Metal-Free [2 + 1 + 2]-Cycloaddition of Tosylhydrazones with Hexahydro-1,3,5-triazines to Form Imidazolidines

Article abstract of DOI:10.1021/acs.orglett.7b00600

A novel protocol toward imidazolidines has been accomplished using tosylhydrazones and hexahydro-1,3,5-triazines as the substrates under metal-free reaction conditions. Importantly, the role of LiO^tBu has been confirmed not only to release the diazo but also to promote the cycloaddition. Further mechanistic investigations reveal that the reaction proceeds through a stepwise [2 + 1 + 2] process.

Full text of DOI:10.1021/acs.orglett.7b00600

Letter
pubs.acs.org/OrgLett
Metal-Free [2 + 1 + 2]-Cycloaddition of Tosylhydrazones with
Hexahydro-1,3,5-triazines To Form Imidazolidines
Pei Liu, Guangyang Xu, and Jiangtao Sun*
Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology and School of Pharmaceutical Engineering & Life Science,
Changzhou University, Changzhou 213164, P. R. China
S
* Supporting Information
ABSTRACT: A novel protocol toward imidazolidines has been
accomplished using tosylhydrazones and hexahydro-1,3,5-triazines as
the substrates under metal-free reaction conditions. Importantly, the
role of LiOtBu has been confirmed not only to release the diazo but
also to promote the cycloaddition. Further mechanistic investigations
reveal that the reaction proceeds through a stepwise [2 + 1 + 2]
process.
s stable and readily available starting materials, tosylhy-
drazones have been extensively employed as diazo
Scheme 2. Initial Attempts and Our Strategy
A
precursors to synthesize structurally diverse molecules in
modern organic synthesis.1 Not surprisingly, generation of a
diazo moiety in situ from tosylhydrazones has enabled the
development of versatile novel reactions under transition-metal
catalysis,2,3 or even more appealing, under metal-free reaction
conditions.4−8 For example, in 2009, Barluenga and Valdes
́
demonstrated an elegant C−C bond formation by reductive
coupling of boronic acids and tosylhydrazones under metal-free
conditions (Scheme 1a).4 Later, they further extended this
Scheme 1. Previous Reports
heterocycle. The initial unsuccessful attempts prompted us to
develop an effective protocol to circumvent this challenge. In
continuation of our ongoing interest in diazo chemistry and
triazine involved cycloadditions,10 we report here a base-
promoted cycloaddition from tosylhydrazones via a [2 + 1 + 2]
process under metal-free reaction conditions (Scheme 2c).
At the outset, we utilized tosylhydrazone 1a and hexahydro-
1,3,5-triazine 2a as model substrates to establish the optimal
reaction conditions (Table 1). When the reaction was
performed in toluene at 60 °C, the use of 2 equiv of Cs2CO3
afforded 3a in 40% yield associated with a small amount of
azine 4a (entry 1), while K2CO3 gave a much lower yield (entry
2). Gratifyingly, when LiOtBu was employed, 3a was obtained
in 84% yield (79% isolated yield) together with a 7% yield of 4a
(entry 3). Switching the base to KOtBu, NaOtBu, and NaH
resulted in moderate yields (entries 4−6), while the use of
KOH and NaOMe gave very low yields (entries 7 and 8).
Then, the solvent was screened. First, the formation of similar
protocol to forge C−C, C−O, and C−N bonds.5 Wang and co-
workers successfully developed metal-free C−B and C−Si
bonds formation by using tosylhydrazones as ideal substrates.6
The Jiang group also reported tosylhydrazones involved metal-
free carbamation and cyclopropanation (Scheme 1b).7 Despite
these advances, new reactions using tosylhydrazones as starting
materials under metal-free conditions are still needed from the
viewpoints of cost and sustainability.
Recently, we reported a gold-catalyzed cycloaddition of
donor/acceptor diazo compounds with hexahydro-1,3,5-
triazines9 to prepare five-membered N-heterocycles (Scheme
2a).10a Unfortunately, this protocol was not applicable to
donor/donor diazo substrates. Under gold catalysis, the
expected cyclization product was not obtained but rather the
coupling products azine and olefin (Scheme 2b). Moreover, the
use of rhodium complexes also did not produce the desired
Received: March 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00600
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a b
,
Table 1. Optimization of Reaction Conditions
Scheme 3. Substrate Scope
b
entry
base
solvent
t (°C)
yield (%) 3a/4a/5a
1
Cs2CO3
K2CO3
LiOtBu
KOtBu
NaOtBu
NaH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
DCE
60
60
60
60
60
60
60
60
60
60
60
60
60
110
80
25
40/6/<5
25/4/<5
84(79)/7/<5
48/5/4
2
3
4
5
43/19/<5
40/5/0
6
7
KOH
12/0/0
8
NaOMe
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
18/3/0
9
46/41/5
65/18/4
54/4/0
10
11
12
13
14
15
16
CH2Cl2
THF
38/7/5
p-xylene
toluene
toluene
toluene
75/12/6
28/64/7
68/16/5
<5/<5/0
a
The reactions were carried out with 1a (0.2 mmol), 2a (0.24 mmol),
b
and base (0.4 mmol) in solvent (5 mL) at 60 °C for 15 h. NMR yield.
The number in parentheses is the isolated yield.
amounts of 3a and 4a were observed when the reaction was
conducted in dioxane, while 1,2-dichloroethane (DCE)
provided 3a and 4a in 65% and 18% yield, respectively
(entry 10). The use of dichloromethane and THF afforded 3a
in moderate yields with a small amount of 4a (entries 11 and
12), while p-xylene furnished 3a in 75% yield associated with a
12% yield of 4a (entry 13). As a result, toluene was the best
solvent regarding reactivity and selectivity. It should be noted
that high temperature is detrimental to the reaction. A larger
amount of 4a formed when the reaction was conducted at high
temperature (entries 14 and 15). Moreover, the reaction was
sluggish under low temperature (entry 16).
With the optimal conditions in hand, we turned our attention
to the scope of this base-promoted cycloaddition. Gratifyingly,
aromatic ketone/aldehyde derived tosylhydrazones with differ-
ent substitution patterns could be employed in this reaction,
providing the corresponding imidazolidines in moderate to
good yields (Scheme 3). Both electron-rich and -deficient
substrates were tolerated. Notably, this cycloaddition tolerates
various functional groups on the aromatic ring of the
tosylhydrazones, including F, Cl, Br, NO2, CF3, and CO2Me,
providing potential application for further transformations.
Moreover, tosylhydrazones bearing electron-donating substitu-
ents furnished the corresponding products in higher yields than
those with electron-withdrawing groups. For bis-phenyl
substituted tosylhydrazone, the cycloaddition proceeded well
to afford 3j in 58% yield. Interestingly, heteroaromatic derived
tosylhydrazones were also tolerated and the corresponding
products were obtained in moderate yields (3l, 3m and 6m,
6n). Notably, benzil derived tosylhydrazone smoothly under-
went the cycloaddition to give the desired product 3n in 38%
yield. Next, different aryl substituted hexahydro-1,3,5-triazines
were examined and the corresponding products (3o and 3p)
were obtained in moderate yields. Unfortunately, aliphatic
ketone/aldehyde derived tosylhydrazones were not applicable
a
All reactions were performed with 1 (0.2 mmol), 2 (0.24 mmol), and
b
LiOtBu (0.4 mmol) in toluene (5 mL) at 60 °C for 15 h. Isolated
yields.
to this reaction. The structures of 3j and 6d were confirmed by
X-ray analysis.
As observed, the condensation of carbonyl compounds with
tosylhydrazines cleanly furnished the corresponding tosylhy-
drazones in quantitative yields in toluene. Thus, we attempted
to combine the condensation and cycloaddition in one pot,
which can be considered a formal reductive coupling of a
carbonyl group to an sp3-carbon atom with the concurrent
construction of C−C and C−N bonds. Indeed, with the
addition of anhydrous MgSO4 to the reaction system, the one-
pot two-step reactions proceeded well and gave the
corresponding products in acceptable yields (Scheme 4). It
should be noted that the presence of MgSO4 is essential to
remove the water generated in situ during the condensation
process. Otherwise, the anticipated cycloaddition would not
occur.
To understand the possible role of LiOtBu, control
experiments were conducted. The reaction of 1a′ with 2a was
B
DOI: 10.1021/acs.orglett.7b00600
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. One-Pot Reaction from Ketones/Aldehydes
Scheme 6. Deuterium-Labelling and Cross Experiments
performed and only a small amount of desired product 3a was
detected, instead of the formation of 4a (76% yield). Moreover,
when 1a′ was slowly added by a syringe pump over 10 h, 3a
was still obtained in low yield (Scheme 5a). Clearly, there is no
Scheme 5. Control Experiments
Based on the former results, a plausible reaction mechanism
has been proposed (Scheme 7). First, diazo 1a′ is slowly
Scheme 7. Proposed Reaction Mechanism
difference between one-portion and slow addition of 1a′,
indicating that the role of LiOtBu is far beyond just releasing
the diazo from tosylhydrazone. Next, the reaction of 1a′ and 2a
with LiOtBu provided 3a in 26% yield associated with the 55%
yield of 4a (Scheme 5b). Furthermore, the slowly addition of
1a′ to the mixture of 2a and LiOtBu provided 3a in 45% yield
and the yield of 4a decreased to 30% (Scheme 5c).
Furthermore, Lewis or Brønsted acid catalyzed reaction of
diazo compounds with imine usually leads to the formation of
aziridines.12 Thus, the cycloaddition might proceed through the
initial aziridination followed by ring opening with another
molecule of hexahydro-1,3,5-triazine.13 So we run the reaction
of aziridine 7 with 2a in the presence of LiOtBu. As a result, 6a
was obtained in 62% yield (Scheme 5d). The control
experiments revealed that LiOtBu worked not only as a base
to slowly generate the diazo from tosylhydrazone but also to
promote the cycloaddition process.
Next, deuterium labeling experiments were performed. First,
the reaction of 1a with D-2a furnished fully deuterated product
D-3a in 77% yield (Scheme 6a). The reaction of 1a with 2a and
D-2a afforded not only 3a and D-3a but also the cross-
deuterated product D-3a′ (Scheme 6b), which could be further
confirmed by HRMS analysis (see Supporting Information for
details). Moreover, a cross reaction involving different
hexahydro-1,3,5-triazines was conducted, and 6p/6q were
observed (Scheme 6c, see Supporting Information). The
incorporation of two different formaldimines indicated the
reaction probably proceeded via a stepwise [2 + 1 + 2] process.
released from tosylhydrazone 1a by LiOtBu. The cycloaddition
would be initiated by the first nucleophilic addition between
diazo and formaldimine 2a′, generating aziridine intermediate
III through transition state I or II. Then, a base-promoted ring-
opening reaction of aziridine by another molecule of 2a′ occurs
and delivers the final product 3a via intermediate IV.
In summary, we have developed a metal-free [2 + 1 + 2]-
cycloaddition reaction between tosylhydrazones and hexahy-
dro-1,3,5-triazines in the presence of LiOtBu, affording
imidazolidines in moderate to good yields under mild reaction
conditions. The construction of C−N and C−C bonds has
been realized under metal-free conditions. Moreover, the
isolation of tosylhydrazones is not necessary and the reaction
can be performed in one pot directly from carbonyl
compounds. Notably, the dual roles of LiOtBu were proven
either to release the diazo or to promote the cycloaddition.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00600.
Experimental procedures along with characterizing data
and copies of NMR spectra (PDF)
C
DOI: 10.1021/acs.orglett.7b00600
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(d) Liu, Z.; Tan, H.; Wang, L.; Fu, T.; Xia, Y.; Zhang, Y.; Wang, J.
Angew. Chem., Int. Ed. 2015, 54, 3056.
AUTHOR INFORMATION
Corresponding Author
■
(7) (a) Xiong, W.; Qi, C.; He, H.; Ouyang, L.; Zhang, M.; Jiang, H.
Angew. Chem., Int. Ed. 2015, 54, 3084. (b) Zhu, C.; Chen, P.; Wu, W.;
Qi, C.; Ren, Y.; Jiang, H. Org. Lett. 2016, 18, 4008. (c) Zhu, C.; Li, J.;
Chen, P.; Wu, W.; Ren, Y.; Jiang, H. Org. Lett. 2016, 18, 1470.
(d) Huang, Y.; Li, X.; Yu, Y.; Zhu, C.; Wu, W.; Jiang, H. J. Org. Chem.
2016, 81, 5014.
*E-mail: jtsun08@gmail.com; jtsun@cczu.edu.cn.
ORCID
Jiangtao Sun: 0000-0003-2516-3466
Notes
(8) (a) Taber, D. F.; Guo, P. J. Org. Chem. 2008, 73, 9479.
(b) Nakagawa, S.; Bainbridge, K. A.; Butcher, K.; Ellis, D.; Klute, W.;
Ryckmans, T. ChemMedChem 2012, 7, 233. (c) Allwood, D. M.;
Blakemore, D. C.; Ley, S. V. Org. Lett. 2014, 16, 3064. (d) Allwood, D.
M.; Blakemore, D. C.; Brown, A. D.; Ley, S. V. J. Org. Chem. 2014, 79,
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Yu, J.-T.; Jiang, Y.; Cheng, J. J. Org. Chem. 2015, 80, 2855. (g) Tsai, A.
S.; Curto, J. M.; Rocke, B. N.; Dechert-Schmitt, A.-M. R.; Ingle, G. K.;
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSF of China (No. 21572024), Natural Science
Foundation of Jiangsu Province (BK20151184), and Jiangsu
Key Laboratory of Advanced Catalytic Materials & Technology
(BM2012110) for their financial support.
Mascitti, V. Org. Lett. 2016, 18, 508. (h) Cyr, P.; Co
Bronner, S. M. Org. Lett. 2016, 18, 6448.
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te-Raiche, A.;
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