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Silver-Catalyzed [3 + 3] Dipolar Cycloaddition of Trifluorodiazoethane and Glycine Imines: Access to Highly Functionalized Trifluoromethyl-Substituted Triazines and Pyridines Zhen Chen, Nan Ren, Xiaoxiao Ma, Jing Nie, Fa-Guang Zhang, and Jun-An Ma ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b00846 • Publication Date (Web): 12 Apr 2019 Downloaded from http://pubs.acs.org on April 12, 2019
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ACS Catalysis
Silver-Catalyzed [3 + 3] Dipolar Cycloaddition of Trifluorodiazoethane and Glycine Imines: Access to Highly Functionalized Trifluoromethyl-Substituted Triazines and Pyridines Zhen Chen,§,† Nan Ren,§,† Xiaoxiao Ma,† Jing Nie,† Fa-Guang Zhang,†,* and Jun-An Ma†,‡,* † Department
of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Tianjin Collaborative Innovation Center of Chemical Science & Engineering, Tianjin University, Tianjin 300072, P.R. China. ‡
State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P.R. China.
Supporting Information
ABSTRACT: Herein we disclose a silver-catalyzed [3 + 3] 1,3CF3 CF3 R1 CF3CHN2 R1 dipolar cycloaddition reaction of trifluorodiazoethane with glycine Ag [O] NH N [3 + 3] + imines. This reaction exhibits manifold remarkable features, such N N N NH 21 examples 34 examples 2 1 as easily available substrates, high regio- and diastereoselectivities, R N CO2R 55-99%, >99:1 dr 42-92% 2 CO2R CO2R2 mild reaction conditions, and good yields across a broad spectrum CF3 CF3 of substrates. Moreover, swift transformations of obtained 3 H 1 R4 R1 R3 R Click ligation R tetrahydrotriazines provide efficient access to a diverse set of or R3COR4 with s-TCO N N 12 examples highly functionalized trifluoromethyl-substituted triazines and OH k up to R4 50-99% 2 H pyridines. Particularly noteworthy is that such trifluoromethylated 2 CO2R2 99.24 M-1 s-1 CO2R 1,2,4-triazines demonstrate competent reactivity toward transcyclooctene (TCO) derivatives with the second order rate constants (k2) up to 99.24 M-1 s-1, which represents the highest value involving 1,2,4-triazines to date. KEYWORDS: dipolar cycloaddition, trifluorodiazoethane, silver catalysis, 1,2,4-triazines, trifluoromethylated hetereocycles 1. INTRODUCTION Scheme 1. Different Patterns of 1,3-Dipolar Cycloaddition Trifluoromethyl-substituted N-heterocycles are important core Reactions with CF3CHN2 structures found in numerous compounds of pharmaceutical, 1 agrochemical, and bioactive significance. Therefore, their a) Previous work: [3 + 2] DPC HN N construction has attracted considerable interest from organic R1 CF3 1 F3C community during the past few decades, and various useful R CH [3 + 2] C N R2 N N synthetic methods have been disclosed.2 Among them, the + N N CF3 1,3-dipolar cycloaddition intermolecular 1,3-dipolar cycloaddition (DPC) reactions R2 N N R3 N N N represent a powerful and atom-economical approach to N CF3 1,3-dipole 2 dipolarophile N versatile trifluoromethyl-substituted N-heterocycles from R3 3 simple and easily available starting materials. In this context, b)This work: [3 + 3] DPC 2,2,2-trifluorodiazoethane (CF3CHN2) has emerged as an Ar CO2R CO2R F3C attractive trifluoromethyl-containing 1,3-dipole in recent CH R5 4 [3 + 3] DPC N years, as demonstrated by a series of DPC reactions with NH N N + N silver catalysis NH alkenes,5 allenes,6 alkynes,7 benzynes,8 aldimines,9 Ar N R4 Ar 10 11 RO C CF3 2 isocynides, and arene-diazonium salts, thus allowing facile CF3 1,3-dipole dipolarophile preparation of trifluoromethyl-substituted pyrazolines, H pyrazoles, triazoles, and tetrazoles (Scheme 1a). However, all CF3 OH CO2R Ar such studies only focused on the [3 + 2] DPC transformations H N N OH to give 5-membered trifluoromethyl-substituted N-heterocycles. H N N fast click ligation with TCOs Ar In sharp contrast, higher-order DPC reactions of CF3CHN2 have H MeO2C CF3 received much less attention.12 Indeed, there is still no report on employing CF3CHN2 in the direct [3 + 3] variant of DPC As part of our continuing interest in the chemistry of reactions until now, albeit the realization of such protocol CF3CHN2,14 we report herein a silver-catalyzed [3 + 3] DPC would offer great promise for the efficient construction of reaction of CF3CHN2 with in situ generated azomethine ylides valuable six-membered trifluoromethyl-substituted N(Scheme 1b).15 This strategy not only diversifies the existing heterocycles, such as CF3-bearing pyridines that have been DPC reaction patterns of CF3CHN2, but also provides a direct widely identified as important scaffolds with diverse biological approach to trifluoromethyl-substituted tetrahydrotriazines in 13 activities.
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moderate to excellent yields with exclusive regio- and diastereoselectivities. Furthermore, the afforded cycloadducts can be readily converted into a diverse array of trifluoromethylsubstituted 1,2,4-triazines and pyridines. Of particular importance, these unique trifluoromethyl-substituted 1,2,4triazines, simultaneously containing a tunable aryl moiety (Ar) and two electron-withdrawing groups (CF3 and CO2Me), hold great promise for translation into bioorthogonal reagents,16 as exemplified by the fast trans-bicyclononene (s-TCO) ligation with the second-order rate constants (k2) impressively amounting to 99.24 M-1 s-1. 2. RESULTS AND DISCUSSION Table 1. Optimization of Reaction Conditions a H N
F3C
N
CO2Me
1a
Cl
Entr y
+ CF3CHN2
catalyst / base solvent, temp, time 4-ClC H 6 4
N 2a
NH CO2Me
Catalyst (mol%)
Base (x equiv)
Solvent / Temp (oC) / Time (h)
Yield (%)b
1
~~
Cs2CO3 (0.5)
THF / 25 / 24
20
2
CuI (10)
Cs2CO3 (0.5)
THF / 25 / 24
0c
3
Cu(OAc)2 (10)
Cs2CO3 (0.5)
THF / 25 / 24
5c
4
Zn(OAc)2 (10)
Cs2CO3 (0.5)
THF / 25 / 24
47
5
FeCl3 (10)
Cs2CO3 (0.5)
THF / 25 / 24
22
6
NiBr2 (10)
Cs2CO3 (0.5)
THF / 25 / 24
34
7
Ag2O (10)
Cs2CO3 (0.5)
THF / 25 / 24
60
8
Ag2CO3 (10)
Cs2CO3 (0.5)
THF / 25 / 24
58
9
AgF (10)
Cs2CO3 (0.5)
THF / 25 / 24
81
10
AgNO3 (10)
Cs2CO3 (0.5)
THF / 25 / 24
51
11
AgOAc (10)
Cs2CO3 (0.5)
THF / 25 / 24
82
12
AgOAc (10)
Na2CO3 (0.5)
THF / 25 / 24
0c
13
AgOAc (10)
K2CO3 (0.5)
THF / 25 / 24
0c
14
AgOAc (10)
Et3N (0.5)
THF / 25 / 24
0c
15
AgOAc (10)
DBU (0.5)
THF / 25 / 24
57
16
AgOAc (10)
Cs2CO3 (0.75)
THF / 25 / 24
88
17
AgOAc (10)
Cs2CO3 (1.0)
THF / 25 / 24
90
18
AgOAc (10)
Cs2CO3 (1.0)
THF / 0 / 24
97
19
AgOAc (5)
Cs2CO3 (1.0)
THF / 0 / 48
85
20
AgOAc (10)
Cs2CO3 (1.0)
toluene / 0 / 24
5c
21
AgOAc (10)
Cs2CO3 (1.0)
CH3CN / 0 / 24
40
22
AgOAc (10)
Cs2CO3 (1.0)
CH2Cl2 / 0 / 24
0c
23
AgOAc (10)
Cs2CO3 (1.0)
DMF / 0 / 24
12c
24d
AgOAc (10)
Cs2CO3 (1.25)
THF / 0 / 24
84
25d
AgF (10)
Cs2CO3 (1.25)
THF / 0 / 24
90
26
d
AgOTf (10)
Cs2CO3 (1.25)
THF / 0 / 24
52
27d
Ag2CO3 (10)
Cs2CO3 (1.25)
THF / 0 / 24
65
a
Reaction conditions: 1a (0.4 mmol), CF3CHN2 (0.8 mmol), solvent (4.0 mL) (Method A). b Isolated yield. dr values (> 99:1) were determined by 19F NMR analysis. c Determined by 19F NMR analysis. d CF3CHN2 was in situ generated from trifluoroethylamine (0.8 mmol) (Method B).
Reaction Optimization. As a starting point to this study, we set out to investigate the DPC reaction of CF3CHN2 with methyl (E)-2-((4-chlorobenzylidene)amino)acetate 1a in the presence of Cs2CO3 at room temperature (Table 1). Despite in low conversion, the desired cycloadduct 2a was isolated with
excellent regio- and diastereoselectivity (entry 1). Next, a series of metal catalysts, including copper, zinc, iron, nickel, and silver salts, were screened for the model reaction (entries 2–11). Among these, it was found that silver salts performed as the most powerful promoters (entries 7–11). Particularly, when AgOAc was employed as the catalyst, the DPC reaction proceeded efficiently to produce cycloadduct 2a in 82% yield (entry 11). On the basis of this observation, further optimization was carried out by screening different bases and lowering the reaction temperature (entries 12–18). Pleasingly, the best result for the formation of 2a was achieved (97% yield, >99:1 dr, entry 18), by performing this reaction with AgOAc (10 mol %) and Cs2CO3 (1.0 equiv) in THF at 0 °C for 24 hours. When the amount of silver was reduced to 5 mol %, the transformation also underwent with good performance, albeit in prolonged reaction time (entry 19). In addition, the solvent was found to have an important effect on the reactivity (entries 20–23), among which THF proves to the one of choice. Encouraged by the seminal studies of Carreira,17 Mykhailiuk,18 and our group19 on in situ preparation of diazo compounds, we also investigated the feasibility for in situ CF3CHN2 generation and its follow-up one-pot reaction with 1a (entries 24-27). In this scenario, a comparable yield was attained in an organic medium with AgF as catalyst (90% yield, >99:1 dr, entry 25). Substrate Scope of the DPC Reaction of Glycine Imines with CF3CHN2. With the optimal reaction conditions in hand (Table 1, entries 17 and 25), the scope of this silver-catalyzed DPC reaction of CF3CHN2 with a variety of glycine imines 1 for the synthesis of CF3-substituted tetrahydrotriazines was investigated. As shown in Scheme 2, the use of the stock solution of CF3CHN2 (Method A) or the in situ generation of CF3CHN2 (Method B) furnished the desired products in comparable or complementary yields. In the case of phenylaldehyde-derived glycine imines, the DPC reaction tolerates various substitution patterns and a range of substituents on the phenyl ring. Halo-, trifluoromethyl-, nitro-, methoxycarbonyl-, cyano-, amino-, alkoxy-, alkyl-, and arylsubstituted phenyl glycine aldimines all underwent the desired reaction to afford cycloadducts 2a–v in good to high yields. The single regio- and stereoisomer of product 2b was readily obtained by simple recrystallization using ethyl acetate/petroleum. X-ray structure analysis revealed the trans relationship between the CF3 group and 4-BrC6H4 substituent at the tetrahydrotriazine ring.20 Polycyclic and heterocyclic glycine aldimines were found to be competent substrates, thereby delivering products 2w–b’ in 73–96% yields. Besides methyl ester substituent, glycine imines with other ester substituents, such as ethyl and tert-butyl groups, were also compatible with this reaction to give cycloadducts 2c’ and 2d’ in decent yields. Remarkably, the tri(perfluorotertbutyl)pentaerythritol-modulated alkyl group (PFC) containing 27 fluorine atoms with identical chemical environment and without adjacent hydrogen atom was readily incorporated (2e’ and 2g’), which provides an unique opportunity for disease diagnosis using 19F magnetic resonance imaging (MRI).21 Moreover, glycine aldimines derived from the star AIEgen tetraphenylethene (TPE) in the
Scheme 2. Substrate Scope of Cycloaddition Reaction of CF3CHN2 with Various Glycine Imine Esters 1
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ACS Catalysis CF3CHN2 + N 1
Ar
HN F3C R
F3C
AgOAc or AgF, Cs2CO3
CO2R
H N
H N
Ar
N
THF, 0 oC, 24 h
H N
N
H N
F3C
NH
H N
F3C
H N
H N
H N
F3C
NH
N R = H, 2a', 81% (73%) R = CF3, 2b', (81%)
NH O
Cl
O
O
F3C
Ar
N
Cs2CO3, THF, 0 oC, 24 h
D2-2a, 96%
H N
Ar
N
Ar
H
N
N
OR'
F3C N N
F3C
R
OR'
N N TS
2f', 78% (92%)
B
O AgLn
O
N
O
O 2g', 71% (76%)
OC(CF3)3 4
HN
OC(CF3)3 F3C OC(CF3)3
CO2 Bu N
CO2R' N 1 AgOAc Cs2CO3
O
Cs2CO3 AgOAc
CF3
R
CsHCO3
N
R N LnAg
2h', 72% (92%)
H N
N
F3C
Ac,
OR'
AgO
N
1
Cs F3C
CO2R'
2
R
CO2R'
N
C
H
3 CO
N
R
N
R
N
O A
Ln = AcO or solvent
field of aggregation-induced emission (AIE)22 also underwent the desired transformation efficiently to forge products 2f’ and 2g’ in good yields, which further highlights the mild nature and broad functional group compatibility of this method. It should be noted that in all cases the diastereoselectivites of these reactions were excellent (> 99:1). In addition to glycine aldimines, glycine ketimine also worked well under the same reaction conditions to give the desired product 2h’. Mechanistic Studies and Proposed Mechanism. To shed light on the mechanism for this [3 + 3] DPC reaction, several isotopic-labelling experiments were carried out (Scheme 3). When deuterium-labeled CF3CHN2 (Scheme 3a) and benzaldehyde-derived glycine imine D1-1a (Scheme 3b) were used as reactants under the standard reaction conditions, the ratios of deuterium to hydrogen at C6- and C5-positions of the tetrahydrotriazine ring were found to be identical to that of the starting materials, indicating that no cleavage of C−H bonds occured at these positions from reactants to products. By using D2-1a as the reactant, we did not observe any incorporation of deuterium at the 1- and/or 2-position of the tetrahydrotriazine ring (Scheme 3c). In the control experiments, however, we detected the deuterated tetrahydrotriazine when D2O was used as additive (Scheme 3d). Therefore, the intermolecular proton Scheme 3. Isotopic-Labeling Experiments (Ar = 4-ClC6H4) and Proposed Mechanism
CsHCO3
AgLn CF3
NH
CO2Me
N
D3-2a, 99%
e)
t
H/D (33/67) N 1 2NH/D (31/69)
2a
CO2Me
CO2Me
2a, 90%
3
CO2Me
NH
H N
3
N
F3C
D2O (5 equiv), THF, rt, 2 h
NH
R
OC(CF3)3 OC(CF3)3
H/D (100/0) N 1 2 NH/D (100/0)
F3C C N N F3C AgOAc (10 mol%) H + (90/10)D/H H/D (10/90) Cs2CO3, THF, 0 oC, 24 h Ar N CO2Me Ar D2-1a H N
CO2Me
N
Ar
CO2Me
NH
6 5 4
(100) D
D1-1a
F3C
H N
F3C
AgOAc (10 mol%)
c)
OC(CF3)3 4
2e', 65% (68%) H N
F3C C N N H (100) D +
R = Et, 2c', 81% (85%) R = tBu, 2d', 77% (90%)
N O
b)
OR
N
CO2Me
N R
2y, 81% (75%)
NH
N
CO2Me
N
CO2Me
F3C F3C
NH
a) F3C H N F3C C N N NH 6 (50/50)D/H AgOAc (10 mol%) H/D (50/50) 5 4 o + Ar CO2Me N Cs2CO3, THF, 0 C, 24 h N CO2Me Ar D1-2a, 95% 1a
d)
NH
S 2z, 85% (93%)
R = 3-Cl, 2l, 78% (86%) R = 3-NO2, 2m, 80% (74%) R = 3-OMe, 2n, 87% (85%) R = 3-NBn2, 2o, 86% (90%) R = 2-Cl, 2p, 66% (89%) R = 2-Br, 2q, 75% (86%) R = 2-Me, 2r, 70% (92%) R = 2-MeO, 2s, 55% (64%) R = 3,4-Cl2, 2t, 72% (73%) R = 3,5-(CF3)2, 2u, (71%) R = 3,4,5-F3, 2v, (75%)
2x, 96% (95%) F3C
CO2Me
yield in Method A CO2R (yield in Method B)
NH
N
CO2Me
2w, 82% (96%)
H N
NH
2
R = 4-Cl, 2a, 97% (90%) R = 4-Br, 2b, 99% (80%) CO2Me R = H, 2c, 75% (79%) R = 4-F, 2d, 96% (85%) R = 4-CF3, 2e, 82% (79%) N R = 4-NO2, 2f, 76% (70%) R = 4-CN, 2g, 81% (72%) R = 4-CO2Me, 2h, 93% (99%) R = 4-Me, 2i, 77% (82%) R = 4-MeO, 2j, 50% (43%) R = 4-Ph, 2k, 76% (86%)
N
F3C
F3C
H N
NH
N 2
CO2R'
exchange between cycloadduct-NH and water is possible. To further probe the progression of this cycloaddition, we monitored the reaction mixture of glycine imine 1a, CF3CHN2, AgOAc, and Cs2CO3 in THF by 19F NMR spectroscopy. 19F NMR analysis of the reaction filtrate revealed the appearance of two new signals at −73.7 (doublet) and −67.2 (doublet) ppm (Figure S5 in the SI). The doublet at −73.7 ppm was identified as the expected cycloadduct 2a. Interestingly, when the reaction was complete, another doublet signal at −67.2 ppm disappeared, probably pointing to the corresponding cycloaddition intermediate species.23 Based on these preliminary results, a tentative reaction mechanism was deduced.24 As depicted in Scheme 3e, in the presence of AgOAc and Cs2CO3, glycine imine was initially converted into silver enolate A. Follow-up [3 + 3] DPC reaction between silver enolate A and CF3CHN2 occurred to give Agcomplex B with excellent regio- and diasteroselective control via a chair-like six-membered transition state (TS), wherein the trifluoromethyl group and two substituents of glycine imines all orientated equatorially to minimize steric interactions.25 Subsequent 1,3-hydrogen shift and protonation Scheme 4. Synthetic Transformation of
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Tetrahydrotriazines 2 into 6-Trifluoromethyl-1,2,4triazines 3 F3C
H N
Ar
N
NH
DDQ (4 equiv)
F3C
N
Ar
N 3
THF, 50 oC, 20 h
CO2R
2 N
N
R = 4-Cl, 3a, 80% R = 4-Br, 3b, 72% R = H, 3c, 83% R = 4-F, 3d, 70% R = 4-CF3, 3e, 67% R = 4-NO2, 3f, 42% R = 4-CN, 3g, 50%
CO2Me N
F3C R
N
N
N
CO2Me N
N
F3C
N
F3C
N
CO2Me
N CO2R
R = 4-CO2Me, 3h, 63% R = 4-Me, 3i, 86% R = 4-MeO, 3j, 92% R = 3-MeO, 3k, 77% R = 3,5-(CF3)2, 3l, 55% R = 3,4,5-F3, 3m, 61% N
CO2Me N
F3C
N
N
CO2Me N
F3C
S
3n, 64%
3o, 66% N
F3C
F3C
N
F3C
N
N
3p, 54%
CO2Me
N
3q, 57%
N O
N
O
4
OC(CF3)3 OC(CF3)3
O 3r, 72% F3C
3t, 72% N N
N CO2Me
F3C
N
N O
N O
3s, 72%
OC(CF3)3
O
OC(CF3)3 4
OC(CF3)3 OC(CF3)3
3u, 90%
assisted by CsHCO3 proceeded rapidly to produce a relatively stable intermediates C. This hydrogen shift pathway was verified to some extent by the fact that no product was generated for alanine- or phenylalanine-derived imines, among which the hydrogen in intermediates B was replaced by methyl or phenyl group, respectively. Finally, another 1,3-hydrogen shift (isomerization) of C occurred to afford the desired product 2. Further Synthetic Transformations. Trifluoromethylated tetrahydrotriazines 2 are versatile synthetic intermediates, and direct oxidation of a series of tetrahydrotriazines using DDQ in THF was examined (Scheme 4). To our delight, tetrahydrotriazines 2 with a broad spectrum of substituents, including phenyl, naphthyl, anthracenyl, thiophenyl and pyridyl, were smoothly oxidized to the corresponding 6-trifluoromethyl1,2,4-triazines 3a–r in moderate to good yields (42–92%). Several tetrahydrotriazines with TPE and/or PFC functional groups also underwent this oxidation transformation successfully, and the expected products 3s–u were isolated in good to high yields. 3-Trifluoromethylpyridine is the core unit of many drugs, agrochemicals, and related candidates. Further synthetic transformation of 1,2,4-triazines 3 into 3trifluoromethylpyridines 4 was achieved by using various dienophile partners (Scheme 5). For example, performing the reaction of 1,2,4-triazines with 2,5-norbornadiene or alkynes in toluene at 110 oC readily delivered the corresponding pyridines 4a–f in 50–99% yields.26 Treatment of 1,2,4-triazines with aliphatic aldehydes by means of Boger’s protocol afforded the highly substituted pyridines 4g–j in good to high yields with
excellent regioselectivities.27 Compound 4g was subjected to Xray crystallographic analysis to further confirm the structure of these molecules.20 Both of cyclopentanone and cyclohexanone were also smoothly coupled with triazines to give products 4k and 4l in 99% and 83% yields, respectively. These promising results indicate that the present protocol provides a reliable and efficient approach for the synthesis of diverse CF3-containing N-heterocycles. Evaluation of the Reactivity of Trifluromethyl 1,2,4triazines 3 with TCOs. Recently, 1,2,4-triazines have been identified as an alternative class of bioorthogonal reagents, but they are still struggling for wide applications due to the limited reaction kinetics.28 We noted that the 6-trifluoromethyl-1,2,4triazines 3 obtained by our method contain a tunable aryl moiety and two electron-withdrawing substituents simultaneously, which quite possibly imparts them good reactivity towards trans-cyclooctene (TCO) derivatives, and thus making them suitable as a novel class of candidates in bioorthogonal reactions.14 To verify the feasibility of these 1,2,4-triazines as biorthogonal reagents, we first conducted a preliminary computational study to predict their reactivity in the inverseelectron-demand Diels–Alder (IEDDA) reactions with TCO. As shown in Scheme 6, the frontier molecular orbital analysis for three previously reported 1,2,4-triazines T1–3 and our newly developed 3f were performed. It turned out that trifluoromethyl-substituted 1,2,4-triazine 3f possesses the lowest energy in the lowest unoccupied molecular orbital (LUMO), indicating that 3f could exhibit exceedingly higher reaction kinetics in the IEDDA reactions compared with T1–3. Furthermore, the activation free energies (ΔG) for the IEDDA reaction between trifluoromethyl-substituted 1,2,4-triazine 3c and TCO was calculated to be only 20.4 kcal / mol. These results indicated that additional improvement on the TCO ligation reactivity might be feasible by fine-tuning the substituents on the triazine ring. Encouraged by these computational analyses, we then investigated the reactivity of CF3-1,2,4-triazines 3 towards TCO or s-TCO by monitoring the reactions with 19F NMR or UV detector. In all cases, the air-oxidized pyridine derivatives were observed, which is consistent with DFT calculations (Figure S8 in the SI). As shown in Table 2 and Table S1 (in the SI), triazines with strong electron-withdrawing substituent (3e–h and 3r) on the phenyl ring exhibited faster reaction rates than those with electron-neutral or donating groups (3c, 3i, and 3j), which is in consistent with the nature of IEDDA reactions. For triazines 3c–j, the ρ value was determined to be 0.68 via Hammett analysis of the IEDDA reaction rate constants (Figure 1), suggesting that only partial charge separation occurs during the reaction. Notably, the use of s-TCO as the reaction partner led to distinct improvements in reactivity (Table 2). For example, a second-order rate constant of 68.27 M-1 s-1 was recorded for the s-TCO ligation with 4-CF3-Ph-substituted CF3triazine 3e. Remarkably, the highest second-order rate constant (k2 = 99.24 M-1 s-1) was observed when 4-NO2-Ph-substituted CF3-triazine 3f was ligated with s-TCO, which represents the fastest reaction kinetics for the IEDDA transformations involving 1,2,4-triazines to date.
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ACS Catalysis
Scheme 5. Further Transformation of 1,2,4-Triazines 3 into 3-Trifluoromethylpyridines 4. F3C
F3C N
F3C N
CO2Me
4a, 95%
N
CO2Me
4b, 82%
Cl
Cl
F3C
toluene, 110 oC F3C N
CO2Me
N
CO2Me
N
F3C
N
Ar
N
Cl CF3
CO2Me 4e, 50%
( )n
benzyne or phenylacetylene toluene, 110 oC
MeO2C Ph 4f, 83%
N
CO2Me Cl
4j 98%
CO2Me
CO2Me
N
N
O
N
Bn CO2 Me
CO2Me
CF3
N
F3C
Hex
N
3
Cl
CO2 Me 4h, 89%
Cl
4i, 92%
Cl
S 4d, 93%
4c, 99%
n
F3C
Pr
N
CO2Me
4g, 85%
RCH2CHO o pyrrolidine, 4A MS toluene, 110 oC
i
F3C
Me
(n = 1, 2) CF3
o
pyrrolidine, 4A MS CHCl3, 45 oC
CF3
Cl
4k, 99%
Cl
4l, 83%
Scheme 6. Preliminary Computational Studies Table 2. Second-Order Rate Constants (k2 in M-1 s-1) of the Click Ligations between CF3-1,2,4-Triazines 3 and Strained Alkenes
a) LUMO energies of various 1,2,4-triazinesa N N E (eV)
N N
N
N N
N
CO2Me N N
N
CF3 Ar
CF3
N
NO2
OH
N N
N
NO2
+
CO2Me
T1
T2
T3
Ar
-1.91
CF3 Ph
G N N
TS-1 20.4
N
F3C 3 Ph
G G
0 SM
G
N N N IM-1' -5.0
N N CF 3 N Ph
CF3 Ph
N N N
+ H s-TCO
OH
OH
k2
F3C
CH3CN Ar H 2O
N
CO2Me
Ar
[O] H
N CO2Me
Entry
1,2,4-triazine (Ar)
k2 with TCO
1 2 3 4 5 6
3c (Ph) 3e (4-CF3-Ph) 3f (4-NO2-Ph) 3g (4-CN-Ph) 3h (4-CO2Me-Ph) 3i (4-MePh)
0.30 ± 0.04 0.70 ± 0.09 1.00 ± 0.06 0.85 ± 0.15 0.39 ± 0.07 0.20 ± 0.04
OH
H F3C H
Ar N CO2Me
k2 with s-TCO 32.55 ± 4.95 68.27 ± 5.80 99.24 ± 4.44 81.19 ± 3.44 63.27 ± 3.02 26.64 ± 0.52
CF3 N Ph N N
TS-2 -1.6
G G
F3C
TS-2' -0.1
IM-1 -6.7
SM = Starting Material IM = Intermediate TS = Transition State
H
CO2Me
b) energetics of CF3-1,2,4-triazine 3c with TCOb
TS-1' 22.5
N N
N
-2.36
N N N
N
H
CF3
G
[O] CO2Me
Ar
-1.33
Gsol (kcal/mol) G = CO2Me
TCO
k2 CH3CN F C 3 D 2O
3f
-0.97
LUMO
HO
HO
N
CF3
CF3 N N N Ph
N2 IM-2 -46.9
Ph H CF3 Ph H G
N
aCalculated at M06-2X/6-31G(d) level. bCalculated at B3LYP/6-31G(d, p) // (SMD)M06-L/6-31++G(d, p) level.
Figure 1. Hammet plot for the reactions between TCO and a panel of CF3-1,2,4-triazines 3
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3. CONCLUSIONS In conclusion, we have successfully developed an efficient silver-catalyzed [3 + 3] DPC reaction of CF3CHN2 with glycine imines. Under simple and mild conditions, the reaction proceeded smoothly to afford a variety of trifluoromethylsubstituted tetrahydrotriazines with excellent regio- and diastereoselectivities. Furthermore, facile transformation of the obtained CF3-tetrahydrotriazines provides a novel process to formulate highly functionalized triazine and pyridine architectures. More importantly, the high reactivity of these triplet-activated triazines is demonstrated by the fast click ligation with TCOs (k2 up to 99.24 M-1 s-1), thus exhibiting exceptional promise for translation into bioorthogonal reagents. Future investigations including mechanistic elucidation, substrate scope expansion, as well as in vitro and in vivo applications in bioconjugate chemistry are ongoing in our laboratory, and these results will be reported in due course.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.xxxx. Experimental procedures, compound characterization data, computation details, and 1H, 19F and 13C NMR spectra for new compounds (PDF) Crystallographic data of 2b (CIF) Crystallographic data of 4g (CIF)
AUTHOR INFORMATION
Corresponding Author *E-mail:
[email protected] *E-mail:
[email protected] ORCID Jun-An Ma: 0000-0002-3902-6799 Fa-Guang Zhang: 0000-0002-0251-0456 Zhen Chen: 0000-0002-6289-4332
Author Contributions §Z.
C. and N. R. contributed equally to this work.
Notes The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the National Natural Science Foundation of China (No. 21472137, 21532008, and 21772142), the National Basic Research Program of China (973 Program, 2014CB745100), and Tianjin Municipal Science & Technology Commission (14JCZDJC33400). We thank Dr. Wei Meng of Institute of Chemistry (CAS) for help with computational studies.
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J.; Chen, P. R. Transition Metal-Mediated Bioorthogonal Protein Chemistry in Living Cells. Chem. Soc. Rev. 2014, 43, 6511−6526. (g) Li, J.; Chen, P. R. Development and Application of Bond Cleavage Reactions in Bioorthogonal Chemistry. Nat. Chem. Biol. 2016, 12, 129–137. (h) Zhang, S.; He, D.; Lin, Z.; Yang, Y.; Song, H.-P.; Chen, P. R. Conditional Chaperone−Client Interactions Revealed by Genetically Encoded Photo-cross-linkers. Acc. Chem. Res. 2017, 50, 1184−1192. (i) Wu, H.; Devaraj, N. K. Advances in Tetrazine Bioorthogonal Chemistry Driven by the Synthesis of Novel Tetrazines and Dienophiles. Acc. Chem. Res. 2018, 51, 1249–1259. (j) Row, R. D.; Prescher, J. A. Constructing New Bioorthogonal Reagents and Reactions. Acc. Chem. Res. 2018, 51, 1073–1081. (k) N. K. Devaraj, The Future of Bioorthogonal Chemistry. ACS Cent. Sci. 2018, 4, 952– 959. (17) (a) Morandi, B.; Carreira, E. M. Iron-Catalyzed Cyclopropanation with Trifluoroethylamine Hydrochloride and Olefins in Aqueous Media: In Situ Generation of Trifluoromethyl Diazomethane. Angew. Chem., Int. Ed. 2010, 49, 938–941. (b) Morandi, B.; Carreira, E. M. Rhodium‐Catalyzed Cyclopropenation of Alkynes: Synthesis of Trifluoromethyl-Substituted Cyclopropenes. Angew. Chem., Int. Ed. 2010, 49, 4294–4296. (c) Morandi, B.; Mariampillai, B.; Carreira, E. M. Enantioselective Cobalt-Catalyzed Preparation of Trifluoromethyl-Substituted Cyclopropanes. Angew. Chem. Int. Ed. 2011, 50, 1101–1104. (d) Morandi, B.; Carreira, E. M. Synthesis of Trifluoroethyl-Substituted Ketones from Aldehydes and Cyclohexanones. Angew. Chem., Int. Ed. 2011, 50, 9085–9088. (18) Mykhailiuk, P. K. Generation of C2F5CHN2 In Situ and Its First Reaction: [3 + 2] Cycloaddition with Alkenes. Chem. Eur. J. 2014, 20, 4942–4947. (b) Mykhailiuk, P. K. In Situ Generation of Difluoromethyl Diazomethane for [3 + 2] Cycloadditions with Alkynes. Angew. Chem., Int. Ed. 2015, 54, 6558–6561. (19) Chen, Z.; Zhang, Y.; Nie, J.; Ma, J.-A. Transition-Metal-Free [3 + 2] Cycloaddition of Nitroolefins and Diazoacetonitrile: A Facile Access to Multisubstituted Cyanopyrazoles. Org Lett. 2018, 20, 2120– 2124. (20) The X-ray crystallographic structures for 2b and 4g have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers CCDC 1408486 and 1572352. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via http://www.ccdc. cam.ac.uk/data_request/cif. (21) Perfluorocarbons (PFCs) have been potent molecular probes for magnetic resonance imaging (MRI). For selected reviews, see: (a) Riess, J. G. Oxygen Carriers (“Blood Substitutes”) Raison d'Etre, Chemistry, and Some Physiology Blut ist ein ganz besondrer Saft. Chem. Rev. 2001, 101, 2797–2920. (b) Tirotta, I.; Dichiarante, V.; Pigliacelli, C.; Cavallo, G.; Terraneo, G.; Bombelli, F.; Metrangolo, B. P.; Resnati, G. 19F Magnetic Resonance Imaging (MRI): From Design of Materials to Clinical Applications. Chem. Rev. 2015, 115, 1106– 1129. For our previous work, see: (c) Shi, H.; Lai, B.; Chen, S.; Zhou, X.; Nie, J.; Ma, J.-A. Facile Synthesis of Novel PerfluorocarbonModulated 4-Anilinoquinazoline Analogues. Chin. J. Chem. 2017, 35, 1693–1700. (22) The tetraphenylethene (TPE) skeleton is one of the most important luminogens in the realm of aggregation-induced emission (AIE), see: (a) Hong, Y.; Lam, J. W. Y.; Tang, B. Z. AggregationInduced Emission. Chem. Soc. Rev. 2011, 40, 5361–5388. (b) Aggregation-Induced Emission: Together We Shine, United We Soar! Mei, J.; Leung, N. L. C.; Kwok, R. T. K.; Lam, J. W. Y.; Tang, B. Z. Chem. Rev. 2015, 115, 11718–11940. (23) All attempts failed in the use of the mass spectrometry (MS) for the further identification of this putative intermediate. (24) For selected previous mechanistic studies on silver catalysis, see (a) Pellissier, H. Enantioselective Silver-Catalyzed Transformations. Chem. Rev. 2016, 116, 14868–14917. (b) FunesArdoiz, I.; Maseras, F. Oxidative Coupling Mechanisms: Current State
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of Understanding. ACS Catal. 2018, 8, 1161−1172. (c) Jia, F.; Luo, J.; Zhang, B. Using a traceless directing group for the silver-mediated synthesis of 3-trifluoromethylpyrazoles: a computational study on the mechanism and origins of regioselectivity. Org. Chem. Front. 2018, 5, 3374−3381. (25) DFT calculations suggest that a stepwise pathway is more likely for the formation of intermediate B during the cycloaddition process. Please see Figure S6 in the Supporting Information for details. (26) For a previous study on the reaction of 1,2,4-triazines and 2,5norbornadiene to afford pyridines, see: (a) Stanforth, S. P.; Tarbit, B.; Watson, M. D. Synthesis of pyridine and 2,2’-bipyridine derivatives from the aza Diels–Alder reaction of substituted 1,2,4-triazines. Tetrahedron 2004, 60, 8893−8897. For selected examples on the reactions of 1,2,4-triazines and arynes to afford isoquinolines: (b) Dhar, R.; Hühnermann, W.; Kampchen, T.; Overheu, W.; Seitz, G. Oxepin und 2,7-Dimethyloxepin als Dienophile bei Diels-Alder Cycloadditionen mit inversem Elektronenbedarf. Chem. Ber. 1983, 116, 97−102. (c) Gonsalves, A M. R.; Melo, T. M. V. D. P.; Gilchrist, T. L. Synthesis of isoquinolines by cycloaddition of arynes to 1,2,4-triazines. Tetrahedron 1992, 48, 6821−6826. (d) Kopchuk, D. S.; Nikonov, I. L.; Zyryanov, G. V.; Kovalev, I. S.; Rusinovl, V. L.; Chupakhin, O. N. Preparation of 3-Cyano-1-(2-Pyridyl)Isoquinolines by Using Aryne Intermediates. Chem. Heterocycl. Compd. 2014, 50, 907−910. (e) Kopchuk, D. S.; Nikonov, I. L.; Khasanov, A. F.; Giri, K.; Santra, S.; Kovalev, I. S.; Nosova, E. V.; Gundala, S.; Venkatapuram, P.; Zyryanov, G. V.; Majee, A.; Chupakhin, O. N. Studies on the interactions of 5-R-3-(2-pyridyl)-1,2,4-triazines with arynes: inverse demand aza-Diels–Alder reaction versus aryne-mediated domino process. Org. Biomol. Chem. 2018, 16, 5119−5135. (27) (a) Boger, D. L.; Panek, J. S. Diels-Alder Reaction of Heterocyclic Azadienes. Thermal Cycloaddition of 1,2,4-Triazine with Enamines: Simple Preparation of Substituted Pyridines. J. Org. Chem. 1981, 46, 2179−2182. (b) Glinkerman, C. M.; Boger, D. L. Catalysis of Heterocyclic Azadiene Cycloaddition Reactions by Solvent Hydrogen Bonding: Concise Total Synthesis of Methoxatin. J. Am. Chem. Soc. 2016, 138, 12408–12413. (c) Suleymanova, A. F.; Kozhevnikov, D. N.; Prokhorov, A. M. The use of the 1,2,4-triazine method of pyridine ligand synthesis for the preparation of a luminescent Pt(II) labeling agent. Tetrahedron Lett. 2012, 53, 5293– 5296. (d) Kovalev, I. S.; Kopchuk, D. S.; Khasanov, A. F.; Zyryanov, G. V.; Rusinov, V. L.; Chupakhin, O. N. The synthesis of polyarenemodified 5-phenyl-2,2'-bipyridines via the SNH methodology and azaDiels–Alder reaction. Mendeleev Commun. 2014, 24, 117–118. (e) Krinochkin, A. P.; Kopchuk, D. S.; Kim, G. A.; Ganebnykh, I. N.; Kovalev, I. S.; Santra, S.; Majee, A.; Zyryanov, G. V.; Rusinov, V. L.; Chupakhin, O. N. Synthesis and photophysical studies of new organicsoluble lanthanide complexes of 4-(4-alkoxyphenyl)-2,2´-bipyridine6-carboxylic acids. J. Mol. Struct. 2019, 1176, 583–590. (f) Starnovskaya, E. S.; Kopchuk, D. S.; Khasanov, A. F.; Tanya, O. S.; Santra, S.; Giric, K.; Rahman, M.; Kovalev, I. S.; Zyryanov, G. V.; Majeed, A.; Charushin, V. N. Synthesis and photophysics of new unsymmetrically substituted 5,5´-diaryl 2,2´-bypiridine-based “pushpull” fluorophores. Dyes Pigm. 2019, 162, 324–330. (28) (a) Kamber, D. N.; Liang, Y.; Blizzard, R. J.; Liu, F.; Mehl, R. A.; Houk, K. N.; Prescher, J. A. 1,2,4-Triazines are Versatile Bioorthogonal Reagents. J. Am. Chem. Soc. 2015, 137, 8388–8391. (b) Horner, K. A.; Valette, N. M.; Webb, M. E. Strain-Promoted Reaction of 1,2,4-Triazines with Bicyclononynes. Chem. Eur. J. 2015, 21, 14376–14381. (c) Siegl, S. J.; Dzijak, R.; V´azquez, A.; Pohl, R.; Vrabel, M. The Discovery of Pyridinium 1,2,4-Triazines with Enhanced Performance in Bioconjugation Reactions. Chem. Sci. 2017, 8, 3593–3598. (d) Peewasan, K.; Wagenknecht, H.-A. 1,2,4-TriazineModified 2′-Deoxyuridine Triphosphate for Efficient Bioorthogonal Fluorescent Labeling of DNA. ChemBioChem 2017, 18, 1473–1476.
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