An expedient route to diaza-spirocycles utilizing a sequential multicomponent α-aminoallylation/ring-closing metathesis strategy

Article abstract of DOI:10.1016/j.tetlet.2006.10.011

A general method for the preparation of diaza-spirocycles is reported. This method used an olefin metathesis in order to construct the desired spirocyclic framework. Beginning with commercially available protected amino ketones, this strategy ultimately p

Full text of DOI:10.1016/j.tetlet.2006.10.011

Tetrahedron Letters 47 (2006) 8977–8980
An expedient route to diaza-spirocycles utilizing a sequential
multicomponent a-aminoallylation/ring-closing metathesis strategy
Vijaya Gracias,* Alan F. Gasiecki, Joel D. Moore,
Irini Akritopoulou-Zanze and Stevan W. Djuric
Scaffold-Oriented Synthesis, Medicinal Chemistry Technologies, Abbott Laboratories, R4CP, AP10,
100 Abbott Park Road, Abbott Park, IL 60064-6099, USA
Received 13 September 2006; accepted 2 October 2006
Available online 30 October 2006
Abstract—A general method for the preparation of diaza-spirocycles is reported. This method used an olefin metathesis in order to
construct the desired spirocyclic framework. Beginning with commercially available protected amino ketones, this strategy ulti-
mately produced pharmacologically relevant diaza-scaffolds in an efficient and high-yielding process.
Ó 2006 Elsevier Ltd. All rights reserved.
The continuing demand for novel lead compounds has
led to the development of our scaffold-oriented synthesis
program that targets pharmaceutically-attractive mole-
cular skeletons primed for subsequent manipulation and
derivatization. In this context, our group became inter-
ested in the synthesis of diaza-spirocycles due to their
presence in a variety of biologically active compounds.
Compounds containing these frameworks have proven
to possess anesthetic,1 antiinflammatory,2 and antioxi-
dant3 properties. In addition, they have served as NK1
receptor antagonists,4 glycoprotein antagonists5 and
CNS agents.6 Furthermore, the clinically useful dop-
amine antagonists such as spiperone and fluspiperone
are spiroannulated piperidine derivatives.7 This notable
pharmacological profile has initiated a number of
synthetic approaches toward diamino-spirocycles (and
related compounds)8 and warrants the continued com-
munication of novel methods toward their synthesis.
Along these lines, we now report on a ring-closing
metathesis-based strategy for the preparation of these
pharmacologically interesting diamino scaffolds.
such example is the a-aminoallylation of carbonyl
compounds, a three-component reaction of aldehydes/
ketones, amines, and an allylating agent.10
Herein, we report on efforts on the a-aminoallylation
reaction of aminoketones as the carbonyl component
followed by a ring-closing metathesis as a route to spiro-
cyclic diamines. The general strategy is outlined in
Figure 1. The reaction of an aminoketone with allyl-
amine generates a ketimine, which is followed by the
addition of the allyl group from pinacol allylboronate
to provide the homoallylic/allylic secondary amine.
The synthesis of spirocyclic frameworks from cyclic
ketones by the addition of allylmagnesium bromide to
preformed ketimines generated from allylamine, fol-
lowed by a ring-closing metathesis reaction (RCM) has
previously been reported by Wright and co-workers.11
Multicomponent reactions (MCRs) continue to attract
considerable interest from the scientific community due
to their ability to construct diversely functionalized
molecules via simple, one-step transformations.9 One
O
NH2
N
N
H
H
O
B
N
P
N
P
N
P
O
*
Corresponding author. Tel.: +1 847 937 6324; fax: +1 847 935
0310; e-mail: vijaya.gracias@abbott.com
Figure 1. General strategy to spirocyclic diamines.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.011

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V. Gracias et al. / Tetrahedron Letters 47 (2006) 8977–8980
Our method uses a concise one-pot procedure for the
addition of the allyl group to the in situ generated
ketimine using pinacol allylboronate. Pinacol allylboro-
nates represent an attractive allylating agent considering
their commercial availability, stability, functional group
tolerance and the non-toxic nature of boronic acids/
esters.
p-TsOH prior to the RCM reaction with the second gen-
eration Grubbs catalyst.12 In the absence of the pretreat-
ment the reaction failed to undergo ring-closure. Thus
reaction of 3 with 1.0 equiv of p-TsOH in CH2Cl2 for
30 min at reflux followed by the addition of the Grubbs
catalyst (5 mol %) gave 4 in 90% yield.13 Under these
conditions, it was observed that the RCM reaction
was complete within 2 h. Alternatively, the amines could
be adequately protected for the RCM reaction as the tri-
fluroacetamide via treatment of the free amine with tri-
fluoroacetic anhydride (TFAA) in pyridine, vida infra.14
Briefly, 1-N-boc-3-piperidone 1, allylamine and the
boronic ester 2 were heated in toluene at 80 °C with
˚
4 A mol sieves for 8 h to provide the amine substrate 3
in 75% yield (Scheme 1). Following purification, inter-
mediate 3 was subjected to RCM conditions. It was
observed that 3 had to be pretreated with 1.0 equiv of
The generality of the a-aminoallylation reaction was
demonstrated by the synthesis of a number of secondary
amines (Table 1). The reaction was found to be quite
general for both the amine and ketone substrates, as
yields ranged from moderate (47%) to excellent (96%).
It is noteworthy to mention that by simply varying the
length (allylic vs homoallylic) of the amine component
used in the MCR, both six- and seven-membered rings
could be accessed in the subsequent RCM.
O
N
HN
NH
a
1
b,c
Boc
N
O
B
N
Attempts were made to access five-membered rings via
the RCM of 5. Unfortunately, however, both the Petasis
boronic acid Mannich reaction15 with pinacol vinyl-
boronate and the addition of vinylmagnesium bromide
to imine 6 failed to give any of the desired product
(Scheme 2).
Boc
Boc
O
3
4
2
Scheme 1. Reagents and conditions: (a) CH2@CHCH2NH2, toluene,
4 A mol sieves, 80 °C, 75%; (b) p-TsOH, CH2Cl2; (c) 5 mol %
˚
(ImesH2)(PCy3)(Cl)2Ru@CHPh, 90%.
Table 1. a-Aminoallylation and RCM products
Entry
Ketone
Amine
a-Aminoallylation product
Yield (%)
74
RCM product
Yield (%)
88
Ph
N
Ph
Ph
Ph
NH2
NH2
1
N
N
O
NH
Ph
Ph
NH
Boc
N
Boc
N
2
3
4
5
6
76a
58
82
96
62
95
75
96
80
94
N
O
O
Boc
Bn
N
H
NH
NH
N
N
Bn
Bn
NH2
NH2
N
Bn
N
N
H
Me
Me
NH
N
Bn
O
O
O
Bn
N
NH
Me
Ph
Ph
Ph
Ph
Ph
N
N
N
NH2
NH
Ph
Bn
NH
N
N
Bn
N
Bn
NH2
NH
NH
Ph
Ph
Ph
Ph
Ph
Ph
CO2Me
NH2
N
N
7
47
74
N
O
NH
NH
MeO2C
MeO2C
a 1.0 equiv of p-TsOH was used prior to the RCM, for all other examples in this table, 2.0 equiv of p-TsOH was used.

V. Gracias et al. / Tetrahedron Letters 47 (2006) 8977–8980
8979
References and notes
1. Kornet, M. J.; Thio, A. P. J. Med. Chem. 1976, 19, 892–
898.
2. Nagy, T.; Jeannin, L.; Sapi, J.; Laronze, J. Y.; Renard, P.;
Pfeiffer, B.; Bizot-Espiard, J. G. Eur. J. Med. Chem. 1995,
30, 575–586.
3. Brown, D. W.; Mahon, M. F.; Ninan, A.; Sainsbury, M.
J. Chem. Soc., Perkin Trans. 1 1997, 2329–2336.
4. (a) Desai, M. C.; Vincent, L. A.; Rizzi, J. P. J. Med. Chem.
1994, 37, 4263–4266; (b) Boks, G. J.; Tollenaere, J. P.;
Kroon, J. Bioorg. Med. Chem. 1997, 5, 535–547; (c)
Kubota, H.; Okamoto, Y.; Fujii, M.; Ikeda, K.; Takeuchi,
M.; Shibanuma, T.; Isomura, Y. Bioorg. Med. Chem. Lett.
1998, 8, 1541–1546.
Scheme 2. Attempts toward five-membered systems.
5. Mehrotra, M. M.; Heath, J. A.; Rose, J. W.; Smyth, M. S.;
Seroogy, J.; Volkots, D. L.; Ruhter, G.; Schotten, T.;
Alaimo, L.; Park, G.; Pandey, A.; Scarborough, R. M.
Bioorg. Med. Chem. Lett. 2002, 12, 1103–1107.
6. (a) Zhu, J.; Quirion, J.-C.; Husson, H.-P. J. Org. Chem.
1993, 58, 6451–6456; (b) Zhu, J.; Quirion, J.-C.; Husson,
H.-P. Tetrahedron Lett. 1989, 30, 6323–6326; (c) Mokrosz,
M. J.; Duszynska, B.; Bojarski, A. J.; Mokrosz, J. L.
Bioorg. Med. Chem. 1995, 3, 533–538.
7. (a) Janssen, P. A. J. U.S. Patent 3,155,669, 1966; Chem.
Abstr. 1964 62, 9142; (b) Janssen, P. A. J. U.S. Patent
3,161,644, 1964; Chem. Abstr. 1964 63, 9952; (c) Janssen,
P. A. J. U.S. Patent 3,238,216, 1966; Chem. Abstr. 1966 65,
8922.
a, b, c
91%
N
N
N
Boc
Boc
Boc
Boc
N
N
H
COCF3
N
N
a, b, c
88%
N
H
COCF3
Boc
N
a, b, c
90%
´
`
8. (a) Compain, P.; Gore, J.; Vatele, J.-M. Tetrahedron 1996,
N
H
N
N
´
`
52, 6647–6664; (b) Compain, P.; Gore, J.; Vatele, J.-M.
Tetrahedron Lett. 1995, 36, 4063–4064; (c) Cossy, J.;
Poitevin, C.; Pardo, D. G.; Peglion, J.-L.; Dessinges, A.
Tetrahedron Lett. 1998, 39, 2965–2968; (d) Cossy, J.;
Poitevin, C.; Pardo, D. G.; Peglion, J.-L.; Dessinges, A.
J. Org. Chem. 1998, 63, 4554–4557; (e) Gemma, S.;
Campiani, G.; Butini, S.; Morelli, E.; Minetti, P.; Tinti,
O.; Nacci, V. Tetrahedron 2002, 58, 3689–3692; (f) Genin,
M. J.; Gleason, W. B.; Johnson, R. L. J. Org. Chem. 1993,
58, 860–866; (g) Montenegra, G.; Fontela, A. G.
J. Heterocycl. Chem. 2001, 38, 837–842; (h) Hedley,
S. J.; Moran, W. J.; Price, D. A.; Harrity, J. P. A.
J. Org. Chem. 2003, 68, 4286–4292.
Boc
COCF3
Scheme 3. Reagents and conditions: (a) TFAA, pyridine; (b) 1 mol %
(ImesH2)(PCy3)(Cl)2Ru@CHPh; (c) H2 Pd/C, MeOH, 60 psi.
As an extension of this chemistry, a series of trifluoro-
acetate-protected RCM adducts were subjected to
hydrogenation conditions to provide the corresponding,
fully saturated spirocyclic framework in excellent yield
(Scheme 3).
9. (a) Do¨mling, A. Chem. Rev. 2006, 106, 17–89;
(b) Maraccini, S.; Torroba, T. In Multicomponent Reac-
In conclusion, we have developed a two-step reaction
sequence using a one-pot a-aminoallylation reaction
followed by the RCM reaction to make a diverse
collection of spirocyclic diamines. The reaction sequence
uses readily available starting materials to afford prod-
ucts in an efficient and concise process. The use of amino
ketones in the a-aminoallylation reaction represents a
valuable extension of this chemistry. The final products
represent structural chemotypes that are useful scaffolds
for lead generation. The diversification of this diamine
collection is currently under way and will be reported
in due course.
´
tions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Weinheim,
2005.
10. (a) Sugiura, M.; Mori, C.; Kobayashi, S. J. Am. Chem.
Soc. 2006, 128, 11038–11039; (b) Sugiura, M.; Hirano, K.;
Kobayashi J. Am. Chem. Soc. 2004, 126, 7182–7183, and
references cited therein.
11. Wright, D. L.; Schulte, J. P., ii; Page, M. A. Org. Lett.
2000, 2, 1847–2850; Also for the synthesis of oxa-aza
spirocycles by the addition of allyl magnesium bromide to
ketones, followed by etherification and RCM, see Walters,
M. A.; La, F.; Deshmukh, P.; Omecinsky, D. O. J. Comb.
Chem. 2002, 4, 125–130.
12. See; Ref. 10 (a) Fu, G. C.; Nguyen, S.-B. T.; Gruggs, R. H.
J. Am. Chem. Soc. 1993, 115, 9856–9857; (b) Gracias, V.;
Gasiecki, A. F.; Djuric, S. W. Org. Lett. 2005, 7, 3183–
3186; (c) Gracias, V.; Gasiecki, A. F.; Djuric, S. W.
Tetrahedron Lett. 2005, 46, 9049–9052.
Acknowledgements
13. A representative procedure is demonstrated by the prep-
aration of tert-butyl 1,8-diazaspiro[5.5]undec-3-ene-8-carb-
oxylate (4). 1-N-Boc-3-piperidone 1 (500 mg, 2.5 mmol),
allylamine (0.94 mL, 12.5 mmol) and boronic ester 2
(420 mg, 2.5 mmol) were heated in toluene (5 mL) at
The authors would like to thank Bryan Macri and
Bhadra Shelat of the high-pressure catalysis lab for
assistance with the olefin reductions, and the structural
chemistry group for NMR and MS measurements.
J.D.M. would like to thank Abbott Laboratories for
the opportunity of a summer internship position.
˚
80 °C with 4 A sieves (850 mg) for 8 h. The reaction
mixture was cooled, filtered through a pad of celite. The

8980
V. Gracias et al. / Tetrahedron Letters 47 (2006) 8977–8980
organic layer was concentrated and purified by flash
was dried (anhyd MgSO4), concentrated and purified by
flash chromatography (90-9-1: CH2Cl2–CH3OH–NH3) to
afford 136 mg (90%) of 4 as a light brown oil. H NMR
chromatography (60% EtOAC/hexane) to afford 524 mg
(75%) of 3 as a clear yellow oil. 1H NMR (300 MHz,
CDCl3): d 1.46 (s, 9H), 1.52–1.66 (m, 6H), 2.13–2.28
(m, 2H), 3.09–3.51 (m, 4H), 5.07–5.22 (m, 4h), 5.82–5.92
(m, 2H); MS (ESI): m/z 281 (M+H); To a solution of 3
(167 mg, 0.6 mmol) in CH2Cl2 (20 mL) was added p-TsOH
(114 mg, 0.6 mmol) and the reaction mixture was heated at
reflux for 30 min. The reaction was cooled to room
temperature and the Grubbs catalyst (25 mg, 0.03 mmol)
was added and the reaction mixture was refluxed for an
additional 2 h (TLC indicated disappearance of the start-
ing material). The reaction was quenched by adding aq
satd K2CO3 and extracted with EtOAc. The organic layer
1
(300 MHz, CDCl3): d 1.45 (s, 9H), 1.52–1.66 (m, 4H), 3.14–
3.57 (m, 8H), 5.70 (s, 2H); MS (ESI): m/z 253 (M+H).
14. For examples of the utilization of trifluoroacetate as an
amine protecting group prior to ring-closing metathesis,
see: (a) Edwards, A. S.; Wybrow, R. A. J.; Johnstone, C.;
Adams, H.; Harrity, J. P. A. Chem. Commun. 2002, 1542–
1543; (b) Pernerstorfer, J.; Schuster, M.; Blechert, S.
Synthesis 1999, 1, 138–144.
15. Maraccini, S.; Torroba, T. In Multicomponent Reactions;
´
Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Weinheim, 2005,
Chapter 7.