Deconstructive Functionalizations of Unstrained Carbon–Nitrogen Cleavage Enabled by Difluorocarbene

Abstract

Transition-metal- or oxidant-promoted deconstructive functionalizations of noncyclic carbon–nitrogen bonds are well established, usually only leaving one moiety functionalized toward the final product. In contrast, concomitant C- and N-functionalizations via the unstrained C(sp³)–N bond under metal- and oxidant-free conditions are very rare, which would favorably confer versatility and product diversity. Disclosed herein is the first difluorocarbene-induced deconstructive functionalizations embodying successive C(sp³)–N bond cleavage of cyclic amines and synchronous functionalization of both constituent atoms which would be preserved in the eventual molecular outputs under transition-metal-free and oxidant-free conditions. Correspondent access to deuterated formamides with ample isotopic incorporation was demonstrated by a switch to heavy water which is conceivably useful in pharmaceutical sciences. The current strategy remarkably administers a very convenient, operationally simple and novel method toward molecular diversity from readily available starting materials. Therefore, we project that these findings would be of broad interest to research endeavors encompassing fluorine chemistry, carbene chemistry, C–N bond activation, as well as medicinal chemistry.

Short abstract

Difluorocarbene-induced C(sp³)−N bond cleavage of tertiary amines is disclosed under transition-metal-free and oxidant-free conditions for the first time, leading to versatile functionalized products.

1. Introduction

The polar disconnection of the C(sp³)–N bond yields two reactive synthons, the carbon electrophile and nitrogen nucleophile which are versatile precursors of synthetically useful functionalities.¹ A consecutive C(sp³)–N cleavage–reassembly strategy is therefore prized to derive compounds of heightened structural diversity and complexity in a single step.² In biological systems, enzymes mediate C(sp³)–N bond scission to generate α-amino acids from proteins³ whereas C–N bond disconnection of tertiary amines is synthetically mediated by transition metals (TMs), oxidants, or the combination of both.⁴⁻⁶ Atom economy is nonetheless compromised in most cases given that only one entity (either C or N) is functionalized toward the final product while the other converts to sacrificial compounds (Figure 1a).^4,5 The efficiency of these methods is also often predicated on expensive and toxic metals^4,5 or stoichiometric oxidants as in oxidative transformations⁶ which generates an equivalent amount of undesired byproducts.¹⁴ Contrarily, concomitant C- and N-functionalization would favorably confer versatility and product diversity.⁷⁻⁹ Sporadic seminal works only exemplified a confined substrate scope typified by 1,4-diazabicyclo[2.2.2]octane (DABCO) and the quaternary ammonium salts (Figure 1b).¹⁰ The von Braun reaction¹¹ is also a C–N bond activation reaction, which refers to the treatment of tertiary amines with cyanogen bromide, resulting in a substituted cyanamide. BrCN is called a counter attack reagent, which is a kind of reagent that achieves the two kinds of transformations needed in the reaction to produce the product. In recent years, many chemists have used this strategy to modify tertiary amines; great achievements have been made in both the organic synthesis methodology and total synthesis.¹² However, the applications of this strategy have some inherent defects. For example, BrCN has strong hygroscopicity and is sensitive to air and moisture, which limits its applications. Moreover, it can only provide bromine and cyano groups and cannot provide more useful modifications. Given the assortment of tertiary amines readily exploitable, eliminating these limitations and, at the same time, conferring mild reaction conditions, broad substrate scope, as well as good functional group tolerance upon this transformation would be highly appealing.

Figure 1.

(a) C(sp³)–N cleavage of noncyclic amines. (b) C(sp³)–N cleavage of cyclic amines. (c) First difluorocarbene-induced C(sp³)–N cleavage of various amines (this work).

The difluorocarbene species is an exceedingly reactive intermediate possessing high electron deficiency¹³ to be used as a robust difluoromethylating reagent¹⁴ or difluoromethylenating reagent.¹⁵ The industrially important tetrafluoroethylene is prepared via dimerization of this species under high temperature.¹⁶ Furthermore, our recent research efforts culminated in the discovery and development of several transformations featuring in situ generated difluorocarbene (:CF₂) as C1 synthons to assemble various valuable N-containing compounds.¹⁷ The synthetic utility of difluorocarbene is nonetheless reckoned to be underexplored considering that in situ generation of difluorocarbene is easy under mild conditions from readily accessible starting materials. Grounded in our previous experience,¹⁷ we envisioned capturing the difluorocarbene species to activate and execute C–N bond cleavage in tertiary amines by leveraging the favorable matched electronics between electron-rich tertiary amines and highly electron-deficient difluorocarbene (Figure 1c).¹³

We considered several formidable challenges to realize the titled transformation: (1) surmounting the high bond dissociation energy of C(sp³)–N without the aid of transition metal and oxidant;¹⁸ (2) the posited interaction between tertiary amines and difluorocarbene as well as the formation of ammonium salt species which found no literature precedence; and (3) chemo- and regioselective cleavage of one single C–N bond.¹ The success of many C–N bond cleavage transformations of tertiary amines resides in the weakened C–N sigma bonds that prime them toward nucleophilic attack when the lone electron pairs are engaged in forming the new N–C bond in ammonium salt. Therefore, if the union of difluorocarbene and tertiary amine indeed generates the hypothesized difluoromethylammonium salt, the stage is set for the occurrence of the proposed reaction. Herein, we report an unprecedented difluorocarbene (derived in situ from BrCF₂COOEt, ICF₂COOEt, TMSCF₂H, and ClCF₂H)-induced tertiary amine activation under transition-metal- and oxidant-free conditions. In situ decomposition of halodifluoroalkyl reagents simultaneously releases difluorocarbene species and halide anions. While the former forms an ammonium entity with the tertiary amine substrate, the halide performs a nucleophilic attack on the α-carbon to enact C(sp³)–N bond fission. Interception by an external nucleophile at this stage would further enrich the architectural diversity of products. Consequently, a novel catalyst- and oxidant-free methodology comprising C–N bond cleavage and C–X (X = I, Br, Nu) bond formation is consummated. The instability of the thus-formed difluoromethyl tertiary amines under basic conditions induces their rapid hydrolyses to formamides (Figure 1c). Meanwhile, deuterated formamides with high isotopic incorporation could be procured when interposed by D₂O. The amide bond is one the most important functional motifs in chemistry and biology. Amides feature as prevalent pharmacophores in small-molecule pharmaceuticals. This procedure would allow facile entry to deuterated drugs and late-stage modification of candidates of medicinal importance.¹⁹

2. Results and Discussion

Development of Mild Reaction Conditions

The validation of our hypothesis commenced with a model reaction of N-phenylmorpholine (1a) and ICF₂COOEt (2a) with the choice of K₂CO₃ as the base. Compound 4a embedded with iodo functionality was successfully isolated in 31% yield when the reaction was conducted at 90 °C in CH₃CN (Table 1, entry 1), indicating the feasibility of our conjecture. Mechanistic scrutiny prompted the inclusion of an external iodide ion source to promote C–N bond cleavage by providing a higher iodide concentration in the reaction mixture. This attempt (Table 1, entries 2–5) fruitfully identified ZnI₂ and KI (Table 1, entry 3 or entry 5) as the more competent candidates to deliver 4a in 79% and 78% yield, respectively. Subscribed to cost and accessibility considerations, KI was opted for subsequent optimization studies. Water was found crucial for the current reaction (Table 1, entries 6–8) where product formation could be significantly enhanced from 63% to 77% (Table 1, entries 7 and 8) when the amount was increased from 0.1 to 0.3 mL. Replacing K₂CO₃ with Na₂CO₃ resulted in a superior result (Table 1, entry 9), yet neither DBU nor NaHCO₃ gave better yields (Table 1, entries 10 and 11). CH₃CN was found impeccable given that other solvents such as DMF, acetone, and CH₃OH furnished the titled product in notably inferior yields (Table 1, entries 12–14). The reaction proceeded most optimally at 90 °C; higher or lower temperature did not further improve the outcomes (Table 1, entries 15 and 16). Exquisitely, the bromide congener of 5a was formed in 70% yield by switching ICF₂COOEt to BrCF₂COOEt and KI to KBr (Table 1, entry 17). This implied that the more cost-effective BrCF₂COOEt was an adequate alternative of ICF₂COOEt in this transformation to introduce the bromo group as a functional handle in the product.

Table 1. Optimization of the Reaction Conditions of the Conversion of N-Phenylmorpholine (1a).

entry	base	additive	H2O (X mL)	solvent	T (°C)	yielda (%)
1	K2CO3		0.5	CH3CN	90	31b
2	K2CO3	Nal	0.5	CH3CN	90	71
3	K2CO3	ZnI	0.5	CH3CN	90	79
4	K2CO3	TBAI	0.5	CH3CN	90	25
5	K2CO3	KI	0.5	CH3CN	90	78
6	K2CO3	KI	0.01	CH3CN	90	trace
7	K2CO3	KI	0.1	CH3CN	90	63
8	K2CO3	KI	0.3	CH3CN	90	77
9	Na2Co3	KI	0.3	CH3CN	90	88 (84)b
10	DBU	KI	0.3	CH3CN	90	68
11	NaHCO3	KI	0.3	CH3CN	90	trace
12	Na2CO3	KI	0.3	DMF	90	trace
13	Na2CO3	KI	0.3	acetone	90	51
14	Na2CO3	KI	0.3	CH3OH	90	70
15	Na2CO3	KI	0.3	CH3CN	80	75
16	Na2CO3	KI	0.3	CH3CN	100	82
17	Na2CO3	KBr	0.3	CH3CN	90	70c

^aReaction condition 1: 1a (0.2 mmol), ICF₂COOEt (2, 0.6 mmol), additive (3 equiv), base (3 equiv), H₂O (X mL), solvent (2 mL), for 10 h, N₂; GC yields.

^bIsolated yields.

^cReaction condition 2: 1a (0.2 mmol), BrCF₂COOEt (3, 0.6 mmol), KBr (3 equiv), Na₂CO₃ (3 equiv), H₂O (0.3 mL), CH₃CN (2 mL) under 90 °C for 10 h, isolated yield. TBAI = tetra-n-butylammoniumiodide, DMF = N,N-dimethylformamide.

Substrate Scope of Cyclic Tertiary Amines

With the optimal reaction conditions in hand (Table 1, entries 9 and 17), various tertiary cyclic amines were perused against proton sources (H₂O) with both ICF₂COOEt-KI and BrCF₂COOEt-KBr systems (Table 2). Under standard reaction conditions, model substrate 1a and the 4-bromo derivative 1b were converted to respective long-chain iodinated tertiary formamide (4a, 4b) as well as brominated (5a, 5b) in equally good yields. Both six-membered (1a–1c) and five-membered (1d–1n) analogues of cyclic tertiary amines were well-suited for this transformation, exhibiting insensitivity toward aryl substitutions (alkyl, alkoxyl, phenoxyl, halo, phenyl, fused, etc.). The corresponding target products (4c–4n and 5c–5n) were isolated in 65%–97% yields. A drug intermediate, 2,3,6,7-tetrahydro-1H,5H-benzop[i, j]quinolizine (1o) (or Julolidine), which contains two six-membered cyclic tertiary amines, selectively cleaving one moiety, delivered iodide (4o) in 41% yield. Interestingly, for the asymmetric cyclic tertiary amines 1p, due to the influence of steric hindrance, we can selectively obtain the product 5p from the less steric hindered side in 82% yield. When 4-methyl-1-phenylpiperidine (3q) was subjected to the standard conditions, the target products (4p and 5p) were obtained in 92% and 81% yields. The target product could not be obtained in a satisfactory yield by using both ICF₂COOEt-KI and BrCF₂COOEt-KBr systems when we examined four-membered analogues of cyclic tertiary amines. After optimizing the conditions, we found that TMSCF₂Br is a suitable difluorocarbene provider, and the target products can be obtained in good yields from the substrates of four-membered aza-rings (1r–1t).

Table 2. Substrate Scope of Cyclic Tertiary Amines (H₂O as the Proton Source)^a.

^aReaction conditions: 1 (0.2 mmol), ICF₂COOEt (3 equiv), Na₂CO₃ (3 equiv), CH₃CN (2 mL), KI (3 equiv), H₂O (0.3 mL) under N₂ atmosphere at 90 °C for 10 h.

^b1 (0.2 mmol), BrCF₂COOEt (3 equiv), Na₂CO₃ (3 equiv), CH₃CN (2 mL), KBr (3 equiv), H₂O (0.3 mL) under N₂ atmosphere at 90 °C for 10 h. All yields are isolated yields.

Substrate Scope of Noncyclic Tertiary Amines

The exploration of substrate scope ensued by examining the reaction generality against noncyclic tertiary amines (Table 3). Expectedly, these substrates were equipotent to afford formylated products in excellent yields under marginally reoptimized conditions as follows: K₂CO₃ as the base and MeCN as the solvent without any halide salt additives at 90 °C for 10 h under a N₂ atmosphere (see the SI for details).

Table 3. Substrate Scope of the Noncyclic Tertiary Amines (H₂O as the Proton Source)^a.

^aReaction conditions: 6 (0.2 mmol), 3 (3 equiv.), K₂CO₃ (3 equiv.), CH₃CN (2 mL), H₂O (0.5 mL) under N₂ atmosphere at 90 °C for 10 h.

^b3 (2.4 equiv.)

^c3 (4 equiv.), K₂CO₃ (4 equiv.), H₂O (0.7 mL).

^d6 (0.2 mmol), BrCF₂COOEt (3 equiv.), K₂CO₃ (3 equiv.), CH₃CN (2 mL), CH₃OH (0.5 mL), under N₂ atmosphere at 90 °C for 30 h.

^e6 (0.1 mmol), CClF₂H (3 equiv.), S₈ (35 mol %), K₂CO₃ (3 equiv.), CH₃CN (2 mL), H₂O (0.5 mL) at 90 °C for 10 h. All yields are the isolated yields, and the numbers in parentheses are the conversion rate of raw materials.

Employing BrCF₂COOEt as the model reaction partner, varied para-substituted N,N-dimethylanilines (6a–6d) afforded the corresponding desired products (7a–7d) in good to excellent yields. Subsequently, N,N-dimethyl-[1,1′-biphenyl]-4-amines with differing substituents on Ar² rings including electron-neutral (6e), electron-rich (6f–6h, 6k), as well as electron-withdrawing groups (6i and 6j) underwent the current transformation without event to furnish formamides 7e–7k in excellent yields. Diazo functionality in (E)-N,N-dimethyl-4-(phenyldiazenyl)aniline (6l) was left unscathed which reacted with commendable efficiency. Heterocycle-containing N,N-dimethylpyridin-2-amine (6m) and aliphatic tertiary amines (6n–6t), both cyclic and chain amines, led to corresponding products in exemplary yields without event. Interestingly, substrate tethered with two N,N-dimethylamines (6u, 6w) could undergo selective aza-Arbuzov reaction to deliver mono- or bis-formylated products (7u–7x) by modulating the proportion of BrCF₂COOEt and tertiary amines. Remarkably, when diphenhydramine (6y, antihistamine), cyproheptadine (6z, anticoagulant and antiallergic), caulophylline (6aa, hypoglycemic), (R)-tomoxetine (6ab, attention deficit hyperactivity disorder, ADHD), fluoxetine (6ac, antidepressant), desloratadine (6ad, antiallergic), tropisetron (6ae, 5-HT3 receptor antagonists), and amoxapine (6af, tricyclic antidepressants) were subjected to the standard conditions, formylated products (7y–7af) were obtained in 41–90% yields. Importantly, ClCF₂H as the smallest halodifluoroalkyl reagent with wide industrial applications is also a known precursor of difluorocarbene. When treated with various tertiary amines (6ag–6an), good yields were delightfully mirrored in target products (7ag–7an) which carry a gamut of functional groups.

To assess the susceptibility of different C–N bonds toward scission, a panel of N-substituted tertiary amines was reacted under the standard conditions (Table 4). N-Methylanilines with a different N-substituent (6ag, 6ao–6aq) were first inspected, and the target products (7ag, 7ao–7aq) were obtained in 99%, 63%, and 42% yield and a trace amount. When N,N-dimethylaniline (6ag) was studied against different N,N-disubstituted anilines such as N,N-diethyl (6ar), N,N-diⁿpropyl (6as), and N,N-diⁿbutyl (6at) under the same reaction conditions, only the former two substrates rendered 7ag and 7ao in 99% and 32% yield, while the latter two (6as and 6at) could not be processed under our system. Based on these results, we speculated that the bulkier N-substituent would incur steric hindrance toward difluorocarbene species, which is reflected in low to nil product yields as the tethering alkyl group gets larger. This imparts chemo- and site-selectivity to the current strategy for selective functionalization in the existence of multiple C–N bonds.

Table 4. Effect of Substituents on N Atoms^a.

^aReaction conditions: 6 (0.2 mmol), BrCF₂COOEt (3 equiv.), K₂CO₃ (3 equiv.), CH₃CN (2 mL), H₂O (0.5 mL) under N₂ atmosphere at 90 °C for 10 h, isolated yield.

Deuteration Results

Deuterium incorporation as part of isotope labeling has a broad range of applications, including in the investigation of reaction mechanisms and the analysis of drug absorption, distribution, metabolism, and excretion (ADME), as well as in nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS).²⁰ In 2017, FDA approval for the first deuterated drug, deutetrabenazine (Austedo),²¹ has created an urgent demand for synthetic methods that efficiently generate deuterated building blocks. Grounded in our current successful formamide formation via C(sp³)–N bond activation of tertiary amines with H₂O, herein, we invented a mild and generic method for the deuteration of formamides with D₂O, an inexpensive deuterium source. Delightfully, when H₂O was replaced with D₂O under the standard conditions, the yields of the products were barely affected along with excellent deuteration ratios (Table 5). Both cyclic and noncyclic tertiary amines were inspected under the corresponding reaction conditions with either ICF₂COOEt (a), BrCF₂COOEt (b), or ClCF₂H (c) as difluorocarbene sources. Gratifyingly, the corresponding target products (8a–8ao) were procured in up to 97% yields accompanied by excellent deuteration ratios. Of note, like before, the drug molecule intermediate 2,3,6,7-tetrahydro-1H,5H-benzop[i, j]quinolizine (Julolidine) (1o) as well as drug molecules diphenhydramine (6y) and cyproheptadine (6z) were all competent to our systems, and the corresponding deuterated products (8l, 8aj–8ak) were obtained in good yields along with excellent deuteration ratios.

Table 5. Deuteration with D₂O as the Deuterium Source.

^aReaction condition: 1 (0.2 mmol), ICF₂COOEt (3 equiv.), Na₂CO₃ (3 equiv.), CH₃CN (2 mL), KI (3 equiv.), D₂O (0.3 mL) under N₂ atmosphere at 90 °C for 10 h.

^b1 (0.2 mmol), BrCF₂COOEt (3 equiv.), Na₂CO₃ (3 equiv.), CH₃CN (2 mL), KBr (3 equiv.), D₂O (0.3 mL) under N₂ atmosphere at 90 °C for 10 h.

^c6 (0.2 mmol), BrCF₂COOEt (3 equiv.), K₂CO₃ (3 equiv.), CH₃CN (2 mL), D₂O (0.5 mL) under N₂ atmosphere at 90 °C for 10 h, isolated yield.

^d3 (2.4 equiv.).

^e3 (4 equiv.), K₂CO₃ (4 equiv.), D₂O (0.7 mL).

^f6 (0.1 mmol), CClF₂H (3 equiv.), S₈ (35 mmol %), K₂CO₃ (3 equiv.), CH₃CN (2 mL), D₂O (0.5 mL) at 90 °C for 10 h. All yields are the isolated yields, and the numbers in parentheses are the deuteration ratios of the corresponding deuterated products.

This system could be extrapolated to a three-component reaction with thiols as extraneous nucleophiles (Table 6). The C(sp³)–S bond plays a pivotal role in modern organic synthesis, natural products, and pharmaceuticals. Clinical trials demonstrated that the introduction of C(sp³)–S moieties could improve their biological activities, such as antitumor, anti-inflammatory, and immunomodulatory properties.²² Besides that, the C(sp³)–S bond can also be found in the natural amino acid, such as cysteine, and facilitate the metabolism process of the related protein in the organism.²³ Then, we introduce a sulfur-containing nucleophilic reagent, which could directly assemble the C(sp³)–S bond through direct C–N difunctionalization. Relevant optimization efforts utilizing 1-phenylpyrrolidine (1d), BrCF₂COOEt (3), and thiol 9 as model substrates (see the SI for details) concluded the optimal conditions herewith: Na₂CO₃ as the base and KBr as an additive in CH₃CN at 90 °C for a 10 h reaction. As shown in Table 6, both aromatic (9a–9f) and aliphatic thiols (9g–9j) were auspiciously coupled onto formamide products in moderate to excellent yields. Except the substrate 1d, the four-membered (1r) and six-membered (1c) analogues of cyclic tertiary amines were well-suited for this transformation, rendering the corresponding products 10k–10l and 10m in excellent yields (Table 6). Phenol acted as an equally fitting nucleophile for this three-component reaction with 1-phenylpyrrolidine (1d) and BrCF₂COOEt (3) to afford N-(4-phenoxybutyl)-N-phenylformamide (12) in excellent yield with DMF as the cosolvent.

Table 6. Substrate Scope of the External Nucleophiles^a.

^aReaction conditions: 1d (0.2 mmol), 3 (3 equiv.), 9 (3 equiv.), Na₂CO₃ (3 equiv.), CH₃CN (2 mL), KBr (3 equiv.), H₂O (0.3 mL) under air atmosphere 90 °C for 10 h, isolated yield.

Synthetic Elaborations

Under standard conditions, product 4d was scalably prepared from tertiary amine 1d in excellent yields (96%). Having sufficient 4d compound at our disposal, structural elaborations were performed (Figure 2). Alkylboronic ester (13) was readily obtained in 55% yield from 4d and B₂pin₂,²⁴ which is amenable toward chemical modifications through various coupling protocols. 4d readily reacted with diethylamine, phenol,²⁵ and benzoic acid in DMF to furnish 1,4-diamine compounds (14), N-(4-phenoxybutyl)-N-phenylformamide (12), and 4-(N-phenylformamido) butyl benzoate (17) in 99% yield. For complex drug molecules, such as sertraline and (S)-(+)-ibuprofen, they can achieve their late-stage modification products 15 and 16 with 4d under mild conditions.

Figure 2.

Synthetic applications.

Mechanistic Investigation

Mechanistic insights on the current reaction were gathered via several control experiments (Figure 3). Smooth reactions were observed in the presence of radical scavengers (TEMPO, BHT, and 1,1-diphenylethylene) to produce 4d in 77%, 79%, and 82% yields, respectively, which could possibly rule out an operating radical process (Figure 3, eq 1). When carbene trapping reagents, namely, 2-aminopyridine 15 and aniline 17, were added individually into this system, the formation of N-(difluoromethyl)pyridin-2-amine 16 (detected by GC-MS) and the formylated product 18 in 91% yield alongside a trace amount of 4d attested to the intermediacy of difluorocarbene species (Figure 3, eqs 2 and 3). For a comprehensive understanding of reactions with thiol substrates, several control experiments were carried out: cotreatment of 1d with BrCF₂COOEt in the absence of KBr did not yield product 5d, while in standard conditions with 3 equiv of KBr, the product 5d was procured in 84% yield (Figure 3, eq 4). When 5d was exposed to 4-methylbenzenethiol 9a under basic conditions, the long-chain thioether 10a was obtained in near-quantitative yield (Figure 3, eq 5). However, when 4-methylbenzenethiol 9a was directly added to the mixture of substrate 1d and BrCF₂COOEt under the standard conditions without KBr, only 42% of 10a was observed (Figure 3, eq 6). These results implied that thiols should directly attack the activated carbon of the C–N bond leading to the product 10a. Nonetheless, an alternate pathway that involves the prior formation of 5d followed by nucleophilic substitution of thiol could not be exclusively refuted.

Figure 3.

Control experiment of these transformations.

Proposed Mechanism

Grounded in these empirical data, a proposed mechanism is depicted in Figure 4. Difluorocarbene (:CF₂) should first be unmasked from halodifluoroalkyl reagents (ICF₂COOEt, BrCF₂COOEt, or ClCF₂H) in the presence of the base. Tertiary amine A then reacts with the in situ generated :CF₂ species to deliver ammonium salt B under basic conditions. Internal (X^–) or external nucleophiles (X^–, S^–, or O^–) attack the α carbon of ammonium salt B to render intermediate C via C–N bond cleavage. Upon C–F bond scission in intermediate C, complex D could be hydrolyzed through two different pathways (via complex E or F) to generate the target molecule.^17a

Figure 4.

Proposed mechanism.

3. Discussion

A new deconstructive halogenation reaction that features C–N bond cleavage of various tertiary amines has been developed with in situ generated difluorocarbene as an activating reagent. The long-chain halogen-containing amide compounds prepared via this strategy were inaccessible by any previously known protocols. Densely functionalized formamides and the deuterated congeners were assembled from simple amine building blocks in one-pot reactions without any metal catalyst or oxidant. Further investigations to extend the reaction scope and applications of this process are currently in progress.

Safety Statement

No unexpected or unusually high safety hazards were encountered.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acscentsci.0c00779.

• Experimental details of synthetic procedures and methods and X-ray data (PDF)

• Crystallographic data for 7i (CIF)

Author Contributions

^§ J.S. and X.M. contributed equally to this work

The authors declare no competing financial interest.