Sodium-Ketyl Radical Anions by Reverse Pinacol Reaction and Their Coupling with Iodoarenes

Article abstract of DOI:10.1021/acs.orglett.6b02184

Transition-metal-free C-C bond formation between aryl iodides and pinacols is presented. Pinacols are readily transformed by deprotonation with NaH to their Na-pinacolates. C-C-bond homolysis at room temperature generates in situ the corresponding Na-ketyl radical anions which react with various aryl iodides in a homolytic aromatic substitution reaction to form tertiary Na-alcoholates. Protonation eventually provides tertiary alcohols in an unprecedented route.

Full text of DOI:10.1021/acs.orglett.6b02184

Letter
pubs.acs.org/OrgLett
Sodium-Ketyl Radical Anions by Reverse Pinacol Reaction and Their
Coupling with Iodoarenes
Xinjun Tang and Armido Studer*
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat, Corrensstraße 40, 48149 Munster, Germany
̈
̈
̈
S
* Supporting Information
ABSTRACT: Transition-metal-free C−C bond formation
between aryl iodides and pinacols is presented. Pinacols are
readily transformed by deprotonation with NaH to their Na-
pinacolates. C−C-bond homolysis at room temperature
generates in situ the corresponding Na-ketyl radical anions
which react with various aryl iodides in a homolytic aromatic
substitution reaction to form tertiary Na-alcoholates. Protonation eventually provides tertiary alcohols in an unprecedented route.
For initial studies, benzophenone pinacol 1a and ortho-
he pinacol coupling and follow up reactions such as the
Tpinacol rearrangement have been amply used in organic iodoanisole (2a) were used as model compounds and reactions
synthesis.1 Intermolecular pinacol homocoupling mostly occurs
were conducted in THF under different conditions. Pleasingly,
transformation of equimolar amounts of 1a and 2a (slowly
added over 1 h) using sodium hydride as a base (4 equiv) at
room temperature for 20 h provided 2-methoxyphenyl-
diphenyl-methanol (3aa) in 48% isolated yield (Table 1,
entry 1). As byproducts, diphenylmethanol (4a) and
benzophenone were obtained in 28% and 3% yield,
respectively. An improved yield (68%) was obtained upon
adding the aryl iodide 2a in one portion (Table 1, entry 2).
Conducting the coupling at 60 °C led to a slightly lower yield
(Table 1, entry 3), and changing the amount of base revealed
that the best result is achieved with 5.6 equiv of NaH (Table 1,
entries 4−6). We found that a 1.4-fold excess of 1a with respect
to 2a provides the highest yield and that coupling works best at
a concentration of 0.33 M (Table 1, entries 6−10).
via reduction of a ketone precursor with a one-electron
reducing reagent to give the corresponding ketyl radical anion
which undergoes homocoupling to the pinacolate. Protonation
eventually provides the pinacol coupling product (Scheme 1).1
Scheme 1. Pinacol and Reverse Pinacol Coupling in
Synthesis
The base was varied next. With Na-hexamethyldisilazide
(NaHMDS) in place of NaH, the target product 3aa was not
formed and the starting material 2a was recovered in 36% yield
along with 3% of 4a (Table 1, entry 11). Li-hexamethyl-
disilazide (LiHDMS) provided a similar result (Table 1, entry
13). With K-hexamethyldisilazide (KHMDS) a significant
amount of 4a was obtained; however, 3aa was not identified
in the crude reaction mixture (Table 1, entry 12). NaHBEt3
provided 4a in 74% yield and target 3aa was not identified
(Table 1, entry 14). Using elemental sodium, 3aa was formed
in 4% yield along with 46% of 4a. Based on these screening
studies we can conclude that NaH is the best base for this
reaction.
There are reports in the literature showing that the
dimerization of a ketyl radical anion to the corresponding
pinacolate can be reversible under certain conditions.2
However, to our knowledge this reversibility has not been
applied as a tool in synthetic organic chemistry to date. We
assumed that readily accessible pinacol coupling products can
be used as ketyl radical anion precursors upon simple
deprotonation and subsequent C−C-bond homolysis in a
reverse pinacol coupling step. The thus generated radical anions
might engage as reagents in single-electron reductions3 or in
other radical transformations.
With the optimized reaction conditions in hand, we then
turned to investigate the scope with respect to the aryl iodide
component keeping pinacol 1a as the reaction partner (Scheme
2). As expected, the 2-ethoxy-substituted iodobenzene provided
3ab in a good yield (70%). 2-Iodothioanisole 2c was also a
Herein we show that ketyl radical anions generated by
reverse pinacol coupling react in the absence of any transition
metal with iodoarenes to afford the corresponding alcoholates
which upon protonation eventually provide tertiary alcohols.
Received: July 25, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02184
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Reaction Optimization
Scheme 2. Reaction Scope: Variation of the Aryl Iodide
a
a
entry
base (equiv)
1a (equiv)
3aa (%)
4a (%)
b
c
c
1
NaH (4.0)
1.0
1.0
1.0
1.0
1.0
1.4
1.6
1.4
1.4
1.4
1.0
1.0
1.0
1.0
1.0
48
28
d
2
NaH (4.0)
68
57
56
65
74
72
69
76
68
−
8
de
,
3
NaH (4.0)
7
d
d
d
d
4
NaH (3.0)
10
13
20
11
15
8
5
NaH (5.0)
6
NaH (5.6)
7
NaH (6.4)
df
,
8
NaH (5.6)
dg
,
9
NaH (5.6)
NaH (5.6)
dh
,
10
11
12
13
14
15
7
b
b
b
b
b
NaHMDS (4.0)
KHMDS (4.0)
LiHMDS (4.0)
NaHBEt3 (4.0)
Na (4.0)
2
−
−
−
4
20
3
37
23
a
Reaction conducted with 0.5 mmol of 2a in 2 mL of THF, and yield
1
determined by H NMR spectroscopy using CH2Br2 as an internal
standard. The pinacol 1a was first reacted with the base for 2 h, and
b
c
then 2a was added using a syringe pump over 1 h. Isolated yield.
d
The pinacol 1a was first reacted with NaH for 5 min, and then 2a was
e
f
added in one portion. The reaction was conducted at 60 °C. 3 mL of
THF were used. 1.5 mL of THF was used. 1 mL of THF was used.
g
h
a
suitable coupling partner for this reaction to give 3ac in
moderate yield. Unfortunately, upon using the unsubstituted
parent iodobenzene, a complex reaction mixture resulted and
the target product could not be isolated. Also 4-methoxy
iodobenzene was not a substrate in this reaction indicating that
a heterosubstituent at the ortho-position of the leaving group
plays an activating role in this transformation. We further found
that the substitution reaction does not work on aryl bromides
as shown by the failed experiment with 2-methoxy
bromobenzene. Interestingly, an ortho-substituent was not
required for 1-iodonaphthalene 2d and the tertiary alcohol 3ad
was isolated in 50% yield. As compared to benzene and its
congeners, the π-system in naphthalene is more reactive.
Heteroaryl iodides can also be applied as substrates in this
reaction. Hence, transformation of 1a with 2-iodofuran (2e), 2-
iodopyridine (2f), and 1-iodoisoquinoline (2g) afforded the
alcohols 3ae, 3af, and 3ag in 49%, 44%, and 40% yield,
respectively. However, 2-iodopyridine and 3-iodopyridine were
not suitable for this reaction, again indicating the importance of
a coordinating functionality in the ortho-position to the I-
substituent. To our delight, 2-iodothiophene 2h worked very
well and the alcohol 3ah was isolated in 83% yield. Good
results were also achieved with 2-iodobenzothiophene 2i and 4-
iododibenzothiophene 2j as iodoarene components in the
reaction with benzophenone pinacol 1a to provide 3ai and 3aj
in good yields.
The reaction was conducted using 1a (1.4 equiv), 2 (0.5 mmol),
NaH (5.6 equiv) in 1.5 mL of THF at room temperature for 20 h.
Isolated yields are given.
Scheme 3. Reaction Scope: Variation of the Pinacol
We then explored the scope of the novel transformation
varying the pinacol component 1 using iododarene 2a as a
reaction partner. We were pleased to see that the symmetrical
pinacols 1b and 1c worked in this sequence and products 3ba
and 3ca were isolated in 58% and 65% yield, respectively
(Scheme 3). The unsymmetrical pinacols 1d, 1e, and 1f worked
equally well (see 3da, 3ea, and 3fa). 9H,9′H-[9,9′-Bixanthene]-
9,9′-diol (1g) could also be applied in this transformation
yielding 3ga in 39% yield. However, with the pinacol derived
from acetophenone, coupling did not occur and the target
product was not identified in the crude reaction mixture.
In order to investigate the reaction mechanism, we ran
additional mechanistic experiments. To check whether free aryl
radicals are involved in these processes, aryl iodides 2k−2m
B
DOI: 10.1021/acs.orglett.6b02184
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
were tested. To our surprise, products of type 5 derived from a
5-exo-aryl radical cyclization were not identified and the tertiary
alcohols 3ak−3am were obtained in 55−62% yield (Scheme 4).
alcohol 4 as a major byproduct can be explained by this
reduction.
In summary, we have presented transition-metal-free C−C
bond formation of Na-ketyl radical anions with various aryl and
heteroaryl iodides to provide tertiary Na-alcoholates. The
intermediate ketyl radical anions are readily generated by
thermal reverse pinacol coupling of the corresponding Na-
pinacolates. NaH turned out to be best suited for
deprotonation of the pinacols. Interestingly, free aryl radials
are not involved in these transformations and C−C bond
formation is suggested to occur via homolytic aromatic ipso-
substitution with the iodine atom acting as a radical leaving
group. These reactions are experimentally easy to conduct and
occur under mild conditions at room temperature. NaH used as
a reagent is commercially available and not costly.
Scheme 4. Mechanistic Studies
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02184.
These results show that free aryl radicals are not generated in
these transformations. Moreover, in the reaction of 1a with aryl
iodide 2a, the presence of TEMPO (1 equiv) did not suppress
the coupling and 3aa was formed albeit in a slightly lower yield.
In this experiment the byproducts 4a and benzophenone (6a)
were obtained in 20% and 4% yield, respectively. Also this
result indicates that a free aryl radical is likely not formed.
Based on these experiments we propose the following
mechanism for the overall process as exemplified for the
reaction of pinacols 1 with iodoarene 2a (Scheme 5).
Experimental procedures and full spectroscopic data for
all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: studer@uni-muenster.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the WWU Munster and the Deutsche
Forschungsgemeinschaft (DFG) are greatly acknowledged.
■
Scheme 5. Suggested Mechanism
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REFERENCES
■
(1) For reviews, see: (a) Gansauer, A.; Bluhm, H. Chem. Rev. 2000,
100, 2771. (b) Overman, L.; Pennington, L. J. Org. Chem. 2003, 68,
7143. (c) Kagan, H. Tetrahedron 2003, 59, 10351. (d) Chatterjee, A.;
̈
Joshi, N. Tetrahedron 2006, 62, 12137. (e) Furstner, A.; Bogdanovic,
́
̈
B. Angew. Chem., Int. Ed. Engl. 1996, 35, 2442. (f) Snape, T. Chem. Soc.
Rev. 2007, 36, 1823. (g) Hirao, T. Top. Curr. Chem. 2007, 279, 53.
(h) Szostak, M.; Fazakerley, N. J.; Parmar, D.; Procter, D. J. Chem. Rev.
2014, 114, 5959.
(2) (a) Russell, G. A.; Young, M. C. J. Am. Chem. Soc. 1966, 88, 2007.
(b) Hou, Z.; Jia, X.; Fujita, A.; Tezuka, H.; Yamazaki, H.; Wakatsuki, Y.
Chem. - Eur. J. 2000, 6, 2994. (c) Zalibera, M.; Nesvadba, P.;
Gescheidt, G. Org. Lett. 2013, 15, 4627.
(3) Dewanji, A.; Muck-Lichtenfeld, C.; Studer, A. Angew. Chem., Int.
Ed. 2016, 55, 6749.
(4) Traynham, J. G. Chem. Rev. 1979, 79, 323.
(5) Too, P.; Chan, G.; Tnay, Y.; Hirao, H.; Chiba, S. Angew. Chem.,
Int. Ed. 2016, 55, 3719.
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Deprotonation of 1 with NaH gives the corresponding Na-
pinacolate which is in equilibrium with its Na-ketyl radical
anion A.2c The blue color of the ketyl radical anion A in THF is
indeed observed after deprotonation of the pinacols. We
assume that this radical anion A then adds to the arene of 2a,
likely assisted by complexation of the sodium cation with the
ether O atom of 2a, to generate the cyclohexadienyl radical B.
Fragmentation of the iodine atom affords the product Na-
alcoholate C. Note that homolytic ipso-substitutions with
halogen atoms as leaving groups are known.4 The iodine atom
then gets reduced by the ketyl radical anion A to give ketone 6
along with NaI. As recently shown by Chiba et al., the NaH/
NaI-couple can act as a reducing reagent,5 and in a separate
experiment we could show that benzophenone gets reduced by
NaH/NaI under the reaction conditions. Hence, formation of
C
DOI: 10.1021/acs.orglett.6b02184
Org. Lett. XXXX, XXX, XXX−XXX