Nucleophilic Substitution Reactions of (Alkoxymethylene)dimethylammonium Chloride

Article abstract of DOI:10.1021/jo980583j

The use of imidate esters as potential replacements for diethyl azodicarboxylate and triphenylphosphine in the Mitsunobu reaction is described. A series of secondary alcohols were allowed to react with (chloromethylene)dimethylammonium chloride, generated from dimethylformamide (DMF) and oxalyl chloride, to give imidate esters. Reaction of these salts with potassium benzoate or potassium phthalimide gave the products of S_N2 substitution in excellent yields with clean inversion of stereochemistry. Optimization of reaction conditions is discussed as a means to increase the atom economy of the process by minimizing the quantity of nucleophile required.

Full text of DOI:10.1021/jo980583j

J . Org. Chem. 1998, 63, 6273-6280
6273
Nu cleop h ilic Su bstitu tion Rea ction s of
(Alk oxym eth ylen e)d im eth yla m m on iu m Ch lor id e
Anthony G. M. Barrett,*,† D. Christopher Braddock,† Rachel A. J ames,† Nobuyuki Koike,† and
Panayiotis A. Procopiou‡
Department of Chemistry, Imperial College of Science, Technology and Medicine, London, U.K. SW7 2AY,
and Department of Medicinal Chemistry, Glaxo Wellcome Research and Development Ltd,
Stevenage, Hertfordshire, U.K. SG1 2NY
Received March 30, 1998
The use of imidate esters as potential replacements for diethyl azodicarboxylate and triphenylphos-
phine in the Mitsunobu reaction is described. A series of secondary alcohols were allowed to react
with (chloromethylene)dimethylammonium chloride, generated from dimethylformamide (DMF)
and oxalyl chloride, to give imidate esters. Reaction of these salts with potassium benzoate or
potassium phthalimide gave the products of SN2 substitution in excellent yields with clean inversion
of stereochemistry. Optimization of reaction conditions is discussed as a means to increase the
atom economy of the process by minimizing the quantity of nucleophile required.
In tr od u ction
acetals in the esterifications of carboxylic acids.6 These
reactions proceed in good yields, with clean inversion of
stereochemistry, but by necessity require two equivalents
of alcohol and also suffer from restrictions with respect
to the structure of the alcoholic component.
Recently, one of us reported the use of Vilsmeier
chemistry to effect the stereospecific cyclization of hy-
droxyphenols 1 to provide dihydrobenzodioxans 3 via
(alkoxymethylene)dimethylammonium salts 2 and in-
tramolecular displacement by phenoxide (Scheme 1).7
This methodology was subsequently extended to clean
inversion with carboxylates8 and phthalimide.9
The innocuous DMF and potassium chloride formed as
side products in these reactions of imidate esters are
easily removed, making this methodology more suitable
for large-scale operations. Herein we report full details
and extensions of this methodology for the formation of
esters and phthalimide derivatives from alcohols with net
inversion of stereochemistry.
The conversion of secondary alcohols into esters with
net inversion of configuration is a reaction of considerable
importance in synthesis. The Mitsunobu reaction is the
process par excellence for this transformation.1,2 In this
reaction, an alcohol is treated with triphenylphosphine
and diethyl azodicarboxylate and a carboxylic acid to
provide the target ester. The Mitsunobu reaction is
applicable for a diverse array of secondary alcohols and
has also been utilized in lactonization and macrolacton-
ization reactions.3 This reaction has been extended to a
wide range of nucleophiles in addition to carboxylic acids
to provide a variety of SN2 substitution products. For
example, the stereospecific preparation of amines from
the corresponding alcohol can be effected via formation
of the phthalimido derivative.4 There are, however,
disadvantages associated with the Mitsunobu reaction.
Diethyl azodicarboxylate is unstable and potentially
explosive, and the byproducts triphenylphosphine oxide
and diethyl hydrazinedicarboxylate are of considerable
mass, making the process nonideal from the point of view
of atom economy.5 Clearly, for large-scale applications,
there is a need for a general alternative to the Mitsunobu
reaction that is both safe and atom economic. Eschen-
moser has reported the use of dimethylformamide (DMF)
Resu lts a n d Discu ssion
F or m a tion of Ben zoa te Ester s w ith In ver sion of
Ster eoch em istr y. The starting point for this investiga-
tion was an examination of the reaction of a series of
secondary alcohols with (chloromethylene)dimethylam-
monium chloride, generated from DMF and oxalyl chlo-
ride,10 to give the corresponding imidate esters. These
were allowed to react with potassium benzoate in tet-
rahydrofuran (THF) to provide the benzoate esters 4-13
(Table 1).8
* Author to whom all correspondence should be sent.
† Department of Chemistry.
‡ Department of Medicinal Chemistry.
(1) For reviews see: (a) Mitsunobu, O. Synthesis 1981, 1; (b) Hughes,
D. L. Org. React. 1992, 42, 335.
(2) For some recent applications see: (a) Castro, J . L.; Matassa, V.
G. J . Org. Chem. 1994, 59, 2289; (b) Tsunoda, T.; Yamamiya, Y.;
Kawamura, Y.; Ito, S. Tetrahedron Lett. 1995, 36, 2529.
(3) For recent examples see: (a) Rychnovsky, S. D.; Hwang, K. J .
Org. Chem. 1994, 59, 5414; (b) J ustus, K.; Steglich, W. Tetrahedron
Lett. 1991, 32, 5781; (c) Barrett, A. G. M.; Carr, A. E.; Attwood, S. V.;
Richardson, G.; Walshe, N. D. A. J . Org. Chem. 1986, 51, 4840.
(4) (a) Mitsunobu, O.; Wada, M.; Sano, T. J . Am. Chem. Soc. 1972,
94, 679; (b) Mulzer, J .; Funk, G. Synthesis 1995, 101; (c) Mulzer, J .;
Brand, C. Tetrahedron 1986, 42, 5961; (d) Simon, C.; Hosztafi, S.;
Makleit, S. Tetrahedron 1994, 50, 9757; (e) Grunewald, G. L.; Parad-
kar, V. M.; Pazhenchevsky, B.; Pleiss, M. A.; Sall, D. J .; Seibel, W. L.;
Reitz, T. J . J . Org. Chem. 1983, 48, 2321.
(6) (a) Bu¨chi, H.; Steen, K.; Eschenmoser, A. Angew. Chem., Int. Ed.
Engl. 1964, 3, 62; (b) Brechbuhler, H.; Bu¨chi, H.; Hatz, E.; Schreiber,
J .; Eschenmoser, A. Helv. Chim. Acta 1965, 48, 1746.
(7) (a) Procopiou, P. A.; Brodie, A. C.; Deal, M. J .; Hayman, D. F.
Tetrahedron Lett. 1993, 34, 7483; (b) Procopiou, P. A.; Brodie, A. C.;
Deal, M. J .; Hayman, D. F.; Smith, G. M. J . Chem. Soc., Perkin Trans.
1 1996, 2249.
(8) Barrett, A. G. M.; Koike, N.; Procopiou, P. A. J . Chem. Soc.,
Chem. Commun. 1995, 1403.
(9) Barrett, A. G. M.; Braddock, D. C.; J ames, R. A.; Procopiou, P.
A. Chem. Commun. 1997, 433.
(5) For a review on atom economy see: Trost, B. M. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 259.
(10) Reichardt, C.; Schagerer, K. Angew. Chem., Int. Ed. Engl. 1973,
12, 323.
S0022-3263(98)00583-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/08/1998

6274 J . Org. Chem., Vol. 63, No. 18, 1998
Barrett et al.
Sch em e 1
sion (51% ee). It is reasonable to speculate that this
example involved either a mixed SN2/SN1 reaction or took
place in part via the corresponding benzylic chloride. In
the case of entry 10, where 13 was obtained with
complete retention of configuration (albeit in 34% yield),
it can be assumed that the reaction took place via an SN1
mechanism or through a competing pathway whereby
benzoate reacts directly with the Vilsmeier reagent
followed by transacylation as a result of steric hindrance
in the alcoholic component.11 THF was found to be a
better solvent for the reactions than dichloromethane or
DMF, as previously found for the Mitsunobu reaction.12
In the case of DMF, the target esters were still obtained
in good to excellent yields (80-95%), but with partial
racemization having occurred. This partial loss of ster-
eochemical integrity may be attributed to nucleophilic
participation of the solvent (DMF) leading to inverted
imidates or acceleration of substitution via the alkyl
chloride. Inspection of the results in Table 1 reveals that
this imidate methodology is applicable to a wide range
of secondary alcohols. Furthermore, yields obtained from
these imidate reactions compare very favorably with the
Mitsunobu reaction. For example, sterically hindered
menthol gives only a poor yield (20%) under Mitsunobu
conditions,12 although a 67% yield has been reported for
a carefully conducted experiment,11 compared with the
70% yield of inverted ester 9 obtained by reaction of the
imidate. The reaction was extended to 5R-cholestan-3â-
ol 14 and its 3R epimer 15.8 Thus, sterols 14 and 15 were
smoothly converted into the 3R ester 1613 (65%) and 3â
ester 1714 (53%), respectively. Although no elimination
products were observed for the 3â sterol 14, the 3R
epimer 15, which is set up favorably for trans-diaxial
elimination, gave only small quantities (18%) of alkene
18.
e2
e2
l
H
2
2
Ta ble 1. F or m a tion of Ben zoa te Ester s w ith In ver sion
of Ster eoch em istr ya
The threonine derivative 19 was explored as a potential
“worst case” substrate because exposure of this alcohol
to Mitsunobu conditions is known to give only the
elimination product 20.15
2
a
All reactions performed with 5 equivalents of potassium
b
benzoate
Determined by comparison of optical rotation with
literature values. c Confirmed by comparison with authentic sample
Disappointingly, reaction of the derived imidate with
potassium benzoate under the standard conditions pro-
d
prepared from alcohol and benzoyl chloride in pyridine. Diaste-
reoselectivities determined by HPLC and 1H NMR spectroscopy.
e Racemic substrate employed. f Retention of configuration.
(11) For a discussion of the competing pathways in the Mitsunobu
reaction and hence rational optimization of inverted ester yields see:
Hughes, D. L.; Reamer, R. A. J . Org. Chem. 1996, 61, 2967.
(12) Dodge, J . A.; Trujillo, J . I.; Presnell, M. J . Org. Chem. 1994,
59, 234.
In all cases (with the exceptions of entries 3 and 10),
the reactions were highly stereoselective and cleanly gave
the products of SN2 inversion. For 1-phenylethanol
(entry 3), the reaction proceeded only with partial inver-
(13) Camp, D.; J enkins, I. A. Aust. J . Chem. 1988, 41, 1835.

(Alkoxymethylene)dimethylammonium Chloride Reactions
J . Org. Chem., Vol. 63, No. 18, 1998 6275
Ta ble 2. Nu cleop h ilic In ver sion of 2-Octa n ol w ith a
Ra n ge of Ca r boxyla tesa
Ta ble 3. F or m a tion of P h th a lim id o Der iva tives w ith
In ver sion of Ster eoch em istr ya
a
All reactions performed with 7 equivalents of potassium
b
phthalimide in acetonitrile at 60-70 °C for 18 h. NPhth )
phthalimido derivative. c Determined by HPLC on a chiral station-
a
All reactions performed with 5 equivalents of nucleophile.
d
b Greater than 95% ee as determined by comparison with authentic
ary phase. Racemic substrate employed.
sample prepared via Mitsunobu reaction of (R)-2-octanol.
up). Interestingly, this is in direct contrast to the trend
observed in the Mitsunobu reaction in which higher
yields are obtained with the more acidic substrates.12
F or m a tion of P h th a lim id o Der iva tives fr om Sec-
on d a r y Alcoh ols. Treatment of imidate esters derived
from secondary alcohols with potassium phthalimide at
60-70 °C provide the phthalimide derivatives 28-36
with inversion of stereochemistry (Table 3).9
vided none of the desired SN2 product, and crotonate 2016
was the major isolable product (60%).
Va r ia tion of Ca r boxyla te Moiety; p Ka Dep en -
d en ce. With a view to variation of potassium benzoate
as nucleophile, representative aliphatic carboxylic acids
were examined. The substitution reactions of the imidate
ester derived from 2-octanol with a variety of carboxylate
salts were therefore explored yielding esters 21-27
(Table 2).
The use of sodium or potassium acetate as nucleophile
proved unsuccessful, presumably due to the low solubility
of sodium and potassium acetates in THF. The impor-
tance of anion solubility is apparent from the contrast
between the lack of reaction observed with the acetates
and the excellent yield of ester 22 obtained in the reaction
of potassium decanoate (Table 2, entry 2). Moreover, a
distinct correlation was observed in the reaction of
substituted benzoates in which less acidic substrates (p-
MeO and p-Me, entries 3 and 4) provide target esters 23
and 24 in substantially higher yields than those of 26
and 27 obtained with the more acidic substrates (p-NO2
and p-CN, entries 6 and 7). In these cases, the mass
balance was found to comprise of unreacted imidates
(isolated as their formate esters after an aqueous work-
Clean inversion of stereochemistry was observed in the
formation of representative phthalimido derivatives 28
and 32 (entries 1 and 5). We were pleased to find that
no allylic rearrangement occurred in the substitution
reaction of but-3-en-2-ol, and the phthalimido derivative
34 was isolated in excellent yield (entry 7). However,
substitution of (R)-1-phenylethanol (entry 6) proceeded
with partial racemization as previously observed in the
esterification reaction for attempted substitution at ben-
zylic positions (Table 1, entry 3). Several solvents were
examined for these reactions of which acetonitrile was
found to be superior. No reaction was observed in THF,
whereas reaction in DMF or 1,2-dimethoxyethane DME
gave the desired product in only moderate yield. Fur-
thermore, the use of DMF as solvent led to partial
racemization as was previously noted in the esterification
reactions. The reaction of (S)-methyl lactate (entry 9)
proceeded to give only a low yield of phthalimide deriva-
tive 36 with complete racemization having occurred.
In addition, the reaction of the imidate ester derived
from 2-octanol with a variety of other nitrogen nucleo-
philes was investigated. The use of benzylamine and
(14) Ellis, J .; Schibeci, R. A. Aust. J . Chem., 1974, 27, 429.
(15) Wojciechowska, H.; Pawlowiez, R.; Andruszkiewicz, R.; Gryzbows-
ka, J . Tetrahedron Lett. 1978, 4063.
(16) Srinivasan, A.; Richards, K. D.; Olsen, R. K. Tetrahedron Lett.
1976, 891.

6276 J . Org. Chem., Vol. 63, No. 18, 1998
Barrett et al.
Ta ble 4. Effect of Ben zoa te Cou n ter ion on Nu cleop h ilic
Atta ck on Im id a te Der ived fr om 2-Octa n ol
benzenesulfonamide salts proved unsuccessful, with none
of the desired SN2 products being isolated. However,
utilization of the sodium salts of saccharin and 1,8-
naphthosultam gave more encouraging results, and the
target compounds 37 and 38 could be isolated in modest
yields (62 and 34%, respectively). In these reactions,
DME (reactions performed at 70 °C with 5 equivalents
of nucleophile) was found to be a better solvent than THF,
acetonitrile, or DMF.
)
2
entry
M+
X
conditions
%yield 4
1
2
3
4
5
6
7
8
9
K+
K+
5
3
5
5
5
3
5
3
2
THF/sonificationa
THF/sonificationa
THF/reflux/16 h
THF/reflux/16 h
THF/reflux/16 h
THF/reflux/16 h
THF/reflux/16 h
THF/reflux/16 h
THF/reflux/16 h +
Et3N (2 eq)
86
44
0
Bu4N+b
Et4N+
Et3NH+c
Et3NH+c
Ag+
0
88
56
96
53
31
Ag+
K+
10
K+
2
THF/reflux/16 h +
Hu¨nig’s base (2 eq)
53
a
b
Kerry Pulsatron bath, 4-6 h, 30 °C. Formed from silver
benzoate and tetrabutylammonium iodide. c Generated in situ
from triethylamine and benzoic acid (1:1 ratio).
Op tim iza tion of Rea ction Con d ition s. In the work
just described, all imidate reactions were carried out (by
necessity) in the presence of a considerable excess of
nucleophile. For example, all reaction with carboxylates
utilized 5 equivalents of nucleophile, making these reac-
tions nonideal from the point of view of atom economy.
When the quantity of carboxylate was reduced, the yield
of target ester fell and formation of alkyl chlorides
predominated. For example, with 3 equivalents of potas-
sium benzoate, 2-octyl benzoate 4 is formed in only a 48%
yield compared with the 91% yield obtained when em-
ploying 5 equivalents (Table 1, entry 1). In the presence
of 2 equivalents of nucleophile, only trace amounts of
benzoate ester 4 could be detected. The observed chloride
formation can be attributed to nucleophilic substitution
by chloride ions present in the reaction medium.
The use of supposedly more soluble benzoate salts in
place of potassium benzoate was then investigated.
Reactions of tetrabutylammonium and tetraethylammo-
nium benzoate (Table 4, entries 3 and 4) proved less
successful than with potassium benzoate, and formate
ester 3919 (presumably derived from hydrolysis on work
up of unreacted imidate) was the major isolable product
(typically 25-40%).
To eliminate the possibility of alkyl chloride formation,
the reaction of imidate esters with nonnucleophilic coun-
terions was examined. A triflate counterion was incor-
porated into the imidate ester by formation of the
Vilsmeier reagent from DMF and triflic anhydride.17
Under the standard reaction conditions (THF, reflux, 16
h), considerable quantities of polymeric products, pre-
sumably derived from ring opening of THF, were isolated
with only a small quantity (20%) of the desired ester
being obtained. Addition of Hu¨nig’s base to remove
traces of triflic acid from the reaction mixture failed to
suppress the polymerization reaction, and attempts to
repeat these reactions in alternative solvents (DMF,
toluene, and 1,2-DCE) also proved unsuccessful.
A series of reactions of the imidate ester derived from
2-octanol were then performed to study the effects of
variation in benzoate nucleophile and reaction conditions
(Table 4). It was considered possible that the solubility
of the benzoate nucleophile may be a limiting factor in
these reactions. Attempts to increase the nucleophile
solubility by carrying out reactions under sonification
conditions18 proved partially successful in that these
reactions were found to proceed at 30 °C, a significantly
lower temperature, and over a shorter reaction time
(Table 4, entries 1 and 2). However, these reactions only
provided satisfactory yields of ester in the presence of 5
equivalents of carboxylate.
e2
e2
The use of a triethylammonium salt, generated by in situ
reaction of triethylamine and benzoic acid gave more
encouraging results as did the use of silver benzoate
(entries 5 and 7), and the benzoate ester 4 could be
isolated in excellent yields in the presence of 5 equiva-
lents of nucleophile. However, in both these instances,
the yield fell substantially when the number of equiva-
lents of nucleophile was reduced to 3 equivalents (entries
6 and 8).
One equivalent of HCl is necessarily generated as a
consequence of imidate formation, and this HCl should
dispense with at least 1 equivalent of nucleophile via
acid-base neutralization. Accordingly, a series of reac-
tions were carried out in the presence of base. Tertiary
nitrogen bases, such as triethylamine and Hu¨nig’s base,
proved moderately successful and reasonable yields of
benzoate ester 4 were isolated from runs with 2 equiva-
lents of nucleophile (Table 4, entries 9 and 10). Surpris-
ingly, incremental increases in base (2-20 equivalents
of Hu¨nig’s base) led to a corresponding decrease in yield
of ester as determined by semiquantitative HPLC experi-
ments using the UV-active 4-phenylbutan-2-ol 40 as the
substrate.
(17) Martinez, A. G.; Alvarez, R. M.; Barcina, J . O.; de la Moya
Cerero, S.; Vilar, E. T.; Fraile, A. G.; Hanack, M.; Subramanian, L. R.
J . Chem. Soc., Chem. Commun. 1990, 1571.
(18) Sonification conditions; Kerry Pulsatron bath for 4-6 h, ≈30
°C.
(19) Mori, K.; Kuwahara, S. Tetrahedron 1986, 42, 5539.

(Alkoxymethylene)dimethylammonium Chloride Reactions
J . Org. Chem., Vol. 63, No. 18, 1998 6277
Ta ble 5. Effect of Va r ia tion of P ota ssiu m Ben zoa te a s a
F u n ction of Qu a n tity of Vilsm eier Rea gen t
Addition of 2 equivalents of Hu¨nig’s base to compensate
was partially successful (entry 9) and a low yield of ester
46 was obtained. However, the major product in this
reaction was the alkyl chloride 47. Because it is reason-
able to assume that nucleophilic attack by benzoate and
chloride ions are competing processes, the fact that
chloride 47 is the predominant product indicates that
substitution with chloride occurs faster than substitution
by the benzoate nucleophile under these conditions.
)
2
entrya
Y
Z
%yield 46
%yield 47
44b
1
2
3
4
5
6
7
8
9
1.15
1.15
1.15
1.00
1.00
1.00
1.00
1.00
1.00
5
4
2
5
4
3
2
1
1
86
62
0
11
37
88
3
4
4
13
76
68
-
-
-
69
70
70
71
0
23
21
-
16
22
3
Con clu sion s
c
The imidate methodology in this paper should be of
use as an alternative to the Mitsunobu reaction particu-
larly for larger scale applications and especially because
the side products are innocuous (DMF and potassium
chloride). The method is mechanistically similar to the
synthesis of glycosides22 and benzyl, allyl, and tert-butyl
esters via trichloroacetimidate activation.23 The opti-
mized reaction conditions enabling good yields of esters
to be obtained in the presence of only 2 equivalents of
nucleophile make this methodology preferable to the
Mitsunobu reaction from the point of view of atom
economy.
19d
a
b
All runs performed at least twice. Recovered alcohol. c Re-
d
sidual alcohol present but not isolated. Two equivalents of
Hu¨nig’s base added.
In the study of the reaction of imidate 41 derived from
40, a 77% yield of benzoate ester 4220 was obtained under
the standard conditions of 5 equivalents of potassium
benzoate in refluxing THF. With 3 equivalents of potas-
sium benzoate, ester 42 was obtained in a vastly reduced
30% yield and 41% of chloride 4321 was also isolated.
These, and all the reactions already described were
carried out utilizing a slight excess (1.15 equivalents) of
the Vilsmeier reagent. The use of exactly 1.0 equivalent
of Vilsmeier reagent in conjunction with just 3 equiva-
lents of potasssium benzoate yielded ester 42 in an
increased 63% yield with minimal chloride formation
(<5%).
To investigate this effect further, a series of reactions
were carried out using 4-(2-naphthyl)-butan-2-ol 44,
which was prepared via aldol condensation of 2-naph-
thaldehyde and acetone followed by reduction with
lithium aluminum hydride. This alcohol was considered
a suitable substrate because all possible side-products,
such as the chloride 47 and alkenes, would be nonvolatile,
allowing for quantitative isolation of all products. The
SN2 substitution of alcohol 44 was then carried out in
the presence of either 1.15 or 1.00 equivalents Vilsmeier
reagent and varying quantities of potassium benzoate as
nucleophile (Table 5). Employing 1.15 equivalents of
Vilsmeier reagent resulted in markedly reduced ester
formation and a concomitant increase in alkyl chloride
47 as the number of equivalents of potassium benzoate
was reduced from 5 to 2 (entries 1-3). Runs performed
in the presence of exactly 1.0 equivalent of Vilsmeier
reagent showed no decrease in yield of 46 as the number
of equivalents of potassium benzoate was lowered from
5 to 2 and only small quantities of alkyl chloride 47 were
isolated (entries 4-7). Thus, careful control of Vilsmeier
stoichiometry allows for the use of two equivalents of
nucleophile with little or no detriment to the overall
isolated yield of inverted ester 46. This remarkable
difference in product distribution as a function of the
quantity of the Vilsmeier reagent is unexpected and may
be a manifestation of the heterogeneous nature of the
reaction mixtures. When the displacement was at-
tempted in the presence of only one equivalent of nu-
cleophile (entry 8) no ester 46 was obtained, presumably
because all the carboxylate salt is neutralized by HCl.
Exp er im en ta l Section
Gen er a l In for m a tion . Potassium benzoate, carboxylic
acids, potassium phthalimide, and secondary alcohols were
purchased from commercial sources and employed without
further purification. All reactions were carried out under a
nitrogen atmosphere in oven-dried glassware and using freshly
distilled solvents. Chromatography was carried out on silica
gel purchased from BDH (40-63 µm). Eluants are given in
parentheses.
Rep r esen ta tive P r oced u r e for Rea ction of Im id a te
Ester s w ith P ota ssiu m Ben zoa te (Ta ble 1). To a solution
of DMF (1.3 mmol, 94 mg, 0.10 mL in CH2Cl2 (1 mL) under
nitrogen at room temperature, oxalyl chloride (1.15 mmol, 145
mg, 0.10 mL) was added in a dropwise manner to form
(chloromethylene)dimethylammonium chloride as a white
solid. Stirring was continued for another 5 min, and the salt
was suspended in THF (8 mL). 4-(2-Naphthyl)-2-butanol 44
(1.0 mmol, 200 mg) was added to form a homogeneous solution
of the imidate ester 45. Potassium benzoate (5 mmol, 0.80 g)
was added, and the reaction mixture was heated to reflux for
16 h. The mixture was allowed to cool to room temperature,
and the organic solution washed with water (3 × 10 mL), dried
(MgSO4), and concentrated under reduced pressure. Chroma-
tography (hexanes:EtOAc, 10:1; Rf ) 0.39) gave the benzoate
ester 46 as a colorless oil (267 mg, 86%); IR (neat) 3056, 2976,
2933, 1711, 1275, 1114 cm-1 1H NMR (CDCl3, 270 MHz) δ
;
8.05 (m, 2H), 7.78 (m, 3H), 7.63 (s, 1H), 7.30-7.59 (m, 6H),
5.25 (m, 1H), 2.88 (m, 2H), 2.06 (m, 2H), 1.41 (d, J ) 6.2 Hz,
3H); 13C NMR (CDCl3, 75 MHz) δ 166.2, 139.1, 133.7, 132.8,
132.1, 130.8, 129.6, 128.3, 128.0, 127.6, 127.4, 127.2, 126.4,
125.9, 125.2, 71.3, 37.3, 30.1, 20.2; high-resolution mass
spectrometry (HRMS): Calcd for C21H20O2 (M+•): 304.1463.
Found: 304.1460.
(S)-2-Octyl ben zoa te (4).24 [R]D25 ) +33.3° (c 1.5, CH2Cl2)
[lit.24 [R]2D5 ) +38.9° (c 0.8, THF)]; 1H NMR (CDCl3, 270 MHz)
δ 8.04 (d, J ) 7.7 Hz, 2H), 7.54 (m, 1H), 7.45 (m, 2H), 5.25 (m,
1H), 1.70 (m, 1H), 1.60 (m, 1H), 1.27-1.42 (m, 11H), 0.87 (t, J
(22) Schmidt, R. R. Synthesis of Glycosides in Comprehensive
Organic Synthesis; Trost, B. M.; Fleming, I.; Winterfeldt, E., Eds.;
Pergamon: Oxford, 1991; Vol. 6, pp 49-54.
(23) (a) Armstrong, A.; Brackenridge, I.; J ackson, R. F. W.; Kirk, J .
M. Tetrahedron Lett. 1988, 29, 2483; (b) Wessel, H.-P.; Iversen, T.;
Bundle, D. R. J . Chem. Soc., Perkin Trans. 1. 1985, 2247; (c) Iversen,
T.; Bundle, D. R. J . Chem. Soc., Chem. Commun. 1981, 1240.
(24) Mitsunobu, O.; Eguchi, M. Bull. Chem. Soc. J pn. 1971, 44, 3427.
(20) Miyashita, M.; Shiina, I.; Miyoshi, S.; Mukaiyama, T. Bull.
Chem. Soc. J pn. 1993, 66, 1516.
(21) Bhar, S.; Ranu, B. C. J . Org. Chem. 1995, 60, 745.

6278 J . Org. Chem., Vol. 63, No. 18, 1998
Barrett et al.
) 6.3 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 166.2, 132.7, 131.0,
8.0 Hz, 2H), 5.94 (d, J ) 3.5 Hz, 1H), 5.50 (d, J ) 3.0 Hz, 1H),
4.63 (d, J ) 3.5 Hz, 1H), 4.35 (m, 2H), 4.10 (m, 2H), 1.55 (s,
3H), 1.41 (s, 3H), 1.32 (s, 3H), 1.26 (s, 3H).
5r-Ch olesta n yl-3r-ben zoa te (16).13 1H NMR (CDCl3, 300
MHz) δ 8.09 (d, J ) 6.2 Hz, 2H), 7.57 (t, J ) 6.4 Hz, 1H), 7.50
(t, J ) 7.8 Hz, 2H), 5.30 (br s, 1H), 0.86-2.07 (m, 44 H), 0.68
(s, 3H); 13C NMR (CDCl3, 75 MHz) δ 165.9, 132.7, 131.3, 129.6,
128.3, 70.8, 56.6, 56.4, 54.4, 42.6, 40.5, 40.1, 39.6, 36.2, 35.9,
35.9, 35.5, 33.3, 33.1, 32.0, 28.5, 28.3, 28.0, 26.4, 24.2, 23.9,
22.9, 22.6, 20.9, 18.7, 12.1, 11.5.
5r-Ch olesta n yl-3â-ben zoa te (17).14 1H NMR (CDCl3, 300
MHz) δ 8.05 (d, J ) 7.1 Hz, 2H), 7.55 (t, J ) 7.4 Hz, 1H), 7.44
(t, J ) 7.2 Hz, 2H), 4.97 (m, 1H), 0.88-2.02 (m, 44H), 0.68 (s,
3H); 13C NMR (CDCl3, 75 MHz) δ 166.1, 132.6, 131.0, 129.5,
128.2, 74.4, 56.5, 56.3, 54.3, 44.8, 42.6, 40.0, 39.6, 36.9, 36.2,
35.8, 35.6, 34.2, 32.0, 28.7, 28.3, 28.0, 27.6, 24.3, 23.9, 22.9,
22.6, 21.3, 18.7, 12.3, 12.1.
(Z)-2-(Ben zyloxycar bon yl)am in o-2-bu ten oic acid (20).16
1H NMR (CDCl3, 400 MHz) δ 7.30-7.40 (m, 5H), 6.72 (q, J )
7.4 Hz, 1H), 6.15 (br s, 1H), 5.15 (s, 2H), 3.75 (s, 3H), 1.81 (d,
J ) 7.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 165.0, 153.9,
136.0, 133.4, 128.6, 128.3, 128.2, 126.3, 67.4, 52.4, 14.3.
129.5, 128.3, 71.7, 36.1, 31.8, 29.2, 25.4, 22.6, 20.1, 14.1.
(R)-3-Meth yl-2-bu tyl ben zoa te (5).25 [R]D25 ) -35.0° (c
0.7, CH2Cl2). (S)-3-Methyl-2-butyl benzoate prepared from (S)-
3-methyl-butan-2-ol and benzoyl chloride in pyridine; [R]D25
)
+36.0° (c 0.8, CH2Cl2) [lit.25 [R]D25 ) +41.1° (c 2.35, CHCl3)];
1H NMR (CDCl3, 300 MHz) δ 8.07 (d, J ) 7.0 Hz, 2H), 7.57
(m, 1H), 7.46 (t, J ) 6.8 Hz, 2H), 5.01 (m, 1H), 1.92-1.98 (m,
1H), 1.31 (d, J ) 6.4 Hz, 3H), 1.30 (d, J ) 6.4 Hz, 3H), 1.02 (d,
J ) 6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 166.2, 132.7,
131.0, 129.5, 128.3, 75.8, 32.9, 18.2, 18.0, 16.8.
(S)-1-P h en yl-1-eth yl ben zoa te (6).26 [R]D25 ) +11.2° (c
3.0, EtOH) [lit.26 [R]D25 ) +20.9° (c 2.78, EtOH)]; 1H NMR
(CDCl3, 300 MHz) δ 8.19 (d, J ) 7.0 Hz, 2H), 7.30-7.64 (m,
8H), 6.25 (q, J ) 6.6 Hz, 1H), 1.76 (d, J ) 6.6 Hz, 3H); 13C
NMR (CDCl3, 75 MHz) δ 165.8, 141.9, 133.0, 130.7, 129.7,
128.7, 128.4, 128.0, 126.1, 73.0, 22.5.
cis-4-ter t-Bu t ylcycloh exyl b en zoa t e (7).27 1H NMR
(CDCl3, 300 MHz) δ 8.08 (d, J ) 7.0 Hz, 2H), 7.57 (m, 1H),
7.47 (t, J ) 7.5 Hz, 2H), 5.30 (m, 1H), 1.08-2.16 (m, 9H), 0.92
(s, 9H).
tr a n s-4-ter t-Bu tylcycloh exyl ben zoa te (8).27 1H NMR
(CDCl3, 300 MHz) δ 8.06 (d, J ) 7.5 Hz, 2H), 7.53 (t, J ) 7.4
Hz, 1H), 7.42 (t, J ) 7.5 Hz, 2H), 4.89 (m, 1H), 0.98-2.23 (m,
9H), 0.89 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ 166.1, 132.6,
131.0, 129.6, 128.2, 74.3, 47.2, 32.5, 32.2, 27.6, 25.2; m/z (CI+;
Rep r esen ta tive P r oced u r e for Rea ction of Ca r boxy-
la tes w ith Im id a te Ester Der ived fr om 2-Octa n ol (Ta ble
2). To a suspension of KH (10 mmol, 0.40 g) in THF (5 mL),
a solution of 4-nitrobenzoic acid (10 mmol, 1.67 g) in THF (10
mL) was added gradually. The reaction mixture was stirred
until evolution of hydrogen gas ceased. Separately, oxalyl
chloride (2.30 mmol, 0.20 mL) was added in a dropwise manner
with stirring to DMF (2.58 mmol, 0.20 mL) in CH2Cl2 (2 mL)
to form (chloromethylene)dimethylammonium chloride as a
white solid. This salt was suspended in THF (10 mL), and
2-octanol (2.0 mmol, 0.32 mL) added. This homogeneous
solution was added to the suspension of the carboxylate salt,
and the reaction mixture heated to reflux overnight. The
mixture was cooled, filtered through Celite, concentrated under
reduced pressure, and chromatographed (hexanes: EtOAc 20:
1, Rf ) 0.26) to give 2-octyl 4-nitrobenzoate 2631 as a colorless
oil (0.087 g, 31%); IR (neat) 3112, 2954, 2931, 2859, 1723, 1529,
NH3) 261 (M+H)+, 278 (M+NH4)+. Anal. Calcd for C17H24
O2: C, 78.42; H, 9.29. Found: C, 78.17; H, 9.05.
-
(1R, 2R, 5S)-2-iso-P r op yl-5-m eth ylcycloh exyl ben zoa te
(9).12 1H NMR (CDCl3, 300 MHz) δ 8.08 (d, J ) 7.1 Hz, 2H),
7.56 (t, J ) 7.0 Hz, 1H), 7.46 (m, 2H), 5.48 (m, 1H), 0.82-2.19
(m, 18H); 13C NMR (CDCl3, 75 MHz) δ 165.8, 132.7, 131.1,
129.6, 128.6, 71.7, 47.1, 39.3, 34.9, 29.4, 26.8, 25.5, 22.2, 21.0,
20.9.
cis-2-Meth ylcyclop en tyl ben zoa te (10). 1H NMR (CDCl3,
300 MHz) δ 8.06 (d, J ) 7.5 Hz, 2H), 7.57 (t, J ) 7.3 Hz, 1H),
7.46 (t, J ) 7.4 Hz, 2H), 5.36 (m, 1H), 1.45-2.28 (m, 7H), 1.07
(d, J ) 6.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 166.3, 132.7,
131.0, 129.5, 128.3, 79.5, 38.9, 32.5, 31.8, 22.4, 14.1; m/z (CI+;
NH3) 205 (M+H)+, 222 (M+NH4)+. Anal. Calcd for
1
1279 cm-1; H NMR (CDCl3, 270 MHz) δ 8.27 (d, J ) 9 Hz,
C
13H16O2: C, 76.44; H, 7.89. Found: C, 76.38; H, 7.64.
tr a n s-2-Meth ylcyclop en tyl ben zoa te (11).28 1H NMR
2H), 8.19 (d, J ) 9 Hz, 2H), 5.18 (m, 1H), 1.72 (m, 1H), 1.63
(m, 1H), 1.20-1.61 (m, 11H), 0.87 (t, J ) 7.2 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) δ 164.3, 150.5, 136.3, 130.6, 123.5, 73.2, 35.9,
31.7, 29.1, 25.4, 22.6, 20.0, 14.0; HRMS: Calcd for C15H21NO4
(M+•): 279.1471. Found: 279.1471.
(CDCl3, 300 MHz) δ 8.05 (d, J ) 7.0 Hz, 2H), 7.57 (t, J ) 7.3
Hz, 1H), 7.45 (t, J ) 7.3 Hz, 2H), 4.96 (m, 1H), 1.21-2.29 (m,
7H), 1.08 (d, J ) 7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ
166.5, 132.7, 130.9, 129.5, 128.3, 83.2, 40.1, 32.0, 31.5, 22.6,
18.3.
2-Octyl P h en yla ceta te (21).32 1H NMR (CDCl3, 270 MHz)
δ 7.33 (m, 5H), 4.90 (m, 1H), 3.59 (s, 2H), 1.27-1.50 (m, 2H),
1.19-1.24 (m, 11H), 0.86 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3,
75 MHz) δ 171.3, 134.4, 129.2, 128.5, 126.9, 71.6, 41.9, 35.9,
31.7, 29.1, 25.2, 22.5, 19.9, 14.1.
(R)-Eth yl-2-(Ben zoyloxy)p r op a n oa te (12).29 [R]D25
)
-13.8° (c 1.0, CHCl3) [lit.29 (S)-12 [R]D25 ) +13.6° (c 3.5,
1
CHCl3)]; H NMR (CDCl3, 250 MHz) δ 8.09 (dd, J ) 8.0, 1.0
2-Octyl Deca n oa te (22).33 1H NMR (CDCl3, 300 MHz) δ
4.89 (m, 1H), 2.27 (t, J ) 7.4 Hz, 2H), 1.50-1.68 (m, 2H), 1.28-
1.48 (m, 22H), 1.20 (d, J ) 6.3 Hz, 3H), 0.88 (t, J ) 6.3 Hz,
6H); 13C NMR (CDCl3, 75 MHz) δ 173.6, 70.7, 36.0, 35.6, 34.8,
31.9, 31.8, 29.5, 29.3, 29.2, 25.4, 25.1, 22.7, 22.6, 20.0, 19.7,
14.1.
2-Octyl p-Meth oxyben zoa te (23).31 1H NMR (CDCl3, 300
MHz) δ 8.00 (d, J ) 8.9 Hz, 2H), 6.92 (d, J ) 8.9 Hz, 2H), 5.13
(m, 1H), 3.87 (s, 3H), 1.62 (m, 2H), 1.29-1.42 (m, 11H), 0.89
(t, J ) 6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 166.0, 163.2,
131.5, 123.5, 113.5, 71.4, 55.4, 36.1, 31.8, 29.2, 25.4, 22.6, 20.1,
14.1.
Hz, 2H), 7.58 (m, 1H), 7.45 (m, 2H), 5.31 (q, J ) 7.0 Hz, 1H),
4.23 (q, J ) 7.0 Hz, 2H), 1.62 (d, J ) 7.0 Hz, 3H), 1.27 (t, J )
7.0 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz) δ 172.3, 147.5, 134.8,
131.3, 131.0, 129.0, 70.7, 62.9, 18.6, 15.6.
3-O-Ben zoyl-1,2;5,6-d i-O-isop r op ylid en e-r-D-glu cofu r a -
n ose (13).30 [R]D25 ) -55.0° (c 1.0, CHCl3) [lit.30 [R]D25 ) -26.2°
(c 1.0, EtOH); authentic 3-O-benzoyl-1,2;5.6-di-O-isopropy-
lidene-R-D-glucofuranose prepared from benzoyl chloride and
1,2;5.6-di-O-isopropylidene-R-D-glucofuranose in pyridine;
[R]2D5 ) -53.5° (c 1.6, CHCl3)]; H NMR (CDCl3, 400 MHz) δ
1
8.03 (d, J ) 8.0 Hz, 2H), 7.59 (t, J ) 8.0 Hz, 1H), 7.45 (t, J )
2-Octyl p-Meth ylben zoa te (24).34 1H NMR (CDCl3, 250
MHz) δ 7.93 (d, J ) 8.0 Hz, 2H), 7.21 (d, J ) 8.0 Hz, 2H), 5.13
(m, 1H), 2.40 (s, 3H), 1.55-1.82 (m, 2H), 1.21-1.41 (m, 11H),
0.87 (t, J ) 6.8 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz) δ 166.2,
143.2, 129.5, 128.9, 128.2, 71.4, 36.0, 31.7, 29.0, 25.3, 22.5, 21.6,
20.0, 14.0.
(25) Fujisawa, T.; Hayashi, H.; Kishioka, Y.; Chem. Lett. 1987, 129.
(26) Kabuto, K.; Imuta, M.; Kempner, E. S.; Ziffer, H. J . Org. Chem.
1978, 43, 2357.
(27) Pautard, A. M.; Evans, S. A J . Org. Chem. 1988, 53, 2300.
(28) Partridge, J . J .; Chadha, N. K.; Uskokovic, M. R. J . Am. Chem.
Soc. 1973, 95, 532.
(29) Laarhoven, W. H.; Cuppen, T. J . H. M. J . Chem. Soc., Perkin
Trans. 2. 1978, 315.
(30) Gramera, R. E.; Bruce, R. E.; Hirase, S.; Whistler, J . Org. Chem.
1963, 28, 1401. For an interesting rearrangement and concomitant
chloride incorporation when the imidate ester (chloride counterion) of
1, 2; 5,6-di-O-isopropylidene-R-D-glucofuranose is heated, see: Han-
essian, S.; Plessas, N. R. Chem. Commun. 1967, 1152.
(31) Rule, H. G.; Numbers, A. H. J . Chem. Soc. 1926, 2116.
(32) Mitsunobu, O.; Takemasa, A.; Endo, R. Chem. Lett. 1984, 855.
(33) Schlenk, W. Liebigs Ann. Chem. 1973, 1179.
(34) Steliou, K.; Poupart, M.-A. J . Am. Chem. Soc. 1983, 105, 7130.

(Alkoxymethylene)dimethylammonium Chloride Reactions
J . Org. Chem., Vol. 63, No. 18, 1998 6279
2-Octyl p-Br om oben zoa te (25).35 1H NMR (CDCl3, 270
MHz) δ 7.88 (d, J ) 8.7 Hz, 2H), 7.56 (d, J ) 8.7 Hz, 2H), 5.14
(m, 1H), 1.50-1.90 (m, 2H), 1.19-1.39 (m, 11H), 0.87 (t, J )
7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 165.5, 131.6, 131.1,
129.8, 127.8, 72.16, 36.0, 31.7, 29.2, 25.4, 22.6, 20.1, 14.1.
2-Octyl p-Cya n oben zoa te (27). IR (neat) 2955, 2929,
2858, 2231, 1714, 1277, 1106 cm-1; 1H NMR (CDCl3, 250 MHz)
δ 8.14 (d, J ) 8.0 Hz, 2H), 7.73 (d, J ) 8.0 Hz, 2H), 5.17 (m,
1H), 1.55-1.82 (m, 2H), 1.21-1.43 (m, 11H), 0.87 (t, J ) 6.7
Hz, 3H); 13C NMR (CDCl3, 62.5 MHz) δ 164.5, 134.7, 132.0,
130.0, 118.0, 116.1, 72.9, 35.9, 31.6, 29.0, 25.3, 22.5, 19.9, 14.0;
HRMS: Calcd for C16H21NO2 [(M+NH4)+•]: 277.1916. Found:
277.1912.
2H), 4.91 (m, 1H), 1.57 (d, J ) 7.2 Hz, 3H); 13C NMR (CDCl3,
75 MHz) δ 167.9, 136.9, 133.9, 132.1, 123.1, 116.3, 49.0, 18.2.
N-(Cycloh exen -2-yl)ph th alim ide (35).40 1H NMR (CDCl3,
270 MHz) δ 7.84 (m, 2H), 7.70 (m, 2H), 5.96 (m, 1H), 5.58 (m,
1H), 4.92 (m, 1H), 1.67-2.27 (m, 6H); 13C NMR (CDCl3, 75
MHz) δ 168.2, 133.9, 132.1, 130.1, 126.6, 123.1, 47.5, 27.1, 24.3,
21.8.
Meth yl 2-(N-P h th a lim id o)p r op a n oa te (36).41 1H NMR
(CDCl3, 300 MHz) δ 7.86 (m, 2H), 7.74 (m, 2H), 4.98 (q, J )
7.3 Hz, 1H), 3.74 (s, 3H), 1.69 (d, J ) 7.3 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) δ 170.2, 167.4, 134.2, 131.9, 123.5, 52.8, 47.4,
15.3.
P r oced u r e for F or m a tion of N-(2-Octyl)sa cch a r in e
(37). To a suspension of NaH (5.0 mmol, 0.12 g) in THF (5
mL), a solution of saccharin (5.0 mmol, 0.91 g) in THF (10 mL)
was gradually added. The mixture was stirred for 1 h, and
the solvent was removed under reduced pressure to provide
the sodium salt of saccharin as a white solid. Separately,
oxalyl chloride (1.15 mmol, 0.10 mL) was gradually added to
a solution of DMF (1.29 mmol, 0.10 mL) in CH2Cl2 (1 mL) to
form (chloromethylene)dimethylammonium chloride as a white
solid. This solid was suspended in DME (15 mL), and
2-octanol (1.0 mmol, 0.13 g, 0.16 mL) was added to form a
homogeneous solution that was added to the sodium saccharin
salt, and the mixture was heated to 70 °C overnight. The
reaction mixture was cooled, filtered through Celite, concen-
trated under reduced pressure, and chromatographed (hex-
anes:EtOAc, 20:1) to give the product 37 as a colorless oil
(0.183 g, 62%); IR (neat) 2929, 2859, 1726, 1460, 1335, 1294,
Rep r esen ta tive P r oced u r e for Rea ction of Im id a te
Ester s w ith P ota ssiu m P h th a lim id e (Ta ble 3). To a
solution of DMF (1.29 mmol, 0.094 g, 0.10 mL) in CH2Cl2 (1
mL) under nitrogen at room temperature, oxalyl chloride (1.15
mmol, 0.145 g, 0.10 mL) was added in a dropwise manner to
form (chloromethylene)dimethylammonium chloride as a white
solid. Stirring was continued for another 5 min, and the salt
was suspended in MeCN (20 mL) when 3-octanol (1.0 mmol,
0.130 g, 0.16 mL) and potassium phthalimide (7.0 mmol, 1.30
g) were added sequentially. The reaction mixture was heated
to 65 °C for 16 h, cooled, and filtered through Celite. The
residue, after evaporation, was chromatographed (EtOAc:
hexanes, 1:20, Rf ) 0.23) to provide N-(3-octyl)phthalimide 30
as a colorless oil (0.211 g, 90%); IR (neat) 2960, 2931, 2859,
1770, 1710, 1466, 1369, 1062 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 7.83 (m, 2H), 7.72 (m, 2H), 4.12 (m, 1H), 2.06 (m, 2H), 1.82
(m, 2H), 1.26 (m, 6H), 0.86 (m, 6H); 13C NMR (CDCl3, 75 MHz)
δ 168.9, 133.8, 131.9, 123.1, 54.0, 32.2, 31.5, 26.4, 25.6, 22.5,
14.0, 11.1; HRMS: Calcd for C16H21NO2 (M+•): 259.1572.
Found 259.1583.
1
1253, 1182 cm-1; H NMR (CDCl3, 300 MHz) δ 8.05 (m, 1H),
7.86 (m, 3H), 4.30 (m, 1H), 2.19 (m, 1H), 1.85 (m, 1H), 1.60 (d,
J ) 6.9 Hz, 3H), 1.28-1.37 (m, 8H), 0.88 (t, J ) 6.7 Hz, 3H);
13C NMR (CDCl3, 75 MHz) δ 158.9, 137.8, 134.5, 134.2, 127.5,
125.0, 120.7, 51.5, 34.0, 31.7, 28.9, 26.7, 22.6, 18.8, 14.1; Anal.
Calcd for C15H21NO3S: C, 60.99; H, 7.17; N, 4.74. Found: C,
61.22; H, 7.07; N, 4.78.
(S)-N-(2-Octyl)p h th a lim id e (28).36 [R]D25 ) +14.0° (c 1.1,
CHCl3) [lit.36 [R]D25 ) +15.2° (c 4.1, EtOH)]; H NMR (CDCl3,
1
300 MHz) δ 7.82 (m, 2H), 7.70 (m, 2H), 4.34 (m, 1H), 2.06 (m,
1H), 1.69-1.79 (m, 1H), 1.46 (d, J ) 6.9 Hz, 3H), 1.24-1.36
(m, 8H), 0.85 (t, J ) 6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
δ 168.6, 133.8, 132.0, 123.0, 47.5, 33.8, 31.7, 28.9, 26.8, 22.6,
18.7, 14.0.
N-(2-Octyl)-1,8-n a p h th osu lta m (38). IR (CHCl3) 2932,
2859, 1590, 1460, 1378, 1312, 1178, 1136 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 8.06 (d, J ) 8.1 Hz, 1H), 7.96 (d, J ) 7.1
Hz, 1H), 7.75 (m, 1H), 7.53 (m, 2H), 6.84 (d, J ) 7.2 Hz, 1H),
4.31 (m, J ) 6.9 Hz, 1H), 2.15 (m, 1H), 1.90 (m, 1H), 1.60 (d,
J ) 6.9 Hz, 3H), 1.23-1.42 (m, 8H), 0.87 (t, J ) 6.8 Hz, 3H);
13C NMR (CDCl3, 75 MHz) δ 135.0, 131.1, 130.9, 130.5, 129.2,
127.9, 119.5, 119.4, 117.7, 104.4, 51.2, 34.2, 31.7, 29.0, 26.9,
22.6, 18.2, 14.1; m/z (CI+; NH3) 318 (M+H)+•, 335 (M+NH4)+;
Anal. Calcd for C18H23NO2S: C, 68.11; H, 7.31; N, 4.42.
Found: C, 67.92; H, 7.54; N, 4.41.
N-(2-Decyl)p h th a lim id e (29). IR (neat) 2926, 2856, 1774,
1710, 1467, 1367 cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.82 (m,
2H), 7.70 (m, 2H), 4.34 (m, 1H), 2.05 (m, 1H), 1.74 (m, 1H),
1.47 (d, J ) 6.9 Hz, 3H), 1.24 (m, 12H), 0.84 (t, J ) 6.7 Hz,
3H); 13C NMR (CDCl3, 75 MHz); δ 168.6, 133.8, 132.1, 123.0,
47.5, 33.7, 31.8, 29.4, 29.2, 29.2, 19.2, 26.8, 22.6, 18.7, 14.1;
HRMS: Calcd for C18H25NO2 (M+•) 287.1885. Found: 287.1873;
N-(3-P en tyl)p h th a lim id e (31).37 1H NMR (CDCl3, 300
MHz) δ 7.82 (m, 2H), 7.71 (m, 2H), 4.04 (m, 1H), 2.05 (m, 2H),
1.78 (m, 2H), 0.87 (t, J ) 7.4 Hz, 6H); 13C NMR (CDCl3, 75
MHz) δ 168.8, 133.8, 131.8, 123.0, 55.6, 25.3, 11.1.
2-Octyl F or m a te (39).19 1H NMR (CDCl3, 270 MHz) δ 8.03
(s, 1H), 5.00 (m, 1H), 1.48-1.56 (m, 2H), 1.17-1.34 (m, 11H),
0.87 (t, J ) 6.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 160.9,
71.1, 35.8, 31.7, 29.0, 25.3, 22.6, 20.0, 14.0.
2-(4-P h en yl)bu tyl Ben zoa te (42).20 1H NMR (CDCl3, 250
MHz) δ 8.05 (d, J ) 8.0 Hz, 2H), 7.39-7.60 (m, 3H), 7.13-
7.29 (m, 5H), 5.18 (m, 1H), 2.75 (m, 2H), 1.87-2.18 (m, 2H),
1.47 (d, J ) 7.0 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 166.2,
141.5, 132.8, 130.8, 129.5, 128.4, 128.3, 125.9, 71.2, 37.8, 31.8,
20.1.
(R)-N-(2-Bu tyl)p h th a lim id e (32).38 [R]D25 ) -12.8° (c 1.1,
1
CHCl3); H NMR (CDCl3, 270 MHz) δ 7.79 (m, 2H), 7.67 (m,
2H), 4.24 (m, 1H), 2.02 (m, 1H), 1.77 (m, 1H), 1.44 (d, J ) 6.9
Hz, 3H), 0.86 (t, J ) 7.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
δ 168.6, 133.8, 132.1, 123.0, 49.1, 26.9, 18.4, 11.2.
(S)-N-((1-P h en yl)-1-eth yl)p h th a lim id e (33).38 [R]D25
)
4-P h en yl-2-ch lor obu ta n e (43).21 1H NMR (CDCl3, 250
MHz) δ 7.15-7.35 (m, 5H), 3.99 (m, 1H), 2.68-2.94 (m, 2H),
2.00 (m, 2H), 1.53 (d, J ) 7.0 Hz, 3H).
1
-31.4° (c 0.5, CHCl3); H NMR (CDCl3, 270 MHz) δ 7.78 (m,
2H), 7.68 (m, 2H), 7.47-7.53 (m, 2H), 7.22-7.36 (m, 3H), 5.57
(q, J ) 7.4 Hz, 1H), 1.93 (d, J ) 7.4 Hz, 3H); 13C NMR (CDCl3,
75 MHz) δ 168.2, 140.4, 133.9, 132.0, 128.5, 127.7, 127.5, 123.2,
49.7, 17.6.
4-(2-Na p h t h yl)-2-b u t a n ol (44). IR (CHCl3) 3358, 3052,
2967, 2931, 1599 cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.82 (m,
3H), 7.67 (br s, 1H), 7.47 (m, 2H),7.38 (d, J ) 8.4 Hz, 1H),
3.89 (m, 1H), 2.91 (m, 2H), 1.90 (m, 1H), 1.28 (d, J ) 6.2 Hz,
3H); 13C NMR (CDCl3, 75 MHz) δ 139.6, 133.7, 132.0, 128.0,
127.6, 127.4, 127.3, 126.4, 126.0, 125.2, 67.53, 40.7, 32.3, 23.7;
HRMS calcd for C14H16O (M+•) 218.1544, found 218.1542.
4-(2-Na p h th yl)-2-ch lor obu ta n e (47). IR (neat) 3052,
2970, 2926, 1600, 1508, 1445, 1378 cm-1; 1H NMR (CDCl3, 270
MHz) δ 7.81 (m, 3H) 7.67 (s, 1H), 7.34-7.48 (m, 3H), 4.00 (m,
N-(2-Bu ten -3-yl)p h th a lim id e (34).39 1H NMR (CDCl3,
270 MHz) δ 7.81 (m, 2H), 7.69 (m, 2H), 6.18 (m, 1H), 5.20 (m,
(35) Seto, K.; Shimojitosho, H.; Imazaki, H.; Matsubara, H.; Taka-
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(36) Landini, D.; Rolla, F. Synthesis, 1976, 389.
(37) Shibita, Y.; Shickita, M.; Sasaki, K.; Nishimura, K.; Hashimoto,
Y.; Iwaski, S. Chem. Pharm. Bull. 1995, 43, 177.
(38) Toda, F.; Soda, S.; Goldberg, I. J . Chem. Soc., Perkin Trans. 1.
1993, 2357.
(40) Sammes, P. G.; Thetford, D. J . Chem. Soc., Perkin Trans. 1
(39) (a) Inoue, Y.; Taguchi, M.; Toyofuku, M.; Hashimoto, H. Bull.
Chem. Soc. J pn. 1984, 57, 3021; (b) Mumm, O.; Richter, H. Chem. Ber.
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1989, 655.
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6280 J . Org. Chem., Vol. 63, No. 18, 1998
Barrett et al.
J ) 5.8 Hz, 1H), 3.00 (m, 2H), 2.12 (m, 2H), 1.56 (d, J ) 6.6
Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 138.6, 133.7, 132.1,
128.1, 127.7, 127.5, 127.3, 126.7, 126.1, 125.3, 57.9, 41.8, 33.1,
22.5; HRMS calcd for C14H1535Cl (M+•) 218.0862, found 218.0862.
in Medical Science at Imperial College, and the EPSRC
for providing a CASE studentship (to R. A. J .).
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of 27, 29, 30, 44, 46, and 47 (12 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
Ack n ow led gm en t. We thank Glaxo Wellcome Re-
search and Development Ltd. for the most generous
endowment (to A. G. M. B.) and for providing a CASE
studentship (to R. A. J .); the Wolfson Foundation for
establishing the Wolfson Centre for Organic Chemistry
J O980583J