Synthesis of 5-Iodo-1,2,3,4-tetrahydropyridines by Rhodium-Catalyzed Tandem Nucleophilic Attacks Involving 1-Sulfonyl-1,2,3-triazoles and Iodides

Article abstract of DOI:10.1021/acs.orglett.6b02428

Sodium iodide is used for the first time as a nucleophile to trap an α-imino rhodium carbene, which triggers a tandem process involving intermolecular nucleophilic attack and intramolecular S_N2 reaction. A series of 5-iodo-1,2,3,4-tetrahydropyridines are obtained in high yield, and the synthetic utility of the products is demonstrated in cross-coupling reactions and the construction of biorelated polycyclic compounds.

Full text of DOI:10.1021/acs.orglett.6b02428

Letter
pubs.acs.org/OrgLett
Synthesis of 5‑Iodo-1,2,3,4-tetrahydropyridines by
Rhodium-Catalyzed Tandem Nucleophilic Attacks Involving
1‑Sulfonyl-1,2,3-triazoles and Iodides
Zengming Man, Haican Dai, Yinping Shi, Dongdong Yang, and Chuan-Ying Li*
Department of Chemistry, Zhejiang Sci-Tech University, Xiasha West Higher Education District, Hangzhou 310018, China
S
* Supporting Information
ABSTRACT: Sodium iodide is used for the first time as a
nucleophile to trap an α-imino rhodium carbene, which triggers a
tandem process involving intermolecular nucleophilic attack and
intramolecular SN2 reaction. A series of 5-iodo-1,2,3,4-tetrahydro-
pyridines are obtained in high yield, and the synthetic utility of the
products is demonstrated in cross-coupling reactions and the
construction of biorelated polycyclic compounds.
s one of the most important intermediates, metal carbenes
derived from diazo compounds or N-tosylhydrazones have
β-hydride migration, (b) the nucleophilic attack by the leaving
group intramolecularly or intermolecularly, and (c) quenching
of intermediate A by the counterion of the nucleophile.
We believe that the nucleophilicity of Nu− is the key factor, and
after several experiments, we found that when 1a was employed
as the substrate and NaI as the nucleophile, 5-iodo-1,2,3,4-
tetrahydropyridine 2a could be obtained in 65% yield in the pre-
sence of 3 mol % Rh2(piv)4 and 0.5 equiv of 18-crown-6 (eq 1).
A
been applied in various powerful transformations.1 Environ-
mentally benign approaches starting from alkynes have also
been extensively studied in recent years.2 With landmark con-
tributions from the groups of Fokin, Gevorgyan, and Murakami3
and subsequent research from other groups,4 1-sulfonyl-1,2,3-
triazoles, readily available from copper-catalyzed azide−alkyne
cycloaddition,5 can now be conveniently used as precursors of
α-imino carbenes. Compared with the traditional α-oxo carbene
species, the increased nucleophilic activity of the nitrogen atom
makes α-imino carbenes better dipoles, which participate in
numerous cycloaddition reactions leading to N-heterocycles.6
However, as far as we know, in all previous reports the
electrophilic part and the nucleophilic part were installed in the
same trapping reagent.7 If the two parts can be set up in two
different reagents, more opportunity could be offered for the
design of efficient transformations. As part of our research
on carbene-mediated chemical transformations,8 4-bromo-1,2-
dihydroisoquinolines were obtained via intramolecular trapping
of α-imino carbenes by tethered benzyl bromide.8f This reaction
proved the strong electrophilicity of α-imino carbenes. We
envisioned that if we installed a leaving group in the triazole,
then intermolecular nucleophilic attack at the carbene carbon
could be realized by an appropriate reactant, and the increased
nucleophilicity of the nitrogen atom would facilitate the intra-
molecular nucleophilic substitution, leading to the formation
of 1,2,3,4-tetrahydropyridines 2 (Scheme 1). It is apparent that
several issues should be addressed here: (a) the participation of
The 1,2,3,4-tetrahydropyridine ring is the key substructure of
various natural products,9 and some of its derivatives are used
as food additives, vacuolar pigments, or agricultural pesticides.10
Thus, the efficient synthesis of this structure is of great
importance. Moreover, the vinyl iodide moiety in 2a provides
the possibility of further functionalization using transition-metal-
catalyzed coupling reactions.
With the original result in hand (Table 1, entry 1), we first
screened different solvents (toluene, ClCH2CHCl2, and CHCl3).
When chloroform was used, the yield of 2a increased to 88%
(entry 4). Gratifyingly, the use of other Rh(II) catalysts was also
efficient (entries 5−8), and the yield of 2a was further improved
to 94% when 3 mol % Rh2(esp)2 was used (entry 8). Switching
18-crown-6 to dibenzo-18-crown-6 did not result in a better
yield (entry 9). When the catalyst loading was decreased to
1 mol %, 2a was obtained in only 59% yield (entry 10). When
the reaction was carried out in the presence of 0.3 equiv of
18-crown-6, the cyclization went to completion in 130 min, and
2a was isolated in 83% yield (entry 11).
Scheme 1. Initial Hypothesis
Received: August 14, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02428
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Letter
a
Electron-donating substituents on the aromatic ring had a
negative effect on the yield of the products (2f and 2g), whereas
halo-substituted substrates furnished the tetrahydropyridines in
better yields (2h, 2j, and 2k). When substrate 1i bearing a
p-bromophenyl group was treated with NaI in the presence
of Rh2(esp)2, 2i was isolated in 68% yield after 1.2 h. The
substituent at the 3-position of the N-heterocycle could also be
an alkyl group. 2l and 2n were produced in 70% and 52% yield,
respectively, and the optimal conditions were compatible with
the TBSO group. We also tried a substrate with two MsO
groups (1m; see the Supporting Information). In this case,
2.5 equiv of NaI was used. One MsO group participated in
the cyclization, and the other one was substituted with an
iodide group (2m). When substrates with an alkyl group at the
α-position of the MsO group were used, 2o and 2p were
synthesized in lower yields. Finally, substrates with a phenyl
linker were also tested, and 4-iodo-1,2-dihydroisoquinolines
2q and 2r were obtained smoothly in high yields.
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
solvent
t (min)
yield (%)
1
2
3
4
5
6
7
8
Rh2(piv)4
Rh2(piv)4
Rh2(piv)4
Rh2(piv)4
Rh2(OAc)4
Rh2(oct)4
Rh2(S-nttl)4
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
1,2-DCE
35
45
65
68
14
88
50
77
61
94
81
59
83
toluene
ClCH2CHCl2
chloroform
chloroform
chloroform
chloroform
chloroform
chloroform
chloroform
chloroform
70
30
80
60
90
70
c
9
100
105
130
d
10
e
11
As shown in Scheme 3, two plausible pathways are proposed
for this novel cyclization. In path a, substitution of OMs with
a
0.2 mmol 1a, 0.3 mmol NaI, 0.1 mmol 18-crown-6 and 0.006 mmol
rhodium(II) catalyst dissolved in 2 mL of solvent and heated to reflux
under N2. Isolated yield. 0.5 equiv of dibenzo-18-crown-6 was added
b
c
Scheme 3. Proposed Mechanism
d
e
instead of 18-crown-6. 1 mol % of Rh2(esp)2 was added. 0.3 equiv of
18-crown-6 was added.
a
Scheme 2. Reaction Scope
iodide leads to the formation of 1a′, which then undergoes
rhodium-catalyzed denitrogenation to afford intermediate C.
Subsequent intramolecular attack of iodide on the carbene
carbon produces iodonium ylide D, which undergoes cleavage
of the C−I bond and nucleophilic attack to give the final
product 2a. On the other hand, in path b the rhodium carbene
species B is generated initially. Then the attack of iodide on the
carbene carbon gives intermediate A. Finally, reproduction of
the rhodium catalyst and an intramolecular SN2 reaction result
in the formation of 2a. We noticed that carbocation E is
involved in path a. Thus, any factors that increase the stability
of intermediate E should facilitate the formation of 2a.
However, 2o and 2p were obtained in inferior yields, which
may indicate that path a is not the real mechanism. Moreover,
compound 1a′ was synthesized and subjected to the optimized
reaction conditions. 1a′ decomposed to an unknown complex
mixture after 150 min, and no 2a was obtained (eq 2).
a
Conditions: 0.2 mmol of 1, 0.3 mmol of NaI, 0.1 mmol of 18-crown-6,
and 0.006 mmol of Rh2(esp)2 were dissolved in 2 mL of chloroform,
and the solution was heated to reflux under N2. 0.5 mmol of NaI
was used.
b
The scope of this transformation is depicted in Scheme 2.
This strategy results in the practical preparation of 5-iodo-
1,2,3,4-tetrahydropyridines with a high degree of functional
group tolerance. Sterically and electronically different arylsul-
fonyl-substituted triazoles led to the formation of the
corresponding products in yields ranging from 64% to 94%
(2a−d). Compound 2e with a phenyl group at the 3-position
of the N-heterocycle was obtained conveniently in 74% yield.
B
DOI: 10.1021/acs.orglett.6b02428
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Scheme 4. Synthesis of Compound 9
2-aminobenzaldehyde (10) to furnish tetrahydrobenzo[b][1,8]-
naphthyridine 11 in 75% yield (eq 9).12
In conclusion, various 5-iodo-1,2,3,4-tetrahydropyridines
were efficiently synthesized by a novel rhodium-catalyzed
tandem process. The reaction proceeds under mild conditions,
and a broad range of functional groups are well-tolerated. For
the first time, NaI has been employed as a nucleophile to attack
α-imino carbenes, and the nucleophilic part and electrophilic
part are from different trapping reagents. A series of one-pot
reactions and syntheses of several valuable polycyclic com-
pounds have been realized, which means this work should find
broad application in the construction of biologically relevant
molecules.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02428.
Experimental procedures, characterization data, and NMR
spectra for new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*licy@zstu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was generously supported by the National Natural
Science Foundation of China (21372204) and the Program for
Innovative Research Team of Zhejiang Sci-Tech University
(13060052-Y).
On the basis of the above experiments, path a could be ruled
out and path b, which includes an intermolecular nucleophilic
attack on the carbene by iodide, is the most plausible
mechanism.
Compound 2a bearing an iodovinyl group was successfully
employed in several classical cross-coupling reactions. Tetrahy-
dropyridine derivatives 3, 4, and 5 were obtained in high
yields (eqs 3−5). To simplify the operating procedure, we tried
one-pot sequential reactions.8f After reaction for 70 min, the
reaction mixture was cooled to room temperature, and chloro-
form was evaporated. New catalysts and reaction reagents were
added, and the reaction proceeded at certain temperature until
the full conversion of 2a. Compounds 3−5 were isolated in
moderate to high yields (eqs 6−8). Starting from 2a and
2-aminophenylpinacolborane (6), pyrido[2,3-b]indoline 9 could
be generated via Suzuki−Miyaura coupling and subsequent
oxidative cyclization (Scheme 4).11 Moreover, in the presence
of a catalytic amount of CuI and glycine, 2a condensed with
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