Single electron transfer-induced Grignard cross-coupling involving ion radicals as exclusive intermediates

Article abstract of DOI:10.1039/c2cc37643a

The mechanism of the previously developed cross-coupling reaction of aryl Grignard reagents with aryl halides was explored in more detail. Single electron transfer from an aryl Grignard reagent to an aryl halide initiates a radical chain by giving an anion radical of the aryl halide. The following propagation cycle consists entirely of anion radical intermediates.

Full text of DOI:10.1039/c2cc37643a

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Single Electron Transfer-Induced Grignard Cross-Coupling Involving
Ion Radicals as Exclusive Intermediates
Nanase Uchiyama,a Eiji Shirakawa,*a and Tamio Hayashi*b
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
The mechanism of the previously developed cross-coupling
reaction of aryl Grignard reagents with aryl halides was
explored in more detail. Single electron transfer from an aryl
THF (6 equiv)
Ar1–MgBr
+
Ar2–X
Ar1–Ar2
(1)
toluene, 110 °C
1
2
3
10 Grignard reagent to an aryl halide initiates a radical chain by
giving an anion radical of the aryl halide. The following
propagation cycle consists entirely of anion radical
intermediates.
Propagation
X–
Path A
Initiation
Ar2•
b
Cross-coupling of arylmetals with aryl halides is one of the most
15 straightforward and reliable methods to obtain biaryls, where
transition metal catalysts have inevitably been used.1 On the other
hand, we have recently reported the first transition metal-free
coupling of arylmagnesium bromides (Ar1–MgBr) with aryl
halides (Ar2–X) (eqn (1)), utilizing activation of Ar2–X by single
20 electron transfer (SET).2 We proposed an SRN1 mechanism3
shown as Path A in Scheme 1. Thus, SET from Ar1–MgBr to
Ar2–X gives [Ar2–X]• – (step a), which is converted to Ar2 • upon
elimination of X– (step b). After nucleophilic attack of Ar1–MgBr
to Ar2 • (step c), SET from the resulting [Ar1–Ar2]• – to Ar2–X
25 gives coupling product Ar1–Ar2 and regenerates [Ar2–X]• – to
reenter the radical chain (step d).4 We disclosed that addition of
an anion radical of a biaryl as a single electron equivalent
drastically accelerates the reaction, and that aryl halides show
higher reactivities when they have lower reduction potentials.
30 These results support that the reaction pathway includes SET as
in steps a and d,5 but elucidation of the rest steps (b and c) are left
unexplored. Here we report what intermediates are involved in
the Grignard cross-coupling, where [Ar2–X]• – is transformed not
through Ar2 • but directly to [Ar1–Ar2]• – as Path B in Scheme 1.6
Ar1–MgBr
MgBrX
Ar1–MgBr
[Ar1–MgBr]• +
Ar1–MgBr
MgBrX
c
e
a
[Ar2–X]•–
Ar2–X
Path B
SET
(Single Electron Transfer)
Ar1–Ar2
SET
[Ar1–Ar2]•–
d
Ar2–X
Scheme 1
50 be readily fulfilled, considering that the resulting anion radicals,
[Ar1–Ar2]• –, are much more stable than [ArNH2]• –, which is
reported to be involved as intermediates in the SRN1 reaction.9
However, the reaction of an aryl radical precursor with an aryl
Grignard reagent gave a contradictory result. Thus, treatment of
55 phenylazo(triphenyl)methane (PAT), which is known to generate
Ph• upon heating,10 with p-methoxyphenylmagnesium bromide
(1b) in toluene gave 4-methoxybiphenyl (5) only in 2% yield,
along with a regioisomeric mixture (o/m/p = 63/23/14) of
methylbiphenyls (6) as a major product (25% yield) (eqn (3)).11
60 The result shows that aryl radicals react much preferentially with
a solvent amount of toluene over with aryl Grignard reagents,12
and thus that Ar2 • derived from Ar2–X is unlikely to be involved
in the cross-coupling reaction.
35
The cross-coupling we developed gives biaryls in high
yields.2 For example, the reaction of PhMgBr (1a: 1.5 equiv) with
2-iodonaphthalene (2m) in toluene in the presence of THF (6
equiv) at 110 °C for 24 h gave 97% yield of 2-phenylnaphthalene
(3am) (eqn (2)).7 The yield was reasonably high but GC analysis
I
Ph
THF (6 equiv)
PhMgBr
+
+
(2)
toluene
110 °C, 24 h
1a
(1.5 equiv)
2m
3am
97% yield
4
0.3% yield
(o/m/p = 63/22/15)
40 of the reaction mixture showed existence of a trace amount
(0.3%) of a regioisomeric mixture of 2-naphthyltoluenes (4:
o/m/p = 63/22/15), which is likely to be produced through
addition of the 2m-derived naphthyl radical to toluene. The
characteristic
high
ortho-selectivity
strongly
supports
THF
Ph
MeO
MeO
45 involvement of the radical addition to the benzene ring.8 The
N
Ph
Ph
(120 equiv)
+
+
(3)
Ph
Ph
N
toluene
110 °C, 1 h
generation of Ar2 from Ar2–X in the reaction mixture is
consistent with operation of SRN1 mechanism (Path A of Scheme
1), on condition that aryl radicals (Ar2 •) react preferentially with
aryl Grignard reagents (Ar1–MgBr). This requirement seemed to
MgBr
Ph
•
PAT
5
2% yield
6
25% yield
(o/m/p = 63/23/14)
1b
(40 equiv)
65
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[journal], [year], [vol], 00–00 | 1

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Page 12 of 13
No involvement of aryl radical intermediates was further
Br
Ph
THF (6 equiv)
confirmed by a radical clock reaction using 2-(3-butenyl)phenyl
iodide (2n), the corresponding aryl radical of which is known to
readily cyclize (kc = 5 x 108 s–1 at 50 °C).13 The reaction of 2n
with 1a gave no cyclization products but direct phenylation
product 3an (eqn (4)). Considering the observation that aryl
radicals do not react smoothly with aryl Grignard reagents, no
production of cyclization products supports no involvement of
aryl radicals.14
PhMgBr
+
toluene
80 °C, 12 h
3am
1a
(2 equiv)
2"m
View Online
5
Li+
• –
Ph
Ph
Ph
t-Bu
t-Bu
N
Ph
N
additive
(amount)
none
LDBB
(0.2 equiv)
PAT
(0.2 equiv)
R
conv. of 2"m
yield of 3am
2%
1%
98%
80%
2%
I
Ph
THF (6 equiv)
<1%
+
+
PhMgBr
(4)
toluene (0.1 M)
110 °C, 13 h
Scheme 3
1a
(1.5 equiv)
2n
3an
90% yield
(R = H, Ph)
<1% yield
10
than Ar1–Ar1. Taking it into account that aryl radicals react
21
preferentially with a solvent amount of toluene over with aryl
Taking into account the previous conclusion that SET to
Ar2–X to give [Ar2–X]• – as steps a and d in Scheme 1 is operative,
no participation of Ar2 • implies that [Ar2–X]• – reacts directly
with Ar1–MgBr as shown in step e in Scheme 1.15 In that event,
•
45 Grignard reagents (eqn (3)), this result shows that Ar1 is
generated only in a trace amount. Consequently, Ar1–Ar1 is likely
to be produced by the reaction of [Ar1–MgBr]• + with Ar1–MgBr
in a similar manner that the reaction of [Ar2–X]• – with Ar1–MgBr
gives Ar1–Ar2.
15 the kind of X possibly affects the reaction with aryl Grignard
reagents. This holds true, thus in competition reactions between
tolylmagnesium bromides 1c and 1d, both 2-naphthyl iodide
(2m) and chloride (2'm) reacted preferentially with less hindered
p-tolyl derivative 1c, where the selectivity was considerably
20 higher in the reaction of 2'm (74:26) than 2m (62:38) (Scheme
2).16–18
50
Aryl Grignard reagents are known to act as single electron
donors toward certain electrophiles.22 For example, SET from
PhMgBr (1a) to cinnamyl chloride (7) to give [PhMgBr]• + and
[7]• –, respectively, is reported to take place during substitution
reaction between 1a and 7.22b In this report, homocoupling
55 products (9 and 9') of 7 are regarded as end products of
intermediate [7]• –, but the course of cation radical [PhMgBr]• + is
not disclosed. Then we conducted the reaction in our hands,
paying attention to the course of [PhMgBr]• + (Scheme 4). The
reaction of 1a (0.60 mmol) with 7 (0.20 mmol) under the reported
60 conditions gave Ph–Ph (10) in an amount (0.048 mmol)
comparable to that (0.044 mmol) of 9/9' in addition to
substitution product 8. The yields of 10 and 9/9' were increased
by use of the solvent system (toluene with 6 equiv of THF) used
in the cross-coupling, giving no methylbiphenyls (6). No
65 production of methylbiphenyls in use of toluene as a solvent
shows that Ph• is not present in the reaction mixture.
Consequently, [PhMgBr]• +, with no fragmentation to Ph• and
[MgBr]+, reacts with PhMgBr to give Ph–Ph via [Ph–Ph]• –. It is
most likely that Ph–Ph is produced in the same manner also in
70 our cross-coupling and thus SET from aryl Grignard reagents to
aryl halides is operative.
X
THF (6 equiv)
+
+
toluene, 110 °C
MgBr
1c
(1 equiv)
MgBr
1d
(1 equiv)
2
(1 equiv)
+
3cm
3dm
X in 2
time
conv. of 2
yield of 3 3cm:3dm
I (2m)
0.5 h
24 h
23%
12%
22%
7%
62:38
74:26
Cl (2'm)
Scheme 2
In the previous report,2 we demonstrated the involvement of
anion radical intermediates by the fact that addition of a similar
25 anion radical accelerates the reaction (Scheme 3). Thus, the rate
of the reaction of PhMgBr (1a) with unreactive 2-
bromonaphthalene (2"m) was drastically increased by addition of
lithium di-tert-butylbiphenylide (LDBB: 0.2 equiv). In contrast,
addition of PAT (0.2 equiv) did not accelerate the reaction, where
30 the generated phenyl radical was converted mainly to
methylbiphenyls (6).19 The result is rationally understood that
acceleration is possible with addition of an anion radical
intermediate but not with addition of an aryl radical, which is not
an intermediate.
+
PhMgBr
Cl
Ph
30 °C, 3 h
Ph
1a
(0.60 mmol)
7
(0.20 mmol)
Ph
Ph
+
+
+
Ph–Ph
Ph
Ph
8
9 + 9'
10
Ph
in THF
0.112 mmol
0.078 mmol
0.044 mmol (64:36)
0.052 mmol (29:71)
0.048 mmol
0.076 mmol
in toluene
with THF (6 equiv)
35
In this cross-coupling, an oxidative homocoupling product
(Ar1–Ar1) of Ar1–MgBr is always produced in a small but certain
amount.20 In the previous report, we took this result as a proof
that SET from Ar1–MgBr to Ar2–X is operative in the initiation
step (a in Scheme 1), considering that Ar1–Ar1 is produced
Scheme 4
All these results are compiled into a mechanism shown in
Scheme 5, exemplified by the reaction of PhMgBr (1a) with 2-
75 iodonaphthalene (Np–I: 2m). The whole scheme consists of three
SETs toward Np–I giving [Np–I]• – and two C–C bond forming
reactions (BFR) of PhMgBr with an ion radical. Two single
electrons generated at the expense of two PhMgBr in the
40 through fragmentation of [Ar1–MgBr]• + followed by the reaction
•
of the resulting Ar1 with Ar1–MgBr. However, an isomeric
mixture of Ar1–C6H4Me is produced only in a much less amount
2 | Journal Name, [year], [vol], 00–00
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Page 13 of 13
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initiation step are handed over to Np–I to give [Np–I]• –, and then
promote the propagation cycle.
Denney, D. Z. Denney, Tetrahedron, 1991, 47, 6577–6600; J. F.
Bunnett, Tetrahedron, 1993, 49, 4477–4484; R. A. Rossi, S. M.
Palacios, Tetrahedron, 1993, 49, 4485–4494.
55
60
65
70
75
80
85
90
95
100
7
8
We used the same magnesium turnings and toluene as those used in
the previous report. For their ICP analysis, see ref. 2.
Np–I
[Ph–Ph] • –
Propagation
View Online
2 [MgBr] +
PhMgBr
Addition of aryl radicals to benzene rings is known to lead to biaryls
through homolytic aromatic substitution (HAS), where both electron-
donating and -withdrawing substituents on the benzene ring
accelerate the addition, especially to their ortho-positions. For recent
reviews on HAS, see: A. Studer, M. Bossart, in Radicals in Organic
Synthesis, Vol. 2, ed. P. Renaud, M. P. Sibi, Wiley-VCH, Weinheim,
2001, chap. 1.4, pp. 62–80; W. R. Bowman, J. M. D. Storey, Chem.
Soc. Rev., 2007, 36, 1803–1822.
PhMgBr
MgBrI
SET
BFR
BFR
SET
PhMgBr [PhMgBr] • +
Ph–Ph
[Np–I] • –
[Ph–Np] • –
Np–I
SET
Initiation
Np = 2-naphthyl
9
J. K. Kim, J. F. Bunnett, J. Am. Chem. Soc., 1970, 92, 7463–7464; J.
K. Kim, J. F. Bunnett, J. Am. Chem. Soc., 1970, 92, 7464–7466. See
also ref. 3.
Ph–Np
Np–I
Scheme 5
10 PAT is known to undergo decomposition into Ph•, N2, and Ph3C • in
toluene at 60 °C. (a) G. A. Russell, R. F. Bridger, Tetrahedron Lett.,
1963, 4, 737–740; (b) T. Suehiro, A. Suzuki, Y. Tsuchida, J.
Yamazaki, Bull. Chem. Soc. Jpn., 1977, 50, 3324–3328.
In conclusion, we have revealed that the transition metal-free
coupling of Ar1–MgBr with Ar2–X is initiated by SET from
Ar1–MgBr to Ar2–X and propagated by a scheme consisting of
the reaction of the resulting [Ar2–X]• – with Ar1–MgBr and SET
from [Ar1–Ar2]• – to Ar2–X. No involvement of Ar2 •, which would
induce side reactions such as hydrogen abstraction from solvents
5
11 Thermolysis of PAT in the absence of an aryl Grignard reagent (in
toluene with 120 equiv of THF, 110 °C, 1 h) gave 31% yield (o/m/p =
59:24:17) of 6. A similar result is reported in ref. 10b.
12 Toluene:1b is 47:1 in eqn (3), whereas toluene:1 is 63:1 under the
standard cross-coupling conditions, e.g., in eqn (2).
13 A. N. Abeywickrema, A. L. J. Beckwith, J. Chem. Soc., Chem.
Commun., 1986, 464–465; H. Yasuda, Y. Uenoyama, O. Nobuta, S.
Kobayashi, I. Ryu, Tetrahedron Lett., 2008, 49, 367–370. We
conducted reduction of 2n in toluene (0.2 M, 110 °C, 1 h) with
Bu3SnH (1.3 equiv) in the presence of AIBN (0.1 equiv) to give 70%
yield of cyclization products (1-methylindane and 1,2,3,4-
tetrahydronaphthalene, 93:7) with 7% yield of the simple reduction
product (4-phenyl-1-butene).
10 and addition to benzene rings, is likely to contribute to high
selectivity and thus high yields of the cross-coupling.
This work has been supported financially in part by Grant-in-
Aids for Scientific Research on Innovative Areas “Molecular
Activation Directed toward Straightforward Synthesis”
15 (23105521 to E.S.) from the Ministry of Education, Culture,
Sports, Science and Technology of Japan. N.U. thanks the JSPS
for a Research Fellowship for Young Scientists.
14 Generation of cyclization products in a similar radical clock reaction
was used as a support for exclusion of SRN2 mechanism. A. L. J.
Beckwith, S. M. Palacios, J. Phys. Org. Chem., 1991, 4, 404–412.
15 The lifetime of [Ar2–X]• – is reported to be too short to react with
some substrates due to fast fragmentation of [Ar2–X]• – into Ar2 • 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,
20 Kyoto, 606-8502, Japan. E-mail: shirakawa@kuchem.kyoto-u.ac.jp
b Institute of Materials Research and Engineering, 3, Research Link,
117602 (Singapore) E-mail: tamioh@imre.a-star.edu.sg
† Electronic Supplementary Information (ESI) available: Experimental
procedure and spectral data. See DOI: 10.1039/b000000x
–
–
16 Transformation of [Ar2–X]• into [Ar1–Ar2]• possibly takes more
25 1 For reviews, see: 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.
than one step. In any case, the reaction of Ar1–MgBr with [Ar2–X]• –
,
not with Ar2 •, should take place, though, at present, we do not have
any convincing experimental data and/or theoretical explanation as to
how this process proceeds. We consider it to be an important future
subject to elucidate the mechanism of this process.
2
E. Shirakawa, Y. Hayashi, K. Itoh, R. Watabe, N. Uchiyama, W.
Konagaya, S. Masui, T. Hayashi, Angew. Chem., Int. Ed., 2012, 51,
218–221.
30
17 Low reactivity of 2-naphthyl chloride (2'm) compared with the
iodide (2m) is ascribed mainly to its low electron acceptor character
in steps a and d in Scheme 1.
3
For reviews of SRN1 reactions, see: J. F. Bunnett, Acc. Chem. Res.,
1978, 11, 413–420; R. A. Rossi, A. B. Pierini, A. B. Peñéñory, Chem.
Rev., 2003, 103, 71–167.
105 18 The absence of the leaving group effect on the selectivity in similar
competition reactions is used as a proof for SRN1 mechanism. C. Galli,
J. F. Bunnett, J. Am. Chem. Soc., 1981, 103, 7140–7147.
35 4 Various anionic nucleophiles such as enolates and thiolates act as
reaction partners of Ar2 • in SRN1 reaction but arylmetals had never
been used. See ref. 3. The reaction of Grignard reagents (R–MgX)
including arylmagnesium bromides with tert-alkyl halides (R'–X) to
give R–R' is reported to involve SET from R–MgX to R'–X.
19 Methylbiphenyls (6) were produced in a yield (30% based on PAT)
similar to that (31%) in the reaction in the absence of 1a and 2"m.
110
115
120
See footnote 11.
40
45
50
However, the coupling is considered to proceed not through SRN1
20 For example, in the reaction of 1a (0.30 mmol) with 2m (0.20 mmol)
shown in eqn (2), the amount of biphenyl was determined to be 0.010
mmol by GC analysis.
mechanism but through radical coupling between the resulting R• and
R' •. M. Ohno, K. Shimizu, K. Ishizaki, T. Sasaki, S. Eguchi, J. Org.
Chem., 1988, 53, 729–733.
21 In the reaction of 1a with 2m shown in footnote 20, methylbiphenyls
were produced in 0.0003 mmol (0.1% GC yield based on 1a, o/m/p =
63/23/14), where ratio of Ar1–C6H4Me:Ar1–Ar1 is 1:33.
22 For SET from aryl Grignard reagents to benzophenones, see: (a) K.
Maruyama, Bull. Chem. Soc. Jpn., 1964, 37, 897–898. To tert-alkyl
halides: ref. 4. To cinnamyl chlorides: (b) K. Muraoka, M. Nojima, S.
Kusabayashi, S. Nagase, J. Chem. Soc., Perkin Trans. 2, 1986, 761–
767.
5
6
The possibilities that the cross-coupling reaction proceeds through
transition metal catalysis, aryne intermediates, or nucleophilic
aromatic substitution are excluded from the considerations described
in the previous report (ref. 2).
This kind of mechanism, which includes the reaction of anion
radicals of aryl halides with anionic nucleophiles, has sometimes
been called as SRN2 mechanism in comparison with SRN1 mechanism,
which includes aryl radical intermediates. There have been debates as
to which one is operative. For an example of the debates, see: D. B.
This journal is © The Royal Society of Chemistry [year]
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