Alkyl-aryl ketone synthesis via nickel-catalyzed reductive coupling of alkyl halides with aryl acids and anhydrides

Article abstract of DOI:10.1039/c5cc03113c

The present work disclosed a considerably improved method for the construction of alkyl-aryl ketones by the direct coupling of unactivated alkyl bromides with 1.5 equiv. of acids. In addition, the synthesis of aroyl C-glycosides was first achieved by the

Full text of DOI:10.1039/c5cc03113c

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: X. Jia, X. Zhang,
Q. qian and H. Gong, Chem. Commun., 2015, DOI: 10.1039/C5CC03113C.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/chemcomm

Please do not adjust margins
Page 1 of 4
ChemComm
View Article Online
DOI: 10.1039/C5CC03113C
Journal Name
COMMUNICATION
Alkyl-Aryl Ketone Synthesis via Nickel-Catalyzed Reductive
†
Coupling of Alkyl Halides with Aryl Acids and Anhydrides
Xiao Jia,a Xinghua, Zhang,b* Qun Qiana* and Hegui Gonga*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The present work disclosed a much improved method for the
construction of alkyl‒aryl ketones by direct coupling of unactivated
alkyl bromides with 1.5 equiv of acids. In addition, the synthesis of
aroyl C-glycosides was first achieved by reductive coupling of 1-
glycosyl bromides with acid derivatives, which may otherwise
require multi-step synthesis.
Construction of ketones is conventionally achieved by addition of
organo nucleophiles to acid derivatives.1 However, over addition of
the organo nucleophiles to the resultant ketones can be problematic,
and hence requires special conditions e.g., low temperature, or
special acid derivatives.2 To avoid this issue, mild catalytic ketone
synthesis has been well-established which generally involves the
coupling of organometallic reagents with acid derivatives.3-6
However, preparation of alkyl organometallics, particularly those
bearing β-functional groups often suffers β-elimination issues.7-8
Reductive coupling of alkyl halides with a variety of other
electrophiles has led to facile construction of a number of C(sp3)‒
C(sp3) and C(sp3)‒C(sp2) bonds.9-16 The formation of alkyl ketones, for
example, can now be efficiently achieved when coupling of alkyl
halides with acid chlorides, anhydrides and in situ activated acids in
the presence of MgCl2 and Boc2O.14, 15b, 16 Direct coupling of alkyl
halides with acids is particularly intriguing as both electrophiles are
readily available, which avoids pre-preparation of alkyl nucleophiles
and acid derivatives. Recently, we have demonstrated that the most
challenging tertiary alkyl bromides can effectively couple with in situ
activated alkyl acids.16 Extension of this protocol to the α-selective
synthesis of alkanoyl C-glycosides is also satisfactory (Figure 1).16
However, the previous conditions for alkyl acids or their anhydrides
were not applicable to aryl acids and their derivatives, possibly due
to unmatched reactivities of alkyl halides with in situ formed aryl acid
anhydrides.16
Scheme 1. Methods to ketones by the coupling of alkyl halides with
acids
Although our early studies disclosed that the coupling of
unactivated primary and secondary alkyl iodides react with 4 equiv
of aryl acids with a narrow range of substrate scope,14b in general low
to moderate yields were obtained except for 4-H- and 4-tBu-
substituted benzoic acids. In the present work, we describe a much
improved process for the coupling of unactivated alkyl bromides with
in situ activated acids by formation of acid anhydrides in the
presence of Boc2O and MgCl2. The reaction conditions allow use of
1.5 equiv of acids in excess. In addition, the coupling strategy can be
extended to efficient coupling of glycosyl bromides with aryl acid
derivatives, particularly anhydrides to generate α-selective aroyl C-
glycosides, which may require multistep synthesis due to the
a.Department of Chemistry, Shanghai University, 99 Shang-Da Road, Shanghai
200444, China. hegui_gong@shu.edu.cn, qianqun@shu.edu.cn
b.College of Chemical and Environmental Engineering, Shanghai Institute of
Technology, 100 Hai-Quan Road, Shanghai 201418, China. zxhxmu@126.com.
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
challenges of coupling with classic glycosyl and acyl nucleophiles.17-
19
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 4
COMMUNICATION
Journal Name
At the outset, we chose 4-bromo-1-tosylpiperidine 1a and 1.5
equiv of benzoic acid as the model substrates. Under the previously
developed reaction conditions for the coupling of alkyl halides with
alkyl acids,16 and alkyl iodides with 4 equiv of aryl acids,14b the ketone
product 2 was obtained in very low yields. With significant amount
of optimization efforts, we eventually identified that a combination
of Ni(acac)2/4b/DMF in the presence of MgCl2 and Boc2O in
CH3CN/DMF (1/4) enabled the reaction to generate 2 in 88% yield at
ambient temperature (Table 1, entry 1). The amount of Ni precatalyst
loading was reduced to only 5% as opposed to 10% in the previous
conditions for the coupling of alkyl iodides with aryl acids using air
sensitive Ni(COD)2.14b Other ligands (entries 2‒10), nickel sources
(entries 11‒14) and solvents (15‒19) were inferior. A mixture of
CH3CN and DMF in a ratio of 2/8 proved to be optimal which is more
efficient than any of the single solvent (entries 16 and 18). In general,
the major side reaction comprised of hydrodehalogenation
reduction of 1.
12
13
14
15
16
17
18
19
NiBr2, instead of Ni(acac)2
NiCl2, instead of Ni(acac)2
NiI2, instead of Ni(acac)2
DMF, instead of CH3CN/DMF 0.2/0.8
DMA, instead of CH3CN/DMF 0.2/0.8
THF, instead of CH3CN/DMF 0.2/0.8
CH3CN, instead of CH3CN/DMF 0.2/0.8
DME/DMF 0.2/0.8 , instead of
CH3CN/DMF 0.2/0.8
62
View Article Online
c
DOI: 10.1039/C5CC03113C
ND
59
63
38
20
16
77
a Reaction Conditions: 1a (0.15 mmol), Ni(acac)2 (5 mol %), Zn (300 mol
%), MgCl2 (250 mol %) Ligand (7 mol %), CH3CN/DMF 1/4 (1 mL), 25 oC.
b Isolated yields. c Not detected.
With the optimized conditions in hand, a wide set of alkyl
bromides and aryl acids was examined (Figure 2). The coupling of
variety of para-substituted aryl acids with 1 disclosed that the
electron-rich aryl rings were generally more effective than electron-
poor ones, as evident in 2b‒k. While acids containing alkyl, chloro,
fluoro and methoxyl groups generated ketones in good to high yields,
the electron deficient acids bearing CF3 and CO2Me produced the
ketones 2f and 2g in low yields. Under the present method the yield
for 2k was 58%, which is enhanced from 40% under the previous
method for the coupling of 4-iodo-1-tosylpiperidine 1b with 4 equiv
of aryl acid. Other secondary alkyl bromides bearing functional
groups such as ester, ether, amide and silyl ethers proved to be
effective as evident in 8‒17. More sterically demanding TBS group in
the neighboring positions also gave the ketone products 16 and 17 in
excellent yields with high diasteroselectivities. The alkyl bromides
without functionality such as cyclohexyl bromide and isopropyl
bromide produced the ketones 18 and 19 in low yields which is much
less effective than the previous methods using iodo alkanes with 4
equiv of acids.14b However, under the conditions developed for 1-
glycosyl bromides (Figure 3, vide infra), the unfunctionalized iodo
substrates effectively coupled with 1.5 equiv of aryl acids.
Figure 1. Structures of ligands
Table 1. Optimization for the cyclization of 1a
entra
variation from the "standard"
conditions
Yield (%)b
1
2
3
4
5
6
7
8
none
88
22
27
23
47
53
71
14
23
17
70
3a, instead of 4b
3b, instead of 4b
3c, instead of 4b
4a, instead of 4b
4c, instead of 4b
5a, instead of4b
5b, instead of 4b
5c,instead of 4b
6, instead of 4b
Figure 2. (a) Same as Table 1, entry 1. (b) Isolated yields. (c)
DME/DMF = 1/9 (1 mL). (d) CN3CN/DMF (4/1, 0.5 mL). (e) 10%
Ni(acac)2 and 15% 4b were used. (f) dr > 20:1 (g) Alkyl iodide (0.3
mmol) was used under the reaction conditions in Table 2, entry 12
except CN3CN/DMF (4/1, 1 mL).
9
10
11
Ni(cod)2, instead of Ni(acac)2
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 4
ChemComm
Please do not adjust margins
Journal Name
COMMUNICATION
Encouraged by the success in the efficient coupling of aryl acids
with alkyl bromides, we then extended the optimized reaction
conditions to the coupling of glucosyl bromide with benzoic acid.
However, even with 10% Ni(acac)2, only trace amount of the desired
ketone was obtained (Table 2, entry 1 and Table S3, entry 1).20 By
addition of 20% of Bu4NI (TBAI), the ketone product 21 was obtained
in 47% with an α/β ratio of 2.8:1 (entry 2). While changes of ligands
or the acid derivative to PhCOCl did not yield better results (Table 2,
entries 3‒5), optimization using benzoic acid anhydride in CH3CN
with ligand 5a was able to generate 21 in 62% yield, although the α
selectivity slightly dropped (Table 2, entries 6‒8). Use of a mixture of
solvent CH3CN/DMF in a ratio of 4:1 with ligand 4a increased the yield
to 68% (Table 2, entries 9‒10). Replacement of Ni(acac)2 with
Ni(ClO4)2∙6H2O further enhance the yield to 74%. Finally, CH3CN/DMF
in a ratio of 9:1 gave the product in a highest 92% yield with an α/β
ratio of 2.7:1.
View Article Online
DOI: 10.1039/C5CC03113C
The scope and limitation of acyl C-glycoside formation was next
examined. When coupling with glucosyl bromides, the electron-rich
aryl acid anhydrides generally gave ketones in high yields with
moderate α selectivities as evident in 22‒26. The reaction conditions
also tolerate 2-furyl acid chloride, although a low coupling yield for
was observed.21 The formation of acyl galactosides displayed high
coupling efficiency as evident in 27‒31 with higher α selectivities
Figure 3. (a) Reaction conditions: same as Table 2, entry 12. (b)
Isolated yields. (c) Ni(acac)2 (10 mol %), Ligand (4b, 12 mol %),
than glucosides. Finally, mannoside 32 with only α anomer was also CH3CN/DMF 4/1 (1 mL).
successfully obtained. The low yield for 32 was due to rapid E-2
elimination during silica column chromatography.
In conclusion, we have described the coupling of aryl acids with
unactivated alkyl bromides which displayed much higher coupling
efficiency than the previous conditions for the coupling with alkyl
iodides by significantly reducing the catalyst and acid loading. The
use of easy-to-handle Ni(acac)2 renders this method more practical
for the synthesis of secondary alkyl aryl ketones. The first efficient
synthesis of aroyl C-glycosides by direct reductive coupling of 1-
glycosyl bromides with acid derivatives provided a rapid access to the
construction of C-C bonds on carbohydrates, which may find
applications to the synthesis of bioactivally relevant compounds.
Table 2. Optimization for benzoylation of glucosyl bromides
entrya
PhCOY
Ni/ligand/additive CH3CN yield%
/DMF
(α:β)b
1c
2 c
3 c
PhCOOH
PhCOOH
Ni(acac)2/4b/none 4:1
trace (NA)
47 (2.8:1)
Ni(acac)2/4b/TBAI
Ni(acac)2/4a/TBAI
4:1
4:1
Acknowledgement
PhCOOH
PhCOCl
28 (2.1:1)
Dr Hongmei Deng (Shanghai University) is thanked for helping use
of the NMR facility. Financial support was provided by the Chinese
NSF (Nos. 21172140, 21302127 and 21372151), the Program for
Professor of Special Appointment at Shanghai Institutions of Higher
Learning (Dong fang Scholar) Shanghai Education Committee.
4
NiBr2∙diglyme/4a/ CH3CN 33 (3.6:1)
TBAI
5
PhCOCl
NiBr2∙diglyme/3c/ CH3CN 45 (2.8:1)
TBAI
6
7
8
9
10
11
(PhCO)2O
(PhCO)2O
(PhCO)2O
(PhCO)2O
(PhCO)2O
(PhCO)2O
Ni(acac)2/4b/TBAI
Ni(acac)2/4a/TBAI
Ni(acac)2/5a/TBAI
Ni(acac)2/5a/TBAI
Ni(acac)2/4a/TBAI
CH3CN 25 (7:1)
CH3CN 37 (4.3:1)
CH3CN 62 (2.4:1)
Notes and references
1
2
R. K. Diete, Tetrahedron, 1999, 55, 4177.
4:1
4:1
59 (2.5:1)
68 (3.2:1)
74 (3.1:1)
(a) W. S. Bechara, G. Pelletier and A. B. Charette, Nature Chem.,
2011, 4, 228; (b) A. R. Katritzky, K. N. B. Le and L. Khelashvili, P. P.
Mohapatra, J. Org. Chem., 2006, 71, 9861.
Ni(ClO4)2∙6H2O/4a 4:1
/TBAI
3
4
J. B. Johnson and T. Rovis, Acc. Chem. Res., 2008, 41, 327.
For selected examples of acylation of aryl and
alkynylnucleophiles,Negishi: (a) H. H. Xu , K. 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. Müller,
Angew. Chem. Int. Ed., 2011, 50, 10448; Fukuyama: (e) Y. Yu and
L. S. Liebeskind, J. Org. Chem., 2004, 69, 3554.
12
(PhCO)2O Ni(ClO4)2∙6H2O/4a 9:1
92(2.7:1)d
/TBAI
a Reaction Conditions: 20 (0.3 mmol), Ni(ClO4)2∙6H2O (10 mol %),
Zn (300 mol %), ligand (12 mol %), TBAI (20 mol %), CN3CN/DMF
(9/1,1 mL), 25 oC. b NMR yield using trimethyl(phenyl)silane as the
internal standard. c Boc2O (300% was added. d Isolated yields.
5
For selected examples of Pd-catalyzed acylation of alkyl-
metallics: (a) M. Asaoka, A. Kosaka, M. Tanaka, T. Ueda, T.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 4
COMMUNICATION
Journal Name
Houkawa and H. Takei, J. Chem. Soc. Perkin Trans. 1, 1997, 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.
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. Fürstner, Acc. Chem. Res., 2008,
41, 1500; Cu: (c) N. Coia, N. Mokhtari, J.‒L. Vasse and J.
Szymoniak, Org. Lett., 2011, 13, 6292.
(a) A. K. Steib, T. Thaler, K. Komeyama, P. Mayer and P. Knochel,
Angew. Chem. Int. Ed., 2011, 50, 3303; (b) X.–F. Wu, H. Neumann
and M. Beller, Chem. Soc. Rev., 2011, 40, 4986.
For a review on alkyl-organometallics, see: R.J. Jana, T. P. Pathak
and M. S. Sigman, Chem. Rev., 2011, 111, 1417.
W. Lu, Z. Liang, Y. Zhang, F. Wu, Q. Qian and H. Gong, Synthesis,
View Article Online
DOI: 10.1039/C5CC03113C
2013, 45, 2234-2240.
15 For Ni-catalyzed asymmetric vinylation and acylation of benylic
halides, see: (a) A. H. Cherney, N. T. Kadunce and S. E. Reisman,
J. Am. Chem. Soc., 2013, 135, 7442; (b) Alan H. Cherney and S. E.
Reisman, J. Am. Chem. Soc., 2014, 136, 14365−14368.
16 For Ni-catalyzed reductive acylation of 3o alkyl halides with acid
derivatives, see: C. Zhao, X. Jia, X. Wang and H. Gong, J. Am.
Chem. Soc., 2014, 136, 17645.
17 Synthesis of β-acyl C-glycosides, from: sugar benzothiazoles (a)
A. Dondoni, N. Catozzi and A. Marra, J. Org. Chem., 2005, 70,
9257; Sugar CN: (b) S. Knapp, W.‒C. Shieh, C. Jaramillo, R. V.
Trilles and S. R. Nandan, J. Org. Chem., 1994, 59, 946; Sugar acids:
(c) Wolfgang Weiser, J. Lehmann, C. F. Brewer, E. J. Hehre,
Carbohydrate Res., 1988, 183, 287.
6
7
8
9
For recent reviews on reductive coupling of two electrophiles,
see: (a) C. E. I. Knappke, S. Grupe, D. Gꢀrtner, M. Corpet, C.
Gosmini and A. J. von Wangelin, Chem.‒Eur. J., 2014, 20, 6828;
(b) D. A. Everson and D. J. Weix, J. Org. Chem., 2014, 79, 4793; (c)
T. Moragas, A. Correa and R. Martin, Chem.‒Eur. J., 2014, 20,
8242.
18 Synthesis of α-acyl C-glycosides from: sugar alkyne: (a) D.
Álvarez-Dorta, E. I. León, A. R. Kennedy, C. Riesco-Fagundo and E.
Suárez, Angew. Chem. Int. Ed., 2008, 47, 8917; Sugar allene: (b)
Y. Geng, A. Kumar, H. M. Faidallah, H. A. Albar, I. A. Mhkalid and
R. R. Schmidt, Bioorg. Med. Chem., 2013, 21, 4793; Sugar acyl
oxazoline: (c) C. M. Jensen, K. B. Lindsay, R. H. Taaning, J. Karaffa,
A. Mette Hansen and T. Skrydstrup, J. Am. Chem. Soc., 2005, 127,
6544. Sugar alkene to α-C-glycosyl acid; (d) C.-H. Wong, F. Moris-
Varas, S.‒C. Hung, T.‒G. Marron, C.‒C. Lin, K. W. Gong and G.
Weitz-Schmidt, J. Am. Chem. Soc., 1997, 119, 8152.
10 For catalytic C(sp3)–C(sp3) bond formation via cross-coupling of
two alkyl electrophiles, see: (a) (a) X. Yu, T. Yang, S. Wang, H. Xu
and H. G. Gong, Org. Lett., 2011, 13, 2138; (b) H. L. Xu, C. Zhao,
Q. Qian, W. Deng and H. G. Gong, Chem. Sci., 2013, 4, 4022; (c) Z.
Liang, W. Xue, K. Lin and H. G. Gong, Org. Lett., 2014, 16, 5620;
(d) W. Xue. H. Xu, Z. Liang, Q. Qian and H. G. Gong, Org. Lett.,
2014, 16, 4984.
11 For Ni-catalyzed reductive arylation of alkyl halides with aryl
halides, see: (a) D. A. Everson, R. Shrestha and D. J. Weix, J. Am.
Chem. Soc., 2010, 132, 920; (b) C.-S. Yan, Y. Peng, X.-B. Xu and Y.-
W. Wang, Chem. Eur. J., 2012, 18, 6039; (c) D. A. Everson, B. A.
Jones and D. J. Weix, J. Am. Chem. Soc., 2012, 134, 6146; (d) S.
Wang, Q. Qian and H. G. Gong, Org. Lett., 2012, 14, 3352. (e) L.
K. G. Ackerman, L. L. Anka-Lufford, M. Naodovic and D. J. Weix,
Chem. Sci., 2015, 6, 1115
19 For selected examples of acyl nucleophiles: (a) J. R. Schmink and
S. W. Krska, J. Am. Chem. Soc., 2011, 133, 19574; (b) D. A. DiRocco
and T. Rovis, J. Am. Chem. Soc., 2012, 134, 8094.
20 See the Supporting Information for details.
21 Ni(ClO4)2∙6H2O (20 mol %), 4b (20 mol %) and furan-2-carbonyl
chloride were used. ~25% NMR yield for the α anomer using
trimethyl(phenyl)silane as internal standard was shown in the
supporting information; α/β ratio is not available due to
interference of inseparable impurities.
12 For reductive allylation of aryl and alkyl halides, see: (a) Y. Dai, F.
Wu, Z. Zang and H. You, H. Gong, Chem.‒Eur. J., 2012, 16, 808;
(b) X. Cui, S. Wang, Y. Zhang, Q. Qian and H. Gong, Org. Biomol.
Chem., 2013, 11, 3094; (c) X. Qian, A. Auffrant, A. Felouat and C.
Gosmini, Angew. Chem. Int. Ed., 2011, 50, 10402; (d) L. L. Anka-
Lufford, M. R. Prinsell and D. J. Weix, J. Org. Chem., 2012, 77,
9989.
13 For Ni-catalyzed CO2 trapping with alkyl halides and allylic
acetates, see: (a) Y. Liu, J. Cornella and R. Martin, J. Am. Chem.
Soc., 2014, 136, 11212; (b) T. León, A. Correa and R. Martin, J.
Am. Chem. Soc., 2013, 135, 1221; (c) T. Moragas, J. Cornella and
R. Martin, J. Am. Chem. Soc., 2014, 136, 17702; (d) A. Correa, T.
León and R. Martin, J. Am. Chem. Soc., 2014, 136, 1062.
14 For Ni-catalyzed reductive acylation of 1o and 2o alkyl halides with
acid derivatives, see: (a) F. Wu, W. Lu, Q. Qian, Q. Ren and H.
Gong, Org. Lett., 2012, 14, 3044; (b) H. Y. Yin, C. L. Zhao, H. Z. You,
K. H. Lin and H. G. Gong, Chem. Commun., 2012, 48, 7034; (c) A.
C. Wotal and D. J. Weix, Org. Lett., 2012, 14, 1476; (d) M. Onaka,
Y. Matsuoka and T. Mukaiyama, Chem. Lett., 1981, 10, 531; (e)
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins