Mild Base Promoted Nucleophilic Substitution of Unactivated sp3-Carbon Electrophiles with Alkenylboronic Acids

Article abstract of DOI:10.1002/adsc.201800826

Diverse alkenylboronic acids react smoothly with various sp³-carbon electrophiles such as unactivated alkyl triflates in the presence of mild bases such as K₃PO₄. The reaction protocol is very mild and thereby enables high functional group tolerance. This transition metal-free condition is orthogonal towards the classic transition metal catalyzed Suzuki coupling. (Figure presented.).

Full text of DOI:10.1002/adsc.201800826

Title: Mild Base Promoted Nucleophilic Substitution of Unactivated sp3-
Carbon Electrophiles with Alkenylboronic Acids
Authors: Gerald B. Hammond, Bo Xu, Shiwen Liu, and Xiaojun Zeng
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10.1002/adsc.201800826
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Mild Base Promoted Nucleophilic Substitution of Unactivated
sp3-Carbon Electrophiles with Alkenylboronic Acids
Shiwen Liu,[a] Xiaojun Zeng,[a] Gerald B. Hammond[b], * and Bo Xu[a], *
[a] Key Laboratory of Science and Technology of Eco-Textiles, Ministry of Education, College of Chemistry, Chemical
Engineering and Biotechnology, Donghua University, Shanghai 201620, China. [b] Department of Chemistry, University
of Louisville, Louisville, KY 40292, USA.
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. Diverse alkenylboronic acids react smoothly
with various sp3-carbon electrophiles such as unactivated
alkyl triflates in the presence of mild bases such as
K3PO4. The reaction protocol is very mild and thereby
enables high functional group tolerance. This transition
metal-free condition is orthogonal towards the classic
transition metal catalyzed Suzuki coupling.
Keywords: Transition metal-free, cross-coupling,
alkenylboronic acids, sp3-carbon electrophiles
Introduction
The transition metal-catalyzed cross-coupling
between organometallic reagents and carbon
electrophiles is an extremely important carbon–
carbon bond formation protocol in organic
synthesis.[1] In this context, the Suzuki-Miyaura
coupling is by far the most widely used cross-
coupling protocol due to its good functional group
tolerance and the low toxicity of organoboron
reagents.[1-2] In general, Csp2-Csp2 (aryl-aryl, alkenyl-
alkenyl or aryl-alkenyl) bond formations via Suzuki
couplings are highly efficient, while cross-coupling of Scheme 1. Literature background.
sp3 carbon electrophiles with organoborons are more
Despite the progress summarized above, limitations
problematic due to the low reactivity and side
still exist for the cross-coupling of sp3-carbon
reactions such as β-hydride elimination.[3] In the last
electrophiles. To overcome side reactions such as β-
two decades, there has been meaningful progress on
hydride elimination, a highly optimized metal/ligand
Pd/Ni,[2-4] Cu,[5] Fe[6] catalyzed or metal-free[7] cross-
combination is needed, which leads to a lack of
couplings of sp3 carbon electrophiles (Scheme 1a).
general and mild conditions. Also, reactive/sensitive
Notable examples include Fu and coworkers’ Ni-
organoborons, such as R-BBN, and air-sensitive
catalyzed stereoconvergent Suzuki reaction using 9-
ligands have been often utilized.[2b] The loading of
BBN reagents[8] and Falck and coworkers’ Pd-
expensive metal/ligand is frequently high (e.g. >5%),
catalyzed stereospecific Suzuki cross-coupling of
which is a problem when transition metal residues
alkyl α-cyanohydrin triflates with organoboronic
matter in the synthesis of biologically active
acids[1g] (Scheme 1a).
compounds.
Pioneering work on transition metal-free
coupling[9] of alkenyl or aryl boronic acids has been
1
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10.1002/adsc.201800826
Advanced Synthesis & Catalysis
reported by the groups of Tang, Wang, Huang and stronger bases (t-BuOK) or weaker bases (Cs2CO3,
10]
Ryu (Scheme 1b).[9d,
protocols are still limited to relatively reactive sp3- reaction occurred when less reactive styrylboronic
carbon electrophiles such as benzyl or allyl ester 2b was used, while potassium
However, most of these K2CO3, KOAc, and KF). On the other hand, no
electrophiles. We envision that a nucleophilic styryltrifluoroborate 2c gave a comparably low yield
substitution between alkenylboronic acids with (Table 1, entries 11-12). Besides, the yield could not
diverse unactivated sp3-carbon electrophiles could be be further improved when the reaction temperature
viable through a careful choice of bases and leaving was raised to 90 ℃ (Table 1, entry 16). We also
groups. Herein, we are glad to report a versatile base explored the reaction of secondary alkyl triflates.
promoted nucleophilic substitution protocol of Similarly, excellent chemical yield was obtained for
alkenyl boronic acids with a diverse range of sp3- secondary triflate 1h (Table 1, entry 20), while
carbon electrophiles, including unactivated alkyl secondary electrophiles with other leaving groups like
triflates. A significant advantage of our protocol is the bromide, tosylate, and methanesulfonate were
simple and mild conditions needed, which is the result unreactive (Table 1, entry 17-19). It should be noted
of employing a mild metal phosphate base.
that there was no reaction in the absence of a base.
Table 2. Scope of reaction between alkenylboronic acids
with primary alkyl triflate.a
Results and discussion
Table 1. Optimization of reaction conditions.a
entry
1
2
base
solvent
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16c
17
18
19
20
21
KOtBu
KOtBu
KOtBu
KOtBu
K2CO3
Cs2CO3
K3PO4
Na3PO4
KOAc
KF
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
-
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
0
0
0
41
78
84
91
83
5
1a
1b
1c
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1e
1f
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2a
2a
2a
2a
2a
2a
2a
2a
2a
69
0
21
74
30
14
90
0
THF
DMF
toluene
toluene
toluene
toluene
toluene
toluene
0
0
1g
1h
1d
Using the newly founded reaction conditions, we
first examined the substrate scope of coupling
reactions of primary alkyl triflates with various
organoboronic acids (Table 2). Most unactivated
primary alkyl triflates gave moderate to good yields
of desired products. This protocol could be used with
aryl and alkyl- substituted alkenylboronic acids. Also,
the functional group tolerance was good: common
functional groups such as alkene (3b), aryl iodides
(3d, 3p), ketone (3e), nitriles (3m, 3r), nitro (3i),
alkyl bromides (3h, 3n), heterocycle (3j-3k),
hydroxyl (3l) and cyclopropane (3m-3p) were well
tolerated. However, linear alkyl substituted
alkenylboronic acids (3q) could not react with alkyl
triflates, possibly due to its lower nucleophilicity
compared to aryl alkenylboronic acids. Besides, we
observed the formation of regioisomers when
substituted aryl boronic acids were used (Table 2, 3t).
92d
0
a Conditions: 1 (0.1 mmol), 2 (0.15 mmol), base (0.2 mmol) in solvent (1 mL),
12 h. b Determined by GC-MS. c The temperature is 90℃. d Isolated yield.
Our studies of nucleophilic substitution reaction
were shown in Table 1. First, we investigated the
reactions of relatively unreactive alkyl electrophiles
(1a-1d) containing various leaving groups (Table 1,
entries 1-4) with alkenylboronic acid 2a. In the
presence of weakly nucleophilic base KOtBu, alkyl
bromide (1a), alkyl tosylate (1b) and alkyl
methanesulfonate (1c) did not give any product
(Table 1, entries 1-3). To our delight, the desired
coupling product was obtained in 41% yield when
alkyl triflate 1d (Table 1, entry 4) was used.
Screening of bases of different strength (Table 1,
entries 4−10) revealed metal phosphate is better than
2
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10.1002/adsc.201800826
Advanced Synthesis & Catalysis
The formation of regioisomers was consistent with This protocol worked very well even with substrates
Wang and coworkers’ report[10b] on metal-free containing a complex natural product skeleton (3e and
coupling of arylboronic acids with benzyl halides.
4ae). We believed that the high functional group
tolerance is due to the fact that the only reagent used
is a mild base – K3PO4. In general, compared to
reactions of α-cyanohydrin triflates, -triflate
aliphatic esters gave relatively lower yields (Table 3,
4af – 4ah). This may be due to the higher steric
hindrance of ester groups.
Table 3. Scope of reaction between alkenylboronic acids
with secondary alkyl triflates.
To get some mechanistic insights, we added a
cation catcher (N-methylindole)[10] and a radical
quencher (TEMPO) to the reaction, both of them had
no effect on the progress of reactions. This result
indicated the reaction may not go through a SN1 or a
radical mechanism. Based on these experimental
results, we propose a possible reaction pathway
(Scheme 2). First, the base (K3PO4) attacks the
organoboronic acid to form an ate type complex A,
whose anionic nature leads to enhanced
nucleophilicity.[12] When the reaction is conducted in
non-polar solvents such as toluene, this complex is
likely to exist as a contact ion pair.[13] Then complex
A reacts with a sp3-carbon electrophile through a SN2-
like process to give the final product.
Scheme 2. Proposed mechanism.
It should be noted that our metal-free protocol is
orthogonal to the classic transition metal catalyzed
Suzuki reactions. For example, reactive aryl iodides
(Table 2, 3d, 3l) showed no reactivity towards
alkenylboronic acids under our conditions. Alkyl
bromides (Table 2, 3n, 3p, 3q; Table 3, 4h, 4aa) also
were untouched. This means that our metal-free
protocol and the classic Pd-catalyzed Suzuki reaction
are complementary to each other. This feature could
be more powerful when the two are used together
(Scheme 4). For example, a building block containing
both alkyl triflate (X1) and aryl halide (X2) (e.g., 1d)
could couple with two different boronic acids in a
tandem manner (Scheme 3). This strategy could be
potentially used in the Suzuki reaction-based iterative
synthesis of small molecules developed by Burke and
coworkers.[14]
Then, we started to investigate the coupling of
unactivated secondary alkyl triflates. However,
secondary alkyl triflates without a geminal electron-
withdrawing group were not stable[11], so we explored
the coupling of secondary alkyl triflates with a
geminal electron-withdrawing group such as nitrile.
These reactions gave excellent chemical yields and
showed good functional group tolerance. Functional
groups such as alkenes (Table 3, 4c, 4f), organo
azides (Table 3, 4d, 4ad), terminal alkyne (Table 3,
4e), thioether (Table 3, 4g), alkyl bromide (Table 3,
4h), nitro (Table 3, 4i), ether (Table 3, 4i, 4l, 4q, 4ab,
4ae), esters (Table 3, 4j, 4k, 4x), nitrile (Table 3, 4l),
amide (Table 3, 4m, 4ac), thiophene (Table 3, 4p),
benzothiophene (Table 3, 4y) were well tolerated.
Scheme 3. Tandem metal-free coupling and classic
Suzuki reactions.
3
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10.1002/adsc.201800826
Advanced Synthesis & Catalysis
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Conclusion
In conclusion, we have developed a highly versatile
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Only a mild metal phosphate base is needed; the mild
conditions led to excellent functional group tolerance.
Our metal-free condition is orthogonal towards the
transition metal catalyzed Suzuki reaction, which
means that our method is complementary to the
classic Suzuki coupling for the synthesis of complex
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Acknowledgements
We are grateful to the National Science Foundation of
China for financial support (NSFC-21472018,
21672035) and to the National Science Foundation
(CHE-1401700). SL is thankful to the China
Scholarship Council for financial support.
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4
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10.1002/adsc.201800826
Advanced Synthesis & Catalysis
COMMUNICATION
Mild Base Promoted Nucleophilic Substitution of
Unactivated sp3-Carbon Electrophiles with
Alkenylboronic Acids
Adv. Synth. Catal. Year, Volume, Page – Page
Shiwen Liu, Xiaojun Zeng, Gerald B. Hammond,*
Bo Xu*
5
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