Highly selective synthesis of (E)-alkenyl-(pentafluorosulfanyl)benzenes through Horner-Wadsworth-Emmons reaction

Article abstract of DOI:10.3762/bjoc.8.131

Diethyl 2-nitro-(pentafluorosulfanyl)benzylphosphonates, available by the vicarious nucleophilic substitution reaction of meta- and para-nitro- (pentafluorosulfanyl)benzenes and diethyl chloromethylphosphonate, undergo Horner-Wadsworth-Emmons reaction with aldehydes in the presence of potassium hydroxide in acetonitrile at ambient temperature to give (E)-2-nitro-1-alkenyl- (pentafluorosulfanyl) benzenes in good yields and high stereoselectivities. Follow-up transformations of the primary products provided (E)-1-alkenyl- (pentafluorosulfanyl)benzenes and 2-(2-arylethyl)-(pentafluorosulfanyl)anilines.

Full text of DOI:10.3762/bjoc.8.131

Highly selective synthesis of
(E)-alkenyl-(pentafluorosulfanyl)benzenes
through Horner–Wadsworth–Emmons reaction
George Iakobson and Petr Beier*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1185–1190.
Institute of Organic Chemistry and Biochemistry, Academy of
Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague,
Czech Republic
doi:10.3762/bjoc.8.131
Received: 31 May 2012
Accepted: 27 June 2012
Published: 25 July 2012
Email:
Petr Beier* - beier@uochb.cas.cz
Associate Editor: D. O'Hagan
* Corresponding author
© 2012 Iakobson and Beier; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
Horner–Wadsworth–Emmons reaction; pentafluorosulfanyl group;
phosphonates; sulfurpentafluoride
Abstract
Diethyl 2-nitro-(pentafluorosulfanyl)benzylphosphonates, available by the vicarious nucleophilic substitution reaction of meta- and
para-nitro-(pentafluorosulfanyl)benzenes and diethyl chloromethylphosphonate, undergo Horner–Wadsworth–Emmons reaction
with aldehydes in the presence of potassium hydroxide in acetonitrile at ambient temperature to give (E)-2-nitro-1-alkenyl-(penta-
fluorosulfanyl)benzenes in good yields and high stereoselectivities. Follow-up transformations of the primary products provided
(E)-1-alkenyl-(pentafluorosulfanyl)benzenes and 2-(2-arylethyl)-(pentafluorosulfanyl)anilines.
Introduction
Although the pentafluorosulfanyl (SF5) containing compounds ation of the corresponding bis(nitrophenyl)disulfides [10-12].
have been known for more than half a century [1-4], they A recent report also described a two step synthesis of SF5-
remain a relatively underdeveloped class of compounds. This is benzenes from diaryl disulfides avoiding the use of elemental
so despite the unusual combination of properties that the SF5 fluorine [13]. While the only known SEAr of 1 or 2 is the nitra-
group possesses, such as high thermal and chemical stability, tion of 2 under harsh conditions and in low yield [14], we have
high electronegativity and strong lipophilic character [2-7]. The recently described SNAr of the nitro group in compounds 1 and
availability of SF5-containing compounds is very limited. Ali- 2 with alkoxides and thiolates [15], vicarious nucleophilic
phatic SF5-containing compounds are available through free- substitution (VNS) of the hydrogen with carbon [16], oxygen
radical addition of toxic and expensive SF5Cl to unsaturated [17] and nitrogen [18] nucleophiles, and the oxidative nucleo-
compounds [8,9], and aromatic meta- and para-nitro-(penta- philic substitution with Grignard and alkyllithium reagents [19].
fluorosufanyl)benzenes (1 and 2) are made by direct fluorin- Reduction of the nitro group in 1 or 2 to (pentafluorosul-
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Beilstein J. Org. Chem. 2012, 8, 1185–1190.
fanyl)anilines followed by acylation, SEAr halogenation or carried out starting from isolated phosphonate 3. We found that
diazotization (with follow-up reactions) has also been described various bases mediate the HWE reaction. t-BuOK in THF gave
[11,20-22].
good results; however, the reaction required heating to 50 °C
for at least one hour. With n-BuLi the reaction is complete at
Alkenyl substituted SF5-benzenes or SF5-containing stilbene ambient temperature in about half an hour. By using an
derivatives are not known and would represent basic synthetic extended reaction time, much less basic potassium or caesium
intermediates towards more elaborate structures. We envi- carbonate in acetonitrile could also be used successfully.
sioned a synthetic route towards these compounds through Finally, we have identified potassium hydroxide as a very inex-
Horner–Wadsworth–Emmons (HWE) reaction of phosphonates pensive and convenient base. The best results were obtained by
3 and 4, which are available by vicarious nucleophilic substitu- using 1.8 equiv of KOH in acetonitrile. The addition of small
tion (VNS) of commercial nitrobenzenes 1 and 2 with diethyl amounts of water increased the reaction rate, presumably by
chloromethylphosphonate [16]. If required, the nitro group can better solubilization of KOH and the formed potassium
be removed by a reduction/diazotization/reduction sequence diethylphosphate, and gave the required product 5a in 84%
before or after the HWE reaction (Scheme 1).
isolated yield and high E/Z selectivity (Table 1, entry 13).
The HWE reaction is a modification of the Wittig olefination in Using optimized reaction conditions (Table 1, entry 13), the
which a phosphoryl-stabilized carbanion reacts with an alde- scope of the HWE reaction of various aldehydes with phospho-
hyde or ketone to form an alkene and a water-soluble phos- nate 3 was explored (Table 2). Aromatic aldehydes with elec-
phate ester [23-25]. In general, this reaction preferentially gives tron-donating groups required longer reaction times than those
more stable E-disubstituted alkenes, although several successful with electron-acceptor groups. All tested aromatic aldehydes
attempts have been made to favor Z-alkenes [26-28].
provided compounds 5 in high isolated yields and selectivities.
Application of (E)-cinnamaldehyde (3f) led to the formation of
5f in only 43% yield. Compound 5f was configurationally stable
Results and Discussion
The HWE reaction of phosphonate 3 with benzaldehyde in the in solid form; however, we observed slow isomerization in solu-
presence of a base giving stilbene derivative 5a was investi- tion (CDCl3) at ambient temperature and in daylight (from E/Z
gated. At first, attempts were made to form 5a directly from 1 93:7 to 66:33 after 10 days). Reactions with ketones, even elec-
and diethyl chloromethylphosphonate by a two-step one-pot trophilic and non-enolizable ones such as 4,4'-dichlorobenzo-
process, involving VNS reaction in DMF with a three-fold phenone or 2,2,2-trifluoroacetophenone, did not provide the
excess of t-BuOK (−60 °C, 10 min), followed by the addition of expected alkene products.
benzaldehyde (1.5 equiv) and warming of the reaction mixture
to 50 °C (Table 1, entry 1). These conditions provided the Next, we investigated analogous HWE reactions of isomeric
expected 5a in good GCMS yield and high E/Z selectivity, but phosphonate 4 with various aldehydes. Good yields of products
called for rather long reaction time. By changing the solvent 6 were obtained with both aromatic and aliphatic aldehydes. In
from DMF to THF, we observed a less efficient first step (the contrast to most of the reactions with 3, phosphonate 4 gave
VNS reaction) with many unidentified side products being exclusively E-isomers of 6 (Table 3). This improved selectivity
formed (Table 1, entry 2). Therefore, all other experiments were can be explained by relative differences in the stabilities and
Scheme 1: Proposed synthesis of alkenyl-(pentafluorosulfanyl)benzenes.
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Beilstein J. Org. Chem. 2012, 8, 1185–1190.
Table 1: Optimization of HWE reaction of phosphonate 3 with benzaldehyde.
Entry
Base (equiv)
Solvent
T (°C)
t (min)
5a, Yield (%)a
E/Zb
1c
2c
3
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (1.8)
t-BuOK (1.3)
n-BuLi (2.0)
LiHMDS (2.0)
K2CO3 (3.0)
Cs2CO3 (1.8)
KOH (1.3)
DMF
THF
50
50
50
50
50
rt
960
120
240
60
83
97:3
>98:2
95:5
94:6
95:5
92:8
92:8
91:9
93:7
95:5
95:5
97:3
98:2
58
THF
98
4
THF
98
5
THF
60
94 (68)
93
6
THF
30
7
THF
rt
60
59
8
MeCN
MeCN
THF
60
rt
960
360
7
81
9
97
10
11
12
13
rt
89
KOH (1.9)
THF
rt
7
92
KOH (1.8)
MeCN
MeCNd
rt
60
90 (67)
98 (84)
KOH (1.8)
rt
30
aDetermined by GCMS analysis (in brackets isolated yield). bDetermined by GCMS analysis of the crude reaction mixture. cPhosphonate 3 was
prepared in situ from 1 and diethyl chloromethylphosphonate (−60 °C, 10 min). dWater (8 equiv) was added.
Table 2: HWE reactions of phosphonate 3 with aldehydes.
Table 3: HWE reactions of phosphonate 4 with aldehydes.
Entry R (equiv)
t (min) 5, Yield (%)a 5, E/Zb
Entry R (equiv)
t (min)
6, Yield (%)a
1
2
3
4
5
6
7
Ph (1.5)
30
5
5a, 84
5b, 84
5c, 85
5d, 86
5e, 80
5f, 43c
5g, 67
98:2
>99:1
98:2
99:1
92:8
93:7d
94:6
1
2
3
4
4-NO2C6H4 (1.2)
30
6b, 97
6c, 85
6d, 76
6h, 84
4-NO2C6H4 (1.7)
4-ClC6H4 (1.1)
4-MeOC6H4 (1.5)
1-Naphthyl (1.2)
4-ClC6H4 (1.1)
4-MeOC6H4 (1.1)
n-C6H13 (1.1)
80
30
90
30
260
90
aIsolated yield.
(E)-PhCH=CH (1.2) 40
Et (1.5) 90
aIsolated yield refers to the pure E-isomer unless noted otherwise.
bDetermined by GCMS analysis of the crude reaction mixture.
cIsolated yield referring to the 93:7 E/Z mixture. dThis ratio changed to
66:33 upon storage in CDCl3 solution at rt for 10 d.
mediates B and B’ giving Z-alkene (Scheme 2). In our reac-
tions, the stabilization of the negative charge in the deproto-
nated phosphonate is higher for 4 than for 3 due to conjugation
of the negative charge with the SF5 group in the former case
reactivities of carbanions derived from phosphonates and reac- (σI(SF5) = 0.55, σR(SF5) = 0.11 [5]). Consequently, 4− is more
tive intermediates. In reactions of phosphoryl-stabilized carban- stable and less nucleophilic than 3−, and therefore, in compari-
ions with aldehydes, several intermediates are formed son to the A-to-B equilibrium the A’-to-B’ equilibrium is
reversibly. Less-hindered intermediates A and A’, which elimi- shifted more towards A’ providing only (E)-6 product
nate to E-alkene, exist in equilibrium with more-hindered inter- (Scheme 2).
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Beilstein J. Org. Chem. 2012, 8, 1185–1190.
Scheme 2: Reactive intermediates involved in HWE reactions to alkenes 5 and 6.
To demonstrate the versatility of this methodology leading to
Table 4: Hydrogenation of stilbene derivatives 5 and 6.
new carbon-substituted SF5-benzenes, several transformations
of primary products 5 and 6 were performed. Reduction with
hydrogen (1 atm) in the presence of catalytic Raney nickel did
not provide full conversion to the respective anilines. Further-
more, the reaction mixtures contained products 7 and 8. At
higher pressure (20 atm), complete nitro group and C=C reduc-
tion of stilbenes 5 and 6 to compounds 7 and 8, respectively,
took place (Table 4). Several other conditions were tested, but
no system for selective reduction of the nitro group was found.
Entry 5 or 6
X
Y
H
R
7 or 8, Yield (%)a
1
2
3
5a
6c
6d
SF5
H
Ph
7a, 87
8c, 64
SF5 4-ClC6H4
H
SF5 4-MeOC6H4 8d, 82
Diazotization was carried out with the aim to prepare 1,2-
diarylethane 9d from aniline 8d (Scheme 3). A combination of
sodium nitrite and phosphoric acid was used. (With HCl, substi-
tution of the amino function by a chlorine atom was observed,
aIsolated yield.
and the use of H2SO4 resulted in low solubility of the formed substituted phenyl cation intermediate (formed by the decompo-
anilinium in water.) An ether cosolvent (Et2O or t-BuOMe) im- sition of the diazonium salt), to the electron-rich anisole ring in
proved the yield compared to aqueous or aqueous/THF an unusual meta-position relative to the methoxy group. The
mixtures. The presence of reducing hypophosphorous acid more activated para-position is unavailable, and the reaction in
provided a mixture of the expected 9d and the cyclized product ortho-positions would give too strained a product. The forma-
10d resulting from electrophilic aromatic substitution of the tion of the cyclized side product is not restricted to compounds
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Beilstein J. Org. Chem. 2012, 8, 1185–1190.
Scheme 3: Diazotization/reduction of 8d to 9d and the formation of unexpected cyclized product 10d.
with an electron-donor substituent on the aromatic ring. Simi- nate 4 was removed by a reduction/diazotization/reduction
larly to 8d, the cyclic product was detected by GCMS in diazo- sequence to give phosphonate 12 in good yield. The following
tization of compound 8c (product not isolated). Compound 10d HWE reaction with 4-methoxybenzaldehyde afforded 13d in
was fully characterized by spectroscopic methods, and the yield good yield, exclusively as the E-isomer.
was increased to 51% by performing the diazotization reaction
in the absence of a reducing reagent (Scheme 3). Aromatization Conclusion
of 10d by oxidation using CAN was performed to give SF5- In conclusion, we have shown access to (E)-2-nitro-1-alkenyl-
substituted phenanthrene 11d in good yield (Scheme 4).
(pentafluorosulfanyl)benzenes from nitro-(pentafluoro-
sulfonyl)benzenes by VNS reaction with diethyl chloromethyl-
phosphonate followed by stereoselective HWE reaction with
aldehydes. Reduction of (E)-2-nitro-1-alkenyl-(pentafluorosul-
fanyl)benzenes provided 2-(2-arylethyl)-(pentafluoro-
sulfanyl)anilines, and the formation of (E)-1-alkenyl-4-(penta-
fluorosulfanyl)benzenes was demonstrated from diethyl
4-(pentafluorosulfanyl)benzylphosphonates.
Supporting Information
Scheme 4: Synthesis of substituted phenanthrene 11d.
Supporting Information File 1
Experimental details and characterization data for all new
compounds.
To avoid problems with alkene reduction and electrophilic
aromatic substitution during nitro group removal, we decided to
try a different approach to the general synthesis of SF5-
containing stilbene derivatives, as demonstrated in the syn-
thesis of 13d shown in Scheme 5. The nitro group in phospho-
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-131-S1.pdf]
Scheme 5: Synthesis of phosphonate 12 and SF5-stilbene derivative 13d.
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Beilstein J. Org. Chem. 2012, 8, 1185–1190.
21.Kirsch, P.; Bremer, M.; Heckmeier, M.; Tarumi, K.
Acknowledgements
This work was financially supported by the Academy of
Sciences of the Czech Republic (RVO: 61388963) and by the
Grant Agency of the Czech Republic (P207/12/0072).
Angew. Chem., Int. Ed. 1999, 38, 1989–1992.
doi:10.1002/(SICI)1521-3773(19990712)38:13/14<1989::AID-ANIE198
9>3.0.CO;2-K
22.Sheppard, W. A. J. Am. Chem. Soc. 1962, 84, 3064–3072.
doi:10.1021/ja00875a006
23.Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927.
doi:10.1021/cr00094a007
References
1. Case, J. R.; Ray, N. H.; Roberts, H. L. J. Chem. Soc. 1961,
24.Boutagy, J.; Thomas, R. Chem. Rev. 1974, 74, 87–99.
doi:10.1021/cr60287a005
2066–2070. doi:10.1039/JR9610002066
2. Ray, N. H. J. Chem. Soc. 1963, 1440–1441.
25.Rein, T.; Pedersen, T. M. Synthesis 2002, 579–594.
doi:10.1055/s-2002-23535
doi:10.1039/JR9630001440
3. Merrill, C. I.; Cady, G. H. J. Am. Chem. Soc. 1961, 83, 298–300.
doi:10.1021/ja01463a011
26.Ando, K. J. Synth. Org. Chem., Jpn. 2000, 58, 869–876.
27.Ando, K. J. Org. Chem. 1997, 62, 1934–1939. doi:10.1021/jo970057c
28.Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–4408.
doi:10.1016/S0040-4039(00)85909-2
4. Dudley, F. B.; Cady, G. H.; Eggers, D. F., Jr. J. Am. Chem. Soc. 1956,
78, 1553–1557. doi:10.1021/ja01589a013
5. Kirsch, P. Synthesis of complex Organofluorine Compounds. Modern
Fluoroorganic Chemistry; Wiley-VCH: Weinheim, Germany, 2004;
pp 146–156. doi:10.1002/352760393X.ch2
6. Winter, R. W.; Dodean, R. A.; Gard, G. L. SF5-Synthons: Pathways to
Organic Derivatives of SF6. In Fluorine-Containing Synthons;
Soloshonok, V. A., Ed.; ACS Symposium Series, Vol. 911; American
Chemical Society: Washington, DC, 2005; pp 87–118.
doi:10.1021/bk-2005-0911.ch004
License and Terms
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Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
7. Kirsch, P.; Röschenthaler, G.-V. Functional Compounds Based on
Hypervalent Sulfur Fluorides. In Current Fluoroorganic Chemistry;
Soloshonok, V. A.; Mikami, K.; Yamazaki, T.; Welch, J. T.; Honek, J. F.,
Eds.; ACS Symposium Series, Vol. 949; American Chemical Society:
Washington, DC, 2007; pp 221–243. doi:10.1021/bk-2007-0949.ch013
8. Aït-Mohand, S.; Dolbier, W. R., Jr. Org. Lett. 2002, 4, 3013–3015.
doi:10.1021/ol026483o
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
9. Dolbier, W. R., Jr.; Aït-Mohand, S.; Schertz, T. D.; Sergeeva, T. A.;
Cradlebaugh, J. A.; Mitani, A.; Gard, G. L.; Winter, R. W.;
Thrasher, J. S. J. Fluorine Chem. 2006, 127, 1302–1310.
doi:10.1016/j.jfluchem.2006.05.003
The definitive version of this article is the electronic one
which can be found at:
10.Bowden, R. D.; Greenhall, M. P.; Moilliet, J. S.; Thomson, J. The
Preparation Of Fluorinated Organic Compounds. WO Patent
WO1997005106, Feb 13, 1997.
doi:10.3762/bjoc.8.131
11.Bowden, R. D.; Comina, P. J.; Greenhall, M. P.; Kariuki, B. M.;
Loveday, A.; Philp, D. Tetrahedron 2000, 56, 3399–3408.
doi:10.1016/S0040-4020(00)00184-8
12.Chambers, R. D.; Spink, R. C. H. Chem. Commun. 1999, 883–884.
doi:10.1039/A901473J
13.Umemoto, T.; Garrick, L. M.; Saito, N. Beilstein J. Org. Chem. 2012, 8,
461–471. doi:10.3762/bjoc.8.53
14.Umemoto, T.; Chika, J. Processes for preparing
1,3-dinitro-5-(pentafluorosulfanyl)benzene and its intermediates. U.S.
Patent Appl. 2011/0301382 A1, Dec 8, 2011.
15.Beier, P.; Pastýříková, T.; Vida, N.; Iakobson, G. Org. Lett. 2011, 13,
1466–1469. doi:10.1021/ol2001478
16.Beier, P.; Pastýříková, T.; Iakobson, G. J. Org. Chem. 2011, 76,
4781–4786. doi:10.1021/jo200618p
17.Beier, P.; Pastýříková, T. Tetrahedron Lett. 2011, 52, 4392–4394.
doi:10.1016/j.tetlet.2011.06.011
18.Pastýříková, T.; Iakobson, G.; Vida, N.; Pohl, R.; Beier, P.
Eur. J. Org. Chem. 2012, 2123–2126. doi:10.1002/ejoc.201200127
19.Vida, N.; Beier, P. J. Fluorine Chem., in press.
doi:10.1016/j.jfluchem.2012.04.001
20.Crowley, P. J.; Mitchell, G.; Salmon, R.; Worthington, P. A. Chimia
2004, 58, 138–142.
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