The Different Faces of Photoredox Catalysts: Visible Light Mediated

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The Different Faces of Photoredox Catalysts: Visible Light Mediated Atom Transfer Radical Addition (ATRA) Reactions of Perfluoroalkyliodides with Styrenes and Phenylacetylenes Thomas Rawner, Eugen Lutsker, Christian Kaiser, and Oliver Reiser ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00847 • Publication Date (Web): 03 Apr 2018 Downloaded from http://pubs.acs.org on April 3, 2018

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ACS Catalysis

The Different Faces of Photoredox Catalysts: Visible Light Mediated Atom Transfer Radical Addition (ATRA) Reactions of Perfluoroalkyliodides with Styrenes and Phenylacetylenes Thomas Rawner,‡ Eugen Lutsker,‡ Christian A. Kaiser‡ and Oliver Reiser* Institut für Organische Chemie, Universität Regensburg, Universitätsstraße 31, 93053 Regensburg, Germany

ABSTRACT: A photoredox-catalyzed procedure for the iodoperfluoroalkylation of styrenes and phenylacetylenes using readily available copper phenanthroline catalyst is reported. In contrast to commonly employed [Ru(bpy) 3]Cl2, [Ru(phen)3]Cl2 or fac-Ir(ppy)3, [Cu(dap)2]Cl is capable to convert styrenes to the corresponding perfluoroalkyl tagged ethyl benzenes, pointing towards an additional role of the copper catalyst beyond photoinduced electron transfer. An inner sphere catalytic cycle involving Cu(III) intermediates or ligand abstraction from a [CuI] + intermediate is proposed.

KEYWORDS: photoredox catalysis, copper, ATRA, iodoperfluoroalkylation, visible light

INTRODUCTION During the last years the potential of visible light triggered, copper photoredox catalysis is reflected by an increasing number of reports.1 Following the pioneering work of Mitani2 and Pintauer3 who demonstrated the advantageous combination of copper(I) or copper(II) salts and UV irradiation for atom transfer radical addition (ATRA),4 ATRA reactions between organohalides or organosulfonylchlorides under visible light irradiation utilizing [Cu(dap)2]Cl5 (dap = 2,9-di(p-anisyl)-1,10-phenanthroline) were successfully developed.6,7 In parallel, visible light induced ATRA reactions catalyzed by [Ru(bpy)3]Cl2 were disclosed by Stephenson, demonstrating excellent substrate scope both for organohalides and alkene substrates.8 Particularly useful is the tagging of alkenes with perfluoroalkyl groups by the latter protocol, given the great utility of fluorous mixture synthesis (FMS) introduced by Curran.9 As a notable exception, styrene and its derivatives were found to be unsuitable substrates: the desired perfluorinated products could not be obtained due to side reactions arising from decomposition of the starting materials or product.8 Yajima disclosed the iodoperfluorination of alkenes by employing Eosin Y as photocatalyst, however styrene derivatives were not reported.10 Furthermore, in 2016 Vincent published an efficient protocol for an UV-light-promoted ATRA reaction catalyzed by copper/benzophenone,11 while Yu presented a metal-free halogen-bond-promoted ATRA reaction of terminal alkynes with perfluoroalkyl iodides under visible light irradiation in the presence of sacrificial amine.12 In all those studies, styrenes were reported to be not suitable substrates for this transformation. The efficient protocols for iodotrifluoromethylation of alkynes by Cho employing

ruthenium catalysts13 can also not be applied for the transformation of styrenes.14 Other studies on photocatalyzed ATRA reactions using different types of catalysts include examples for iodoperfluoroalkylation of alkenes, however, styrenes were again not being reported in these transformations.15 In contrast, we show in this study that the visible light mediated photoaddition of perfluoroalkyl iodides with styrenes proceeds well employing [Cu(dap)2]Cl as photocatalyst, pointing to its unique role beyond initiating the ATRA process by a photo electron transfer. Furthermore, [Cu(dap)2]Cl also gives excellent results in iodoperfluoroalkylation of other alkenes as well as phenylalkynes.

RESULTS AND DISCUSSION Stephenson and coworkers reported the failure of visible light/[Ru(bpy)3]Cl2 catalyzed addition of C8F17I (2) to styrene (1a) utilizing either the reductive or oxidative quenching catalyst cycle, which was also unsuccessful in our hands (Table 1, entries 1-2).8 In addition, we tested various other conditions employing [Ru(bpy)3]Cl2 or fac-Ir(ppy)3 as photocatalysts under irradiation with green or blue light (entries 3-6), accessing either the oxidative or reductive quenching cycle: in all cases, only very low yields of the ATRA product 3a were obtained. However, we were pleased to see that upon irradiation at 530 nm (green light) in the presence of 1.0 mol% [Cu(dap)2]Cl the iodoperfluorooctyl product 3a was obtained in 60% yield after 48 h (entry 7). Further screening indicated that the reaction proceeds faster at higher concentration of the substrates, giving rise to 3a in 84% yield after 16 h (entry 8). Reducing the catalyst loading to 0.3 mol% still gave a respectable yield of 57% of 3a (entry 9), while by lowering the stoichiometry from 2.0 to 1.0 equivalents of perfluorooctyl iodide (2) a

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sharper decline in yield of 3a was observed (entry 10). Thus, all reactions were subsequently carried out with 2.0 equivalents of the perfluoroiodide 2 and 1.0 mol% of [Cu(dap)2]Cl. Table 1. Screening of Photoredox Catalyzed Iodoperfluorination of Styrene (1a)a

Entry

Catalyst

1b

[Ru(bpy)3]Cl2

2b, c

[Ru(bpy)3]Cl2

3 4b

[Ru(bpy)3]Cl2 [Ru(bpy)3]Cl2 [Ru(bpy)3]Cl2/ iPr2NEt fac-Ir(ppy)3 [Cu(dap)2]Cl [Cu(dap)2]Cl [Cu(dap)2]Cl [Cu(dap)2]Cl [Cu(dap)2]Cl [Cu(dap)2]Cl [Cu(dap)2]Cl Cu(MeCN)4BF4 CuCl [Cu(dap)2]Cl no catalyst dap CuCl/1,10-phen (1:2) CuCl/dap (1:2) AIBN FeBr2/Cs2CO3 [Cu(dap)2]Cl

5b,d 6b 7e 8 9f 10g 11 12 13 14 15 16h 17 18 19 20 21h, i 22h, j 23b

Yield (%)

Solvent MeCN/MeOH (4:3) MeCN/MeOH (4:3) MeCN MeCN

9 10

MeCN

9

MeCN MeCN MeCN MeCN MeCN CH2Cl2 DMF DMSO MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN

16 60 84 57 44 49 35 16 n.r. n.r. n.r. n.r. 11 7 83 2 3 13

2 3

aReaction conditions: 1a (1.0 mmol), 2 (2.0 equiv), catalyst (1.0 mol%) in dry degassed solvent (0.5 mL), irradiation at 530 nm (green LED) for 16 h. bIrradiation at 455 nm (blue LED). cSodium ascorbate (0.35 equiv), reductive quenching cycle. diPr2NEt (2.0 equiv) as sacrificial electron donor. e48 h, solvent 1 mL. fCatalyst loading 0.3 mol%. g2 (1.0 equiv). hDark reaction. iAIBN (10 mol%), 80 °C. jFeBr2 (10 mol%) and Cs2CO3 (0.8 equiv).16

Acetonitrile proved to be the best solvent, others resulted in a decrease in yield (entries 11-13). No conversion was observed with Cu(MeCN)4BF4 or CuCl as copper(I)sources (entries 14-15), proving the significance of the phenanthroline ligand dap for the visible light mediated transformations. When either light (entry 16) or a photocatalyst (entry 17) was absent, no reaction was observed. Employing the dap ligand as potential photocatalyst alone (entry 18) or the combination of CuCl and 1,10-phenanthroline (entry 19) resulted in poor yields. In contrast using CuCl and dap ligand provided the product in high yield indicating

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fast in situ formation of [Cu(dap)2]Cl (entry 20). Initiating the reaction with AIBN under thermal conditions led to a complex reaction mixture, and only trace amounts of 3a were detected (entry 21). Hu et al. reported iron-catalyzed 1,2-addition of perfluoroalkyl iodides to alkenes and alkynes,16 however, also under these conditions only traces of 3a were obtained (entry 22). Surprisingly in light of its significantly stronger absorption at 455 nm (ε = 10210 L·mol1·cm-1) than at 530 nm (ε = 5353 L·mol-1·cm-1, see SI for details), [Cu(dap)2]Cl irradiated at 455 nm promotes the formation of 3a only in low yield (entry 23), thus, irradiation at 530 nm (entry 8) proved to be essential for the reaction to proceed. It must be stressed that the light intensity of the LEDs used was twice as high at 455 nm as at 530 nm (see SI for details). With the optimized conditions in hand (Table 1, entry 8), the reaction between styrene (1a) and various commercially available perfluoroalkyl iodides was investigated (Scheme 1). Scheme 1. Scope of the Copper Catalyzed Iodoperfluorination with Different Fluorous Tagsa

aReaction

conditions: 1a or 4a (1.0 mmol), 2-2`` (2.0 equiv), catalyst (1.0 mol%) in MeCN (dry, degassed, 0.5 mL), irradiation at 530 nm (green LED) for [Cu(dap)2]Cl or irradiation at 455 nm (blue LED) for fac-Ir(ppy)3, [Ru(bpy)3]Cl2, [Ru(phen)3]Cl2 3-48 h. b1a (0.25 mmol), 2 (1.3 equiv), sodium ascorbate (0.35 equiv), catalyst (1.0 mol%) in MeCN/MeOH (4:3, 3.5 mL), irradiation for 24 h.8 c3a (0.5 mmol), 2 (2.0 equiv), TMEDA (2.0 equiv), [Ru(phen)3]Cl2 (0.5 mol%) in MeCN (2.0 mL), irradiation at 455 nm for 20 h. d1a (0.2 mmol), 2 (1.2 equiv), benzophenone (1.0 mol%) in CD3OD (1 mL), with 365 nm for 1 h.11 e1a (0.5 mmol), 2 (1.3 equiv), sodium ascorbate (0.35 equiv), catalyst (1.0 mol%) in MeCN/MeOH (4:3, 3.5 mL), irradiation for 24 h. f4a (1.0 mmol), 2´´ (3.0 equiv), TMEDA (2.0 equiv), [Ru(phen)3]Cl2 (0.5 mol%) in MeCN (4.0 mL), irradiation at 455 nm for 3 h.13

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ACS Catalysis By employing CnF2n+1I (2-2´´) (n = 1, 4, 8) in the presence of [Cu(dap)2]Cl good yields were generally obtained. We attribute the lower yield of 3a`` to difficulties in handling the gaseous CF3I (2´´). Employing [Ru(bpy)3]Cl2 or fac-Ir(ppy)3 as photocatalyst gave greatly inferior results in all cases. [Ru(phen)3]Cl2 which was reported as highly efficient catalyst for the iodotrifluoromethylation of alkynes showed no product formation in the case of styrene substrate.13 The catalyst benzophenone or copper(II)-polyamine complex such as [Cu(dmeda)2(H2O)2](3-benzoyl-benzoate)2 reported by Vincent et al. for ATRA reactions also showed a very poor yield of 3a. For comparison, phenylacetylene (4a) was tested as substrate, leading to the formation of 5a in improved yields for all catalysts tested. The scope with respect to alkenes of the copper-catalyzed photochemical iodoperfluorooctylation reaction was explored next (Scheme 2). A wide range of styrenes 1a-m containing both electron rich or electron deficient groups could be transformed into the corresponding fluorine tagged benzyl iodides 3a-m. When p-methyl styrene (1b) was employed, the product 3b was obtained in low yield with 20% of additional HI elimination product. Changing the solvent to CH2Cl2 provided 3b in 88% yield. Substitution of the aryl ring with a methoxy group in para position 3f resulted only in polymerization of the starting material. Scheme 2. Scope for Alkenesa

syn/anti = 50:50. Methyl substitution in -position did not yield the ATRA product but rather 3h, being formed by formal HI elimination from the initial addition product. Electron poor styrenes proved to be particular suitable substrates for the photo-copper catalyzed iodoperfluoroalkylation. The ester derivative 1c gave rise to 3c in 59% yield, furthermore, chlorine substitution at various positions of the aryl ring (para 3d, meta 3i, and ortho 3k) was tolerated well, providing the products in 72-85% yield. Even more electron deficient alkenes such as the trifluoromethyl substituted styrene 1l and the pentafluorosubstituted styrene 1m gave the corresponding adducts 3l and 3m in >80% yield. Styrene 1e, however, proved to be incompatible in the desired transformation and resulted in its almost quantitative reisolation, reflecting the efficient quenching of excited states by nitro groups. Moreover, the functional group tolerance towards N-protected amines was demonstrated by formation of 3n in 85%. Likewise, unactivated alkenes such as 1-octene and 4-pentenoic acid were transformed into 3o and 3p in good yields. Extending the substrate scope to terminal alkynes, yields were generally even higher than compared to the corresponding alkenes (Scheme 3). Notably, p-methoxy substitution is now tolerated, giving rise to 5d in 92% yield. Moreover, the internal alkyne 4e is suitable for the transformation giving rise to 5e with excellent stereoselectivity but moderate yield of 40%. Scheme 3. Scope for Alkynesa

aReaction conditions: 1 (1.0 mmol), 2 (2.0 equiv), [Cu(dap)2]Cl (1.0 mol%) in MeCN (dry, degassed, 0.5 mL), irradiation at 530 nm (green LED) for 16-20 h. bHI elimination product in 20% yield isolated. cSolvent CH2Cl2.

The meta-methoxy substrate 1j provided the desired product 3j in moderate yield, indicating electron rich styrenes are problematic for the title reaction. Introduction of a methyl group in -position of styrene gave rise to the 1,2 adduct 3g in 77% yield with a diastereomeric ratio of

aReaction conditions: 4 (1.0 mmol), 2 (2.0 equiv), [Cu(dap)2]Cl (1.0 mol%) in MeCN (dry, degassed, 0.5 mL), irradiation at 530 nm for 16-20 h. E/Z ratio was determined via NMR spectroscopy. b4 (0.2 mmol), 2 (2.0 equiv), benzophenone (2.0-4.0 mol%) in CD3OD (1 mL), with 365 nm TLC lamp for 1-3 h.11 cReaction time 42 h.

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The reaction between the benzylated N-Boc-propargylamine 4g and C8F17I (2) led to the formation of 5g as a single diastereomer in good yield. In contrast, no diastereoselectivity was observed utilizing propargyl alcohol (4h), being in accordance with a recently published report using benzophenone / UV irradiation.11 Moderate to very good yield and good diastereoselectivity were achieved for alkylated or silylated alkynes 4i and 4j. When cyclopropylacetylene was subjected to the standard reaction conditions, the product 5k was isolated with a moderate yield of 52% with no ring opening products observed.17 When the symmetrical internal alkyne 4l bearing a nonconjugated triple bond was employed, the desired ATRAproduct was obtained in both high yield and diastereomeric ratio, whereas exploring substrates 4m and 4n in which the triple bond is in conjugation with a phenyl or ester group showed no conversion. Scheme 4. Mechanistic Studiesa

aReaction conditions: Alkene (1.0 mmol), 2 (2.0 equiv), [Cu(dap)2]Cl (1.0 mol%) in MeCN (dry, degassed, 0.5 mL), irradiation at 530 nm (green LED) for 17-18 h.

In order to gain deeper insight into the reaction mechanism (Scheme 4) several experiments were carried out. Firstly, it was established that the formed ATRA products are stable under irradiation with various photoredox catalysts, ruling out the possibility of decomposition by a subsequent photoredox process initiated e.g. by [Ru(bpy)3]Cl2.

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Especially, it was not possible to utilize the ATRA-product 3a in a second ATRA reaction with styrene under irradiation with either blue light (LED455) or green light (LED530): no conversion was observed employing a variety of photoredox catalysts and conditions (cf. Table 1). In line with a radical pathway of the perfluorination reaction the addition of TEMPO (6) leads exclusively to the formation of the adduct 7. Moreover, diallyl malonester 8 provided the cyclization product 10, suggesting a radical 5-exo-trig ring closure via intermediate 9. Radical clock experiments between C8F17I (2) and 11 gave rise exclusively to 12, being in agreement with the initial formation of radical 13, which undergoes regioselective ring opening to yield the more stable secondary alkyl radical 14´. The two commonly discussed and generally accepted mechanistic proposals for ATRA reactions as described here call either for a radical chain18 or a photoredox cycle4a, 8, 19 (Scheme 5). Initially, a radical 15 is generated, e.g. thermally via a radical starter or photochemically via an electron transfer. Both modes of initiation are possible with perfluoroalkyliodides: AIBN initiated ATRA processes of such iodides with a variety of alkyl substituted alkenes have been described in the literature.20 Likewise, the reduction potential of [Ru(bpy)3]Cl2 (reductive quenching cycle: Ru2+/Ru+ = –1.33 V vs SCE)19a or [Cu(dap)2]Cl (oxidative quenching cycle: Cu2+/Cu+* = –1.43 V vs SCE)19a is well in reach for an SET with C8F17I (2) (–1.32 V vs SCE)8 to generate a perfluoroalkylradical 15. Radical 15 could then add to an alkene 1 to form a new radical 16 (Scheme 5). At this point, the reaction could propagate via a radical chain mechanism (Scheme 5, Path A) by abstracting iodide from the perfluoroiodide 2 to give rise to product 3 with concurrent regeneration of radical 15. Alternatively, radical 16 could be oxidized to a cation 17 that combines with iodide to 3 and concurrent regeneration of the photocatalyst 18 (Scheme 5, Path B). Both mechanistic proposals are not in agreement with the experimental observations made for the iodoperfluoroalkylation of styrenes. While clearly perfluororadicals are being formed under the photochemical conditions as evidenced by the trapping experiment with TEMPO (6) (Scheme 4a) and the radical clock experiments (Scheme 4c), a radical chain mechanism appears not to be plausible given the failure to carry out the iodoperfluoroalkylations of styrene (1a) thermally initiated by AIBN (cf. Table 1, entry 21 and Scheme 6). Likewise, a photoredox cycle is not plausible in this case, given the failure to carry out the transformation with [Ru(bpy)3]Cl2 (cf. Table 1, entries 1-5 and Scheme 6). It should be noted that the oxidation of benzyl radicals (PhCH2+/PhCH2• = +0.73 V vs SCE)21 and (PhCH+CH3/ PhCH•CH3 = +0.37 V vs SCE)22 to benzyl cations is facile by [Ru(bpy)3]Cl2 (reductive quenching cycle: Ru2+/ Ru+ = +0.77 V vs SCE)19a and still possible though thermodynamically less favored by [Cu(dap)2]Cl (Cu2+/ Cu+ = +0.62 V vs SCE).19a We propose however that such a benzyl cation does not couple well with iodide to give rise to 3.

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ACS Catalysis Scheme 5. Proposed Reaction Mechanism F2n+1Cn I

*[CuI(dap)2]Cl

2 I CnF2n+1

R

CnF2n+1 15

3 Radical Chain Cycle

2

Visible Light

19

N = dap N

[CuI(dap)2]Cl 18 Rebound Cycle dap Path C

1

16

I R

Reductive Elimination

CuIIIdap Cl CnF2n+1 21

Back Electron Transfer Path B

CnF2n+1

R

dap

Photoredox Cycle

R

Path A

F2n+1Cn I

SET dap N II Cl Cu I N 20

CnF2n+1 + I

R

Ligand Transfer Cycle Path D

I CnF2n+1

R 3

17

As an alternative, we suggest a mechanism pathway, involving a rebound (Path C) or ligand transfer cycle (Path D): photoexcited *[Cu(dap)2]Cl (19) reduces CnF2n+1I 2 by a single electron transfer (SET), thus generating perfluoroalkyl radical 15 and iodide forming a Cu(II)-species such as [CuII(dap)ClI] (20) (Scheme 5). The radical 15 adds to the alkene 1 forming a benzyl radical 16, which however is not able to engage with the perfluoroalkyliodide 2 in a radical chain propargation. Alternatively, the intermediary radical 16 can be trapped by the iodine ligand of the Cu(II) species 20 forming the ATRA product 3 and regenerating [Cu(dap)2]Cl (18) (Path D). A related pathway is the formation of a copper(III) species 21 by trapping the intermediary radical 16 with CuII-complex 20, which can be regarded as a persistent radical. This rebound cycle is closed by reductive elimination and simultaneous substitution with iodine forming [CuI(dap)2]Cl (18) and ATRA-product 3 (Path C). The concept of an inner sphere mechanism for copper-catalyzed transformations has been considered before.6c,6d,22 Choosing the ATRA reaction between allyl alcohol (22) or styrene 1a and perfluorooctyliodide (2) illustrates the different mechanistic pathways that are involved depending on the catalyst employed: 23 was formed in good yields under visible light irradiation catalyzed either by [Ru(bpy)3]Cl2 or by [Cu(dap)2]Cl or under thermal conditions using AIBN as radical initiator (Scheme 6). In contrast, neither AIBN or [Ru(bpy)3]Cl2 are able to promote this transformation for styrene (1a). When we carried out a competitive reaction between styrene (1a) and allyl alcohol (22) under standard conditions, with [Cu(dap)2]Cl the predominant formation of product 3a is observed indicating the higher reactivity of styrene (1a) in this reaction compared to allyl alcohol (22) (Scheme 7). In contrast, performing the reaction with [Ru(bpy)3]Cl2 resulted in a very unclean reaction in which only low amounts of the both ATRAproducts (