Synthesis of Polar Aromatic Substituted Terminal Alkynes from Propargyl Amine

A series of small molecules containing polar aromatic substituents and alkynes have been synthesized. One–pot preparations of polar aromatic molecules containing an alkynyl imine and alkynyl amide are reported. A one-pot preparation of a catechol containing an alkynyl amine was also attempted but in our hands it proved much better to synthesize this target molecule via a three step synthesis which we also report here.


Introduction
A series of small molecules containing polar aromatic substituents and propargyl amines were synthesized so that they could potentially be incorporated into hydrogel systems as an approach to developing a better hydrogen bonded and more rigid hydrogel via a thiol-alkyne click reaction [1][2][3][4][5][6]. Propargyl amines are also an important class of molecules in their own right, and are used as building blocks in heterocyclic chemistry and pharmaceutical chemistry [7,8]. Three main structural aspects of the small molecules to be synthesized were considered: (1) a polar functional group for enhanced hydrogen bonding, (2) an alkyne functional group for attachment to thiol containing hydrogels via the thiol-alkyne click reaction, and (3) ease of synthesis of the small molecule, i.e., where possible, one-pot reactions from inexpensive, commercially available starting materials.

Introduction
A series of small molecules containing polar aromatic substituents and propargyl amines were synthesized so that they could potentially be incorporated into hydrogel systems as an approach to developing a better hydrogen bonded and more rigid hydrogel via a thiol-alkyne click reaction [1][2][3][4][5][6]. Propargyl amines are also an important class of molecules in their own right, and are used as building blocks in heterocyclic chemistry and pharmaceutical chemistry [7,8]. Three main structural aspects of the small molecules to be synthesized were considered: (1) a polar functional group for enhanced hydrogen bonding, (2) an alkyne functional group for attachment to thiol containing hydrogels via the thiol-alkyne click reaction, and (3) ease of synthesis of the small molecule, i.e., where possible, one-pot reactions from inexpensive, commercially available starting materials.
Likewise, the coupling of propargyl amine (2) with the benzoic acids (9) using EDC as a coupling agent led to the amides (10, 11) also in good isolated yield (Scheme 2).

Scheme 2. Preparation of propargyl amides from propargylamine.
Preparation of the amine (15) proved much more complicated. There is a reported literature procedure for reductive amination of 3,4-dihydroxybenzaldehyde with propargyl amine, [9] but the reported yield is low (31%). The product is reported as a red solid, which seems unlikely for a pure compound with just a benzene ring or alkyne as a chromophore and it could be that this material also contains some charge transfer complexes produced under these conditions. When we performed the literature reaction, we isolated mixtures of amine 15 and what we think may possibly be the catecholboronate dimer. Rather than spend a lot of time trying to rigorously identify this byproduct, we chose to investigate an alternate, straightforward route for the preparation of compound 15 (Scheme 3. See Supplementary Materials). Ultimately, to obtain pure amine (15), we found that we first had to protect the catechol (1, R1 = R2 = OH) as previously reported acetonide (12) [10,11], which was then subjected to reductive amination to produce (13) as shown in Scheme 3. Acetonide (13) was deprotected to yield ammonium salt (14) which was then deprotonated to yield the desired amine (15).

General Methods
NMR spectra were obtained on a Bruker 400 MHz spectrometer and mass spectrometry was performed on a Thermo LTQ Orbitrap XL. All reagents and materials were obtained from the suppliers listed below. Fischer Scientific: sodium sulfate; Acros: 1,2-Dichloroethane, 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide, propargylamine; Sigma Aldrich: all aromatic aldehydes and acids; Cambridge Isotope Laboratories: Preparation of the amine (15) proved much more complicated. There is a reported literature procedure for reductive amination of 3,4-dihydroxybenzaldehyde with propargyl amine [9], but the reported yield is low (31%). The product is reported as a red solid, which seems unlikely for a pure compound with just a benzene ring or alkyne as a chromophore and it could be that this material also contains some charge transfer complexes produced under these conditions. When we performed the literature reaction, we isolated mixtures of amine 15 and what we think may possibly be the catecholboronate dimer. Rather than spend a lot of time trying to rigorously identify this byproduct, we chose to investigate an alternate, straightforward route for the preparation of compound 15 (Scheme 3. See Supplementary Materials). Ultimately, to obtain pure amine (15), we found that we first had to protect the catechol (1, R 1 = R 2 = OH) as previously reported acetonide (12) [10,11], which was then subjected to reductive amination to produce (13) as shown in Scheme 3. Acetonide (13) was deprotected to yield ammonium salt (14) which was then deprotonated to yield the desired amine (15). Likewise, the coupling of propargyl amine (2) with the benzoic acids (9) using EDC as a coupling agent led to the amides (10, 11) also in good isolated yield (Scheme 2).

Scheme 2. Preparation of propargyl amides from propargylamine.
Preparation of the amine (15) proved much more complicated. There is a reported literature procedure for reductive amination of 3,4-dihydroxybenzaldehyde with propargyl amine, [9] but the reported yield is low (31%). The product is reported as a red solid, which seems unlikely for a pure compound with just a benzene ring or alkyne as a chromophore and it could be that this material also contains some charge transfer complexes produced under these conditions. When we performed the literature reaction, we isolated mixtures of amine 15 and what we think may possibly be the catecholboronate dimer. Rather than spend a lot of time trying to rigorously identify this byproduct, we chose to investigate an alternate, straightforward route for the preparation of compound 15 (Scheme 3. See Supplementary Materials). Ultimately, to obtain pure amine (15), we found that we first had to protect the catechol (1, R1 = R2 = OH) as previously reported acetonide (12) [10,11], which was then subjected to reductive amination to produce (13) as shown in Scheme 3. Acetonide (13) was deprotected to yield ammonium salt (14) which was then deprotonated to yield the desired amine (15).

Conclusions
We successfully prepared a number of new polar aromatic substituted terminal alkynes from propargyl amine and we hope scientists working with thiolated hydrogels will incorporate them into their hydrogels and that they will also be used in pharmaceutical chemistry, with the anticipation that those modified molecules will have interesting new properties.

Data Availability Statement:
The data presented in this study are available upon request from the corresponding author.