A Synthesis of acetamidines

Article abstract of DOI:10.1021/jo102358d

The condensation of primary amine with N,N-dimethylacetamide dimethyl acetal yields amixture of acetamidine and imidate ester. The product distribution in this reaction depends on the temperature, solvent, and structure of the primary amine. It is possible to suppress the formation of imidate ester by performing the reaction in the presence of excess dimethyl amine, yielding acetamidine as the exclusive product. For acetamidines that cannot be purified either by crystallization or distillation, this new method is necessary for the generation of pure acetamidines in good yields.

Full text of DOI:10.1021/jo102358d

ARTICLE
pubs.acs.org/joc
A Synthesis of Acetamidines
Jitendra R. Harjani, Chen Liang, and Philip G. Jessop*
Department of Chemistry, Queen’s University, Kingston, Ontario K7L 3N6, Canada
S Supporting Information
b
ABSTRACT: The condensation of primary amine with N,N-dim-
ethylacetamide dimethyl acetal yields a mixture of acetamidine and
imidate ester. The product distribution in this reaction depends on
the temperature, solvent, and structure of the primary amine. It is
possible to suppress the formation of imidate ester by performing
the reaction in the presence of excess dimethyl amine, yielding
acetamidine as the exclusive product. For acetamidines that cannot
be purified either by crystallization or distillation, this new method
is necessary for the generation of pure acetamidines in good yields.
Amidines have applications in diverse areas such as catalyst
design,1 material science,2 medicinal chemistry,3 and superbase4
promoted reactions. Our interest in this functional group stems
from its application in materials that can change their properties
depending on the concentration of carbon dioxide. Amidines readily
form ionic amidinium bicarbonate salts in the presence of carbon
dioxide and water. We have used amidines as switchable solvents,5
switchable surfactants,6a,b and solutes.6c Other research groups are
now using amidine switchable materials for a variety of applications.7
A review of synthetic methods indicates that nitriles and
(thio)amides are the two most common building blocks for
amidines.8 The activation of the cyano group, by making it
electron-deficient, with either protic acid, Lewis acid, or as
nitrilium salts is warranted when nitriles are used for the synthesis
of amidines (Scheme 1a).8 (Thio)amides can be used for the
synthesis of amidines (Scheme 1b), but like nitriles, they also
require either Brønsted or Lewis acid to become sufficiently
electrophilic. Alternatively, (thio)amides can be converted into
(thio)imidate esters or imidoyl chlorides that offer good reactivity
toward the nitrogen nucleophiles. Carboxylic acids can be used for
the synthesis of amidines but often require harsher conditions than
esters or ortho esters.8 The activation of an amine as opposed to an
amide isless frequentlyused. For the synthesis of acetamidines, the
method developed by Raczyꢀnska et al. (Scheme 1c) is particularly
attractive because it appears to be a general method for the
synthesis of both aryl and alkyl acetamidines in high yields. The
method reacts the primary amine with modified ortho ester, N,N-
dimethylacetamide dimethyl acetal.9
The commercial availability of the PEG-based alcohols with
assorted alkyl chain lengths and oxygen contents makes them
good synthons for amidine syntheses. The proposed methodol-
ogy depends on the conversion of the alcohol to a tosylate
followed by substitution of the tosylate with the phthaloyl group
from potassium phthalimide. Gabriel’s dephthaloylation then
would yield the primary amine,11 which can be easily converted
to amidine in one step, by N,N-dimethylacetamide dimethyl
acetal using the method developed earlier by Raczyꢀnska et al.9 In
addition to the desired amidine, unfortunately, the condensation
of primary amines with N,N-dimethylacetamide dimethyl acetal
yields an unwanted byproduct. While post-reaction purifica-
tion is not difficult for very simple acetamidines, it is difficult
for nonvolatile acetamidines, especially those that exhibit some
surfactancy. The purification method some of us described
some time ago for long-chain acetamidines6b (purification by
precipitation of the bicarbonate salt) is, regrettably, not general.
Therefore, it was necessary to identify a method that yields
acetamidines with much greater selectivity. This article presents a
study aimed at the characterization of the impurity and the
development of a new method to improve the product selectivity
of this reaction, evading the purification step. Some studies were
carried out to uncover the factors that influence the extent of
formation of the impurity.
’ RESULTS AND DISCUSSION
Amines from Poly(ethylene glycol)s. Each of a series of
alcohols containing one or more ethylene glycol segments
(compounds 1 in Scheme 2) was converted into the correspond-
ing tosylate ester using a slight excess of the alcohol. The reaction
was catalyzed by triethylamine and 4-(N,N-dimethylamino)-
pyridine and was completed in 3 h, as indicated by the con-
sumption of tosyl chloride by TLC and 1H NMR spectroscopy.
During our studies of long chain acetamidines as surfactants,
we realized a need to create long-chain acetamidines with greater
water solubility. Our original acetamidines had dodecyl or
hexadecyl chains, which gave them very little water solubility.
Poly(ethylene glycol) (PEG) is known to have good solubility in
hexanes, ethers, and even water.10 We envisioned that integrating
a short PEG segment between the alkyl chain and the acetami-
dine headgroup might generate long-chain acetamidines with
greater solubility in water.
Received: November 27, 2010
Published: February 11, 2011
r
2011 American Chemical Society
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Scheme 1. General Methods for the Synthesis of Amidines
Scheme 3. Syntheses of Acetamidines by Condensation of
Primary Amines with 5
precipitation, extraction, and/or evaporation under reduced
pressure.
The synthesis of amine from the N-alkylphthalimide was
accomplished by Gabriel’s amine synthesis.11 The amine was
isolated in good yield from the reaction mixture by ensuring the
complete removal of ethanol, followed by the separation of the
amine from the phthalhydrazide using cold diethyl ether.
We made an attempt to bypass column chromatography of the
phthalimide and postpone the purification to the workup after
the amine synthesis, assuming that the distillation of the amine
might be a good way to purify it. Thus for series f, a continuous
tosylation, phthaloylation, and hydrazinolysis was attempted to
yield a crude amine that was subjected to vacuum distillation.
Scheme 2. Synthesis of Acetamidines with a Poly(ethylene
glycol) Chaina
1
From the H NMR analysis of the crude product at different
steps, it appears that significant detosylation occurs during
phthaloylation that results in the formation of alcohol, which
was distilled with the amine. Although a careful fractional
distillation might be possible in some cases, we preferred to
purify the phthalimide instead.
Condensation of Poly(ethylene glycol) Based Amines
with N,N-Dimethylacetamide Dimethyl Acetal. The synth-
esis of amidines from primary amines and 5 (last step of
Scheme 2, method 1 in Scheme 3) has only moderate selectivity
for the amidine. For example, NMR spectroscopy showed that
the product of condensation of 3g with 5 at 60 °C and 2 h
reaction time also contained a significant impurity. Similar
impurities were observed in other acetamidines prepared by this
method. An NMR study including 1H, 13C{1H}, DEPT-135, and
HSQC NMR spectroscopy showed that the impurity contains
two new methyl groups at δC 14.50/δH 1.58 and δC 52.06/δH
3.55, a new CH2 group at δC 49.69/δH 3.28 and at least three
CH2 peaks at 70.05, 70.96, and 72.41 that are visible beside the
peaks of 4g in the 13C NMR spectrum.12 All of those CH2 peaks
of the impurity are very closely matched to the CH2 peaks for 4g,
suggesting that the impurity had the same tail group as the
desired amidine 4g but a different headgroup. On the basis of the
NMR evidence, the most probable structure for the impurity
seems to be the imidate ester 6a. However, the ESI mass
spectrum of the reaction mixture indicated the presence of
amidine 7a.
a Reagents and conditions: (i) TsCl, Et3N, cat. DMAP, CH2Cl2, rt, 3 h;
then potassium phthalimide, DMF, 80 °C, 18 h; (ii) N2H4.H2O, EtOH,
76 °C, 3 h; (iii) N,N-dimethylacetamide dimethyl acetal 5, Me2NH,
rt, 18 h.
The conversion of the alcohol into the tosylate was quantitative
or near quantitative. In certain cases, some alcohol remained
unreacted with the tosylate ester after the aqueous workup;
fortunately, the unreacted alcohol does not interfere with the
subsequent phthaloylation and was easily removed after that
step.
To convert the tosylate into alkyl phthalimide, the tosylate was
allowed to react with a slight excess of potassium phthalimide in
DMF at 80 °C. The reaction was allowed to run for 18 h at 80 °C.
From the 1H NMR spectra, it was apparent that approximately
10% detosylation to the alcohol occurred as a side reaction during
the phthaloylation reaction of the tosylate obtained from 1e. The
isolation of phthalimide was modified to maximize its recovery,
and column chromatography (ethyl acetate in hexanes) was used
to obtain the final product in high purity. The purification step
was crucial to get rid of phthalimide, DMF, and any of the original
alcohol (either remaining from the tosylation or produced by
detosylation during the phthaloylation step). This is the only step
of the synthesis where column chromatography is required.
Isolation of the pure product in the subsequent steps of the
syntheses was easily accomplished by simple procedures such as
To resolve this apparent disagreement between the NMR and
MS evidence, a pure sample of an imidate ester was prepared by a
literature method. Because the purification of imidate ester 6b is
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Scheme 4. Synthesis of Amidines with Terminal Di(ethylene glycol) Chaina
a Reagents and conditions: (i) 120 °C, 3 h; TsCl, Et3N, cat. DMAP, CH2Cl2, rt, 18 h; (ii) C6H5-CH2-O-(CH2)2-O-(CH2)2-OH, NaH, THF, 65 °C, 18 h;
(iii) Pd-C (10%), EtOH, rt, 6 h; (iv) N2H4 H2O, EtOH, 76 °C, 3 h; then HCl, 76 °C, 3 h; (v) N,N-dimethylacetamide dimethyl acetal 5, Me2NH,
3
rt, 18 h.
easier than 6a, 6b was derived from N-acetyl octylamine by the
procedure reported earlier by Pilotti et al.,13 replacing distillation
by column chromatography (50% ethyl acetate, 1% triethylamine
in hexanes) for the final purification. By 1H and 13C{1H} NMR, it
is clear that 6b was pure; no additional peaks were detected and
the integration of the methyl groups relative to the octyl chain
was correct for structure 6b and not for 7b. Nevertheless, the
ESI-MS of the imidate ester 6b showed equally prominent peaks
at m/z 186.16 and 283.34 amu corresponding to imidate 6b
[M þ H]þ and amidine 7b [M þ H]þ, respectively. Amidine 7
appears to be formed in the mass spectrometer. Similarly,
ESI-MS of imidate ester 6a present in the product obtained
from the reaction of 3g with 5 using method 1 includes a
peak at m/z 415.25, corresponding to 7a [M þ H]þ. The 1H
and 13C{1H} NMR spectra of 6b prepared by the litera-
ture method match those of the impurity obtained from the
reaction of 3g with 5.
The PEG chain in the targeted amidines imparts desirable
properties (liquids at room temperature, optimal viscosity, low
mp, good hydrophilicity) but results in an increase in their
boiling points (when compared to the corresponding nono-
xygenated counterparts). This can become disadvantageous
because a liquid with a very high boiling point cannot be separated
by common distillation procedures. The higher oxygen content
and the presence of a basic amidine headgroup increases the
polarity of the PEG-based amidines, making the purification by
column chromatography quite tedious. Therefore, a method
that generates these amidines in a pure form was desirable, so
that post-reaction purification would be unnecessary.
dimethylamine, Me2NH (2 M) in THF (method 3 in Scheme 3).
These reaction conditions indeed favored the formation of
the desired amidine over the imidate ester. For example,
the amount of imidate ester (calculated from the relative
integration of the triplet at 3.28 δH with respect to the triplet
at 3.73 δH) decreased only from 14% to 11% when the reaction
was attempted at room temperature; the imidate ester was
1
practically undetectable by H NMR spectroscopy when the
reaction was attempted in the presence of 2 equiv of Me2NH.
The protocol thus seems to have eliminated the need for a
purification step.
Synthesis of Amidines Starting with Protected Di(ethylene
glycol) Chain. An alternative design of a PEG-containing acet-
amidine would be 12 (Scheme 4), where the amidine and ethylene
glycol units are separated by long alkyl chain. The synthesis of
12 involved connecting monoprotected di(ethylene glycol) with
N-protected 6-amino-1-hexanol via a Williamson’s ether synthesis.
This was followed by Pd/C catalyzed hydrogenolysis to deprotect
the blocked -OH and hydrazinolysis to release the -NH2 group.
Unlike 2(a-h), generation of the amine from phthalimide 10
involved its reaction with hydrazine hydrate followed by acid-
catalyzed hydrolysis to yield the amino alcohol 11. We observed
a remarkable regioselectivity of 5 toward the amino group in the
presence of the alcoholic -OH group. This may be a cumulative
effect of the higher nucleophilicity of the -NH2 group and favorable
formation of the nitrogen-carbon double bond. The condensa-
tion of amine 11 with 5 was carried out in the presence of 2 equiv of
Me2NH to avoid the possibility of the formation of any imidate
ester during the reaction.
Variations on the method were compared. Imidate ester is
also formed when a PEG-amine and 5 are heated for only a short
time (20 min at 60 °C). For example, 12% of the imidate ester
Improved Preparation of a Range of Acetamidines. The
three methods for the preparation of acetamidines (Scheme 3)
were compared for a series of amines (Table 1). For the solid
amines, THF was used as a solvent. Generally, the recovery of the
product from the reactions was very good in all cases.
For the conversion of short-chain amines and benzyl amines
to acetamidines, there is no benefit to the addition of Me2NH.
Butyl amine produced the desired product with good purity
by methods 1, 2, and 3. Benzyl amines seem to produce only
1
was detected by H NMR spectroscopy after the reaction of 5
with 3f. Performing the reaction of 3g with 5 at room tempera-
ture instead of 60 °C (method 2 in Scheme 3) did not greatly
increase the purity of the product. Because imidate ester forma-
tion was a result of loss of dimethylamine from the reaction
mixture, the reaction was attempted in the presence of 2 equiv of
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Table 1. Synthesis of Acetamidines from Primary Amines
a The yield from the amine. Values shown in parentheses are the overall yields from the original alcohol.
negligible quantities of imidate ester when reacted with 5 at
room temperature in the absence of Me2NH, although another
unidentified impurity was apparent; distillation might prove
useful for improving the purity and appearance of the product
particularly in entries 9 and 11.
Table 2. Imidate Ester Formation As a Function of Alkyl
Chain Length for the Syntheses Carried out by Method 1
entry
primary amine
yield (%)a
imidate ester (%)
Longer-chain acetamidines, in contrast, must be prepared by
method 3. Some imidate ester was detected by NMR spectros-
copy in the product obtained from the reaction of hexyl or
octylamine with 5 by method 1 (Table 1). When method 1 was
used for the synthesis of amidines, the extent of the formation of
the imidate ester was higher for amines with longer alkyl chains
(Table 2). For example, 18% of the imidate ester was detected in
the product from hexadecyl amine using method 1. Method 3
offers product of good purity without need for post-reaction
purification. Although the separation/purification of this parti-
cular amidine is fairly easy,6b increased formation of the imidate
ester means a reduction in the yield of the desired amidine. The
1
2
3
4
5
6
7
C4H9NH2
92
91
0
4
C6H13NH2
C8H17NH2
C10H21NH2
C12H25NH2
C14H29NH2
C16H33NH2
98
4
quantitative
98
9
9
quantitative
quantitative
13
18
a Yield of impure amidine.
imidate ester from the amine with the PEG chain because of the
ethereal O-atom on the β-carbon atom.
1
δ values of the signals in H and 13C NMR spectra of methyl
An increase in the percentage of the imidate ester with an
increase in the alkyl chain length may also be a result of a solvent
effect caused by THF, because higher amines are solids and were
dissolved in THF to achieve the synthesis. When tetradecyl- and
hexadecylamine were heated with 5 at 60 °C for 2 h in the absence
of any solvent, the products contained 6% and 7% of imidate ester,
respectively. However, the use of THF as a solvent had no effect on
N-octylacetimidate 6b perfectly matched the new signals of the
impurity in the sample obtained from the reaction of higher
amines such as tetradecyl and hexadecyl amine by method 1. The
chemical shifts of the R -CH2- of the imidate ester derived from
the simple aliphatic amines (Table 2, entries 1-7) are downfield
(by approximately 0.2 δ) compared to the peaks obtained for the
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the formation of imidate ester during the similar conversion of
octylamine (4% imidate ester with and without THF).
condenser was removed from the mouth of the round-bottom flask
and replaced by a stopper. The reaction mixture was stirred for 2 h, after
which it was treated with 1 M hydrochloric acid solution (200 mL). The
dichloromethane layer was separated from the aqueous layer, washed
with water (200 mL), dried over anhydrous magnesium sulfate, and
evaporated under reduced pressure to yield the tosylate ester in near-
quantitative yields. This product was carried through to the phthaloyla-
tion step without purification except for 1h, which was crystallized using
dichloromethane (50 mL) and hexanes (400 mL).
Synthesis of 2. A mixture of tosylate ester from 1f (12.0 g, 34.8
mmol), finely powdered potassium phthalimide (7.73 g, 41.8 mmol),
and N,N-dimethylformamide (30 mL) were combined in a round-
bottom flask. The reaction mixture was stirred at 80 °C under an air
condenser for 18 h. Diethyl ether (250 mL) was added to the reaction
mixture, which was then filtered to remove precipitated potassium
tosylate. The salt was washed with diethyl ether and the washings were
combined with the filtrate. To remove the solvents, diethyl ether was
first evaporated under reduced pressure on a rotary evaporator. This was
followed by vacuum distillation of N,N-dimethylformamide until ap-
proximately 25-27 mL was collected in the receiving flask. The residue
was purified by column chromatography using 15-40% ethyl acetate in
hexanes. The optimal polarity of the solvent system used for the
separation of the phthalimide depends on its polarity. The only
exception was 2h, where the ether washing was not attempted. Instead,
N,N-dimethylformamide was first removed at reduced pressure and then
the product was purified by crystallization using dichloromethane (100
mL) and hexanes (400 mL).
2-(2-(2-Methoxyethoxy)ethyl)isoindoline-1,3-dione (2a).
Yield: 76%. Eluent: 40% EtOAc in hexanes. 1H NMR (400 MHz,
CDCl3): 3.26 (s, 3H), 3.43-3.46 (t, J = 4.6 Hz, 2H), 3.59-3.61 (t, J =
4.6 Hz, 2H), 3.69-3.72 (t, J = 6.0 Hz, 2H), 3.84-3.87 (t, J = 6.0 Hz,
2H), 7.65-7.67 (m, 2H), 7.76-7.79 (m, 2H). 13C NMR (100 MHz,
CDCl3): 37.21, 59.03, 67.98, 69.95, 71.94, 123.25, 132.20, 133.96,
168.28.
2-(2-(2-(2-Ethoxyethoxy)ethoxy)ethyl)isoindoline-1,3-dione
(2b). Yield: 83%. Eluent: 40% EtOAc in hexanes. 1H NMR (400 MHz,
CDCl3): 1.08-1.11 (t, J = 7.0 Hz, 3H), 3.38-3.45 (m, 4H,), 3.49-3.59
(m, 6H), 3.65-3.68 (t, 2H, J = 5.8 Hz), 3.80-3.83 (t, 2H, J = 6.0 Hz),
7.63-7.66 (m, 2H), 7.73-7.77 (m, 2H). 13C NMR (100 MHz, CDCl3):
15.13, 37.24, 66.52, 67.85, 69.75, 70.10, 70.53, 70.65, 123.15, 132.11,
133.89, 168.15.
Reacting a mixture of acetamidine and imidate ester
with Me2NH does not convert the imidate ester into an amidine.
Thus the product obtained from the reaction of hexadecyl amine
(Table 2, entry 7) with 5, containing 18% of the imidate ester,
when stirred with a solution of Me2NH in THF for 18 h, did not
show any reduction in the percentage of the imidate ester.
Considering this reaction might require higher temperatures,
we diverted our attention to the reaction of imidate ester with a
secondary amine such as Pr2NH, having a boiling point much
higher than Me2NH. When the same hexadecyl acetamidine
(contaminated with 18% imidate ester) was reacted with Pr2NH
at 60 °C for 2 h, 12% imidate ester was detected in the product by
1H NMR analysis. Therefore, high temperatures might favor the
formation of amidines from the imidate esters.
’ CONCLUSION
In our quest to achieve the synthesis of a range of long-chain
acetamidines, we have found that the post-synthesis purification
of certain acetamidines is difficult or impossible. The last step of
the synthesis, a condensation reaction of primary amines with N,
N-dimethylacetamide dimethyl acetal 5, was modified to increase
the selectivity for acetamidine so that a subsequent purification
would be unnecessary. Imidate ester is the primary byproduct
formed in these condensations. The identity of the imidate ester
byproduct has been established by 1H, 13C, 13C DEPT-135, and
HSQC NMR spectroscopy. Pure acetamidine, without imidate
ester, can be generated by performing the condensation reaction
in the presence of Me2NH. The method is compatible with the
presence of ether and alcohol functional groups in the amine.
’ EXPERIMENTAL SECTION
The signal frequency of the 1H NMR experiment was 400 MHz, and
for 13C NMR experiments was 100 MHz. Unless stated otherwise, NMR
samples of phthalimides and amines were prepared in CDCl3 (δH 7.26
(s) and δC 77.23 (t)), and those of amidines were prepared in C6D6 (δH
7.15 (s) and δC 128.00 (t)). Commercial CDCl3 contains too much acid
to be used as an inert solvent for NMR spectroscopy of amidines. SiliaFlash
F60 (40-63 μm) obtained from SiliCycle was used for flash column
chromatography. The yields of phthalimides are based on alcohols.
Alcohols (compounds 1a-h) and the amines required to make entries
1-13 in Table 1 were all purchased and used as received. N,N-
Dimethylacetamide dimethyl acetal (stabilized with 5-10% methanol)
was used as received from TCI America.
The synthesis of tosylate was performed starting with 20.0 g of
alcohol. In all of the syntheses of phthalimide derivatives, 12.0 g of
tosylate was used. For the synthesis of amine, 2.00 g of phthalimide was
deprotected by hydrazinolysis to yield the corresponding amine. A
typical procedure for each synthetic transformation for series f has been
outlined below.
Synthesis of Tosylate Esters from 1. In a typical synthesis,
alcohol 1f, (20.0 g, 105 mmol) was mixed with dichloromethane (250
mL) in a round-bottom flask, and p-toluenesulfonyl chloride (19.7 g, 103
mmol) and 4-(N,N dimethylamino)pyridine (100 mg) were added to
this solution. A reflux condenser was attached to the round-bottom flask,
and the mixture was stirred for 10 min. Triethylamine (11.7 g, 116
mmol) was added to the reaction mixture dropwise over 15 min, and as
the stirring was continued, a white solid (triethylammonium chloride)
precipitated out of the reaction mixture. This was accompanied by the
liberation of heat that caused visible evaporation and condensation of
dichloromethane from the reaction mixture. After 1 h, the reflux
2-(2-(2-Butoxyethoxy)ethyl)isoindoline-1,3-dione (2c). Yield:
1
78%. Eluent: 20% EtOAc in hexanes. H NMR (400 MHz, CDCl3):
0.84-0.88 (t, 3H, J = 7.2 Hz), 1.24-1.33 (m, 2H), 1.44-1.51 (m, 2H),
3.36-3.40 (t, J = 6.6 Hz, 2H), 3.51-3.53 (t, J = 4.4 Hz, 2H), 3.61-3.64
(t, J = 4.6 Hz, 2H), 3.72-3.75 (t, J = 5.8 Hz, 2H), 3.88-3.91 (t, J = 5.8
Hz, 2H), 7.69-7.71 (m, 2H), 7.82-7.84 (m, 2H). 13C NMR (100
MHz, CDCl3): 14.06, 19.38, 31.84, 37.40, 68.04, 70.20, 70.26, 71.36,
123.37, 132.33, 134.04, 168.41.
2-(2-(2-(2-Butoxyethoxy)ethoxy)ethyl)isoindoline-1,3-di-
one (2d). Yield: 83%. Eluent: 25% EtOAc in hexanes. 1H NMR (400
MHz, CDCl3): 0.88-0.92 (t, J = 7.4 Hz, 3H), 1.31-1.37 (m, 2H),
1.51-1.56 (m, 2H), 3.41-3.44 (t, J = 6.6 Hz, 2H), 3.50-3.52 (m, 2H),
3.57-3.67 (m, 6H), 3.73-3.76 (t, J = 5.8 Hz, 2H), 3.89-3.92 (t, J = 5.8
Hz, 2H), 7.71-7.73 (m, 2H), 7.84-7.86 (m, 2H). 13C NMR (100
MHz, CDCl3): 13.98, 19.30, 31.72, 37.31, 67.94, 70.06, 70.17, 70.60,
70.68, 71.19, 123.25, 132.18, 133.97, 168.27.
2-(2-(Hexyloxy)ethyl)isoindoline-1,3-dione (2e). Yield: 83%.
Eluent: 15% EtOAc in hexanes. 1H NMR (400 MHz, CDCl3): 0.81-0.84
(t, J = 6.8 Hz, 3H), 1.22-1.29 (m, 6H), 1.47-1.54 (m, 2H), 3.43-3.46 (t,
J = 6.6 Hz, 2H), 3.66-3.69 (t, J = 6.0 Hz, 2H), 3.88-3.91 (t, J = 6.0 Hz,
2H), 7.70-7.77 (m, 2H), 7.83-7.88 (m, 2H). 13C NMR (100 MHz,
CDCl3): 14.14, 22.72, 25.83, 29.66, 31.74, 37.60, 67.49, 71.12, 123.36,
132.30, 134.03, 168.42.
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2-(2-(2-(Hexyloxy)ethoxy)ethyl)isoindoline-1,3-dione (2f).
Yield: 83%. Eluent: 25% EtOAc in hexanes. 1H NMR (400 MHz,
CDCl3): 0.83-0.87 (t, 3H, J = 6.8 Hz), 1.19-1.29 (m, 6H), 1.45-1.50
(m, 2H), 3.35-3.39 (t, J = 6.8 Hz, 2H), 3.50-3.53 (m, 2H), 3.61-3.64
(m, 2H), 3.72-3.75 (t, J = 5.8 Hz, 2H), 3.88-3.90 (t, J = 5.8 Hz, 2H),
7.68-7.72 (m, 2H), 7.80-7.84 (m, 2H). 13C NMR (100 MHz, CDCl3):
14.11, 22.65, 25.77, 29.64, 31.73, 37.30, 67.93, 70.10, 70.16, 71.58,
123.25, 132.22, 133.94, 168.28.
2-(2-(2-(Benzyloxy)ethoxy)ethyl)isoindoline-1,3-dione (2g).
Yield: 75%. Eluent: 25% EtOAc in hexanes. 1H NMR (400 MHz,
CDCl3): 3.59-3.61 (m, 2H), 3.67-3.70 (m, 2H), 3.76-3.79 (t, J = 5.8
Hz, 2H), 3.91-3.94 (t, J = 5.8 Hz, 2H), 4.51 (s, 2H), 7.23-7.33 (m,
5H), 7.68-7.72 (m, 2H), 7.81-7.85 (m, 2H). 13C NMR (100 MHz,
CDCl3): 37.44, 68.06, 69.53, 70.32, 73.29, 123.32, 127.60, 127.72,
128.42, 132.25, 133.99, 138.37, 168.36.
3.58-3.64 (m, 4H). 13C NMR (100 MHz, CDCl3): 14.03, 22.62, 25.78,
29.61, 31.69, 41.79, 70.03, 70.36, 71.54, 73.41.
2-(2-(Benzyloxy)ethoxy)ethanamine (3g). Yield: 92%. 1H
NMR (400 MHz, CDCl3): 1.51 (bs, 2H), 2.88-2.90 (t, J = 5.2 Hz,
2H), 3.52-3.55 (t, J = 5.2 Hz, 2H), 3.64-3.68 (m, 4H), 4.60 (s, 2H),
7.28-7.37 (m, 5H). 13C NMR (100 MHz, CDCl3): 41.84, 69.41, 70.37,
73.23, 73.50, 127.60, 127.71, 128.36, 138.26.
2-(Phenyloxy)ethanamine (3h). Yield: 91%. 1H NMR (400
MHz, CDCl3): 1.51 (bs, 2H), 3.10-3.12 (t, J = 5.2 Hz, 2H), 4.00-4.02
(t, J = 5.2 Hz, 2H), 6.93-6.99 (m, 3H), 7.28-7.33 (m, 2H). 13C NMR
(100 MHz, CDCl3): 41.70, 70.12, 114.59, 120.90, 129.57, 158.98.
Synthesis of 4. Amine 3f (1.00 g, 5.29 mmol) was condensed with
5 (0.845 g, 6.35 mmol) in the presence of Me2NH (5.3 mL of 2 M
solution in THF, 10.6 mmol) following the procedure described in
method 3 below.
N0-(2-(2-Methoxyethoxy)ethyl)-N,N-dimethylacetimidamide
2-(2-Phenoxyethyl)isoindoline-1,3-dione (2h). Yield: 75%.
1H NMR (400 MHz, CDCl3): 4.03-4.06 (t, J = 5.8 Hz, 2H), 4.14-
4.17 (t, J = 5.8 Hz, 2H), 6.80-6.87 (m, 3H), 7.15-7.19 (m, 2H),
7.63-7.67 (m, 2H), 7.77-7.81 (m, 2H); 13C NMR (100 MHz,
CDCl3): 37.55, 64.79, 114.80, 121.30, 123.55, 129.64, 132.24, 134.23,
158.48, 168.37.
1
(4a). Yield: 92%. H NMR (400 MHz, C6D6): 1.46 (s, 3H), 2.59 (s,
6H), 3.14 (s, 3H), 3.39-3.41 (t, J = 5.0 Hz, 2H), 3.52-3.55 (t, J = 6.6
Hz, 2H), 3.58-3.60 (t, J = 5.0 Hz, 2H), 3.79-3.83 (t, J = 6.6 Hz, 2H).
13C NMR (100 MHz, C6D6): 12.23, 37.75, 50.72, 58.64, 70.88, 72.42,
73.65, 158.43. HRMS (ESþ) calcd (C9H20N2O2 þ H) 189.1603, obsd
189.1605.
Synthesis of 3. The phthalimide 2f (2.00 g, 6.27 mmol), hydrazine
hydrate (0.63 mL of 64 wt.% solution, 12.5 mmol), and ethanol (30 mL)
were combined in a round-bottom flask. The reaction mixture was
stirred while being refluxed at 76 °C for 3 h, during which a white solid
(phthalhydrazide) was formed in the reaction mixture. Ethanol was
removed from the reaction mixture by rotary evaporation until the
precipitate was nearly dry. Cold diethyl ether (75 mL) was added in to
the round-bottom flask, and the amine was extracted from the fluffy
phthalhydrazide by stirring the mixture over a magnetic stir plate. The
solution was filtered and the residual phthalhydrazide was washed using
cold diethyl ether (2 ꢀ 10 mL). The combined filtrate and washings
were evaporated under reduced pressure to obtain 3f in good yield.
2-(2-Methoxyethoxy)ethanamine (3a). Yield: 66%. 1H NMR
(400 MHz, CDCl3): 1.42 (bs, 2H), 2.86-2.89 (t, J = 5.4 Hz, 2H), 3.39
(s, 3H), 3.50-3.52 (t, J = 5.2 Hz, 2H), 3.54-3.56 (m, 2H), 3.61-3.63
(m, 2H). 13C NMR (100 MHz, CDCl3): 41.79, 59.06, 70.26, 71.94,
73.56.
N0-(2-(2-(2-Ethoxyethoxy)ethoxy)ethyl)-N,N-dimethyl-
acetimidamide (4b). Yield: 94%. 1H NMR (400 MHz, C6D6):
1.06-1.09 (t, J = 6.8 Hz, 3H), 1.47 (s, 3H), 2.59 (s, 6H), 3.27-3.32
(q, J = 6.9 Hz, 2H), 3.42-3.45 (t, J = 4.8 Hz, 2H), 3.50-3.55 (m, 6H),
3.58-3.61 (t, J = 4.8 Hz, 2H), 3.77-3.80 (t, J = 6.6 Hz, 2H). 13C NMR
(100 MHz, C6D6): 12.30, 15.44, 37.80, 50.60, 66.53, 70.36, 71.02, 71.05,
71.09, 73.53, 158.61. HRMS (ESþ) calcd (C12H26N2O3 þ H) 247.2022,
obsd 247.2012.
N0-(2-(2-Butoxyethoxy)ethyl)-N,N-dimethylacetimidamide
(4c). Yield: 92%. 1H NMR (400 MHz, C6D6): 0.82-0.86 (t, J = 7.2 Hz,
3H), 1.32-1.38 (m, 2H), 1.46-1.53 (m, 5H), 2.59 (s, 6H), 3.31-3.34
(t, J = 6.4 Hz, 2H,), 3.49-3.56 (m, 4H), 3.63-3.64 (t, J = 5.0 Hz, 2H),
3.81-3.84 (t, J = 6.6 Hz, 2H). 13C NMR (100 MHz, C6D6): 12.36,
14.08, 19.69, 32.33, 37.86, 50.47, 70.69, 71.06, 71.09, 73.53, 158.65.
HRMS (ESþ) calcd 231.2073 (C12H26N2O2 þ H), obsd 231.2079.
N0-(2-(2-(2-Butoxyethoxy)ethoxy)ethyl)-N,N-dimethyl-
acetimidamide (4d). Yield: 96%. 1H NMR (400 MHz, C6D6):
0.83-0.87 (t, J = 7.4 Hz, 3H), 1.32-1.37 (m, 2H), 1.48-1.53 (m,
5H), 2.60 (s, 6H), 3.30-3.33 (t, J = 6.4 Hz, 2H), 3.45-3.61 (m, 10H),
3.78-3.81 (t, J = 6.6 Hz, 2H). 13C NMR (100 MHz, C6D6): 12.25,
14.08, 19.68, 32.30, 37.77, 50.68, 70.66, 71.06, 71.10, 71.12, 73.61,
158.41. HRMS (ESþ) calcd (C14H30N2O3 þ H) 275.2335, obsd
275.2341.
2-(2-(2-Ethoxyethoxy)ethoxy)ethanamine (3b). Yield: qua-
ntitative. 1H NMR (400 MHz, CDCl3): 1.16-1.20 (t, J = 7.0 Hz, 3H),
1.64 (bs, 2H), 2.82-2.85 (t, J = 5.2 Hz, 2H), 3.47-3.64 (m, 12H). 13C
NMR (100 MHz, CDCl3): 15.28, 41.93, 66.76, 69.96, 70.42, 70.72,
70.82, 73.58.
2-(2-Butoxyethoxy)ethanamine (3c). Yield: 92%. 1H NMR
(400 MHz, CDCl3): 0.90-0.94 (t, J = 7.4 Hz, 3H), 1.32-1.42 (m, 2H),
1.54-1.61 (m, 2H), 1.73 (bs, 2H), 2.86-2.89 (t, J = 5.2 Hz, 2H),
3.45-3.49 (t, J = 6.8 Hz, 2H), 3.51-3.53 (t, J = 5.2 Hz, 2H), 3.58-3.63
(m, 4H). 13C NMR (100 MHz, CDCl3): 13.86, 19.23, 31.67, 41.62,
69.99, 70.32, 71.14, 73.11.
N0-(2-(Hexyloxy)ethyl)-N,N-dimethylacetimidamide (4e).
1
Yield: 91%. H NMR (400 MHz, C6D6): 0.83-0.86 (t, J = 7.0 Hz,
3H), 1.20-1.25 (m, 4H), 1.33-1.37 (m, 2H), 1.50 (s, 3H), 1.56-1.60
(m, 2H), 2.61 (s, 6H), 3.41-3.45 (t, J = 6.6 Hz, 2H), 3.53-3.56 (t, J =
6.8 Hz, 2H), 3.76-3.79 (t, J = 6.6 Hz, 2H). 13C NMR (100 MHz,
C6D6): 12.26, 14.24, 23.03, 26.36, 30.39, 32.10, 37.78, 50.74, 71.41,
73.27, 158.36. HRMS (ESþ) calcd (C12H26N2O þ H) 215.2123, obsd
215.2124.
2-(2-(2-Butoxyethoxy)ethoxy)ethanamine (3d). Yield: 94%.
1H NMR (400 MHz, CDCl3): 0.85-0.89 (t, J = 7.4 Hz, 3H), 1.27-
1.36 (m, 2H), 1.49-1.56 (m, 4H), 2.81-2.84 (t, J = 4.6 Hz, 2H),
3.40-3.43 (t, J = 6.8 Hz, 2H), 3.46-3.48 (t, J = 5.2 Hz, 2H), 3.53-3.64
(m, 8H). 13C NMR (100 MHz, CDCl3): 14.03, 19.37, 31.81, 41.90, 70.18,
70.41, 70.70, 70.77, 71.31, 73.53.
N0-(2-(2-(Hexyloxy)ethoxy)ethyl)-N,N-dimethylacetimida-
mide (4f). Yield: quantitative. 1H NMR (400 MHz, C6D6): 0.84-0.87
(t, J = 6.6 Hz, 3H), 1.19-1.28 (m, 4H), 1.30-1.37 (m, 2H), 1.47 (s,
3H), 1.53-1.57 (m, 2H), 2.60 (s, 6H), 3.33-3.36 (t, J = 6.4 Hz, 2H),
3.51-3.56 (m, 4H), 3.64-3.66 (t, J = 5.2 Hz, 2H), 3.82-3.85 (t, J = 6.6
Hz, 2H). 13C NMR (100 MHz, C6D6): 12.24, 14.24, 23.00, 26.29, 30.28,
32.06, 37.76, 50.75, 70.74, 71.09, 71.48, 73.68, 158.36. HRMS (ESþ)
calcd (C14H30N2O2 þ H) 259.2386, obsd 259.2372.
2-(Hexyloxy)ethanamine (3e). Yield: 93%. 1H NMR (400
MHz, CDCl3): 0.88-0.91 (t, J = 6.8 Hz, 3H), 1.31-1.39 (m, 6H),
1.55-1.62 (m, 2H), 1.86 (bs, 2H), 2.87-2.89 (t, J = 5.2 Hz, 2H),
3.43-3.48 (m, 4H). 13C NMR (100 MHz, CDCl3): 14.16, 22.74, 25.96,
29.81, 31.82, 42.04, 71.35, 73.01.
2-(2-(Hexyloxy)ethoxy)ethanamine (3f). Yield: 90%. 1H
NMR (400 MHz, CDCl3): 0.87-0.91 (t, J = 6.8 Hz, 3H), 1.30-1.37
(m, 6H), 1.55-1.63 (m, 2H), 1.84 (bs, 2H), 2.87-2.90 (t, J = 5.2 Hz,
2H), 3.45-3.48 (t, J = 6.8 Hz, 2H), 3.52-3.54 (t, J = 5.2 Hz, 2H),
N0-(2-(2-(Benzyloxy)ethoxy)ethyl)-N,N-dimethylacetimi-
damide (4g). Yield: 97%. 1H NMR: (400 MHz, C6D6): 1.46 (s, 3H),
2.59 (s, 6H), 3.50-3.56 (m, 4H), 3.61-3.64 (t, J = 5.0 Hz, 2H),
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ARTICLE
3.81-3.84 (t, J = 6.6 Hz, 2H), 4.39 (s, 2H), 7.08-7.10 (m, 1H),
7.14-7.19 (m, 2H), 7.28-7.30 (m, 2H). 13C NMR (100 MHz, C6D6):
12.28, 37.77, 50.66, 70.13, 71.00, 73.15, 73.60, 127.46, 127.71, 128.43,
139.39, 158.52. HRMS (ESþ) calcd (C15H24N2O2 þ H) 265.1916, obsd
265.1900.
to the resulting mass causing the white solid to separate from the sticky
mass. This solution was filtered and the residue was washed with diethyl
ether (3 ꢀ 50 mL) to separate the crude product from the salt. The
filtrate and washings were evaporated under reduced pressure to yield a
crude product, which was purified further by column chromatography
using 30% ethyl acetate in hexanes to yield 9. Yield: 24.64 g, 71%. 1H
NMR (400 MHz, CDCl3): 1.37-1.38 (m, 4H), 1.55-1.64 (m, 2H),
1.64-1.70 (m, 2H), 3.44-3.47 (t, J = 6.6 Hz, 2H), 3.57-3.70 (m, 10H),
4.58 (s, 2H), 7.26-7.35 (m, 5H), 7.70-7.73 (m, 2H), 7.82-7.85 (m,
2H). 13C NMR (100 MHz, CDCl3): 25.77, 26.76, 28.61, 29.54, 38.01,
69.54, 70.17, 70.74, 71.32, 73.27, 123.19, 127.60, 127.77, 128.39, 132.23,
133.90, 138.40, 168.44.
N,N-Dimethyl-N0-(2-phenoxyethyl)acetimidamide (4h). Yield:
94%. 1H NMR (400 MHz, THF-d8): 1.84 (s, 3H), 2.83 (s, 6H),
3.49-3.52 (t, J = 6.8 Hz, 2H), 4.03-4.07 (t, J = 6.8 Hz, 2H),
6.81-6.90 (m, 3H), 7.17-7.22 (m, 2H). 13C NMR(100 MHz, THF-
d8): 12.57, 38.08, 50.21, 70.26, 115.21, 120.81, 129.93, 159.63, 160.46.
HRMS (ESþ) calcd (C12H18N2O þ H) 207.1497, obsd 207.1494.
Methyl N-octylimidate (6b). The imidate was derived from N-
acetyl octylamine by the procedure reported earlier by Torssell et al.,
replacing distillation by column chromatography (50% ethyl acetate, 1%
2-(6-(2-(2-Hydroxyethoxy)ethoxy)hexyl)isoindoline-1,3-
dione (10). To the solution of 9 (19.2 g, 45.2 mmol) in ethanol (200
mL) in a two neck round-bottom flask, a 10% Pd-C (0.950 g) was
added. The solution was allowed to stir at rt for 6 h, while hydrogen
atmosphere was maintained with a continuous and gentle flow of
gaseous hydrogen. The reaction mixture was filtered and washed with
ethanol (3 ꢀ 20 mL). The filtrate and washings were combined and
evaporated first under reduced pressure on a rotary evaporator and
1
triethylamine in hexanes) for the final purification.13 Yield: 36%. H
NMR (400 MHz, C6D6): 0.88-0.92 (t, J = 6.8 Hz, 3H), 1.27-1.31 (m,
8H), 1.39-1.43 (m, 2H), 1.58 (s, 3H), 1.63-1.67 (m, 2H), 3.09-3.12
(t, J = 6.8 Hz, 2H), 3.63 (s, 3H). 13C NMR (100 MHz, C6D6): 14.17,
14.33, 23.07, 27.88, 29.81, 30.00, 32.11, 32.28, 49.39, 51.96, 160.29.
HRMS (ESþ) calcd (C11H23NO þ H) 186.1858, obsd 186.1853.
6-(1,3-Dioxoisoindolin-2-yl)hexyl 4-methylbenzenesulfo-
nate (8). The mixture of finely powdered phthalic anhydride (29.6 g,
200 mmol) and 6-amino-1-hexanol (23.4 g, 200 mmol) are combined in
a 500 mL round-bottom flask and the mixture was heated at 120 °C for
3 h, while being stirred. The condensation was marked by liberation of
water, which was very vigorous during the initial stages of the reaction.
The fused mass was dissolved in dichloromethane (250 mL). para-
Toluenesulfonyl chloride (42.0 g, 220 mmol) and 4-(N,N-dimethyla-
mino)pyridine (200 mg) were added to this solution and the mixture
was stirred to obtain a clear solution. A reflux condenser was attached to
the round-bottom flask and triethylamine (40.4 g, 400 mmol) was added
dropwise to the reaction mixture while being stirred. The stirring was
continued for 18 h after the addition of triethylamine. Hydrochloric acid
(20.9 mL of 35 wt.% HCl mixed with 200 mL of water, 200 mmol) was
added to the reaction and the mixture was stirred vigorously for 15 min.
Dichloromethane was separated from the aqueous layer, dried over
anhydrous magnesium sulfate (10 g) and evaporated under reduced
pressure. Ethanol (300 mL) was added to the residue and the mixture
was heated at 76 °C with stirring for 1 h. This solution was allowed to
slowly cool down to 0 °C (while been stirred) to obtain a crystalline
white solid (seeding with crystals obtained from earlier batches was very
helpful). The solution was allowed to remain at 0 °C for 3 h and then
filtered while cold. This was followed by washing (2 ꢀ 20 mL) with cold
ethanol. The crystallization process was repeated to obtain 8. Yield:
43.36 g, 54%. 1H NMR (400 MHz, CDCl3): 1.26-1.38 (m, 4H),
1.61-1.67 (m, 4H), 2.46 (s, 3H), 3.63-3.66 (t, J = 7.2 Hz, 2H),
4.00-4.04 (t, J = 6.4 Hz, 2H), 7.34-7.36 (d, J = 8.0 Hz, 2H) 7.71-7.73
(m, 2H), 7.78-7.80 (d, J = 8.0 Hz, 2H), 7.84-7.86 (m, 2H). 13C NMR
(100 MHz, CDCl3): 21.80, 25.13, 26.35, 28.53, 28.85, 37.92, 70.58,
123.36, 128.05, 130.01, 132.29, 133.36, 134.09, 144.86, 168.58.
1
finally under high vacuum to yield 10. Yield: 15.15 g, quantitative. H
NMR (400 MHz, CDCl3): 1.38-1.40 (m, 4H), 1.56-1.63 (m, 2H),
1.65-1.72 (m, 2H), 1.97 (s, 1H), 3.45-3.48 (t, J = 6.6 Hz, 2H),
3.57-3.75 (m, 10H), 7.70-7.73 (m, 2H), 7.84-7.86 (m, 2H). 13C
NMR (100 MHz, CDCl3): 25.77, 26.75, 28.64, 29.51, 38.05, 61.93,
70.28, 70.58, 71.43, 72.67, 123.29, 132.28, 133.99, 168.58.
2-(2-((6-Aminohexyl)oxy)ethoxy)ethanol (11). To the solu-
tion of 10 (15.0 g, 44.8 mmol) in ethanol (250 mL), hydrazine hydrate
(4.48 mL of 64 wt.% solution, 89.6 mmol) was added and the reaction
mixture was refluxed at 76 °C for 3 h. Hydrochloric acid (9.3 mL of
35 wt.% solution in 80 mL of water, 89.6 mmol) was added to the
reaction mixture and the heating/stirring was further continued under
the reflux condenser at 76 °C for 3 h. A solution of potassium hydroxide
(7.64 g, 134 mmol) in ethanol (20 mL) was added to the reaction
mixture and the mixture was allowed to stir for 5 min at rt. Ethanol was
evaporated first under reduced pressure on a rotary evaporator and
finally under high vacuum to yield a sticky white solid. Dichloromethane
(3 ꢀ 100 mL) was used for separation/extraction of amino alcohol
from the hydrazinolysis byproduct. Dichloromethane extracts were com-
bined and evaporated first under reduced pressure on a rotary evapora-
1
tor and finally under high vacuum to yield 11. Yield: 7.53 g, 82%, H
NMR (400 MHz, CDCl3): 1.36-1.38 (m, 4H), 1.41-1.49 (m, 2H),
1.58-1.65 (m, 2H), 2.49 (s, 3H), 2.68-2.72 (t, J = 6.8 Hz, 2H),
3.47-3.50 (t, J = 6.6 Hz, 2H), 3.58-3.74 (m, 8H). 13C NMR (100
MHz, CDCl3): 25.89, 26.52, 29.53, 33.23, 41.91, 61.79, 70.33, 70.64,
71.43, 72.89.
N0-(6-(2-(2-Hydroxyethoxy)ethoxy)hexyl)-N,N-dimethyl-
acetimidamide (12). The aminoalcohol 11 (5.73 g, 27.9 mmol) and
Me2NH (27.9 mL of 2 M solution in THF, 55.8 mmol) were combined in
a round-bottom flask and allowed to stir at rt. N, N-Dimethylacetamide
dimethyl acetal 5 (4.46 g, 33.5 mmol) was added to this combination
dropwise over 5 min. The reaction mixture was stirred for 10 min and then
left standing for 18 h in the dark. Most of the THF and Me2NH were
removed from the reaction mixture by rotary evaporation. This was followed
by heating the contents at 55 °C with stirring on high vacuum for 8 h.
Yield: 7.66 g, 99%. 1H NMR (400 MHz, C6D6): 1.45-1.51 (m, 7H), 1.56-
1.66 (m, 2H), 1.73-1.78 (m, 2H), 2.62 (s, 6H), 3.24-3.42 (m, 10H),
3.56-3.59 (t, J = 4.6 Hz, 2H). 13C NMR (100 MHz, C6D6): 12.16, 26.56,
27.79, 30.21, 32.74, 37.93, 50.13, 61.63, 70.54, 70.75, 71.48, 73.26, 158.08.
HRMS (EIþ) calcd (C14H30N2O3) 274.2256, obsd 274.2263.
2-(6-(2-(2-(Benzyloxy)ethoxy)ethoxy)hexyl)isoindoline-
1,3-dione (9). In a 250 mL round-bottom flask, 8 (32.8 g, 81.6 mmol)
was heated at 100 °C under high vacuum for 1 h to remove any bound
water or water of crystallization. The flask was slowly brought down to rt
and then purged with argon. Dry THF (150 mL) was added to this
tosylate. A solution of sodium salt of diethyleneglycol monobenzyl ether
was prepared by adding the diethyleneglycol monobenzyl ether (18.4 g,
93.8 mmol) dropwise in to a suspension of NaH (3.75 g of 60 wt.%
suspension in mineral oil, 93.8 mmol) in dry THF (150 mL) under inert
atmosphere. The solution of 8 was gradually transferred in to the
solution of the alkoxide at rt while continuing to maintain the inert
atmosphere. The reaction mixture was heated at 65 °C under a reflux
condenser for 18 h and then allowed to cool down to rt. THF was
evaporated under reduced pressure and diethyl ether (300 mL) was added
Synthesis of Amidines from Primary Amines (Table 1). For
each amine the reactions were performed using methods 1, 2 and 3. The
reactions were typically performed on 0.500 g scale with respect to the
amine. The three procedures are described below.
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ARTICLE
Method 1. The mixture of decylamine (0.500 g, 3.18 mmol) and 5
(0.508 g, 3.82 mmol) were heated at 60 °C for 2 h. The reaction mixture
was evaporated at rt on a rotary evaporator. The contents were further
heated at 55 °C on high vacuum for 8 h to yield the product. For solid
amines, THF (5 mL) was used as a solvent.
Method 2. Decylamine (0.500 g, 3.18 mmol) was added dropwise in
to 5 (0.508 g, 3.82 mmol) over 5 min, while it was stirred for 10 min at rt.
The reaction mixture was allowed to stand for 18 h at rt. The work up
involved evaporation on a rotary evaporator at rt followed by evapora-
tion at 55 °C under high vacuum for 8 h to yield the product. For solid
amines, THF (5 mL) was used as a solvent and 5 was added dropwise in
to the solution of amine in THF.
N,N-Dimethyl-N0-(pyridin-4-ylmethyl)acetimidamide. 1H
NMR (400 MHz, C6D6): 1.41 (s, 3H), 2.62 (s, 6H), 4.19 (s, 2H),
7.24-7.25 (m, 2H), 8.58-8.60 (m, 2H). 13C NMR (100 MHz, C6D6):
12.5, 37.7, 52.5, 122.8, 149.9, 152.4, 159.0. HRMS (EIþ) calcd
(C10H15N3) 177.1266, obsd 177.1272.
N0-Benzyl-N,N-dimethylacetimidamide. 1H NMR (400 MHz,
C6D6): 1.58 (s, 3H), 2.76 (s, 6H), 4.54 (s, 2H), 7.21-7.25 (m, 1H),
7.35-7.39 (m, 2H), 7.60-7.62 (m, 2H). 13C NMR (100 MHz, C6D6):
12.4, 37.8, 53.7, 126.1, 127.7, 128.3, 143.8, 158.5. HRMS (EIþ) calcd
(C11H16N2) 176.1313, obsd 176.1326.
N,N-Dimethyl-N0-(1-phenylethyl)acetimidamide. 1H NMR
(400 MHz, C6D6): 1.44 (s, 3H), 1.53-1.55 (m, 3H), 2.62 (s, 6H),
4.42-4.48 (q, J = 6.4 Hz, 1H), 7.08-7.12 (m, 1H), 7.23-7.27 (m, 2H),
7.53-7.55 (m, 2H). 13C NMR (100 MHz, C6D6): 12.3, 27.7, 37.7, 58.4,
126.2, 127.0, 128.5, 149.5, 156.6. HRMS (EIþ) calcd (C12H18N2)
190.1470, obsd 190.1472.
Method 3. N,N-Dimethylacetamide dimethyl acetal 5 (0.508 g, 3.82
mmol) and Me2NH (3.8 mL of 2 M solution in THF, 7.64 mmol) are
combined in a round-bottom flask and allowed to stir at rt. Decylamine
(0.500 g, 3.18 mmol) was added to this combination dropwise over
5 min at rt. The reaction mixture was allowed to stir for 10 min and then
left standing for 18 h in the dark. Most of the THF and Me2NH were
removed from the reaction mixture by rotary evaporation. This was
followed by stirring the contents at 55 °C under high vacuum for 8 h. For
solid amines, THF was used as a solvent and 5 was added dropwise to the
solution of amine and Me2NH in THF.
N,N-Dimethyl-N0-(thiophen-2-ylmethyl)acetimidamide. 1H
NMR (400 MHz, C6D6): 1.40 (s, 3H), 2.61 (s, 6H), 4.51 (s, 2H),
6.85-6.87 (m, 2H), 6.96-6.98 (m, 1H). 13C NMR (100 MHz, C6D6):
12.3, 37.7, 49.3, 122.0, 123.3, 126.6, 149.0, 158.6. HRMS (EIþ) calcd
(C9H14N2S) 182.0878, obsd 182.0883.
N0,N00,N000-(Nitrilotris(ethane-2,1-diyl))tris(N,N-dimethyl-
acetimidamide). 1H NMR (400 MHz, C6D6): 1.53 (s, 9H), 2.61 (s,
18H), 2.92-2.96 (t, J = 7.6 Hz, 6H), 3.38-3.42 (t, J = 7.6 Hz, 6H). 13C
NMR (100 MHz, C6D6): 12.2, 37.9, 49.9, 58.6, 157.7. HRMS (ESþ)
calcd (C18H39N7 þ H) 354.3345, obsd 354.3347.
N0-Butyl-N,N-dimethylacetimidamide. 1H NMR (400 MHz,
C6D6): 0.92-0.95 (t, J = 7.6 Hz, 3H), 1.44-1.52 (m, 5H), 1.66-1.67
(m, 2H), 2.62 (s, 6H), 3.15-3.18 (t, J = 6.8 Hz, 2H). 13C NMR (100
MHz, C6D6): 12.0, 14.4, 21.1, 35.3, 37.8, 50.0, 157.2. HRMS (ESþ)
calcd (C8H18N2 þ H) 143.1548, obsd 143.1545.
N0,N00-((Ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis-
(N,N-dimethylacetimidamide). 1H NMR (400 MHz, C6D6): 1.50
(s, 6H), 2.59 (s, 12H), 3.41-3.44 (t, J = 6.8 Hz, 4H), 3.57 (bs, 4H),
3.68-3.72 (t, J = 6.8 Hz, 4H). 13C NMR (100 MHz, C6D6): 12.2, 37.8,
50.7, 71.1, 73.6, 158.4. HRMS (ESþ) calcd (C14H30N4O2 þ H)
287.2447, obsd 287.2443.
N0-Hexyl-N,N-dimethylacetimidamide. 1H NMR (400 MHz,
C6D6): 0.86-0.89 (t, J = 7.2 Hz, 3H), 1.30-1.33 (m, 4H), 1.44-1.47
(m, 2H), 1.53 (s, 3H), 1.63-1.71 (m, 2H), 2.63 (s, 6H), 3.16-3.20 (t,
J = 7.0 Hz, 2H). 13C NMR (100 MHz, C6D6): 11.98, 14.35, 23.23, 27.82,
32.45, 33.07, 37.83, 50.39, 157.07. HRMS (EIþ) calcd (C10H22N2)
170.1783, obsd 170.1788.
N0-Octyl-N,N-dimethylacetimidamide. 1H NMR (400 MHz,
C6D6): 0.86-0.89 (t, J = 6.8 Hz, 3H), 1.26-1.39 (m, 8H), 1.52 (bs,
5H), 1.73-1.77 (m, 2H), 2.64 (s, 6H), 3.23-3.26 (t, J = 6.8 Hz, 2H).
13C NMR (100 MHz, C6D6): 11.99, 14.33, 23.10, 28.18, 29.94, 30.21,
32.36, 33.14, 37.83, 50.44, 157.11. HRMS (EIþ) calcd (C12H26N2)
198.2096, obsd 198.2097.
’ ASSOCIATED CONTENT
1
Supporting Information. Comparison of H and 13C
S
b
NMR spectra of product obtained by condensation of 3g with
5 by methods 1, 2, and 3, 13C DEPT-135 and HSQC NMR
spectra of the product obtained by condensation of 3g with 5 by
method 1, 1H and 13C spectra of compounds 2-4(a-h), 6b, and
8-12 and for all compounds in Table 1. This material is available
free of charge via the Internet at http://pubs.acs.org.
N0-Decyl-N,N-dimethylacetimidamide. 1H NMR (400 MHz,
C6D6): 0.86-0.90 (t, J = 6.8 Hz, 3H), 1.25-1.41 (m, 12H), 1.49-1.54
(m, 5H), 1.73-1.77 (m, 2H), 2.64 (s, 6H), 3.22-3.26 (t, J = 7.0 Hz,
2H). 13C NMR (100 MHz, C6D6): 12.01, 14.35, 23.11, 28.20, 29.84,
30.15, 30.28, 30.31, 32.35, 33.15, 37.84, 50.44, 157.11. HRMS (EIþ)
calcd (C14H30N2) 226.2409, obsd 226.2407.
’ AUTHOR INFORMATION
N0-Dodecyl-N,N-dimethylacetimidamide. 1H NMR (400
MHz, C6D6): 0.87-0.91 (t, J = 6.8 Hz, 3H), 1.26-1.40 (m, 16H),
1.52-1.55 (m, 5H), 1.74-1.77 (m, 2H), 2.64 (s, 6H), 3.23-3.26 (t, J =
6.8 Hz, 2H). 13C NMR (100 MHz, C6D6): 12.01, 14.35, 23.12, 28.21,
29.84, 30.14, 30.20, 30.22, 30.30, 30.33, 32.35, 33.16, 37.85, 50.44,
157.09. HRMS (EIþ) calcd (C16H34N2) 254.2722, obsd 254.2732.
N0-Tetradecyl-N,N-dimethylacetimidamide. 1H NMR (400
MHz, C6D6): 0.88-0.91 (t, J = 6.8 Hz, 3H), 1.28-1.40 (m, 20H), 1.52
(bs, 5H), 1.74-1.78 (m, 2H), 2.64 (s, 6H), 3.23-3.26 (t, J = 6.8 Hz,
2H). 13C NMR (100 MHz, C6D6): 12.02, 14.36, 23.12, 28.21, 29.84,
30.14, 30.20, 30.21, 30.22, 30.31, 30.34, 32.36, 33.16, 37.85, 50.44,
157.09. HRMS (EIþ) calcd (C18H38N2) 282.3035, obsd 282.3040.
N0-Hexadecyl-N,N-dimethylacetimidamide. 1H NMR (400
MHz, C6D6): 0.89-0.92 (t, J = 6.8 Hz, 3H), 1.31-1.43 (m, 24H),
1.51-1.59 (m, 5H), 1.80-1.83 (m, 2H), 2.64 (s, 6H), 3.27-3.31 (t, J =
7.0 Hz, 2H). 13C NMR (100 MHz, C6D6): 12.02, 14.35, 23.10, 28.22,
29.82, 30.12, 30.17, 30.18, 30.19, 30.21, 30.22, 30.30, 30.33, 32.33, 33.17,
37.84, 50.45, 157.18. HRMS (EIþ) calcd (C20H42N2) 310.3348, obsd
310.3347.
Corresponding Author
*E-mail: jessop@chem.queenu.ca.
’ ACKNOWLEDGMENT
The authors gratefully acknowledge Chevron Energy Tech-
nology Company, the Natural Sciences and Engineering Re-
search Council (NSERC), and the Canada Research Chairs
program for funding.
’ REFERENCES
(1) Edelmann, F. T. Chem. Soc. Rev. 2009, 38, 2253–2268.
(2) Edelmann, F. T. Adv. Organomet. Chem. 2008, 57, 183–352.
(3) (a) Guile, S. D.; Alcaraz, L.; Birkinshaw, T. N.; Bowers, K. C.;
Ebden, M. R.; Furber, M.; Stocks, M. J. J. Med. Chem. 2009, 52, 3123–
3141. (b) Greenhill, J. V.; Lue, P. Prog. Med. Chem. 1993, 30, 203–326.
(c) Caron, S.; Wei, L.; Douville, J.; Ghosh, A. J. Org. Chem. 2010, 75,
945–947.
1690
dx.doi.org/10.1021/jo102358d |J. Org. Chem. 2011, 76, 1683–1691

The Journal of Organic Chemistry
ARTICLE
(4) Nagasawa, K. In Superbases for Organic Synthesis; John Wiley &
Sons Limited: Chichester, U.K., 2009; pp 211-250.
(5) (a) Jessop, P. G.; Heldebrant, D. J.; Li, X.; Eckert, C. A.; Liotta,
C. L. Nature 2005, 436, 1102. (b) Phan, L.; Chiu, D.; Heldebrant, D. J.;
Huttenhower, H.; John, E.; Li, X.; Pollet, P.; Wang, R.; Eckert, C. A.;
Liotta, C. L.; Jessop, P. G. Ind. Eng. Chem. Res. 2008, 47, 539–545.
(c) Jessop, P. G.; Phan, L.; Carrier, A.; Robinson, S.; D€urr, C. J.; Harjani,
J. R. Green Chem. 2010, 12, 809–813.
(6) (a) Jessop, P. G. Reversibly switchable amidine surfactants and
methods of use thereof. PCT Int. Appl. WO 2007056859, 2007. (b) Liu,
Y.; Jessop, P. G.; Cunningham, M.; Eckert, C. A.; Liotta, C. L. Science
2006, 313, 958–960. (c) Phan, L.; Jessop, P. G. Green Chem. 2009, 11,
307–308.
(7) (a) Yamada, T.; Lukac, P. J.; George, M.; Weiss, R. G. Chem.
Mater. 2007, 19, 967–969. (b) Hart, R.; Pollet, P.; Hahne, D. J.; John, E.;
Llopis-Mestre, V.; Blasucci, V.; Huttenhower, H.; Leitner, W.; Eckert,
C. A.; Liotta, C. L. Tetrahedron 2010, 66, 1082–1090. (c) Desset, S. L.;
Cole-Hamilton, D. J. Angew. Chem., Int. Ed. 2009, 48, 1472–1474.
(8) (a) Dunn, P. J. In Comprehensive Organic Functional Group
Transformations II; Elsevier: Oxford, U.K., 2005; Vol. 5, pp 655-699.
(b) Ostrowska, K.; Kolasa, A. In Science of Synthesis; Georg Thieme
Verlag: Germany, 2005; Vol. 22, pp 379-488.
(9) Oszczapowicz, J.; Raczyꢀnska, E. J. Chem. Soc., Perkin Trans. 2
1984, 1643–1646.
(10) Forkner, M. W.; Robson, J. H.; Snellings, W. M.; Martin, A. E.;
Murphy, F. H.; Parsons, T. E. In Kirk-Othmer Encyclopedia of Chemical
Technology; Wiley: Oxford, U.K., 2004; Vol. 12, pp 644-682.
(11) Gabriel, S. Ber. Dtsch. Chem. Ges. 1887, 20, 2224.
(12) Refer to the Supporting Information for details.
(13) Pilotti, Å; Reuterh€all, A.; Torssell, K. Acta Chem. Scand. 1969,
23, 818–824.
1691
dx.doi.org/10.1021/jo102358d |J. Org. Chem. 2011, 76, 1683–1691