A highly efficient gold-catalyzed photoredox α-C(sp3)-H alkynylation of tertiary aliphatic amines with sunlight

Article abstract of DOI:10.1002/anie.201412399

A new α-C(sp³)-H alkynylation of unactivated tertiary aliphatic amines with 1-iodoalkynes as radical alkynylating reagents in the presence of [Au₂(μ-dppm)₂]²⁺ in sunlight provides propargylic amines. Based on mechanistic studies, a C-C coupling of an α-aminoalkyl radical and an alkynyl radical is proposed for the C(sp³)-C(sp) bond formation. The mild, convenient, efficient, and highly selective C(sp³)-H alkynylation reaction shows excellent regioselectivity and good functional-group compatibility. A scale-up to gram quantities is possible with sunlight used as a clean and sustainable energy source.

Full text of DOI:10.1002/anie.201412399

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201412399
German Edition: DOI: 10.1002/ange.201412399
Gold Photocatalysis
3
À
A Highly Efficient Gold-Catalyzed Photoredox a-C(sp ) H
Alkynylation of Tertiary Aliphatic Amines with Sunlight
Jin Xie, Shuai Shi, Tuo Zhang, Nina Mehrkens, Matthias Rudolph, and A. Stephen K. Hashmi*
3
À
Abstract: A new a-C(sp ) H alkynylation of unactivated
tertiary aliphatic amines with 1-iodoalkynes as radical alky-
nylating reagents in the presence of [Au2(m-dppm)2]2+ in
sunlight provides propargylic amines. Based on mechanistic
strates or special photoreactors. In a continuation of our work
[12,13]
À
on gold-catalyzed C H activation,
we now present the
first example of a gold-catalyzed redox-neutral radical a-
3
À
C(sp ) H alkynylation of unactivated tertiary aliphatic
studies, a C C coupling of an a-aminoalkyl radical and an
alkynyl radical is proposed for the C(sp ) C(sp) bond
formation. The mild, convenient, efficient, and highly selective
C(sp ) H alkynylation reaction shows excellent regioselectiv-
ity and good functional-group compatibility. A scale-up to
gram quantities is possible with sunlight used as a clean and
sustainable energy source.
amines that is based on photoredox catalysis with sunlight[11]
and thus obviates prefunctionalization of the substrates
(Scheme 1). The products are formed by the coupling of an
À
3
À
3
À
C
-Alkynylation reactions are important for organic syn-
thesis, as alkyne moieties are not only versatile building
blocks, but also important structural motives in organic
materials and biologically active molecules.[1] Sonogashira
coupling is a very powerful method for the formation of
2
[2]
À
C(sp ) C(sp) bonds, but the chemospecific construction of
C(sp ) C(sp) bonds still remains a challenge, which was
3
À
addressed during the past decade by the development of
nucleophilic[3] and electrophilic[4] C(sp ) C(sp) bond forma-
3
À
3
À
Scheme 1. Different strategies for radical C(sp ) C(sp) coupling
reactions.
tion, but much less by radical alkynylation of C(sp3) centers.
The pioneering contributions in this field used alkylmercury
[7]
halides,[5] alkyl halides,[6] and even C H bonds as C(sp3)
À
radical precursors and combined them with alkynyl sulfones
and radical initiators under UV conditions. In 2006, a radical
deboronative alkynylation of B-alkylcatecholboranes with
alkynyl sulfones using di-tert-butylhyponitrite as a radical
initiator was reported.[8] Recently, the silver-catalyzed oxida-
tive decarboxylative alkynylation of aliphatic carboxylic
acids[9] and visible-light-induced deboronative alkynylation
of alkyl trifluoroborates were achieved by using ethynylben-
ziodoxolones (EBX) as a radical alkynylating reagent.[10] The
a-aminoalkyl radical[14] and an alkynyl radical[15] instead of
the previously reported radical addition/elimination path-
ways.
Organic halides and tertiary amines were usually used in
photoredox reactions as the oxidative and reductive
quencher, respectively, undergoing reductive dehalogenation
3
reactions.[16] As the radical C(sp ) H alkynylation of tertiary
À
amines was unprecedented,[17] we studied the feasibility of
radical C(sp ) C(sp) coupling reactions of a-aminoalkyl
3
À
broad substrate scope is a further advantage of the radical
radicals and alkynyl radicals generated from tertiary amines
and electrophilic alkynes under photoredox conditions. The
bench-stable and easily available [Au2(m-dppm)2]2+ (dppm =
bis(diphenylphosphanyl)methane) is a promising photosensi-
tizer,[18] which was recently applied by Barriault and co-
workers in elegant photoredox reactions with unactivated
halogen-substituted starting materials.[16c] As a consequence,
we started to investigate the reaction of N,N-diisopropylme-
thylamine (2a) with various electrophilic alkynes 3a–c in
sunlight and using [Au2(m-dppm)2]Cl2 1a as a photocatalyst
(Table 1, entries 1–3). Trace amounts of the desired redox-
neutral coupling product 4aa were obtained with 3a or 3b as
the alkynylating reagents (entries 1 and 2). A 53% yield of
4aa (the by-products 5a and diyne 6a were observed by GC-
MS analysis) was obtained with 3c[19] (entry 3). The use of
K2HPO4 as an additional base delivered slightly higher yields
(51% versus 40% without K2HPO4; entry 4). Of the gold
3
À
C(sp ) C(sp) coupling methods—but most of these methods
rely on the use of hazardous radical initiators or external
oxidants (organostannanes, iodine(III) reagents, AIBN,
K2S2O8 etc.) and require prefunctionalization of the sub-
[*] Dr. J. Xie, Dr. S. Shi, M. Sc. T. Zhang, Dr. M. Rudolph,
Prof. Dr. A. S. K. Hashmi
Organisch-Chemisches Institut, Universitꢀt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
E-mail: hashmi@hashmi.de
Homepage: http://www.hashmi.de
M. Sc. N. Mehrkens
Anorganisch-Chemisches Institut, Universitꢀt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201412399.
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Table 1: Optimization of the reaction conditions.[a]
Table 2: Reaction scope with regard to the 1-iodoalkynes.[a]
Entry Photocatalyst
(mol%)
X
Base
(2.0 equiv) 2a
Equiv Time Yield of 4aa
[h]
[%][b]
1
2
3
4
5
6
7
8
9
1a (3)
1a (3)
1a (3)
1a (3)
1b (3)
1c (3)
1b (3)
1b (1)
BX K2HPO4
Br K2HPO4
3
3
3
3
3
3
5
5
5
6
6
6
6
6
6
1.5
1.5
6
trace
trace
53
40
62
60
81
81
62
I
I
I
I
I
I
I
K2HPO4
–
K2HPO4
K2HPO4
–
–
–
[Ru(bpy)3]Cl2
(1)
10
[Ir(ppy)3] (1)
I
I
I
I
I
I
H
–
–
–
–
–
–
–
5
5
5
5
5
5
5
1.5
1.5
2
1.5
1.5
1.5
6
76
trace
78
trace
trace
28
11[c] 1b (1)
12[d] 1b (1)
13[e] 1b (1)
14[f] 1b (1)
15
–
–
16[g]
0
[a] Reaction conditions: 3a–d (0.1 mmol), 2a (3–5 equiv), MeCN
(0.25 mL), sunlight. [b] Yield of isolated product. [c] UV light
(l=254 nm). [d] UVA light (l=315–400 nm). [e] 35 W fluorescent bulb.
[f] In the dark. [g] 10 mol% I2 and 3.0 equiv TBHP at room temperature.
bpy=2,2’-bipyridine, ppy=2-phenylpyridine, TBHP=tert-butyl hydro-
peroxide.
[a] Reaction conditions: [Au2(m-dppm)2](OTf)2 (1 mol%), 1-iodoalkyne
(0.2 mmol), 2a (5.0 equiv), MeCN (0.5 mL), room temperature, sun-
light.
of the phenylacetylene derivatives gave the corresponding
coupling products 4aa–am selectively in 71–91% yield. The
heteroaromatic 4an and 4ao were isolated in yields of 75%
and 81%. 3-Iodopropiolate furnished 4ap in 51% yield.
When an aliphatic group was present, 4aq was obtained in
only 18% yield; hex-1-yne was the main product—which
suggests that a hydrogen abstraction seems to be favored over
a radical–radical cross-coupling for alkylalkynyl radicals. 1-
(Iodoethynyl)cyclohex-1-ene furnished the desired 4ar in
66% yield.
photocatalysts screened, 1b showed the highest catalytic
activity (entries 3, 5, and 6). By adding 2.0 equiv N,N-
diisopropylmethylamine, K2HPO4 could not only be substi-
tuted as an external base, but the yield of the reaction
improved to 81% of 4aa in 1.5 h (entry 7). Even the loading
of photocatalyst 1b could be reduced to 1 mol% (entry 8).
MeCN was the best solvent.[20] The use of [Ru(bpy)3]Cl2 or
fac-[Ir(ppy)3] instead of the gold complex 1b resulted in
a lower yield (entries 9 and 10). Besides sunlight, UVA light
(l = 315–400 nm) could also efficiently promote the reaction
(entry 12). However, irradiation of the reaction mixture with
either UV light (l = 254 nm) or a fluorescent bulb delivered
only traces of the desired product (entries 11 and 13). The
control experiments demonstrated that both light and photo-
catalyst were necessary for the formation of 4aa (entries 14
and 15). 3d and the tertiary amine 2a did not provide 4aa with
the very efficient I2-TBHP oxidative catalytic system
(entry 16).[21]
While N,N-dialkylanilines[3d] and N-aryltetrahydroisoqui-
3
nolines[3p] are more reactive, mild alkynylations of a-C(sp )
À
H bonds of tertiary aliphatic amines are relatively rare.[22] Our
new procedure gave moderate to good yields of 4aa–4oa
(Table 3). In the absence of 1b, only a small amount of 4ba is
obtained, thus emphasizing the necessity of a photocatalyst.
For the unsymmetrical tertiary amines bearing various func-
tional groups (-OH, ether, acetal, -CHO, N-Boc, etc.) from
Table 3, exclusively 4aa, 4ba and 4ea–4ga, or mainly 4ha–
4oa were obtained, which indicated a reaction at the methyl
group adjacent to the nitrogen atom instead of the methylene
or methine group. The redox-neutral radical alkynylation
3
À
procedure was applied in the selective C(sp ) H alkynylation
A variety of substituted 1-iodoalkynes were examined
under the optimized reaction conditions (Table 2). Both
donor and acceptor substituents in the o-, m-, or p-position
of the antidepressant drug citalopram (4oa). N-Arylamines
failed to undergo the radical alkynylation reaction.[20] A gram-
scale conversion gave a 75% yield of 4aa (Scheme 2).
2
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Table 3: Reaction scope with regard to the tertiary aliphatic amines.[a]
[a] Reaction conditions: [Au2(m-dppm)2](OTf)2 (1 mol%), 3c (0.2 mmol),
tertiary amines (5.0 equiv), MeCN (0.5 mL), room temperature, sunlight.
The regioisomeric ratio (r.r.) was determined by 1H NMR. Yields of the
isolated product. [b] 1.2 equiv 4-dimethylaminopyridine (DMAP) was
added. [c] Without photocatalyst 1b. [d] UVA light was used instead of
sunlight.
Scheme 3. Mechanistic experiments.
tertiary amines/base is essential for the reaction, as the
generation of the a-aminoalkyl radical is favored under basic
conditions.[14g] With K2HPO4 instead of the tertiary amine, 6a
was produced in 11% yield (substoichiometric with respect to
the catalyst), despite a low conversion of 3c [Eq. (3)]. The
conversion of 3c failed in the absence of a photocatalyst or in
the dark [Eq. (4)]. No reaction occurred if phenylacetylene
was employed instead of the iodoalkyne [Eq. (5)]. Electron-
Scheme 2. Gram-scale experiment.
rich furan was used to trap the alkynyl radical,[15a,b] and the
2
À
The mechanistic experiments are shown in Scheme 3. The
addition of the radical inhibitors TEMPO or hydroquinone or
the electron-transfer scavenger 1,4-dinitrobenzene signifi-
cantly inhibits the transformation. This finding implies
a radical pathway that proceeds through a single-electron-
transfer (SET) process should be involved. Under the
optimized reaction conditions, besides the desired 4aa, 5a
(13%) and diyne 6a (trace) were also detected as by-products
by GC-MS analysis [Eq. (1)]. Lowering the concentration of
the tertiary amine slowed down the a-deprotonation of the
amino-centered radical, thus favoring the competing homo-
dimerization and hydrogen abstraction. Indeed, 5a and 6a
were formed in 23% and 28% yield, respectively, with only
two equivalents of amine 2a [Eq. (2)]. Thus, an excess of
expected C(sp ) C(sp) coupling product was observed (see
the Supporting Information for details). These control experi-
ments indicate the generation of an alkynyl radical from 1-
iodoalkyne in the presence of photocatalyst 1b in sunlight.
The dimerization of 2a to 7[14c] was observed by GC-MS
analysis during optimization of the reaction with aliphatic 1-
iodohex-1-yne [Eq. (6)].[20] The nucleophilicity of an a-
aminoalkyl radical[14a–d] results in the addition of Michael
acceptor 8 delivering the expected addition product 9
[Eq. (7)]. These results strongly indicate that an a-aminoalkyl
radical is another important intermediate. The model reac-
tion (1) needed continuous irradiation with sunlight; no
conversion of (iodoethynyl)benzene 3c was detected in the
dark.[20]
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Scheme 4. Possible reaction mechanism.
A possible mechanism is shown in Scheme 4 based on the
3
À
visible-light-mediated a-C(sp ) H arylation of tertiary
amines with 1,4-dicyanobenzene[14g] and on our results. First
the excited-state form of dinuclear gold complex 10 is
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In summary, a highly efficient gold-catalyzed radical
3
À
C(sp ) H alkynylation of tertiary aliphatic amines using
readily available 1-iodoalkynes as a radical alkynylating
reagent in the presence of [Au2(m-dppm)2]2+ under mild
reaction conditions was developed. Mechanistic studies
indicate a coupling of an a-aminoalkyl radical and an alkynyl
radical.
À
Keywords: C H activation · gold catalysis ·
À
photoredox catalysis · radical C C coupling · sunlight
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[26] Although initially discovered with “persistent” radicals, this
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[27] The lifetime of an a-aminoalkyl radical (Et2NCHMe) and
phenylethynyl radical are about 700 ns and 2 ns, respectively;
see a) J. C. Scaiano, J. Phys. Chem. 1981, 85, 2851 – 2855; b) X.
Gu, Y. Guo, F. Zhang, A. M. Mebel, R. I. Kaiser, Chem. Phys.
Lett. 2007, 436, 7 – 14. Thus, a-aminoalkyl radical 14 is more
long-lived and the initially preferred dimerization of the alkynyl
radical is in full accord with the mechanistic model.
[15] For rare examples of alkynyl radicals in organic synthesis, see
a) G. Martelli, P. Spagnolo, M. Tiecco, J. Chem. Soc. D 1969,
282 – 283; b) G. Martelli, P. Spagnolo, M. Tiecco, J. Chem. Soc. B
1970, 1413 – 1418; c) P. Boutillier, S. Z. Zard, Chem. Commun.
2001, 1304 – 1305.
[16] For selective light-mediated reductive dehalogenation reactions,
see a) J. D. Nguyen, E. M. D’Amato, J. M. R. Narayanam,
C. R. J. Stephenson, Nat. Chem. 2012, 4, 854 – 859; b) H. Kim,
C. Lee, Angew. Chem. Int. Ed. 2012, 51, 12303 – 12306; Angew.
Chem. 2012, 124, 12469 – 12472; c) G. Revol, T. McCallum, M.
Morin, F. Gagosz, L. Barriault, Angew. Chem. Int. Ed. 2013, 52,
13342 – 13345; Angew. Chem. 2013, 125, 13584 – 13587.
3
À
[17] The oxidative a-C(sp ) H nucleophilic alkynylation of tertiary
amines were developed in the last decade, but sacrificial external
oxidants were usually required.
[18] The dinuclear gold complex absorbs light at about 300 nm to
form a high-energy and long-lived photoexcited state with
a quantum yield of 0.23, see D. Li, C.-M. Che, H.-L. Kwong,
V. W.-W. Yam, J. Chem. Soc. Dalton Trans. 1992, 3325 – 3329.
[19] The 1-iodoalkynes can be easily prepared in high yields from
various commercially available alkynes, see
Received: December 26, 2014
Revised: February 24, 2015
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Gold Photocatalysis
J. Xie, S. Shi, T. Zhang, N. Mehrkens,
M. Rudolph,
A. S. K. Hashmi*
&&&& — &&&&
A Highly Efficient Gold-Catalyzed
3
À
Photoredox a-C(sp ) H Alkynylation of
Tertiary Aliphatic Amines with Sunlight
À
Golden sunshine: With 1-iodoalkynes as
radical alkynylation reagents, unactivated
tertiary aliphatic amines react in the
presence of [Au2(m-dppm)2]2+ (dppm=
bis(diphenylphosphanyl)methane) in
sunlight to afford propargylamines. A C
C coupling of an a-aminoalkyl radical and
an alkynyl radical was proposed as the
mechanism.
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!