Synthesis of 3-substituted 2-cyclohexenones through umpoled functionalization

Article abstract of DOI:10.1016/j.tetlet.2017.07.007

A new protocol to obtain 3-substituted 2-cyclohexenones, was developed by reversing the chemical reactivity of 2-cyclohexenone. One-pot synthesis of 3-substituted 2-cyclohexenones can be achieved by treatment of 3-phenylthiosilyl enol ether with a mixture of t-BuLi/HMPA that allows hydrogen-selective exchange in presence of reactive electrophiles such as aldehydes, ketones and alkyl halides. This affords the corresponding product in moderate overall yield, after silyl enol ether cleavage and concomitant thiophenol elimination initiated with TBAF.

Full text of DOI:10.1016/j.tetlet.2017.07.007

Accepted Manuscript
Synthesis of 3-substituted 2-cyclohexenones through umpoled functionalization
Harim Lechuga-Eduardo, Eduardo Zarza-Acuña, Moisés Romero-Ortega
PII:
S0040-4039(17)30845-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.007
TETL 49089
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
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22 June 2017
1 July 2017
Please cite this article as: Lechuga-Eduardo, H., Zarza-Acuña, E., Romero-Ortega, M., Synthesis of 3-substituted
2-cyclohexenones through umpoled functionalization, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/
j.tetlet.2017.07.007
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Harim Lechuga-Eduardo, Eduardo Zarza-Acuña and Moisés Romero-Ortega

1
Tetrahedron Letters
Synthesis of 3-substituted 2-cyclohexenones through umpoled
functionalization
Harim Lechuga-Eduardo, Eduardo Zarza-Acuña and Moisés Romero-Ortega
Departamento de Química Orgánica, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón/Paseo Tollocan, Toluca Estado de
México, México.
ARTICLE INFO
ABSTRACT
A new protocol to obtain 3-substituted 2-cyclohexenones, was developed by reversing the
chemical reactivity of 2-cyclohexenone. One-pot synthesis of 3-substituted 2-cyclohexenones can
be achieved by treatment of 3-phenylthiosilyl enol ether with a mixture of t-BuLi/HMPA that
allows hydrogen-selective exchange in presence of reactive electrophiles such as aldehydes,
ketones and alkyl halides. This affords the corresponding product in moderate overall yield,
after silyl enol ether cleavage and concomitant thiophenol elimination initiated with TBAF.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
umpolung
2009 Elsevier Ltd. All rights reserved.
metallation reaction
electrophiles
silyl enol ether
———
 Corresponding author. Tel.: +52-722-217-3890; fax: +52-722-217-5109; e-mail: mromeroo@uaemex.mx

2
Tetrahedron
1. Introduction
2. Results and Discussion
The development of new methods for the efficient construction of
organic molecules continues to be essential for accessing natural
products and their structural analogues. In this context, the
concept of umpolung or polarity inversion is associated with a
temporal masking of a functional group to reverse its polarity and
perform secondary reactions that would otherwise not be
possible.1-3 Since retrosynthetic analysis was pioneered by E. J.
Corey and co-workers in the early 1970s,4 the umpolung
approaches attracted more attention because it enables the usage
of a wider variety of starting materials for building complex
natural products. From the perspective of natural product
synthesis, little is known about 2-cyclohexenone, a cheap and
widely available compound with great synthetic potential. 2-
cyclohexenone has been used to synthesize highly valuable
molecules, such as antimalarial-drug (+)-artemisinin, via normal
reactivity.5 An example of an umpolung strategy was described
in a protocol for insertion of side chains at the 3-position of the
2-cyclohexenone allowed the formation of epoxyquinol
analogues.6 For this reason, 3-substituted 2-cyclohexenones 4 are
highlighted as recurrent building blocks for many purposes. They
can be accessed through the umpolung reactivity of 2-
cyclohexenone by means of its synthetic equivalents such as 1,3-
bis(phenylthio)cyclohex-1-ene,7 3-cyanocyclohexanone,8 1-dioxo
The (phenylthio)silanes 1 were prepared using Davis’ protocol.16
It involves a condensation between thiophenol and corresponding
trialkylsilyl chloride in presence of Et3N. While triisopropyl 1b
and t-butyldimethyl 1c derivatives were isolated in yields of 80%
and 54% respectively, the (phenylthio)trimethylsilane 1a was
unstable during the heating process for vacuum distillation.16b
Scheme 2. Synthesis of (phenylthio)trialkylsilanes 1
With compounds 1b and 1c at hand, we proceeded to find the
best reaction conditions for generating 1,4-adducts 2 (Table 1). In
the first experiment,
a neat equimolar mixture of 2-
cyclohexenone and (phenylthio)triisopropylsilane 1b did not
afford any product 2b after stirring for 2 hours even in the
presence of potassium cyanide-18-crown-6 complex17 (0.3%
mol) as initiator (Entry 1). These conditions were reported by
Evans to produce 2a using (phenylthio)trimethylsilane 1a.14,15
However, an increase in the reaction time to 18 h resulted in the
desired compound 2b, but with a poor yield of 21% (Entry 2).
Moreover, when the amount of the anionic initiator was increased
by 5 times with a reaction time of 2 h, the yield was slightly
improved to 28% (Entry 3). Interestingly, carrying out the
reaction in THF, while applying 0.9 %-mol of the complex for 18
h, dramatically increased the yield provided 2b to 60% (entry 4);
a higher quantity of the complex, longer stirring time, or even
heating, had a worse yield of the 1,4-adduct 2b. On the other
hand, the treatment of 2-cyclohehexenone and (phenylthio)t-
butyldimethylsilane 1c under similar conditions (THF, 0.9 % mol
of the complex, 18 h), provided a moderate yield of compound 2c
(37 %, entry 5).
lanyl-3-tosylcyclohexane,9
or
(3-(tert-butyldimethylsiloxy)
cyclohex-2-en-1-yl)triphenylphosphonium triflate.10-12 These
methods required multi-step transformations and overall yields
are moderate.
An interesting and practical methodology to achieve the 3-
electrophilic substitution of 2-cyclohexenone was reported by
Katritzky’s group in 1995.13 It consisted in the reaction between
2-cyclohexenone and trimethylsilylbenzotriazole to generate a
1,4-adduct similar to compound 2b. Treatment of this non-
isolated-intermediate with LDA promoted the formation of an
allylic anion which was then trapped by an electrophile.
Subsequent addition of aqueous acid obtained the corresponding
3-substituted 2-cyclohexenones 4 (yields 50-75%).
Table 1. Screening of the 2-cyclohexenone activation process.
On the other hand, Evans demonstrated in 1977 that
(phenylthio)trimethylsilane 1a14,15 can be used as a protecting
group of aldehydes and α,β-unsaturated carbonyls due to the high
affinity between silicon and oxygen atoms. Interestingly, the 1,4-
adduct 2a that arises from the reaction between 1a and 2-
cyclohexenone is also air-labile. Therefore, we thought that a
more stable analogue such as (phenylthio)triisopropylsilane 1b
might afford an analogue of 2a which also would undergo a 3-
electrophilic substitution after its treatment with a base. Finally,
TBAF would trigger a one-pot transformation of corresponding
Entry
SM
1b
1b
1b
1b
1c
Complex (%)
Solvent
neat
neat
neat
THF
THF
Time (h)
Product
2b
2b
2b
2b
Yield (%)
1
2
3
4
5
0.3
0.3
1.5
0.9
0.9
2
18
2
18
18
0
21
28
60
37
2c
intermediates
3 into 3-susbtituted 2-cyclohexenones 4 as
described in Scheme 1.
Because of the 1,4-adduct 2b was obtained with the highest
yield, we decided to take it as the synthetic equivalent of 2-
cyclohexenone in order to develop our umpolung procedure. A
typical experiment consisted in the reaction of a base and 2b at
low temperatures, where the allylic anion could be trapped by an
electrophile. Initial screening that employed Ph2CO, allyl
bromide, or PhCHO as electrophiles, demonstrated that bases
such as LDA or n-BuLi were not sufficiently reactive to carry out
the α-lithiation of sulfide-derivative 2b. In all these experiments
only the starting material 2b was recovered. We believe that the
reason for which the acid-base reaction did not happen was due
to the short half-life time that n-BuLi exhibits in THF at -78
°C.18,19 Likewise, the proton abstraction by the base on the sulfide
2b was not accomplished when Et2O was used instead of THF.
Nor was it achieved by employing a much stronger base such as
t-BuLi at 0 °C. It is known that the presence of TMEDA or
HMPA as additives has an important effect on the generation and
Scheme 1. General procedure to synthesize 3-substituted 2-cyclohexen-1-
ones

3
stabilization of the respective carbanion.20 Consequently, when
experiments were carried out at 0 °C in the presence of TMEDA
using benzaldehyde as an electrophile, it was evident that the β-
lithiation reaction took place in the thiophenyl ring instead of the
α-lithiation reaction of the sulfide-side of 2b because the alcohol
8 was isolated (Fig 1). It is worth noting that at -78 °C the
directed o-metalation of 2b did not occur in THF. The finding
that TMEDA readily promotes the β-lithiation increased
expectations for positive outcomes by using HMPA.
Gratifyingly, when the reaction was carried out in THF/HMPA
(2.5 equiv) at -78 °C, the expected anion of sulfide 2b was
consumed by PhCHO, resulting in intermediate 3a. The crude
Figure 1. o-Metallation of thiophenyl ring.
Aldehydes showed unusual behavior and exhibited a poor
performance (Entries 2 and 3) especially paraformaldehyde
(entry 8). We believe that low yields are due to an
isomerization/oxidation process that happened, especially for 2-
cyclohexenones 4a and 4h in a slightly acidic or basic media. For
example, when 2-cyclohexenones 4a or 4h remained dissolved in
CDCl3 for a long time, the formation of compounds 7a and 7h
was observed (Scheme 3). Apparently, delocalization of the
electron density in the α,β-unsaturated system would allow
tautomerization to bis-enol intermediate 5. Then, the keto-enol
equilibrium would stimulate the obtaining of 1,4-dicarbonyl
compound 6, which might be oxidized to the 2-cyclohexenones 7
by air. This mechanism of reaction was proposed because it was
possible to isolate and characterize the 2-cyclohexanone 6a and
the 2-cyclohexenone 7a after the reaction of 2-cyclohexenone 4a
with TFA (1.0 equiv) in DCM at room temperature for 24 h.
product 3a went through
a slow one-pot process of
deprotection/β-elimination when TBAF was added, and
ultimately led to the isolation of 2-cyclohexenone 4a with a yield
of 71% (table 2, entry 1).This umpolung strategy was expanded
when derivatives 4b-h were synthesized using m-anisaldehyde,
piperonal, acetophenone, chloromethyl pivalate, benzyl bromide,
2-cyclohexenone and paraformaldehyde as electrophiles (Table
2). Hence, the procedure could be applied to ketones (Entry 4),
alkyl halides (Entries 5-6) and even α,β-unsaturated compounds
such as 2-cyclohexenone (Entry 7). Here it is worth mentioning
that this methodology comprises two continuous reactions in a
single step, therefore yields are acceptable.
Table 2. Preparation of 3-substituted 2-cyclohexenones 4 by an
Additionally,
the
oxidation
of
3-(hydroxymethyl)-2-
umpolung electrophilic-substitution procedure[a]
cyclohexenone 4h to the 3-carbaldehyde derivative 7h was also
promoted by a base such as K2CO3. The observation of this
behavior turned out to be relevant since it has not been
previously described in the literature.
Entry
1
E+
4 (E=)
Yield (%)
71
Benzaldehyde
2
m-Anisaldehyde
38
Scheme 3. Isomerization/oxidation of 2-cyclohexenones 4a and 4b.
In summary, we have developed a novel and direct methodology
for the preparation of 3-substituted 2-cyclohexenones
4
3
4
Piperonal
27
58
employing an umpolung strategy. The versatility and potential
this methodology possess is revealed by the use of a variety of
electrophilic species, notably the cheap and widely available 2-
cyclohexenone, to generate in one-pot process 3-substituted 2-
cyclohexenones 4 which could serve as useful buildings blocks to
synthesize highly valuable molecules. Further investigation in
this area is being carried out in our laboratory.
Acetophenone
Chloromethyl
pivalate
5
6
60
50
Benzyl bromide
Cyclohexenone
Paraformaldehyde
Acknowledgments
The Consejo Nacional de Ciencia y Tecnologia is gratefully
acknowledged for providing a doctoral fellowship to Harim
Lechuga (CONACyT 360339). The authors wish to thank M. Sc.
Maria de las Nieves Zavala Segovia (CCIQS UNAM-UAEM) for
obtaining NMR spectra, M. Sc. Lizbeth Triana Cruz for obtaining
mass spectra and to Prof. Joseph M. Muchowski (UNAM) for
helpful discussions and interests in our work.
7
8
55
12
[a] Reactions were performed by using (phenylthio)silane 2b (1.0 equiv),
HMPA (2.25 equiv), t-BuLi (2.25 equiv), 1.5-2.0 equiv of E+, and TBAF (1.2
equiv)
References and notes
1. Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231.
2. GrÖBel, B.-T.; Seebach, D. Synthesis 1977, 357.

4
Tetrahedron
3. Seebach, D. Angew. Chem. Int. Ed.1979, 18, 239.
4. Corey, E. J. Pure Appl. Chem. 1967, 14, 19.
t-butyldimethyl(((3-(phenylthio)cyclohex-1-en-1-yl)oxy)silane
(2c). The general procedure was applied using 100 mg of
cyclohexenone (1.04 mmol), 233 mg of 1c and 5.0 mg of
KCN/18-crown-6 complex (0.02 mmol) in 0.8 mL of anhydrous
THF. The product was purified by column chromatography (3.0 x
9.0 cm, silica gel; Hexanes 100 %), affording 123 mg (37 %) of 2c
as a colorless oil. TLC-Rf (Hexanes, 100%) 0.23; NMR-1H (300
MHz, CDCl3) δ 7.26 (d, J = 6.6 Hz, 2H), 7.10 (dd, J = 16.0, 6.9
Hz, 3H), 4.85 (s, 1H), 3.83 (s, 1H), 1.89 (s, 3H), 1.71 – 1.43 (m,
3H), 0.78 (s, 9H), 0.00 (s, 6H); NMR-13C (126 MHz, CDCl3) δ
154.2, 136.3, 131.3, 128.8, 126.5, 104.4, 44.8, 29.8, 28.2, 25.6,
19.1, 18.0, -4.4, -4.5.
5. Zhu, C.; Cook, S. P. J. Am. Chem. Soc. 2012, 134, 13577.
6. Heguaburu, V.; Schapiro, V.; Pandolfi, E. Tetrahedron Let.
2010, 51, 6921.
7. Cohen, T.; Bennett, D. A.; Mura, A. J. J. Org. Chem. 1976, 41,
2506.
8. Debal, A.; Cuvigny, T. r. s.; Larcheveˆque, M. Tetrahedron
Let. 1977, 18, 3187.
9. Huang, P.-Q.; Zhou, W.-S. Syn. Comm. 1991, 21, 2369.
10. Kozikowski, A. P.; Jung, S. H. J. Org. Chem. 1986, 51, 3400.
11. Kim, S.; Lee, P. H. Tetrahedron Let. 1988, 29, 5413.
12. Kim, S.; Lee, P. H.; Kim, S. S. Bull. Kor. Chem. Soc. 1989, 10,
218.
13. Katritzky, A. R.; Soloducho, J.; Musgrave, R. P.; Breytenbach,
J. C. Tetrahedron Let. 1995, 36, 5491.
14. Evans, D. A.; Grimm, K. G.; Truesdale, L. K. J. Am. Chem.
Soc. 1975, 97, 3229.
Synthesis of 2-cyclohexen-1-one-3-sustituted 4. A solution of 1.0
equiv of 2b and HMPA (2.0-2.5 equiv) in anhydrous THF [0.092
M] was cooled at -78 °C (N2 atmosphere). t-BuLi (1.5 M, 2.0-2.5
equiv) was added dropwise over 5 min period. Stirring at -78 °C
was continued for 30 minutes, and then the respective electrophile
(1.5-2.0 equiv) was added and then the reaction mixture was
stirred for 30 minutes at -78 °C. The reaction temperature was
allowed to rise to room temperature for 2 hours and the reaction
was quenched with saturated NH4Cl solution. The product was
extracted with EtOAc (3 x 15 mL). The combined organic layers
were dried over Na2SO4, filtered and concentrated in vacuum. The
crude reaction was dissolved in anhydrous THF [0.069 M] and
was cooled at 0 °C. TBAF (1.0 M, 1.25 equiv) was added and the
reaction temperature was allowed to rise the room temperature and
stirred for 18 hours. At the end of this period of time, the reaction
was quenched by adding brine and the product was extracted with
EtOAc (3 x 15 mL). The combined organic layers were dried over
Na2SO4, filtered and concentrated in vacuum and the product was
purified by column chromatography on silica gel.
15. Evans, D. A.; Truesdale, L. K.; Grimm, K. G.; Nesbitt, S. L. J.
Am. Chem. Soc. 1977, 99, 5009.
16. (a) Davis, F. A.; Rizvi, S. Q. A.; Ardecky, R.; Gosciniak, D. J.;
Friedman, A. J.; Yocklovich, S. G. J. Org. Chem. 1980, 45,
1650.
(b) Synthesis of phenyl(trialkylsilyl)sulfides 1b and 1c. To a
solution of thiophenol (1.0 equiv) and the corresponding
trialkylsilyl chloride (1.1 equiv) in anhydrous THF [1.95 M],
under nitrogen atmosphere, triethylamine (1.2 equiv) dissolved
in anhydrous THF [2.37 M] was added dropwise. Immediately
the triethylammonium chloride is observed as a white solid.
After stirring for 18 hours at room temperature, the reaction
mixture was filtered through celite, the filter was washed with
10 mL of THF, and the filtrate was washed with 10 mL of an
aqueous solution of KOH (10 %) in order to eliminate the
excess of tiophenol. The organic layers were dried over
Na2SO4 and evaporated in vacuo. The crude reaction was then
distillated under reduced pressure affording the corresponding
phenyl(trialkylsilyl)sulfide 1.
Compound 4a:13 The general procedure was applied using 105 mg
of 2b (0.28 mmol), 0.10 mL of HMPA (103 mg, 0.58 mmol), t-
BuLi (0.45 mL, 1.5 M, 0.60 mmol) and 65 µL of benzaldehyde
(63 mg, 0.59 mmol) in 3.5 mL of anhydrous THF. For the
deprotection 0.36 mL of TBAF (1.0 M, 95 mg, 0.36 mmol) were
used in 4 mL anhydrous THF. The reaction crude was purified by
column chromatography (2.0
x 8.0 cm, silica gel; 55:45
Compound 1b: The general procedure was applied using 1.0
mL of thiophenol (1.073 g, 9.74 mmol), 2.3 mL of TIPSCl
(2.072 g, 10.75 mmol) in 5 mL of anhydrous THF. This
reaction afforded 2.07 g (80%) of 2b as a colorless oil. TLC-
Rf (Hexanes 100%) 0.62; bp 109 °C (9.0 mmHg); NMR-1H
(300 MHz, CDCl3) δ 7.50 (dd, J = 6.5, 3.0 Hz, 2H), 7.24 –
7.18 (m, 3H), 1.25 (ddd, J = 15.6, 13.0, 7.1 Hz, 3H), 1.09 (d, J
= 7.1 Hz, 18H); NMR-13C (75 MHz, CDCl3) δ 135.4, 131.5,
128.5, 126.6, 18.4, 13.1. Mass spectrum m/z [M+] 266,
223(100%).
Hexanes/EtOAc) affording 41 mg (71 %) of 4a as a yellow oil.
TLC-Rf (Hexanes/EtOAc 3:2) 0.23; NMR-1H (300 MHz, CDCl3) δ
7.41 – 7.30 (m, 5H), 6.35 (d, J = 1.4 Hz, 1H), 5.24 (s, 1H), 2.38 (t,
J = 6.6 Hz, 2H), 2.27 (s, 1H), 2.15 (t, J = 5.5 Hz, 2H), 1.93 (dq, J
= 12.2, 7.0, 6.3 Hz, 2H); NMR-13C (75 MHz, CDCl3) δ 200.0,
165.0, 140.4, 128.9, 128.6, 126.8, 124.0, 76.7 , 37.8, 25.9, 22.6.
Mass spectrum m/z [M+] 246, 93(84%).
Compound 4b: The general procedure was applied using 100 mg
of 2b (0.28 mmol), 0.12 mL of HMPA (124 mg, 0.69 mmol), t-
BuLi (0.45 mL, 1.5 M, 0.60 mmol) and 70 µL of m-anisaldehyde
(75 mg, 0.55 mmol) in 3.0 mL of anhydrous THF. For the
deprotection 0.33 mL of TBAF (1.0 M, 86 mg, 0.33 mmol) were
used in 4 mL anhydrous THF. The product was purified by
Compound 1c:16 The general procedure was applied using 1.0
mL of thiophenol (1.073 g, 9.74 mmol), 1.62 g of TBDMSCl
(10.75 mmol) in 5 mL of anhydrous THF. This reaction
afforded 1.173 g (54%) of 1c as a colorless oil. TLC-Rf
(Hexanes 100%) 0.55; bp 90 °C (9.0 mmHg); NMR-1H (300
MHz, CDCl3) δ 7.26 (dd, J = 6.6, 3.0 Hz, 2H), 7.08 – 7.01 (m,
3H), 0.80 (s, 9H), -0.00 (s, 6H); NMR-13C (75 MHz, CDCl3) δ
135.6, 131.5, 128.6, 126.8, 26.4, 19.0, -3.3.
column chromatography (2.0
x 10.0 cm, silica gel; 55:45
Hexanes/EtOAc) affording 24 mg (38 %) of 4b as a yellow pallid
oil. TLC-Rf (Hexanes/EtOAc 55:45) 0.30; 1H NMR (300 MHz,
CDCl3) δ 7.20 (d, J = 7.6 Hz, 3H), 6.87 – 6.78 (m, 3H), 6.27 (s,
1H), 5.14 (s, 1H), 3.74 (s, 3H), 2.34 – 2.28 (m, 2H), 2.13 – 2.07
(m, 2H), 1.86 (d, J = 6.3 Hz, 3H), 1.26 (s, 1H); 13C NMR (75
MHz, CDCl3) δ 200.09, 165.00, 159.99, 142.07, 129.90, 124.05,
119.07, 113.92, 55.29, 37.79, 25.82, 22.60.Mass spectrum m/z
[M+] 232, 232 (100%).
Synthesis of 3-phenylthio-1-(trialkylsilyloxy)cyclohex-1-ene 2: The
KCN/18-crown-6 complex was added to a well-stirred solution of
2-cyclohexenone
(1.0
equiv)
and
the
respective
phenyl(trialkylsilyl)sulfide (1.0 equiv) in freshly distilled dry THF
[1.6 M]. Stirring under nitrogen atmosphere at room temperature
was continued for 18 h and the yellow solution was concentrated
in vacuum and the products were obtained as oils and used in their
crude form.
Compound 4c: The general procedure was applied using 100 mg
of 2b (0.28 mmol), 0.12 mL of HMPA (124 mg, 0.69 mmol), t-
BuLi (0,45 mL, 1.5 M, 0.60 mmol) and 83 mg of piperonal
(dissolved in 1 mL of THF, 0.55 mmol) in 3.0 mL of anhydrous
THF. For the deprotection 0.33 mL of TBAF (1.0 M, 86 mg, 0.33
mmol) were used in 4 mL anhydrous THF. The reaction crude was
purified by column chromatography (2.0 x 8.0 cm, silica gel;
55:45 Hexanes/EtOAc) affording 18 mg (27 %) of 4c as a yellow
pallid oil. TLC-Rf (Hexanes/EtOAc 55:45) 0.30; 1H NMR (300
MHz, CDCl3) δ 6.82 (d, J = 5.3 Hz, 3H), 6.34 (d, J = 1.5 Hz, 1H),
5.98 (s, 2H), 5.15 (s, 1H), 2.44 – 2.35 (m, 3H), 2.15 (d, J = 6.0 Hz,
2H), 2.00 – 1.88 (m, 2H), 1.34 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 200.06, 165.19, 148.13, 147.79, 134.42, 123.80, 120.60,
108.35, 107.06, 101.25, 37.79, 25.99, 22.60. Mass spectrum m/z
[M+] 246.
Compound 2b: The general procedure was applied using 376 mg
of 2-cyclohexenone (3.91 mmol), 1.04 g of 1b and 12 mg of
KCN/18-crown-6 complex (0.04 mmol) in anhydrous THF (2.5
mL). The reaction crude was purified by column chromatography
(4.0 x 10.0 cm, silica gel; Hexanes 100 %), affording 847 mg (60
%) of 2b as a yellow pallid oil. TLC-Rf (Hexanes, 100%) 0.26;
NMR-1H (300 MHz, CDCl3) δ 7.39 (d, J = 7.1 Hz, 2H), 7.27 (t, J
= 7.3 Hz, 2H), 7.20 (d, J = 7.1 Hz, 1H), 4.99 (d, J = 4.4 Hz, 1H),
3.99 (d, J = 4.2 Hz, 1H), 2.14 – 1.94 (m, 3H), 1.72 (ddtq, J = 27.8,
22.2, 11.6, 5.8, 5.2 Hz, 3H), 1.17 – 0.98 (m, 21H); NMR-13C (126
MHz, CDCl3) δ 154.4, 136.4, 131.3, 128.7, 126.4, 103.7, 44.9,
29.8, 28.1, 19.2, 18.0, 12.6. MS (EI, 70 eV) m/z [M+] 361, 255
(100%).
Compound 4d: The general procedure was applied using 100 mg
of 2b (0.28 mmol), 0.12 mL of HMPA (124 mg, 0.69 mmol), t-
BuLi (0.45 mL, 1.5 M, 0.675 mmol) and 70 µL of acetophenone
(72 mg, 0.60 mmol) in 3.0 mL of anhydrous THF. For the

5
deprotection 0.33 mL of TBAF (1.0 M, 86 mg, 0.33 mmol) were
used in 4 mL anhydrous THF. The reaction crude was purified by
Supplementary Material
column chromatography (2.0
x 10.0 cm, silica gel; 65:35
1
13
Copies of H and C NMR and Ms spectra for 1b, 1c, 2b, 2c
and 4a-4h
Hexanes/EtOAc) affording 35 mg (58 %) of 4d as a yellow oil.
TLC-Rf (Hexanes/EtOAc 67:33) 0.28; NMR-1H (300 MHz,
CDCl3) δ 7.44 – 7.28 (m, 5H), 6.35 (s, 1H), 2.37 (t, J = 6.6, 6.2
Hz, 2H), 2.22 – 2.11 (m, 2H), 2.06 (s, 1H), 1.87 (p, J = 6.1, 5.6
Hz, 2H), 1.76 (s, 3H); NMR-13C (75 MHz, CDCl3) δ 200.5, 168.6,
144.2, 128.6, 127.7, 125.3, 123.6, 76.4, 37.6, 27.5, 25.9, 23.0.
Mass spectrum m/z [M+] 217, 173 (100%).
Compound 4e: 21 The general procedure was applied using 100 mg
of 2b (0.28 mmol), 0.12 mL of HMPA (124 mg, 0.69 mmol), 0.45
mL of t-BuLi (0.45 mL, 1.5 M, 0.675 mmol) and 90 µL of
chloromethyl pivalate (94 mg, 0.62 mmol) in 3.0 mL of anhydrous
THF. For the deprotection 0.33 mL of TBAF (1.0 M, 86 mg, 0.33
mmol) were used in 4 mL anhydrous THF. The reaction crude was
purified by column chromatography (2.0 x 10.0 cm, silica gel; 4:1
Hexanes/EtOAc) affording 35 mg (60 %) of 4e as a yellow pallid
oil. TLC-Rf (Hexanes/EtOAc 4:1) 0.28; NMR-1H (300 MHz,
CDCl3) δ 6.02 (s, 1H), 4.67 (s, 2H), 2.43 (t, J = 6.0, 5.5 Hz, 2H),
2.28 (t, J = 6.5, 5.5 Hz, 2H), 2.05 (q, J = 10.5, 5.1 Hz, 2H), 1.25
(s, 9H); NMR-13C (75 MHz, CDCl3) δ 199.0, 177.7, 158.7, 124.3,
64.8, 38.9, 37.6, 27.2, 26.3, 22.3.
Compound 4f:22 The general procedure was applied using 100 mg
of 2b (0.28 mmol), 0.12 mL of HMPA (124 mg, 0.69 mmol), t-
BuLi (0.45 mL, 1.5 M, 0.675 mmol) and 66 µL of benzyl bromide
(96 mg, 0.55 mmol) in 3.0 mL of anhydrous THF. For the
deprotection 0.33 mL of TBAF (1.0 M, 86 mg, 0.33 mmol) were
used in 4 mL anhydrous THF. The reaction crude was purified by
column chromatography (2.0
x 10.0 cm, silica gel; 3:2
Hexanes/EtOAc) affording 23.1 mg (45 %) of 4f as a yellow pallid
oil. TLC-Rf (Hexanes/EtOAc 3:2) 0.29; NMR-1H (300 MHz,
CDCl3) δ 7.39 – 7.31 (m, 5H), 6.35 (d, J = 1.3 Hz, 1H), 5.30 (s,
1H), 5.24 (s, 1H), 2.38 (t, J = 6.4 Hz, 2H), 2.16 (t, J = 5.9 Hz, 2H),
1.94 (p, J = 12.6, 6.1 Hz, 2H); NMR-13C (126 MHz, CDCl3) δ
200.1, 165.2, 140.4, 128.8, 128.5, 126.8, 124.0, 76.7, 37.8, 25.9,
22.6.
Compound 4g: The general procedure was applied using 100 mg
of 2b (0.28 mmol), 0.12 mL of HMPA (124 mg, 0.69 mmol), t-
BuLi (0.45 mL, 1.5 M, 0.675 mmol) and 50 µL of 2-cyclohexen-
1-one (50 mg, 0.52 mmol) in 3.0 mL of anhydrous THF. For the
deprotection 0.33 mL of TBAF (1.0 M, 86 mg, 0.33 mmol) were
used in 4 mL anhydrous THF. The reaction crude was purified by
column chromatography (2.0
x 8.0 cm, silica gel; 55:45
Hexanes/EtOAc) affording 29 mg (55 %) of 4g as a white solid.
TLC-Rf (Hexanes/EtOAc 1:1) 0.36; m.p.: 46-48 °C; NMR-1H (500
MHz, CDCl3) δ 5.89 (d, J = 1.1 Hz, 1H), 2.58 – 2.37 (m, 5H), 2.36
– 2.28 (m, 4H), 2.16 (ddt, J = 13.0, 6.5, 3.2 Hz, 1H), 2.02 (dt, J =
12.6, 6.1 Hz, 3H), 1.75 – 1.63 (m, 2H); NMR- 13C NMR (75 MHz,
CDCl3) δ 209.55, 199.70, 166.30, 124.81, 45.87, 45.47, 41.07,
37.48, 29.40, 28.18, 25.13, 22.77.Mass spectrum m/z [M+] 192, 95
(100%).
3-(hydroxymethyl)cyclohex-2-en-1-one (4h):21 The general
procedure was applied using 100 mg of 147b (0.28 mmol), 0.12
mL of HMPA (124 mg, 0.69 mmol), t-BuLi (0.45 mL, 1.5 M,
0.675 mmol) and 35 mg of paraformaldehyde (1.2 mmol) in 3.0
mL of anhydrous THF. For the deprotection 0.33 mL of TBAF
(1.0 M, 86 mg, 0.33 mmol) were used in 4 mL anhydrous THF.
The reaction crude was purified by column chromatography (2.0 x
8.0 cm, silica gel; 3:7 Hexanes/EtOAc) affording 4 mg (12 %) of
4h as a yellow pallid oil. TLC-Rf (Hexanes/EtOAc 3:7) 0.27;
NMR-1H (500 MHz, CDCl3) δ 6.15 (s, 1H), 4.27 (s, 2H), 2.42 (t, J
= 6.5 Hz, 2H), 2.27 (t, J = 5.7 Hz, 2H), 2.04 (p, J = 14.9, 6.9, 6.2
Hz, 2H); NMR-13C (126 MHz, CDCl3) δ 199.2, 166.9, 123.3, 65.0,
37.8, 26.1, 22.5.
17. Evans, D. A.; Truesdale, L. K. Tetrahedron Let. 1973, 14,
4929.
18. Jung, M. E.; Blum, R. B. Tetrahedron Let. 1977, 18, 3791.
19. Stanetty, P.; Koller, H.; Mihovilovic, M. J. Org. Chem. 1992,
57, 6833.
20. Dolak, T. M.; Bryson, T. A. Tetrahedron. Let. 1977, 18, 1961.
21. Lechuga-Eduardo, H.; Romero-Ortega, M.; Olivo, H.F. Eur. J.
Org. Chem. 2016, 51.
22. Kozikowski, A. P.; Jung S. H. J. Org. Chem. 1986, 51, 3402.

6
Tetrahedron
Synthesis of 3-substituted 2-cyclohexenones
through umpoled functionalization.
Harim Lechuga-Eduardo, Eduardo Zarza-Acuña and
Moisés Romero-Ortega
Highlights
1. 3-Sustituted -2-cyclohexenones from 2-
Cyclohexenone
2. A convenient one pot procedure to generate
3-substiuted-2-cyclohexenones
3. Aldehydes, Alkyl Halides, Ketones and -
unsaturated compounds can be employed
4. Our methodology produces molecules with
high potential
5. Different kind of electrophiles were used

7
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Synthesis of 3-substituted
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Harim Lechuga-Eduardo, Eduardo Zarza-Acuña and Moisés Romero-Ortega
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