Intermolecular Photocatalyzed Heck-like Coupling of Unactivated Alkyl Bromides by a Dinuclear Gold Complex

Article abstract of DOI:10.1002/chem.201602939

A practical protocol for a photocatalyzed alkyl-Heck-like reaction of unactivated alkyl bromides and different alkenes promoted by dinuclear gold photoredox catalysis in the presence of an inorganic base is reported. Primary, secondary, and tertiary unactivated alkyl bromides with β-hydrogen can be applied. Esters, aldehydes, ketones, nitriles, alcohols, heterocycles, alkynes, alkenes, ethers, and halogen moieties are all well tolerated. In addition to 1,1-diarylalkenes, silylenolethers and enamides can also be applied, which further increases the synthetic potential of the reaction. The mild reaction conditions, broad substrate scope, and an excellent functional-group tolerance deliver an ideal tool for synthetic chemists that can even be used for challenging late-stage modifications of complex natural products.

Full text of DOI:10.1002/chem.201602939

A Journal of
Accepted Article
Title: Intermolecular Photocatalyzed Heck-like Coupling of Unactivated Alkyl Bromi-
des by a Dinuclear Gold Complex
Authors: A. Stephen K. Hashmi
This manuscript has been accepted after peer review and the authors have elected
to post their Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by using the Digital
Object Identifier (DOI) given below. The VoR will be published online in Early View as
soon as possible and may be different to this Accepted Article as a result of editing.
Readers should obtain the VoR from the journal website shown below when it is pu-
blished to ensure accuracy of information. The authors are responsible for the content
of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201602939
Link to VoR: http://dx.doi.org/10.1002/chem.201602939
Supported by

Chemistry - A European Journal
10.1002/chem.201602939
Intermolecular Photocatalyzed Heck-like Coupling of
Unactivated Alkyl Bromides by a Dinuclear Gold Complex
Jin Xie, Jian Li, Vanessa Weingand, Matthias Rudolph, A. Stephen K. Hashmi*
Organisch-Chemisches Institut, Universität Heidelberg, Im Neuenheimer Feld 270, 69120
Heidelberg (Germany)
E-mail: hashmi@hashmi.de
Keywords: alkenes; gold catalysis; photoredox catalysis; radicals; unactivated alkyl
halides
Abstract: A practical protocol for a photocatalyzed alkyl-Heck-like reaction of
unactivated alkyl bromides and different alkenes by dinuclear gold photoredox
catalysis in the presence of an inorganic base is reported. Primary, secondary and
tertiary unactivated alkyl bromides with -hydrogen can be applied. Esters, aldehydes,
ketones, nitriles, alcohols, heterocycles, alkynes, alkenes, ethers and halogen moieties
are all well tolerated. Besides 1,1-diarylalkenes also silylenolether and enamides can
be applied which further increases the synthetic potential of the reaction. The mild
reaction conditions, broad substrate scope and an excellent functional-group tolerance
deliver an ideal tool for synthetic chemists that can even be used for challenging
late-stage modification of complex natural products.
The development of efficient methods for the construction of new C-C bonds is a
central problem of organic synthesis. One of the most important tools for C-C
couplings is the Pd-catalyzed Heck reaction of alkenes. While the reaction with
sp2-halides is an widespread and well established protocol for synthetic chemistry and
organic materials,[1] unactivated sp3-halides are still intractable coupling partners,
especially for intermolecular couplings.[2] This can be rationalized by their low rate
for oxidative addition and their high tendency to undergo a fast -hydride
elimination.[3] To solve this problem, a transition-metal-mediated intermolecular
radical alkyl-Heck like coupling was assumed to be a good choice.[4] In 2002, Oshima

Chemistry - A European Journal
10.1002/chem.201602939
and co-workers developed an efficient Co-mediated radical Heck coupling of
unactivated alkyl bromides with styrenes, but the requirement of stoichiometric
alkylmetal reagents generally resulted in a poor functional group tolerance and thus in
a limited applicability.[5] Recent efforts elegantly enabled a radical alkyl-Heck
reaction of activated alkyl bromides[6] and unactivated alkyl iodides[7] in the absence
of alkyl metal reagents. However, despite these achievements, the use of unactivated
alkyl bromides bearing versatile functional groups as starting materials remains a
major challenge in this area. To address this unsolved challenge, a general and
efficient catalytic system to enable an alkyl-Heck coupling should meet the following
requirements: 1) efficient generation of carbon-centered alkyl radicals from alkyl
bromides under mild reaction conditions; 2) prevention of the oxidation of the
generated, highly active initial alkyl radical; 3) compatibility with versatile functional
groups. In this context we envisioned that the dinuclear gold-complex, which was
recently established by Barriault’s and our group as highly effective photocatalyst,[8]
would allow to achieve this aim. Photoredox catalysis has already proven to be a
powerful tool as it offers the opportunity to handle radical chemistry under mild
reaction conditions.[9]
Scheme 1. Different strategies for an intermolecular radical Heck coupling of alkyl

Chemistry - A European Journal
10.1002/chem.201602939
halides.
Scheme 2. Proposed mechanism.
Based on recent work about light-mediated reductive radical couplings of alkyl
halides with alkenes in the presence of sacrificial electron and hydrogen donors,[10] we
assumed that an oxidative quenching pathway of unactivated alkyl bromides might
enable an intermolecular alkyl-Heck-like reaction (Scheme 2).[11] We first examined
the alkyl-Heck coupling of the unactivated alkyl bromide 2a[12] and styrene under
UVA light (λ = 315-400 nm) with the dinuclear gold-complex 3, which is known for
its ability to form a high-energy photo-excited state with a strong reduction
potential.[13] As no desired alkyl-Heck product was detected, we considered that a
more stabilized, less reactive and easier oxidizable radical B would prevent competing
side reactions (Scheme 2). Due to the lower reactivity of this radical, Br-atom transfer,
H-atom abstraction, dimerization and oligomerization, all well-reported side reactions
of photoredox catalysis, might be prevented that way.
Table 1: Optimization of the reaction conditions.[a]

Chemistry - A European Journal
10.1002/chem.201602939
Entry Catalyst
(3 mol%)
Base (equiv)
Yield of 4aa[b]
1[c]
Et3N (2)
Bu3N (2)
NaHCO3 (1.5) 71%
NaHCO3 (1.5) 91%
NaHCO3 (1.5)
NaHCO3 (1.5)
NaHCO3 (1.5)
36% (35% 5aa)
37% (36% 5aa)
3
3
3
2[c]
3[c]
4
3
5[d]
6[d]
7[c,e]
Ir(ppy)3
Ru(bpy)3Cl2
0
0
0
Pd(PPh3)4
(10 mol%)
3
-
8[f]
9
NaHCO3 (1.5) 57%
NaHCO3 (1.5)
NaHCO3 (1.5)
0
0
10[g]
3
[a] Reaction conditions: 1,1-diphenylethylene 1a (1.5
equiv), ethyl 4-bromobutanoate 2a (0.2 mmol), catalyst
(0-10 mol%), Na-ascorbate (0.5 equiv), base (1.5-2
equiv), MeCN (0.4 mL), UVA light (λ = 315-400 nm),
1
30-36 hours; [b] H NMR yield determined with
CH2Br2 as internal standard; [c] Without Na-ascorbate
as additive; [d] Under irradiation with 12 W blue LEDs
or 23 W CFL; [e] Heating at 100 oC for 36 hours; [f] 1.5
equiv 2a and 1 equiv 1a were tested; [g] In the dark.
Based on this considerations, we turned our attention to 1,1-disubstituted alkenes in
order to obtain a less reactive radical intermediate B. Indeed, the gold-catalyzed
Heck-like cross coupling of 1,1-diphenylethylene 1a and 4-bromobutanoate 2a
afforded the desired product 4aa in moderate yield in the presence of tertiary amines,
accompanied by significant amounts of undesired reduction product 5aa and traces of
a two-fold Heck reaction (6aa, Table 1, entries 1 and 2). As the poor selectivity could
have been due to a competing reduction of the gold catalyst by the amine instead of
radical B, other bases were considered next. When NaHCO3 was used, the yield of

Chemistry - A European Journal
10.1002/chem.201602939
4aa reached 71% and no reduction product was observed (entry 3). Remarkably, the
use of 0.5 equiv Na-ascorbate as additive could deliver 4aa in an excellent yield of
91% (entry 4). We assumed that trace soluble Na-ascorbate in MeCN would inhibit
the decomposition of unstable gold intermediate D. Other applied bases and solvents
did not improve this alkyl-Heck coupling further (see Supporting Information for
reaction condition optimization). Not surprisingly, photocatalysts with a weaker
reduction ability failed to undergo the radical alkyl-Heck-like reaction (entries 5 and
o
6). When [Pd(PPh3)4] was used as catalyst, even upon heating to 100 C no product
4aa was observed (entry 7).[14] In addition, it was found that a slight excess of
1,1-diphenylethylene was beneficial for the Heck-like reaction (entry 4 vs entry 8).
The control experiments demonstrated that the radical alkyl-Heck coupling could
proceed neither in the absence of a dinuclear gold photocatalyst 3 nor in absence of
light.
Under the optimized reaction conditions, a wide variety of unactivated alkyl bromides
2a-u were examined (Table 2). In general, this protocol tolerates a broad scope of
alkyl bromides. A number of versatile functional groups, such as, esters, aldehydes,
ketones, nitriles, alcohols, heterocycles, alkynes, ethers and halogens, were
compatible, and all of these test substrates delivered the desired alkyl-Heck-like
coupling products 4aa-au in moderate to good yields. The versatility of this
gold-catalyzed alkyl-Heck-like coupling is also shown by its good tolerance of
primary, secondary and tertiary alkyl bromides. This is noteworthy as it overcomes
the difficulties of Pd-catalyzed -elimination processes and thus enables the
applicability of unactivated alkyl bromides bearing functional groups in alkyl-Heck
reactions. When bromobenzene was used instead of alkyl bromides, little Heck
product was produced.
Table 2: The reaction scope with regard to alkyl bromides.[a]

Chemistry - A European Journal
10.1002/chem.201602939
[a] Reaction conditions: Alkene 1a (1.5 equiv), alkyl bromide (0.2 mmol),
photocatalyst 3 (3 mol%), Na-ascorbate (0.5 equiv), NaHCO3 (1.5 equiv), MeCN (0.4
mL), UVA light (λ = 315-400 nm), 30-36 hours. [c] 0.5 mmol scale.
Table 3: Reaction scope with regard to alkenes.[a]
Alkenes
Product and yield[b]

Chemistry - A European Journal
10.1002/chem.201602939
[a] Reaction conditions as mentioned in Table 2. E/Z ratio of 4fa-ha range from 1.2:1
to 1:1. [b] Isolated yields. [c] 2.5 equiv 1j were used. [d] 48 hours. [e] Alkene (0.2
mmol), activated alkyl bromides (1.5 equiv), NaHCO3 (1.5 equiv), sunlight, 6-8
hours.
As shown in Table 3, a series of different alkenes was investigated next. All of the
applied 1,1-diarylalkenes delivered the desired products 4aa-ha in moderate to good
yields, while trisubstituted alkene 1i only gave a moderate yield most probably due to
its steric hindrance. Importantly, electron-rich trimethylsiloxyethylene 1j and
enamides 1k-m turned out to be good coupling partners, too. They directly yielded the
long-chained ketones 4ja-jb and enamides 4ka-ma in satisfactory yields. Although
styrene gave poor efficiency with the unactivated alkyl bromides, we found that they
can smoothly undergo the alkyl-Heck coupling with activated alkyl bromides to
deliver products 4na, 4nb and 4oa in 63%-73% yield.

Chemistry - A European Journal
10.1002/chem.201602939
Scheme 3. Late-stage functionalization of bioactive molecules.
To demonstrate further the general applicability, the derivatives of biologically
important pregenenolone and oleanic acid were subjected to the standard conditions
(Scheme 3). Several important functional groups (alkene, ketone and ester moieties)
are involved in these complex molecules, but despite this fact clean gold-catalyzed
radical alkyl-Heck-like reactions furnished the desired products 8 and 10 in
acceptable yields.
To support the proposed mechanism from Scheme 2, some mechanistic experiments
were performed (Scheme 4). The addition of radical inhibitor TEMPO and
electron-transfer scavenger 1,4-dinitrobenzene fully inhibited the alkyl-Heck reaction,
which indicates that a radical pathway that proceeds through a single-electron transfer
process is highly possible in this transformation. A radical-clock experiment with
6-bromohex-1-ene 11 further verifies a radical mechanism as the cyclic coupling
product 12 was observed as the main product with only 3% of linear coupling product
13 (Scheme 4b). To capture a possible carbenium ion intermediate C, water was
added to the reaction mixture and indeed the resulting tertiary alcohol 14 was isolated
in 36% yield. The intermolecular competition KIE experimental result indicates that
C-H bond cleavage is not involved in the rate-determining step of the alkyl-Heck
process. At present, the mechanism depicted in Scheme 2 appears highly probable.

Chemistry - A European Journal
10.1002/chem.201602939
Scheme 4. Studies to probe the reaction mechanism.
In conclusion, the new and practical protocol for a photocatalyzed alkyl-Heck-like
reaction of unactivated alkyl bromides and different alkenes by dinuclear gold
photoredox catalysis in the presence of an inorganic base overcomrd the inherent
limitation of Pd-catalyzed Heck reactions of unactivated alkyl bromides. We
anticipate that it will become a powerful protocol for the formation of such
C(sp2)-C(sp3) bonds. Further studies on substrate scope and detailed mechanism are in
progress.

Chemistry - A European Journal
10.1002/chem.201602939
Acknowledgement: Prof. Samir Zard at Ecole Polytechnique is kindly acknowledged
for his helpful discussion on this chemistry.
Reference:
[1]
[2]
The Mizoroki-Heck Reaction (Ed.: M. Oestreich), Wiley, Chichester, 2009.
For leading works on intramolecular alkyl-Heck cross-coupling of unactivated
alkyl halides: a) L. Firmansjah, G. C. Fu, J. Am. Chem. Soc. 2007, 129,
11340-11341; b) M. Parasram, V. O. Iaroshenko, V. Gevorgyan, J. Am. Chem.
Soc. 2014, 136, 17926-17929; c) M. E. Weiss, L. M. Kreis, A. Lauber, E. M.
Carreira, Angew. Chem. Int. Ed. 2011, 50, 11125-11128; for an excellent
intermolecular alkyl-Heck reaction of activated benzyl halides see: d) R.
Matsubara, A. C. Gutierrez, T. F. Jamison, J. Am. Chem. Soc. 2011, 133,
19020-19023.
[3]
A. C. Bissember, A. Levina, G. C. Fu, J. Am. Chem. Soc. 2012, 134,
14232-14237.
[4]
[5]
S. Tang, K. Liu, C. Liu, A. Lei, Chem. Soc. Rev. 2015, 44, 1070-1082.
a) Y. Ikeda, T. Nakamura, H. Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2002,
124, 6514-6515; b) W. Affo, H. Ohmiya, T. Fujioka, Y. Ikeda, T. Nakamura, H.
Yorimitsu, K. Oshima, Y. Imamura, T. Mizuta, K. Miyoshi, J. Am. Chem. Soc.
2006, 128, 8068-8077.
[6]
[7]
[8]
Activated alkyl bromides were defined as compounds that at least bear one
strong electron-withdrawing group directly connected to the carbon of the
C-Br bond. For intermolecular alkyl-Heck couplings with activated alkyl
bromides see: a) C. Liu, S. Tang, D. Liu, J. Yuan, L. Zheng, L. Meng, A. Lei,
Angew. Chem. Int. Ed. 2012, 51, 3638-3641; b) Q. Liu, H. Yi, J. Liu, Y. Yang,
X. Zhang, Z. Zeng, A. Lei, Chem. Eur. J. 2013, 19, 5120-5126; c) T. Nishikata,
Y. Noda, R. Fujimoto, T. Sakashita, J. Am. Chem. Soc. 2013, 135,
16372-16375; d) Z. Feng, Q.-Q. Min, H.-Y. Zhao, J.-W. Gu, X. Zhang, Angew.
Chem. Int. Ed. 2015, 54, 1270-1274.
For recent work on inter- and intra-molecular alkyl-Heck-like reactions of
unactivated R-I, see: a) K. S. Bloome, E. J. Alexanian, J. Am. Chem. Soc.
2010, 132, 12823-12825; b) K. S. Bloome, R. L. McMahen, E. J. Alexanian, J.
Am. Chem. Soc. 2011, 133, 20146-20148; c) A. Millán, L. Álvarez de
Cienfuegos, D. Miguel, A. G. Campaña, J. M. Cuerva, Org. Lett. 2012, 14,
5984-5987; d) C. M. McMahon, E. J. Alexanian, Angew. Chem. Int. Ed. 2014,
53, 5974-5977; for a Pd-catalyzed intermolecular alkyl-Heck cross-coupling
of alkyl iodide generated in situ from alkyl bromides at 110 oC see: e) Y. Zou,
J. Zhou, Chem. Comm. 2014, 50, 3725-3728.
a) G. Revol, T. McCallum, M. Morin, F. Gagosz, L. Barriault, Angew. Chem.
Int. Ed. 2013, 52, 13342-13345; b) J. Xie, S. Shi, T. Zhang, N. Mehrkens, M.
Rudolph, A. S. K. Hashmi, Angew. Chem. Int. Ed. 2015, 54, 6046-6050; c) S.

Chemistry - A European Journal
10.1002/chem.201602939
J. Kaldas, A. Cannillo, T. McCallum, L. Barriault, Org. Lett. 2015, 17,
2864-2866; d) J. Xie, T. Zhang, F. Chen, N. Mehrkens, F. Rominger, M.
Rudolph, A. S. K. Hashmi, Angew. Chem. Int. Ed. 2016, 18, 2934-2938; e) T.
McCallum, E., Slavko, M. Morin, L. Barriault, Eur. J. Org. Chem. 2015, 81-85;
f) C. D. Mctiernan, M. Morin, T. McCallum, J. C. Scaiano, L. Barriault, Catal.
Sci. Technol. 2016, 6, 201-207; g) T. F. Nzulu, S. Telitel, F. Stoffelbach, B.
Graff, F. Marlet-Savary, J. Lalevee, L. Fensterbank, J.-P. Goddard, C. Oliver,
Polym. Chem. 2015, 6, 4605-4611; h) C. Ma, C. Chan, W. To, W.-M. Kwok,
C.-M. Che, Chem. Eur. J. 2015, 21, 13888-13893.
[9]
Selected reviews on photoredox catalysis: a) D. M. Schultz, T. P. Yoon,
Science 2014, 343; b) J. Xie, H. Jin, P. Xu, C. Zhu, Tetrahedron Lett. 2014, 55,
36-48; c) C. K. Prier, D. A. Rankic, D. W. C. MacMillan, Chem. Rev. 2013,
113, 5322-5363; d) J. Xuan, W.-J. Xiao, Angew. Chem. Int. Ed. 2012, 51,
6828-6838; e) D. P. Hari, B. König, Angew. Chem. Int. Ed. 2013, 52,
4734-4743; f) J. M. R. Narayanam, C. R. J. Stephenson, Chem. Soc. Rev. 2011,
40, 102-113.
[10] For an light-mediated radical reductive C-C coupling of alkyl halides with
alkenes 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; c) M. Nakajima, Q. Lefebvre, M. Rueping,
Chem. Comm. 2014, 50, 3619-3622; d) R. S. Andrews, J. J. Becker, M. R.
Gagné, Angew. Chem. Int. Ed. 2010, 49, 7274-7276.
[11] The oxidative quenching of activated alkyl halides with alkenes usually
follows an ATRA reaction, see: a) C.-J. Wallentin, J. D. Nguyen, P. Finkbeiner,
C. R. J. Stephenson, J. Am. Chem. Soc. 2012, 134, 8875-8884; b) C. Yu, N.
Iqbal, S. Park, E. J. Cho, Chem. Comm. 2014, 50, 12884-12887.
[12] The reudction potential of unactivated alkyl bromides are usully ranged from
-1.9 to -2.5 V versus the saturated calomel electrode, see: a) A. J. Fry, R. L.
Krieger, J. Org. Chem. 1976, 41, 54-57; b) S. Rondinini, P. R. Mussini, P.
Muttini, G. Sello, Electrochimica Acta 2001, 46, 3254-3258.
[13] Pioneering work: a) C.-M. Che, H.-L. Kwong, C.-K. Poon, V. W.-W. Yam, J.
Chem. Soc., Dalton Trans. 1990, 3215-3219; b) C.-M. Che, H.-L. Kwong, V.
W.-W. Yam, K.-C. Cho, J. Chem. Soc., Chem. Comm. 1989, 885-886; c) C.
King, J. C. Wang, M. N. I. Khan, J. P. Fackler, Inorg. Chem. 1989, 28,
2145-2149.
[14] Alexanian et al. recently notified that unactivated alkyl bromides under their
o
standard conditions ([PdCl2(dppf)], K2CO3, 100 C) failed to undergo
Heck-like coupling, see 7d.

Chemistry - A European Journal
10.1002/chem.201602939
TOC graphic
Abstract: A general and mild method for an intermolecular radical Heck-like
coupling of unactivated primary, secondary and tertiary alkyl bromides catalyzed by a
dinuclear gold complex is presented. A variety of alkenes and densely functionalized
unactivated alkyl bromides tolerated the reaction conditions well, including substrates
containing esters, aldehydes, ketones, nitriles, alcohols, heterocycles, alkynes, alkenes,
ethers and halogens moieties. This notable features offer an ideal protocol for
challenging late-stage intermolecular C-C couplings of complex molecules.