A mild procedure for the Lewis acid-catalyzed ring-opening of activated cyclopropanes with amine nucleophiles

Article abstract of DOI:10.1021/ol8009286

(Chemical Equation Presented) The Lewis acid-catalyzed ring-opening of methyl 1-nitrocyclopropanecarboxylates with amine nucleophiles is described. The reaction proceeds at room temperature and with complete preservation of the enantiomeric purity from th

Full text of DOI:10.1021/ol8009286

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2809-2812
A Mild Procedure for the Lewis
Acid-Catalyzed Ring-Opening of
Activated Cyclopropanes with Amine
Nucleophiles
Olga Lifchits and Andre´ B. Charette*
Department of Chemistry, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Quebec, Canada H3C 3J7
andre.charette@umontreal.ca
Received April 22, 2008
ABSTRACT
The Lewis acid-catalyzed ring-opening of methyl 1-nitrocyclopropanecarboxylates with amine nucleophiles is described. The reaction proceeds
at room temperature and with complete preservation of the enantiomeric purity from the electrophilic center of the cyclopropane to the acyclic
product. The methodology was applied in an enantioselective synthesis of the dual serotonin/norepinephrine reuptake inhibitor
(3R)-3-(1H-indol-1-yl)-N-methyl-3-phenylpropan-1-amine.
The ring opening of activated cyclopropanes provides a
versatile route for the construction of functionalized carbon
skeletons.1 The numerous approaches that have been used
to fragment the three-membered ring depend on the func-
tionalities present on the cyclopropane and can be broadly
divided into two classes. The first class includes the reactions
of donor-acceptor cyclopropanes that bear oxygen or amine
functionalities as the donor substituents and electron-
withdrawing groups as the acceptor substituents.1b,2 The
second class involves the reactions of the electrophilic
cyclopropanes, which may be activated by cation-stabilizing
groups and electron-withdrawing groups in a similar 1,2
relationship.1a Within the latter class of reactions, much work
has recently been reported on the formal [3 + 2] cyclo-
additions,3 which typically employ mild conditions (Lewis
acid catalysis and ambient temperature) to yield various
cyclic products. However, the generation of acyclic products
via strictly nucleophilic processes4 almost invariably requires
elevated temperatures and/or basic conditions,5 with the
exception of organometallic reagents.6 Such vigorous reaction
conditions can lead to various undesired side reactions, such
(2) (a) Gnad, F.; Reiser, O. Chem. ReV. 2003, 103, 1603. (b) Bajtos,
B.; Yu, M.; Zhao, H.; Pagenkopf, B. L. J. Am. Chem. Soc. 2007, 129, 9631.
(c) Morales, C. L.; Pagenkopf, B. L. Org. Lett. 2008, 10, 157.
(3) For recent examples, see: (a) Pohlhaus, P. D.; Johnson, J. S. J. Am.
Chem. Soc. 2005, 127, 16014. (b) Young, I. S.; Kerr, M. A. Angew. Chem.,
Int. Ed. 2003, 42, 3023. (c) Jackson, S. K.; Karadeolian, A.; Driega, A. B.;
Kerr, M. A. J. Am. Chem. Soc. 2008, 130, 4196. (d) Perreault, C.; Goudreau,
S.; Zimmer, L.; Charette, A. B. Org. Lett. 2008, 10, 689.
(4) Such processes do not involve an intitial reaction of the cyclopropane
with an electrophile. For examples of this class of reactions, see: (a) Miller,
R. D.; McKean, D. R. J. Org. Chem. 1981, 46, 2414, and references therein.
(b) Dieter, R. K.; Pounds, S. J. Org. Chem. 1982, 47, 3174.
(5) Only a 2-unsubstituted and highly activated gem-1,1-dinitro-cylo-
propane has been ring-opened with amine nucleophiles at ambient temper-
ature and under neutral conditions: Budynina, E. M.; Ivanova, O. A.;
Averina, E. B.; Kuznetsova, T. S.; Zefirov, N. S. Tetrahedron Lett. 2006,
47, 647. For typical conditions, see: (a) Stewart, J. M.; Westberg, H. H. J.
Org. Chem. 1965, 30, 1951. (b) Wurz, R. P.; Charette, A. B. Org. Lett.
2005, 7, 2313. (c) Vettiger, T.; Seebach, D. Liebigs Ann. Chem. 1990, 195.
(d) Seebach, D.; Haener, R.; Vettiger, T. HelV. Chim. Acta 1987, 70, 1507.
(e) O’Bannon, P. E.; Dailey, W. P. Tetrahedron 1990, 21, 7341. (f)
Blanchard, L. A.; Schneider, J. A. J. Org. Chem. 1981, 46, 4042. (g)
Magolan, J.; Kerr, M. A. Org. Lett. 2006, 8, 4561.
(1) For reviews, see: (a) Danishefsky, S. Acc. Chem. Res. 1979, 12, 66.
(b) Reissig, H.-U.; Zimmer, R. Chem. ReV. 2003, 103, 1151. (c) Wong,
H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.; Hudlicky, T.
Chem. ReV. 1989, 89, 165. (d) Burritt, A.; Coron, J. M.; Steel, P. J. Trends
Org. Chem. 1993, 4, 517.
(6) See, for example: (a) Bambal, R.; Kemmitt, R. D. W. J. Chem. Soc.,
Chem. Commun. 1988, 734. (b) Corey, E. J.; Gant, T. G. Tetrahedron Lett.
1994, 35, 5373.
10.1021/ol8009286 CCC: $40.75
Published on Web 06/04/2008
2008 American Chemical Society

as an intramolecular rearrangement of the cyclo-
propane.5a,c–e,7
Scheme 2
.
Ring Opening of (()-1a with Aniline Under
Optimized Thermal Conditions
Our group has recently developed efficient methodologies
to generate diverse 1-nitrocyclopropane-carbonyls in both
racemic8 and enantiomerically enriched9 forms, which have
been used to synthesize substituted dihydropyrroles and
pyrroles,5b and cyclopropane R-amino acids10 and esters9
(Scheme 1).
o-bromoaniline under the optimized conditions afforded the
ring-opened product in only 15% yield. To overcome this,
we turned our attention to the development of a Lewis acid-
catalyzed version of this reaction at ambient temperature. It
became evident that the relative strength of the Lewis acid
was critical in determining the mechanistic pathway of the
ring-opening reaction (Scheme 3). Highly activating bidentate
Scheme 1. Synthesis of Racemic and Enantioenriched
1-Nitrocyclopropanecarbonyls and Their Applications5c,8–10
Scheme 3. Possible Mechanisms of a Bidentate Lewis
Acid-Catalyzed Cyclopropane Ring Opening
To further extend the utility of these cyclopropanes, we
sought to develop a procedure for their ring-opening with
heteroatom nucleophiles, thereby generating acyclic 1,3-
bifunctional molecules. Herein, we report such a method for
the ring-opening of methyl 1-nitrocyclopropane carboxylates
with amine nucleophiles under Lewis acid catalysis and at
ambient temperature, which completely preserves the enan-
tiomeric excess of the cyclopropane at the electrophilic
center. The methodology was applied toward the synthesis
of a dual serotonin/norepinephrine reuptake inhibitor (3R)-
3-(1H-indol-1-yl)-N-methyl-3-phenylpropan-1-amine 9.11
We first tested the ring-opening under thermal conditions,
reacting (()-1a with a 5-fold excess of aniline in refluxing
methanol. Complete conversion was achieved after 17 h,
affording the desired product 3a in 78% yield. By optimizing
the reaction conditions, we found that the aniline loading
could be reduced to 1.5 equiv. Carrying out the reaction in
acetonitrile at 90 °C suppressed minor side reactions,12
affording the product cleanly in 86% yield (Scheme 2).
However, the reaction of the more sterically hindered
(AlCl3, SnCl4) and monodentate (BF3•Et2O) Lewis acids
generated, in addition to the ring-opened product, the
rearrangement product 4 in varying amounts and with loss
of enantiomeric excess.13 This presumably occurs by a
Lewis-acid catalyzed ring-opening of the cyclopropane into
a zwitterionic species prior to the nucleophilic attack (Scheme
3, pathway c). Such unimolecular ionization14 could also
result in the racemization of the stereogenic center at C-1 in
the ring-opened product (pathway b). In contrast, weakly
activating Lewis acids (Cu(OTf)2, ZnCl2, Ti(OiPr)4), though
preserving the enantiomeric excess at C-1, gave only very
low conversion.13 Although Y(OTf)3 was found to be a good
catalyst,13 the optimal results were obtained with
Ni(ClO4)2•6H2O (10 mol %),15 which cleanly catalyzed the
ring-opening of 1a by aniline with full conversion after 17 h
and complete preservation of the enantiomeric excess at the
(12) A lactam product resulting from the condensation of the ester and
amine moieties in 3a was observed in small amounts (< 10%) when the
reaction was carried out in toluene in a sealed tube at 110 °C for 17 h.
Only with longer reaction time (2d) could the lactam product be obtained
with significant conversion (78% by 1H NMR, with the remaining material
being 3a), suggesting that temperatures above 90 °C are required for this
transformation.
(7) Nitrocyclopropanecarboxylates can isomerize to nitroisoxazoline
N-oxides by the action of heat, halide ions and certain Lewis and protic
acids: Bianchini, L.; Dell’Erba, C.; Gasparrini, F.; Novi, M.; Petrillo, G.;
Sancassan, F.; Tavani, C. ArkiVoc 2002, 142
.
(8) Wurz, R. P.; Charette, A. B. Org. Lett. 2003, 5, 2327.
(9) Moreau, B.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 18014.
(10) Wurz, R. P.; Charette, A. B. J. Org. Chem. 2004, 69, 1262.
(11) Mahaney, P. E.; Vu, A. T.; McComas, C. C.; Zhang, P.; Nogle,
L. M.; Watts, W. L.; Sarkahian, A.; Leventhal, L.; Sullivan, N. R.; Uveges,
A. J.; Trybulski, E. J. Bioorg. Med. Chem. 2006, 14, 8455.
(13) See Supporting information for Lewis acid screening.
(14) (a) Danishefsky, S.; Rovnyak, G. J. Chem. Soc., Chem. Commun.
1972, 821, and references therein. (b) Sapeta, K.; Kerr, M. A. J. Org. Chem.
2007, 72, 8597.
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Org. Lett., Vol. 10, No. 13, 2008

Table 1. Ni(ClO4)2•6H2O-Catalyzed Ring Opening of 1-Nitro-cyclopropanecarboxylates by Amine Nucleophilesa
a Reaction conditions: 1 (1 equiv), 2 (1.5 equiv), Ni(ClO4)2•6H2O (10 mol %), CH2Cl2 (2.3 M), rt, 16 h. b Yield of isolated product. c Reaction time 48 h.
d 2i (2.1 equiv) was used.
electrophilic center. Interestingly, addition of molecular
sieves to the reaction changed the nature of this Lewis acid
dramatically, giving only the rearrangement product 4 after
1 h in the absence of the nucleophile, and a sluggish
conversion in the presence of the nucleophile.
With the optimal conditions in hand, we examined the
substrate scope using various amine nucleophiles (Table 1).
Reaction with aniline afforded the ring-opened product in
82% yield and with complete preservation of the cyclopro-
pane’s enantiomeric excess at the electrophilic center (Table
1, entry 1). We were pleased to find that the sterically
hindered o-bromoaniline worked equally well, affording the
ring-opened product in 83% yield (entry 2). Secondary
aromatic amines (entries 6, 9) similarly gave the ring-opened
product in good to excellent yields, as did electron-rich (entry
7) and halogen-substituted (entries 2, 4) aniline derivatives.
As expected, the electron-poor p-nitroaniline (entry 8)
resulted in a slower reaction, but full conversion was
achieved after 48 h, with an excellent isolated yield. Boc-
protected amines were found to be stable to the reaction
conditions, allowing for the introduction of a second amine
functionality (entry 5), which could potentially be deprotected
and further derivatized. Varying the substituents at the
2-position of the cyclopropane to a p-chlorobenzyl (entry
3), naphthyl, indenyl, and vinyl groups (entries 10-12) also
gave the addition products in good yields and with the same
regioselectivity. Finally, aliphatic amines were tested under
the reaction conditions. Unfortunately, their high basicity
resulted in a strong complexation to the catalytic Lewis acid,
which considerably slowed down the reaction. Only the more
nucleophilic pyrrolidine (entry 13) and piperidine (entry 14)
gave synthetically useful isolated yields with longer reaction
times.
(15) For the use of Ni(ClO4)2 to activate cyclopropane gem-diester
derivatives, see ref 3d and: (a) Kang, Y.-B.; Sun, X. L.; Tang, Y. Angew.
Chem., Int. Ed. 2007, 46, 3918. (b) Sibi, M. P.; Ma, Z. H.; Jasperse, C. P.
J. Am. Chem. Soc. 2005, 127, 5764.
In all cases, a mixture of interconverting diastereomers at
C-3 (Scheme 3) was obtained, in approximately a 1:1 ratio,
except for the products 3k (70:30 dr) and 3m (60:40 dr).
Org. Lett., Vol. 10, No. 13, 2008
2811

1-amine 9 (Scheme 4).11 Starting for the readily synthesized
adduct 3i (Table 1, entry 9), saponification and decarboxyl-
ation of the methyl ester with aqueous LiOH at 80 °C
afforded the nitro compound 5 which was reduced to the
primary amine 6 in 89% yield over 2 steps. The amine was
N-methylated in two steps via a carbamate derivative 7 to
give the indoline compound 8 which was oxidized to indole,
furnishing the neurotransmitter reuptake inhibitor 9 in an
overall 65% yield and 90% ee. A similar approach was used
to synthesize the N-dimethyl analogue 3-(1H-indol-1-yl)-N,N-
dimethyl-3-phenyl-propan-1-amine 11.11 Starting from (()-
6, reductive amination and indoline oxidation afforded the
neurotransmitter reuptake inhibitor 11 in a 60% overall yield
over 5 steps (Scheme 4). By varying the substituents on the
cyclopropane and the indole reagents which have been shown
to impart different biological activity,11 various enantioen-
riched derivatives of the inhibitor could in principle be easily
accessed.
Scheme 4. Synthesis of the Dual Serotonin/Norepinephrine
Reuptake Inhibitor 9 and its N-Dimethyl Analogue 11
In conclusion, we developed a very mild and efficient
Lewis acid-catalyzed ring opening reaction of methyl 1-nitro-
cyclopropanecarboxylates with amine nucleophiles. The
reaction proceeds at room temperature and with complete
preservation of the enantiomeric excess at the electrophilic
center of the cyclopropane, tolerating a variety of amine
nucleophiles as well as substituents in the 2-position of
cyclopropane ring. The racemic or enantioenriched 1,3-
bifunctional molecules generated can serve as useful synthetic
precursors for further functionalization. A dual serotonin/
norepinephrine reuptake inhibitor was synthesized in an
expedient and high-yielding route employing the cyclopro-
pane ring-opening reaction as the first step of the synthesis.
Acknowledgment. This work was supported by the
Natural Science and Engineering Research Council of
Canada (NSERC), Merck Frosst Canada Ltd., Boehringer
Ingelheim (Canada), Ltd., the Canada Research Chairs
Program, the Canadian Foundation for Innovation, and the
Universite´ de Montre´al. O.L. is grateful to NSERC for a
postgraduate scholarship (CGSM). We thank Dr. Dino
Alberico for helpful discussions and Jad Tannous (Universite´
de Montre´al) for SFC analyses.
When enantioenriched cyclopropanes were used as starting
materials, the reactions proceeded with an SN2 inversion of
the absolute stereochemistry at C-1 (Scheme 3).16
We next applied the methodology in an enantioselective
synthesis of the dual serotonin/ norepinephrine reuptake
inhibitor (3R)-3-(1H-indol-1-yl)-N-methyl-3-phenylpropan-
Supporting Information Available: Experimental pro-
cedures, NMR spectra, SFC chromatograms, and compound
characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
(16) Absolute stereochemistry was established by comparing the optical
rotation of the compound 9 derived from the ring-opening of cyclopropane
ent-1a, with the literature value (see Supporting information). The observed
[R]D suggests an inversion of the absolute stereochemistry at C-1 (Scheme
9
3) from the starting cyclopropane (see ref. for absolute stereochemistry
of ent-1a) and hence an SN2 mechanism.
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