An N-(acetoxy)phthalimide motif as a visible-light pro-photosensitizer in photoredox decarboxylative arylthiation

Article abstract of DOI:10.1039/c6cc06994k

An efficient visible-light photoredox decarboxylative coupling of N-(acetoxy)phthalimides with aryl thiols has been developed. The reaction was performed well at room temperature with good tolerance of functional groups. Importantly, the visible-light photoredox decarboxylative arylthiation did not need an added photocatalyst.

Full text of DOI:10.1039/c6cc06994k

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Communication
N-(Acetoxy)phthalimide motif as a visible-light pro-photosensitizer in
photoredox decarboxylative arylthiation
Yunhe Jin, Haijun Yang and Hua Fu*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
in the presence of catalysts.15 Herein, we report a photoredox
An efficient visible-light photoredox decarboxylative coupling
50 arylthiation of N-(acetoxy)phthalimides at room temperature
under irradiation of visible light without requirement of an added
photocatalyst, and the corresponding mechanism is explored.
Coupling of 1k with 4-isopropylbenzenethiol (2e) was
selected as the model to optimize conditions of visible-light
55 photoredox catalysis including photocatalysts, bases and solvents
(see Table S1 in Supporting Information). The results showed
that the optimal photoredox conditions are as follows: 1.5 equiv
of Cs2CO3 as the base and DMF as the solvent under an Ar
atmosphere and irradiation of visible light with 40 W compact
60 fluorescent light (CFL) or 3 W blue LED. After obtaining the
optimized visible-light photoredox conditions, the substrate scope
for decarboxylative coupling of N-(acetoxy)phthalimides (1) with
aryl thiols (2) was surveyed. As shown in Table 1, ten common
organic carboxylic acid active esters were first tested, and the
65 active esters of secondary and tertiary carboxylic acids displayed
higher reactivity than the primary ones (see 3a-j). A carboxylic
acid containing an alkene gave a low yield with the production of
unknown by-products (see 3f). The reactivity of various N-
protected amino acid active esters was investigated, and N-
70 Boc/Cbz-Pro-OPht and N-Boc-pipecolinic acid active esters gave
excellent yields (see 3k, 3w-x). Active esters of three neutral
amino acids including alanine, leucine and phenylalnine were
applied as the radical precursors, and phenylalanine derivative
provided a slightly lower yield than two other neutral amino acid
75 derivatives (see 3y-aa). N,O-Protected serine active ester gave
arylthiation product 3ab in 80% yield, and other amino acid
(methionine, lysine, glutamic acid and glutamine) derivatives
containing different functional groups also were good substrates
(see 3ac-af). We also attempted active ester of Glu on the side
80 chain carboxyl, N-Bis(Boc)-Glu(OPht)-OMe, and it afforded
target product 3ag in 57% yield. Interestingly, tripeptide active
ester, N-Boc-Gly-Gly-Pro-OPht, was tested, and it donated 3ah
containing tripeptide fragment in 73% yield. Natural cis-9-
octadecenoic acid and oleanic acid derivatives were used as the
85 substrates, and they provided the corresponding arylthiation
products 3ai and 3aj in 63% and 55% yields, respectively. The
substrate scope of aryl thiols was explored using N-Boc-Pro-OPht
as the partner (see 3k-v), and aryl thiols containing electron-
withdrawing groups exhibited faster reaction rate than those
90 containing electron-donating groups. One main factor was that
the aryl thiols containing electron-donating groups were of higher
nucleophilicity and more easily formed carboxylic acid thiol
esters, which was not favorable for subsequent visible-light
photoredox decarboxylative arylthiation (see reaction mechanism
95 in Scheme 2). The visible-light photoredox decarboxylicative
arylthiation displayed tolerance of various functional groups
including amides, esters, ethers, C-F bond, C-Cl bond, C-Br bond
of N-(acetoxy)phthalimides with aryl thiols has been
developed. The reaction was performed well at room
temperature with good tolerance of functional groups.
10 Importantly, the visible-light photoredox decarboxylative
arylthiation did not need an added photocatalyst.
Carbon-sulfur bond formation is of great concern in organic
synthesis because sulfur-containing compounds widely occur in
natural products, biologically active molecules, and materials,1 so
15 it is high desirable to develop a convenient and efficient protocol
for the formation of C-S bonds using readily available starting
materials under mild conditions. Carboxylic acids and their
derivatives are common chemicals and widely occur in organic
molecules and natural products,2 and some classical
20 decarboxylative coupling reactions,3 such as Heck-type
reactions,4 allylations,5 redox-neutral cross-coupling reactions,6
and oxidative arylations,7 have been developed. In fact, C-S bond
formation via the decarboxylative couplings has been developed.
Unfortunately, higher temperatures and oxidants are usually
25 required.8a
Barton
and
co-workers
have
developed
decarboxylative arylthiation of thiohydroxamate esters,8b,c and
Procopiou’s group realized the formation of C-S bonds using
Barton’s thiohydroxamate esters under irradiation of two 200 W
tungsten filament light bulbs at 0 °C.8d However, only disulfides
30 were effective. Recently, visible-light photoredox catalysis has
emerged as a powerful activation protocol in new chemical
transformations,9 and some achievements have been made on the
visible-light photoredox decarboxylative couplings of carboxylic
acids and their derivatives by some groups10 and us.11 However,
35 visible-light photocatalysts usually are necessary. In 1989, Okada
and co-workers reported their pioneering research on the
decarboxylative coupling of N-(acetoxy)phthalimides under
irradiation of UV.12 Since this discovery, the direct
photogeneration of radicals from the phthalimide derivatives with
40 UV in the absence of photocatalyst has been established.13
Unfortunately, the visible-light photoredox decarboxylative
coupling in the absence of photocatalyst has been ignored thus far.
Very recently, Overman’s group observed the Michael addition
of N-(acyloxy)phthalimides to electron-deficient olefins with
45 irradiation of low-energy blue LEDs without addition of a
photocatalyst, and they thought that the transformation was
poorly understood at the time.14 Several photoinduced cross-
couplings of aryl halides with aryl thiols have also been described
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and CF3. It is worthwhile to note that some products contain
1g+Na2CO3 in Figure 1a) and Cs2CO3 (line 1g+Cs2CO3 in Figure
amino acid fragments, and their further modification can provide
diverse molecules after removal of the protective groups on them.
20 1a), were added to DMF solution of 1g, respectively, and some
absorption peaks in the range of 400-800 nm were observed, in
which the effect of Cs2CO3 was the most conspicuous. To make
out what happened with 1g, we prepared 15N-labeled N-
(acetoxy)phthalimide, cyclohexanecarboxylic acid active ester [c-
25 Hex-COOPht (1h')] (see Supporting Information for the details),
and its 15N NMR spectrum in DMF showed a peak at -199.9 ppm
(Figure 1b). When Cs2CO3 was added to a DMF solution of 1h', a
new peak at -149.1 ppm corresponding to complex IIh' of Ih'
with Cs2CO3 was observed (see Figure 1b). It is worthwhile to
30 note that the signal at -149.1 ppm is not intense because Cs2CO3
is not highly soluble in DMF. The UV-visible absorption spectra
of 4-(trifluoromethyl)thiophenol (TFTP) (2l) and 1,2-bis(4-
(trifluoromethyl)phenyl)disulfane (BTFPD) were detected in the
absence or presence of Cs2CO3, and no new absorption peak was
35 observed beyond 400 nm (see Figure S1-I,II in Supporting
information), which implied that neither aryl thiols nor disulfides
could be the visible light photosensitizers in the reactions.
Investigation on treatment of cyclopentanecarboxylic acid active
ester (c-Pen-COOPht (1g)) with 4-cyanobenzyl bromide by
40 HRESI-MS exhibited that another resonance structure Ig of 1g
could occur in the solution (see Figure S2, S3 and Scheme S1 in
Supporting information). The radical-trapping experiments
displayed that the reactions involved free-radical intermediate
process (see Figure S4 and Scheme S2 in Supporting
45 information). We performed Stern-Volmer fluorescence
quenching experiments (see Figure S5-S9 in Supporting
information), and the results showed that complex IIg of Ig with
Cs2CO3 could be a photosensitizer of visible light.
Table 1 Scope for visible-light photoredox decarboxylative arylthiationa
O
R2
Cs2CO3, DMF
Ar, rt, 0.5-48 h
O
S
+
R1
HS
R2
N
R1
O
40 W CFL
O
3
2
1
5
3 (time, yieldb)
a Reaction conditions: under an Ar atmosphere and irradiation of visible
light, carboxylic acid active ester (R1COOPht) (1) (0.15 mmol), aryl thiol
(2) (0.18 mmol), Cs2CO3 (0.225 mmol), DMF (1.5 mL), temperature (rt,
~25 oC), time (0.5-48 h) in a sealed Schlenk tube. bIsolated yield. Boc =
tert-butyloxycarbonyl. Cbz = benzyloxycarbonyl. Trt = trityl. tBu = tert-
butyl. CFL = compact fluorescent light.
To explore the mechanism for the visible-light photoredox
decarboxylative arylthiation, cyclopentanecarboxylic acid active
ester [c-Pen-COOPht (1g)] was chosen as the model substrate to
investigate its UV-visible absorption spectra under different
10 conditions in the range of 200-800 nm (Figure 1a). c-Pen-
COOPht (1g) in DMF only exhibited UV absorption peaks
between 200-330 nm (line 1g in Figure 1a). Addition of NaCl did
not lead to any variation of UV-visible absorption spectrum (line
1g+NaCl in Figure 1a), which showed that 1g could not
15 transform into a photosensitizer in the presence of the alkali-
metal ion. Interestingly, different UV-visible absorption spectra
were displayed when different bases, diisopropylethylamine
(DIPEA) (line 1g+DIPEA in Figure 1a), Na2CO3 (line
50 Figure 1 (a) The UV-visible absorption spectra of cyclopentanecarboxylic acid
active ester (c-Pen-COOPht (1g)) under different conditions. (b) 15N NMR spectra
of 15N-cyclohexanecarboxylic acid active ester [c-Hex-COOPht (1h')] (0.02 M in
DMF) in the absence or presence of Cs2CO3 (using Me15NO2 as the external
standard).
2
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Furthermore, several control experiments were performed
phthalimide anion (IV) from III provides carboxyl radical V, and
release of carbon dioxide in V provides radical VI. Reaction of
VI with diaryl disulfide leads to the target product (3).18
under different conditions. (A) Using N-Boc-proline thiol ester
(3u') as the substrate: (a) No reaction took place for 3u' in DMF
under irradiation of visible light (Scheme 1Aa). (b) Addition of
1.5 equiv of Cs2CO3 (relative to amount of 3u') led to formation
of small amount of product 3u (Scheme 1Ab), but the
transformation is poorly understood at this time. (c) The reaction
provided 3u in 88% yield in the presence of 1.1 equiv of N-
hydroxyphthalimide (PhtOH) and 1.5 equiv of Cs2CO3 (Scheme
45
5
10 1Ac). The results demonstrated that formation of N-
(acetoxy)phthalimide derivatives through displacement of the
thiol ester by PhtOH was of great concern for the visible-light
photoredox decarboxylative arylthiation. (B) Using N-Boc-Pro-
OPht (1k) as the substrate irradiated with different light sources:
15 (a) A similar yield was obtained with sunlight instead of 40 W
CFL (Scheme 1Ba). (b) The reaction was performed well when
lights below 420 nm were filtered under irradiation of 40 W CFL
(Scheme 1Bb). (c) Irradiation with 3 W blue LEDs provided 3u
in 92% yield (Scheme 1Bc). The later two experiments showed
20 that the reaction was not activated by UV-light from CFL bulbs.
(C) In the presence of dimethyl 4,4'-disulfanediyldibenzoate (4):
(a) Reaction of 1k with 4 did not work under the standard
conditions (Scheme 1Ca). (b) Treatment of 1k (1.0 equiv), 2a
(0.2 equiv) and 4 (1.0 equiv) provided 3u in only 18% yield
25 (Scheme 1Cb). (c) Reaction of 1k (1.0 equiv), 4-
(trifluoromethyl)thiophenol (2l) (1.2 equiv) and 4 (1.2 equiv)
gave 3u and 3v in 43% and 38% yields, respectively (Scheme
1Cc), and the result exhibited that coupling of carbon radical with
diaryl disulfide was reasonable.
Scheme 2 A Possible mechanism for the visible-light photoredox
decarboxylative arylthiation
In summary, we have developed a novel and efficient
50 visible-light photoredox decarboxylative arylthiation. The
coupling performed well at room temperature and exhibited great
universality of substrates. Importantly, no extra photocatalyst was
required in the photoredox decarboxylative arylthiation. The
mechanism investigations show that N-(acetoxy)phthalimide unit
55 is a pro-photosensitizer, and its complex with the inorganic base
can absorb visible light. Therefore, the novel and efficient
method will find wide application in synthesis of aryl sulfides.
The authors would like to thank Dr. Haifang Li for her great
helps in analysis of high resolution mass spectrometry, the
60 National Natural Science Foundation of China (Grant Nos.
21372139 and 21221062) and Shenzhen Sci & Tech Bureau
(CXB201104210014A) for financial support.
Notes and references
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
65 Biology (Ministry of Education), Department of Chemistry, Tsinghua
University, Beijing 100084, P. R. China. Fax: 86 10 62781695; E-mail:
fuhua@mail.tsinghua.edu.cn
† Electronic supplementary information (ESI) available: Optimization of
conditions,
mechanism
investigations,
synthetic
procedures,
1
70 characterization data and 15N, H, 13C NMR spectra of these synthesized
compounds 3a-ah. See http://dx.doi.org/10.1039/b000000x/
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A possible mechanism for the visible-light photoredox
decarboxylative arylthiation is proposed in Scheme 2 according
to the results above. Reversible treatment of 1 with aryl thiol (2)
35 in the presence of base (Cs2CO3) leads to thiol ester (3') and
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