Structural reevaluation of the electrophilic hypervalent iodine reagent for trifluoromethylthiolation supported by the crystalline sponge method for x-ray analysis

Article abstract of DOI:10.1002/anie.201310897

Hypervalent iodine λ³-benziodoxoles are common electrophilic transfer reagents known for their enhanced stability compared to their non-cyclic analogues. Herein we present data showing that chlorobenziodoxole reacts with two different thiolate nucleophiles (thiocyanate and trifluoromethylthiolate), resulting in the formation of stable thioperoxy complexes rather than the expected benziodoxole derivatives. We further report a revised structure for the earlier described electrophilic trifluoromethylthiolation reagent (1), which was previously believed to contain the benziodoxole framework. Our findings, which are based on a combination of analytical techniques, including the recently introduced crystalline sponge method for X-ray analysis, unambiguously demonstrate that 1 is a thioperoxy compound both in solution and the solid state. Not-so-hypervalent iodine: Studies of several benziodoxole thiolate derivatives revealed that these species lack the hypervalent iodine motif, instead adopting a thioperoxide configuration. Crystallographic analysis of a liquid trifluoromethylthiolation reagent trapped inside a metal-organic framework provided direct structural proof for the observed phenomenon. These thioperoxide reagents were also shown to be reactive in electrophilic substitution reactions.

Full text of DOI:10.1002/anie.201310897

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DOI: 10.1002/anie.201310897
Hypervalent Iodine Reagents Very Important Paper
Structural Reevaluation of the Electrophilic Hypervalent Iodine
Reagent for Trifluoromethylthiolation Supported by the Crystalline
Sponge Method for X-ray Analysis**
Ekaterina V. Vinogradova, Peter Mꢀller, and Stephen L. Buchwald*
Abstract: Hypervalent iodine l3-benziodoxoles are common
electrophilic transfer reagents known for their enhanced
stability compared to their non-cyclic analogues. Herein we
present data showing that chlorobenziodoxole reacts with two
different thiolate nucleophiles (thiocyanate and trifluorome-
thylthiolate), resulting in the formation of stable thioperoxy
complexes rather than the expected benziodoxole derivatives.
We further report a revised structure for the earlier described
electrophilic trifluoromethylthiolation reagent (1), which was
previously believed to contain the benziodoxole framework.
Our findings, which are based on a combination of analytical
techniques, including the recently introduced crystalline sponge
method for X-ray analysis, unambiguously demonstrate that
1 is a thioperoxy compound both in solution and the solid state.
Figure 1. The reported structure of the reagent for electrophilic trifluor-
omethylthiolation (1) recently introduced by Shen et al., and represen-
tative examples of other reported benziodoxole-based hypervalent
iodine transfer reagents.
(oxygen or sulfur) nucleophilic sites. Indeed, when 3 was
treated with silver cyanate, a mixture of isomeric 1-cyanato-
benziodoxoles was obtained, with the major product arising
from reaction at the nitrogen atom (4; Scheme 1a). In
contrast, the reaction of 3 with silver thiocyanate yielded
a single compound that did not contain the expected
benziodoxole scaffold (5; Scheme 1b). As shown in
Scheme 1, the single crystal X-ray analysis of compound 5
revealed that the thiocyanate-group was S-bound to the
oxygen atom of 2 rather than to the iodine.[11,12]
R
ecently, Shen et al. introduced a new hypervalent iodine
reagent for the transfer of an electrophilic trifluoromethyl-
sulfur group (Figure 1, 1).[1] Compound 1 was isolated as
a colorless liquid and characterized by 1H, 13C, and 19F NMR
spectroscopy, as well as elemental analysis. Based on these
data, Shen proposed that 1 contains the sulfur-bound hyper-
valent iodine motif, similar to all previously reported
benziodoxole and benziodoxolone transfer reagents
(Figure 1).[2–9]
Intrigued by this result, we conducted a brief comparison
1
of the H NMR spectra of the benziodoxoles and 2-iodoben-
As part of our work on the synthesis of aryl isocyanates,[10]
we were interested in developing new reagents based on the
benziodoxole motif for isocyanate and isothiocyanate group
transfer chemistry. We anticipated that the ambidentate
cyanate and thiocyanate nucleophiles could potentially react
with reagent 3 at either the nitrogen or group 16 element
zyl alcohol-derivatives that are shown in Figure 2. We found
that the two compound classes (closed benziodoxole vs. open
benzyl alcohol) generally display different characteristic
signals in the aromatic region. Most notably, the aromatic
protons that are para to the alkyl group (Hb) exhibited
significant (0.5 ppm or greater) downfield shifts in the closed
[*] E. V. Vinogradova, Dr. P. Mꢀller, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490, Massachusetts Institute of
Technology, Cambridge, MA 02139 (USA)
E-mail: sbuchwal@mit.edu
[**] Research reported in this publication was supported by the National
Institute of Health under award number GM58160. The depart-
mental X-ray diffraction instrumentation was purchased with the
help of funding from the National Science Foundation (CHE-
0946721). We are grateful to Dr. Stacey J. Smith for help in obtaining
crystal structures of compounds 4 and 5. We thank Dr. Alex M.
Spokoyny and Dr. Katrin Niedermann for helpful discussions, and
Dr. Alex M. Spokoyny, Dr. Sean M. Smith and Dr. Nathan T. Jui for
help with preparing this manuscript. We would also like to
acknowledge a reviewer for drawing our attention to reference [13]
and the use of 13C NMR spectroscopy as a diagnostic tool for the
structural elucidation of 1. The content is solely the responsibility of
the authors and does not necessarily represent the official views of
the National Institutes of Health.
Scheme 1. Synthesis of novel electrophilic transfer reagents and crystal
structures of reagents 4 and 5. Thermal ellipsoid plots are drawn at
50% probability, hydrogen atoms are omitted for clarity.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310897.
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Scheme 2. Synthesis of a solid trifluoromethylthiolation reagent and
the crystal structure of reagent 6. Thermal ellipsoid plot is drawn at
50% probability, hydrogen atoms are omitted for clarity. Reaction
conditions: a) Ar’I (1 equiv), ArB(OH)2 (1.5 equiv), Pd(OAc)2
(2 mol%), SPhos (4 mol%), K3PO4 (2 equiv), toluene, 1108C, 18 h;
b) pTsOH (3 equiv), CH3CN, then KI (2.5 equiv), NaNO2 (2 equiv),
H2O, 5 h; c) MeMgBr (4 equiv), Et2O, 408C, 5 h; d) tBuOCl (4 equiv),
THF/CH2Cl2 (2:1), 2 h; e) AgSCF3 (1 equiv), THF, 508C, 1 h. pTsOH=
para-toluenesulfonic acid, SPhos=2-dicyclohexylphosphino-2’,6’-dime-
thoxy-1,1’-biphenyl.
1
Figure 2. Comparison of the aromatic region of the H NMR spectra of
hypervalent-iodine-based transfer reagents and novel thioperoxide
reagents.
compounds (Figure 2a,b) when compared to the open ones
(Figure 2c,d). As described above, the sulfur-based nucleo-
phile afforded the corresponding open compound (Figure 2d)
with complete selectivity, which is in contrast to the reported
benziodoxole structure of the related trifluoromethylthiola-
tion reagent 1. Compound 1 was synthesized according to the
literature procedure[1a] and exhibited identical spectral prop-
erties to those reported. To our surprise, the 1H NMR
spectrum of 1 (Figure 2e) resembles those of the open-form
compounds more closely than the spectra of the closed-form
ones, suggesting that 1 could potentially exist as the open
thioperoxy compound rather than the benziodoxole. The
oxidation state of iodine in 1, 5, and 6 as II in solution was
further corroborated by 13C NMR spectroscopy, as outlined
previously by Katritzky et al.[13]
To further evaluate the structure of the Shen reagent, we
undertook two parallel studies that would allow us to obtain
X-ray crystallographic structural data.[14,15] We first sought to
prepare a solid analogue of the trifluoromethylthio-transfer
reagent. According to the route outlined in Scheme 2, we
were able to construct a modified reagent 6 that contained the
dichlorotrimethoxyphenyl substituent at C4 of the phenyl
ring. This new reagent displayed the characteristic aromatic
1H NMR signal that indicated a compound that did not
contain the benziodoxole scaffold (Figure 2 f). X-ray diffrac-
tion analysis of single crystals of 6 provided unequivocal
structural evidence that the SCF3 group is bound to oxygen
rather than to iodine (Scheme 2).
Scheme 3. Representative reactions of reagents 1 and 6 with b-
ketoesters (a) and arylboronic acids (b). For detailed reaction con-
ditions, see: Ref. [1a] and the Supporting Information. DMAP=N,N-
dimethylaminopyridine.
Although it is possible that there exists a Curtin–Hammet
scenario where both forms of the reagent exist in equilibrium
in solution and the reactivity arises from the hypervalent
iodine structure, no evidence for such an equilibrium was
observed by 1H or 19F NMR spectroscopy, even at low
temperatures (À808C). Furthermore, the similarity of the
thioperoxide structure to the previously reported nitrogen-
based electrophilic trifluoromethylthiolation reagents by the
groups of Billard[16] and Rueping[17] (Scheme 4a and b), as
well as the disulfide reagents used for directed Cu-promoted
2
[18]
À
sulfenylation of sp C H bonds by Daugulis et al. (Sche-
me 4c) supports the hypothesis that the observed reactivi-
ty[1a,c] could arise from the thioperoxide fragment itself.
To evaluate the potential steric and electronic effects that
installation of the functionalized aromatic substituent could
impart to the reagent, we compared the reactivity of 6 and 1 in
previously reported SCF3-transfer reactions. Under the opti-
mized conditions reported by Shen et al. for b-ketoester-
(Scheme 3a) or Cu-catalyzed arylboronic acid trifluorome-
thylthiolation (Scheme 3b),[1a] the two reagents displayed
nearly identical reactivity profiles (Scheme 3).
Scheme 4. Trifluoromethylthiolation reagents reported by the goups of
Billard (a), Rueping (b), and Daugulis (c).
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Wang, T. Yang, X. Cheng, Q. Shen, Angew. Chem. 2013, 125,
Fujita recently introduced a new method for the structure
determination of liquid compounds trapped in the pores of
a host metal organic framework (MOF).[19] We were inter-
ested in applying this method to gain access to the X-ray
structure of the parent reagent 1. The MOF material was
prepared by slow diffusion of a solution of ZnI2 in methanol
into the solution of 2,4,6-tri(4-pyridyl)-1,3,5-triazine in a mix-
ture of nitrobenzene and methanol. Soaking the resulting
crystals in cyclohexane at 508C for two weeks (used solvent
was replaced by fresh solvent each day) allowed for the
majority of nitrobenzene in the pores of the MOF to be
13098 – 13102; Angew. Chem. Int. Ed. 2013, 52, 12860 – 12864;
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[2] Reviews on benziodoxole and benziodoxolone reagents: a) V. V.
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[3] Benziodoxole and benziodoxolone reagents have gained partic-
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iodine analogues; see: a) M. Ochiai, T. Ito, Y. Masaki, M. Shiro,
J. Am. Chem. Soc. 1992, 114, 6269 – 6270; b) M. Ochiai, T. Sueda,
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exchanged with more labile cyclohexane molecules.[20]
A
consecutive soak of the crystals in the analyte provided X-ray
quality crystals of the host–guest complex 1@MOF. Subse-
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refinement techniques[21] revealed the presence of 92% of
reagent 1 per asymmetric unit of the crystal structure of
1@MOF, disordered over three crystallographically inde-
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shown in Scheme 5, the crystallographically-derived structure
of 1 does not contain the benziodoxole fragment, and the
SCF3-group is bound to the oxygen atom.
[5] For hypervalent iodine cyano group transfer reagents, see: V. V.
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Frei, J. Waser, J. Am. Chem. Soc. 2013, 135, 9620 – 9623; e) Y. Li,
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Gonzꢀlez, J. P. Brand, R. Mondiꢂre, J. Waser, Adv. Synth. Catal.
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Scheme 5. Crystal structure of the guest molecule 1 observed in the
cavities of the MOF. Thermal ellipsoid plot is drawn at 50%
probability, hydrogen atoms are omitted for clarity.
In summary, we have discovered that the reaction of
chlorobenziodoxole with two sulfur-containing nucleophiles
leads to the formation of rearranged products containing
stable thioperoxy groups. A combination of spectroscopic
techniques, derivatization experiments, and the crystalline
sponge method recently introduced by Fujita et al.,[19] allowed
for unambiguous confirmation of the open form thioperoxide
structure of the recently reported trifluoromethylthiolation
reagent 1, both in solution and in the solid state at room
temperature. Importantly, whereas these results do not affect
the chemical reactivity studies utilizing reagent 1, as recently
reported by Shen and co-workers,[1a] they do suggest that
other mechanistic pathways for electrophilic trifluorome-
thylthiolation are possible.[1c]
[7] For hypervalent iodine fluorine atom transfer reagents, see:
G. C. Geary, E. G. Hope, K. Singh, A. M. Stuart, Chem.
Commun. 2013, 49, 9263 – 9265.
[8] For hypervalent iodine difluoromethyl group transfer reagents,
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124, 4010 – 4013; Angew. Chem. Int. Ed. 2012, 51, 3944 – 3947.
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Zhdankin, A. P. Krasutsky, C. J. Kuehl, A. J. Simonsen, J. K.
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Soc. 2012, 134, 11132 – 11135; b) E. V. Vinogradova, N. H. Park,
B. P. Fors, S. L. Buchwald, Org. Lett. 2013, 15, 1394 – 1397.
[11] Although an exact mechanism for the formation of thioperoxide
species is not known, a plausible mechanism involves reductive
elimination from the intermediate hypervalent iodine species
facilitated by the strongly electron-withdrawing substituent on
the sulfur. Similar reactivity has been observed in reactions with
Togni reagents, where unreactive trifluoromethyl ethers and
esters were obtained as byproducts in the trifluoromethylations;
see: a) K. Niedermann, N. Frꢁh, R. Senn, B. Czarniecki, R.
Verel, A. Togni, Angew. Chem. 2012, 124, 6617 – 6621; Angew.
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shown to be accelerated by strongly Lewis and Brønsted acidic
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Received: December 16, 2013
Published online: February 14, 2014
Keywords: crystalline sponge crystallography ·
.
host-guest systems · hypervalent compounds · thioperoxides ·
trifluoromethylthiolation
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