Efficient phosphine-mediated formal C(sp3)-C(sp3) coupling reactions of alkyl halides in batch and flow

Article abstract of DOI:10.1039/c7cc02033c

The construction of C(sp³)-C(sp³) bond is an essential chemical transformation in synthetic chemistry due to its abundance in organic scaffolds. Here we demonstrate a valuable adaptation of the Wittig-type chemical procedure to efficiently facilitate C(sp³)-C(sp³) bond formation utilizing a range of alkyl building blocks. Additionally the method is amenable with flow synthesis to afford coupled products in good to excellent yields without laborious purification process.

Full text of DOI:10.1039/c7cc02033c

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
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DOI: 10.1039/C7CC02033C
Chemical Communications
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Efficient Phosphine-Mediated Formal C(sp3)-C(sp3) Coupling
Reactions of Alkyl Halides in Batch and Flow
U. P. N. Tran,a K. J. Hock,a,b C. P. Gordon,c,* R. M. Koenigsb,* and T. V. Nguyena,*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The construction of C(sp3)-C(sp3) bond is an essential chemical halides.7 Until now, however the latter type of reactions has
transformation in synthetic chemistry due to its abundance in been overshadowed by the more appealing reactivity of
organic scaffolds. Here we demonstrate a valuable adaptation of phosphonium ylides in Wittig reactions.8
the Wittig-type chemical procedure to efficiently facilitate C(sp3)- Hence, we envisaged that a phosphonium ylide, readily
C(sp3) bond formation utilizing a range of alkyl building blocks. synthesized from an alkyl halide and a phosphine, could couple
Additionaly the method is amenable with flow synthesis to afford with another alkyl halide in a nucleophilic substitution reaction
coupled products in good to excellent yields without laborous to form a secondary phosphonium salt. Subsequent cleavage
of the resulting phosphorus moiety by hydrolysis9 could then
purification process.
afford the formal C(sp3)-C(sp3) cross coupling product of the
The C(sp3)-C(sp3) bond is the most abundant type of C-C bond
two original alkyl halides. Prior to our work, this phosphine-
in organic structures.1 However, the construction of complex
organic molecules generally does not involve retrosynthetic
disconnections at C(sp3)-C(sp3) bonds2 which is primarily due
to a paucity of reliable methods to effect this transformation
relative to analogous bond connections such as C(sp2)-C(sp2).3
At present, standard approaches for C(sp3)-C(sp3) bond
formation entail palladium or nickel catalyzed coupling
reactions of electrophilic alkyl halides/pseudo-halides with
alkyl organometallic reagents,3-4 which can also be produced
from alkyl halides (Scheme 1). Although there have been
numerous seminal developments in this field,1-5 the
applicability of these processes remains limited by competing
reactions as well as the inherent instability the organometallic
coupling reagents and catalysts.5b Therefore, the development
of reliable methods for C(sp3)-C(sp3) coupling reaction remains
a challenging issue in organic synthesis.
mediated C(sp3)-C(sp3) bond formation has never been
systematic studied or utilized in this sense. Thus, we herein
report a valuable utilization of phosphines as synthetic
auxiliaries to facilitate formal C(sp3)-C(sp3) coupling reactions
on a broad range of alkyl building blocks (Scheme 1). The
method can be efficiently implemented in batch or flow to
afford coupled products in good to excellent yields. Most
notably, the flow setup allowed access to the products without
laborious purification process, which enable future practical
applications of this alkyl-alkyl coupling protocol.
Initial investigation focused on the ‘homo’-coupling reaction of
benzylbromide (1a, Table 1). Upon initial screening of several
trialkyl- and triarylphosphines (entries 1-10) as auxiliaries for
the reaction, we observed the formation of the target dibenzyl
product 4a in moderate to good yields. The by-product 4a’,
that presumably formed from the base-assisted elimination
side-reaction (see proposed mechanism9a in Table 1), was also
formed in these processes. Further studies revealed that
trialkylphosphines with H-C-P moiety (entries 1, 3) were not
Phosphonium ylides have been commonly utilized as
nucleophilic reagents for synthetically versatile Wittig and
related olefination reactions.6 Apart from coupling with
carbonyl compounds, their nucleophilicity also renders them
reactive towards other types of chemical transformations,
including the nucleophilic substitution reactions with alkyl
Traditional C(sp3)-C(sp3) coupling methods
R1
R1
cat. = Pd, Ni, etc
R3
[M]
R3
R2
R2 Hal1
M = ZnR', B(OR'')2, etc
R4
R4
This work: transition metal free formal C(sp3)-C(sp3) couplings
R1
R1
R3P auxiliary (3)
R3
Hal2
R3
R2
R2 Hal1
three-step one-pot sequence
in batch or flow
4
2
1
R4
R4
Scheme 1. Phosphine mediated C(sp3)-C(sp3) coupling reactions
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Chem. Commun. 2017, 53, 1-4 | 1
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Table 1: Phosphine auxiliary screening and optimization of the reactiona
bromides proved superior to other non-activated alkyl
View Article Online
bromides in the role of alkyl halide 1 (e.DgO. IH: 1a0l1.10=3H9/aCl7C=C0B2r0,343aC-
2
1. R3P (3), solvent, reflux, 3 h
2. base, 1a, reflux, 12 h
4i, Table 2), most likely due to better formation of the first
phosphonium salt (analogous to 5 in Table 1). Overall the
method tolerated a range of functional groups (e.g. 4e-4i,
Table 2) however the efficiency decreased with utilization of
secondary bromides (4j-4l, Table 2), which was attributed to
steric hindrance of the alkyl moieties. Tertiary alkyl bromide
(to 4m) gave no product, apparently due to the fact that no
ylide can be formed from its phosphonium derivative.
The replacement of bromides with iodides or other reactive
pseudo-halides such as mesylates and tosylates afforded
excellent outcomes (note superior yields of 4b’’, 4j’, 4o’ and
4s’ when Hal1 or Hal2 changed from Br to I or OMs).
Interestingly, double coupling reaction was possible to form
cyclic product with moderate yield (4t, Table 2).10 Hence
overall, an efficient three-step one-pot procedure10 to couple
primary alkyl halides in a formal C(sp3)-C(sp3) bond formation
was achieved using triphenylphosphine as synthetic auxiliary.
Br
3. H2O/HO-, T, 12 h
one-pot
1a
4a
4a'
H
H
H
δ-
1. R3P
solvent
2. base
Br
δ+
PR3
Br
PR3
Ph
Ph
Ph
6
1a
5
δ'-
Br
Ph
δ'+
OH
H
1a
H
H
H
R3P
Ph
3.
Ph
H
Ph
2O/HO
Ph
- R3P=O
-
addition
H
4a
H
8
R3P
H
Ph
-
Ph
Br
HO
H
3.
d
e
st
7
H
Ph
ssi
n
-a
mi
o
i
t
se
a
a
n
+
R3P
+
HOH
b
Ph
i
l
e
4a'
Entry
1
2
3
4
5
6
7
8
R3P (3)
Cy3P
base/solventb
KHMDS/THF
KHMDS/THF
KHMDS/THF
KHMDS/THF
KHMDS/THF
KHMDS/THF
KHMDS/THF
KHMDS/THF
KHMDS/THF
KHMDS/THF
KHMDS/Tol
temp.
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
70 °C
150 °C
150 °C
4a/4a’ (%)c
21/trace
58/11
15/trace
60/12
49/n.d.
57/n.d.
40/32
tBu3P
nBu3P
Ph3P
o-Tol3P
p-Tol3P
Table 2: Substrate scope under microwave-assisted conditionsa
(1-naphthyl)3P
(2-furyl)3P
(2,4,6-MeO3Ph)3P
(C6F5)3P
Ph3P
R1
R1
1. Ph3P, MeCN
2. KHMDS, 2
64/15
R3
Hal2
R3
R2
R2 Hal1
9
51/n.d.
trace/n.d.
49/trace
66/trace
94/trace
89/trace
Ph3P=O
R4
3. H2O/HO-
MW, one-pot
R4
2 (step 2)
10
11
12
13d
14d
4
1
Ph3P
KHMDS/MeCN
KHMDS/MeCN
KHMDS/MeCN
Ph3P
F3C
CF3
TPP-resine
4a, 94%
4b, 64%
4b', 79%
a Reaction conditions: bromide 1a (1.0 mmol) and phosphine 3 (1.0 mmol) in THF
(3 mL), followed by the addition of 1a (1.0 mmol) and base (1.0 mmol), finally aq.
4c, 74%
4c', 53%
b
NaOH (1 mL) with conventional heating; See Supporting Information for more
4d, 52%
c
details on base, solvent and concentration optimization; Yield of isolated
product; d All steps were carried out in MW reactor (step 1 = 2 h at 150 °C, step 2
= 3 h at 150 °C, step 3 = 1 h at 100 °C); e Ph3P on polymer support (~3 mmol/g)
Hal1 = Br
Hal2 = Br
Br
NC
4f, 63%
4e, 70%
F3C
4g, 57%
F
suitable for the reaction, which is unsurprising given that they
are susceptible to side-reactions on unwanted positions.
Among all triarylphosphines investigated (entries 4-10),
triphenylphosphine and tris(2-furyl)phosphine gave most
promising outcomes, presumably due to their optimal
stereoelectronic properties for these chemical processes.
Optimization of reaction conditions on the more readily
available triphenylphosphine concluded that this sequential
one-pot alkyl-alkyl coupling process was best performed at
150 °C in acetonitrile under microwave irradiation.10 2 M
aqueous sodium hydroxide solution was optimal10 for the
hydrolysis of phosphonium salt 7 (Table 1) to the target
product 4a via phosphonium hydroxide intermediate 8.9a
Interestingly, polymer-supported triphenyl phosphine (TPP-
resin, entry 14, Table 1) also gave comparable results,
prompting our subsequent exploration of the scope of the
protocol under flow chemistry11 conditions (vide infra).10
F
F
H3C
F
4j, 60%
4i, 57%
O2N
4h, 66%
F
CH3
4m, trace
4k, 27%
4l, trace
nC3H7
nC4H9
nC5H11
4n, 63%
4q, 64%
4o, 67%
4r, 70%
4p, 48%
4s, 57%
Hal1 = Br
Hal2 = I
nC7H15
nC8H17
nC14H29
CH3
4j', 71%
4k', 67%
4t,b 46%[10]
Hal1 = I
nC4H9
4o', 70%
nC14H29
4s', 68%
nC6H13
Hal2 = Br
4u, 66%
nC13H27
Hal1 = Br
Hal1 = Br
HO2C
Hal2 = OMs
Hal2 = OTs
CF3
Prior to flow chemistry investigation, the optimized
microwave-assisted reaction conditions were applied to couple
a wide range of alkyl halide substrates (Table 2). This
triphenylphosphine-mediated protocol typically furnished the
desired coupled products in good to excellent yields. Benzylic
4v, 80% (CO2Et to CO2H)
4b'', 71%
a
Reaction conditions: halide 1 (1.0 mmol) and Ph3P (1.0 mmol) in MeCN (3 mL),
followed by the addition of halide 2 (1.0 mmol) and KHMDS (1.0 mmol), finally
aq. NaOH (2 M, 1 mL). Step 1 = 2 h at 150 °C, step 2 = 3 h at 150 °C, step 3 = 1 h at
100 °C); b From benzyl bromide and 1,5-diiodopentane.10
2 | Chem. Commun. 2017, 53, 1-4
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Ph
Ph
R4
View Article Online
Ph2SiH2
flow 5
polymer
P
DOI: 10.1039/C7CC02033C
R1
R3
R1
Br
flow 3
BPR
2
R3
R2
100 psi
R2 Br
flow 1
R4
4
1
flow 2
KHMDS
flow 4
NaOH (aq)
packed bed column reactor
Scheme 2[12]
(outstream of flow 4)
MeCN wash
In terms of synthetic strategy, the generation of phosphine
oxide waste in our earlier batch settings was unfavourable in
comparison to other traditional catalytic methods for C(sp3)-
C(sp3) coupling reactions. For the flow setup, this issue can be
easily circumvented in light of current technological and
methodological advances in recycling phosphine oxides.13
Preliminary studies on our TPP packed bed column reactor
showed that after the NaOH hydrolysis step, the resulting
phosphine oxide on the resin could be recycled to the reactive
TPP-resin form with utilization of hydrosilanes.14 Indeed,
Ph2SiH2 was pumped into the column reactor (flow 5,
120 °C)12,15 to reduce the TPP-oxide to TPP-resin, which could
then be reused for another reaction cycle.
The efficiency of the process remained at > 60% even after the
8th cycle (Scheme 3a),10 which allowed access to multiple
grams of the coupled product 4a. The product yield of the
second cycle was actually higher than that of the first cycle due
to the fact that the TPP-resin from commercial suppliers
contained some proportion of TPP-oxide. After reduction with
Ph2SiH2, the performance of this packed bed column peaked at
the second cycle before decreasing gradually over time. The
presence of the phosphine, phosphine oxide and phosphonium
salts intermediates in the reaction was confirmed by solid-
state 31P NMR study of the TPP-resin in the homocoupling
reaction of 1a to form 4a (Scheme 3b).16
CF3
4a, 90%
4c, 65%
4v, 63%
4b, 75%
6.87 g after 8 cycles
nC13H27
nC8H17
HO2C
nC6H13
4u', 79%
4r, 71%
Scheme 2. Phosphine mediated C(sp3)-C(sp3) coupling reactions in flow. Typical
reactions and conditions: i) Pump 1: alkyl bromide 1 in acetonitrile (0.08 M), 0.3
mL/min, column T = 120 °C, 5 h; ii) Pump 2: 1.0 M KHMDS, THF, 0.3 mL/min, column T =
20 °C, 50 min; iii) Pump 3: alkyl bromide 2 in acetonitrile (0.08 M), 0.3 mL/min, column
T = 120 °C, 5 h; iv) Pump 4: 2.0 M NaOH(aq), 0.3 mL/min, column T = 20 °C, 4 h; v) Pump
5 (optional for regeneration of TPP-resin): Ph2SiH2 in acetonitrile (0.08 M), 0.3 mL/min,
column T = 120 °C, 5 h. Yields based on molar amount of Ph3P on TPP-resin used.12
Subsequent investigations focused on adapting the MW
protocol to a total flow chemistry approach. As outlined in
Scheme 2, the flow system utilized was comprised of five
syringe pumps connected to an inline manual switching valve
(Scheme 2) with the TPP-resin contained within a standard
omnifit column.12 The flow protocol mirrored the MW
approach with alkyl bromide 1 initially flowed through the
column followed by sequential flows of KHMDS, alkyl bromide
2 and NaOH solutions.12 Gratifyingly, this rudimentary flow
approach efficiently mediated the coupling reactions of a
number of selected alkyl bromides to afford the desired
products in good to excellent yields.
This initial study demonstrated that the polymer-supported
TPP mediated C(sp3)-C(sp3) coupling reaction is amenable to
total flow synthesis and provides the advantage of removing
physical handling requirements throughout the multi-step
process. We also note that extensive scope for optimization of
the flow protocol remains. Current investigations on
adaptation of this to multiple-reactor system as well as further
variations of solvent/temperature/flow-rate are on-going in
our laboratories and will be reported in due course.
In conclusion, we have developed a new adaptation of the
commonly known Wittig-type chemical procedure to
efficiently enable C(sp3)-C(sp3) coupling reactions on a broad
range of alkyl building blocks. This method can be
implemented in batch or flow to afford coupled products in
good to excellent yields. The flow setup allowed direct access
to the products without laborious purification process, which
paves ways for practical applications of this new alkyl-alkyl
coupling protocol in the future.
We acknowledge the Australian Research Council (grant
DE150100517 awarded to TVN and DE130100513 awarded to
CPG) and the Excellence Initiative of the German federal and
state governments (RMK) for funding this work. RMK gratefully
thanks the Fonds der Chemischen Industrie for generous
support (Sachkostenbeihilfe).
Scheme 3. (a) Recyclability of TPP packed bed column reactor; (b) Solid-state 31P NMR
(121.4 MHz, 25 °C) of TPP-resin after selected flows (homocoupling of 1a to 4a).
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11. (a) D. N. Tran, C. Battilocchio, S.-B. Lou, J. M. Hawkins and S. V.
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Notes and references
1. S. Z. Tasker, E. A. Standley and T. F. Jamison, Nature, 2014, 509,
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DOI: 10.1039/C7CC02033C
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12. TPP-resin: triphenylphosphine, styrene polymer-bound, 100-
200 mesh, ~3.0 mmol/g loading, 2% cross-linked with
divinylbenzene. For 4a, 2 g of TPP-resin was used; for other flow
setups, 1 g TPP-resin was used.
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unstable nature of this species.
10. See Supporting Information for more details.
1
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