Nucleophilic addition of phenol derivatives to methyl 1- nitrocyclopropanecarboxylates

Article abstract of DOI:10.1021/jo8010705

(Chemical Equation Presented) Nucleophilic ring opening of methyl 1-nitrocyclopropane-carboxylates by phenol derivatives in the presence of Cs₂CO₃ is described. The reaction tolerates a variety of substituents on both the aromatic alcohol and the cyclopropane and affords the products in good yields (53-84%) and with complete preservation of the enantiomeric excess at C-4. The methodology was applied in an enantioselective synthesis of the norepinephrine reuptake inhibitor atomoxetine (Strattera).

Full text of DOI:10.1021/jo8010705

SCHEME 1. Optimized Reaction Conditions for the
Nucleophilic Ring Opening of Cyclopropane (()-1a with
Phenol
Nucleophilic Addition of Phenol Derivatives to
Methyl 1-Nitrocyclopropanecarboxylates
Olga Lifchits, Dino Alberico, Irina Zakharian, and
Andre´ B. Charette*
Department of Chemistry, UniVersite´ de Montre´al,
P. O. 6128, Station Downtown, Montre´al, Quebec,
Canada H3C 3J7
Our group has recently reported efficient methodologies to
generate racemic5 and enantioenriched6 1-nitrocyclopropyl
carbonyls, which have been used in the synthesis of cyclopro-
pane R-amino acids7 and esters,6,7 and substituted dihydropy-
rroles and pyrroles.2c Most recently, we have shown that these
cyclopropanes can undergo Lewis acid catalyzed ring opening
by amine nucleophiles with complete preservation of the
enantiomeric excess from the cyclopropane.8 As a further
extension of this methodology, we now report the addition of
aromatic alcohols9 to cyclopropanes of type 1 (Scheme 1). The
3-aryl-3-phenoxypropane motif generated in the ring-opened
products is present in the core structure of several monoamine
reuptake inhibitors (Figure 1).10,11 These compounds are widely
used in the clinical treatment of various psychiatric disorders
including attention deficit hyperactivity disorder (ADHD) and
anxiety and depression (atomoxetine, fluoxetine),10 as well as
in biochemical research (nisoxetine).11
andre.charette@umontreal.ca
ReceiVed May 20, 2008
Nucleophilic ring opening of methyl 1-nitrocyclopropane-
carboxylates by phenol derivatives in the presence of Cs2CO3
is described. The reaction tolerates a variety of substituents
on both the aromatic alcohol and the cyclopropane and
affords the products in good yields (53-84%) and with
complete preservation of the enantiomeric excess at C-4. The
methodology was applied in an enantioselective synthesis
of the norepinephrine reuptake inhibitor atomoxetine (Strattera).
Activated cyclopropanes have found wide use in organic
synthesis as versatile electrophilic or 1,3-zwitterionic synthons.1–3
In particular, their ring opening by heteroatom nucleophiles can
serve as a facile route to 1,3-bifunctional molecules that are
present in the core of many small molecules with biological or
pharmaceutical activity.4
FIGURE 1. Examples of monoamine reuptake inhibitors containing a
3-aryl-3-phenoxypropylamine motif.
We began our studies by examining the nucleophilic ring
opening of racemic cyclopropane (()-1a with phenol. Several
bases and numbers of equivalents were examined, and Cs2CO3
(2.5 equiv) proved to be optimal. By screening solvents and
reaction temperatures, we found that stirring the reaction mixture
in tetrahydrofuran at 65 °C in a sealed tube for 12 h led to a
clean reaction with complete conversion and a good isolated
yield of 2a (Scheme 1).
(1) For reviews, see: (a) Seebach, D. Angew. Chem., Int. Ed. 1979, 18, 239.
(b) Danishefsky, S. Acc. Chem. Res. 1979, 12, 66. (c) Reissig, H.-U.; Zimmer,
R. Chem. ReV. 2003, 103, 1151. (d) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.;
Yip, Y.-C.; Tanko, J.; Hudlicky, T. Chem. ReV. 1989, 89, 165. (e) Burritt, A.;
Coron, J. M.; Steel, P. J. Trends Org. Chem. 1993, 4, 517.
(2) For examples of reactions and reaction cascades involving ring opening
of electrophilic cyclopropanes, see: (a) Yang, Y.-H.; Shi, M. Org. Lett. 2006, 8,
1709. (b) Shi, M.; Tang, X.-Y.; Yang, Y.-H. Org. Lett. 2007, 9, 4017. (c) Wurz,
R. P.; Charette, A. B. Org. Lett. 2005, 7, 2313. (d) Budynina, E. M.; Ivanova,
O. A.; Averina, E. B.; Kuznetsova, T. S.; Zefirov, N. S. Tetrahedron Lett. 2006,
47, 647. (e) England, D. B.; Woo, T. K.; Kerr, M. A. Can. J. Chem. 2002, 80,
992.
(3) For recent examples of [2 + 3]-cycloaddition reactions of cyclopropanes,
see: (a) Jackson, S. K.; Karadeolian, A.; Driega, A. B.; Kerr, M. A. J. Am. Chem.
Soc. 2008, 130, 4196. (b) Bajtos, B.; Yu, M.; Zhao, H.; Pagenkopf, B. L. J. Am.
Chem. Soc. 2007, 129, 9631. (c) Perreault, C.; Goudreau, S.; Zimmer, L.;
Charette, A. B. Org. Lett. 2008, 10, 689. (d) Pohlhaus, P. D.; Johnson, J. S.
J. Am. Chem. Soc. 2005, 127, 16014. (e) Young, I. S.; Kerr, M. A. Angew.
Chem., Int. Ed. 2003, 42, 3023.
(4) See, for example: (a) Tanimori, S.; Tsubota, M.; He, M.; Nakayama, M.
Biosci. Biotechnol. Biochem. 1995, 59, 2091. (b) Tanaka, M.; Ubukata, M.;
Matsuo, T.; Yasue, K.; Matsumoto, K.; Kajimoto, Y.; Ogo, T.; Inaba, T. Org.
Lett. 2007, 9, 3331. (c) Bose, G.; Langer, P. Tetrahedron Lett. 2004, 45, 3861.
With the optimal conditions in hand, we examined the scope
of the ring opening reaction, first employing the readily
(5) Wurz, R. P.; Charette, A. B. Org. Lett. 2003, 5, 2327.
(6) Moreau, B.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 18014.
(7) Wurz, R. P.; Charette, A. B. J. Org. Chem. 2004, 69, 1262.
(8) Lifchits, O.; Charette, A. B. Org. Lett. 2008, 10, 2809.
(9) Few examples of the addition of aromatic alcohols to electrophilic
cyclopropanes have been reported and involve only racemic or achiral starting
materials: (a) Seebach, D.; Haener, R.; Vettiger, T. HelV. Chim. Acta 1987, 70,
1507. (b) Schweizer, E. E.; Berniger, C. J.; Thompson, J. G. J. Org. Chem.
1968, 33, 336. (c) Fuchs, P. L. J. Am. Chem. Soc. 1974, 96, 1607. (d) Stewart,
J. M.; Westberg, H. H. J. Org. Chem. 1965, 30, 1951.
(10) Walter, M. W. Drug DeV. Res. 2005, 65, 97.
(11) Graham, D.; Langer, S. Z. Life Sci. 1992, 51, 631.
6838 J. Org. Chem. 2008, 73, 6838–6840
10.1021/jo8010705 CCC: $40.75 2008 American Chemical Society
Published on Web 08/01/2008

TABLE 1. Scope of the Cyclopropane Ring-Opening Reaction
with Phenol Derivatives
TABLE 2. Ring Opening of Enantioenriched Cyclopropanes
a Reaction conditions: 1 (1 equiv), ArOH (3 equiv), Cs2CO3 (2.5
equiv), THF (0.2 M), 65 °C (sealed tube), 12 h. b Isolated yield.
the p-(trifluoromethyl)phenol (entry 3) on a 1 g scale under
reflux cleanly afforded 1.5 g of 2d, a potential fluoxetine
precursor (84% yield).
We next turned our attention to the ring opening of enan-
tioenriched cyclopropanes as a method to access nonracemic
adducts. Indeed, ring opening of (1R,2S)-1a (90% ee)6 with
o-cresol afforded the product with complete preservation of the
enantiomeric excess and an inversion of the absolute configu-
ration at C-4 via an SN2 pathway (Table 2, entry 1).13 Similarly,
the addition of o-bromophenol to (1R,2S)-1a (entry 2) afforded
the adduct 2k in 74% yield and with 90% ee. Ring opening of
(1S,2R)-1a (95% ee) with o-methoxyphenol (entry 3) gave 2l,
a potential (R)-nisoxetine precursor, in a 78% yield and with
95% ee.
Having established a route to the enantioenriched products,
we then applied the methodology to the synthesis of (R)-
atomoxetine (Strattera), a selective norepinephrine inhibitor used
in the treatment of ADHD (Scheme 2).10 Starting from the
enantioenriched adduct 2j (90% ee), the ester group was
saponified and decarboxylated with aqueous LiOH to give the
nitropropyl intermediate 3 in 99% yield and without any loss
of the optical purity. The nitro group was reduced with LiAlH4
to a primary amine affording compound 4 in 96% yield.
Monomethylation of the amine via a carbamate intermediate
gave (R)-atomoxetine in an overall yield of 74% from 2j and
90% ee.
a Reaction conditions: 1 (1 equiv), ArOH (3 equiv), Cs2CO3 (2.5
equiv), THF (0.2 M), 65 °C (sealed tube), 12 h. b Isolated yield.
c Reaction performed on 1 g scale under reflux.
synthesized racemic cyclopropanes 1a-1d5 and various aro-
matic alcohols (Table 1). Phenol derivatives substituted with
both electron-donating (entry 1) and electron-withdrawing (entry
2) substituents were well tolerated. Slightly lower yields were
obtained with m-chlorophenol (entry 3) and with the bulkier
1-naphthol (entry 4). Phenol bearing a Boc-protected amine
group (entry 5) afforded the desired product in good yield.
Varying the 2-substituents on the electrophilic cyclopropane to
more sterically encumbered naphthyl (entry 6) and indenyl (entry
7) groups resulted in slightly lower but synthetically useful
yields. The presence of substituents on both the nucleophile and
the electrophile (entry 8) was unproblematic, and the desired
functionalized product was obtained in a good yield. In all cases
the adducts were isolated as mixtures of interconvertible
diastereomers at C-2 in an approximately 1:1 ratio except for
2k (60:40 dr) and 2l (70:30 dr).12 We were pleased to find that
the reaction could be easily scaled up: nucleophilic addition of
In conclusion, we have developed a simple and practical
method for the nucleophilic ring opening of methyl 1-nitrocy-
clopropyl carboxylates with phenol derivatives. The reaction
(13) The absolute configuration of 2j and hence the SN2 pathway was
established by comparing the optical rotation of the corresponding derivative 6
with the literature value (see Supporting information for data; see ref 6 for the
absolute configuration of the starting cyclopropane 1a). The absolute confiigu-
ration of 2k and 2l was assigned by analogy. X-ray diffraction analysis of co-
cyrstallized enantiomers 2h confirmed the expected trans-relationship of HA and
HB, serving as further proof of the SN2 inversion at C-4 in the ring open-
ing reaction.
(12) Crystalline compound 2h was furthermore seen to undergo a self-
catalyzed enrichment of the diastereomeric ratio at C-2 to 90:10 in the solid
state. See Supporting Information for details.
J. Org. Chem. Vol. 73, No. 17, 2008 6839

SCHEME 2. Enantioselective Synthesis of Atomoxetine
Specific Procedure for Synthesis of Methyl (4R)-4-(2-Meth-
ylphenoxy)-2-nitro-4-phenylbutanoate (2j). In a 2-mL microwave
vial equipped with a stirbar, cyclopropane (1R,2S)-1a6 (100.0 mg,
0.45 mmol, 1 equiv, 90% ee), o-cresol (146.6 mg, 1.36 mmol, 3
equiv), and anhydrous Cs2CO3 (317.3 mg, 1.13 mmol, 2.5 equiv)
were combined with anhydrous THF (2 mL), and the vial was sealed
with a Teflon cap. The reaction mixture was stirred at 65 °C for
12 h, quenched with saturated aqueous NH4Cl (5 mL), and
partitioned between water and diethyl ether. The aqueous layer was
extracted with diethyl ether (10 mL) three times, and the combined
organic layers were washed with saturated aqueous NaCl, dried
over MgSO4, and evaporated under reduced pressure. Flash
chromatography eluting with 100% benzene afforded the spectro-
scopically pure product as a pale yellow solid (112.4 mg, 0.34
mmol, 76%, 50:50 dr, 90% ee). Mp 83-90 °C; Rf ) 0.69 (25%
EtOAc/hexane); 1H NMR (300 MHz, CDCl3, mixture of 2 diaster-
eomers d1 and d2) δ 7.41-7.28 (m, 5H), 7.13 (d, J ) 7.3 Hz, 1H),
6.99-6.92 (m, 1H), 6.84-6.79 (m, 1H), 6.57 (d, J ) 7.6 Hz, 1Hd1),
6.52 (d, J ) 7.3 Hz, 1Hd2), 5.59 (dd, J ) 3.5 Hz, 10.5 Hz, 1Hd1),
5.37-5.31 (m, 1Hd2 + 1Hd1), 5.25 (dd, J ) 3.2 Hz, 9.3 Hz, 1Hd2),
3.83 (s, 3Hd1), 3.81 (s, 3Hd2), 3.08-2.90 (m, 1H), 2.81-2.71 (m,
1H), 2.32 (s, 3Hd1), 2.30 (s, 3Hd2); 13C NMR (75 MHz, CDCl3,
mixture of 2 diastereomers) δ 165.0, 164.7, 155.0, 154.9, 139.5,
139.4, 130.9, 130.8, 129.02, 129.00, 128.4, 128.3, 127.1, 126.9,
126.6, 126.5, 125.8, 125.6, 121.0, 120.9, 112.6, 112.4, 85.1, 75.2,
53.73, 53.72, 39.1, 38.9, 16.4, 16.3; FTIR (neat) 3708, 3680, 2951,
2844, 1754, 1561, 1454, 1235, 1053, 1121, 750, 701 cm-1; HRMS
calcd for C18H18NO5 (M - H)- 328.1191, found 328.1195. SFC
(Chiralcel OD-H, 3% MeOH, 2 mL/min, 200 bar, 30 °C) tR 5.7
min (minor enantiomer, d1), tR 6.4 min (minor enantiomer, d2), tR
7.0 min (major enantiomer, d2), tR 8.5 min (major enantiomer, d1).
tolerates a variety of substituents on both the aromatic alcohol
and the cyclopropane and affords products with complete
retention of the enantiomeric excess stemming from the cyclo-
propane. The methodology was applied to an expedient and
high-yielding enantioselective synthesis of the norepinephrine
reuptake inhibitor atomoxetine (Strattera).
Experimental Section
General Procedure for Ring Opening of Cyclopropanes 1
with Phenol Derivatives. In an oven-dried 2-mL microwave vial,
cyclopropane 1 (0.45 mmol, 1 equiv) was combined with the
appropriate phenol derivative (1.36 mmol, 3 equiv), anhydrous
Cs2CO3 (0.32 g, 1.13 mmol, 2.5 equiv), and anhydrous tetrahy-
drofuran (2 mL). The vial was sealed with a Teflon cap, and the
reaction mixture was stirred at 65 °C in an oil bath for 12 h,
quenched with saturated aqueous NH4Cl (5 mL), and partitioned
between water and diethyl ether. The aqueous layer was extracted
with diethyl ether (10 mL) three times, and the combined organic
layers were washed with saturated aqueous NaCl, dried over
MgSO4, and evaporated under reduced pressure. Flash chromatog-
raphy eluting with 100% benzene afforded the spectroscopically
pure product (method A). In the cases in which the remaining excess
phenol derivative was difficult to separate by flash chromatography,
it was removed by the following aqueous workup (method B): The
reaction was quenched with saturated aqueous NH4Cl (5 mL) and
the mixture partitioned between water and diethyl ether. The
aqueous layer was extracted with diethyl ether (10 mL) three times,
and the combined organic layers were washed with 0.1 M NaOH
(5 mL) three times, dried over MgSO4, and evaporated under
reduced pressure. Flash chromatography eluting with 10-20%
EtOAc/hexane afforded the spectroscopically pure product.
On large scale, the reaction was performed in a round-bottom
flask equipped with a reflux condenser and heated at reflux in an
oil bath for 12 h.
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. We are grateful
to NSERC for a postgraduate scholarship (CGSM) to OL and
a postdoctoral fellowship (PDF) to D.A. We thank Jad Tannous
for SFC analyses and Francine Be´langer-Garie´py for X-ray
analysis.
Supporting Information Available: General information,
specific experimental conditions, characterization data for all
new compounds, NMR spectra, SFC chromatograms. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO8010705
6840 J. Org. Chem. Vol. 73, No. 17, 2008