Expected and unexpected results in reactions of fluorinated nitrile imines with (cyclo)aliphatic thioketones

Article abstract of DOI:10.1016/j.jfluchem.2017.07.014

A series of (cyclo)aliphatic thioketones have been tested towards trifluoroacetonitrile imines, generated in situ via base-induced dehydrohalogenation of the respective hydrazonoyl bromides. Typically, non-enolisable thioketones yielded exclusively 3-trif

Full text of DOI:10.1016/j.jfluchem.2017.07.014

Accepted Manuscript
Title: Expected and unexpected results in reactions of
fluorinated nitrile imines with (cyclo)aliphatic thioketones
´
Authors: Greta Utecht, Justyna Sioma, Marcin Jasinski,
´
Grzegorz Mloston
PII:
S0022-1139(17)30308-1
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2017.07.014
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24-7-2017
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Please cite this article as: Greta Utecht, Justyna Sioma, Marcin Jasinski,
´
Grzegorz Mloston, Expected and unexpected results in reactions of
fluorinated nitrile imines with (cyclo)aliphatic thioketones, Journal of Fluorine
Chemistryhttp://dx.doi.org/10.1016/j.jfluchem.2017.07.014
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Journal of Fluorine Chemistry, July 10, 2017
Revised – July 24th, 2017
Expected and unexpected results in reactions of fluorinated nitrile imines with
(cyclo)aliphatic thioketones
Greta Utecht, Justyna Sioma, Marcin Jasiński,* Grzegorz Mlostoń
aFaculty
of
Chemistry,
University
of
Łódź,
Tamka
12,
91-403
Łódź,
Poland,
corresponding author: E-mail: mjasinski@uni.lodz.pl
Marcin Jasiński
Faculty of Chemistry, University of Łódź
Tamka 12, 91-403 Łódź, Poland
Tel.: +48 42 635 57 66
Fax: +48 42 665 51 62
e-mail: mjasinski@uni.lodz.pl
Graphical abstract:
Ph
N NH
S
R
[1,7]-H-shift
N
H
S
N
Ph
(68%)
(30%)
R = CF3
R = Ph
R
H
R
Ph
N
N
1,5-ring
closure
THF, Et3N, rt
S
S
(21%)
(61%)
R = CF3
R = Ph
N
Ph
N
R
Highlights
Cycloaliphatic thioketones undergo (3+2)-cycloaddition with fluorinated nitrile imines. 2,3-Dihydro-
1,3,4-thiadiazoles were obtained in a fully regio- and diastereoselective manner. Unexpectedly,
enolisable thiocamphor yielded the insertion product of the thioenol form as the major product.
Abstract
A series of (cyclo)aliphatic thioketones have been tested towards trifluoroacetonitrile imines, generated in
situ via base-induced dehydrohalogenation of the respective hydrazonoyl bromides. Typically, non-enolisable
thioketones yielded exclusively 3-trifluromethyl-2,3-dihydro-1,3,4-thiadiazoles as a result of completely regio-,
1

chemo-, and diastereoselective (3+2)-cycloaddition, depending on the starting material, while in the case of
2,2,4,4-tetramethylcyclobutane-1,3-dithione a competitive rearrangement followed by trapping of title 1,3-dipole
by the C=S group of the initially formed dithioester was observed. Enolizable (1R)-thiocamphor also provided
the expected (3+2)-cycloadducts along with the insertion products in ratio reflecting electronic properties of the
nitrile imine. The latter results indicate remarkable electrophilic nature of the electron-deficient fluorinated
nitrile imines, and implies possible step-wise mechanism of the studied reaction.
Keywords: fluorinated nitrile imines, thioketones, (3+2)-cycloaddition, fluoroalkylated heterocycles,
trifluoromethylated 1,3,4-thiadiazoles.
1. Introduction
In spite of bad reputation attributed to thioketones as odorous and unstable sulfur analogs of ketones,
recent three decades witnessed rapid development of synthetic methods based on new application of aryl,
hetaryl, and non-enolisable aliphatic thiones [1,2]. Especially important are cycloaddition reactions as since
many years thioketones are considered as superdipolarophilic [3] and superdienophilic [4] reagents. In recent
three decades, both aromatic and cycloaliphatic thioketones were tested in reactions with diverse 1,3-dipoles, and
5-membered heterocycles such as 1,3-dithiolanes, 1,3-oxathiolanes, 1,3-thiazoles, 1,4,2-oxathiazoles, and 1,3,4-
thiadiazoles were obtained as final products [1,3,5]. In addition, hetero-Diels-Alder reactions with aryl and
hetaryl thioketones as heterodienophiles or heterodienes offer an excellent access to 6-membered thiopyran
derivatives [6]. Moreover, in a recent publication we reported the first asymmetric version of a thia-Diels-Alder
reaction [7]. Along with growing number of publications focused on synthetic exploration of thioketones,
important observations related to mechanistic aspects of the cycloaddition reactions with thioketones were also
discussed. Thus, reactions of hetaryl thioketones with diazomethane and thiocarbonyl S-methanides were shown
to occur via stepwise mechanism with delocalized diradicals as key intermediates [8]. Similarly, [4+2]-
cycloadditions of aryl and heteroaryl thioketones with electron-rich 2,4-hexadienes were evidenced to involve
intermediate diradicals [9].
In general, (3+2)-cycloadditions of thioketones with diazomethane and its derivatives can be considered
as an excellent method for the construction of 2,5-dihydro-1,3,4-thiadiazole skeleton (Figure 1) [10]. The
cycloadducts obtained thereby are prepared either as target products or as precursors of the in situ generated
reactive thiocarbonyl ylides (thiocarbonyl S-methanides), which are formed via thermal elimination of nitrogen
((3+2)-cycloreversion reactions). It is well known that such 1,3,4-thiadiazole derivatives obtained from
diazomethane and aromatic thioketones are stable only at ca. 70 °C but analogous products derived from
adamantanethione or other non-enolizable cycloaliphatic thioketones undergo decomposition only upon heating
[10d]. On the other hand, derivatives of 2,3-dihydro-1,3,4-thiadiazoles are available via [3+2]-cycloaddition of
thioketones with nitrile imines [11]. Thus, due to well documented significance of 1,3,4-thiadiazoles and their
dihydro derivatives [12], (3+2)-cycloadditions with thioketones and appropriate 1,3-dipoles deserve attention as
a straightforward method for their preparation.
2

R1
R2
S
R3
R1
R2
R3
R4
S
N N
N N
R4
2,5-dihydro-1,3,4-thiadiazole
2,3-dihydro-1,3,4-thiadiazole
Figure 1. Structures of 1,3,4-thiadiazole derivatives available via (3+2)-cycloadditions with thioketones with diazoalkanes
and nitrile imines, respectively.
In recent publications we demonstrated that aryl and hetaryl thioketones [13] as well as structurally
similar thiochalcones [14] are superior trapping reagents for the in situ generated nitrile imines of type 1 derived
from trifluoroacetonitrile, and these (3+2)-cyloadditions opens a convenient access to trifluoromethylated 2,3-
dihydro-1,3,4-thiadiazoles 2 and 3, which in all cases were formed in a regio- and chemoselective manner
(Scheme 1).
Ar2
X
S
S
X
N
Ar1
Ar1
Ar2
Ar1
Ar1
Ar2
N
Ar2
N
N
CF3
N
S
X
S
THF, rt
THF, rt
N
CF3
1
CF3
3
2
X = H, EWG, EDG
Scheme 1. Chemo- and regioselective (3+2)-cycloadditions of fluorinated nitrile imines 1 with (het)aryl thioketones and
thiochalcones leading to 2,3-dihydro-1,3,4-thiadiazoles 2 and 3, respectively.
Prompted by earlier results we decided to examine (3+2)-cycloadditon reactions of fluorinated nitrile
imines 1 with selected (cyclo)aliphatic thioketones 4a-4g (Figure 2). The latter are known as relatively stable
compounds which can be prepared in the lab using standard methods and subsequently applied in cycloaddition
experiments without special precautions. It is worth of mentioning, that thiocamphor (4g) belongs to the class of
the enolizable thioketones but in contrast to other representatives of that type (e.g. thioacetone or
thioacetophenone) does not undergo decomposition under standard conditions and can be used as a reactive C=S
dipolarophile [15]. In contrast to diverse aryl and hetaryl thioketones, which have extensively been studied in the
(3+2)-cycloaddition reactions with nitrile imines [11], cycloaliphatic analogs 4 have only occasionally been
tested as dipolarophiles in reactions of that type [16].
S
S
X
S
S
S
S
4c X = O
4d X = S
4a
4b
rac-4e
(1R)-4f
(1R)-4g
Figure 2. Thioketones 4a-4g selected for the study in the (3+2)-cycloadditions with fluorinated nitrile imines 1.
As demonstrated in earlier studies, fluorinated nitrile imines 1 are attractive 1,3-dipoles which can
efficiently be explored in the synthesis of trifluoromethylated 5-membered nitrogen heterocycles. They can be
generated in situ by treatment of hydrazonoyl halides with triethylamine in the presence of suitable dipolarophile
[17]. After the first publications by Tanaka et al. who described their reactions initially with ethylenic and
3

acetylenic dipolarophiles [17,18], and later on with some imines [19], we reported on their explorations in
reactions with aryl and hetaryl thioketones [13] as well as thiochalcones acting as C=S dipolarophiles,
exclusively. In continuation of our study, the aim of the present work was examination of the scope and
limitations in reactions of fluorinated nitrile imines 1 with less reactive, sterically crowded thioketones; hence,
one aliphatic 4b and six cycloaliphatic i. e. 4a,4c-g thioketones including bifunctional dithione 4d and three
chiral representatives 4e-g were selected for the study (Figure 2).
2. Results and Discussion
As shown in Scheme 2, readily available hydrazonoyl bromides of type 5 were used as suitable
precursors of nitrile imines 1. The starting compounds were prepared in a two-step procedure from fluoral
hydrate (5) and arylhydrazones 6. Thus, condensation of 5 and 6 was carried out according to general protocol
elaborated for trifluoroacetaldehyde arylhydrazones and related compounds [20], and led after 16 hrs heating at
75 °C in methanolic solution, in the presence of freshly activated molecular sieves 4Å, to a series of
arylhydrazones 7. The expected products 7a-7f were subsequently converted into the respective hydrazonoyl
bromides of type 8 via chemoselective radical bromination of the CH=N group using NBS, in dry DMF solution
[13,21]. The desired bromides 8a-8f were obtained as spectroscopically pure samples after single flash
chromatographic purification, and were isolated in high overall yield of 50-70%.
The first, test experiments were carried out using adamantanethione (4a) and bromide 8a used as
precursor of nitrile imine 1a (Scheme 2). Typically, the reaction was performed in dry THF, at room
temperature, in the presence of Et3N as a base, using a slight excess of bromide 8a (1.1 equiv.). The reaction
progress was monitored by TLC until the starting thioketone 4a was fully consumed; in most cases reaction
times of 3-4 hours were required for the completion. As expected, the 1H NMR spectrum registered for the crude
reaction mixture showed only one set of the signals attributed to a sole (3+2)-cycloadduct; the subsequent flash
CC purification provided pure product isolated as a pale yellow solid, in 62% yield. Two sets of signals found in
aromatic region of the 1H NMR spectrum clearly indicated the presence of the Ph group. On the other hand, two
characteristic quartets found in the 13C NMR spectrum at 119.8 (1JC-F = 272.9 Hz) and 144.1 ppm (2JC-F = 37.9
Hz) as well as singlet at –65.1 ppm present in the 19F NMR spectrum evidenced the presence of the CF3-C= unit.
In addition, in the 13C NMR spectrum another Csp3 signal attributed to the spiro-C atom was found in the
expected, diagnostic region ( = 97.5 ppm). Similar signals with comparable chemical shifts were observed for a
previously described series of 5-trifluoromethyl-2,3-dihydro-1,3,4-thiadiazoles 2 [13], and therefore the structure
of the isolated product was elucidated as the expected (3+2)-cycloadduct 9a. Moreover, its structure was further
confirmed by the high resolution (ESI-TOF) MS spectrum in which the molecular peak of [M+H]+ found at m/z
= 353.13 corresponded to the expected molecular formula C18H20F3N2S.
In continuation of the study, the same thioketone 4a was briefly checked towards selected nitrile imines
1b-1f functionalized with either electron-donating or electron-withdrawing groups located at the para position of
the aryl ring. In all cases, the expected 1,3,4-thiadiazole derivatives 9b-9f were isolated as sole (3+2)-
cycloadducts in fair yields (56-80%), irrespectively to the electronic nature of the para-substituent. However, in
the case of bromides 8e and 8f bearing strongly electron-withdrawing groups (CF3 and CN, respectively), longer
4

reaction times (up to 6 hrs) were needed to complete the conversion of these substrates into the respective
products 9e and 9f.
OH
F3C
OH
5
H
N
N
CF3
+
NBS, DMF, rt
Br
MeOH
75 oC, 16h,
mol sieves 4A
H
N
X
7a-f
NH2
H
X
N
N
CF3
6a-f
X
8a-f
Et3N, THF
S
CF3
a, X = H
S
b, X = Me
c, X = OMe
d, X = Br
e, X = CF3
f, X = CN
N
N
N
4a
N
CF3
X
1a-f
9a-f (56-80%)
X
Scheme 2. Two-step synthesis of hydrazonoyl bromides 8, generation of nitrile imines 1a-1f via base-induced
dehydrobromination of 8, and their trapping with adamantanethione (4a) leading to 2,3-dihydro-1,3,4-thiadiazoles 9a-9f.
Following the general protocol developed for the synthesis of 2,3-dihydro-1,3,4-thiadiazoles 9, a series
of thioketones 4b, 4c, 4e and 4g was examined in the reaction with the model nitrile imine 1a yielding expected
(3+2)-cycloadducts 10-13 (Figure 3). The smooth formation of 10 (69% yield, reaction time 1 hr) derived from
bulky di(tert-butyl)thioketone (4b) deserves a brief comment, as this extremely crowded thioketone was shown
to react only with highly reactive, small 1,3-dipoles such as diazomethane [22]. The observed result is consistent
with our more recent finding, that thioketone 4b is a suitable reaction partner also for more sterically demanding
D-glyceraldehyde-derived N-benzyl nitrone, however, in that case remarkably longer reaction time was necessary
to complete the reaction [2c]. Treatment of 2,2,4,4-tetramethyl-3-thioxocyclobutanone (4c) with 1a also
provided single product 11 in excellent yield (>98%), as a result of a fully chemoselective (3+2)-cycloaddition
1
of nitrile imine molecule onto the C=S bond. The H NMR of the crude reaction mixture confirmed complete
conversion of the starting thione after 2 hrs; however, analytically pure material 11 was isolated in 48% yield
only, due to partial decomposition of the product during purification on silica.
As the first chiral model we selected ‘cage thioketone’ rac-4e, which was reacted with nitrile imine 1a
in a typical manner. As expected, the corresponding 1,3,4-thiadiazole rac-12 was formed solely via the exclusive
exo-face attack of 1a onto the C=S group. The observed result is in full accordance to other reports on both
nucleophilic additions and (3+2)-cycloadditions with Cookson’s ‘birdcage’ thioketone 4e and related compounds
[2a,23]. Similarly, excellent facial stereoselectivity was observed in the reaction of enantiomerically pure
tiofenchone ((1R)-4g), which captured 1a from the endo-face only. Standard flash chromatography enabled
isolation of this single diastereomer 13 in moderate yield of 56%.
5

CF3
CF3
S
S
O
N
N
N
N
Ph
Ph
10 (69%)
11 (48%)
Ph
N
S
S
N
S
N
N
N
Ph
PhN
CF3
CF3
CF3
rac-12 (66%)
13 (56%)
Figure 3. Achiral and chiral 2,3-dihydro-1,3,4-thiadiazoles 10-13 obtained from nitrile imine 1a and corresponding
thioketones 4.
In contrast to 2,2,4,4-tetramethyl-3-thioxocyclobutanone (4c) the reaction with dithione 4d performed
in the presence of 2.2 equivalents of hydrazonoyl bromide 8a and excess Et3N led to a mixture of two products
in a ratio of ca. 2:3 (14:15) (Scheme 3). The reaction mixture was separated chromatographically, and two
1
fractions were obtained in fair yields of 32 and 41%, respectively. The H NMR spectrum of the less polar
fraction revealed the presence of four signals (singlets) located at 1.32, 1.50, 1.68 and 1.74 ppm attributed to four
non-equivalent Me groups. In the 13C NMR spectrum, along with characteristic signal of the =C-CF3 found at
2
131.6 (q, JC-F = 40.8 Hz) ppm, two another signals of the Csp2 atoms were found at 120.6 and 129.7 ppm,
respectively, indicating the presence of the C=CMe2 unit. The low-field shift of the latter Csp2 suggested that it
belongs to the thietanethione skeleton. It is known that dithione 4d undergoes ring rearrangement induced by a
strong base such us sodium methanolate or fluoride anion [24], and isomerizes via intermediates A and B
yielding dithiolactone 16. Apparently, also in the presence of Et3N, in the THF solution, dithione 4d undergoes a
competitive isomerisation to 16, which is subsequently trapped with 1a yielding the (3+2)-cycloadduct 15 as the
major product.
NEt3
Et3N
THF
NEt3
S
S
S
S
S
S
-Et3N
S
S
4d
THF [1a]
A
B
16
[1a]
THF
F3C
CF3
CF3
S
S
S
N
N
N
S
N
N
N
Ph
Ph
Ph
14 (32%)
15 (41%)
Scheme 3. Two competitive (3+2)-cycloaddition reactions observed in the case of 2,2,4,4-tetramethylcyclobutane-1,3-
dithione (4d).
Remarkably, the starting dithione 4d undergoes (3+2)-cycloaddition with 1a onto both C=S bonds to
afford the cis-configured bis-cycloadduct 14 as the single stereoisomer. The structure of the isolated product 14
was unambigously confirmed by X-ray diffraction analysis (Figure 4). It is worth mentioning that in contrast to
the presented reaction with nitrile imine 1a, the (3+2)-cycloaddition of 4d with diazomethane led to a 1:3
mixture of cis- and trans-configured bis-cycloadducts, respectively [25]. The observed result points out that the
6

subsequent formation of the second 1,3,4-thiadiazole ring in 14 occurs with preferred syn orientation of both
heterocyclic rings.
Figure 4. A view of the molecular structure of 14. Displacement ellipsoids are drawn at the 50% probability level.
Reaction of C,N-diaryl nitrile imines with ()-thiocamphor ((1R)-4f) have recently been studied, and the
diastereoselective formation of (3+2)-cycloadducts of type 18 as single products was reported [16b,c]. The
structure of two 1,3,4-thiadiazole derivatives of that type was unambigously confirmed by the X-ray diffraction
analysis [16c]. In our case, however, fluorinated nitrile imine 1a was reacted with (1R)-4f yielding unexpectedly
a mixture of two products which were separated by flash chromatography. Whereas the more polar fraction
forming a minor product was identified as the expected 1,3,4-thiadiazole 18a (21%), the structure of the less
1
polar compound (major fraction) was elucidated as carbothiohydrazonate 19a (68%). In the H NMR of 19a
diagnostic signal located at 5.62 ppm (d, J = 3.4 Hz) was attributed to the ethylenic proton =CH. In the same
spectrum, a broad, H/D-exchangeable singlet of the PhNH group was also observed. In the 13C NMR spectrum
of this compound two characteristic signals attributed to Csp2 atoms, found at 131.8 and 134.0 ppm, clearly
confirmed the presence of the enthiol-ether (C=C-S) unit (for comparison with a similar structure of the Me-
sulfide, see Ref. [26]).
N
Ph
N
R
Ph
N NH
1a or 17
+
S
S
N
THF or CH2Cl2
rt
S
Ph
R
N
R
(1R)-4f
(21%)
(61%)
(68%)
(30%)
18a, R = CF3
18b, R = Ph
19a, R = CF3
19b, R = Ph
Scheme 4. Comparison of the reaction outcomes of ()-thiocamphor ((1R)-1f) with fluorinated and non-fluorinated nitrile
imines 1a and 17, respectively.
The formation of the products of type 19 has not been reported for the reaction of thiocamphor and C,N-
diaryl nitrile imines [16]. Therefore, the reaction of the well known nitrile imine 17 with 4f was carefully
1
examined, and the H NMR analysis of crude reaction mixture confirmed the presence of the already reported
(3+2)-cycloadduct 18b along with compound 19b (Scheme 4). However, in that case the ratio of both
intermolecular products was 64:36 in favor of the 1,3,4-thiadiazole derivative 18b, isolated in high 61% yield.
7

Based on this result we conclude, that the fluorinated nitrile imine 1a prefers the formation of acyclic derivative
19a, which formally corresponds to the insertion product of thioenolate form of 4f into 1a. The influence of the
solvent and the base used was briefly examined, using variable amounts of Et3N (from 1 to 5 equiv.) and
changing the solvent to dichloromethane. Irrespective of the applied reaction conditions, in all cases the
formation of the same 3:7 mixture of 18a:19a was observed. The enhanced amount of the insertion product 19a
formed in the reaction with fluorinated nitrile imine 1a deserves a comment. It seems likely, that the presence of
electron-withdrawing CF3 group enhances electrophilic character of the 1,3-dipole 1a, and favors its interaction
with the nucleophilic sulfur atom. This interaction results in increasing CH-acidity of the neighboring CH2
group, and enables departure of proton. The formation of the 18/19 mixture suggests that the reaction of
thiocamphor 4f with nitrile imines 1 may occur via an intermediate zwitterion C in which the 1,5-ring closure
competes with the proton transfer (Scheme 5). Attempted trapping of the postulated intermediate C with MeOH
added to the reaction mixture was unsuccessful. On the other hand, an insertion reaction of the enethiol form of
thiocamphor, presumably existing in a very low concentration with its thione form in THF solution, can’t be
1
excluded. However, in the H NMR spectrum (600 MHz, CDCl3) of a mixture of thiocamphor and excess Et3N,
the respective enethiol form of 4f could not be detected.
[1,7]-H-shift
19a
H
H
Ph
S
N
N
4f
1,5-ring
closure
S
N
N
Ph
CF3
F3C
18a
1a
C
Scheme 5. Postulated step-wise reaction of thiocamphor (1R)-4f with fluorinated nitrile imine 1a leading to a formal (3+2)-
cycloadduct 18a and the isomeric insertion product 19a.
3. Conclusions
The presented study showed, that cycloaliphatic thioketones 4 in analogy to hetaryl representatives are
suitable trapping agents for the in situ generated C-trifluoromethylated nitrile imines 1 yielding, in most cases,
spiro-2,3-dihydro-1,3,4-thiadiazoles functionalized with the CF3 group. Depending on the substitution pattern of
the starting thioketone, the reactions proceeded in a regio-, chemo- and diastereoselective manner to afford the
expected (3+2)-cycloadducts in high yields. Unexpectedly, in contrast to classical C,N-diaryl nitrile imines, the
reaction of fluorinated analogue 1a with enolizable thiocamphor provided carbothiohydrazonate derivative 19a
as a major product formed, very likely, via competitive stepwise, zwitterionic pathway. Taking into account the
importance of 1,3,4-thiadiazole derivatives [12,27], and in general, rapidly growing interest in fluorinated
heterocycles [28], presented approach can be of interest in the context of practical applications in medicinal,
materials, and agro-chemistry. In addition, presented systems in which an electron rich heterodipolarophile
(thioketone) reacts with an electron deficient 1,3-dipole (fluorinated nitrile imine) is of interest for the
development of the discussion on the cycloaddition mechanisms, which can follow a step-wise, zwitterionic
pathway [5a,29].
8

4. Experimental Part
4.1. General information
All solvents were purchased and used as received without further purification. THF was dried over
sodiumbenzophenone and freshly distilled before usage. If not stated otherwise, reactions were carried out
under argon in flame-dried flasks with addition of the reactants by using syringes; subsequent manipulations
were conducted in air. Products were purified by standard chromatography column on silica gel (230–400 mesh,
Merck or Fluka). NMR spectra were measured on a Bruker AVIII 600 MHz (1H NMR [600MHz]; 13C NMR
[151 MHz]) or with a Varian Gemini 2000BB 200 MHz (19F NMR [188 MHz]) instruments. Chemical shifts are
reported relative to solvent residual peaks (1H NMR: δ = 7.26 ppm [CDCl3]; 13C NMR: δ = 77.0 ppm [CDCl3]).
For detailed peak assignments 2D spectra were measured (COSY, HMQC, HMBC). IR spectra were measured
with a FTIR NEXUS spectrometer (as thin film or KBr pellets). MS were performed with a Varian 500-MS LC
Ion Trap (ESI) or with a Waters MaldiSYNAPT G2-S HDMS (ESI-TOF-HRMS). Elemental analyses were
obtained with a Vario EL III (Elementar Analysensysteme GmbH) instrument. Melting points were determined
in capillaries with a MEL-TEMP II apparatus (Aldrich), and are uncorrected. Optical rotations were measured
with an Anton-Paar MCP 500 at the temperatures indicated. Single crystal X-ray data were collected with a
Rigaku Oxford Diffraction XtaLAB Synergy, Pilatus 300K diffractometer (Cu Kα radiation, λ = 1.54178 Å,
PhotonJet (Cu) X-ray Source with mirror); the structure solution and refinement was performed by using
SHELXS-97 [30] and SHELXL-2014 [31]. CCDC-1547224 (14) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre
via http://www.ccdc.cam.ac.uk/data_request/cif. Starting materials: Adamantanethione (4a) [32], 2,2,4,4-
tetramethyl-3-thioxocyclobutanone (4c) [3a], 2,2,4,4-tetramethylcyclobutane-l,3-dithione (4d) [3a], and
pentacyclo[5.4.0.02,6.03,10.05,9]undecan-8-thione (rac-4e) [33], were obtained by thionation of the corresponding
ketones with P4S10, in pyridine. For the synthesis of di(tert-butyl)thioketone (4b) a protocol involving reaction of
di(tert-butyl)ketimines lithium salt with CS2 was applied [34], while thiofenchone ((R)-4g) was prepared from
the corresponding ketone in methanolic solution by passing through mixed streams of H2S and HCl gas, in the
presence of trimethyl orthoformate [35]. (1R)-()-Thiocamphor ((R)-4f) is commercially available (TCI).
Trifluoroacetaldehyde arylhydrazones 7 were prepared by heating methanolic solutions of the appropriate
hydrazine and excess fluoral hydrate in a closed ampoule at 75 C overnight, in the presence of molecular sieves
4Å according to literature protocol [20b]. Hydrazonoyl bromides 8 were obtained by treatment of the
corresponding arylhydrazones 7 with NBS in dry DMF as described in an earlier report [13].
4.2. General procedure for the reaction of thioketones 4a-4g with nitrile imines
To a mixture of the respective hydrazonoyl halide (1.1 equiv. for each C=S group) and thioketone 4 (1.0
mmol) in dry THF (5 mL) was added dropwise Et3N (0.8 mL) and the resulting mixture was stirred at room
temperature until the starting thioketone was fully consumed (TLC monitoring, petroleum ether/CH2Cl2 4:1,
visualization: p-anisaldehyde stain; typically up to 4 hrs for nitrile imines 1, and 16 hrs for nitrile imine 17). The
precipitate triethylamine salt was filtered off, and the solvents were removed under reduced pressure. The
resulting mixture was purified by flash chromatography column (FCC) on SiO2 (deactivated with 2% Et3N in
9

petroleum ether) using petroleum ether/dichloromethane mixtures as an eluent, and the isolated products were
analyzed by spectroscopic methods.
4.2.1. Spiro[adamantane-2,2’-(3’-phenyl-5’-trifluoromethyl-2’,3’-dihydro-1’,3’,4’-thiadiazole)] (9a):
Reaction time 2h; FCC (SiO2, petroleum ether/CH2Cl2 4:1), pale yellow solid, 218 mg (62%); mp
1
7677 °C. H NMR (600 MHz, CDCl3):  1.52, 1.71, 1.83, 2.072.09, 2.36 (5 m, 2H, 2H, 4H, 4H, 2H, Ad),
7.33-7.39, 7.517.53 (2 m, 3H, 2H, Ph) ppm; 13C NMR (CDCl3, 151 MHz):  26.4, 32.9, 37.5, 37.8, 38.1 (Ad),
1
2
97.5 (s, spiro-C), 119.8 (q, JC-F = 272.9 Hz, CF3), 128.7, 129.0, 130.2, 142.8 (3 d, s, Ph), 144.1 (q, JC-F = 37.9
Hz, C-5) ppm; 19F NMR (CDCl3, 188 MHz):  –65.1 (s, CF3) ppm; IR (KBr): v 29372854, 1596, 1331, 1194,
1149, 1137, 1024, 1008, 964, 774, 701 cm-1; HRMS (ESI-TOF): m/z [M+H]+ calcd for C18H20F3N2S: 353.1299;
found: 353.1292.
4.2.2. Spiro{adamantane-2,2’-[3’-(p-tolyl)-5’-trifluoromethyl-2’,3’-dihydro-1’,3’,4’-thiadiazole]} (9b):
Reaction time 2h; FCC (SiO2, petroleum ether/CH2Cl2 85:15), colorless solid, 293 mg (80%); mp 7071
1
C. H NMR (600 MHz, CDCl3):  1.52, 1.71, 1.83, 2.082.10, 2.34 (5 m, 2H, 2H, 4H, 4H, 2H, Ad), 2.36 (s,
3H, Me), 7.16-7.17, 7.397.41 (2 m, 2H, 2H, Tol) ppm; 13C NMR (CDCl3, 151 MHz):  21.2 (q, Me), 26.4,
33.0, 37.7, 37.8, 38.1 (Ad), 97.6 (s, spiro-C), 119.8 (q, 1JC-F = 272.9 Hz, CF3), 129.6, 129.9, 138.6, 140.1 (2 d, 2
2
s, Tol), 144.0 (q, JC-F = 37.7 Hz, C-5) ppm; 19F NMR (CDCl3, 188 MHz):  –65.1 (s, CF3) ppm; IR (KBr): v
29612906, 1507, 1452, 1334, 1216, 1132, 1024, 1010, 961, 825 cm-1; HRMS (ESI-TOF): m/z [M+H]+ calcd for
C19H22F3N2S: 367.1456; found: 367.1449.
4.2.3. Spiro{adamantane-2,2’-[3’-(4’’-methoxyphenyl)-5’-trifluoromethyl-2’,3’-dihydro-1’,3’,4’-thiadiazole]}
(9c)
1
Reaction time 4h; FCC (SiO2, petroleum ether/CH2Cl2 7:3), pale yellow oil, 244 mg (64%). H NMR
(600 MHz, CDCl3):  1.44, 1.71, 1.83, 2.08-2.10, 2.31 (5 m, 2H, 2H, 4H, 4H, 2H, Ad), 3.81 (s, 3H, OMe),
6.866.88, 7.427.45 (2 m, 2H, 2H, C6H4) ppm; 13C NMR (CDCl3, 151 MHz):  26.4, 33.0, 37.7, 37.9, 38.1
(Ad), 55.4 (q, OMe), 97.6 (s, spiro-C), 114.0 (d, C6H4), 119.8 (q, 1JC-F = 272.9 Hz, CF3), 131.2 (d, C6H4), 135.2
2
(s, C6H4), 144.0 (q, JC-F = 37.8 Hz, C-5), 159.5 (s, C6H4) ppm; 19F NMR (CDCl3, 188 MHz):  –65.1 (s, CF3)
ppm; IR (film): v 30042858, 1605, 1508, 1454, 1333, 1248, 1186, 1144, 1024, 837 cm-1; HRMS (ESI-TOF):
m/z [M+Na]+ calcd for C19H21F3N2OSNa: 405.1224; found: 405.1219.
4.2.4. Spiro{adamantane-2,2’-[3’-(4’’-bromophenyl)-5’-trifluoromethyl-2’,3’-dihydro-1’,3’,4’-thiadiazole]} (9d)
Reaction time 2h; FCC (SiO2, petroleum ether/CH2Cl2 7:3), pale yellow solid, 289 mg (67%); mp
9395 C. 1H NMR (600 MHz, CDCl3):  = 1.53, 1.72, 1.79-1.88, 2.04-2.07, 2.32 (5 m, 2 H, 2 H, 4 H, 4 H, 2 H,
Ad), 7.39-7.41, 7.49-7.51 (2 m, 2 H, 2 H) ppm; 13C NMR (CDCl3, 151 MHz):  = 26.2, 26.5, 33.0, 37.5, 37.7,
38.0 (Ad), 97.4 (s, spiro-C), 119.6 (q, 1JC-F = 273.1 Hz, CF3), 122.5, 131.7, 132.2, 141.8 (s, 2 d, s, C6H4), 145.1
(q, 2JC-F = 38.1 Hz, C-5) ppm; 19F NMR (CDCl3, 188 MHz):  = –65.1 (s, CF3) ppm; IR (KBr): 3054-2858, 1557,
1483, 1331, 1189, 1146, 1027, 965, 838 cm-1; HRMS (ESI-TOF): m/z [M+H]+ calcd for C18H19BrF3N2S:
431.0404; found: 431.0387.
10

4.2.5.
thiadiazole]} (9e)
Reaction time 6h; FCC (SiO2, petroleum ether/ CH2Cl2 7:3), pale yellow oil, 239 mg (57%). 1H NMR
Spiro{adamantane-2,2’-[3’-(4’’-trifluoromethylphenyl)-5’-trifluoromethyl-2’,3’-dihydro-1’,3’,4’-
(600 MHz, CDCl3):  1.54, 1.72, 1.79, 1.90, 2.042.07, 2.37 (6 m, 2H, 2H, 1H, 3H, 4H, 2H, Ad), 7.65 (s, 4H,
C6H4) ppm; 13C NMR (CDCl3, 151 MHz):  26.1, 26.6, 33.0, 37.5, 37.7, 38.0 (Ad), 97.5 (s, spiro-C), 119.6 (q,
1
3
1JC-F = 273.2 Hz, CF3), 123.8 (q, JC-F = 272.3 Hz, CF3), 126.2 (q, JC-F = 3.6 Hz, C6H4), 130.4 (d, C6H4), 130.7
2
(q, 2JC-F = 32.8 Hz, i-C, C6H4), 145.3 (q, JC-F = 38.2 Hz, C-5), 146.2 (s, i-C, C6H4) ppm; 19F NMR (CDCl3, 188
MHz):  –65.2, –63.2 (2 s, 2 CF3) ppm; IR (film): v 29162860, 1614, 1562, 1454, 1409, 1321, 12771020,
848 cm-1; HRMS (ESI-TOF): m/z [M+H]+ calcd for C19H19F6N2S: 421.1173; found: 421.1161.
4.2.6. Spiro{adamantane-2,2’-[3’-(4’’-cyanophenyl)-5’-trifluoromethyl-2’,3’-dihydro-1’,3’,4’-thiadiazole]} (9f)
Reaction time 6h; FCC (SiO2, petroleum ether/CH2Cl2 1:1), colorless solid, 211 mg (56%); mp 107108
1
°C. H NMR (600 MHz, CDCl3):  1.531.59, 1.72, 1.78, 1.902.06, 2.37 (5 m, 2H, 2H, 1H, 7H, 2H, Ad),
7.627.63, 7.677.69 (2 m, 2H, 2H, C6H4) ppm; 13C NMR (CDCl3, 151 MHz):  26.0, 26.5, 33.0, 37.47, 37.54,
37.8 (Ad), 97.6 (s, spiro-C), 112.2 (s, CN), 118.0 (s, i-C, C6H4), 119.5 (q, 1JC-F = 273.1 Hz, CF3), 130.7, 133.0 (2
2
d, C6H4), 145.4 (q, JC-F = 38.4 Hz, C-5), 147.2 (s, i-C, C6H4) ppm; 19F NMR (CDCl3, 188 MHz):  –65.2 (s,
CF3) ppm; IR (KBr): v 29342917, 2230, 1603, 1500, 1337, 1200, 1133, 1022, 847 cm-1; HRMS (ESI-TOF):
m/z [M+H]+ calcd for C19H19F3N3S: 378.1252; found: 378.1237.
4.2.7. 2,2-Bis-(tert-butyl)-3-phenyl-5-trifluoromethyl-2,3-dihydro-1,3,4-thiadiazole (10)
1
Reaction time 1h; FCC (SiO2, petroleum ether/CH2Cl2 4:1), light orange oil, 237 mg (69 %). H NMR
(600 MHz, CDCl3):  1.31 (s, 18H, 2-tBu), 7.187.20, 7.317.33, 7.567.57 (3 m, 1H, 2H, 2H, Ph) ppm; 13C
1
NMR (CDCl3, 151 MHz):  30.2, 46.2 (q, s, 2-tBu), 113.1 (s, spiro-C), 120.2 (q, JC-F = 270.1 Hz, CF3) 125.9,
126.1 (2 d, 3CHarom.), 126.8 (q, 2JC-F = 39.6 Hz, C-5), 128.5 (d, 2CHarom.), 145.9 (s, i-C) ppm; 19F NMR (CDCl3,
188 MHz):  –63.5 (s, CF3) ppm; IR (film): v 34312932, 1584, 1494, 1362, 1244, 1180, 1125, 1106, 1026,
714 cm-1; HRMS (ESI-TOF): m/z [M+H]+ calcd for C17H24F3N2S: 345.1612; found: 345.1605.
4.2.8. 5-Phenyl-1,1,3,3-tetramethyl-7-trifluoromethyl-8-thia-5,6-diazaspiro[3,4]oct-6-en-2-one (11):
1
Reaction time 2h; FCC (SiO2, petroleum ether/CH2Cl2 4:1), light orange oil, 164 mg (48%). H NMR
(600 MHz, CDCl3):  1.23, 1.39 (2 sbr, 6H each, 4Me), 7.257.28, 7.337.36, 7.387.40 (3 m, 1H, 2H, 2H, Ph)
ppm; 13C NMR (CDCl3, 151 MHz):  22.2, 25.0 (2 q, 4Me), 67.9 (s, 2 i-C, 2CMe2), 95.2 (s, spiro-C), 119.5 (q,
2
1JC-F = 272.4 Hz, CF3), 125.5, 127.2, 129.3 (3 d, Ph), 140.1 (q, JC-F = 39.3 Hz, C-5), 143.9 (s, Carom.), 217.3
(C=O) ppm; 19F NMR (CDCl3, 188 MHz):  –66.8 (s, CF3) ppm; IR (film): v 30882872, 1788 (C=O), 1491,
1195, 1144, 1026 cm-1; ESI-MS (m/z): 343.1 (100, [M+H]+), 327.1 (54).
4.2.9.
1’,3’,4’-thiadiazole} (rac-12):
()-Spiro{pentacyclo[5.4.0.02,6.03,10.05,8]undecane-8,2’-(3’-phenyl-5’-trifluoromethyl-2’,3’-dihydro-
11

Reaction time 3h; FCC (SiO2, petroleum ether/CH2Cl2 4:1), colorless solid, 148 mg (66%); mp 9697
°C. 1H NMR (600 MHz, CDCl3):  1.17 (dbr, J  10.5 Hz, 1H), 1.191.24 (m, 1H), 1.58 (dbr, J  10.5 Hz, 1H),
1.96 (sbr, 1 H), 2.242.27 (m, 2H), 2.392.41 (m, 2H), 2.512.54 (m, 1H), 2.692.70 (m, 1H), 2.732.80 (m,
1H), 2.892.93 (m, 1H), 7.227.32 (m, 5H, Ph) ppm; 13C NMR (CDCl3, 151 MHz):  28.5, 33.6, 35.6, 41.0,
42.3, 42.8, 44.5, 45.9, 46.9, 52.8 (2 t, 8 d, cage), 94.7 (s, spiro-C), 119.9 (q, 1JC-F = 271.7 Hz, CF3), 126.8, 127.0,
128.7 (3 d, Ph), 143.4 (s, i-C) ppm, the signal of the C-CF3 was not found; 19F NMR (CDCl3, 188 MHz):  –
64.5 (s, CF3) ppm; IR (KBr): v 30232870, 1596, 1491, 1363, 1267, 1183, 1140, 1022, 960, 774, 711, 695 cm-1;
HRMS (ESI-TOF): m/z [M+H]+ calcd for C19H18F3N2S: 363.1143; found: 363.1128.
4.2.10. (1R,2R,4S)-Spiro{1,3,3-trimethylbicyclo[2.2.1]heptane-2,2’-(3’-phenyl-5’-trifluoromethyl-2’,3’-dihydro-
1’,3’,4’-thiadiazole)} (13)
20
Reaction time 5h; FCC (SiO2, petroleum ether/CH2Cl2 9:1), colorless oil, 198 mg (56%). [α]D +195.6
1
(c 0.31, CHCl3). H NMR (600 MHz, CDCl3):  0.95 (m, 3H, Me), 1.231.25 (m, 4H), 1.36-1.42 (m, 4H),
1.531.64 (m, 3H), 1.75 (s, 1H), 2.42 (sbr, 1H), 7.18, 7.287.31, 7.477.49 (3 m, 1H, 2H, 2H, Ph) ppm; 13C
NMR (CDCl3, 151 MHz):  19.3 (q, Me), 23.8 (t, 2CH2), 28.2 (q, Me), 29.9 (q, Me), 40.4 (t, CH2), 49.0 (d, CH),
53.6 (s, 2 i-C), 110.4 (s, spiro-C), 120.1 (q, 1JC-F = 270.8 Hz, CF3), 125.4, 126.0, 128.2 (2 dbr, d, Ph), 145.9 (s, i-
C, Ph) ppm, the signal of the =C-CF3 was not found due to low intensity; 19F NMR (CDCl3, 188 MHz):  –64.4
(s, CF3) ppm; IR (film): v 2966, 2875, 1593, 1491, 1462, 1360, 1240, 1190, 1132, 1099, 1026, 985, 748, 696
cm-1; HRMS (ESI-TOF): m/z [M+Na]+ calcd for C18H21F3N2SNa: 377.1275; found: 377.1262.
4.3. Reaction of dithione 4d with nitrile imine 1a
Following the general procedure, the reaction of 2,2,4,4-tetramethylcyclobutane-1,3-dithione (4d, 1.0
mmol) with hydrazonoyl bromide 8a (2.2 equiv.) provided after 3h at room temperature a mixture containing 14
and 15 in a 2:3 ratio. Purification by flash column chromatography (SiO2, petroleum ether/CH2Cl2 4:1) provided
pure 15 (148 mg, 41%, first eluted) and 14 (174 mg, 32%, second eluted).
4.3.1.
cis-6,6,12,12-Tetramethyl-1,8-diphenyl-3,10-bis(trifluoromethyl)-4,11-dithia-1,2,8,9-
tetraazadispio[4.1.4.1]dodeca-2,9-diene (14):
1
Colourless solid, mp 177178 C. H NMR (600 MHz, CDCl3):  1.09, 1.28 (2 sbr, 6H each, 4Me),
7.40 (sbr, 10H, 2Ph) ppm; 13C NMR (CDCl3, 151 MHz):  23.6, 27.1 (2 q, 2Me each), 58.4 (s, 2 i-C, 2 C-Me2),
96.5 (s, 2 spiro-C), 119.5 (q, 1JC-F = 272.9 Hz, 2 CF3), 129.2, 129.4, 129.5 (3 d, 2Ph), 143.3 (q, 2JC-F = 38.4 Hz, 2
=CCF3), 143.5 (s, 2 i-C, 2Ph) ppm; 19F NMR (CDCl3, 188 MHz):  –65.3 (s, 2CF3) ppm; IR (KBr): v
30972959, 1557, 1490, 1385, 1336, 1198, 1044, 894, 770, 696 cm-1; HRMS (ESI-TOF): m/z [M+H]+ calcd for
C24H23F6N4S2: 545.1268; found: 545.1262; elemental analysis calcd (%) for C24H22F6N4S2 (544.1): C 52.93, H
4.07, N 10.29, S 11.78; found: C 52.97, H 4.27, N 10.41, S 11.83.
Suitable crystals of 14 for an X-ray crystal structure determination were obtained from petroleum
ether/CH2Cl2 mixture by slow evaporation of the solvents.
4.3.2. 3,3-Dimethyl-2-isopropylidene-5-phenyl-7-trifluoromethyl-1,8-dithia-5,6-diazaspiro[3.4]oct-6-ene (15):
12

1
Light orange oil. H NMR (600 MHz, CDCl3):  1.32 (sbr, 3H, Me), 1.50 (s, 3H, Me), 1.68 (sbr, 3H,
Me), 1.74 (s, 3H, Me), 7.157.18, 7.317.34, 7.687.70 (3 m, 1H, 2H, 2H, Ph) ppm; 13C NMR (CDCl3, 151
1
MHz):  19.7, 21.7, 23.0, 29.8 (4 q, 4Me), 67.1 (s, i-C, CMe2), 101.4 (s, spiro-C), 119.6 (q, JC-F = 271.1 Hz,
CF3), 120.6 (s, =CMe2), 122.6, 124.9, 128.4 (3 d, Ph), 129.7 (s, C=CMe2), 131.6 (q, 2JC-F = 40.8 Hz, C-5), 142.8
(s, i-C, Ph) ppm; 19F NMR (CDCl3, 188 MHz):  –63.6 (s, CF3) ppm; IR (film): v 2970, 2934, 2859, 1493,
1363, 1257, 1194, 1138, 1028 cm-1; HRMS (ESI-TOF): m/z [M+H]+ calcd for C16H18F3N2S2: 359.0863; found:
359.0861.
4.4. Reaction of thiocamphor ((1R)-4f) with nitrile imine 1a
According to general protocol, the reaction of thioketone (1R)-4f (1.0 mmol) with hydrazonoyl bromide
8a (1.1 equiv.) yielded after 2h at room temperature a mixture of (3+2)-cycloadduct 18a and product 19a in a
29:71 ratio, respectively. Chromatography purification (SiO2, petroleum ether/CH2Cl2 4:1) provided pure 19a
(241 mg, 68%, first eluted) and 18a (74 mg, 21%, second eluted).
4.4.1. (1R,2R,4R)-Spiro[camphane-2,2’-(3’-phenyl-5’-trifluoromethyl-2’,3’-dihydro-1’,3’,4’-thiadiazole)] (18a)
Light orange oil; [α]D20 +80.2 (c 0.06, CHCl3). 1H NMR (600 MHz, CDCl3):  0.93, 1.03 (2 s, 3H, 6H,
3Me), 1.071.13 (m, 1H), 1.511.56 (m, 1H), 1.701.75 (m, 2H), 1.851.87 (m, 1H), 2.262.28 (m, 1H),
2.492.58 (m, 1H), 7.317.40 (m, 5H, Ph) ppm; 13C NMR (CDCl3, 151 MHz):  11.5, 20.7, 20.8 (3 q, 3Me),
1
26.4, 28.2, 40.1 (3 t), 45.2 (d), 49.2, 58.4 (2 s), 96.7 (s, spiro-C) 119.7 (q, JC-F = 273.0 Hz, CF3), 128.1, 128.3,
129.1 (3 d, Ph), 143.1 (s, Ph) ppm, the signal of the =C-CF3 was not found due to low intensity; 19F NMR
(CDCl3, 188 MHz):  –65.2 (s, CF3) ppm; IR (film): v 30922889, 1570, 1491, 1392, 1190, 1140, 1022 cm-1;
HRMS (ESI-TOF): m/z [M+H]+ calcd for C18H22F3N2S: 355.1456; found: 355.1447.
4.4.2.
(1’R,4’R)-1’,7’,7’-Trimethylbicyclo[2.2.1]hept-2’-en-2’-yl
2,2,2-trifluoro-N’-
phenylethanehydrazonothioate (19a):
Light orange oil; [α]D20 +29.7 (c 0.31, CHCl3). 1H NMR (600 MHz, CDCl3):  0.81, 0.86 (2 s, 3H each,
2Me), 1.01 (ddd, J = 3.6, 9.2, 12.3 Hz, 1H), 1.11 (s, 3H, Me), 1.19 (ddd, J = 3.7, 9.2, 12.4 Hz, 1H), 1.65 (ddd, J
= 3.6, 8.6, 12.4 Hz, 1H), 1.90 (ddt, J  3.7, 8.6, 12.3 Hz, 1H), 2.37 (tbr, J  3.6 Hz, 1H), 5.62 (d, J = 3.4 Hz, 1H),
7.017.03, 7.127.13, 7.307.33 (3 m, 1H, 2H, 2H, Ph) 8.57 (s, 1H, NH) ppm; 13C NMR (CDCl3, 151 MHz): 
11.2, 19.4, 19.6 (3 q, 3Me), 26.0, 31.7 (2 t), 52.4 (d), 56.8, 56.9 (2 s, 2 i-C), 114.1 (d, Ph), 118.6 (q, 2JC-F = 38.3
Hz, C-5), 121.1 (q, 1JC-F = 271.9 Hz, CF3), 122.8, 129.5 (2 d, Ph), 131.8 (d, =CH), 134.0 (s, =C-S), 141.9 (s, Ph)
ppm; 19F NMR (CDCl3, 188 MHz):  –67.0 (s, CF3) ppm; IR (film): v 30892873, 1604, 1544, 1506, 1333,
1298, 1244, 1163, 1126, 987, 752 cm-1; HRMS (ESI-TOF): m/z [M+H]+ calcd for C18H22F3N2S: 355.1456;
found: 355.1443.
4.5. Reaction of thiocamphor ((1R)-4f) with nitrile imine 17
Following the general method, the reaction of thioketone (1R)-4f (1.0 mmol) with N-
phenylbenzohydrazonoyl chloride [36] (1.1 equiv.) used as precursor of nitrile imine 17 afforded after 16h at
room temperature a mixture of cycloadduct 18b and insertion product 19b in 64:36 ratio, respectively.
13

Purification of crude reaction mixture by flash column chromatography (SiO2, petroleum ether/CH2Cl2 4:1)
yielded analytically pure 19b (109 mg, 30%, first eluted) and 18b (221 mg, 61%, second eluted).
4.5.1. (1R,2R,4R)-Spiro[camphane-2,2’-(3’,5’-diphenyl-2’,3’-dihydro-1’,3’,4’-thiadiazole)] [16c] (18b)
20
1
Colorless oil; [α]D +674.8 (c 0.06, CHCl3), +687.6 (c 0.44, CHCl3). H NMR (600 MHz, CDCl3): 
0.96, 1.06, 1.13 (3 s, 3H each, 3Me), 1.321.24 (m, 1H), 1.57 (ddd, J = 4.4, 12.0, 13.2 Hz, 1H), 1.68 (tbr, J  4.5
Hz, 1H), 1.741.79 (m, 1H), 1.78 (d, J = 15.4 Hz, 1H), 2.22 (ddd, J = 3.2, 4.5, 15.4 Hz, 1H), 2.82 (ddd, J = 4.4,
9.6, 13.8 Hz, 1H), 7.247.27, 7.317.37, 7.407.42, 7.827.84 (4 m, 1H, 4H, 3H, 2H, 2 Ph) ppm; ESI-MS (m/z):
363.1 (100, [M+H]+).
4.5.2. (1’R,4’R)-1’,7’,7’-Trimethylbicyclo[2.2.1]hept-2’-en-2’-yl N’-phenylbenzohydrazonothioate (19b)
20
1
Colorless oil; [α]D +76.7 (c 0.37, CHCl3). H NMR (600 MHz, CDCl3):  0.82, 0.84 (2 s, 3H each,
2Me), 0.98 (ddd, J = 3.6, 9.2, 12.3 Hz, 1H), 1.17 (s, 3H, Me), 1.24 (ddd, J = 3.7, 9.2, 12.4 Hz, 1H), 1.67 (ddd, J
= 3.6, 8.7, 12.4 Hz, 1H), 1.90 (ddt, J  3.7, 8.7, 12.3 Hz, 1H), 2.35 (tbr, J  3.5 Hz, 1H), 5.69 (d, J = 3.4 Hz, 1H),
6.987.02, 7.247.27, 7.367.40, 7.437.46, 8.018.03 (5 m, 1H, 2H, 3H, 2H, 2H, 2Ph) 8.74 (s, 1H, NH) ppm;
13C NMR (CDCl3, 151 MHz):  11.4, 19.3, 19.7 (3 q, 3Me), 25.9, 31.7 (2 t), 52.3 (d), 56.5, 57.1 (2 s, 2 i-C),
113.3, 120.8, 126.9, 128.1, 128.2, 129.3 (6 d, 2Ph), 131.3 (s, i-C), 132.4 (d, =CH), 136.6, 137.8, 143.8 (3 s, 3 i-
C) ppm; ESI-MS (m/z): 363.2 (100, [M+H]+); elemental analysis calcd (%) for C23H26N2S (362.2): C 76.20, H
7.23, N 7.73, S 8.84; found: C 76.24, H 7.20, N 7.68, S 8.78.
Acknowledgements
The authors thank the National Science Center (Cracow, Poland) for financial support in the framework
of the Maestro-3 #2012/06A/ST5/00219 (MJ), Opus-7 #2014/13/B/ST5/04004 (GM), and Preludium
#2016/21/N/ST5/01254 (GU) grants.
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