Redox Economic Synthesis of TrisubstitutedPiperidones via Ruthenium Catalyzed Atom-Economic Couplings of N-Protected 1,5-Aminoalcohols and Michael Acceptors

Article abstract of DOI:10.1002/adsc.201900881

An efficient atom-economic coupling of 1,5-amino alcohols and Michael acceptors has been developed employing [CpRu(MeCN)₃]PF₆ as a key catalyst to synthesize α,β-unsaturated ketones with exclusive generation of E-geometrical isomers at room temperature without any co-catalyst and additives. A base catalysed 6-endo-trig cyclization of the α,β-unsaturated ketone delivers a direct access to tri-substituted piperidones.

Full text of DOI:10.1002/adsc.201900881

Title: Redox Economic Synthesis of Trisubstituted Piperidones via
Ruthenium Catalyzed Atom-economic Couplings of N-protected
1,5-Aminoalcohols and Michael Acceptors
Authors: Barry Trost, Debayan Sarkar, and Nabakumar Bera
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900881
Link to VoR: http://dx.doi.org/10.1002/adsc.201900881

10.1002/adsc.201900881
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Redox Economic Synthesis of Trisubstituted Piperidones via Ruthenium Catalyzed
Atom-economic Couplings of N-protected 1,5-Aminoalcohols and Michael Acceptors
Barry M. Trosta*, Debayan Sarkarb* and Nabakumar Berab
a
Department of Chemistry, Stanford University, Stanford, California 94305-5080, United States, e-mail:
bmtrost@stanford.edu
b
Department of Chemistry, National Institute of Technology, Rourkela-769008, India. Phone: 0661-2462667 and e-
mail: sarkard@nitrkl.ac.in
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))
The
recent
identification
of
3,5-
Abstract. An efficient atom-economic coupling of 1,5-
amino alcohols and Michael acceptors has been
developed employing [CpRu(MeCN)3]PF6 as a key
catalyst to synthesize α,β-unsaturated ketones with
exclusive generation of E-geometrical isomers at room
temperature without any co-catalyst and additives. A
base catalysed 6-endo-trig cyclization of the α,β-
unsaturated ketone delivers a direct access to tri-
substituted piperidones.
bis(phenylmethylene)-1-(N-acyl)-4-piperidones as present
in b-AP-15 as prominent cytotoxic agents has further
hyped the synthetic attraction.[3],[4],[5],[6] The piperidones
serve as among the best available precursors to piperidines.
The available literature exemplifies
a
significant
bioactivity associated with the plethora of such aza-
heterocycles.[7] Interestingly, ring contraction strategies of
piperidines to form pyrrolidines can be an easy way
towards the synthesis of these five membered heterocyles
as well.[8] Further 2- and/or 6- substituted piperidones are
found to unveil more biological activity.[9] Access to 2,6-
disubstituted-4-piperidones via an acid and base catalysed
cyclization of (E)-enones has been disclosed by the
Sutherland group, but the synthesized piperidones always
required a vinylic methyl-substitution for the planned 6-
endo-trig cyclization as depicted in Scheme 1.[10a,10b]
Keywords: Atom-economic coupling; Michael acceptor;
Tris(acetonitrile)cyclopentadienylruthenium(II)
hexafluorophosphate; E-geometrical isomer; 6-endo-trig
cyclization
The remodelling of reactions towards synthetically
efficient transformations of simple building blocks into
complex molecular targets constitute a fundamental goal.
The piperidines resemble one of such important alkaloid
cores mentioned for clinical and pre-clinical trials.[1],[2]
Thus, catalytic synthetic approaches towards synthesis of
these nitrogen heterocycles are highly sought after.
Scheme 1. Acid and base catalyzed piperidone synthesis from
amino acid
The Hartley group employed a Petasis olefination for
the piperidone synthesis as depicted in Scheme 2.[11]
Scheme 2. Acid catalyzed trisubstituted piperidone synthesis via
Petasis Methylenation from β-amino acids
Fig 1. Bioactive Piperidine and Piperidone molecules.
1
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10.1002/adsc.201900881
Advanced Synthesis & Catalysis
Previous Work
Davis disclosed a TFA mediated intramolecular
Mannich reaction of S-amino β-keto ester with aldehyde
and ketones to deliver poly substituted piperidones as
depicted in Scheme 3.[12]
Scheme 5. CpRu(COD)Cl catalyzed coupling reaction of
propargyl alcohol and Michael acceptor
Thus, we sought an improved replacement of the
earlier protocol with the concomitant generation of
substituted piperidones in the process. The study began
with the reactions of Boc-amino alcohol (1) and α,β-
unsaturated ketones (2) in presence of 10 mol%
[CpRu(MeCN)3]PF6 (3) at room temperature (Scheme 6) .
The tris-acetonitrile ruthenium catalyst (3) was prepared as
per our protocol.[15]
Scheme 3. Tetrasubstituted piperidone synthesis employing
intramolecular Mannich reaction of δ-amino β-keto esters with
aldehydes and ketone
An approach, we developed uses Zn-prophenol
catalysed addition of ynones to N-Boc imines followed by
6-endo-dig cyclisation with in-situ generated IprAuNTf2 to
deliver dihyropiperidin-4-one synthesis as depicted in
Scheme 4.[13]
The coupling reaction generates only a single
isomer with high regioselectivity. The stereochemistry of
the E-isomer (4) has been confirmed from nOe studies, the
details of which have been provided in the supporting
information. It is noteworthy, that no additives and co-
catalysts were necessary for successful completion of the
reaction as depicted in Scheme 6.
Present Work
Scheme 4. Gold catalyzed trisubstituted dihydropiperidone-4-one
synthesis via addition of alkynyl ketone to imine
Thus, efficient syntheses of substituted piperidones
especially emphasizing catalysis represents an immediate
key challenge to be addressed. Herein, we report a simple
and efficient atom-economic coupling reaction of N-
protected-5-aminopent-2-yn-ol with Michael acceptors
using [CpRu(MeCN)3]PF6 as a key step to generate the
precursors to substituted 4-piperidones with excellent
yields. Further, these may be easily reduced to the
corresponding piperidine analogues. A second key step
involves a 6-endo-trig ring annulation.
Entry Catalyst
(mol%)
Solvent
Temp. Yield
1.
2.5
Acetone:H2O(20:1)
RT
50%
2.
3.
4.
5.
6.
7.
5
Acetone:H2O(20:1)
Acetone:H2O(10:1)
Acetone:H2O(10:1)
Acetone:H2O(10:1)
DMF
RT
RT
65%
72%
86%
10%
35%
5%
5
10
10
10
10
RT
60°C
RT
The rationale behind electing the ruthenium catalysed
coupling arrives from our earlier efforts to add ruthenium
complexed allenols with Michael acceptors like methyl
vinyl ketones in the presence of the first generation
ruthenium catalyst CpRu(COD)Cl.[14] The reactions
delivered modest yields along with unwanted generation of
branched alcohol as a by-product. The presence of a co-
catalyst and elevated temperatures were also required for
the reaction as shown in Scheme 5.
Dry Acetone
RT
Scheme 6. [CpRu(MeCN)3]PF6 catalyzed coupling reaction and
optimization of the reaction condition
Optimization of the reaction conditions as outlined in
Scheme 6 shows the sensitivity of the process to the
amount of water present and the concentration of catalyst
loading. Thus, 10 mol% catalyst in 10:1 (by volume)
acetone:water at room temperature, gave 86% yield of the
adduct. Raising the temperature led to decomposition of
2
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10.1002/adsc.201900881
Advanced Synthesis & Catalysis
the catalyst with unreacted substrates. Varying the
concentration of methyl vinyl ketone (coupling partner)
did not affect the reaction at all.
coordinated ruthenocycle (III) via pathway (I→III→V→4)
rather than (II→IV→VI→5).
The rich substrate scope of the coupling reaction was
explored with differently substituted propargyl alcohols in
presence of a variety of Michael acceptors. In every case, a
satisfactory yield of 63-87% was obtained as a single E-
geometrical isomer as depicted in Table 1.
Table 1. Substrate Scope of Coupling Product
Scheme 7. Mechanistic Rationale of Coupling Reaction
The completion of the synthesis of the 4-piperidone
required a 6-endo-trig cyclization of the coupling product.
Available acid and base catalytic protocols for the
cyclization have been scanty and were limited to
disubstituted piperidones only.[17] The 6-endo-trig
cyclization appeared to be a facile one but slowly turned
out to a challenging transformation. Attempted PTSA
mediated ring closure of the unsaturated ketone (4a)
delivered a di-ketal (6) rather than the cyclised piperidone.
Reaction with palladium salts like Pd(CH3CN)2Cl2 and
Pd(OAc)2 did not prove useful. Reacting with TMS-OTf
led to a four-membered carbocycle (7). Performing the
reaction in the presence of mild solid phase acidic reagents
like Amberlyst resin-15 and silica gel did not afford any
desired product. In presence of zinc and NH4Cl in MeCN,
no cyclization product was obtained; rather an elimination
product (8) was produced as shown in Scheme 8.
The wide scope of the reaction was demonstrated
by its effectiveness in 31 varied examples. From
experimental outcome and from existing literature
procedures,[16] the presence of water was needed for the
reaction which lead us to propose that the reaction
proceeded via the formation of
a five membered
ruthenocycle and a H2O molecule participated in the
catalytic cycle as depicted in Scheme 7. The presence of
single E-geometrical isomer and the structure of the
coupling product confirms that the reaction favours a more
Scheme 8. Trials for 6-endo trig cyclization
3
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10.1002/adsc.201900881
Advanced Synthesis & Catalysis
Treatment of the carbamate (4t) with 4N H2SO4 in
this 6-endo-trig cyclization employing various Lewis acids
and transition metals were found to be unproductive.
Interestingly, the carbamate (4j) was treated with H2SO4 to
remove the Boc group followed by basification with
saturated NaHCO3 solution with pH maintained at 8 at 0°C
to 20°C for 1-6 hours delivered the desired piperidones (9f1
& 9f2) in 89% yield with a 1:1 ratio. The isomers are
separated by flash chromatography and the relative
stereochemistry was confirmed by multiple nOe studies
(details are provided in the supporting information) as
depicted in Scheme 11.
trifluoroethanol at 40ºC for 4 hrs led to the expected 6-
endo cyclization and yielded two diastereomers (9a1 and
9a2) in the ratio 1:1.58 with an overall yield of 81% as
shown in Scheme 9. As observed, the achieved dr was not
satisfactory, although the isomers could be separated with
flash chromatography. The relative stereochemistry was
confirmed by multiple nOe studies (details are provided in
the supporting information). The (2S,3R,6R), 9a2 isomer
was the major product in all cases.
Scheme 9. Acid catalysed 6-endo-trig Cyclisation
Scheme 11. Mild base catalysed 6-endo-trig Cyclisation
The substrate scope of the cyclized piperidones
employing H2SO4 is shown in Table 3.
The temperature and pH were found to have
important effects on the cyclization outcome. Increase of
temperature delivered the carbamate eliminated product of
the type 8 and increase of pH by addition of strong base
gave lower yields of piperidones along with minor
amounts of aldol product 10 as in Scheme 10. The
substrate scope of base catalyzed 6-endo-trig cyclization
for 4-piperidone synthesis are summarised in Table 4.
Table 3. Substrate Scope for Acid-Catalysed Cyclisation
Table 4. Substrate Scope for Base-Catalysed Cyclisation
However, a limitation for acid catalyzed cyclization
was that the projected 6-endo trig cyclization happened
only when R2 in the coupling product was a methyl
substituent. Repeated attempts to cyclize the coupling
product with varied R2 substituents other than methyl was
found to be unsatisfactory under acid catalyzed conditions.
Employing the cyclization of carbamate (4p) with
potassium carbonate gave trace cyclized piperidones in
very low yields. Reaction with organic base like Et3N does
not give any cyclized product. Further studies of
cyclization of 4j via enamine type reaction with piperidine,
pyrrolidine and L-proline were not fruitful. Use of strong
bases like potassium tert-butoxide with (4p) did not deliver
any N-cyclized product; rather the aldol condensation
product (10) was obtained as depicted in Scheme 10.
It should be noted that the 2,6-stereochemistry
achieved was trans; whereas, the stereochemistry at C-3
was mixed. These results indicate the conjugate addition of
the amine proceeds with high stereoselectivity, but there
are no significant effects on the stereochemistry of C-3
protonation. Fortunately, C-3 is easily epimerizable so that
either epimer would be obtained in presence of an
appropriate base.
In summary, we have reported an atom-economic
coupling of varied N-protected amino-2-pent-2-yn-1-ol and
Michael acceptors in presence of the second generation
catalyst [CpRu(MeCN)3]PF6 to generate α,β-unsaturated
Scheme 10. Aldol product
A generalized ring annulation was indispensable for
the tri-substituted piperidone synthesis. Albeit, trials on
4
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10.1002/adsc.201900881
Advanced Synthesis & Catalysis
ketones with high geometrical selectivity. After removing
the Boc group, the 6-endo-trig cyclization occurred
smoothly upon treatment with mild base to deliver tri-
substituted-4-piperidones in excellent yields. To the best of
our knowledge, a catalytic synthesis of carbon tri-
substituted piperidones from an acyclic enone is very
rare.[18]
D. Bailey, P. A. Millwood, P. D. Smith, Chem.
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[3] a) W. Chen, X. Zheng, Y. P. Ruan, P. Q. Huang,
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Rafiei, S. Das, B. Bandy, U. Das, S. S. Karki, J. R.
Dimmock, Bioorganic & Medicinal Chemistry Letters
2017, 27, 3669-3673.
[4] J. Dimmock, A. Jha, G. A. Zello, J. W. Quail, E. O.
Oloo, K. H. Nienaber, E. S. Kowalczyk, T. M. Allen, C.
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Experimental Section
General procedure for synthesis of coupling product (4)
from propargyl alcohol (1) and Michael acceptor (2)
[5] J. R. Dimmock, M. P. Padmanilayam, R. N. Puthucode,
A. J. Nazarali, N. L. Motaganahalli, G. A. Zello, J. W.
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To a well-stirred solution of the propargyl alcohol (1) [1
eq] in a (10:1) mixture of acetone and water was added the
catalyst CpRu(CH3CN)3PF6 (3) [10 mol%] and Michael
acceptor (2) [1 eq] sequentially and stirred at room
temperature for 2-4 hrs. Then acetone was evaporated out
under vacuum. The reaction mixture was extracted with
ether (3 X 5ml) and the organic extract was separated and
concentrated under vacuum to give a yellow liquid. The
crude yellow liquid was chromatographed with silica gel
and eluted with 9:1 [Petroleum ether: EtOAc] to give the
coupling product (4).
[6] N. Li, W. Y. Xin, B. R. Yao, C. H. Wang, W. Cong, F.
Zhao, H. J. Li, Y. Hou, Q. W. Meng, G. G. Hou,
European Journal of Medicinal Chemistry 2018, 147,
21-33.
[7] a) P. S. Watson, B. Jiang, B. Scott, Org. Lett. 2000, 2,
3679-3681. b) D. A. Horton, G. T. Bourne, M. L.
Smythe, Chem. Rev. 2003, 103, 893-930. c) M. E.
Welsch, S. A. Snyder, B. R. Stockwell, Curr. Opin.
Chem. Biol. 2010, 14, 347-361.
General procedure for synthesis of piperidones (9) from
coupling product (4)
[8]A. H. Aldmairi, C. G. Jones, A. Dupauw, L. Henderson,
D. W. Knight, Tetrahedron Letters 2017, 58, 3690–
3694.
In a well-stirred solution of coupling product (4)
in trifluoroethanol was added 4 (N) H2SO4 and the reaction
mixture was stirred at room temperature for 3 hours. Then
the reaction mixture was cooled below 20°C and basified
upto pH = 8 by dropwise addition of saturated NaHCO3
solution. Then the reaction mixture was allowed to stir at
0°C-20°C for 1-6 hours. After that the organic part was
separated by extraction with DCM and dried over
anhydrous Na2SO4. Evaporation of the organic solvent
followed by flash chromatography with silica gel and
eluted with 10-30% EtOAc in Petroleum ether afforded the
piperidones (9).
[9] S. Singh, V. K. Rai, P. Singh, L. S. Yadav, Synthesis
2010, 17, 2957-2964.
[10] a) J. D. Bell, A. H. Harkiss, C. R. Wellaway, A.
Sutherland, Org. Biomol. Chem. 2018, 16, 6410-6422.
b) A. H. Harkiss, A. Sutherland, J. Org. Chem. 2018,
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[11] L. V. Adriaenssens, R. C. Hartley, J. Org. Chem.
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[12] F. A. Davis, B. Chao, A. Rao, Org. Lett. 2001, 3 (20),
Acknowledgements
3169-3171.
[13] B. M. Trost, C.-I. Hung, J. Am. Chem. Soc. 2015, 137,
DS would to thank the Department of Science and
Technology (DST), Government of India (Grant No.
EEQ/2016/000518), INSPIRE-DST, Government of India
(Grant No.04/2013/000751) and NIT Rourkela for funding
support.
15940-15946.
[14] B. M. Trost, L. Krause, M. Portnoy, J. Am. Chem.
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10.1002/adsc.201900881
Advanced Synthesis & Catalysis
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6
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10.1002/adsc.201900881
Advanced Synthesis & Catalysis
UPDATE
Redox Economic Synthesis of Trisubstituted
Piperidones via Ruthenium Catalyzed Atom-
economic Couplings of N-protected 1,5-
Aminoalcohols and Michael Acceptors
Adv. Synth. Catal. Year, Volume, Page – Page
Barry M. Trosta*, Debayan Sarkarb* and
Nabakumar Berab
7
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