Mild deuteration method of terminal alkynes in heavy water using reusable basic resin

Abstract

The mild and efficient deuteration of terminal alkynes (mono-substituted alkynes) proceeded in the presence of a basic anion exchange resin, WA30, which is a polystyrene polymer bearing a tertiary amine residue on the aromatic nuclei, in heavy water (D₂O) at room temperature. WA30 could be easily removed by a simple filtration and repeatedly reused.

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The utility of deuterium-labeled compounds is widely recognized in various scientific fields, such as human metabolic, reaction mechanistic, analytic and material studies.^1,2 Among them, deuterated terminal alkynes were also utilized for mechanistic reaction studies³ and as useful building blocks to construct deuterium labeled materials (e.g., deuterated alkenes^3a,b,h,4 by hydrogenation, 1,2,3-triazole⁵ by Huisgen cycloaddition with azido compounds, and aromatics^3f,g by Lewis acid-catalyzed intra or intermolecular annulation and aromatization, etc.). The deuterated terminal alkynes are traditionally prepared via an acetylide, generated by the stoichiometric use of organolithium,^3a,b,c,g Grignard reagents^3f or Na metal^3h in a non-protic solvent, and subsequent quench using deuterium sources, such as D₂O and CD₃OD, in association with the production of a large amount of metal sludge. Additionally, the deuteration using the silver salt/CD₃CO₂D combination⁶ or triazabicyclodecene (TBD)⁷ and N-heterocyclic carbene⁸ in CDCl₃ has also been reported. Bew et al. recently developed a mild deuteration method of terminal alkynes under basic reaction conditions in the presence of K₂CO₃ in a D₂O/CH₃CN mixed-solvent.⁵ We have also reported a deuteration method using Et₃N as an organic base in a D₂O/THF mixed-solvent at nearly the same time.⁴ However, the development of the deuterium-labeled method using a reusable catalyst in D₂O as a neutral and cheapest deuterium source without an organic co-solvent is still challenging from the viewpoint of green sustainable chemistry. We now demonstrate a clean and mild deuteration method of terminal alkynes using a reusable solid organic base in D₂O at room temperature.

Various polystyrene polymer resins bearing an amine residue within the basic skeleton are readily available, and we have previously utilized basic and neutral resins (WA30, CR11, CR20 and HP20 shown in Table 1) as supports of a heterogeneous transition metal-catalyst for coupling reactions,⁹ chemoselective reductions¹⁰ and oxidations.¹¹ We first investigated the effect of the substituent connected to the polystyrene polymer backbone for the direct deuteration of 4-ethynylanisole (1a) as a terminal alkyne (Table 1). The deuteration of 1a (0.25 mmol: oil) using 115 weight% (wt%) of the polystyrene WA30 resin bearing the tertiary amine residue purchased from the Mitsubishi Chemical Corporation in D₂O smoothly proceeded to give the desired deuterated terminal alkyne (1a-d₁) with an excellent deuterium content (99% D) and yield (93%) for 8 h (Entry 1). While AMBERLYST™ A21 possessing a structure similar to WA30 (ref. 12) and CR11 bearing the iminodiacetic acid residue as a kind of tertiary amine were also effective (Entries 2 and 3), CR20 possessing secondary and primary amine moieties within the molecule was inefficient as a deuteration catalyst (Entry 4). Meanwhile, the use of the polystyrene resin without amine moieties (HP20) never facilitated the desired deuteration of 1a (Entry 5). WA30 possessing a physically durable structure was chosen as the optimal basic solid catalyst to achieve the high deuterium content of 1a-d₁.

Table 1 Effect of resin^a

Entry	Resin	D content (%)	Yield^a (%)
a WA30, CR11, CR20 and HP20 were commercially available from Mitsubishi Chemical Corporation. AMBERLYST™ A21 was commercially available from the ORGANO Corporation. All resins were washed with water and methanol, then dried in vacuo before using them.
1	WA30	99	93
2	AMBERLYST™ A21	93	86
3	CR11	98	93
4	CR20	34	96
5	HP20	0	100

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We next examined the efficiency based on the WA30 usage (Table 2). The deuterium contents of 1a increased in tandem with the WA30 usage (Entries 1, 3 and 5). The efficient deuterium incorporation of 1a to 1a-d₁ was never achieved using 10 or 50 wt% WA30 (Entries 2 and 4). Although 115 wt% of WA30 versus 1a was required to obtain the quantitative deuterium efficiency for the shorter reaction time (Entries 4 vs. 5), it is remarkable that WA30 could be reused at least 5 times without any deactivation and technical loss to accomplish the excellent D contents and isolated yield of 1a-d₁ (Table 3).

Table 2 Effect of resin usage

Entry	X	Time (h)	D content (%)
a Isolated yield.
1	13.2 (10 wt%)	8	23
2	13.2 (10 wt%)	24	45
3	66.1 (50 wt%)	8	75
4	66.1 (50 wt%)	12	94
5	152 (115 wt%)	8	99 (93^a)

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Table 3 Reuse test

Try	D content (%)	Yield (%)	Recovery yield of WA30 (%)
1^st	99	95	97
2^nd	99	96	99
3^rd	99	97	>99
4^th	99	97	99
5^th	98	Quant.	99

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The present reaction efficiencies were significantly affected by the physical state of the substrates (oil or solid, Table 3 vs. eqn (1) and Table 4). An oily substrate, such as 1a, smoothly and efficiently underwent the deuteration in D₂O (Table 3). While 1-ethynyl-4-phenylbenzene (1b) as a solid-state substrate was never deuterated in D₂O (eqn (1)), the addition of a small amount of toluene as a co-solvent to dissolve the substrate dramatically improved the deuterium content to give the quantitatively deuterated 1b-d₁ (the effect of other organic solvents are described in the ESI†). Furthermore, WA30 used in a D₂O/toluene mixed-solvent could also be repeatedly reused (see ESI†).

Table 4 Scope of substrates

Entry		Product	Co-solvent	Time (h)	D content (%) [yield (%)]
a At 50 °C.b 0.5 mL of the co-solvent was added.
Oily substrates
1			—	8	96 [95]
2			—	8	99 [59]
3			—	8	99 [quant.]
4			—	8	99 [90]
5			—	8	95 [93]
6^a			—	16	93 [65]
Solid-state substrates
7			—	8	15 [91]
8			Toluene	12	97 [97]
9			—	8	18 [94]
10			Toluene^b	12	94 [97]
11			—	8	19 [98]
12			Toluene	12	96 [quant.]
13			—	8	19 [86]
14^a			Toluene	12	35 [89]
15			—	8	0 [84]
16^a			AcOEt^b	24	92 [94]

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Various mono aryl- and alkyl-substituted alkynes could be efficiently deuterated to give the corresponding mono-deuterium labeled alkynes (Table 4). 2-Methoxy (1c) and trifluoromethyl (1d) ethynylbenzene as oily substrates were smoothly deuterated with excellent deuterium efficiencies in D₂O (1c-d₁ and 1d-d₁) (Entries 1 and 2). The oily propargyl alcohol derivatives (1e–g) were also efficiently deuterated in quantitative deuterium contents (1e-d₁, 1f-d₁, 1g-d₁) accompanied without hydrolysis of the ester (1e) or decomposition of the benzyl ether (1f) and sulfide moiety (1g) under the present reaction conditions (Entries 3–5). Dodecyne (1h) as an oily aliphatic terminal alkyne was effectively deuterated in D₂O by heating at 50 °C (Entry 6). Although the 4-amino (1i) and nitro (1j) ethynylbenzenes and a naphthalene derivative (1k) as solid-state substrates were inefficiently deuterated in D₂O (Entries 7, 9 and 11), the addition of toluene as a co-solvent facilitated the deuteration of 1i, 1j and 1k to give the corresponding deuterium-labeled alkynes, respectively (1i-d₁, 1j-d₁ and 1k-d₁) (Entries 8, 10 and 12). On the other hand, the deuteration of the solid-state N-(propargyloxy)-phthalimide (1l) resulted in the low deuterium incorporation regardless of the addition of toluene as a co-solvent (1l-d₁) for some unaccountable reason (Entries 13 and 14). Ethynylestradiol (1m), which is crucial medicinal compound as the solid-state substrate, never underwent the deuteration in D₂O. The addition of AcOEt as a co-solvent facilitated the deuteration of 1m (Entries 15 vs. 16), while the addition of toluene was ineffective (see ESI†).

Conclusions

We have developed a mild and efficient deuteration method of terminal alkynes by using a heterogeneous basic polystyrene resin (WA30) in D₂O under mild conditions. It is noteworthy that oily substrates smoothly underwent the direct deuteration in D₂O, while the deuteration of solid substrates could be facilitated by the addition of a small quantity of a co-solvent, such as toluene and AcOEt. A wide variety of functional groups (e.g., nitro, propargyl ester, sulfide, benzyl ether, etc.) could be tolerant under the present mild reaction conditions. WA30 could be repeatedly used without any loss of catalyst activity. The present clean deuteration method of terminal alkynes is expected to be utilized in not only laboratories, but also industrial fields as an economic and eco-friendly reaction.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Details of the general procedure for deuteration, and NMR spectral data of the products. See DOI: 10.1039/c5ra18921g

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