Mild and selective reductions of aryl halides catalyzed by low-valent nickel complexes

Article abstract of DOI:10.1016/S0040-4039(01)01522-2

Treatment of aryl chlorides with catalytic amounts of (PPh₃)₂NiCl₂+PPh₃ in the presence of an equivalent of Me₂NH·BH₃ and either K₂CO₃ or Cs₂CO₃ in CH₃CN under mild conditions leads to the corresponding product of reduction. Aryl bromides and iodides can also be reduced, selectively, using this reagent combination.

Full text of DOI:10.1016/S0040-4039(01)01522-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7737–7740
Mild and selective reductions of aryl halides catalyzed by
low-valent nickel complexes
Bruce H. Lipshutz,* Takashi Tomioka and Steven S. Pfeiffer
Department of Chemistry & Biochemistry. University of California, Santa Barbara, CA 93106, USA
Received 22 May 2001; accepted 17 July 2001
Abstract—Treatment of aryl chlorides with catalytic amounts of (PPh3)2NiCl2+PPh3 in the presence of an equivalent of
Me2NH·BH3 and either K2CO3 or Cs2CO3 in CH3CN under mild conditions leads to the corresponding product of reduction.
Aryl bromides and iodides can also be reduced, selectively, using this reagent combination. © 2001 Elsevier Science Ltd. All rights
reserved.
For the past few years, there has been a considerable
effort aimed at devising methods by which aryl chlo-
rides can be effectively used as substrates in several
palladium- and nickel-catalyzed displacement reac-
tions.1 While most are carried out under homogeneous
conditions, alternatives involving both Pd/C2 and more
recently, Ni/C,3 offer benefits usually ascribed to het-
erogeneous catalysis.4 While both CꢀC5 and CꢀN6 bond
constructions have been documented under the influ-
ence of Ni/C, more recently this easily prepared and
inexpensive catalyst has been found to mediate the
corresponding reductions of aromatic CꢀCl bonds
when in the presence of an equivalent of Me2NH·BH3/
K2CO3.7 Although highly effective in most situations,
the process requires refluxing acetonitrile, temperatures
at which certain valued functionalities such as ketones
and olefins are unfortunately reduced competitively
with that occurring at the CꢀCl site. Moreover, for
small scale experiments, it may be simpler to effect such
reductions in solution, rather than first preparing
Ni(II)/C.8 We now report that by conducting these
reactions using an in-situ derived nickel catalyst, con-
version of aryl CꢀCl bonds to the corresponding C-H
derivatives can be accomplished under mild conditions
without affecting most common functional groups. The
method is also applicable to reductions of both aryl
bromides and iodides.
A standard set of conditions was established which calls
for 3 mole% (Ph3P)2NiCl2 relative to substrate and an
equal amount of Ph3P (thus, 3 equiv. of Ph3P per
nickel), along with 1.1 equiv. of Me2NH·BH3/K2CO3
(1:1) in CH3CN. The 10% excess amine borane–base
combination was employed to provide sufficient reduc-
ing agent for the Ni(II) salt. Reactions were conducted
at 40°C mainly to increase solubility of the reductant,
which is limited at room temperature.9 In those cases
where preformed Ni(0) is needed so as to avoid, e.g.
hydroboration of an isolated olefin, Cs2CO3 was found
to be the base of choice. Perhaps due to enhanced
solubility, the cesiated amide borane is far faster at
reducing the initially green Ni(II) to arrive at red
solutions usually indicative of Ni(0). Cs2CO3 also pre-
vents the occasionally observed (when using K2CO3)
formation of off-white–yellow complex NiCl2·(CH3-
CN)2,10 which ties up nickel and prevents active catalyst
formation. Upon addition of substrate, the mixture
turns from red–orange to yellow and eventually dark as
the reaction progresses. Attempts to replace CH3CN
with several alternative solvents, including THF, glyme,
diglyme, DMF, and DMA, invariably led to inferior
yields.
Table 1 illustrates a broad sampling of aryl chlorides,
which are cleanly reduced using this methodology.11
Most notably, aryl ketones (entry 6, and Eq. (1) below)
are untouched, while the outcome with isolated double
bonds (e.g. entry 4) may be dependent upon substitu-
tion pattern and surrounding functionality.12 Dialkyl
ketones, unfortunately, are slowly reduced at a rate
competitive with that of aryl chlorides. Both activated
(entries 1, 4) and electron-rich substrates (entry 2)
participated with equal efficiency. Heteroaromatics
(entries 3, 5–7) behaved similarly. Both free and pro-
Keywords: dehalogenation; nickel catalyst; aryl halides; amine-
boranes.
* Corresponding author. Tel.: 805-893-2521; fax: 805-893-8265;
e-mail: lipshutz@chem.ucsb.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01522-2

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tected amines did not complicate the reduction (entries
5 and 6, respectively). Acidic protons, such as in a
secondary amide (entry 8) are of no consequence; in
fact, use of 2% aqueous CH3CN does not alter the
reactions’ outcome (entry 7). A free alcohol (entry 2),
not surprisingly, therefore, does not require protection.
Noteworthy is the clean reduction of the benzoate
derivative of densely functionalized haloperidol (Eq.
(1)),11 further attesting to the functional group compat-
ibility offered by this combination of reagents.
•
(1)
°
Table 1. Ni(0)-catalyzed reductions of aromatic and heteroaromatic chlorides
3% (PPh ) NiCl , 3% PPh
3 2
2
Aryl chloride ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ3ꢀꢀꢀꢁ reduced aromatic15
1.1 equiv. Me NH·BH , base, CH CN
2
3
3
•

B. H. Lipshutz et al. / Tetrahedron Letters 42 (2001) 7737–7740
7739
•
Scheme 1. Competitive reduction of an aryl bromide versus aryl chloride, and reduction of an electron-rich iodide.
Based on the above results, it is perhaps not unexpected
that an aryl bromide (e.g. 1) rapidly reduced as well,
even at room temperature, conditions under which the
corresponding chloride (2) is unreactive (Scheme 1).
Aryl iodides, which are commonly reduced using
Bu3SnH (AIBN, benzene, D),13 are also prone toward
reduction under these conditions, as illustrated by con-
version of the highly electron-rich species 3 to 4
(Scheme 1).
6. Lipshutz, B. H.; Ueda, H. Angew. Chem., Int. Ed. 2000,
39, 4492.
7. Lipshutz, B. H.; Tomioka, T.; Sato, K. Synlett 2001, 970.
8. Lipshutz, B. H.; Tasler, S. Adv. Synth. Catal. 2001, 343,
327.
9. Nonetheless, at room temperature, the reduction may
take place (cf. Table 1, entry 6). Using Ni/C for this
substrate, which required refluxing CH3CN, the corre-
sponding carbinol was obtained.
10. Suzuki, H.; Ishiguro, S. Bull. Chem. Soc. Jpn. 1993, 66,
83.
11. All products were compared spectroscopically with
authentic samples, or if new, were fully characterized by
IR, NMR, MS, and HRMS data.
12. Although a simple mono-substituted olefin (e.g. i) appears
to be unresponsive to these reductive conditions, this
course may be substrate-dependent. For example, we
have observed the potential for both significant amounts
of alkene hydrogenation as well as olefin isomerization,
as in the case of ii.
In summary, a mild and operationally simple method is
described for reductions of aryl halides, in particular,
relatively stable and inexpensive aryl chlorides.14 Many
functional groups are tolerated by the combination of
reagents: catalytic NiCl2(Ph2P)2/Ph3P+Me2NH·BH3/
K2CO3 in CH3CN. Both bromides and iodides are more
readily and selectively reduced over the corresponding
aryl chlorides under these conditions. Further applica-
tions of this nickel-catalyzed reductive chemistry (e.g.
to protecting group chemistry) will be reported shortly.
Acknowledgements
Financial support provided by the NSF is warmly
acknowledged with thanks.
References
1. Sturmer, R. Angew. Chem., Int. Ed. 1999, 38, 3307. For
some representative recent examples, see: Dai, C.; Fu, G.
C. J. Am Chem. Soc. 2001, 123, 2719; Bohm, V. P. W.;
Weskamp, T.; Gstottmayr, C. W. K.; Herrmann, W. A.
Angew. Chem., Int. Ed. 2000, 39, 1602.
2. For one very recent report, see: Shimizu, T.; Seki, M.
Tetrahedron Lett. 2001, 42, 429.
3. Lipshutz, B. H. Adv. Synth. Catal. 2001, 343, 313.
4. Smith, G. V.; Notheisz, F. Heterogeneous Catalysis in
Organic Chemistry; Academic Press: San Diego, 1999.
5. (a) Lipshutz, B. H.; Blomgren, P. A. J. Am. Chem. Soc.
1999, 121, 5819; (b) Lipshutz, B. H.; Tomioka, T.; Blom-
gren, P. A.; Sclafani, J. Inorg. Chim. Acta 1999, 296, 164;
(c) Lipshutz, B. H.; Sclafani, J. A.; Blomgren, P. A.
Tetrahedron 2000, 56, 2139.

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B. H. Lipshutz et al. / Tetrahedron Letters 42 (2001) 7737–7740
13. Neumann, W. P. Synthesis 1987, 665.
J=7.6 Hz, 2H), 7.33 (t, J=7.6 Hz, 2H), 7.28–7.24 (m,
2H), 7.13 (t, J=7.6 Hz, 2H), 3.01 (t, J=7.0 Hz, 2H), 2.94
(d, J=10.4 Hz, 2H), 2.67 (d, J=12.8 Hz, 2H), 2.53–2.40
(m, 4H), 2.13 (t, J=12 Hz, 2H), 2.01 (p, J=7.0 Hz, 2H).
13C NMR (100 MHz, CDCl3): l 198.51, 164.86, 133.77,
133.10, 131.35, 130.91, 130.81, 129.78, 128.67, 128.63,
127.60, 124.68, 115.94, 115.73, 81.17, 57.83, 49.59, 36.38,
35.80, 21.93. IR (neat) 2926, 2851, 2815, 1718, 1684,
1104. HRMS-ESI (M+H)+ calcd for C28H29NO3F
446.2131, obsd 446.2148.
14. The following procedure is representative (Table 1, entry
3). Into a flame-dried 10 mL round-bottomed flask
equipped with a stir bar and septum were added aryl
chloride (293 mg, 1.0 mmol), (PPh3)2NiCl2 (20 mg, 0.03
mmol, 3 mol%), PPh3 (8 mg, 0.03 mmol), 98% borane–
dimethylamine complex (66 mg, 1.1 mmol), and K2CO3
(152 mg, 1.1 mmol) under argon. Dry, deoxygenated
acetonitrile (2 mL) was added via syringe and the slurry
was allowed to stir for 6 h at 40°C. Upon completion, the
mixture was cooled to room temperature and filtered
through Celite, the filter cake being further washed with
ether. The solvents were then removed on a rotary evapo-
rator. The crude material was purified by column chro-
matography on silica gel (4% diethyl ether in pet ether) to
give 232 mg (90%) of the reduced product.
Methyl 4-(2-methylphenoxy)butyrate: 1H NMR (400
MHz, CDCl3): l 7.17–7.13 (m, 2H), 6.89–6.80 (m, 2H),
4.02 (t, J=6.0 Hz, 2H), 3.70 (s, 3H), 2.58 (t, J=7.4 Hz,
2H), 2.23 (s, 3H), 2.19–2.12 (m, 2H). 13C NMR (100
MHz, CDCl3): l 173.69, 156.92, 130.66, 126.81, 126.73,
120.38, 110.80, 66.53, 51.60, 30.67, 24.78, 16.24. IR (neat)
1739, 1245. HRMS-ESI (M+H)+ calcd for C12H16O3
208.10995, obsd 208.10995.
15. Products for all entries in Table 1 and Scheme 1 were
either compared with known data in the literature, or if
new, were fully characterized by IR, NMR, 13C NMR,
MS, and HRMS data (below).
16. Premixing (PPh3)2NiCl2, PPh3, Me2NH·BH3, and Cs2CO3
in CH3CN (ca. 0.5 M in stoichiometric reagents) is
necessary to prevent olefin reduction. Usually ca. 2 h are
needed for the mixture to turn to a red–brown solution,
to which is added the substrate (neat).
1
Peridol derivative (Eq. (1)): H NMR (400 MHz, CDCl3)
l 8.06 (d, J=6.8 Hz, 2H), 8.01 (dd, J=8.8 Hz, 1H), 7.58
(t, J=7.6 Hz, 1H), 7.46 (t, J=7.6 Hz, 2H), 7.39 (d,