Synthesis of thiazolines by copper catalyzed aminobromination of thiohydroximic acids

Article abstract of DOI:10.1021/ol500588v

A copper catalyzed aminobromination of alkene tethered thiohydroximic acids is described, providing a rapid approach to unnatural thiazoline scaffolds not readily available via existing methods. Moderate to high yields of bromothiazolines are obtained with alkyl- and aryl-substituted thiohydroximic acid building blocks containing mono-, di-, and trisubstituted alkenes. The reaction provides high levels of 5-exo selectivity, and terminally monosubstituted alkenes result in predominant syn-diastereoselectivity.

Full text of DOI:10.1021/ol500588v

Letter
pubs.acs.org/OrgLett
Synthesis of Thiazolines by Copper Catalyzed Aminobromination of
Thiohydroximic Acids
Berenice C. Lemercier and Joshua G. Pierce*
́
́
Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695, United States
S
* Supporting Information
ABSTRACT: A copper catalyzed aminobromination of alkene
tethered thiohydroximic acids is described, providing a rapid
approach to unnatural thiazoline scaffolds not readily available
via existing methods. Moderate to high yields of bromothiazo-
lines are obtained with alkyl- and aryl-substituted thiohydroxi-
mic acid building blocks containing mono-, di-, and trisubstituted alkenes. The reaction provides high levels of 5-exo selectivity,
and terminally monosubstituted alkenes result in predominant syn-diastereoselectivity.
hiazolines are important heterocycles present in many
natural products and biologically active compounds such
form amidinyl radicals that cyclize to form imidazoline
derivatives.9 Building on this precedent we began an
exploration into the copper-catalyzed10 aminobromination of
thiohydroximic acids to prepare thiazolines.
Thiohydroximic acid derivatives were prepared in a two-step,
one-pot process via S-alkylation/O-acylation of the correspond-
ing thiohydroxamic acids.11 With these building blocks in hand
we began exploring their reactivity in copper catalyzed
aminobromination reactions (Table 1). Initially we chose to
T
as curacin A,1 an antimitotic agent; largazole,2 an HDAC
inhibitor; and bacitracin A,3 an antibiotic used in topical
ointments and in animal feed. Moreover, thiazoline-containing
natural products are found in aromas, flavors, and luminescent
molecules such as D-luciferin, which is responsible for the
bioluminescence of fireflies. The D-luciferin/luciferase system
and analogues have been extensively studied and used for in
vivo imaging.4 Thiazolines have also been used as chiral ligands
for asymmetric catalysis and chiral ionic liquids as their
thiazolidinium salts.5 Due to their importance in numerous
fields of research, many synthetic efforts have been devoted
toward their synthesis.6 Common methods for thiazoline
synthesis employ β-amino alcohol or β-amino thiol derivatives
as starting materials, and these approaches are straightforward
when the required alcohol or thiol is readily available. However,
further substitution at the 4-position and compounds not
arising from natural amino acids require multistep preparation
of the required amino-alcohols or are prepared through
alkylation of simpler derivatives7 (Figure 1). Therefore novel
methods to access substituted thiazolines in a rapid and
stereoselective fashion are needed.
Table 1. Optimization of the Aminobromination Reaction
a
b
c
c
no.
R
conditions
2 (%)
3 (%)
1
2
3
4
5
6
7
8
Me (1a)
Bz (1b)
Bz
LiBr (3 equiv), dioxane, 24 h
LiBr (3 equiv), dioxane, 3 h
dioxane, 3 h
−
23
−
3
3
−
−
6
Bz
LiOBz (3 equiv), dioxane, 3 h
LiBr (3 equiv), dioxane, 45 min
LiBr (3 equiv), toluene, 4 h
LiBr (3 equiv), DCE, 24 h
−
BzF (1c)
BzF
27
21
27
52
21
18
12
BzF
d
BzF
LiBr (3 equiv), dioxane, 6 h
a
b
Bz = benzoyl; BzF = pentafluorobenzoyl. Performed at 80 °C on a
c
d
50 mg scale. Isolated yields. Performed at 40 °C.
employ the disubstituted alkene derivative 1 (a−c) since this
substrate would represent a difficult compound for the
proposed reaction due to a competing 6-endo cyclization
pathway. Employing copper(I) bromide dimethylsulfide as our
catalyst, we screened N−O bond activating groups (R, Table
1), additives, solvents, and temperatures. Although methyl
substituted derivatives proved unreactive (entry 1, Table 1)
Figure 1. Approaches to thiazoline synthesis.
As part of our program to investigate the synthetic utility of
thiohydroxamic acids and their derivatives as synthetic building
blocks, we envisioned employing thiohydroximic acids to form
thiazolines via intramolecular amination. Oxime derivatives
have been shown to form iminyl radicals that readily cyclize
onto an appended alkene to generate dihydropyrrole
derivatives.8 Amidine derivatives have also been shown to
Received: February 24, 2014
Published: March 19, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
both benzoyl (entry 2, Table 1) and pentafluorobenzoyl
(entries 5−8, Table 1) proved to effectively activate the N−O
bond for cleavage, with the pentafluoro compounds allowing
for remarkably mild reaction conditions (entry 8, Table 1).12,13
The addition of lithium bromide proved critical for turnover of
the catalyst and dioxane was the solvent of choice, paralleling
the optimized conditions for oxime cyclizations.8b Significant
improvement was achieved by conducting the reaction at 40 °C
(vs 80 °C), and reaction yields generally were improved on
scale (>200 mg) to provide 2 in 50% yield (entry 8, Table 1)
with 12% of the six-membered compound being formed under
these conditions. We felt that compound 2 served as a rigorous
test of this chemistry and were gratified to observe a successful
reaction with thiohydroximic acid 1c.14
Table 3. Scope of Thiohydroximic Acid Substitution
With optimized conditions in hand we explored the substrate
scope of the alkene group (Table 2). Subjection of
Table 2. Scope of Alkene Substitution
a
b
10:1 inseparable mixture with thiazole. Single diastereomer.
heteroaromatic (15 and 16, Table 3) groups smoothly
underwent cyclization and provided bromothiazoline products
in good yields. Of particular interest is the excellent yield for
thiazole−thiazoline product 15 due to the frequent incorpo-
ration of this motif in bioactive natural products.2,18 In addition
to heteroaromatic products, p-bromophenyl derivative 17
underwent aminobromination in excellent yield.
Finally, we evaluated the feasibility of further functionaliza-
tion of the bromothiazoline products. Subjection of 2 to
sodium azide, allylthiol, or potassium cyanide provided the
corresponding substitution products in moderate to excellent
yields (18−20, Scheme 1). These reactions highlight the
versatility of the thiazoline products and provide access to
molecules with handles for further derivatization.
Scheme 1. Substitution of Bromothiazoline 2
a
b
c
2:1 mixture of diastereomers. Single diastereomer (X-ray). One
d
e
diastereomer. 6.7:1 mixture of diastereomers. 10:1 inseparable
mixture with thiazole. Slow decomposition of SM was observed.
f
thiohydroximic acids 4a−g to the copper(I) conditions
provided a range of substituted thiazolines in moderate to
high yields.15 Terminally monosubstituted alkenes provided a
high level of cis-diastereoselectivity (5−8, Table 2), which was
confirmed by X-ray analysis of compound 6 (see Supporting
Information). The high syn-diastereoselectivity observed in this
reaction points to a mechanism in which copper remains
coordinated to the iminyl radical and alkene partner to deliver
the bromide from the same face.16 Thiohydroximic acids
bearing alkene (7), ester (8), and TMS (10) substituents were
well tolerated to provide functionalized thiazoline products
poised for further derivatization. Unfortunately, the substrate
bearing an ester substituent at the R1 position did not yield the
desired thiazoline 11 even under forcing conditions.17
In conclusion, we have developed a new synthesis of
thiazolines bearing a range of functional groups in good yields
and diastereoselectivities. These initial studies on thiohydroxi-
mic acids demonstrate their potential as building blocks in
organic synthesis. Furthermore, the bromothiazoline products
are useful compounds for both medicinal and materials
applications. Further explorations into the potential of
thiohydroxamic acids as reagents for heterocycle construction,
optimization of the copper-catalyzed aminobromination
Variation of the thiohydroximic acid substituent was then
explored (Table 3). Both aliphatic (13 and 14, Table 3) and
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Letter
1994, 35, 249. For a related example of an amino-radical, see: Noack,
reaction, and development of an asymmetric process will be
reported in due course.
M.; Gottlich, R. Chem. Commun. 2002, 536.
̈
(9) (a) Gennet, D.; Zard, S. Z.; Zhang, H. Chem. Commun. 2003,
1870. (b) Sanjaya, S.; Chiba, S. Org. Lett. 2012, 14, 5342.
(10) Copper(I) has been shown to be efficient at cleaving activated
oximes to form iminyl radicals: (a) John, A.; Nicholas, K. M.
Organometallics 2012, 31, 7914. (b) Zard, S. Z. Chem. Soc. Rev. 2008,
37, 1603.
ASSOCIATED CONTENT
* Supporting Information
■
S
1
Experimental procedures, characterization of products, H and
13C NMR spectra, and the CIF file for 6 are provided. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(11) Lemercier, B. C.; Pierce, J. G. J. Org. Chem. 2014, 79, 2321.
(12) These reactions also progress slowly at room temperature,
providing similar yields and selectivities (24−48 h reaction times).
(13) Pentafluorobenzoate oximes are known to prevent competing
hydrolysis and Beckmann rearrangement: (a) Zaman, S.; Mitsuru, K.;
Abell, A. D. Org. Lett. 2005, 7, 609. (b) Tsutsui, H.; Kitamura, M.;
Narasaka, K. Bull. Chem. Soc. Jpn. 2002, 75, 1451.
(14) Thiohydroxamic and thiohydroximic acids have been reported
to have limited stability to both N−O bond activation and heating
(due to rearrangement processes). In our hands, we found these
compounds to be remarkably stable to all but the most forceful
conditions and bench stable for months.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jgpierce@ncsu.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(15) The lower yields of some bromothiazolines are a result of the
formation of byproducts such as thiazolines with a terminal alkene
derived from an elimination reaction and thiols derived from a
Beckmann rearrangement.
(16) The extent in which copper plays a role in the reaction after the
initial N−O bond cleavage has not been well studied (refs 8b and 9b).
This work represents the first use of internal alkenes in such iminyl-
type radical cyclizations to generate potential mixtures of diaster-
eomers.
■
We gratefully acknowledge North Carolina State University for
generous start-up support, and acknowledgement is made to
the Donors of the American Chemical Society Petroleum
Research Fund for partial support of this research. Mass spectra
were obtained at the Mass Spectrometry Laboratory at North
Carolina State University. We thank Dr. Roger Sommer
(NCSU) for X-ray crystallographic analysis of 6.
(17) In general, electron-withdrawing substituents at the internal
alkene position were not tolerated in this chemistry and electron-
deficient alkenes that were successful had a significantly slower
reaction rate. These results suggest an intermediate iminyl radical with
electrophilic character; for discussion, see: (a) Le Tadic-Biadatti, M.-
H.; Callier-Dublanchet, A.-C.; Horner, J. H.; Quiclet-Sire, B.; Zard, S.
Z.; Newcomb, M. J. Org. Chem. 1997, 62, 559. (b) Guindon, Y.;
Guerin, B.; Landry, S. R. Org. Lett. 2001, 3, 2293. (c) Chi, Y.-J.; Yu, H.-
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T. Comput. Theor. Chem. 2013, 1005, 75.
(18) (a) Carmeli, S.; Moore, R. E.; Patterson, G. M. L.; Corbett, T.
H.; Valeriote, F. A. J. Am. Chem. Soc. 1990, 112, 8195. (b) Jurkiewicz,
E.; Jansen, R.; Kunze, B.; Trowitzsch-Kienast, W. Antiviral Chem.
Chemother. 1992, 3, 189. (c) Jansen, R.; Kunze, B.; Reichenbach, H.;
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