Chemoselective Transamidation of Thioamides by Transition-Metal-Free N–C(S) Transacylation

Abstract

Thioamides represent highly valuable isosteric in the strictest sense “single atom substitution” analogues of amides that have found broad applications in chemistry and biology. A long-standing challenge is the direct transamidation of thioamides, a process which would convert one thioamide bond (R–C(S)–NR¹R²) into another (R–C(S)–NR³N⁴). Herein, we report the first general method for the direct transamidation of thioamides by highly chemoselective N–C(S) transacylation. The method relies on site-selective N-tert-butoxycarbonyl activation of 2° and 1° thioamides, resulting in ground-state-destabilization of thioamides, thus enabling to rationally manipulate nucleophilic addition to the thioamide bond. This method showcases a remarkably broad scope including late-stage functionalization (>100 examples). We further present extensive DFT studies that provide insight into the chemoselectivity and provide guidelines for the development of transamidation methods of the thioamide bond.

Graphical Abstract

We report the first general, mild and highly chemoselective method for transamidation of thioamides by N–C(S) transacylation. This process exploits concept of site-selective N-tert-butoxycarbonyl activation, resulting in ground-state-destabilization of thioamides. The study establishes a powerful direction to the development of new molecules in chemistry and biology by rational modification of n_N→π*_C=S resonance of the thioamide bond.

Introduction

The center of chemical synthesis relies on functional group interconversions. Functional group interconversions of the amide bond have a tremendous impact on organic synthesis,^[1–8] allowing to manipulate the historically challenging N–C(O) linkage by exploiting the inherent properties of amides resulting from n_N→π*_C=O conjugation.^[9,10] In this context, thioamides have recently emerged as particularly attractive amide bond isosteres, wherein a single atom oxygen-to-sulphur substitution renders thioamides the closest analogues of amides in their strictest sense (Figure 1A).^[11–18]

Figure 1.

Thioamides as “single-atom” amide bond isosteres. (A) Thioamide resonance. (B) The challenge of transamidation of thioamides. (C) This study: highly chemoselective, transition-metal-free transamidation of thioamides.

Thioamides have long been considered as attractive intermediates in organic synthesis, particularly utilized in the synthesis of heterocycles, desulfurization reactions, enolate alkylations and organocatalysis, among others.^[11–15] In biochemistry, thioamides have found significant utility as amide bond bioisosteres to increase the stability and conformational rigidity of peptides, including recent elegant studies on n → π* carbonyl–carbonyl interactions in N-acetyl prolines and macrocyclic amide to thioamide replacement.^[16–24] The privileged role of sulfur in medicinal chemistry, where around 25% of the 200 most prescribed drugs in the US in 2011 contain sulfur, has rendered compounds containing sulfur pivotal in medicinal chemistry and drug discovery programs.^[25–27] Furthermore, thioamides have become attractive as photoswitches enabling trans to cis isomerization owing to red-shifted π→π* transition,^[28–31] while affinity of the sulfur atom to certain metals in thioamides has found applications in the development of new coordination complexes.^[32] Furthermore, the presence of thioamides in natural products and recent studies indicating posttranslational thioamidation by Nature,^[11,12] highlight the role of thioamides as one of the most fundamental amide-derived linkages in chemistry.

In terms of structural and electronic properties, thioamides feature longer C=S bonds than the corresponding C=O bonds in amides (1.64 Å vs. 1.19 Å, H–C(X)–NH₂), while the large van der Waals radius of sulfur (1.85 Å) vs. oxygen (1.40 Å) and lower electronegativity of sulfur (S: 2.58) vs. oxygen (O: 3.44) results in a significantly higher contribution of the polar resonance contribution form in thioamides and much higher barrier to rotation around the N–C(S) axis (by approximately 5–7 kcal/mol).^[33–35] The higher n_N→π*_C=S conjugation in thioamides translates into the fact that thioamides are even more resistant to hydrolysis and nucleophilic addition than amides. For example, the rate of hydrolysis of PhC(S)NR¹R² (NR¹R² = morpholine) in aq. KOH is 10-times slower than that of the corresponding PhC(O)NR¹R².^[36] Another important consideration in reactivity of thioamides is electrophilic addition at sulfur and desulfurization reactions reverting the thioamide bond to the amide bond under oxidative and acid-base conditions.^[12,14]

As a result of their electronic and steric properties, thioamides represent valuable synthetic intermediates,^[11–15] however, a long-standing challenge is the direct transamidation of thioamides, a process which would convert one thioamide bond (R–C(S)–NR¹R²) into another (R–C(S)–NR³N⁴) and expand the repertoire of functional group interconversions in organic synthesis to thioamide to thioamide transform. Thus far, very few methods for the direct transamidation of thioamides have been reported and all of them have been exclusively limited to 1° thioamides and aliphatic amines (Figure 1B).^[37–39] This paucity if particularly notable in light of amide bond transamidation methods,^[40–50] which are well developed and play a central role in the synthesis of biological and synthetic molecules to diversify the amide bond motifs and enable the synthesis of broadly valuable amides.

Herein, we report the first general method for the direct transamidation of thioamides by highly chemoselective N–C(S) transacylation using non-nucleophilic anilines (Figure 1C). Thioamides are most important single-atom replacement isosteres of the amide bond of great interest in diverse fields of science, including chemistry, biology, medicinal chemistry and materials science.^[11–15] The present study reports the first transamidation of thioamides with non-nucleophilic anilines and introduces the concept of ground-state-destabilization of the thioamide bond^[1,2,52,60] for broad applications in chemistry. The following features of our study are noteworthy:

1. This process enables to rationally manipulate nucleophilic amine addition to the thioamide bond and represents a powerful new concept to control thioamide bond n_N→π*_C=S resonance. The method works by exploiting the uncommon cleavage of the C(S)–N bond after previously unknown site-selective N-tert-butoxycarbonyl activation of 2° and 1° thioamides resulting in a broadly general ground-state-destabilization of thioamides (Scheme 1).

2. The method is operationally-simple, user-friendly, conducted in the absence of toxic transition metals or air-sensitive reagents under mild room temperature conditions.

3. The method showcases a remarkably broad range of sensitive functional groups as well as medicinally-relevant heterocycles and was successfully applied to the late-stage functionalization of drug molecules (>100 examples).

4. The method is broadly compatible not only with 2° and 1° thioamides after site-selective N-tert-butoxycarbonylation, but also with N-Ar tertiary thioamides as well as N-thioacyl-azoles as selective N-thioacyl transfer reagents.

5. We present extensive DFT studies that provide insight into the mechanism and chemoselectivity of the process and provide guidelines for the development of future transamidation methods of the thioamide bond.

Scheme 1.

Ground-State-Destabilization of Thioamides.

Overall, in light of the importance of thioamides as amide bond isosteres, this conceptually novel process represents a powerful entry into the development of new thioamide-based molecules in various facets of chemistry and biology.

Results and Discussion

One of the strategies used for the direct functionalization of the amide bond is ground-state destabilization of the amide linkage.^[51–53] In this reactivity paradigm, introduced by our group and others in 2015,^[54–58] amide bond is functionalized at the nitrogen atom so that amidic resonance gradually decreases to enable selective nucleophilic addition to the amide bond.^[59–61] Another recent development is biomimetic nicotinate-directed transamidation enabled by nic-amide chelation to a zinc catalyst.^[62] In the ground-state-destabilization approach, the nucleophilic addition affords a tetrahedral intermediate, which then collapses to afford synthetically valuable acyl substitution products. In this reactivity platform, amide bond destabilization kinetically facilitates the nucleophilic addition step, while collapse is favored thermodynamically by the electronic properties of the leaving group. In this scenario, the amide functionalization step is accomplished by site-selective tert-butoxycarbonylation at nitrogen, thus rendering common 1° and 2° amides as chemoselective acyl transfer reagents in organic synthesis.^[63] In this context, we postulated that this general amide bond activation concept could be translated to the direct transamidation of thioamides, a process that had been elusive prior to our study.

At the outset of this study, we postulated that hitherto unknown isosteric N-Boc thioamides could be prepared by selective tert-butoxycarbonylation at the nitrogen atom of the thioamide bond. Although the capacity of sulfur to easily engage in electrophilic addition at sulfur made this scenario uncertain, we were delighted to find that the synthesis of N-mono-Boc and N,N-Boc₂-thioamides from the corresponding 2° and 1° thioamides proceeded readily after modification of the reaction conditions, and that, crucially, the ground-state-destabilized thioamide products were stable to the standard isolation and storage conditions (Scheme 2). The thioamide substrates are accessible by a direct thionation of the corresponding amides or nitriles.^[11–15] Importantly, this tert-butoxycarbonylation method is both (1) site-selective with respect to the nitrogen atom, and (2) remarkably wide in scope, tolerating Lewis basic functional groups, sensitive halides and heterocycles on the thioamide component, thus rendering the process broadly useful.

Scheme 2.

One-Step Synthesis of N-Boc-Thioamides.

With the access to N-mono-Boc and N,N-Boc₂ thioamides in hand,^[60] we conducted optimization studies using N-Boc-N-phenyl benzamide 1a as model system. To our delight, we found that the proposed transamidation occurred in excellent 90% yield using NaHMDS (NaHMDS = sodium hexamethyldisilazane, 3.0 equiv) as a base and 4-toluidine (2.0 equiv) as a non-nucleophilic aniline in toluene at room temperature conditions (eq 1). Crucially, the reaction could be readily performed on a gram scale (88% yield) at ambient conditions, demonstrating scalability of the method. See Table S1 the Supporting Information (Supporting Information, SI) for optimization data. Of note, other silazane bases can also be used in this process (e.g., KHMDS, 87%; LiHMDS, 82%). The choice of solvent is critical with toluene (90%) and THF (88%) giving the optimal results. Other bases, such as n-BuLi, KOtBu, NaOH are ineffective, leading to starting material decomposition. No reaction occurs in the absence of the base.

(1)

There are several important points that should be noted: (1) the reaction proceeds in the absence of toxic transition-metal-catalysts; (2) furthermore, there is no need for the strict precautions to exclude air; (3) full selectivity for the N–C(S) bond cleavage is observed (cf. unselective N–Boc cleavage, thioamide hydrolysis or S-electrophilic addition). These results are consistent with the selective nucleophilic addition of the deprotonated aniline to the ground-state-destabilized thioamide bond (vide infra). Overall, this results in a highly attractive, user-friendly method using inexpensive reagents that obviate the need of removal of toxic contaminants from the reaction mixtures,^[64] which is preferred from academic and industrial standpoints and in line with the urgent need for the development of new methods for (thio)amide synthesis as the fundamental functional motif in chemistry.^[65,66]

With the optimized transamidation conditions in hand, we next determined the scope of this new protocol. As shown in Figure 2, the scope is remarkably broad and accommodates a variety of sensitive functional groups that would be problematic or not compatible with related transamidation reactions of amides (bromo, nitro, ester, primary amide, sulfonamide, hydroxyl). As such, a broad spectrum of anilines can be employed as nucleophilic substrates in this thioamide transamidation, encompassing electronic variation of electron-neutral (3a), electron-rich (3b) and electron-deficient (3c-3h) anilines. It is particularly noteworthy that a bouquet of sensitive and easily modifiable functional groups is compatible with this reaction, including bromides (3c), nitro groups (3e), aliphatic esters (3f), amides (3g), sulfonamides (3h), and unprotected phenols (3i), thus providing useful functional handles for functionalization in subsequent transformations.^[67] Further, medicinally privileged anilines,^[68,69] such as [1,1’-biphenyl]-2-amine (3j), quinolin-8-amine (3n) or 9H-carbazol-3-amine (3o), as well as sterically-hindered anilinesthat are of significant synthetic interest in materials chemistry, including even the extremely hindered 2,6-dimethylaniline (3l) and 2,6-diisopropylaniline (3m) are competent nucleophiles. The substrate scope further includes sensitive cyano groups (3p), fluorinated anilines (3q) and polychlorinated anilines (3r) that represent another class of privileged anilines in medicinal chemistry. The reaction is not limited to primary amines and can be applied to secondary anilines (3s). This result is of particular note as it suggests that amide deprotonation is not required to drive the reaction to completion and/or stabilize the final product by deprotonation (vide infra). Finally, aliphatic amines are also compatible, albeit result in lower yields (3t), thus suggesting that amine deprotonation is a relevant mechanistic step in the process (vide infra). We next examined the generality of the thioamide component in the reaction. Gratifyingly, electron-neutral (3u) electron-rich (3v) and electron-deficient (3w) as well as sterically-hindered (3x) N-Boc-activated thioamides undergo transamidation with the challenging sterically-hindered 2,6-dimethylaniline in high yields. Furthermore, chloro (3y) and fluoro-substituted thioamides (3z) as well as heterocyclic thioamides as demonstrated by the electron-rich deactivating 2-furyl (3aa) are well tolerated in this method. At present stage, thioamides derived from aliphatic carboxylic acids are not compatible due to α-deprotonation, resulting in starting material recovery. For select examples, DMF has been identified as a co-solvent to improve solubility.

Figure 2.

Transition-metal-free transamidation of N-mono-Boc-thioamides: reaction scope.^{a a}Thioamide (1.0 equiv), 2 (2.0 equiv), NaHMDS (3.0 equiv), toluene (0.25 M), 23 °C, 15 h. Isolated yields. ^b2 (1.5 equiv), NaHMDS (2.3 equiv). ^cNaHMDS (5 equiv), toluene/DMF, 1:1 v/vol. ^dNaHMDS (4 equiv). ^eTHF (0.33 M). ^fNaHMDS (2 equiv). See SI for details.

In order to further demonstrate the utility of this transamidation method, we applied it to the transamidation using an array of medicinally-privileged heterocycles (Figure 3).^[70] Typically, transamidations with electron-deficient heterocyclic amines, such as in Figure 2, are particularly challenging due to low nucleophilicity and the potential to undergo side reactions of the heterocyclic ring.^[40–50] As such, we were delighted to find that a remarkably broad range of heterocyclic amines, including 3-pyridyl (3ab), electronically-differentiated 2-pyridyl (3ac-3ad), 5-pyrazolyl (3ae), 4-pyrimidyl (3af), 4-isoxazolyl (3ag) as well as 2-benzothioazolyl (3ah), 2-thiadiazolyl (3al) and 2-quinolinyl (3aj) provided the transamidation products with excellent efficiency, thus demonstrating the potential utility of this new protocol in medicinal chemistry research. Of further note is the fact that heteroatom scission of 5-membered heterocycles (N–O, isoxazole; N–N, pyrazole; N–N, thiadiazole) was not observed, while the anilines used in examples 3ae (5-pyrazolyl) and 3aj (2- quinolinyl) are the key feature of pharmaceuticals and natural products.

Figure 3.

Transition-metal-free transamidation of N-mono-Boc-thioamides with heterocyclic amines: reaction scope.^{a a}See Figure 2. ^btoluene (0.10 M). ^ctoluene/DMF, 1:1 v/vol (0.05 M). See SI for details.

Having established that N-mono-Boc activated thioamides can be employed successfully in this thioamide transamidation to rapidly generate new thioamide bonds, we next examined the generality of the reaction with respect to N,N-Boc₂-thioamides. As previously outlined (Schemes 1–2), N-mono-Boc and N,N-Boc₂-thioamides are prepared by a site-selective mono or double tert-butoxycarbonylation of 2° and 1° thioamides, thus providing a comprehensive access to ground-state destabilized thioamides that undergo transamidation under exceedingly mild reaction conditions and furnish the products that would not be readily accessible using conventional transamidation technologies. Thus, we were delighted to find that transamidation of N,N-Boc₂-thioamides was feasible under the developed conditions with a remarkable scope matching that observed for mono-Boc thioamides (Figure 4). The same compounds have been used for comparison purposes. The two methods are complementary, pertaining to different classes of thioamides. As such, this transamidation of N,N-Boc₂-thioamides was also found to be compatible with an impressive range of functional groups (3c-3aa). Importantly, this transamidation of N,N-Boc₂-thioamides is also readily scalable, delivering the thioamide product in excellent yield on a gram scale (1.0 g, 3ak, 80%). As a further demonstration of the utility of transamidation of N,N-Boc₂-thioamides, we applied this method to transamidation using medicinally-privileged heterocyclic amines (Figure 5). These reactions proceeded with remarkable efficiency with an array of challenging heterocyclic amines, matching the results observed with N-mono-Boc thioamides (Figure 3) and illustrating that this method may likely find broad use in medicinal chemistry programs.

Figure 4.

Transition-metal-free transamidation of N,N-Boc₂-thioamides: reaction scope.^{a a}Thioamide (1.0 equiv), 2 (2.0 equiv), NaHMDS (3.0 equiv), toluene (0.25 M), 23 °C, 15 h. Isolated yields. ^b2 (1.5 equiv), NaHMDS (2.3 equiv). ^cNaHMDS (5 equiv), toluene/DMF, 1:1 v/vol. ^dNaHMDS (4 equiv). ^eTHF (0.33 M). ^fNaHMDS (2 equiv). See SI for details.

Figure 5.

Transition-metal-free transamidation of N,N-Boc₂-thioamides with heterocyclic amines: reaction scope.^{a a}See Figure 2. ^btoluene (0.10 M). ^ctoluene/DMF, 1:1 v/vol (0.05 M). See SI for details.

To highlight the efficiency of this new approach for transamidation by ground-state-destabilization of thioamides, we tested this transformation using various N-activated thioamides (Figure 6).^53–61 As shown, a broad array of N-acyclic and N-cyclic thioamides can be employed, including N-alkyl-N-Boc activated thioamides (5a-6a) and N-pyrrolyl-activated thioamides (7a) (Figure 6A). Most remarkably, simple N-aryl thioamides that lack n_N→π*_C=O conjugation (cf. n_N→Ar conjugation) on the external acyl group can also be readily employed in this transamidation method at exceedingly mild room temperature conditions (8a-8c) (Figure 6B). Furthermore, N,N-di-aryl thioamides (8d), N-indolyl-activated thioamides (8e) and N-tetrahydroquinolinyl thioamides (8f) readily undergo efficient transamidation, albeit the latter requires higher temperature for the reaction, consistent with thioamide ground-state-destabilization (vide infra). To further highlight the value of this transition-metal-free transamidation of thioamides, we have demonstrated that this protocol can be used in late-stage derivatization of pharmaceutical derivatives (Figure 7). Thus, transamidation of N-mono-Boc-activated thioamide of probenecid (antihyperuricemic, 3am), bexarotene (anticancer, 3an) and ataluren (muscular dystrophy, 3ao) with anilines containing sensitive functional handles (bromo, primary amide, primary sulfonamide) produced the desired transamidation products in 77–81% yields. Thus, this method has a potential to accelerate the synthesis of diverse thioamides for the synthesis of important medicinally relevant products. In this context, it is worthwhile to point out that prior to this study, transamidation of thioamides with anilines had not been possible under any conditions, while the present method of ground-state-activation not only enables this transform for the first time, but also proceeds with a remarkably broad scope under mild, user-friendly and practical reaction conditions.

Figure 6.

Transition-metal-free transamidation of thioamides: thioamide scope.^{a a}Figure 6A: see Figure 2; Figure 6B: thioamide (1.0 equiv), 2 (3.0 equiv), NaHMDS (4.0 equiv), toluene (0.25M), 23 °C, 15 h. ^b80 °C. See SI for details.

Figure 7.

Transition-metal-free transamidation of thioamides: late-stage functionalization.^{a a}thioamide (1.0 equiv), 2 (2.0 equiv), NaHMDS (3–5 equiv), toluene (0.25M), 23 °C, 15 h. See SI for details.

To expand the utility of the method to aliphatic amines, we conducted studies using nucleophilic transamidation^[58–60] of ground-state-destabilized thioamides (Figure 8 and 9). As expected, transamidation of 2° and 1° ground-state-destabilized thioamides proceeded smoothly, expanding the utility to either non-nucleophilic amines or nucleophilic amines, including benzylic, cyclic and aliphatic amines.

Figure 8.

Transition-metal-free transamidation of N-mono-Boc-thioamides with aliphatic amines: reaction scope.^{a a}thioamide (1.0 equiv), 2 (2.0 equiv), K₃PO₄ (2.5 equiv), THF (1.0 M), 23 °C, 15 h. See SI for details.

Figure 9.

Transition-metal-free transamidation of N,N-Boc₂-thioamides with aliphatic amines: reaction scope.^{a a}thioamide (1.0 equiv), 2 (2.0 equiv), THF (1.0 M), 23 °C, 15 h. ^b120 °C. ^cNaHMDS (1.0 equiv). See SI for details.

To gain insight into the mechanism of the reaction, selectivity studies were conducted (see SI). As such, intermolecular competition experiments revealed that electron-deficient anilines are inherently more reactive than their electron-rich counterparts (4-CF₃:4-MeO = 60:40), while anilines are more reactive than aliphatic amines (4-Tol-NH₂:n-Bu-NH₂ >95:5). Moreover, electron-deficient thioamides are significantly more reactive than their electron-rich counterparts (4-CF₃:4-MeO = 93:7). Overall, these selectivity studies are consistent with the reaction pathway involving amine deprotonation, followed by nucleophilic addition to the thioamide N–C(S) bond by a net transacylation process (vide infra). As a key feature of this process, previously unattainable selectivity of the transamidation is achieved through ground-state-destabilization of the thioamide bond, a process that may open up a plethora of potential strategies for thioamide bond functionalization by transition-metal-free and metal-catalyzed synthetic strategies.

Preliminary results indicate that aliphatic thioamides are suitable substrates. Specifically, the reaction of C₉H₁₉-C(S)-N-Ph/Boc thioamide afforded the transamidation product in 87% yield (pyrrolidine, 2 equiv, RT, CH₃CN, 15 h) (see the Supporting Information, page S135). This reactivity bodes well for the use of both aromatic and aliphatic thioamides as electrophiles in ground-state-destabilization platform.

DFT studies.

We next investigated the reaction mechanism and reactivity pattern using density functional theory (DFT)calculations. The DFT-computed free energy profile of NaHMDS-mediated transamidation of thioamides, using N-Boc-N-phenyl benzamide 1a and 4-toluidine as model, is shown in Figure 10. From the 4-toluidine-coordinated NaHMDS dimer INT1, the N-H deprotonation occurs via TS1 to generate the heterodimer complex INT2. Subsequent complexation with thioamides 1a leads to INT3, and INT3 undergoes the nucleophilic addition through TS2 to irreversibly produce the tetrahedral intermediate INT4. INT4 undergoes the isomerization step via TS3 to have the Boc-substituted amino leaving group coordinated to sodium in INT5. From INT5, the elimination step via TS4 produces the transamidation product-coordinated complex INT6. Due to the N-H acidity of the transamidation product, further deprotonation can occur to generate the more stable complex INT7, which provides additional thermodynamic driving force for the overall transamidation process. Based on the DFT-computed free energy profile, the nucleophilic addition step via TS2 is the rate-determining step, which requires a barrier of 16.3 kcal/mol as compared to the NaHMDS dimer INT1.

Figure 10.

DFT-computed free energy profile of NaHMDS-mediated transamidation of thioamides at the M06–2X/def2-TZVPP-SMD(toluene)//B3LYP-D3(BJ)/def2-SVP level of theory. All C-H bonds are hidden for simplicity. See SI for details.

Our computations also provide a mechanistic basis for the observed reactivity pattern. Based on the competition experiment between thioamides 1c and 1d (Scheme S2) and the competition experiment between anilines 2a and 2t (Scheme S3), we further explored the free energy changes of these intermolecular competitions, and the results are shown in Figure 11. For the competition between CF₃-substituted thioamide 1c and OMe-substituted thioamide 1d (Figure 11A), the pre-nucleophilic addition intermediates INT10 and INT12 have comparable stabilities and exist in an equilibrium. Subsequent rate-determining nucleophilic addition favors the electron-deficient thioamide 1c by 2.0 kcal/mol (TS6 vs. TS7), which agrees well with the experimental observed selectivity (93:7, Scheme S2). For the competition between aniline 2a and aliphatic amine 2t, the deprotonation is still facile and reversible. It is the N-H acidity that differentiates the two types of amines. The more acidic aniline favors the N-H deprotonation and the formation of the heterodimer intermediate INT2, while the corresponding heterodimer intermediate INT15 for the less acidic aliphatic amine 2t is much less stable. INT15 is 9.6 kcal/mol higher in free energy as compared to INT2. This energy difference contributes to the overall barrier in the rate-determining nucleophilic addition (TS9 vs. TS2), which inhibits the transamidation with aliphatic amine 2t. These results also agrees well with the experimentally observed exclusive chemoselectivity (Scheme S3).

Figure 11.

DFT calculations on the competition between thioamides 1c and 1d (A), and the competition between anilines 2a and 2t (B).

Note that we have explored the possibility of additional toluene coordinations, however found this mechanistic possibility unfavorable. This is because the NaHMDS dimer complex have two vacant sodium sites for coordination. One is necessary for the substrate thioamide coordination, and the other for one toluene coordination. Additional toluene coordination is unlikely due to the repulsions with the existing coordinating substrate or toluene (see the Supporting Information, page S9, Figure S1).

Conclusion

In summary, we have developed the first general, mild and highly chemoselective method for transamidation of thioamides by N–C(S) transacylation using non-nucleophilic anilines. This process exploits the uncommon cleavage of the C(S)–N bond after site-selective N-tert-butoxycarbonyl activation of 2° and 1° thioamides resulting in a ground-state-destabilization of the thioamide bond. The transamidation process proceeds under exceedingly mild ambient conditions, affords the products in high yields and shows excellent selectivity for the N–C(S) cleavage. The method shows a remarkably broad functional group tolerance to sensitive functional groups, can be used for transamidations with challenging heterocyclic amides and was successfully applied to the late-state derivatization of drug molecules. Furthermore, the method is broadly compatible with N-Ar tertiary thioamides and N-thioacyl-azoles as selective N-thioacyl transfer reagents. Noteworthy features of this protocol also include operational simplicity and the absence of transition metals to promote transamidation. Crucially, this transformation also marks the first application of the powerful thioamide ground-state-destabilization concept, which offers new avenues to rationally manipulate reactivity of thioamides. We further presented extensive DFT studies that provided insight into the chemoselectivity of this new transamidation method and provided guidelines for the development of future transamidation methods of the thioamide bond. In a broader context, although thioamides represent highly valuable “single atom substitution” isosteres of amide bonds with broad applications in chemistry and biology, the direct transamidation of thioamides had been elusive due to the increase in n_N→π*_C=S resonance by higher contribution of the polar form in thioamides. The present study establishes a powerful direction to the development of new thioamide-based molecules in various facets of chemistry and biology.