Base-Promoted/Gold-Catalyzed Intramolecular Highly Selective and Controllable Detosylative Cyclization

Article abstract of DOI:10.1002/chem.201502073

A highly selective, controllable and synthetically useful base-promoted intramolecular detosylative cyclization of bis-N-tosylhydrazones has been achieved, affording N-containing heterocycles and cyclic olefins under transition-metal-free or gold-catalyzed procedures, respectively. Moreover, an effective and practical metal-free or gold-catalyzed approach to synthesize polycyclic aromatic compounds is also reported. Basic cyclizations: A highly selective, controllable, and synthetically useful base-promoted intramolecular detosylative cyclization of bis-N-tosylhydrazones affords N-containing heterocycles and cyclic olefins under transition-metal-free or gold-catalyzed procedures, respectively. Moreover, an effective and practical metal-free or gold-catalyzed approach to synthesize polycyclic aromatic compounds is also reported.

Full text of DOI:10.1002/chem.201502073

DOI: 10.1002/chem.201502073
Communication
&
Cyclization
Base-Promoted/Gold-Catalyzed Intramolecular Highly Selective
and Controllable Detosylative Cyclization
Chenghao Zhu, Lin Qiu, Guangyang Xu, Jian Li, and Jiangtao Sun*[a]
Abstract: A highly selective, controllable and synthetically
useful base-promoted intramolecular detosylative cycliza-
tion of bis-N-tosylhydrazones has been achieved, affording
N-containing heterocycles and cyclic olefins under transi-
tion-metal-free or gold-catalyzed procedures, respectively.
Moreover, an effective and practical metal-free or gold-cat-
alyzed approach to synthesize polycyclic aromatic com-
Scheme 1. Previous reports on intramolecular reactions: a) Rh/Ru-catalyzed
pounds is also reported.
macrocyclization through intramolecular diazo coupling;[9,10] b) Rh-catalyzed
intramolecular coupling of bis-N-tosylhydrazones.[11]
Transition metal-catalyzed carbene transfer from diazo com-
pounds plays an important role in constructing various
carbon–carbon and carbon–heteroatom bonds.[1] Since the
diazo compounds are usually unstable, the in situ generation
of diazo intermediates from readily available N-tosylhydra-
zones, via a formal Bamford–Stevens process,[2] has been alter-
natively employed.[3] Nevertheless, the N-tosylhydrazone
chemistry has some unique characteristics, particularly in the
absence of metal catalysts, and variety of related transforma-
tions,[4] such as XÀH insertions (X=N, O, etc.),[5] cross-cou-
plings[6] and carbonylations,[7] have been carried out with high
efficiency.
The intermolecular dimerization of diazo compounds to pro-
duce alkenes has been known for decades,[8] but, in compari-
son, the intramolecular coupling has been less investigated.
Previously, the groups of Doyle[9] and Che[10] have reported Rh/
Ru-catalyzed macrocyclization through intramolecular diazo
coupling (Scheme 1a). Later, Wang and co-workers reported
a seminal Rh-catalyzed intramolecular coupling of bis-N-tosyl-
hydrazones to give polycyclic aromatic compounds
(Scheme 1b).[11] However, the aforementioned metal-catalyzed
procedures were nonselective and uncontrollable, with com-
plete decomposition of the two diazo moieties.
Given their unique behavior, we envisaged that the intramo-
lecular coupling of bis-N-tosylhydrazones would exhibit
a range of chemoselectivities under different reaction condi-
tions (Scheme 2A). First, treated with a strong base under ele-
Scheme 2. Rationalized mechanism analysis and our strategy: A) Possibilities
for intramolecular coupling of bis-N-tosylhydrazones; B) this work.
[a] C. Zhu, Dr. L. Qiu, G. Xu, Dr. J. Li, Prof. Dr. J. Sun
School of Pharmaceutical Engineering & Life Science and
Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology
Changzhou University, 1 Gehu Road, Changzhou 213164 (China)
Fax: (+86)519-86334598
E-mail: jtsun08@gmail.com
vated temperature, bis-N-tosylhydrazones would afford diazo
intermediate I by completely removing two tosyl moieties
through a Bamford–Stevens process (path a). Consequently,
jtsun@cczu.edu.cn
thermolysis of I under metal-free conditions would produce IV
or V,[3v] whereas metal carbene VI would form in the presence
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502073.
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of metal complexes. Then, extrusion of another molecule of ni-
trogen from IV, V, or VI would generate olefin VII. Secondly,
the Bamford-Stevens process would also effect selective deto-
sylation to afford intermediate II (path b), in which one diazo is
formed and the other tosylhydrazone remains. Direct thermoly-
sis of II would then generate carbene intermediate VIII
(Scheme 2, b1) and subsequent intramolecular NÀH insertion
would yield heterocycle X. The presence of a metal catalyst
would afford metal carbene IX, which could also form X by NÀ
H insertion (Scheme 1, b2).
Table 1. Optimizations of the reaction conditions.[a]
Entry
Catalyst
Base
2a [%][b] 3a [%][b]
1
2
3
4
5
6
–
–
–
–
–
–
LiOtBu 30
K2CO3
Li2CO3
Cs2CO3 75
KOtBu 78
15
10
–
56
–
5
0
Moreover, there is another competitive process, namely the
classical base-induced Shapiro[12] or Bamford–Stevens reaction,
which would yield alkene III as dominant product of the elimi-
nation of the hydrogen atom from the hydrazone and the
acidic proton a to the hydrazone carbon (Scheme 2, path c).
Based on the above analysis, we rationalized that the intra-
molecular coupling of bis-N-tosylhydrazones would furnish
two major types of products, namely the olefin VII and hetero-
cycle X, either in the absence of or in the presence of a metal
catalyst (Scheme 2). Thus, the focus of this investigation was to
establish an effective approach that would allow selective and
controllable decomposition of N-tosylhydrazones. Inspired by
our previous studies,[13] especially those on gold-catalyzed in-
termolecular diazo cross-coupling,[13c,d] herein we describe effi-
cient and practical procedures to deliver cyclic olefins and het-
erocycles with excellent selectivity, with or without the pres-
ence of a gold complex (Scheme 2B).
NaH
58
0
7
8
9
[IPrAuNTf2]/NaBArF
[Ph3PAuCl]/NaBArF
[Et3PAuCl]/NaBArF
LiOtBu 38
LiOtBu 38
LiOtBu 45
LiOtBu 44
LiOtBu 40
LiOtBu 45
LiOtBu 30
LiOtBu 48
LiOtBu 35
LiOtBu
LiOtBu
KOtBu
LiOtBu
5
35
7
3
7
6
31
9
10
11
12
13
14
15
16
17
18
19
[Cy3PAuCl]/NaBArF
[(PhO)3PAuCl]/NaBArF
[(2,4-tBu2C6H3O)3PAuCl]/NaBArF
[(C6F5)3PAuCl]/NaBArF
[XantPhos(AuNTf2)2]/NaBArF
[XPhosAuCl]/NaBArF
[tBuXPhosAuCl]/NaBArF
[tBuXPhosAuCl]
[tBuXPhosAuCl]/NaBArF
[tBuXPhosAuCl]/AgSbF6
10
85
23
45
55
3
0
3
9
[a] Reaction conditions: To a solution of 1a (0.2 mmol) in DCE (5 mL) was
added base (3 equiv) in the absence/presence of gold complex
(2.5 mol%) and NaBArF (2.5 mol%) at RT. Then the mixture was heated to
reflux and stirred for 12 h; [b] yields of isolated product. DCE=1,2-di-
chloroethane.
At the outset, bis-N-tosylhydrazones 1a was used as the
model substrate to establish the optimal reaction conditions
(Table 1). First, treatment of 1a with LiOtBu in 1,2-dichloro-
ethane at reflux for 12 h afforded diazepine 2a in 30% yield,
alongside a 15% yield of cyclopentene 3a (Table 1, entry 1).
The use of K2CO3 gave 2a and of 3a in 56% and 10% yield, re-
spectively (Table 1, entry 2). When Cs2CO3 was employed, 75%
yield of 2a and 5% yield of 3a were isolated (Table 1, entry 4).
Further using KOtBu produced 2a as single product in 78%
yield (Table 1, entry 5), whereas NaH furnished 2a in moderate
yield (entry 6). Next, various gold catalysts were evaluated
combined with NaBArF (BArF =[B{3,5-(CF3)2C6H3}4]À) and LiOtBu.
A gold–N-heterocyclic carbene catalyst afforded 2a as the
major isomer, albeit in lower yield (Table 1, entry 7) and phos-
phine or phosphite ligand-derived gold complexes gave poor
reactivities and selectivities (Table 1, entries 9 to 15). Gratifying-
ly, the combination of tBuXphosAuCl/NaBArF and LiOtBu deliv-
ered 3a as the major isomer in 85% yield (Table 1, entry 16).
Consistent with our former observations on gold-catalyzed
diazo coupling,[13] the reaction was sluggish in the absence of
NaBArF (Table 1, entry 17). Moreover, using KOtBu as base and
replacing NaBArF with AgSbF6 resulted in low conversion
(Table 1, entries 18 and 19). The different outcomes with or
without the gold catalyst [tBuXPhosAuCl] (tBuXPhos=2-di-tert-
butylphosphino-2’,4’,6’-triisopropylbiphenyl) were probably
a resultant of the reactions following different reaction path-
ways; path a of Scheme 2 is preferred in the presence of [tBuX-
phosAuCl], whereas path b is dominant without the gold cata-
lyst. Moreover, Wang and co-workers reported a seminal rhodi-
um-catalyzed approach towards the olefin formation.[11]
Based on the above optimization, we next investigated the
substrate scope under transition-metal-free conditions (Table 1,
entry 5; condition A) and with gold catalyst(Table 1, entry 16;
condition B). For most cases, the desired heterocycles and ole-
fins were obtained in moderate to high yields (Table 2). For the
unsymmetric diaryl bis-tosylhydrazone 1e, heterocycle 2e was
obtained as the major isomer under metal-free condition (75%
yield; Table 2, entry 5).[14] For bis-tosylhydrazone 1 f, removal of
the aldehyde-derived tosylhydrazone has been prioritized, and
the corresponding product was obtained in 75% yield (Table 2,
entry 6). However, for the aryl alkyl bis-tosylhydrazone 1g, the
tosylhydrazone adjacent to the inner aryl group was selectively
removed and produced 2g as single isomer (68% yield;
Table 2, entry 7). For the above-mentioned unsymmetric bis-N-
tosylhydrazones, only one regioisomer was isolated, which can
probably be attributed to the faster decomposition of one to-
sylhydrazone in relation to the other moiety under the reaction
conditions. For 1,5-bis-tosylhydrazones, the corresponding het-
erocycles (2h–j) were isolated in high yields (Table 2, entries 8
to 10; trans/cis=2:1 or 1:1). The 1,6-bis-tosylhydrazone was
also applicable and the corresponding products 2m and 3m
were isolated in high yields. Notably, the 12-membered hetero-
cycle 2n and olefin 3n were obtained in 76% and 48% yields,
respectively (Table 2, entry 14). The similar phenomenon was
observed for bis-tosylhydrazone 1o. The 14-membered hetero-
cycle 2o and 12-membered olefin 3o were obtained in moder-
ate yields (Table 2, entry 15). These results indicate that this is
a practical and efficient approach to preparing large-ring het-
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erocycles and cyclic olefins. Moreover, the methodology also
provides a valuable alternative means of olefin formation via
the classical McMurry coupling.[15]
Table 2. Substrate scope.[a,b]
Next, we investigated the intramolecular coupling of bis-N-
tosylhydrazones to prepare polycyclic aromatic compounds,
for which Wang and co-workers pioneered the use of rhodium
catalyst to achieve high efficiency.[11] However, after carefully
screening the reaction conditions (see the Supporting Informa-
tion for details), we found that, even in the absence of a gold
catalyst, the cyclization of 4a still proceeded well to afford the
desired phenanthrene in 73% yield with 3 equivalents of
LiOtBu, which indicated that path a1 is feasible according to
the former analysis (Scheme 2). In contrast, consistent with
Wang’s rhodium-catalyzed methodology,[11] the presence of
a gold catalyst gave 5a in slightly higher yield (Table 3), which
indicated that the metal catalysts did improve the reaction ac-
tivity.
Entry
Substrate
2
3
Table 3. Synthesis of polycyclic aromatic compounds.
Next, a series of bis-N-tosylhydrazones were subjected to
the intramolecular coupling reactions by methods A and B
(Table 3). The polycyclic aromatic compounds 5c and 5h were
obtained in similar yields under both sets of reaction condi-
tions. Other polycyclic aromatic compounds were isolated in
slighter lower yields when LiOtBu was used than for the gold-
catalyzed processes.
Pyridazines and diazepines are versatile motifs in natural
products and leading compounds with various pharmaceutical
activities.[16,17] For example, these compounds have been used
as potential nonsteroidal progesterone receptor regulators and
agonists (I, II and III)[16d,e,f,g] and neurotransmitter inhibitors[16h]
(IV, Scheme 3). To examine the practicability of these novel
methodologies, we performed further investigations. For exam-
ple, tetrahydropyridazine 7 was obtained in 52% total yield
from 6 after two steps at 10 mmol scale when KOtBu was em-
ployed as base. The yield was improved to 70% by using
Cs2CO3 instead (Scheme 3a). Next, bis-carbonyl compound 1 f’
was subjected to the reaction to yield diazepine 2 f in 70%
total yield (Scheme 3b). Moreover, when ketone 8 (10 mmol)
was used, the fused diazepine 10 was obtained in 53% yield
(trans/cis=1:1), whereas olefin 11 was isolated in 56% yield
[a] Reaction conditions: 0.2 mmol of 1 was used. Condition A (for the
synthesis of 2): KOtBu (3 equiv), at reflux for 12 h; Condition B (for the
synthesis of 3): LiOtBu (3 equiv), [tBuXphosAuCl]/NaBArF (2.5 mol%), at
reflux for 12 h; [b] yields of isolated product.
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Communication
pines, and other related heterocycles. Moreover, by combina-
tion of a gold catalyst and a strong base, an effective approach
has also been realized to access polysubstituted cyclic olefins.
Furthermore, we presented herein metal-free/gold-catalyzed
syntheses of polycyclic aromatic compounds in moderate to
high yields. Clearly, the practical and selective de-N-tosylative
cyclizations might find broad applications in preparing versa-
tile and valuable synthons.
Experimental Section
General procedure (Table 2)
Condition A: Under argon atmosphere, bis-N-tosylhydrazone
(0.20 mmol), KOtBu (67 mg, 0.60 mmol), and DCE (5 mL) were
added to a 25 mL sealed tube. The resulting solution was stirred at
reflux for 12 h. The mixture was cooled to room temperature and
the solvent was removed under reduced pressure. The crude resi-
due was purified by column chromatography (eluent= petroleum
ether/ethyl acetate 30:1) to afford product 2.
Condition B: Under argon atmosphere, bis-N-tosylhydrazone
(0.2 mmol), LiOtBu (48 mg, 0.60 mmol), tBuXphosAuCl (3.3 mg,
0.005 mmol), NaBArF (4.4 mg, 0.005 mmol), and DCE (5 mL) were
added to a 25 mL sealed tube. The resulting solution was stirred at
reflux for 12 h under argon atmosphere. The mixture was cooled
to room temperature and solvent was removed under reduced
pressure. The crude residue was purified by column chromatogra-
phy (eluent=petroleum ether/ethyl acetate 40:1) to afford prod-
uct 3.
Scheme 3. Synthetic applications of base-promoted cyclizations: a) Pyrida-
zine synthesis (10 mmol scale); b) diazepine synthesis (10 mmol scale);
c) fused diazepine synthesis.
following the gold-catalyzed procedure with NaH as base
(Scheme 3c).
We next tested the synthetic applications of our methodolo-
gy.[18] Pyrrole 13 was synthesized in 52% total yield from
ketone 12 by sequential condensation, cyclization, and oxida-
tion, which offered a straightforward way to prepare polysub-
stituted pyrroles (Scheme 4a). Next, in the absence or presence
Acknowledgements
This project was supported by the NSFC (21172023), a Project
Funded by the Priority Academic Program Development of
Jiangsu Higher Education Institutions (PAPD), and Jiangsu Key
Laboratory of Advanced Catalytic Materials and Technology
(BM2012110).
Keywords: cross-coupling · cyclization · gold · hydrazones ·
olefination
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Published online on July 29, 2015
Chem. Eur. J. 2015, 21, 12871 – 12875
www.chemeurj.org
12875
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