3-(Dimethylamino)-1-propylamine: A cheap and versatile reagent for removal of byproducts in carbohydrate chemistry

Article abstract of DOI:10.1021/acs.orglett.5b00041

Inexpensive 3-(dimethylamino)-1-propylamine (DMAPA) was found to be effective in anomeric deacylation reactions giving 1-O deprotected sugars in high yield as precursors for the formation of imidate glycosyl donors. DMAPA was also found to be useful for removing excess reagents such as benzoyl chloride, tosyl chloride, and 2,2,2-trifluoro-N-phenylacetimidoyl chloride. The deacylation reaction could be conducted in moist THF and did not require chromatographic purification since an acidic wash was sufficient to remove excess reagent and the formed byproduct.

Full text of DOI:10.1021/acs.orglett.5b00041

Letter
pubs.acs.org/OrgLett
3‑(Dimethylamino)-1-propylamine: A Cheap and Versatile Reagent
for Removal of Byproducts in Carbohydrate Chemistry
Sofie Meng Andersen, Mads Heuckendorff, and Henrik H. Jensen*
Department of Chemistry, Aarhus University, Langelandsgade 140, DK-8000, Aarhus C, Denmark
S
* Supporting Information
ABSTRACT: Inexpensive 3-(dimethylamino)-1-propylamine
(DMAPA) was found to be effective in anomeric deacylation
reactions giving 1-O deprotected sugars in high yield as
precursors for the formation of imidate glycosyl donors.
DMAPA was also found to be useful for removing excess
reagents such as benzoyl chloride, tosyl chloride, and 2,2,2-
trifluoro-N-phenylacetimidoyl chloride. The deacylation reaction could be conducted in moist THF and did not require
chromatographic purification since an acidic wash was sufficient to remove excess reagent and the formed byproduct.
additive to fuels. It furthermore has a safety profile17 comparable
hemical glycobiology has for a long time been predicted to
Chave a bright future, and much progress has been made. to both BnNH2 and Et3N.
We believed that the bifunctional nature of DMAPA could
make it useful as a nucleophile for selective anomeric acylations
in carbohydrate chemistry, and it could subsequently be removed
easily from the reaction mixture by acidic workup due to
presence of the tertiary amine functionality.18 DMAPA has
previously been found useful in cleaning reaction mixtures.19−29
To investigate the potential of DMAPA in anomeric
deacylation, we chose β-D-glucose pentaacetate 1 as a model
substrate. To our delight, DMAPA (1.5 equiv) in THF was found
to cleanly provide the desired lactol 2 after acidic workup
consisting of a single wash with 1 M hydrochloric acid in a
separation funnel. Lowering the amount of DMAPA to 1.3 equiv
resulted in incomplete reaction but increasing the amount of
DMAPA to 3 or 5 equiv gave a substantially shorter reaction time
and an equally selective reaction in a largely unperturbed yield
(Table 1).
The field heavily depends on access to pure and uniform glycans,
which are often prepared through synthetic methods. In spite of
important developments in automated synthesis and click
reactions, every oligosaccharide molecule is still a unique
synthetic target with no general synthetic strategy available.1
For new discoveries in chemical glycobiology, it is therefore of
utmost importance to develop new and improved synthetic
methods to allow for the continued demand of glycans.
Among the most successful glycosyl donors2 for the synthesis
of oligosaccharides are the trichloroacetimidates3 and the N-
phenyl trifluoroacetimidates,4−6 which both use reducing 1-O
deprotected lactols for their preparation. In addition, 1-O
deprotected lactols can be used directly in dehydrative
glycosylations7 or be converted to glycosyl thiols8 by treatment
with Lawesson’s reagent9 for subsequent attachment to
proteins.10
Changing the reaction medium to CH2Cl2 (entry 5, Table 1)
A literature survey suggests that little progress in methods
leading to selective anomeric deacylations has been made since
the classical method using hydrazinium acetate (H2NNH3-
OAc)11 in DMF was developed. This protocol still seems to be
the most popular despite the apparent drawbacks of this reagent
being shelf stability, price,12 and toxicity.13 In addition, there are
also drawbacks to the use of the hazardous solvent DMF, which
often complicates workup due to its physical properties. A less
used and alternative protocol to hydrazinium acetate is the
employment of an alkyl amine (e.g., ethylene diamine/AcOH14
or BnNH215) in the less hazardous and more volatile solvent
THF. Alkylamines like benzylamine, however, yield a lipophilic
amide byproduct, which later needs to be removed by time-
consuming column chromatography.
resulted in a slightly lower yield and a significantly prolonged
Table 1. Optimization Results
a
entry
solvent
DMAPA (equiv)
time (h)
yield (%)
1
2
3
4
5
THF
1.3
1.5
3
72
24
3
b
95
88
92
83
THF
THF
THF
5
1.5
3
CH2Cl2
5
a
Yield after acidic workup without chromatographic purification.
Reaction did not go to completion according to TLC analysis.
We had previously used 3-(dimethylamino)-1-propylamine
(DMAPA) as a nucleophile in a Pd-catalyzed Buchwald
reaction16 and noticed its low price compared to both BnNH2
and Et3N. DMAPA is a bulk chemical used, e.g., for the synthesis
of betaines in shampoos, for curing epoxy resins, and as an
b
Received: January 6, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00041
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Letter
reaction time. A range of other solvents including 2-
methyltetrahydrofuran were also investigated but did not provide
improved results compared to THF and CH2Cl2 (see the
Supporting Information). Regardless of the reaction medium,
Table 2. Anomeric Deacylations with DMAPA
1
the reaction product was identical by H NMR analysis. Some
effort was invested in trying to understand what the yield-
diminishing and water-soluble byproduct(s) could be, but
without success. NMR spectra of the water-soluble byproducts
identified only N-acetyl-DMAPA and unreacted DMAPA. One
could speculate on imine formation between the reducing sugar
and DMAPA, which could lead to Amadori rearrangement.
For comparison, the same reaction as mentioned above was
explored with the often used hydrazinium acetate in DMF (1.5
and 5 equiv) and BnNH2 in THF (1.5 and 5 equiv) at ambient
temperature. Here, hydrazinium acetate gave a faster reaction
than DMAPA, whereas BnNH2 reacted more sluggishly.
Reaction yields from both reagents were slightly lower than
those found for DMAPA (see the Supporting Information).
We then investigated the workup procedure by exchanging
hydrochloric acid for other acids, which resulted in slightly
eroded isolated yields (see the Supporting Information).
After establishing useful reaction conditions, we moved on to
test the reaction on a range of different acetyl- and benzoyl-
protected carbohydrates (Table 2). Given the price of DMAPA
and the low reaction time, it was decided to continue with 5 equiv
of the reagent. First, the influence of anomeric configuration was
investigated by reaction of α-acetate 3 with DMAPA. Both
reaction time and yield were found to be largely unaffected by a
change in C-1 stereochemistry. In addition, other per-acetylated
monosaccharides including those of galactose (4), mannose (6),
2-deoxy-2-azidoglucose (8), and GlcNAc (10) successfully
underwent anomeric deacylation with DMAPA, providing the
corresponding lactols in 82−86% yield. Chloroform, however,
had to be used in the workup procedure for GlcNAc derivative 11
to avoid losing the lactol product in the aqueous phase and obtain
an acceptable isolated yield. It is well known that the solubility of
acetamido-2-deoxysugars can be problematic in practice.30
Octaacetyl lactose (12) gave similar results (11/2 h, 89%) as
found for the monosaccharides described above.
Another frequently used protecting group of the hydroxyl
function in carbohydrate chemistry is the benzoyl ester, which is
known to be more robust than the acetyl group. Benzoylated β-
mannose derivative 14 required a longer reaction time and
needed 6 equiv of DMAPA to obtain a satisfactory result. As
anticipated, the anomeric benzoyl of 14 was less prone to
aminolysis, but still the product was obtained in a satisfying 79%
yield (Table 2, Entry 7). Until this point, all reactions had been
carried out using dried solvents from a purification system (water
content <42 ppm). To investigate whether the presence of water
in THF would have a measurable effect on the reaction outcome,
solvent from a bottle kept in the laboratory was used (water
content: 425 ppm). As can be seen from Table 2, entry 8, no
significant effect could be observed on either reaction time or
yield for β-glucose pentaacetate (1) in undried THF. Finally, a 10
g scale (26 mmol) deacetylation was conducted on 1 in undried
THF, which again gave a similar outcome as found for those
described for a smaller scale (Table 1, entry 4, and Table 2, entry
8). This demonstrated the robustness of the present protocol and
that it is suitable for large-scale preparation.
a
Yield after acidic workup without chromatographic purification.
Reaction performed in undried THF. Reaction performed on 10 g
b
c
scale.
the lactol product. Consequently, we next speculated whether
the successful protocol also could be used as the first step in a
two-step, one-pot approach to prepare a useful glycosyl
trichloroacetimidate directly from an acylated sugars. Since
trichloroacetonitrile/DBU was found to react very sluggishly
with a lactol in THF, the one-pot strategy was explored in
CH2Cl2 instead. To the acylated sugar of choice was added
DMAPA, and upon reaction completion as judged by TLC
analysis, trichloroacetonitrile (10 equiv) and a catalytic amount
The above-mentioned results demonstrate a vast improve-
ment of commonly used protocols for selective anomeric
deacylation since it uses a cheap and relatively harmless chemical
and omits the need for column-chromatographic purification of
B
DOI: 10.1021/acs.orglett.5b00041
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Letter
of DBU were added. The formation of the imidate product was
easily monitored by TLC analysis, and the crude product could
be purified by passing it through a short path silica column. In the
presence of trichloroacetonitrile, the DMAPA base itself was
found to be insufficient to promote the formation of imidate
product, and the addition of DBU was hence necessary. As seen
from Table 3, entries 1 and 2, the one-pot approach successfully
produced the desired trichloroacetimidate glycosyl donor
directly from the 1-O-acyl compounds 1 and 4 in good yields
(78−82%).
Table 4. Removing Excess BzCl, TsCl, and PFAI-Cl with
DMAPA
Table 3. One-Pot Deacylation and Trichloroacetimidate
Formation
a
Lastly, the possibility of removing excess of reagents
commonly used in carbohydrate chemistry or organic chemistry
in general with DMAPA was investigated. Excess of the three
reagents, benzoyl chloride, tosyl chloride, and 2,2,2-trifluoro-N-
phenylacetimidoyl chloride (PFAI-Cl), was explored in this
context. All reactions were performed in CH2Cl2, which is
commonly accepted as a rather cheap solvent that is less harmful
than, e.g., pyridine or chloroform. Quenching the reagent excess
in, e.g., benzoylation and tosylation reactions with water to
obtain an easily removable salt can be difficult due to the
immiscibility of water and CH2Cl2.
Yield after acidic workup without chromatographic purification.
was stirred for another 10 min. After washing with hydrochloric
acid, drying, and evaporation of the organic solvent, the product
mixture was analyzed by NMR showing that 2,2,2-trifluoro-N-
phenylacetimidoyl chloride was removed. Trace amounts of N-
phenyltrifluoroacetamide were observed in the 1H NMR spectra
of the crude reaction mixture, which otherwise was found to only
contain the expected glycosyl donor product as an α/β-E/Z
mixture. This again demonstrates the usefulness of DMAPA in
carbohydrate chemistry or organic chemistry in general.
In conclusion, we have shown that the inexpensive reagent,
DMAPA, provides excellent yields in anomeric deacylation
reactions without the need for chromatographic purification.
Acidic washing of the crude reaction mixture was found to be
sufficient to remove reaction byproducts. It was also demon-
strated that the resulting lactol obtained after anomeric
deacylation could be used in a one-pot procedure to provide a
glycosyl trichloroacetimidate upon addition of trichloroacetoni-
trile and DBU.
As substrates for benzoylations and tosylations, isopropylidene
-protected D-galactose, D-fructose, and D-xylose were chosen.
Excess (4 equiv) of either benzoyl chloride or tosyl chloride was
used per alcohol together with triethylamine and DMAP (see
Table 4). Upon reaction completion as judged by TLC analysis,
DMAPA (1 equiv per chloride reagent) was added. After the
reaction was stirred with DMAPA for 30 min, the reaction was
washed with hydrochloric acid to remove the amines from the
mixture. After drying and evaporation of the organic solvent, the
1
purity of the product was determined with H NMR (see the
Supporting Information). We were delighted to see that the
expected product had formed in excellent yield and that the
acidic workup had removed unwanted byproducts. (Table 4,
entries 1−3). When the reactions were quenched with water, on
the other hand, extended mixing times were necessary and the
products were shown to be not pure but contaminated with
anhydrides and unreacted reagents, underscoring the power of
DMAPA.
DMAPA could furthermore be used to remove benzoyl
chloride, tosyl chloride, and 2,2,2-trifluoro-N-phenylacetimidoyl
chloride.
Given the low cost and utility of DMAPA, it can be
recommended that it becomes a standard laboratory chemical
to ease reaction workup procedures in organic chemistry.
2,3,4,6-Tetra-O-acetyl-D-glucopyranose, 2,3,4,6-tetra-O-ben-
zoyl-D-mannopyranose, and 2,3,4,6-tetra-O-benzyl-D-glucopyr-
anose were chosen for the reaction with 2,2,2-trifluoro-N-
phenylacetimidoyl chloride. In these reactions, 2 equiv of 2,2,2-
trifluoro-N-phenylacetimidoyl chloride and 2 equiv of K2CO3
were reacted with the reducing sugars. The reactions were
quenched by addition of DMAPA (1.5 equiv), and the reaction
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data, and NMR
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org
C
DOI: 10.1021/acs.orglett.5b00041
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Letter
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hhj@chem.au.dk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from The Villum
Foundation.
■
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DOI: 10.1021/acs.orglett.5b00041
Org. Lett. XXXX, XXX, XXX−XXX