Metal-free reductive cyclization and isomerization of sulfanyl-1,6-diynes using sodium borohydride

Article abstract of DOI:10.1246/cl.140688

In this study, we demonstrated the metal-free reductive cyclization of sulfanyl-1,6-diynes with sodium borohydride in ethanol in the presence of diazabicyclo[5.4.0]undec-7-ene. 1,6-Diynes 1 and 5a-5h bearing hydrogen or phenyl as the R² group a

Full text of DOI:10.1246/cl.140688

CL-140688
Received: July 22, 2014 | Accepted: August 12, 2014 | Web Released: August 22, 2014
Metal-free Reductive Cyclization and Isomerization of Sulfanyl-1,6-diynes
Using Sodium Borohydride
Yukiteru Ito and Mitsuhiro Yoshimatsu*
Department of Chemistry, Faculty of Education, Gifu University, Gifu 501-1193
(E-mail: yoshimae@gifu-u.ac.jp)
In this study, we demonstrated the metal-free reductive
cyclization of 1 easily proceeded under reflux conditions to
afford the desired 4-methyl-3-(phenylsulfanylmethyl)-N-tosyl-
pyrrole (2) in 64% yield. The structure of 2 was determined
based on spectral data. This revealed two types of singlet protons
due to the 4-methyl group on pyrrole at ¤ 1.99 and the methylene
group at ¤ 3.82 and two broad singlets due to the pyrrole ring
at ¤ 6.83 and 6.86. Since the reductive cyclization in aprotic
solvent such as THF, toluene, and 1,2-dichloroethane gave
rise to a complex mixture containing desired 2 and 3,4-
bis(phenylsulfanylmethyl)pyrrole, a screening of reaction con-
ditions was performed using sodium borohydride in some
alcohols (Table 1).
cyclization of sulfanyl-1,6-diynes with sodium borohydride in
ethanol in the presence of diazabicyclo[5.4.0]undec-7-ene. 1,6-
Diynes 1 and 5a-5h bearing hydrogen or phenyl as the R2 group
afforded pyrroles 2 and 6a-6e in high yields without any side
reaction products such as enynyl sulfides. 1,6-Diyne (R2 = Et)
produced both pyrrole and enynyl sulfides; however, the use
of cesium fluoride succeeded in the selective formation of
pyrrole 6f.
Transition-metal-catalyzed reductive cyclization of diynes
and enynes is one of the most efficient methods for the
construction of various five-membered rings, including hetero-
cycles.1 In particular, the cyclization of nitrogen-tethered 1,6-
diynes is recognized as a practical method of attaining pyrrole,
2,5-dihydro-1H-pyrrole and 3,4-bis(methylene)-2,3,4,5-tetrahy-
dro-1H-pyrrole,2 which are found in natural products and
biologically active molecules and used in material science
and supramolecular chemistry.3 Various synthetic methods for
preparing highly functionalized pyrroles have been developed;
however, most methods are limited by the substituent and
its pattern. The Paar-Knorr synthesis for pyrrole rings is a
convenient method suitable for the preparation of 2,5-dialkyl-
and 2,3-dialkyl or polysubstituted pyrroles.4 To date, much focus
has been put on 2,5-unsubstituted pyrroles, which are the most
important precursors for the synthesis of numerous porphyrinoid
dyes and polypyrroles.5 The previously reported methods for
2,5-unsubstituted pyrroles6 are convenient; however, all these
methods require transition metals to complete the reaction.
Recently, we reported a novel method for synthesizing 3-
alkoxymethyl- and 3-aminomethylfurans and -pyrroles by the
functionalization-cyclization of 4-oxahepta-1,6-diynes and 4-
azahepta-1,6-diynes.7 Because this unique cyclization directly
yielded 2,5-unsubstituted pyrroles, even in the absence of
transition metals, we further intended to perform the metal-
free cyclization of N-tethered 1,6-diyne with readily available
reducing agents (Scheme 1). Here, we report a convenient
cyclization of sulfur-substituted 1,6-diyne using sodium boro-
hydride in ethanol.
The reaction of 1 in methanol was examined. The obtained
product was not reductively cyclized pyrrole 2, but methoxy-
methylpyrrole 3 (Entry 2). On the other hand, the reaction in
isopropanol produced the expected pyrrole 2 in 63% yield
(Entry 3). Even when the usual reducing agents such as lithium
aluminum hydride, triethylsilane, and nickel borohydride were
used, isolating the products was not possible. Furthermore,
cyanoborohydride was not effective in the reductive cyclizations
(Entry 4). Based on our experience in this field, the addition of a
base has sometimes accelerated the cyclization, triggered by
certain functionalizations. Therefore, we next examined reduc-
tive cyclization reactions in the presence of a base. Indeed,
the use of triethylamine afforded 2 in good yield (Entry 5).
Diethylamine led to the formation of vinyl sulfide 4, which was
obtained from the unexpected reduction of alkynyl sulfide
(Entry 6). Other bases such as 2,2¤-bipyridyl (2,2¤-Py) and
diazabicyclo[5.4.0]undec-7-ene (DBU) also caused the reductive
cyclization of sulfanyl 1,6-diynes. Among these, DBU was
Table 1. Reductive cyclization of 1,6-diyne 1 with sodium
borohydride
PhS
SPh
SPh
NaBH4 (3 equiv)
Tos
Tos
N
+
Tos
N
N
CH2R
(R = H)
1
4
2
(Tos: p-toluenesulfonyl)
3 (R = OMe)
Product/%
Entry Condition
First, we performed the usual reduction using sodium
borohydride in ethanol according to our previous alkoxide-
mediated cyclization of 1,6-diynes.7 Surprisingly, the reductive
2 or 3
2 (64)
3 (88)
2 (63)
2 (12)
2 (76)
4
1
2
3
4
5
6
7
8
EtOH, 78 °C, 0.25 h
MeOH, 78 °C, 1 h
i-PrOH, 78 °C, 10 min
EtOH, 78 °C, 9 ha
®
®
®
®
®
SR
RS
H
H
Et3N (3 equiv), EtOH, 78 °C, 0.25 h
N
N
R
Et2NH (3 equiv), EtOH, 78 °C, 0.3 h 2 (51) 4 (49)
R
2,2¤-Py (2 equiv), EtOH, 78 °C, 0.5 h 2 (78)
DBU (3 equiv), EtOH, 78 °C, 10 min 2 (90)
®
®
Scheme 1. Metal-free reductive cyclization of N-tethered
sulfanyl 1,6-diynes.
aNa(CN)BH3 (3 equiv) was used.
1758 | Chem. Lett. 2014, 43, 1758–1760 | doi:10.1246/cl.140688
© 2014 The Chemical Society of Japan

path c
Table 2. Reductive cyclization of 1,6-diyne 5
H
X
HOEt or
R3
DOEt
SR1
SR1
R2
SR1
R2
R3
R2
R3
NaBH4, EtOH
X
X
R1SO2
R1SO2
+
N
N
R2
R2
DBU (3 equiv)
N
Tos
11c
R2
11b
11a
(R2 = H)
5
6
a or
b
8
(R2 = OEt)
R2 = H
SR1
D
7
base
c
path a
Temp/°C,
time/min
R1S
Product/%
5 or 6 7 and 8
Entry R1
R2 R3
H (D)
X
SR1
R2
R2
X
1
2
3
4
5
6
7
8
9
MeOC6H4
NO2C6H4
NO2C6H4
MeC6H4
MeC6H4
MeC6H4
MeC6H4
MeC6H4
MeC6H4
MeC6H4
H
H
H
H
H
SPh
SPh
SPh
SePh 78, 13
Ph
78, 10
78, 5
25, 120 6b (73)
6a (72)
6b (12)
®
®
®
®
®
®
12
X
13
HOR3
path b
16
a
H (D)
R1S
H(D)
6c (52)
5d (99)
6e (57)
6f (33) 8f (27)c
6g (20)
6h (9)
6f (57) 8f (20)e
H(D)
R2
b
78, 90
78, 30
78, 30
R1S
H (D)
Ph SPh
Et SPh
Et SMe 78, 20
Et SAra 78, 8b
X
R3O
14
®
®
R2
X
15
10
Et SPh
78, 20d
Ar = 2,4,6-triisopropylphenyl. bBoth i-Pr2NEt (3 equiv) and
NaBH4 (10 equiv) were used in EtOH. cThe compound 7f
was obtained in 27% yield. dReaction condition: Both CsF
(3 equiv) and NaBH4 (3 equiv) were used in EtOH-H2O (1:1).
eThe compound 7f was obtained in 17% yield.
Scheme 2. Proposed mechanism.
triisopropylphenylsulfanyl derivative did not proceed, but at a
lower yield (Entry 9). Further investigation of the reaction
condition of ethyl-substituted 1,6-diyne indicated that the weak
base such as cesium fluoride significantly affected the regiose-
lective reductive cyclization (Entry 10).
suitable for the completion of 1 with sodium borohydride
reductive cyclizations (Entries 7 and 8).
SPh
PhS
R1
R1
NaBH4-EtOH
DBU
ð1Þ
(R1 = 2-naphthyl) (47%)
(R1 = 2-thienyl) (40%)
We explored the scope of this reaction using the above
optimal reaction conditions, as shown in Table 2. Diyne 5a,
possessing an electron-donating substituent, p-methoxyphenyl
group, underwent reductive cyclization to give pyrrole 6a in
72% yield (Entry 1). However, bearing an electron-withdrawing
substituent, p-nitrophenyl group, significantly lowered the yield
of pyrrole 6b under the reflux condition (Entry 2). Our detailed
research revealed that even if the reductive cyclization of 5b
using NaBH4 in ethanol was performed at room temperature,
it afforded 73% yield (Entry 3). The electron-withdrawing
sulfonyl group effectively accelerated the reductive cyclization
producing pyrroles. Phenylselanyl-1,6-diyne 5c furnished the
selanylmethylpyrrole in a similar yield as that of sulfanyl-1,6-
diyne (Entry 4). Since phenyl-1,6-diyne 5d could not participate
in this reductive cyclization leading to pyrroles, to complete the
cyclizations of 1,6-diynes, organosulfanyl groups must exist at
the alkyne termini (Entry 5). We subsequently examined the
reaction of disubstituted 1,6-diynes possessing both phenyl and
ethyl groups at the alkyne termini. Although phenyl-1,6-diyne
succeeded in generating pyrrole 6e, the ethyldiyne lowered the
yield of 6f (Entries 6 and 7). We investigated the resulting
mixture in detail, detecting the formation of both ethoxy-
methylpyrrole 7 and enyne 8, the former was produced by
alkoxylation-cyclization process and the latter was obtained
by the unexpected reduction of the sulfanyl alkyne of 1,6-diyne.
We further investigated the reductive cyclization of ethyl-
substituted 1,6-diynes, possessing both the methanesulfanyl
and bulky 2,4,6-triisopropylphenylsulfanyl R3 groups to assess
complete regioselective reductive cyclizations. The reaction
of small methanesulfanyl-1,6-diyne lowered the yield of 6g
(Entry 8). On the other hand, the reaction of the bulky
10a
10b
O
O
Me
9a, b
Fortunately, O-tethered 1,6-diynes 9a and 9b underwent
reductive cyclization to give furan derivatives 10a and 10b in
moderate yields (eq 1).
A possible mechanism for our metal-free reductive cycliza-
tion-isomerization of sulfanyl-1,6-diynes is shown in Scheme 2.
Based on our previously reported alkoxylation-cyclizations,
it is very important for this type of cyclization process to initiate
the reaction by adding the base. Indeed, the addition of a base
accelerated the cyclization described above. Therefore, we
suggest a similar cyclization sequence to our previously reported
alkoxylation-cyclization. Base-promoted alkyne-allene isomer-
ization of 11a-11c easily takes place via acetylide 127,8 in the
case of diyne (R2 = H); however, disubstituted 1,6-diynes (R2 =
Ph, Et) could not. The speculation was supported by the fact that
the reaction of 1 with sodium borohydride in ethanol-d1 almost
gave 2-d4, as shown in Scheme 3. Intramolecular cyclization of
11 affords a cationic intermediate 13, which in a nucleophilic
addition of either hydrogen or alcohols, produced either
reductively cyclized 14 or alkoxylated 15 (path a or b). This
was proved by the fact that the reaction of 1 with sodium
borodeuteride in ethanol afforded monodeuterated pyrrole 2-d1
under an excellent deuterium purity. Furthermore, the reaction
of 1 with NaBD4 in ethanol-d1 under an Ar atmosphere
surprisingly afforded pentadeuterated pyrrole 2-d5 (92-93%
purity) (Scheme 3). These results show that the reductive
cyclization of 1,6-diynes would lead to pyrroles under a base-
promoted sequential reaction: i, isomerization; ii, protonation;
iii, cyclization; and iv, nucleophilic addition of hydride in
Chem. Lett. 2014, 43, 1758–1760 | doi:10.1246/cl.140688
© 2014 The Chemical Society of Japan | 1759

(D:93%)
D
2
3
K. T. Sylvester, P. J. Chirik, J. Am. Chem. Soc. 2009, 131,
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D
PhS
CD3 (D:92%)
SPh
DBU/Ar
NaBD4, EtOD
DBU/Ar
Tos
N
N
2-d
5 (75%)
Tos
NaBD4, EtOH
DBU/Ar
H
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H
CH2D
NaBH4, EtOD
PhS
(D:99%)
1 (66%)
N
(D:73%)
2-d
D
Tos
D
CHD2
(D:55%)
PhS
N
2-d
4 (63%)
Tos
Scheme 3. Reductive cyclization with sodium borodeuteride.
alcohols. The result of Entry 5 in Table 2 indicates that the
reaction of 1,6-diyne bearing no-sulfur functional group did not
proceed at all. The fact is that the sulfur functional groups on
the alkyne termini play a crucial role in the cyclization process
(most likely because of the formation of carbanions stabilized by
the organosulfur functional groups). 1,6-Diynes (R2 = H) easily
underwent isomerization via acetylide 12 and hydrogenation
to give pyrrole 14. However, it is very difficult to control the
reaction of disubstituted 1,6-diynes because the base-promoted
isomerization-cyclization of 11a (R2 = Et) to 11b would not be
easier than that of 11a (R2 = H). As a result, disubstituted 1,6-
diynes (R2 = Et) generated further products such as alkoxylated
15 (path b) and enynes 16 (path c).
Finally, the organosulfanylmethyl group at the alkyne
termini was easily oxidized with ceric ammonium nitrate
(CAN) to give the corresponding pyrrolecarboxaldehydes 17
and 18, utilizable for further transformations (eq 2).
In summary, we reported a novel metal-free reductive
cyclization reaction of sulfanyl-1,6-diynes with sodium borohy-
dride. The reaction of N-tethered 1,6-diynes afforded 2,5-
unsubstituted pyrroles in good yields. The CAN oxidation of
the pyrrole sulfanylmethyl group generated the corresponding
pyrrolecarboxaldehyde.
4
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PhS
CHO
CAN
N
Me
N
Me
ð2Þ
p-RC6H4SO2
MeOH-H2O
p-RC6H4SO2
2, 6b
17
(R = CH3)(42%)
18 (R = NO2)(57%)
Supporting Information is available electronically on J-STAGE.
References and Notes
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1760 | Chem. Lett. 2014, 43, 1758–1760 | doi:10.1246/cl.140688
© 2014 The Chemical Society of Japan