TiCl4 promoted formal [3 + 3] cycloaddition of cyclopropane 1,1-diesters with azides: Synthesis of highly functionalized triazinines and azetidines

Article abstract of DOI:10.1021/ol5024079

A TiCl₄ promoted formal [3 + 3] cycloaddition of cyclopropane 1,1-diesters with azides has been developed for the synthesis of highly functionalized triazinines. Both stoichiometric and substoichiometric versions of this reaction were accomplished dependent on the choice of solvent. It is noteworthy that the corresponding products could be easily converted to biologically important azetidines by simple thermolysis.

Full text of DOI:10.1021/ol5024079

Letter
pubs.acs.org/OrgLett
TiCl4 Promoted Formal [3 + 3] Cycloaddition of Cyclopropane 1,1-
Diesters with Azides: Synthesis of Highly Functionalized Triazinines
and Azetidines
Huan-Huan Zhang, Yong-Chun Luo,* Hua-Peng Wang, Wei Chen, and Peng-Fei Xu*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou
730000, PR China
S
* Supporting Information
ABSTRACT: A TiCl4 promoted formal [3 + 3] cycloaddition
of cyclopropane 1,1-diesters with azides has been developed
for the synthesis of highly functionalized triazinines. Both
stoichiometric and substoichiometric versions of this reaction
were accomplished dependent on the choice of solvent. It is
noteworthy that the corresponding products could be easily
converted to biologically important azetidines by simple thermolysis.
any heterocycles with NNN linkages in their cyclic
arrangement embrace interesting biological activities.1
Cyclopropane 1,1-diesters, a kind of versatile three-carbon
zwitterionic synthons, have been widely used to assemble
various cyclic skeletons by means of [3 + n] cycloaddition
reactions promoted by Lewis acid.6 In these reactions, the
scope and applicability of its [3 + 3] process are limited to a few
1,3-dipoles.7,8 So far, alkyl azides have not been employed in
this [3 + 3] process. Herein, we report an efficient synthesis of
triazinines derivatives by the formal [3 + 3] cycloaddition of
azides with cyclopropane 1,1-diesters.
In our initial trials, benzyl azide 1a and dimethyl 2-
phenylcyclopropane-1,1-dicarboxylate 2a were employed to
optimize the reaction conditions, and the results are
summarized in Table 1. In order to activate 2a, a variety of
common Lewis acids were attempted. At first, a stoichiometric
M
Among them, 1,2,3-triazine represents a widely used lead
structure with a multitude of interesting applications in
numerous pharmacological fields. Various synthetic analogues
of 1,2,3-triazine have been synthesized, and some of them have
shown excellent pharmacological activity.2 Combined with our
interest in the cycloaddition of donor−acceptor cyclopropanes,
we attempted to develop an efficient method for the
straightforward synthesis of functionalized 1,4,5,6-tetrahydro-
1,2,3-triazines, also named triazinines,3 from azides and
cyclopropanes under mild conditions.
To date, several reactions between azides and cyclopropanes
have been reported.4 Among which, Aube
́
and co-workers
developed the reaction of alkyl azides with triethyl(1-methoxy-
2,2-dimethyl-cyclopropoxy)silane to prepare a series of α-
amino-α′-diazomethyl ketone.4d,e They speculated that a
triazine intermediate was formed by [3 + 3] cycloaddition in
this reaction but decomposed immediately (Figure 1). In
addition, in several other reactions, some triazines were
prepared from azides,3,5 but the synthesis of triazinines via
the cycloaddition of cyclopropane with azides has not been
reported.
Table 1. Optimization of the Reaction Conditions
a
c
entry
Lewis acid (mol %)
solvent
time (h)
yield (%)
1
2
3
SnCl4 (100)
FeCl3 (100)
AlCl3 (100)
TiCl4 (100)
TiCl4 (50)
TiCl4 (20)
TiCl4 (10)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
HFIP
16
16
16
2
complex
complex
25
b
4
89
b
5
2
47
b
6
12
48
87
b
7
HFIP
61
a
Reaction conditions: unless otherwise noted, the reactions were
carried out under a N2 atmosphere with 1a (0.5 mmol) and 2a (0.5
b
mmol) in 5 mL of solvent at rt and stirred for the indicated time. The
c
reaction was carried out at 0 °C to rt. Isolated yield.
Received: August 13, 2014
Published: September 5, 2014
Figure 1. Cycloaddition of azide with cyclopropanes.
© 2014 American Chemical Society
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Organic Letters
Letter
amount of Lewis acids was added and the reactions were
carried out in dichloromethane. Using SnCl4 and FeCl3, the
reaction mixture was very complex (entries 1, 2). Using CeCl3
and Ti(iPrO)4, desired product was not detected. However,
when AlCl3 was added, triazinine 3aa was obtained in 25% yield
(entry 3). This result encouraged us to continue the study.
Fortunately, we found that 1.0 equiv of TiCl4 enabled full
conversion of the starting materials to 3aa in 89% yield after 2 h
(entry 4). Further screening of the reaction solvents
demonstrated that this reaction is sensitive to the solvent.
Compound 3aa could not be formed when the reaction was
conducted in 1,2-dichloroethane, chloroform or tetrachloro-
methane.
Table 2. Investigation of the Reaction Scope
a
yield (%)
b
c
entry
1
2
R2
C6H5
3
A
B
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
2a
2b
2c
2d
2e
2f
3aa
3ab
3ac
3ad
3ae
3af
89
75
79
77
86
89
88
87
89
85
85
81
91
78
84
83
85
90
87
88
89
91
85
86
87
57
80
49
41
86
85
74
80
89
70
58
91
74
81
83
87
88
87
84
94
98
87
61
2
o-MeOC6H4
o-MeC6H4
o-ClC6H4
p-MeOC6H4
p-MeC6H4
p-ClC6H4
p-BrC6H4
p-FC6H4
3
4
5
6
Furthermore, on the basis of above results, we continued our
efforts to develop substoichiometric version of this reaction. At
first, the amount of TiCl4 was reduced to 50 mol %, but the
yield of 3aa decreased dramatically (47%, entry 5). This result
suggested that the generated product sequestered TiCl4 in an
unproductive manner and interrupted the circulation of TiCl4.
Thus, several other trifluoromethanesulfonate salts, such as
Sc(OTf)3, Yb(OTf)3, Zn(OTf)2, In(OTf)3 were examined with
20 mol % catalyst loading. However, no reaction was observed
even by prolonging the reaction time or raising the temper-
ature. Similar result was obtained in the presence of Ni(ClO4)2.
Right at that moment, TiCl4 catalyzed intramolecular Schmidt
7
2g
2h
2i
3ag
3ah
3ai
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
2j
m-MeC6H4
m-BrC6H4
H2CCH
C6H5
3aj
2k
2l
3ak
3al
2a
2b
2c
2d
2e
2f
3ba
3bb
3bc
3bd
3be
3bf
3bg
3bh
3bi
3bj
3bk
3bl
o-MeOC6H4
o-MeC6H4
o-ClC6H4
p-MeOC6H4
p-MeC6H4
p-ClC6H4
p-BrC6H4
p-FC6H4
reaction was developed by Aube
́
and co-workers.9 Using strong
2g
2h
2i
hydrogen-bond-donating solvent hexafluoro-2-propanol
(HFIP) effectively overcame the inhabitation of product in
catalysis. In this catalytic system, in situ-generated HCl from
the reaction of HFIP with TiCl4 is the catalytically active
species. We were greatly inspired by this discovery and carried
out our reaction in HFIP in the presence of 20 mol % TiCl4.
After 12 h, 3aa was obtained in 87% yield (entry 6). Reducing
the catalyst loading to 10 mol %, the reaction became very slow.
After 48 h, 3aa was obtained in 61% yield (entry 7). According
to the above results, both stoichiometric and substoichiometric
versions of this reaction have been developed. With the optimal
conditions (entries 4, 6) in hand, we set forth to survey the
substrate scope of this interesting reaction and demonstrate the
utility of this process.
2j
m-MeC6H4
m-BrC6H4
H2CCH
2k
2l
a
b
Isolated yield. Stoichiometric conditions: cyclopropane (0.5 mmol),
azide (0.5 mmol), TiCl4 (0.5 mmol, 100 mol %), CH2Cl2 (5 mL), 0
c
°C to rt, 2 h. Substoichiometric conditions: cyclopropane (0.3 mmol),
azide (0.3 mmol), TiCl4 (0.06 mmol, 20 mol %), HFIP (3 mL), 0 °C
to rt, 12 h. See Supporting Information for more details.
performed on a 5.0 mmol (1.17 g) scale. The reaction
proceeded similarly to the small-scale experiment and provided
3aa in 82% yield after 4 h. The molecular structure of 3ab was
unambiguously established by X-ray crystallographic analysis
(see Supporting Information).10
When the reaction was conducted in HFIP with 20 mol %
TiCl4, benzyl azide generally gave lower yields than decyl azide
probably due to the partial decomposition of benzyl azide
under this conditions.11 When vinyl substituted cyclopropane
was employed, the yields reduced dramatically (entries 12, 24).
This may be attributed to the electrophilic addition of
carbocation to the vinyl group on cyclopropane. When o-
MeOC6H4- and p-MeOC6H4-substituted cylcopropanes reacted
with benzyl azide, the lower yields were obtained due to
cyclodimerization of cyclopropanes (entries 2, 5).12 Because of
steric effect, o-ClC6H4-substituted cyclopropane also gave lower
yield than p-ClC6H4- substituted ones (entries 4, 7).
The scope of the reaction was investigated under
stoichiometric and substoichiometric conditions, respectively.
Various cyclopropane 1,1-diesters and azides were employed
and the results are summarized in Table 2. The stoichiometric
protocol was found to be tolerant to both electron-withdrawing
and electron-donating substituents in cyclopropane 1,1-diesters,
and all of them gave the corresponding triazinine derivatives
3aa−3bl as a single product in moderate to high yields. No
significant difference in reactivity was observed between the
benzyl azides 1a and decyl azides 1b in the reaction. The
position of the substituent on the aryl group slightly influences
the reactivity and sterically demanding ortho-substituted
cyclopropanes always gave relatively lower yields of the desired
product. For example, the reaction of o-ClC6H4- and p-ClC6H4-
substituted cyclopropanes 2d and 2g with 1a gave the
corresponding 3ad and 3ag in 77% and 88% yield respectively,
probably due to the larger steric effect relative to the latter
(entries 4, 7). A vinyl group could also be used as substituent,
offering 3al and 3bl in good yield (entries 12, 24).
Unfortunately, when the aryl group on cyclopropane was
replaced by methyl or hexyl group, the reactions did not work.
To examine the feasibility of this method on a larger
preparative scale, the model reaction leading to 3aa was also
An attractive feature of this cycloaddition reaction is the
opportunity for ready access to spiro-triazinines. We were
pleased to find that the [3 + 3] cycloaddition of cyclopropane
1,1-diester 2m13 with 1b under the stoichiometric conditions
also proceeded well to give spiro-triazinine 3bm, albeit with a
modest yield (46%) (Scheme 1).
In an effort to gain knowledge on the mechanism of our
reaction, the reaction between (S)-2a14 and 1b was carried out
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Letter
Scheme 1. Synthesis of spiro-Triazinine
Scheme 4. Thermolysis of Triazinines
in the presence of 1.0 equiv of TiCl4 and racemic mixture of
3ba was obtained (Scheme 2). This indicated that the
Scheme 2. [3 + 3] Cycloaddition of Enantioenriched
Cyclopropane
mechanism of this cycloaddition is stepwise, rather than
concerted process. In view of this, plausible reaction
mechanism for these transformations is proposed in Scheme
3. Initially, under the activation of TiCl4, the ring-opening of
Scheme 5. Proposed Pathways of Thermolysis
Scheme 3. Proposed Mechanism for [3 + 3] Cycloaddition
medicinally valuable azetidines by means of simple thermolysis
of the triazinine products. Further related studies utilizing this
novel [3 + 3] cycloaddition for the development of other
methodologies are currently underway in our laboratory.
cyclopropane 2 affords 1,3-zwitterionic intermediate A.
Subsequently, a nucleophilic attack of an azide15 happens to
form a new zwitterion B, which then undergoes an intra-
molecular nucleophilic attack to form the product 3.
As early as 1989, Dunkin and co-workers reported that the
thermal decomposition of 1-methyl-1,2,3-benzotriazin-4(1H)-
one offered benzazetinone by loss of nitrogen.16 If our products
decomposed in the same way, azetidines, a class of useful
molecular,17 will be obtained. Therefore, the solution of 3aa in
xylene was heated to reflux. After 4 h, 3aa was exhausted and
4aa was obtained in 46% yield (Scheme 4). In order to improve
the yield, we changed the solvent to toluene or dimethyl
sulfoxide to promote the reaction. But no expected increase of
yield developed. Thermolysis of 3al, 3bc, 3bf and 3bh offered
4al, 4bc, 4bf and 4bh respectively in 40−52% yield. Among
these reactions, imine 5 was obtained along with 4bh. This
disclosed that the decomposition occurred via two pathways
(Scheme 5). Under the thermolysis conditions, the cleavage of
N−N bond affords intermediate C. Which undergoes an
intramolecular nucleophilic substitution to furnish the desired
azetidine 4 in path A or a Grob fragmentation to furnish the
imine 5 in path B.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedure and characterization data for all
1
products, including H NMR and 13C NMR spectra, X-ray
structural information on 3ab (CIF) and chiral HPLC
chromatograms of (S)-2a and rac-3ba. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: luoych@lzu.edu.cn.
*E-mail: xupf@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
In conclusion, we have discovered the first TiCl4 promoted
[3 + 3] cycloaddition of 2-substituted cyclopropane-1,1-diesters
with azides to devise complex triazinines with diverse
substituent patterns in good yields. Both stoichiometric and
substoichiometric versions of this reaction were investigated
through judicious choice of solvent. Notably, this chemistry
offers an efficient and practical strategy for the construction of
■
We are grateful for the NSFC (21202070, 21402073),
Specialized Research Fund for the Doctoral Program of Higher
Education (SRFDP 20110211120017), Gansu Provincial
Natural Science Fund (2011GS04143) and the Fundamental
Research Funds for the Central Universities (Lzujbky-2014-95
and Lzujbky-2014-65).
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Letter
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