Ring opening of methylenecyclopropanes with halides in liquid sulfur dioxide

Article abstract of DOI:10.1016/j.tetlet.2020.152528

Methylenecyclopropanes (MCP) undergo ring opening reactions with group I and II metal halides and ammonium halides in liquid SO₂ to afford homoallylic halides, which are versatile reagents in organic synthesis. The developed reaction conditions are compatible with acid-labile substrates such as N-Boc-protected compounds. Liquid SO₂ is a polar reaction medium with Lewis acid properties that solubilizes inorganic salts. The unique properties of SO₂ were demonstrated by control experiments: 1) upon performing the reactions with the aforementioned salts in conventional solvents, the MCP ring opening was not observed either in the presence of catalytic amounts of H₃PO₄ (similar pK_a to that of H₂SO₃), or in the absence of H₃PO₄; 2) a solution of SO₂ in THF exhibited similar properties to that of liquid SO₂.

Full text of DOI:10.1016/j.tetlet.2020.152528

Tetrahedron Letters 61 (2020) 152528
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ring opening of methylenecyclopropanes with halides
in liquid sulfur dioxide
Kristaps Leškovskis a, Krista Gulbe a, Anatoly Mishnev b, Maris Turks a
¯
a Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, P. Valdena str. 3, Riga LV-1048, Latvia
b Latvian Institute of Organic Synthesis, Aizkraukles str. 21, Riga LV-1006, Latvia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 July 2020
Revised 27 September 2020
Accepted 30 September 2020
Available online 7 October 2020
Methylenecyclopropanes (MCP) undergo ring opening reactions with group I and II metal halides and
ammonium halides in liquid SO2 to afford homoallylic halides, which are versatile reagents in organic
synthesis. The developed reaction conditions are compatible with acid-labile substrates such as N-Boc-
protected compounds. Liquid SO2 is a polar reaction medium with Lewis acid properties that solubilizes
inorganic salts. The unique properties of SO2 were demonstrated by control experiments: 1) upon per-
forming the reactions with the aforementioned salts in conventional solvents, the MCP ring opening
was not observed either in the presence of catalytic amounts of H3PO4 (similar pKa to that of H2SO3),
or in the absence of H3PO4; 2) a solution of SO2 in THF exhibited similar properties to that of liquid SO2.
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Methylencyclopropanes
Homoallylic halides
Liquid SO2
Group I and II metal halides
Introduction
commercially available (3-bromopropyl)triphenylphosphonium
bromide and the corresponding aldehyde or ketone (Scheme 1;
Methylenecyclopropanes (MCP) are readily accessible and func-
tion as useful building blocks in organic synthesis. MCPs are reac-
tive molecules and their various ring opening reactions occur
under facile reaction conditions due to the release of ring strain [1].
Notable studies have been devoted to the opening of MCPs
using various transition metal halides as Lewis acids. The Shi group
firstly reported use of TiCl4 in CH2Cl2 as a halogen source in MCP
ring opening reactions [2]. Subsequently they demonstrated MCP
ring opening using alkali metal salts in acetic acid as solvent and
the dihalogenation of MCP using a combination of LiBr and NBS [3].
Liquid SO2 is a unique polar solvent and reagent with Lewis
acidic properties [4] and we have demonstrated its application
for transformations involving carbocation intermediates [5]. Addi-
tionally, inorganic salts are soluble in liquid SO2 and it can be used
as a reaction medium which brings together organic and inorganic
reagents and additionally activates electrophilic reaction compo-
nents towards nucleophile attack [5,6]. Hence, we have developed
MCP ring opening reactions with group I and II metal halides in liq-
uid SO2.
for full details see ESI) [7].
We began our investigation of their ring-opening by screening
the reactivity of various group I and II metal halides towards ben-
zaldehyde-derived phenyl-MCP 1a as a model substrate. The MCP
in liquid SO2 was treated with the metal halide MX (3 equiv.)
and H2O (1.2 equiv.) for 6 h at 100 °C. Water was not added in
experiments when ammonium salts were employed as they
already possess an intrinsic proton source [5a]. We have found that
the ring opening of model substrate 1a is productive with almost
all group I and II metal halides (Table 1). We were able to establish
a cation reactivity order: Li+ > Mg2+ > Cs+ > K+ > Na+ > NH4+ and an
anion reactivity order: IÀ > BrÀ > ClÀ.
LiI and MgI2 both consist of a Lewis acidic cation and the most
nucleophilic halide anion. Therefore, in these cases only degrada-
tion products were formed (Table 1, entries 7 and 16). Additionally,
NaI exhibited high reactivity that lead to the degradation of model
substrate 1a (Table 1, entry 4). Iodides containing less Lewis acidic
cations such as K+, Cs+ and NH4+ gave a relatively clean conversion
to the ring opening product 2a (Table 1, entries 1, 10 and 13),
which was isolated in 42–68% yield. In contrast, for bromide and
chloride salts only Lewis acidic cations were capable of ring open-
ing (Table 1, entries 8, 9, 17 and 18) giving products 2b and 2c
while Na+, K+, Cs+ and NH+4 salts exhibited low reactivity.
With the initial information in hand, we proceeded to examine
aryl-MCPs 1b-f bearing various substituents on the phenyl ring.
Mesityl-MCP 1b gave the ring opening products 2d-f in excellent
Results and Discussion
Methylenecyclopropanes 1a-f, 3, 5 and 8 were prepared using a
previously described tandem cyclization-Wittig reaction from
E-mail address: maris.turks@rtu.lv (M. Turks)
https://doi.org/10.1016/j.tetlet.2020.152528
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

K. Leškovskis, K. Gulbe, A. Mishnev et al.
Tetrahedron Letters 61 (2020) 152528
(88%). A similar high yield in the MCP ring opening with LiCl was
observed for product 2n, which contains electron rich 3,4-
dimethoxyphenyl substituents. (Table 2, entry 11). Due to
enhanced reactivity of the substrate, LiCl reacted at 80 °C, but
the ring opening of substrate 1e with iodides led to degradation
products: in this particular case LiI showed reactivity at ambient
temperature, but only 32% of product 2l was obtained. A compro-
mise between sufficient reactivity and degradation was achieved
with LiBr at 25 °C (2m: 62%). Methylthio-substituted MCP 1f
showed reasonably high reactivity and its ring opening products
2o-r were obtained in moderate yields with NaI and LiBr at 60 °C
and with LiCl at 120 °C (Table 2, entries 12–14).
Scheme 1. Synthesis of methylenecyclopropane starting materials.
Table 1
Screening of group I and II metal halides in the ring opening of MCP 1a.a.
MCP 1c,d containing electron-withdrawing substituents such as
fluoride or trifluoromethyl group required 100 °C and gave addi-
tion products 2g-k in moderate yields (Table 2, entries 4–8). The
deactivating nature of the trifluoromethyl group prevented the
ring opening of substrate 1d with chloride salts even at tempera-
tures as high as 140 °C. It should be noted that products 2a-r were
all obtained as pure (E)-isomers with their vicinal coupling con-
stant being between 15.7 Hz and 16.1 Hz.
The unique role of liquid SO2 as the reaction medium was
proved in two test reactions: 1) when the very reactive substrate
1e was mixed with LiBr in conventional solvents (DMF, DMSO,
NMP, CH2Cl2, THF, toluene, MeCN, MeOH, EtOH, i–PrOH, HFIP, ace-
tone) in the absence of SO2, it provided only unreacted 1e even at
the solvent reflux temperatures; 2) the ring opening reactions of
substrates 1b and 1d-f was attempted under the conditions previ-
ously reported by the Shi group [2] (TiCl4 in CH2Cl2 at À78 °C). In
these experiments employing a strong Lewis acid only electron-
rich substrates 1b and 1e gave products 2f and 2n in 21% and 6%
yield, respectively (1H NMR with an internal standard), while sub-
strates 1d and 1f lead to degradation products.
Entry
MX
Isolated yield (or conversionc)
1b
2b
3b
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
IÀ
2a, 68
2b, (12)
2c, (6)
–
2b, (19)
2c, (6)
–
2b, 67
2c, 55
2a, 43
2b, (25)
2c, (4)
2a, 42
2b, (33)
–
BrÀ
ClÀ
IÀ
NH+4
Na+
Li+
Br–
ClÀ
IÀ
BrÀ
ClÀ
IÀ
BrÀ
ClÀ
IÀ
K+
BrÀ
ClÀ
IÀ
Cs+
Mg2+
–
BrÀ
ClÀ
2b, 44
2c, 35
a
Reactions were carried out in a pressure reactor with MCP 1a (50 mg, 1 equiv.),
salt (3 equiv.) and water (1.2 equiv.);
determined by GC–MS.
b
c
Next, we examined the MCP ring opening of frequently used
[3,8] benzophenone-derived diphenyl-MCP 3 (Table 3). We began
by screening Li+ salts at 100 °C and observed complete substrate
conversion to the expected products 4a-c. By optimizing the reac-
tion conditions we were able to obtain products 4a,b in excellent
yields at ambient temperature with LiI or NaI and at –10 °C with
LiBr. Substrate 3 also reacted with NH4I (in the absence of water
without water additive; conversion
yields (Table 2, entries 1–3). The electron-rich aromatic system of
substrate 1b ensures stabilization of the aryl cyclopropylmethyl
cation; therefore chloride adduct 2f was also obtained in high yield
Table 2
Ring opening of benzaldehyde-derived MCP.a.
Entry
Starting materials
Reaction conditions
Products 2d-r
1b-f
MX
Temp. (°C)
General structure
X
Yield (%)
1
NaI
LiBr
LiCl
60
60
140
I
Br
Cl
2d, 93
2e, 92
2f, 88
2
3b
4
NaI
LiBr
LiCl
NaI
LiBr
100
100
140
100
100
I
2g, 43
2h, 55
2i, 44
2j, 55
2k, 52
5
Br
Cl
I
6b
7
8
Br
9
10
11
LiI
LiBr
LiCl
25
25
80
I
Br
Cl
2l, 32
2m, 62
2n, 89
12
NaI
LiBr
LiCl
60
60
120
I
Br
Cl
2o, 55
2p, 52
2r, 54
13
14b
a
Reactions were carried out in a pressure reactor with MCP 1 (100 mg, 1 equiv.), salt (3 equiv.) and water (1.2 equiv.) for 1 h at the
b
indicated temperature; reaction was carried out overnight.
2

K. Leškovskis, K. Gulbe, A. Mishnev et al.
Tetrahedron Letters 61 (2020) 152528
Table 3
Ring opening of benzophenone-derived MCP 3.a.
Entry
Reaction conditions
Product 4a-c
Scheme 3. Ring opening of N-Boc protected MCP 8.
MX
Temp. (oC)
X
Yield (%)
1
LiI
25
25
100
25
I
I
I
Br
Br
Cl
4a, 89
4a, 86c
4a, 79c
4b, 89
4b, 89
4c, 80
2
NaI
NH4I
LiBr
LiBr
LiCl
3b
4
5
6
À10 (reflux)
100
a
Reactions were carried out with MCP 3 (50 mg, 1 equiv.), salt (3 equiv.) and
b
c
water (1.2 equiv.) for 1 h at the indicated temperature; without water additive;
conversion determined by GC–MS.
additive) and 79% conversion to product 4a at 100 °C was observed
by GC–MS. As previously discussed, the less reactive LiCl required a
higher reaction temperature (100 °C) and gave chloride adduct 4c
in 80% yield. It should be noted that heating a mixture of 3 and LiI
at reflux in various solvents (CH2Cl2, THF, Toluene, MeCN, MeNO2)
in the absence of SO2 only resulted in the recovery of unreacted
starting material.
We have also examined the developed method using an alipha-
tic-MCP, which possesses lower reactivity. The decanal-derived
MCP did not provide the ring opening products with group I and
II metal halides in liquid SO2, but cyclohexanone-derived MCP 5
underwent rapid ring opening with NaI and gave product 6a in
43% yield (1H NMR with an internal standard) (Scheme 2). From
all tested combinations of MCP 5 and group I and II halides only
the use of KBr and KCl resulted in bromide and chloride adducts
6b,c, albeit in low yields (1H NMR with an internal standard). Addi-
tionally, isomerization of the double bond was observed for prod-
ucts 7b,c. The low isolated yields of products 6b,c and 7b,c are
presumably due to both the volatility and polymerization rate of
these compounds. It is important to note that very few examples
of the ring opening of alkyl-substituted MCP have been reported
Fig. 1. X-ray structure analysis of carbamate 9c (CCDC-1935449).
unidentified degradation products even at À78 °C. This example
clearly demonstrates the compromise achieved between the Lewis
acidic/protic activation of the starting material, solubility of the
group I and II metal halides and substrate stability in the liquid
SO2 medium.
Finally, additional experimental evidence was obtained to show
that the developed MCP ring opening methodology benefits from
the SO2 medium and not only from the proton source in the form
of H2SO3. A combination of MCP 1e and LiBr in THF (+1.2 equiv.
of water) containing catalytic H3PO4 (1 mol%) gave only trace
amounts of bromide adduct 2m (2%) (Table 4). We selected
H3PO4 as a protic acid additive with a similar pKa value to that of
H2SO3. It means that protic catalysis of the putative H2SO3 present
in liquid SO2 is not the basis of our methodology. More impor-
tantly, the combination of MCPs 1e,3 and LiX in a 3 M solution of
SO2 in THF provided similar isolated yields of products 2l,m and
4a,b to those obtained in liquid SO2 as the sole reaction medium.
The above mentioned facts together with the good isolated yields
of acid-labile N-Boc protected products 9a-c demonstrate the
unique properties of SO2 as the reaction medium which is far
beyond the simple acidity of H2SO3. We had previously hypothe-
sized [5a] that liquid SO2 as a solvent is a weak Lewis acid which
can promote various reactions involving ionic intermediates, yet
it is not efficient in stabilizing the HSOÀ3 anion. Therefore, the
[3b,3d]. In this context the 43% yield of product 6a is
a
commendable result.
Furthermore, we examined the reaction of halides with an ace-
tophenone-derived MCP ((1-cyclopropylideneethyl)benzene),
which appeared to be a highly unstable substrate even at 0 °C.
The ring opening reactions were performed with NH4I, LiBr and
LiCl immediately after the preparation of the substrate and gave
unstable products in 21–23% yield (1H NMR with an internal
standard).
To our delight, acetophenone-derived MCP 8, which contains a
para-N-Boc substituent, showed superior reactivity and products
9a-c were obtained with excellent yields and E-selectivity
(Scheme 3). It is important to note that the acid-labile Boc-group
in products 9a-c remained intact. The structure of product 9c
was unambiguously established by single crystal X–ray analysis
(Fig. 1).
Table 4
The role of SO2 in the ring opening of MCP 1e and 3.a.
In this case our newly developed methodology was superior to
the previously reported protocol (TiCl4, CH2Cl2) which gave
Product
Yield depending on the solvent system.b
THF
Liquid SO2
3 M solution
of SO2 in THF
H3PO4 (1 mol%)
in THF
2l
0%
0%
0%
0%
32%
62%
89%
89%
35%
70%
80%
66%
–
2%
–
2m
4a
4b
–
a
Reactions (except for liquid SO2 conditions see Tables 2 and 3) were carried out
with MCP 1e or 3 (50 mg, 1 equiv.), LiX (3 equiv.) and water (1.2 equiv.) for 1 h at
b
70 °C; isolated yields.
Scheme 2. Ring opening of cyclohexanone-derived MCP 5.
3

K. Leškovskis, K. Gulbe, A. Mishnev et al.
Tetrahedron Letters 61 (2020) 152528
equilibrium SO2 + 2H2O ? H3O+ + HSOÀ3 is not efficiently shifted to
the right in liquid SO2 [5a].
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Org. Chem. (2017) 7060–7067;
In summary, we have reported the synthesis of homoallylic
halides via the reaction of MCP with group I and II metal halides
in liquid SO2 as the reaction medium. Due to the mild acidity of liq-
uid SO2, the developed reaction conditions are compatible with
acid labile protecting groups such as the Boc-group. It was also
found that for these reactions a solution of SO2 in THF exhibits sim-
ilar properties to that of liquid SO2.
(e) M. Shi, J.-M. Lu, Y. Wei, L.-H. Shao, Acc. Chem. Res. 45 (2012) 641–652.
[2] B. Xu, M. Shi, Org. Lett. 5 (2003) 1415–1418.
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Declaration of Competing Interest
(d) P. Vogel, D. Markovic, M. Turks, Sulfur Dioxide: A Powerful Tool for the
Stereoselective Construction of C-C bonds, in: V. Andrushko, N. Andrushko
(Eds.), Stereoselective Synthesis of Drugs and Natural Products, John Wiley &
Sons, Hoboken, NJ, 2013, pp. 1–44;
(e) J.M. Bakke, I.J. Hegbom, Chem. Soc. Perk. Trans. 2 (1995) 1211–1215;
(f) L.A. Tinker, A.J. Bard, J. Am. Chem. Soc. 101 (1979) 2316–2319;
(g) P. Vogel, M. Turks, L. Bouchez, C. Craita, M.C. Murcia, F. Fonquerne, C. Didier,
C. Flowers, Pure Appl. Chem. 80 (2008) 791–805;
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
(h) K. Suta, M. Turks, Chem. Heterocycl. Comp. 54 (2018) 584–586;
(i) A. Stikute, J. Luginßina, M. Turks, Tetrahedron Lett. 58 (2017) 2727–2731;
(j) A. Stikute, V. Peipinßš, M. Turks, Tetrahedron Lett. 56 (2015) 4578–4581.
[5] (a) K. Suta, M. Turks, ACS Omega 3 (2018) 18065–18077;
(b) J. Luginßina, M. Turks, Synlett 28 (2017) 939–943;
The authors thank the Latvian Council of Science Grant LZP–
2018/1-0315. K.L. thanks Riga Technical University Master student
research grant ZM-2020/3.
(c) D. Posevins, K. Suta, M. Turks, Eur. J. Org. Chem. 2016 (2016) 1414–1419;
(d) K. Leškovskis, J. Luginßina, K. Suta, M. Turks, Key Eng. Mater. 800 (2019) 42–
46.
Appendix A. Supplementary data
[6] (a) J. Luginßina, J. Uzulenßa, D. Posevins, M. Turks, Eur. J. Org. Chem. 2016 (2016)
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152528.
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