Preparation and reactions of aliphatic 2-pentafluorosulfanyl aldehydes

Article abstract of DOI:10.1002/ejoc.201200763

A facile preparation of aliphatic 2-pentafluorosulfanyl aldehydes is described. To investigate the utility of the aldehydes as synthetic building blocks, various transformations of the aldehydes were explored. The pentafluorosulfanyl group was stable under a variety of reaction conditions, and the pentafluorosulfanylated products were obtained in moderate to good yields in most cases. An efficient method to prepare aliphatic 2-pentafluorosulfanyl aldehydes was developed. An investigation of various aldehyde transformations showed that the pentafluorosulfanyl group was stable under a variety of reaction conditions, and the products were obtained in moderate to good yields. Copyright

Full text of DOI:10.1002/ejoc.201200763

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200763
Preparation and Reactions of Aliphatic 2-Pentafluorosulfanyl Aldehydes
Silvana C. Ngo,[a] Jin-Hong Lin,[a] Paul R. Savoie,[a] Erica M. Hines,[a]
Kaitlin M. Pugliese,[a] and John T. Welch*[a]
Keywords: Aldehydes / Diastereoselectivity / Grignard reaction / Oxidation / Conformation analysis
A facile preparation of aliphatic 2-pentafluorosulfanyl alde-
hydes is described. To investigate the utility of the aldehydes
as synthetic building blocks, various transformations of the
aldehydes were explored. The pentafluorosulfanyl group
was stable under a variety of reaction conditions, and the
pentafluorosulfanylated products were obtained in moderate
to good yields in most cases.
synthesis and the reactivity of these compounds are inter-
esting but still remain to be addressed.
Introduction
The growing importance of pentafluorosulfanylated aro-
matic compounds is demonstrated by their utility in liquid
crystalline displays,[1] in agrochemicals,[2] and in medicinal
chemistry.[3] To date, the chemistry of aliphatic penta-
fluorosulfanylated compounds has been much less well ex-
plored, in part, because of a paucity of available building
blocks or synthetic methods to construct these com-
pounds.[4] To address this shortcoming, a general synthesis
of pentafluorosulfanylated (SF5) aliphatic aldehydes was
developed and the reactivities of these materials were com-
pared with the corresponding trifluoromethylated analogs.
The preparation of SF5-containing aliphatics[4a] is princi-
pally effected by SF5X (X = Cl or Br) addition across mul-
tiple bonds. Case[5] first incorporated the SF5 group into
hydrocarbons by treating SF5Cl with olefins under free-rad-
ical conditions. Gard subsequently studied the addition of
SF5X to acrylates, allylic esters, and fluorinated alkenes by
using standard thermal and/or photochemical condi-
tions,[4a,6] but it was Dolbier’s utilization of triethylborane
to promote addition reactions of SF5X that was the crucial
advance in this chemistry.[4b,7]
By analogy to the addition of perfluoroalkyl iodide to
vinyl acetate,[8] Gard reported the successful addition of
SF5Cl and SF5Br to vinyl acetate under pressure.[4a,6a] The
conversion of chloroacetate 2a to parent aldehyde 3 was
successful, but the product usually exists as a hydrate.[9] In
the presence of powdered P4Ol0, trimer 4 formed readily
(Scheme 1).[10] However methanolysis of 2a led to forma-
tion of ketal 5 that was readily oxidized to methyl ester
6 (Scheme 2).[4b] Those are the only reports about the 2-
pentafluorosulfanylated aliphatic aldehydes. The general
Scheme 1. Synthesis of SF5-acetaldehyde.
Scheme 2. The oxidation of ketal 5.
Results and Discussion
We found that with Et3B initiation, SF5Br adds easily to
enol acetates, prepared by using either isopropenyl acetate
with p-toluensulfonic acid[11] or a mixture of potassium
acetate and acetic anhydride,[12] to form bromo-SF5-acet-
ates 8 as a 3:1 mixture of diastereomers (Scheme 3).
Scheme 3. Addition of SF5Br to enol acetates.
[a] Department of Chemistry, University at Albany, SUNY,
1440 Washington Ave., Albany, NY 12222, USA
E-mail: jwelch@albany.edu
SF5Br addition was effected quickly under mild condi-
tions (0 °C, 20 min).[4c] Formation of 8 was accompanied
by less than 10% of the ionic addition product of bromo-
Homepage: http://www.albany.edu/chemistry/jwelch.shtml
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200763.
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J. T. Welch et al.
SHORT COMMUNICATION
fluorination 8Ј. The attempted reactions of more hindered ous debromoacetylation during normal workup following
enol acetates such as that derived from isovaleraldehyde, or SF5Br addition; however, attempts at steam distillation of
of the enol acetate derived from phenylacetaldehyde, where the product under nonacidic conditions resulted in incom-
the intermediate cation formed by electrophilic addition can plete conversion into 9 (Scheme 4).[15] In contrast to the
be stabilized by the adjacent aromatic ring, primarily gave propensity of parent aldehyde 3 to trimerize,[10] the higher
the ionic addition products.
Pentafluorosulfanyl bromoacetates 8 were easily con- were subjected to additional transformations.
verted into dimethyl acetals 10 or hydrolyzed directly into Little has been reported about the reactions of SF5-con-
molecular weight aldehydes were easily handled and, thus,
α-SF5-aldehydes 9. Dimethyl acetals 10 resulting from heat- taining aldehydes, yet 9 underwent many of the common
ing under reflux with methanol can easily be hydrolyzed to reactions of aldehydes easily (Scheme 5). Reduction with
9 (Scheme 4).[13] Alternatively, direct hydrolysis of 8 by sodium borohydride gave the corresponding primary
using a mixture of hydrochloric acid and glacial acetic acid alcohols 11. The generally high yields of this process are
is efficient.[12] Attempts to use milder conditions with lith- indicative of the stability of the SF5 group to the reaction
ium halide or metal oxide salts were not effective.[14] The conditions.
lower yield of 2-pentafluorosulfanylpentanal 9a (Ͻ30%)
Nucleophilic addition to the carbonyl group by using
was attributed to mechanical losses as a result of the volatil- organolithium or Grignard reagents, as anticipated, gave
ity of the compound. There was evidence of some spontane- the corresponding alcohols 12 with high diastereoselectivity
(Ͼ99%). In contrast to decomposition that occurred upon
the exposure of aromatic SF5-compounds to n-butyllith-
ium,[16] the aliphatic SF5 group was observed to be quite
robust.
The addition of nonsterically demanding methyllithium
or vinylmagnesium bromide was highly diastereoselective;
only a single diastereomeric pair was observed by NMR
spectroscopy, or a diastereomer ratio of at least 20:1. By
analogy to the reactions of trifluoromethyl aldehydes such
as 3,3,3-trifluoropropanal, ul attack was predicted as with
B (Figure 1).[17] The ul attack was favored in reactions with
a nonsterically demanding nucleophile in only a 2.6:1 ra-
tio.[17] In reactions of 9b, addition to either conformation
Scheme 4. The preparation of aldehydes.
Scheme 5. Reactions of α-SF5-aldehydes.
2
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Preparation and Reactions of Aliphatic 2-Pentafluorosulfanyl Aldehydes
C or D of the α-SF5-aldehydes would lead to the same ul 6 is known.[4b] Unfortunately, the preparation of 2-halo-2-
stereochemical outcome. The remarkably large C–SF5 bond pentafluorosulfanyl carboxylic acids 16e and 16f by success-
dipole moment may contribute to the relative importance ive addition of SF5Cl to methoxy- or ethoxyethyne or pro-
of the Cornforth conformation[18] D in the additions and pyne followed by halogenation and hydrolysis (Figure 2)[19]
may amplify the diastereoselectivity of the process observed required either the use of pressure or low temperature pho-
in reactions of α-SF5-aldehydes 9.
tolysis. Those results were predicated on even earlier work
from the same group that involved hydrolysis of a SF5Cl
ketene adduct.[20] Surprisingly, attempts to effect oxidation
of 9 under mild conditions such as with the use of Ag2O[21]
gave no reaction. Fortunately, simple treatment with
KMnO4 or NH2SO3H/NaClO2 readily formed the corre-
sponding carboxylic acids 16a and 16c (Scheme 5).
Figure 2. 2-Halo-2-SF5-carboxylic acids.
Conclusions
An efficient method for the preparation of aliphatic 2-
pentafluorosulfanyl aldehydes was developed. Various
transformations of aldehydes proceeded smoothly to give
the products in moderate to good yields. The nucleophilic
addition to the carbonyl group showed excellent diastereo-
selectivity that can be readily rationalized. Peterson ole-
fination and Horner–Wadsworth–Emmons olefination af-
forded the alkene in moderate yields. The epoxidation of the
aldehyde with dimethylsulfonium ethoxycarbonlymethylide
also went well. With careful selection of the oxidant rea-
gent, the oxidation gave the product in excellent yield. Fur-
ther studies on the chemistry of aliphatic pentafluorosul-
fanylated compounds are currently underway.
Figure 1. Diastereoselectivity of addition to α-SF5-aldehydes.
The failure to observe coupling between Ha and Hb is
consistent with a product conformation where the Ha–Hb
torsional angle is near 90°. On this basis alone it is not
possible to establish the relative stereochemistry of the vinyl
alcohol. However, the clear evidence of a NOE between Hc
and the pentyl substituent is in accord with the proximity
of Hc to the first methylene of the pentyl chain in E. For
the product diastereomer to be lk diastereomer F¸ the experi-
mentally determined NOE and coupling requires the mole-
cule to assume a highly unfavorable conformation. The vi-
nyl group would be required to be simultaneously gauche to
both the SF5 group and the pentyl chain, a conformation
that also precludes the favorable hydroxy SF5 interaction.
The acidity of aldehyde 9 could be obviated by the care-
ful choice of the carbanion nucleophile. The addition of
trimethylsilylmethyllithium to 9c proceeds smoothly to yield
alcohol 12f (Scheme 5). Subsequent treatment of 12f with
BF3·OEt2 yielded olefin 13f. However the Wittig reagent,
methylene triphenylphosphane, gave no olefination reac-
tion, only products of decomposition. In contrast, the more
nucleophilic Horner–Wadsworth–Emmons reagent pre-
pared from triethyl phosphonoacetate reacted efficiently
and exclusively to form predicted E alkenes 14. Whereas
Supporting Information (see footnote on the first page of this arti-
cle): General procedures, characterization data, and NMR spectra
for compounds synthesized.
Acknowledgments
We acknowledge the support of the Donors of the American
Chemical Society Petroleum Research Fund (46219-AC4) and the
National Science Foundation (CHE0957544) for partial support of
this work.
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Received: June 7, 2012
Published Online: ᭿
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Preparation and Reactions of Aliphatic 2-Pentafluorosulfanyl Aldehydes
Aldehyde Tranformations
An efficient method to prepare aliphatic 2-
pentafluorosulfanyl aldehydes was devel-
oped. An investigation of various aldehyde
transformations showed that the penta-
fluorosulfanyl group was stable under a
variety of reaction conditions, and the
products were obtained in moderate to
good yields.
S. C. Ngo, J.-H. Lin, P. R. Savoie,
E. M. Hines, K. M. Pugliese,
J. T. Welch* ...................................... 1–5
Preparation and Reactions of Aliphatic 2-
Pentafluorosulfanyl Aldehydes
Keywords: Aldehydes / Diastereoselectiv-
ity / Grignard reaction / Oxidation / Con-
formation analysis
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