Diastereoselective N-sulfonylaminoalkenylation of azulenes from terminal alkynes and azides via N-sulfonyl-1,2,3-triazoles

Article abstract of DOI:10.1021/ol502208w

The development of rhodium-catalyzed diastereoselective N-sulfonylaminoalkenylation of azulenes using N-sulfonyltriazoles is described. This procedure can be successfully applied to rhodium-catalyzed diastereoselective N-sulfonylaminoalkenylation of azule

Full text of DOI:10.1021/ol502208w

Letter
pubs.acs.org/OrgLett
Diastereoselective N‑Sulfonylaminoalkenylation of Azulenes from
Terminal Alkynes and Azides via N-Sulfonyl-1,2,3-triazoles
Sangjune Park, Woo-Soon Yong, Sanghyuck Kim, and Phil Ho Lee*
Department of Chemistry, Kangwon National University, Chuncheon 200-701, Republic of Korea
S
* Supporting Information
ABSTRACT: The development of rhodium-catalyzed diastereoselective N-sulfonylaminoalkenylation of azulenes using N-
sulfonyltriazoles is described. This procedure can be successfully applied to rhodium-catalyzed diastereoselective N-
sulfonylaminoalkenylation of azulenes starting from terminal alkynes and N-sulfonylazides via a three-component semi-one-
pot process.
a
Table 1. Reaction Optimization
zulenes, which are known to be a class of nonbenzenoid
aromatic hydrocarbons, have attracted notable attention
A
because of their significance as natural products,1 biologically
active compounds,2 and molecular materials.3 Thus, develop-
ment of efficient synthetic methods of these compounds from
readily available starting materials has been in continuous
demand.4 Although Hafner and co-workers reported a novel
synthetic approach of azulene in one pot,5 introduction of
valuable substituents onto azulene have limitations due to its
unusual reactivity caused by the polarized π-electron system. For
this reason, synthetic strategies of azulene through an
introduction of a new functional group and its transformation
are extremely desirable for the preparation of azulene derivatives.
Herein, we report diastereoselective introduction of an enamine
functionality on the azulenes from terminal alkynes and azides via
N-sulfonyl-1,2,3-triazoles (Scheme 1).6
a
1 (0.2 mmol) and 2a (0.3 mmol) in the presence of Rh2(Oct)4 (1.0
mol %) were heated in DCE (1.0 mL) at 60 °C for 4−5 h under air.
Ratios in parentheses are Z/E ratios.
conditions could be obtained with Rh2(Oct)4 (1.0 mol %) in
DCE (0.2 M) at 60 °C after 2 h under air and selectively provided
the N-sulfonylaminoalkenylated product 3d in 96% (Z/E = 10:1)
yield (see the Supporting Information).
Scheme 1. Aminoalkenylation of Azulenes
Having established the optimal reaction conditions, we next
examined the scope of this new reaction with respect to variously
substituted 1-tosyl-1,2,3-triazoles 1 to react with azulene (2a)
(Scheme 2). Electronic variation of substituents at the arene
moiety of 4-aryl-1-tosyl-1,2,3-trazoles 1 had little effect on the
reaction efficiency. In fact, 1-[(N-sulfonylamino)alkenyl]-
azulenes 1h and 1i having electron-donating methyl groups on
the phenyl ring were selectively obtained in good to excellent
yields. Triazoles having methoxy substituents on the phenyl ring
were selectively alkenylated to the desired azulenes 3j (84%) and
3k (94%). Halide functional groups commonly used in cross-
coupling reactions were tolerated. For example, substrates
possessing chloro (1l and 1m) and bromo (1n) groups were
First, triazoles 1 having a diversity of sulfonyl groups at the N1
were examined in the reaction with azulene (2a) (Table 1). A
variation of the sulfonyl groups at the N1 of triazoles 1 did not
affect the reaction efficiency. Methane-, n-butane-, and
isopropanesulfonyl triazoles7 selectively afforded the N-
sulfonylaminoalkenylated azulenes at the C1-position in
excellent yields ranging from 91% and 96% (entries 1−3). N-
[(4-Methoxybenzene)sulfonyl]triazole 1e is slightly less reactive
(entry 5). In contrast, (benzenesulfonyl)triazoles having
electron-withdrawing chloro and trifluoromethyl groups gave
the desired azulenes 3f and 3g in excellent yields and
diastereoselectivities (entries 6 and 7). The optimal reaction
Received: July 9, 2014
© XXXX American Chemical Society
A
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Letter
a
a
Scheme 2. Aminoalkenylation of Azulenes
Scheme 3. Aminoalkenylation of Guaiazulenes
a
1 (0.2 mmol) and 2b (0.3 mmol) in the presence of Rh2(Oct)4 (1.0
mol %) were heated in DCE (1.0 mL) at 60 °C for 2−6 h under air.
a
1 (0.2 mmol) and 2a (0.3 mmol) in the presence of Rh2(Oct)4 (1.0
mol %) were heated in DCE (1.0 mL) at 60 °C for 3−12 h under air.
Ratios in parentheses are Z/E ratios.
exclusively with 2-thiophenyl-substituted triazoles to deliver (Z)-
4e (89%). Although 4-n-butyl-1-tosyl-1,2,3-triazole (1r) gave the
desired product 4f in low yield (43%), cyclohexenyl-substituted
triazole (1s) was subjected to 2b in the presence of rhodium
catalyst, producing (Z)-4g in 87% yield.
To demonstrate the synthetic practicability of this N-
sulfonylaminoalkenylation, we next conducted a three-compo-
nent one-pot synthesis of the azulene derivatives (3 and 4)
starting from terminal alkynes 5, N-sulfonyl azides 6, and azulene
2a or guaiazulene 2b (Table 2).8 Although the aminoalkenylated
product 3a was produced from phenylacetylene, tosyl azide, and
azulene in the presence of copper(I) thiophene-2-carboxylate
(CuTC) and Rh2(Oct)4 in DCE, it was slowly decomposed
depending on reaction time under the optimal reaction
all smoothly aminoalkenylated in yields ranging from 77% and
86%. However, introduction of substituents such as bromide and
methoxy at ortho position on the phenyl ring decreased the
diastereoselectivities due to steric reason between phenyl and
azulenyl groups. Electron-withdrawing trifluoromethyl-substi-
tuted triazole 1o underwent N-sulfonylaminoalkenylation in 94%
yield. It is noteworthy that triazoles having electron-withdrawing
chloro and trifluoromethyl groups at the C4 position on the
phenyl ring gave excellent selectivities (Z/E = 20:1). 4-
Nitrophenyl-substituted triazole 1p was less reactive, producing
the desired product 3p in 71% yield (Z/E = 10:1). NOE
experiments indicate that the major isomer of 3p is Z-form (see
the Supporting Information). (Methanesulfonyl)triazole 1q
having a 2-thiophenyl group was smoothly converted to the
aminoalkenylated product 3q in 94% yield. When 4-n-butyl-1-
tosyl-1,2,3-triazole was treated with 2a in the presence of
rhodium catalyst, the desired azulene 3r was obtained in 40%
yield. [(4-Cyclohexenyl)methanesulfonyl]triazole 1s turned out
to be compatible with the optimal reaction conditions, providing
the desired azulene 3s in 89% yield.
a
Table 2. Aminoalkenylation in a Semi-One-Pot Process
Guaiazulene (1,4-dimethyl-7-isopropylazulene) was then
investigated in the N-sulfonylaminoalkenylation using various
triazoles (Scheme 3). Under the optimal reaction conditions,
guaiazulene (2b) was readily aminoalkenylated with 4-phenyl-1-
tosyl-1,2,3-triazole (1a), producing exclusively (Z)-4a in 96%
yield. The structure of (Z)-4a was unambiguously determined by
X-ray crystallography and NOE (see the Supporting Informa-
tion). Likewise, the reaction efficiency was not influenced by the
electronic properties of the triazoles. Triazoles having methyl and
chloro groups on the phenyl ring worked equally well in the
reaction with guaiazulene to give the corresponding azulenes 4b
(96%) and 4c (85%). 4-Aryl-1-mesyl-1,2,3-triazoles did not
effect the reaction efficiency. Guaiazulene was subjected to 1-
mesyl-4-phenyl-1,2,3-triazole, leading to the formation of 4d in
93% yield. The aminoalkenylation of guaiazulene proceeded
a
Reactions were carried out in a semi-one-pot process (see the
Supporting Information for detailed procedures). Ratios in paren-
theses are Z/E ratios.
B
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Letter
conditions. As a control experiment, when the azulene 3a was
treated with CuTC, it was decomposed without isolable
compounds, indicating that azulene is sensitive to Cu catalyst.
Thus, we attempted synthesis of the azulene derivatives (3 and 4)
via a three-component semi-one-pot method. Phenylacetylene
5a (0.20 mmol) and tosyl azide 6a (0.22 mmol) in the presence
of CuTC (10 mol %) in DCE (1 mL) were placed in a reaction
vessel, and the reaction mixture was stirred at 50 °C. After
disappearance of both 5a and 6a on TLC for 3 h at room
temperature, the reaction mixture, including a newly prepared N-
tosyltriazole, was filtered via a short pad of silica and used as the
crude product in the following Rh-catalyzed N-sulfonylaminoal-
kenylation with azulene to produce 3a in 73% (Z/E = 10:1) yield
(entry 1). The three-component semi-one-pot method worked
equally well with aromatic acetylene having 3-methyl, 4-methyl,
4-methoxy, 3-chloro, and 4-trifluoromethyl groups on the phenyl
ring, producing a wide range of N-sulfonylaminoalkenylated
azulenes (3h−o) in yields ranging from 56% to 78% (entries 2−
6). We were pleased to obtain guaiazulene derivatives (4a−c) in
good to excellent yields using guaiazulene (2b) and N-
tosyltriazole (1a) generated in situ from terminal aromatic
alkyne and tosyl azide 6a (entries 8−10). N-Mesyltriazole
generated in situ from alkyne and mesyl azide 6b turned out to be
compatible with the reaction conditions, producing 3b and 4d in
good yields (entries 7 and 11).
Scheme 4. Plausible Mechanism
Next, second N-sulfonylaminoalkenylation of 3 obtained from
triazole 1 and azulene 2 was attempted. When 3a was again
treated with 1a (1.5 equiv) under the optimal reaction
conditions, the desired compound 3t was produced in 63%
yield (eq 1). N-Sulfonylaminoalkenylated 3n was also subjected
together with liberation of molecular nitrogen. Nucleophilic
addition of azulene 2a to the electrophilic carbene center of II
affords the rhodium-bound zwitterionic intermediate III (path
A). Then, anionic rhodium of III releases an electron pair, which
moves into the imine moiety to make the nitrogen atom basic
enough to abstract an allylic proton to provide the (N-
sulfonylamino)alkenylated azulene (3 and 4) with regeneration
of the rhodium(II) catalyst. Alternatively, [2 + 1] cycloaddition
of α-imino carbene II to 1,2-olefin in a five-membered ring of
azulene 2a could give rise to the cyclopropylimine IV. After that,
intramolecular proton transfer of IV furnishes the N-
sulfonylaminoalkenylated azulene (path B). Another plausible
mechanism is that the concerted directed insertion of II into a
C−H bond of azulene would lead to the formation of V, which
upon imine−enamine tautomerization affords 3 and 4 (path C).
However, because the cyclopropyl imine IV and imine-
substituted azulene V were not observed in NMR studies in
DCE-d4, paths B and C are ruled out in the catalytic cycle at the
present stage (see the Supporting Information). There is no
formation of VI via Clock rearrangement of cyclopropyl imine IV
(path D). The elucidation of the detailed mechanism of the N-
sulfonyl aminoalkenylation of azulene derivatives must wait
further study.
to triazole 1n to provide 3u in 66% yield. The structure of (Z,Z)-
3u was unambiguously determined by X-ray crystallography (eq
2, see the Supporting Information).
To our delight, when azulene 3n (Z/E = 1.3:1) having a 2-
bromophenyl-substituted enamine moiety was treated with CuI
(5 mol %), DMEDA (10 mol %), and K3PO4 (2 equiv) in toluene
at 70 °C for 2 h, the cross-coupling product, 3-(azulen-1-
yl)indole (7a), was obtained in quantitative yield (eq 3).9 This
result indicates that isomerization of the enamine double bond in
3n easily occurred during the coupling reaction. Employment of
this intramolecular cross-coupling reaction to 1,3-bis(N-
sulfonylamino)alkenyl-substituted azulene 3u provided 1,3-
bis(indolin-3-yl)azulene 7b in 74% yield (eq 4).
A plausible mechanism for the N-sulfonylaminoalkenylation of
azulene derivatives is described in Scheme 4. First, a reversible
ring−chain tautomerization of N-sulfonyl-1,2,3-triazole 1
provides α-diazo imine I.10 The sequential irreversible reaction
of I with rhodium(II) affords α-imino rhodium(II) carbenoid II
In conclusion, we have reported an efficient rhodium-catalyzed
diastereoselective N-sulfonylaminoalkenylation of azulenes with
N-sulfonyl-1,2,3-azides, producing a myriad of aminoalkenylated
azulenes together with N2 as the single byproduct. This
procedure can be successfully applied to rhodium-catalyzed
diastereoselective N-sulfonylaminoalkenylation of azulene de-
rivatives starting from terminal alkynes and N-sulfonylazides
through a three-component semi-one-pot process.
C
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data, X-ray crystallo-
graphic data for 3u and 4a (CIF), and 1H, 13C NMR, and NOE
spectra for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: phlee@kangwon.ac.kr.
Notes
(10) (a) Grunanger, P.; Finzi, P. V. Tetrahedron Lett. 1963, 4, 1839.
̈
The authors declare no competing financial interest.
(b) Harmon, R. E.; Stanley, F., Jr.; Gupta, S. K.; Johnson, J. J. Org. Chem.
1970, 35, 3444. (c) Mckinney, M. A.; Patel, P. P. J. Org. Chem. 1973, 38,
4059. (d) Himbert, G.; Frank, D.; Regit, M. Chem. Ber. 1976, 109, 370.
ACKNOWLEDGMENTS
■
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government (MSIP)
(2014001403).
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