(R/S)-BINOL-α-phosphoryloxy enecarbamate-mediated and (R/S)-Titanium(IV) BINOLates-catalyzed enantioselective intramolecular heck/aza-diels-alder cycloaddition (IHADA): An expedient methodology

Article abstract of DOI:10.1002/adsc.201300522

An (R/S)-titanium(IV) BINOLate-catalyzed highly enantioselective intramolecular Heck/aza-Diels-Alder cycloaddition (IHADA) cascade was developed to prepare tetrahydropyridoindoles (tHPs) and octahydropyrazinopyridoindoles (oHPPs) from in situ generated (R/S)-BINOL α-phosphoryloxy carbamate (αPPC2) in one pot. Chiral cooperativity between (R/S)-αPPC2 and (R/S)-titanium(IV) BINOLate was observed and successfully utilized for the construction of various tHPs (7 examples) and oHPPs (17 examples). Copyright

Full text of DOI:10.1002/adsc.201300522

FULL PAPERS
DOI: 10.1002/adsc.201300522
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Intramolecular Heck/Aza-Diels–Alder Cycloaddition (IHADA):
An Expedient Methodology
Imran A. Khana and Anil K. Saxenaa,*
a
Medicinal and Process Chemistry Division, CSIR–Central Drug Research Institute (CSIR–CDRI), Chattar Manzil Palace,
Fax : (+91)-522-262-3405, (+91)-522-262-3938; phone: (+91)-522-261-2411, (+91)-522-262-4273;
e-mail: anilsak@gmail.com or ak_saxena@cdri.res.in
Received: June 14, 2013; Revised: July 11, 2013; Published online: September 10, 2013
CDRI communication number awarded is 8515.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300522.
Abstract: An (R/S)-titanium(IV) BINOLate-cata- BINOLate was observed and successfully utilized for
lyzed highly enantioselective intramolecular Heck/ the construction of various tHPs (7 examples) and
aza-Diels–Alder cycloaddition (IHADA) cascade oHPPs (17 examples).
was developed to prepare tetrahydropyridoindoles
(tHPs) and octahydropyrazinopyridoindoles (oHPPs)
from in situ generated (R/S)-BINOL a-phosphoryl- Keywords: aza-Diels–Alder reaction; cyclopallada-
ACHTUNGTRENNUNGoxy carbamate (aPPC2) in one pot. Chiral coopera- tion; octahydropyrazinopyridoindoles; phosphono-
tivity between (R/S)-aPPC2 and (R/S)-titanium(IV)
ACHTUNGTRENNeUNG ne carbamate; synergistic catalysis
Introduction
cesses are ideal organic transformations with respect
to atom economy and overall efficiency.[10]
Hetero Diels–Alder reactions are the mainstay in het-
Our recent research endeavours on developing ef-
erocycle and natural product synthesis.[1] The aza- fective methodologies for useful organic transforma-
Diels–Alder reaction is an important tool in regio-, tions[11] to construct molecules of interest led us to de-
diastereo- and enantioselective syntheses of the func- velop a highly enantioselective method of intramolec-
tionalized heterocycles[2] due to recent advancements ular Heck/aza-Diels–Alder coupling using indole-2,3-
in the activation of imine systems towards cycloaddi- quinodimethanes as the diene and various imines as
tion.[3] Therefore efforts have been made towards the the dienophile.
intramolecular Heck/aza-Diels–Alder (IHADA) cy-
cloaddition cascade by reacting Ti(IV)-BINOLate-sta-
bilized imines and in situ generated acyclic a-phos- Results and Discussion
phoryloxy enecarbamate. This cycloaddition reaction
may proceed either in a concerted and/or in a stepwise Indole-2,3-quinodimethane (1) could be generated
manner using tandem Mannich–Michael reaction and/ from acyclic a-phosphoryloxy enecarbamate by an in-
or [4p+2p]cycloaddition respectively.[4]
tramolecular Heck reaction[7a] which, in turn, may be
The 2,3-bis(methylene)-2,3-dihydroindole system, trapped in situ by an appropriate dienophile (imine)
particularly indole-2,3-quinodimethane (1),[5,6] is a dis- to provide tetrahydropyridoindole (tHP, Figure 1).The
tinguished diene in the Diels–Alder reaction which ef- Heck coupling mediated approach for the generation
ficiently provides tetrahydro- or dihydrocarbazoles of aPPC1 as diene precursor is more effective than
and their related compounds.[7] Recently, several re- the reported methods of preparation for indole-2,3-
ports have appeared[8] on the synthesis of heterocycles quinodimethanes,[5,12] via either 1,4-elimination of 2,3-
by intramolecular Heck reaction.[9] Such cascade pro- disubstituted indoles[13] or thermal degradation of
thienoACHTUNGTRNEUNG
[3,4-b]-indole dioxides.[14] Furthermore, we en-
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Figure 1. Schematic representation of plausible chiral cooperativity during the aza-Diels–Alder coupling in an IHADA cas-
cade showing the chiral space generated by chiral (R/S)-Ti(IV) BINOLate and phosphoryl reagents.
visaged that this strategy could be extended to a gen- creased by employing chiral Ti(IV) complexes with
eral enantioselective synthesis of octahydropyrazino- BINOL[16] and (À)-menthol.[17]
pyridoindoles (oHPP), which is a key intermediate
The optimized reaction conditions were successfully
for the neuroleptic drug Centbutindole (Biriperone) utilized in the cycloaddition reaction of diethyl fum-
as well as for several biologically active molecules.[15] rate (D1) and N-phenylsuccinimide (D2, entries 18–
The a-phosphoryloxy enecarbamate (aPPC1) was 20, Table 1) to give the respective products tHC1a
generated in situ and was used as a model precursor and tHC2a in good yield with excellent enantioselec-
for the formation of indole-2, 3-quinodimethane (1). tivity in presence of the (R or S)-Ti(IV) BINOLates
After protection of the o-vinylamides with Boc2O/ and achiral aPPC1. The same reagent system gave
DMAP, the treatment of the resultant imide with low enantioselectivity in the case of an imine as dien-
KHMDS (1.2 equiv.) and (PhO)2P(O)Cl afforded ophile (D3, entries 21–23, Table 1). This may be due
aPPC1, which was used as such with 10 mol% of to the geometrical orientation of the imine lone
PdACHTUNGTRENNUNG
(PPh3)4 in the presence of KHMDS (1.02 equiv.), pair.[18] In order to explore the possibility of generat-
Ti(IV) reagents (10 mol%) and diethyl fumrate in ing stereoselectivity in the cycloaddition reaction, the
DMF at À408C to give the enantioselective formation R- or S-binapthol-derived phosphoryl chloride was
of tetrahydrocarbazoles (tHC, entries 1–5, Table 1). synthesized and used with Ti(IV) chiral complex (BI-
The preparation of various o-vinylamides was accom- NOLate) as Lewis acid catalyst under the same opti-
plished by our earlier reported methodology of oxida- mized conditions. It was found that BINOL-derived
tive–decarboxylative coupling using desired acrylic phosphoryloxy enecarbamate (aPPC2) intermediate
acid and phenylacetamide derivatives in the presence and Ti(IV) BINOLate alone could not generate the
of PdACHTUNGTRENNUNG(OAc)2 (10 mol%) as catalyst and Fe- chiral scaffolds (entry 22, Table 1 and entry 8,
ACHTUNGTRENNUNG
(III)-EDTA-H2O2 complex (1.0 equiv.) as oxidant in Table 2), but resulted in excellent enantioselectivity
aqueous media (pH~7.8).[11b] Utilization of trans-di- when used in combination (Figure 1), the capability
ethyl fumarate (D1, entries 1–17, Table 1) for the of the BINOL-phosphoric acid as imine activator was
standardization of the reaction at lower temperature also analyzed by the set of experiment replacing the
was carried out in polar solvents, where N,N-dime- Ti complex, where we have obtained poor results
thylformamide (DMF) and N,N’-dimethylpropylene- both in terms of yield and enantioselectivity under
ACHTUNGTRENNUNG
ene and hexaflourobenzene (HFB) were less effec-
The mechanism involves a Heck/aza-Diels–Alder
tive. The enantioselectivity of the reaction was in- cascade in the formation of the five-membered inter-
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ACHTUNGTRENNUNG(R/S)-BINOL-a-Phosphoryloxy Enecarbamate-Mediated and (R/S)-Titanium(IV) BINOLates-Catalyzed
Table 1. Optimization of the conditions for the intramolecular aza-Diels–Alder reaction.
[b]
Entry[a]
Solvent, Temperature
Base
TiX4
Yield [%]
tHC1a/tHC1b [%][c]
1
2
3
4
5
6
7
8
DMF, À208C
K2CO3
K2CO3
K2CO3
K2CO3
Ti(IV)Cl4
10
25
16
24
21
48
44
69
64
12
62
79
58
41
72
65
55
41
62
60
32
71
45
1:1
1:1
1:1
Ti(IV)
Ti(IV)
U
(+)-Ti(IV)
(+)-Ti(IV)
(+)-Ti(IV)
G
ACHTUNGTRENNUNG
R
1:1.25
1:1.53
1:1.66
1:1.85
1:2.08
1:2.5
nd
1:2.5
1:3.33
1:2
K2CO3
LiHMDS
LiHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
CHTUNGTRENNUNG
Ti(IV)AHCTUGNTENRN(UG BINOL) CTHUNGTRENNUNG
(+)-Ti(IV)
(+)-Ti(IV)
(+)-Ti(IV)
(+)-Ti(IV)
(+)-Ti(IV)
(+)-Ti(IV)
(+)-Ti(IV)
(+)-Ti(IV)
(+)-Ti(IV)
(+)-Ti(IV)
(+)-Ti(IV)
(+)-Ti(IV)
(+)-Ti(IV)
(+)-Ti(IV)
(+)-Ti(IV)
(+)-Ti(IV)
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
G
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
E
T
R
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
G
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
MeTHF, À208C
DMA, À208C
DMPU, À208C
CH3CN, À208C
HFB, À208C
nd
1:4
DMPU, À308C
DMPU, À408C
DMPU, À508C
DMF, À408C
DMPU, À408C
DMA, À408C
DMF, À408C
DMPU, À408C
DMA, À408C
1:12.5
1:100
1:2.5
1:50
1:2.85
1:1.66
1:2.5
1:1.85
[a]
Entries 1–17 are with D1, entries 18–20 are with D2 as dienophile [for intramolecular Heck/aza-Diels–Alder (IHDA)]
and entries 21–23 are with D3 as imine as dienophile [for intramolecular aza-Diels–Alder (IHADA)].
10 mol% Lewis acid was used.
[b]
[c]
1
Determined through H NMR and HPLC.
mediate via cyclopalladation (2, Figure 1). The chiral sponding R,R-combination. The lowered stereoselec-
phosphoryl substrate may get chelated with the Pd to tion in the latter cases supports the mutual chiral
form a chiral intermediate which on subsequent stabi- space reinforcement resulting enhanced stereoselec-
lization with the Ti(IV) BINOLates-imine complex tivity in the former case. Similar results were obtained
[formed in situ using TiCl4 (1.0 equiv.), R- or S- in the absence of imine (dienophile) where the [4p+
BINOL (0.9 equiv.) and desired imine] provides 2p]cycloadduct was formed between the two mole-
greater chiral space or in other terms enhances posi- cules of chiral aPPC2a enantioselectively and afford-
tive synergistic chiral catalysis[19] to increase the ste- ed the stereoisomers tHP2a and tHP2b in a 97.5:2.5
reoselectivity due to the effective trapping of the geo- ratio. The stereochemistry of the obtained tHP1a–2a
metrical arrangement of the imine (3 and 4, Figure 1). was determined through converting them to their de-
Ti(IV) BINOLate plays a primary role in imine acti- protected analogues (S)-2,3,4,9-tetrahydro-1H-pyrido-
vation by suppressing the plausible role of in situ gen-
[3,4-b]indole-3-carboxylic acid[21] known in the litera-
ACHTUNGTRENNUNG
erated chiral phosphate as imine activator and forms ture by treating them with HCl-dioxane followed by
the ion-pair association with the cationic palladium basic hydrolysis. Utilization of different imines D3–
complex (3) resulting in the chiral synergism through D18 (Table 3) as dienophile imine, provided moderate
asymmetric counter anion-directed catalysis.[20]
to good yields with excellent enantioselectivities for
The R,R-spatial arrangement of aPPC2a and the compounds tHP3a–10a and oHPP1a–17a[22] under
Ti(IV) complex was found to provide positive chiral the optimized reaction conditions. The use of DMPU
synergistic catalysis whereas R,S and S,R combina- not only increased the rate of the reaction but was
tions showed lesser enantioselectivity than the corre- also easily removed by a simple aqueous treatment.
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Table 2. The standardization of the reaction conditions using (R or S)-BINOL-derived phosphoryl chloride under the intra-
molecular Heck/aza-Diels–Alder cascade conditions for 4.5 h at À408C using D8 as dienophile.
Entry
Solvent, Temperature
Base
TiX4 (0.1 equiv)
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
DMPU, À208C
DMPU, À208C
DMPU, À208C
DMPU, À208C
DMPU À408C
MeTHF, À408C
DMF, À408C
K2CO3
Ti(IV)
Ti(IV)
Ti(IV)
Ti(IV)
Ti(IV)
Ti(IV)
Ti(IV)
N
38
48
44
69
64
48
32
23[b]
12
85.1
66
90.4
78.5
92
73.8
78.5
24.8
16
LHMDS
LHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
DMPU, À408C
DMPU, À408C
[a]
LA=Lewis acid, BINOL=(R)-BINOL and M=(À)-menthol.
[b]
[c]
The reaction was operated for 9.5 h under similar conditions.
The reaction carried out in the presence of (R)-BINOL-phosphoric acid.
The BINOL residue was purified and reused after re- Experimental Section
generation. In an alternative work-up procedure the
reaction mixture was triturated with n-hexane to iso- Representative Two-Pot Procedure
late the desired solid products in high NMR purity. In
Step 1: To a solution of desired imide (1.2 mmol) in MeTHF
(24 mL) were added HMPA (0.23 mL, 1.32 mmol) and
(PhO)2P(O)Cl (0.28 mL, 1.35 mmol). The resultant mixture
was cooled to À788C and treated with KHMDS (0.5M solu-
tion in toluene, 5.80 mL, 2.7 mmol). After being stirred at
À788C for 0.5 h, the reaction was quenched with 3%
NH4OH and diluted with diethyl ether. The resultant mix-
ture was allowed to warm to room temperature over 20 min
and extracted with EtOAc. The organic extracts were
washed with brine, dried over Na2SO4, filtered, and concen-
trated under reduced pressure. The crude a-phosphoryloxy
enecarbamate (aPPC1) thus obtained was used immediately
without further purification.
order to make the process more practical, a one-pot
reaction cascade was developed using DMPU in the
presence of KHMDS (2.2 equiv.) as base to provide
the desired products (tHP1a–9a and oHPP1a–17a) in
moderate to good yields with excellent enantioselec-
tivity using various a-phosphoryloxy enecarbamates
(a-PPC2a–g) and dienophiles (D3–D18, Table 3).
Conclusions
In conclusion we have successfully synthesized vari-
ous tHPs- and oHPPs-based molecules using an intra-
molecular Heck/aza-Diels–Alder coupling cascade as
a fast, one-pot access. This may be useful to construct
heterocyclic scaffolds under easily workable and mild
reaction conditions with an easy work-up procedure.
Hence, it may be considered as a powerful tool in de-
veloping ideal reaction processes and has high utility
as transition metal-mediated homogenous synergistic
dual catalysis in the synthesis of natural products in-
corporating tetrahydropyridoindole substructures.
Step 2: To a solution of the above crude material in
DMPU (4 mL) were added KHMDS (1.1 mmol), PdACHTUNGTRENNUNG(PPh3)4
(0.52 mg, 0.045 mmol), D1–2 (4.0 mL, 1 mmol), TiCl4
(0.05 mL. 0.1 mmol) and BINOL (28.3 mg, 0.1 mmol). The
resultant mixture was stirred at À408C for 4.5 h. Work-up
procedure A: after the completion of the reaction the mix-
ture was warmed to room temperature and the stagnant re-
action mixture was diluted with hexane from the side of the
RB flask which allowed the slow dissolution with the solvent
mixture, which results in separation of the desired octahy-
dropyrazinopyridoindole as a solid that was filtered through
a G3 sinter and washed with Et2O:MeOH (10:0.5 mL) to
afford the pure compound. Work-up B: after warming to
room temperature, the resultant mixture was quenched with
1 mL saturated NH4Cl solution, diluted with EtOAc, washed
with H2O and brine, dried over Na2SO4, filtered, and con-
centrated under reduced pressure. Purification by flash chro-
matography (silica gel, 5% EtOAc/hexanes) gave ca. 2:1
mixture of tHC1a (pale yellow oil or solid).
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ACHTUNGTRENNUNG(R/S)-BINOL-a-Phosphoryloxy Enecarbamate-Mediated and (R/S)-Titanium(IV) BINOLates-Catalyzed
Table 3. Scope of the reaction with various imines (D4–17) and chiral-aPPC (aPPC2a–g) derivatives under Heck/aza-Diels–
Alder cascade, the yield and ee are reported following the one-pot access procedure in DMPU as solvent at À408C.
Adv. Synth. Catal. 2013, 355, 2617 – 2626
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Table 3. (Continued)
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ACHTUNGTRENNUNG(R/S)-BINOL-a-Phosphoryloxy Enecarbamate-Mediated and (R/S)-Titanium(IV) BINOLates-Catalyzed
Table 3. (Continued)
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Table 3. (Continued)
[a]
a-Phosphoryloxy enecarbamates (a-PPC2a–g) were synthesized in situ and used without purification.
Formation of imine was carried out using a Dean-Stark apparatus in the presence of TiCl4 (5 mol%) in benzene.
Isolated yield.
[b]
[c]
[d]
1
Determined through H NMR and chiral HPLC.
sired dienophile (D3–D18) and after 3.5 h at À788C, and
step 2 was followed within the same pot without carrying
out work-up.
One Pot Procedure
The general procedure of the two-pot methodology (step 1)
was performed in DMPU (0.5 mL) in place of HMPA using
(R)-BINOL-phosphoryl chloride (1.02 mmol) with the de-
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ACHTUNGTRENNUNG(R/S)-BINOL-a-Phosphoryloxy Enecarbamate-Mediated and (R/S)-Titanium(IV) BINOLates-Catalyzed
d) S. M. Bachrach, M. Liu, J. Org. Chem. 1992, 57,
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Acknowledgements
We thankfully acknowledge the technical and analytical sup-
port by Mr. R. K. Purshottam, Mr. D. N. Viswakarma, Mr.
A. S. Kushwaha, Mr. Zahid Ali and SAIF-CDRI. One of us
(IAK) is thankful to CSIR–UGC, New Delhi for the award
of SRF and to Jawaharlal Nehru University (JNU) for the
registration in Ph.D.
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[22] The compounds oHPP7a–9a, 11a and 13a are octahy-
dropiperidino-pyridoindole derivatives therefore are
also abbreviated as oHPP.
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