Regioselective Ene-Type Allylic Chlorination of Electron-Rich Alkenes by Activated DMSO

Article abstract of DOI:10.1021/acs.joc.7b01103

A simple protocol involving the activation of DMSO by chlorotrimethysilane is described for the chemoselective chlorination of polyprenoids. The proposed protocol provides a versatile and scalable alternative to existing routes for accessing useful synthe

Full text of DOI:10.1021/acs.joc.7b01103

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Note
Regioselective Ene-Type Allylic Chlorination
of Electron Rich Alkenes by Activated DMSO
Vera P. Demertzidou, Stavroula Pappa, Vasiliki Sarli, and Alexandros L. Zografos
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01103 • Publication Date (Web): 28 Jul 2017
Downloaded from http://pubs.acs.org on July 28, 2017
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Despite the previous efforts to establish a general chlorination method for styrenes by utilizing activated
DMSO that led to rather unpredictable mixtures of mono- and dichlorinated products,9 ene-type allylic
halogenation of alkenes with stable hydrohalide salts of DMSO ,16 supports the feasibility of our idea.
Forced by our constant interest in the synthesis of complex sesquiterpenoids,17 we sought to develop a
versatile, scalable protocol for the regioselective formation of allylic chlorides of polyprenoids under
mild reaction conditions.
Rationalizing the idea above (Figure 1), we started by investigating the feasibility of interrupting the
chlorosulfenylation process, in the known DMSO-TMSCl protocol, to selectively produce allylic
chlorides. Geraniol acetate (3), bearing two electronically different alkenes was chosen as a simple
model for this study (Table 1). Our first attempt, utilizing the exact previously reported
chlorosulfenylation conditions, failed to provide the desired product 4, producing only compound 5,
albeit in low yield (entry 1; Table 1). As expected, allowing the substrate to react at higher temperature
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(60 C) led only to decomposition (entry 2; Table 1). On the other hand, a clear indication for the
interruption of this process came from the utilization of higher excess of chlorotrimethylsilane (6 equiv)
at ambient temperature, providing the desired compound 4, as the minor component, along with the
thiochlorinated derivative 5, as an inseparable mixture of products (entry 3; Table 1). Further
experimentation, utilizing DMSO in DCM or nitromethane as solvents allowed the chemoselective
production of the desired chloride 4, in moderate yields, but still without avoiding the
chlorosulfenylated product 5 (entries 4-5; Table 1).
Gratifyingly, a great improvement was made when a 5 min premixing time period of
chlorotrimethylsilane and DMSO was allowed before the introduction of the substrate. In these cases,
1
cleaner reaction profiles were evidenced by H-NMR indicating the absence of chlorosulfenylated
products. Longer premixing times led to unidentified products and low conversion rates of the substrate.
Thus, the premixing time was kept to a strict 5 min window in all further attempts (entries 6-10; Table
1). Polarity screening, under these premixing conditions, led to the identification of DCM as the optimal
solvent. Excess of trimethylsilane compared to DMSO, at lower temperatures, was advantageous not
only for the higher conversion rates of the substrate but also for the minimization of the byproduct 5
(entries 6-7; Table 1). In general, high excess of DMSO (up to 5 equiv) usually does not affect the
regioselective monochlorination of the product leading to faster reactions. However, harsher reaction
conditions, as described by the presence of more equiv of DMSO and/or the addition of LiCl in the
reaction mixture, force the reaction to also chlorinate the next more electron rich alkene, though usually
in low yields (approx. 25-30%).
Table 1. Reaction Optimization[a]
Cl
Cl
Conditions
OAc
+
OAc
OAc
SMe
4
3
5
Entry
Solvent
Condi-
tions[a]
equiv
TMSCl
equiv
DMSO
Conve- Yield
rsion of (%)[b]
3 (%)
38
100
90
84
100
70
100
100
30
100
75
80
4; 5
0; 23
1[c]
2[c]
3[c]
4[c]
5[c]
6
7
8
9
DMSO
DMSO
DMSO
DCM
MeNO2
DCM
DCM
DCM
toluene
THF
48h, rt
1.5
excess
excess
5h, 60 oC
3.5h, rt
1.5
6.0
1.5
1.5
1.5
5.0
10
10
10
10
10
Decomp.
22; 37
52; 25
41; 45
55; traces
91; 0
excess
3.0
3.0
1.5
2.5
5
5
5
5
5
48h, rt
5h, rt
24h, rt
5h, 0 oC
2h, 0 oC
12h, 0 oC
12h, 0 oC
12h, 0 oC
12h, 0 oC
92; 0
Unknown
Unknown
50, 30
40, 40
10
11
12
CH3CN
AcOEt
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time to provide compound 6 (52 mg, 87% yield). Rf = 0.77 (hexanes/EtOAc = 3:1). H and 13C NMR
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are identical to the reported.5
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3-chloro-2-methyl-6-methyleneocta-1,7-diene (7).21 Prepared according to the general experimental
procedure starting from 27 mg (0.2 mmoles) of myrcene in 1.5h reaction time to provide compound 7
(31 mg, 91% yield). Rf = 0.68 (hexanes/EtOAc = 3:1). 1H and 13C NMR are identical to the reported.21
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(2E,10E)-methyl 12-acetoxy-7-chloro-2,10-dimethyl-6-methylenedodeca-2,10-dienoate (8). Prepared
according to the general experimental procedure starting from 62 mg (0.2 mmoles) of (2E,6E,10E)-
methyl 12-acetoxy-2,6,10-trimethyldodeca-2,6,10-trienoate22 in 12 h reaction time to provide compound
8 (47 mg, 68% yield), as a clear oil.Rf = 0.61 (hexanes/EtOAc = 4:1). 1H NMR (500 MHz, CDCl3): / =
6.75 (m, 1H), 5.37 (dt, 1H), 5.15 (s, 1H), 4.95 (d, 1H), 4.58 (d, 1H), 4.33 (m, 1H), 3.73 (s, 3H), 2.41-
2.34 (m, 4H), 2.06 (s, 3H), 2.00-1.92 (m 1H), 1.70 (d, 3H); 13C NMR (125 MHz, CDCl3): / = 171.1,
169.4, 147.2 (two carbons), 141.3, 140.4, 119.4, 113.3, 65.5, 61.2, 52.2, 36.5, 34.5, 29.3, 26.8, 16.5,
15.6, 12.5; Elemental Anal. Calcd for C18H27ClO4: C, 63.06; H, 7.94; Cl, 10.34. Found: C, 63.21; H,
7.65; Cl, 10.38.
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(E)-ethyl 7-chloro-2,4,8-trimethylnona-2,8-dienoate (9). Prepared according to the general experimental
procedure starting from 45 mg (0.2 mmoles) of (E)-ethyl 2,4,8-trimethylnona-2,7-dienoate23 in 4.5 h
reaction time to provide compound 9 (42 mg, 82% yield) as a mixture of isomers. Further purification
was accomplished by flash chromatography of the mixture of isomers to deliver the pure enantiomer in
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35% yield, as a clear oil. [a]D = - 33.21 (c 0.4, CHCl3). Rf = 0.72 (hexanes/EtOAc = 4:1. H NMR
(500 MHz, CDCl3): / =6.50 (d, J = 9.7Hz, 1H), 4.98 (s, 1H), 4.89 (s, 1H), 4.38-4.25 (m, 1H), 4.19 (q, J
= 7.1 Hz, 2H), 2.55-2.39 (m, 1H), 1.84 (s, 3H), 1.78 (s, 3H), 1.61-1.51 (m, 2H), 1.46-1.37 (m, 1H), 1.29
(t, J = 7.2Hz, 3H), 1.27-1.22 (m, 1H), 1.02 (d, J = 6.7Hz, 3H); 13C NMR (125 MHz, CDCl3): / = 168.2,
146.7, 144.2, 127.0, 114.2, 66.7, 60.5, 34.4, 34.3, 32.8, 20.0, 16.8, 14.2, 12.6; Elemental Anal. Calcd for
C14H23ClO2: C, 64.98; H, 8.96; Cl, 13.70. Found: C, 65.22; H, 8.81; Cl, 13.61.
3-chloro-2,3-dimethylbut-1-ene (10).24 Prepared according to the general experimental procedure
starting from 420 mg (5.0 mmoles) of 2,3-dimethyl-2-butene in 2 h reaction time to provide compound
10 (249 mg, 42% yield). The compound is highly volatile, labile and polymerizes in column and upon
standing. The compound is purified by micro-distillation. 1H is identical to the reported.24
(3S,5R,10R,13R,14R,17R)-17-((2R)-5-chloro-6-methylhept-6-en-2-yl)-4,4,5,10,13-pentamethyl-
2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol (11). Prepared
according to the general experimental procedure starting from 85 mg (0.2 mmoles) of lanosterol in 3 h
reaction time to provide compound 11 (72 mg, 78% yield) as a mixture of isomers. Off white solid, Rf
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= 0.54 (hexanes/EtOAc = 4:1). H NMR (500 MHz, CDCl3): / = 5.00 (s, 1H), 4.88 (s, 1H), 4.39-4.28
(m, 1H), 3.55 (d, J = 5.1Hz, 1H), 3.22 (dt, J = 14.2, 7.2 Hz, 1H), 2.07-1.13 (m, 23H), 1.79 (d, J = 6.4
Hz, 3H), 1.00 (s, 3H), 0.98 (s, 3H), 0.91 (d, J = 6.1Hz, 3H), 0.87 (s, 3H), 0.81 (s, 3H), 0.69 (s, 3H); 13C
NMR (125 MHz, CDCl3): / =144.7, 144.3, 134.4, 134.3 (two peaks), 114.3, 113.9, 79.0, 78.9, 67.5,
67.4, 50.4, 50.2 (two peaks), 49.8, 44.5 (two peaks), 42.0, 41.9, 39.5, 38.9, 37.0, 36.5, 36.0, 35.6, 33.4
(three peaks), 33.3, 30.9 (two peaks), 30.8 (two peaks), 30.2, 30.1, 29.7, 29.1, 28.2 (two peaks), 28.1
(two peaks), 28.0, 27.9, 27.8, 26.5, 24.2 (two peaks), 24.1, 22.8, 22.5, 21.0 (two peaks), 19.1, 18.7, 18.6,
18.2, 17.0, 16.7, 15.7, 15.4; Elemental Anal. Calcd for C30H49ClO: C, 78.13; H, 10.71; Cl, 7.69. Found:
C, 78.38; H, 10.90; Cl, 7.50.
(E)-methyl 12-acetoxy-7-chloro-2,10-dimethyl-6-methylenedodec-2-enoate (12). Prepared according to
the general experimental procedure starting from 62 mg (0.2 mmoles) of (2E,6E)-methyl 12-acetoxy-
2,6,10-trimethyldodeca-2,6-dienoate25 in 12 h reaction time to provide compound 12 (43 mg, 62%
1
yield) as a mixture of isomers. Clear oil, Rf = 0.59 (hexanes/EtOAc = 3:1). H NMR (500 MHz,
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CDCl3): / = 6.80-6.69 (m, 1H), 5.14 (d, J = 1.1 Hz, 1H), 4.94 (d, J = 1.9 Hz, 1H), 4.41-4.30 (m, 1H),
4.12-4.03 (m, 2H), 3.73 (s, 3H), 2.42-2.08 (m, 4H), 2.04 (s, 3H), 1.86 (s, 3H), 1.74-1.67 (m, 1H), 1.61-
1.52 (m, 5H), 1.37-1.30 (m, 1H), 0.92 (dd, J = 6.6, 1.4 Hz, 3H); 13C NMR (125 MHz, CDCl3): / =
171.1, 171.0, 168.5, 168.4, 147.5, 147.3, 141.3 (two peaks), 128.1 (two peaks), 113.2, 113.1, 66.5, 66.4,
62.7 (two peaks), 51.8, 51.7, 35.4 (two peaks), 34.1 (two peaks), 34.0, 33.9, 29.6, 29.5, 29.3, 26.9 (three
peaks), 21.0 (two peaks), 19.4, 19.3, 12.5; Elemental Anal. Calcd for C18H29ClO4: C, 62.69; H, 8.48; Cl,
10.28. Found: C, 62.61; H, 8.20; Cl, 10.46.
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(E)-methyl 7-chloro-2,4,8-trimethylnona-2,8-dienoate (13). Prepared according the general
experimental procedure starting from 42 mg (0.2 mmoles) of (E)-methyl 2,4,8-trimethylnona-2,7-
dienoate23 in 2 h reaction time to provide compound 13 (42 mg, 87% yield) as a mixture of isomers.
Further purification by flash chromatography (hexanes/EtOAc = 80:1) delivered one diastereomeric pair
of the mixture in 40% yield. Clear oil, Rf = 0.58 (PS / EA= 4:1). 1H NMR (500 MHz, CDCl3): / = 6.56-
6.45 (m, 1H), 4.98 (s, 1H), 4.88 (d, J = 1.2 Hz, 1H), 4.32 (td, J = 7.2, 2.9 Hz, 1H), 3.73 (s, 3H), 2.56-
2.45 (m, 1H), 1.84 (s, 3H), 1.77 (s, 3H), 1.75-1.27 (m, 4H), 1.01 (d, J = 6.6 Hz, 3H); 13C NMR (126
MHz, CDCl3) / = 168.7, 147.2, 144.2, 124.2, 114.3, 66.8, 51.8, 34.4, 34.0, 32.9, 20.0, 16.9, 12.6;
Elemental Anal. Calcd for C13H21ClO2: C, 63.79; H, 8.65; Cl, 14.48. Found: C, 63.71; H, 8.71; Cl,
14.45.
(E)-ethyl 8-chloro-2,5,9-trimethyldeca-2,9-dienoate (14). Prepared according the general experimental
procedure starting from 48 mg (0.2 mmoles) of (E)-ethyl 2,5,9-trimethyldeca-2,8-dienoate26 in 5.5 h
reaction time to provide compound 14 (38 mg, 69% yield) as a mixture of isomers. Clear oil Rf = 0.68
(hexanes/EtOAc = 4:1). 1H NMR (500 MHz, CDCl3): / = 6.79-6.71 (m, 1H), 5.00 (s, 1H), 4.88 (s, 1H),
4.39-4.30 (pt, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.22-2.13 (m, 1H), 2.08-2.00 (m, 1H), 1.95-1.85 (m, 1H),
1.82 (s, 3H), 1.79 (s, 3H), 1.68-1.63 (m, 1H), 1.52-1.42 (m, 1H), 1.36-1.31 (m, 1H), 1.29 (t, J = 7.1Hz,
3H), 1.14 (m, 1H), 0.92 (d, J = 7.3 Hz, 3H); 13C NMR (126 MHz, CDCl3) / = 168.2, 168.1, 144.4, 144.2,
140.6, 140.5, 128.6, 124.5, 114.3, 114.1, 67.0, 66.9, 60.4, 60.3, 35.8 (two peaks), 34.2, 34.1, 33.9, 33.8,
32.7, 32.6, 19.6 (two peaks), 16.9, 16.8, 14.3 (two peaks), 12.5 (two peaks); Elemental Anal. Calcd for
C15H25ClO2: C, 66.04; H, 9.24; Cl, 13.00. Found: C, 66.12; H, 9.01; Cl, 13.07.
(E)-10-chloro-3,7,11-trimethyldodeca-1,6,11-trien-3-yl acetate (15).5 Prepared according the general
experimental procedure starting from 26 mg (0.1 mmoles) of (E)-3,7,11-trimethyldodeca-1,6,10-trien-3-
yl acetate in 4 h reaction time to provide compound 15 (22 mg, 75% yield). Rf = 0.64 (hexanes/EtOAc =
3:1). Elemental Anal. Calcd for C17H27ClO2: C, 68.32; H, 9.11; Cl, 11.86. Found: C, 68.38; H, 9.32; Cl,
11.55; 1H and 13C NMR are identical to the reported.5
(2E,6E,10E)-14-chloro-3,7,11,15-tetramethylhexadeca-2,6,10,15-tetraen-1-yl acetate (16).5 Prepared
according the general experimental procedure starting from 33 mg (0.1 mmoles) of geranylgeranyl
acetate in 2.5 h reaction time to provide compound 16 (30 mg, 81% yield) Rf = 0.62 (hexanes/EtOAc =
3:1). Elemental Anal. Calcd for C22H35ClO2: C, 72.01; H, 9.61; Cl, 9.66. Found: C, 72.12; H, 9.50; Cl,
9.60; 1H and 13C NMR are consistent with the reported.5
(E)-3,8-dichloro-2,6-dimethylocta-1,6-diene (17).4a Prepared according the general experimental
procedure starting from 60 mg (0.4 mmoles) of geraniol in 3 h reaction time to provide compound 17
(112 mg, 78% yield) Rf = 0.58 (hexanes/EtOAc = 3:1). 1H and 13C NMR are identical to the reported.4a
(E)-6,10-dichloro-11-hydroxy-3,11-dimethyl-7-methylenedodec-2-enyl acetate (18). Prepared according
the general experimental procedure starting from 63mg (0.2 mmoles) of (2E,6E)-10-chloro-11-hydroxy-
3,7,11-trimethyldodeca-2,6-dienyl acetate24 in 12 h reaction time to provide compound 18 (30mg, 42%
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yield) or alternatively prepared according to the general experimental procedure starting from 56 mg
(0.2 mmoles) of (2E,6E)-9-(3,3-dimethyloxiran-2-yl)-3,7-dimethylnona-2,6-dienyl acetate.24 The
o
mixture is stirred for 2 h at 0 C before readditing a premixed mixture of DMSO (5 equiv) and TMSCl
(10 equiv) in DCM. The mixture is stirred for an additional 10 h at the same temperature to provide
compound 20 as a mixture of isomers (30 mg, 43% yield). Clear oil, Rf = 0.51 (hexanes/EtOAc = 3:1).
1H NMR (500 MHz, CDCl3): / = 5.37 (t, J = 7.0 Hz, 1H), 5.16 (s, 1H), 4.97 (s, 1H), 4.58 (d, J = 7.0 Hz,
2H), 4.34 (td, J = 8.1, 4.8 Hz, 1H), 3.91-3.82 (m, 1H), 2.65-2.55 (m, 1H), 2.24-1.92 (m, 6H), 2.05 (s,
3H), 1.85-1.72 (m, 2H), 1.71 (s, 3H), 1.32 (s, 3H), 1.31 (s, 3H); 13C NMR (126 MHz, CDCl3) / = 171.1
(two peaks), 147.3, 147.0, 140.35 (two peaks), 119.6, 119.4, 113.8, 113.4, 73.1, 72.8, 65.5, 65.1, 61.3,
61.2, 61.1, 61.0, 36.5 (two peaks), 34.6, 34.4, 31.4, 31.3, 28.8, 28.7, 26.4 (two peaks), 25.5, 25.4, 21.1,
21.0, 16.5, 16.4; Elemental Anal. Calcd for C17H28Cl2O3: C, 58.12; H, 8.03; Cl, 20.18. Found: C, 58.41;
H, 7.86; Cl, 20.31.
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trans-(+)-6-chloro-p-mentha-1,8-diene (19).27 Prepared according the general experimental procedure
starting from 27 mg (0.2 mmoles) of a-pinene in 12 h reaction time to provide compound 19 (28 mg,
1
82% yield). Rf = 0.49 (hexanes/EtOAc = 3:1). H and 13C NMR and optical rotation are identical to the
reported.28
trans-6-chloro-p-mentha-1,8-diene (19) and cis-6-chloro-p-mentha-1,8-diene (20).27 Prepared according
the general experimental procedure starting from 30 mg (0.2 mmoles) of trans-carveol in 3.5 h reaction
time to provide an inseparable mixture of compounds 19 and 20 (30 mg, 88% yield). Rf = 0.8
(hexanes/EtOAc = 5:1). 1H and 13C NMR are identical to the reported.28
Aknowledgements
We would like to thank Ms. Eleni Lada for preliminary studies on the topic and also Ms. Athanasia
Karina for providing some of the substrates for the study. The described protocol has been implemented
in the facilities of OPENSCREEN-GR. Part of the project was inspired by helpful discussions within
CHAOS-COST Action CA15106.
Supporting Information
1
Indicative copies of H and 13C NMR spectra of known compounds and of all newly synthesized
compounds are provided. The material is available free of charge via the Internet at http://pubs.acs.org
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