Cobalt-Porphyrin-Catalyzed Intramolecular Buchner Reaction and Arene Cyclopropanation of In Situ Generated Alkyl Diazomethanes

Article abstract of DOI:10.1002/adsc.201700205

Cobalt(II)-porphyrin catalyzed intramolecular Buchner reaction and arene cyclopropanation of alkyl diazomethanes generated in situ from N-tosylhydrazones gave a range of bicyclic cycloheptatriene fused pyrrolidines and tetracyclic cyclopropane fused pyrro

Full text of DOI:10.1002/adsc.201700205

Title: Cobalt-Porphyrin-Catalyzed Intramolecular Buchner Reaction
and Arene Cyclopropanation of In Situ Generated Alkyl
Diazomethanes
Authors: Haixu Wang, Cong-Ying Zhou, and Chi-Ming Che
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Advanced Synthesis & Catalysis
10.1002/adsc.201700205
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Cobalt-Porphyrin-Catalyzed Intramolecular Buchner Reaction
and Arene Cyclopropanation of In Situ Generated Alkyl
Diazomethanes
a,b
a,b,
a,b,
Haixu Wang, Cong-Ying Zhou * and Chi-Ming Che *
a
State Key Laboratory of Synthetic Chemistry and Department of Chemistry, The University of Hong Kong, Hong
Kong, China.
Email: cyzhou@hku.hk; cmche@hku.hk
HKU Shenzhen Institute of Research & Innovation, Shenzhen, China
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: Cobalt(II)-porphyrin catalyzed intramolecular
Buchner reaction and arene cyclopropanation of alkyl
diazomethanes generated in situ from N-tosylhydrazones
cyclopropanation with α-diazocarbonyl compounds
as carbene source. Dirhodium carboxylates and
Cu(I/II) complexes have been reported to be highly
[2]
gave
a
range of bicyclic cycloheptatriene fused
effective catalysts for such reactions.
pyrrolidines and tetracyclic cyclopropane fused
pyrrolidines in good to high yields and with high chemo-
and regioselectivities. The obtained cyclopropane fused
pyrrolidines can be readily converted into other N-
heterocycles with potential synthetic and biological
interest.
Keywords: Carbenoids; Buchner reaction; Arene
cyclopropanation; Cobalt catalysis; Heterocycles
Scheme 1. Metal-catalyzed intramolecular Buchner
reaction with α-diazocarbonyl compounds.
Dearomatization is an appealing strategy for the
construction of complex cyclic molecules as
numerous aromatic compounds are commercially
[1]
available or readily accessible. Among the various
dearomatization reactions, transition-metal-catalyzed
Buchner reaction and arene cyclopropanation with
diazo compounds are efficient methods for the
construction of cycloheptatrienes and norcaradienes,
both of which are useful building blocks in organic
synthesis (Scheme 1).[
2,3,4]
It is generally conceived
that the first step of Buchner reaction is the
cyclopropanation of a benzenoid double bond with
metal carbene to generate a norcaradiene. The initial
product is prone to electrocyclic ring opening leading
Scheme
2.
Intramolecular
heteroaromatic
cyclopropanation of in situ generated alkyl diazomethanes
catalyzed by cobalt(II)-porphyrin.
to
a
more stable tautomer cycloheptatriene.
Intramolecular Buchner reaction could be controlled
to stop at the arene cyclopropanation stage by
destabilization of cycloheptatriene through tuning the
linker between arene and diazo group or adjusting
substituent (R) on metal carbene (Scheme 1).
However, due to the facile tautomerization of
norcaradiene to cycloheptatriene, reports on arene
cyclopropanation [ are sparse compared to Buchner
reactions. Over the past decades, there have been
extensive studies on Buchner reaction and arene
In 2014, we reported that alkyl diazomethanes, in
situ generated from N-tosylhydrazones, are effective
3
carbene source for intramolecular sp C-H insertion
to give substituted tetrahydrofurans and pyrrolidines
in
high
yields
and
with
excellent
4]
[5]
diastereoselectivity. In 2015, May and co-workers
reported a rhodium(II)-catalyzed hydrazone-initiated
alkylcarbene/alkyne cascade reaction to form
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201700205
polycyclic products.[6] With chiral Rh(I)/BINAP
catalyst, Pla-Quintana and co-workers achieved an
hexanediamine], Co(OAc)
·4H
O, Rh
(OAc) ,
2
2
2
4
Ru(TTP)CO or [Ru(cymene)Cl
2 2
]
as catalyst led
enantioselective
cascade
diazomethanes.[ Very recently, we found that alkyl
diazomethanes underwent
reaction of
alkyl
to alkene 3a as major product (entry 4-8). When
Ir(TTP)Me or CuI was used as catalyst, both
7]
chemoselective alkene products 3a (3a' and 3a'') and tosylation
cyclopropanation with N-alkyl indoles/pyrroles with product 4a were obtained as major products
cobalt(II)-porphyrin as catalyst (Scheme 2), which (entry 9-10). The absence of catalyst led to low
enables rapid construction of a range of nitrogen- product yield and poor chemoselectivity (entry
containing polycycles in good yields from readily 11). With Co(TTP) as catalyst, the effect of
have solvent was examined (entry 12-14). The use of
demonstrated that alkyl diazomethanes can be used toluene and PhCF led to 2a in 75% and 59%
materials.[
8]
These
works
accessible
3
for various carbene transfer reactions with diastereo- yield respectively, along with alkene 3a in 12-
and chemo-selectivity. Despite these advances, the
alkylcarbene chemistry remains largely
32% yield. When 1,2-dichloroethane was used as
solvent, trace amount of 2a was obtained.
underdeveloped compared to that of acceptor-
carbenes. So far the reports on metal-catalyzed
alkylcarbene transfer reactions are rare. To further
explore the reactivity and selectivity of alkylcarbenes,
we turned our attention to Buchner reaction and arene
cyclopropanation. Herein, is described a cobalt-
porphyrin catalyzed intramolecular Buchner reaction
and cyclopropanation of arenes with alkylcarbene.
Screening of bases revealed that K
2
CO was the best,
3
t
whereas other bases, including NaH, LiO Bu and
TMSONa, were less effective (see Supporting
Information).
Table 1. Screening of catalyst and reaction condition.[a]
We first examined the use of aniline-derived
N-tosylhydrazone
1a
as
substrate
for
intramolecular Buchner reaction. The target
product 2a has a cyclohepta[b]pyrrole structure
which is found in some bioactive compounds
(
Figure 1). However, chemoselectivity of the
reaction could be a challenge as there are several
potential side reactions including 1) 1,2-hydride
shift of carbene intermediate to form alkene 3a
(
3a' and 3a''), such a reaction has been observed
[
5,8]
9]
in our previous work;
2) tosylation of N-
3) intramolecular
tosylhydrazones
(
4a);[
aromatic C-H bond insertion (5a), similar
reaction was found to be major when analogous
α-diazocarbonyl compounds were used as
substrates in dirhodium(II) catalysis.[10]
Overall
Ratio[b]
Entry
Catalyst
Solvent
Yield
2
a:3a:4a:5a
[
b]
[
%]
1
2
3
4
5
6
7
8
9
Co(TTP)
Co(F20-TPP)
Co(PC)
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
94
99
52
60
40
23
89
79
90
70
22
99:1:0:0
97:3:0:0
63:37:0:0
15:85:0:0
7:93:0:0
Co(salen)
Co(OAc)
2
2
·4H O
Figure 1. Examples of bioactive compounds containing
Rh (OAc)
2
4
14:86:0:0
4:96:0:0
cyclohepta[b]pyrrole structure
.
Ru(TTP)CO
[Ru(cymene)Cl
Ir(TTP)Me
CuI
2
]
2
11:89:0:0
1:77:22:0
2:55:43:0
15:67:18:0
86:14:0:0
65:35:0:0
67:33:0:0
At the outset, we examined the catalytic
activity of a panel of transition metal catalysts
towards the Buchner reaction of 1a. Treatment of
1
0
N-tosylhydrazone 1a with K
Co(TTP) (2 mol %) in 1,4-dioxane at 105 °C for
5 h led to cycloheptatriene fused pyrrolidine 2a
2
CO
3
(3 equiv.) and
11
None
1
1
1
2
3
4
Co(TTP)
Co(TTP)
Co(TTP)
Toluene 87
1
PhCF
3
91
3
in 93% yield (Table1, entry 1), comparable yield
was obtained with Co(F20-TPP) as catalyst. When
Co(PC) (PC = phthalocyanine) was used as
catalyst, 2a was obtained in moderate yield and
low chemoselectivity (entry 3). The use of
Co(salen) [salen = N,N′-bis(salicylidene)-1,2-cyclo-
DCEc)
[
a]
The reaction was carried out with 1a (0.2 mmol), K
3 equiv.) and catalyst (2 mol %) in 1 mL solvent under
2 3
CO
(
N .
2
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201700205
[
[
b]
c]
1
Determined by H NMR.
,2-Dichloroethane, reaction was carried out at 84 C.
underwent intramolecular Buchner reactions to
give cycloheptatriene fused pyrrolidines in good
to high yields. The reaction is tolerant of a variety
of functional groups (Table 2). When para-
o
1
1
Table 2. Co(TTP)-catalyzed intramolecular Buchner
reaction of aniline derived N-tosylhydrazones
substituent R of arene is H or Br, corresponding
[a,b]
cycloheptatriene fused pyrrolidine 2a and 2b
were obtained in 93% and 1 90% yield,
respectively. However, when R is electron-
withdrawing group (NO ), the reaction furnished
2
Buchner product 2c in 68% yield. These results
are indicative of the electrophilic nature of the as
formed cobalt-alkylcarbene intermediate. In the
reaction of 1c, alkene was found to be the major
byproduct (around 20% yield) revealing that 1,2-
hydride migration of carbene intermediate would
become competitive when substrate is less
1
reactive. Interestingly, when R is the electron-
donating methoxy group (1d), similar result (2d
)
was obtained. This suggests that electronic
properties of arene substituents may not be the sole
factors affecting the Buchner reaction. Monitoring
the reaction course by TLC revealed that aryl
substitution has little influence on the reaction
rate as all of the reactions of 1a-1d required
around 15 h for completion. This indicates that
the cyclopropanation/tautomerization step might
not be rate-determining in the Co(II)-catalyzed
Buchner reaction of N-tosylhydrazones.
The Co(II) catalyzed Buchner reaction was
found to be highly regioselective. For example,
the reaction of N-tosylhydrazone 1e bearing a
meta methyl substitution gave the sole isomeric
product 2e derived from the attack of carbene to
the π bond most remote to meta substituent. The
analogous
reaction
of
2
α-diazocarbonyl
(OAc) was reported
compounds catalyzed by Rh
4
to give corresponding cycloheptatriene in high
yields but with moderate regioselectivity (rr =
11]
7
0:30).[ For the reaction of 1f having an ortho
methyl substituent, corresponding 2f was
obtained as sole isomer in 38% yield presumably
due to steric hindrance. Besides the ketone-based
substrates, aldehyde-based N-tosylhydrazones 1g
and 1h were also reactive towards the Buchner
reaction leading to corresponding products 2g and
2
h
in 83% and 94% yield, respectively. The
effect of N-substitution was also examined.
Various N-substituents (2i 2q) were found to be
-
compatible with the Co(II)-catalyzed Buchner
reaction, including Alloc, Cbz, Ts and carbamide,
all of which can be readily removed according to
literature method.[
12]
With the optimised conditions, we examined
the substrate scope of the Co(II)-catalyzed
Buchner reaction. As depicted in Table 2, various
N-tosylhydrazones derived from different anilines
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201700205
intramolecular arene cyclopropanation. Several
naphthylamine
bearing electron-donating
derived
N-tosylhydrazones
(OMe) and
withdrawing (Br and CN) groups respectively
were examined with Co(TTP) as catalyst. The
results revealed that electronic property of the
substituents has only a slight influence on the
arene cyclopropanation as similar product yields
(
83-99%) were obtained (7b
the Buchner reaction of 1c
byproduct alkenes were observed in the
cyclopropanation of 6b 6e possible
-
7e). In contrast with
-
1d (Table 2), no
Notably, when the two naphthylamine derived
N-tosylhydrazones 1r and 6a were used (eq. 1
and 2), in which amino substitution is
respectively at 2 and 1 position of naphthalene,
two different types of products (2r and 7a) were
formed. Like aniline derived N-tosylhydrazones,
-
.
A
explanation for this phenomenon could be that
naphthalene, compared to benzene, is more
reactive due to lower resonance energy, which
would facilitate the cyclopropanation reaction,
thus suppressing the competitive side reaction of
[
13]
1r underwent cyclopropanation with the less
sterically hindered double bond of naphthalene
and subsequent electrocyclic ring opening to give
the Buchner product 2r in 93% yield with high
regio- and chemo-selectivity. In contrast, the
reaction of 6a stopped at the cyclopropanation
stage to give a tetracyclic compound 7a in 76%
yield, no Buchner product 7b was observed. The
electrocyclic ring opening of 7a to 7b might be
1
,2-hydride shift of carbene intermediate. High
product yields were also obtained when the N-
substituent was Boc (7f, 93% yield). However,
the use of Ts as N protecting group has
detrimental effect on the reaction leading to 7g in
4
7% yield, and retro-Michael addition product
was found to be the major byproduct. N-
tosylhydrazones derived from aldehydes were
also reactive towards the cyclopropanation giving
corresponding products in high yields (7h and 7i).
The relative stereochemistry of compound 7f was
determined by NOE experiments (spectra are
provided in the Supporting Information).
kinetically and thermodynamically disfavoured by
concomitant dearomatization.
a
Table 3. Co(TTP)-catalyzed intramolecular arene
cyclopropanation of naphthylamine derived N-
[
a,b]
tosylhydrazones
The thus obtained tetracyclic cyclopropane
products can be readily converted to other N-
heterocycles. Treatment of 7f with acyl chloride
in MeOH under open air led to benzo[h]quinoline
8
in 70% yield (eq. 3). Benzo[h]quinolines are
commonly used as ligand in the preparation of
[
14]
luminescent cyclometalated Ir complexes.
They have also been found to display central
nervous system action and antibacterial
activity.[ When 7f was subjected to TfOH in
benzene, a tricyclic spiro-2,5-dihydro-1H-pyrrole
15]
[
16]
9
was obtained in 89% yield presumably
through cyclopropane ring opening and arylation
with benzene (eq. 4). Compound 7f also
underwent cyclopropane ring opening by treating
with NBS and H O to give a tricycle-fused
2
pyrrolidine 10 in 77% yield (eq. 5), its analogues
[
17]
have often been found in bioactive compounds.
In contrast to the well-studied Buchner
reaction, arene cyclopropanation remains far less
explored due to facile tautomerization of
norcaradiene. In this work, we performed a study
on this transformation by designing substrates
analogous to 6a (Table 3). Firstly, we examined
1
the effect of naphthalene substitution (R ) on the
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201700205
[
[
2] Reviews: a) M. P. Doyle, M. A. McKervey, T. Ye in
Modern Catalytic Methods for Organic Synthesis
with Diazo Compounds, Wiley, 1998; b) O. A.
McNamara, A. R. Maguire, Tetrahedron 2011, 67, 9;
c) S. E. Reisman, R. R. Nani, S. Levin, Synlett 2011,
2
437; d) A. Ford, H. Miel, A. Ring, C. N. Slattery, A.
R. Maguire, M. A. McKervey, Chem. Rev. 2015, 115,
981.
9
3] For recent examples of Buchner reaction: a) P. A.
McDowell, D. A. Foley, P. O’Leary, A. Ford, A. R.
Maguire, J. Org. Chem. 2012, 77, 2035; b) S. Mo,
Jiaxi Xu, ChemCatChem 2014, 6, 1679; c) X. Xu, X.
Wang, P. Y. Zavalij, M. P. Doyle, Org. Lett. 2015, 17,
Scheme 3. Ring opening and related transformations of 7f
7
90; d) Y. Liu, Y. Deng, P. Y. Zavalij, R. Liu, M. P.
Doyle, Chem. Commun. 2015, 51, 565; for examples
of metal-free Buchner reaction: e) H. Scherer, A.
Hartmann, M. Regitz, B. D. Tunggal, H. Giinther
Chem. Ber. 1972, 105, 3357; f) H. Tomioka, K.
Hiraia, Y. Tanimoto, J. Chem. Soc. Perkin Trans. 2
In conclusion, we have demonstrated that alkyl
diazomethanes generated in situ from N-
tosylhydrazones are effective carbene source for
Co(II)-porphyrin
catalyzed
intramolecular
Buchner reaction and arene cyclopropanation in
chemo- and regio-selective manner. The unique
1
994, 633; g) Z. Liu, H. Tan, L. Wang, T. Fu, Y. Xia,
Y. Zhang, J. Wang, Angew. Chem. Int. Ed. 2015, 54,
056.
tetracyclic
intramolecular
N-heterocycles
obtained
from
of
3
cyclopropanation
naphthylamine derived N-tosylhydrazones can be
readily converted to other N-heterocycles with
potential synthetic and biological interests. To our
best knowledge, this work represents the first
example of metal catalyzed Buchner reaction and
arene cyclopropanation via intermediacy of
alkylcarbene.
[4] For examples of arene cyclopropanation: a) G. R.
King, L. N. Mander, N. J. T. Monck, J. C. Morris, H.
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Doyle, D. G. Ene, D. C. Forbes, T. H. Pillow, Chem.
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Reisman, Org. Lett. 2010, 12, 780; d) R. R. Nani, S.
E. Reisman, J. Am. Chem. Soc. 2013, 135, 7304.
[
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intramolecular
procedure
Buchner
for
Co(TTP)-catalyzed
and arene
12219.
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cyclopropanation reaction of alkyl diazomethanes in
situ generated from N-tosylhydrazones
A reaction vessel was charged with N-tosylhydrazone (0.2
mmol), potassium carbonate (83 mg, 3 equiv), Co(TTP) (3
mg, 2 mol %) and dry 1,4-dioxane (1.0 mL). The mixture
[8] A. R. Reddy, F. Hao, K. Wu, C.-Y. Zhou, C.-M. Che,
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o
was stirred at 105 C until the substrate was fully
[
9] X.-W. Feng, J. Wang, J. Zhang, J. Yang, N. Wang,
consumed. The reaction mixture was cooled to room
temperature and filtered, the filtrate was concentrated, and
the residue was purified by silica gel column
chromatography to give corresponding products.
X.-Q. Yu, Org. Lett. 2010, 12, 4408.
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[
11] M. Kennedy, M. A. McKervey, A. R. Maguire, S. M.
This work was supported by National Natural Science
Foundation of China (NSFC 21472159, 21272197), Hong Kong
Research Grants Council General Research Fund (700813,
Tuladhar, M. F. Twohig, J. Chem. Soc., Perkin Trans.
1
1990, 1047.
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[
[
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Chang for X-ray crystallographic analysis.
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chemistry. Part A: structure and mechanism. 5th ed.,
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Advanced Synthesis & Catalysis
10.1002/adsc.201700205
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6
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Advanced Synthesis & Catalysis
10.1002/adsc.201700205
COMMUNICATION
Cobalt-Porphyrin-Catalyzed
Intramolecular Buchner Reaction and
Arene Cyclopropanation of In Situ
Generated Alkyl Diazomethanes
Adv. Synth. Catal. Year, Volume, Page
–
Page
Haixu Wang, Cong-Ying Zhou* and
Chi-Ming Che*
7
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