1-Methyl-1H-tetrazol-5-yl (MT) sulfones in the Julia-Kocienski olefination: Comparison with the PT and the TBT sulfones

Article abstract of DOI:10.1016/j.tetlet.2019.05.007

The stability and the stereoselectivity of newly prepared n-pentyl 1-methyl-1H-tetrazol-5-yl (MT) sulfone 1a in the Julia-Kocienski reactions were compared with those of the PT sulfone 1b and the TBT sulfone 1c. The improved stability of the anion derived from the n-pentyl MT sulfone 1a enhanced the efficiency of the olefination reactions and gave higher yields of the product alkenes 3 compared with the PT sulfone 1b. Especially high E-selectivity and high yields were obtained from the reaction with aromatic aldehydes and α,β-unsaturated aldehydes. The selectivity of 1a was not so sensitive to the change of base counter ion compared with the PT sulfone 1b. The reaction of the MT sulfones having either ethyl or a longer alkyl chain also gave E-alkenes selectively in high yields.

Full text of DOI:10.1016/j.tetlet.2019.05.007

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
1-Methyl-1H-tetrazol-5-yl (MT) sulfones in the Julia-Kocienski
olefination: Comparison with the PT and the TBT sulfones
⇑
Kaori Ando , Daiki Kawano, Daiki Takama, Yutaka Semii
Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido 1-1, Gifu 501-1193, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The stability and the stereoselectivity of newly prepared n-pentyl 1-methyl-1H-tetrazol-5-yl (MT) sul-
fone 1a in the Julia-Kocienski reactions were compared with those of the PT sulfone 1b and the TBT sul-
fone 1c. The improved stability of the anion derived from the n-pentyl MT sulfone 1a enhanced the
efficiency of the olefination reactions and gave higher yields of the product alkenes 3 compared with
the PT sulfone 1b. Especially high E-selectivity and high yields were obtained from the reaction with aro-
Received 1 April 2019
Revised 29 April 2019
Accepted 7 May 2019
Available online xxxx
matic aldehydes and a,b-unsaturated aldehydes. The selectivity of 1a was not so sensitive to the change
Keywords:
Julia-Kocienski reaction
Olefination
of base counter ion compared with the PT sulfone 1b. The reaction of the MT sulfones having either ethyl
or a longer alkyl chain also gave E-alkenes selectively in high yields.
Ó 2019 Elsevier Ltd. All rights reserved.
E-selectivity
MT sulfone
Stereodefined formation of carbon–carbon double bonds with
high selectivity is critically important for the synthesis of both bio-
logically active compounds and substrates for stereoselective reac-
tions. A variety of different approaches to alkene syntheses have
been developed. Among them, one-pot Julia olefination reaction
has emerged as a powerful tool for fragment connection in conver-
gent synthesis. Julia and co-workers reported a one-pot olefination
reaction using 1,3-benzothiazol-2-yl (BT) sulfones with carbonyl
compounds (Scheme 1) [1]. The stereoselectivity of the BT sulfones
is generally substrate controlled and simple alkyl BT sulfones
reacted with saturated aliphatic aldehydes to yield alkenes with
low E-selectivity. Because of the low stability of its anion and the
moderate stereoselectivity, Kocienski and co-workers introduced
1-phenyl-1H-tetrazol-5-yl (PT) sulfones [2] and 1-tert-butyl-1H-
tetrazol-5-yl (TBT) sulfones [3]. Although 1-methylimidazol-2-yl
sulfones [4], 2-pyridyl sulfones [5], 2-pyrimidyl sulfones [6], benz-
imidazolyl sulfones [7] and others [8] have been also reported for
the one-pot olefination reactions, both BT and PT sulfones are most
frequently used for the synthetic study and the one-pot Julia type
olefination reaction is commonly named Julia-Kocienski reaction
[9]. Simple alkyl PT sulfones having a bulky and electron with-
drawing N-phenyl substituent generally react with saturated ali-
phatic aldehydes to yield alkenes with E selectivity and the
selectivity increases when the more polar solvent is used and base
having a more electropositive counter cation (K+) is used. The use
of KHMDS as base and DME as solvent results in high E selectivity
albeit with a sacrifice in yield compared with LiHMDS or NaHMDS
as base [2]. Simple alkyl TBT sulfones having a bulky and electron
donating N-t-butyl substituent is less E selective than the PT sul-
fones, and the reactions of either allyl or benzyl TBT sulfone with
n-decanal was reported to give conjugated olefins with high Z
selectivity [3]. In these cases, the corresponding PT sulfones gave
conjugated olefins with either low E or low Z selectivity. We are
interested in the Julia-Kocienski reaction using reagents having a
small and electron donating N-methyl substituent (MT sulfones).
Here we would like to report our results obtained from the reac-
tions of simple alkyl MT sulfones with aldehydes.
As shown in Scheme 2, the n-pentyl MT sulfone 1a, the n-pentyl
PT sulfone 1b, and the n-pentyl TBT sulfone 1c were prepared by
the Mitsunobu reaction of the 5-mercaptotetrazoles 2 with 1-pen-
tanol followed by oxidation with m-CPBA in high yields. The thiol
2a and 2b were commercially available and 2c was prepared from
t-butyl isothiocyanate and sodium azide in 79% yield by following
the literature procedure [10].
The results of the Julia-Kocienski reaction of 1 were summa-
rized in Table 1 [11]. When our new reagent 1a was treated with
KHMDS in the presence of PhCHO in DME (1,2-dimethoxyethane)
at À55 °C for 30 min and the reaction mixture was warmed to
room temperature over 1 h, E-alkene 3a was obtained in 91% yield
with E:Z = 98:2 ratio (entry 1). Using NaHMDS as base, 3a was
obtained in a higher 93% yield with the same selectivity (entry
2). When the same reaction was performed using the PT sulfone
1b, the same 98:2 selectivity was obtained in lower 67% and 87%
yields using KHMDS and NaHMDS, respectively (entries 3 and 4).
Thus, the reaction of the new MT sulfone 1a with benzaldehyde
⇑
Corresponding author.
E-mail address: ando@gifu-u.ac.jp (K. Ando).
https://doi.org/10.1016/j.tetlet.2019.05.007
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: K. Ando, D. Kawano, D. Takama et al., 1-Methyl-1H-tetrazol-5-yl (MT) sulfones in the Julia-Kocienski olefination: Comparison
with the PT and the TBT sulfones, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.05.007

2
K. Ando et al. / Tetrahedron Letters xxx (xxxx) xxx
78% yield with E:Z = 84:16 ratio (entry 6). Both the selectivity and
the yield were not much different from the reaction using NaHMDS
(85:15, 74% yield) (entry 7). On the other hand, the selectivity of 1b
was depending on the base used (entries 8 and 9). KHMDS gave the
highest 90:10 selectivity in the lowest 50% yield, while NaHMDS
gave the lowest 83:17 selectivity in 60% yield. The reaction of 1c
using KHMDS gave 3b with 82:18 E-selectivity in 45% yield (entry
10). Although the best selectivity of 1a was slightly lower than that
of 1b, the higher yields and the less sensitivity to the reaction con-
ditions are advantageous. The TBT sulfone 1c is the least E-selec-
Scheme 1. Julia-Kocienski reaction.
tive among the reagents 1a–1c. The reaction of 1a with
a-
branched aldehyde, cyclohexanecarbaldehyde was similarly per-
formed using KHMDS to give the alkene 3c in 67% yield with
88:12 selectivity (entry 11). NaHMDS again gave a similar result
(86:14, 74% yield) (entry 12). In order to increase the selectivity,
1a was treated with KHMDS in the presence of the aldehyde at
À78 °C and then gradually warmed to room temperature to give
3c with slightly higher 89:11 selectivity in 69% yield (entry 13).
The use of THF instead of DME as solvent gave lower E selectivity
(entry 14). The same reaction of 1b gave 94:6 selectivity in the
lowest 53% yield using KHMDS and 84:16 selectivity in 62% yield
using NaHMDS (entries 15 and 16). Although the best selectivity
of 1a was slightly lower than that of 1b, the higher yields and
the less sensitivity to the reaction conditions were also found for
the reaction of 1a with cyclohexanecarbaldehyde. To test the rela-
tive stability of the metallated sulfone, 1a was treated with KHMDS
in DME at À60 °C for 2 h and then quenched with water. The sul-
fone 1a was recovered in 61% yield while the same treatment of
1b and 1c was reported to give 1b in only 20% yield and 1c in
91% yield [3]. Thus, the higher yields obtained in the reactions of
Table 1 can be explained by the more stability of the anion derived
from 1a compared with 1b. Although the anion derived from 1c is
the most stable, the reactivity might be lowest due to the steric
hindrance.
Scheme 2. Preparation of n-pentyl sulfone reagents 1.
gave 3a in higher yields with the same 98:2 E-selectivity compared
with the PT sulfone 1b. Rather surprisingly, the same reaction
using the TBT sulfone 1c gave 3a with 31:69 Z-selectivity in 99%
yield (entry 5). The stereoselectivity of the reaction with n-octanal
was further compared. The reaction of 1a using KHMDS gave 3b in
Table 1
Comparison of the Julia-Kocienski reaction of 1 with aldehydes.
entry
1
R
base
3
yield(%)
E:Z
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1a
1a
1b
1b
1c
1a
1a
1a
1a
1b
1b
Ph
Ph
Ph
Ph
KHMDS
NaHMDS
KHMDS
NaHMDS
NaHMDS
KHMDS
NaHMDS
KHMDS
NaHMDS
KHMDS
KHMDS
NaHMDS
KHMDS
KHMDS
KHMDS
NaHMDS
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3c
3c
3c
3c
3c
3c
91
93
67
87
99
78
74
50
60
45
67
74
69
71
53
62
98:2
98:2
98:2
98:2
Ph
31:69
84:16
85:15
90:10
83:17
82:18
88:12
86:14
89:11
78:22
94:6
n-C7H15
n-C7H15
n-C7H15
n-C7H15
n-C7H15
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
9
10
11
12
13a
14a,b
15
16
84:16
1 (0.30 mmol) was treated with base (1.4 eq) in the presence of RCHO (1.0 eq) in DME at À55 °C for 30 min and then warmed to rt over 1 h unless otherwise stated.
a
: base was added at À78 °C.
b
: THF was used instead of DME.
Please cite this article as: K. Ando, D. Kawano, D. Takama et al., 1-Methyl-1H-tetrazol-5-yl (MT) sulfones in the Julia-Kocienski olefination: Comparison
with the PT and the TBT sulfones, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.05.007

K. Ando et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Since the reaction of 1a with benzaldehyde gave the alkene 3a
in high yields with extremely high E-selectivity, we further exam-
ined the reaction of 1a with other aromatic and ,b-unsaturated
a
aldehydes (Table 2). When 1a was treated with NaHMDS in the
presence of p-tolualdehyde in DME at À55 °C and the reaction mix-
ture was warmed to room temperature, E-alkene 3d was obtained
in 99% yield with E:Z = 97:3 ratio (entry 2). In the same way, the
reaction with p-anisaldehyde gave 3e with 98:2 E-selectivity in
78% yield (entry 3). Thus, the reactions with aromatic aldehydes
having electron donating groups gave E-alkenes with extremely
high selectivity in good to high yields. The reactions with p-chloro-
and p-nitrobenzaldehyde also gave 3f and 3g with 94:6 and 91:9 E-
selectivity in 99% and 76% yields, respectively (entries 4 and 5). A
slight decrease of the stereoselectivity was detected with the aro-
matic aldehydes having electron withdrawing chloro and nitro
substituents. The reaction with furfural gave E-alkene 3h with
91:9 ratio in 93% yield (entry 6). When 1a was treated with
NaHMDS in the presence of furfural at À78 °C and then gradually
warmed to room temperature, 3h was obtained with the same
selectivity in slightly reduced 88% yield (entry 7). The reactions
with
a,b-unsaturated aldehydes were also performed in a similar
manner. The trans-cinnamaldehyde reacted with the anion of 1a
to give the alkene 3i with E:Z = 87:13 ratio in 81% yield (entry 8).
The less conjugated trans-2-hexenal gave 3j with higher 91:9 E-
selectivity in 72% yield (entry 9). Thus, E-dienes were obtained in
good selectivity in good yields.
Scheme 3. Preparation and reaction of ethyl sulfone 4.
mixture was warmed to room temperature, E-alkene 7a was
obtained in 95% yield with E:Z = 97:3 selectivity (Scheme 4). In
the same way, the reaction with p-anisaldehyde gave 7b with
97:3 E-selectivity in 94% yield.
In summary, the stability and the stereoselectivity of newly pre-
pared n-pentyl 1-methyl-1H-tetrazol-5-yl (MT) sulfone 1a in the
Julia-Kocienski olefination reactions were compared with those
of the PT sulfone 1b and the TBT sulfone 1c. The improved stability
of the anion derived from 1a enhanced the efficiency of the olefina-
tion reactions and gave higher yields of the product E-alkenes. Fur-
thermore, the MT sulfones are easily prepared from inexpensive
starting materials. High E-selectivity and high yields were obtained
In order to see the generality of this reaction, the ethyl MT sul-
fone 4 having a shorter alkyl group was prepared by ethylation of
thiol 2a using NaH in THF followed by oxidation using H2O2 cat-
alyzed by (NH4)6Mo7O24 [1,12] in high yield (Scheme 3). Both the
reagents, H2O2 and (NH4)6Mo7O24 are much cheaper than m-CPBA.
When 4 was treated with NaHMDS in the presence of 3,4-
dimethoxybenzaldehyde in DME at À55 °C and the reaction mix-
ture was warmed to room temperature, E-alkene 5a was obtained
in 99% yield with E:Z = 98:2 selectivity. In the same way, the reac-
tion with 2-naphthaldehyde gave 5b with 90:10 E-selectivity in
94% yield. The reaction of 3,7-dimethyl-2,6-octadienal (trans:
cis = 94:6) is also E-selective to give 5c with 90:10 ratio in 94%
yield.
from the reaction of 1a with aromatic and a,b-unsaturated aldehy-
des, and good E-selectivity and high yields were obtained with ali-
phatic aldehydes. The stereoselectivity of the MT sulfones was not
so sensitive to the change of base counter ion compared with the
PT sulfones. These features make the MT sulfones useful for not
only alkene synthesis but also fragment connection in convergent
synthesis.
In addition, the reagent 6 having a longer alkyl chain was pre-
pared from citronellol [13]. When 6 was treated with NaHMDS in
the presence of benzaldehyde in DME at À55 °C and the reaction
1-Methyl-1H-tetrazol-5-yl pentyl sulfone 1a. To a solution of
5-mercapto-1-methyltetrazol 2a (0.929 g, 8.00 mmol), PPh3
(2.099 g, 8.00 mmol), and 1-pentanol (0.87 mL, 8.0 mmol) in THF
(40 mL) was added a 40% (w/w) solution of DEAD in toluene
(3.64 mL, 8.00 mmol) dropwise at 0 °C. After stirring at room tem-
perature for 18 h, the mixture was concentrated under reduced
pressure. The resulting solid was triturated and washed with
hex:AcOEt = 5:1 (24 mL, 40 mL) and the filtrate was concentrated
under reduced pressure. The residue was purified by column chro-
matography (hex:AcOEt = 4:1) to give the sulfide (1.177 g, y.79%)
Table 2
Julia-Kocienski reaction of 1a with aromatic and
a,b-unsaturated aldehydes.
entry
R
3
yield(%)
E:Z
1
2
3
4
5
6
7a
8
9
Ph
3a
3d
3e
3f
3g
3h
3h
3i
93
99
78
99
76
93
88
81
72
98:2
97:3
98:2
94:6
91:9
91:9
91:9
87:13
91:9
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-NO2C6H4
2-furyl
2-furyl
E-PhCH = CH
E-C3H7CH = CH
3j
a
: After the treatment with base at À78 °C for 30 min, the mixture was warmed
to rt over 1 h.
Scheme 4. Reaction of 6 having a longer alkyl chain.
Please cite this article as: K. Ando, D. Kawano, D. Takama et al., 1-Methyl-1H-tetrazol-5-yl (MT) sulfones in the Julia-Kocienski olefination: Comparison
with the PT and the TBT sulfones, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.05.007

4
K. Ando et al. / Tetrahedron Letters xxx (xxxx) xxx
as pale yellow oil: 1H NMR (400 MHz, CDCl3) d 0.91 (3H, t,
J = 7.1 Hz), 1.33–1.47 (4H, m), 1.81 (2H, quin, J = 7.6 Hz), 3.35
(2H, t, J = 7.6 Hz), 3.92 (3H, s). To a solution of the sulfide
(1.177 g, 6.32 mmol) in CH2Cl2 (25 mL) was added m-CPBA
(3.546 g , 16.4 mmol) at 0 °C and the resulting mixture was stirred
at room temperature for 5 h. The reaction mixture was poured into
a mixture of aq. sat. NaHCO3 (25 mL) and aq. 10% Na2S2O3 (25 mL)
and extracted with AcOEt (20 mL Â 2). The combined extracts were
washed with brine and dried with Mg2SO4, and concentrated. The
residue was purified by column chromatography (hex:AcOEt = 6:1)
to give 1a as colorless oil (1.187 g, y. 86%). 1H NMR (400 MHz,
CDCl3) d 0.93 (3H, t, J = 7.2 Hz), 1.34–1.52 (4H, m), 1.93 (2H, quin,
J = 8.0 Hz), 3.66 (2H, t, J = 8.0 Hz), 4.36 (3H, s); MS m/e 219 ((M
+ H)+); HRMS calcd for C7H15N4O2S: 219.0910, found: 219.0920.
A typical procedure for the Julia-Kocienski reaction (entry 1
in Table 2): A 38% (w/w) solution of NaHMDS in THF (0.22 mL,
0.42 mmol) was added to a solution of 1a (0.0656 g, 0.30 mmol)
and PhCHO (0.032 mL, 0.30 mmol) in DME (2.4 mL) at À55 °C
and the mixture was stirred for 30 min. Then the mixture was
gradually warmed to 0 °C over 1 h and stirred at room temperature
for 30 min. The reaction was quenched with aqueous NH4Cl, and
the mixture was extracted with AcOEt (10 mL Â 2). The combined
extracts were washed with brine, dried with MgSO4, and concen-
trated. The residue was purified by column chromatography
(hex:AcOEt = 30:1) to give 3a as colorless oil (0.0447 g, y. 93%).
1H NMR (400 MHz, CDCl3) d 0.92 (3H, t, J = 7.2 Hz), 1.32–1.52
(4H, m), 2.21 (2H, q, J = 7.4 Hz), 6.23 (1H, dt, J = 16.0, 7.0 Hz),
6.37 (1H, d, J = 16.0 Hz), 7.18 (1H, t, J = 7.1 Hz), 7.26–7.35 (4H, m).
Acknowledgments
This research was partially supported by the JSPS KAKENHI
Grant Number 17K05781.
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Please cite this article as: K. Ando, D. Kawano, D. Takama et al., 1-Methyl-1H-tetrazol-5-yl (MT) sulfones in the Julia-Kocienski olefination: Comparison
with the PT and the TBT sulfones, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.05.007