Rhodium-catalyzed carbonylative coupling of alkyl halides with thiols: a radical process faster than easier nucleophilic substitution

Article abstract of DOI:10.1039/d0cc07578g

How to make a carbonylative coupling faster than the easier nucleophilic substitution? In this communication, a rhodium-catalyzed radical-based carbonylative coupling of alkyl halides with thiolphenols has been realized. Thioesters were isolated in good y

Full text of DOI:10.1039/d0cc07578g

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Rhodium-catalyzed carbonylative coupling
of alkyl halides with thiols: a radical process faster
than easier nucleophilic substitution†‡
Cite this: Chem. Commun., 2021,
57, 1466
Received 18th November 2020,
Accepted 8th January 2021
a
a
a
ab
Han-Jun Ai,
Jabor Rabeah,
Angelika Bruckner
and Xiao-Feng Wu
*
¨
DOI: 10.1039/d0cc07578g
rsc.li/chemcomm
How to make a carbonylative coupling faster than the easier Directly thiocarbonylative coupling of aryl halides or alkyl
nucleophilic substitution? In this communication, rhodium- halides thus provides a straightforward approach for their
a
catalyzed radical-based carbonylative coupling of alkyl halides with synthesis. However, although the carbonylative coupling reac-
thiolphenols has been realized. Thioesters were isolated in good tion of thiols with aryl halides or alkenes have been
yields in general.
established,8 the successful example of alkyl halides as the
coupling partner remain rare. The only case was given by
Transition metal-catalyzed carbonylative coupling reaction has Arndtsen and co-workers very recently. By utilizing a dual
emerged as one of the most common methods for the synthesis light-driven palladium catalyst, they developed an elegant
of carbonyl-containing compounds.1 By manipulating the electro- carbonylation under ambient reaction conditions, which
philes, nucleophiles, and CO sources, researchers have developed allowed alkyl halides to be converted into acid chlorides and
numerous reactions over the past several decades. Alkyl halides, which subsequently reacted with thiols to form the corres-
are considered as more challenging2 but simple and useful ponding thioesters (Scheme 1C).9 Although such a strategy
electrophiles in carbonylation, have received increasing attention expands the scope of products available via a two-step process,
in recent years.3 Unfortunately, alkylation with nucleophile, the however, the key issue, strong competitive of SN reaction to the
annoying side reaction in carbonylation, is prone to proceed, thus carbonylation, has not been fundamentally solved.
restricts the use of many key substrates. Thiophenols are one of
With the idea that discovery of new carbonylative protocols
the most representative substrates owing to their high polariz- in this field will lead to efficient synthetic routes toward
ability and strong nucleophilicity. Due to the high nucleophilicity advanced intermediates, and the known achievements of the
of ArSÀ, SN reaction (nucleophilic substitution reaction) between rhodium catalyst in organic chemistry,10,11 our approach to this
alkyl halides and thiophenols is extremely prone to proceed challenge is focused on developing Rh-catalyzed method for
(Scheme 1A).4 For example, at room temperature under air, only thiocarbonylation of alkyl halides. After systematic studies,
for 30 minutes, phenyl butyl sulfide was formed in 97% yield from we herein report the first Rh-catalyzed direct carbonylative
thiophenol and iodobutane (Scheme 1B).5 In addition to this,
thiols possess strong binding affinities to late-transition metals
and could cause the loss of catalyst activity.6 Consequently, makes
the thiocarbonylation of alkyl halides a winner of the competition
between carbonylation and SN reaction is very challenge.
Thioesters are a class of useful intermediates that could
serve as entry points to various classes of functionalities.6,7
a
¨
¨
Leibniz-Institut fur Katalyse e. V. an der Universitat Rostock,
Albert-Einstein-Strabe 29a, Rostock 18059, Germany
E-mail: xiao-feng.wu@catalysis.de
b Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical
Physics, Chinese Academy of Sciences, Dalian, Liaoning, 116023, China.
E-mail: xwu2020@dicp.ac.cn
† In Memory of Professor Paul C. J. Kamer!
Scheme 1 Challenges and strategies for carbonylative coupling of thiophenols
and alkyl halides.
‡ Electronic supplementary information (ESI) available: General information,
analytic data, NMR spectra. See DOI: 10.1039/d0cc07578g
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coupling of thiophenols with alkyl halides, leading to thioesters
instead of thioethers as the main reaction products (Scheme 1D).
Our studies began with the carbonylative coupling of thio-
phenol 1 and iodobutane 2 (Table 1). We determined that the
catalytic system comprising 1 mol% [Rh(nbd)Cl]2 and 6 mol%
bidentate ligand 1,3-bis(diphenylphosphino)propane (DPPP)
facilitates efficient thiocarbonylation of substrate 2, provided
the desired thioester 3 in high yield (80%; entry 1).12 Other
precatalysts, such as, RhCl3, [Rh(cod)Cl]2 and Rh(cod)acac,
were inferior to [Rh(nbd)Cl]2 (entries 2–4). Slightly decreased
or increased the bite angle of the ligand,13 the yield of 3 dropped
significantly (entries 5 and 6). When 4,5-bis(diphenylphosphino)-9,9-
dimethyl (Xantphos) was used, only undesired thioether 4 could be
obtained (entry 7). These results imply that the right bite angel is
crucial for the success. Monodentate ligand such as triphenylpho-
sphine (PPh3) gave only a 6% yield of 3 (entry 8). Without NaF or
used NaCl instead of it, the yield was slightly reduced (entries 9 and
10). The reaction was sensitive to moisture, as shown in entry 11, no
carbonylation product could be detected when 1 equivalent of H2O
was added. The use of Cs2CO3 was critical for the reaction, thioether
4 became the main product if it replaced with Na2CO3, Rb2CO3, or
CsF, (entries 12–14). Finally, performing the reaction in toluene
diminished the yield of 3 (entry 15).
Table 2 Scope of the thiolsa
a
Thiophenols (0.5 mmol), iodobutane (1 mmol), [Rh(nbd)Cl]2 (1 mol%),
DPPP (6 mol%), Cs2CO3 (0.5 mmol), NaF (0.1 mmol, 20 mol%), dioxane
b
(1.5 mL), isolated yields. The reaction was performed on a 0.2 mmol
With the optimal conditions in hand, we then turned our
attention to investigate the scope of this reaction. As shown in
Table 2, employing iodobutane 2 as the coupling partner,
c
scale. 0.25 mmol of the thiol was used.
various thiols could be converted into the corresponding thioe- (5, 6), 4-methylthio (7), 4-N,N-dimethylamino (8), 4-methoxy
sters in moderate to good yields. Generally, carbonylation (9). Meanwhile, electron-withdrawing substituents, including
of thiophenols bearing electron-donating substituents pro- fluoro (12, 13), chloro (14), and bromo (15) groups, were
ceeded well, such as substrates substituted with 4-alkyl tolerated as well. It is worth mentioning that methylthio group
could be successfully retained (7), implying that the reaction
did not go through a thioether intermediate. Furthermore, as
shown for 16–19, the reaction was not seriously hampered by
the presence of ortho-substituent. Likewise, naphthylthiols
could provide similar yields of 20 and 21, respectively. The
presence of oxygen-containing heterocycles did not interfere
the carbonylative coupling (22). Subsequently, dithiophenols
were successfully converted into the corresponding dithioesters
23–24 in good yields. As expected, alkyl mercaptan can be
converted into the desired thioester in good yield as well (25).
Encouraged by the findings in Table 2, we then evaluated the
scope with different alkyl iodides (Table 3). By decreasing or
increasing the carbon chain of the alkyl iodides, good yields
of the desired products could be obtained without exception
(26–29). Likewise, excellent functional group compatibility was
observed including trifluoromethyl (30), cyanide (31), ketone
(32), imide (33), ethers (34, 35), and indole (36). In addition,
diiodoalkanes were successfully converted into iodide-substituted
thioesters (37, 38), offering potential opportunities for further
structure modifications.
Table 1 Representative results for the optimization of the Rh-catalyzed
carbonylative coupling of 1 and 2a
Entry
Variation from standard conditions
3b (%)
4b (%)
1
2
3
4
5
6
7
8
None
80
26
72
78
23
25
0
16
72
25
17
76
73
99
91
22
21
98
80
85
71
86
RhCl3 instead of [Rh(nbd)Cl]2
[Rh(cod)Cl]2 instead of [Rh(nbd)Cl]2
Rh(cod)acac instead of [Rh(nbd)Cl]2
DPPE instead of DPPP
DPPB instead of DPPP
Xantphos instead of DPPP
12 mol% PPh3 instead of DPPP
Without NaF
NaCl instead of NaF
With H2O (1 equiv.)
Na2CO3 instead of Cs2CO3
Rb2CO3 instead of Cs2CO3
CsF instead of Cs2CO3
Toluene instead of dioxane
6
9
75
78
0
18
11
25
11
10
11
12
13
14
15
As we expected, alkyl bromides could also be successfully
converted to the corresponding thioesters with NaI as the
a
Reaction conditions: thiophenol (0.5 mmol), iodobutane (1 mmol), additive, although the yields were slightly decreased (Table 4).
catalyst (2 mol% Rh), ligand (0.03 mmol, 6 mol%), Cs2CO3 (0.5 mmol),
Here, NaI is needed for the in situ alkyl iodides formation via
b
NaF (0.1 mmol, 20 mol%), dioxane (1.5 mL). GC yields were deter-
mined relative to hexadecane internal standard. nbd = 2,5-norbo-
Finkelstein reaction14 and then ready for the designed carbony-
rnadiene; cod = 1,5-cyclooctadiene; acac = acetylacetone.
lation reaction. Without NaI, only a 9% yield of 3 was obtained.
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Table 3 Scope of the alkyl iodidesa
a
Thiophenol (0.5 mmol), alkyl iodides (1 mmol), [Rh(nbd)Cl]2
(1 mol%), DPPP (6 mol%), Cs2CO3 (0.5 mmol), NaF (0.1 mmol,
b
20 mol%), dioxane (1.5 mL), isolated yields. p-Methoxythiophenol
c
was used. The reaction was performed on
a 0.2 mmol scale.
NPhth = phthalimide group; PMP = p-methoxyphenyl; Bn = benzyl.
Fig. 1 EPR spectra of the control experiments in the presence of DMPO
(0.13 mM) under Ar.
This is due to the lower activity of alkyl bromides compared to
alkyl iodides in carbonylation reactions.15 In analogy with the
results in Table 3, the length of the carbon chain of the alkyl
bromides hardly affects the reaction outcomes (3, 28, 29).
Similarly, different alkyl chains (39, 40, 41) and functional
groups such as cyano (44), olefin (43) could also be equally
accommodated in moderate to good yields. Under these condi-
tions, no thioester products could be formed from alkyl tosylates
(OTs) or alkyl chlorides.
conditions,16 afforded the ring-opening expansion product 43 in
28% yield along with 35% ring-retaining product 46. These
preliminary studies suggest that the alkyl radical was likely
involved, however, instead of free radical, the formation of
metal-involved tightly associated or caged radical intermediates
more likely.17
To further determine the radical pathway18 and further
verify our speculation, in situ electron paramagnetic resonance
(EPR) experiments were designed utilizing 5,5-dimethyl-1-
pyrroline N-oxide (DMPO) as the spin trap to detect and identify
the free radical intermediates (Fig. 1). Under the standard
conditions at room temperature, no signal could be detected
from the model reaction19 (Fig. 1a). Two multiple-line EPR
signals at g = 2.007 were detected during heating the reaction
mixture at 90 1C, due to the formation of DMPO-H (47)
[AN = 14.58 G and AH (2H) = 18.59 G] and DMPO-nBu (48)
[AN = 14.68 G and AH = 18.92 G] spin adducts (Fig. 1b).20 These
spin adducts were nicely fitted by the simulation of the experi-
To gain some mechanistic insight into the reaction pathway,
several control experiments were conducted (See ESI‡). Under
the standard conditions, the thioether 4 could not be converted
to the thioester 3, which was consistent with the previous
result, indicating the carbonylative coupling did not undergo a
carbonylation-after-coupling process. Subsequently, to explore
whether a radical process was involved, radical trapping, inhibi-
tion, and clock experiments were performed. When TEMPO was
added into the reaction, the thioester 3 was hardly formed and
the radical trapping product 44 was detected by GC–MS. How-
ever, 3 could still be obtained in 51% yield even in the presence
of 3 equivalent of radical scavenger butylated hydroxytoluene
(BHT). Furthermore, the radical clock experiment, by the reac-
tion of 1 and iodomethyl-cyclopropane 45 under the standard
n
mental spectrum (Fig. 1c).21 In the absence of BuI, the signal
of 47 was still detected (Fig. 1d). On the other hand, without
PhSH, the spin adduct of 48 could be detected (Fig. 1e).
However, only the DMPO-SPh (49) spin adduct was detected
in the absence of the rhodium catalyst (Fig. 1f). These results
Table 4 Scope of the alkyl bromidesa
n
suggest that the Hꢀ and Buꢀ are involved in the process, and
the rhodium catalyst plays a vital role in the formation of them.
To figure out the beginning of the catalytic cycle, we
designed additional EPR experiments. At 20 1C under Ar, when
PhSH was added to the mixture of the dioxane, [Rh(nbd)Cl]2,
DPPP, and Cs2CO3, a signal of [RhII] at g = 2.094 with AL = 102 G
was detected in addition to sharp signal at g =2.006 due to the
formation of radical (Fig. S1, a, ESI‡).22 Meanwhile, the signal
decayed very fest with time. Using nBuI instead of PhSH, the
[RhII] could also be detected, however, the signal was very weak
(Fig. S1, b, ESI‡).
a
Thiophenol (0.5 mmol), alkyl bromides (1 mmol), [Rh(nbd)Cl]2 (1 mol%),
DPPP (6 mol%), Cs2CO3 (0.5 mmol), NaF (0.1 mmol, 20 mol%), dioxane
(1.5 mL), NaI (1 equiv.), isolated yields. Without NaI.
b
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The rhodium(I) complex A irreversibly reacts with the thiol to
generate the rhodium(II) tightly associated radical complex B. In
the presence of base, the carbon-centered radical intermediate C
is then formed by the radical transfer process. This step is
followed by combination of the carbon-centered radical and the
rhodium(II) complex. The resulting alkylrhodium(III) species D
then provide the acylrhodium complex E through CO migratory
insertion. The overall catalytic conversion is then completed by
reductive elimination to produce the final thioester product and
meanwhile releases Rh(I) complex for the next catalytic cycle. It is
important to note that the possibility, the catalytic cycle begin
with the rhodium(I) catalyst abstracts a halogen atom to form the
rhodium(II) species, cannot be fully excluded (path b).
In summary, we have discovered a rhodium-catalyzed carbony-
lative coupling of thiophenols with alkyl halides. This study
suggests that rhodium catalyst might lead to the foundation of
discoveries within the field of carbonylative coupling of alkyl
halides and strong nucleophiles. The wide substrates scope of
the method suggests this protocol can be a powerful alternative
to known methodologies for thioesters synthesis. The mechanism
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Conflicts of interest
19 see Table 1 for the details of the model reaction.
20 G. R. Buettner, Free Radical Biol. Med., 1987, 3, 259–303.
21 The specific parameters of the simulation: see ESI‡.
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There are no conflicts to declare.
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1469 | Chem. Commun., 2021, 57, 1466À1469
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