Mechanistic diversity of the van Leusen reaction applied to 6-ketomorphinans and synthetic potential of the resulting acrylonitrile substructures

Article abstract of DOI:10.1021/jo050362v

Tosylmethyl isocyanide was used to convert 7,8-didehydro-6-ketomorphinans to 6,7-didehydromorphinan-6-carbonitriles with retainment of the 4,5-epoxy ring. However, ring opening occurred in the presence of NaH giving 5,6,7,8-tetradehydromorphinan-6-carboni

Full text of DOI:10.1021/jo050362v

SCHEME 1. van Leusen Reaction Applied to
Codeinones
Mechanistic Diversity of the van Leusen
Reaction Applied to 6-Ketomorphinans and
Synthetic Potential of the Resulting
Acrylonitrile Substructures
Johannes Schu¨tz,† Petra Windisch,† Elka Kristeva,†
Klaus Wurst,‡ Karl-Hans Ongania,§
Ulrike E. I. Horvath,‡ Herwig Schottenberger,*,‡
Gerhard Laus,*,† and Helmut Schmidhammer*,†
Department of Pharmaceutical Chemistry, Institute of
Pharmacy and Center for Molecular Biosciences Innsbruck,
University of Innsbruck, 6020 Innsbruck, Austria,
Institute of Inorganic Chemistry, University of Innsbruck,
6020 Innsbruck, Austria, and Institute of Organic
Chemistry, University of Innsbruck,
6020 Innsbruck, Austria
herwig.schottenberger@uibk.ac.at; g.laus@gmx.net;
helmut.schmidhammer@uibk.ac.at
Received February 26, 2005
Tosylmethyl isocyanide was used to convert 7,8-didehydro-
6-ketomorphinans to 6,7-didehydromorphinan-6-carboni-
triles with retainment of the 4,5-epoxy ring. However, ring
opening occurred in the presence of NaH giving 5,6,7,8-
tetradehydromorphinan-6-carbonitriles. Addition of nucleo-
philes such as Li diisopropylamide or Grignard reagents to
the acrylonitrile substructure yielded ring-opened 5,6-dide-
hydro products. Seven products were characterized by X-ray
crystal structure analysis and revealed insight into the
mechanistic diversity of the van Leusen reaction.
Functionalization and modification of opioid alkaloids
of the natural series continue to be topics of high interest
in medicinal chemistry. Recently, it was found that 14-
phenylpropyloxy derivatives of 6-ketomorphinans possess
unanticipated opioid agonist properties1 and analgesic
potencies.2 Therefore, 14-O-substituents of the com-
pounds in this study include not only H and CH3 but also
cinnamyl as precursor of the phenylpropyl group.
The reductive cyanation of ketones with tosylmethyl
isocyanide (TosMIC)3 is a valuable tool for the introduc-
tion of new functionalities to 6-ketomorphinans. The
mechanism of this (van Leusen) reaction4 allows for a
considerable range of diverse products depending on the
conditions and substrates. As previously reported, TosMIC
converted saturated 6-ketomorphinans such as oxycodone
[76-42-6] into 4,5-epoxy ring-opened 5,6-didehydromor-
phinan-6-carbonitriles.5
In contrast, 7,8-didehydro-6-ketomorphinans such as
14-hydroxycodeinone [508-54-3], 14-methoxycodeinone
[38252-24-3] and 14-cinnamyloxycodeinone [528854-52-
6] now were found to yield 6,7-didehydromorphinan-6-
carbonitriles 1-3 with retainment of the 4,5-epoxy ring
under these conditions. Obviously, an alternative path-
way is operative when a double bond is available for
accepting the transfer of charge (Scheme 1). The molec-
ular structure of 1 was confirmed by X-ray diffraction
(see the Supporting Information). Compounds 2 and 3
† Institute of Pharmacy.
‡ Institute of Inorganic Chemistry.
§ Institute of Organic Chemistry.
(1) Greiner, E.; Spetea, M.; Krassnig, R.; Schu¨llner, F.; Aceto, M.;
Harris, L. S.; Traynor, J. R.; Woods, J. H.; Coop, A.; Schmidhammer,
H. J. Med. Chem. 2003, 46, 1758-1763.
(4) Oldenziel, O. H.; Leusen, D. v.; Leusen, A. M. v. J. Org. Chem.
1977, 42, 3114-3118.
(5) Greiner, E.; Schottenberger, H.; Wurst, K.; Schmidhammer, H.
J. Am. Chem. Soc. 2001, 123, 3840-3841.
(2) Schu¨tz, J.; Spetea, M.; Koch, M.; Aceto, M. D.; Harris, L. S.; Coop,
A.; Schmidhammer, H. J. Med. Chem. 2003, 46, 4182-4187.
(3) Leusen, D. v.; Leusen, A. M. v. Org. React. 2001, 57, 417-666.
10.1021/jo050362v CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/01/2005
J. Org. Chem. 2005, 70, 5323-5326
5323

SCHEME 2. Reactions of
Morphinan-6-carbonitriles
rivative 9 was obtained when alkylation of 1 was at-
tempted in the presence of Li diisopropylamide (LDA),
as evidenced by the X-ray structure. The asymmetric
addition of lithium amides7 opens a plethora of possibili-
ties such as synthesis of 7-aminomorphinans, thus
facilitating the subsequent construction of heterocycles
involving the nitrile or derived functional groups. Simi-
larly, addition of Grignard reagents as observed in a
related system8 resulted in ring-open 5,6-didehydro
compounds, exemplified by the 7-benzyl derivatives
10a,b. The ratio of isolated 7R/â epimers was approxi-
mately 1:9. The stereochemistry of the major product 10b
was shown to be 7â-benzyl by X-ray diffraction.
It is envisioned that the new acrylonitrile system
created by the scission of the ether bridge would allow
another nucleophilic addition, thus further functionaliz-
ing the morphinan backbone. Furthermore, hydrolysis of
the nitrile group is expected to give pharmacologically
very interesting compounds due to the increased polarity
of the functional groups created. These products are likely
to exhibit enhanced peripheral activity.10 Hydrolysis with
NaOH/H2O2 necessitated the presence of a sacrificial
tertiary amine (Et3N) in order to avoid oxidation of the
morphinan nitrogen by the intermediate peroxyimidate.11
Thus, 5,6-didehydro-3,4,14-trimethoxy-17-methylmorphi-
nan-6-carbonitrile 11, obtained by selective catalytic
hydrogenation of the 5,7-diene 7, was converted to the
corresponding amide 12 in good yield. However, hydroly-
sis of 1 yielded the unusual 6â,7â-epoxyamide 13 as the
only isolable product (Scheme 2).
In the first paper on TosMIC cyanation of 6-ketomor-
phinans,5 it was reasonably argued that the 4-phenolate
leaving group ability and structural strain imposed by
the 4,5-ether bridge are the major driving forces of the
preferred course of the reaction to 4,5-ring-opened prod-
ucts.
There is now evidence that a different mechanism is
possible, at least in addition to the previously proposed
one. Upon reaction of 14-O-(3-phenylpropyl)oxycodone
[528854-53-7] with excess TosMIC, along with the ex-
pected ring-opened product, a byproduct was isolated and
identified by X-ray diffraction as the imidazole 14. The
fact that this compound retained the 4,5-epoxy ring
reveals that in saturated ring systems the formation of
a 5,6-double bond is not the only viable path but the 6,7-
double bond is also feasible. The loss of toluenesulfinate
must have occurred in an earlier step than previously
suggested, and the ketenimine intermediate apparently
was not skipped in this case, enabling the addition of a
second TosMIC molecule. TosMIC is known to react with
aldimines to give imidazoles,9 and obviously this pathway
is also viable for a ketenimine as outlined in Scheme 3
to give an alkenylimidazole. Another intermediate was
isolated after cyanation of 14-O-methyloxycodone5 [38252-
were obtained in rather low yields. A yet unidentified,
unstable, tosyl group-bearing byproduct was observed in
the synthesis of 2. Another byproduct was isolated in the
synthesis of 3, the 6,8-diene 4, which obviously originated
from elimination of cinnamyl alcohol.
Known methods for 4,5-epoxy ring scission include
reductive systems such as Zn/KOH, Zn/AcOH, and Li-
AlH4.6 Therefore, it was surprising that attempts to
alkylate the 14-OH group in 1 using NaH/RX yielded
ring-opened 5,7-dienes 5 and 6 with concomitant alky-
lation of the newly created phenolate group in position 4
(Scheme 2). The 14-OCH3 analogue 2 behaved similarly
and gave 7, indicating that creation of an anion at C-8
might be the probable first step in this reaction. It was
consequently shown that opening of the 4,5-epoxy ring
occurred by sole action of NaH upon 1, affording com-
pound 8. In this case, an equilibrium between O-14 and
C-8 anions in the initial step is suggested.
(7) Doi, H.; Sakai, T.; Iguchi, M.; Yamada, K.; Tomioka, K. J. Am.
Chem. Soc. 2003, 125, 2886-2887 and references therein.
(8) Fleming, F. F.; Pu, Y.; Tercek, F. J. Org. Chem. 1997, 62, 4883-
4885 and references therein.
(9) (a) Leusen, A. M. v.; Wildeman, J.; Oldenziel, O. H. J. Org. Chem.
1977, 42, 1153-1159. (b) Grimmett, M. R. In Science of Synthesis;
Neier, R., Ed.; Thieme: Stuttgart, New York, 2002; Vol. 12, pp 325-
528.
Addition of nucleophiles to the acrylonitrile moiety,
however, gave ring-opened 5,6-didehydromorphinan-6-
carbonitriles (Scheme 2). The 7â-diisopropylamino de-
(10) Schu¨tz, J.; Schmidhammer, H. PCT Int. Appl. 2003. Patent No.
WO 03/051888 A1.
(11) Laus, G. J. Chem. Soc., Perkin Trans. 2 2001, 864-868.
(6) Linders, J. T. M.; Adriaansens, R. J. O.; Lie, T. S.; Maat, L. Recl.
Trav. Chim. Pay-Bas 1986, 105, 27-29.
5324 J. Org. Chem., Vol. 70, No. 13, 2005

was added to a cooled (0 °C) suspension of NaH (0.30 g 60%,
7.50 mmol) in 15 mL of anhydrous DMF, and the mixture was
stirred for 30 min. Then CH3I (0.42 mL, 6.73 mmol) was added,
and the brown solution was stirred for another 90 min. After
addition of ice and water (100 mL), the mixture was extracted
with CH2Cl2 (2 × 50 mL, 2 × 20 mL). The combined extracts
were washed with water (5 × 200 mL) and brine (200 mL), dried
over Na2SO4, and evaporated to afford a foam which was
crystallized from 2-propanol to give compound 7 (338 mg, 31%):
mp 160-164 °C; [R]20D 151 (CHCl3, c 0.7); 1H NMR (CDCl3, ppm)
δ 7.24 (br s, 1H), 6.76 (s, 2H ar), 6.01 (dd, 1H olef, J ) 9.5 Hz,
J ) 1.5 Hz), 5.85 (d, 1H olef, J ) 9.5 Hz), 3.82 (s, 6H), 3.24 (s,
3H), 2.40 (s, 3H); 13C NMR (CDCl3, ppm) δ 156.0, 152.3, 146.5,
131.2, 125.5, 122.6, 119.3, 112.2, 106.3, 74.1, 61.2, 56.4, 55.6,
51.1, 47.6, 43.9, 43.2, 29.3, 26.2; IR (KBr, cm-1) 2932, 2835,
2216, 1487, 1279, 1089, 1048; HRMS (FAB) calcd for C21H25N2O3
(M + H)+ 353.1860, found 353.1868.
SCHEME 3. Byproducts of the van Leusen
Reaction Applied to Saturated 6-Ketomorphinans
Compound 7 was also obtained by the following procedure:
2 (130 mg, 0.38 mmol) was added to a cooled (0 °C) suspension
of NaH (14 mg 95%, 0.55 mmol) in 2.5 mL of anhydrous DMF,
and the mixture was stirred for 30 min. Then CH3I (30 µL, 0.48
mmol) was added, and the brown solution was stirred for another
50 min. After addition of ice and water (25 mL), the mixture
was extracted with CH2Cl2 (1 × 25 mL, 2 × 10 mL). The
combined extracts were washed with water (5 × 50 mL) and
brine (50 mL), dried over Na2SO4, and evaporated to afford a
foam which was crystallized from 2-propanol to give compound
7 (35 mg, 26%).
4-Cinnamyloxy-5,6-didehydro-14â-hydroxy-3-methoxy-
17-methyl-7â-(diisopropylamino)morphinan-6-carboni-
trile (9). A solution of LDA‚THF (3.5 mL 1.5 M in cyclohexane,
5.25 mmol) was added dropwise to a cooled (-70 °C) suspension
of 1 (1.10 g, 3.39 mmol) in 30 mL of anhydrous THF, and the
mixture was stirred for 35 min at -40 °C. Cinnamyl bromide
(0.85 g, 4.10 mmol) was added, and stirring was continued for
20 h at room temperature. Then water (5 mL) was added, and
volatiles were removed under reduced pressure. The residue was
dissolved in CH2Cl2 (100 mL), the solution was washed with
water (2 × 100 mL) and brine (100 mL), dried over Na2SO4, and
evaporated to afford a foam which was purified by repeated
column chromatography (100 g silica, mesh 230-400) eluting
with CH2Cl2/MeOH/NH4OH concd (500:4:1). Crystallization from
MeOH yielded compound 9 (0.23 g, 13%): mp 174-178 °C dec;
28-7] under protic conditions, which was demonstrated
for the first time by X-ray diffraction to be the postulated
primary van Leusen adduct,4 the spiro oxazoline 15.
In summary, the van Leusen reaction applied to
6-ketomorphinans shows a high degree of mechanistic
diversity, and the resulting acrylonitriles provide ex-
tremely versatile access to a structural pool of functional
combinations. Biological and pharmacological studies on
the described compounds are in progress and will be
published in due course.
[R]20 -9.4 (CHCl3, c 0.8); 1H NMR (CDCl3, ppm) δ 7.17-7.51
D
(m, 6H), 6.90 (d, 1H olef, J ) 16.0 Hz), 6.81 (s, 2H ar), 6.52 (Dt,
1H olef, J ) 16.0 Hz, J ) ∼6 Hz), 4.89 (dd, 1H, J ) 11.4 Hz,
J ) 5.5 Hz), 4.44 (dd, 1H, J ) 11.4 Hz, J ) 6.8 Hz), 3.85 (s, 3H),
2.34 (s, 3H), 1.12 (d, 6H, J ) 6.6 Hz), 1.01 (d, 6H, J ) 6.6 Hz);
13C NMR (CDCl3, ppm) δ 154.2, 152.1, 145.8, 137.5, 135.7, 134.0,
129.2, 129.0, 128.4, 127.5, 125.7, 123.3, 121.3, 117.8, 111.9, 73.3,
68.5, 62.8, 56.4, 48.1, 46.1, 43.3, 42.1, 38.4, 33.2, 25.0, 24.1, 23.5;
IR (KBr, cm-1) 3321, 2962, 2857, 2217, 1599, 1484, 1276, 1220,
1113, 1049, 960, 802, 729; HRMS (FAB) calcd for C34H44N3O3
(M + H)+ 542.3378, found 542.3336. Crystal structure: see the
Supporting Information (CCDC 236732).
Experimental Section
6,7-Didehydro-4,5r-epoxy-14â-hydroxy-3-methoxy-17-
methylmorphinan-6-carbonitrile (1). t-BuOK (5.61 g, 50.0
mmol) was added to a stirred and cooled (-40 °C) solution of
TosMIC (4.30 g, 22.0 mmol) in 50 mL of anhydrous DME. After
the solution was stirred for 10 min under N2, a solution of 14-
hydroxycodeinone [508-54-3] (6.27 g, 20.0 mmol) in DME (15 mL)
was added, and the mixture was stirred at 0 °C for 90 min. Then
2-propanol (1.68 mL, 22.5 mmol) was added, and stirring was
continued at room temperature for another 90 min. The solution
was diluted with water (200 mL) and brine (30 mL) and
extracted with CH2Cl2 (2 × 50 mL, 2 × 20 mL). The combined
extracts were washed with water (3 × 200 mL) and brine (100
mL), dried over Na2SO4, and evaporated to afford a foam which
was crystallized from MeOH to yield compound 1 (4.07 g, 63%):
mp 262-266 °C dec; [R]20D -359 (CHCl3, c 0.9); 1H NMR (CDCl3,
ppm) δ 6.73 (d, 1H ar, J ) 8.6 Hz), 6.70 (dd, 1H olef, J ) 5.8 Hz,
J ) 2.6 Hz), 6.64 (d, 1H ar, J ) 8.6 Hz), 4.97 (s, 1H), 3.89 (s,
3H), 2.39 (s, 3H); 13C NMR (CDCl3, ppm) δ 147.2, 144.7, 144.4,
130.8, 126.0, 120.2, 118.3, 116.0, 112.8, 85.6, 70.6, 64.4, 57.7,
45.8, 43.7, 33.7, 31.4, 22.7; IR (KBr, cm-1) 3361, 2963, 2942,
2911, 2829, 2216, 1638, 1509, 1453, 1286, 1167, 1055, 929, 786;
HRMS (FAB) calcd for C19H21N2O3 (M + H)+ 325.1547, found
325.1534. Crystal structure: see the Supporting Information
(CCDC 236727).
7r-Benzyl-5,6-didehydro-4,14â-dihydroxy-3-methoxy-17-
methylmorphinan-6-carbonitrile (10a) and 7â-Benzyl-5,6-
didehydro-4,14â-dihydroxy-3-methoxy-17-methylmorphi-
nan-6-carbonitrile (10b). To a cooled (-40 °C) suspension of
1 (0.20 g, 0.62 mmol) in 10 mL of anhydrous THF was added a
solution of benzylmagnesium chloride (1.86 mL 1M in Et2O, 1.86
mmol). The mixture was stirred at room temperature for 5 h.
To the resulting solution saturated NH4Cl solution (50 mL) was
added, pH was adjusted to 8.5 with concentrated NH4OH, THF
was removed under reduced pressure, and the remaining
mixture was extracted with CH2Cl2 (3 × 30 mL). The combined
extracts were washed with water (4 × 100 mL) and brine (100
mL), dried over Na2SO4, and evaporated to afford a foam which
was subjected to column chromatography (60 g silica, mesh 230-
400) eluting with CH2Cl2/MeOH/NH4OH conc (500:4:1). The
isomeric products 10a (10 mg, 4%) and 10b (90 mg, 35%) were
crystallized from MeOH.
5,6,7,8-Tetradehydro-3,4,14â-trimethoxy-17-methylmor-
phinan-6-carbonitrile (7). Compound 1 (1.00 g, 3.08 mmol)
Minor isomer 10a: mp 205-211 °C; 1H NMR (CDCl3, ppm) δ
7.28 (d, 1H olef, J ) 2.2 Hz), 7.04-7.20 (m, 5H ar), 6.67 (d, 1H
J. Org. Chem, Vol. 70, No. 13, 2005 5325

ar, J ) 8.4 Hz), 6.55 (d, 1H ar, J ) 8.4 Hz), 3.87 (s, 3H), 2.30 (s,
3H); IR (KBr, cm-1) 3385, 2924, 2851, 2210, 1610, 1489, 1438,
1280, 1224, 1109, 1045, 797, 702; HRMS (FAB) calcd for
C26H29N2O3 (M + H)+ 417.2173, found 417.2170.
Acknowledgment. We thank Tasmanian Alkaloids
Pty, Ltd., Australia, for the generous gift of thebaine
[115-37-7] as starting material. We are indebted to Dr.
M. Andre, Sandoz, Austria, for the optical rotation
determinations.
Major isomer 10b: mp. 217-222 °C; [R]20D -46 (CHCl3, c 0.9);
1H NMR (CDCl3, ppm) δ 7.20-7.34 (m, 6H), 6.67 (d, 1H ar, J )
8.4 Hz), 6.53 (d, 1H ar, J ) 8.4 Hz), 3.83 (s, 3H), 2.34 (s, 3H);
13C NMR (CDCl3, ppm) δ 151.5, 145.5, 143.9, 141.3, 130.4, 129.0,
128.5, 127.3, 126.7, 120.7, 118.9, 114.8, 109.8, 69.3, 63.4, 56.8,
46.7, 43.1, 42.7, 40.1, 37.1, 31.0, 29.5, 24.8; IR (KBr, cm-1) 3385,
2939, 2848, 2221, 1605, 1486, 1441, 1283, 1224, 1048, 807;
HRMS (FAB) calcd for C26H29N2O3 (M + H)+ 417.2173, found
417.2142. Crystal structure: see the Supporting Information
(CCDC 236730).
Supporting Information Available: Experimental pro-
cedures and spectral data of compounds 2-5, 6, 8, and 11-
14; crystal data and structure refinement details of 1, 2, 9,
10b, and 13-15. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO050362V
5326 J. Org. Chem., Vol. 70, No. 13, 2005