Ketone formation via mild Nickel-catalyzed reductive coupling of alkyl halides with aryl acid chlorides

Article abstract of DOI:10.1021/ol3011198

The present work highlights unprecedented Ni-catalyzed reductive coupling of unactivated alkyl iodides with aryl acid chlorides to efficiently generate alkyl aryl ketones under mild conditions.

Full text of DOI:10.1021/ol3011198

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Ketone Formation via Mild Nickel-Catalyzed
Reductive Coupling of Alkyl Halides with
Aryl Acid Chlorides
Fan Wu, Wenbin Lu, Qun Qian, Qinghua Ren,* and Hegui Gong*
Department of Chemistry, Shanghai University, 99 Shang-Da Road,
Shanghai 200444, China
hegui_gong@shu.edu.cn; qinghua.ren@shu.edu.cn
Received April 26, 2012
ABSTRACT
The present work highlights unprecedented Ni-catalyzed reductive coupling of unactivated alkyl iodides with aryl acid chlorides to efficiently
generate alkyl aryl ketones under mild conditions.
In recent years, transition-metal-catalyzed acylation1À3
and carbonylation4À6 of carbon nucleophiles have ad-
vanced rapidly, leading to facile formation of ketones. In
general, however, the catalytic ketone formation employing
aliphatic, particularly functionalized bulky secondary alkylÀ
metallic, nucleophiles has been less explored,1b,2a,2b,2f,3a,3c,3d
probably owing to slow reductive elimination and β-elimination
of the alkylÀorganometallic intermediates.7 These challenges
are also evident in the recent development of Ni- and Pd-
catalyzed coupling of secondary alkylzinc reagents with
organic halides.8 Moreover, preparation of alkylÀmetallic
reagents may be difficult, particularly for those bearing
β-leaving groups as pointed out by Knochel.9
To avoid the limitation of using alkylÀmetallic nucleo-
philes, syntheses of ketones via acylation or carbonylation
of readily accessible alkyl electrophiles are intriguing
alternatives.10 While carbonylation of alkyl halides is
restricted to scarce examples of radical and Pd-catalyzed
methods under a high pressure of CO,11,12 employment of
acyl nucleophiles in catalytic reversed polarity strategies is
efficient only for aryl and activated alkyl electrophiles.13
(1) For leading reviews, see: (a) Dieter, R. K. Tetrahedron 1999, 55,
4177. (b) Johnson, J. B.; Rovis, T. Acc. Chem. Res. 2008, 41, 327.
(2) For selected examples of Pd-catalyzed, in situ Negishi reactions:
(a) Tamaru, Y.; Ochiai, H.; Nakamura, T.; Yoshida, Z. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 1157. (b) Harada, T.; Kotani, Y.; Katsuhira, T.;
Oku, A. Tetrahedron Lett. 1991, 32, 1573. Suzuki reactions: (c) Gooßen,
L. J.; Ghosh, K. Angew. Chem., Int. Ed. 2001, 40, 458. Stille reactions:
(d) Lerebours, R.; Camacho-Soto, A.; Wolf, C. J. Org. Chem. 2005, 70,
€
8601. Sonogashira reactions: (e) Boersch, C.; Merkul, E.; Muller, T. J. J.
Angew. Chem., Int. Ed. 2011, 50, 10448. Fukuyama reactions: (f) Yu, Y.;
Liebeskind, L. S. J. Org. Chem. 2004, 69, 3554.
(3) For other metal-catalyzed reactions, e.g., Co: (a) Reddy, C. K.;
Knochel, P. Angew. Chem., Int. Ed. Engl. 1996, 35, 1700. Fe: (b) Duplais,
C.; Bures, F.; Sapountzis, I.; Korn, T. J.; Cahiez, G.; Knochel, P. Angew.
€
Chem., Int. Ed. 2004, 43, 2968. (c) Sherry, B. D.; Furstner, A. Acc. Chem.
Res. 2008, 41, 1500. Cu: (d) Coia, N.; Mokhtari, N.; Vasse, J.-L.;
Szymoniak, J. Org. Lett. 2011, 13, 6292. Rh: (e) Frost, C. G.; Wadsworth,
K. J. Chem. Commun. 2001, 2316. Ni: (f) Bercot, E. A.; Rovis, T. J. Am.
Chem. Soc. 2002, 124, 174.
(7) For a review on alkyl-organometallics, see: Jana, R.; Pathak,
T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417.
(4) For a review, see: Wu, X.-F.; Neumann, H.; Beller, M. Chem. Soc.
Rev. 2011, 40, 4986.
(8) (a) Smith, S. C.; Fu, G. C. Angew. Chem., Int. Ed. 2008, 47, 9334.
(b) Han, C.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 7532.
(c) Thaler, T.; Haag, B.; Gavryushin, A.; Schober, K.; Hartmann, E.;
Gschwind, R. M.; Zipse, H.; Mayer, P.; Knochel, P. Nature Chem. 2010,
2, 125. (d) Joshi-Pangu, A.; Ganesh, M.; Biscoe, M. R. Org. Lett. 2011,
13, 1218.
(9) Steib, A. K.; Thaler, T.; Komeyama, K.; Mayer, P.; Knochel, P.
Angew. Chem., Int. Ed. 2011, 50, 3303.
(10) For selected reviews on coupling of alkyl halides, see:
(a) Rudolph, A.; Lautens, M. Angew. Chem. Int. 2009, 48, 2656. (b) Frisch,
A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674. (c) Hu, X. Chem. Sci.
2011, 2, 1867.
(5) For selected examples of carbonylative coupling of ArX, with
alkylborane, see: (a) Ishiyama, T.; Miyaura, N.; Suzuki, A. Bull. Chem.
Soc. Jpn. 1991, 64, 1999. With alkylindium: (b) Lee, S. W.; Lee, K.;
Seomoon, D.; Kim, S.; Kim, H.; Kim, H.; Shim, E.; Lee, M.; Lee, S.;
Kim, M.; Lee, P. H. J. Org. Chem. 2004, 69, 4852. With R-ketone:
(c) Gøgsig, T. M.; Taaning, R. H.; Lindhardt, A. T.; Skrydstrup, T.
Angew. Chem., Int. Ed. 2012, 51, 798.
(6) For a review including oxidative carbonylative coupling of alkyl-
zinc reagents, see: Liu, Q.; Hua Zhang, H.; Lei, A. Angew. Chem., Int.
Ed. 2011, 50, 10788.
r
10.1021/ol3011198
XXXX American Chemical Society

On the other hand, direct coupling of acyl electrophiles with
alkyl electrophiles would provide a straightforward means to
ketones. The known methods, however, are effective for the
coupling of activated halides and unactivated alkyl iodides
with essentially alkyl acid derivatives.2a,14 Addition of
[BnNi0(bpy)]À and LnÀNi(alkyl)2 to RalkylCOCl has been
proposed for the Ni-catalyzed chemically and electrochemi-
cally reductive alkyl alkyl ketone synthesis (Figure 1).14
Notably, coupling of unactivated alkyl bromides and synthe-
sis of alkyl aryl ketones from readily available aryl acid
chlorides remain challenging.
Recent advances of Ni- and Co-catalyzed reductive
coupling of alkyl halides with alkyl, aryl, and allylic
electrophiles15,16 suggest redox pathways without involve-
ment of in situ organometallic nucleophiles.17,2a,2b Similar
to these strategies, we herein report a mild efficient
Ni-catalyzed ketone formation via reductive coupling
of unactivated alkyl iodides and activated halides with
acid chlorides. This protocol accommodates sterically
hindered secondary halides and a variety of alkyl and
aryl acid chlorides using Zn as the reductant. Our initial
studies are in favor of a probable unprecedented NiI/NiIII
redox process for the formation of alkyl aryl ketones
(Figure 1).
combination of Ni(COD)2/3a/Zn/CH3CN gave the de-
sired ketone 2a in 85% yield (Table 1, entry 1). Whereas
screening of other ligands (e.g., 3b, 4a, 5, and 6, entries 2À5
and Figure 2), reductants, and solvents did not yield better
results, the survey of different Ni sources revealed that
Ni(acac)2 was comparable to Ni(COD)2 (entry 6).18 Addi-
tion of 1.5 equiv of MgCl2 further boosted the yield to 91%
(entries 7À8).18,19 Use of 1.5 equiv of PhCOCl only slightly
eroded the yield (88%). In general, the excess benzoyl
chloride was converted to benzyl benzoate. The coupling
of 4-bromo-1-tosylpiperidine 1b with benzoyl chloride was
also studied (entries 9À11).18 An extensive search for the
optimal reaction conditions only resulted in a best 40%
yield under the Ni(COD)2/3a/Zn conditions in CH3CN
(entry 10). Nearly 60% of 1b was recovered while benzoyl
chlorides were all consumed after 4 h.
Figure 2. Structures of ligands.
Table 1. Optimization for the Reaction of 1 and PhCOCla
entry
1/Ni/ligand
additives
none
time (h) yieldb (%)
Figure 1. Pathways for Ni-catalyzed reductive ketone formation.
1
2
1a/Ni(COD)2/3a
1a/Ni(COD)2/3b
1a/Ni(COD)2/4a
1a/Ni(COD)2/5
1a/Ni(COD)2/6
1a/Ni(acac)2/3a
12
12
12
12
12
12
12
4
85
78
75
30
68
82
91
91
40
15
33
none
none
none
none
none
3
We first examined the coupling of 4-iodo-1-tosylpiper-
idine 1a and benzoyl chloride and identified that a
4
5
6
7
1a/Ni(acac)2/3a MgCl2 (150%)
(11) Schiesser, C. H.; Wille, U.; Matsubara, H.; Ryu, I. Acc. Chem.
Res. 2007, 40, 303.
8
1a/Ni(acac)2/3a
1b/Ni(COD)2/3a
MgCl2 (150%)
none
9
12
12
12
€
(12) (a) Karimi, F.; Barletta, J.; Langstrom, B. Eur. J. Org. Chem.
10
11
1b/Ni(COD)2/3b none
1b/Ni(COD)2/3a MgCl2 (150%)
2005, 2374. (b) Bloome, K. S.; Alexanian, E. J. J. Am. Chem. Soc. 2010,
132, 12823. (c) Shimizu, R.; Fuchikami, T. Tetrahedron Lett. 1996, 37,
8405.
a Reaction conditions: 1 (0.15 mmol, 100 mol %), benzoyl chloride
(200 mol %), Ni source (10 mol %), ligand (15 mol %), Zn (300 mol %),
CH3CN (1 mL). b Isolated yields.
(13) For selected examples, see: (a) Schmink, J. R.; Krska, S. W.
J. Am. Chem. Soc. 2011, 133, 19574. (b) Hanzawa, Y.; Tabuchi, N.;
Taguchi, T. Tetrahedron Lett. 1998, 39, 6249. (c) Obora, Y.; Nakanishi,
M.; Tokunaga, M.; Tsuji, Y. J. Org. Chem. 2002, 67, 5835.
(14) (a) Wotal, A. C.; Daniel J. Weix, D. J. Org. Lett. 2012, 14, 1476.
ꢀ ꢀ
ꢀ
(b) Marzouk, H.; Rollin, Y.; Folest, J. C.; Nedelec, J. Y.; Perichon, J.
Extension of the optimized conditions (Table 1, entry 7)
for the coupling of a wide range of unactivated alkyl
iodides and acid chlorides is summarized in Figure 3.
J. Organomet. Chem. 1989, 369, C47. (c) Amatore, C.; Jutand, A.;
ꢀ
Perichon, J.; Rollin, Y. Monatsh. Chem. 2000, 131, 1293. (d) d’Incan,
ꢀ
E.; Sibille, S.; Perichon, J.; Moingeon, M.ÀO.; Chaussard, J. Tetrahe-
dron Lett. 1986, 27, 4175. (e) Onaka, M.; Matsuoka, Y.; Mukaiyama, T.
Chem. Lett. 1981, 10, 531.
(17) For in situ generation of organometallics, see: (a) Krasovskiy,
A.; Duplais, C; Lipshutz, B. H. Org. Lett. 2010, 12, 4742. (b) Czaplik,
W. M.; Mayer, M.; Jacobi von Wangelin, A. Angew. Chem., Int. Ed.
2009, 48, 607. (c) Krasovskiy, A.; Duplais, C.; Lipshutz, B. H. J. Am.
Chem. Soc. 2009, 131, 15592. (d) Gomes, P.; Gosmini, C.; Perichon, J.
Org. Lett. 2003, 5, 1043.
(18) See the Supporting Information for details.
(19) The role of MgCl2 is not clear. We speculate that it may activate
Zn by removing the salts on the surface of Zn.
(15) For reductive allylic alkylation, see: (a) Qian, X.; Auffrant, A.;
Felouat, A.; Gosimini, C. Angew. Chem., Int. Ed. 2011, 50, 10402. (b)
Dai, Y.; Wu, F.; Zang, Z.; You, H.; Gong, H. Chem.;Eur. J. 2012, 16,
808.
(16) For reductive coupling of unactivated alkyl halides, see: (a) Yu,
X.; Yang, T.; Wang, S.; Xu, H.; Gong, H. Org. Lett. 2011, 13, 2138. (b)
Everson, D. A.; Shrestha, R.; Weix, D. J. J. Am. Chem. Soc. 2010, 132,
920. (c) Goldup, S. M.; Leigh, D. A.; McBurney, R. T.; McGonigal,
P. R.; Plant, A. Chem. Sci. 2010, 1, 383.
ꢀ
B
Org. Lett., Vol. XX, No. XX, XXXX

A variety of cyclic and open-chain secondary iodides
provided ketones 2 and 7À15 in good to excellent yields.
Good to excellent diastereoselectivities were observed for
10À12. No product was observed when the 4-nitro group
was introduced as in 2c. Good coupling yields were also
produced for primary iodides as evident in 16aÀ18a. Alkyl
acid chlorides, such as pivaloyl and 2-phenylacetyl chlor-
ides, were also compatible with the reaction conditions,
giving 2d and 14b in moderate to excellent yields. More-
over, employment of furan-2-carbonyl chloride generated
14c in 45% yield. Using Ni(COD)2/4b catalytic conditions,
the coupling protocol was also effective to generate allylic
and benzylic ketones (19À20). In general, moderate to
excellent yields were resulted. The control experiments
indicated that no to low desired coupling products were
produced with no Ni.
Figure 4. Coupling of alkyl halides with freshly prepared crude
acid chlorides. (a) Standard conditions as in entry 7, Table 1
except freshly prepared acid chlorides (<2.5 equiv) were
used. (b) Unless otherwise mentioned, X = I. (c) Isolated yields.
(d) dr >20:1. (e) Standard conditions except Ni(COD)2 and 4b
were used.
note is that high coupling efficiencies were attained for
alkyl halides bearing neighboring groups that are sterically
bulky or vulnerable to β-elimination as in 9a, 11a,b, 12a,
and 18a.
To understand whether in situ Negishi mechanism
operates, benzoyl chloride was first exposed to an equi-
molar mixture of n-Bu-ZnI and n-propyl iodide under
optimized conditions (Scheme 1). 1-Phenylbutanone and
1-phenylpentanone were obtained in a ratio of 5:1, sug-
gesting that a Negishi pathway is kinetically less feasible
for unactivated alkyl iodides.20 More importantly, treat-
ment of PhC(O)O(CH2)3I (0.15 M in CH3CN) with Zn in
the presence or absence of Ni(acac)2 leads to formation of
no or a trace amount of organozinc reagents even after
12 h. This again supports that a Negishi process is less
likely to be involved. Interestingly, addition of MgCl2
(150 mol %) led to complete conversion to organozinc
after3 h. Theseobservationsmay explain whytheyield was
boosted from 82% (entry 6, Table 1) to 91% (entry 7,
Table 1) by addition of MgCl2, possibly due to the
participation of small amount of in situ organozinc,
although the Negishi process is slower than the reductive
coupling path.
Figure 3. Coupling of alkyl halides with acid chlorides.
(a) Standard conditions as in entry 7, Table 1. (b) Unless
otherwise mentioned, X = I. (c) Isolated yields. (d) ND: not
detected. (e) Standard conditions except Ni(COD)2 was used.
(f) dr >20:1. (g) Standard conditions except Ni(COD)2 and 4b
were used.
An additional survey of various substituted aromatic
acid chlorides was carried out using freshly prepared crude
acid chlorides by removal of excess thionyl chloride,
wherein 2.5 equiv of acid was used to ensure the coupling
effectiveness (Figure 4). This modified procedure allowed
us to easily access ketones 2eÀi and 9bÀd. In general, aroyl
chlorides containing electron-withdrawing groups (e.g., 9c)
and ortho-substituents (e.g., 2h and 9d) diminished the
yields. Other secondary and primary halides gave ketones
21aÀ27a, also in good yields.
Next, treatment of a 1:1 mixture of 2-iodo-2,3-dihydro-
1H-indene and benzoyl chloride with Ni(COD)2 (1 equiv)/
3a/MgCl2 (1:1:1.5) in CH3CN for 10 min led to about 75%
(20) Coupling of a 1:1:2 mixture of n-Pr-I, n-Bu-I, and PhCOCl gave
n-Pr-COPh and n-BuCOPh in a 4:5 ratio and 55% total yield.
(21) Tracking the reaction progress for the coupling of PhCOCl
(2 equiv) with 2-iodo-2,3-dihydro-1H-indene (1 equiv) under the optimized
conditions disclosed that acylation completed after 30 min (see the
Supporting Information), while for 1a, it took 4 h, suggesting the former
iodide is more reactive.
The collective examples in Figures 2 and 3 indicated that
the coupling conditions displayed excellent functional
group tolerance. These included ketone, acetal, fluorine
and chlorine, cyanide, lactone, silyl, and alkene. Of special
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 1. Ni-Catalyzed Acylation of n-BuZnI and n-PrI
Scheme 2. Coupling of 28 and Benzoyl Chloride
conversion of PhCOCl, and trace amount of conversion
for the alkyl iodide.21 Thus, PhCOCl is kinetically favored
in oxidative addition to Ni0.22
In summary, we have disclosed an efficient Ni-catalyzed
reductive coupling of alkyl halides with acid chlorides
under mild conditions that are tolerant of various func-
tional groups. A wide range of activated and unactivated
alkyl halides as well as aryl and alkyl acid chlorides
are competent, generally offering ketones in good yields.
Our initial mechanistic studies suggest that for unactivated
alkyl iodides a NiI/NiIII process for the synthesis of alkyl
aryl ketones may operate. The use of zinc powder as the
terminal reductant avoids preparation of organozinc
reagents, which would otherwise be difficult to achieve
for alkyl halides bearing functional groups amenable for
β-elimination. Further understanding the reaction mechan-
ism for this mild, easy-to-operate ketone formation method
is under investigation.
The previous studies in the Ni-catalyzed Negishi cou-
pling of alkyl halides suggest that oxidative addition of
alkyl halides toa NiI species23,24 first involvesgeneration of
an alkyl radical and a NiII intermediate which rapidly
combine (k > 107 s), leading to an alkyl-NiIII species.24c
Acylation of 28 indeed produced a cyclization product 29a
in good yields, confirming that a radical intermediate
may be involved, likely via oxidative addition of alkyl
halide to PhCO-NiI to produce a PhCO-NiIII-alkyl species
(Scheme 2).24,25 Although to our knowledge PhCO-NiI is
unknown, we propose that it could be generated by reduc-
tion of the PhCO-NiII intermediate with Zn.26 A working
model for the catalytic process can thus be completed by
reductive elimination of a PhCO-NiIII-alkyl intermediate
to yield the ketone product and a Ni(I) species. Subsequent
reduction of the NiI to regenerate Ni0 allows the catalysis
to proceed.
Acknowledgment. Dr. Hongmei Deng (Shanghai
University) and Dr. Pengcheng Xu (SIMIT, CAS) are
thanked for assistance with use of the NMR and GCÀMS
instruments, respectively. Financial support was provided
by the Chinese NSF (Nos. 2097209 and 21172140), the
Program for Professor of Special Appointment at Shanghai
Institutions of Higher Learning Shanghai Education Com-
mittee, and Shanghai Leading Academic Discipline Project
(Nos. S30107 and J50101).
(22) (a) Inaba, S.-i.; Rieke, R. D. J. Org. Chem. 1985, 50, 1373.
(b) Fahey, D. R.; Mahan, J. E. J. Am. Chem. Soc. 1977, 99, 2501.
(23) For seminal work using N-containing ligands, see: Zhou, J.; Fu,
G. C. J. Am. Chem. Soc. 2003, 125, 14726.
(24) For mechanistic discussions on Ni-catalyzed Negishi reactions,
see: (a) Lin, X.; Sun, J.; Xi, Y.; Lin, D. Organometallics 2011, 30, 3284.
(b) Lin, X.; Phillips, D. L. J. Org. Chem. 2008, 73, 3680. (c) Phapale,
~
ꢀ
V. B.; Bunuel, E.; Garcıa-Iglesias, M.; Cardenas, D. J. Angew. Chem.,
Int. Ed. 2007, 46, 8790. (d) Jones, G. D.; Martin, J. L.; McFarland, C.;
Allen, O. R.; Hall, R. E.; Haley, A. D.; Brandon, R. J.; Konovalova, T.;
Desrochers, P. J.; Pulay, P.; Vicic, D. A. J. Am. Chem. Soc. 2006, 128,
13175.
Supporting Information Available.
Spectral data of
new compounds and experimental details. This material
is available free of charge via the Internet at http://pubs.
acs.org.
ꢀ
(25) (a) Gonzalez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 128,
5360–5361 and reference cited therein. (b) Gong, H.; Andrews, R. S.;
ꢀ
Zuccarello, J. L.; Lee, S. J.; Gagne, M. R. Org. Lett. 2009, 11, 879–882.
(26) BnCONi(I) is evidenced in the electrochemical reduction process
(ref 14c).
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX