General and facile method for exo -methlyene synthesis via regioselective C-C double-bond formation using a copper-amine catalyst system

Article abstract of DOI:10.1021/ol502953w

In this study, for distal-selective β-hydride elimination to produce exomethylene compounds with a newly formed Csp³-Csp³ bond between tertiary alkyl halides and -alkylated styrenes, a combination of a Cu(I) salt and a pyridine-based amine ligand (TPMA) is found to be a very efficient catalyst system. The yields and regioselectivities were high, and the regioselectivity was found to be dependent on the structure of the alkyl halide, with bulky alkyl halides showing the highest distal selectivities.

Full text of DOI:10.1021/ol502953w

Letter
pubs.acs.org/OrgLett
General and Facile Method for exo-Methlyene Synthesis via
Regioselective C−C Double-Bond Formation Using a Copper−Amine
Catalyst System
Takashi Nishikata,* Kimiaki Nakamura, Kohei Itonaga, and Shingo Ishikawa
Graduate School of Science and Engineering,Yamaguchi University, Ube, Yamaguchi 755-8611, Japan
S
* Supporting Information
ABSTRACT: In this study, for distal-selective β-hydride
elimination to produce exomethylene compounds with a newly
formed Csp3−Csp3 bond between tertiary alkyl halides and α-
alkylated styrenes, a combination of a Cu(I) salt and a pyridine-
based amine ligand (TPMA) is found to be a very efficient catalyst
system. The yields and regioselectivities were high, and the
regioselectivity was found to be dependent on the structure of the
alkyl halide, with bulky alkyl halides showing the highest distal
selectivities.
Heck reaction is problematic.15 This undesired isomerization
he Heck reaction, which is widely known due to the award
Tof the Nobel prize in Chemistry in 2010, is one of the most makes the distal-selective Heck reaction much more difficult.
Although biased olefins, such as cyclic olefins16 or allylic alcohol
powerful options to obtain arylated or alkenylated alkenes. Over
the past few decades, tremendous progress, including mecha-
derivatives,17 are good substrates to obtain high distal
selectivities, this subtle phenomenon could be one reason for
the slow development and limited scope of the transformations
in the regisoselective Heck reaction with unbiased olefins, such as
α-alkylated olefins. Chirik et al.18 and Watson et al.19−21 very
recently reported distal-selective C−C double-bond formations
with nonbiased olefins achieved by elegant ligand choice in silyl-
Heck reactions, whereas regioselectivities in alkylative Heck
reactions are still unsolved.
In this context, we envisaged the development of a highly
distal-selective alkylative Heck-type reaction with α-alkylated
styrene 2, an unbiased acyclic olefin, to generate distal product 5
with a terminal C−C double bond (Scheme 2 bottom). Recently,
we reported that the copper(I)-catalyzed tertiary-alkylative
Heck-type reaction between α-halocarbonyl compounds 1 and
styrenes 2 gave Heck-type products 4 in high yields.22 This
reaction does not involve an ordinary carbometalation reaction
followed by β-hydride elimination step but proceeds through an
atom-transfer radical addition (ATRA)23 to generate an
intermediate I followed by elimination with a base to produce
Heck-type product 4 (Scheme 2 top). On the other hand,
reaction with α-alkylated styrene 2 generates intermediate II,
which produces isomer 4 or 5 as in traditional Heck reactions
(Scheme 2 bottom). Considering the intermediate II, a steric
contribution would give distal product 5 but an electronic
contribution would give proximal product 4 (HB increases the
acidity due to an electron withdrawing group). If the
regiochemistry follows from site-selective elimination with a
base by a steric effect, the copper(I)-catalyzed Heck-type
nistic insights, has been made in this area, and our knowledge of
this reaction is increasing all the time.1,2 The Heck reaction is
mainly used for the synthesis of internal alkenes because the
synthesis of external alkenes is very challenging due to a serious
limitation of the Heck reaction, namely the low regioselectivity in
the formation of the C−C double bond after β-hydride
elimination.3−6 In the Heck reaction of olefin 2, there are two
possible pathways for β-hydride elimination; i.e., the proximal
hydrogen atom (HB) or the distal hydrogen atom (HA) with
respect to the newly formed C−C bond can be eliminated to
form olefin 4 (proximal double bond) or 5 (distal double bond),
respectively (Scheme 1). Although steric and/or electronic
factors in an intermediate may govern the regioselectivity of the
C−C double-bond formation, this reaction tends to give the
proximal product 4 as the major product in most cases because an
internal alkene is more stable than a terminal one.7−14 Even if 5 is
generated selectively through intermediate 3, the double-bond
isomerization of 5 into 4 due to the presence of the Pd used in the
Scheme 1. Proximal versus Distal Selective β-Hydride
Elimination in the Heck Reaction
Received: October 6, 2014
© XXXX American Chemical Society
A
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a
Scheme 2. Our Previous Work on the Alkylative Heck-Type
Reaction Involving ATRA (Top) and This Work (Bottom)
Table 1. Optimization of tert-Alkylation in Heck Reaction
reaction of 1 with α-alkylated styrene 2 would give the highly
distal-selective Heck-type product 5 (Scheme 2 bottom). Herein,
we report a highly regioselective C−C double bond formation in
tertiary-alkylative Heck-type reactions leading to exomethylene
compounds.
As expected, the reaction of 2a with 6a in the presence of CuI,
triethylamine (TEA), and benzyltributylammonium bromide
gave the desired product in 21% yield with high distal selectivity
(proximal/distal = 9:91, Table 1). In ATRA or ATRP (atom-
transfer radical polymerization) reactions,23 the combination of
Cu(I) and multidentate amines is an effective way to generate
alkyl radicals.24 The presence of 1 equiv of a multidentate
nitrogen-based ligand with respect to the Cu(I) complex resulted
in the formation of a very stable Cu(amine)X (X = Br, Cl or I)
complex.25 Indeed, the yield in the reaction with a tridentate
amine (PMDETA: N,N,N′,N″,N″-pentamethyldiethylenetri-
amine) was higher than that obtained with a bidentate amine,
e.g., TMEDA (N,N,N′,N′-tetramethylethylenediamine),
TMPDA (N,N,N′,N′-tetramethyl-1,3-diaminopropane), or
TMBDA (N,N,N′,N′-tetramethylethyl-1,4-diaminobutane).
Tetradentate amines, such as Me6TREN (tris[2-(dimethyl-
amino)ethyl]amine) and TPMA (tris(2-pyridylmethyl)amine),
resulted in good yields, 70% and 87%, respectively, with high
regioselectivities. The reactivity depends on the efficient
generation of radical species in a process that is defined by kact
values. These values are obtained from the reaction of an alkyl
halide with an excess of the Cu(I) complex and irreversible
trapping of the resulting radicals by nitroxides or by redox
potentials.23 According to the literature, kact values increase in the
following order: TMEDA (0.015) < TPMA (62) < Me6TREN
(450). In our reaction, TPMA was more effective than
Me6TREN, probably due to the moderate efficiency of the
radical generation leading to a relatively mild reaction. In this
reaction, using phosphine ligands, which are effective in the
nickel-catalyzed alkylative Heck reaction,26 proved unsuccessful.
Various copper(I) salts were effective as catalysts, but CuI gave
the highest yield. The effect of an ammonium salt is unclear;
however, it may be needed to support the solubility of the copper
species. Generally, the combination of radical species and styrene
derivatives is very effective in promoting ATRP, but the desired
a
Conducted at 100 °C for 20 h in toluene with 2a (1 equiv), 6a (1.5
equiv), CuI (10 mol %), ligand (5 mol %), TEA (2 equiv), and
BnBu3NBr (20 mol %). The selectivities are determined by H NMR
analysis of the crude mixture. 1.5 equiv of PMDETA was used instead
of TEA. Conducted at 100 °C for 20 h in toluene with 2a (1 equiv),
6a (1.5 equiv), Cu (10 mol %), TPMA (5 mol %), TEA (2 equiv), and
BnBu3NBr (20 mol %).
1
b
c
reaction predominated over ATRP because excess amine
suppressed the polymer growth.25
The results for the distal-selective Heck reactions with several
structures of 6 under conditions A or B are shown in Table 2.
Almost all substrates 6 possessing sterically bulky substituents or
various functional groups reacted smoothly with 2b to give
moderate-to-good yields with high distal selectivities. These
results demonstrate the broad applicability of our protocol. The
steric bulkiness of 6 tended to increase distal selectivities.
For example, ethyl 2-bromoisobutyrate led to 5b with a 9:91
selectivity, whereas the substituted isobutyrate that led to 5c or
5d resulted in 5:>95 selectivities. A similar trend was observed in
the synthesis of 5h, 5i, and 5j. Substituted phenoxy esters leading
to 5e, 5f, or 5g tended to give slightly higher selectivities than 5b,
and electronic effects were not observed. Applicable functional
groups for this reaction include not only esters but also ketones
and nitro groups, as exemplified by 5k and 5m, respectively.
However, the reaction was sluggish with an amide group (see
5n). In this case, methacrylamide was obtained in high yields.
The reactivities of substituted styrenes 2 under conditions A−
D are listed in Table 3. To compare the regioselectivities for
various styrenes 2, compound 6b was used as a reaction partner
as it previously showed a range of selectivities (see Table 2). The
product yields did not strongly depend on the stereo and/or
electronic properties of the aromatic rings in styrenes 6. For
B
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a
a
Table 2. Reactions of Alkyl Halides with 2b
Table 3. Reactions of Substituted α-Methyl Styrenes with 6b
a
All reactions were carried out under conditions A−D. The
selectivities are determined by NMR analysis of the crude mixture.
Conditions A: 2 (1 equiv), 6b (1.5 equiv), CuI (10 mol %), TPMA (5
mol %), TEA (2 equiv), TBABr (20 mol %), toluene, 100 °C.
Conditions B: 2 (1 equiv), 6b (1.5 equiv), CuI (10 mol %), TPMA (5
mol %), PMDETA (1.5 equiv), BnBu3NBr (20 mol %), toluene, 100
°C. Conditions C: 2 (1 equiv), 6b (1.5 equiv), CuI (10 mol %),
Me6TREN (10 mol %), PMDETA (1.5 equiv), BnBu3NBr (20 mol
%), toluene, 100 °C. Conditions D: 2 (1 equiv), 6b (1.5 equiv), CuI
(10 mol %), PMDETA (1 equiv), BnBu3NBr (20 mol %), CH2Cl2, rt.
a
All reactions were carried out under the conditions A or B. The
selectivities are determined by NMR analysis of the crude mixture.
Conditions A: 2b (1 equiv), 6 (1.5 equiv), CuI (10 mol %), TPMA (5
mol %), TEA (2 equiv), TBABr (20 mol %), toluene, 100 °C.
Conditions B: 2b (1 equiv), 6 (1.5 equiv), CuI (10 mol %), TPMA (5
mol %), PMDETA (1.5 equiv), BnBu3NBr (20 mol %), toluene, 100
b
°C. 1,4-Dioxane was used instead of toluene.
b
1,4-Dioxane was used instead of toluene.
example, the yield of 5o, which contains an electron-donating
group, was virtually identical to that of the halogen-substituted
products 5r, 5s, and 5t. The ester-substituted styrene that led to
5u gave a lower yield. Although the bulky substrate leading to 5z
gave a good yield, simple 2-methyl-substituted styrene, leading to
5y, showed only moderate reactivity. In this reaction, silyl-
protected phenol derivatives leading to 5w did not show high
reactivity even at an elevated temperature when compared with
4-methoxy-α-methystyrene, which gave 5o. Styrenes containing
a nitrile group or an internal double bond provided good yields of
the products 5x and 5aa, respectively. In most cases, the use of a
high temperature enabled efficient Heck reactions, whereas the
reactions of α-methylstyrenes containing electron-donating
groups in the para-position of the benzene rings proceeded
with 6b to afford the products 5o, 5w, and 5x at room
temperature. The regioselectivities were all very similar in the
reaction with substituted styrenes.
Although the reaction of α-methylstyrene derivatives 2 gave
good distal selectivities, comparable results were also obtained
with α-alkylated styrene derivatives. α-Ethylstyrene 2c reacted
smoothly with 6b to produce the desired product 5bb with high
distal selectivity (Scheme 3A). In the case of the reaction with 2d,
5cc was produced exclusively (Scheme 3B). These results
suggest that the distal selectivities obtained in our reactions are
not dependent on the size of the α-substituents in the styrenes.
The products synthesized by the reaction reported here can
provide ready access to lactone derivatives, one of which is a key
fragment of plakortone (Scheme 4A).27 Thus, in the presence of
mild electrophiles, such as m-CPBA or Me2SBr2, electrophilic
cyclization can afford lactone building blocks that possess alcohol
or bromine functional groups in good yields. Our mild conditions
can realize the one-pot transformation, Heck-type reaction
followed by bromo lactonization, to produce a 78% yield of 7b
(total yield in two steps) (Scheme 4B).
C
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Letter
(2) Oestreich, M. The Mizoroki−Heck Reaction; Wiley-VCH: West
Sussex, UK, 2009.
(3) Oestreich, M. Angew. Chem., Int. Ed. 2014, 53, 2282−2285.
(4) Beller, M.; Riermeier, T. H. Tetrahedron Lett. 1996, 37, 6535−
6538.
Scheme 3. Reaction with Other α-Alkylated Styrene
Derivatives
(5) Beller, M.; Riermeier, T. H. Eur. J. Inorg. Chem. 1998, 29−35.
(6) Kondolff, I.; Doucet, H.; Santelli, M. Tetrahedron Lett. 2003, 44,
8487−8491.
(7) Filippini, L.; Gusmeroli, M.; Riva, R. Tetrahedron Lett. 1993, 34,
1643−1646.
(8) Cho, C. S.; Uemura, S. J. Organomet. Chem. 1994, 465, 85−92.
(9) Matoba, K.; Motofusa, S.; Cho, C. S.; Ohe, K.; Uemura, S. J.
Organomet. Chem. 1999, 574, 3−10.
(10) Gurtler, C.; Buchward, S. L. Chem.Eur. J. 1999, 5, 3107−3112.
̈
(11) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295−4298.
́
(12) Albeniz, A. C.; Espinet, P.; Martín-Ruiz, B.; Milstein, D. J. Am.
Chem. Soc. 2001, 123, 11504−11505.
Scheme 4. Electrophilic Cyclizations
(13) The Heck reaction of α-methylstyrenes with alkyl fragments also
provides the mixture of proximal and distal isomers: Liwosz, T. W.;
Chemler, S. R. Org. Lett. 2013, 15, 3034−3037.
(14) The Heck reaction with allylbenzene to give distal products; see:
Hussain, N.; Frensch, G.; Zhang, J.; Walsh, P. J. Angew. Chem., Int. Ed.
2014, 53, 3693−3697.
(15) (a) Larsen, C. R.; Grotjahn, D. B. J. Am. Chem. Soc. 2012, 134,
10357−10360. (b) Sen, A.; Lai, T. W. Inorg. Chem. 1981, 20, 4036−
4038.
(16) A cyclic olefin enables the distal-selective reaction due to
conformational rigidity allowing syn-elimination: Shibasaki, M.; Boden,
C. D. J.; Kojima, A. Tetrahedron 1997, 53, 7371−7395.
(17) (a) Chalk, A. J.; Magennis, S. A. J. Org. Chem. 1976, 41, 273−278.
(b) Melpolder, J. B.; Heck, R. F. J. Org. Chem. 1976, 41, 265−272.
(c) Tamaru, Y.; Yamada, Y.; Yoshida, Z. Tetrahedron 1979, 35, 329−
340. (d) Jeffery, T. Tetrahedron Lett. 1990, 31, 6641−6644. (e) Jeffery,
T. Tetrahedron Lett. 1991, 32, 2121−2124. (f) Berthiol, F.; Doucet, H.;
Santelli, M. Synthesis 2005, 3589−3602. (g) Barbero, M.; Cadamuro, S.;
Dughera, S. Synthesis 2006, 3443−3452. (h) Werner, E. W.; Mei, T.-S.;
Burckle, A. J.; Sigman, M. S. Science 2012, 338, 1455−1458.
(18) Atienza, C. C. H.; Diao, T.; Weller, K. J.; Nye, S. A.; Lewis, K. M.;
Delis, J. G. P.; Boyer, J. L.; Roy, A. K.; Chirik, P. J. J. Am. Chem. Soc. 2014,
136, 12108−12118.
a
b
Conducted at rt in CH2Cl2 with m-CPBA. Conducted at rt in
CH2Cl2 with Me2SBr2.
In summary, the distal-selective α-hydride elimination in the
Heck-type olefination to give various exomethylene com-
pounds28−30 in good yields and with high regioselectivities is
described. The regioselectivities are dependent on the structure
of 6. These reactions were carried out using a copper(I)−TPMA
catalyst system at room temperature or at 100 °C. Further
investigations, including other types of addition and mechanistic
studies, are currently underway.
(19) McAtee, J. R.; Yap, G. P. A.; Watson, D. A. J. Am. Chem. Soc. 2014,
136, 10166−10172.
(20) McAtee, J. R.; Martin, S. E. S.; Ahneman, D. T.; Johnson, K. A.;
Watson, D. A. Angew. Chem., Int. Ed. 2012, 51, 3663−3667.
(21) For other examples on alkylations, see: (a) Gietter, A. A. S.;
Glinder, P. G.; Cinderella, A. P.; Watson, D. A. Org. Lett. 2014, 16,
3166−3169. (b) Glinder, P. G.; Gietter, A. A. S.; Cui, D.; Watson, D. A. J.
Am. Chem. Soc. 2012, 134, 9942−9945.
(22) Nishikata, T.; Noda, Y.; Fujimoto, R.; Sakashita, T. J. Am. Chem.
Soc. 2013, 135, 16372−16375.
(23) Eckenhoff, W. T.; Pintauer, T. Catal. Rev.: Sci. Eng. 2010, 52, 1−
59.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
(24) Tsarevsky, N. V.; Matyjaszewski, K. Chem. Rev. 2007, 107, 2270−
2299.
Corresponding Author
*E-mail: nisikata@yamaguchi-u.ac.jp.
Notes
́
(25) Bednarek, M.; Biedron, T.; Kubisa, P. Macromol. Rapid Commun.
1999, 20, 59−65.
(26) Liu, C.; Tang, S.; Liu, D.; Yuan, J.; Zheng, L.; Meng, L.; Lei, A.
Angew. Chem., Int. Ed. 2012, 51, 3638−3641.
The authors declare no competing financial interest.
(27) Hayes, P. Y.; Kitching, W. J. Am. Chem. Soc. 2002, 124, 9718−
ACKNOWLEDGMENTS
■
9719.
Financial support provided by a Grant-in-Aid for Young
Scientists (B) (24750043), and the program to disseminate
tenure tracking system, MEXT, Japan, is gratefully acknowl-
edged. We also thank Prof. Dr. Akio Kamimura (YU) for
measuring HRMS.
(28) For the synthesis of exo-methylene compounds using the Heck
reaction, see: Tasker, S. Z.; Gutierrez, A. C.; Jamison, T. F. Angew. Chem.,
Int. Ed. 2014, 53, 1858−1861.
(29) Eric, A.; Standley, A.; Jamison, T. F. J. Am. Chem. Soc. 2013, 135,
1585−1592.
(30) Ruan, J.; Xiao, J. Acc. Chem. Res. 2011, 44, 614−626.
REFERENCES
■
(1) Seechurn, C. C. C. J.; Kitching, M. O.; Colacot, T. J.; Snieckus, V.
Angew. Chem., Int. Ed. 2012, 51, 5062−5085.
D
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