An unexpected aminocyclopropane reductive rearrangement

Article abstract of DOI:10.1016/j.tetlet.2007.12.054

A reductive rearrangement of aminocyclopropanes is described for the synthesis of cis- or trans-fused bicyclic 1,2-diaminocyclobutanes. Ionization of a cyclic aminal using BF₃·OEt₂ induces rearrangement to a cyclobutyl iminium ion, w

Full text of DOI:10.1016/j.tetlet.2007.12.054

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1155–1159
An unexpected aminocyclopropane reductive rearrangement
Joey L. Methot *, Theresa A. Dunstan , Dawn M. Mampreian, Bruce Adams,
Michael D. Altman
Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States
Received 27 November 2007; revised 10 December 2007; accepted 11 December 2007
Available online 8 January 2008
Abstract
A reductive rearrangement of aminocyclopropanes is described for the synthesis of cis- or trans-fused bicyclic 1,2-diaminocyclo-
butanes. Ionization of a cyclic aminal using BF3ÁOEt2 induces rearrangement to a cyclobutyl iminium ion, which is subsequently reduced
by Et3SiH. Substitution with allyltrimethylsilane allows carbon incorporation, giving a quaternary center. Silyloxy-substituted cyclo-
propanes rearrange rapidly to cyclobutanones which react with NaBH4 to provide 1,2-aminohydroxycyclobutanes. These aminals were
generated by the reduction of a Boc-imide with DIBAL-H or LiBH4.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Aminocyclopropane; Cyclobutane; Piperazine; Imidazolidinone; Rearrangement
Piperazines are versatile heterocycles in medicinal chem-
istry, for example, as solubilizing or hydrophobic groups,
or as scaffolds that can orient substituents in a rigid fash-
ion.1 A recent search of the MDL drug report database
listed over 70 marketed drugs containing a piperazine,2
with examples including the active ingredients in ViagraTM,
JanuviaTM, and CrixivanTM. However, piperazines are also
prone to metabolism through imine formation, a process
that can occasionally be prevented with substitution about
the ring.3 Imidazolidinones are somewhat less popular,
Tanatril TM being recently launched for the treatment of
hypertension. As part of a medicinal chemistry program
we became interested in cyclopropyl piperazine 5.
We planned to prepare piperazine 5 by the reduction of
diketopiperazine 4, a well-established approach for the syn-
thesis of substituted piperazines.4 Commercially available
N-Cbz cyclopropyl amino acid 1 was coupled to glycine
methyl ester using HOBt and EDC giving dipeptide 2 in
68% yield. Hydrogenolysis followed by heating oily 3 to
150 °C neat for 10 min cleanly provided 4 as a white solid.
However, numerous attempts at reduction of the bislactam
rendered unreacted substrate and/or complex mixtures
containing 5.
Concerned about the sensitivity of the aminocyclopro-
pane moiety to the typically harsh reaction conditions
required for amide reduction, we considered a milder
two-step reduction process via Boc diimide 6; prepared
from 4 by treatment with Boc2O and DMAP at ambient
temperature. A solution of 6 in THF was treated at
À78 °C with 4 equiv of DIBAL-H for 1 h giving diol 7 in
84% yield as a 3:1 mixture of diastereomers after an aque-
ous work-up. Next, a solution 7 in DCM was treated at
À78 °C with 4 equiv each of BF3ÁOEt2 and Et3SiH for
2 h.5 To our surprise, the white solid product isolated
was not the planned cyclopropyl piperazine derivative but
instead the rearranged cyclobutyl piperazine 8.6
Bicycle 8 is a new piperazine which rigidifies the confor-
mation of the piperazine scaffold and may also hinder
metabolism. The symmetry of 8 however complicates
stereochemical analysis, and so derivative 97 was prepared
to desymmetrize the piperazine, which was then subjected
to NOESY experiments. The lack of any observed NOE
*
Corresponding author. Tel.: +1 617 992 2054.
E-mail address: joey_methot@merck.com (J. L. Methot).
Northeastern University co-op program participant.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.054

1156
J. L. Methot et al. / Tetrahedron Letters 49 (2008) 1155–1159
O
N
F
F
N
HN
O
NH2
O
O O
S
N
N
N
N
N
N
F
N
JanuviaTM
CF3
ViagraTM
dipeptidyl peptidase IV
inhibitor
phosphodiesterase V
inhibitor
O
O
N
O
OH
OH
O
H
N
N
O
O
N
N
N
OH
O
NH
TanatrilTM
ACE inhibitor
N
CrixivanTM
HIV protease
inhibitor
O
O
ClNH3-Gly-OMe
H2, Pd/C
O
NHCbz
NHCbz
N
HO
HOBt, EDC, NEt3,
DMF; 68%
MeOH, EtOAc;
99%
H
O
1
2
BH3,
BF3/NaBH4,
H
N
H
O
N
O
150 °C
O
NH2
N
Neat, 10 min;
68%
or LiAlH4
H
N
H
O
N
H
O
4
3
5
Boc
N
H
N
4 equiv. DIBAL-H
(1.0 M in hexanes)
O
O
Boc2O, DMAP
DCM; 81%
THF, −78 °C, 1 hr;
O
N
H
O
N
84%
Boc
6
4
Boc
N
Boc
4 equiv. BF3 OEt2
4 equiv. Et3SiH
H
H
OH
N
DCM, −78 °C, 2 hr
HO
N
steps
N
66%
Boc
Boc
7
8
O
N
N
H
NH2
N
H
O
N
H
9
H
H
NOE
O
H
at either methine when the other is inverted, coupled with
transannular effects around cyclobutane and with the adja-
cent pyridine ring clearly indicates that the bicycle is trans-
fused. The coupling constant of ꢀ7 Hz between methine
protons is consistent with this assignment.
Reduction of diol 7 was nearly as effective using EtMe2-
SiH (50% yield) but not with CyMe2SiH (29% yield), while
(MeO)3SiH gave an uncharacterized mixture of products.
Efforts to combine the separate reduction steps in a single
pot from 6 failed to yield product 8 in good yield.8
It is reasonable that the more accessible alcohol of 7 is
reduced first, giving intermediate 10. A second ionization
would then lead to iminium ion 11 which would rearrange
to a more stable iminium ion 12, followed by triethylsilane
reduction that would follow an axial trajectory. We esti-
mate that iminium ion 12 is 2–4 kcal/mol lower in energy

J. L. Methot et al. / Tetrahedron Letters 49 (2008) 1155–1159
1157
than iminium ion 11, based on DFT and HF calculations
at the B3LYP/6-31G* and RHF/6-31++G** levels of
theory, respectively.9 This is consistent with the ring strain
energy of a cyclopropane being ꢀ3 kcal/mol greater than
that of a cyclobutane.10
Over the course of exploring this sequence with various
imides, we turned to imidazolidinediones such as 17 formed
from cyclopropyl aminoamide 15 by treatment with Boc2O
and DMAP at elevated temperature. In contrast, methyl-
amine 16 cyclized rapidly to 18 at ambient temperature.12
Imidazolidinediones 17 and 18 both react cleanly with
DIBAL-H at À78 °C to give hydroxyimidazolidinones 19
and 20 in 61% and 69% yield, respectively. Then as
expected treatment with 2 equiv each of BF3ÁOEt2 and
Et3SiH at À78 °C gave rearrangement to the bicyclic
imidazolidinones 21 and 22 in 57% and 73% yields, respec-
tively. Alternatively, trapping the intermediate iminium
ions with 2 equiv of allyl trimethylsilane giving 23 and 24
in 43–51% yield is promising for more general carbon
incorporation.13 In contrast to piperazine 8, NOESY
experiments with 22 and 24 indicate a cis-fused bicycle.
Oxazolidinedione 26 was prepared in an analogous fash-
ion from amide 25 and reduced with LiBH4 at ambient
temperature to give the intermediate hydroxyoxazolidi-
none. Then in stark contrast to the imidazolidinone series,
exposure to 3 equiv each of BF3ÁOEt2 and Et3SiH at
À78 °C gave clean reduction to 27 in 72% overall yield; this
time with the cyclopropane intact. It is likely that the nitro-
gen in the imidazolidinone series is a better donor than the
oxygen in the oxazolidinone.
Boc
N
OH
BF3 OEt2
Et3SiH
BF3 OEt2
Et3SiH
7
N
Boc
10
Boc
N
Boc
H
N
8
N
Boc
N
N
N
2-4
kcal/mol
Boc
H
Boc
Boc
axial delivery
11
12
While the rearrangement to form novel bicyclic pipera-
zine 8 is of interest, there remained a need to access cyclo-
propyl piperazine. Lactam cyclopropanation using a
modified Kulinkovich reaction with MeTi(OiPr)3/EtMgBr
is a well-established method for the preparation of cyclo-
propyl amines.11 Lactam 13 derived from the commercially
available phenylpiperazinone undergoes clean cyclopropa-
nation to give 14.
An alternative route to bicyclic oxazolidinones is from
the acyclic silyloxy cyclopropane 28. Treatment with
DIBAL-H at À78 °C gave the acyclic aminal 29 following
an aqueous work-up.14 When a solution of crude aminal
29 in DCM was treated at À78 °C with BF3ÁOEt2, a rear-
rangement and concommitant loss of the silyl protective
group gave cyclobutanone 30 in 59% overall two-step
yield.15 The addition of triethylsilane had no effect in this
transformation. Finally, reduction with NaBH4 provides
Boc
N
Boc
N
MeTi(Oi-Pr)3, EtMgBr
THF, -78 oC to rt; 80%
N
O
N
Et
Et
13
14
O
O
H
Boc2O, DMAP
R
N
N
N
R
N
toluene,
100 oC (for 17)
rt (for 18)
H
O
15 (R = H)
16 (R = Me)
17 (R=H; 81%)
18 (R=Me; 69%)
O
O
BF3 OEt2,
Et3SiH,
DIBAL-H
THF, −78 oC
R
R
N
N
N
N
DCM, -78 oC
H
H
HO
19 (R=H; 61%)
20 (R=Me; 69%)
21 (R=H; 57%)
22 (R=Me; 73%)
BF3 OEt2,
Me3Si
O
R
N
N
O
O
DCM, -78 oC
H
N
N
N
N
23 (R=H; 43%)
24 (R=Me; 51%)
H
H
H
H
H
22
24
NOE

1158
J. L. Methot et al. / Tetrahedron Letters 49 (2008) 1155–1159
O
O
O
Boc2O, DMAP
1) LiBH4, MeOH
N
O
N
O
OH
N
H
DCE, 70 oC;
71%
2) BF3 OEt2, Et3SiH,
DCM, −78 °C; 72%
O
27
25
26
OH
O
DIBAL-H
OTBS
OTBS
N
N
DCM,
−78 °C
Boc
Boc
28
29
O
O
BF3 OEt2
NaBH4
N
O
N
DCM, −78 °C;
THF; 81%
H
H
59%
Boc
30
31
6. For related rearrangements of aminocyclopropanes, see: (a) Vergne,
F.; Aitken, D. J.; Husson, H.-P. J. Org. Chem. 1992, 57, 6071; (b)
Vergne, F.; Partogyan, K.; Aitken, D. J.; Husson, H.-P. Tetrahedron
1996, 52, 2421; (c) Notzel, M. W.; Rauch, K.; Labahn, T.; de Meijere,
A. Org. Lett. 2002, 4, 839.
access to the bicyclic oxazolidinone 31. This represents a
novel route to 2-aminocyclobutanones which are useful
substrates for the preparation of various 1,2-disubstituted
cyclobutanes.16
In conclusion, cyclopropyl ketopiperazinyl and imidazo-
linedionyl imides undergo reductive rearrangement to the
corresponding bicyclic trans- or cis-fused cyclobutyl deriv-
atives, respectively, by sequential treatment with DIBAL-H
and BF3ÁOEt2/Et3SiH. The incorporation of an allyl group
upon the replacement of Et3SiH with TMS–allylsilane sug-
gests a more general use for this transformation. The exten-
sive utility of piperazines and imidazolidinones and their
derivatives in medicinal chemistry will render these unique
analogs of interest in drug discovery.17
7. Hamblett, C. L.; Methot, J. L.; Mampreian, D. M.; Sloman, D. L.;
Stanton, M. G.; Kral, A. M.; Fleming, J. C.; Cruz, J. C.; Chenard,
M.; Ozerova, N.; Hitz, A. M.; Wang, H.; Deshmukh, S. V.; Nazef, N.;
Harsch, A.; Hughes, B.; Dahlberg, W. K.; Szewczak, A. A.;
Middleton, R. E.; Mosley, R. T.; Secrist, J. P.; Miller, T. A. Bioorg.
Med. Chem. Lett. 2007, 17, 5300.
8. As expected, the treatment of diol 7 with BF3ÁOEt2 and Et3SiD gave
deuterium incorporation:
Boc
N
Boc
N
OH
BF3 OEt2
Et3SiD
D
N
HO
N
D
Boc
32
Boc
7
References and notes
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J. J. S.; Norman, Mark H. J. Med. Chem. 2006, 49, 3719; (b) Plobeck,
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Walpole, C.; Brown, W.; Zhou, E.; Labarre, M.; Payza, K.; St-Onge,
S.; Kamassah, A.; Morin, P.-E.; Projean, D.; Ducharme, J.; Roberts,
E. J. Med. Chem. 2000, 43, 3878; (c) Chu, D. T. W.; Nordeen, C. W.;
Hardy, D. J.; Swanson, R. N.; Giardina, W. J.; Pernet, A. G.;
Plattner, J. J. J. Med. Chem. 1991, 34, 168.
9. Participation by either of the Boc protective groups (33 and 34 below)
would not be long-lived species as both were calculated to be of high
energy. In addition, 34 was found to be unstable during QM geometry
optimization, converting directly to 12.
Boc
O
N
N
O
H
N
O
H
N
O
Boc
33
34
10. Khoury, P. R.; Goddard, J. D.; Tam, W. Tetrahedron 2004, 60, 8103.
11. (a) Chaplinski, V.; de Meijere, A. Angew. Chem., Int. Ed. Engl. 1996,
35, 413; (b) Martin, R. E.; Lack, O. Tetrahedron Lett. 2005, 46, 8207;
(c) Aertgeerts, K.; Brennan, N. K.; Cao, S. X.; Chang, E.; Kiryanov,
A. A.; Liu, Y. Arylsulfonylpiperazines and related compounds as
hydroxysteroid dehydrogenase inhibitors and their preparation and
pharmaceutical compositions. PCT Int. Appl. 2006, WO 2006105127
A2. For alternative methods for the synthesis of cyclopropylpiper-
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Claiborne, A. K.; Clement, J. J.; Plattner, J. J. Can. J. Chem. 1992, 70,
1328; (e) Bakshi, R. K.; Nargund, R. P.; Palucki, B. L.; Park, M. K.;
5. (a) Pedregal, C.; Ezquerra, J.; Escribano, A.; Carreno, M. C.; Ruano,
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reduction is highly substrate dependent, see: Davies, S. G.; Hunter, I.
A.; Nicholson, R. L.; Roberts, P. M.; Savory, E. D.; Smith, A. D.
Tetrahedron 2004, 60, 7553.
15. For a related acid-induced rearrangement of an hydroxycyclopropane
to a cyclobutanone, see: (a) Truong, M.; Lecornue, F.; Fadel, A.
Tetrahedron: Asymmetry 2003, 14, 1063; (b) Barnier, J. P.; Garnier,
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Tetrahedron Lett. 2001, 42, 8769.
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1998, 729.
12. Attempted reduction of imide 35 with DIBAL-H induced cyclization
giving cyclic urea 18 as the only isolable product. Likewise, Cbz-
protected amine 36 was bisprotected as Boc imides at elevated
temperature with excess Boc anhydride. However, hydrogenolysis of
the Cbz protective group led to rapid cyclization giving 37.
O
DIBAL-H
N
18
N
THF, −78 °C
Boc
O
35
17. Representative procedure: di-tert-butyl (1R,6R and 1S,6S)-2,5-diazabi-
cyclo[4.2.0]octane-2,5-dicarboxylate (8).
A
stirred solution of
1) Boc2O, DMAP,
O
di-tert-butyl 5,8-dioxo-4,7-diazaspiro[2.5]octane-4,7-dicarboxylate 6
(150 mg, 0.441 mmol) in 2 mL of THF was treated at À78 °C with a
1.0 M solution of DIBAL-H in hexane (1.80 mL, 1.80 mmol) and
stirred for 1 h. The reaction mixture was quenched with 2 N
Rochelle’s salt solution and extracted with DCM. The organic layer
was dried (Na2SO4), filtered, and concentrated leaving 128 mg (84%)
of diol 7 as a 3:1 mixture of diastereomers. Diol 7 (91 mg, 0.26 mmol)
was next dissolved in 1.5 mL of DCM and treated at À78 °C with
BF3ÁOEt2 (0.15 mL, 1.2 mmol) and Et3SiH (0.20 mL, 1.25 mmol) and
stirred for 2 h. The reaction mixture was quenched with water and
extracted with DCM. The organic layer was dried (Na2SO4), filtered,
and concentrated. The white solid residue was triturated with hexanes
to provide 57 mg of 8 (66%). 1H NMR (600 MHz, DMSO-d6): 4.22
(br s, 2H), 3.55 (br s, 2H), 3.35 (br s, 2H), 2.08 (br s, 4H), 1.45 (s,
18H); 13C NMR (150 MHz, DMSO-d6): 155.5, 80.6, 49.8, 41.3,
28.7, 24.7; MS (M+Na+) calculated for C16H28N2O4Na 335.2, found
335.3.
H
N
toluene, 100
°C
N
Cbz
H
2) H2, Pd/C,
MeOH, EtOAc
36
O
Boc
N
N
O
37
13. For diverse nucleophilic carbon additions to iminium ions, see:
Veerman, J. J. N.; Bon, R. S.; Hue, B. T. B.; Girones, D.; Rutjes, F. P.
J. T.; van Maarseveen, J. H.; Hiemstra, H. J. Org. Chem. 2003, 68,
4486.
14. A small degree of hydrolysis to the aldehyde could not be avoided
with this substrate. Stability of the aminal following DIBAL-H