2,6-Diazaspiro[3.3]heptanes: Synthesis and application in Pd-catalyzed aryl amination reactions

Article abstract of DOI:10.1021/ol801293f

(Chemical Equation Presented) A concise and scalable synthesis of a 2,6-diazaspiro[3.3]heptane building block is reported. The usefulness of this structural surrogate of piperazine is shown in arene amination reactions yielding a variety of W-Boc-W-aryl-2,6-diazaspiro[3.3]heptanes.

Full text of DOI:10.1021/ol801293f

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3525-3526
2,6-Diazaspiro[3.3]heptanes: Synthesis
and Application in Pd-Catalyzed Aryl
Amination Reactions
Johannes Burkhard and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH Zu¨rich, CH-8093 Zu¨rich, Switzerland
carreira@org.chem.ethz.ch
Received June 9, 2008
ABSTRACT
A concise and scalable synthesis of a 2,6-diazaspiro[3.3]heptane building block is reported. The usefulness of this structural surrogate of
piperazine is shown in arene amination reactions yielding a variety of N-Boc-N′-aryl-2,6-diazaspiro[3.3]heptanes.
We have studied and documented the potential role of
oxetanes and related spirocyclic compounds as useful build-
ing blocks for drug discovery.1 In this context, we have
become interested in further exploring the chemical space
of small heterocyclic compounds for applications in medici-
nal chemistry. 2,6-Diazaspiro[3.3]heptane (1) is an intriguing
ring system that may be considered at the very least as a
structural surrogate for piperazines. Additionally, the spiro-
cyclic framework confers upon it the ability to populate
structural space not accessible to the parent piperazine. Its
potential use as a small-molecule modulator of pharmaco-
kinetic properties, in analogy to what we have shown with
oxetanes, would require an efficient synthesis and the study
of reaction chemistry that allows its ready incorporation onto
molecular scaffolds. Herein, we report a convenient access
route to monoprotected 1 and its participation in Pd-mediated
amination reactions to furnish a variety of N-Boc-N′-aryl-
2,6-diazaspiro[3.3]heptanes.
The recent advances in aryl amination processes3 have made
it common to integrate piperazines onto aromatic systems in
the early stages of discovery of pharmaceutical agents.4 In
contrast, the closely related “homospiropiperazine” 1 (Figure
13) is an underrepresented structural motif in drug design and
Figure 1. Comparison of piperazine and 2,6-diazaspiro[3.3]heptane,
indicated as calculated N-N distances.2
discovery, even though the ring system has been known for
some time.5,6 The handful of reports on its preparation suffer
from two drawbacks: lengthy syntheses or delivery of
compounds that leave the two ends undifferentiated.
(1) (a) Wuitschik, G.; Rogers-Evans, M.; Mu¨ller, K.; Fischer, H.;
Wagner, B.; Schuler, F.; Polonchuk, L.; Carreira, E. M. Angew. Chem.,
Int. Ed 2006, 45, 7736. (b) Wuitschik, G.; Rogers-Evans, M.; Buckl, A.;
Bernasconi, M.; Ma¨rki, M.; Godel, T.; Fischer, H.; Wagner, B.; Parrilla, I.;
Schuler, F.; Schneider, J.; Alker, A.; Schweizer, W. B.; Mu¨ller, K.; Carreira,
E. M. Angew. Chem., Int. Ed. 2008, 47, 4512.
(3) For recent reviews see: (a) Yang, B. H.; Buchwald, S. L. J.
Organomet. Chem. 1999, 576, 125. (b) Muci, A. R.; Buchwald, S. L. Top.
Curr. Chem. 2002, 219, 131.
(2) Calculation was performed using CambridgeSoft ChemBio3D Ultra
11.0.
(4) (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L Chem. ReV. 2003,
103, 893, and references therein.
10.1021/ol801293f CCC: $40.75
Published on Web 07/17/2008
2008 American Chemical Society

Scheme 1
.
Synthesis of 2,6-Diazaspiro[3.3]heptane 6
Table 1. Reactions with Building Block 6a
In the approach we have developed (Scheme 1), the
synthesis of monoprotected 1 commenced with tribromopen-
taerythritol (2), which is commercially available because of
its use as a flame retardant.7 Following its conversion to
2-oxa-6-azaspiro[3.3]heptane 3,1b oxetane opening with HBr
gave a bromoalcohol,8 which was easily transformed into 4
in two steps and 76% overall yield. Hydrogenolytic cleavage
of the N-benzyl group and subsequent treatment with Boc2O
gave N-Boc protected azetidine 5. Of various derivatives that
could be prepared, we have found that oxalate salt 6 is most
convenient to handle. It is accessed following cleavage of
the tosyl amide with Mg/MeOH followed by treatment with
oxalic acid.
To establish the synthetic potential of compound 6 in the
setting commonly observed for piperazines, we have investi-
gated its use in arene coupling reactions. Upon screening for
optimum procedures, we observed that the application of
standard conditions (aryl bromide, Pd2(dba)3, (()-BINAP (1.5/
Pd), tert-BuOK, toluene, 110 °C) resulted in unsatisfactory
coupling yields. Interestingly, under otherwise identical condi-
tions for the Buchwald-Hartwig amination, the presence of
small amounts of Et3N (∼0.5 equiv) led to the corresponding
aryl amines in useful yields.9 As shown in Table 1, diazaspiro-
heptane 6 can be coupled to a variety of aryl bromides. The
best yields were observed when these included alkyl and
fluorine substituents (77-97%, products 7a-7c, 7e). Coupling
to 2-bromopyridine and electron-rich as well as electron-
deficient bromobenzenes furnished products in acceptable yields
(56-83%, products 7d, 7f-7j).
a Typical reaction conditions: aryl bromide (0.4 mmol, 1 equiv), 6 (0.55
equiv), Pd2(dba)3 (1-2.5 mol %), (()-BINAP (1.5/Pd), KOtBu (3 equiv),
Et3N (5 drops), toluene (5 mL), 110 °C, 12-46 h. b Cs2CO3 used as base
instead of KOtBu.
In summary, we have developed an effective route to
monoprotected 2,6-diazaspiro[3.3]heptane, which should
permit its wide use in a number of applications, such as
reductive alkylations and acylations. This is demonstrated
in its successful use in arene amination reactions, a trans-
formation of great interest in the pharmaceutical industry.
Further studies of this fascinating ring system and its
application in drug discovery are ongoing and will be
reported in due course.
(5) (a) Govaert, F. J. Proc. Acad. Sci. Amsterdam 1934, 37, 156. (b)
Litherland, A.; Mann, F. G. J. Chem. Soc. 1938, 1588. (c) Govaert, F.;
Beyaert, M. Bull. Soc. Chim. Belg. 1946, 55, 106. (d) Engel, W.; Eberlein,
W.; Trummlitz, G.; Mihm, G.; Doods, H.; Mayer, N.; De Jonge, A. Eur.
Patent 0 417 631, 1991. (e) Hillier, M. C.; Chen, C.-Y. J. Org. Chem. 2006,
71, 7885.
Acknowledgment. We thank the ETH for support of this
research in the form of a grant (0-20449-07 and INIT No.
0-23617-05). We are also grateful to F. Hoffmann-LaRoche
for generous support of our research program.
(6) (a) Hamza, D.; Stocks, M. J.; De´cor, A.; Pairaudeau, G.; Stonehouse,
J. P. Synlett 2007, 2584. (b) Stocks, M. J.; Hamza, D.; Pairaudeau, G.;
Stonehouse, J. P.; Thorne, P. V. Synlett 2007, 2587.
Supporting Information Available: Experimental pro-
cedures and characterization for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(7) See for example: Bertrand, J.-N. B. U.S. Patent 4 699 943, 1987.
(8) Hoste, J.; Govaert, F. Bull. Soc. Chim. Belg. 1949, 58, 157.
(9) The role of the Et3N catalyst is unclear at present. It may be that it
facilitates deprotonation of the ammonium oxalate 6 as a phase-transfer
agent.
OL801293F
3526
Org. Lett., Vol. 10, No. 16, 2008