Divergent Halogenation Pathways of 2,2-Dichlorobut-3-yn-1-ols to 3-Chloro-4-Iodofurans and α-Chloro-γ-Iodoallenes: Electrophilic versus Pd(II)-Catalyzed Halogenation Strategies

Article abstract of DOI:10.1002/adsc.202001033

Divergent halogenation pathways of 2,2-dichlorobut-3-yn-1-ols have been developed to give 3,4-dihalofurans and 1,3-dihaloallenyl ketones in good to excellent yields. Thus, the readily accessible 2,2-dichlorobut-3-yn-1-ols were treated with the electrophil

Full text of DOI:10.1002/adsc.202001033

Title: Divergent Halogenation Pathways of 2,2-Dichlorobut-3-yn-1-
ols to 3-Chloro-4-iodofurans and α-Chloro-γ-Iodoallenes:
Electrophilic versus Pd(II)-Catalyzed Halogenation Strategies
Authors: Kyungsoo Oh, Hun Young Kim, and Mohamed Ahmed
Abozeid
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202001033
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10.1002/adsc.202001033
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Divergent Halogenation Pathways of 2,2-Dichlorobut-3-yn-1-ols
to 3-Chloro-4-iodofurans and -Chloro--Iodoallenes:
Electrophilic versus Pd(II)-Catalyzed Halogenation Strategies
Mohamed Ahmed Abozeid,a Hun Young Kim,b* and and Kyungsoo Oha*
a
Center for Metareceptome Research, Graduate School of Pharmaceutical Sciences, Chung-Ang University, 84
Heukseok-ro, Dongjak, Seoul 06974, Republic of Korea
Department of Global Innovative Drugs, Chung-Ang University, 84 Heukseok-ro, Dongjak, Seoul 06974, Republic of
b
Korea
E-mail: kyungsoooh@cau.ac.kr
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
difluorobut-3-yn-1-ol derivatives provide a ready
dichlorobut-3-yn-1-ols have been developed to give 3,4- access to 3-fluorofuran derivatives, the corresponding
Abstract. Divergent halogenation pathways of 2,2-
dihalofurans and 1,3-dihaloallenyl ketones in good to
excellent yields. Thus, the readily accessible 2,2-
dichlorobut-3-yn-1-ols were treated with the electrophilic
halogen source to provide the 1,3-dihalogen-substituted
allenyl ketones, whereas the use of Pd(II) catalyst promoted
the oxypalladation followed by the electrophilic
halogenation to give 3,4-dihalogen-substituted furan
derivatives. The synthetic utility of 3,4-dihalofurans and
1,3-dihaloallenyl ketones is demonstrated in the sequential
Suzuki cross coupling strategies.
2,2-dichlorobut-3-yn-1-ols are not known and their
chemical reactivity is yet to be explored. The devoid
of synthetic methods to 2,2-dichlorobut-3-yn-1-ol
derivatives prompted us to utilize ,-
dichloropropargyl ketones, readily accessed from the
selective chlorination of (E)--chlorovinyl ketones[9]
(Scheme 1b). Given that the bond dissociation
energies of C-F bonds are higher than those of C-
Cl bonds,[10] different bond cleavage events are
anticipated for the halogenation of 2,2-dichlorobut-3-
yn-1-ols. Herein, we describe the divergent
halogenation pathways of 2,2-dichlorobut-3-yn-1-ols
to 1,3-dihaloallenyl ketones and 3,4-dihalofurans
(Scheme 1c). The strikingly different reactivity
behavior of 2,2-dichlorobut-3-yn-1-ols highlights the
unique stereoelectronic effect of chlorine atoms[11]
and the superior  interactions of the Pd(II) catalysts.
Keywords: Haloallenes; Dehydrochlorination; Divergent
Halogenation; Halofurans; Palladium Catalysis
The halogenated compounds play indispensable roles
in drug discovery with improved metabolic stability
and lipophilicity.[1] The ,-dihalo carbonyl
compounds are useful synthetic intermediates,
particularly serving as the precursors for halogen-
containing chemical entities.[2] The reduction of ,-
difluoro carbonyl ketones, for example, provides 2,2-
difluoro alcohols, and the presence of a suitable
alkyne moiety has provided a facile access to 3-
fluorofuran derivatives under the basic[3] and the
AgNO3 catalysis conditions[4] (Scheme 1a). In this
context, the Hammond group in 2008 achieved the
microwave-mediated
iodocylization
of
2,2-
difluorobut-3-yn-1-ols with ICl to give 3-fluoro-4-
iodofuran derivatives after the aromatization using
silica gel.[5] The electrophilic halogenation of
propargyl ketones to 3,4-dihalofurans has been
developed by the Müller group[6] and Yamamoto
group,[7] respectively, and the Dembinski group in
2012 reported the sequential halogenation of alkenyl
silyl ethers with Selectfluor followed by the NBS or
NIS treatment to give 3,4-dihalogenated furans under
the catalysis of AuCl/ZnBr2.[8] While the 2,2-
1
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10.1002/adsc.202001033
Advanced Synthesis & Catalysis
Scheme 1. Divergent electrophilic cyclization of ,-
Motivated by the possibility of Pd-catalyzed
halogenation without the use of directing groups,[12]
further synthetic exploration of the Pd(TFA)2-
catalyzed 5-endo-dig cyclization of 2,2-dichlorobut-
3-yn-1-ols was examined in the presence of
electrophilic halogen sources (Table 2). Thus, under
the optimized Pd(TFA)2-catalyzed conditions the
electrophilic chlorine source was added (entry 1).
dihalobut-3-yn-1-ols.
To establish a ready access to 2,2-dichlorobut-3-
yn-1-ols, the ,-dichloropropargyl ketone 1a was
reduced by NaBH4 at ambient temperature (Table 1).
After work-up and removal of solvent, an analytically
pure 2,2-dichlorobut-3-yn-1-ol 2a was obtained. Thus, Unfortunately, the chlorocyclization of 2,2-
without further purification the THF solution of 2a
was subjected to a variety of metal catalysts. The use
of copper (CuCl, CuCl2), zinc (Zn(OTf)2), indium
(In(OTf)3), and nickel (Ni(OAc)2) catalysts did not
promote the cyclization of 2a, however the utilization
of AgNO3 under refluxing THF provided the desired
3-chlorofuran 3a in 21% yield (entry 1). While the
AgNO3-catalyzed cyclization of 2,2-difluorobut-3-yn-
1-ols was demonstrated with 10 mol% catalyst
loading by Hammond,[3] a stoichiometric amount of
AgNO3 was required for the cyclization of 2,2-
dichlorobut-3-yn-1-ol 2a. To our delight, the high
catalytic activity was observed with Au(I) catalyst
(entry 2) and Pd(II) catalysts (entries 3-6). Among
them, the use of Pd(TFA)2 provided the desired
product 3a in 81% yield (entry 6). The Pd(TFA)2-
catalyzed reaction also proceeded in other solvents,
although somewhat diminished yields of 3a was
observed in 47-61% (entries 7-9). The control
experiment confirmed the optimal Pd(TFA)2 catalyst
loading to be 5 mol%, where the use of 1 mol%
loading significantly slowed down the reaction (entry
10).
dichlorobut-3-yn-1-ol 2a was not observed, only
leading to 3-chlorofuran 3a in 20% yield. The use of
electrophilic brominating reagents provided the
desired 3-bromo-4-chlorofuran 4a in 13-23% yields,
however the formation of 3a was also accompanied
(entries 2-5). The employment of iodinating reagent,
I2, provided the desired 3-chloro-4-iodofuran 5a in
10% yield (entry 6). Switching the iodinating reagent
to N-iodosuccinimde (NIS) improved the yield of 5a
to 66% yield (entry 7). A 1:5.3 mixture of 3-
chlorofuran 3a and 3-chloro-4-iodofuran 5a was
observed upon using N-iodophthalimide (NIP) (entry
8). The varied amounts of NIS revealed that 1.1 equiv
of NIS was optimal for the iodocyclization of 2,2-
dichlorobut-3-yn-1-ol (entry 9), where the desired
product 3-chloro-4-iodofuran 5a was obtained in 79%
yield.
Table 2. Optimization of Pd(TFA)2-Catalyzed 5-endo-dig
Halocyclization.[a]
Table 1. Optimization of metal-catalyzed 5-endo-dig
cyclization.[a]
entry
1
halogen (equiv)
NCS (1.5)
T (h)
24
9
yield (%)[b]
20% (3a)
2[c]
3[c]
4[c]
5[c]
6[c]
7
NBS (1.5)
28%+13% (3a+4a)
14%+23% (3a+4a)
28%+21% (3a+4a)
10%+18% (3a+4a)
10%, 5a
entry
cat. (mol%)
solvent
T (h)
yield
(%)[b]
NBP (1.5)
4
1[c]
2
AgNO3 (20)
Me2SAuCl (5)
PdCl2 (5)
THF
THF
6
6
21
64
NBSaccharin (1.5)
DBDMH (2.0)
I2 (1.5)
1
1
1
3
THF
6
68
NIS (1.5)
1
66%, 5a
4
Pd(CH3CN)2Cl2
THF
3
72
8[c]
NIP (1.5)
1
5%+27% (3a+5a)
79 (81)[d], 5a
(5)
5
Pd(OAc)2 (5)
THF
3
64
9
NIS (1.1)
3
6
Pd(TFA)2 (5)
Pd(TFA)2 (5)
Pd(TFA)2 (5)
Pd(TFA)2 (5)
Pd(TFA)2 (1)
THF
3
81(83)[d]
7
CH2Cl2
PhCH3
CH3OH
THF
3
61
[a] The crude 2a (0.3 mmol) from the NaBH4 reduction was
dissolved in 1 mL solvent (0.1 M) with Pd(TFA)2 (5
mol%) at ambient temperature under argon atmosphere.
8
5
55
9
3
47
[c]
[b]Isolated yields after column chromatography.
10
72
19
Halofurans obtained as an inseparable mixture. [d] Reaction
in 1 mmol scale.
[a]
Thee crude 2a (0.3 mmol) from the NaBH4 reduction
was dissolved in 1 mL solvent (0.1 M) with metal catalyst
(x mol%) at ambient temperature under argon atmosphere.
[b]Isolated yields after column chromatography. [c]Reaction
at 66 C. [d] Reaction in 1 mmol scale.
Under the optimized Pd(TFA)2-catalyzed 5-
endo-dig (iodo)cyclization conditions, the substrate
scope of 2,2-dichlorobut-3-yn-1-ols was examined
(Scheme 2). The reactions, in general, worked well
2
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10.1002/adsc.202001033
Advanced Synthesis & Catalysis
for various 2,2-dichlorobut-3-yn-1-ols, where the aryl
bromide 3h/5h-3i/5i, heterocycle 3l/5l-3n/5n, alkene
3o/5o, alkyl chloride 3r/5r, and ester 3s/5s moieties
were tolerated to give the desired 3-chlorofurans 3
and 3-chloro-4-iodofurans 5 in 43-97% yields.
reaction (entry 12), possibly mopping the HCl by-
product.
Table 3. Optimization of dehydrochlorinative iodination.[a]
entry
halogen
(equiv)
base
(equiv)
additive
-
yield (%)[b]
5a
6a
1
NIS (3.3) NaHCO3
(3.3)
37%
13%
2
NIS (3.3) NaHCO3 4 Å MS 15%
8%
47%
20%
45%
56%
76%
46%
42%
0%
(3.3)
3
NIS (3.3) NaHCO3 Na2SO4 15%
(3.3)
NIS (3.3) Na2CO3 Na2SO4 51%
(3.3)
4
5
NIS (3.3) LiOH (3) Na2SO4 15%
6
NIS (3.0) NaHCO3 Na2SO4 13%
(3.0)
7[c]
8[c]
9[c]
10[c]
11[c]
12[c]
NIS (3.0) NaHCO3 Na2SO4
(3.0)
0%
NIS (2.5) NaHCO3 Na2SO4 15%
(2.5)
NIS (3.5) NaHCO3 Na2SO4
7%
(3.5)
NIP (3.0) NaHCO3 Na2SO4
(3.0)
0%
Scheme 2. Substrate scope of Pd(TFA)2-catalyzed 5-endo-dig
(iodo)cyclization.
I2 (3.0)
NaHCO3
(3.0)
-
-
64%
0%
0%
NIS (3.0)
-
27%
The 5-endo-dig iodocyclization pathway of 2,2-
dichlorobut-3-yn-1-ol 2a was suppressed in the
absence of Pd(TFA)2 catalyst (Table 3). Thus, the use
of 3 equiv of NIS in combination of NaHCO3
provided a mixture of 3-chloro-4-iodofuran 5a and -
chloro--iodoallenyl ketone 6a in 37% and 13% yield,
respectively (entry 1). Since the reaction outcome
was precarious due to the small amount of
water/MeOH impurities from the reduction of allenyl
ketone 1a, the purified 2,2-dichlorobut-3-yn-1-ol 2a
was used in the presence of dehydrating agents
(entries 2-3). The use of Na2SO4 improved the
formation of 6a to 47% yield, however the allenyl
product 6a could not be separated from the furanyl
product 5a (entry 3). The nature of base was critical
since Na2CO3 instead of NaHCO3 provided the 3-
chloro-4-iodofuran 5a as a major product in 51%
yield (entry 4). The use of LiOH provided a similar
outcome as NaHCO3, leading to a 1:3 mixture of 5a
and 6a (entry 5). The final fine-tuning of the reaction
conditions focused on to the use of 3.0 equiv of NIS
and degassed MeCN (entry 7). Gratifyingly, such
modification provided the exclusive formation of 6a
in 76% yield without the formation of 5a. The control
experiment demonstrated the importance of NIS and
NaHCO3 amounts for the selective formation of -
chloro--iodoallenyl ketone 6a (entries 8-9). The
current dehydrochlorinative iodination of 2a did not
work with other iodinating reagents (entries 10-11),
and the use of NaHCO3 was needed for the faster
[a] Reaction using 2a (0.3 mmol) in MeCN (3 mL, 0.10 M)
with halogen source (x equiv), base (x equiv), and additive
(300 mg) at ambient temperature under argon atmosphere.
[c]
[b]Isolated yields after column chromatography.
Degassed for 20 min.
The scope and limitation of dehydrochlorinative
iodination
of
2,2-dichlorobut-3-yn-1-ols
are
illustrated in Scheme 3. Of note, the -chloro--
iodoallenyl ketones were not stable upon prolonged
exposure to the reaction conditions, thus speeding-up
the reaction was required in more concentrated
conditions. Thus, the reactions of 2,2-dichlorobut-3-
yn-1-ols 2b and 2c were performed in 0.6 M
concentration, where the formation of the
corresponding products 6b and 6c was accomplished
within 5 min. Also, the 2,2-dichlorobut-3-yn-1-ols 2g
and 2h were subjected to the 0.3 M concentration to
give the products 6g and 6h in 66% and 69% yields,
respectively. While the presence of furan and ester
moieties in 2l and 2s presented the functional group
compatibility issue, the corresponding -chloro--
iodoallenyl ketones with thiophene 6m-6n, alkene 6o,
and alkyl chloride 6r were obtained in 30-69% yields.
3
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10.1002/adsc.202001033
Advanced Synthesis & Catalysis
,-dichloroallenyl ketone 1a under the optimized
conditions, illustrating the unique reactivity pattern of
2,2-dichlorobut-3-yn-1ols 2.
Scheme 4. Mechanistic rationale for divergent halogenation
pathways of 2,2-dichlorobut-3-yn-1ols.
Scheme 3. Substrate scope of dehydrochlorinative iodination
to -chloro--iodoallenyl ketones ([a]Reaction for 5 min in 0.6 M.
The synthetic utilization of 3-chloro-4-iodofuran
[b]Reaction for 10 min in 0.3 M. [c]Decomposition).
5
and -chloro--iodoallenyl ketone
6
was
The divergent halogenation of 2,2-dichlorobut-3-
yn-1ols 2 to 3-chloro-4-iodofuran 5 and -chloro--
iodoallenyl ketones 6 could be rationalized based on
the -acidity of Pd(II) species (Scheme 4). Thus, the
presence of highly electrophilic Pd(TFA)2 promotes
the -coordination of Pd(II) catalyst A. The
subsequent 5-endo-dig cyclization of A leads to the
formation of the cyclic palladate B, which undergoes
the dehydrochlorination to C. The fate of furanyl
palladate C is guided by the electrophilic species in
the reaction mixture, diverging to 3-chlorofurans 3
and 3-chloro-4-iodofurans 5. The fact that the highly
electrophilic iodinating reagent, NIS, readily
demonstrated in the cross-coupling strategies
(Scheme 5). Thus, the Suzuki coupling of furan 5a
with electronically different boronic acids smoothly
provided the corresponding 3-chlorofurans 7a-7b in
73-99% yields. The subsequent Sonogashira coupling
with hept-1-yne also led to the formation of fully
substituted furans 8a-8b in 69-74% yields. Likewise,
the selective Suzuki coupling of allenyl ketone 6a
could be achieved in 60% to give the allenyl ketone 9.
provided the 3-chloro-4-iodofurans
5
clearly
demonstrates the preferential -coordination of
Pd(TFA)2 over the electrophilic halogen source, NIS.
Our control experiment confirmed that the 3-
chlorofurans 3 were not converted to the 3-chloro-4-
iodofurans 5 under the halogenation conditions. The
treatment of 2,2-dichlorobut-3-yn-1ols 2 with NIS in
the absence of Pd(II) catalyst allows the -
coordination of NIS. Since NaHCO3 alone did not
promote the dehydrochlorination of 2,2-dichlorobut-
3-yn-1ols 2, the electrophilic activation of 2 by NIS
parameterizes the CH bond of the alcohol moiety,
promoting the dehydrochlorination to the enol species
E. The iodination occurs at the -position due to the
steric reasons.[13] The use of 2-OMe substrate without
an alcohol moiety did not lead to the formation of -
chloro--iodoallenyl ketone 6a and the non-basic
reaction condition was also confirmed with -
chloroallenyl ketone 1-H. These results collectively
suggest the possible role of the alcohol moiety for the
Scheme 5. Synthesis of fully substituted furans and allenyl
ketone.
In summary, we have developed the divergent
halogenation pathways of 2,2-dichlorobut-3-yn-1ols
to give dihalofurans and dihaloallenyl ketones. The
preferential -acidity of Pd(II) catalyst allowed the 5-
endo-dig (halo)cyclization pathway of 2,2-
dichlorobut-3-yn-1ols, whereas the H-bonding
assisted direct halogenation pathway was observed in
the absence of Pd(II) catalyst. Given that the Csp2-Cl
and Csp2-I bonds are selectively functionalized using
the metal-catalyzed cross coupling strategies, the
divergent halogenation reactions of 2,2-dichlorobut-
H-bonding assistance.
A complex mixture of
unknown products was observed from the reaction of
4
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10.1002/adsc.202001033
Advanced Synthesis & Catalysis
2-Butyl-4-chloro-3-iodo-5-(p-tolyl)furan (5a): Colorless
3-yn-1ols should contribute to the synthetic toolbox
in the arsenal of synthetic methods. Our current
research efforts are directed to the synthetic utility of
,-dichloroallenyl ketones, and these results will be
reported in near future.
1
oil (301.7 mg, 81%); H-NMR (600 MHz, CDCl3): δ 7.76
(d, 2H, Ar-H, J = 8.40 Hz), 7.23 (d, 2H, Ar-H, J = 8.40
Hz), 2.74 (t, 2H, CH2(CH2)2CH3, J = 7.20 Hz), 2.37 (s, 3H,
Ar-CH3), 1.70-1.65 (m, 2H, CH2CH2CH2CH3), 1.43-1.37
(m, 2H, CH2CH2CH2CH3), 0.96 (t, 3H, (CH2)3CH3, J =
7.80 Hz); 13C-NMR (150 MHz, CDCl3): δ 155.6, 146.6,
137.8, 129.2, 126.5, 124.8, 115.2, 70.8, 30.0, 28.0, 22.1,
21.3, 13.8; HRMS (ESI): m/z calcd for C15H17ClIO
[(M+H)+] 375.0007, found 374.9995; IR (Neat, Thermo
Nicolet): 2956, 2928, 2871, 2860, 1588, 1558, 1501, 1464,
1457, 1107, 1088, 1020, 1014 cm-1.
Experimental Section
General Procedure for the Pd(TFA)2-Catalyzed 5-endo-
dig Cyclization
General Procedure for the Dehydrochlorinative
Iodination
Sodium borohydride (1 equiv., 1 mmol, 37.8 mg) was
added portion-wise to a solution of α,α-dichloropropargyl
ketone 1a (1 mmol, 283.2 mg) in anhydrous methanol (0.1
M, 10 mL) at 0 C, and the reaction mixture was stirred for
1 minute at the same temperature. After concentrating
under vacuum, the remaining residue was dissolved in
ethyl acetate (30 mL), washed with water and extracted
with ethyl acetate (30 mL x 2). The combined organic
layers were dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. The resulting crude
compound 2a was used in the next step without
purification. After dissolving the compound 2a in
anhydrous THF (0.1 M, 10 mL), Pd(TFA)2 (5 mol%, 0.05
mmol, 16.6 mg) was added, and the reaction was stirred
under nitrogen at room temperature until the reaction was
complete by TLC (3 h). The reaction mixture was
concentrated in vacuo and purified by silica gel column
chromatography to provide 3a (eluent: Hexanes) in 83%
yield.
To a degassed 50 mL round bottom flask charged with 2,2-
dichlorobut-3-yn-1-ols 2a (1 mmol, 285.2 mg) and
anhydrous sodium sulfate (999.5 mg), anhydrous and
degassed acetonitrile (0.1 M, 10 mL) was added under
nitrogen followed by stirring at room temperature until the
complete dissolving of 2a. Sodium bicarbonate (3 equiv.,
3mmol, 251.9 mg) and N-iodosuccinimide (3 equiv.,
3mmol, 674.7 mg) were subsequently added and the
reaction was stirred at room temperature for 1 h under
nitrogen atmosphere. The reaction mixture color changed
gradually from colorless to yellow and then to deep brown.
After the compete conversion of 2a (monitored by TLC),
the reaction was quenched by adding saturated aqueous
sodium thiosulfate solution until the appearance of pale
yellow color. The reaction mixture was extracted using
ethyl acetate (30 mL x 3), washed with brine, dried over
anhydrous magnesium sulfate and then the solvent was
removed in vacuo to give the crude 6a as a yellowish
residue. Pure product 6a was obtained by silica gel column
chromatography using a mixture of hexanes and ethyl
acetate (v:v = 98:2) as yellow oil in 76% yield.
5-Butyl-3-chloro-2-(p-tolyl)furan (3a): Colorless oil
1
(206.2 mg, 83%); H-NMR (600 MHz, CDCl3): δ 7.77 (d,
2H, Ar-H, J = 8.40 Hz), 7.21 (d, 2H, Ar-H, J = 8.40 Hz),
6.07 (s, 1H, Furan-CH), 2.64 (t, 2H, CH2(CH2)2CH3, J =
7.80 Hz), 2.37 (s, 3H, Ar-CH3), 1.68-1.63 (m, 2H,
CH2CH2CH2CH3), 1.44-1.38 (m, 2H, CH2CH2CH2CH3),
0.95 (t, 3H, (CH2)3CH3, J = 7.20 Hz); 13C-NMR (150 MHz,
CDCl3): δ 154.9, 145.7, 137.1, 129.1, 127.2, 124.6, 110.9,
109.2, 29.9, 27.8, 22.2, 21.3, 13.8; HRMS (ESI): m/z calcd
for C15H18ClO [(M+H)+] 249.1041, found 249.1030; IR
(Neat, Thermo Nicolet): 2958, 2930, 2872, 2862, 1602,
1558, 1502 cm-1.
2-Chloro-4-iodo-1-(p-tolyl)octa-2,3-dien-1-one
(6a):
1
Yellow oil (85.8 mg, 76%); H-NMR (600 MHz, CDCl3):
δ 7.74 (d, 2H, Ar-H, J = 7.80 Hz), 7.28 (d, 2H, Ar-H, J =
7.80 Hz), 2.89 (t, 2H, CH2(CH2) 2CH3, J = 7.20 Hz), 2.42
(s, 3H, Ar-CH3), 1.51-1.46 (m, 2H, CH2CH2CH2CH3),
1.29-1.23 (m, 2H, CH2CH2CH2CH3), 0.86 (t, 3H,
(CH2)3CH3, J = 7.20 Hz); 13C-NMR (150 MHz, CDCl3): δ
197.2, 187.8, 146.1, 145.3, 130.9, 129.6, 129.5, 104.4, 41.4,
26.1, 21.9, 21.8, 13.7; HRMS (ESI): m/z calcd for
C15H17ClIO [(M+H)+] 375.0007, found 375.0014; IR (Neat,
Thermo Nicolet): 2958, 2930, 2871, 1678, 1605, 1543 cm-1.
General Procedure for the Pd(TFA)2-Catalyzed 5-endo-
dig Iodocyclization
α,α-Dichloropropargyl ketone 1a (1 mmol, 283.2 mg) was
dissolved in anhydrous methanol (0.1 M, 10 mL) under
nitrogen followed by the portion-wise addition of sodium
borohydride (1 equiv., 1 mmol, 37.8 mg) at 0 C. After 1
min stirring at the same temperature, methanol was
completely removed under vacuum and then the remaining
residues were dissolved in ethyl acetate (30 mL), washed
with water and further extracted with ethyl acetate (30 mL
x 2). After drying the combined organic layers using
anhydrous magnesium sulfate, the ethyl acetate was
completely evaporated under reduced pressure followed by
azeotropic drying using anhydrous toluene to provide a
fully dried crude alcohol 2a. The resulting crude alcohol
2a was dissolved in anhydrous THF (0.1 M, 10 mL) with
the addition of N-iodosuccinimide (1.1 equiv, 1.1 mmol,
247.5 mg) under nitrogen. The reaction mixture was stirred
until N-iodosuccinimide was completely dissolved (about 1
min), and then Pd(TFA)2 (5 mol%, 0.05 mmol, 16.6 mg)
was added to this solution. The reaction was stirred for 3 h
at room temperature and terminated by the dropwise
addition of aqueous saturated sodium thiosulfate until the
solution became pale-yellow. The crude product 5a was
extracted with ethyl acetate (30 mL x 3), washed with
brine and dried over magnesium sulfate. Purification by
silica gel column chromatography gave pure 5a (eluent:
Hexanes) in 81% yield.
Acknowledgements
This research was supported by the National Research
Foundation of Korea (NRF) grants funded by the Korean
government (MSICT) (NRF-2015R1A5A1008958, and NRF-
2019R1A2C2089953).
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COMMUNICATION
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7
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