An expedient enantioselective route to diaminotetralins: application in the preparation of analgesic compounds.

Article abstract of DOI:10.1021/ol026579i

Advances to the rhodium-catalyzed asymmetric ring-opening protocol have allowed this methodology to be extended to azabicyclic alkenes, the first time that rhodium has been used in allylic functionalizations with nitrogen leaving groups. The product diami

Full text of DOI:10.1021/ol026579i

ORGANIC
LETTERS
2002
Vol. 4, No. 20
3465-3468
An Expedient Enantioselective Route to
Diaminotetralins: Application in the
Preparation of Analgesic Compounds
Mark Lautens,* Keith Fagnou, and Valentin Zunic
DaVenport Research Laboratories, UniVersity of Toronto, Department of Chemistry,
80 St. George Street, Toronto, Ontario, Canada M5H 3H6
mlautens@alchemy.chem.utoronto.ca
Received July 22, 2002
ABSTRACT
Advances to the rhodium-catalyzed asymmetric ring-opening protocol have allowed this methodology to be extended to azabicyclic alkenes,
the first time that rhodium has been used in allylic functionalizations with nitrogen leaving groups. The product diaminotetralins are important
medicinal compounds. The synthetic utility of this methodology has been demonstrated in the total synthesis of an analgesic compound
where the tetralin core, the regiochemistry, and the relative and absolute stereochemistry are all established in the ring-opening step.
We recently reported a rhodium-catalyzed asymmetric ring-
opening (ARO) reaction of oxabicyclic alkenes to produce
dihydronaphthalenol products in high yield and excellent
enantioselectivity (>90% ee).1 This methodology was also
applied to the diastereoselective ring opening of vinyl
epoxides.2 We next focused our attention on expanding the
scope of the reaction to include amine-induced ring opening
of azabicyclic alkenes so as to have rapid and efficient access
to cyclohexyl 1,2-diamino moieties with control of the regio-,
diastereo-, and enantioselectivity. A synthetic route to
cyclohexyl-1,2-diamines would be valuable and comple-
mentary to existing methods that rely on ring-opening
reactions of aziridines and aziridinium ions.
sessing a 1,2-diamino motif (e.g., 2 and 3) have been reported
to be highly selective κ-opioid agonists (Figure 1).6 In
Cyclohexyl-1,2-diamines are an important class of com-
pounds for a variety of reasons including their use as
scaffolds for chiral ligands3 and their biological activity. For
instance, U-50,4884,5 1 and other structural analogues pos-
Figure 1. Analgesic diamine compounds.
(1) (a) Lautens, M.; Fagnou, K.; Rovis, T. J. Am. Chem. Soc. 2000, 122,
5650. (b) Lautens, M.; Fagnou, K.; Taylor, M. Org. Lett. 2000, 2, 1677.
(c) Lautens, M.; Fagnou, K.; Taylor, M.; Rovis, T. J. Organomet. Chem.
2001, 624, 259. (d) Lautens, M.; Fagnou, K. J. Am. Chem. Soc. 2001, 123,
7170. (e) Lautens, M.; Fagnou, K. Tetrahedron 2001, 57, 5067.
(2) Fagnou, K.; Lautens, M. Org. Lett. 2000, 2, 2319.
addition to analgesic activity, aminotetralins have been shown
to possess a variety of other useful biological properties.7
10.1021/ol026579i CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/13/2002

Two main obstacles needed to be overcome before an
efficient ring opening of azabicyclic substrates could be
achieved. First, nitrogen functionalities are poorer leaving
groups than those based on oxygen, and as a result,
azabicycles are far less reactive than the corresponding
oxabicycles. This diminished reactivity is mirrored in aziri-
dines compared to epoxides. Second, a nucleophilic nitrogen
anion is generated during the ring-opening process, which
could lead to the formation of oligomerization byproducts.8
Our previous results with oxabicyclic alkenes and nitrogen
nucleophiles indicated that rhodium catalysis might offer a
solution to the challenges associated with nitrogen leaving
groups. For example, while benzenesulfonamide is a good
nucleophile in the rhodium-catalyzed ring opening of oxa-
bicyclic alkenes,1a N-benzylbenzenesulfonamide is not, in-
dicating that the reaction is sensitive to the steric bulk of
the nucleophile.9 Amides and carboxamides have also proved
to be very poor nucleophiles.9 Importantly, these function-
alities can be considered “activating” groups for the nitrogen
functionality. We reasoned that by properly choosing the
activating group on the nitrogen of the azabicycle, both the
decreased reactivity and the oligomerization problems could
be avoided.
The nature of the activating group was found to be an
important factor in the reactivity of 4 (Table 1). For example,
Table 1. Effect of Activating Group and Additives on the
Rhodium-Catalyzed Ring Opening with Pyrrolidinee
Entry
R-Group
Additives
Time (h)
Yielda (%)
1
2
3
4d
5d
6
7
8
9
10
11c
Me
Bn
CO2tBu
CO2tBu
CO2tBu
Tos
Tos
Nos
Nos
Nos
Et3N‚HCl
Et3N‚HCl
Et3N‚HCl
none
Et3N‚HCl
none
Et3N‚HCl
Et3N‚HCl
Bu4NI/CSAb
NH4I
24
24
24
24
24
24
24
24
4
nr
nr
nr
50
82
nr
91
89
72
94
91
2
18
Nos
NH4I
Since no method was available for the practical large-scale
preparation of azabicyclic material, our initial efforts focused
on this task. We could not determine from the outset which
N-activating group would be required, so a flexible approach
allowing installation of a variety of N-substituents was
established. Our preferred procedure involves the cycload-
dition of benzyne, generated in situ from anthranilic acid
and isoamyl nitrite, and commercially available N-Boc
pyrrole.10 In this way, N-Boc 4 can be produced on a 20 g
scale in 60-70% yield. A one-pot exchange of the N-group
is achieved by treating N-Boc 4 dissolved in CH2Cl2 with
Et3N and TMSI followed by a slight excess of MeOH and
the desired sulfonyl chloride or other electrophile (Scheme
1). Importantly, no recourse to chromatography is required
a Isolated yield. b 5 equiv of Bu4NI and 2.5 equiv of CSA used. c 0.5
mol % of [Rh(COD)Cl]2, 1.5 mol % of DPPF, 1.5 equiv of NH4I, and 3
equiv of pyrrolidine used. d Tetrahydropyran was used as the solvent, and
the reaction was run at 100 °C. e Conditions: [Rh(COD)Cl]2 (2.5 mol %),
DPPF (5 mol %), 4 dissolved in THF (0.2 M) followed by the addition of
the additive (5 equiv to 4). Solution heated to reflux followed by the addition
of pyrrolidine (10 equiv to 4). Reacted at reflux until complete as determined
by TLC analysis.
N-methyl- and N-benzylazabicycles do not react under the
standard conditions used with oxabicyclic alkenes. Reaction
of N-Boc 4 in refluxing THF gives traces of 5 after prolonged
reaction time (Table 1, entry 3). By using tetrahydropyran
(THP) as solvent and increasing the reaction temperature,
however, 5 was obtained in 82% yield (Table 1, entry 6).12
On the other hand, N-tosyl and N-nosyl 4 both showed
enhanced reactivity, giving 5 in 91 and 89% yields in
refluxing THF.13
Scheme 1. Preparation of Azabicyclic Alkenes
(4) Szmuszkovicz, J.; Vov, Voigtlander, P. F. J. Med. Chem. 1982, 25,
31.
(5) (a) Cowan, A.; Gmerek, D. E. Trends Pharmacol. Sci. 1986, 7, 69.
(b) Millan, M. J. Trends. Pharmacol. Sci. 1990, 11, 70.
(6) Costello, G. F.; James, R.; Shaw, J. S.; Slater, A. M.; Stutchbury, N.
C. J. J. Med. Chem. 1991, 34, 181.
(7) For example, see: (a) van Vliet, L. A.; Tepper, P. G.; Dijkstra, D.;
Damsma, G.; Wikstro¨m, H.; Pugsley, T. A.; Akunne, H. C.; Heffner, T.
G.; Glase, S. A.; Wise, L. D. J. Med. Chem. 1996, 39, 4233 and references
therein. (b) Degnan, A. P.; Meyers, A. I. J. Org. Chem. 2000, 65, 3503 and
references therein.
(8) These challenges likely contribute to the diminished focus on
vinylaziridines in π-allylmetal chemistry compared to vinyl epoxides.
(9) Lautens, M.; Fagnou, K. Unpublished results.
(10) Use of high reaction concentration (∼2.5 M) is key to obtaining
high yields. Under lower concentrations, yields of 10-20% are typically
obtained. See the Supporting Information.
since purification for both steps can be performed by
recrystallization.11
(11) Yields of up to 80% can be obtained with recourse to chromato-
graphic purification techniques.
(12) This temperature effect has previously been observed in the ring
opening of oxabicycles: Lautens, M.; Fagnou, K. J. Am. Chem. Soc. 2001,
123, 7170-7171.
(13) The relative trans stereochemistry was proven for N-Tos 5 by X-ray
crystallography.
(3) (a) Lucet, D.; LeGall, T.; Mioskowski, C. Angew. Chem., Int. Ed.
1998, 37, 2580. (b) Bennani, Y. L.; Hanessian, S. Chem. ReV. 1997, 97,
3161. (c) Mukaiyama, T.; Asami, M. Top. Curr. Chem. 1985,127, 133. (c)
Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 2282. (d)
Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc.
Chem. Res. 1996, 29, 552.
3466
Org. Lett., Vol. 4, No. 20, 2002

As with oxabicyclic substrates, the effect of protic and
halide additives played an important role in the ring opening
with aliphatic amines. Reaction times were extremely slow,
and several substrates failed to react completely in the
absence of an additive (Table 1, entries 4 and 6). The nature
of the halide was also found to influence the time required
for complete conversion.14 For example, slow reactions
occurred with Et3N‚HCl, whereas a combination of Bu4NI
and camphorsulfonic acid (CSA) resulted in much faster
reactions (Table 1, entry 8 vs entry 9). The use of excess
tetraalkylammonium salts is not practical, however, since
they lead to emulsions that greatly impede the isolation of
5. Gratifyingly, NH4I, which is soluble in water, can be used
in place of Bu4NI.1d,15 A wide variety of amines reacted in
high yield, allowing rapid access to a range of diaminotet-
ralins including cyclic amines (Table 2, entries 1-6) and
secondary aliphatic amines (Table 2, entries 7-9).
Table 3. Asymmetric Ring Opening of
N-Boc-azabenzonorbornadienee
Table 2. Scope of Amine Ring-Opening Reactionse
a Isolated yield. b ee determined by CSP HPLC with a Chiralcel AD
column. c Two equivalents of ligand to rhodium metal was used. d (R,S)-
PPF-PtBu2 used as the chiral ligand.
e Conditions: [Rh(COD)Cl]2 (2.5 mol %), ligand (5 mol %), 4 dissolved
in THP (0.2 M) followed by the addition of the additive (5 equiv to 4).
Solution heated to 100 °C followed by the addition of pyrrolidine (10 equiv
to 4). Reacted at 100 °C until complete as determined by TLC analysis.
a Isolated yield. b These reactions were performed on a 4-5 g scale.
c Et2NH (10 equiv) used due to volatility of the amine. d Reaction performed
at 100 °C in tetrahydropyran. e Conditions: [Rh(COD)Cl]2 (0.5-1 mol %),
DPPF (1.5-3 mol %), 4 dissolved in THF (0.2 M) followed by the addition
of the NH4I (1.5 equiv to 4). Solution heated to reflux followed by the
addition of the amine (3 equiv to 4). Reacted at reflux until complete as
determined by TLC analysis.
use of Et3N‚HCl in THP18 at 100 °C gives 5 in 77% yield
and 86% ee. While the reaction can take place without an
additive,19 higher product yields and enantioselectivities are
obtained with Et3N‚HCl. The reasons for the lower selectivi-
ties with azabicyclic alkenes compared to oxabicycle sub-
strates may be due to the availability of different binding
modes of the rhodium to the N-activating group on the
substrate.
The nature of the nucleophile was found to influence the
reaction outcome, but by varying the reaction conditions
excellent results can be obtained in all cases. For example,
with simple aliphatic amines, best results are obtained with
Et3N‚HCl (Table 3, entries 6, 8, and 9). In contrast, amines
possessing a second heteroatom, such as N-phenylpiperazine
We have also achieved asymmetric ring opening of the
N-Boc-protected azabicycle.16 Under optimized conditions
for the analogous oxabicyclic alkene using (R,S)-PPF-PtBu2
as the chiral ligand with NH4I as the additive, 5 was obtained
in 65% yield and only 25% ee. Changing to C2-Ferriphos17
and examining the effect of an additive revealed that the
(14) For a review on halide effects in transition metal catalysis, see:
Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41, 26.
(15) Application of these new conditions to the asymmetric ring opening
of oxabicyclic alkenes will be reported in due course.
(16) The absolute stereochemistry of the ring opened products was shown
to be (1S,2S) by X-ray crystallography. Crystals suitable for X-ray analysis
were obtained by deprotecting N-Boc 10, followed by protection of the
free amine with 4-bromobenzenesulfonyl chloride. This is the opposite sense
of induction that we have observed for the oxabicyclic series using the
same sense of chirality in the ligands.
(18) We screened a variety of typical high boiling solvents and found
that while DMF and toluene gave the product in decent ee (80% and 79%
ee, respectively), THP was the preferred solvent.
(19) We have previously observed that halide and protic additives were
necessary for the addition of pyrrolidine to oxabicycles. The higher
temperatures used in our present reaction conditions most likely facilitate
reversible binding of the basic amine to the metal center. See ref 10.
(17) This ligand was prepared from (R)-2-methyl-CBS-oxazaborilidine:
Schwink, L.; Knochel, P. Chem. Eur. J. 1998, 4, No.5, 950.
Org. Lett., Vol. 4, No. 20, 2002
3467

and -morpholine, react best in the absence of additive and
can be performed with or without solvent (Table 3, entries
10-12). The more sterically hindered dibenzylamine also
reacts well in the absence of additive (Table 3, entry 13).
Current efforts are directed at understanding the possible
interactions of the protic and halide additives as well possible
interactions of the nucleophiles at the metal center.
Scheme 2. Synthesis Designed for Maximum Variabilitya
Having established a new route to the diaminotetralin core,
we sought an efficient synthesis of analgesic 3. A first
approach commenced with the methylation of sulfonamide
5a with iodomethane and K2CO3 in acetone followed by
hydrogenation with catalytic Pt/C to give 17a (both steps
occur in 96% isolated yield) Photolytic cleavage of the tosyl
group according to the method of Hamada and co-workers20
provides 18 in 91% yield. DCC coupling of the correspond-
ing arylacetic acid gives 3 in 86% yield. This approach has
the added benefit that the sulfonyl group makes many of
the products crystalline and easy to handle.
a Key: (a) MeI, K2CO3, acetone, rt, >95% or KH, THF, rt,
>95%; (b) H2, Pt/C, EtOAc, 96%; (c) NaIO4, H2NNH2, EtOH, THF,
H2O, >95%; (d) hν/NaBH4, p-MeOC6H4OMe, 80% EtOH(aq), 91%;
(e) TFA/CH2Cl2 (1:4), rt, 1 h, 90%; (f) ArCH2CO2H, EDCl, 86%.
Our efforts were then directed toward an enantioselective
synthesis of 3. Asymmetric ring opening of 4 with pyrrolidine
proceeded smoothly in the presence of [Rh(COD)Cl]2, C2-
Ferriphos, and Et3NHCl to produce 5b in 77% isolated yield
and 86% ee (Table 3). Methylation of N-Boc 5b with
iodomethane and KH in THF generates 16b in 96% yield.
A diimide hydrogenation of the olefin (>95% yield) followed
by deprotection of the BOC group with trifluoroacetic acid
gives 18 in 91% yield, and an EDCI coupling of the
corresponding arylacetic acid provides enantiomerically
enriched 3 in 86% yield (Scheme 2).
In conclusion, we have established a new and efficient
route to the diaminotetralin core that can now be obtained
in two steps and in high yield from commercially available
N-Boc-pyrrole. The key step in this approach is the rhodium-
catalyzed ARO of azabenzonorbornadienes that establishes
the diaminotetralin core, the regiochemistry, and the relative
and absolute stereochemistry of the diamine moiety simul-
taneously. The successful application of rhodium catalysis
to this substrate class demonstrates that rhodium catalysis
can be successfully applied to allylic systems with nitrogen
leaving groups and may provide a solution to the problems
encountered with other catalysts and analogous substrates.
This methodology has been applied to the preparation of a
previously reported analgesic compound 3. The flexibility
and high variability of nitrogen substituents make this
methodology ideal for the preparation of compound libraries.
Acknowledgment. We thank NSERC, AstraZeneca Re-
search Center Montreal (Edward Roberts), the ORDCF, and
the University of Toronto for valuable support of our
programs. Solvias AG is thanked for supplying us with the
PPF-PtBu2 ligand used in these studies. K.F. thanks NSERC
for a post-graduate scholarship. V.Z. thanks NSERC and
OGS for postgraduate scholarships.
Supporting Information Available: Full characterization
details including 1H and 13C NMR, IR, HRMS. and elemental
analysis. This material is available free of charge via the
Internet at http://pubs.acs.org.
(20) Hamada, T.; Nishida, A.; Yonemitsu, O. J. Am. Chem. Soc. 1986,
108, 140.
OL026579I
3468
Org. Lett., Vol. 4, No. 20, 2002