Transition-metal-free hydrogenation of aryl halides: From alcohol to aldehyde

Article abstract of DOI:10.1021/acs.orglett.7b02399

A transition-metal-and catalyst-free hydrogenation of aryl halides, promoted by bases with either aldehydes or alcohols, is described. One equivalent of benzaldehyde affords an equal yield as that of 0.5 equiv of benzyl alcohol. The kinetic study reveals that the initial rate of PhCHO is much faster than that of BnOH, in the ratio of nearly 4:1. The radical trapping experiments indicate the radical nature of this reaction. Based on the kinetic study, trapping and KIE experiments, and control experiments, a tentative mechanism is proposed. As a consequence, a wide range of (hetero)aryl iodides and bromides were efficiently reduced to their corresponding (hetero)arenes. Thus, for the first time, aldehydes are directly used as hydrogen source instead of other well-established alcohol-hydrogen sources.

Full text of DOI:10.1021/acs.orglett.7b02399

Letter
pubs.acs.org/OrgLett
Transition-Metal-Free Hydrogenation of Aryl Halides: From Alcohol
to Aldehyde
Hong-Xing Zheng,†,§ Xiang-Huan Shan,†,§ Jian-Ping Qu,*,‡ and Yan-Biao Kang*,†
†Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
‡Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for
Advanced Materials, Nanjing Tech University, Nanjing 211816, China
S
* Supporting Information
ABSTRACT: A transition-metal- and catalyst-free hydrogena-
tion of aryl halides, promoted by bases with either aldehydes or
alcohols, is described. One equivalent of benzaldehyde affords an
equal yield as that of 0.5 equiv of benzyl alcohol. The kinetic
study reveals that the initial rate of PhCHO is much faster than
that of BnOH, in the ratio of nearly 4:1. The radical trapping
experiments indicate the radical nature of this reaction. Based on
the kinetic study, trapping and KIE experiments, and control
experiments, a tentative mechanism is proposed. As a
consequence, a wide range of (hetero)aryl iodides and bromides
were efficiently reduced to their corresponding (hetero)arenes. Thus, for the first time, aldehydes are directly used as hydrogen
source instead of other well-established alcohol−hydrogen sources.
a
Table 1. Reaction Conditions
ydrodehalogenation is an important organic transforma-
1
Htion in synthesis. Organic halides such as chlorinated
dibenzo-p-dioxins (dioxins) and polyhalogenated biphenyls
(PCBs and PBBs) are hazardous to the environment are also
health risks.2 The development of new dehalogenation
approaches remains in demand.1 Transition metals have been
widely used as catalysts for the cleavage of C−X bonds of aryl
halides.3 In organic synthesis, radical processes have been widely
applied as an efficient dehalogenation method using stoichio-
metric reagents such as Bu3SnH and SmI2,4,5 despite the
potential health risks. Alcohols have also been used in the
dehalogenation of aryl halide, despite the fact that large excess
amounts of alcohols and strong bases are necessary.6 Never-
theless, among the numerous dehalogenation approaches,
various hydrogen sources have been employed, but aldehydes
have been barely reported as a reductant for such reactions. In
this work, we report an efficient metal-free radical dehalogena-
tion using aldehydes as a powerful hydrogen source.
b
entry
[H]
M
x
solvent
2a (%)
c
1
2
3
4
5
6
7
8
9
BnOH
BnOH
none
K
K
K
K
K
K
K
Na
K
0.5
0.25
0
DMF
DMF
DMF
dioxane
DMF
DMF
DMF
DMF
other
90
61
15
11
none
0
c
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
0.5
0.75
1
60 (55 )
74
86
56
1
d
1
6−21
a
t
Conditions: 1a (0.5 mmol), BuOM (1.0 mmol), [H], solvent (1
b
c
d
mL), 90 °C, argon. By 1H NMR. For 6 h. DMA, dioxane, toluene,
DMSO, and octane.
The reaction conditions were investigated. In the direct
alkylation of amines and the direct Julia olefination, alcohols have
been used as starting materials via a self-hydrogen transferring
process.7 In the dehalogenation reaction herein, both BnOH and
PhCHO were found to be efficient reductants. The yield largely
depended on the amount of hydrogen sources (Table 1, entries
1−7). Without a hydrogen source, the reactions in either DMF
or dioxane gave low yields (entries 3 and 4).
The reaction in the presence of BnOH afforded 2% of dimer
(entry 1), whereas the reaction in the absence of H source gives
rise to the formation of 12% 5-(tert-butoxy)-1-methylindole
(entry 3). The formation of dimers suggests the formation of aryl
radicals, and the formation of ArOtBu suggests either a radical via
SET or benzyne intermediates, which has been discussed
previously.8 No dimer was observed in other cases. The
conditions in entries 1 and 7 were established as the standard
conditions for further investigation of the dehalogenation with
BnOH and aldehyde, respectively.
Under the standard conditions using BnOH as reductant, the
scope, including both heteroaryl iodides and aryl bromides, was
investigated with a variety of aryl halides, and the corresponding
dehalogenation products were obtained in 77−96% of yields
Received: August 3, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02399
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Organic Letters
Letter
a
(Scheme 1, 1a−f). The dehalogenation of 1d and 1f could be
performed at 30 °C, giving corresponding products 2d and 2f in
Scheme 2. Reaction Scope with PhCHO
a
Scheme 1. Reaction Scope with BnOH
a
Conditions: 1 (0.5 mmol), tBuOK (1.0 mmol), BnOH (0.25 mmol),
b
c
a
Conditions: 1 (0.5 mmol), tBuOK (1.0 mmol), PhCHO (0.5 mmol),
DMF (0.5 M), 90 °C, argon, isolated yields. At 30 °C. At 130 °C.
d
1
b
c
Determined by H NMR.
DMF (1 mL), 90 °C, argon, isolated yields. At 30 °C. 1.5 mmol of
d
e
f
tBuOK. At 130 °C. Determined by H NMR. Determined by GC.
1
77 and 84% yield, respectively. Besides heteroaryl halides, the
aryl halides also exhibited high reactivity with 75−99% isolated
yields (1g−1q). Moreover, the electron-donating substituents
and electron-withdrawing substituents on the aryl groups have
shown limited effect on the reaction activity (1i vs 1l). In all
cases, no dimers were isolated except 1a (2%), 1j (4%), and 1k
(4%). In the cases of 1d and 1h, 5% N,N-dimethylcarboxyamide
and 10% 4-dimethylaminostilbene were isolated without dimer,
respectively.
Next, the scope of this dehalogenation with PhCHO was
investigated (Scheme 2). For either heteroaryl halides or aryl
halides, the reduction with PhCHO gave results comparable with
those with BnOH. For example, the dehalogenation of 4-
iodophenol was performed without the protection of the
hydroxyl group, affording 2s in 70% yield. Despite the fact that
comparable results were given in the dehalogenation of aryl
halides with BnOH and PhCHO, what should be noted is that
most reactions in the presence of PhCHO finished in half an hour
(monitored by TLC), which are much faster than those with
BnOH. The kinetic study latterly confirms this phenomenon
(see Scheme 6).
Such dehalogenation could direct the nitration ortho-
specifically into an aromatic ring (eq 1), whereas the traditional
nitration method afforded a mixture of para/ortho in the ratio of
2:1 (eq 2).
To explore the mechanism of this dehalogenation reaction,
radical trapping experiments were carried out (Scheme 3). The
radical clock experiment gave the cyclization product 6 in 23%
yield with 5% of dehalogenation product 2x (eq 3). With typical
radical scavengers, either TEMPO or N-tert-butylphenyl nitrone
could inhibit the dehalogenation reaction (eq 4). In a previous
report, Studer et al. proposed a radical model for such a
Scheme 3. Radical Trapping Experiments
reaction.6b In our work, both the radical clock experiment and the
radical trapping experiment suggest a possible radical pathway for
this dehalogenation reaction. No dimer was observed except 1k,
where 6% of dimer was isolated. A special case is 1u, where 20%
of 3-tBuO-ether, a cross-coupling product of tBuO and 1u,8 was
afforded.
Determining the hydrogen source by isotope labeling
experiments is not efficient because there is a fast hydrogen
exchange between the reagents and the solvent (Scheme 4).
When the reaction was treated with deuterated benzaldehyde,
despite the deuterium incorporation occurring only to 15%, the
reaction in PhCDO was obviously slower than that in PhCHO.
To further amplify the role of PhCHO versus DMF as the
hydrogen source, 1:1 PhCHO and DMF was employed using
B
DOI: 10.1021/acs.orglett.7b02399
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Deuteration Experiments
Scheme 5. Mechanism
dioxane as solvent (Scheme 4, bottom). The reaction in 1 equiv
of PhCHO with 1 equiv of DMF-d7 gave only less than 5% of D-
incorporation, whereas the reaction in 1 equiv of PhCDO with 1
equiv of DMF-h7 gave 25% of D-incorporation. So far, even if
PhCHO is not the sole hydrogen source, it is safe to say that
PhCHO is the main hydrogen source.
The solvent DMF might also act as H-donor considering the
fact that 0.25 equiv of PhCH2OH could give 61% yield of product
(see Table 1), whereas 0.5 equiv of PhCHO could give 60% yield
of product, in which the maximum yield should be 50%.
However, it is obvious that DMF was not the main H source as it
could afford only 15% product in the absence of the extra
reductant such as benzaldehyde or benzyl alcohol. Therefore,
PhCHO or BnOH should act as the mandatory H source because
the yield of dehalogenation is dependent on the amount of
reductant (Table 1, entries 1−7). This could be further
confirmed by the control experiments. The yield of dehaloge-
nation product 2n with PhCHO and DMF as additives in the
presence of dioxane is 97%, whereas the removal of PhCHO,
DMF, or both of them leads to the significant decrease of yield,
especially in case of the removal PhCHO (eq 5). The electron
effect on aromatics also supports that benzaldehyde is the major
H source (eq 6).
Isolation of amide and ester byproducts (eq 7) also supports this
hypothesis.
To determine which mechanism should be more reasonable, a
kinetic study was performed. Although Cannizzaro reaction
could never be avoided under such strong basic conditions, it
does not mean this reaction must pass through a Cannizzaro
pathway. The kinetic study demonstrated in Scheme 6 shows
Based on the above experimental evidence as well as the
previous report on the generation of aryl radical anions in the
presence of BnOH or PhCHO and tBuOK in DMF by Taillefer
et al.,9,10 possible radical pathways for this dehalogenation
focusing different reductants were proposed (Scheme 5). In the
dehalogenation using BnOH as the hydrogen source, a halide
fragmentation of the aryl radical anion A forms after a SET
reduction of Ar−X leads to an aryl radical B. Alcoholate C then
acts as a H source, providing the targeted reduction product Ar−
H together with the radical anion D,6a as it was reported that
alcoholates are excellent H-donors for the reduction of aryl
halides,6a,11 generating aldehydes or ketones as the byproducts.
D further reacts with Ar−X to regenerate A with the formation of
PhCHO. In another case, when PhCHO was used as a hydrogen
source, the in situ generated SET reductant F or G is generated
by the reaction of benzoyl radical E and Me2N− from DMF. The
radical anion F or H then reacts with Ar−X via a SET process to
afford the radical anion A, followed by the formation of B.
Benzoyl radical F is regenerated during the hydrogen transferring
reduction of B. Such benzoyl radical was previously proposed by
Ryu et al. in a transition-metal-free aminocarbonylation of aryl
iodides.12a Similar mechanistic suggestions for acyl radical
trapping with NMe2 was also reported by Studer et al.12b−d
Scheme 6. Kinetic Study
that the initial rate of PhCHO is 35.59 mM/min, which is much
faster than that of PhCH2OH (9.26 mM/min). There is no
sigmoidal behavior of the conversion curve or no point of
inflection for the reaction in the presence of PhCHO, providing
an indication that PhCHO is being involved in the initiation step.
The control experiments further confirms this suggestion. In
the absence of aryl halide substrates, treatment of PhCHO with
tBuOK in DMF gives 22% of PhC(O)NMe2 together with 13%
of PhCH2OH, whereas in the presence of substrate 1a, there is no
PhCH2OH observed (eqs 7 and 8). Therefore, the kinetic study
obviously proves the direct reaction of PhCHO in the
C
DOI: 10.1021/acs.orglett.7b02399
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
dehalogenation other than an indirect pathway via Cannizzaro
reaction.
In the kinetic isotope experiments, a KIE of 2.9 for PhCHO
and 5.7 for PhCH2OH was observed (eqs 9 and 10). The
REFERENCES
■
(1) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2002, 102, 4009.
(2) (a) Sadowsky, D.; McNeill, K.; Cramer, C. J. Environ. Sci. Technol.
2014, 48, 10904. (b) Harrad, S.; Robson, M.; Hazrati, S.; Baxter-Plant,
V. S.; Deplanche, K.; Redwood, M. D.; Macaskie, L. E. J. Environ. Monit.
2007, 9, 314. (c) Mitoma, Y.; Nagashima, S.; Simion, C.; Simion, A. M.;
Yamada, T.; Mimura, K.; Ishimoto, K.; Tashiro, M. Environ. Sci. Technol.
2001, 35, 4145. (d) Hites, R. A. Acc. Chem. Res. 1990, 23, 194.
(3) (a) Zask, A.; Helquist, P. J. Org. Chem. 1978, 43, 1619. (b) Marques,
C. A.; Selva, M.; Tundo, P. J. Org. Chem. 1994, 59, 3830. (c) Maleczka, R.
E., Jr.; Rahaim, R. J., Jr.; Teixeira, R. R. Tetrahedron Lett. 2002, 43, 7087.
(d) Zawisza, A. M.; Muzart, J. Tetrahedron Lett. 2007, 48, 6738. (e) Pyo,
A.; Kim, S.; Kumar, M. R.; Byeun, A.; Eom, M. S.; Han, M. S.; Lee, S.
Tetrahedron Lett. 2013, 54, 5207. (f) Bhattacharjya, A.; Klumphu, P.;
Lipshutz, B. Org. Lett. 2015, 17, 1122. (g) Narisada, M.; Horibe, I.;
Watanabe, F.; Takeda, K. J. Org. Chem. 1989, 54, 5308. (h) Desmarets,
C.; Kuhl, S.; Schneider, R.; Fort, Y. Organometallics 2002, 21, 1554.
(i) Fujita, K.; Owaki, M.; Yamaguchi, R. Chem. Commun. 2002, 2964.
(j) Lewis, J. C.; Wiedemann, S. H.; Bergman, R. G.; Ellman, J. A. Org.
Lett. 2004, 6, 35. (k) Narayanam, J. M. R.; Tucker, J. W.; Stephenson, C.
R. J. J. Am. Chem. Soc. 2009, 131, 8756. (l) Nguyen, J. D.; D’Amato, E.
M.; Narayanam, J. M. R.; Stephenson, C. R. J. Nat. Chem. 2012, 4, 854.
(4) (a) Neumann, W. P. Synthesis 1987, 1987, 665. (b) Baguley, P. A.;
Walton, J. C. Angew. Chem., Int. Ed. 1998, 37, 3072. (c) Studer, A.;
Amrein, S. Synthesis 2002, 2002, 835. (d) Krief, A.; Laval, A.-M. Chem.
Rev. 1999, 99, 745. (e) Szostak, M.; Spain, M.; Procter, D. J. Chem. Soc.
Rev. 2013, 42, 9155.
reaction in the presence of PhCDO in DMF at 50 °C for 5 min
gives 18% of 2n-D, whereas the reaction with PhCD2OH affords
only 4.2% of 2n-D. All these KIE experiments indicate that the
C−H bond cleavage of PhCHO should be the rate-limiting step.
In conclusion, a dehalogenation of aryl halides using benzyl
alcohols or aldehydes as hydrogen sources under basic
conditions has been developed. A radical pathway via a benzoyl
radical has been established based on the experimental evidence
including kinetic study, KIE, trapping reactions, and control
reactions. The kinetic study clearly distinguishes two possible
reaction pathways and thus rules out the Cannizzaro pathway for
the dehalogenation in the presence of PhCHO, where a much
larger initial rate is established than that of PhCH2OH (Scheme
6). The solvent DMF has also participated the dehalogenation as
(5) (a) Fukuzumi, S.; Hironaka, K.; Tanaka, T. J. Am. Chem. Soc. 1983,
105, 4722. (b) Ghosh, I.; Ghosh, T.; Bardagi, J. I.; Konig, B. Science 2014,
346, 725. (c) Discekici, E. H.; Treat, N. J.; Poelma, S. O.; Mattson, K. M.;
Hudson, Z. M.; Luo, Y.; Hawker, C. J.; de Alaniz, J. R. Chem. Commun.
2015, 51, 11705.
̈
10
t
a radical initiator together with BuOK. Due to the fast
hydrogen exchange between hydrogen sources (PhCHO and
PhCH2OH) and DMF, the isotope labeling experiments cannot
be established as a rational evidence to support the source of
hydrogen, whereas other experiments such as the kinetic study
and the KIE experiments exhibit a more clear clue. For the first
time, aldehydes were directly used as hydrogen source other than
the well-established alcohol−hydrogen sources.
(6) (a) Ueno, R.; Shimizu, T.; Shirakawa, E. Synlett 2016, 27, 741.
(b) Dewanji, A.; Muck-Lichtenfeld, C.; Studer, A. Angew. Chem., Int. Ed.
̈
2016, 55, 6749.
(7) (a) Li, Q.-Q.; Xiao, Z.-F.; Yao, C.-Z.; Zheng, H.-X.; Kang, Y.-B. Org.
Lett. 2015, 17, 5328. (b) Yao, C.-Z.; Li, Q.-Q.; Wang, M.-M.; Ning, X.-S.;
Kang, Y.-B. Chem. Commun. 2015, 51, 7729. (c) Zheng, H.-X.; Xiao, Z.-
F.; Yao, C.-Z.; Li, Q.-Q.; Ning, X.-S.; Kang, Y.-B.; Tang, Y. Org. Lett.
2015, 17, 6102.
(8) Dong, Y.; Lipschutz, M. I.; Tilley, T. D. Org. Lett. 2016, 18, 1530.
(9) (a) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2016, 55, 58.
(b) Studer, A.; Curran, D. P. Nat. Chem. 2014, 6, 765. (c) Studer, A.;
Curran, D. P. Angew. Chem., Int. Ed. 2011, 50, 5018. (d) Bolton, R.;
Williams, G. H. Chem. Soc. Rev. 1986, 15, 261.
(10) Pichette Drapeau, M.; Fabre, I.; Grimaud, L.; Ciofini, I.; Ollevier,
T.; Taillefer, M. Angew. Chem., Int. Ed. 2015, 54, 10587.
(11) Boyle, W. J., Jr.; Bunnett, J. F. J. Am. Chem. Soc. 1974, 96, 1418.
(12) (a) Kawamoto, T.; Sato, A.; Ryu, I. Chem. - Eur. J. 2015, 21, 14764.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02399.
Experimental details and spectroscopic data for all
products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(b) Masing, F.; Mardyukov, A.; Doerenkamp, C.; Eckert, H.; Malkus, U.;
̈
Nusse, H.; Klingauf, J.; Studer, A. Angew. Chem., Int. Ed. 2015, 54, 12612.
̈
*E-mail: ias_jpqu@njtech.edu.cn.
*E-mail: ybkang@ustc.edu.cn.
ORCID
(c) Masing, F.; Wang, X.; Nusse, H.; Klingauf, J.; Studer, A. Chem. - Eur.
̈
̈
J. 2017, 23, 6014. (d) Masing, F.; Nusse, H.; Klingauf, J.; Studer, A. Org.
̈
̈
Lett. 2017, 19, 2658.
Jian-Ping Qu: 0000-0002-5002-5594
Yan-Biao Kang: 0000-0002-7537-4627
Author Contributions
§H.-X.Z. and X.-H.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21672196, 21404096, 21602001, U1463202) and Anhui
Provincial Natural Science Foundation (1608085MB24) for
financial support.
D
DOI: 10.1021/acs.orglett.7b02399
Org. Lett. XXXX, XXX, XXX−XXX