Single electron transfer-induced cross-coupling reaction of alkenyl halides with aryl Grignard reagents

Article abstract of DOI:10.1039/c3cc41923a

Alkenyl halides were found to undergo coupling with aryl Grignard reagents to give the corresponding styrene derivatives in a stereo-retained manner. The cross-coupling reaction is considered to proceed through a single electron transfer mechanism.

Full text of DOI:10.1039/c3cc41923a

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Single electron transfer-induced cross-coupling reaction of alkenyl
halides with aryl Grignard reagents
Eiji Shirakawa,*a Ryo Watabe,a Takuya Murakami,a and Tamio Hayashib,c
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Alkenyl halides were found to undergo coupling with aryl
Grignard reagents to give the corresponding styrene
derivatives in stereo-retained manners. The cross-coupling
R3
R3
THF (6 equiv)
I
Ar
+
Ar MgBr
R2
2m–s
R2
toluene, 110 °C, 24 h
R1
R1
1a–g
3
entry: product, yield
10 reaction is considered to proceed through single electron
transfer mechanism.
Hex
Ph
Hex
Ph
Aryl halides (Ar–X) undergo substitution reactions with various
anionic nucleophiles (Nu–) to give functionalized arenes (Ar–Nu)
through SRN1 mechanism, which consists of single electron
15 transfer (SET) to Ar–X to give [Ar–X] • –, elimination of X– to
give Ar •, attack of Nu– toward Ar • to give [Ar–Nu] • –, and SET
to Ar–X to give substitution product Ar–Nu and regenerate [Ar–
X] • –.1 Alkenyl halides also can participate in SRN1 reaction, but
their utility is strictly limited due to stereochemical lability of
20 intermediary alkenyl radicals leading to products as
stereoisomeric mixtures and the competitive dehydrohalogenation
of the alkenyl halides under highly basic conditions common to
SRN1 reactions.2 On the other hand, we have recently developed a
single electron transfer-induced cross-coupling of aryl halides
25 with aryl Grignard reagents (Ar'MgBr), where no transition
1: (E)-3am, 90%a
5: (E)-3ao, 81%
2: (Z)-3am, 91%a
3: (E)-3an, 81%
4: (Z)-3an, 90%a
Hex
6: (E)-3ap, 87%a
7: 3aq, 90%a,b
OMe
Cl
Hex
Ph
8: 3ar, 87%
9: 3as, 86%
10: (E)-3bm, 94%
11: (E)-3bn, 86%
MeO
MeO
Hex
MeO
Ph
MeO
Hex
12: (E)-3cm, 92%a 13: (E)-3cn, 85%a 14: 3cs, 92%
Cl Cl
15: (E)-3dm, 89%a
metals are required.3,4 The reaction was disclosed to follow SRN
1
S
Hex
16: (E)-3em, 91%
Ph
17: (E)-3en, 90%
Hex
Hex
mechanism but skip Ar • intermediates, where [Ar–X] • – reacts
directly with Ar'MgBr to give [Ar–Ar'] • –.5 We expected that the
corresponding reaction of alkenyl halides takes place through a
30 similar pathway skipping σ-radical intermediates and thus
avoiding the E–Z isomerization inherent in SRN1 reaction. Here
we report the cross-coupling of alkenyl halides with aryl
Grignard reagents to give styrene derivatives retaining the
stereochemistry of the alkenyl moieties.6
18: (E)-3fm, 96% 19: (E)-3gm, 92%b
THF (6 equiv)
toluene
X
Ph
R2
+
R2
Ph–MgBr
1b
(1.5 equiv)
(E)-2'm: X = Br, R2 = Hex
(E)-2'n: X = Br, R2 = Ph
(E)-2"n: X = Cl, R2 = Ph
(E)-2"m: X = Cl, R2 = Hex
20: (E)-3bm, 90% (110 °C, 24 h)
21: (E)-3bn, 92% (110 °C, 24 h)
22: (E)-3bn, 62% (110 °C, 24 h)
23: (E)-3bm, 11% (140 °C, 48 h)c
(E)-2't: X = Br, R2 = 4-BrC6H4 24: (E)-3bt, 72% (110 °C, 24 h)d
35
The reaction conditions employed in the coupling of aryl
halides with aryl Grignard reagents were effectively applied to
the reaction of alkenyl halides essentially as they stand (Scheme
1).3 Thus, 2-naphthylmagnesium bromide (1a: 1.5 equiv),
prepared in THF and then evacuated in vacuo, was heated at
Reaction conditions: the reaction was carried out in toluene (2.0 mL) at 110 °C for
24 h under a nitrogen atmosphere using THF (1.2 mmol), an alkenyl iodide (2: 0.20
mmol), and an arylmagnesium bromide (1: 0.30 mmol), which was prepared in THF
and evacuated in vacuo to remove most of the solvent. Isolated yield based on the
alkenyl halide is given. Reaction time = 48 h. At 140 °C. Conversion of (E)-
2"m = 20%. d (E)-4-Phenylstilbene ((E)-3'bt) also was obtained in 13% yield.
a
b
c
40 110 °C for 48 h with (E)-1-octenyl iodide ((E)-2m: 1 equiv) and
THF (6 equiv) in toluene to give (E)-1-(2-naphthyl)-1-octene,
(E)-3am, in 90% yield (entry 1).7,8 The corresponding (Z)-alkene
was obtained from (Z)-2m (entry 2). Worthy of note is that the
stereochemistry is completely conserved in both cases. The
45 stereo-retained coupling proceeded also with E- and Z-isomers of
β-iodostyrene (2n) (entries 3 and 4). Introduction of an electron-
donating or -withdrawing substituent to iodostyrene were tolerant
Scheme 1
(entries 5 and 6). In addition to α-alkyl- and trialkylvinyl iodides,
a cyclic alkenyl iodide underwent the coupling (entries 7–9). As
50 for aryl Grignard reagents, nonsubstituted as well as methoxy-
and chloro-substituted phenylmagnesium bromides coupled with
aliphatic and aromatic alkenyl iodides 2m and 2n (entries 10–17).
Ortho-substitution and use of a heteroaryl Grignard reagent were
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compatible (entries 18 and 19). Alkenyl bromides also underwent 45 iodides (2m and 2n) toward PhMgBr (1b) also gave us further
coupling with 1b under similar conditions (entries 20 and 21). In
contrast, alkenyl chlorides are not good substrates. The reaction
of chlorostyrene 2"n resulted in a low yield due to byproduction
(23% yield) of 1,4-diphenyl-1,3-butadiene (entry 22),9 whereas 1-
support (Scheme 4). Aromatic alkenyl halide 2n, which has a
lower-lying LUMO than aliphatic one 2m, was prefVeirerwedArtiinclethOenline
competition reaction, even though 2n is less reactive than 2m in
the independent reactions. The result is compatible with the
5
octenyl chloride (2"m) was unreactive even at 140 °C (entry 23). 50 mechanism that includes SET in steps a and c. The reactivity
A
bromoalkene having
a
bromoarene moiety reacted
order of alkenyl halides in the independent reactions is rationally
understood, if we consider that the less stable anion radical of
type A is, the faster the carbon–carbon bond formation proceeds
(step b), and that this is the rate-determining step. Here, anion
preferentially at the bromoalkene moiety (entry 24).
Assuming that the reaction proceeds in a similar manner to
10 the aryl–aryl coupling,5 the mechanism in Scheme 2 can be
drawn, exemplified by the reaction of PhMgBr (1b) with (E)-1- 55 radical A derived from 2m having a higher-lying LUMO is less
stable and thus reacts faster with 1b.
octenyl iodide ((E)-2m). The reaction is initiated by SET from 1b
to 2m (step a) to give anion radical A,10 which undergoes a
carbon–carbon bond forming reaction with 1b (step b). SET from
15 the resulting anion radical (B) to 2m gives coupling product 3bm
and regenerates A (step c). The observed conservation of the
stereochemistry is compatible with this mechanism, where
alkenyl radicals are not involved as intermediates leading to the
coupling products. However, existence of alkenyl radicals in the
20 reaction mixture was confirmed by generation of alkenyltoluenes
derived from the alkenyl halides. For example, in the reaction of
1-cyclohexenyl iodide (2s) with 4-methoxyphenylmagnesium
bromide (1c) giving 3cs in 92% yield (Scheme 1, entry 14),
0.04% yield (o:m:p = 50:12:38) of 1-cyclohexenyltoluenes (4s)
25 were observed in the reaction mixture (eqn (1)). The ortho-
selectivity characteristic to radical addition implies the existence
of the cyclohexenyl radical, which is most likely to be produced
through SET from 1c to 2s to give an anion radical like A
followed by elimination of I–. Considering inherent similarity in
30 reactivities between aryl and alkenyl radicals as well as our
previous observation that aryl radicals are not reactive toward
aryl Grignard reagents,5 it is likely that most of the generated
anion radical of type A reacts with the Grignard reagent (1c) and
only a small portion undergoes decomposition into the alkenyl
35 radical leading to 4s.
THF (6 equiv)
I
+
Hex
toluene, 80 °C, 12 h
Hex
MgBr
(E)-2m
(E)-3am
yield of
1a
(1.5 equiv)
additive
• –
conv. of
(E)-2m
Li+
(amount)
(E)-3am
none
5 (0.2 equiv)
15%
43%
12%
38%
5
Scheme 3
THF
(6 equiv)
I
I
Ph
Ph
+
+
+
Ph–MgBr
Hex
(E)-2m
Ph
Hex
(E)-3bm
Ph
toluene
110 °C, 6 h
1b
(E)-2n
(E)-3bn
amount
conv. of the
yield
alkenyl iodides
(E)-3bm
1b
(E)-2m
(E)-2n
(E)-3bn
1.5 equiv
1.5 equiv
1.5 equiv
0.5 equiv
1 equiv
0 equiv
0.5 equiv
0 equiv
1 equiv
45%
95%
59%
16%
92%
—
26%
—
47%
Scheme 4
The type of halogen was shown to affect the reaction with
60 aryl Grignard reagents, as in the case with the aryl–aryl
coupling.5 Thus, in competition reactions of p- and o-
tolylmagnesium bromides (1h and 1f), both 1-octenyl iodide
(2m) and bromide (2'm) reacted preferentially with less hindered
p-tolyl derivative 1h, where a higher selectivity was observed
65 with bromide 2'm (Scheme 5). The result that the type of halogen
affected the reaction, in this particular case on the selectivity, is
consistent with the mechanism shown in Scheme 2, where a
halogen is still attached to the alkenyl moieties on reaction with
aryl Grignard reagents.
PhMgBr
MgBrI
b
1b
PhMgBr [PhMgBr] • +
1b
• –
• –
a
I
I
Ph
Hex
(E)-2m
Hex
Hex
A
B
c
Ph
I
Hex
Hex
(E)-3bm
(E)-2m
70
Scheme 2
THF (6 equiv)
X
+
+
Hex
toluene, 80 °C
MgBr
1h
(0.75 equiv)
MgBr
THF (6 equiv)
1f
(0.75 equiv)
(E)-2m or 2'm
(1 equiv)
+
+
(1)
Ar–MgBr
I
Ar
toluene, 110 °C, 24 h
(Scheme 1, entry 14)
1c
Ar = p-MeOC6H4
2s
3cs
92% yield
4s
0.04% yield
(o:m:p = 50:12:38)
+
Hex
Hex
(E)-3hm
(E)-3fm
Other experimental results that are consistent with operation
of SET in steps a and c of Scheme 2 are available. The yield of
40 the reaction of 1a with (E)-2m at 80 °C for 12 h was increased
from 12% to 38% by addition of lithium naphthalenide (5: 0.2
equiv) (Scheme 3).5 Anion radical 5 is considered to accelerate
the otherwise reluctant SET in the initiation (step a). A
competition reaction between aliphatic and aromatic alkenyl
X
time
conv. of 2
yield of 3 3hm:3fm
I (2m)
Br (2'm)
1 h
3 h
25%
13%
24%
13%
60:40
69:31
Scheme 5
2 | Journal Name, [year], [vol], 00–00
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Grignard reagents in toluene but use of THF as the sole solvent
induces iodine–magnesium exchange. It is likely that THF breaks
In conclusion, we have developed the cross-coupling reaction
of alkenyl halides with aryl Grignard reagents, where a single
electron, instead of a transition metal complex, acts as a catalyst.
Introduction of alkenyl halides into the SRN1-type reaction with
conservation of their stereochemistries will lead to further
development of stereo-retained SRN1-type reactions of alkenyl
halides.
excessive aggregation of aryl Grignard reagents in toluene into
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70
75
80
85
dimers or small oligomers to make them reactive but its monomer as
a from of ArMgBr(THF)2 undergoes the exchange reaction.
This type of reductive homocoupling products of alkenyl halides
were observed also in the reaction of iodo- and bromostyrenes but in
much less extents. The homocoupling products would be produced
by the coupling of alkenyl halides with the Grignard reagents having
the same alkenyl moiety. Halogen–magnesium exchange will provide
the alkenyl Grignard reagents but it is not the case in the present
reaction, because the homocoupling reaction is marked in alkenyl
chlorides, which are less susceptible to the exchange reaction than
bromides and iodides.
5
9
This work has been supported financially in part by Grant-in-
Aids for Scientific Research on Innovative Areas “Molecular
10 Activation Directed toward Straightforward Synthesis”
(23105521 to E.S.) from the Ministry of Education, Culture,
Sports, Science and Technology of Japan.
10 The lifetime of anion radicals of organic halides having a C(sp2)–X
bond is reported to be too short to react with some substrates due to
fast fragmentation into a sp2-carbon radical and X–. However, only
the data in the reaction in polar solvents such as N-methylpyrrolidone
and N,N-dimethylformamide are available. For recent examples, see:
C. Costentin, M. Robert, J.-M. Savéant, J. Am. Chem. Soc., 2004, 126,
16051–16057; N. Takeda, P. V. Poliakov, A. R. Cook, J. R. Miller, J.
Am. Chem. Soc., 2004, 126, 4301–4309.
Notes and references
a Department of Chemistry, Graduate School of Science, Kyoto University,
15 Kyoto, 606-8502, Japan. E-mail: shirakawa@kuchem.kyoto-u.ac.jp
b
Institute of Materials Research and Engineering, 3 Research Link,
117602, Singapore.
Department of Chemistry, National University of Singapore, 3 Science
Drive 3, 117543, Singapore.
c
20 † Electronic Supplementary Information (ESI) available: Experimental
procedure and spectral data. See DOI: 10.1039/b000000x
1
For reviews of SRN1 reactions, see: (a) J. F. Bunnett, Acc. Chem. Res.,
1978, 11, 413–420; (b) R. A. Rossi, A. B. Pierini, A. B. Peñéñory,
Chem. Rev., 2003, 103, 71–167.
25 2 The reaction of (E)-2-(4-methoxyphenyl)-1,2-diphenylethenyl
bromide with a pinacolone enolate under photostimulated conditions
is reported to give the α-alkenylated ketone in 52:48 E:Z ratio,
whereas the product of 55:45 ratio was obtained from the (Z)-alkenyl
bromide. The production of isomeric mixtures in almost the same
30
35
40
45
50
55
60
ratio is discussed from the standpoint of stereochemistry of
intermediary alkenyl radicals. C. Galli, P. Gentili, A. Guarnieri, Z.
Rappoport, J. Org. Chem., 1996, 61, 8878–8884; C. Galli, A.
Guarnieri, H. Koch, P. Mencarelli, Z. Rappoport, J. Org. Chem.,
1997, 62, 4072–4077. For other examples, see Section IX. A. of ref.
1b.
E. Shirakawa, Y. Hayashi, K. Itoh, R. Watabe, N. Uchiyama, W.
Konagaya, S. Masui, T. Hayashi, Angew. Chem., Int. Ed., 2012, 51,
218–221.
3
4
For reviews of transition metal-catalyzed cross-coupling reactions,
see: S. P. Stanforth, Tetrahedron, 1998, 54, 263–303; Cross-
Coupling Reactions: A Practical Guide ed. N. Miyaura, Top. Curr.
Chem., Vol. 219, Springer, Berlin, 2002; S. Huo, E.-I. Negishi, in
Handbook of Organopalladium Chemistry for Organic Synthesis, ed.
E.-I. Negishi, Wiley, New York, 2002, pp 335–408; J. Hassan, M.
Sévignon, C. Gozzi, E. Schulz, M. Lemaire, Chem. Rev., 2002, 102,
1359–1469; Metal-Catalyzed Cross-Coupling Reactions, Vol. 1–2,
2nd ed. ed. A. de Meijere, F. Diederich, Wiley-VCH, Weinheim,
2004; J.-P. Corbet, G. Mignani, Chem. Rev., 2006, 106, 2651–2710.
N. Uchiyama, E. Shirakawa, T. Hayashi, Chem. Commun., 2013, 49,
364–366.
The transtition metal-free cross-coupling reaction of allyl halides
with aryl- and alkenylboronic acids has been reported, where non-
radical mechanism is proposed. A. Scrivanti, V. Beghetto, M.
Bertoldini, U. Matteoli, Eur. J. Org. Chem., 2012, 264–268; M. Ueda,
K. Nishimura, R. Kashima, I. Ryu, Synlett, 2012, 23, 1085–1089.
We used the same magnesium turnings and toluene as those used in
the previous report (ref. 3). Their ICP analysis showed that the
magnesium turnings contains less than 5 ppm (within the detection
limit of the ICP-AES analysis) of Co, Ni, Cu, Ru, Rh, Pd, Ag, Ir, Pt,
and Au, and 13 ppm of Fe, whereas the toluene contains less than 1
ppb (within the detection limit of the ICP-MS analysis) of these
transition metals. We confirmed that iron has a negative effect on the
coupling of aryl halides with aryl Grignard reagents. For the details,
see ref. 3.
5
6
7
65 8 In the previous report (ref. 3), we showed that use of THF as an
additive is indispensable for the coupling of aryl iodides with aryl
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