Mechanism of esterification of 1,3-dimethylamino alcohols by N-acetylimidazole in acetonitrile and the influence of alkyl and geminal dialkyl substitution upon the rate

Article abstract of DOI:10.1039/a608488e

3-(Dimethylamino)propan-1-ol and seven derivatives with alkyl substituents at the 2-position have been prepared by conventional methods, and second-order rate constants for their esterification by N-acetylimidazole in acetonitrile have been measured under pseudo-first-order conditions both by ¹H NMR spectroscopy at a single temperature (23°C) and by a UV spectroscopic method over the temperature range 25-65°C. Evidence is presented that the intermolecular esterifications proceed via an initial rate-determining intramolecular general base catalysed formation of a cyclic tetrahedral intermediate. Effective molarities compared with the third-order reactions of simpler alcohols with acetylimidazole catalysed by triethylamine are estimated to be 13-14 mol dm^-3, but alkyl substitution at the 2-position of the amino alcohol has only a modest effect upon reaction rates. All reactions have substantial negative entropies of activation and only modest enthalpies of activation as expected for concerted bimolecular reactions with highly ordered transition structures. Three structurally related carbocyclic amino alcohols constitute a short isokinetic series with the isokinetic temperature very close to the experimental range. Along this series, decreasing enthalpies of activation are almost exactly balanced in their contributions to the overall free energy of activation near room temperature by increasingly negative entropies of activation.

Full text of DOI:10.1039/a608488e

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Mechanism of esterification of 1,3-dimethylamino alcohols by
N-acetylimidazole in acetonitrile and the influence of alkyl and
geminal dialkyl substitution upon the rate
Annemieke Madder,a Sonny Sebastian,a Dirk Van Haver,a Pierre J. De Clercq*,a
and Howard Maskillb
a University of Gent, Department of Organic Chemistry, Krijgslaan, 281 (S.4), B-9000 Gent,
Belgium
b University of Newcastle upon Tyne, Department of Chemistry, Bedson Building,
Newcastle upon Tyne, UK NE1 7RU
3-(Dimethylamino)propan-1-ol and seven derivatives with alkyl substituents at the 2-position have been
prepared by conventional methods, and second-order rate constants for their esterification by
N-acetylimidazole in acetonitrile have been measured under pseudo-first-order conditions both by 1H
NMR spectroscopy at a single temperature (23 ЊC) and by a UV spectroscopic method over the
temperature range 25–65 ЊC. Evidence is presented that the intermolecular esterifications proceed via an
initial rate-determining intramolecular general base catalysed formation of a cyclic tetrahedral
intermediate. Effective molarities compared with the third-order reactions of simpler alcohols with
acetylimidazole catalysed by triethylamine are estimated to be 13–14 mol dmϪ3, but alkyl substitution at
the 2-position of the amino alcohol has only a modest effect upon reaction rates. All reactions have
substantial negative entropies of activation and only modest enthalpies of activation as expected for
concerted bimolecular reactions with highly ordered transition structures. Three structurally related
carbocyclic amino alcohols constitute a short isokinetic series with the isokinetic temperature very close to
the experimental range. Along this series, decreasing enthalpies of activation are almost exactly balanced
in their contributions to the overall free energy of activation near room temperature by increasingly
negative entropies of activation.
NMe2
OH
Introduction
R
R
NMe2
OH
NMe2
OH
NMe2
OH
R
α
(CH2)n
Recently, in the context of developing a non-enzymic catalyst
for the cleavage of esters and amides, we studied the influence
of anchoring substitution in 1,3-amino alcohols on the rate of
esterification by N-acetylimidazole (AcIm) and by p-
nitrophenyl acetate (PNPA) in acetonitrile.1 We found that
anchoring substitution (1b vs. 1a) led to (i) a rate decrease in the
esterification with PNPA, and (ii) a rate increase in the reaction
with AcIm. We ascribed these effects to enforced intra-
molecular hydrogen bonding between the terminal dimethyl-
amino and hydroxy groups in the case of the 2-tert-butyl substi-
tuted derivative, a nucleophilic catalysis mechanism for reaction
with PNPA, and general base catalysis (GBC) for reaction with
AcIm.2
In continuation of that study, we became interested in
investigating the influence of various 2,2-gem-dialkyl substitu-
ents in the 3-(N,N-dimethylamino)propan-1-ol system upon
esterification with AcIm. We were aware, for example, that alkyl
substitution and, in particular, gem-dialkyl substitution have
long been known to promote ring closure reactions.3 Although
no final ring closed products are formed in the present reac-
tions, cyclic transition structures are involved in the intra-
molecular proton transfers of the GBC mechanism. Con-
sequently, we sought to investigate how the rates of these reac-
tions are influenced by the alkyl substitution pattern in the
chain between the donor and acceptor of the intramolecular
hydrogen bond. We now report fully our results obtained for the
1a: R = H
1b: R = But
2: R = Me
3: R = Prn
4: n = 1
5: n = 2
6: n = 3
7
Results and discussion
Syntheses
Compound 1a was commercially available and the syntheses of
the other amino alcohols investigated, 1b–7, are given in
Schemes 1–3. The synthetic route for the preparation of
N,N,3,3-tetramethyl-2-(hydroxymethyl)butylamine 1b is out-
lined in Scheme 1. Commercially available tert-butylacetic acid
CO2H
OH
a
b
CO2H
But
But
But
62%
90%
OBn
OBn
8
9
c
98%
NMe2
OH
NMe2
OBn
OTs
OBn
e
d
But
But
But
83%
92%
1b
11
10
Scheme 1 Reagents: (a) i NaH LDA, ii ClCH2OBn; (b) LAH, THF;
(c) TsCl, pyridine, DMAP, CH2Cl2; (d) Me2NH (40% aq. sol.), THF,
100 ЊC; (e) H2, Pd/C, EtOH
esterification of
a series of 2,2-dialkyl-3-(N,N-dimethyl-
amino)propan-1-ols (1–7) by AcIm in acetonitrile.
J. Chem. Soc., Perkin Trans. 2, 1997
2787

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was alkylated with benzyl chloromethyl ether to give 8. Sub-
sequent reduction with lithium aluminium hydride followed by
tosylation yielded 10, which was treated with a 40% aqueous
solution of dimethylamine. Finally, debenzylation of 11 led to
the desired amino alcohol 1b.
The synthesis of 3-(dimethylamino)-2,2-dimethylpropan-1-ol
(Scheme 2) started from isobutyric acid. First, the acid was
O
O
O
NMe2
OH
b
a
OH
NMe2
83%
39%
12
13
c
47%
NMe2
OH
2
Fig. 1 Arrhenius plot (ln k vs. 1/T) obtained for the alcoholysis of
Aclm by 4 (᭛), 5 (ᮀ), 6 (᭝) and 7 (*) (lines for 1a, 1b, 2 and 3 are
almost parellel with the line for 7)
Scheme 2 Reagents: (a) i DMF, SOCl2, 0–80 ЊC, ii Me2NH (40% aq.
sol.), CH2Cl2, Ϫ70 ЊC–room temp. (b) i 2,2,6,6-tetramethylpiperidine,
BuLi, THF–HMPA, ii (CH2O)n; (c) BF3ؒEt2O, boraneؒdimethylsulfide,
THF
with AcIm catalysed by triethylamine, i.e. a system capable only
of intermolecular general base catalysis.6 Secondly, the total
reactivity range for compounds 1–7 is narrow (four-fold) indi-
cating only a small dependence of reactivity upon the alkyl
substituents at the central carbon of the 1,3-amino alcohols.
This is in line with the results from previous studies where the
effect of structural variation on the efficiency of intramolecular
general base catalysis was investigated.7 Thirdly, the reactivity
orders between the 2-alkyl and 2,2-dialkyl acyclic compounds,
i.e. 1b > 1a and 3 > 2, are as expected but the differences are
small and there is no evident trend related to structure amongst
these four compounds.8 Fourthly, there is a (modest) structure-
related trend in reactivity amongst the cyclic gem-dialkyl com-
pounds, i.e. 7 > 6 > 5 > 4, which follows the order of the magni-
tude of the internal bond angle α at the 2-position (Table 1).
This suggested that the Thorpe–Ingold angle deformation
could contribute to some degree to the relative reactivities with-
in the series which,9 although expected to be small,10 should be
reflected primarily in the enthalpies of activation.11
transformed into amide 12, then condensation with formalde-
hyde followed by reduction with borane gave the amino alcohol
2. Amino alcohols 3–7 were prepared via essentially the same
strategy starting from the commercially available dialkyl acids
(Scheme 3). In the case of the adamantane derivative, the
R
R
NMe2
OCH3
R
R
R
R
b
a
CO2Me
CO2H
O
19: R,R = Prn
14: R,R = Prn
20: R,R = (CH2)3
21: R,R = (CH2)4
22: R,R = (CH2)5
23: R,R = adamantyl
15: R,R = (CH2)3
16: R,R = (CH2)4
17: R,R = (CH2)5
18: R,R = adamantyl
c
Seeking further insight into these relative reactivities, we
measured the activation parameters for all members of the ser-
ies. Reaction rates were measured in acetonitrile by monitoring
the decrease in UV absorbance at 270 nm due to AcIm over at
least five half-lives with the amino alcohol present in very large
excess (160–1300-fold), and the rate constants were found to be
strictly first-order in AcIm, the limiting reagent. By measuring
the pseudo-first-order rate constants at different high concen-
trations of the amino alcohol, it was also established that the
reactions are first-order in amino alcohol, and second-order
rate constants (at least in duplicate) were measured for the
esterification of compounds 1–7. Activation enthalpies and
entropies were obtained in the usual way from second-order
rate constants at five different temperatures (at least) in the
range of 25–65 ЊC using classical Eyring plots. Activation
parameters are included in Table 1 along with second-order rate
constants k calculated at 25 ЊC which differ slightly from those
R
R
NMe2
OH
3: R,R = Prn
4: R,R = (CH2)3
5: R,R = (CH2)4
6: R,R = (CH2)5
7: R,R = adamantyl
Scheme 3 Reagents: (a) CH2N2, Et2O; (b) LDA, N,N-dimethyl-
methyleneammonium iodide; (c) LAH, Et2O
adamantane-2-carboxylic acid was prepared from adamantan-
2-one via a three-step sequence according to a literature pro-
cedure.4 Conversion of the acids into the methyl esters was fol-
lowed by alkylation with N,N-dimethylmethyleneammonium
iodide (Eschenmoser’s salt).5 The resulting amino esters were
isolated as their hydrochlorides and subsequently transformed
into the desired amino alcohols by lithium aluminium hydride
reduction. Distillation resulted in pure amino alcohols (see
Experimental section for detailed procedures and yields).
1
obtained by H NMR spectroscopy (at 23 ЊC). In view of the
pseudo-first-order requirements and the number of data
involved in their determination, the former are considered to be
more reliable; for 1a and 1b, somewhat different (and better)
values were obtained than were reported originally.1
Kinetics
All the reactions have very substantial negative entropies
of activation and modest enthalpies of activation as expected
for concerted bimolecular reactions in general. Inspection of
the activation parameters in Table 1 reveals, at least for some
compounds, a tendency for compensation between enthalpies
and entropies of activation suggesting that there could be an
At first, half-lives for the esterification at 23 ЊC were determined
1
by H NMR spectroscopy using the amino alcohol in 10-fold
excess over AcIm (Table 1). From these results we note the
following four features. First, compounds show rate enhance-
ments over the reactions of propan-1-ol and hexane-1,6-diol
2788
J. Chem. Soc., Perkin Trans. 2, 1997

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Table 1 Half-lives (23 ЊC),a calculated internal bond angles,b activation enthalpies,c activation entropies,d and second-order rate constants (25 ЊC)e
for the alcoholysis of Aclm by 1a, 1b and 2–7 in acetonitrile
₁
t /min
α/Њ
∆H‡/kJ molϪ1
∆S‡/J KϪ1 molϪ1
Ϫ195
Ϫ180
Ϫ196
Ϫ193
Ϫ171
Ϫ186
Ϫ210
Ϫ188
k/10Ϫ4 dm3 molϪ1 sϪ1
₂
1a
1b
2
721
198
677
462
682
473
421
169
113.9
110.3
111.8
109.8
114.2
111.7
110.1
106.7
33.1
35.3
33.8
33.5
40.9
35.6
27.4
32.5
6.04
14.9
4.26
6.58
4.76
6.25
9.28
17.7
3
4
5
6
7
a Determined by NMR spectroscopy for the pseudo-first-order reaction (0.05 mol dmϪ3 amino alcohol; 10-fold excess over Aclm); for the reaction of
Aclm with hexane-1,6-diol and triethylamine, the estimated pseudo-first-order half-life is 224 h at [hexane-1,6-diol] = [triethylamine] = 0.05 mol
dmϪ3 b In the intramolecular hydrogen bonded global minimum energy form. c Estimated maximum probable error, 4 kJ molϪ1 d Estimated
. .
maximum probable error, 14 J KϪ1 molϪ1 e Determined by UV spectroscopy (see text).
.
isokinetic series amongst our compounds.12 In order to identify
the compounds for which there is an isokinetic relationship
(IKR), we applied the strictest statistical test that has been
recently and convincingly advocated by Linert.13 From inspec-
tion of Arrhenius plots (ln k vs. 1/T) for substrates 1a–7, it was
clear that only the closely related compounds 4, 5 and 6 showed
a common small area of intersection (Fig. 1) and hence could
constitute an isokinetic series with an isokinetic temperature
almost within the experimental range (69 ЊC). We observe that,
along this series 4, 5 and 6, ∆H‡ decreases appreciably (40.9,
35.6 and 27.4 kJ molϪ1), but that this trend is almost exactly
counterbalanced by the corresponding trend in ∆S‡ (Ϫ171,
Ϫ186 and Ϫ210 J KϪ1 molϪ1). For the other compounds,
including the two most reactive substrates investigated (1b and
7), there are no trends in the activation parameters which are
ate to give the isomeric uncharged tetrahedral intermediate.
Calculations indicate that the conformation required for proper
alignment of proton donor and acceptor residues to allow a
third possibility, efficient intramolecular general acid catalysis
in a direct forward step from the zwitterionic tetrahedral inter-
mediate with departure of imidazole, is too strained and may be
dismissed.14a This leaves the formation of the uncharged tetra-
hedral intermediate as the most favourable process from the
first-formed zwitterionic intermediate, and the thermodynamics
of this step may cause it to be essentially irreversible in
acetonitrile.
The pKa values alone of the conjugate acids of the respective
potential leaving groups within the uncharged tetrahedral
intermediate may lead one to expect their departures to be
competitive. However, molecular orbital calculations on N-
acetylimidazole indicate that both N-1 and the carbonyl carbon
bear a net positive charge, and N-3 possesses a net negative
charge.14b This is in accord with the earlier finding by Fife that
imidazole is a much more effective nucleofuge than is predicted
solely on the basis of its pKa value.2c Consequently, we expect
this forward reaction from the uncharged tetrahedral inter-
mediate to be faster than the alternatives; and hence, in the
forward direction of the overall sequence, the initial GBC step
is rate limiting.15
Ϫ1
very similar (∆H‡ = 33.5 2.0 kJ mol and ∆S‡ = Ϫ195 15
J KϪ1 molϪ1).
Mechanism
Whereas it is generally accepted that the esterification of amino
alcohols by AcIm involves intramolecular GBC (Scheme 4), it
H
+ NMe2
–
O
NMe2
k1
Me
N
The remaining unresolved issue is the small size of the effect
of 2-alkyl substitution in the 1,3-amino alcohols upon the rate
constants. Our present working hypothesis is that, in
acetonitrile, all the 1,3-amino alcohols react with the benefit of
fully formed intramolecular hydrogen bonds in their initial
states. Consequently, there is relatively little difference in
reactivity between substrates 1–7 with different sizes or num-
bers of alkyl groups at carbon-2.
+
AcIm
k–1
O
N
OH
Me2N
Me2N
HO
O
Me
HO
O
Me
+
-
N
N
N
N
Experimental
k2
General procedures
All reactions involving air and/or moisture sensitive materials
were conducted under atmospheres of N2 or Ar. All solvents
were purified before use; diethyl ether and tetrahydrofuran
were distilled from sodium benzophenone ketyl, triethylamine
and diisopropylamine were distilled over calcium hydride and
dichloromethane was distilled over phosphorus pentoxide.
Analytical thin-layer chromatography was performed using
NMe2
OAc
HN
N
+
Scheme 4
may not be immediately obvious whether the forward reaction
of the tetrahedral intermediate to products (the k2 process) is
faster than the reverse breakdown to reactants (the kϪ1 process).
The kϪ1 process, being the reverse of an intramolecular general
base catalysed step, involves intramolecular general acid cata-
lysis. This step involves partial proton transfer from the
᎐NMe2Hϩ group to an uncharged oxygen, and departure of an
incipient alcohol as nucleofuge. However, a minor conform-
ational change allows a second and more favourable possibility,
the complete proton transfer to the more strongly basic nega-
tively charged oxygen of the zwitterionic tetrahedral intermedi-
glass plates precoated (0.25 mm layer) with silica gel 60 F254
.
Flash chromatography was performed using Merck silica gel 60
(70–235 or 230–400 mesh). The 1H NMR spectra were
obtained at 500, 360 and 200 MHz, and 13C NMR spectra at
50.3 MHz. Chemical shifts are reported in ppm downfield from
TMS using residual CHCl3 (7.27 ppm) as an internal standard;
J values are given in Hz. Melting points are uncorrected. IR
spectra were recorded on a FTIR spectrometer using KBr
plates with film or in solution; mass spectra were recorded at 70
eV.
J. Chem. Soc., Perkin Trans. 2, 1997
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Kinetics measurements (UV)
saturated aqueous sodium chloride, dried over magnesium sul-
Acetylimidazole was obtained from Aldrich and recrystallized
from dichloromethane–diethyl ether. Acetonitrile (super gradi-
ent, far UV) was obtained from Lab Scan and stored under
nitrogen. 3-(N,N-Dimethylamino)propan-1-ol was obtained
from Aldrich and distilled. Stock solutions of amino alcohols
(1 ) and acetylimidazole (3.3 × 10Ϫ6 ) were prepared and
stored in the dark. New stock solutions were prepared for
duplicate runs.
Rates of reactions were followed spectrophotometrically by
measuring the disappearance of acetylimidazole at 270 nm
using a Varian Cary 3E UV–VIS spectrophotometer equipped
with a thermostatted multi-cell block. The temperature in the
sample compartment was constantly checked using a temper-
ature probe emersed in one of the cells ( 0.1 ЊC). Stoppered
semi-micro cuvettes (1.5 ml) were used. Reactions were initiated
by adding a small volume of amino alcohol solution (30–150 µl)
via a syringe to a cuvette containing the acetylimidazole solu-
tion which had been equilibrated for at least 20 min. Reactions
were followed for at least five half-lives. Cary kinetics applic-
ation software was employed to obtain pseudo-first-order rate
constants using the recursive Marquardt non-linear curve fit-
ting technique as described by Schwartz and Gelb.16
fate and filtered. The solvent was then evaporated under
reduced pressure to yield the carboxylic acid 8 (92.8 g, 62%)
pure enough for direct use in the next step; νmax(KBr)/cmϪ1
3730–2400, 3460, 3020, 2920, 1725, 1520, 1505, 1475, 1455,
1425, 1395, 1380, 1335, 1285, 1240; δH(500 MHz, CDCl3) 1.01
(9 H, s,), 2.60 (1 H, dd, J 3.8 and 10.4), 3.66 (1 H, dd, J 3.8 and
9.0), 3.78 (1 H, dd, J 9.1 and 10.3), 4.54 (2 H, app. s), 7.34–7.25
(5 H, m); m/z 236 (Mϩ, 2%), 190 (2), 179 (2), 107 (50), 92 (100),
79 (10), 65 (12), 57 (24), 41 (19).
2-(Benzyloxymethyl)-3,3-dimethylbutan-1-ol (9).—A suspen-
sion of lithium aluminium hydride (11.4 g, 0.3 mol) in dry tetra-
hydrofuran (400 ml) was heated under reflux and a solution
of the carboxylic acid 8 (35.4 g, 0.15 mol) in dry tetrahydro-
furan (60 ml) was added dropwise to the boiling suspension
over about 30 min. The reaction mixture was stirred for an
additional 10 min at reflux temperature, then overnight at room
temperature. Hydrochloric acid (10%, 200 ml) was then added
dropwise to the suspension at 0 ЊC before the aqueous phase
was extracted with dichloromethane. The combined organic
layers were washed with saturated aqueous sodium chloride,
dried over magnesium sulfate and filtered. The solvent was
evaporated under reduced pressure to give the alcohol as a col-
ourless oil (30 g, 90%); νmax(KBr)/cmϪ1 3440, 3080, 3056, 2960,
2856, 1496, 1472, 1452, 1370, 1116, 1076, 1040, 1026, 1008, 706,
700; δH(360 MHz, CDCl3) 0.91 (9 H, s), 1.73 (1 H, m), 3.04 (1
H, dd, J 2.8 and 8.8), 3.60 (1 H, app. t, J 9.2), 3.71 (1 H, m),
3.89–3.81 (2 H, m), 4.55 (1 H, d, JAB 11.9), 7.38–7.20 (5 H, m);
m/z 222 (Mϩ, 2%), 221 (10), 204 (2), 159 (8), 145 (4), 144 (7), 91
(94), 79 (40), 70 (82), 69 (80), 57 (100), 56 (44), 38 (70).
Plots of kobs (for the pseudo-first-order reaction) vs. amino
alcohol concentration were linear with a correlation of at least
0.997, i.e. the reactions are pure first-order in amino alcohol.
All reactions were run at least in duplicate.
Kinetics measurements (1H NMR)
Half-lives were obtained by this method by adding a small
amount (0.1 equiv.) of acetylimidazole to an NMR tube con-
taining the amino alcohol solution. The concentration of
amino alcohol was 0.05 . Spectra were then recorded at spe-
cific time intervals on a Bruker 500 MHz instrument thermo-
statted at 23 ЊC. The half-life was calculated using the inte-
grations of acetylimidazole peaks in the NMR spectra in the
following way. Acetylimidazole shows three peaks at character-
istic δ-values of 7.0, 7.51 and 8.13, each integrating for one
proton. The imidazole which is formed shows a peak at
δ = 7.55, integrating for one proton and another at δ = 6.95
integrating for two protons. At each moment the ratio of the
integration at δ ≅ 8.13 over the total integration at δ = 7.5
reflects the ratio of the actual acetylimidazole concentration
over the initial acetylimidazole concentration. Plotting the loge
of this ratio vs. time produces a straight line, showing the reac-
tion to be first order in acetylimidazole.
2-(Benzyloxymethyl)-3,3-dimethylbutyl toluene-p-sulfonate
(10).—A solution of alcohol 9 (9.60 g, 43.2 mmol), toluene-p-
sulfonyl chloride (tosyl chloride) (9.26 g, 47.5 mmol) and 4-
(N,N-dimethylamino)pyridine (10 mg) in pyridine (10 ml) and
dichloromethane (40 ml) was stirred at room temperature for 12
h. Ice water (about 10 ml) was added to the reaction mixture
and the resulting solution was stirred for 30 min. Diethyl ether
(100 ml) was then added and the separated organic phase was
extracted with 5% hydrochloric acid then saturated aqueous
sodium chloride, dried over magnesium sulfate, filtered and
concentrated under reduced pressure; the crystallized toluene-
p-sulfonate (tosylate) 10 (15.9 g, 98%) was pure enough to be
used directly in the next step. Further purification of a sample
was achieved by column chromatography on silica gel (diethyl
ether:hexane, 5:95); (Found: C, 66.84; H, 7.47. Calc. for
C21H24O4S: C, 66.99; H, 7.50%); νmax(KBr)/cmϪ1 2960, 2870,
1490, 1470, 1355, 135, 1165, 960, 835, 735, 695; δH(360 MHz,
CDCl3) 0.92 (9 H, s), 1.63 (1 H, m), 2.38 (3 H, s), 3.47 (1 H, dd,
J 6.7 and 9.5), 3.55 (1 H, dd, J 3.9 and 9.5), 4.21 (1 H, dd, J 5.8
and 9.6), 4.25 (1 H, dd, J 4.0 and 9.6), 4.34 (2 H, s), 7.20 (2 H, d,
Syntheses
N,N,3,3-Tetramethyl-2-(hydroxymethyl)butylamine (1b). 2-
2-(Benzyloxymethyl)-3,3-dimethylbutanoic acid (8).—tert-Butyl-
acetic acid (81.6 ml, 0.63 mol) was added to a stirred suspension
of sodium hydride in mineral oil (21.6 g of a 70% suspension,
0.63 mol) and diisopropylamine (88 ml, 0.63 mol) in tetrahydro-
furan (630 ml) maintained below 10 ЊC by the use of an ice
bath. The reaction mixture was then heated up to reflux tem-
perature and stirred for a further 15 min. After the reaction
mixture had then been cooled to 0 ЊC, n-butyllithium (252 ml of
a 2.5  solution in hexane, 0.63 mol) was added dropwise, care
being taken not to exceed a reaction temperature of 10 ЊC. The
reaction mixture was then warmed up to 30 ЊC and stirred for
45 min to complete the metallation, whereupon the suspension
was cooled back down to 0 ЊC and a solution of benzyl chloro-
methyl ether (110 g, 0.7 mol) in tetrahydrofuran (100 ml) was
added dropwise. During this addition, the internal temperature
was kept below 20 ЊC. After being stirred overnight at room
temperature, the reaction mixture was poured into ice water
(1.5 l) and extracted with diethyl ether (4 × 300 ml). The aque-
ous phase was acidified almost to pH 1 with concentrated
hydrochloric acid (37%) after which it was extracted again with
diethyl ether. The combined organic layers were washed with
J 10.2), 7.29 (5 H, m), 7.27 (2 H, d, J 10.2); m/z 204 (M ϩ Ϫ Ts,
᝽
2%), 159 (10), 147 (4), 107, 95 (100), 92 (51), 84 (24), 64 (59), 70
(40), 57 (60), 41 (50).
2-(Benzyloxymethyl)-N,N,3,3-Tetramethylbutylamine (11).—
A solution of tosylate 10 (5.00 g, 13.3 mmol) and dimethyl-
amine (13 ml of a 60% aqueous solution) in tetrahydrofuran (13
ml) was heated in a pressure vessel for 48 h at 100 ЊC. The
reaction mixture was cooled to room temperature, treated with
aqueous potassium hydroxide solution (10%, 50 ml) and then
extracted with diethyl ether (3 × 50 ml). The combined ether
layers were washed with saturated aqueous sodium chloride,
dried over magnesium sulfate, filtered and concentrated under
reduced pressure. Pure amine 11 (3.05 g, 92%) was obtained
after Kugelrohr distillation (150 ЊC, 0.03 mmHg); νmax(KBr)/
cmϪ1 3080, 3050, 3020, 2950, 2850, 2800, 2750, 1490, 1460,
1450, 1390, 1360, 1255, 1235, 1190, 1150, 1110, 1095, 1030, 940,
840, 730, 690; δH(500 MHz, C6D6) 1.01 (9 H, s), 1.45 (1 H, m),
2.08 (1 H, dd, J 3.6 and 12.2), 2.41 (1 H, dd, J 10 and 12.2), 3.56
(1 H, dd, J 3.3 and 9.3), 3.65 (1 H, dd, J 4.6 and 9.3), 4.35 (2 H,
app. s), 7.07–7.32 (5 H, m); m/z 249 (M ϩ, 2%), 234
᝽
2790
J. Chem. Soc., Perkin Trans. 2, 1997

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(M ϩ Ϫ CH3, 1), 219 (2), 192 (M ϩ Ϫ But, 4), 158 (8), 91 (12),
58 (100).
with silica (volume silica = 190 ml); the column is packed using
᝽
᝽
pentane–diethyl ether (50:50); elution is performed successively
with 100 ml of pentane–diethyl ether (50:50), 100 ml of
pentane–diethyl ether (25:75), 100 ml of pentane–diethyl ether
(12.5:87.5) and 100 ml of pure diethyl ether. The Rf value of
the desired compound (eluent 70% ethyl acetate in tolu-
ene) = 0.24; δH(200 MHz, CDCl3) 1.25 (6 H, s), 3.0 (6 H, s), 3.48
(2 H, s), 3.82 (1 H, br s).
N,N,3,3-Tetramethyl-2-(hydroxymethyl)butylamine (1b).—A
solution of benzyl ether 11 (1.1 g, 4.5 mmol) and toluene-p-
sulfonic acid (0.855 g, 4.5 mmol) in ethanol (5 ml) was added to
a prehydrogenated suspension of palladium on carbon (350 mg,
10% Pd on C) in ethanol (2 ml). The reaction mixture was
shaken for 48 h under hydrogen (4 bar). After the reaction mix-
ture had been flushed with nitrogen to remove hydrogen, the
catalyst was removed by filtration through celite. Aqueous
potassium hydroxide solution (10%) was added to the filtrate
which was then extracted with diethyl ether. The combined
organic layers were washed with saturated aqueous sodium
chloride, dried over magnesium sulfate, filtered and concen-
trated under reduced pressure. Finally, the amino alcohol (0.593
g, 83%) was obtained by Kugelrohr distillation (80 ЊC, 0.03
mmHg); (Found: C, 67.73; H, 13.09; N, 8.59. Calc. for
C9H21NO: C, 67.87; H, 13.29; N, 8.79%); νmax(KBr)/cmϪ1 3426,
2956, 2867, 1467, 1396, 1366, 1290, 1238, 1194, 1164, 1098,
1048, 1009, 947, 839, 668; δH(360 MHz, CD3OD) 0.91 (9 H, s),
1.61 (1 H, m), 2.26 (6 H, s), 2.47 (1 H, app. dt, J 2.8, 2.3 and
12.2), 2.56 (1 H, dd, J 12.2 and 12.2), 3.64 (1 H, dd, J 9.2 and
10.3), 3.84 (1 H, ddd, J 2.3, 3.8 and 10.3); δC(50.3 MHz, CDCl3)
3-(Dimethylamino)-2,2-dimethylpropan-1-ol (2).—Boron tri-
fluoride–diethyl ether (6.00 ml, 48 mmol, 1.17 equiv.) followed
by borane–dimethyl sulfide (10.5 ml, 105 mmol, 2.6 equiv.) were
added to a solution of amide 13 (6.0 g, 41 mmol), in tetrahydro-
furan (80 ml) at 0 ЊC. The reaction mixture was warmed to
45 ЊC over 30 min then cooled down before small pieces of ice
were carefully added to destroy the excess borane (caution—
exothermic reaction). Tetrahydrofuran was evaporated under
reduced pressure, then the mixture was acidified with hydro-
chloric acid (6 ) and briefly warmed until a clear solution was
obtained. The cooled reaction mixture was made alkaline with
aqueous sodium hydroxide solution (4 ) then extracted with
ethyl acetate. The organic phase was dried over magnesium sul-
fate, filtered and slowly evaporated under reduced pressure. The
residue was distilled (85 ЊC, 20 mmHg) to yield the amino alco-
hol (6.8 g, 47%); νmax(KBr)/cmϪ1 3357 (br, m), 2952 (s), 2830
(m), 2800 (m), 1463 (m), 1045 (s), 842 (w), 733 (m); δH(200
MHz, CDCl3) 0.92 (6 H, s), 2.30 (6 H, s), 2.36 (2 H, s), 3.50 (2
H, s); δC(50.3 MHz, CDCl3) 23.98, 35.26, 48.07, 71.74, 73.99;
27.41, 30.61, 44.56, 45.13, 62.22, 66.02; m/z 159 (M ϩ, 7%), 112
᝽
(9), 102 (12), 84 (17), 69 (30), 58 (100).
3-(Dimethylamino)-2,2-dimethylpropan-1-ol (2). N,N-Dimeth-
yl-2-methylpropanamide (12).—In a 500 ml flask fitted with a
reflux condenser, stirring bar and gas trap, isobutyric acid (100
ml, 1.08 mol), N,N-dimethylformamide (0.5 ml) and thionyl
chloride (80 ml, 1.10 mol, 1.01 equiv.) were cooled to 0 ЊC. The
reaction mixture was then stirred for 1 h on a warm water bath
as the temperature was gradually raised from 40 to 80 ЊC.
Hydrogen chloride and the excess of thionyl chloride were
removed by an air stream, then the acid chloride (85 ml) was
distilled under reduced pressure from the residue (45–50 ЊC, 40
mmHg). A solution of the acid chloride in dichloromethane
(200 ml) was cooled to Ϫ70 ЊC then added to an aqueous solu-
tion of dimethylamine (40%, 200 ml) at Ϫ30 ЊC. After 30 min,
the mixture was warmed up to room temperature and more
dichloromethane was added. The organic phase was separated,
dried over magnesium sulfate, filtered and the solvent was
evaporated under reduced pressure. The amide (103 g) was dis-
tilled from the residue (68–72 ЊC, 14 mmHg). Since the product
still contained isobutyric acid (15%), it was dissolved in dichloro-
methane and stirred with solid potassium carbonate for 1 h.
After filtration and evaporation of the solution, the product
obtained was pure enough to be used directly in the next step;
δH(200 MHz, CDCl3) 1.10 (6 H, d, J 6.6), 2.81 (1 H, heptuplet,
J 6.6), 2.92 (3 H, s), 3.02 (3 H, s).
N,N,2,2-Tetramethyl-3-hydroxypropanamide (13).—n-Butyl-
lithium (44 ml of a 2.5  solution in hexane, 0.11 mol) was
added to a solution of 2,2,6,6-tetramethylpiperidine (16.8 ml,
0.1 mol, 1.05 equiv.) in dry tetrahydrofuran (120 ml) and hexa-
methylphosphoramide (12 ml) at Ϫ78 ЊC, and the resultant
solution was stirred for 15 min. A solution of amide 12 (11 g,
0.096 mol) in tetrahydrofuran (20 ml) was then added and the
mixture was stirred for 20 min at 0 ЊC then cooled to Ϫ40 ЊC.
Solid paraformaldehyde (3.3 g, 0.11 mol) was added next, then
the mixture was stirred at 10 ЊC for 15 min and at 45 ЊC for 30
min before being cooled to room temperature. Ice was then
added and the reaction mixture was neutralized with hydro-
chloric acid (6 ). The tetrahydrofuran was removed under
reduced pressure and the residual solution was extracted with
ethyl acetate. The organic phase was dried over magnesium sul-
fate, filtered and evaporated. The residue was dissolved in
diethyl ether and percolated through silica gel to remove the
hexamethylphosphoramide. The desired amide 13 (5.4 g, 39%)
was isolated by column chromatography on silica gel (pen-
tane:diethyl ether 1:1→diethyl ether) using the following pro-
cedure; a column of 4 cm diameter is filled to a height of 15 cm
m/z (ESMS), 132, (M ϩ ϩ 1).
᝽
2-(N,N-Dimethylaminomethyl)-2-(hydroxymethyl)adaman-
tane (7). Adamantane-2-carbaldehyde.—Sodium hydride (3.16
g, 79 mmol as a 60% dispersion in mineral oil) was washed three
times with dry hexane, then dimethyl sulfoxide (120 ml, stored
over molecular sieves) was added followed by trimethylsulfox-
onium iodide (16.5 g, 75 mmol) over a 5 min period. Fifteen
minutes after the gas evolution had ceased, the flask was cooled
to room temperature and adamantanone (10 g, 67 mmol) was
added over 3–5 min. The reaction mixture was stirred for 1 h at
room temperature followed by 1.5 h at 55 ЊC, then poured into
ice water (300 ml) which caused the epoxide to precipitate. The
mixture was extracted twice with hexane, then the combined
hexane solution was dried with magnesium sulfate, filtered and
evaporated to give the crude epoxide (10.3 g, 95%). Boron
trifluoride–diethyl ether (5.60 g, 39.5 mmol) was added to the
crude epoxide dissolved in dry benzene, and the reaction mix-
ture was stirred for 10 min then poured into ice water. The
layers were separated and the benzene layer washed twice with
water. The combined aqueous layers were re-extracted with
benzene, then the combined benzene solution was dried with
sodium sulfate, filtered and evaporated to give the unstable
aldehyde (9.2 g, 90%); νmax(KBr)/cmϪ1 2903 (s), 2851 (s), 2697
(m), 1723 (s), 1451 (s), 1267 (w), 1082 (m), 939 (w), 739 (s);
δH(200 MHz, CDCl3) 1.62–1,92 (12 H, complex), 2.37–2.43
(3 H, complex), 9.73 (1 H, s); m/z 164 (M ϩ, 52%), 135 (98),
᝽
121 (12), 105 (56), 93 (56), 91 (50), 79 (100), 67 (66), 58 (80),
41 (68).
Adamantane-2-carboxylic acid.—Jones reagent (prepared by
dissolving 50 g chromium() oxide and 41.5 ml concentrated
sulfuric acid in 190 ml water) was added slowly to a solution of
adamantane-2-carbaldehyde (9.2 g, 56 mmol) in diethyl ether
(150 ml) over 1 h at 10 ЊC. The reaction mixture was then stirred
for 2 h at 20 ЊC, poured into water, and the organic layer was
separated. The aqueous phase was extracted with dichlo-
romethane and the combined organic phase was washed with
water, dried over magnesium sulfate, filtered, and evaporated
under reduced pressure. The residue was purified by column
chromatography (hexane:ethyl acetate 95:5→70:30) to give
the carboxylic acid (8.5 g, 85%); νmax(KBr)/cmϪ1 3436 (br), 2903
(s), 2851 (s), 1682 (s), 1451 (s), 1415 (m), 1272 (s), 1103 (s), 939
(m); δH(500 MHz, CDCl3) 1.63–1.66 (2 H, complex), 1.74–1.78
(4 H, complex), 1.85–1.93 (6 H, complex), 2.35 (2 H, br s), 2.67
J. Chem. Soc., Perkin Trans. 2, 1997
2791

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(1 H, br s); m/z 180 (M ϩ, 22%), 162 (30), 137 (21), 134 (75), 120
(14), 105 (14), 91 (64), 79 (100), 67 (56), 41 (76).
isolated by distillation (bp 85 ЊC, 20 mmHg): νmax(KBr)/cmϪ1
᝽
2958 (s), 2874 (s), 2256 (w), 1738 (s), 1466 (s), 1435 (s), 1379 (s),
1264 (m), 1240 (s), 1194 (s), 1170 (s), 1148 (s), 1106 (m),
1108 (m), 918 (s), 830 (m), 735 (s), 648 (w); δH(500 MHz,
CDCl3) 0.89 (6 H, t, J 7.20), 1.19–1.31 (4 H, m), 1.37–1.44 (2 H,
m), 1.54–1.62 (2 H, m), 2.37 (1 H, tt, J 9.25 and 5.26), 3.68 (3 H,
s); δC(50.3 MHz, CDCl3) 13.74, 20.47, 34.51, 45.06, 50.98,
176.77; m/z 143 (Mϩ Ϫ CH3, 1%), 127 (5), 116 (50), 44 (100), 69
(4), 57 (51).
Methyl adamantane-2-carboxylate (18).—A solution of diazo-
methane in diethyl ether was added dropwise to a solution of
adamantane-2-carboxylic acid (8.4 g, 47 mmol) in dry diethyl
ether (50 ml) at 0 ЊC until the reaction mixture became yellow; it
was stirred for a further 30 min at room temperature. The excess
of diazomethane was destroyed by the addition of a small
amount of silica gel which was then removed by filtration.
Evaporation of the solvent left a residue which was purified by
column chromatography on silica gel (hexane:ethyl acetate
96:4) yielding the methyl ester (8.15 g, 90%); νmax(KBr)/cmϪ1
2913 (s), 2851 (s), 1732 (s), 1451 (m), 1339 (w), 1267 (m), 1200
(s), 1174 (s), 1097 (s), 1046 (m), 1010 (m); δH(500 MHz, CDCl3)
1.59–1.61 (2 H, complex), 1.71–1.76 (4 H, complex), 1.80–1.88
(6 H, complex), 2.31 (2 H, br s), 2.58 (1 H, br s), 3.67 (3 H, s);
Methyl
2-(N,N-dimethylaminomethyl)-2-propylpentanoate
hydrochloride (19).—After alkylation of the methyl ester 14 (4 g,
25.28 mmol) with Eschenmoser’s salt as described above for
compound 23 and isolation as the hydrochloride, the desired
product was obtained (3.65 g, 57%): νmax(KBr)/cmϪ1 3043 (s),
2965 (s), 2875 (m), 2360 (s), 1723 (s), 1474 (s), 1464 (s), 1386
(m), 1229 (s), 1159 (s); δH(500 MHz, CDCl3) 0.94 (6 H, t, J 7.2),
1.12–1.30 (4 H, m), 1.74 (4 H, m), 2.81 (6 H, d, J 3.9), 3.25 (2 H,
d, J 4.6), 3.75 (3 H, s); δC(50.3 MHz, CDCl3) 13.99, 16.67,
34.86, 45.77, 48.82, 52.51, 61.76, 77.14, 174.91.
m/z 193 (M ϩ Ϫ 1, 58%), 165 (8), 162 (18), 149 (16), 135 (50),
᝽
119 (20), 97 (24), 91 (42), 79 (50), 55 (72), 41 (100).
Methyl 2-(N,N-dimethylaminomethyl)adamantane-2-carbox-
ylate (23).—n-Butyllithium (14.17 ml of a 1.6  solution in
hexane, 22.66 mmol, 1.1 equiv.) was added to a solution of
diisopropylamine (2.97 ml, 22.66 mmol, 1.1 equiv.) in tetra-
hydrofuran (60 ml) at 0 ЊC. The reaction mixture was stirred for
30 min then cooled to Ϫ50 ЊC before a solution of methyl
adamantane-2-carboxylate (4 g, 20.6 mmol) in tetrahydrofuran
(10 ml) was added. After 30 min stirring, hexamethylphosphor-
amide (10 ml) was added and the mixture was cooled down to
Ϫ78 ЊC before N,N-dimethylmethyleneammonium iodide (6.86
g, 37 mmol) was added in one portion, then the reaction mix-
ture was stirred at Ϫ78 ЊC for 1 h and at room temperature for 4
h. After being poured into saturated aqueous sodium chloride,
the reaction mixture was extracted with pentane (3 × 80 ml).
The combined organic phase was washed with saturated aque-
ous sodium chloride then with water, dried over magnesium
sulfate, filtered, and evaporated under reduced pressure to give
a residue which was purified by column chromatography on
silica gel (hexane:ethyl acetate 90:10→70:30). The desired
product was obtained as a colourless oil (2.2 g, 43%);
νmax(KBr)/cmϪ1 2913 (s), 2872 (s), 2769 (s), 1736 (s), 1456 (m),
1246 (s), 1205 (s), 1097 (s), 1072 (s), 1041 (m); δH(500 MHz,
CDCl3) 1.61–1.68 (7 H, complex), 1.80–1.82 (3 H, complex),
1.86–1.89 (2 H, complex), 1.95–1.97 (2 H, complex), 2.22 (6 H,
s), 2.67 (2 H, s), 3.69 (3 H, s); m/z 151 (2), 135 (2), 114 (13), 91
(26), 77 (28), 67 (16), 58 (100).
N,N-Dimethyl-2-hydroxymethyl-2-propylpentylamine (3).—
Lithium aluminium hydride reduction of amino ester 19 (1.18
g, 4.7 mmol) in the usual manner followed by distillation (bp
82 ЊC, 1 mmHg) gave the desired amino alcohol 3 (1.82 g, 66%);
(Found: C, 70.60; H, 13.50; N, 7.51. Calc. for C11H25NO: C,
70.53; H, 13.45; N, 7.48%); νmax(KBr)/cmϪ1 3422 (m), 2956 (s),
2931 (s), 2870 (s), 2828 (s), 2778 (s), 1461 (s), 1376 (m), 1329
(m), 1254 (m), 1161 (m), 1098 (m), 1042 (s), 913 (m); δH(500
MHz, CDCl3) 0.89 (6 H, t, J 6.9), 1.13–1.32 (8 H, m), 2.30 (6 H,
s), 2.39 (2 H, s), 3.53 (2 H, s); δC(50.3 MHz, CDCl3) 14.71,
15.87, 35.08, 39.88, 48.27, 66.98, 71.07; m/z 187 (M ϩ, 3%), 166
᝽
(3), 124 (3), 121 (9), 91 (3), 73 (3), 58 (100), 41 (15).
1-(N,N-Dimethylaminomethyl)-1-(hydroxymethyl)cyclo-
butane (4). Methyl cyclobutanecarboxylate (15).—Treatment of
cyclobutanecarboxylic acid (2.9 g, 0.029 mmol) with diazo-
methane as described above, followed by distillation (bp 36 ЊC,
16 mmHg), yielded the methyl ester 15 (3.1 g, 94%): νmax(KBr)/
cmϪ1 2985 (s), 2954 (s), 2872 (w), 1733 (s), 1436 (s), 1359 (s),
1251 (s), 1169 (s), 1056 (m); δH(500 MHz, CDCl3) 1.79–1.87
(1 H, m), 1.89–1.96 (1 H, m), 2.10–2.16 (2 H, m), 2.19–2.27
(2 H, m), 3.08 (1 H, p, J 8.6), 3.61 (3 H, s); m/z 114 (M ϩ, 6%),
᝽
83 (20), 72 (10), 55 (100).
Methyl
1
(N,N-dimethylaminomethyl)cyclobutane-1-carb-
oxylate hydrochloride (20).—After alkylation of ester 15 (3.00
g, 26.3 mmol) with Eschenmoser’s salt as described above, the
product was isolated as the hydrochloride (2.18 g, 40%):
νmax(KBr)/cmϪ1 3415 (s), 2954 (s), 2667 (br, m), 2472 (m), 1731
(s), 1636 (w), 1467 (m), 1344 (w), 1287 (w), 1221 (s), 1159 (s),
1097 (m); δH(500 MHz, CDCl3) 2.07–2.12 (2 H, m), 2.33–2.39
(2 H, m), 2.53–2.59 (2 H, m), 2.71 (6 H, s), 3.51 (2 H, s), 3.83
(3 H, s); m/z 84 (3%), 58 (100).
2-(N,N-Dimethylaminomethyl)-2-hydroxymethyl)adamantane
(7).—A solution of methyl 2-(N,N-dimethylaminomethyl)-
adamantane-2-carboxylate (2.2 g, 8.76 mmol) in dry diethyl
ether (10 ml) was added to a suspension of lithium aluminium
hydride (832 mg, 21.9 mmol, 2.5 equiv.) in dry diethyl ether (30
ml) at 0 ЊC. After 30 min at 0 ЊC the reaction mixture was
stirred overnight at room temperature. The excess of lithium
aluminium hydride was destroyed by stirring with solid sodium
sulfate decahydrate until a white crystalline solid was obtained.
After removal of the solid by filtration and evaporation of the
solvent under reduced pressure, the residue was purified by col-
umn chromatography [isooctane:acetone–ammonia (98:2)
6:4], to yield the amino alcohol (1.7 g, 87%); (Found: C, 75.15;
H, 11.38; N, 6.16. Calc. for C14H25NO: C, 75.28; H, 11.28; N,
6.27%); νmax(KBr)/cmϪ1 3420 (br s), 2912 (s), 2865 (s), 2771 (s),
2668 (w), 1455 (s), 1248 (w), 1065 (m), 1032 (s); δH(500 MHz,
CDCl3) 1.49–1.55 (4 H, complex), 1.65 (2 H, app. br s), 1.73 (2
H, app. br s), 1.82 (1 H, m), 1.86 (1 H, m), 1.99 (2 H, complex),
2.06 (2 H, complex), 2.29 (6 H, s), 2.70 (2 H, s), 3.83 (2 H, s);
δC(50.3 MHz, CDCl3) 27.72, 28.44, 31.17, 32.57, 32.81, 39.42,
1-(N,N-Dimethylaminomethyl)-1-(hydroxymethyl)cyclo-
butane (4).— Lithium aluminium hydride reduction of amino
ester 20 (1.4 g, 6.7 mmol) in the usual manner followed by
recrystallization gave the desired amino alcohol 4 (1.82 g, 66%,
mp 25–27 ЊC); νmax(KBr)/cmϪ1 3323 (br s), 3046 (m), 2944 (s),
2831 (s), 1598 (m), 1456 (m), 1262 (s), 1164 (m), 1031 (s), 733 (s);
δH(500 MHz, CDCl3) 1.76–1.86 (5 H, m), 1.90–2.01 (1 H, m),
2.22 (6 H, s), 2.47 (2 H, s), 3.38 (2 H, s), 5.96 (1 H, br s); m/z 142
(M ϩ Ϫ 1, 1%), 128 (M ϩ Ϫ CH3, 2), 84 (3), 58 (100).
᝽
᝽
1-(N,N-Dimethylaminomethyl)-1-(hydroxymethyl)cyclo-
pentane (5). Methyl cyclopentanecarboxylate (16).—Treatment
of cyclopentanecarboxylic acid (10 g, 87 mmol) with diazo-
methane as described above, followed by distillation (bp 49 ЊC,
14 mmHg) gave the methyl ester 16 (10.6 g, 95%): νmax(KBr)/
cmϪ1 2955 (s), 2872 (s), 1737 (s), 1431 (m), 1361 (m), 1196 (s),
1002 (w); δH(500 MHz, CDCl3) 1.50–1.59 (2 H, m), 1.63–1.72 (2
H, m), 1.73–1.80 (2 H, m), 1.83–1.89 (2 H, m), 2.70 (1 H, p, J
48.38, 68.18, 69.86; m/z 223 (M ϩ, 3%), 105 (7), 91 (31), 79 (35),
᝽
67 (18), 58 (100).
N,N-Dimethyl-2-hydroxymethyl-2-propylpentylamine
(3).
Methyl 2-propylpentanoate (14).—2-Propylpentanoic acid (10.0
g, 69.3 mmol) was converted into its methyl ester using the
procedure described above for 18. The ester (10.2 g, 93%) was
8.0), 3.64 (3 H, s); m/z 128 (M ϩ, 6%), 100 (16), 97 (17), 87
᝽
(100), 69 (54), 67 (16), 55 (22), 41 (45).
Methyl 1-(N,N-dimethylaminomethyl)cyclopentane-1-carb-
2792
J. Chem. Soc., Perkin Trans. 2, 1997

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oxylate hydrochloride (21).— Alkylation of the methyl ester 16
(4.0 g, 13 mmol) with Eschenmoser’s salt as described above
followed by purification on silica (1:1 hexane–ethyl acetate) and
isolation as the hydrochloride gave compound 21 (2.0 g, 35%):
νmax(KBr)/cmϪ1 3413(brs),3025(w),2955(s),2872(w),2649(m),
1725 (s), 1633 (w), 1455 (m), 1267 (m), 1173 (s), 726 (s); δH(500
MHz, CDCl3) 1.51 (1 H, m), 1.75–1.85 (4 H, m), 1.88–1.93 (2 H,
m),2.16–2.22(2H,m),2.78(6H,d,J4.9),3.36(2H,d,J5.8),3.78
References
1 I. Steels, P. J. De Clercq and H. Maskill, J. Chem. Soc., Chem.
Commun., 1993, 294.
2 (a) D. G. Oakenfull and W. P. Jencks, J. Am. Chem. Soc., 1971, 93,
178; (b) D. G. Oakenfull, K. Salvesen and W. P. Jencks, J. Am. Chem.
Soc., 1971, 93, 188; (c) T. H. Fife, Acc. Chem. Res., 1993, 26, 325;
For examples of esterification of amino alcohols with Aclm, see:
(d) L. Anoardi and U. Tonellato, J. Chem. Soc., Chem. Commun.,
1977, 401; (e) M. I. Page and W. P. Jencks, J. Am. Chem. Soc., 1972,
94, 8818.
3 (a) A. J. Kirby, Adv. Phys. Org. Chem., 1980, 17, 183; (b)
L. Mandolini, Adv. Phys. Org. Chem., 1986, 22, 1; (c) P. G. Sammes
and D. J. Weller, Synthesis, 1995, 1205.
(3 H, s); m/z 186 (M ϩ Ϫ Cl, 2%), 171 (2), 81 (3), 58 (100).
᝽
1-(N,N-Dimethylaminomethyl)-1-(hydroxymethyl)cyclopen-
tane (5).—Lithium aluminium hydride reduction of the
amino ester 21 (2.00 g, 10.8 mmol) in the usual way followed by
distillation (bp 105 ЊC, 0.05 mmHg) gave amino alcohol 5 (1.18
g, 70%); (Found: C, 67.88; H, 12.13; N, 9.08. Calc. for
C9H19NO: C, 68.74; H, 12.18; N, 8.91%); νmax(KBr)/cmϪ1 3413
(s), 2943 (s), 2861 (s), 2825 (s), 2778 (s), 1461 (s), 1255 (m), 1155
(m), 1038 (s); δH(500 MHz, CDCl3) 1.20–1.26 (2 H, m), 1.56–
1.61 (4 H, m), 1.62–1.68 (2 H, m), 2.27 (6 H, s), 2.48 (2 H, s),
4 D. Farcasiu, Synthesis, 1972, 615.
5 S. J. Danishefsky, T. Kitahara, R. McKee and P. F. Schuda, J. Am.
Chem. Soc., 1976, 98, 6715.
6 The third-order reactions (investigated under pseudo-first-order
conditions) between propan-1-ol and hexane-1,6-diol with
acetylimidazole in acetonitrile catalysed by triethylamine are rather
slow and were investigated by the initial rates method.17 The ratios
of the second-order rate constant for 1a to the third-order rate
constants for these models are 13 and 14 mol dmϪ3, respectively, at
25 ЊC. These are within the normal range for catalysis by
intramolecular proton transfer reported by A. J. Kirby, Adv. Phys.
Org. Chem., 17, 1980, 183.
7 (a) A. J. Kirby and G. J. Lloyd, J. Chem. Soc., Perkin Trans. 2, 1976,
1753; (b) see ref. 3a; (c) A. J. Kirby and N. H. Williams, J. Chem.
Soc., Chem. Commun., 1991, 1643.
8 D. D. Sternbach, D. M. Rossana and K. D. Onan, Tetrahedron Lett.,
1985, 26, 591.
3.49 (2 H, s), 6.31 (1 H, br s); m/z 157 (M ϩ; 2%), 126 (1), 58
᝽
(100).
1-(N,N-Dimethylaminomethyl)-1-(hydroxymethyl)cyclo-
hexane (6). Methyl cyclohexanecarboxylate (17).—Treatment of
cyclohexanecarboxylic acid (10 g, 78 mmol) with diazomethane
as described above followed by distillation (bp 68 ЊC, 15
mmHg) gave the methyl ester (10.6 g, 96%): νmax(KBr)/cmϪ1
2933 (s), 2851 (s), 1737 (s), 1451 (m), 1246 (s), 1169 (s), 1041
(m); δH(500 MHz, CDCl3) 1.16–1.30 (3 H, m), 1.34–1.46 (2 H,
m), 1.60–1.64 (1 H, m), 1.72–1.76 (2 H, m), 1.86–1.90 (2 H, m),
9 (a) R. M. Beesley, C. K. Ingold and J. F. Thorpe, J. Chem.
Soc., 1915, 107, 1080; (b) C. K. Ingold, J. Chem. Soc., 1921, 305;
(c) C. K. Ingold, E. W. Lanfear and J. F. Thorpe, ibid., 1923, 123,
3140.
2.28 (1 H, tt, J 11.1 and 3.64), 3.64 (3 H, s); m/z 142 (M ϩ, 20%),
᝽
127 (M ϩ Ϫ CH3, 8), 110 (M ϩ Ϫ MeOH, 18), 87 (66), 74 (32),
55 (100).
᝽
᝽
10 (a) P. v. R. Schleyer, J. Am. Chem. Soc., 1961, 83, 1368; (b) see ref.
7a.
Methyl
1-(N,N-dimethylaminomethyl)cyclohexane-1-carb-
11 (a) J. Jager, T. Graafland, H. Schenk, A. J. Kirby and J. Engberts,
J. Am. Chem. Soc., 1984, 106, 139; (b) M. E. Jung and J. Gervay,
J. Am. Chem. Soc., 1991, 113, 224.
12 W. Linert, Chem. Soc. Rev., 1989, 18, 477.
13 W. Linert, Chem. Soc. Rev., 1994, 23, 429.
14 (a) Calculations were carried out using MacroModel V3.0: W. C.
Still, F. Mohamadi, N. G. J. Richards, W. C. Guida, M. Lipton,
R. Liskamp, G. Chang, T. Hendrickson, F. DeGunst and W. Hasel,
Department of Chemistry, Columbia University, New York, USA;
(b) B. Pullman and A. Pullman, Quantum Biochemistry, Wiley
Interscience, New York, 1963, p. 381.
oxylate hydrochloride (22).—Alkylation of the methyl ester 17
(2.0 g, 10 mmol) with Eschenmoser’s salt as described above
was followed by isolation as the hydrochloride. After recrystal-
lization from ethyl acetate, the amino ester hydrochloride (1.32
g, 40%) was obtained: νmax(KBr)/cmϪ1 3413 (br s), 2943 (s),
2849 (w), 1725 (s), 1455 (m), 1261 (m), 1161 (m), 738 (s); δH(500
MHz, CDCl3) 1.39–1.41 (1 H, m), 1.50–1.64 (7 H, m), 2.10–2.13
(2 H, m), 2.78 (6 H, br s), 3.27 (2 H, br s), 3.79 (3 H, s); m/z 199
(M ϩ, HCl, 2%), 81 (4), 58 (100).
᝽
15 The intramolecular GAC pathway from the zwitterionic tetrahedral
intermediate formed from acetylimidazole (which was ruled out by
the calculation of strain involved in the proton transfer to N-3 of the
imidazole residue) should be much easier for the zwitterionic
tetrahedral intermediate formed from acetylpyrazole as this involves
intramolecular proton transfer to the more accessible N-2 of the
pyrazole residue via a less strained transition structure. Further-
more, since pyrazole is a much weaker base than imidazole, it should
be a better nucleofuge, so acetylpyrazole will be more reactive in
these reactions if the second step is rate limiting. We have shown,
however, that acetylpyrazole is actually less reactive than
acetylimidazole with various amino alcohols. We take this as further
evidence that the initial intramolecular GBC nucleophilic attack of
the amino alcohol is rate limiting.
1-(N,N-Dimethylaminomethyl)-1-(hydroxymethyl)cyclo-
hexane (6).—Lithium aluminium hydride reduction of the
amino ester 22 (1.15 g, 4.9 mmol) in the normal manner fol-
lowed by distillation (bp 180 ЊC, 0.05 mm Hg) yielded the
amino alcohol 6 (0.62 g, 75%); (Found: C, 69.99; H, 12.53; N,
8.21. Calc. for C10H21NO: C, 70.12; H, 12.36; N, 8.18%);
νmax(KBr)/cmϪ1 3417 (br s), 2925 (s), 2853 (s), 2781 (s), 1457 (s),
1252 (m), 1150 (m), 1042 (s), 1006 (m); δH(500 MHz, CDCl3)
1.20–1.24 (2 H, m), 1.30–1.35 (1 H, m), 1.40–1.50 (7 H, m), 2.30
(6 H, s), 2.38 (2 H, s), 3.60 (2 H, s); m/z 126 (2), 96 (3), 81 (5), 67
(10), 58 (100), 42 (8).
16 L. M. Schwartz and R. I. Gelb, Anal. Chem., 1978, 50, 1592.
17 A. Madder, unpublished results.
Acknowledgements
A. M. thanks the National Fund for Scientific Research
(NFSR) for a position as research assistant. The NFSR is
thanked for a research grant (Krediet aan Navorsers 1993–
1994). We thank Professor R. Hoffmann (University of
Marburg) for suggesting the use of the adamantyl group and
Professor W. Linert for his help on the statistical IKR analysis.
Paper 6/08488E
Received 18th December 1996
Accepted 29th August 1997
J. Chem. Soc., Perkin Trans. 2, 1997
2793