Unclicking of thioureas: Base catalyzed elimination of anilines and isothiocyanates from thioureas

Article abstract of DOI:10.1016/j.tet.2019.02.035

Bisaromatic thioureas are widely used in e.g. asymmetric organocatalysis and considered to be robust compounds. Herein we show, in strong contrast to common notion, that thioureas dissociate to amines and isothiocyanates in a base catalyzed reaction under mild conditions. This ‘unclicking’ process can occur in the presence of weak organic bases even at moderate temperatures. The influence of the substituents at the aromatic rings of the thiourea on the regioselectivity of this unclicking process is also shown.

Full text of DOI:10.1016/j.tet.2019.02.035

Accepted Manuscript
Unclicking of thioureas: Base catalyzed elimination of anilines and isothiocyanates
from thioureas
Matea Vlatković, Ben L. Feringa
PII:
S0040-4020(19)30194-2
https://doi.org/10.1016/j.tet.2019.02.035
TET 30158
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 January 2019
Revised Date: 13 February 2019
Accepted Date: 15 February 2019
Please cite this article as: Vlatković M, Feringa BL, Unclicking of thioureas: Base catalyzed elimination
of anilines and isothiocyanates from thioureas, Tetrahedron (2019), doi: https://doi.org/10.1016/
j.tet.2019.02.035.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
Unclicking of thioureas: Base catalyzed
elimination of anilines and isothiocyanates
from thioureas
Leave this area blank for abstract info.
Matea Vlatkovića, Ben L. Feringaa
aStratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9749 Groningen, The Netherlands

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Unclicking of thioureas: Base catalyzed elimination of anilines and
isothiocyanates from thioureas
Matea Vlatkovića , Ben L. Feringaa
aStratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 Groningen, The Netherlands
ARTICLE INFO
ABSTRACT
Article history:
Received
Bisaromatic thioureas are widely used in e.g. asymmetric organocatalysis and
considered to be robust compounds. Herein we show, in strong contrast to common
notion, that thioureas dissociate to amines and isothiocyanates in a base catalysed
reaction under mild conditions. This ‘unclicking’ process can occur in the presence
of weak organic bases even at moderate temperatures. The influence of the
substituents at the aromatic rings of the thiourea on the regioselectivity of this
unclicking process is also shown.
Received in revised form
Accepted
Available online
Keywords:
Thioureas
Unclicking of thioureas
Base catalyzed elimination
2009 Elsevier Ltd. All rights reserved
.
*b.l.feringa@rug.nl
1. Introduction
Functional molecules bearing thioureas are widely used (e.g. in catalysis1, medicine2, bioconjugation3a and
supramolecular self-assembly3b-d) and the thiourea motif is considered to be very robust. The formation of thioureas
can be regarded as a click reaction4 and this is one of the main reasons for their broad application; especially in the
preparation of bioconjugates and in material science (e.g. as a linker in nanoparticle and polymer functionalization5).
The synthesis of thioureas is typically accomplished by mixing an appropriate isothiocyanate with an amine at
ambient temperatures, although in the literature there are some procedures that are performed at elevated
temperatures6 (even at reflux7) in the presence of a base (e. g. Et3N). It should be noted that the yields reported in
those cases were typically lower than obtained at milder temperatures.
,
It is known that by heating a mixture of thioureas with acids8 9 above 130 °C or by heating neat thioureas10 above 200
°C, isothiocyanates can be obtained. It was also reported that isothiocyanates can be obtained from thioureas with very
good yields using Viehe’s salt (N-(Dichloromethylene)-N-methylmethanaminium chloride)11 in the presence of a base.
Because of its acidity, the thiourea moiety has been employed in the design of catalysts. Thiourea based
organocatalysts are widely used in carbon-carbon and carbon-heteroatom bond forming reactions.12 Similar to
Takemoto’s pioneer example of a bifunctional thiourea catalyst,13 many of these organocatalysts contain a basic
tertiary alkyl amine group, which together with the thiourea enables simultaneous activation of both electrophilic and
nucleophilic substrates.15,16 Examples of using more nucleophilic bases, e.g. DMAP instead of trialkyl amines in
combination with thiourea are scarce.14 Although there are now numerous examples of reactions employing these
catalysts, decomposition of the catalyst was not reported; even for reactions in which 10 mol % of the catalyst was
used, with reaction time as long as 3 d.17 This created the notion that the thiourea moiety is robust enough not to suffer
from any unwanted decomposition. Our group has used DMAP as a base unit to build motor - based thiourea
organocatalysts (1 and 2) with which dual stereocontrol of Michael and Henry reaction was achieved.14b,c For both
catalysts some degradation was observed during the thermal helix inversion (THI) step (Scheme 1).
1

ACCEPTED MANUSCRIPT
Scheme 1. Thermal helix inversion of catalysts 1 and 2 and side-product X formation.
The first motor-based catalyst 1 made in our group which contained a phenyl spacer in between the motor core and the
catalytic DMAP and thiourea moieties, was reported to undergo partial thermal degradation during the THI process.
Albeit an intriguing observation unfortunately the degradation products were not characterized at that stage. We
discovered a highly relevant elimination process which is of considerable importance in the development of thiourea-
based systems ranging from catalysts to supramolecular materials. Here we will discuss the elimination products
obtained during thermal helix inversion from catalyst 2. Additionally, we will address the implications and generality
of this process focussing on the question, is it specific only for our catalyst or is this a more common phenomenon?
2. Results and discussion
We studied this elimination process in more detail and characterize the formed byproduct for catalyst 2 as well as
examined related thioureas. After heating the cis-unstable form of the catalyst 2 in THF for 16 h, apart from the
expected cis-stable form of the catalyst (the result of thermal helix inversion) also a second product (Scheme 1) was
formed. We anticipated that the degradation product is formed due to the elimination of thiourea, assisted by the basic
nitrogen of the DMAP moiety. In such case, the released molecule could either be the isothiocyanate or the
corresponding aniline. The degradation product could be separated by silica column chromatography and was
characterized by 1H-NMR, 13-C-NMR and HRMS (Scheme 2). Product 3 was isolated in 15% yield and was found to
have an isothiocyanate moiety instead of thiourea at the motor core, suggesting that the leaving group was the 3,5-
bis(trifluoromethyl)aniline, which was isolated and fully characterized.
Scheme 2. Formation of three new products during thermal helix inversion from cis-unstable motor 2.
A possible mechanism for the elimination with intramolecular DMAP assistance followed by THI of cis-unstable
isothiocyanate 3 is presented in Scheme 3.
Scheme 3. Plausible elimination pathway for cis-unstable-2.
Unfortunately, the isothiocyanate 3 was unreactive in its cis-stable configuration, and no product was observed during
24 h after addition of 4-methoxyaniline at room temperature. This low reactivity is most probably due to the steric
reasons, and is likely to be a driving force for the decomposition.
In a control experiment it was found that the water content in the reaction mixture did not influence the elimination.
The experiment was repeated with various THF sources containing 5, 50 and 100 ppm of water, always showing the
same result.
2.1 Elimination from model compounds
2

ACCEPTED MANUSCRIPT
In order to test the generality of the base catalyzed elimination upon prolonged exposure to organic bases and heating
a set of simple model thiourea compounds 4-7 (Figure 1) were synthesized from the corresponding isothiocyanate and
aniline substrates. Both donor and acceptor substituted anilines were used.
Fig. 1. Model thiourea compounds.
The elimination from model compounds 4-7 was followed over time in the presence of one equivalent of DMAP, at
room temperature and at 60 °C in THF. At room temperature during 24 h only traces of elimination products could be
observed (ca. 1% according to 1H-NMR measurements). Figure 2 shows the 1H-NMR spectra of thiourea 4
immediately upon addition of 1 equivalent of DMAP and after 24 h at room temperature, showing only traces of
elimination products.
Fig. 2. 1H-NMR spectra of thiourea 4 in the presence of DMAP and after 24 h at room temperature (arrows indicate
traces of elimination product).
When the elimination process of 4 was followed at 60 °C in THF, in the presence of 1 equivalent of DMAP as a base
(Figure 3), significant elimination was evident within a few hours (after 3 h 30% conversion to the isothiocyanate and
aniline elimination products was observed. After 72 h conversion to the elimination products has reached 44% based
on 1H-NMR measurements.
Fig. 3. 1H-NMR spectra of symmetric thiourea 4 in presence of 1 eq of DMAP at 60 °C followed over time (arrows
indicate elimination product).
The same process was followed for the non-symmetric thioureas 5, 6 and 7. With thiourea 5 which contains the
electron withdrawing CF3 group on one of the phenyl moieties, remarkably no preference for abstraction of a proton
from the two nitrogens was observed. After 3 h, the ratio between the formed aniline and p-(trifluoromethyl)aniline
was approx. 1:1 (Figure 4). Nevertheless, when the reaction was continued, the disappearing of the aniline peaks
could be observed, along with the formation of 1,3-diphenylthiourea (4). After 72 h no aniline peaks could be
observed, showing that the more reactive aniline reacted with the formed isothiocyanate, causing accumulation of the
less reactive p-trifluoromethylaniline (Scheme 4).
3

ACCEPTED MANUSCRIPT
Fig. 4. Elimination from thiourea 5 over time at 60 °C.
Scheme 4. Elimination pathway from thiourea 5 mediated by DMAP.
With thiourea 6 bearing an electron donating group the observed effect was similar (Figure 5). Since the p-
methoxyaniline is more electron rich and hence a better nucleophile, its accumulation cannot be observed as upon
formation it reacts with the available isothiocyanates. With eliminated p-methoxyphenyl isothiocyanate it is forming a
1
symmetric thiourea containing two methoxy groups (as seen in Figure 7 in the H-NMR spectrum after 3 h). After
longer heating period, the formation of symmetric thiourea 4 could also be observed (Scheme 5).
4

ACCEPTED MANUSCRIPT
Fig. 5. 1H-NMR spectra of elimination products from thiourea 6 over time at 60 °C in THF-d6.
Scheme 5. Elimination process from thiourea 6.
Interestingly for thiourea 7 which had an o-methyl substituent on one phenyl ring and p-trifluoromethyl substituent on
the other ring only the elimination products and no new thiourea products were observed. In the beginning both
anilines are observed as elimination products but over time mostly p-trifluoromethylamine is observed and the o-
toluidine signals diminish (Figure 6). Only one aniline was present at the end as the product of elimination (90%
conversion to elimination products in 72 h), indicating a strong preference for elimination of the more electron
deficient aniline. The lack of formation of the new thiourea indicates that sterics plays a crucial role in determining the
thermodynamic equilibrium– the reversed reaction (formation of the thiourea) is strongly hindered by steric crowding.
Fig. 6. 1H NMR spectra of elimination products from thiourea 7 over time at 60 °C in THF.
Since DMAP is a particularly nucleophilic base, we decided to check, whether the character of the organic base also
has an influence on the elimination. For this purpose, elimination studies with thiourea 4 were conducted with triethyl
amine and pyridine, at 60 °C. In the presence of triethyl amine, the elimination was not significant during the first 3h
resulting in only 4% elimination products, but after 72h conversion to the elimination products was 38%. When
pyridine was used as a base, the effect was the same as with DMAP during the first 3 h (30% conversion to the
eliminated products), and after 72 h conversion to the elimination product was 38%. Based on this observation it can
be concluded that the elimination of aniline from thiourea compound always happens in a presence of a base at
elevated temperatures. To which extent elimination is observed depends on the duration of heating and the base used.
5

ACCEPTED MANUSCRIPT
3. Conclusions
Catalyst 2 unexpectedly undergoes elimination of 3,5-bis(trifluoromethyl)aniline during the thermal helix inversion
process. Such elimination appears to be a general reaction for thioureas. It was shown with the model thiourea
compounds that the process of elimination in the presence of a base in THF is slow at room temperature, but becomes
significant at increased temperatures. Preferentially, the electron poor amine is eliminated from thiourea, leaving the
more electron rich isothiocyanate. It is an equilibrium process, as it was demonstrated by following elimination in
time on model thiourea compounds. The reversed reaction does not occur in case steric hindrance is present in the
aniline, as observed with thiourea 7. The rate of elimination is dependent of the nature of the base (it is slower with
triethyl amine than with DMAP). All the observations with model compounds have provided more insight into the
factors determining the elimination process from catalyst 2. Just like with model compounds, elimination from
catalyst 2 was observed at elevated temperatures. Since catalyst 2 contains in its structure the highly electron deficient
3,5-bistrifluoromethyl moiety, it dictates that during the elimination process 3,5-bistrifluoroaniline is released and the
isothiocyanate moiety remains at the motor core. The reversed reaction is disabled most probably due to the steric
reasons as it was observed with the thiourea model compound 7.
These results indicate that during the synthesis of thiourea compounds bases should be omitted, if possible, to avoid
the formation of elimination byproducts. Additionally, these findings suggest that it would be possible to make
dynamic combinatorial libraries composed of thioureas in the presence of base. As far as we know this is the first
study of elimination of anilines, in presence of base, of various aromatic thioureas.
4. Experimental section
General information:
Solvents and commercial starting materials were used as received (from Fluorochem or Sigma Aldrich). Catalyst 2
was prepared as described in reference 14c. Technical grade solvents were used for chromatography. Merck silica gel
60 (230-400 mesh ASTM) was used in flash chromatography. NMR spectra were obtained using a Varian Mercury
Plus (400 MHz) and a Varian VXR-300S (300 MHz). Chemical shift values are reported in ppm with the solvent
resonance as the internal standard (CHCl3: 7.26 for 1H, 77.0 for 13C, THF: 1,73 and 3.58 for 1H, 25.4 and 67.6 for 13C )
Exact mass spectra were recorded on a LTQ Orbitrap XL (ESI+) or on a DART Xevo G2 QTof. All reactions
requiring inert atmosphere were carried out under argon atmosphere using oven dried glassware and standard Schlenk
techniques. Dichloromethane was used from the solvent purification system using a MBraun SPS-800 column. THF
was distilled over sodium under nitrogen atmosphere prior to use. Melting points were determined using a Büchi
Melting Point B-545 apparatus.
Compound 3 N2(Z)-6'-isothiocyanato-2,2',4,4',7,7'-hexamethyl-2,2',3,3'-tetrahydro-[1,1'-biindenylidene]-6-yl)-N4,N4-
dimethylpyridine-2,4-diamine: 15 mg of the stable trans-2-catalyst was irradiated at 312 nm in DCM (3 mg/mL) till
the PSS was reached (containing 93% of cis-unstable form of the catalyst, as determined by 1H-NMR). The resulting
solution in THF was heated for 16 h at 60 °C achieving thermal helix inversion accompanied by the elimination
product 3 which was purified via column chromatography (DCM:MeOH = 95:5), Rf=0.1
mp= 133 °C
1H NMR (400 MHz, CDCl3) δ 7.85(d, J=6.1 Hz,1H), 7.14(s,1H), 6.90(s,1H), 6.08(dd, J=6.2 Hz, J=2.3 Hz, 1H), 6.00
(bs, 1H), 5.73 (d, J=2.3 Hz, 1H), 3.35(m,2H), 3.08(m,2H), 2.94(s,6H), 2.43(m,2H), 2.25(s,3H), 2.22(s,3H), 60(s,3H),
1.38(s,3H), 1.08(m,6H).
13C NMR (101 MHz, CDCl3) δ 158.2, 156.2, 147.9, 143.8, 142.7, 142.2, 141.6, 141.0, 139.5, 137.2, 133.5, 131.9,
131.4, 129.3, 128.2, 128.0, 125.9, 124.8, 100.0, 88.5, 41.9, 41.7, 39.3, 38.6, 38.5, 20.4, 20.3, 18.5, 18.2, 16.8, 16.1.
HRMS (APCI+, m/z): calculated for C32H37N4S [M+H]+: 509.2721, found: 509.2724.
Elimination of model compounds followed by 1H-NMR:
In an NMR tube, 0.1 mL of the solution of 0.02 mmol DMAP in d8-THF was added to a solution of 0.02 mmol of the
model thiourea compound dissolved in 0.5 mL d8-THF. The NMR tube was sealed and placed in an oil bath at 60 °C
and the 1H-NMR spectrum was recorded every hour during the initial 8 h, and then every 12 h.
Synthesis of model compounds: In a dry flask equipped with a stirring bar under nitrogen atmosphere, 1 mmol of
aniline or p- trifluoromethylaniline or o-toluidine was dissolved in 12 mL of dry DCM. 1 mmol of the appropriate
isothiocyanate was added dropwise to the corresponding aniline solution at room temperature. The reaction mixture
was left to stir overnight and then was evaporated to dryness. The thiourea products were purified by column
chromatography on a short column, using pentane/EtOAc as eluent.
181:
yield= 92%
mp= 152-153 °C. (lit. 152 °C)18
1H NMR (400 MHz, THF-d8) δ 9.05 (s, 2H), 7.46 (d, J = 7.9 Hz, 4H), 7.29 (t, J = 7.7 Hz, 4H), 7.09 (t, J = 7.3 Hz,
2H).
13C NMR (101 MHz, THF-d8) δ 181.2, 140.5, 129.5, 125.6, 124.7.
6

ACCEPTED MANUSCRIPT
HRMS (APCI+, m/z): calculated for C13H13N2S [M+H]+: 229.0794, found: 229.0792.
Compound 5 (1-phenyl-3-(4-(trifluoromethyl)phenyl)thiourea):
yield = 80%
mp = 147-148 °C
1H NMR (400 MHz, THF-d8) δ 9.33 (s, 1H), 9.19 (s, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.43 (d, J
= 8.1 Hz, 2H), 7.32 (t, 2H), 7.13 (t, 1H).
13C NMR (101 MHz, THF-d8) δ 181.3, 144.56, 144.55, 140.3, 129.8, 126.4 (q, J = 3.9 Hz), 126.3 (q, J=270.2 Hz),
125.9, 124.6, 123.8.
HRMS (APCI+, m/z): calculated for C14H12F3N2S [M+H]+: 297.0668, found: 259.0666.
Compound 6 (1-(4-methoxyphenyl)-3-phenylthiourea):
yield= 90%
mp = 141 – 142 °C. (lit.reported from 125 °C 19a to 160°C 19b
)
1H NMR (400 MHz, THF-d8) δ 8.87 (s, 1H), 8.76 (s, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.34 – 7.21 (m, 4H), 7.07 (t, J =
7.4 Hz, 1H), 6.86 (d, J = 8.7 Hz, 2H), 3.74 (s, 3H).
13C NMR (101 MHz, thf) δ 181.71, 158.76, 140.79, 133.16, 129.51, 127.32, 125.59, 124.86, 114.87, 55.79.
HRMS (APCI+, m/z): calculated for C14H15N2S [M+H]+: 259.0899, found: 259.0898.
Compound 7 (1-(4-methoxyphenyl)-3-(o-tolyl)thiourea):
yield= 75%
mp= 136 – 137 °C
1H NMR (400 MHz, THF-d8) δ 9.06 (s, 1H), 8.98 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.33 –
7.11 (m, 4H), 2.33 (s, 3H).
13C NMR (101 MHz, THF-d8) δ 181.0, 143.43, 143.42 ,137.2 , 135.2 , 130.7 , 127.4 , 127.0 , 126.5 , 125.3 (q, J = 3.9
Hz), 124.5 (q, J = 270.4 Hz), 123.3 , 17.3.
HRMS (APCI+, m/z): calculated for C15H14F3N2S [M+H]+: 311.0824, found: 311.0825.
Acknowledgments
We gratefully acknowledge support from The Netherlands Organization for Scientific Research (NWO-CW, Top
grant to B. L. F), the Royal Netherlands Academy of Arts and Sciences (KNAW), the Ministry of Education, Culture
and Science (Gravitation program 024.001.035) and the European Research Council (Advanced Investigator Grant no.
694345 to B. L. F.).
References and notes
1. a) Siau, W.-Y. ,. Wang, J. Catal. Sci. Technol. 2011, 1, 1298-1310; b) North, M. Sustainable Catalysis: Without Metals or Other
Endangered Elements, Part 2, Chapter 19, RSC Green Chemistry, London, UK, 2015;, c) Klausen, R. S., Kennedy, C. R., Hyde,
A. M., Jacobsen, E. N. J. Am. Chem. Soc. 2017, 139, 35, 12299-12309; d) Lin, B., Waymouth, R. M. Macromolecules, 2018, 51,
2932-2938.
2. a) D'Cruz, O.J, Uckun, F.M. Curr HIV Res. 2006, 4, 329-345; b) D'Cruz, O.J, Venkatachalam, T. K. , Uckun, F.M. Biol. Reprod.
2000, 63, 196-205.
3. a) Narain, R. Chemistry of Bioconjugates: Synthesis , characterization and biomedical application, Wiley, New Jersey, US,
2014; b) Prusinowska, N., Szymkowiak, J., Kwit, M. J. Org. Chem. 2018, 83, 1167-1175; c) Khansari, M. E., Mirchi A.,
Pramanik, A., Johnson, C.R., Leszczynski, J., Hossain, Md. A., Sci. Rep. 2017; 7, 6032; d) Yanagisawa, Y., Nan, Y., Okuro, K.,
Aida, T. Science, 2017 , 359, 72-76.
4. Kolb, H. C., Finn, H. C., Sharpless, K.B. Angew. Chem. Int. Ed., 2001, 40, 2004-2021.
5. Muhr, N., Puchleitner, R., Kern, W. Eur. Pol. J., 2013, 49, 3114-3124.
6. a) Nagalakshmi, G., Maity, T. K, Maiti, B. C. Int. J. Chem. Tech. Res. 2013, 5, 2079-2089; b) Berber, N., Arslan, M., Yavuz, E.,
Bilen, C., Gencer, N., J. Chem., 2013, Article ID 742178.
7. Hearn, M., Chen, M., Cynamon, M., Wang Ondum, R., Webster, E. J. Sulf. Chem. 2006, 27, 149-164.
8. Bly, R. S., Perkins, G. A., Lewis, W. L., J. Am. Chem. Soc., 1922, 44, 2896- 2903.
9. Bollini, M., Casal, J. J., Alvarez, D. E., Boiani, L., Gonzalez, M., Cerecetto, H., Bruno, A.M. Bioorg. Med. Chem., 2009, 17,
1437-1444.
10. Habib, N., Rieker, A. Synthesis, 1984, 10, 825 -827.
11. Vovk, M. V., Bratenko, M. K. , Samarai, L.I. Ukr. Khim. Zh., 1991, 57, 431-432.
12. Fang, X., Wang, C.-J. Chem. Commun., 2015, 51, 1185-1197.
13. Tomotaka, O., Hoashi, Y., Takemoto, Y. J. Am. Chem. Soc., 2003, 125, 12672-12673.
14. a) Rabalakos, C., Wulff, W. D. J. Am. Chem. Soc., 2008, 130, 13524-13525; b) Wang, J., Feringa, B. L. Science, 2011, 331,
1429-1431; c) Vlatković, M., Bernardi, L., Otten, E., Feringa, B. L. Chem. Comm. 2014, 50, 7773- 7775.
15. Fuerst, D. E., Jacobsen, E. N. J. Am. Chem. Soc., 2005, 127, 8964-8965.
16. a) Benedek, V., Varga, S., Csámpai, A., Soós, T. Org. Lett., 2005, 7, 1967-1969; b) Mc Cooey, S. H., Connon, S. J. Angew.
Chem. Int. Ed. 2005, 44, 6367-6370.
17. Wang, Y.-Q., Song, J., Hongm R., Liand, H., L. Deng, L. J. Am. Chem. Soc., 2006, 128, 8156.
18. Azizi, N., Khajeh-Amiri, A., Ghafuri, H., M. Bolourtchain, M. Mol. Divers. 2011, 15, 157-161.
19. a) Begum, S., Choudhary, M. I., Khalid, M. Nat. Prod. Res. 2009, 23, 1719-1730; b) Natarajan, A., Guo, Y., Arthanari, H.,
Wagner, G., Halperin, J. A., Chorev, M. J.Org.Chem. 2005, 70, 6362-6368.
7