Generation of cycloheptynes and cyclooctynes via a sulfoxide-magnesium exchange reaction of readily synthesized 2-sulfinylcycloalkenyl triflates

Article abstract of DOI:10.1039/c5cc01784j

Cycloheptynes and cyclooctynes were efficiently generated via a sulfoxide-magnesium exchange reaction of readily synthesized 2-sulfinylcycloalkenyl triflates. Cycloadditions between various ynophiles and the cycloalkynes generated by this method proceeded

Full text of DOI:10.1039/c5cc01784j

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DOI: 10.1039/C5CC01784J
COMMUNICATION
Generation of cycloheptynes and cyclooctynes via a
sulfoxide–magnesium exchange reaction of readily
synthesized 2-sulfinylcycloalkenyl triflates
Cite this: DOI:
10.1039/x0xx00000x
Suguru Yoshida, Fumika Karaki, Keisuke Uchida and Takamitsu Hosoya*
Received 00th xxxxx 201x,
Accepted 00th xxxxx 201x
DOI: 10.1039/x0xx00000x
www.rsc.org/
A. E. Guitián, et al., 1998; K. N. Houk, N. K. Garg, et al., 2014
Cycloheptynes and cyclooctynes were efficiently generated via a
sulfoxide–magnesium exchange reaction of readily synthesized 2-
sulfinylcycloalkenyl triflates. Cycloadditions between various
ynophiles and the cycloalkynes generated by this method proceeded
efficiently, providing an easy method to prepare a wide range of
heterocycles fused with a seven- or eight-membered carbocycles.
1. HOCH2CH2OH
HX
2. Me3SiCl, n-BuLi
then H2O
OTf
O
CsF
3. L-Selectride
4. PhNTf2
SiMe3
Br
2
1
3
6
B. K. Banert, et al., 2006
iPr
1. NH3, MeOH
H2NOSO3H
N
N
N
Cycloalkynes with an angled-strained carbon–carbon triple bond are
synthetically useful compounds which exhibit greater reactivity than
acyclic alkynes in a linear structure.1 Since the discovery by Bertozzi
and co-workers in 2004 that cyclooctyne spontaneously reacts with
azides under mild conditions,2 a variety of cyclooctynes as well as
cyclononynes have been developed and applied to the efficient
conjugation of molecules in broad disciplines, including chemical
biology and materials science.3 In contrast to these isolable medium-
sized cycloalkynes, those with a ring size less than seven, such as
cyclopentynes, cyclohexynes, and also arynes,4 are non-isolable.1,5
These remarkably reactive species are generated in situ from their
precursors and are utilized in reactions with various ynophiles; this
approach allows previously inaccessible polycyclic compounds to be
prepared very easily. The fluoride-mediated generation of
cyclohexyne (1) from 2-(trimethylsilyl)cyclohexenyl triflate (2) and
cycloadditions with dienes or 1,3-dipoles are good examples of such
reactions (Fig. 1A).5a,b
N
2. Ag2O
N
40–60 °C
or
hν
N
5
4
iPr
C. Previous Work
sulfoxide–metal
exchange
OTf
OTf
+Mtl
β-elimination
p-tol
S
7
O
D. This Work
1. α-thiolation
2. triflylation
OTf
O
R–Mtl
p-tol
3. oxidation
S
9
simple
cyclic ketone
8
3
O
OTf
sulfoxide–metal
exchange
β-elimination
+Mtl
Fig. 1 Methods for generating highly reactive cycloalkynes.
With some exceptions,6 cycloheptynes are also difficult to isolate
and are therefore synthetically used by generating them from their
corresponding precursors.1,7 For example, cycloheptynes were
generated via oxidation of 1,2-dihydrazonocycloheptane,7a
photolysis of cycloheptene-fused 1-tosylamino-1,2,3-triazole
anion,7b treatment of 1-bromocycloheptene with a base,7c,d
thermolysis of cycloheptenocyclopropenone,7e and treatment of
cyclohexylidenemethyliodonium salt with a base.7f More recently, an
efficient method for generating cycloheptyne (3) based on
thermolytic or photolytic liberation of nitrogens from bis-spirocyclic
diazirine 4, which was prepared from diimine 5, was reported (Fig.
1B).7g Alternatively, cycloheptyne–{Co2(CO)6} complexes were
successfully applied to a [4+2] cycloaddition reaction with acyclic
dienes.7h Because cycloheptynes are potentially useful intermediates
in the preparation of sp3-rich polycyclics and thereby facilitate the
construction of a chemical library which contains diversity-enriched
molecules,8 the development of methods for the efficient generation
of cycloheptynes as well as accessible precursors, which are
applicable to a variety of cycloheptynes remain highly sought after.
In the course of our studies on aryne chemistry,9 we recently
found that benzyne (6) could be efficiently generated from ortho-
sulfinylphenyl triflate 7 by treatment with a Grignard reagent, which
triggered a sulfoxide–magnesium exchange reaction and subsequent
β-elimination of the triflyloxy group (Fig. 1C).9c We hypothesized
that this approach could be applied to the generation of cycloheptyne
(3); we consequently designed 2-sulfinylcycloheptenyl triflate 8 as a
precursor, which was anticipated to be easily prepared from
cycloheptanone (9) (Fig. 1D). Herein, we demonstrate an efficient
method for generating cycloheptynes on the basis of this idea.
This journal is © The Royal Society of Chemistry 201x
Chem. Commun., 201x, 00, 1-4 | 1

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ketone, enol triflylation,11 and oxidation of the sulfur atom (Fig. 3).
Et
a
a
b
a
b
a
b
a
b
For example, 2-(4-tolylsulfinyl)cycloheptenyl triflate (8) was
b
Et
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prepared from cycloheptanone (9) in 76% overall yield. This simple
method was applicable to the synthesiDs OI: 10.1039/C5CC01784J
of a series of 2-
13
3
1
6
internal angles
at the alkyne moiety
(upper: a, lower: b)
178.9°
178.9°
153.1°
154.4°
146.0°
146.0°
131.9°
131.9°
127.2°
127.2°
sulfinylcycloalkenyl triflates, including benzo- or thieno-fused
cycloheptyne precursors 15–17 as well as cyclohexyne precursor 18
and cyclooctyne precursors 19 and 20.
LUMO (eV)
HOMO (eV)
0.0
0.0
–0.4
–6.7
–1.4
–6.8
–2.4
–7.5
–6.9
–6.8
After extensive screening of the conditions for generating
cycloheptyne (3) from precursor 8 using benzyl azide as an ynophile,
we found that several Grignard reagents were suitable for the
efficient activation of 8 (Table 1). Our initial attempt, treating of a
mixture of 8 and benzyl azide (5.0 equiv)12 in THF with
phenylmagnesium bromide (1.8 equiv) at −78 °C, which were the
best conditions for generating arynes from ortho-sulfinylaryl
triflates,9c provided the desired cycloadduct 21a in low yield, and
unreacted 8 was recovered (entry 1). Performing the reaction at a
higher temperature (−40 or 0 °C) significantly improved the yield of
the product (entries 2 and 3). A wide range of alkyl Grignard
reagents such as methyl, ethyl, isopropyl, and turbo-Grignard13
reagents, also triggered the efficient generation of cycloheptyne
(entries 4–7), although tert-butylmagnesium chloride did not work
well (entry 8). (Trimethylsilylmethyl)magnesium chloride, which
served as a good activator for generating highly reactive arynes via
the iodo–magnesium exchange reaction of ortho-iodoaryl
triflates,9d,e,g also gave a poor result in this case (entry 9). In addition,
treatment of the mixture with n-butyllithium14 provided a complex
mixture that contained a small amount of desired 21a (entry 10).
MeN3
S
LUMO –1.2 eV
HOMO –7.3 eV
a
b
a
a
a
b
b
b
10
11
12
14
O
internal angles
at the alkyne moiety
(upper: a, lower: b)
143.1°
145.0°
142.3°
145.7°
140.0°
145.8°
154.7°
154.7°
–0.2 eV
LUMO
LUMO (eV)
HOMO (eV)
–1.1
–6.3
–1.6
–6.2
–1.0
–6.0
–1.6
–6.0
HOMO –6.5 eV
Fig. 2 DFT (B3LYP/6-311+G(d,p)) calculation results for various
alkynes and ynophiles.
Prior to conducting the experimental studies, we performed DFT
calculations at the B3LYP/6-311+G(d,p) level for various
cycloalkynes to estimate their reactivities (Fig. 2). The internal
angles at the alkyne moieties of unstable cycloalkynes 1, 3, and 10–
12 were calculated to be more than 10° smaller than those of isolable
cyclooctynes such as 13 and 14. In particular, the internal angles of
benzo-fused and thieno-fused cycloheptynes 10–12 were smaller
than that of cycloheptyne (3), indicating that these ring-fused
cycloheptynes would be less stable than unfused 3. The slightly
polarized carbon–carbon triple bond of 10–12,10 which is a
consequence of their unsymmetrically distorted structures, implied
the induction of regioselectivity in the cycloaddition with an
unsymmetric ynophile. Moreover, the HOMO energies of these
cycloalkynes were higher than that of benzyne (6), suggesting that
cycloalkynes would exhibit a more electron-rich nature as compared
with benzyne. Given the energy gaps between cycloheptyne (3) and
methyl azide or furan, we chose to use an azide rather than furan as
an ynophile to optimize the conditions for generating cycloheptyne.
2-Sulfinylcycloalkenyl triflates 8, and 15–20, which are the
cycloalkyne precursors used in this study, were easily prepared from
the corresponding cycloalkanones in three steps: α-thiolation of the
Table 1 Optimization of the reaction conditions
BnN3 (5.0 equiv)
OTf
N
N
R–Mtl (1.8 equiv)
N
p-tol
THF
Temp., 15 min
S
Bn
21a
O
8
Entry
1
R–Mtl
Temp. (°C)
Yield (%)a
PhMgBr
PhMgBr
PhMgBr
MeMgBr
EtMgBr
i-PrMgCl
−78
−40
0
37
2
93
3
quant. (91)b
quant. (94)b
4
0
5
0
91
89
79
2
6
0
O
O
p-tol
S
7
i-PrMgCl·LiCl
t-BuMgCl
0
S p-tol
LiN(i-Pr)2
KN(SiMe3)2
PhNTf2
O
OTf
mCPBA
8
0
THF
–78 ºC to rt
THF
–78 ºC
CH2Cl2
0 ºC to rt
p-tol
S
9
Me3SiCH2MgCl
n-BuLi
0
13
2
9
O
8
76%
(3 steps)
10
0
a Yields based on 1H NMR analyses. b Isolated yields in parentheses.
S
OTf
OTf
OTf
The efficient method of generating cycloheptyne (3) from 8 was
applicable to cycloadditions of 3 with an array of ynophiles (Fig. 4).
Sterically hindered 2,6-diisopropylphenyl azide, which has an azido
group with remarkably enhanced ynophilicity,15 efficiently reacted
with cycloheptyne, affording triazole 21b in almost quantitative
yield (Fig. 4A). Cycloadditions of azides bearing halogens or a furan
ring with cycloheptyne also took place without damaging the
reactive moieties, affording cycloadducts 21c and 21d in good to
excellent yields. Azides bearing an electrophilic amide moiety or a
nucleophilic piperidino group also uneventfully provided the
corresponding triazoles 21e and 21f in excellent yields. Other 1,3-
dipoles such as nitrones and (trimethylsilyl)diazomethane also
p-tol
p-tol
p-tol
S
S
S
O
O
O
15
78%
16
68%
17
40%
OTf
OTf
OTf
p-tol
p-tol
S
S
p-tol
S
O
O
O
18
54%
19
69%
20
19%
Fig. 3 Preparation of cycloalkyne precursors. Three-step yields from
corresponding cyclic ketones are shown for 8 and 15–20.
2 | Chem. Commun., 201x, 00, 1-4
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ynophile (5.0 equiv)
PhMgBr (1.8 equiv)
BnN3 (5.0 equiv)
R–Mtl (1.8 equiv)
OTf
OTf
N
N
N
cycloadduct
p-tol
THF
0 ºC, 15 min
p-tol
THF
0 ºC, 15 min
S
S
View Article Online
8
Bn
O
DOI: 10.1039/C5CC01784J
O
A. Reaction with azides
N
N
N
N
N
N
N
N
N
S
N
N
N
N
N
N
N
N
N
N
N
N
N
i-Pr
Br
F
N
N
Bn
Bn
i-Pr
21b
Cl
21c
Bn
Bn
Bn
27
+
28
+
29
+
30
30%
31
78%
21d
93%
O
81%
99%
minor isomer
87%
(74:26)
minor isomer
91%
(77:23)
minor isomer Me3SiCH2MgCl [PhMgBr]
71%
(72:28)
[PhMgBr]
(3.3 equiv)
0 °C to rt, 16 h
N
N
N
N
N
N
[MeMgBr]
[MeMgBr]
N
Fig. 5 Cycloadditions between various cycloalkynes and benzyl
azide. The activator used and the modified conditions are shown in
the brackets.
21e
78%
[at –40 °C]
21f
97%
NMe2
F
O
B. Reaction with nitrones
O
O
O
N
t-Bu
N
t-Bu
N Me
PhMgBr
(1.8 equiv)
OTf
Ph
22a
70%
22b
55%
I
p-tol
THF
0 ºC, 15 min
S
MeO
OMe
22c
51%
Cl
O
[with i-PrMgCl·LiCl at –40 °C]
D. Reaction with dienes
20
14
92%
C. Reaction with Me3SiCHN2
H
N
Scheme 1 Preparation of dibenzo-fused cyclooctyne 14.
N
Ph
N
O
23
83%
24
not detected
[0 °C, 2 h]
25a
not detected
Grignard reagent was used. The moderate regioselectivity observed
in these cases is attributed to steric hindrance and polarized charge
on the alkyne moiety of cycloheptynes as computationally estimated
(Fig. 2). Notably, cycloadduct 28 was obtained without
isomerization of the olefin moiety. Unfortunately, the efficiency of
the cycloaddition of the more strained cyclohexyne (1) with benzyl
azide was lower than that of cycloheptynes, providing cyclohexene-
fused triazole 30 only in low yield. In contrast, comparatively strain-
relaxed cyclooctyne (13) was produced from precursor 19 via our
method, which smoothly formed triazole 31 by reacting with the
azide. Furthermore, the cycloalkyne formation in the absence of an
ynophile enabled the preparation of isolable cyclooctynes, as clearly
demonstrated by the treatment of cycloalkyne precursor 20 with
phenylmagnesium bromide to afford dibenzo-fused cyclooctyne 14
in high yield (Scheme 1).
A competition study showed that the sulfoxide–magnesium
exchange reaction of 2-sulfinylcycloheptenyl triflate 8 was much
slower than that of ortho-sulfinylaryl triflate 7 (Scheme 2). The
treatment of an equimolar mixture of sulfoxides 8 and 7 with a
phenyl Grignard reagent in the presence of an excess amount of
benzyl azide predominantly afforded benzyne-derived cycloadduct
32 with almost complete consumption of benzyne precursor 7; in
contrast, most of cycloheptyne precursor 8 was recovered.
(quant. based on 1H NMR analysis)
Ph
Ph
O
Ph
Ph
Ph
Ph
26
68%
[with tetracyclone, 0 °C, 1.5 h]
25b
88%
[ynophile 1.0 equiv]
Fig. 4 Cycloadditions between cycloheptyne and various ynophiles.
Isolated yields are shown below the compound numbers. The
modified conditions are shown in the brackets.
served as good ynophiles, which reacted with cycloheptyne to afford
cycloheptene-fused dihydrooxazoles 22a–c or a desilylated pyrazole
23 in moderate to good yields (Figs. 4B and 4C). Unfortunately,
attempts to carry out Diels–Alder reactions between cycloheptyne
and N-phenylpyrrole or furan (Fig. 4D), which react with benzyne
efficiently, did not afford the desired products 24 or 25a and yielded
a complex mixture. On the other hand, more reactive dienes such as
1,3-diphenylisobenzofuran and electron-deficient tetracyclone
participated in the Diels–Alder reaction with cycloheptyne (3) to
yield the corresponding cycloadducts 25b and 26 efficiently (Fig.
4D).
The developed method was also successfully applied to the
generation of other cycloheptynes such as benzo- or thieno-fused
10–12 as well as cyclooctynes 13 and 14. Despite the increased ring
strain predicted by the DFT calculations (Fig. 2), cycloheptynes
fused with an aromatic ring at the adjacent to the alkyne moiety were
efficiently generated and reacted with benzyl azide to afford tricyclic
triazoles 27–29 in high yields (Fig. 5). In the case of benzo-fused
substrates, the use of methylmagnesium bromide was more practical
because chromatographic separation of cycloadducts from methyl p-
tolyl sulfoxide, which was formed through the sulfoxide–magnesium
exchange reaction, was easier than in the case where a phenyl
BnN3
(0.98 mmol)
PhMgBr
OTf
OTf
N
N
N
N
(0.40 mmol)
+
N
N
+
+
p-tol
p-tol
THF
–78 ºC, 15 min
S
S
Bn
Bn
O
O
21a
1%
32
54%
(0.11 mmol)
8
(0.20 mmol)
7
(0.20 mmol)
(0.002 mmol)
+
recovery of 8
92%
(0.18 mmol)
recovery of 7
3%
(0.006 mmol)
Scheme 2 A competitive generation of cycloheptyne and benzyne.
Yields based on 1H NMR analysis.
This journal is © The Royal Society of Chemistry 201x
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N3
T. Rutjes, J. C. M. van Hest, D. J. Lefeber, P. Friedl and F. L. van
Delft, Angew. Chem., Int. Ed., 2010, 49, 9422; (f) I. Kii, A. Shiraishi,
T. Hiramatsu, T. Matsushita, H. Uekusa, S. Yoshida, MV.iYewamArtaicmleoOtonl,inAe.
N3
Boc
N
34
N
N
Kudo, M. Hagiwara and T. Hosoya, Org. Biomol. Chem., 2010, 8,
DOI: 10.1039/C5CC01784J
(1.0 equiv)
N
4051; (g) S. Yoshida, Y. Hatakeyama, K. Johmoto, H. Uekusa and T.
Hosoya, J. Am. Chem. Soc., 2014, 136, 13590; (h) R. Ni, N. Mitsuda,
T. Kashiwagi, K. Igawa and K. Tomooka, Angew. Chem., Int. Ed.,
2015, 54, 1190; For reviews, see: (i) E. M. Sletten and C. R. Bertozzi,
Angew. Chem., Int. Ed., 2009, 48, 6974; (j) M. F. Debets, C. W. J. van
der Doelen, F. P. J. T. Rutjes and F. L. van Delft, ChemBioChem,
2010, 11, 1168; (k) J. C. Jewett and C. R. Bertozzi, Chem. Soc. Rev.,
2010, 39, 1272.
33
(5.0 equiv)
(MeCN)4CuBF4
(5.0 mol %)
TBTA
OTf
PhMgBr
(3.0 equiv)
(5.1 mol %)
p-tol
S
N
CH2Cl2
rt, 2 d
THF
–40 ºC, 15 min
O
N
8
N
88%
84%
N
35
Boc
4
5
6
7
For some recent reviews on arynes, see: (a) D. Peña, D. Pérez and E.
Guitián, Angew. Chem., Int. Ed., 2006, 45, 3579; (b) H. Yoshida and K.
Takaki, Heterocycles, 2012, 85, 1333; (c) A. Bhunia, S. R. Yetra and
A. T. Biju, Chem. Soc. Rev., 2012, 41, 3140; (d) A. V. Dubrovskiy, N.
A. Markina and R. C. Larock, Org. Biomol. Chem., 2013, 11, 191.
(a) N. Atanes, S. Escudero, D. Peŕez, E. Guitiań and L. Castedo,
Tetrahedron Lett., 1998, 39, 3039; (b) J. M. Medina, T. C. McMahon,
G. Jiménez-Osés, K. N. Houk and N. K. Garg, J. Am. Chem. Soc.,
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Soc., 2014, 136, 15489.
(a) A. Krebs and H. Kimling, Tetrahedron Lett., 1970, 11, 761; (b) A.
Krebs and H. Kimling, Angew. Chem., Int. Ed. Engl., 1971, 10, 509;
(c) A. Krebs and H. Kimling, Liebigs Ann. Chem., 1974, 2074; (d) G.
de Almeida, E. M. Sletten, H. Nakamura, K. K. Palaniappan and C. R.
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(a) G. Wittig and A. Krebs, Chem. Ber., 1961, 94, 3260; (b) F. G.
Willey, Angew. Chem., Int. Ed. Engl., 1964, 3, 138; (c) W.
Tochtermann, K. Oppenländer and U. Walter, Chem. Ber., 1964, 97,
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Scheme 3 Synthesis of bistriazole 35.
Employing cycloheptynes in a sequential conjugation to an
ynophile bearing another transformable group facilitated the
synthesis of a variety of compounds containing a cycloheptene-
annulated heterocyclic substructure. For example, cycloaddition of
cycloheptyne generated from precursor 8 with 4-ethynylphenyl azide
(33) and subsequent copper-catalyzed azide–alkyne cycloaddition
(CuAAC)16 with azide 34 at the terminal alkyne moiety afforded
bistriazole 35 in high yield (Scheme 3). Thus, the use of different
1,3-dipole platform molecules in combination with other types of
transformations enables expeditious construction of a chemical
library that consists of highly diverse compounds.17
In summary, we demonstrated that highly reactive cycloheptynes
and cyclooctynes could be efficiently generated via sulfoxide–
magnesium exchange reaction of 2-sulfinylcycloalkenyl triflates,
which were readily synthesized from simple cyclic ketones.
Cycloalkynes generated by this method reacted with an array of
ynophiles, easily providing a variety of heterocycles fused with a
medium-sized carbocycle. Further studies on the scope of the method
and construction of a unique chemical library are now in progress.
8 F. Lovering, J. Bikker and C. Humblet, J. Med. Chem., 2009, 52, 6752.
9
(a) S. Yoshida and T. Hosoya, Chem. Lett., 2013, 42, 583; (b) Y.
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Lett., 2015, 44, in press, doi: 10.1246/cl.150060.
Acknowledgements
The authors thank Central Glass Co., Ltd. for their generous gift of
Tf2O. This work was supported by the Platform for Drug Discovery,
Informatics, and Structural Life Science from MEXT, Japan; JSPS
KAKENHI Grant Numbers 24310164 (T.H.), 26350971 (S.Y.) and
256522 (F.K.); Suntory Institute for Bioorganic Research (S.Y.); and
the Cooperative Research Program of the Network Joint Research
Center for Materials and Devices (IMCE, Kyushu University).
10 See ESI†.
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12 The reaction using 2.5 equiv of benzyl azide also afforded the
cycloadduct 21a in an acceptable yield (94%, see ESI†). We used 5.0
equiv of ynophiles in this study to enhance the trapping efficiency of
highly reactive cycloalkynes.
Notes and references
Laboratory of Chemical Bioscience, Institute of Biomaterials and
Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-
Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
*E-mail: thosoya.cb@tmd.ac.jp
†
Electronic Supplementary Information (ESI) available: Experimental
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4 | Chem. Commun., 201x, 00, 1-4
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Graphical abstract for the contents page
View Article Online
DOI: 10.1039/C5CC01784J
xxx
Generation of cycloheptynes and cyclooctynes
via a sulfoxide–magnesium exchange reaction of
readily synthesized 2-sulfinylcycloalkenyl triflates
Suguru Yoshida, Fumika Karaki, Keisuke Uchida and
Takamitsu Hosoya*
Cycloheptynes and cyclooctynes have been efficiently generated
via a sulfoxide–magnesium exchange reaction of readily
synthesized 2-sulfinylcycloalkenyl triflates.
This journal is © The Royal Society of Chemistry 201x
Chem. Commun., 201x, 00, 1-4 | 5