Mild ketone formation via Ni-catalyzed reductive coupling of unactivated alkyl halides with acid anhydrides

Article abstract of DOI:10.1039/c2cc33232a

Ni-catalyzed ketone formation through mild reductive coupling of a diverse set of unactivated alkyl bromides and iodides with particularly aryl acid anhydrides was successfully developed using zinc as the terminal reductant. These conditions also allow direct coupling of alkyl iodides with aryl acids in the presence of Boc₂O and MgCl₂. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc33232a

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COMMUNICATION
Mild ketone formation via Ni-catalyzed reductive coupling of
unactivated alkyl halides with acid anhydridesw
Hongyu Yin, Chenglong Zhao, Hengzhi You, Kunhua Lin* and Hegui Gong*
Received 5th May 2012, Accepted 28th May 2012
DOI: 10.1039/c2cc33232a
Ni-catalyzed ketone formation through mild reductive coupling
of a diverse set of unactivated alkyl bromides and iodides with
particularly aryl acid anhydrides was successfully developed
using zinc as the terminal reductant. These conditions also allow
direct coupling of alkyl iodides with aryl acids in the presence of
Boc2O and MgCl2.
Transition-metal-catalyzed addition of alkyl metallic reagents
Fig. 1 Catalytic ketone formation employing unactivated alkyl
to acid derivatives have attracted considerable attention for
alkyl ketones.1–6 Of special note is the development of the
Ni-catalyzed addition of alkylzinc reagents to less reactive acid
anhydrides by Rovis, which provides ketones in a highly
stereoselective manner.6 Synthesis of ketones from chemically
and electrochemically reductive coupling of readily accessible
alkyl and acyl electrophiles has been reported7,8 but is generally
limited to alkyl ketones from the coupling of alkyl iodides with
alkyloyl chlorides, pyridylthiol and pyridyloxyl esters. To the
best of our knowledge, no reports regarding unactivated alkyl
bromides have been revealed. Meanwhile, the employment of
anhydrides to the synthesis of ketones is still rare.8a,c Only
activated allylic and benzylic electrophiles under electrochemical
conditions have been documented, which requires high loading
of anhydrides but generally produce low yields of ketones.8c
Recently, we and others have demonstrated efficient Ni-catalyzed
reductive coupling methods for the coupling of alkyl halides with
other electrophiles.9–11 This prompts us to study whether acid
anhydrides are competent for reductive coupling with alkyl halides,
particularly alkyl bromides.12 In this paper, we report our studies of
unactivated alkyl iodides and bromides with aryl acid anhydrides to
ketones under a Ni-catalyzed reductive strategy. This work features
the first reductive ketone formation employing unactivated alkyl
bromides, and allows direct coupling of aryl acids and alkyl iodides
through in situ generation of acid anhydrides. Preliminary
mechanistic studies indicate that alkyl bromides may proceed
via a NiI/NiIII process that differs from the previously proposed
acylation of NiII mechanism (Fig. 1).7
halides and acid derivatives.
After tremendous efforts, we identified that a combination of
Ni(COD)2/3a/Zn in CH3CN gave the desired ketone in a 38%
yield (entry 1, Table 1).14 Interestingly, addition of 20% of
MgCl2 boosted the yields to 50% (entry 2). Use of 1.5 equiv. of
MgCl2 gave 2 in an 85% yield (entry 3). We speculate that
roles of MgCl2 are in part to activate anhydrides and Zn by
coordination to the carbonyl oxygen and by removal of salts
on Zn surface, respectively. Extensive screening of other
ligands 3b–d, 4–6 (Fig. 2) did not yield better results (entries 4–9),
although ligand 5 is comparably effective.14 The reaction went to
completion after 8 h (entry 10). The search for different Ni sources
disclosed that the use of Ni(acac)2 only slightly lowered the yield
(entry 11).14 In general, the excess benzoic anhydride remained
Table 1 Optimization of the reaction conditionsa,b
Entry
Ni/ligand
Additives (mol%)
Time/h
Yield (%)
1
2
3
4
5
6
7
8
Ni(COD)2/3a
Ni(COD)2/3a
Ni(COD)2/3a
Ni(COD)2/3b
Ni(COD)2/3c
Ni(COD)2/3d
Ni(COD)2/4a
Ni(COD)2/5
Ni(COD)2/6
Ni(COD)2/3a
Ni(acac)2/3a
None
12
12
12
12
12
12
12
12
12
8
38
50
85
58
60
42
38
80
23
85
82
MgCl2 (20)
MgCl2 (150)
MgCl2 (150)
MgCl2 (150)
MgCl2 (150)
MgCl2 (150)
MgCl2 (150)
MgCl2 (150)
MgCl2 (150)
MgCl2 (150)
To begin with, we first investigated the reaction conditions for the
coupling of 4-iodo-1-tosylpiperidine 1a and benzoic anhydride.13
9
10
11
12
Department of Chemistry, Shanghai University, 99 Shang-Da Road,
Shanghai 200444, China. E-mail: Hegui_gong@shu.edu.cn
w Electronic supplementary information (ESI) available: experimental
details and spectral data for new compounds. See DOI: 10.1039/
c2cc33232a
a
Reaction Conditions: 1a (0.14 mmol, 100 mol%), benzoic anhydride
(200 mol%), Ni source (10 mol%), ligand (15 mol%), Zn (300 mol%),
b
CH3CN (1 mL). Isolated yields.
c
7034 Chem. Commun., 2012, 48, 7034–7036
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Table 3 Coupling of alkyl iodides with aryl acids through in situ
generation of anhydridesa,b
Fig. 2 Structures of ligands.
Table 2 Substrate scope for Ralkyl-Ia,b
a
Reaction Conditions: alkyl iodide (0.14 mmol, 100 mol%), acid (300 or
400 mol%), Ni(COD)2 (10 mol%), 3a (15 mol%), Zn (300 mol%),
b
MgCl2 (200 mol%), CH3CN (1 mL). Isolated yields. 4 equiv of
d
acid. 3 equiv of acid. Not detected.
c
e
Extension of the optimized reaction conditions for alkyl iodides
to the coupling of 4-bromo-1-tosylpiperidine 1b with benzoic
anhydride only gave 2 in less than 40%. Extensive optimization
gave the highest yield of 78% when using a combination of
Ni(COD)2/4b/Zn/MgCl2 in a mixture of acetonitrile and DMF
(N,N-dimethylforamide) (Table 4).14 Various unactivated
21 and 11 alkyl bromides were compatible, giving 2, 7, 12, 18,
23, and 35–41 in moderate to excellent yields.
a
Reaction Conditions: alkyl iodide (0.14 mmol, 100 mol%), anhydride
(200 mol%), Ni(COD)2 (10 mol%), 3a (15 mol%), Zn (300 mol%),
b
MgCl2 (150 mol%), CH3CN (1 mL). Isolated yields.
To understand whether a Negishi mechanism was involved,
the coupling of cyclohexyl–ZnI with 2 equiv. of 4-tBu-benzoic
anhydride under the standard reaction conditions was conducted.
Ketone 14 was obtained in a 78% yield, indicating an in situ
Negishi mechanism is possible.6 However, Table 3 indicates the
effectiveness of ketone formation in the presence of large
excess aryl acids, which seemingly support that existence of
unreacted. Finally, use of 1.5 and 1 equiv. of benzoic anhydride
reduced the yield to 70% and 65%, respectively.
Using the reaction conditions in entry 3, Table 1, a set of alkyl
iodides were examined for the coupling with substituted benzoic
anhydrides, delivering ketones 7–29 in moderate to excellent
yields (Table 2). 4-tBu-benzoic anhydride gave better result than
methoxyl and methyl substituted ones as shown in 7–9. It should
be noted that acetic acid anhydride also resulted in ketone 10 in
68%. Cyclic secondary alkyl iodides generally provided the
desired ketones in good results (e.g. 11–18), which were more
efficient than the open chain analogues (e.g. 19–26). The primary
alkyl iodides also gave ketones 27–29 in good yields.
Table 4 Coupling of unactivated alkyl bromides with acid anhydridesa,b
Next, we investigated ketone formation via in situ generation
of anhydrides under the reductive condtions.15 By addition of
Boc anhydride under the optimized reaction conditions, ketones
2, 7–9, 14–15, 17–19, 21, 30–31, and 33–34 were obtained
successfully (Table 3), although 4 equiv. of acids appeared to
be necessary. Raising the amount of Boc anhydride did not
result in better yields. In general, moderate to excellent yields
could be attained when secondary alkyl iodides were used. For
primary alkyl iodides, low coupling yields were observed as
evident in 28 and 34. Notably, the use of electron-deficient aryl
acid did not result in ketones, e.g. 32. Although the coupling
efficiency for this in situ anhydride method dropped as compared
to those methods using purified anhydrides, to our knowledge,
this work provides the first direct ketone formation from alkyl
halides and acids.
a
Reaction Conditions: alkyl bromide (0.14 mmol, 100 mol%), anhydride
(200 mol%), Ni(COD)2 (10 mol%), 4b (15 mol%), Zn (300 mol%),
b
MgCl2 (150 mol%), CH3CN–DMF 3 : 7 (v/v, 1 mL). Isolated yields.
c
dr 420 : 1
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 7034–7036 7035

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4 For selected examples of acylation of aryl and alkynyl nucleophiles,
Negishi: (a) H. Xu, K. Ekoue-Kovi and C. Wolf, J. Org. Chem.,
2008, 73, 7638; Suzuki: (b) L. J. Gooßen and K. Ghosh, Angew.
Chem., Int. Ed., 2001, 40, 3458; Stille: (c) R. Lerebours,
A. Camacho-Soto and C. Wolf, J. Org. Chem., 2005, 70, 8601;
Sonogashira: (d) C. Boersch, E. Merkul and T. J. J. Muller, Angew.
Chem., Int. Ed., 2011, 50, 10448; Fukuyama: (e) Y. Yu and
L. S. Liebeskind, J. Org. Chem., 2004, 69, 3554.
5 Synthesis of ketones using a reversed polarity strategy has also
been reported, for selected examples: (a) J. R. Schmink and
S. W. Krska, J. Am. Chem. Soc., 2011, 133, 19574;
(b) Y. Hanzawa, N. Tabuchi and T. Taguchi, Tetrahedron Lett.,
1998, 39, 6249; (c) Y. Obora, M. Nakanishi, M. Tokunaga and
Y. Tsuji, J. Org. Chem., 2002, 67, 5835.
Scheme 1 Coupling of 42 with benzoic anhydride.
organozinc is implausible.10a,16 Therefore for unactivated alkyl
iodides, in situ Negishi mechanism cannot be unambiguously
ruled out. For unactivated alkyl bromides, such a process is
implausible since organozincs do not form under Ni-catalyzed
reductive conditions at 25 1C.10a
Next, an equimolar mixture of benzoic anhydride, N(COD)2/4b
and 1b revealed that benzoic anhydride consumed after 12 h, while
1b remained unreacted. Addition of Zn and MgCl2 to the resulting
mixture gave 2 in 40% yield, suggesting a possible PhCO–NiII
species as the initiation step of the catalytic process.6g,17 However,
treatment of a 1 : 1 mixture of 1a and benzoic anhydride with
1 equiv. of Ni(COD)2 for 12 h, resulted in 55% recovered 1a,
and about 40% recovered anhydride, suggesting that alkyl
iodides and aromatic anhydrides possess comparable oxidative
addition rate to Ni0.
6 (a) J. B. Johnson and T. Rovis, Acc. Chem. Res., 2008, 41, 327; (b) J. B.
Johnson, E. A. Bercot, J. M. Rowley, G. W. Coates and T. Rovis,
J. Am. Chem. Soc., 2007, 129, 2718; (c) E. A. Bercot and T. Rovis,
J. Am. Chem. Soc., 2002, 124, 174; (d) E. A. Bercot and T. Rovis, J. Am.
Chem. Soc., 2005, 127, 247; (e) Y. Zhang and T. Rovis, J. Am. Chem.
Soc., 2004, 126, 15964; (f) J. B. Johnson, R. T. Yu, P. Fink, E. A. Bercot
and T. Rovis, Org. Lett., 2006, 8, 4307; (g) S. Kozuch, S. E. Lee and
S. Shaik, Organometallics, 2009, 28, 1303.
7 (a) A. C. Wotal and D. J. Weix, Org. Lett., 2012, 14, 1476;
(b) M. Onaka, Y. Matsuoka and T. Mukaiyama, Chem. Lett.,
1981, 10, 531.
8 (a) H. Marzouk, Y. Rollin, J. C. Folest, J. Y. Nedelec and
J. Perichon, J. Organomet. Chem., 1989, 369, C47; (b) C. Amatore,
A. Jutand, J. Perichon and Y. Rollin, Monatsh. Chem., 2000,
131, 1293; (c) E. d’Incan, S. Sibille, J. Perichon, M.-O. Moingeon
and J. Chaussard, Tetrahedron Lett., 1986, 27, 4175.
Although more studies are required, we propose at least for alkyl
bromides, the reaction may proceed through one electron reduction
of PhC(O)–NiII, leading to PhC(O)–NiI.18 Subsequent oxidative
addition of alkyl bromides generates R–NiIII–C(O)Ph. Reductive
elimination provides the ketone products and a NiI species, which
could be reduced to Ni0 to allow the catalytic cycle to proceed.19
It should be noted that oxidative addition of alkyl halides to
NiI generally involves radical intermediate. Coupling of 42 with
benzoic anhydride gave a cyclization product 43, conforming that
this coupling event involves an alkyl radical (Scheme 1).20
In summary, we have disclosed an efficient method for the
coupling of unactivated alkyl iodides and bromides with
anhydrides, providing ketones in good to excellent yields. This
method allows direct use of carboxylic acids wherein in situ
generation of anhydrides and formation of ketones can be
achieved in one pot. Although the involvement of in situ
organozincs is less likely, it cannot be unambiguously ruled
out for alkyl iodides. Instead, the non-Negishi mechanisms that
proceed through oxidative addition of anhydride to alkyl–NiI
yielding alkyl–NiIII–C(O)Ph for alkyl halides may be operative,
although previously proposed mechanism involving acylation
of an alkyl–NiII intermediate is possible for alkyl iodides.7
9 For reductive allylic alkylation, see: (a) X. Qian, A. Auffrant,
A. Felouat and C. Gosimini, Angew. Chem., Int. Ed., 2011,
50, 10402; (b) Y. Dai, F. Wu, Z. Zang, H. You and H. Gong,
Chem.–Eur. J., 2012, 16, 808.
10 For reductive coupling of unactivated alkyl halides, see: (a) X. Yu,
T. Yang, S. Wang, H. Xu and H. Gong, Org. Lett., 2011, 13, 2138;
(b) D. A. Everson, R. Shrestha and D. J. Weix, J. Am. Chem. Soc.,
2010, 132, 920; (c) S. M. Goldup, D. A. Leigh, R. T. McBurney,
P. R. McGonigal and A. Plant, Chem. Sci., 2010, 1, 383; (d) C.-S. Yan,
Y. Peng, X.-B. Xu and Y.-W. Wang, Chem.–Eur. J., 2012, 18, 6039.
11 For in situ generation of organometallics, see: (a) A. Krasovskiy,
C. Duplais and B. H. Lipshutz, Org. Lett., 2010, 12, 4742;
(b) W. M. Czaplik, M. Mayer and A. Jacobi von Wangelin, Angew.
Chem., Int. Ed., 2009, 48, 607; (c) A. Krasovskiy, C. Duplais and
B. H. Lipshutz, J. Am. Chem. Soc., 2009, 131, 15592; (d) P. Gomes,
C. Gosmini and J. Perichon, Org. Lett., 2003, 5, 1043.
12 For selected reviews on coupling of alkyl halides, see:
(a) A. Rudolph and M. Lautens, Angew. Chem., Int. Ed., 2009,
48, 2656; (b) A. C. Frisch and M. Beller, Angew. Chem., Int. Ed.,
2005, 44, 674; (c) X. Hu, Chem. Sci., 2011, 2, 1867.
13 For seminal work using N-containing ligands, see: J. Zhou and
G. C. Fu, J. Am. Chem. Soc., 2003, 125, 14726.
14 See the supporting information (ESIw) for details.
15 (a) G. Bartoli and M. Bosco, Synthesis, 2007, 22, 3489; (b) For a
review on coupling of acid: L. J. Gooßen, N. Rodrıguez and
K. Gooßen, Angew. Chem., Int. Ed., 2008, 47, 3100.
16 G. Manolikakes, C. M. Hernandez, A. Matthias, M. A. Schade,
A. Metzger and P. Knochel, J. Org. Chem., 2008, 73, 8422.
17 (a) S.-i. Inaba and R. D. Rieke, J. Org. Chem., 1985, 50, 1373;
(b) D. R. Fahey and J. E. Mahan, J. Am. Chem. Soc., 1977, 99, 2501.
18 BnCONi(I) has been detected in the electrochemical reduction
process (ref. 8b).
19 For mechanistic discussions involving NiI/NiIII-catalytic processes,
see: (a) X. Lin, J. Sun, Y. Xi and D. Lin, Organometallics, 2011,
30, 3284; (b) X. Lin and D. L. Phillips, J. Org. Chem., 2008, 73, 3680;
(c) V. B. Phapale, E. Bunuel, M. Garcıa-Iglesias and D. J. Cardenas,
Angew. Chem., Int.Ed., 2007, 46, 8790; (d) G. D. Jones, J. L. Martin,
C. McFarland, O. R Allen, R. E. Hall, A. D. Haley, R. J. Brandon,
T. Konovalova, P. J. Desrochers, P. Pulay and D. A. Vicic, J. Am.
Chem. Soc., 2006, 128, 13175.
Notes and references
1 For a review: R. K. Dieter, Tetrahedron, 1999, 55, 4177.
2 For selected examples of Pd-catalyzed acylation of alkyl-metallics:
(a) M. Asaoka, A. Kosaka, M. Tanaka, T. Ueda, T. Houkawa and
H. Takei, J. Chem. Soc., Perkin Trans. 1, 1997, 1, 2949;
(b) Y. Tamaru, H. Ochiai, T. Nakamura and Z. Yoshida, Angew.
Chem., Int. Ed. Engl., 1987, 26, 1157; (c) T. Harada, Y. Kotani,
T. Katsuhira and A. Oku, Tetrahedron Lett., 1991, 32, 1573;
(d) Y. Yu and L. S. Liebeskind, J. Org. Chem., 2004, 69, 3554;
(e) B. W. Fausett and L. S. Liebeskind, J. Org. Chem., 2005, 70, 4851.
3 For other metal catalyzed acylation of alkyl nucleophiles, Co:
(a) C. K. Reddy and P. Knochel, Angew. Chem., Int. Ed. Engl.,
1996, 35, 1700; Fe: (b) B. D. Sherry and A. Furstner, Acc. Chem.
Res., 2008, 41, 1500; Cu: (c) N. Coia, N. Mokhtari, J.-L. Vasse and
J. Szymoniak, Org. Lett., 2011, 13, 6292.
20 F. Gonzalez-Bobes and G. C. Fu, J. Am. Chem. Soc., 2006,
128, 5360 and references therein.
c
7036 Chem. Commun., 2012, 48, 7034–7036
This journal is The Royal Society of Chemistry 2012