Intramolecular alkene carboamination reactions for the synthesis of enantiomerically enriched tropane derivatives

Article abstract of DOI:10.1021/ol201051q

The synthesis of tropane derivatives via intramolecular Pd-catalyzed alkene difunctionalization reactions is described. Enantiopure N-aryl-γ- aminoalkenes bearing an aryl or alkenyl halide adjacent to the amino group were converted to benzo- or cycloalken

Full text of DOI:10.1021/ol201051q

ORGANIC
LETTERS
2
011
Vol. 13, No. 11
962–2965
Intramolecular Alkene Carboamination
Reactions for the Synthesis of
Enantiomerically Enriched Tropane
Derivatives
2
Danielle M. Schultz and John P. Wolfe*
Department of Chemistry, University of Michigan, 930 North University Avenue,
Ann Arbor, Michigan 48109-1055, United States
jpwolfe@umich.edu
Received April 20, 2011
ABSTRACT
The synthesis of tropane derivatives via intramolecular Pd-catalyzed alkene difunctionalization reactions is described. Enantiopure N-aryl-
γ-aminoalkenes bearing an aryl or alkenyl halide adjacent to the amino group were converted to benzo- or cycloalkenyl-fused tropane products in
good yield and with no loss of enantiopurity.
The azabicyclic frameworkiswidespreadin both natural
products and pharmaceutical targets that have a range of
central nervous system (CNS) activities including antic-
(dizocilipine), a related heterocycle bearing two fused aryl
4
rings, has exhibited anticonvulsant activity and has also
a
4
b
been used in animal models of schizophrenia.
1
holinergic, sedatory, and cognitive. Benzo-fused tropanes
are an interesting and important subclass of azabicycloalk-
anes. These ring systems are displayed in numerous drug
leads and pharmaceuticals including 1, which has been
2
studied for the treatment of Type 2 diabetes, and 2, which
3
is an antitumor drug candidate (Figure 1). MK-801
(
1) Grynkiewicz, G.; Gadzikowska, M. Pharmacol. Rep. 2008, 60,
39.
2) Ammenn, J.; Paal, M.; Ruehter, G.; Schotten, T.; Stenzel, W.
PCT Int. Appl. WO 2000078724, 2000.
3) Ahmed, G.; Bohnstedt, A.; Breslin, H. J.; Burke, J.; Curry, M. A.;
Diebold, J. L.; Dorsey, B.; Dugan, B. J.; Feng, D.; Gingrich, D. E.; Guo,
T.; Ho, K. -K.; Learn, K. S.; Lisko, J. G.; Liu, R. -Q.; Mesaros, E. F.;
Milkiewicz, K.; Ott, G. R.; Parrish, J.; Theroff, J. P.; Thieu, T. V.;
Tripathy, R.; Underiner, T. L.; Wagner, J. C.; Weinberg, L.; Wells, G. J.;
You, M.; Zificsak, C. A. PCT Int. Appl. WO 2008051547, 2008.
4
Figure 1. Biologically active benzo-fused tropanes.
(
(
The medicinal relevance of azabicycloalkanes has sti-
mulated considerable interest among synthetic chemists,
(5) For a recent review, see: Pollini, G. P.; Benetti, S.; De Risi, C.;
Zanirato, V. Chem. Rev. 2006, 106, 2434.
(4) (a) Thompson, W. J.; Anderson, P. S.; Britcher, S. F.; Lyle, T. A.;
Thies, J. E.; Magill, C. A.; Varga, S. L.; Schwering, J. E.; Lyle, P. A.;
Christy, M. E.; Evans, B. E.; Colton, C. D.; Holloway, M. K.; Springer,
J. P.; Hirschfield, J. M.; Ball, R. G.; Amato, J. S.; Larsen, R. D.; Wong,
E. H. F.; Kemp, J. A.; Tricklebank, M. D.; Singh, L.; Oles, R.; Priestly,
T.; Marshall, G. R.; Knight, A. R.; Middlemiss, D. N.; Woodruff, G. N.;
Iversen, L. L. J. Med. Chem. 1990, 33, 789. (b) Rung, J. P.; Carlsson, A.;
Markinhuhta, K. R.; Carlsson, M. L. Prog. Neuro-psychopharmacol.
Biol. Psych. 2005, 29, 827.
(6) For selected recent examples, see: (a) Lin, G. -J.; Zheng, X.;
Huang, P. -Q. Chem. Commun. 2011, 47, 1545. (b) Davis, F. A.; Theddu,
N.; Edupuganti, R. Org. Lett. 2010, 12, 4118. (c) Reddy, R. P.; Davies,
H. M. L. J. Am. Chem. Soc. 2007, 129, 10312 and references cited therein.
(d) Shing, T. K. M.; Wong, W. F.; Ikeno, T.; Yamada, T. Org. Lett.
2007, 9, 207. (e) Martin, S. F. Pure Appl. Chem. 2005, 77, 1207. (f) Mans,
D. M.; Pearson, W. H. Org. Lett. 2004, 6, 3305 and references cited
therein. (g) Mikami, K.; Ohmura, H. Chem. Commun. 2002, 2626.
1
0.1021/ol201051q r 2011 American Chemical Society
Published on Web 05/11/2011

1
6
and a great number of methods have been developed for
5
amines 8. The Grignard addition reactions typically pro-
ceeded with 4ꢀ13:1 dr, but after flash chromatography the
desired amine products were obtained with a high degree of
stereochemical purity in moderate to good yields (51ꢀ76%).
In the few instances when the diastereoselectivity of the
Grignard addition to the aldimine was poor (2ꢀ3:1), lower
yields (38ꢀ46%) of amine products were obtained after
separation of the stereoisomers. Acid-mediated cleavage of
the chiral auxiliary to give primary amines 9, followed by a
Pd/Xantphos-catalyzed N-arylation with bromobenzene,
afforded desired N-phenyl-γ-aminoalkene substrates 4aꢀh
in good yield. Although these conditions usually provided
good chemoselectivity for the desired N-arylation, in a few
instances competing 2-benzyl pyrrolidine formation oc-
curred, which led to modest yields.
ꢀ7
the construction of saturated frameworks.
In con-
trast, only a handful of routes have previously been
developed for the synthesis of benzo-fused tropane
8
ꢀ12
scaffolds.
Pd-catalyzed carboamination reaction
We envisioned that an intramolecular
1
3,14
of a γ-ami-
noalkene substrate such as 4, which contains a 2-bromoar-
yl (or 2-bromoalkenyl) group adjacent to the amino
moiety, could provide a complementary approach to the
benzo-tropane framework 3 (Scheme 1). This transforma-
tion would generate two bonds and 1ꢀ2 stereocenters
17
(
at C8 and C9) in a controlled fashion, and the requisite
substrates could be prepared in enantiopure form via
addition of unsaturated Grignard reagents 6 to readily
available chiral imines 5.
Scheme 1. Intramolecular Carboamination Strategy for the
Synthesis of Benzo-Fused Tropane Derivatives
a
Scheme 2. Synthesis of Tropane Substrates
The enantioenriched substrates 4 required for the strat-
egy outlined above were synthesized in four steps from
readily accessible o-bromobenzaldehydes or β-bromo-R,
β-unsaturated aldehydes (Scheme 2). Specifically, conden-
a
Overall yields of 4aꢀh over four steps: 4a, 20%; 4b, 36%; 4c, 27%;
sation of an appropriate bromoaldehyde with (R )-(þ)-
4d, 14%; 4e, 41%; 4f, 31%; 4g, 39%; 4h, 41%.
S
1
5
tert-butanesulfinamide afforded aldimine 7 as a single
enantiomer. Subsequent 1,2-addition of a homoallylic
Grignard reagent to 7 afforded N-tert-butanesulfinyl
Our prior studies on Pd-catalyzed carboamination
reactions that yield substituted pyrrolidines suggested the
conversion of 4 to 3 was likely to occur via a key intramo-
lecular aminopalladation of an intermediate Pd(aryl)-
(
7) For pioneering studies, see: (a) Robinson, R. J. Chem. Soc. Trans.
917, 111, 762. (b) Willst €a tter, R.; Wolfes, O.; Mader, H. Liebigs Ann.
Chem. 1923, 434, 111. (c) Schopf, C.; Lehman, G. Liebigs Ann. Chem. 1935,
18, 1.
8) For radical cyclization approaches, see: (a) Funabashi, K.;
Ratni, H.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123,
0784. (b) Ikeda, M.; Hamada, M.; El Bialy, S. A. A.; Matsui, K.;
Kawakami, S.; Nakano, Y.; Bayomi, S. M. M.; Sato, T. Heterocycles
000, 52, 571.
1
5
1
3,14
(
amido) complex such as 10 (Scheme 3).
The general
(
feasibility of this process was supported by prior studies
in our lab, which illustrated that intramolecular carboa-
minations of substrates such as 11 effectively generated
1
2
1
8
(
9) For approaches involving DielsꢀAlder reactions, see: (a) Constable,
pyrrolidines bearing attached carbocyclic rings (e.g., 13).
K. P.;Blough,B.E.;Carroll, F.I.Chem. Commun. 1996, 717. (b) Grunewald,
G. L.; Sall, D. J.; Monn, J. A. J. Med. Chem. 1988, 31, 433.
This latter transformation is believed to proceed via in-
tramolecular (transannular) insertion of the alkene into
macrocyclic Pd(aryl)(amido) complex 12, which bears a
single phosphine ligand. As such, we elected to examine
catalysts supported by monodentate phosphines in our
initial optimization experiments.
(
10) For [3 þ 2] cycloaddition approaches, see: (a) Xing, S.; Pan, W.;
Liu, C.; Ren, J.; Wang, Z. Angew. Chem., Int. Ed. 2010, 49, 3215. (b) Grigg,
R.; Somasunderam, A.; Sridharan, V.; Keep, A. Synlett 2009, 97. (c) Yeom,
H.-S.; Lee, J.-E.; Shin, S. Angew. Chem., Int. Ed. 2008, 47, 7040. (d) Padwa,
A.; Dean, D. C.; Osterhout, M. H.; Precedo, L.; Semones, M. A. J. Org.
Chem. 1994, 59, 5347.
1
9
(
11) For an approach involving Pd-catalyzed allylic alkylation, see:
Li, Q.; Jiang, X.; Fu, C.; Ma, S. Org. Lett. 2011, 13, 466.
12) For a hydroamination approach, see: Molander, G. A.; Dowdy,
E. D. J. Org. Chem. 1999, 64, 6515.
13) For reviews, see: (a) Wolfe, J. P. Eur. J. Org. Chem. 2007, 571.
b) Wolfe, J. P. Synlett 2008, 2913.
14) (a) Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed. 2004, 43, 3605.
b) Bertrand, M. B.; Neukom, J. D.; Wolfe, J. P. J. Org. Chem. 2008, 73,
(
(17) (a) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35. (b) Janey,
J. M. In Name Reactions for Functional Group Transformations; Li, J. J.,
Ed.; John Wiley & Sons: Hoboken, NJ, 2007; pp 566ꢀ611.
(18) Nakhla, J. S.; Kampf, J. W.; Wolfe, J. P. J. Am. Chem. Soc. 2006,
128, 2893.
(
(
(
(
8
851. (c) Lemen, G. S.; Wolfe, J. P. Org. Lett. 2010, 12, 2322.
15) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010,
10, 3600.
16) Efforts to prepare substrates bearing quaternary stereocenters
(19) Recent mechanistic studies also suggest that alkene aminopalla-
dation occurs most rapidly from palladium complexes bearing one
phosphine ligand. See: (a) Neukom, J. D.; Perch, N. S.; Wolfe, J. P.
Organometallics 2011, 30, 1269. (b) Neukom, J. D.; Perch, N. S.; Wolfe,
J. P. J. Am. Chem. Soc. 2010, 132, 6276. (c) Hanley, P. S.; Markovic, D.;
Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 6302.
(
1
(
adjacent to the amino group were unsuccessful due to the low reactivity
of N-sulfinyl ketimines towards organometallic nucleophiles.
Org. Lett., Vol. 13, No. 11, 2011
2963

With optimized reaction conditions in hand, the scope
and limitations of the intramolecular carboamination
reactions were explored. Overall these transformations
proved to be quite general and afforded various tropane
derivatives in good yields and with no loss of enantiopurity
Scheme 3. Intramolecular Carboamination Mechanism
(Table 2). The presence of a methylenedioxy group on the
aryl bromide was tolerated (entry 3), and the heteroaryl-
fused tropane17was generatedfrom pyridine derivative4d
in good yield. Cyclic alkenyl halides were also viable
a
Table 2. Pd-Catalyzed Synthesis of Tropanes
The optimization of conditions for the tropane-forming
reactions was explored using substrate 4a (Table 1). Our
optimization studies focused on the phosphine ligand
structure, using otherwise standard conditions known to
give satisfactory results in most carboamination reactions
t
(
NaO Bu, toluene, 90ꢀ110 °C). Use of P(o-tol) as the
3
ligand led to incomplete conversion of the starting material
and only afforded small quantities of the desired tropane
product. Improved results were obtained with the bulky
electron-rich DavePhos
failed to reach completion. However, use of the slightly
2
0a
ligand, but the reaction still
2
1
smaller electron-rich ligand PCy3 led to complete con-
sumption of the starting material and provided 14 in 77%
isolated yield (entry 4). Finally, to probe the hypothesis
that the key intermediate bears a single phosphine ligand,
the efficacy of the bidentate ligand dppf was examined. As
postulated, poor conversion of the starting material oc-
curred and only a low yield of 14 was obtained (entry 5).
a
Table 1. Optimization of Reaction Conditions
b
entry
ligand
conversion (%)
yield of 14 (%)
1
2
3
4
5
P(o-tol)
P(p-F-C
DavePhos
3
59
100
76
21
69
40
6
4 3
H )
c
3
PCy •HBF
4
100
35
80 (77)
dppf
11
a
t
Conditions: 1.0 equiv of 4a, 2.0 equiv of NaO Bu, 2 mol %
Pd (dba) , 8 mol % ligand (4 mol % of dppf was used for the experiment
2 3
b
shown in entry 5), toluene (0.1 M), 95 °C, 14 h. Yields were determined
by H NMR analysis of crude reaction mixtures that contained phenan-
1
c
threne as an internal standard. Isolated yield (average of two experiments).
a
t
Conditions: 1 equiv of amine, 1.5 equiv of NaO Bu, 2 mol %
b
Pd
(dba) , 8 mol % PCy
2 3
3
•HBF
4
, toluene (0.1 M), 95 °C, 10 h. Isolated
c
yield (average of two experiments). No racemization of the substrates
occurred during the transformation; the enantiopurities of the starting
materials were within 1% ee of the tropane products as determined
by chiral HPLC analysis. The reaction was conducted at 125 °C using
2
8 mol % of PPh Cy as the ligand.
(20) Ligand definitions: (a) DavePhos = 2-dicyclohexylphosphino-
-(N,N-dimethylamino)-biphenyl. (b) S-Phos = 2-dicyclohexylpho-
sphino-2 ,6 -dimethoxybiphenyl.
21) This ligand was employed as the air-stable tetrafluoroborate
salt, which was obtained from commercial sources.
0
2
d
0
0
(
2
964
Org. Lett., Vol. 13, No. 11, 2011

substrates, as 4eꢀf were efficiently transformed to unsa-
turated tropanes 18ꢀ19 (entries 5 and 6, respectively).
Unfortunately, efforts to transform noncyclic alkenyl
halide substrates into tropane products were unsuccessful,
as alkene isomerization and substrate decomposition oc-
curred more rapidly than tropane formation.
place of the N-phenyl substituent. Initial efforts to employ
N-Boc-protected variants of 4b were unsuccessful and led to
either low conversion or decomposition of the starting
material. As such, an N-PMP group was selected as the
amine substituent, as this aryl protecting group can be
cleaved under oxidizing conditions. The requisite substrate
22 was prepared in three steps and with 37% overall yield
from o-chlorobenzaldehyde using the route described above
The method is also amenable to the generation of
quaternary stereocenters, as seen in the conversion of
25
1
1
,1-disubstituted alkene substrates 4c and 4f to 16 and
9, respectively. The stereospecific conversion of E- and
in Scheme 2. The Pd (dba) /PCy •HBF catalyst was not
2
3
3
4
sufficiently reactive to promote complete conversion of 22
to 23, and a significant amount of unreacted starting
material was recovered. However, we were gratified to find
Z-alkene substrates 4g and 4h proceeded smoothly to
provide disubstituted tropane products 20 and 21. In these
latter transformations, use of the slightly smaller ligand
PPh Cy provided better results thanour standardPd/PCy
20b
that S-Phos, an electron-rich ligand recently shown to be
effective in intermolecular carboamination reactions be-
2
3
26
catalyst system. Styrene-derived substrate 4b smoothly
underwent the intramolecular carboamination reaction
to yield dibenzotropane 15 in good yield.
tween aryl chlorides and N-substituted-γ-amino alkenes,
led to complete substrate conversion. These conditions
provided desired tropane 23 in excellent yield and with no
loss of enantiopurity. Treatment of 23 with CAN in aqueous
acetonitrile at 0 °C led to clean removal of the PMP group
and provided 24 in 74% yield.
Scheme 4. Pd-Catalyzed Synthesis of NMDA Antagonist 24
In conclusion, we have developed a new method for the
synthesis of benzo-fused tropanes via an intramolecular
Pd-catalyzed alkene carboamination reaction. This meth-
od allows for straightforward preparation of N-aryl ben-
zotropanes bearing substituents at C8, C9, or on the fused
arene ring. In addition, N-H tropanes can be accessed
through deprotection of N-PMP derivatives. Further stu-
dies on the application of this method to the construction
of complex tropane alkaloids are currently underway.
Acknowledgment. The authors acknowledge the NIH-
NIGMS for financial support of this work. Additional
funding was provided by GlaxoSmithKline, Amgen, and
Eli Lilly. D.M.S. acknowledges the ACS Division of Or-
ganic Chemistry for a graduate fellowship and the Univer-
sity of Michigan for a Rackham predoctoral fellowship.
To further demonstrate the utility of this method, we
sought to prepare the MK-801 analog 24 (Scheme 4). This
compound has served as a common intermediate en route
to MK-801 and derivatives and also exhibits modest
4
a,22
NMDA antagonist activity.
The synthesis of 24 has
previously been accomplished via base-mediated transan-
nular hydroamination of an amino alkene. This route
afforded (()-24 in three steps from commercially available
Supporting Information Available. Experimental pro-
cedures, characterization data for all new compounds,
descriptions of stereochemical assignments with support-
ing structural data, and copies of H and C NMR
spectra for all new compounds reported in the text. This
material is available free of charge via the Internet at
http://pubs.acs.org.
2
3
material. Although this is an effective approach to the
racemate, an analogous route to enantioenriched samples
1
13
2
4
of 24 has not been developed.
In our synthesis of 24 we sought to effect the carboamina-
tion of a substrate related to diphenylmethylamine deriva-
tive 4b, but with a cleavable group on the nitrogen atom in
(24) Enantiopure samples of 24 have previously been generated via
resolution of the racemate. See ref 4a.
(
Monn, J. A.; Thurkauf, A.; Mattson, M. V.; Jacobson, A. E.; Rice, K. C.
J. Med. Chem. 1990, 33, 1069.
22) (a) Monn, J. A.; Rice, K. C. Tetrahedron Lett. 1989, 30, 911. (b)
(25) Initial efforts to use 2-bromobenzaldehyde for the construction
of the aryl bromide analog of 22 were unsuccessful, as N-arylation of the
primary diarylmethylamine with 4-bromoanisole suffered from a com-
peting intramolecular Heck reaction of the bromoalkene.
(26) Rosen, B. R.; Ney, J. E.; Wolfe, J. P. J. Org. Chem. 2010, 75, 2756.
(23) Lamanec, T. R.; Bender, D. R.; DeMarco, A. M.; Karady, S.;
Reamer, R. A.; Weinstock, L. M. J. Org. Chem. 1988, 53, 1768.
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