Mechanistic studies on the metal-free decarboxylativecoupling reaction for synthesis of propargylamines by NMR

Metal-free decarboxylative coupling reaction of phenylpropiolic acid, paraformaldehyde, and morpholine was monitored by NMR spectroscopy ( 1 H, 13 C NMR, NOE, DOSY, COSY HMBC, and HSQC). Hemiaminal and bisaminal were obtained from the reaction with paraformaldehyde and morpholine. The resulting hemiaminal was more reactive than the corresponding bisaminal in the reaction with phenylpropiolic acid. The decarboxylative coupling with hemiaminal and phenylpropiolic acid may be the major pathway, producing the desired phenylpropargylamine.


Introduction
In recent years metal-catalyzed decarboxylative coupling reactions have received much attention in organic chemistry. 1,2As the starting materials, carboxylic acids, are stable and environmentally friendly because they release nontoxic carbon dioxide as the by-product in the coupling reactions.The decarboxylative coupling reaction with aromatic carboxylic acids has been developed since Goossen first reported Pd-catalyzed decarboxylative coupling in 2007. 3We first reported the Pd-catalyzed decarboxylative coupling of alkynylcarboxylic acids in 2008. 4,5][8][9][10][11][12][13][14][15][16] The decarboxylative coupling of alkynylcarboxylic acids showed a similar reaction pattern to the Sonogashira reaction of terminal alkynes.8][19][20][21] In particular, propiolic acid has been widely used as a source of acetylene because it can be easily handled and stored.
][36][37][38][39][40][41][42][43][44][45] Recently, we reported the Cu-catalyzed three-component reaction of arylalkynylcarboxylic acids with aldehydes and amines to provide the corresponding propargyl amines. 46This threecomponent coupling provides the desired products even in the absence of metal catalysts when paraformaldehyde is used. 47This report was the first example of the metal-free decarboxylative coupling reaction of alkynylcarboxylic acids.In continuation of our efforts to develop decarboxylative coupling reactions and investigate their reaction pathways, a systematic study was conducted on the mechanism of metal-free synthesis of propargylamines.Herein, we report NMR studies on the reaction pathways to the decarboxylative coupling with phenylpropiolic acid (PPA), paraformaldehyde, and amine (morpholine).

Results and Discussion
In the metal-free three-component reaction, we expect that the formation of an aldimine is the initial reaction step. 48,49When formaldehyde and morpholine were reacted at 25 °C in CD 3 CN, both hemiaminal (HA) and bisaminal (BA) were formed in 56 and 44% yields, respectively, in the reaction mixture as shown by the 1 H NMR analysis (Figure 1a and Table 1).The experiment was carried out without any drying process for the reagents.All the peaks were assigned by 2D NMR analysis (see Supplementary Material, Figure S1).The singlet peaks of the methylene protons in HA and BA appeared at 4.09 and 2.86 ppm, respectively, in the 1 H NMR spectra.When the amount of morpholine was doubled, and the ratio of paraformaldehyde to morpholine was 1:2, only BA was observed in the 1 H NMR spectrum of the reaction mixture.When the temperature was increased to 65 °C, HA and BA reached the equilibrium state (HA = 60% and BA = 40%).
We added an equal amount of phenylpropiolic acid (PPA) into this resulting mixture and monitored the progress of the reaction by 1 H and 13 C NMR (Figure 2).Interestingly, the desired product, phenylpropargylamine (PGA), was formed in 40% yield in 10 min after adding the PPA.However, there was no further increase in this product after a further 24 h at room temperature.As shown in Table 2, we assigned all the peaks using 2D NMR analysis (COSY, HSQC, and HMBC) (see Supporting Information, Figure S2).All the peaks of free HA and BA in the mixture with PPA shifted to high frequency value in the 1 H NMR spectra.This might result from the interactions with PPA through hydrogen bonding.We propose their intermediate structures as A and B (Figure 3), in which the morpholine moiety is close to the phenyl ring of PPA, because NOE effect was observed between the phenyl protons of PPA and H b of HA and BA.    a All the peaks were assigned based on the 2D NMR analysis  We were able to observe DOSY peaks, which can be attributed to the adducts of the starting materials, HA and PPA (denoted as HA−PPA, Figure 4).The three components of dimeric PPA, HA−PPA adduct, and PGA were observed in the order of diffusion coefficients according to the respective formula weights.The reaction intermediate, HA−PPA, is shown between the dimeric PPA, the largest formula weight compound with the lowest diffusion coefficient, and PGA, the smallest formula weight compound with a higher diffusion coefficient.
Moreover, the carbon peak of the carboxylic acid in free PPA shifted to high frequency value in the 13 C NMR when PPA was reacted with a mixture of paraformaldehyde and morpholine.As shown in Figure 5b, the carbonyl carbon of PPA was observed at δ 155.0 ppm; however, it appeared at δ 160.2 ppm in the reaction mixture.The alkynyl carbons shifted to low frequency value in the intermediate.
To follow the reaction profile, this reaction mixture was monitored at 65 °C by NMR.As shown in Figure 6, the integration values of proton peaks from HA and BA decreased, and those from product (PGA) increased with time.The proton peak of the carboxylic acid shifted to low frequency value, and its intensity decreased (see Supporting Information of Figure 3).Based on these spectroscopic data, the reaction profile was plotted as shown in Figure 7.The yields were determined using the internal standard tetramethylsilane.When PPA was added to a mixture of paraformaldehyde and morpholine, 40% of PPA was converted to the desired product in 10 min.As expected, the yield of propargylamine increased to 86% in 5 h; however, PPA was not completely consumed.Based on these results, we proposed the reaction pathway as shown in Scheme 1. First, the reaction of paraformaldehyde and morpholine afforded the corresponding HA and BA.HA might be more reactive than BA in the decarboxylative coupling reaction.When the amount of morpholine was doubled, only BA was formed, and the desired product was obtained in a low yield (5%).However, the iminium ion C which is derived from the HA was not detected in the reaction mixture by 1 H− 13 C HMBC 2D NMR analysis.The interaction of HA with PPA produced the hydrogen-bonding adduct A and provided the desired propargylamine through decarboxylation (path A).Path A is much favored than path B, because adduct B not detected in NMR.Although vinyl carbocation intermediate D proposed in the previous report 47 was not detected in the reaction mixture by 1 H− 13 C HMBC 2D NMR analysis, the NMR data analysis support that the decarboxylative coupling might proceed through the intermediate A. However, we do not rule out the possible pathway B in which the intermediate B reacts so fast.

Conclusions
In summary, the reaction pathway of the decarboxylative coupling reaction of PPA with paraformaldehyde and morpholine was studied by NMR spectroscopic analysis.Two aminals (HA and BA) were formed in the reaction mixture, and HA showed higher reactivity than BA.Moreover, the interactions of these aminals with PPA formed the corresponding adducts, which were identified by 2D NMR analysis and DOSY.The decarboxylative coupling reaction of HA and PPA may be the major pathway in the formation of propargylamines.

Figure 1 .
Figure 1.NMR spectra of HA and BA in CD 3 CN.

Figure 2 .
Figure 2. NMR spectra of the reaction mixture of PPA, paraformaldehyde and morpholine in CD 3 CN.

Figure 3 .
Figure 3. Proposed reaction intermediates A and B.

Figure 4 .
Figure 4. DOSY spectrum.DOSY analysis of a HA−BA−PPA mixture after 72 h of reaction at 65 °C in CD 3 CN.Ordinate (F1 axis) represents the diffusion coefficient in 10 10 m 2 /s, and the other axis (F2 axis), abscissa, represents a regular one-dimensional 1 H NMR spectrum.

Figure 6 .
Figure 6. 1 H NMR data of the reaction mixture with PPA, paraformaldehyde and morpholine in CD 3 CN.

Figure 7 .
Figure 7.The reaction profile of the formation of PGA from PPA and paraformaldehyde and morpholine.

Scheme 1 .
Scheme 1. Proposed pathway of the formation of PGA from decarboxylative coupling reaction.

Table 1 .
13signment of 1 H and13C NMR of HA and BA a a Reaction conditions: paraformaldehyde (9.0 mg, 0.3 mmol) and morpholine (26.1 mg, 0.3 mmol) were dissolved in CD 3 CN (0.8 mL) and mixed for 2 h at 25 °C, and the resulting solution was monitored by NMR (500 MHz).ARKAT-USA, Inc