Palladium-catalyzed cascade cyclization of allylamine-tethered alkylidenecyclopropanes: Facile access to iodine/difluoromethylene- and perfluoroalkyl-containing 1-benzazepine scaffolds

Article abstract of DOI:10.1039/c6cc02496c

The unprecedented palladium-catalyzed cascade cyclization of allylamine-tethered alkylidenecyclopropanes with an ethyl difluoroiodoacetate or perfluoroalkylated reagent is developed, providing facile access to a variety of synthetically and medicinally valuable iodine/difluoromethylene- and perfluoroalkyl-containing 1-benzazepine frameworks. These reactions exhibited good yields and functional group tolerance via a radical mechanism.

Full text of DOI:10.1039/c6cc02496c

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Palladium-catalyzed cascade cyclization of allylamine-tethered
alkylidenecyclopropanes: facile access to
iodine/difluoromethylene- and perfluoroalkyl-containing 1-
benzazepine scaffolds†
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Liu-Zhu Yu,a Zi-Zhong Zhu,a Xu-Bo Hu,a Xiang-Ying Tangb and Min Shi*a,b
www.rsc.org/
An unprecedented palladium-catalyzed cascade cyclization of construct C(sp2)-CF2R bonds utilizing aryl halides or aryl
allylamine-tethered alkylidenecycloproanes with
ethyl boronic acids as coupling partners.6 Additionally, Baran et al.
difluoroiodoacetate or perfluoroalkylated reagent is developed, disclosed an elegant process for the direct difluoromethylation
providing facile access to a variety of synthetically and medicinally of arenes via radical mechanism.7 Moreover, the group of Hu
valuable iodine/difluoromethylene- and perfluoroalkyl-containing and Liu have independently developed a protocol for vinylic
1-benzazepine framework. These reactions exhibited good yields difluoromethylation of α, β-unsaturated carboxylic acids.8
and functional group tolerance via a radical mechanism.
More recently, Zhang’s group reported a palladium-catalyzed
The introduction of fluorine and fluorine-containing Heck-type reaction of fluoroalkyl bromides with alkenes to
functional group into organic molecules has been an intensive afford fluoroalkylated alkenes.9 Recently, transition-metal-
topic in synthetic and medicinal chemistry because of its catalyzed difluoromethylation or difluoroalkylation to
effective improvements on physical and chemical properties construct C(sp3)-CF2R bonds have also attracted intensive
such as membrane permeability, bioavailability and metabolic attention.10 In 2012, Hu et al. reported a copper-catalyzed
stability compared to their nonfluorinated counterparts.1 As a difluoromethylation of β, γ-unsaturated carboxylic acids for
consequence, fluorine-containing compounds have been the regiospecific construction of allylic C(sp3)-CF2R bonds.10b
widely used in pharmaceuticals, agrochemicals and material Thereafter, Wang et al. developed a palladium or iron-
science. Notably, the difluoromethyl group (CF2) is of catalyzed radical aryldifluoromethylation of activated alkenes
significant importance in medicinal chemistry owing to its to provide a variety of difluoromethylated oxindoles.10d, f More
unique role acting as a bio-isostere of alcohols and thiols and recently, Liang et al. also described a palladium-catalyzed
as a lipophilic hydrogen-donor, and its wide existence in radical cascade iododifluoromethylation/cyclization of 1,6-
biologically active compounds.2 Therefore, the developments enynes to afford iodine/difluoromethylene-containing
of versatile and efficacious methods to construct C-CF2 bond pyrrolidines with simultaneous formation of C(sp3)-CF2R
have been vigorously pursued.3
bonds.10g
Traditional methods for the synthesis of difluoroalkylated
compounds are mainly through deoxyfluorination of aldehydes
or ketones with SF4, N,N-diethylaminosulfur trifluoride (DAST)
or other new developed deoxofluorinating reagents, which
suffer from poor functional group tolerance.4 Recent years
have witnessed the intensive developments of transition-
metal-catalyzed difluoroalkylation strategies to synthesize
fascinating difluoromethyl-containing scaffolds.5 In particular,
numerous synthetic methods have been developed to
Scheme 1 Our recent radical strategy for the construction of 1-benzazepine scaffold.
Recently, we have reported a mild and convenient protocol
to afford two types of CF3-containing tetracyclic benzazepine
a.Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East
China University of Science and Technology, Meilong Road No. 130, Shanghai,
200237 (China).
derivatives using acrylamide-tethered ACPs by
a radical
b.State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032
China. E-mail: mshi@mail.sioc.ac.cn
process (Scheme 1).11 Benzazepines, especially 1-benzazepines,
represent the core structure of numerous pharmacologically
important compounds and exhibit significant bioactivities.12
Therefore, we hypothesized whether difluoromethylene-
† Electronic Supplementary Information (ESI) available: Experimental procedures,
characterization data of new compounds, and CCDC 1440523 See DOI:
10.1039/b000000x
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containing benzazepines could be formed via
a metal- other solvents such as DCE (1,2-dichloroethane) and DME (1,2-
catalyzed radical cascade process. Herein, we gave our primary dimethoxyethane), the desired product was isolated in only
investigation.
60% and 68% yields, respectively (Table 1, entries 11 and 13).
Gratifyingly, when decreasing the Cs2CO3 loading to 1.5 equiv
afforded 2a in 76% yield, probably because excess base
hampered the reductive elimination process to deliver the
product (Table 1, entry 14). Product 2a was obtained in a
relatively lower yield upon decreasing the palladium catalyst
loading to 5 mol% (Table 1, entry 15). Finally, no product was
obtained in the absence of base or palladium catalyst (Table 1,
entries 16 and 17).14 The use of Cs2CO3 may assist the
formation of Pd(0) in the presence of phosphine ligand.
Table 1 Optimization of the reaction conditions for the synthesis of 2a
Table
2 Reaction Scope: Synthesis of iodine/difluoromethylene-containing 1-
benzazepinesa, b
a
Reaction conditions unless specified otherwise: 1a (0.10 mmol, 1.0 equiv),
ICF2CO2Et (0.20 mmol, 2.0 equiv), Pd cat. (0.01 mmol, 0.10 equiv), ligand (0.02
mmol, 0.20 equiv), base (0.20 mmol, 2.0 equiv), solvent (1.0 mL), 50 oC for 12 h. b
e
Isolated yield. c At 30 oC. d At 70 oC. The reaction system was slightly complex. f
g
h
1.5 equiv Cs2CO3 was added. 5 mol% palladium catalyst was used. No desired
product was detected.
Our
study
commended
with
N-(2-
(cyclopropylidene(phenyl)methyl)phenyl)-4-methyl-N-(2-
methylallyl)benzenesulfonamide 1a as the pilot substrate and
the commercially available reagent ethyl difluoroiodoacetate
(2.0 equiv) as difluoromethyl source, in the presence of
Pd(PPh3)2Cl2 (10 mol%), DPE-Phos (20 mol%), and Cs2CO3 (2.0
equiv) in 1,4-dioxane (1.0 mL) at 50 oC under an argon
atmosphere on the basis of recent work reported by Liang’s
research group.10g To our delight, the desired
iodine/difluoromethylene containing 1-benazepine 2a was
obtained in 70% yield after 12 h and its structure has been
unambiguously confirmed by X-ray diffraction (Table 1, entry
1).13 We next examined the palladium catalysts such as
a Reaction conditions: 1 (0.15 mmol, 1.0 equiv), ICF2CO2Et (0.30 mmol, 2.0 equiv),
Pd(PPh3)2Cl2 (0.015 mmol, 0.10 equiv), DPE-Phos (0.030 mmol, 0.20 equiv),
Cs2CO3 (0.225 mmol, 1.5 equiv), 1,4-dioxane (1.5 mL), 50 oC, 12 h. b Isolated yield.
Pd(OAc)2, Pd(MeCN)2Cl2 and Pd2(dba)3 using DPE-Phos as the c The reaction run for 24 h. d Diastereoselectivity derived from a pair of rotamers
was determined by 1H NMR analysis of crude residue.
phosphine ligand and the corresponding desired product 2a
was also produced in the yields ranging from 47% to 55%, thus
Under the optimized conditions (1.0 equiv
1, 2.0 equiv
identifying Pd(PPh3)2Cl2 as the best catalyst for this reaction
(Table 1, entries 2-4). Further study was focused on the
reaction temperature effect, and we found that increasing the
temperature to 70 oC or lowering the temperature to 30 oC
was detrimental to reaction efficiency (Table 1, entries 5-6). In
contrast to DPE-Phos, the other phosphine ligand such as
XantPhos used by Zhang’s group in the palladium-catalyzed
radical difluoromethylation reactions failed to improve the
ICF2CO2Et, 10 mol% Pd(PPh3)2Cl2, 20 mol% DPE-Phos, 1.5 equiv
Cs2CO3 in 1,4-dioxane at 50 oC for 12 h), we next surveyed the
substrate scope of this reaction and the results are shown in
Table 2. Other N-sulfonyl protecting groups such as 4-
bromobenzene sulfonyl (Bs) and methyl sulfonyl (Ms) and N-
carbonyl protecting group were compatible and the
corresponding products 2b, 2c and 2f were obtained in good
yields. Nitrobenzene sulfonyl (Ns) protecting 1-benzazepine 2d
was isolated in 64% yield although the reaction time should be
prolonged to 24 h. N-methyl protecting group also worked
smoothly, giving the desired product 2e albeit in 56% yield.
When R1 is an aryl group, we firstly examined the electronic
effect at the para-position of the benzene ring: as for
9
yield of 2a (Table 1, entry 7).6g, A subsequent survey on
several representative bases including K2CO3, K3PO4 and KOAc
were also examined and no better results could be realized
(Table 1, entries 8-10). Furthermore, the examination of
solvent effect revealed that MeCN gave similar reaction
outcome as that of 1,4-dioxane (Table 1, entry 12). While in
substrates 1g
-1m, the reactions could all proceed smoothly to
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react with 1a under the optimized conditions and the
corresponding perfluorobutyl-containing 1-benzazepine 3aa
was formed in 72% yield. Moreover, perfluorohexyl iodide was
also a suitable perfluoroalkyl source, thus providing the
desired product 3ab with an increased yield of 78%. As for
furnish the corresponding products 2g-2m in the yields ranging
from 61% to 85% regardless of whether they have electron-
donating or electron-withdrawing groups. However, substrates
with electron-rich aromatic ring gave relatively better yields
than those with electron-poor ones. In addition, an electron-
donating substituent at meta-position of the aromatic ring also
afforded the desired product 2n in 71% yield. For the ortho-
substituted substrates 1o and 1p, the reactions also proceeded
efficiently to furnish the corresponding 1-benzazepine
derivatives 2o and 2p in good yields with 3:2
para-tbutyl-substituted substrate 3e
, the perfluorohexyl-
containing benzazepine 3eb could be isolated in up to 84%
yield. The results also demonstrated that electron-rich
aromatic ring gave better reaction efficiency. When R2 was
replaced by a Cl atom or both phenyl rings were substituted by
OMe group, the reactions also proceeded smoothly to deliver
the corresponding products 3nb and 3rb in 71% and 81% yields.
diastereoselectivities derived from
Changing R2 to OMe group or Cl atom, the reaction still worked
smoothly and the desired products 2q 2s were isolated in good
a pair of rotamers.
For substrate 3u
, bearing a
methyl group at R1, the
corresponding product 3ub could also be furnished in 80%
isolated yield.
-
yields as well, indicating that electronic effect and substituent
position had no obvious impact to the reaction outcomes.
Both phenyl ring substituted substrates 1t and 1u were also
suitable for current reaction conditions, giving the
corresponding products 2t and 2u in 74% and 67% yields,
respectively. When R4 on the allylic moiety was replaced by
phenyl substituent, the reaction took place efficiently to afford
the product 2v in up to 88% yield. However, when R4 or R1 was
unsubstituted, only trace amount of products were detected,
probably because of the less stability of the in situ generated
radical intermediates. We next examined the reaction
efficiency when R1 is a methyl group. Gratifyingly, the desired
product 2x was also isolated in 80% yield. Allylether-tethered
ACP could not be converted into the desired 1-benzoxepine
and the reaction system was complex, probably due to the less
stability of the formed 1-benzoxepine.
To gain more insights into the reaction mechanism for this
novel radical cascade cyclizaton reaction, a well-known radical
scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was
used to react with 1a under the above optimized reaction
conditions. The desired product 2a was not detected and
instead, the TEMPO-trapping adduct
4 was formed in 43%
yield on the basis of 19F NMR spectroscopic analysis,
suggesting that the difluoromethyl radical is likely to be the
real reactive specie under the current reaction conditions.
Moreover, the other conventional radical scavenger, 2,6-di-
tert-butyl-4-methylphenol (BHT) also inhibited the cascade
reaction to a great extent with only 38% isolated yield.
Furthermore, on the basis of our previous copper-catalyzed
radical cascade cyclization of acrylamide-tethered ACPs,11 1a
was conducted with 2.0 equiv Togni reagent II in the presence
o
of catalytic amount of CuTc (20 mol%) at 60 C in MeCN. We
Table 3 Reaction Scope: Synthesis of perfluoroalkyl-containing 1-benzazepinesa, b
were pleased to find similar tetracyclic 1-benzazepine
derivative
5
was obtained in 72% yield (Scheme 2; Schemes S1
).16 This unexpected result remedied the substrate
and S2, ESI
†
limitation of our previous work that tosylated substrate failed
to produce the corresponding polycyclic benzazepine scaffolds
and demonstrated that the allylamine moiety preferentially
accepted the radical attack including CF3 radical and CF2 radical.
a
Reaction conditions: 1 (0.15 mmol, 1.0 equiv), RfI (0.30 mmol, 2.0 equiv),
Pd(PPh3)4 (0.015 mmol, 0.10 equiv), DPE-Phos (0.030 mmol, 0.20 equiv), Cs2CO3
(0.225 mmol, 1.5 equiv), 1,4-dioxane (1.5 mL), 50 oC, 5 h. b Isolated yield.
The success to introduce difluoromethyl group into 1-
benzazepine scaffold encouraged us to further investigate
whether perfluoroalkyl reagent was tolerable under current
reaction conditions. After a simplified screening of reaction
conditions, we identified the optimized reaction conditions as
Scheme 2 Control experiments.
Based on the above results and the previously reported
literature,5,6f, g, 10g a plausible mechanism of this radical cascade
cyclization of ACPs to construct fluoroalkyl-containing 1-
benzazepine has been proposed in Scheme 3. First, CF2 radical
or Rf radical is released from ethyl difluoroiodoacetate or
perfluoroalkyl reagent via single electron transfer (SET)
process in the presence of palladium catalyst and base,14
accompanied by PdI(I) complex formation. Subsequently, the
follows: 1.0 equiv 1, 2.0 equiv RfI, 10 mol% Pd(PPh3)4, 20 mol%
DPE-Phos, 1.5 equiv Cs2CO3 in 1,4-dioxane at 50 oC for 5 h.
Then the optimized reaction conditions were employed to
investigate the substrate scope for the synthesis of
perfluoroalkyl-containing 1-benzazepines and the results are
shown in Table 3. Firstly, perfluorobutyl iodide was used to
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radical addition to the less hindered central carbon of
alkylidenecyclopropane producing radical intermediate II. Then
a ring-opening process occurs to produce homoallylic radical
intermediate III because of high strain of cyclopropane ring.15
Finally, the recombination of the formed radical intermediate
III with PdI(I) complex and reductive elimination process
successively take place to afford the final product 2a or 3a and
regenerate the Pd(0) catalyst. However, we can not exclude
another scenario that alkyl radical III abstracts the iodine atom
from Pd(I)I complex directly to deliver the final product.
í
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13 The crystal data of 2a have been deposited in CCDC with
number 1440523.
14 Cs2CO3 alone could promote the production of perfluoroalkyl
radical: T. Xu, C. W. Cheung and X. Hu, Angew. Chem., Int. Ed.,
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16 Alkyl radical intermediate produced in trifluoromethylation
reaction conditions is difficult to combine with Cu(II) to form
Cu(III) complex, but trapped by phenyl ring to deliver
polycyclic benzazepine: B. L. Tran, B. Li, M. Driess and J. F.
Hartwig, J. Am. Chem. Soc., 2014, 136, 2555.
Scheme 3 A plausible reaction mechanism.
In summary, we have developed
a facile synthetic
approach for the construction of structurally diverse
iodine/difluoromethylene and perfluoroalkyl-containing 1-
benzazepine scaffolds via palladium-catalyzed radical
cyclization strategy. The reaction exhibits a broad substrate
and excellent functional group tolerance under mild and
convenient conditions, giving the desired products in good
yields. The potential utilization, extension of the scope and
enantioselective
investigation.
modulation
are
currently
under
We are grateful for the financial support from the National
Basic Research Program of China (973)-2015CB856603, and
the National Natural Science Foundation of China (20472096,
21372241, 21361140350, 20672127, 21102166, 21121062,
21302203, 20732008 and 21572052).
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