Synthesis of a stable iminium salt and propellane derivatives

Article abstract of DOI:10.1021/jo801276z

(Chemical Equation Presented) The treatment of morphinan 1 with NaH and MsCl provided very stable iminium salt 7 possessing propellane skeleton. One of the synthesized iminium salts 7, isobutyl derivative 7b, was crystallized and its structure was determined by X-ray crystallography. The natural bond orbital analysis suggested that the stability of the iminium should result from the stereoelectronic effect (hyperconjugation) attributed to their own structures.

Full text of DOI:10.1021/jo801276z

SCHEME 1. Dehydration of Morphinan 1a and
4,5-Epoxymorphinan 2
Synthesis of a Stable Iminium Salt and
Propellane Derivatives
Hiroshi Nagase,*,† Naoshi Yamamoto,† Toru Nemoto,†
Kenji Yoza,‡ Kenshu Kamiya,§ Shuichi Hirono,†
Shinobu Momen,| Naoki Izumimoto,| Ko Hasebe,|
Hidenori Mochizuki,| and Hideaki Fujii†
School of Pharmacy, Kitasato UniVersity, 5-9-1, Shirokane,
Minato-ku, Tokyo 108-8641, Japan, AdVanced X-ray
Solutions, BRUKER AXS K.K., 3-9-A, Moriya-cho,
Kanagawa-ku, Yokohama-shi, Kanagawa 211-0022, Japan,
School of Science, Kitasato UniVersity, 1-15-1, Kitasato,
Sagamihara, Kanagawa 228-8555, Japan, and
Pharmaceutical Research Laboratories, Toray Industries,
Inc., 6-10-1, Tebiro, Kamakura, Kanagawa, 248-8555, Japan
nagaseh@pharm.kitasato-u.ac.jp
receptor.3 However, the role of the 14-hydroxyl group for the
receptor binding has not yet been clarified. We attempted to
remove the 14-hydroxyl group in order to compare the
pharmacological profiles of the 14-hydroxy derivatives and the
14-hydrogen variants. In the course of these investigations, we
obtained iminium salt 3, which has a propellane skeleton.
Surprisingly, the iminium salt 3 was stable and could be purified
by silica gel column chromatography. Herein, we report the
synthesis of this stable iminium ion bearing a propellane skeleton
and discuss its stability.
ReceiVed June 20, 2008
Morphinan derivative 1a, which was synthesized from
naltrexone,4 was dehydrated with SOCl2 in pyridine to afford
dehydrated product 4 and abnormal rearrangement product 3
(iminium salt) (Scheme 1). Silica gel column chromatography
of the reaction mixture with CHCl3/MeOH as eluent successfully
afforded pure iminium ion 3 in 28% yield along with the
dehydrated product 4 in 71% yield. In 1H NMR, a vinyl proton
of iminium chloride 3 was observed at 10.13 ppm, suggesting
that 3 was an iminium compound and not an R-chloroamine.
In contrast to morphinan 1a, the reaction of 4,5-epoxymorphinan
2 under the same reaction conditions afforded only dehydrated
product 5 (Scheme 1).5 We became interested in the abnormal
stability of the iminium salt and attempted to improve its yield.
A plausible mechanism for the rearrangement reaction to yield
the iminium chloride 3 is shown in Scheme 2. Lone pair
electrons of the 17-nitrogen could play a crucial role for
facilitating the rearrangement. We hypothesized that a proton
acquired during the reaction would protonate the 17-nitrogen
to interrupt the rearrangement reaction. We postulated that
reaction conditions in the absence of protons could facilitate
the rearrangement to afford the iminium salt 3. After extensive
investigation based on our working hypothesis, the reaction of
morphinan 1a with MsCl and NaH provided the objective
The treatment of morphinan 1 with NaH and MsCl provided
very stable iminium salt 7 possessing propellane skeleton.
One of the synthesized iminium salts 7, isobutyl derivative
7b, was crystallized and its structure was determined by
X-ray crystallography. The natural bond orbital analysis
suggested that the stability of the iminium should result from
the stereoelectronic effect (hyperconjugation) attributed to
their own structures.
Naturally occurring morphine and semisynthetic naltrexone
are representative opioid ligands and are used as potent
analgesics and a therapeutic agent for alcohol addiction or opioid
dependence, respectively.1 A common structure of these ligands,
the 4,5-epoxymorphinan skeleton, is believed to influence the
intrinsic activity of the opioid receptor,2 and has been considered
to contribute to three points of association between the drug
molecule and the receptor site, namely an ionic interaction of
the 17-nitrogen, a π-π interaction of the phenol ring, and a
hydrogen bond between the phenol hydroxyl and the opioid
† School of Pharmacy, Kitasato University
‡ BRUKER AXS K.K.
§ School of Science, Kitasato University
(3) (a) Beckett, A. H.; Casy, A. F. J. Pharm. Pharmacol. 1954, 6, 986. (b)
Beckett, A. H. J. Pharm. Pharmacol. 1956, 8, 848.
| Toray Industries, Inc.
(1) Gutstein, H. B.; Akil, H. In Goodman & Gilman’s The Pharmacological
Basis of Therapeutics, 11th ed.; Brunton, L. L., Lazo, J. S., Parker, K. L., Eds.;
McGraw-Hill: New York, 2006; pp 547-590.
(2) (a) Portoghese, P. S. Trends Pharmacol. Sci. 1989, 10, 230. (b)
Portoghese, P. S.; Sultana, M.; Takemori, A. E. J. Med. Chem. 1990, 33, 1714.
(c) Portoghese, P. S. J. Med. Chem. 1991, 34, 1757.
(4) (a) Sawa, Y. K.; Toda, H. Tetrahedron Lett. 1968, 24, 6185. (b) Nemoto,
T.; Fujii, H.; Nagase, H. Tetrahedron Lett. 2007, 48, 7413. (c) Nemoto, T.; Fujii,
H.; Narita, M.; Miyoshi, K.; Nakamura, A.; Suzuki, T.; Nagase, H. Bioorg. Med.
Chem. 2008, 16, 4304.
(5) Osa, Y.; Ida, Y.; Yano, Y.; Furuhata, K.; Nagase, H. Heterocycles 2006,
69, 271.
10.1021/jo801276z CCC: $40.75
Published on Web 09/24/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8093–8096 8093

SCHEME 2. Plausible Mechanism of the Rearrangement
TABLE 1. Substituent Effect on Rearrangement Reaction
FIGURE 2. Iminium ions whose structures were determined by X-ray
crystallography.
as a crystalline product and its structure was determined by
X-ray crystallography. To the best of our knowledge, examples
of X-ray crystallography of iminium ions are very rare8 except
for the case of conjugated iminium ions.9 An example most
resembling the desired iminiums 3 and 7 is Fe(CO)3 complex
of iminium tetrafluoroborate 8 (Figure 2).8b,10 In the case of
the iminium 8, anchimeric participation of the double bond
derived from a homoallylic system and an inert counteranion,
tetrafluoroborate would stabilize the iminium ion. Moreover,
the bulky Fe(CO)3 group may contribute to the stability of the
iminium ion 8. The other examples of nonconjugated iminium
ions 9-11 (Figure 2) whose structures were determined by X-
ray crystallography also had inert counteranions8 and would be
stabilized by an intramolecular interaction with an olefin moiety
(iminium 9)8c or by intermolecular interactions with phenyl
groups of a counteranion (iminium 10).8d In contrast, iminium
compounds 3 and 7 had neither an olefin moiety nor a Fe(CO)3
group participating in stabilization of the iminium ion. Further-
more, iminium ion 3 had a reactive counteranion, the chloride
ion. The X-ray crystallography indicated that the length of
C5-C6 (1.545 Å) in iminium 7b, which was parallel to the
π-orbital of the N1-C23 double bond, was longer than that of
the corresponding C11-C13 bond in saturated compound 12
(1.532 Å) derived from iminium 7a (Figure 1). Parallel bonds
can easily overlap each other. This observation suggested that
the σ bond C5-C6 would interact with the π* bond of the
iminium and that the electronic interaction (hyperconjugation)
may play a crucial role in stabilization of the iminium ion. To
investigate hyperconjugative stabilization of the iminium, we
performed natural bond orbital (NBO) analysis11 with the ab
entry morphinan product
R
yield (%) reaction time (h)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
7a
7b
7c
7d
7e
7f
CPM
i-Bu
Me
Et
allyl
CF3
93
39
95a
93
92
0b
1
2
1.25
1.25
3.5
31.5
a Including some amount of inseparable impurities. b Only the
morphinan 1f was recovered.
FIGURE 1. Structures of compounds 7b and 12 (see the Supporting
Information for CIF files and ORTEP plots of compounds 7b and 12).
iminium 7a in 93% yield without dehydrated product 4 (Table
1, entry 1). The rearrangement reactions of morphinans 1a-e
with some 17-substituents proceeded in moderate to excellent
yields, but iminium 7f was not obtained from morphinan 1f
with the strong electron-withdrawing CF3 group6 at the 17-
position and only the starting material 1f was recovered (entry
6). These results suggested that the 14-hydroxy group may not
be directly mesylated. If the lone pair electrons on the
17-nitrogen initially attacked the sulfene prepared in situ,
followed by migration of the Ms group from the 17-nitrogen to
the 14-hydroxy group, the results shown in Table 1 could be
reasonably explained.7 The strong electron-withdrawing CF3
group6 would drastically reduce the electron density on the 17-
nitrogen and decrease its nucleophilicity, resulting in recovery
of the starting material 1f. Purifications of all the synthesized
iminium 7 compounds (Figure 1) by silica gel column chro-
(8) For X-ray crystallography of nonconjugated iminium salt, see: (a)
Trefonas, L. M.; Flurry, R. L., Jr.; Majeste, R.; Meyers, E. A.; Copeland, R. F.
J. Am. Chem. Soc. 1966, 88, 2145. (b) Birch, A. J.; Fitton, H.; McPartlin, M.;
Mason, M. R. Chem. Commun. 1968, 531. (c) Hollenstein, S.; Laube, T. Angew.
Chem., Int. Ed. Engl. 1990, 29, 188. (d) Knop, O.; Cameron, T. S.; Bakshi,
P. K.; Kwiatkowski, W.; Choi, S. C.; Adhikesavalu, D. Can. J. Chem. 1993, 71,
1495.
(9) For X-ray crystallography of conjugated iminium salt, see: (a) Childs,
R. F.; Dickie, B. D.; Faggiani, R.; Fyfe, C. A.; Lock, C. J. L.; Wasylishen, R. E.
J. Crystallogr. Spectrosc. Res. 1985, 15, 73. (b) Childs, R. F.; Shaw, G. S.;
Lock, C. J. L. J. Am. Chem. Soc. 1989, 111, 5424. (c) Santarsiero, B. D.; James,
M. N. G.; Mahendran, M.; Childs, R. F. J. Am. Chem. Soc. 1990, 112, 9416. (d)
Maas, G.; Rahm, R.; Mayer, D.; Baumann, W. Organometallics 1995, 14, 1061.
(e) Elia, G. R.; Childs, R. F.; Britten, J. F.; Yang, D. S. C.; Santarsiero, B. D.
Can. J. Chem. 1996, 74, 591. (f) Greci, L.; Rossetti, M.; Galeazzi, R.; Stipa, P.;
Sgarabotto, P.; Cozzini, P. J. Chem. Soc., Perkin Trans. 2 1998, 2683. (g) Herz,
H.-G.; Schatz, J.; Maas, G. J. Org. Chem. 2001, 66, 3176. (h) Nikolai, J.;
Schlegel, J.; Regitz, M.; Maas, G. Synthesis 2002, 497. (i) Reisser, M.; Maier,
A.; Maas, G. Eur. J. Org. Chem. 2003, 2071. (j) Levin, V. V.; Dilman, A. D.;
Belyakov, P. A.; Korlyukov, A. A.; Struchkova, M. I.; Tartakovsky, V. A.
Tetrahedron Lett. 2005, 46, 3729. (k) Espenlaub, S.; Gerster, H.; Maas, G.
ARKIVOC (GainesVille, FL, U.S.) 2007, 114.
1
matography were effected. In H NMR, a vinyl proton was
observed at around 9.5 ppm for each iminium mesylate 7.
Among them, compound 7b with a 17-i-Bu group was isolated
(6) Morgenthaler, M.; Schweizer, E.; Hoffmann-Ro¨der, A.; Benini, F.; Martin,
R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.;
Schneider, J.; Diederich, F.; Kansy, M.; Mu¨ller, K. Chem. Med. Chem. 2007, 2,
1100.
(7) The reaction of morphinan 1a with the CPM group seemed to proceed
the most rapidly. This observation might be explained by the consideration of
the very stable cyclopropylcarbinyl cation. A detailed discussion is presented in
the Supporting Information.
(10) (a) Birch, A. J.; Fitton, H. Aust. J. Chem. 1969, 22, 971. (b) Birch,
A. J.; Kelly, L. F.; Liepa, A. J. Tetrahedron Lett. 1985, 26, 501.
8094 J. Org. Chem. Vol. 73, No. 20, 2008

FIGURE 3. Structure of iminium 7a. The hyperconjugation was
showen by dotted lines.
FIGURE 4. Structures of compounds 12 and 16.
In a preliminary pharmacological evaluation, saturated pro-
pellane 12 and its 17-CPM derivative 16, which were synthe-
sized from propellane 13,15 selectively bound to µ (Ki ) 3.6
nM) and κ opioid receptor (Ki ) 17.4 nM), respectively (Figure
4). The result suggests that propellane 12, which was readily
prepared from stable iminium ion 7, could be a fundamental
skeleton for opioid ligand. Birch et al. described the synthesis
of a propellane derivative from a Fe(CO)3 complex of an
iminium ion 8 and its application for opioid ligand. Nevertheless,
neither yield of the iminium ion having Fe(CO)3 8 nor the
application data of the propellane derivative as an opioid ligand
was shown.10 Furthermore, their synthesis of propellane deriva-
tive required both flammable, toxic Fe(CO)5 as a crucial reagent
and thebaine (narcotics) as a starting material, which is not
readily available. In distinct contrast, our practical synthetic route
to the propellane derivative started with readily available
naltrexone and required no toxic reagents.
SCHEME 3. Reaction of Iminium 7a
In conclusion, the novel stable iminiums 3 and 7 were
synthesized and isolated by silica gel column chromatography.
Iminium compound 7b was crystallized and its structure was
determined by X-ray crystallography. The NBO analysis sug-
gested that stability of the iminiums should result from
hyperconjugation attributed to their own structures. The iminium
ion is expected to be a key intermediate for synthesis of novel
opioid ligands.
initio molecular orbital calculation at the HF/6-31G* level. The
analysis with use of the second order perturbation theory of
the Fock operator with NBO basis showed substantial interaction
from σ (C5-C6) to π* (N1-C23) (interaction energy: 6.31 kcal/
mol). The optimal bond length of C5-C6 was 0.011 Å longer
than that of the corresponding bond in 12.12 Taken together,
the stereoelectronic effect (hyperconjugation) attributed to the
structure of iminiums 3 and 7a could play an important role in
the extreme stabilization of these iminiums.
Experimental Section
We next examined the reactivity of the stable iminium ion
7a (Scheme 3). When the iminium 7a was treated with NaOAc
or NaN3, only the starting material was recovered. The reaction
of 7a with n-BuLi or lithiated dithiane afforded complex
mixtures. The stronger basic nucleophiles like n-BuLi and
lithiated dithiane may attack not only the iminium carbon (C23)
but the hyperconjugated carbons (C5) to give complex mixtures
Typical Procedure for the Synthesis of Iminium Salt 7. Under
an argon atmosphere, NaH (60% in oil, 480 mg, 12.0 mmol) was
washed with dry hexane and suspended in THF (1 mL). MsCl (390
µL, 5.04 mmol) was added dropwise to the suspension at 0 °C and
the mixture was stirred for 30 min at the same temperature. To the
reaction mixture was added the solution of 1 (0.50 mmol) in THF
(1.5 mL) at 0 °C with stirring at rt for several hours (see Table 1).
The reaction mixture was quenched with cooled 2-butanol, followed
by purification of the crude product to give iminium ion 7.
Iminium Salt 7a: pale yellow amorphous; IR (film) 3428, 2943,
1685, 1611, 1492, 1459, 1331, 1285, 1196, 1119, 1075, 1041, 950,
13
(Figure 3). However, reduction of the iminium 7a with NaBH4
afforded saturated propellane derivative 13. Reaction of iminium
7a with NaCN14 gave nitrile 14, followed by reduction of the
nitrile 14 to give amine 15 as a mixture of diastereomers along
with compound 13. Compound 13 may be obtained by reduction
of the iminium derived from nitrile 14 via elimination of cyanide
ion. These observations suggested that adduct 14 would be easily
returned to the starting iminium ion 7a because of its extreme
stability.
1
770 cm-1; H NMR (300 MHz, CDCl3) δ 0.21-0.34 (m, 1H),
0.36-0.54 (m, 2H), 0.54-0.66 (m, 1H), 0.87-1.06 (m, 1H),
1.68-1.87 (m, 4H), 1.94-2.09 (m, 1H), 2.10-2.23 (m, 2H),
2.32-2.44 (m, 1H), 2.73 (s, 3H), 3.33 (d, J ) 16.8 Hz, 1H), 3.37
(d, J ) 16.8 Hz, 1H), 3.41-3.61 (m, 2H), 3.77 (s, 3H), 3.84-4.03
(m, 6H), 6.58 (d, J ) 2.4 Hz, 1H), 6.74 (dd, J ) 2.4, 8.4 Hz, 1H),
7.19 (d, J ) 8.4 Hz, 1H), 9.40 (s, 1H); HRMS (FAB) [M]+ calcd
for C23H30NO3 368.2226, found 368.2221.
(11) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. ReV. 1988, 88, 899.
(12) The NBO analysis showed that the optimal bond length of C6-C7 was
also 0.07 Å longer than that of the corresponding bond in 12, with interaction
energy between σ (C6-C7) and π* (N1-C23) of 4.98 kcal/mol, although by
X-ray crystallography, C6-C7 in 7b showed the same bond length (1.551 Å)
as C13-C12 in 12. This result suggested that C5-C6 might also partially, if at
all, participate in the stabilization of the iminium ion.
(13) In the case of the Fe(CO)3 complex 8, the reduction was reported to
take 20 min (see ref 10b). On the other hand, the reduction of 7a was completed
within 5 min.
Reduction of Iminium Salt 7a. To the solution of 7a (800 mg,
1.73 mmol) in MeOH (12 mL) was added NaBH4 (198 mg, 5.23
mmol) at 0 °C with stirring for 5 min. To the reaction mixture was
added 50% AcOH, then saturated NaHCO3 solution was added to
adjust the reaction mixture to pH 9. After extraction and subsequent
concentration, the residue was chromatographed to give 520 mg
(82%) of 13 as a brown oil. IR (neat) 2913, 1726, 1610, 1489,
(14) The reaction of the Fe(CO)3 complex 8 with NaCN was reported to
proceed in acetone under reflux for 5 min (see ref 10a). In contrast, the reaction
of 7a was completed at rt within 5 min.
(15) See the Supporting Infromation.
J. Org. Chem. Vol. 73, No. 20, 2008 8095

1527, 1282, 1224, 1202, 1117, 1092, 1058, 1034, 949, 802, 748
cm-1 1H NMR (300 MHz, CDCl3) δ -0.06-0.11 (m, 2H),
0.36-0.56 (m, 2H), 0.73-0.86 (m, 1H), 1.52-1.83 (m, 6H),
1.94-2.67 (m, 9H), 2.83 (br d, J ) 12.9 Hz, 1H), 3.67-4.03 (m,
4H), 3.78 (s, 3H), 6.60 (d, J ) 2.7 Hz, 1H), 6.66 (dd, J ) 2.7, 8.1
Hz, 1H), 7.09 (d, J ) 8.1 Hz, 1H). HRMS (FAB) [M + H]+ calcd
for C23H32NO3 370.2382, found 370.2388.
tartrate solution, then the reaction mixture was stirred. The
precipitate was filtered and the filtrate was concentrated. The residue
was chromatographed to give 395 mg (74%) of 13 and 149 mg
(26%) of 15 as a mixture of diastereomers, which could not be
purified from each diastereomer. 15: IR (film) 3376, 2938, 1611,
.
1489, 1371, 1330, 1275, 1196, 1096, 1035, 912, 800, 732 cm-1
.
HRMS (FAB) [M + H]+ calcd for C24H35N2O3 399.2648, found
399.2650.
Reaction of Iminium Salt 7a with NaCN. Under an Ar
atmosphere, NaCN (794 mg, 16 mmol) was added to the aqueous
solution (40 mL) of 7a (1.5 g, 3.2 mmol) with stirring at rt.
Immediately white precipitate appeared. The reaction mixture was
worked up by the general procedure, followed by concentration to
give the crude product of 14 (1.1 g) as a white amorphous. The
crude product was used for the next reaction without purification.
IR (film) 2937, 2240, 1612, 1587, 1489, 1456, 1370, 1334, 1283,
Acknowledgment. We acknowledge a Grant-in-Aid for
Scientific Research (C) (19590105) and the Uehara Memorial
Foundation for financial support. We also acknowledge the
Institute of Instrumental Analysis of Kitasato University, School
of Pharmacy for its facilities.
1237, 1204, 1093, 1033, 948, 923, 806, 754 cm-1
.
Supporting Information Available: Experimental proce-
dures and spectra for obtained new compounds; X-ray data for
7b and 12 (CIF files and ORTEP plots). This material is
available free of charge via the Internet at http://pubs.acs.org.
Reduction of Cyano Adduct 14. Under an Ar atmosphere, the
solution of crude 14 (570 mg, about 1.4 mmol) in THF (1 mL)
was added to the suspension of LiAlH4 (546 mg, 14 mmol) in THF
(1 mL) at 0 °C with stirring for 2.5 h at rt. To the reaction mixture
was added AcOEt and subsequently saturated sodium potassium
JO801276Z
8096 J. Org. Chem. Vol. 73, No. 20, 2008