Nickel-catalyzed alkyl-alkyl cross-coupling reactions of non-activated secondary alkyl bromides with aldehydes as alkyl carbanion equivalents

Article abstract of DOI:10.1039/c9cc00307j

A novel nickel-catalyzed alkyl-alkyl cross coupling of non-activated secondary alkyl bromides with aldehydes via hydrazone intermediates has been developed. Aldehydes as alkyl carbanion equivalents replace traditional organometallic reagents. This coupling occurs on the carbon of the hydrazone rather than the nitrogen. In addition, non-activated primary and tertiary alkyl bromides also undergo the cross-coupling reaction to form new C(sp³)-C(sp³) bonds in moderate yields.

Full text of DOI:10.1039/c9cc00307j

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
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DOI: 10.1039/C9CC00307J
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Nickel-Catalyzed Alkyl-Alkyl Cross-Coupling Reactions of Non-
activated Secondary Alkyl Bromides with Aldehydes as Alkyl
Carbanion Equivalents
Received 00th January 20xx,
Accepted 00th January 20xx
Chenghao Zhu, Junliang Zhang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel nickel-catalyzed alkyl-alkyl cross coupling of unactivated undoubtedly cause metal waste and environmental pollution. So we
secondary alkyl bromides with aldehydes via hydrazone need to find new alkyl nucleophiles and new transition metal
intermediates has been developed. Aldehyde as an alkyl carbanion catalysis mode to solve above challenges.
equivalent replaces traditional organometallic reagents. This
alkyl
X
alkyl
alkyl
Metal
+
coupling occurs on the carbon of the hydrazone rather than the
nitrogen. In addition, non-activated primary and tertiary alkyl
bromides also undergo the cross-coupling reaction to form new
C(sp3)-C(sp3) bond in moderate yield.
a)
M
alkyl
alkyl
alkyl
X = Br, Cl, I, F
M = Mg, Zn, Li, B, etc.
Metal = Ni, Cu, Pd, Co, Fe, Ag, etc.
alkyl
alkyl
alkyl
Reducing metal
b)
c)
+
X
R
alkyl
OAc
alkyl
X
Transition metal-catalyzed cross-coupling reactions to form
carbon-carbon bonds have been extensively developed for many
years.1 The cross coupling reactions of alkyl halides had been difficult
to achieve because of the reluctance of alkyl halides to undergo
oxidative addition, reductive elimination and alkyl metal
intermediates are more reactive and cause more side reactions such
as β-H elimination and protonation.2 For all that, this coupling
reaction of alkyl halides is still getting faster development, especially
primary alkyl halides.3, 4
X = Br, I, OTs, etc.
R = aryl, alkyl, alkenyl
Reducing metal = Mg, Zn, etc.
NH2
R'
R'
O
N
N H H O
2
•
2
4
R
R'
NH2
-N2
R
R
up to 98% yield
Ni(COD)2, ligand, base
50 o
N
+
X
Ar
R
Ar
d)
e)
R
C
up to 93% yield
R = aryl, alkyl
X = Br, I
Compared to primary alkyl halides, alkyl-alkyl cross-coupling
reactions of secondary alkyl halides to form C(sp3)-C(sp3) bond pose
more considerable challenge, especially non-activated secondary
alkyl halides.4 Fu, Kambe, Hu and other groups developed cross
coupling reactions of non-activated secondary alkyl halides with
organometallic reagents5 (Scheme 1a). Gong, Liu, Peng and others
achieved reductive coupling reactions between alkyl halides to form
C(sp3)-C(sp3) bond by using stoichiometric reducing metals (Scheme
1b).6 Yu and co-workers have successfully developed palladium-
catalyzed radical alkylation of C-H bonds with unactivated alkyl
bromides to form C(sp3)-C(sp3) bonds driven by visible-light.7 The
main disadvantage of generating C(sp3)-C(sp3) bonds is the use of
stoichiometric metals according to existing reports which would
Br
this work
alkyl
N H H O
•
2
2
4
alkyl
alkyl
R
R
alkyl
NNH2
R
O
THF, r.t., 30 min
R = alkyl, aryl
Ni
Scheme 1. Alkyl-alkyl cross-coupling reactions
In 2017, Li and co-workers have developed an elegant strategy for
C-C bond formation reaction via umpolung of carbonyl groups as
alkyl carbanion equivalents to react various electrophiles.8 Very
recently, they successfully extend this strategy to palladium-
catalyzed cross-coupling with allylic actetae (Scheme 1c) and nickel-
catalyzed cross-coupling with aryl halides (Scheme 1d).8e This novel
alkyl carbanion equivalent had not well employed in coupling with
the more challenging unactivated secondary and tertiary alkyl
bromides. Inspired by Li’s work, we reported herein a nickel-
catalyzed alkyl-alkyl cross-coupling between non-activated
secondary bromides and aldehyde hydrazones to form C(sp3)-C(sp3)
bonds (Scheme 1e), in which no N-coupling products or not C-
coupling products were observed.10
Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of
Chemistry and Molecular Engineering, East China Normal University, 3663 N.
Zhongshan Road, Shanghai 200062, China; E-mail: jlzhang@chem.ecnu.edu.cn; Fax:
+86-21-6223-3213
†
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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To study this alkyl-alkyl cross coupling reaction, the hydrazone (1a) slightly lower yields. However, to our disappointment,VwieewdAirdticnleoOtnglienet
generated in situ from benzaldehyde and (3-bromobutyl)benzene the coupling products when ketone hydrazDoOneI:s10w.1e0r3e9/sCu9bCjeCc0t0e3d07toJ
(2a) were selected as the model substrates. Fortunately, the desired the reaction (3r, 3s, 3t), even though more reactive primary alkyl
product 3a was obtained in nickel-catalyzed system (Table 1, entries bromide was used (3t). We reasoned that this poor reactivity may be
1-4). We screened different ligands but the yield was not improved caused by steric hindrance and electronic effects difference between
(Table 1, entries 5-8). The yield can be slightly improved with aromatic aldehyde and ketone.8a
increasing the catalyst loading (Table 1, entry 9). While the coupling
product 3a was not detected when other bases such as DBU, K3PO4,
Ni(COD)2 (10 mol%),
dppf (20 mol%)
Br
R
Ph
NaOtBu (2 equiv.), THF, 80 o
C
Cs2CO3 were uesd (Table 1, entries 10-12). With the temperature
R
+
NNH2
Ph
1
2a
12 h
3
increases, the yield of 3a was improved to 65% when the reaction
was run at 80 oC (oil bath, Table 1, entry 15). When either nickel, dppf,
or NaOtBu was removed, the yield dropped (Table 1, entries 16-18).
When Hydrazine hydrate was added, the product was not detected
(Table 1, entry 19).
OMe
Ph
Ph
Me
Ph
Ph
Ph
Ph
3c
, 53%
3a
, 58%
3b
3e
, 61%
Cl
F
Cl
O
3f
, 68%
OMe
Cl
Table 1. Optimization reaction conditions
3d
, 54%
, 59%
Br
CF3
[Ni] (5 mol%), Ligand (10 mol%)
Ph
Ph
+
Ph
NNH2
Ph
Base (2 equiv.), THF, 60 oC, 12 h
Ph
Ph
Ph
3a
1a
2a
3i
, 61%
Entry
1
[Ni]
NiI2
Ligand
dppf
dppf
dppf
dppf
PPh3
PCy3
bpy
Base
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
DBU
Yield (%)d
30
3g
3j
, 54%
3h
, 62%
3k
, 62%
3n
, 61%
S
Ph
O
Ph
Ph
Ph
Ph
2
NiBr2
11
Ph
Ph
3l
, 42%
, 41%
3
Ni(PPh3)4
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
-
13
4
31
Fe
5
7
3o
, 20%
3m
, 53%
6
16
Ph
Ph
7
n.d.
25
Ph
Ph
Ph
Ph
Ph
8
9a
dmpe
dppf
dppf
dppf
dppf
dppf
dppf
dppf
-
3p
3q
3r
, n.d.
, 38%
, 48%
OMe
42
10a
11a
12a
13a
15a, b
16a, b
17a, b
18a, b
19a, b, c
n. d.
n. d.
n. d.
22
K3PO4
3s
, n.d.
3t 3b
(
), n.d.
Cs2CO3
KOtBu
NaOtBu
NaOtBu
NaOtBu
-
Scheme 2. Substrate scope of aldehyde hydrazones
Ni(COD)2 (10 mol%),
Br
Ph
65
NNH2
dppf (20 mol%)
+
alkyl
NaOtBu (2 equiv.), THF, 80 o
C
alkyl
alkyl
Ph
n. d.
39
alkyl
12 h
1k
2b-j
4
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ph
Ph
Ph
Ph
Ph
dppf
dppf
n. d.
n. d.
CF3
NaOtBu
Ph
Ph
Ph
4b, 52%
4e, 54%
4c, 36%
4d, 43%
Reaction condition: 1a (0.6 mmol), 2a (0.3 mmol), [Ni] (10 mol%), ligand (20
mol%), NaOtBu (0.6 mmol), THF (3 mL), 60 oC, 12 h. a Ni(COD)2 (10 mol%), dppf
(20 mol%). b 80 oC. c N2H4·H2O (0.6 mmol). d Yields were determined by crude
Ph
Ph
Ph
O
Ph
Ph
4g, 53%
4f, 42%
Ph
e
1H NMR using CH2Br2 as an internal standard.
dppf
=
1,1'-
1,2-
Bis(diphenylphosphino)ferrocene, bpy
= 2,2'-bipyridine, dmpe =
4j, 55%
4i, 61%
4h, 60%
Bis(dimethylphosphino)ethane, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene,
n.d. = not detected.
Scheme 3. Substrate scope of secondary alkyl bromides
Having studied the scope of aldehyde hydrazones, we turned our
attention to non-activated secondary alkyl bromides (Scheme 3).
Considering the fluorescence of the product, we chose 1k as the
model substrate. Compared with 2a, longer linear secondary alkyl
bromides include branched alkyl and alkenyl gave relatively lower
yield (4b, 4c). Secondary alkyl bromide containing trifluoromethyl
also obtained the corresponding product in 43% yield (Scheme 3, 4d).
54% yield was obtainded for ether-substituted alkyl bromide
(Scheme 3, 4e). Converts shorter linear alkyl bromide to the desired
product in 42% yield (Scheme 3, 4f). 3-bromopentane also provided
With the optimized conditions in hand, the substrate scope of
aldehyde hydrazones for this alkyl-alkyl cross coupling was
investigated (Scheme 2). The reactions of aromatic aldehydes with
electron-withdrawing and electron-donating groups delivered the
corresponding products 3b-3k in moderate yields. Specifically, meta-,
ortho-substituted aromatic hydrazones have no significant impact on
yield. Moreover, hydrazones derived from aldehydes such as 1-
naphthaldehyde, 2-furaldehyde, ferrocenecarbaldehyde could
deliver the desired products 3l-3n in 42-61% yields. Aliphatic
aldehyde hydrazones also gave the cross coupling products 3o-3q in
2 | J. Name., 2012, 00, 1-3
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allowed single electron oxidation addition to give interVmieewdAiratitceleBOnalninde
alkyl radical C, where an oxidative radical aDdOdiIt:i1o0n.10o3c9c/uCr9sCtCo0g0i3v0e7aJ
nickel(II)–dialkyl complex D, which underwent transmetalation with
carbon-nucleophile H derived from deprotonation of hydrazone 1 to
form the intermediate E. Reductive elimination gave the diimide F
moderate yield of 53% (Scheme 3, 4g). In addition, cyclic alkyl
bromides including 1-bromocyclopentane, 1-bromocyclohexane,
bromocycloheptane accomplished this conversion (Scheme 3, 4h-4i).
Finally, the cross coupling reactions with primary and tertiary alkyl
bromides were investigated. 1-Bromoheptane 2k and 1- and regenerated Ni (0) catalyst. Finally, the desired product 3 was
formed by denitrogenation assisted with the base.
bromoadamantane 2l smoothly converted into the corresponding
products in 43% and 45% yield, respectively (Eq 1 and 2). These
results indicate our strategy for catalyzing alkyl-alkyl coupling was
not limited to secondary alkyl bromide.
In summary, a novel nickel-catalyzed alkyl-alkyl cross coupling
reactions of non-activated secondary alkyl bromides with aldehydes
as alkyl carbanion equivalents has been successfully developed. The
method provides a simple strategy for alkyl-alkyl cross-couplings
using naturally abundant aldehydes instead of organometallic
reagents to synthesize some useful synthetic precursors having
tertiary carbon centers,5e filling the gaps in the classical cross-
coupling reactions. Further studies on enantioselective version of
this novel cross-coupling chemistry are underway in our laboratory.
We gratefully acknowledge the funding support of NSFC (21425205,
21672067), 973 Program (2015CB856600), and the Program of
Eastern Scholar at Shanghai Institutions of Higher Learning, and the
China Postdoctoral Science Foundation (2017M610236).
Ph
Ni(COD)2 (10 mol%),
NNH2
dppf (20 mol%)
n-hex
2k
Br
+
(1)
n-hex
Ph
Ph
NaOtBu (2 equiv.)
THF, 80 oC, 12 h
5
, 43%
1k
Ni(COD)2 (10 mol%),
dppf (20 mol%)
Ph
NNH2
Br +
(2)
NaOtBu (2 equiv.)
THF, 80 oC, 12 h
2l
1k
6
, 45%
Although the exact mechanism is still unclear at this stage, we still
tried hard to explore. We found that a mixture of olefin by-product
was produced in the presence of base without the nickel catalyst (eq.
3). Cyclopropanecarbaldehyde derived hydrazone 1u could not
deliver the desired products under the reaction conditions (eq. 4).
Secondary alkyl bromide 2m with cyclopropyl group gave a mixture
of ring opening products 9 rather than the corresponding product 4m
(eq. 5). This suggests that the reaction might involve a free radical
process.
Notes and references
1
(a) F. Diederich and P. J. Stang, Metal-Catalyzed Cross-Coupling
Reactions, Wiley-VCH, Weinheim, Germany, 1998; (b) A. de
Meijere and F. Diederich, Metal-Catalyzed Cross-Coupling
Reactions, Wiley-VCH, Weinheim, Germany, 2004; (c) M. R.
Netherton and G. C. Fu, Topics in Organometallic Chemistry:
Palladium in Organic Synthesis, Springer, New York, 2005, 85; (d)
Cross-Coupling Reactions: A Practical Guide, Topics in Current
Chemistry Series 219 (Ed.: Miyaura N.), Springer, New York,
2002.
Br
NaOtBu, THF, 80 o
C
(3)
+
Ph
Ph
Ph
12 h
2b
7
mixture of , 80%
2
3
(a) L. Peng, Y. Li, Y. Li, W. Wang, H. Pang, and G. Yin, ACS Catal.,
2018, 8, 310; (b) S. Dupuy, K. Zhang, A. Goutierre and O. Baudoin,
Angew. Chem. Int. Ed., 2016, 55, 14793; (c) M. C. Henningsen, S.
Jeropoulos, and E. H. Smith, J. Org. Chem., 1989, 54, 3015; (d) A.
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Zhu, J. Am. Chem. Soc., 2017, 139, 13929.
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Standard condition
(4)
(5)
+
NNH2
+
Ph
2a
Ph
3u
, n. d.
1u
8
, n. d.
Ph
Br
4m
, n. d.
Standard condition
Ph
1k
Ph
+
+
2m
Ph
Ph
9
, 45%
Ln-Ni(0)
dppf
alkyl
N
4
5
(a) F. Glorius, Angew. Chem. Int. Ed., 2008, 47, 8347; (b) A.
Rudolph and M. Lautens, Angew. Chem. Int. Ed., 2009, 48, 2656;
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674; (d) M. R. Netherton and G. C. Fu, Adv. Synth. Catal., 2004,
346, 1525.
Base
N2
Br
3
alkyl
NH
P
P
Ni(0)
alkyl
alkyl
R
F
2
A
(a) J. T. Binder, C. J. Cordier and G. C. Fu, J. Am. Chem. Soc., 2012,
134, 17003; (b) S. W. Smith and G. C. Fu, Angew. Chem. Int. Ed.,
2008, 47, 9334; (c) Z. Lu and G. C. Fu, Angew. Chem. Int. Ed.,
2010, 49, 6676; (d) G. Cahiez, C. Chaboche, C. Duplais, A.
Giulliani and A. Moyeux, Adv. Synth. Catal., 2008, 350, 1484; (e)
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132, 11908; (h) Z. Lu, A. Wilsily and G. C. Fu, J. Am. Chem. Soc.,
2011, 133, 8154; (i) B. Saito and G. C. Fu, J. Am. Chem. Soc., 2007,
129, 9602; (j) V. B. Phapale, E. Bunuel, M. G. Iglesias and D. J.
Cárdenas, Angew. Chem. Int. Ed., 2007, 46, 8790; (k) P. Ren, O.
Vechorkin, K. Allmen, R. Scopelliti and X. Hu, J. Am. Chem. Soc.,
2011, 133, 7084; (l) T. Tsuji, H. Yorimitsu and K. Oshima, Angew.
Br
Ni(I)
alkyl
alkyl
P
P
P
P
Ni(II)
N
alkyl
+
alkyl
C
B
R
NH
E
Br
Ni(II)
alkyl
P
P
NH
N
NH
NH
N
2 Base
-H+
N
alkyl
R
R
D
R
G
H
1
Scheme 4. Proposed mechanism
According to our previous works and literature reports4b, 5o, 8d, 11
,
a plausible reaction pathway was depicted in Scheme 4. Ni(0)
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Br
alkyl
N H H O
•
4 2
2
R
alkyl
alkyl
alkyl
R
NNH2
R
O
THF, r.t., 30 min
R = akyl, aryl
Ni
26 examples
form C(sp3)-C(sp3) bonds
broad substrate scope
no organometallic reagent
mild reaction conditions
no reducing metal
selective C-coupling
A novel nickel-catalyzed alkyl-alkyl cross coupling of unactivated secondary alkyl bromides with aldehydes via hydrazone intermediates has
been developed.
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