Copper-catalyzed propargylation of diborylmethane

Article abstract of DOI:10.1039/c7cc00129k

A Cu/PPh₃-catalyzed propargylic substitution reaction of diborylmethane is reported. Different substituted propargyl electrophiles can be employed in this reaction, and various synthetic valuable functional groups can be tolerated. Di-deuterate

Full text of DOI:10.1039/c7cc00129k

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Copper-catalyzed propargylation of
diborylmethane†
Cite this:DOI: 10.1039/c7cc00129k
Feng Li, Zhen-Qi Zhang, Xi Lu, Bin Xiao* and Yao Fu*
Received 7th January 2017,
Accepted 27th February 2017
DOI: 10.1039/c7cc00129k
rsc.li/chemcomm
A Cu/PPh3-catalyzed propargylic substitution reaction of diboryl- (such as the Click reaction,8 allene synthesis9 and so on10).
methane is reported. Different substituted propargyl electrophiles Nevertheless, to the best of our knowledge, reports of the Suzuki–
can be employed in this reaction, and various synthetic valuable Miyaura reaction between the propargyl electrophiles and gem-
functional groups can be tolerated. Di-deuterated diborylmethane diborylated compounds are rare. In this regard, we report the
can also be used under these conditions and generates a-deuterated first example of cross-coupling between propargyl derivatives
alkylboronic esters in good yield.
and gem-diborylalkanes. In our study, a copper catalyst has been
used to achieve the cross-coupling between diborylmethane and
The Suzuki–Miyaura cross-coupling reaction has been widely primary/secondary propargyl electrophiles. Meanwhile, we have
utilized in the fields of organic synthesis,1 in the pharmaceutical also successfully prepared di-deuterated gem-diborylalkanes,
industry, and even in material sciences, due to the advantages which were then employed in the cross-coupling reaction
that organoboron reagents possess. Compared to other organo- mentioned above.
metallic reagents (i.e., Grignard reagents, organozinc reagents,
Inspired by our recent work on the cross-coupling reaction
organolithium reagents), organoboron compounds are easy to between gem-diborylalkanes and allyl electrophiles, we envisaged
access and are more stable. Moreover, the utilization of the that such a reaction may still be applicable if the allyl electro-
above reagents provides an efficient way to construct C–C and philes are switched to propargyl derivatives. Our experimental
C-heteroatom bonds with mild reaction conditions.2 Recently, study commenced by using different copper catalysts and con-
gem-diborylated compounds, as novel organoboronic reagents, ditions in the reaction between phenyl propargyl phosphate (1a)
have attracted people’s attention due to their broad applications and diborylmethane (1). As can be observed in Table 1, based on
in organic chemistry,3 such as: reaction with aldehydes and our previous work, CuI, LiOMe and DMF were initially chosen as
ketones under a strongly basic environment;4 addition to carbonyl the catalyst, base and solvent, respectively (entry 1). However,
compounds;5 reaction with C(sp2) electrophiles;6 and reaction only lower than moderate yield (38%) could be achieved under
with alkyl electrophiles7 (Scheme 1a). Meanwhile, propargyl such conditions. Further improvement of the yield (from 38% to
alcohol plays vital roles in organic synthesis, as many reactions 56%) was realized by switching the base from LiOMe to LiOtBu
can be carried out starting from propargyl alcohol derivatives (entry 2). Along with the change of base, we also increased
the catalyst loading, which did not really help to promote the
yield (entry 3). The change of catalyst from CuI to IMesCuCl
significantly slowed the reaction, regardless of solvents (entries 4
and 5). Therefore, we stuck to our initial condition in which CuI
is employed as the catalyst and varied the solvents. We found
that the use of THF as the solvent can promote the yield to a
practically acceptable level (64%, entry 9). The ligands were also
screened to reach a maximum yield, including mono-dentate
phosphine ligands as CyPPh2, PPh3 and L3 (entries 10, 11 and 14),
Scheme 1 Substitution reactions of diborylmethane.
bi-dentate phosphine ligands L4 (entry 15), and the bi-dentate
nitrogen ligand L1 (entry 12) and L2 (entry 13). The experiment
revealed that the simple and easily accessible triphenylphosphine
Hefei National Laboratory for Physical Sciences at the Microscale, iChEM,
CAS Key Laboratory of Urban Pollutant Conversion, Anhui Province Key Laboratory
of Biomass Clean Energy, University of Science and Technology of China,
(PPh3) is highly effective in increasing the yield to an excellent
Hefei 230026, China. E-mail: binxiao@ustc.edu.cn, fuyao@ustc.edu.cn
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c7cc00129k level (90%). When the catalyst was not added, only a trace amount
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Table 1 Optimization of reaction conditionsa
Table 2 Substrate scope for the reaction of propargyl phosphates with
diborymethanea
Entry
Solvent
Catalyst
Ligand
Yield (%)
1b
2b
3c
DMF
DMF
DMF
Dioxane
Toluene
DMSO
Toluene
Dioxane
THF
CuI
CuI
CuI
IMesCuCl
IMesCuCl
CuI
CuI
CuI
—
—
—
—
—
—
—
—
38
56
52
18
20
47
Trace
6
64
4d
5d
6
7
8
9
CuI
—
10
11
12
13
14
15
16
17
18f
19g
THF
THF
THF
THF
THF
THF
THF
THF
CuI
CuI
CuI
CuI
CuI
CuI
—
CuCl
CuI
CyPPh2
PPh3
L1
L2
L3
78
90(83e)
13
19
28
34
Trace
81
Trace
79
L4
PPh3
PPh3
PPh3
PPh3
THF
THF
CuI
a
All reactions were carried out at 60 1C on a 0.2 mmol scale, 10 mol%
CuI, 20 mol% ligand, 3.0 equiv. LiOtBu, 2.0 equiv. of diborylmethane
(1), and 1 mL of solvent were used. The yields were determined by GC
b
and triphenylmethane was used as the standard material. LiOMe was
used as base. 20 mol% CuI was used. 10 mol% IMesCuCl was used as
catalyst. Isolated yield. 5 mol% LiOtBu was used as base. 2.0 equiv.
LiOtBu was used as base.
c
d
e
f
g
of product was observed (entry 16). Upon the change of the
catalyst from CuI to CuCl, the yield decreased to 81% (entry 17).
We also considered the effect of the amount of base (entries 18
and 19); when a catalytic amount of base was used, almost no
product was obtained. So far, we have confirmed the optimal
a
All reactions were carried out under the conditions shown and on a
b
0.2 mmol scale. Isolated yields are reported. N.R. = No reaction.
conditions for this reaction, in which the CuI (with PPh3) is used groups, such as methyl (16a), ethyl (17a) and n-pentyl (18a) could
as the catalytic system, LiOtBu is employed as the base and THF is be tolerated well to give moderate yields. Besides the substituent
engaged as the solvent.
groups mentioned above, the TMS-substituted and TBS-protected
With the optimal conditions in hand, we set about evaluating substrates (19a and 20a) could also undergo the transformation to
the scope of substrates. We first studied the substituent effect on give the desired products in acceptable yields.
the phenyl ring of the primary aromatic propargyl phosphates.
Unfortunately, the optimal conditions for primary propargyl
Our investigation indicated that substrates with both electron- substrates are not applicable to the secondary ones. A significant
withdrawing groups (EWGs) and electron-donating groups (EDGs) drop in yield (only 33%) and the formation of a large amount of
can be tolerated well, and the yields are moderate to good (as byproduct were detected12 when a secondary propargyl substrate 1c
shown in Table 2). Switching the substituent patterns on the reacted with diborylmethane under the same conditions (entry 1,
phenyl ring to halides does not affect the good yield of this Table 4). Hence, extra efforts were carried out to re-optimize the
reaction (8b and 9b). Reactions with substrates containing other conditions for secondary propargyl substrates. The substrates were
heterocyclic rings rather than the phenyl ring (such as thiophene modified by changing the leaving group to OBoc and chloride
and furan, 12b and 13b) proceeded smoothly and afforded the (entries 2 and 3), and we noticed that a Cl leaving group is the most
corresponding cross-coupling products in good yields. We also productive, albeit the formation of byproducts is still significant
tested heterocycles containing nitrogen-atoms such as 14b and (1d :1f = 1.6 : 1). Interestingly, simply increasing the base loading to
15b; however, no desired product was obtained.
6 equivalents can restrict the formation of byproducts (1d :1f = 5:1)
Further examinations were conducted by changing the aro- and increased the total yield to 70%, indicating the main reaction
matic ring to alkyl groups (see Table 3). We found that simple alkyl should proceed in a strong basic environment.
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Table 3 Substrate scope for the reaction of propargyl phosphates with
diborylmethanea
Table 5 Substrate scope of the reaction using secondary propargyl
substratesa
a
All reactions were carried out under the conditions shown and on a
0.2 mmol scale. Isolated yields are reported.
Table 4 Optimization of the secondary propargylic reaction conditionsa
a
All reactions were carried out under the conditions shown and on a
0.2 mmol scale, 6 equiv. LiOtBu were used. Isolated yields are reported.
b
Propargyl phosphate was used as substrate, 3 equiv. LiOtBu were
c
used. Propargyl chloride was used as substrate, 3 equiv. LiOtBu were
used. N.R. = No reaction.
d
Entry
X
Solvent
Base (y)
Yield (%) (1d : 1f)
1
2
3
4
5
OPO(OEt)2
–OBoc
Cl
Cl
Cl
THF
THF
THF
THF
3
3
3
6
3
67(33 : 34)
47(19 : 28)
74(46 : 28)
84(70 : 14)
78(3 : 75)
CH3CN
Scheme 2 The reaction of propargyl phosphates with deuterated diboryl-
methanes.
a
All reactions were carried out at 60 1C on a 0.2 mmol scale, 10 mol% CuI,
20 mol% PPh3, LiOtBu as base, 2.0 equiv. of diborylmethane (1), and 1 mL
of solvent were used. The yields and the ratio of 1d and 1f were determined
by GC and triphenylmethane was used as the standard material.
Having the optimal conditions for secondary propargyl
derivatives established, we extended the substrate scope as
shown in Table 5. The tolerance of functional groups on the
phenyl ring was firstly investigated, and the results showed that
similar moderate yields were obtained when the substituents
vary from –OMe to –OCF3 and –Br (1d, 3d and 4d). When the
methyl group is switched to ethyl, n-propyl and i-propyl, a
moderate yield was obtained (5d–7d). However, the changing
of substrate to a tertiary chloride (8d) blocked the reaction and
only a trace amount of product was observed.
Gratified by the positive results received so far, we also tested
the cross-coupling reaction starting from di-deuterated diboryl-
Scheme 3 Mechanism for copper-catalyzed propargylation of diboryl-
methanes which provides a useful strategy for the synthesis of methane.
alpha-deuterated boron-containing compounds. The reaction
proceeded smoothly, and the yield is up to 87% (Scheme 2).
In this study, we proposed the copper anion is exchanged phosphate went through an oxidative addition process and ensued
with lithium tert-butoxide to form an alkyl-Cu complex (A). And to afford the Cu complex (C). Finally, reductive elimination
then, the alkyl-Cu complex (A) reacted with diborylmethane to occurred to generate the desired product leaving a Cu complex
generate the intermediate B. For intermediate B, the propargyl (E) to enter the next catalytic cycle. It should be pointed out that
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Cu(III) intermediate (C) could also isomerize to generate inter-
mediate D for side reactions (Scheme 3).
In conclusion, we have demonstrated a novel Suzuki cross-
coupling reaction in which a propargyl derivative reacts with
diborylmethane.11 Moderate to good yields were obtained under
our optimal conditions for both primary and secondary propargyl
compounds with good tolerance of functional groups. Besides the
mentioned work, we have also successfully prepared di-deuterated
diborylmethane, which was subsequently utilized as the substrate
in the cross-coupling reaction. We have not observed the formation
of g-site-selective products in this reaction,12 but other by-products
were obtained through the g-site nucleophilic substitution of the
secondary propargyl electrophiles. Further research for obtaining
the direct g-site-selective products is ongoing in our laboratory.
We thank the support by NSFC (21302178, 21325208,
21361140372, 21572212, 21502184), FANEDD (201424), CAS
(XDB20000000, YZ201563), Anhui science and technology project
(1604a0702027) and FRFCU, PCSIRT, Youth Innovation Promo-
tion Association of the Chinese Academy of Sciences (2015371).
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2,20-(ethane-1,1-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)
failed under our optimal reaction conditions, desired product was
not obtained.
12 Note: the diborylmethane reacted with propargyl electrophiles at
g-site via a SN2’ process, and intermediate (1g) was formed. Compared
to diborylmethane, 1g exhibited higher activity, and reacted rapidly
with propargyl electrophiles to form the obtained by-products (as
eqn (1) shown)
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