Twisted amide reduction under Wolff-Kishner conditions: Synthesis of a benzo-1-aza-adamantane derivative

Article abstract of DOI:10.1021/ja028152c

A synthesis of 4,5-benzo-1-aza-tricyclo[4.3.1.1^3.8]undecane (1), a benzo-1-aza-adamantane derivative, is described and features a previously unknown application of the Wolff-Kishner reduction of a nonresonance stabilized or "twisted" amide. An intermediate amino ester is converted to a severely "twisted amide", which, when exposed to hydrazine in alcohol, provides the corresponding "twisted" amino hydrazone. Wolff-Kishner conditions (KOH/ethylene glycol, 200 °C) provide the reduced target 1 without hydrolysis to amino acid derivatives. These operations are conveniently performed in a single flask in high yield.

Full text of DOI:10.1021/ja028152c

Published on Web 02/22/2003
Twisted Amide Reduction under Wolff-Kishner Conditions:
Synthesis of a Benzo-1-Aza-Adamantane Derivative
Crystal G. Bashore, Ivan J. Samardjiev, Jon Bordner, and Jotham W. Coe*
Contribution from Pfizer Global Research and DeVelopment, Groton Laboratories, Pfizer Inc.,
Groton, Connecticut 06340
Received August 15, 2002 ; E-mail: coejw@groton.pfizer.com
Abstract: A synthesis of 4,5-benzo-1-aza-tricyclo[4.3.1.13,8]undecane (1), a benzo-1-aza-adamantane
derivative, is described and features a previously unknown application of the Wolff-Kishner reduction of
a nonresonance stabilized or “twisted” amide. An intermediate amino ester is converted to a severely “twisted
amide”, which, when exposed to hydrazine in alcohol, provides the corresponding “twisted” amino hydrazone.
Wolff-Kishner conditions (KOH/ethylene glycol, 200 °C) provide the reduced target 1 without hydrolysis to
amino acid derivatives. These operations are conveniently performed in a single flask in high yield.
Scheme 1 a
Amino and carboxylate substituted adamantane derivatives
have proven to be valuable tools in the service of both physical
organic and medicinal chemistry. Indeed, this structural motif
is found in numerous medicinal agents and drug candidates.1
We sought variations of aza-adamantane as novel nicotinic
receptor ligands to probe both structural and pharmacological
properties. Herein we describe a synthesis of the rigid tricyclic
amine, 4,5-benzo-1-aza-tricyclo[4.3.1.13,8]undecane (1), a novel
aryl fused aza-adamantane derivative (Figure 1).2
a (a) 1 equiv of LDA, THF, -78 °C, 3 h, then 3, -78 to 20 °C. (b) 2.9
mol % Pd(OAc)2, 5.8 mol % P(o-tol)3, 2 equiv of TEA, CH3CN, 83 °C, 6
h, 53%. (c) (CH2)5NCH3O‚H2O, 0.5 mol % OsO4, acetone/H2O, 100%. (d)
1 equiv of NaIO4, DCE/H2O. (e) 1.02 equiv of C6H5CH2NH2, 3.6 equiv of
Figure 1. Structure of 4,5-benzo-1-aza-tricyclo[4.3.1.13,8]undecane (1).
NaBH(OAc)3, DCE, 78%.
Our synthesis begins by alkylation of (2-bromo-phenyl)-acetic
two-pot sequence: dihydroxylation (cat. OsO4, (CH2)5NCH3O),6
acid methyl ester (2) with cyclopent-3-enylmethyl trifluoro-
oxidative cleavage (NaIO4),7 and reductive amination (PhCH2-
methane sulfonate (3).3,4 The product, cyclopentene 4, was
NH2, NaBH(OAc)3)8 provided 6 in 78% yield from 5. Benzyl-
amine 6 contains all of the atoms present in the target structure.
We initially planned to accomplish the final ring closure via
the epimerized ester of 6, which after reduction to the corre-
sponding alcohol would provide the requisite geometry for SN2
closure. We found that while enolization (LHMDS) was
cyclized under standard Heck conditions5 to give a single
bicyclic olefin 5 in 53% yield (Scheme 1). Benzylic methyne
coupling constants (1H NMR, J ) 12.5, 3.3 Hz) of 5 are
consistent with the indicated pseudoequatorial ester configura-
tion. The N-benzyl piperidine was introduced in a three-step,
possible, acidic quenches (AcOH) produced pseudoequatorial
(1) For a general discussion of adamantane related structures of pharmacological
interest, see: Jasys, J. V.; Lombardo, F.; Appleton, T. A.; Bordner, J.;
Ziliox, M.; Volkmann, R. A. J. Am. Chem. Soc. 2000, 122, 466-473.
(2) Preliminary accounts of this work have been presented: 37th National
Organic Symposium, June 2001, Bozeman, MT; Poster A65. ACS National
Meeting, August 2001, Chicago, IL; Abstr. 61.
(6) VanRheenen, V.; Cha, D. Y.; Hartley, W. M. Org. Synth., Coll. Vol. 1988,
6, 342-348.
(7) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J. Org. Chem.
1956, 21, 478-479.
(3) This alcohol is readily available as described. See: (a) Depre´s, J.-P.; Greene,
A. E. J. Org. Chem. 1984, 49, 928-931; Org. Synth. 1997, 75, 195-200.
For more recent approaches, see: (b) Nugent, W. A.; Feldman, J.; Calabrese,
J. C. J. Am. Chem. Soc. 1995, 117, 8992-8998. (c) Mar´ınez, L. E.; Nugent,
W. A.; Jacobsen, E. N. J. Org. Chem. 1996, 61, 7963-7966. (d) Briot, A.;
Bujard, M.; Gouverneur, V.; Nolanz, S. P.; Mioskowski, C. Org. Lett. 2000,
2, 1517-1519. For a similar use of this alcohol, see: Coe, J. W. Org.
Lett. 2000, 2, 4205-4208.
(8) (a) Emerson, W. S. Organic Reactions; Wiley: New York, 1982; Vol. 4,
Chapter 3. (b) Bols, M.; Persson, M. P.; Butt, W. M.; Jørgensen, M.;
Christensen, P.; Hansen, L. T. Tetrahedron Lett. 1996, 37, 2097-2100.
(c) Evans, D. A.; Illig, C. R.; Saddler, J. C. J. Am. Chem. Soc. 1986, 108,
2478-2479. (d) Kawaguchi, M.; Ohashi, J.; Kawakami, Y.; Yamamoto,
Y.; Oda, J. Synthesis 1985, 701-703. (e) Fray, A. H.; Augeri, D. J.;
Kleinman, E. F. J. Org. Chem. 1988, 53, 896-899. (f) Wolin, R.; Wang,
D.; Kelly, J.; Afonso, A.; James, L.; Kirschmeier, P.; McPhail, A. T. Bioorg.
Med. Chem. Lett. 1996, 6, 195-200. (g) Meyers, A. I.; Nguyen, T. H.
Tetrahedron Lett. 1995, 36, 5873-5876. (h) Abdel-Magid, A. F.; Carson,
K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996,
61, 3849-3862.
(4) (a) Su, T. M.; Sliwinski, W. F.; Schleyer, P. v. R. J. Am. Chem. Soc. 1969,
91, 5386-5388. (b) Stang, P. J.; Hanack, M.; Subramanian, L. R. Synthesis
1982, 85-126.
(5) Heck, R. F. Organic Reactions; Wiley: New York, 1982; Vol. 27, p 345.
9
3268
J. AM. CHEM. SOC. 2003, 125, 3268-3272
10.1021/ja028152c CCC: $25.00 © 2003 American Chemical Society

Wolff−Kishner Reduction of a Twisted Amide
A R T I C L E S
Scheme 2 a
a (a) 1 equiv of LHMDS, THF, -78 °C, 1 h, then AcOH. (b) 1 equiv of
LHMDS, THF, -78 °C, 1 h, camphor sulfonic acid, -78 °C, 15 min, then
LiAlH4. (c) LiAlH4, THF, -78 to 0 °C, 100%.
ester 6 exclusively (Scheme 2). An attempt to kinetically quench
the preformed enolate with an organic acid at low temperature
(camphor sulfonic acid) to generate the epimerized ester
followed by low-temperature reduction (LiAlH4, -78 °C)
provided amino alcohol 7. LiAlH4 reduction of 6 also produced
7. A similar investigation with the olefinic ester 5 (see Scheme
1) failed to provide products resulting from epimerization.
Figure 2. Crystal data and structure refinement for 11.
Treatment of a solution of 8 in methylene chloride with
bromine resulted in the precipitation of a crystalline solid. H
1
NMR and GCMS analysis showed this crude material to be a
∼1:1 mixture of two isomers. A material suitable for single
crystal X-ray analysis was obtained upon recrystallization from
acetonitrile and identified as the quarternized perbromide 11,
the result of closure at the benzylic carbon (Figure 2). Attempts
to isolate the second isomer as an X-ray quality crystalline
material were unsuccessful, as were our efforts to preparatively
isolate homogeneous components by both reverse phase and
supercritical fluid HPLC techniques. On the basis of elemental,
chromatographic, and NMR analysis, we believe the other
component is isomer 10. We conclude that the geometric
considerations that led us to anticipate 10 to be produced under
these conditions were partially correct; the competitive benzylic
ring opening to produce 11 is not so surprising.
Scheme 3 a
a (a) CH3SO2Cl, TEA, CH2Cl2, 0-23 °C, 2 h, 62%. (b) Br2, CH2Cl2, 0
°C, 10 min, 55%.
These results led us to an alternative end game strategy. After
removal of the benzyl group of 6, could the resulting amine act
to trap the epimerized ester and form a twisted “amide”, and, if
so, would it be possible to reduce the resulting carbonyl directly?
In recent work by Kirby et al., twisted amide 12 was isolated
and studied (Scheme 4).13 The nonepimerizable ring system
derived from the Kemp triacid provided an ideal platform to
probe the chemistry of the resulting amino ketones. Indeed, they
behaved like amines (N-alkylation by Meerwin’s reagent) and
ketones (ketalization, Wittig chemistry).
Debenzylation of 6 provided amino ester 13, and base-
catalyzed ring closure in hot toluene provided twisted amide
14. This crude material exhibited a ketone IR stretch (1728
cm-1) similar to Kirby’s observation with ketone 12. Typically
14 was isolated by simple evaporation of the reaction medium;
as expected, 14 was found to be unstable under aqueous
conditions (see Supporting Information).13
Closure via bromoamination of the exo-olefin 8 was next
explored (Scheme 3). Treatment of 7 with methanesulfonyl
chloride/triethylamine9 produced 8. These mild conditions
facilitated the room temperature E2 elimination of methane-
sulfonic acid presumably through activation by the proximal
tertiary amine.10 Bromination of 8 offered a potential avenue
to the desired ring closure product 10.11 Indeed, examination
of models revealed that olefin rehybridization from sp2 to sp3
in developing bromonium ion 9 would promote ideal alignment
for SN2 displacement at the exo-carbon favoring the formation
of 10. The alternative nonsynchronous SN1 mediated closure
via the tertiary benzylic cation would provide 11, a strained
polycyclic structure.
(9) O’Donnell, C. J.; Burke, S. D. J. Org. Chem. 1998, 63, 8614-8616.
(10) For literature insights, see: Grieco, P. A.; Gilman, S.; Nishizawa, M. J.
Org. Chem. 1976, 41, 1485. For a discussion of E2 elimination, see: March,
J. AdVanced Organic Chemistry, 4th ed.; Wiley: New York, 1992; pp 982-
1050.
With ready access to amino-ketone 14, we studied various
reduction conditions. Formation of the corresponding tosylhy-
(11) For examples of bromo-amination, see: (a) Stevens C.; Verbeke, A.; De
Kimpe, N. Synlett 1998, 180-183. (b) Corey, E. J.; Chen, C.-P.; Reichard,
G. A. Tetrahedron Lett. 1989, 30, 5547-5550. (c) Horning, D. E.;
Muchowski, J. M. Can. J. Chem. 1974, 52, 1321-1330 and references
therein. For involvement by amides, see: (d) Sakurai, O.; Takahashi, M.;
Ogiku, T.; Hayashi, M.; Horikawa, H.; Iwasaki, T. Tetrahedron Lett. 1994,
35, 6317-6320. (e) Corey, E. J.; Loh, T.-P.; AchyuthaRao, S.; Daley, D.
C.; Sarshar, S. J. Org. Chem. 1993, 58, 5600-5602. (f) Balko, T. W.;
Brinkmeyer, R. S.; Terando, N. H. Tetrahedron Lett. 1989, 30, 2045-
2048. (g) Knapp, S.; Levorse, A. T.; Potenza, J. A. J. Org. Chem. 1988,
53, 4773-4779 and references therein.
(12) C-N bond lengths in 11 confirm the additional strain inherent in the bicyclic
C-N (benzylic) bond: 1.627 versus 1.515, 1.532 (benzylic), and 1.512 Å;
see Supporting Information and compare to an analogous quaternary
ammonium salt, 2 in: Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc.
1997, 119, 12414-12415, Supporting Information. Efforts to equilibrate
10 and 11 via solvolysis with bromide and iodide salts failed to alter the
product ratios.
(13) (a) Kirby, A. J.; Komarov, I. V.; Wothers, P. D.; Feeder, N. Angew. Chem.,
Int. Ed. 1998, 37, 785-786. (b) Kirby, A. J.; Komarov, I. V.; Feeder, N.
J. Am. Chem. Soc. 1998, 120, 7101-7102. (c) Kirby, A. J.; Komarov, I.
V.; Feeder, N. J. Chem. Soc., Perkin Trans. 2 2001, 522-529.
9
J. AM. CHEM. SOC. VOL. 125, NO. 11, 2003 3269

A R T I C L E S
Bashore et al.
Scheme 4 a
Scheme 6 a
a (a) 5 equiv of NH2NH2, EtOH, 24 h, 68 °C. (b) KOH, (HOCH2)2, 200
°C, 62%. (c) 4.5 equiv of NH2NH2, (HOCH2)2, 48 h, 90 °C, then KOH,
(HOCH2)2, 200 °C, 7-24 h, 64-85%.
of an intermediate “anti-Bredt” iminium ion15 in reduction of
14 with NaBH4 or LiAlH4 also favors the ejection of H2O or
alcohol in this hydrazone formation sequence. Furthermore,
torsional restriction prevents amide resonance stabilization and
insulates the “ketone” and “amino” functionalities during the
Wolff-Kishner reduction.17 Although the behavior of this
“ketone” has been anticipated by R. B. Woodward,18 we are
unaware of any example of a Wolff-Kishner reduction of a
substrate such as 14 (or amino hydrazone 17). In fact, the
hydrolytic instability of a 2-quinuclidone “ketone” to t-BuOK/
t-BuOH observed by Doering and Chanley18 makes the stability
of 14 and 17 under the hydrolytic hydrazine/ethanol and KOH/
ethylene glycol Wolff-Kishner conditions all the more surpris-
ing. These results highlight the additional degree of structural
stabilization in this polycyclic structure. Presumably the ad-
ditional structural rigidity conferred by the 3,5-bis axially
bridged bicyclic piperidine aids the performance of this platform
under Wolff-Kishner conditions, insulating against solvolysis
as observed under nonaqueous conditions with 2-quinuclidone.
a (a) H2, Pd(OH)2, CH3OH, 84%. (b) 10 mol % t-BuOK, toluene
(-CH3OH), 110 °C, 49-58%. (c) LiAlH4, THF or NaBH4, EtOH.
drazone (TsNHNH2, EtOH) was observed in low yield, and
reduction failed to produce 1 (KBH4 or (PhCOO2)2BH).14 As
would be expected for such a structure, treatment of 14 with
NaBH4 or LiAlH4 led to formation of a stable hemiaminal 15;
further reduction via iminium intermediates is precluded by
geometric constraints.15
Scheme 5 a
In a preferred procedure, ester 13 was treated with hydrazine
to prepare the amino hydrazone 17 directly (Scheme 6,
hydrazine, 11 equiv, EtOH, 48 h). We do not have evidence
that intermediate amino acyl hydrazide 18 is on the path to 17
and suspect that epimerization and “amide” formation precedes
hydrazine condensation to generate 17. This product can then
be converted to 1 upon exposure to KOH in ethylene glycol.
These operations were most simply performed in situ. An
ethylene glycol solution of amino ester 13 was converted to
the intermediate 17 upon exposure to excess hydrazine at 70
°C (4.5 equiv). Once the conversion is complete (TLC, 24-48
h), KOH was added (2.1 equiv), and the mixture was heated to
200 °C for 7-24 h. The desired product was formed in 64-
85% yield. This approach is operationally simple and completes
an efficient preparation of the target structure.
a (a) NH2NH2, EtOH, 1 h, 68 °C. (b) KOH, (HOCH2)2, 200 °C, 2 h,
68%.
Although early on we had dismissed Wolff-Kishner reduc-
tion conditions as too harsh,16 exposure of ketone 14 to
hydrazine in boiling ethanol produced the mixed ethanol-amino-
hydrazine intermediate(s) 16 (detectable by APCI MS analysis),
which converted to hydrazone 17 after removal of solvent.
Gratifyingly, amino hydrazone 17 was readily converted to the
desired reduction target 1 in the absence of additional hydrazine
in 68% yield (KOH, hot ethylene glycol, 200 °C, 1.5 h, Scheme
5). In retrospect, the stereoelectronic bias that prevents formation
In summary, the synthesis of 4,5-benzo-1-aza-tricyclo-
[4.3.1.13,8]undecane (1), a novel aryl fused aza-adamantane
analogue, has been described and proceeds in six steps and 22-
27% overall yield (Figure 3). The ketone-like character of
twisted amide 14 has been used advantageously to generate the
corresponding tertiary amine under Wolff-Kishner conditions.
(14) (a) Caglioti, L. Tetrahedron 1966, 22, 487-493. (b) Kabalka, G. W.;
Summers, S. T. J. Org. Chem. 1981, 46, 1217-1218.
(15) For examples of bridgehead imines, see: Eguchi, S.; Okano, T.; Takeuchi,
H. Heterocycles 1987, 26, 3265-3284. For bridgehead iminium ion
chemistry, see: (a) Yamazaki, N.; Suzuki, H.; Kibayashi, C. J. Org. Chem.
1997, 62, 8280-8281. (b) Suzuki, H.; Yamazaki, N.; Kibayashi, C.
Tetrahedron Lett. 2001, 42, 3013-3015. (c) Brummond, K. M.; Jianliang,
L. Org. Lett. 2001, 3, 1347-1349.
(16) For reviews, see: (a) Todd, D. Organic Reactions; Wiley: New York,
1948; Vol. 4, pp 378-422. (b) March, J. AdVanced Organic Chemistry,
4th ed.; Wiley: New York, 1992; pp 1209-1211. (c) For the mechanism
of the Wolff-Kishner reduction, elimination, and isomerization reactions,
see: Szmant, H. Angew. Chem., Int. Ed. Engl. 1968, 7, 120-128.
(17) The connectivity of these atoms is identical to that of the “amidrazone”,
see: Rapaport, H.; Bonner, R. M. J. Am. Chem. Soc. 1950, 72, 2783-
2784. However, 17 is constrained to behave like an “amino hydrazone”.
(18) Doering, W. E.; Chanley, J. D. J. Am. Chem. Soc. 1946, 68, 586-588. See
ref 12 therein.
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Wolff−Kishner Reduction of a Twisted Amide
A R T I C L E S
layer was dried over Na2SO4, filtered, and concentrated. The resulting
red oil was filtered through silica gel pad eluting with 5% EtOAc/
hexanes to yield an oil (37.9 g, 100%).
Data for 4: (TLC 20% EtOAc/hexanes Rf 0.60); 1H NMR (CDCl3)
δ 7.53 (dd, J ) 7.2, 1.2 Hz, 1H), 7.38 (dd, J ) 7.8, 1.6 Hz, 1H), 7.26
(m, 1H), 7.08 (m, 1H), 5.61 (br s, 2H), 4.21 (t, J ) 7.0 Hz), 3.65 (s,
3H), 2.52-1.82 (7H); 13C NMR (CDCl3, 100 MHz) δ 174.0, 139.0,
133.2, 129.9, 129.1, 128.8, 127.7, 124.9, 52.1, 49.0, 40.1, 39.1, 35.8;
GCMS m/z 308, 310 (M)+.
Tricyclo[8.2.1.02,7]trideca-2(7),3,5,11-tetraene-8-carboxylic Acid
Methyl Ester (5). 2-(2-Bromo-phenyl)-3-cyclopent-3-enyl-propionic
acid methyl ester (3, 53.0 g, 171 mmol) and tri-o-tolylphosphine (3.12
g, 10 mmol) were dissolved in anhydrous CH3CN (1.1 L) and degassed
(three vacuum (10 mm)/nitrogen purge cycles). This solution was treated
with freshly distilled triethylamine (47.6 mL, 343 mmol) and palladium-
(II) acetate (1.12 g, 5.0 mmol). The resulting mixture was warmed under
reflux and stirred until judged complete (6 h). The reaction solution
was concentrated in vacuo, cooled, and treated with saturated aqueous
NH4Cl solution (150 mL). The organics were extracted with CH2Cl2
(3 × 100 mL) and washed with saturated aqueous NaCl solution (1 ×
100 mL). The organic layer was dried through a cotton filter and
concentrated to an oil (45 g) that was purified by chromatography
through silica gel to yield an oil (20.7 g, 53%). (TLC 20% EtOAc/
Figure 3. Crystal data and structure refinement for 1 (succinate).
Experimental Procedures
General Methods. Unless otherwise noted, all materials were
purchased from commercial sources. Anhydrous solvents were used
as provided (in Sure/Seal bottles), and reactions were performed under
dry nitrogen atmosphere. Thin-layer chromatography was performed
with EM Separations Technology silica gel F254. Silica gel chroma-
tography was carried out with J. T. Baker 40 µm silica gel according
to Still’s procedure (Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem.
1978, 43, 2923). All glassware was flame dried under dry nitrogen
1
purge before use. H NMR spectra were collected at 400 MHz with
1
residual 1H-solvent as internal standard (e.g., CHCl3, 7.26 ppm). Melting
points are uncorrected. All spectroscopic data for known compounds
were in complete accord with literature values.
hexanes Rf 0.55); H NMR (CDCl3) δ 7.16-7.07 (m, 3H), 6.85 (d, J
) 7.5 Hz, 1H), 6.05 (dd, J ) 5.5, 2.8 Hz, 1H), 5.88 (dd, J ) 5.5, 3.1
Hz, 1H), 4.13 (dd, J ) 12.5, 3.3 Hz, 1H), 3.78 (s, 3H), 3.65 (dd, J )
7.6, 3.3 Hz, 1H), 2.98 (m, 1H), 2.27 (m, 1H), 2.17 (m, 1H), 2.04 (m,
1H), 1.57 (d, J ) 11.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 176.1,
143.7, 138.2, 135.2, 130.8, 129.6, 128.6, 127.1, 126.3, 52.7, 51.9, 47.7,
42.8, 42.7, 38.0; GCMS m/z 228 (M)+; Anal. Calcd for C15H16O2: C,
78.92; H, 7.06. Found: C, 78.33; H, 7.21. Anal. Calcd for C15H16O2‚
1/8H2O: C, 78.15; H, 7.10.
2-(Bromo-phenyl)-acetic Acid Methyl Ester (2). 2-(Bromo-phen-
yl)-acetic acid (76.6 g, 356 mmol) and catalytic concentrated HCl (2
mL) in methanol (500 mL) were heated under reflux for 2.5 h. The
reaction mixture was cooled to ambient temperature and concentrated
in vacuo. The resulting product was diluted with diethyl ether (250
mL) and then washed with a saturated aqueous NaHCO3 solution (250
mL) and saturated aqueous NaCl solution (250 mL). The organic layer
was dried over Na2SO4, filtered, and concentrated in vacuo to yield
81.3 g (99%) of clear oil.
Trifluoro-methanesulfonic Acid Cyclopent-3-enylmethyl Ester
(3). Cyclopent-3-enyl-methanol2a (12 g, 122 mmol) and pyridine (23.7
mL, 23.2 g, 293 mmol) were stirred in CH2Cl2 (125 mL) in a 0.5 L
3NRB flask equipped with an N2 inlet and addition funnel at -78 °C.
To this solution was added trifluoromethane sulfonic anhydride (24.6
mL, 41.2 g, 146 mmol) dropwise over 30 min via addition funnel. The
mixture was stirred and allowed to warm to 0 °C (pink solution, some
white ppts).
The reaction was quenched at 0 °C by addition of cold aqueous
HCl solution (25 mL of concentrated HCl, 0.3 mol, and H2O, 150 mL).
The layers were separated and the aqueous layer was extracted with
CH2Cl2 (3 × 80 mL). The combined organic layers were washed with
cold 50% saturated aqueous NaHCO3 solution (100 mL), cold H2O (2
× 100 mL), and cold saturated aqueous NaCl solution (100 mL). The
organic layer was dried through a cotton plug and concentrated in vacuo
with a room temperature bath to a dark red liquid (>25 g, 89.9% of
theory (28.1 g), MW 230.21). This material was taken on directly in
the next step (TLC 20% EtOAc/hexanes Rf 0.67).
2-(2-Bromo-phenyl)-3-cyclopent-3-enyl-propionic Acid Methyl
Ester (4). 2-(Bromo-phenyl)-acetic acid methyl ester (3, 23.6 g, 103
mmol) was stirred in THF (100 mL) and cooled to -78 °C and then
treated with 2.0 M lithium diisopropylamide in THF (54 mL, 108 mmol)
dropwise via an addition funnel over 30 min. A yellow slurry forms.
After 3 h at -78 °C, freshly prepared trifluoro-methanesulfonic acid
cyclopent-3-enylmethyl ester (23.7 g, 103 mmol) in THF (50 mL) was
added via cannula, while the reaction mixture was maintained at -78
°C. The reaction mixture was allowed to warm slowly to ambient
temperature overnight. The resulting red solution was concentrated in
vacuo, quenched with a saturated aqueous NH4Cl solution (150 mL),
extracted with EtOAc (4 × 100 mL), and washed with H2O (2 × 100
mL) and saturated aqueous NaCl solution (1 × 100 mL). The organic
11,12-Dihydroxy-tricyclo[8.2.1.02,7]trideca-2(7),3,5-triene-8-car-
boxylic Acid Methyl Ester. Tricyclo[8.2.1.02,7]trideca-2(7),3,5,11-
tetraene-8-carboxylic acid methyl ester (5, 42.3 g, 185 mmol) in acetone
(900 mL) and H2O (50 mL) was treated with N-methylmorpholine-N-
oxide hydrate (27.5 g, 204 mmol) and OsO4 (9.4 mL of a 2.5 wt %
solution in t-BuOH, 0.93 mmol, 0.5 mol %). After being stirred for 24
h, the solution was quenched with 25 g of florisil and saturated aqueous
NaHSO3 solution (300 mL). After 1 h, the dispersion was filtered
through a Celite pad and concentrated to remove organic solvent. The
aqueous mixture was extracted with CH2Cl2 (6 × 75 mL), and the
resulting organic layer was washed with H2O (2 × 100 mL) and
saturated aqueous NaCl solution (1 × 100 mL). The organic layer was
dried through a cotton filter, concentrated, and filtered through a silica
gel pad (3 × 5 in.) eluting with 50% EtOAc/hexanes and concentrated
to yield an oil (48.5 g, 100%). (TLC EtOAc, Rf 0.62); 1H NMR (CDCl3)
δ 7.15-7.06 (m, 3H), 6.86 (d, J ) 7.0 Hz, 1H), 4.44 (m, 1H), 4.21
(m, 1H), 3.78 (s, 3H), 3.65 (dd, J ) 11.9, 2.7 Hz, 1H), 3.10 (d, J )
8.3 Hz, 1H), 2.87 (m, 2-OH), 2.60 (m, 1H), 2.44 (m, 1H), 2.07 (br dd,
J ) 14.4, 11.9 Hz, 1H), 1.93 (br d, J ) 14.4 Hz, 1H), 1.39 (d, J )
12.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 175.3, 145.3, 136.0,
130.2, 128.7, 127.2, 126.4, 78.4, 77.0, 57.0, 52.2, 48.9, 46.5, 35.5, 33.2;
GCMS m/z 262 (M)+; Anal. Calcd for C15H16O4: C, 68.69; H, 6.92.
Found: C, 69.57; H, 6.95.
12-Benzyl-12-aza-tricyclo[8.3.1.02,7]tetradeca-2(7),3,5-triene-8-
carboxylic Acid Methyl Ester (6). 11,12-Dihydroxy-tricyclo[8.2.1.02,7]-
trideca-2(7),3,5-triene-8-carboxylic acid methyl ester (48.5 g, 185 mmol)
was vigorously stirred in H2O (570 mL) and 1,2-dichloroethane (DCE)
(350 mL) under nitrogen in a cool water bath (∼10 °C) and treated
with sodium periodate (NaIO4) (39.6 g, 185 mmol). After 30 min, the
layers were separated, and the aqueous layer was extracted with DCE
(2 × 80 mL). The organic layer was washed with H2O (4 × 200 mL,
until no reaction to starch iodide is observed in the aqueous wash) and
then dried through a cotton plug. To this was added benzylamine (20.8
g, 194 mmol), and this mixture was stirred for 10 min and then
9
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A R T I C L E S
Bashore et al.
transferred via filtration through a cotton plug into an addition funnel.
This mixture was added over 30 min to a magnetically stirred slurry
of NaBH(OAc)3 (126 g, 592 mmol) in DCE (400 mL). After it was
stirred for 18 h, the reaction was quenched with saturated aqueous Na2-
CO3 solution (∼200 mL) carefully at first, and the mixture was stirred
for 1 h (pH 9). The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 100 mL). The organic layer was washed
with saturated aqueous NaCl solution (200 mL), dried through a cotton
plug, and evaporated to an oil (48.5 g, 78%). (TLC CH2Cl2 Rf 0.30);
1H NMR (CDCl3) δ 7.31-7.06 (m, 8H), 6.96 (m, 1H), 5.35 (dd, J )
8.3, 2.5 Hz, 1H), 3.56 (s, 3H), 3.49 (AB d, J ) 13.3 Hz, 1H), 3.30
(AB d, J ) 13.3 Hz, 1H), 3.11 (dd, J ) 11.2, 1.7 Hz, 1H), 3.05 (br s,
1H), 2.79 (br d, J ) 10.8 Hz, 1H), 2.40 (dd, J ) 11.2, 4.0 Hz, 1H),
2.27-2.15 (m, 4H), 1.91 (br d, J ) 11.9 Hz, 1H), 1.79 (br d, J ) 11.9
Hz, 1H); GCMS m/z 335 (M)+; Anal. Calcd for C22H25NO2‚1/4H2O:
C, 77.73; H, 7.56; N, 4.12. Found: C, 77.88; H, 7.40; N, 3.94.
12-Aza-tricyclo[8.3.1.02,7]tetradeca-2(7),3,5-triene-8-carboxylic Acid
Methyl Ester (13). 12-Benzyl-12-aza-tricyclo[8.3.1.02,7]tetradeca-
2(7),3,5-triene-8-carboxylic acid methyl ester (6, 48.5 g, 145 mmol)
was stirred in CH3OH (200 mL) and treated with 3 N HCl EtOAc (70
mL). After 5 min, the solution was concentrated to a yellow oil. This
was dissolved in CH3OH (1.0 L), treated with ammonium formate (183
g, 2.89 mol) and Pd(OH)2 (9.6 g of 20 wt %/C), and then warmed
under reflux temperature. After 20 min, the conversion was deemed
complete (TLC), and the reaction mixture was cooled, filtered through
a Celite pad, and concentrated. The residues were dissolved in CHCl3
(200 mL) and washed with saturated aqueous Na2CO3 solution (200
mL). The aqueous layer was extracted with CHCl3 (3 × 100 mL),
washed with saturated aqueous NaCl solution (200 mL), dried through
a cotton plug, and evaporated to an oil (29.9 g, 84%). (TLC 10% CH3-
with hydrazine (8.9 mL, 285 mmol) and then warmed to 90 °C for 24
h. Additional hydrazine was added (4.5 mL, 142 mmol), and the reaction
solution was maintained at 90 °C for an additional 24 h, at which time
complete consumption of starting material was observed (TLC). To
this solution was added KOH (13.3 g, 202 mmol based on 85% KOH
content), and the reaction solution was warmed to 200 °C for 24 h. (In
other experiments, this conversion was monitored (APCI MS and TLC)
and deemed complete after 7 h.) After being cooled to ambient
temperature, the mixture was treated with 1 N HCl (1.0 L) and extracted
with Et2O (3 × 150 mL). Saturated aqueous Na2CO3 solution was added
to the aqueous mixture to achieve pH 9, and this solution was extracted
with CHCl3 (6 × 150 mL). This organic solution was washed with
saturated aqueous NaCl solution (200 mL), dried through a cotton plug,
and evaporated to a white solid (12.2 g, 64%). (On a 3.28 g scale, a
yield of 2.26 g or 85% was recovered.) (TLC 1% NH4OH in 10% CH3-
1
OH/CH2Cl2 Rf 0.35); H NMR (CDCl3) δ 7.19-7.00 (m, 4H), 3.36
(dd, J ) 13.3, 5.0 Hz, 2H), 3.25 (d, J ) 13.7 Hz, 2H), 3.18 (s, 2H),
2.64 (m, 2H), 2.20 (br d, J ) 13.3 Hz, 2H), 2.00 (br d, J ) 13.7 Hz,
2H), 1.21 (br s, 1H); 13C NMR (free base, CDCl3, 100 MHz) δ 146.53,
128.15 (CH), 126.50 (CH), 56.19 (CH2), 55.38 (CH2), 41.20 (CH), 33.88
(CH), 25.99 (CH); GC MS m/z 199 (M)+. A sample of this material
was converted to the HCl salt (excess 3 N HCl, EtOAc in EtOAc),
stripped to dryness, and analyzed. Anal. Calcd for C14H17N‚HCl‚1/
3H2O: C, 69.55; H, 7.78; N, 5.79. Found: C, 69.49; H, 7.48; N, 5.93.
Acknowledgment. We thank David A. Koss and Thomas N.
O’Connell for their commitment and efforts to separate per-
bromide salts 10 and 11, Diane M. Rescek for NMR expertise,
and Michael P. DeNinno, Michael A. Brodney, Stanton McHar-
dy, Brian T. O’Neill, David A. Clark, Daniel S. Kemp, and E.
J. Corey for their kind and thoughtful assistance reviewing the
manuscript.
1
OH/CH2Cl2 Rf 0.20); H NMR (CDCl3) δ 7.31-7.02 (m, 8H), 4.30
(dd, J ) 6.2, 3.1 Hz, 1H), 3.68 (s, 3H), 3.18 (d, J ) 12.5 Hz, 1H),
3.09 (dd, J ) 12.5, 4.0 Hz, 1H), 3.00 (br s, 1H), 2.90 (dd, J ) 12.2,
3.0 Hz, 1H), 2.78 (d, J ) 12.2 Hz, 1H), 2.59 (m, 1H), 2.18 (m, 1H),
2.08-2.00 (m, 2H), 1.83 (ddd, J ) 14.5, 4.5, 4.5 Hz, 1H); APCI MS
m/z 246 (M + 1)+; Anal. Calcd for C15H19NO2‚H2O: C, 68.42; H,
8.04; N, 5.32. Found: C, 67.98; H, 7.47; N, 5.12.
4,5-Benzo-1-aza-tricyclo[4.3.1.13,8]undecane (1). 12-Aza-tricyclo-
[8.3.1.02,7]tetradeca-2(7),3,5-triene-8-carboxylic acid methyl ester (13,
23.3 g, 95 mmol) was stirred in ethylene glycol (100 mL) and treated
Supporting Information Available: Full experimental condi-
tions and characterization for 7, 8, 10, 11, 14, and 17, stereoview
X-ray structures for 1 and 11, and X-ray data tables for structures
1 and 11 (PDF and TXT). This material is available free of
charge via the Internet at http://pubs.acs.org.
JA028152C
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3272 J. AM. CHEM. SOC. VOL. 125, NO. 11, 2003