Base-Mediated Deuteration of Organic Molecules: A Mechanistic Insight

Abstract

A base-promoted, step-economical, and cost-effective strategy for introducing heavy isotopes into the organic molecules has been developed. The schemes involve the selective deuteration of various electronically distinct molecules that are formed because of deuterioamination, deuteriothiolation, deuteriophenoxylation, and deuterioalkoxylation as well as tandem cyclization using dimethyl sulfoxide (DMSO)-d₆ as a deuterium source. The reaction involves a metal-, ligand-, and additive-free route and provides a high level of deuterium incorporation in the presence of DMSO-d₆ as an inflammable and ecological reagent. The reaction is well tolerated across the electronically varied substrates for the successful incorporation of deuterium into the product. The proposed mechanistic pathway for various transformations has been well supported by NMR studies.

Introduction

Deuterium-labeled molecules are significant tools for the study of metabolic pathways and reaction mechanisms as interior standards in analytical protocols.¹ Deuterium is generally used in isotope labeling and as the primary source for determining the kinetic isotope effects in mechanistic studies.² A wide diversity of deuterated compounds are commercially accessible; however, they can be prohibited because of their high cost. It is believed that the introduction of deuterium in any existing drug molecule enters new breathe into the drug,³ for instance, AVP-786 is the deuterated version of the cough suppressant dextromethorphan. Scientists created a version of dextromethorphan that has deuterium instead of hydrogens on the key site of the molecule that is involved in metabolism (Figure 1i).⁴ Similarly, deuterium in fludalanine was preamble to block the formation of toxic metabolites (Figure 1ii).⁴ The molecule DRX-065 is the deuterated form of the diabetes treatment, pioglitazone, which is formed to lower the side effects caused due to hydrogenated drugs (Figure 1iii).⁴

Figure 1.

Selected deuterated drug molecules: (i) AVP-786, the deuterated version of dextromethorphan. (ii) Fludalanine, the deuterated drug molecule. (iii) DRX-065, the derivative of pioglitazone.

The literature survey revealed that various C–H bond functionalization reactions combined with the deuteration of the activated substrate have been developed using transition-metal catalysts.⁵ In 1997, Junk and co-workers⁶ extended their research on deuterium labeling of pyrazoles and quinoxalines through a base-induced isotope exchange in superheated deuterium oxide for the synthesis of 3,5-dimethyl-1D-pyrazole-d₂. Other N-heterocyclic moieties such as 2-methylquinoxaline-d₈, 2,3-dimethylquinoxaline-d₁₀, 3,5-dimethylpyrazole-d₈, and 3,5-diphenylpyrazole-d₁₂ were also deuterated using the same methodology (Scheme 1a). In 2004, Matsubara’s group⁷ demonstrated a Pt­(IV)-catalyzed H–D exchange of arylsilanes under hydrothermal conditions. The arylsilanes were regioselectively labeled with deuterium oxide. Arylsilanols were also tagged with deuterium using a similar strategy. They have also extended the H–D exchange chemistry on the benzene ring of polystyrene in D₂O with platinum oxide as the catalyst. The same group⁸ has also explored the Pd-catalyzed decarboxylation and decarbonylation under a hydrothermal condition of Pd/C (5 mol %) and D₂O at 250 °C. The combination of the palladium catalyst and hydrothermal water was fruitful for the decarboxylation of free carboxylic acids and decarbonylation of aldehydes. Later, the Sajiki group⁹ has established a proficient isotopic exchange reaction on the alkyl side chain of aromatic compounds using a heterogeneous Pd/C-D₂O–H₂ catalytic system into many different types of unactivated C–H bond positions. An elegant approach for the hydrogenation of alkynyl stannanes using the Ru catalyst via the migration of the stannyl group giving α-substituted vinylstannanes has been described by Shirakawa and co-workers¹⁰ in 2004 (Scheme 1b). Significant progress on the deuteration of cyclopentadienyl ligand was made by the Shapiro group¹¹ in 2005. The thermal heating of the cyclopentadienyl ligand in dimethyl sulfoxide (DMSO)-d₆ provided Cp₂Ca-d₁₀ with 97% of D exchange. The H–D exchange occurred at the 2,5-position of the 1-cyclopentenyl substituent (Scheme 1c). The selective deuteration of alkene has been well documented by Hartwig¹² and researchers in 2008 for the deuteration of the vinyl group using the iridium catalyst. It is noteworthy that the olefin group did not undergo isomerization (Scheme 1d). In 2012, Schnürch and co-workers¹³ reported a selective Ru(0)-catalyzed deuteration of N-heteroarenes as well as benzylic −CH₂ group under conventional heating. They have also established a microwave-assisted deuteration of electron-rich N-heterocycles (Scheme 1e). Recently, Gunanathan and researcher¹⁴ demonstrated a facile route for the selective ruthenium-catalyzed α-deuteration of primary alcohols and α,β-deuteration of secondary alcohols using D₂O as an isotopic source. They have also utilized the similar protocol for the deuteration of terminal alkyne (Scheme 1f). In 2016, Rosales and Rodríguez-García have reported an elegant approach for the deuteration of organic compounds in the presence of Cp₂TiCl/D₂O/Mn.¹⁵ To the best of our knowledge, the phenomena of deuteration have not been applied to the organic reactions such as nucleophilic addition reaction and domino processes. As an extension of our current research on superbasic chemistry,¹⁶ we endeavor to propose our new finding of N-,S-,O-nucleophilic deuterioaddition reaction with alkynes using DMSO-d₆ as a deuterium source (Scheme 1g).

Scheme 1. Strategies for Deuteration: (a) Deuteration of Pyrazoles; (b) Synthesis of Vinylstannanes; (c) H–D Exchange of 1-Cyclopentenyl; (d) Deuteration of Alkene; (e) Deuteration of N-Heterocycles; (f) Deuteration of Secondary Alcohols and Alkyne; and (g) Our Strategy.

Results and Discussion

Scope of Deuterioamination Chemistry

Inspired by our previous knowledge of superbase chemistry,¹⁶ we applied our developed protocol for deuteration on hydroamination chemistry (Table 1). We began our investigation using indole 1a and 5-methyl indole 1b as a starting substrate with electron-donating alkynes such as −Me, −Et, and −ⁿBu at para position to the distal end of triple bond of the phenyl ring and showed the capability to trigger the nucleophilic addition products 3a–d in 85–79% yields. It was interesting to note that deuteration also occurred at the styryl protons, the nucleophilic position of the indole ring, and the acidic proton of the alkyl group (Table 1, entries 1–4). The deuterium exchange occurs at moderately acidic sites in the precursors, and probably because of the +I effect (inductive effect), the acidity of the long-chain alkyl group decreases; hence, deuteration occurs only at benzylic positions. In the case of 5-methoxyindole 1c, because of the presence of the ether group, the degree of deuteration was lowered at the C-3 position in the addition product 3e with an 83% yield (entry 5). The pyrrole moiety 1d being highly reactive provided the deuterioaminated product 3f in lesser reaction times; as a consequence, deuteration did not occur at nucleophilic sites (entry 6). Exploring the reaction of N-heterocycles 1d and 1b with unactivated internal alkyne 2f in the presence of DMSO-d₆ for 18 h afforded 100% deuterium incorporation at styryl and nucleophilic positions, providing the deuterioaminated products 3g and 3h in good yields (entries 7 and 8). The electronic effect of the substrate influences the distribution of deuterium at different positions, favoring the formation of deuterated products.

Table 1. Scope of Deuterioamination^a,b.

^aReaction conditions: N-heterocycle 1 (0.5 mmol), alkyne 2 (0.5 mmol), KOH (20 mol %) in 2.0 mL of DMSO-d₆ at 120 °C for 20 min.

^bIsolated yields.

^cTime = 15 min.

^dTime = 18 h and KOH (2.0 equiv).

In order to support the above results of Table 1, we proposed a plausible mechanistic pathway in a superbasic system (Scheme 2). Presumably, the base-promoted H–D exchange occurs into the terminal alkyne. Then, the mechanism is initiated by the proton abstraction II from the N-heterocycles I, followed by the nucleophilic addition onto alkyne in an anti-Markovnikov manner to develop alkenyl ion species III. Consequent substitution of deuterium from DMSO-d₆ with hydrogen leads to the generation of DOH. Deuteration of the alkenyl anion with DOH afforded the deuterioaminated product IV. The second phase of the mechanism is a simple H–D exchange reaction, which began with the attack of deuterium by a π-bond of the aromatic ring. Simultaneously, breaking of the C–H bond and formation of the C–D bond restore the aromaticity via the generation of a carbocation species V, leading to the synthesis of a deuterated product VI. Similarly, another substitution reaction occurs at the C-2 position (species VII) of the heterocyclic ring, leading to the formation of the deuterioaminated product 3.

Scheme 2. Plausible Mechanistic Pathway.

Scope of Deuteriothiolation and Deuteriophenoxylation

After attaining successful incorporation of deuterium in hydroamination chemistry and to probe the synthetic utility of the designed protocol, we endeavor to focus our attention toward the H–D exchange in hydrothiolation and hydrophenoxylation chemistry (Scheme 3). The reaction of thiophenol 4a–c and phenol 4d–f with alkyne 2 successfully provided 100% styryl deuteration in the addition product 5a–f in good yields. We observe that the H–D exchange of the alkyl group on the phenol side did not occur; however, deuteration of the −Me group takes place on the alkyne side (5d vs 5e). This is probably due to the electronic effect of the direct ether linkage of the ethyl group at the distal end of the phenolic ring in the case of 5e; however, the methyl group is present at the distal end of the electron-rich alkynic benzene ring.

Scheme 3. Deuteriothiolation and Deuteriophenoxylation.

Scope of Deuterioalkoxylation

To further enhance the feasibility of the developed methodology, we were intrigued to extend the scope of reaction on alcohols (Scheme 4). We began our investigation with the addition reaction of methanol 6a by treating with phenylacetylene 2g in DMSO-d₆ at 120 °C for 10 h to obtain the deuterated product 7a in a 78% yield. The reaction of ethanol 6b with electron-neutral 2g and electron-withdrawing alkyne 2h provided the styryldeuterated products 7b and 7c in 78 and 71% yields, respectively.

Scheme 4. Deuterioalkoxylation.

Mechanistic Studies

In order to study the detailed mechanistic pathway, we performed several experiments as depicted in Scheme 5. The reaction of thiophenol 4g and alkyne 2d in a superbasic medium at 120 °C for 4 h gave the hydrothiolated product 5g″ without the replacement of styryl protons with heavy hydrogen (Scheme 5i). In order to confirm the incorporation of olefinic deuterium in the product, we carry out another control experiment. The reaction of thiophenol 4g in DMSO/DMSO-d₆ (1:1 ratio) provided the product 5g′ with 50% H–D exchange of alkenyl protons (Scheme 5ii). By further utilizing DMSO-d₆ as a solvent for the above reaction, the addition product 5g was obtained with 100% inclusion of deuterium at styryl positions (Scheme 5iii). All the above experiments suggest that the solvent plays a crucial role of deuterium incorporation in the addition product.

Scheme 5. Deuterium-Labeling Studies for Deuteriothiolation Based on Solvent Condition: (i) Hydrothiolation in Solvent DMSO; (ii) Hydrothiolation in Solvent DMSO/DMSO-d₆ (1:1); and (iii) Hydrothiolation in Solvent DMSO-d₆.

Another phase of the experiment depicted in Scheme 6 suggests that the base abstracts the acidic proton from the substrate, and then an interexchange of protons occurs between the substrate and the solvent DMSO. A comparative study of ¹H NMR of DMSO and DMSO-d₆ has been represented in Scheme 6ia,ib.

Scheme 6. Comparative Reference ¹H NMR of Solvents for the Confirmation of the Mechanism.

Then, the reaction of DMSO/DMSO-d₆ in KOH has been performed at 120 °C; however, a significant change in ¹H NMR was observed that in the absence of KOH, the water peak is taller than the residual proton peak of DMSO-d₆. In the presence of KOH, the DMSO signal is much larger than the water peak, which remains sharp. This suggests that the H–D exchange between DMSO-d₆ and the residual water is promoted by KOH (Scheme 6iia,iib). Interestingly, when we performed the reaction of thiophenol 4g with alkyne 2d in KOH/DMSO-d₆ at 120 °C, the crude ¹H NMR of the product illustrated the styryl deuteration of product 5g along with a singlet at δ 2.48 ppm, suggesting the reformation after scrambling of DMSO with in situ generation of D₂O/DOH. The result also shows the complete scrambling of the water and exchanged organic protons into DMSO. The fact that no water signal is observed suggests that the water protons have also been exchanged with deuterium.

Scope of Tandem Cyclization

The extent of the reaction was inspected for the deuteration of fused indolo, pyrrolo­[2,1-a]­isoquinoline 8a–f via tandem cyclization (Table 2). When an ortho-bromo arylalkyne 2i–k was employed for tandem cyclization using indole 1a, 3-methylindole 1b, and 5-methoxyindole 1c, the selective H–D exchange occurs at the active site of the N-heterocycle and alkyne.

Table 2. Scope of Deuteration in Tandem Cyclization^a.

^aReaction conditions: N-heterocycle 1 (0.5 mmol), haloarylalkyne 2 (0.5 mmol), CuI (5 mol %), BtCH₂OH (10 mol %), and KO^tBu (1.4 equiv) in 2.0 mL of DMSO-d₆ at 120 °C for 18 h.

^bIsolated yields.

When indole 1a underwent tandem cyclization with alkyne 2i–j in the presence of CuI/BtCH₂OH, KO^tBu, and DMSO-d₆, the deuterated products 8a–b were obtained in 71 and 69% yields, respectively, with a high degree of deuteration at nucleophilic positions (Table 2, entries 1–2). Blocking the C-3 position of indole with methyl provided the selective deuteration at alkyl, styryl, and C-4 positions of the annulated products 8c–d in good yields (entries 3 and 4). The reaction of 3-methylindole 1b with an internal alkyne 2k afforded the deuterated product 8e in a 73% yield (entry 5). It was peculiar to note that on using an ether-linked N-heterocycle such as 5-methoxyindole 1c, the fused product 8f was obtained in a 66% yield with deuteration at alkyl, styryl, and C-7 positions of the heterocyclic moiety because of the presence of the −OMe group at the C-5 position (entry 6).

On the basis of the above results reported in Table 2, we have studied the mechanistic pathway to gain additional insights into the reaction and disclose the nature of the addition steps occurring in tandem cyclization (Scheme 7). The superior addition reaction of N-heterocycles 1 with bromoarylalkyne 2 suggested that the conversion of the copper-catalyzed tandem synthesis of indolo- and pyrrolo-[2,1-a]­isoquinolines 7 proceeds via regio- and stereoselective base-promoted deuterioamination B, followed by oxidative addition (C). The copper complex D is formed by the intramolecular C-2 attack of nucleophile 1, which subsequently undergoes deprotonation, resulting in the formation of species E. Reductive elimination of E afforded the annulated product and regenerates copper complex A. When DMSO-d₆ was used in the place of DMSO, the incorporation of deuterium in the cyclized product supports the reaction pathway.

Scheme 7. Plausible Mechanism.

Conclusions

In summary, we have envisaged a robust reaction condition for the selective deuteration of various electronically distinct molecules. The technique of step-economical deuteration has been implemented over nucleophilic addition reactions such as deuterioamination, deuteriothiolation, deuteriophenoxylation, and deuterioalkoxylation as well as tandem cyclization. The reaction involves a metal-, ligand-, and additive-free route for a high level of deuterium incorporation using DMSO-d₆ as an inflammable and environment-friendly solvent. An electronic effect of the substrates plays a crucial role in controlling the degree of deuteration in the reaction. The comparative ¹H NMR studies support the proposed mechanistic pathway, which disclosed that the base abstracts the acidic proton from the substrate and then an interexchange of protons occurs between the substrate and the solvent DMSO. It is likely that the operational simplicity of the developed protocol will make it attractive for the chemists and biologists because of the relevance of deuterated molecules.

Experimental Section

General Information and Method

All the reactions were performed in an oven-dried Schlenk flask under an argon atmosphere. Column chromatography was performed using a neutral and basic alumina and silica gel. Thin-layer chromatography (TLC) analysis was performed on commercially prepared 60 F₂₅₄ silica gel plates. Visualization of spots on the TLC plate was accomplished with UV light (254 nm) and by staining over the I₂ chamber. The ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were recorded in CDCl₃ and DMSO-d₆. The chemical shifts for carbons are reported in parts per million from tetramethylsilane and are referenced to the carbon resonance of the solvent. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, br s = broad), coupling constants in hertz, and integration. The high-resolution mass spectra were recorded with a q-TOF electrospray mass spectrometer. All purchased chemicals were used as received. All melting points are uncorrected.

General Procedure for the Synthesis of Internal Alkynes 2

The 1,2-diarylalkynes were prepared by the Sonogashira coupling reaction of the corresponding aryl iodide with terminal alkynes using the reported procedures.¹⁶ The chemical structure and purity of the known compounds were established by the comparison of their physical and spectral data (¹H NMR, ¹³C NMR, and HRMS) with those reported in the literature.

General Procedure for the Synthesis of Deuterated Enamines 3a–h

In an oven-dried sample vial, a solution of N-heterocycle 1­(0.5 mmol) with alkyne 2 (0.5 mmol) in 2.0 mL of DMSO-d₆, finely crushed KOH (20 mol %), was added. The resulting reaction mixture was stirred at 120 °C for 15–20 min for terminal alkynes and 18 h for internal alkynes. The progression of the reaction was monitored by TLC; while noticing complete consumption of alkynes, the reaction was brought to room temperature. The reaction mixture was diluted with ethyl acetate and water (10 mL × 3). The organic layer was concentrated under reduced pressure. The crude material so obtained was purified by column chromatography on a silica gel mesh of size 100–200 (hexane).

1-(4-Deuteritedmethylstyryl)-1H-indole-D (3a)

The product was obtained as a pale white oil (102.0 mg, 85%); ¹H NMR (400 MHz, CDCl₃): δ 7.78 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.41–7.36 (m, 1H), 7.34–7.30 (m, 1H), 7.22 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 137.2, 135.8, 131.8, 129.0, 128.5, 128.4, 127.0–126.4 (m, 1C), 122.5–122.2 (m, 1C), 120.8, 120.6, 119.5–119.0 (m, 1C), 110.1, 103.6–103.1 (m, 1C), 21.0–20.0 (m, 1C). HRMS (ESI): [M + H]⁺ calcd for [C₁₇H₈D₇N], 241.1722; found, 241.1712.

1-(4-Deuteritedethylstyryl)-1H-indole (3b)

The product was obtained as a pale white oil (104.9 mg, 82%); ¹H NMR (400 MHz, CDCl₃): δ 7.78 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.27–7.20 (m, 4H + 1H for CDCl₃); ¹³C NMR (100 MHz, CDCl₃): δ 143.6, 135.8, 132.0, 128.6, 128.4, 128.2, 127.8, 126.8 (t, J = 28.7 Hz, 1C), 122.5, 122.3, 120.8, 120.6, 119.3 (t, J = 23.0 Hz, 1C), 110.1, 103.3 (t, J = 22.0 Hz, 1C), 28.4–27.4 (m, 1C), 15.2 (t, J = 7.6 Hz, 1C). HRMS (EI-TOF): [M]⁺ calcd for [C₁₈H₈D₉N], 256.1926; found, 256.1924.

1-(4-Butylstyryl)-1H-indole-D (3c)

The product was obtained as a pale white oil (110.9 mg, 79%); ¹H NMR (400 MHz, CDCl₃): δ 7.71 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.32 (t, J = 6.8 Hz, 1H), 7.27–7.24 (m, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 1.64 (t, J = 7.6 Hz, 2H), 1.47–1.36 (m, 2H), 1.01 (t, J = 8.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 142.4, 135.8, 132.0, 128.6, 128.4, 126.8 (t, J = 36.4 Hz, 1C), 122.3 (t, J = 24.9 Hz, 1C), 120.8, 120.6, 119.2 (t, J = 17.2 Hz, 1C), 110.1, 103.3 (t, J = 23.9 Hz, 1C), 35.2–34.2 (m, 1C), 33.2, 22.3, 13.9. HRMS (ESI): [M + H]⁺ calcd for [C₂₀H₁₅D₆N], 282.2129; found, 282.2115.

1-(4-Deuteritedethylstyryl)-5-methyl-1H-indole-D (3d)

The product was obtained as a pale white oil (108.0 mg, 80%); ¹H NMR (400 MHz, CDCl₃): δ 7.53 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 7.6 Hz, 2H), 7.19 (d, J = 8.4 Hz, 3H), 2.60 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 143.4, 134.2, 132.1, 129.8, 128.6, 127.8, 127.1–126.5 (m, 1C), 123.8, 122.6–122.0 (m, 1C), 120.6, 118.9–118.4 (m, 1C), 109.7, 103.2, 28.6–27.1 (m, 1C), 21.4, 15.4–15.2 (m, 1C). HRMS (EI-TOF): [M]⁺ calcd for [C₁₉H₁₀D₉N], 270.2082; found, 270.2095.

1-(4-Bromostyryl)-5-methoxy-1H-indole-D (3e)

The product was obtained as a pale white oil (136.9 mg, 83%); ¹H NMR (400 MHz, CDCl₃): δ 7.46–7.41 (m, 3H), 7.34 (d, J = 8.7 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1.33H), 7.08–7.02 (m, 2H), 6.96–6.88 (m, 1H), 3.85 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 155.0, 135.1, 131.8, 131.5, 130.8–130.7 (m, 1C), 130.2, 129.6, 127.0, 124.1–123.7 (m, 1C), 121.2, 120.2, 112.7–112.4 (m, 1C), 110.8, 110.3, 103.2–102.9 (m, 1C), 55.8. HRMS (EI-TOF): [M]⁺ calcd for [C₁₇H₁₁D₃BrNO], 330.0447; found, 330.0438.

1-(2-Bromostyryl)-1H-pyrrole-D (3f)

The product was obtained as a pale white oil (101.2 mg, 81%); ¹H NMR (400 MHz, CDCl₃): δ 7.59–7.54 (m, 1H), 7.48–7.46 (m, 1H), 7.28–7.24 (m, 1H), 7.10–7.05 (m, 1H), 7.01–6.99 (m, 2H), 6.29–6.28 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 135.9, 132.7, 130.6, 129.0, 127.2, 124.0, 120.9, 114.7–114.1 (m, 1C), 109.7. HRMS (ESI): [M + H]⁺ calcd for [C₁₂H₈D₂BrN], 250.0200; found, 250.0219.

1-(1,2-Diphenylvinyl)-1H-pyrrole-D (3g)

The product was obtained as a pale white oil (89.2 mg, 72%); ¹H NMR (400 MHz, CDCl₃): δ 7.44–7.36 (m, 5H), 7.32–7.24 (m, 3H), 6.94–6.92 (m, 2H), 6.68 (s, 1H), 6.42–6.41 (m, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 138.7, 138.0, 134.6, 128.7, 128.69, 128.4, 128.3, 127.7, 126.2, 122.5 (t, J = 28.7 Hz, 1C), 121.2 (t, J = 8.6 Hz, 1C), 109.5 (q, J = 10.5 Hz, 1C). HRMS (ESI): [M – H]⁺ calcd for [C₁₈H₁₂D₃N], 247.1315; found, 247.1349.

1-(1,2-Diphenylvinyl)-3-methyl-1H-indole-D (3h)

The product was obtained as a pale white oil (115.0 mg, 74%); ¹H NMR (400 MHz, CDCl₃): δ 7.78 (d, J = 7.6, 1H), 7.44–7.37 (m, 6H), 7.28 (d, J = 6.8, 1H), 7.25–7.23 (m, 2H + 1H for CDCl₃), 7.16 (t, J = 8.3 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 7.00–6.98 (m, 2H), 2.51 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 138.6, 136.1, 135.6, 134.8, 130.0, 129.3, 128.6, 128.5, 128.2, 127.6, 126.2, 125.7, 122.0, 119.5, 118.7, 112.9, 111.7 (d, J = 21.0 Hz, 1C), 9.7. HRMS (EI): [M]⁺ calcd for [C₂₃H₁₇D₂N], 311.1643; found, 311.1645.

General Procedure for Deuteriothiolation and Deuteriophenoxylation 5a–f

In an oven-dried sample vial, a solution of phenol/thiophenol 4 (0.5 mmol) with alkyne 2 (0.5 mmol) in 2.0 mL of DMSO-d₆, finely crushed KOH (0.5–1.0 equiv), was added. The resulting reaction mixture was stirred at 120 °C for 4–24 h. The progression of the reaction was monitored by TLC; while noticing complete consumption of alkynes, the reaction was brought to room temperature. The reaction mixture was diluted with ethyl acetate (10 mL × 3) and water (15 × 3 mL). The organic layer was concentrated under reduced pressure. The crude material so obtained was purified by column chromatography on a silica gel mesh of size 100–200 (hexane).

(4-Bromostyryl)­(naphthalen-2-yl)­sulfane-D (5a)

The product was obtained as a yellow needle (128.6 mg, 75% yield): mp 60–63 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.90 (d, J = 1.4 Hz, 1H), 7.82–7.76 (m, 3H), 7.52–7.46 (m, 5H), 7.41 (d, J = 9.6 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 135.3, 133.6–133.0 (m, 1C), 132.3, 131.4, 130.3, 128.9, 128.7, 127.7, 127.6, 127.4, 126.9, 126.8–126.3 (m, 1C), 120.9; HRMS (ESI-TOF): [M + H]⁺ calcd for [C₁₈H₁₁D₂BrS], 343.0125; found, 343.0123.

(4-Bromostyryl)­(4-(tert-butyl)­phenyl)­sulfane-D (5b)

The product was obtained as a pale yellow semisolid (136.1 mg, 78% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.50–7.47 (m, 2H), 7.39–7.37 (m, 6H), 1.31 (s, 9H); ¹³C NMR (100 MHz, CDCl₃): δ 150.8, 135.4, 132.2, 131.3, 130.3, 130.2, 128.1, 126.3, 125.2, 120.7, 34.6, 31.2; HRMS (ESI-TOF): [M + H]⁺ calcd for [C₁₈H₁₇D₂BrS], 349.0595; found, 349.0589.

(2-Bromostyryl)­(4-methoxyphenyl)­sulfane-D (5c)

The product was obtained as a pale white semisolid (122.7 mg, 76% yield); ¹H NMR (400 MHz, DMSO-d₆): δ 7.69 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.40–7.37 (m, 1H), 7.34–7.31 (t, J = 6.8 Hz, 1H), 7.26–7.24 (m, 1H), 7.11–7.06 (m, 1H), 6.87–6.81 (m, 2H), 3.77 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 159.3, 132.8, 132.3, 129.4–129.2 (m, 1C), 127.6, 124.8, 123.0, 115.2, 55.3; HRMS (ESI-TOF): [M + H]⁺ calcd for [C₁₅H₁₁D₂BrOS], 323.0074; found, 323.0057.

1-(Methyl-d₃)-4-(2-phenoxyvinyl-1,2-d₂)­benzene (5d)

The product was obtained as a pale yellow oil (82.7 mg, 77% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.58 (d, J = 8.4 Hz, 2H), 7.38–7.33 (m, 2H), 7.15–7.09 (m, 5H); ¹³C NMR (100 MHz, CDCl₃): δ 157.3, 140.9–140.3 (m, 1C), 136.3, 131.9, 129.7, 129.5, 129.0, 128.5, 123.2, 116.8, 110.2–109.7 (m, 1C), 21.2–20.1 (m, 1C); HRMS (ESI): [M + H]⁺ calcd for [C₁₅H₉D₅O], 216.1436; found, 216.1434.

1-Ethyl-4-(styryloxy)­benzene-D (5e)

The product was obtained as a pale white oil (89.2 mg, 79%); ¹H NMR (400 MHz, CDCl₃): δ 7.77 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.29–7.24 (m, 3H), 7.11 (d, J = 8.3 Hz, 2H), 2.71 (q, J = 7.6 Hz, 2H), 1.31 (t, J = 6.9 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 155.3, 141.8 (t, J = 28.7 Hz, 1C), 139.2, 134.9, 128.9, 128.8, 128.6, 128.3, 126.5, 125.4, 119.8, 116.8, 109.3 (t, J = 31.6 Hz, 1C), 28.1, 15.8. HRMS (ESI): [M + H]⁺ calcd for [C₁₆H₁₄D₂O], 227.1405; found, 227.1415.

2-(Styryloxy)­naphthalene-D (5f)

The product was obtained as a pale white oil (90.5 mg, 73%); ¹H NMR (400 MHz, CDCl₃): δ 7.83–7.70 (m, 5H), 7.48–7.32 (m, 6H), 7.23–7.19 (m, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 154.9, 141.1 (t, J = 28.7 Hz, 1C), 134.8, 134.1, 130.1, 129.8, 128.7, 128.4, 127.7, 127.0, 126.7, 126.67, 124.6, 118.6, 111.0 (t, J = 31.6 Hz, 1C). HRMS (ESI): [M + H]⁺ calcd for [C₁₈H₁₂D₂O], 249.1248; found, 249.1242.

General Procedure for Deuteriothiolation and Deuteriophenoxylation 7a–c

In an oven-dried sample vial, a solution of alcohol 6 (0.5 mmol) with alkyne 2 (0.5 mmol) in 2.0 mL of DMSO-d₆, finely crushed KOH (1.0 equiv), was added. The resulting reaction mixture was stirred at 120 °C for 10 h. The progression of the reaction was monitored by TLC; while noticing complete consumption of alkynes, the reaction was brought to room temperature. The reaction mixture was diluted with ethyl acetate (10 mL × 3) and water (15 × 3 mL). The organic layer was concentrated under reduced pressure. The crude material so obtained was purified by column chromatography on a silica gel mesh of size 100–200 (hexane).

(2-Methoxyvinyl)­benzene-D (7a)

The product was obtained as a white oil (53.0 mg, 78% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.40–7.30 (m, 4H), 7.24–7.21 (m, 1H), 3.74 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 148.8, 136.3, 128.5, 128.1, 125.6–125.0 (m, 1C), 104.9, 56.4. HRMS (ESI): [M + H]⁺ calcd for [C₉H₈D₂O], 137.0935; found, 137.0930.

(2-Ethoxyvinyl)­benzene-D (7b)

The product was obtained as a pale white oil (56.2 mg, 75% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.52 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 9.1 Hz, 1H), 6.83–6.79 (m, 3H), 3.92 (q, J = 6.9 Hz, 2H), 1.32 (t, J = 6.9 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 144.8, 133.5, 129.2, 128.9, 114.0–113.5 (m, 1C), 104.9, 55.1, 15.3. HRMS (ESI): [M + K]⁺ calcd for [C₁₀H₁₀D₂O], 189.0651; found, 189.0654.

1-(2-Ethoxyvinyl)-4-(trifluoromethyl)­benzene-D (7c)

The product was obtained as a pale white oil (77.3 mg, 71% yield); ¹H NMR (400 MHz, CDCl₃): δ 7.45 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 3.88 (q, J = 6.9 Hz, 2H), 1.31 (t, J = 7.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 149.7, 127.7–126.8 (m, 1C), 125.7, 125.5 (q, J = 3.8 Hz, 1C), 124.8, 123.0, 104.6–104.2 (m, 1C), 65.8, 14.7. HRMS (ESI): [M + H]⁺ calcd for [C₁₁H₉ D₂F₃O], 219.0966; found, 219.0964.

Analytical Data for the Chemoselective Deuterium Labeling of Tandem Synthesis 8a–f

In an oven-dried pressure tube, to a solution of orthohaloalkyne 2 (0.5 mmol) using N-heterocycles 1 in DMSO-d₆, CuI (5 mol %), BtCH₂OH (10 mol %), and KO^tBu (1.4 equiv) were added under inert atmosphere. The resulting reaction mixture was heated at 120 °C for 18 h. The progression of the reaction was monitored by TLC; while noticing complete consumption of alkynes, the reaction was brought to room temperature. The reaction mixture was diluted with ethyl acetate and water (10 mL × 3). The organic layer was concentrated under reduced pressure. The crude material so obtained was purified by column chromatography on a silica gel (hexane).

6-(m-Tolyl)­indolo­[2,1-a]­isoquinoline-D (8a)

The product was obtained as a pale yellow oil (111.1 mg, 71%); ¹H NMR (400 MHz, DMSO-d₆): δ 8.34 (d, J = 7.6 Hz, 0.29H), 7.76 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.54–7.45 (m, 4H), 7.42–7.36 (m, 2H), 7.18 (t, J = 7.6 Hz, 1H), 6.86 (t, J = 8.3 Hz, 1H), 6.33 (d, J = 8.3 Hz, 1H), 5.74 (s, 0.34H); ¹³C NMR (100 MHz, DMSO-d₆): δ 138.4, 137.8, 135.7, 131.6, 130.2, 129.6, 129.5, 129.1, 128.9, 128.4, 127.9, 127.4, 127.3, 126.5, 126.2, 124.6 (d, J = 6.7 Hz, 1C), 123.4, 121.6, 120.4, 120.0, 113.9, 94.6 (d, J = 6.7 Hz, 1C), 20.7–20.3 (m, 1C). HRMS (ESI): [M + H]⁺ calcd for [C₂₃H₁₁D₆N], 314.1816; found, 314.1817.

6-(4-Ethylphenyl)­indolo­[2,1-a]­isoquinoline-D (8b)

The product was obtained as a pale yellow oil (113.5 mg, 69%); ¹H NMR (400 MHz, DMSO-d₆): δ 7.61 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 6.8 Hz, 0.8H), 7.46 (s, 0.17H), 7.24–7.22 (m, 2H), 7.16–7.12 (m, 3H), 7.05–6.94 (m, 2H), 6.90 (t, J = 7.6 Hz, 1H), 6.82–6.80 (m, 1H), 6.44–6.42 (m, 1H), 5.75 (s, 0.1H); ¹³C NMR (100 MHz, CDCl₃): δ 145.6, 138.1, 135.7, 135.4, 135.2, 132.5, 129.9, 129.0, 128.8, 128.7, 128.6, 128.2, 127.0, 126.7, 124.60 (d, J = 8.6 Hz, 1C), 122.1, 120.6, 120.2–119.9 (m, 1C), 111.8, 103.8–103.3 (m, 1C), 29.7–28.9 (m, 1C), 15.4–15.2 (m 1C). HRMS (ESI): [M + H]⁺ calcd for [C₂₄H₁₁D₈N], 330.2098; found, 330.2140.

12-Methyl-6-(m-tolyl)­indolo­[2,1-a]­isoquinoline-D (8c)

The product was obtained as a pale yellow oil (110.8 mg, 68%); ¹H NMR (400 MHz, DMSO-d₆): δ 8.41 (d, J = 8.3 Hz, 0.47H), 7.83 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.58–7.55 (m, 1H), 7.51–7.44 (m, 3H), 7.39 (s, 1H), 7.34 (d, J = 6.8 Hz, 1H), 7.24–7.19 (m, 1H), 6.90–6.86 (m, 1H), 6.30 (d, J = 8.3 Hz, 1H), 2.82 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 138.4, 137.9, 136.0, 130.6, 130.1, 129.7, 129.4, 128.9, 127.1 (d, J = 10.5 Hz, 1C), 126.3 (t, J = 8.6 Hz, 1C), 126.0, 124.1, 121.1, 120.4, 118.3, 113.7, 104.9, 26.3–26.1 (m, 1C), 11.4. HRMS (ESI): [M + H]⁺ calcd for [C₂₄H₁₄D₅N], 327.1909; found, 327.1903.

6-(4-Ethylphenyl)-12-methylindolo­[2,1-a]­isoquinoline-D (8d)

The product was obtained as a pale yellow oil (121.4 mg, 71%); ¹H NMR (400 MHz, DMSO-d₆): δ 8.41 (d, J = 8.4 Hz, 0.5H), 7.83 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.58–7.55 (m, 1H), 7.50–7.43 (m, 5H), 7.21 (t, J = 7.6 Hz, 1H), 6.87 (t, J = 8.4 Hz, 1H), 6.31 (d, J = 8.3 Hz, 1H), 2.82 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 145.2, 138.2, 137.8, 133.5, 130.9, 130.6, 130.2, 129.7, 129.5, 128.9, 128.5, 127.1–126.9 (m, 1C), 126.5–126.3 (m, 1C), 124.1, 121.1, 120.4, 118.3, 113.7, 104.9, 15.5, 11.5–11.4 (m, 1C). HRMS (ESI-TOF): [M + H]⁺ calcd for [C₂₅H₁₄D₇N], 343.2192; found, 343.2190.

12-Methyl-6-(thiophen-3-yl)­indolo­[2,1-a]­isoquinoline-D (8e)

The product was obtained as a pale yellow oil (115.7 mg, 73%); ¹H NMR (400 MHz, CDCl₃): δ 8.43 (d, J = 7.6 Hz, 0.96H), 7.81 (d, J = 8.3 Hz, 1H), 7.54–7.49 (m, 2H), 7.44–7.40 (m, 1H), 7.29 (t, J = 6.8 Hz, 1H), 7.20 (s, 0.2H), 6.99 (t, J = 7.6 Hz, 1H), 6.53 (d, J = 9.1 Hz, 1H), 2.89 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 136.9 (d, J = 8.6 Hz, 1C), 133.3, 131.3, 130.8, 130.1, 129.6, 128.6, 127.3 (d, J = 8.6 Hz, 1C), 126.8, 126.6, 126.1, 125.2–124.8 (m, 1C), 124.4, 121.1, 120.5, 118.0, 113.8, 111.2–111.1 (m, 1C), 105.5, 11.8. HRMS (EI-TOF): [M]⁺ calcd for [C₂₁H₁₀D₅NS], 318.1239; found, 318.1239.

10-Methoxy-6-(m-tolyl)­indolo­[2,1-a]­isoquinoline-D (8f)

The product was obtained as a pale yellow oil (112.8 mg, 66%); ¹H NMR (400 MHz, CDCl₃): δ 8.18 (d, J = 8.4 Hz, 0.32H), 7.53 (d, J = 7.6 Hz, 1H), 7.48–7.40 (m, 3H), 7.39–7.34 (m, 3H), 7.18 (d, J = 2.3 Hz, 1H), 6.54 (dd, J = 9.2 and 2.3 Hz, 1H), 6.34 (d, J = 9.2 Hz, 1H), 3.85 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 155.1, 138.6, 138.2, 136.9, 136.2, 130.4, 130.0, 129.8, 128.9, 128.8, 127.4, 126.8 (d, J = 11.4 Hz, 1C), 126.3, 126.27, 125.1 (d, J = 8.6 Hz, 1C), 123.2, 115.3, 110.4, 100.8, 93.9, 55.5, 29.7–29.5 (m, 1C). HRMS (EI-TOF): [M + H]⁺ calcd for [C₂₄H₁₃D₆NO], 344.1921; found, 344.1915.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b01329.

• ¹H and ¹³C NMR and HRMS spectra for selected compounds (PDF)

The authors declare no competing financial interest.