The photoredox-catalyzed meerwein addition reaction: Intermolecular amino-arylation of alkenes

Article abstract of DOI:10.1002/anie.201307051

A variety of amides are efficiently accessible under mild conditions by intermolecular amino-arylation using a photo Meerwein addition with visible light. The reaction has a broad substrate scope, tolerates a large range of functional groups, and was applied to the synthesis of a 3-aryl-3,4- dihydroisoquinoline. From elimination to addition: A variety of amides are efficiently accessible under mild conditions by intermolecular amino-arylation using a photo Meerwein addition with visible light. The reaction has a broad substrate scope, tolerates a large range of functional groups, and was applied to the synthesis of 3-aryl-3,4-dihydroisoquinoline. Copyright

Full text of DOI:10.1002/anie.201307051

Angewandte
Chemie
DOI: 10.1002/anie.201307051
Photo Meerwein Addition
The Photoredox-Catalyzed Meerwein Addition Reaction:
Intermolecular Amino-Arylation of Alkenes**
Durga Prasad Hari, Thea Hering, and Burkhard Kçnig*
Abstract: A variety of amides are efficiently accessible under
mild conditions by intermolecular amino-arylation using
a photo Meerwein addition with visible light. The reaction
has a broad substrate scope, tolerates a large range of
functional groups, and was applied to the synthesis of a 3-
aryl-3,4-dihydroisoquinoline.
been used in industrial processes for the synthesis of the anti-
HIV drug Crixivan, the alkaloid aristotelone, and amanta-
dine.[2d,4] We utilize the Ritter reaction conditions to trap the
carbenium ion, which is generated during the photoredox
Meerwein arylation, thus allowing the intermolecular amino-
arylation of alkenes mediated by visible light.
Our initial studies began with the attempted reaction of
diazonium salt 1a (0.25 mmol) with 5 equiv of styrene 2a
using 2 mol% of [Ru(bpy)3]Cl2 in 1.0 mL of CH3CN contain-
ing 10 equiv of water under visible-light irradiation for 4 h at
208C; the desired product 3a was obtained in 42% yield
(Table 1, entry 1) along with 1,2-diphenylethanol as a byprod-
T
he Meerwein arylation is a valuable synthetic transforma-
tion based on aryl radical chemistry.[1] The classic Meerwein
arylation has two alternative reaction pathways: a) Meerwein
arylation–elimination, in which aryl–alkene cross-coupling
products are formed exclusively, and b) Meerwein arylation–
addition, in which the aryl radical and a halogen atom add to
an olefinic substrate.[1b] The addition of atoms other than
halogen has also been reported.[1b] However, photo Meerwein
arylations have been applied so far only for the formation of
aryl–alkene coupling products and have not been extended to
the valuable alkene addition products[2] obtainable under
classical Meerwein arylation conditions.[3] The challenge in
obtaining the addition product is the competing reaction of
the trapping reagent or nucleophile with the diazonium salt
leading to undesired products (Scheme 1).[1b]
Table 1: Optimizing reaction conditions.
Entry
Conditions
Yield [%][a]
1
2
3
4
5
6
7
9
10
11
12
13
14
15
[Ru(bpy)3]Cl2 (2 mol%), 2a (5 equiv)
[Ru(bpy)3]Cl2 (2 mol%), 2a (5 equiv)
[Ru(bpy)3]Cl2 (2 mol%), 2a (5 equiv)
[Ru(bpy)3]Cl2 (2 mol%), 2a (5 equiv)
[Ru(bpy)3]Cl2 (0.5 mol%), 2a (5 equiv)
[Ru(bpy)3]Cl2 (0.5 mol%), 2a (2 equiv)
[Ru(bpy)3]Cl2 (0.5 mol%), 2a (1.1 equiv)
Eosin Y (0.5 mol%), 2a (2 equiv)
[Ir(ppy)3] (0.5 mol%), 2a (2 equiv)
Rhodamine B (0.5 mol%), 2a (2 equiv)
Rose bengal (0.5 mol%), 2a (2 equiv)
C50H40CuF6N2OP3 (0.5 mol%), 2a (2 equiv)
no photocatalyst, 2a (2 equiv)
42[b]
75
65[c]
74[d]
75
88
72
38
76
5
The Ritter-type amination reaction is a most useful
À
transformation for the formation of C N bonds and has
37
21
5
[Ru(bpy)3]Cl2 (0.5 mol%), 2a (2 equiv), no light
0
[a] Yield determined by GC using a calibrated internal standard. [b] The
reaction was carried out with 10 equiv of H2O. [c] The reaction was
carried out in 0.5 mL of CH3CN. [d] The reaction was carried out in
2.0 mL of CH3CN. Unless otherwise noted, in all other cases the
reactions were carried out in 1.0 mL of CH3CN using 1 equiv of H2O.
Scheme 1. Types of photo Meerwein arylation reactions: a) photo
Meerwein arylation–elimination, b) photo Meerwein arylation–addition.
uct. We examined the influence of the amount of water, the
catalyst loading, and the number of equivalents of styrene on
this multicomponent photoreaction. To our delight, the
desired product 3a was obtained in 88% yield (Table 1,
entry 6) when diazonium salt 1a (0.25 mmol), 0.5 mol% of
[Ru(bpy)3]Cl2, 2 equiv of styrene 2a, and 1 equiv of water
were used in 1.0 mL of CH3CN. The reaction yields of 3a are
significantly affected by the amount of water: a larger amount
of water results in the formation of the 1,2-diphenylethanol
(Table 1, entry 1 vs. 2).
[*] M. Sc. D. Prasad Hari, M. Sc. T. Hering, Prof. Dr. B. Kçnig
Department of Chemistry and Pharmacy, Universitꢀt Regensburg
Universitꢀtsstrasse 31, 93040 Regensburg (Germany)
E-mail: burkhard.koenig@ur.de
[**] This work was supported by the German Science Foundation (DFG)
(GRK 1626, Chemical Photocatalysis) and the Fonds der Chem-
ischen Industrie (graduate fellowship to T.H.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307051.
Angew. Chem. Int. Ed. 2014, 53, 725 –728
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
725

.
Angewandte
Communications
After having optimized the reaction conditions we
screened different photocatalysts (Table 1, entries 6 and 9–
13). [Ru(bpy)3]Cl2 was found to be the best one for this
transformation. To prove the significance of the photoreac-
tion, we carried out control experiments without the photo-
catalyst and without light. As expected, we observed little
(5% yield) or no product, respectively (Table 1, entries 14
and 15). When we employed dichloromethane as a solvent
and 10 equiv of acetonitrile in this photoreaction, product 3a
was obtained in 70% yield.[5] This shows that the use of the
organic nitrile as a solvent is not required. In addition, we also
replaced the photocatalyst and visible light by copper
catalysts, which are commonly employed in Meerwein
arylations. However, under these conditions the reaction
does not proceed showing that the photoredox system is
essential.[5]
Furthermore, we investigated the scope of the diazonium
salts for this photoreaction and the results are summarized in
Table 2. Aryl diazonium salts bearing electron-withdrawing,
-neutral, and -donating substituents react smoothly affording
the corresponding products in good to excellent yields.
Several functional groups including ester, nitro, halide,
ether, and alkyl groups are tolerated in the photoreaction.
In addition to aryl diazonium salts, heteroaryl diazonium salt
1j was used in this reaction giving the corresponding product
3j in 75% yield (Table 2, entry 10).
Carbon–halogen bonds remain intact during the photo-
reaction providing access to halogen-substituted amides in
a single step (Table 2, entries 5 and 9). The halide functional
groups can be used for further transformations in transition-
metal-catalyzed or organometallic reactions.
Table 2: Scope of the aryl diazonium salts.[a]
Entry
1
Substrate
Product
Yield [%][b]
82
2
3
4
5
6
7
92
70
82
76
70
73
Table 3: Scope of nitriles.[a]
Entry
1
Nitrile
Product
Yield [%][b]
92
2
3
4
5
6
7
84
65
71
80
72
60
8
9
87
50
10
11
75
70
[a] The reaction was performed with 1 (0.25 mmol), styrene 2a (2 equiv),
[Ru(bpy)3]Cl2 (0.005 equiv), and 1 equiv of water in 1.0 mL of CH3CN.
[b] Yield of isolated product after purification by flash column chroma-
tography using silica gel.
[a] The reaction was performed with 1b (0.25 mmol), styrene 2a
(2 equiv), [Ru(bpy)3]Cl2 (0.005 equiv), and 1 equiv of water in 1.0 mL of
nitrile. [b] Yield of isolated product after purification by flash column
chromatography using silica gel.
726
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 725 –728

Angewandte
Chemie
We then expanded the scope of the reaction by varying the
nitrile, which proved to be of general applicability in the
photoreaction. The products obtained from the reactions of
diazonium salt 1b and styrene 2a with different nitriles are
shown in Table 3. The results demonstrate that primary,
secondary, and tertiary alkyl nitriles undergo the transforma-
tion cleanly providing the corresponding products in good to
excellent yields. We were also pleased to find that cyclo-
propane carbonitrile was tolerated well affording the corre-
sponding product 3m in 65% yield after 4 h of irradiation
with blue light at room temperature (Table 3, entry 3).
Having established the scope of both diazonium salts and
nitriles in this photoreaction, we investigated various alkenes.
The results are summarized in the Table 4. Styrenes with
electron-withdrawing, -neutral, and -donating substituents at
the para position smoothly give the corresponding products in
moderate to excellent yields upon irradiation for 4 h (Table 4,
entries 1, 3, 6, and 7). In addition, this photoreaction could
also be applied to internal alkenes. The reaction of diazonium
salt 1b with trans-b-methylstyrene regioselectively provided
the corresponding product 3u in 75% yield (d.r. 65:35).[2d]
Notably, trans-stilbene, cinnamic acid ester, and benzalace-
tone can be used in this multicomponent photoreaction and
afford the corresponding products as single regioisomers in
moderate yields (Table 4, entries 2, 4, and 8).
We used the photoreaction product 3a for the synthesis of
3-aryl-3,4-dihydroisoquinoline to demonstrate its application
and adopted a previously reported method by Larsen and co-
workers (Scheme 2).[6] The reaction of diazonium salt 1a with
styrene 2a under standard photoreaction conditions provided
the corresponding product 3a, which was then further
converted into 3-aryl-3,4-dihydroisoquinoline 4 using oxalyl
chloride and FeCl3.[6a]
Table 4: Scope of alkenes.[a]
Entry R1
R2
H
Product
Yield [%][b]
92
1
2
H
Ph
H
Cl
H
53
87
20
3
4
H
Scheme 2. Application of the photoreaction in the synthesis of 3-aryl-
3,4-dihydroisoquinoline.
COOMe
The suggested mechanism of the photoreaction based on
the trapping of intermediates and related literature reports is
depicted in Scheme 3.[2d,3a,7] Aryl radical 5 is formed initially
by a single-electron transfer from the excited state of the
photocatalyst [Ru(bpy)3]2+* to diazonium salt 1a. Addition of
aryl radical 5 to alkene 2 yields the corresponding radical
intermediate 6, which is then further oxidized to give
carbenium intermediate 7.[3e] Finally, the intermediate 7 is
attacked by a nitrile (R3CN), followed by hydrolysis to give
the amino-arylated product 3a.[2d] Radical intermediate 6 is
either oxidized by the strong oxidant [Ru(bpy)3]3+ to com-
plete the photocatalytic cycle or by the diazonium salt 1a in
a chain-transfer mechanism. Radical intermediates 5 and 6
were trapped with TEMPO, which supports radical inter-
mediates during the photoreaction.[3c–e,5] In addition, the
carbenium ion intermediate was also trapped with water and
methanol; these results indicate the formation of intermedi-
ate 7 in the reaction.[5]
5
6
Me
H
H
75[c]
COOH
97
7
8
H
Me
H
55
43
COMe
In conclusion, the reported protocol allows the formation
[a] The reaction was performed with 1b (0.25 mmol), alkene 2 (2 equiv),
[Ru(bpy)3]Cl2 (0.005 equiv) and 1 equiv of water in 1.0 mL of CH3CN.
[b] Yield of isolated product after purification by flash column chroma-
tography using silica gel. [c] d.r. (65:35).
À
of Calkyl N bonds by an intermolecular amino-arylation of
alkenes mediated by visible light. It is, to the best of our
knowledge, the first example of a photocatalytic Meerwein
Angew. Chem. Int. Ed. 2014, 53, 725 –728
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
727

.
Angewandte
Communications
Synthesis III, Vol. 320 (Eds.: M. Heinrich, A. Gansꢁuer), Springer,
Berlin, 2012, pp. 33 – 59; i) A. Wetzel, G. Pratsch, R. Kolb, M. R.
Heinrich, Chem. Eur. J. 2010, 16, 2547 – 2556; j) H. Zollinger, Acc.
Chem. Res. 1973, 6, 335 – 341; k) M. K. Staples, R. L. Grange, J. A.
Angus, J. Ziogas, N. P. H. Tan, M. K. Taylor, C. H. Schiesser, Org.
Biomol. Chem. 2011, 9, 473 – 479; l) R. Leardini, G. F. Pedulli, A.
Tundo, G. Zanardi, J. Chem. Soc. Chem. Commun. 1985, 1390 –
1391; m) M. Mahesh, J. A. Murphy, F. LeStrat, H. P. Wessel,
Beilstein J. Org. Chem. 2009, DOI: 10.3762/bjoc.5.1.
[2] Recent examples of alkene functionalization by visible-light-
mediated reactions: a) S. Donck, A. Baroudi, L. Fensterbank, J.-P.
Goddard, C. Ollivier, Adv. Synth. Catal. 2013, 355, 1477 – 1482;
b) G. Fumagalli, S. Boyd, M. F. Greaney, Org. Lett. 2013, 15,
4398 – 4401; c) Y. Yasu, T. Koike, M. Akita, Adv. Synth. Catal.
2012, 354, 3414 – 3420; d) Y. Yasu, T. Koike, M. Akita, Org. Lett.
2013, 15, 2136 – 2139.
[3] a) D. P. Hari, B. Kçnig, Angew. Chem. 2013, 125, 4832 – 4842;
Angew. Chem. Int. Ed. 2013, 52, 4734 – 4743; b) D. P. Hari, T.
Hering, B. Kçnig, Chim. Oggi 2013, 31, 59 – 62; c) D. P. Hari, T.
Hering, B. Kçnig, Org. Lett. 2012, 14, 5334 – 5337; d) D. P. Hari, P.
Schroll, B. Kçnig, J. Am. Chem. Soc. 2012, 134, 2958 – 2961; e) P.
Schroll, D. P. Hari, B. Kçnig, ChemistryOpen 2012, 1, 130 – 133;
f) T. Hering, D. P. Hari, B. Kçnig, J. Org. Chem. 2012, 77, 10347 –
10352; g) F. Mo, G. Dong, Y. Zhang, J. Wang, Org. Biomol. Chem.
2013, 11, 1582 – 1593; h) D. Kalyani, K. B. McMurtrey, S. R.
Neufeldt, M. S. Sanford, J. Am. Chem. Soc. 2011, 133, 18566 –
18569.
[4] a) J. J. Ritter, P. P. Minieri, J. Am. Chem. Soc. 1948, 70, 4045 –
4048; b) J. J. Ritter, J. Kalish, J. Am. Chem. Soc. 1948, 70, 4048 –
4050; c) J. Clayden, N. Greeves, S. Warren, P. Wothers, Organic
Chemistry, Oxford Press, New York, 2011; d) R. Vardanyan, V. J.
Hruby, Synthesis of Essential Drugs, Elsevier, Amsterdam, 2006;
e) L. Kurti, B. Czako, Strategic Applications of Named Reactions
in Organic Synthesis, Elsevier/Academic Press, Burlington, 2005;
f) M. Y. Lebedev, M. B. Erman, Tetrahedron Lett. 2002, 43, 1397 –
1399; g) H. Fernholz, H. J. Schmidt, Angew. Chem. 1969, 81, 496 –
496; Angew. Chem. Int. Ed. Engl. 1969, 8, 521 – 521; h) L. I.
Krimen, D. J. Cota, Organic Reactions, Wiley, Hoboken, 2004;
i) A. Garcꢂa Martꢂnez, R. Martꢂnez Alvarez, E. Teso Vilar, A.
Garcꢂa Fraile, M. Hanack, L. R. Subramanian, Tetrahedron Lett.
1989, 30, 581 – 582.
Scheme 3. Proposed mechanism for the photo Meerwein addition
reaction.
addition reaction. The multicomponent reaction gives effi-
cient access to different types of amides under mild reaction
conditions and tolerates a broad range of functional groups.
The substrate scope of the diazonium salts, nitriles, and
alkenes is broad. Many products of the photoreaction are not
easily accessible by other methods and have, due to the
presence of halide functional groups, the potential for further
synthetic elaboration. For example, one photoreaction prod-
uct was used for the synthesis of a 3-aryl-3,4-dihydroisoquino-
line. Experiments to elucidate the mechanism of the reaction
in detail, and applications of the reaction to the synthesis of
other potential biologically active molecules are ongoing in
our laboratory.
[5] See the Supporting Information for more details.
Received: August 11, 2013
Revised: October 17, 2013
Published online: December 4, 2013
[6] a) R. D. Larsen, R. A. Reamer, E. G. Corley, P. Davis, E. J. J.
Grabowski, P. J. Reider, I. Shinkai, J. Org. Chem. 1991, 56, 6034 –
6038; b) M. Movassaghi, M. D. Hill, Org. Lett. 2008, 10, 3485 –
3488.
Keywords: amino-arylation · aryl radicals · Meerwein addition ·
[7] a) C. K. Prier, D. A. Rankic, D. W. Macmillan, Chem. Rev. 2013,
113, 5322 – 5363; b) J. M. R. Narayanam, C. R. J. Stephenson,
Chem. Soc. Rev. 2011, 40, 102 – 113; c) J. Xuan, W.-J. Xiao, Angew.
Chem. 2012, 124, 6934 – 6944; Angew. Chem. Int. Ed. 2012, 51,
6828 – 6838; d) J. Yu, L. Zhang, G. Yan, Adv. Synth. Catal. 2012,
354, 2625 – 2628; e) Y. Yasu, T. Koike, M. Akita, Angew. Chem.
2012, 124, 9705 – 9709; Angew. Chem. Int. Ed. 2012, 51, 9567 –
9571; f) E. Kim, S. Choi, H. Kim, E. J. Cho, Chem. Eur. J. 2013, 19,
6209 – 6212; g) H. Cano-Yelo, A. Deronzier, Tetrahedron Lett.
1984, 25, 5517 – 5520; h) H. Cano-Yelo, A. Deronzier, J. Chem.
Soc. Perkin Trans. 2 1984, 1093 – 1098; i) H. Cano-Yelo, A.
Deronzier, New J. Chem. 1987, 11, 479 – 485.
.
photocatalysis · visible light
[1] a) H. Meerwein, E. Bꢀchner, K. van Emster, J. Prakt. Chem. 1939,
152, 237 – 266; b) M. R. Heinrich, Chem. Eur. J. 2009, 15, 820 –
833; c) M. R. Heinrich, O. Blank, D. Ullrich, M. Kirschstein, J.
Org. Chem. 2007, 72, 9609 – 9616; d) M. R. Heinrich, O. Blank, S.
Wçlfel, Org. Lett. 2006, 8, 3323 – 3325; e) S. B. Hçfling, A. L.
Bartuschat, M. R. Heinrich, Angew. Chem. 2010, 122, 9963 – 9966;
Angew. Chem. Int. Ed. 2010, 49, 9769 – 9772; f) M. R. Heinrich, A.
Wetzel, M. Kirschstein, Org. Lett. 2007, 9, 3833 – 3835; g) G.
Pratsch, C. A. Anger, K. Ritter, M. R. Heinrich, Chem. Eur. J.
2011, 17, 4104 – 4108; h) G. Pratsch, M. Heinrich in Radicals in
728
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 725 –728