu ssion
Syn th eses. Commercially available 4 (R ) H) was
methylated in 96% yield through its dianion21 and then
cyclized in 77% yield via the acid chloride.22 Treatment
of 5 with Me3SiCN and BF3‚OEt2 gave the protected
cyanohydrin, which was not isolated but subjected di-
rectly to elimination by treatment with SOCl2 and
pyridine, providing a 65% yield of 6.23 Methylation of 6
in THF led to a product contaminated with up to 15% of
the γ-methylated 7, which was difficult to separate from
8. This was overcome by careful temperature control, plus
use of N,N′-dimethylpropyleneurea24 as a cosolvent. This
gave a 92% yield of 8 containing only ca. 5% of 7, which
could be removed in later steps.
Sch em e 3
The transformations of nitrile 8 into the carboxylic acid
15 and the other functional groups required followed the
routes outlined in Schemes 2 and 3. Hydrolysis of 8 to
15 could be carried out in good yield (92%) but illustrates
the difficulties inherent in this molecular system. Acidic
conditions could not be used because of the sensitivity of
the styrene subunit, while, even with base, rather severe
conditions were required because the R group is neo-
pentyl. Several steps required careful control of reaction
conditions.
Reduction of 8 with DIBAL-H at -78 °C25 led in 82%
yield to the aldehyde 9, which could be transformed
straightforwardly to 11 and 12. However, attempts at
further reduction of 8 to 13 with DIBAL-H led to multiple
impurities, as did trials with LiB(Et)3H, 9-BBN, and
(MeOCH2CH2O)2AlH2Na. Attempts at producing 13 via
the aldoxime 11 and by reductive amination of 9 with a
variety of systems were equally unsuccessful. Interest-
ingly, reductions of either 8 or carboxamide 17 with
LiAlH4 yielded products in which the double bond had
suffered reduction. This was useful to us later in estab-
lishing the stereochemistry of the reduced species, but
not for producing 13. A poor yield of 13 could be achieved
by converting alcohol 22 to its phthalimide derivative.
Our success in reducing 8 to 9 had shown that these
difficulties with 13 arose in further DIBAL-H reduction
of the imine species. On this basis, we ultimately devised
a tandem two-step reduction involving DIBAL-H followed
by NaBH4. With careful temperature control of the steps,
this led in 82% yield to pure 13, which could be trans-
formed easily to its acetamide 14. Reductive NaBH4
amination of 9 using titanium isopropoxide26 gave the
dimethylamino species 10 in 60% yield; however, analo-
gous reactions failed to provide the monomethylated
amine or 13 (above), leading instead to double-bond loss;
this is suspected to have involved internal nitrogen
additions to the styrene system. Transformation of car-
boxylic acid 15 into the other species of Scheme 3
proceeded as outlined.
All the members of this series of compounds display
unsplit pairs of singlets attributable to the exo-methylene
1
function in the δ 5.2-6.1 region of their H NMR spectra.
1
A H NOESY spectrum of methyl ester 18 established
that the downfield member in the pair (δ 5.93, 5.45) has
the cis relationship to the aromatic nucleus, consistent
with expected deshielding effects. Although NOESY
determinations were not made for the remainder of the
series, the analogous assignment is fully consistent with
every case. The average positions for the downfield and
upfield singlets, respectively, are δ 5.95 ( 0.04 and 5.42
( 0.11 (average separation ) 0.53 ( 0.09 ppm), and the
ranges for the two do not overlap. The methyl singlets
appear at δ 1.62 ( 0.13.
(21) Meyers, A. I.; Lefker, B. A. J . Org. Chem. 1986, 51, 1541.
(22) Sing, Y. L.; Lee, L. F. J . Org. Chem. 1985, 50, 4642.
(23) J ouanno, C.; Le Floc’H, Y. L.; Gree, R. Bull. Soc. Chim. Belg.
1995, 104, 49.
(24) Mukhopadhyay, T.; Seebach, D. Helv. Chim. Acta 1982, 65, 385.
(25) Grieco, P. A.; Parker, D. T. J . Org. Chem. 1988, 53, 3658.
(26) (a) Mattson, R. J .; Pham, K. M.; Leuk, D. J .; Cowen, K. A. J .
Org. Chem. 1990, 55, 5, (b) Bhattacharyya, S. J . Org. Chem. 1995, 60,
4928.

Haptophilicity Studies
J . Org. Chem., Vol. 67, No. 9, 2002 2815
Sch em e 4
Sch em e 5
P r od u ct Ster eoch em istr y. We also needed to estab-
lish with certainty the stereochemistry of all our ex-
pected hydrogenation products via synthetic sequences
independent of the individual hydrogenations. Our ap-
proach to this typically involves establishing unambigu-
ous stereochemistry for at least one hydrogenation
product, which is then used to synthesize the others in
the same stereochemical series.2,9 For this purpose,
synthetic conversions such as R ) COOH f CH2NH2 are
obviously much easier to carry out than the reverse.
Hence, even though we anticipated product ratios strongly
favoring proximofacial9 H2 addition with R ) CH2NH2,
13 was not a useful starting point for this process.
However, hydrogenation of the unsaturated acid 15
provided a mixture rich in what was shown to be the
distofacial9 reduction product (15c:15t ) 19:81). (The
notations c (cis) and t (trans) specify the relative stereo-
chemistry of the two methyl groups in the product,
corresponding, respectively, to proximofacial and disto-
facial hydrogenation processes.) Although this product,
like many of our cis/trans mixtures, was not readily
separable, the absence of byproducts and the simplicity
1
of the H NMR spectra of its two components facilitated
quantitation and enabled its direct use as a mixture for
transformations to identify product stereochemistries by
NMR.
The success of this approach depended on our being
able, for every reduced mixture, to partition the inte-
1
gratable H NMR signals and assign them to the indi-
vidual diastereomers present. In practice, the peaks used
were invariably the alkane signals, and most frequently
the 1H benzylic quartet and the methyl doublet arising
from reduction of the 2-methylene function, rather than
the singlet for the 1-methyl group. Utilizing mixtures for
the process of identifying these peaks in the first place
would, of course, not be possible with mixtures close to
50:50. However, the 19:81 ratio for 15c:15t offered us
reasonable certainty that, e.g., the 19:81 ratio found for
the carboxamide mixture directly derived from 15c:15t
represented 17c:17t, and not 17t:17c (Scheme 4).
Fortunately, the 1H NMR spectra of the mixtures
produced in Scheme 4 were sufficiently clean that all
peaks were readily assignable in every case. For each step
in the set of transformations depicted, the cis:trans ratio
for the product was thus readily assessable by H NMR
and remained quite close to that of its starting material.
The sole exception involved the esterification 15 f 18,
1

2816 J . Org. Chem., Vol. 67, No. 9, 2002
Thompson and Rashid
Sch em e 6
Sch em e 7
in which the ratio changed from 19:81 to 30:70. Although
most of the actual proofs of stereochemistry for the
reduced materials in our study hinged on compounds in
the cis series (see below), this change is consistent with
the assigned stereochemistries, which require greater
hindrance about the substituent in 18t.
This same hindrance about the substituent allowed us
fortuitous entry into the cis series of reduced compounds
via hydrogenation of the unsaturated nitrile 8 (Scheme
5), despite the fact that the initial binary product mix
was rich in the trans diastereomer (8c:8t ) 20:80).
Selective hydrolysis gave a mixture from which all nitrile
had been removed, but the cis amide 17c was also
essentially absent, as a result of its sterically less difficult
hydrolysis compared to that of 17t. The latter material
persisted in the mixture and was separable in good purity
from the reduced acids present by means of base extrac-
tion. The kinetically favored hydrolysis of 8c and 17c
thus led to a recovered mixture of acids found to be rich
in the cis diastereomer (15c:15t ) 87:13), providing
1
confirmation of our H NMR assignments for the previous
19:81 mixture of 15c:15t. Although the absolute yield of
15c in this step was poor, its production gave us both
confidence in our stereochemical assignments and enough
material to carry forward the functional-group transfor-
mations shown in Scheme 6.
The transformations within Scheme 6 utilized reagents
and conditions similar to those in the trans series
(Scheme 4) but led to several alterations in the cis-trans
product ratio, again consistent with greater hindrance
about the functional group in the diastereomers assigned
trans stereochemistry (Scheme 6). The sequence 15 f
18 f 22 f 23 produced a steady increase in cis content
from 87 to 99%, while the transformation 9 f 12 gave a
change in the cis:trans ratio from 80:20 to 87:13. Beyond
these kinetic evidences, we were able to confirm the
correctness of our stereochemical assignments by two
other means.
For two of our unsaturated materials, 8 and 15,
treatment with LiAlH4 led to reduction of the alkene in
addition to reduction of the functional group R (Scheme
7) and yielded 13c and 22c, respectively. Such internal
delivery of hydride to alkenes by LiAlH4 has been
reported in several cases where combinations of favorable
factors exist that have included strain in the alkene,
advantageous ring size for the hydride delivery and

Haptophilicity Studies
J . Org. Chem., Vol. 67, No. 9, 2002 2817
Ta ble 1. P er cen t P r oxim ofa cia la P r od u ct fr om
Hyd r ogen a tion of Com p ou n d s 8-23 Com p a r ed w ith
Resu lts fr om System s 1-3
favorable ring size and/or carbanion stabilization for the
(ultimately hydrolyzed) organoaluminum species formed.6
A stereochemical study of one such case has demon-
strated net syn addition of hydrogen, reflecting both
internal hydride delivery and retention of configuration
in the C-Al bond hydrolysis.27
percent proximofcial productb
compd
R
P - 55c
8-23d
1e
2d,f
3d
13
10
22
11
23
9
17
14
19
12
8
16
15
18
20
21
CH2NH2
CH2NMe2
CH2OH
CHNOH
CH2OMe
CHO
CONH2
CH2NHAc
COO- K+
COMe
CN
CONHOH
COOH
COOMe
COO- Na+
COO- Li+
33
115
21
36
67
10
37
122
87
62
48
45
44
42
33
33
30
22
20
18
17
16
10
7
100
63
Our previous demonstration of product stereochemistry
consistent with such intramolecular hydride delivery in
the case of 2 (R ) CH2OH) required high temperatures
(142 °C).6 In the present instance, the reactions of both
8 and 15 proceeded readily at 35 °C and both yielded 91:9
ratios of reduced-alkene products, consistent with the
stereochemical assignments already made, i.e., cis:trans
) 91:9. With 8, lowering the hydride:substrate ratio from
5.5 to 2.5 equiv led to a product consisting entirely of
13c, presumably by suppressing a minor intermolecular
component of the reaction. In the case of 15, although
carboxyl reduction was complete, half of the product
retained the alkene function, so that the product ratio
for the entire isolated mixture was 22:22c:22t ) 49:44:
4. Of the two obvious combinations of transition state
plus organoaluminum intermediate for these processes,
we have no direct evidence for but favor that involving
seven-centered hydride delivery and five-membered or-
ganoaluminum species because of the benzylic stabiliza-
tion the latter offers the polar C-Al bond.6
95
65
9
95
76
19
93
10
18
0
0
49
11
57
20
64
14
75
1
26
9
70
60
18
15
55
23
0
0
0
0
a
“Proximofacial” and “distofacial” describe the stereochemistry
of the reduction process itself, since cis/trans or syn/anti product
b
nomenclature may not always accurately reflect this. All hydro-
genations were conducted at 25 °C and atmospheric pressure and
assessed by NMR and/or GC. c Group parachors minus the value
d
for methyl (55). Solvent: absolute EtOH. e Solvent: 2-methoxy-
ethanol. f Thompson, H. W.; O’Lenick, A. J ., J r. Unpublished
results.
Further confirmation of our stereochemical assign-
1
entries, so that the internal haptophilic order is unknown
for the remaining six R groups in that system, which are
“off-scale” at the lower end. This was the result in 3 of
an alkene so blocked at one face by the R group as to
force exclusively distofacial hydrogenation wherever R
did not provide strong haptophilic assistance.9 This
contrasts with system 2, whose results may be viewed
as off-scale at the opposite end (R ) CH2NH2). With the
present system, both diastereomers were detected in
every product mixture, putting every group on scale.
That the haptophilic effect depends strongly on basicity
or electron availability is seen in the pattern for the
carboxylate salts but is most evident from the positions
of the amines (13 and 10) as compared to those of the
amides (17 and 14) and all other groups, a result also
observed in system 3. It is also clear from 13 vs 10, from
22 vs 23, and from the acids vs their methyl esters that
steric effects play a measurable role. Alongside the
haptophilic order for 8-23, Table 1 presents approximate
steric volumes for the R groups, based on group parachors
(P).28 Because the two faces of our system differ only in
the C-1 substituents, each product ratio represents a
haptophilic competition between the R group present and
methyl. We have therefore subtracted from each parachor
the value for methyl (55), so that the resulting numbers
simultaneously describe the relative group sizes and the
size differences between R and methyl. The scatter of
these tabulated parachors makes it evident that no
explanation of haptophilicity is possible on the basis of
size alone.
ments was achieved by means of a H NOESY spectrum
of a mixture of reduced oximes (11c:11t ) 45:55). Of the
six signals in the alkyl spectral region, we had assigned
the 1H benzylic quartet (H-2) at δ 3.58, the methyl
doublet at δ 1.42, and the methyl singlet at δ 1.64 all to
11t. A NOESY cross-peak at δ 3.58-δ 1.42 confirmed this
(vicinally coupled) relationship, and one at δ 3.58-δ 1.64
confirmed the cis stereochemical relationship between
H-2 and the C-1 methyl, consistent with 11t, where the
distance between H-2 and the C-1 methyl carbon is ca.
2.45 Å. For 11c, where this distance is ca. 3.15 Å, H-2 (δ
3.84) displayed a cross-peak with the methyl at C-2 but
not with the methyl at C-1. These stereochemical assign-
ments allowed reliable identification of all alkyl peaks
in the 1H NMR spectra of all our reduced compounds and
revealed consistent patterns. The benzylic quartet in the
cis isomers (av δ ) 3.90) was invariably found farther
downfield than in the corresponding trans species (av δ
) 3.53), while the reverse was true for the methyl singlet
(av δ ) 1.61 for trans and 1.43 for cis).
We were now able to undertake the systematic hydro-
genation of our unsaturated series 8-23 with confidence
in our ability to assign correct stereochemistries and
assess cis-trans ratios in our product mixtures. These
hydrogenations were carried out at atmospheric pressure
and room temperature, and the conditions, which em-
ployed absolute EtOH and the same batch of 5% Pd/C
catalyst used previously with 1-3, were chosen to allow
as much comparison as possible with those systems.3,9
Hyd r ogen a tion Resu lts. Table 1 shows the results
of our hydrogenations of 8-23, compared with those for
our previously studied systems, including among the
sixteen entries three functional groups we have never
previously assessed (10, 14, 23). The entries are arranged
in the “haptophilic order” found for 8-23, i.e., decreasing
content of proximofacial (cis) product. The previous case
that this order most resembles (3) has only three nonzero
On the basis of the results from 8-23, the function-
alities involved may be divided, somewhat arbitrarily,
into four groups, presenting high, moderate, low, and no
haptophilicity. The two amino functions, 13 and 10, both
produce well over 50% of proximofacial product, clearly
(28) (a) Sugden, S. The Parachor and Valency; Rutledge: London,
1929. (b) Quayle, O. R. Chem. Rev. 1953, 53, 439. (c) Isemura, T. In
Handbook of Organic Structural Analysis; Yukawa, Y., Ed.; W. A.
Benjamin: New York, 1965; p 466.
(27) Franzus, B.; Snyder, E. I. J . Am. Chem. Soc. 1965, 87, 3423.

2818 J . Org. Chem., Vol. 67, No. 9, 2002
Thompson and Rashid
Ta ble 2. P er cen t Cis P r od u ct fr om Hyd r ogen a tion s
Em p loyin g Solven ts of Low Dielectr ic Con sta n ta
demonstrating an interaction with the catalyst that is
strong and only modestly diminished by substitution. The
alcohol, aldoxime, methyl ether, and aldehyde display
little internal differentiation and give a proximofacial
product in the range of 42-48%. Since the group sizes
involved range from slightly to significantly larger than
methyl, this result suggests moderate haptophilic behav-
ior. The two amides and the potassium salt produce
proximofacial/distofacial ratios in the range of 1:2, argu-
ably not much different from what might be expected on
the basis of steric effects alone, while the remaining
groups all behave essentially as would be predicted on
the basis of merely steric hindrance. In our previous
discussions of the origins of haptophilicity, we have
viewed it as a catalyst adsorption intermediate in strength
and duration between poisoning and the sort of weak π
“chemisorption” commonly invoked in the early stages
of detailed hydrogenation mechanisms. It is noteworthy
that amines are well-known as mild catalyst poisons, an
effect that can be obviated by quaternization.
Hopes of controlling hydrogenation stereochemistry
require that experimental haptophilicities be transferable
in some degree from one molecular system to another.
Hence, some importance becomes attached to the simi-
larities and differences revealed by Table 1 among the
haptophilic orders found in the four substrate systems
so far employed. There appears to be good conformity
between systems 8-23 and 3, but this may mostly reflect
the scant data on the internal ordering within 3. For
system 2, the entries out of place in the present hapto-
philic ordering are the Na and Li carboxylates, plus
CH2OH. For system 1, the entries most out of place with
the present ordering are the same two carboxylates, plus
CONH2 and CN. The most striking consistencies overall
involve CH2NH2, CHO, COMe, COOH, and COOMe,
although data for specific entries are lacking for some of
the systems. Taking into account the consistencies and
inconsistencies in Table 1, together with the general
utility of the various groups toward further synthetic
transformations, it would appear that, in the absence of
specific studies on any system of potential interest, the
most generally useful group for inducing proximofacial
H2 addition may be CHO. At the other end of the scale,
the group most generally useful for inducing distofacial
H2 addition is probably COOMe (or esters of even greater
bulk). Below, we describe further experiments that
extend the practical usefulness of the principle of hap-
tophilicity.
% cis in
EtOH
solvent
(ratio)
%
cis
improve-
mentb
compd
R
22
17
8
CH2OH
CONH2
CN
48
33
20
17
cyclohexane
cyclohexane/Et2O (1:1) 57
cyclohexane
hexane/CHCl3 (9:1)
75
1.56
1.73
2.7
54
40
15
COOH
2.35
a
Hydrogenations were conducted under standard conditions
(5% Pd/C at 25 °C and atmospheric pressure) and assessed by
b
NMR and/or GC. Percent cis in the specified solvent divided by
percent cis in EtOH.
acid (15), and carboxamide (17) as well. Table 2 shows
these results, which not only offer a means of signifi-
cantly enhancing haptophilicities for several specific
groups but also suggest that such solvent enhancement
may be quite general. We have intentionally chosen the
compounds tested here to reflect a broad range of
haptophilic behavior (in EtOH), so it is worth noting that
this solvent enhancement operates over the entire range
of groups chosen, giving an average “improvement ratio”
of roughly 2.1 ( 0.4. It should also be noted that the
ordering of the groups is unchanged and that the
improvement in haptophilicity is proportionally the
greatest for the entries of low haptophilicity, although
that may be in part simply because those species start
from lower base values. The results suggest that low
haptophilicities may in part reflect a poor ability to
compete with polar solvents, particularly ones containing
alcohol and ether functions, which are commonly used
and are seen in system 8-23 as moderately effective
haptophiles. It appears that, even for groups of low
relative haptophilicity, their absolute haptophilicities
may be considerably improved by suppressing this com-
petition.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were taken in open
capillaries and are uncorrected. Unless otherwise specified,
NMR spectra were taken on CDCl3 solutions operating at
199.785 and 399.798 MHz for 1H and 100.554 MHz for 13C.
1H NMR coupling constants (J ) are given in hertz. Low-
resolution electron-impact (EI) and isobutane chemical-ioniza-
tion (CI) mass spectra were obtained by direct injection into a
mass spectrometer at typical energies of 70 eV and an ionizing
current of approximately 30 microamps. Fast-atom bombard-
ment mass spectra (FABMS) utilized a matrix of 3-nitrobenzyl
alcohol; the primary Xe beam had a maximum energy of 8 keV,
and positive ions were accelerated over a potential of 7 keV.
High-resolution mass spectra (HRMS) were obtained in the
peak-matching mode using an instrument calibrated to a
resolution of 10 000 with a 10% valley between peaks, using
perfluorokerosene. Gas chromatograms (GC) were obtained
using a system equipped with a 15 m × 0.20 mm × 0.33µ
column and with the oven programmed from 100 to 325 °C.
Flash chromatography employed a column packed with Silica
Gel 60, pore size 60 Å, particle size 200-500 µm, or 40-140
mesh silica gel. Thin-layer chromatography (TLC) employed
plates coated with Silica Gel 60 F254; developed plates were
visualized either with I2 or a UV lamp.
Solven t En h a n cem en t of Ha p top h ilicity. Hydro-
genation stereochemistry is sometimes markedly influ-
enced by the solvent chosen.29 Enhancement of hapto-
philicity by this means has been demonstrated in some
cases14 and is generally interpreted in terms of dimin-
ished solvent-substrate competition for the catalyst sites
the haptophile must occupy in order to be effective. Our
previous results in this area employed system 2 (R )
CH2OH), where we showed that a clear and progressive
increase in haptophilic effectiveness accompanied a
lowering of the solvent dielectric constant.5 By extending
this to the present system, we have now demonstrated
significant solvent-based enhancements of haptophilicity
not only for CH2OH (22) but for the nitrile (8), carboxylic
1-(1-Na p h th yl)p r op ion ic Acid (4, R ) Me). To a stirred
-78 °C solution of 200 mL (400 mmol) of LiN(iPr)2 in 800 mL
of dry THF under Ar was added 37.24 g (200 mmol) of
1-naphthylacetic acid in 200 mL of dry THF dropwise over 25
min. The solution was stirred at 0 °C for 1 h and recooled to
-78 °C, and a single portion of 18.75 mL (301 mmol) of MeI
was added. After the mixture was stirred overnight at room
temperature, the reaction was quenched with water; the
mixture was vacuum-concentrated, and the residue was dis-
(29) (a) Augustine, R. L. Catalytic Hydrogenation: Techniques and
Applications in Organic Synthesis; Marcel Dekker: New York, 1965;
pp 45-49. (b) House, H. O. Modern Synthetic Reactions, 2nd ed.;
Benjamin/Cummings: Menlo Park, CA, 1972; pp 26-28.

Haptophilicity Studies
J . Org. Chem., Vol. 67, No. 9, 2002 2819
solved in water. Extraction with Et2O both before and after
acidification yielded 38.38 g (96%) of 4 (R ) Me) as a white
solid: mp 141-143 °C (lit. 152-3 °C,30 140-142 °C31); IR
(CHCl3) 3500-2200 (br), 1747, 1710 cm-1; 1H NMR (400 MHz)
δ 8.08 (1 H, d, J ) 7.7), 7.87 (1 H, d, J ) 8.5), 7.78 (1 H, d, J
) 7.7), 7.50 (4 H, complex), 4.54 (1 H, q, J ) 6.8), 1.67 (3 H, d,
J ) 6.8); MS (EI), m/e (relative intensity) 599.2 (13), 400.2 (24),
399.2 (100), 200.2 (6), 199.2 (43), 155.1(22); HRMS (EI) calcd
for C13H12O2 200.0837, found 200.0841.
176.2 (5), 163.2 (9), 81.7 (7); HRMS (EI) calcd for C15H11
205.0891, found 205.0891.
N
1-Cya n o-tr a n s-1,2-d im eth yla cen a p h th en e (8t). Meth od
A. To a stirred 25 °C solution of 200 mg (0.89 mmol) of the
subsequently described mixture of carboxamides 17t (84%) and
17c (16%) in an anhydrous mixture of 25 mL of 4:1 THF/
pyridine under N2 was added 1.0 mL (14 mmol) of SOCl2. The
mixture was refluxed for 1 h, poured onto ice, and extracted
with CH2Cl2. The combined organic layers were washed
successively with 2 N NaOH and brine, dried, and vacuum-
concentrated. Flash chromatography on silica gel afforded 140
mg (76%) of a mixture of 8t (84%) and 8c (16%) as a faintly
yellowish solid: mp 46-49 °C; IR of the mixture (CH2Cl2) 2233,
1624 cm-1; 1H NMR of the major component (400 MHz) δ 7.76
(1 H, d, J ) 8.1), 7.70 (1 H, d, J ) 8.1), 7.58 (1 H, d, J ) 7.1),
7.54 (2 H, complex), 7.30 (1 H, d, J ) 6.8), 3.59 (1 H, q, J )
7.2), 1.83 (3 H, s), 1.67 (3 H, d, J ) 7.1); MS (EI) of the mixture,
m/e (relative intensity) 207.1 (67), 192.1 (89), 165.0 (100), 152.1
(13); MS (CI) of the mixture 208.1 (6), 181.1 (100), 81.1 (11),
2-Meth yla cen a p h th on e (5). To a stirred 25 °C suspension
of 38.38 g (191.8 mmol) of 4 (R ) Me) in 650 mL of dry CH2Cl2
under Ar was added 21.8 mL (250 mmol) of (COCl2)2 dropwise
over 30 min. After stirring at 25 °C for 3.5 h, the solution was
vacuum-concentrated. To the residue, stirred in 550 mL of dry
CH2Cl2 under a strong stream of Ar at -78 °C, was added 44.5
g (334 mmol) of AlCl3 in portions. After the mixture was stirred
overnight at room temperature, the reaction was quenched at
-78 °C by dropwise addition of 200 mL of 4 N HCl. The organic
layer combined with the CH2Cl2 extracts of the aqueous layer
yielded a crude oil. Flash chromatography on silica gel afforded
27 g (77%) of 5 as a colorless oil, which solidified when
chilled: mp 32-34 °C (lit.29 33-34 °C); IR (CHCl3) 1717, 1626
71.1 (15), 70.1 (11), 69.1 (15); HRMS (EI) calcd for C15H13
207.1048, found 207.1044.
N
Meth od B. Catalytic hydrogenation of 1.0 g (4.9 mmol) of
nitrile 8 under the standard conditions described below yielded
a yellowish oil containing some solvent. The product was
loaded onto a plug of silica gel; solvent was washed out, and
the product was eluted, giving 1.0 g (99.5%) of a mixture of 8t
(80%) and 8c (20%) as a faintly yellowish solid with NMR
essentially identical to that obtained by Method A.
1
cm-1; H NMR (400 MHz) δ 8.10 (1 H, d, J ) 7.7), 7.97 (1 H,
d, J ) 6.8), 7.83 (1 H, d, J ) 7.7), 7.73 (1 H, t, J ) 7.7), 7.63
(1H, t, J ) 6.8), 7.47 (1 H, d, J ) 6.8), 3.75 (1 H, q, J ) 7.7),
1.58 (3 H, d, J ) 7.7); MS (EI), m/e (relative intensity) 182.1
(97), 167.1 (14), 154.2 (54), 153.1 (100), 139.1 (13), 76.1 (26),
63.0 (24); HRMS (EI) calcd for C13H10O 182.0732, found
182.0730.
1-Cya n o-cis-1,2-d im eth yla cen a p h th en e (8c). A stirred
25 °C solution of 270 mg (1.20 mmol) of a mixture of
carboxamides 17c (81%) and 17t (19%) in 37.5 mL of anhy-
drous 4:1 THF/pyridine under N2 was treated with 1.5 mL (21
mmol) of SOCl2 and worked up as described above for 8t
(Method A), affording 200 mg (81%) of a mixture of 8c (84%)
and 8t (16%) as a yellowish solid: mp 88-94 °C; IR (CH2Cl2)
1-Cya n o-2-m eth yla cen a p h th ylen e (6). To a stirred 25 °C
mixture of 9.0 g (49 mmol) of ketone 5 and 9.0 mL (68 mmol)
of Me3SiCN under Ar was added 10 drops of BF3‚OEt2
dropwise. The mixture was heated to 60 °C, and another 10
drops of BF3‚OEt2 was added, followed by 45 mL of anhydrous
pyridine and 9.0 mL (97 mmol) of POCl3. The mixture was
then heated at 100 °C for 1 h, cooled, poured onto 100 g of ice,
and extracted with EtOAc. The combined extracts were
of the mixture 2233, 1603 cm-1 1H NMR of the major
;
component (200 MHz) δ 7.76 (1 H, d, J ) 8.2), 7.70 (1 H, d, J
) 8.1), 7.55 (3 H, complex), 7.26 (1 H, d, J ) 7.3), 4.20 (1 H, q,
J ) 7.6), 1.61 (3 H, s), 1.58 (3 H, d, J ) 7.6); 13C NMR of the
mixture δ 144.68, 144.52, 131.38, 128.60, 128.26, 124.91,
124.00, 123.63, 119.81, 119.43, 119.22, 119.09, 48.77, 29.71,
27.71, 23.30, 13.74; MS (EI) of the mixture, m/e (relative
intensity) 207.1 (75), 192.1 (100), 165.0 (95), 152.1 (12); MS
(CI) of the mixture 208.1 (5), 182.1 (9), 181.1 (100); HRMS (EI)
calcd for C15H13N 207.1048, found 207.1051.
1-Am in om et h yl-1-m et h yl-2-m et h ylen ea cen a p h t h en e
(13). Meth od A. To a stirred -78 °C solution of 200 mg (0.98
mmol) of nitrile 8 in 6 mL of dry Et2O under Ar was added
5.0 mmol of DIBAL-H (5.0 mL, 1.0 M in toluene). After the
mixture was stirred for 25 min, 223 mg (5.8 mmol) of NaBH4
was added and this mixture was stirred for 30 min. It was
then allowed to warm to -15 °C, and an additional 200 mg
(5.3 mmol) of NaBH4 was added. This mixture was kept
between -10 and -15 °C for 15 min and then cooled to -78
°C, and the reaction was quenched by slow, careful addition
of MeOH, followed by saturated NaHCO3. After filtration and
CH2Cl2 extraction, the extracts were washed with NaOH and
brine, dried, and concentrated. Flash chromatography afforded
140 mg (68%) of 13 as a faintly brownish oil: IR (CH2Cl2) 3361,
washed with
1 N HCl and brine, dried, and vacuum-
concentrated. Flash chromatography on silica gel afforded 6.13
g (65%) of 6 as a yellow powder: mp 108-110 °C; IR (CHCl3)
2216, 1625 cm-1; 1H NMR (400 MHz) δ 7.99 (1 H, d, J ) 7.7),
7.86 (1 H, d, J ) 6.8), 7.84 (1H, d, J ) 7.7), 7.75 (1 H, d, J )
6.8), 7.65 (1 H, t, J ) 7.7), 7.59 (1 H, t, J ) 6.8), 2.66 (3 H, s);
13C NMR δ 153.28, 137.69, 136.07, 130.63, 128.26 (2C), 128.12,
127.72, 127.43, 125.249, 122.93, 115.86, 108.04, 12.97; MS (EI),
m/e (relative intensity) 192.1 (6), 191.1 (58), 190.1 (100), 189.1
(5), 188.1 (7), 186.0 (6); HRMS (EI) calcd for C14H9N 191.0735,
found 191.0732.
1-Cya n o-1-m eth yl-2-m eth ylen ea cen a p h th en e (8). To a
stirred 0 °C solution of 25.3 mL (181 mmol) of (iPr)2NH in 250
mL of dry THF under Ar was added 110 mL of n-BuLi (1.6 N
in hexane, 176 mmol). After stirring for 15 min, the mixture
was cooled to -78 °C and 16.78 g (87.8 mmol) of 6 in 100 mL
of dry THF was added dropwise over 15 min. The mixture was
stirred for 45 min at 0 °C and then recooled to -78 °C, and
11.6 mL (95.9 mmol) of N,N′-dimethylpropyleneurea was
added, followed by 16.3 mL (262 mmol) of CH3I in 65 mL of
dry THF, added dropwise over 15 min. The mixture was stirred
for 30 min, transferred to a -40 °C bath, and allowed to warm
to -15 °C over 20 min. The cold bath was removed for 20 min,
and the reaction was quenched with water; the mixture was
then vacuum-concentrated and redissolved in CH2Cl2. After
successive washes with 3% HCl and brine, the organic layer
was dried and vacuum-concentrated. Flash chromatography
on silica gel afforded 16.65 g (92%) of 8 as an oil that solidified
3296, 1660, 1615 cm-1 1H NMR (400 MHz) δ 7.68 (2 H,
;
complex), 7.58 (3 H, complex), 7.25 (1 H, d, J ) 6.8), 5.93 (1
H, s), 5.28 (1 H, s), 3.03 (2 H, dd, J ) 12, 8), 1.43 (3 H, s); MS
(EI), m/e (relative intensity) 209.1 (6), 181.1 (17), 180.1 (100),
179.1 (67), 178.0 (55), 84.1 (44); HRMS (EI) calcd for C15H15
209.1204, found 209.1208.
N
1
when chilled: mp 54-57 °C; IR (CHCl3) 2239, 1622 cm-1; H
Meth od B. To a stirred 25 °C solution of 210 mg (1.0 mmol)
of alcohol 22, 151 mg (1.03 mmol) of phthalimide, and 270 mg
(1.03 mmol) of Ph3P in 8 mL of freshly distilled THF was added
213 µL (1.03 mmol) of diethyl azodicarboxylate in 1 mL of
toluene dropwise, and stirring was continued for 16 h. Con-
centration to a crude oil and flash chromatography afforded
150 mg of the N-phthalimidomethyl species as a white foam:
NMR (400 MHz) δ 7.79 (2 H, d, J ) 6.0), 7.62 (3 H, complex),
7.53 (1 H, d, J ) 6.8), 6.05 (1 H, s), 5.72 (1 H, s), 1.87 (3 H, s);
13C NMR δ 150.28, 141.54, 136.77, 136.61, 131.39, 128.70,
128.36, 125.54, 125.06, 122.02, 122.02, 118.74, 117.40, 108.88,
28.25; MS (EI), m/e (relative intensity) 205.2 (42), 190.2 (100),
IR (CH2Cl2) 1618 cm-1 1H NMR (400 MHz) δ 7.79 (2 H,
;
complex), 7.69 (4 H, complex), 7.59 (1 H, d, J ) 6.8), 7.50 (2
H, overlapping t, J ) 7.7, 8.5), 7.26 (1H, d, J ) 6.8), 5.90 (1 H,
(30) Bosch, A.; Brown, R. K. Can. J . Chem. 1968, 46, 715.
(31) Cornforth, D. A.; Opara, A. E.; Read, G. J . Chem. Soc. C 1969,
2799.

2820 J . Org. Chem., Vol. 67, No. 9, 2002
Thompson and Rashid
s), 5.38 (1 H, s), 4.00 (2 H, s), 1.63 (3 H, s); MS (FAB+), m/e
(relative intensity) 340.1 (58), 339.1 (57), 307.1 (27), 289.1 (14),
279.1 (24), 154.0 (100), 136 1(69); HRMS (EI) calcd for
H, complex), 7.58 (3 H, complex), 7.30 (1 H, d, J ) 6.8), 5.91
(1 H, s), 5.37 (1 H, s), 5.03 (1 H, broad), 3.80 (1 H, dd, J )
7.4), 3.67 (1H, dd, J ) 7.8), 1.65 (3 H, s), 1.45 (3 H, s); MS
(EI), m/e (relative intensity) 192.1 (39), 179.1 (100), 152.1 (11),
69.1 (15); HRMS (EI) calcd for C17H17NO 251.1310, found
251.1321.
C
23H17NO2 339.1259, found 339.1260.
To a stirred 25 °C solution of 87 mg (0.26 mmol) of the above
N-phthalimidomethyl derivative in 8 mL of absolute EtOH was
added 300 µL (2.6 mmol) of N2H4‚H2O. After 16 h of reflux,
the mixture was concentrated to dryness and extracted with
aqueous NaHCO3 and Et2O. The combined organic layers
afforded 40 mg of crude product with 1H NMR spectrum
essentially identical to that of 13 produced by Method A.
1-Am in om eth yl-tr a n s-1,2-d im eth yla cen a p h th en e (13t).
Meth od A. A stirred -78 °C solution of a mixture of nitriles
8t (80%) and 8c (20%) (300 mg, 1.45 mmol) in 10 mL of
anhydrous THF under Ar was treated with 12.0 mmol of
DIBAL-H (12.0 mL, 1.0 M in toluene) followed by a single
portion of 78 mg (2.0 mmol) of NaBH4, as described above for
13 (Method A). Workup afforded 123 mg (40%) of a mixture of
13t (80%) and 13c (20%) as a faintly yellowish oil: IR of the
1-Ac e t a m i d o m e t h y l-t r a n s-1,2-d i m e t h y la c e n a p h -
th en e (14t). Treatment of 60 mg (0.28 mmol) of a mixture of
amines 13t (83%) and 13c (17%) with 500 µL (5.3 mmol) of
Ac2O as described above for 14 afforded 48 mg (68%) of a
mixture of 14t (82%) and 14c (18%) as a white solid: mp 155-
165 °C; IR of the mixture (CH2Cl2) 3285, 1661, 1566, cm-1; 1H
NMR of the major component (400 MHz) δ 7.67 (1 H, d, J )
8.4), 7.64 (1 H, d, J ) 8.4), 7.52 (2 H, overlapping t), 7.25 (2
H, complex), 4.85 (1 H, broad), 3.57 (1 H, dd, J ) 6.0, 7.4),
3.45 (1 H, q, J ) 7.3), 3.29 (1 H, dd, J ) 5.7, 7.7), 1.73 (3 H, s),
1.51 (3 H, d, J ) 7.4), 1.50 (3H, s); MS (EI), m/e (relative
intensity) 253.1 (1), 194.1 (12), 183.1 (13), 182.1 (22), 181 (100),
167 (27), 166.1 (32), 165.1 (72) 153 (16.1), 153.1 (16), 152.1
(21), 83.1 (12), 71.1 (12), 57.1 (28), 55.1 (18); MS (CI) 255.1
(18), 254.1 (100), 226.1 (34), 181.1 (12), 91.1 (18); HRMS (EI)
calcd for C17H19NO 253.1467, found 253.1476.
1
mixture (CH2Cl2) 3338 (br), 1666, 1603 cm-1; H NMR of the
major component (400 MHz) δ 7.65 (1 H, d, J ) 8.2), 7.62 (1
H, d, J ) 8.1), 7.50 (2 H, complex), 7.25 (1 H, d, J ) 7.6), 7.21
(1 H, d, J ) 6.3), 3.44 (1 H, q, J ) 7.4), 2.83 (2 H, broad), 1.52
(3 H, d, J ) 7.4), 1.48 (3 H, s); MS (EI) of the mixture, m/e
(relative intensity) 211.1 (4), 167.1 (64), 166.1 (40), 165.1 (100),
153.1 (13), 152.1 (26), 83.1 (10), 70.1 (31); MS (CI) of the
mixture 212.1 (100), 183.1 (84), 181.0 (24); HRMS (EI) calcd
for C15H17N 211.1361, found 211.1352.
1-Acetam idom eth yl-cis-1,2-dim eth ylacen aph th en e (14c).
Treatment of 30 mg (0.14 mmol) of a mixture of amines 13c
(80%) and 13t (20%) with 400 µL (4.2 mmol) of Ac2O as
described above for 14 afforded 27 mg (76%) of a mixture of
14c (80%) and 14t (20%) as a white solid: mp 170-177 °C; IR
of the mixture (CH2Cl2) 3285, 3222, 2868, 1647, 1566, cm-1
;
Meth od B. To a stirred solution of a mixture of 150 mg
(0.67 mmol) of carboxamides 17t (84%) and 17c (16%) in 10
mL of anhydrous THF cooled in an ice bath was added 150
mg (3.95 mmol) of LiAlH4, and the mixture was stirred for 1
h. An additional 10 mL of anhydrous THF and 150 mg (3.95
mmol) of LiAlH4 were added, and the mixture was stirred for
1 h. The mixture was chilled; the reaction was quenched by
slow addition of H2O followed by 2 N NaOH, and then the
mixture was extracted. The combined, washed, and dried
organic portions were concentrated and flash-chromatographed
to afford 100 mg (71%) of a mixture of 13t (83%) and 13c (17%)
1H NMR of the major component (200 MHz) δ 7.71 (2 H,
complex), 7.56 (2 H, complex), 7.27 (2 H, complex), 5.15 (1 H,
broad), 3.85 (1 H, pair of doublets, J ) 8.1, 8.1), 3.51 (1 H, q,
J ) 7.2), 3.45(1 H, pair of doublets, J ) 4.4, 4.4), 1.78 (3 H, s),
1.38 (3 H, d, J ) 7.1), 1.28 (3 H, s); MS (EI), m/e (relative
intensity) 253.1 (4), 194 (30), 181.1 (100), 166.1 (22), 165.1 (53),
73.1 (13), 69.1 (13), 57.1 (24), 55.1 (18); MS (CI) 256.1 (6), 255.1
(15), 254.1 (100); HRMS (EI) calcd for C17H19NO 253.1467,
found 253.1468.
1-Me t h yl-2-m e t h yle n e a ce n a p h t h e n e -1-ca r b oxa ld e -
h yd e (9). Meth od A. To a stirred -78 °C solution of 1.0 g
(4.9 mmol) of nitrile 8 in 30 mL of dry Et2O under Ar was
added 25.0 mmol of DIBAL-H (25.0 mL, 1.0 M in toluene). The
solution was stirred for 30 min at -78 °C before the reaction
was quenched by slow addition of EtOH. The warmed solution
was filtered through a short layer of Celite, which was washed
with excess Et2O. The combined, concentrated organic portions
were flash-chromatographed on 75 g of silica gel with 3:2
hexane/CH2Cl2 to afford 840 mg (82%) of 9 as a colorless oil:
IR (CHCl3) 2824, 1720, 1601 cm-1; 1H NMR (400 MHz) δ 9.32
(1 H, s), 7.77 (2 H, t, J ) 8.5), 7.66 (1 H, d, J ) 6.8), 7.60 (1 H,
d, J ) 7.7), 7.55 (1 H, t, J ) 8.5), 7.25 (1 H, d, J ) 6.8), 6.03
(1 H, s), 5.32 (1 H, s), 1.56 (3 H, s); MS (EI), m/e (relative
intensity) 208.1 (56), 195.1 (54), 179.1 (100), 165.1 (29), 152.1
(23); HRMS (EI) calcd for C15H12O 208.0888, found 208.0894.
1
as a faintly yellowish oil with H NMR essentially identical to
that of the material obtained by Method A.
1-Am in om eth yl-cis-1,2-d im eth yla cen a p h th en e (13c).
Meth od A. A stirred -78 °C solution of a mixture of 65 mg
(0.31 mmol) of nitriles 8c (84%) and 8t (16%) in 2.0 mL of
anhydrous THF under Ar was treated with 2.0 mmol of
DIBAL-H (2.0 mL, 1.0 M in toluene) followed by 148 mg (3.8
mmol) of NaBH4 in two portions, as described above for 13
(Method A), to afford 30 mg (46%) of a mixture of 13c (82%)
and 13t (18%) as a faintly yellowish oil: IR of the mixture
(CH2Cl2) 3700-3100 (br), 1660, 1618 cm-1 1H NMR of the
;
major component (200 MHz) δ 7.69 (2 H, complex), 7.51 (2 H,
complex), 7.32 (2 H, complex), 3.58 (1H, q, J ) 7.4), 3.02 (2 H,
broad), 1.38 (3 H, d, J ) 7.1), 1.28 (3 H, s); MS (EI), m/e
(relative intensity) 182.1 (69), 181.1 (100), 167.0 (23), 166.1
(37), 165.1 (94); MS (CI) 213.1 (14), 212.1 (100), 183.1 (4), 182.1
(2); HRMS (EI) calcd for C15H17N 211.1361, found 211.1359.
Meth od B. In ter n a l Deliver y of Hyd r id e Usin g LiAlH4.
To a 25 °C slurry of 100 mg (2.6 mmol) of LiAlH4 in 5.0 mL of
anhydrous Et2O was added 100 mg (0.49 mmol) of nitrile 8
dropwise over 5 min. The reaction mixture was stirred for 15
min, refluxed for 1.5 h, and cooled, and the reaction was
quenched by slow H2O addition. Concentration of the dried
extracts yielded 89 mg (87%) of a mixture of 13c (91%) and
13t (9%) as a crude oil with 1H NMR essentially identical to
that of 13c obtained by Method A. A similar reaction carried
out with only half as much LiAlH4 produced 13c exclusively.
1-Acet a m id om et h yl-1-m et h yl-2-m et h ylen ea cen a p h -
th en e (14). To a stirred 25 °C solution of 140 mg (0.67 mmol)
of amine 13 in 2.5 mL of anhydrous MeOH under Ar was
added 700 µL (7.4 mmol) of Ac2O. After this solution had been
stirred for 16 h and concentrated to dryness, the residue was
dissolved in CH2Cl2 and washed with 6 N NaOH and then
brine. The dried and concentrated organic layer yielded 140
mg (84%) of 14 as an off-white solid: mp 125-126 °C; IR
(CHCl3) 3289, 1654, 1550 cm-1; 1H NMR (400 MHz) δ 7.72 (2
Meth od B. To a stirred 25 °C solution of 575 mg (2.74
mmol) of alcohol 22 in 20 mL of anhydrous CH2Cl2 was added
1.38 g (3.65 mmol) of pyridinium dichromate, and the mixture
was stirred for 16 h. The solution was diluted with CH2Cl2,
filtered through Celite, washed alternately with brine and
NaHCO3, dried, and passed through a plug of silica gel to
afford 200 mg (35%) of 9 as a colorless oil with 1H NMR
essentially identical to that produced by Method A.
tr a n s-1,2-Dim et h yla cen a p h t h en e-1-ca r b oxa ld eh yd e
(9t). After 300 mg (1.45 mmol) of a mixture of nitriles 8t (84%)
and 8c (16%) had been treated with 8.0 mmol of DIBAL-H
(8.0 mL, 1.0 M in toluene) and stirred for 30 min as described
above for 9 (Method A), the mixture was kept at between -20
and -10 °C for 2.5 h and worked up to afford 170 mg (56%) of
a mixture of 9t (83%) and 9c (17%) as a colorless oil: IR of
1
the mixture (CH2Cl2) 2812, 2712, 1721, 1603 cm-1; H NMR
of the major component (400 MHz) δ 9.44 (1 H, s), 7.72 (1 H,
d, J ) 8.5), 7.69 (1 H, d, J ) 8.4), 7.54 (2 H, complex), 7.28 (1
H, d, J ) 6.9), 7.18 (1 H, d, J ) 7.0), 3.66 (1 H, q, J ) 7.6),
1.60 (3 H, s), 1.52 (3 H, d, J ) 7.7); MS (EI) of the mixture,
m/e (relative intensity) 210.1 (8), 182 (7), 181.1 (100), 166.1

Haptophilicity Studies
J . Org. Chem., Vol. 67, No. 9, 2002 2821
brownish oil: IR (CHCl3) 1601 cm-1 1H NMR (200 MHz,
(24), 165.0 (64); MS (CI) of the mixture 212.1 (13), 211.1 (100),
181.1 (2); HRMS (EI) calcd for C15H14O 210.1045, found
210.1037.
;
CD3OD) δ 7.68 (3 H, complex), 7.55 (2 H, complex), 7.33 (1 H,
d, J ) 7.7), 5.95 (1 H, s), 5.35 (1 H, s), 2.90 (2 H, dd, J ) 12,
8), 1.95 (6 H, s), 1.40 (3 H, s); MS (EI), m/e (relative intensity)
237.1 (36), 178.1 (32), 165.0 (23), 152.0 (19), 74.1 (30), 58.0
(100); HRMS (EI) calcd for C17H19N 237.1518, found 237.1508.
1-(N ,N -Dim e t h yla m in om e t h yl)-t r a n s-1,2-d im e t h yl-
a cen a p h th en e (10t). Treatment, as described above for 10,
of 25 mg (0.24 mmol) of a mixture of aldehydes 9t (83%) and
9c (17%) with 100 mg (1.0 mmol) of Et3N, 160 mg (0.56 mmol)
of Ti(IV) isopropoxide and 50 mg (0.6 mmol) of Me2NH‚HCl,
followed by 150 mg (3.95 mmol) of NaBH4, afforded 7 mg (12%)
of a mixture of 10t (72%) and 10c (28%) as a yellowish oil: IR
cis-1,2-Dim eth yla cen a p h th en e-1-ca r boxa ld eh yd e (9c).
After 110 mg (0.53 mmol) of a mixture of nitriles 8c (84%)
and 8t (16%) had been treated with 3.0 mmol of DIBAL-H (3.0
mL, 1.0 M in toluene) as described above for 9 (Method A),
the solution was kept at between -20 and -10 °C for 30 min
and worked up to afford 73 mg (66%) of a mixture of 9c (80%)
and 9t (20%) as a colorless oil: IR of the mixture (CH2Cl2)
2871, 1720, 1596 cm-1; 1H NMR of the major component (200
MHz) δ 9.57 (1 H, s), 7.75 (2 H, overlapping d), 7.54 (2 H,
overlapping t), 7.38 (1 H, d, J ) 7.7), 7.23 (1 H, d, J ) 7.2),
4.07 (1 H, q, J ) 7.5), 1.48 (3 H, s), 1.40 (3 H, d, J ) 7.1); MS
(EI) of the mixture, m/e (relative intensity) 210.1 (8), 182.1
(12), 181.1 (100), 166.1 (23), 165.1 (63); MS (CI) of the mixture
212.1 (14), 211.1 (100), 197.1 (21), 181.1 (66); HRMS (EI) calcd
for C15H14O 210.1045, found 210.1042.
of the mixture (CH2Cl2) 1639 cm-1 1H NMR of the major
;
component (400 MHz) δ 7.60 (4 H, complex), 7.25 (2 H,
complex), 3.39 (1 H, q, J ) 7.5), 2.62 (2 H, overlapping d, J )
5.7), 1.94 (6 H, s), 1.48 (3 H, s), 1.47 (3 H, d, J ) 7.4); MS (EI)
of the mixture, m/e relative intensity) 165.1 (6), 59.1 (3), 58.1
(100); MS (CI) of the mixture 241.1 (12), 240.1 (100), 195.1
(4); HRMS (CI) calcd for C17H21N 239.1674, found 239.1686.
1-(N ,N -D i m e t h y la m i n o m e t h y l)-c i s -1,2-d i m e t h y l-
a cen a p h th en e (10c). Treatment, as described above for 10,
of 27 mg (0.13 mmol) of a mixture of aldehydes 9c (80%) and
9t (20%) with 60 mg (0.6 mmol) of NEt3, 150 mg (0.53 mmol)
of Ti(IV) isopropoxide, and 42 mg (0.5 mmol) of HNMe2‚HCl,
followed by 50 mg (1.32 mmol) of NaBH4, afforded 15 mg (48%)
of a mixture of 10c (80%) and 10t (20%) as a colorless oil: IR
1-Met h yl-2-m et h ylen ea cen a p h t h en e-1-ca r b oxa ld ox-
im e (11). To a stirred 25 °C solution of 140 mg (0.67 mmol) of
aldehyde 9 in 25 mL of absolute EtOH under Ar was added
308 mg (3.37 mmol) of NaOAc and 257 mg (3.37 mmol) of
HONH2‚HCl, and the mixture was refluxed for 16 h. After
vacuum concentration, the mixture was extracted with water
and CH2Cl2 and the combined organic layers were washed with
2 N HCl, dried, and concentrated to afford 106 mg (71%) of 11
as an off-white solid: mp 110-112 °C; IR (CHCl3) 3583, 2846
1
cm-1; H NMR (400 MHz) δ 7.76 (1 H, d, J ) 7.7), 7.72 (1 H,
of the mixture (CH2Cl2) 1662, 1617, 1603 cm-1 1H NMR of
;
d, J ) 7.7), 7.63 (1 H, d, J ) 6.8), 7.56 (2 H, complex), 7.44 (1
H, s), 7.30 (1 H, d, J ) 5.1), 5.95 (1 H, s), 5.36 (1 H, s), 1.67 (3
H, s), 1.25 (1 H, s); MS (EI), m/e (relative intensity) 223.1 (79),
206.1 (72), 191.1 (49), 179.1 (100), 152.1 (28); HRMS (EI) calcd
for C15H12O 223.0997, found 223.0989.
the major component (200 MHz) δ 7.63 (2 H, complex), 7.50
(2 H, complex), 7.28 (2 H, complex), 3.86 (1 H, q, J ) 7.3),
2.62 (2 H, overlapping d, J ) 4.4, 5.9), 2.17 (6 H, s), 1.42 (3 H,
d, J ) 7.5), 1.24 (3 H, s); MS (EI) of the mixture, m/e (relative
intensity) 165.1 (4), 58.1 (100); MS (CI) of the mixture 241.1
(14), 240.1 (100), 195.1 (13), 181.0 (20); HRMS (CI) calcd for
tr a n s-1,2-Dim et h yla cen a p h t h en e-1-ca r b oxa ld oxim e
(11t). Treatment of 60 mg (0.28 mmol) of a mixture of
aldehydes 9t (83%) and 9c (17%) with 150 mg (1.64 mmol) of
NaOAc and 125 mg (1.64 mmol) of HONH2‚HCl as described
above for 11 afforded 45 mg (71%) of a mixture of 11t (85%)
and 11c (15%) as an off white solid: mp 94-96 °C; IR of the
mixture (CH2Cl2) 3316, 2870, 1603 cm-1; 1H NMR of the major
component (400 MHz) δ 7.68 (2 H, overlapping d, J ) 8.3, 7.4),
7.51 (2 H, overlapping t, J ) 7.6, 7.5), 7.45 (1 H, s, CHN), 7.25
(2 H, overlapping d), 3.58 (1 H, q, J ) 7.5), 1.64 (3 H, s), 1.42
(3 H, d, J ) 7.5), 1.26 (1H, s); MS (EI) of the mixture, m/e
(relative intensity) 225.1 (36), 208.1 (48), 193.1 (88), 181 (57),
165.1 (100), 82.1 (31), 57.1 (13); MS (CI) of the mixture 227.1
(13), 226.1 (100), 181.1 (22); HRMS (EI) calcd for C15H15NO
225.1154, found 225.1152.
cis-1,2-Dim eth ylacen aph th en e-1-car boxaldoxim e (11c).
Treatment of 20 mg (0.095 mmol) of a mixture of aldehydes
9c (80%) and 9t (20%) with 80 mg (0.87 mmol) of NaOAc and
60 mg (0.79 mmol) of HONH2‚HCl as described above for 11
afforded 21 mg (97%) of a mixture of 11c (79%) and 11t (21%)
as a white solid: mp 83-87 °C; IR of the mixture (CH2Cl2)
3315, 2870, 1621, 1603 cm-1; 1H NMR of the major component
(200 MHz) δ 7.77 (1 H, s), 7.68 (2 H, complex), 7.52 (2 H,
overlapping t), 7.28 (2 H, complex), 3.84 (1 H, q, J ) 7.4), 1.46
(3 H, d, J ) 7.5), 1.41 (3 H, s), 1.28 (1 H, s); MS (EI) of the
mixture, m/e (relative intensity) 225.1 (39), 208.3 (53), 193.1
(78), 181.1 (48), 165.2 (100); MS (CI) of the mixture 227.1 (15),
226.1 (91), 210.1 (100), 181.1 (78); HRMS (EI) calcd for
C
17H21N 239.1674, found 239.1671.
1-Acetyl-1-m eth yl-2-m eth ylen ea cen a p h th en e (12). To
a stirred -78 °C solution of 121 mg (0.58 mmol) of aldehyde 9
in 4.0 mL of freshly distilled THF was added 1.0 mL (3.0 mmol)
of 3.0 M MeMgBr in Et2O. After 5 min of stirring at -78 °C,
the reaction was quenched by slow addition of anhydrous
CH3OH. The solution was partitioned with CH2Cl2 and 3%
HCl, dried, filtered through a plug of silica, and concentrated
to yield 63 mg (0.28 mmol) of the alcohol as a faintly yellow
oil. All of this alcohol in 2.0 mL of distilled Et2O was oxidized
at room temperature by adding 200 mg (0.53 mmol) of
pyridinium dichromate (PDC) to the stirred solution. After 30
min, 7.0 mL of distilled CH2Cl2 was added, followed by an
additional 300 mg (0.80 mmol) of PDC, and the mixture was
stirred for 16 h. The mixture was diluted with CH2Cl2, filtered
through Celite, concentrated under vacuum, and flash-chro-
matographed on silica gel. This afforded 30 mg (23%) of 12 as
a faintly yellow oil: IR (CHCl3) 1708 cm-1; 1H NMR (400 MHz)
δ 7.72 (3 H, complex), 7.58 (1 H, d, J ) 8.5), 7.53 (1 H, d, J )
8.5), 7.17 (1 H, d, J ) 7.7), 5.92 (1 H, s), 5.26 (1 H, s), 1.72 (3
H, s), 1.59 (3 H, s); MS (EI), m/e (relative intensity) 223.1 (14),
222.1 (82), 179.1 (100), 178.0 (30), 152.0 (13); HRMS (EI) calcd
for C16H14NO 222.1044, found 222.1042.
1-Acet yl-tr a n s-1,2-d im et h yla cen a p h t h en e (12t ). Ac-
cording to the procedure described above for 12, 40 mg (0.19
mmol) of a mixture of aldehydes 9t (83%) and 9c (17%) was
treated with 3.0 mmol of ethereal MeMgBr and the entire
product (32 mg, 0.14 mmol) oxidized with two portions of PDC
totalling 400 mg (1.05 mmol) to afford 25 mg (59%) of a mixture
of 12t (83%) and 12c (17%) as a colorless oil: IR of the mixture
C
15H15NO 225.1154, found 225.1154.
1-(N,N-Dim eth yla m in om eth yl)-1-m eth yl-2-m eth ylen e-
a cen a p h th en e (10). To 270 mg (1.3 mmol) of aldehyde 9
under Ar at 25 °C was added 260 mg (2.6 mmol) of Et3N in
1.0 mL of anhydrous EtOH followed by 741 mg (2.6 mmol) of
Ti(IV) isopropoxide in 1.0 mL of anhydrous EtOH. To the
resulting solution was added 214.5 mg (2.6 mmol) of Me2NH‚
HCl, and the mixture was stirred for 9 h at 25 °C before the
addition of 74.1 mg (1.95 mmol) of NaBH4; the mixture was
stirred for an additional 16 h. The mixture was worked up by
adding 4 mL of 2 N NH4OH and extracting with CH2Cl2. The
combined extracts were washed with brine, dried, concen-
trated, and flash-chromatographed on silica gel with 9:1
CH2Cl2/MeOH, affording 185 mg (60%) of 10 as a faintly
(CH2Cl2) 1707, 1620, 1604 cm-1 1H NMR of the major
;
component (400 MHz) δ 7.71 (1 H, d, J ) 8.6), 7.68 (1 H, d, J
) 8.3), 7.52 (2 H, complex), 7.26 (1 H, d, J ) 6.3), 7.19 (1 H, d,
J ) 6.7), 3.61 (1 H, q, J ) 7.4), 1.63 (3 H, s), 1.59 (3 H, s), 1.43
(3 H, d, J ) 7.5); MS (EI) of the mixture m/e (relative intensity)
224.1 (7), 182.1 (13), 181.1 (100), 166.1 (29), 165.1 (61); MS
(CI) of the mixture 226.1 (12), 225.1 (100), 181.1 (2), 167.1 (4),
81.1 (2), 71.1 (2), 70.1 (2), 69.1 (2); HRMS (EI) calcd for C16H16
224.1201, found 224.1190.
O
1-Acetyl-cis-1,2-d im eth yla cen a p h th en e (12c). According
to the procedure described above for 12, 25 mg (0.12 mmol) of

2822 J . Org. Chem., Vol. 67, No. 9, 2002
Thompson and Rashid
a mixture of aldehydes 9c (80%) and 9t (20%) was converted
to 19 mg (71%) of a mixture of 12c (87%) and 12t (13%) as a
colorless oil: IR of the mixture (CH2Cl2) 1706, 1595, cm-1; 1H
NMR of the major component (200 MHz) δ 7.75 (2 H,
overlapping d, J ) 8.1, 8.4), 7.55 (2 H, overlapping t, J ) 7.0,
7.0), 7.28 (2 H, overlapping d, J ) 7.0, 6.6), 3.94 (1 H, q, J )
7.4), 1.96 (3 H, s), 1.59 (3 H, s), 1.42 (3 H, d, J ) 7.4); MS (EI)
m/e (relative intensity) 224.1 (5), 182.0 (9), 181.1 (100), 166.1
(28), 165.1 (43); MS (CI) 226.1 (14), 225.1 (100), 207.1 (3), 181.0
(2), 167.1 (5); HRMS (EI) calcd for C16H16O 224.1201, found
224.1197.
1-Ca r boxy-1-m eth yl-2-m eth ylen ea cen a p h th en e (15). A
stirred mixture of 1.00 g (4.88 mmol) of nitrile 8 and 2.15 g
(38.3 mmol) of KOH in 20 mL of ethylene glycol under Ar was
heated at 105 °C for 16 h. The hot solution was poured onto
ice and extracted with CH2Cl2, and the acidified aqueous layers
were then extracted with CH2Cl2, dried, and concentrated to
afford 1.0 g (92%) of 15 as a white solid: mp 149-151 °C; IR
(CHCl3) 3550-2550 (br), 1743 (shoulder), 1704 cm-1; 1H NMR
(400 MHz) δ 7.73 (2 H, overlapping d, J ) 8.5, 9.4), 7.62 (1 H,
d, J ) 6.8), 7.55 (2 H, complex), 7.36 (1 H, d, J ) 6.8), 5.96 (1
H, s), 5.50 (1 H, s), 1.75 (3 H, s); 13C NMR (100 MHz) δ 179.59,
151.86, 144.40, 138.67, 137.76, 131.37, 128.31, 128.13, 125.08,
124.12, 118.71, 116.73, 107.63, 57.30, 24.78; MS (EI), m/e
(relative intensity) 448.1 (33), 447.1 (100), 285.1 (15), 241.0
(13), 223.1 (18); HRMS (EI) calcd for C15H12O2 224.0837, found
224.0836.
with hexane/petroleum ether to remove residual 15, yielding
330 mg (83%) of 20 as an off-white solid: IR (KBr) 1644, 1576,
1454, 1363 cm-1, no absorption was observed at 1700 cm-1
.
P ota ssiu m 1-Meth yl-2-m eth ylen ea cen a p h th en e-1-ca r -
boxyla te (19). A room-temperature suspension of 193 mg
(0.86 mmol) of acid 15 and 51 mg (0.772 mmol) of KOH in 1.0
mL of anhydrous MeOH was stirred under Ar for 1 h. Vacuum-
concentration, coevaporation (three times) with CHCl3, and
washing with hexane/petroleum ether to remove residual 15
provided 200 mg (89%) of 19 as an off-white solid: IR (KBr)
2966, 1594, 1490, 1378, 1340 cm-1, no absorption was observed
at 1700 cm-1
.
Meth yl 1-Meth yl-2-m eth ylen ea cen a p h th en e-1-ca r box-
yla te (18). To a stirred -78 °C solution of 2.50 g (11.2 mmol)
of acid 15 in 250 mL of anhydous MeOH under Ar was added
3.3 mL (45 mmol) of SOCl2 dropwise over 5 min. The mixture
warmed to room temperature as it stirred overnight and then
was vacuum-concentrated, coevaporated twice with EtOH, and
flash-chromatographed on silica gel to afford 2.1 g (79%) of
18 as an off-white solid: mp 63-65 °C; IR (CHCl3) 1728, 1642
1
cm-1; H NMR (400 MHz) δ 7.75 (1 H, d, J ) 7.7), 7.72 (1 H,
d, J ) 8.5), 7.63 (1 H, d, J ) 6.8), 7.54 (2 H, overlapping t),
7.32 (1 H, d, J ) 6.8), 5.93 (1 H, s), 5.45 (1 H, s), 3.60 (3 H, s),
1.75 (3 H, s); 13C NMR (100 MHz) δ 174.31, 152.45, 145.17,
138.91, 137.85, 131.38, 128.26, 128.14, 125.00, 123.86, 118.33,
116.68, 106.96, 57.43, 52.56, 25.13; MS (CI), m/e (relative
intensity) 274.1 (M + 2NH4, 58), 256.1 (M + NH4, 100), 239.1
(M + H, 94); HRMS (EI) calcd for C16H14O2 238.0994, found
238.0996.
1-Car boxy-tr a n s-1,2-dim eth ylacen aph th en e (15t). Cata-
lytic hydrogenation of acid 15 under the standard conditions
described below provided a colorless oil shown to contain 81%
of 15t and 19% of 15c by 1H NMR: IR of the mixture (CH2Cl2)
Met h yl tr a n s-1,2-Dim et h yla cen a p h t h en e-1-ca r b ox-
yla te (18t). Treatment of 250 mg (1.1 mmol) of a mixture of
acids 15t (81%) and 15c (19%) with 25 mL of anhydrous MeOH
and two portions of SOCl2 totalling 0.90 mL (12.4 mmol), as
described above for 18, afforded 130 mg (49%) of a mixture of
18t (70%) and 18c (30%) as a white solid: mp 58-64 °C; IR of
1
3600-2400 (br), 1725 (shoulder), 1700, 1602 cm-1; H NMR
of the major component (200 MHz) δ 7.68 (2 H, overlapping d,
J ) 7.7, 8.3), 7.52 (2 H, overlapping t), 7.30 (1 H, d, J ) 7.7),
7.23 (1 H, d, J ) 7.2), 3.60 (1 H, q, J ) 7.2), 1.70 (3 H, s), 1.53
(3 H, d, J ) 7.1); MS (EI) of the mixture, m/e (relative intensity)
226.1 (13), 198.1 (18), 196.1 (11), 183.1 (64), 182.0 (38), 181.1
(90), 171.1 (28), 169.1 (13), 168.1 (11), 167.1 (48), 166.0 (28),
165.1 (100), 153.1 (32), 152.1 (44), 151.1 (11), 115.1 (10), 82.0
(14), 76.0 (12); MS (CI) of the mixture 228.1 (14), 227.2 (100),
213.1 (8), 197.0 (23), 183.2 (17), 181.1 (63); HRMS (EI) calcd
for C15H14O2 226.0994, found 226.0992.
1
the mixture (CH2Cl2) 1729, 1603 cm-1; H NMR of the major
component (400 MHz) δ 7.67 (2 H, complex), 7.50 (2 H, t, J )
7.7), 7.24 (2 H, complex), 3.56 (1 H, q, J ) 7.4), 3.58 (3 H, s),
1.70 (3 H, s), 1.41 (3 H, d, J ) 7.3); 13C NMR of the mixture
(100 MHz) δ 174.85, 147.43, 147.07, 137.15, 137.15, 131.32,
128.06, 127.98, 123.75, 123.58, 123.05, 122.94, 119.48, 118.89,
118.64, 118.39, 58.67, 52.37, 51.67, 45.89, 25.31, 22.92, 15.92,
14.56; MS (EI) of the mixture, m/e (relative intensity) 240 (18),
182 (10), 181 (100), 166 (20), 165 (48); MS (CI) of the mixture,
243.1 (3), 242.1 (10), 241.1 (100), 181.1 (11); HRMS (EI) calcd
for C16H16O2 240.1150, found 240.1162.
Meth yl cis-1,2-Dim eth yla cen a p h th en e-1-ca r boxyla te
(18c). Treatment of 120 mg (0.53 mmol) of a mixture of acids
15c (87%) and 15t (13%) in 12 mL of anhydrous MeOH plus
10 mL of CHCl3 with 0.50 mL (6.9 mmol) of SOCl2, as described
above for 18, afforded 81 mg (64%) of a mixture of 18c (91%)
and 18t (9%) as a colorless oil: IR of the mixture (CH2Cl2)
1731, 1602 cm-1; 1H NMR of the major component (400 MHz)
δ 7.68 (1 H, d, J ) 8.3), 7.65 (1 H, d, J ) 8.5), 7.50 (2 H,
overlapping t, J ) 7.0, 7.2), 7.41 (1 H, d, J ) 7.2), 7.26 (1 H,
d, J ) 7.0), 4.26 (1 H, q, J ) 7.5), 3.74 (3 H, s), 1.51 (3 H, s),
1.49 (3 H, d, J ) 7.5); MS (EI) of the mixture, m/e (relative
intensity) 240.3 (21), 181.2 (100), 180.2 (26), 165.2 (57); MS
(CI) of the mixture, 241.1 (100), 240.1 (10), 181.1 96), 85.1 (2),
81.1 (3); HRMS (EI) calcd for C16H16O2 240.1150, found
240.1148.
1-Meth yl-2-m eth ylen eacen aph th en e-1-h ydr oxam ic Acid
(16). To a stirred 25 °C solution of 112 mg (0.50 mmol) of acid
15 in 2 mL of distilled CH2Cl2 under Ar was added 300 µL
(3.44 mmol) of (COCl)2. After the mixture was refluxed for 3
h, an additional 300 µL (3.44 mmol) of (COCl)2 was added and
reflux was continued for 1 h before the mixture was stirred
for 16 h at room temperature. Removal of (COCl)2 with a
stream of Ar yielded a white solid that was redissolved in 2
mL of CH2Cl2, and the drying was repeated. In a separate
flask, 500 µL (3.6 mmol) of Et3N was added to 200 mg (2.88
mmol) of a suspension of NH2OH‚HCl in 2 mL of anhydrous
DMF; this solution was then cooled in an ice bath and
transferred by syringe to the flask containing the acid chloride.
After stirring for 16 h, the mixture was diluted with CH2Cl2
1-Ca r boxy-cis-1,2-d im eth ya cen a p h th en e (15c). Selec-
t ive Hyd r olysis of a Mixt u r e of Nit r iles 8t a n d 8c.
Catalytic hydrogenation of 1.0 g (4.9 mmol) of nitrile 8 under
the standard conditions provided 1.0 g of a mixture of 8t (80%)
and 8c (20%), which was heated with 5.0 g of KOH in 30 mL
of ethylene glycol at 115 °C for 16 h. Workup as described
above for the hydrolysis of 8 provided a 30% yield of carbox-
amide 17t (described below) from the neutral fraction. The
acidic portion afforded 255 mg (23%) of a mixture of 15c (87%)
and 15t (13%) as a colorless oil: IR of the mixture (CH2Cl2)
3500-2300 (br), 1698, 1621, 1602 cm-1; 1H NMR of the major
component (400 MHz) δ 7.69 (1 H, d, J ) 7.8), 7.67 (1 H, d, J
) 8.4), 7.49 (3 H, complex), 7.27 (1 H, d, J ) 7.7), 4.27 (1 H, q,
J ) 7.2), 1.54 (3 H, s), 1.49 (3 H, d, J ) 7.1); MS (EI) of the
mixture, m/e (relative intensity) 226.1 (20), 181.1 (100), 166.0
(18), 165.1 (59), 83.1 (10), 69.1 (16), 57.1 (20), 55.1 (21); MS
(CI) of the mixture, 228.1 (12), 227.1 (100), 181.1 (5); HRMS
(EI) calcd for C15H14O2 226.0994, found 226.0996.
Lit h iu m 1-Met h yl-2-m et h ylen ea cen a p h t h en e-1-ca r -
boxyla te (21). A 25 °C suspension of 260 mg (1.16 mmol) of
acid 15 and 46 mg (1.1 mmol) of LiOH in 10 mL of anhydrous
MeOH was stirred under Ar for 16 h. The mixture was
vacuum- concentrated to dryness and coevaporated three times
with CHCl3. The resulting solid was washed with hexane/
petroleum ether to remove residual 15, yielding 204 mg (80%)
of 21 as an off-white solid: IR (KBr) 3042, 2974, 1575, 1386,
1356 cm-1, no absorption was observed at 1700 cm-1
.
Sodiu m 1-Meth yl-2-m eth ylen ea cen a ph th en e-1-ca r box-
yla te (20). A 25 °C suspension of 360 mg (1.61 mmol) of acid
15 and 63.0 mg (1.58 mmol) of NaOH in 13 mL of anhydrous
MeOH plus 2 mL of anhydrous EtOH was stirred under Ar
for 16 h. Vacuum-concentration and coevaporation (three times
each) with CH3OH and CHCl3 gave a solid that was washed

Haptophilicity Studies
J . Org. Chem., Vol. 67, No. 9, 2002 2823
and the reaction was quenched with saturated NaHCO3. The
organic layer, washed with saturated NaHCO3 and water, was
dried and vacuum-concentrated. The resulting crude oil was
loaded onto a plug of silica and washed with CH2Cl2 before
elution with 9:1 CH2Cl2/MeOH afforded 95 mg (79%) of 16 as
an off-white solid: mp 85-86 °C; IR (CHCl3) 3290 (br), 1651
δ 7.73 (1 H, d, J ) 8.5), 7.68 (1 H, d, J ) 8.5), 7.55 (2H,
overlapping t), 7.30 (2H, complex), 5.33 (1 H, broad), 4.96 (1
H, broad), 3.56 (1 H, q, J ) 7.3), 1.72 (3 H, s), 1.52 (3 H, d, J
) 7.4); MS (EI) of the mixture, m/e (relative intensity) 225.1
(9), 182.1 (10), 181.1 (100), 166.1 (21), 165.1 (50); MS (CI) of
the mixture, 228.1 (3), 227.1 (15), 226.1 (100), 181.1 (1), 89.1
(3), 74.1 (4); HRMS (EI) calcd for C15H15NO 225.1154, found
225.1153.
Meth od B. P r ep a r a tion of P u r e 17t by Selective Hy-
d r olysis of a Mixtu r e of 8t a n d 8c. Catalytic hydrogenation
of 1.0 g (4.9 mmol) of nitrile 8 under the standard conditions
described below provided 1.0 g of a mixture of 8t (80%) and
8c (20%). Hydrolysis of this with KOH in (CH2OH)2, as
described above for 15, yielded a CH2Cl2-soluble neutral
fraction that was washed, dried, vacuum-concentrated, and
flash-chromatographed on silica gel. Elution with 9:1 CH2Cl2/
acetone afforded 300 mg (30%) of pure 17t: mp 109-111 °C;
1H NMR was essentially identical to that of the major
component of the 17t /17c mixture produced by Method A
above; 13C NMR (100 MHz) δ 175.92, 147.66, 147.14, 131.54,
128.67 (2C), 128.28, 124.23, 123.19, 119.46, 119.13, 58.95,
51.34, 24.82, 15.21.
cm-1 1H NMR (400 MHz) δ 8.15 (1 H, broad), 7.76 (2 H,
;
complex), 7.59 (3 H, complex), 7.45 (1H, d, J ) 8.5), 5.98 (1 H,
s), 5.63 (1 H, s), 1.82 (3 H, s); MS (EI), m/e (relative intensity)
239.3 (39), 221.2 (88), 178.2 (100), 165.2 (58), 152.2 (50), 44.0
(48); HRMS (EI) calcd for C15H13NO2 239.0946, found 239.0941.
tr a n s-1,2-Dim eth yla cen a p h th en e-1-h yd r oxa m ic Acid
(16t). Treatment of 100 mg (0.44 mmol) of a mixture of acids
15t (81%) and 15c (19%) with 800 µL (9.2 mmol) of (COCl)2,
as described above for 16, provided the crude acid chloride,
which was then treated with 500 µL (3.6 mmol) of Et3N and
200 mg (2.88 mmol) of NH2OH‚HCl in anhydrous DMF to
afford 16 mg (15%) of a mixture of 16t (82%) and 16c (18%)
as a white solid: mp 90-92 °C; IR of the mixture (CH2Cl2)
3378, 3210 (br), 1660, 1603 cm-1 1H NMR of the major
;
component (400 MHz) δ 8.36 (1 H, broad), 7.76 (1 H, d, J )
8.5), 7.70 (1 H, d, J ) 7.7), 7.55 (2 H, overlapping t, J ) 7.2,
6.7), 7.33 (1 H, d, J ) 7.1), 7.28 (1 H, d, J ) 6.8), 3.56 (1 H, q,
J ) 7.4), 1.73 (3 H, s), 1.45 (3 H, d, J ) 7.5); 13C NMR of the
mixture (100 MHz) δ 171.21, 128.9, 128.18, 124.82, 123.31,
119.68, 119.39, 57.11, 51.75, 25.01, 24.82; MS (EI) of the
mixture, m/e (relative intensity) 241.1 (9), 182.1 (10), 181.1
(100), 180.1 (48), 179.1 (10), 166.1 (26), 165.1 (78), 164.1 (11),
152.1 (9), 86.1 (17), 85.0 (33), 84.1 (25), 83.1 (51), 82.1 (23);
MS (CI) of the mixture 242.1 (100), 226.1 (14), 181.0 (38), 180.1
(24); HRMS (EI) calcd for C15H15NO2 241.1103, found 241.1108.
cis-1,2-Dim eth ylacen aph th en e-1-h ydr oxam ic Acid (16c).
Treatment of 100 mg (0.44 mmol) of a mixture of acids 15c
(87%) and 15t (13%) with 400 µL (4.6 mmol) of (COCl)2 and
subsequent reaction with NH2OH, as described above for 16,
yielded 40 mg (38%) of a mixture of 16c (82%) and 16t (18%)
as a white solid: mp 141-144 °C; IR (CH2Cl2) 3227 (br), 1628,
cis-1,2-Dim et h yla cen a p h t h en e-1-ca r b oxa m id e (17c).
Portionwise treatment of 300 mg (1.33 mmol) of a mixture of
acids 15c (87%) and 17t (13%) with a total of 500 mg (3.1
mmol) of 1,1′-carbonyldiimidazole, followed by 0.6 mL of
concentrated NH4OH, as described above for 17, afforded 300
mg (100%) of a mixture of 17c (81%) and 17t (19%) as a
colorless oil: IR of the mixture (CH2Cl2) 3473, 1668, 1600,
1
cm-1; H NMR of the major component (400 MHz) δ 7.73 (1
H, d, J ) 8.1), 7.68 (1 H, d, J ) 8.3), 7.55 (2 H, overlapping t),
7.36 (1 H, d, J ) 6.9), 7.30 (1 H, d, J ) 6.7), 5.42 (1 H, broad),
5.32 (1H, broad), 3.97 (1 H, q, J ) 7.5), 1.54 (3 H, s), 1.49 (3
H, d, J ) 7.4); MS (EI) of the mixture, m/e (relative intensity)
225 (14), 182 (15), 181 (100), 166 (25), 165 (53); MS (CI) of the
mixture 228.1 (3), 227.1 (15), 226.1 (100), 181.1 (1), 89.1 (3),
74.1 (4); HRMS (EI) calcd for C15H15NO 225.1154, found
225.1150.
1
1600 cm-1; H NMR (400 MHz) δ 8.0 (1 H, d, broad), 7.76 (1
H, d, J ) 8.5), 7.69 (1 H, d, J ) 8.3), 7.55 (2 H, overlapping t,
J ) 6.9), 7.35 (1 H, d, J ) 6.9), 7.29 (1 H, d, J ) 6.8), 3.91 (1
H, q, J ) 7.3), 1.58 (3 H, s), 1.48 (3 H, d, J ) 7.5); MS (EI) of
the mixture, (relative intensity) 241.1 (96), 182.1 (10), 181.1
(100), 180.1 (19), 179.1 (12), 166.1 (27), 165.1 (98), 152.1 (9),
89.0 (5), 83.1 (6), 76.1 (5), 69.1 (8), 57.1 (15), 55.1 (9); MS (CI)
242 (100), 226 (77), 182 (12), 181 (91); HRMS (EI) calcd for
1-H y d r o x y m e t h y l-1-m e t h y l-2-m e t h y le n e a c e n a p h -
th en e (22). Meth od A. To a stirred -78 °C solution of 2.1 g
(8.82 mmol) of methyl ester 18 in 53 mL of dry THF under Ar
was added 40 mL (40 mmol) of DIBAL-H (1 M in THF)
dropwise. The mixture was warmed to 25 °C over 1.5 h, and
then the reaction was quenched at -78 °C by slowly adding
90 mL of 2 N HCl. Vacuum-concentration and CH2Cl2-
extraction led to a crude product that was flash-chromato-
graphed from silica gel with 7:3 CH2Cl2/hexane to afford 1.75
g (94%) of 22 as a colorless oil: IR (CHCl3) 3550-3000 (br)
C
15H15NO2 241.1103, found 241.1100.
1-Met h yl-2-m et h ylen ea cen a p h t h en e-1-ca r b oxa m id e
(17). To a stirred 25 °C solution of 896 mg (4.0 mmol) of acid
15 in 12 mL of anhydrous DMF under Ar was added 988 mg
(6.1 mmol) of 1,1′-carbonyldiimidazole in portions. The solution
was stirred for 30 min at 25 °C, heated for 30 min at 40 °C,
treated with 1.3 mL of concentrated NH4OH dissolved in 2.7
mL of DMF and heated for 30 min at 80 °C. The mixture was
cooled to 4 °C, and the reaction was quenched by slow addition
of 15 mL of 2 N HCl. The crude product provided by CH2Cl2
extraction and vacuum-concentration was flash-chromato-
graphed from 50 g of silica gel with 9:1 CH2Cl2/MeOH to afford
697 mg (78%) of 17 as an off-white solid: mp 122-123 °C; IR
1
cm-1; H NMR (400 MHz) δ 7.74 (1 H, d, J ) 7.7), 7.69 (1 H,
d, J ) 8.5), 7.62 (1 H, d, J ) 6.8), 7.55 (2 H, overlapping t),
7.32 (1 H, d, J ) 6.8), 5.93 (1 H, s), 5.34 (1 H, s), 3.79 (2 H, m),
1.52 (3 H, s), 1.48 (1 H, t, J ) 6.8); 13C NMR (100 MHz) δ
153.77, 146.88, 139.55, 137.81, 131.30, 128.18, 128.16, 124.95,
123.53, 117.76, 116.45, 105.58, 70.71, 53.19, 22.90; MS(EI),
m/e (relative intensity) 210.0 (70), 179.0 (100), 165.0 (10), 152.0
(11); HRMS (EI) calcd for C15H14O 210.1045, found 210.1044.
Meth od B. To a stirred 25 °C solution of 1.16 g (5.2 mmol)
of acid 15 in 16 mL of anhydrous DMF under Ar was added
1.2 g (7.4 mmol) of 1,1′-carbonyldiimidazole in portions. After
stirring for 30 min at 25 °C and then 30 min at 40 °C, the
warm solution was treated with 388 mg (10.3 mmol) of NaBH4
in portions. The cooled mixture was quenched by slow addition
of H2O and then vacuum-concentrated. The residue in CH2Cl2
was washed with 1 N HCl and brine, dried, and vacuum-
concentrated at 50 °C for 2 h to afford a yellowish oil. Flash
chromatography on silica gel and elution with 1:1 CH2Cl2/
hexane afforded 1.02 g (92%) of 22 as a colorless oil with 1H
NMR essentially identical to that described for Method A
above.
1
(CHCl3) 3522, 3407, 1682, 1580 cm-1; H NMR (400 MHz) δ
7.78 (1 H, d, J ) 8.5), 7.74 (1 H, d, J ) 7.7), 7.66 (1 H, d, J )
6.8), 7.58 (2 H, complex), 7.44 (1 H, d, J ) 6.8), 5.99 (1 H, s),
5.60 (1H, s), 5.30 (2 H, broad), 1.76 (3 H, s); 13C NMR (100
MHz) δ 175.86, 153.03, 145.48, 138.52, 137.47, 131.42, 128.46
(2C), 125.22, 124.12, 118.92, 116.93, 107.87, 58.12, 24.94; MS
(FAB+), m/e (relative intensity) 447.3 (60), 224 (52), 181.1
(100), 165.1 (26), 154.0 (32), 136.0 (22); HRMS (EI) calcd for
C
15H13NO 223.0997, found 223.1000.
tr a n s-1,2-Dim eth yla cen a p h th en e-1-ca r boxa m id e (17t).
Meth od A. Portionwise treatment of 900 mg (4.0 mmol) of a
mixture of acids 15t (81%) and 15c (19%) in 3:1 DMF/CH2Cl2
with a total of 1.5 g (9.3 mmol) of 1,1′-carbonyldiimidazole,
followed by 2.7 mL of concentrated NH4OH, as described above
for 17, afforded 550 mg (61%) of a mixture of 17t (84%) and
17c (16%) as a colorless oil: IR of the mixture (CH2Cl2) 3475,
1673, 1600 cm-1; 1H NMR of the major component (400 MHz)
1-Hydr oxym eth yl-tr a n s-1,2-dim eth ylacenaphth en e (22t).
Treatment of 120 mg (0.5 mmol) of a mixture of methyl esters
18t (70%) and 18c (30%) in 6:5 THF/CHCl3 with 5.0 mL (5.0
mmol) of DIBAL-H (1 M in toluene), as described above for
22, afforded 67 mg (63%) of a mixture of 22t (69%) and 22c
(31%) as a colorless oil: IR of the mixture (CH2Cl2) 3600-

2824 J . Org. Chem., Vol. 67, No. 9, 2002
3100 (br), 1620, 1604, 1593 cm-1 1H NMR of the major
component (400 MHz) δ 7.67 (1 H, d, J ) 8.2), 7.63 (1 H, d, J
) 8.2), 7.51 (2 H, overlapping t), 7.28 (1 H, d, J ) 6.9), 7.24 (1
H, d, J ) 7.0), 3.71 (1 H, d, J ) 7.3), 3.69 (1H, d, J ) 7.2), 3.45
(1 H, q, J ) 7.5), 1.55 (3 H, d, J ) 7.4), 1.49 (3 H, s); MS (EI)
of the mixture, m/e (relative intensity) 212.1 (13), 181.2 (100),
166.1 (21), 165.0 (46), 152.1 (4); MS (CI) of the mixture 213.1
Thompson and Rashid
;
(31%) as a colorless oil: IR (CH2Cl2) of the mixture 2871, 2826,
1604 cm-1; 1H NMR of the major component (400 MHz) δ 7.64
(1 H, d, J ) 7.6), 7.62 (1 H, d, J ) 7.5), 7.48 (2 H, overlapping
t, J ) 7.2, 8.1), 7.27 (1 H, d, J ) 6.9), 7.22 (1 H, d, J ) 6.3),
3.50 (1 H, d, J ) 7.7), 3.46 (1 H, d, J ) 7.8), 3.41 (1 H, q, J )
7.2), 3.25 (3 H, s), 1.46 (3 H, s), 1.45 (3 H, d, J ) 7.1); MS (EI)
of the mixture, m/e (relative intensity) 226.1 (10), 181.1 (100),
166.2 (19), 165.1 (37); MS (CI) of the mixture, 227.1 (9), 195.2
(100); HRMS (EI) calcd for C16H18O 226.1358, found 226.1365.
(52), 196.1 (10), 195.1 (100); HRMS (EI) calcd for C15H16
212.1201, found 212.1204.
O
1-Hyd r oxym eth yl-cis-1,2-d im eth yla cen a p h th en e (22c).
Treatment of 50 mg (0.21 mmol) of a mixture of methyl esters
18c (91%) and 18t (9%) in 2:1 THF/CHCl3 with 3.0 mL (3.0
mmol) of DIBAL-H (1 M in toluene), as described for 22,
afforded 40 mg (90%) of a mixture of 22c (93%) and 22t (7%)
as a white powder: mp 63-65 °C: IR (CH2Cl2) of the mixture
3368, 1604 cm-1; 1H NMR of the major component (400 MHz)
δ 7.66 (1 H, d, J ) 8.3), 7.63 (1 H, d, J ) 8.2), 7.50 (2 H,
overlapping t), 7.27 (1 H, d, J ) 9.1), 7.25 (1 H, d, J ) 7.5),
3.81 (1 H, d, J ) 10.7), 3.69 (1 H, d, J ) 11.0), 3.65 (1H, q, J
) 7.4), 1.39 (3 H, d, J ) 7.4), 1.31 (3 H, s); MS (EI) of the
mixture, m/e (relative intensity) 212.1 (17), 181.1 (100), 166.1
(26), 165.0 (54), 152.1 (9); MS (CI) of the mixture 214.1 (5),
213.1 (43), 196.1 (13), 195.1 (100), 71.1 (4), 69.0 (4); HRMS
(EI) calcd for C15H16O 212.1201, found 212.1205.
Meth od B. In ter n al Deliver y of Hydr ide Usin g Lith iu m
Alu m in u m Hyd r id e. To a 25 °C slurry of 200 mg (5.2 mmol)
of LiAlH4 in 5 mL of Et2O was added 115 mg (0.51 mmol) of
acid 15 in 4 mL of Et2O dropwise over 10 min. The mixture
was stirred at 25 °C for 15 min, refluxed for 15 min, and cooled
to -78 °C, and the reaction was quenched by slow addition of
H2O. The combined CHCl3 extracts were washed, dried, and
vacuum-concentrated to afford 100 mg (93%) of a mixture of
22 (49%), 22c (44%), and 22t (4%), accompanied by ca. 3% of
a byproduct shown to have structure 24 and presumed to arise
by air-oxidation of an organoaluminum intermediate.
1-Meth oxym eth yl-cis-1,2-d im eth yla cen a p h th en e (23c).
Treatment of 30 mg (0.14 mmol) of a mixture of alcohols 22c
(93%) and 22t (7%) with 100 mg (2.5 mmol) of 60% NaH
followed by 100 µL (1.61 mmol) of MeI, as described for 23,
afforded 20 mg (63%) of pure 23c as a colorless oil: IR (CH2Cl2)
1
2869, 2823, 1604 cm-1; H NMR (400 MHz) δ 7.63 (1 H, d, J
) 6.1), 7.61 (1 H, d, J ) 6.0), 7.48 (2 H, overlapping t), 7.25 (1
H, d, J ) 5.4), 7.24 (1 H, d, J ) 6.9), 3.63 (1 H, q, J ) 7.5),
3.53 (1 H, d, J ) 9.1), 3.47 (1 H, d, J ) 9.1), 3.34 (3 H, s), 1.39
(3 H, d, J ) 7.4), 1.32 (3 H, s); MS (EI) of the mixture, m/e
(relative intensity) 226.1 (14), 181.1 (100), 166.1 (29), 165.1
(46); MS (CI) of the mixture 228.1 (4), 227.1 (23), 226.1 (9),
196.2 (16), 195.2 (100); HRMS (EI) calcd for C16H18O 226.1358,
found 226.1347.
P r oced u r e for Heter ogen eou s Ca ta lytic Hyd r ogen a -
tion s. Hydrogenations were carried out with a low-pressure
apparatus at 1 atm (76 ( 2 cm) and room temperature (25 (
2 °C) in absolute EtOH with 5% Pd/C for 25-56 min. The same
lot of catalyst used previously for systems 1-3 was used for
all reactions, in the ratio of 30 mg of Pd/C and 10 mL of solvent
per mmol of olefin.
To a flask containing a Teflon-covered magnetic stirring bar
and a solution of the olefin in absolute EtOH was added the
appropriate quantity of catalyst. The flask was then alter-
nately evacuated and filled with H2 five times to displace air.
The pressure was adjusted to 1 atm, and vigorous stirring was
started. When at least the theoretical quantity of H2 had been
absorbed, the reaction mixture was filtered and the catalyst
was washed several times with EtOH and CHCl3. The solution
was vacuum-concentrated at 50 °C for 2 h, redissolved in
CHCl3, and vacuum-concentrated (three times). For the metal
carboxylates, the hydrogenation product was dissolved in
water, the pH adjusted to 2 using 2 N HCl, and the product
extracted with CH2Cl2, dried over MgSO4, and vacuum-
concentrated; volatiles were pumped off three times with
CHCl3. Recovered yields were 89-99%.
A similar reaction involving 500 mg (2.2 mmol) of acid 15,
refluxed for 3 h, yielded 140 mg (28%) of 24, crystallized from
MeCN/H2O to afford a colorless solid: mp 94-96 °C; IR (KBr)
3450 (broad), 3049, 2991, 2939, 2892, 1602, 1504 cm-1 1H
;
NMR (400 MHz) δ 7.75 (2 H, complex), 7.45 (3 H, complex),
7.37 (1 H, d, J ) 7.1), 3.91 (1 H, d, J ) 6.7), 3.90 (1H, d, J )
6.6), 2.07 (3 H, s), 1.96 (3 H, s); 13C NMR (100 MHz) δ 139.81,
137.56, 133.19, 127.85, 126.91, 125.72, 125.66, 118.65, 118.57,
106.98, 78.07, 77.31, 76.69, 20.86, 19.75; HRMS (EI) calcd for
C
15H14O2 226.0994, found 226.0992.
X-ray crystal data for 24: C15H14O2; M ) 226.26; cell setting,
An a lysis of P r od u ct Mixtu r es. The residue obtained from
each hydrogenation was dissolved in CDCl3 and used directly
for 1H NMR and GC analyses. The ratio of cis and trans
products was determined by integrating the benzylic protons
and confirmed by gas chromatography for most of the com-
pounds.
orthorhombic; space group, Pbca; a ) 13.858(7) Å; b ) 9.802(5)
Å; c ) 17.239(9) Å; V ) 2342(2) Å3; Z ) 8; T ) 293(2) K; d )
1.284 g/cm3; total reflections, 2194; observed reflections,
[>2σ(I)] 1097; parameters refined, 154; least squares R factor
(all), 0.170; least squares R factor, [>2σ(I)] 0.072 (see Ac-
knowledgments).
Con tr ol Rea ction s, Usin g Sta n d a r d Hyd r ogen a tion
1-Me t h o x y m e t h y l-1-m e t h y l-2-m e t h y le n e a c e n a p h -
th en e (23). To a stirred 25 °C solution of 50 mg (0.24 mmol)
of alcohol 22 in 2 mL of distilled THF under Ar was added
100 mg (2.5 mmol) of NaH (60% in mineral oil). After the
mixture was heated for 1.5 h at 40 °C, 80 µL (1.29 mmol) of
MeI was added to the warm solution and stirring was
continued for 30 min. The mixture was cooled to 0 °C and
diluted with CH2Cl2 followed by concentrated aqueous NH4Cl.
The CH2Cl2 extracts were washed, dried, and vacuum-
concentrated to a crude oil. Elution from silica gel with 2:3
CH2Cl2/hexane afforded 45 mg (84%) of 23 as a colorless oil:
IR (CH2Cl2) 3046, 2924, 2869, 1615 cm-1; 1H NMR (400 MHz)
δ 7.71 (1 H, d, J ) 7.9), 7.66 (1 H, d, J ) 8.0), 7.59 (1 H, d, J
) 6.4), 7.52 (2 H, complex), 7.35 (1 H, d, J ) 6.85), 5.88 (1 H,
s), 5.34 (1 H, s), 3.57 (1 H, d, J ) 9.0), 3.50 (1 H, d, J ) 9.0),
3.29 (3 H, s), 1.52 (3 H, s); MS (EI), m/e (relative intensity)
224 (14), 180 (13), 179 (100), 152 (9), 151 (4); HRMS (EI) calcd
for C16H16O 224.1201, found 224.1202.
Con d ition s. Treatment of the pure trans nitrile 8t with H2
for 24 h gave 91% of recovered starting material, and H NMR
showed no trace of the cis isomer.
When the acid 15 was hydrogenated for five different time
periods (25 min, 1 h, 3 h, 6 h, and 16 h), the cis/trans ratio
was essentially identical for all five.
When the nitrile 8 was hydrogenated for three different time
periods (1, 3, and 16 h), the cis/trans ratio was essentially
identical for all three.
1
When the aldehyde 9 was hydrogenated for 40 min and for
4 h, the cis/trans ratio was essentially identical for both.
Hyd r ogen a tion s Em p loyin g Solven ts of Low Dielec-
tr ic Con sta n t. Compound 15, hydrogenated in a 9:1 mixture
of hexane and CHCl3 under standard conditions, afforded a
mixture of 15c (40%) and 15t (60%) in 91% yield.
Compound 8, hydrogenated in cyclohexane under standard
conditions, afforded a mixture of 8c (54%) and 8t (46%) in 99%
yield.
Compound 17, hydrogenated in a 1:1 mixture of cyclohexane
and Et2O under standard conditions, afforded a mixture of 17c
(57%) and 17t (43%) in 97% yield.
1-Me t h oxym e t h yl-t r a n s-1,2-d im e t h yla ce n a p h t h e n e
(23t). Treatment of 50 mg (0.24 mmol) of a mixture of alcohols
22t (69%) and 22c (31%) with 100 mg (2.5 mmol) of 60% NaH
followed by 100 µL (1.61 mmol) of MeI, as described above for
23, afforded 26 mg (48%) of a mixture of 23t (69%) and 23c

Haptophilicity Studies
J . Org. Chem., Vol. 67, No. 9, 2002 2825
Compound 22, hydrogenated in cyclohexane under standard
conditions, afforded a mixture of 22c (75%) and 22t (25%) in
92% yield.
Gree Loober Spoog for invaluable consultations and
advice.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
4-6, 8-18, 22, and 23 and for all the cis/trans mixtures
described in Schemes 4 and 6. This material is available free
of charge via the Internet at http://pubs.acs.org.
Ackn owledgm en t. The authors express their thanks
to Roche Diagnostics for generous support of S.Y.R. with
time, services, and materials. We also thank Prof. R.
A. Lalancette for the X-ray structure of 24 and Prof.
J O010633B