Catalyst-Free Csp?Csp3 Cross-Coupling of Bromodifluoroacetamides with 1-Iodoalkynes under Visible-Light Irradiation

Article abstract of DOI:10.1002/adsc.202100846

We describe herein that the cross-coupling of bromodifluoroacetamides with (iodoethynyl)arenes proceeds without recourse to any photocatalyst when exposed to visible light at room temperature to afford alkynyldifluoroacetamides in 62–83% yields (27 examples). Several control experiments suggest that the reaction involves the homolysis of bromodifluoroacetamides and the coupling of the resultant difluoromethyl radical species with the 1-iodoalkynes via a radical chain process. Divergent transformations of the coupling products led to various organofluorine compounds, demonstrating the synthetic utility of the developed photo-coupling method. (Figure presented.).

Full text of DOI:10.1002/adsc.202100846

RESEARCH ARTICLE
doi.org/10.1002/adsc.202100846
Catalyst-Free CspÀ Csp3 Cross-Coupling of
Bromodifluoroacetamides with 1-Iodoalkynes under Visible-Light
Irradiation
Yoshihiko Yamamoto,a,* Eisuke Kuroyanagi,a Harufumi Suzuki,a and
Takeshi Yasuia
a
Department of Basic Medicinal Sciences,
Graduate School of Pharmaceutical Sciences,
Nagoya University,
Chikusa, Nagoya 464-8601, Japan
E-mail: yamamoto-yoshi@ps.nagoya-u.ac.jp
Manuscript received: July 7, 2021; Revised manuscript received: August 23, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100846
Abstract: We describe herein that the cross-coupling of bromodifluoroacetamides with (iodoethynyl)arenes
proceeds without recourse to any photocatalyst when exposed to visible light at room temperature to afford
alkynyldifluoroacetamides in 62–83% yields (27 examples). Several control experiments suggest that the
reaction involves the homolysis of bromodifluoroacetamides and the coupling of the resultant difluoromethyl
radical species with the 1-iodoalkynes via a radical chain process. Divergent transformations of the coupling
products led to various organofluorine compounds, demonstrating the synthetic utility of the developed photo-
coupling method.
Keywords: Alkyne; Cross-coupling; Difluoroalkylation; Photoreaction; Radical
Introduction
synthesis of organofluorine compounds has been
sought after. One viable approach is the building
Alkynes are highly useful starting materials in organic block method, in which reactive fluorinated small
synthesis. Diverse methods to introduce alkynyl sub- molecules are used as versatile molecular scaffolds
stituents via transition-metal-catalyzed CspÀ Csp2 to assemble complex fluorinated molecular
cross-couplings (Sonogashira–Hagihara and related architectures.[4] In this respect, fluoroalkyl-substi-
reactions) for the synthesis of arylalkynes and 1,3- tuted alkynes are particularly intriguing as their
enynes
have
been
extensively
developed carbon-carbon triple bonds undergo a diverse array
(Scheme 1a).[1] On the other hand, aliphatic alkynes of organic transformations.[5] Although the synthesis
have been conventionally prepared via the alkylation of fluoroalkyl-substituted alkynes has been inves-
of metal acetylides. However, this method is not tigated extensively, the reported methods are largely
compatible with reactive functional groups because of limited to the introduction of saturated fluoroalkyl
the high nucleophilicity of acetylides. Therefore, groups using stoichiometric copper salts and/or
radical alkynylations have recently been investigated expensive fluoroalkylating reagents.[6] Thus, the
as an alternative method with a wide functional group development of
a
new method to introduce
tolerance.[2]
difluoromethyl carbonyl groups without recourse to
The introduction of fluorine atoms into drug stoichiometric copper salts (Scheme 1b) and expen-
molecules can enhance their biological activity by sive reagents is desired.[7] To meet these require-
modifying various molecular properties, such as ments, several methods to synthesize alkynes bear-
lipophilicity, metabolic stability, conformational ri- ing a difluoroacetate moiety by taking advantage of
gidity, and binding affinity to target proteins.[3] visible light photoredox catalysis have been recently
Therefore, an efficient and divergent method for the developed (Scheme 1c).[8] Noël and coworkers re-
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the Cu-catalyzed hydroarylation of (trifluoromethyl)
alkynes and a mechanistic study of this reaction using
density functional theory (DFT) calculations.[10] As a
part of our research project, we became interested in
the synthesis of alkynes bearing a functionalized
difluoroalkyl group and their transformations via Cu-
catalyzed hydrofunctionalization. However, two chal-
lenges must be overcome. First, the previously
reported methods (Scheme 1c) require a precious metal
photocatalyst and the product yields and scalability
should be improved. Second, alkynyldifluoroacetates
readily undergo ester exchange under Cu-catalyzed
°
hydroarylation conditions (in methanol at 28 C) to
afford a mixture of inseparable products. Therefore,
we developed a new catalyst-free photo-induced cross-
coupling reaction of bromodifluoroacetamides with 1-
iodoalkynes (Scheme 1d). Herein, we present the
results of this study and the divergent transformations
of the coupling products obtained.
Results and Discussion
Initial assessment of bromodifluoromethyl carbonyl
compounds. We revisited the Cho’s cross-electrophile
coupling of 1-iodoalkynes with ethyl bromodifluoroa-
cetate to develop metal-free conditions using an
organophotocatalyst instead of an Ir photocatalyst. A
solution of p-methoxyphenyl (PMP)-substituted io-
doalkyne 1a (0.3 mmol), ethyl bromodifluoroacetate
(2a, 2 equiv), and N,N,N’,N’-tetramethylenediamine
(TMEDA) (2 equiv) in dry degassed acetonitrile was
irradiated using a LED lamp equipped inside the
reaction tube (Scheme 2). Unexpectedly, we found that
Scheme 1. Previous examples of the synthesis of alkynyldi-
fluoroacetates under photocatalytic conditions and catalyst-free
synthesis of alkynyldifluoroacetamides.
ported the decarboxylative cross-coupling reaction the reaction proceeded without any photocatalyst under
of 3-arylpropiolic acids with ethyl bromodifluoroa- irradiation (blue LED, 448 nm) for 24 h to afford the
cetate under photocatalytic conditions, producing desired product 3aa in a modest yield, along with
alkynyl-substituted difluoroacetates in 17–62% several byproducts having two ester groups (Sche-
yields.[8a] Later, Cho and coworkers developed the me 2a). However, we failed to improve the yield
coupling of 1-iodoalkynes with ethyl bromodifluor- although various reaction parameters were examined
oacetate under different photocatalytic conditions.[8b] (Table S1 in the Supporting Information).
In the latter study, heteroaryl-substituted alkynes
We further investigated this catalyst-free reaction
were compatible, and the product yields were some- in detail. At the outset, we checked the product
what improved (46–74%). In addition, Ko and yields and conversion of 1-iodoalkyne 1a during the
coworkers reported the photocatalytic coupling of reaction to gain insights into the reaction progress
terminal arylalkynes with perfluoroalkyl iodides, (Figure S1 in Supporting Information). The yield of
albeit requiring a long reaction time (40 h).[8c] 3aa gradually increased and reached a maximum
Although these methods are advantageous, as di- (57%) in approximately 6 h. However, the yield did
fluoroalkylation proceeds under mild reaction con- not increase after this period and slightly decreased
ditions, an expensive iridium-based photoredox (55%) after 24 h with an increase in the proportion
catalyst is required and the product yield is less than of byproducts. Notably, the difference between the
74%. Moreover, the synthetic potential of the yield of 3aa and the conversion of 1a gradually
coupling products was not demonstrated in these increased during the reaction period. These reaction
reports.
profiles suggest that the 1:1 coupling of 1a with 2a
Our group have been involved in the development stops at approximately 6 h and that 3aa reacts with
of the Cu-catalyzed hydroarylation of electron-defi- 2a to form byproducts throughout the reaction time.
cient alkynes and its application to the synthesis of Therefore, we decided to use 2a as the limiting
biologically active compounds.[9] We recently reported agent and an excess of 1a to suppress the formation
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was investigated. When ketone 2c was used, the
corresponding coupling product 4 was obtained in a
comparable yield (64%) with that of 3ab. No side
products were detected in the crude reaction mixture.
In contrast, the reaction using amide 5a afforded
6aa in a much higher yield (81%).
These results imply that the stability of the above
bromodifluoromethyl carbonyl compounds under pho-
to-coupling conditions depends on the electrophilicity
of the carbonyl groups. In fact, ester 2b and ketone 2c
were subjected to the reaction conditions in the
absence of 1a to obtain unreacted compounds in 41%
and 32% recovery yields, respectively (Scheme 2d).
Notably, the decomposition of 2b was observed with-
out irradiation; 2b was recovered in 60% yield, and 2-
(1-adamantyl)ethanol was obtained in 34% yield. In
contrast, upon irradiation in the absence of TMEDA,
most 2b was recovered, and 2-(1-adamantyl)ethanol
was not detected. Accordingly, the decomposition is
likely induced by TMEDA and is enhanced by photo-
irradiation, although the details are unclear at this
stage. Less electrophilic amide 5a was recovered in
91% yield after irradiation in the presence of TMEDA,
showing the robustness of 5a under photo-coupling
conditions. Therefore, bromodifluoroacetamides were
identified as the optimal coupling partners for photo-
coupling with 1-iodoalkynes. The tolerability of 1-
iodoalkyne 1a under irradiation conditions was also
tested (Scheme 2e). When 1a was subjected to photo-
coupling conditions in the absence of a coupling
partner for 24 h, 87% of 1a was recovered. Only small
amounts of the de-iodinated byproduct were detected
in the crude product mixture.
Scope and limitations of photo-coupling of
bromodifluoroacetamides with 1-iodoalkynes. The
scope of the photo-coupling of bromodifluoroaceta-
mide 5a with 1-iodoalkynes was investigated, as
outlined in Scheme 3. Phenyl-, p-tolyl-, p-
(hydroxymethyl)phenyl-, and p-fluorophenyl-substi-
tuted 1-iodoalkynes 1b–e gave the corresponding
Scheme 2. Coupling of 1-iodoalkyne 1a with bromodifluoro-
carbonyl compounds and robustness tests of bromodifluorocar-
bonyl compounds 2 and 1-iodoalkyne 1a (PMP=p-meth-
oxyphenyl).
of byproducts. Thus, 2a (0.3 mmol) was allowed to coupling products 6ba–ea in good yields. Notably,
react with 1a (2 equiv) under irradiation (blue LED) the benzylic alcohol moiety of 1d was well
for 5 h to afford 3aa in a slightly improved 61% tolerated. The reaction of iodoalkynes 1f and 1g,
yield (Scheme 2b). Although 2a was fully consumed bearing a p-chlorophenyl or p-bromophenyl substitu-
after the reaction, no byproduct was detected in the ent, also delivered 6fa and 6ga in good yields,
1
crude product by 19F and H NMR spectroscopy, although prolonged reaction times were required. 1-
suggesting that 2a decomposed during the reaction. Iodoalkynes 1h and 1i bearing an electron-with-
To identify the decomposition products, the coupling drawing group such as CO2Me and CF3 on the aryl
reaction was repeated using 2-(1-adamantyl)ethyl terminal, furnished the corresponding coupling prod-
ester 2b instead of 2a (Scheme 2c). Accordingly, 2- ucts 6ha and 6ia in 69% and 70% yields, respec-
(1-adamantyl)ethanol was detected in the crude tively. In addition to p-substituted aryl groups, m- or
product mixture, and the corresponding coupling o-substituted aryl groups were also compatible with
product 3ab was isolated in 69% yield. Because the this method, as coupling products 6ja–na were
decomposition of bromodifluoroacetates under reac- obtained in 70–81% yields. 1-Naphthyl derivative
tion conditions was suggested, the reactivity of 6oa was also obtained in 62% yield. As heteroaryl
bromodifluoromethyl phenyl ketone (2c) and bro- derivatives, iodoalkynes 1p–r, bearing a 2-pyridyl,
modifluoroacetamide 5a toward 1-iodoalkyne 1a 3-pyridyl, or 3-thiophenyl group, underwent the
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Scheme 4. Scope of bromodifluoroacetamides (PMP=p-meth-
oxyphenyl).
cyclic amine moiety was unnecessary. Secondary
amide 5i also participated in the coupling reaction,
affording 6ai in a good yield. In addition to these
amides, 2-bromodifluoromethyl-1,3-benzoxazole (5j)
successfully reacted with 1a to produce 6aj in 72%
yield.
Mechanistic considerations. To obtain insights
into the mechanism of the catalyst-free photo-coupling,
several control experiments were conducted as follows.
UV/Vis spectroscopic measurements of the reaction
components were carried out (Figures S2–S5 in Sup-
porting Information). The UV/Vis spectral charts of a
Scheme 3. Scope of 1-iodoalkyne substrates.
photo-coupling to give 6pa–ra in 62–66% yields. mixture of TMEDA and bromodifluoroacetamide 5a
The present catalyst-free photo-coupling reaction is or a mixture of TMEDA and 1-idoalkyne 1a in
scalable: the reaction of 1a and 5a was performed in acetonitrile were almost identical to that of a solution
a 5 mmol scale for 12 h to afford 6aa (1.38 g) in of TMEDA alone (Figures S3 and S4). No coloration
83% yield.
was observed when 1a and 5a were mixed with
In contrast to (hetero)aryl-substituted 1-iodoal- TMEDA in acetonitrile (Figure S5 in Supporting
kynes, aliphatic 1-iodoalkynes exhibited lower reac- Information). Moreover, the UV/Vis spectral charts of
tivity. The reaction of cyclohexenyl-substituted 1- solutions of 5a and TMEDA with different ratios (5a:
iodoalkyne 1s required a much longer reaction time TMEDA=1:2 and 1:6) were similar with that of the
(20 h), and the desired product 6sa was obtained in a 1:1 solution (Figure S6). These facts suggest that the
moderate yield (40%). The reaction of alkyl-substituted formation of an electron-donor-acceptor (EDA) com-
1-iodoalkyne 1t with 5a gave the expected product plex from 5a and TMEDA is less possible. This was
6ta in 30% yield along with byproduct 7ta in a low also corroborated by DFT calculations. Model EDA
yield. This result suggests that the unsaturated terminal complexes between trimethylamine and α-halocarbonyl
group of 1-iodoalkynes is necessary for the regioselec- compounds were optimized at the ωB97XÀ D [SMD
tive radical addition.
(MeCN)]6-311+G(d,p)–SDD(d) level of theory (Ta-
The scope of bromodifluoroacetamides was also ble S2 in Supporting Information). The calculation of
investigated, and the results are summarized in the EDA complex of Br3CCONMe2 (s1) gave an
Scheme 4. N-Phenylpiperadine and thiomorpholine N(amine)–Br distance (2.715 Å), which is similar to
moieties in amides 5b and 5c were well tolerated that reported for the EDA complex between
under the reaction conditions to furnish the desired Br3CCONH2 and tetramethyl-p-phenylenediamine
products 6ab and 6ac in 82% yield. Similarly, amides (2.722 Å).[11] The interaction energy (ΔE) value esti-
with a five- to seven-membered carbocyclic amine mated for the former (À 3.36 kcal/mol) is also similar
moiety (5d–g) gave the corresponding products 6ad– to that reported for the latter (À 4.53 kcal/mol).[11]
A
ag in 76–83% yields. The use of N,N-diethylacetamide model EDA complex of BrCF2CONMe2 (s2), which is
5h afforded 6ah in a good yield, indicating that the relevant to this study, was compared to those of
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BrCF2CO2Me and ICF2CO2Me (s3 and s4, respec-
tively) because the latter types of esters were employed
in the photoreactions involving EDA complexes.[12]
Although the N(amine)–X distance in s2 (2.824 Å) is
shorter than the sum of the van der Waals radii of the
Br and N atoms (3.40 Å),[13] it is significantly longer
than those of s3 (2.794 Å) and s4 (2.765 Å), implying
that s2 is much less stable than s3 and s4. Instability is
also indicated by the calculated interaction energies
(À 1.85 kcal/mol for s2 vs. À 3.70 and À 5.79 kcal/mol
for s3 and s4, respectively). Natural bond orbitals
(NBO) analyses also showed that the donor-acceptor
interaction energy of s2 was the smallest among the
calculated models. Therefore, the formation of EDA
complexes from bromodifluoroacetamides with TME-
DA is less favored than those of bromodifluoroacetates
and iododifluoroacetates.
Because the reaction mixture turned pale yellow
after reaction completion, we checked the UV/Vis
spectra of the supernatant solution and a solution of
6aa in MeCN; however, no significant absorption
was observed in the visible spectral region (Figur-
es S8 and S9 in Supporting Information). Previously,
Postigo et al. proposed that TMEDA/I2 complex acts
as a radical initiator.[14] However, the reaction of 1a
and 5a in the presence of I2 (30 mol%) under
irradiation with a blue LED was incomplete within
5 h; 6aa was obtained in 75% yield and 10% of 5a
was remained intact. Therefore, the initiation by
TMEDA/I2 is unlikely. Accordingly, the initiation
Scheme 5. Control experiments (PMP=p-methoxyphenyl).
mechanism is unclear, although the generation of an (385 nm) in the presence of the photocatalyst [fac-
*
EDA complex 5 TMEDA in a very low concen- Ir(ppy)3] for 2 h, affording TEMPO adduct 8 in 88%
tration cannot be completely excluded. The photo- yield (Scheme 5c). On the other hand, 1a and TEMPO
coupling of 1a with 5a was repeated upon irradi- (2 equiv) were also irradiated (385 nm) for 24 h.
ation using LEDs of different wavelengths (Sche- However, the TEMPO-alkyne adduct was not detected.
me 5a). Upon irradiation using a purple LED These control experiments suggest that the homolytic
(385 nm), 6aa was obtained in a slightly higher cleavage of the CÀ Br bond of 5a is facilitated under
yield than that for the reaction using a blue LED, photo-irradiation to produce
a
difluorometh-
albeit with a shorter irradiation time. On the other ylacetamide radical species. However, its concentration
hand, when a green LED (502 nm) was used, the is much lower than that under photoredox catalytic
reaction was very sluggish. The yield of 6aa conditions.
decreased to 68%, even after irradiation for 24 h. No
reaction occurred in the dark.
The photo-coupling of 1a and 5a was performed
under irradiation with a blue LED for 1 h, and the
Subsequently, the coupling of 1a with 5a was reaction was quenched by adding TEMPO (2 equiv),
performed using a blue LED in the presence of 2,2,6,6- affording 6aa in 31% yield based on 1H NMR analysis
tetramethylpiperidine-1-oxyl (TEMPO) (2 equiv) as of the crude reaction mixture (Scheme 5d). In contrast,
the radical-trapping agent for 5 h (Scheme 5b). As a the yield of 6aa increased up to 51% when the reaction
result, the coupling product 6aa was not detected in mixture was irradiated for 1 h, and then was stirred for
the crude reaction mixture by 1H and 19F NMR another 1 h in the dark. These results suggest that the
analyses. The coupling reaction in the presence of coupling reaction could continue after photoirradiation
TEMPO was repeated with irradiation using a purple is stopped. However, continuous irradiation is required
LED for 3 h. The TEMPO adduct (8) could be to ensure complete conversion of amide 5a, due to
1
detected, albeit in only 4% yield, as estimated by H termination pathway(s); 6aa was obtained in 24% and
NMR analysis of the crude mixture. These results 59% of 5a was recovered when the reaction was
imply that the radical species are involved in the performed with irradiation for 10 min and then the
photo-coupling reaction. Moreover, 5a and TEMPO reaction mixture was stirred for 5 h in the dark.
(2.6 equiv) was irradiated using a purple LED
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Scheme 6 shows a plausible mechanism based on ucts obtained in this study. At the outset, Cu-catalyzed
the control experiments above. Under catalyst-free hydroarylation with arylboron reagents was applied to
conditions, the coupling of bromodifluroacetamides 5 coupling products 6 (Scheme 7). The reaction of
with iodoalkynes 1 proceeds via a radical chain alkynyldifluoroacetamide 6aa with p- and o-tolylbor-
mechanism. The initiation step is the photo-induced onic acids was performed in the presence of 10 mol%
°
homolytic cleavage of the CÀ Br bond in 5, generating Cu(OAc)2 in methanol at 28 C for 6 h. The corre-
a difluoroalkyl radical species 9. The addition of 9 to sponding hydroarylation products 12a and 12b were
1-iodoalkyne 1 generates vinyl radical 10. This step obtained in 96% and 87% yields, respectively, based
proceeds regioselectively because of the stabilization on 1H NMR analysis of the crude products. In contrast,
of vinyl radical with the conjugated aryl group. the reaction of 6aa with p-chlorophenylboronic acid
Subsequent elimination of the iodine atom (I·) produ- was sluggish at room temperature, and undesired
ces coupling product 6. The generated iodine atom protodeboration occurred at elevated temperatures.
undergoes single-electron reduction by TMEDA to
DFT calculations of the model reactions revealed
generate radical species 11, as depicted in the inset that the activation barrier calculated for the rate-
scheme. Finally, single-electron transfer from 11 to determining carbocupration of (2-phenylethynyl)
bromodifluroacetamides 5 regenerates difluoroalkyl difluoroacetate (18.4 kcal/mol) was slightly lower than
radical 9, closing the propagation cycle. It is note- that for phenyl(trifluoromethyl)acetylene (19.7 kcal/
worthy that the iodoalkynes play a significant role as mol),[10c] as shown in Figure S10 (Supporting Informa-
radical acceptors. The reaction of 1-bromoalkyne 1a- tion). In contrast, the corresponding activation barrier
Br with bromodifluoroacetamide 5a under the
standard conditions afforded coupling product 6aa in
78% yield, although a longer reaction time (7 h) was
required (Scheme S1a, in Supporting Information). In
striking contrast, coupling product 6ba was not
obtained from 3-phenylpropiolic acid. Moreover, the
reaction of indole-2-carboxylate s5 with bromodifluor-
oacetamide 5a did not proceed under the catalyst-free
conditions, while the expected coupling product s6 was
obtained in 55% yield under the photoredox catalytic
conditions reported by Cho et al. (Scheme S1, in
Supporting Information).[15] These results imply that
the chain propagation step mediated by iodine atom
and TMEDA is more decisive than the initiation step
in the present catalyst-free photo-coupling.
Divergent transformation of the coupling prod-
ucts. Because alkynes equipped with a difluoroaceta-
mide group are potentially useful building blocks, we
investigated the transformations of the coupling prod-
Scheme 7. Hydrofunctionalization of coupling products. [a]
Yields were determined by 1H NMR analysis of the crude
products. Yields of recovered starting materials are shown in
Scheme 6. Plausible reaction mechanism.
parentheses. [b] Cu(OAc)2 (15 mol%) were used.
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estimated for (2-phenylethynyl)difluoroacetamide
(24.6 kcal/mol) is approximately 5 kcal/mol higher
than those of (2-phenylethynyl)difluoroacetate and
phenyl(trifluoromethyl)acetylene. Thus, the hydroary-
lation of alkynyldifluoroaetamides requires harsher
reaction conditions. Therefore, p-chlorophenylboronic
acid neopentyl glycol ester was used to avoid proto-
deborylation at an elevated temperature. The reaction
of 6aa with p-chlorophenylboronate was conducted at
°
40 C for 3 h to obtain the desired product 12c in 97%
yield. Similarly, 12a and 12b were quantitatively
obtained using the corresponding arylboronates at
°
40 C. The reactions using other arylboronates also
furnished hydroarylation products 12dÀ h in high
yields, although 15 mol% Cu(OAc)2 was necessary for
the formation of 12g. It is worth noting that constitu-
tional and stereoisomers (e.g., 12c, 12d, and 12g)
could be precisely synthesized using this method. The
2-thienyl ring of the alkyne substrate was also
tolerated, as 12i was obtained, albeit with a slightly
diminished yield (82%). Similarly, hydrovinylation
product 12j was successfully obtained in 83% yield.
Moreover, the reaction of 6aa with allylboronic acid
pinacol ester efficiently furnished skipped diene 12k
in 93% yield.
N-Difluoroacetylmorpholines are versatile difluor-
oalkyl building blocks because their amide moieties
can be readily transformed into various functional
groups.[16] Thus, we investigated the selective carbonyl
transformations of the alkynyldifluoroacetamide prod-
uct with its alkyne moiety preserved. The reduction of
6aa was carried out using NaBH4 (2 equiv) in ethanol
at room temperature for 3 h to afford the desired
alcohol 13 in 87% yield along with trace amounts of 3-
fluorofuran 14a (Scheme 8a). Furan 14a should be
Scheme 8. Transformations of amide moiety of 6aa (PMP=p-
methoxyphenyl).
produced via cyclization of 13 under basic conditions, next investigated (Scheme 8d). In the presence of
since base-promoted cyclization of similar 2-alkynyl- 10 mol% Cp*RuCl(cod), 17 reacted with 1-hexyne
2,2-difluoro alcohols has been reported.[17] Furan 14a (4 equiv) at ambient temperature to regioselectively
was obtained in a moderate yield when alcohol 13 was afford the desired fused benzene 18a in 88% yield.[20a,b]
heated in THF in the presence of 10 mol% AgNO3.[18] Similarly, terphenyl derivative 18b was obtained in
The treatment of 6aa with organolithium reagents 73% yield when p-tolylacetylene was used at a reflux
°
(2 equiv) in THF at –78 C for 30 min afforded the temperature. Furthermore, the reaction of 17 with ethyl
corresponding ketones 4 and 15 in high yields cyanoformate afforded pyridine derivative 18c, albeit
(Scheme 8b). Aromatic ketone 4 was reduced with in a moderate yield (54%).[20c,d]
NaBH4, and the resultant alcohol was directly sub-
jected to 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-
Conclusion
promoted cyclization/aromatization[17b] to afford 3-
fluorofuran 14b in 71% yield over two steps. We have developed a catalyst-free photo-coupling
Similarly, aliphatic ketone 15 was transformed into the reaction of bromodifluoroacetamides with 1-iodoal-
corresponding furan 14c in 63% yield over two steps, kynes. The catalyst-free method has a wide scope for
although heating for 48 h was required in the cycliza- both bromodifluoroacetamides and 1-iodoalkynes with
tion step. A related cyclization of amide 6ai was also a (hetero)aromatic terminal substituents. A total of 27
conducted upon treatment with tetra-n-butylammonium coupling products were obtained in 62–83% yield,
fluoride (TBAF) in THF at room temperature for 6 h, although the reaction of 1-iodoalkynes bearing a
affording lactam 16 in 61% yield (Scheme 8c).[19]
cyclohexenyl terminal substituent resulted in a lower
Because 1,7-diyne 17 was readily prepared from yield of 40%. Several control experiments suggest that
alcohol 13, the [2+2+2] cycloadditions of 17 were the present coupling proceeds via a radical chain
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Kelly, M. A. Mercadante, N. E. Leadbeater, Chem.
mechanism involving the photolysis of bromodifluor-
oacetamides. Subsequently, the addition of the resul-
tant difluoroalkyl radical species to 1-iodoalkynes is
followed by iodine atom elimination. The synthetic
utility of the coupling products was further demon-
strated by their divergent transformation into various
organofluorine compounds such as trisubstituted
difluoromethylalkenes, 3-fluorofurans, and fused aro-
matic compounds containing a difluoromethylene unit.
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Fluorine Chem. 2015, 175, 36–46; e) J. Doolfen, N.
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Experimental Section
Reaction of 1a with 5a:
A solution of 5a (77.7 mg,
0.318 mmol), iodoalkyne 1a (165 mg, 0.639 mmol), and TME-
DA (90 μL, 0.6 mmol) in degassed MeCN (3 mL) was stirred
under irradiation (LED 448 nm, Techno Sigma PER-AMP) at
room temperature under an Ar atmosphere for 5 h. The reaction
was quenched by adding H2O (20 mL) and sat. aq. Na2S2O3
(5 mL). The aqueous phase was extracted with AcOEt (3×
10 mL). The combined organic extract was washed with brine
(10 mL), dried over anhydrous Na2SO4. The solvents were
evaporated in vacuo, and the obtained crude product was
purified by silica gel column chromatography (hexane/AcOEt
90:1~2:1) to afford 6aa (76.2 mg, 81%) as a colorless solid
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°
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Acknowledgements
This research is partially supported by the Platform Project for
Supporting Drug Discovery and Life Science Research (Basis
for Supporting Innovative Drug Discovery and Life Science
Research (BINDS) from AMED under Grant Number
JP21am0101099).
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Catalyst-Free CspÀ Csp3 Cross-Coupling of Bromodifluoroa-
cetamides with 1-Iodoalkynes under Visible-Light Irradiation
Adv. Synth. Catal. 2021, 363, 1–10
Y. Yamamoto*, E. Kuroyanagi, H. Suzuki, T. Yasui