Synthesis of N-heteroaryl-7-azabicyclo[2.2.1]heptane derivatives via palladium-bisimidazol-2-ylidene complex catalyzed amination reactions

Article abstract of DOI:10.1021/ol015746w

(equation presented) A one-step approach to novel N-heteroaryl-substituted-7-azabicyclo[2.2.1]heptanes from readily available heteroaryl halides and 7-azabicyclo-[2.2.1]heptane has been achieved. The cross-coupling amination reaction employs palladium-bis

Full text of DOI:10.1021/ol015746w

ORGANIC
LETTERS
2001
Vol. 3, No. 9
1371-1374
Synthesis of
N-Heteroaryl-7-azabicyclo[2.2.1]heptane
Derivatives via
Palladium−Bisimidazol-2-ylidene
Complex Catalyzed Amination Reactions
Jie Cheng and Mark L. Trudell*
Department of Chemistry, UniVersity of New Orleans, New Orleans, Louisiana 70148
mtrudell@uno.edu
Received February 21, 2001
ABSTRACT
A one-step approach to novel N-heteroaryl-substituted-7-azabicyclo[2.2.1]heptanes from readily available heteroaryl halides and 7-azabicyclo-
[2.2.1]heptane has been achieved. The cross-coupling amination reaction employs palladium−bisimidazol-2-ylidene complexes as catalysts to
give good to moderate yields over a wide variety of substrates.
Recently developed palladium- or nickel-catalyzed amination
of aryl halides and triflates has opened great opportunities
in many areas of organic synthesis.1 General, reliable, and
practical N-arylations of a wide variety of amines and anilines
with both electron-rich and electron-deficient aryl halides
have been achieved.2-6 These pioneering studies have shown
that a well-tailored metal-ligand catalyst system is crucial
for successful aryl C-N bond formation.7
The nucleophilic N-heterocyclic carbenes have attracted
considerable attention as ligands for a variety of palladium-
catalyzed coupling reactions.4,8 We recently reported on the
utility of the Pd2(dba)3-Imes‚HCl and Pd(OAc)2-DiImes‚
HCl catalyst systems for Suzuki-type C-C bond formation
reactions of aryl chlorides and arylboronic acids.9,10 As part
of a drug discovery program aimed at the synthesis of
N-heteroaryl-substituted 7-azabicyclo[2.2.1]heptanes, we sought
to investigate the Pd-DiImes‚HCl catalyst system in cross-
coupling amination reactions of heteroaryl halides with
7-azabicyclo[2.2.1]heptane.
(1) For a recent review of metal-catalyzed amination reactions, see: (a)
Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125-146.
(b) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046-2067.
(2) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.;
Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575-5580.
(3) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J.
Org. Chem. 2000, 65, 1158-1174.
(4) Huang, J.; Grasa, G.; Nolan, S. P. Org. Lett. 1999, 1, 1307-1309.
(5) Bei, X.; Guram, A. S.; Turner, H. W.; Weinberg, W. H. Tetrahedron
Lett. 1999, 40, 1237-1240.
(6) Desmarets, C.; Schneider, R.; Fort, Y. Tetrahedron Lett. 2000, 41,
2875-2879.
(7) For recent examples of catalytic aryl amination, see: (a) Old, D.
W.; Harris, M. C.; Buchwald, S. L. Org. Lett. 2000, 2, 1403-1406. (b)
Harris, M. C.; Buchwald, S. L. J.Org. Chem. 2000, 65, 5327-5333. (c)
Bei, X.; Uno, T.; Norris, J.; Turner, H. W.; Weinberg, W. H.; Guram, A.
S.; Petersen, J. L. Organometallics 1999, 18, 1840-1853. (d) Hamann, B.
C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369-7370.
Prior to development of the amination methodology, it was
necessary to develop an efficient and practical route for the
preparation of 7-azabicyclo[2.2.1]heptane hydrochloride (1).11
To date, the most practical synthesis of 1 was reported by
(8) (a) Regitz, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 725-728. (b)
Hermann, W. A.; Kocher, C. Angew. Chem., Int. Ed. Engl. 1997, 36, 2163-
2187.
(9) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem.
1999, 64, 3804-3805.
(10) Zhang, C.; Trudell, M. L. Tetrahedron Lett. 2000, 41, 595-598.
(11) For a recent review on 7-azabicyclo[2.2.1]heptanes, see: Chen. Z.;
Trudell, M. L. Chem. ReV. 1996, 96, 1179-1193.
10.1021/ol015746w CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/07/2001

Fraser and Swingle.12 Their five-step sequence furnished 1
with an overall yield of 18-36%. Alternatively, Nelsen et
al. demonstrated that trans-4-aminocyclohexanol could be
directly converted into 1 (26%) when diethoxytriphenylphos-
phorane was employed as a cyclodehydrating reagent.13
However, the utility of this approach was limited due to the
formation of 7-ethyl-7-azabicyclo[2.2.1]heptane (18% yield)
as a side product which required additional steps to separate
it from 1.
attempted with HBr/HOAc. However, this method was less
effective. As previously reported, due to the volatile nature
of 1, the 7-azabicyclo[2.2.1]heptane was routinely isolated
as the hydrochloride salt.12 This short and practical synthetic
sequence afforded 7-azabicyclo[2.2.1]heptane (1) in 53%
overall yield.
The catalytic cross-coupling reaction of 7-azabicyclo-
[2.2.1]heptane (1) and 2-bromopyridine in dioxane at 100-
110 °C which furnished 7-(2-pyridinyl)-7-azabiyclo[2.2.1]-
heptane (4) was selected as a model reaction for investigation
of the efficiencies of different Pd-ligand catalyst systems
(Table 1). As summarized in Table 1, the PPh3, DPPB, DPPP,
As illustrated in Scheme 1, a three-step synthesis of 1 from
commercially available trans-4-aminocyclohexanol hydro-
Scheme 1a
Table 1. Influence of the Pd/Ligand Catalyst System on the
Cross-Coupling Amination of 1 with 2-Bromopyridine
a Reagents and conditions: (a) TsCl, KOH, Et3N (catalytic),
CH3CN; (b) PPh3, DEAD, THF, 25 °C; (c) NaNp, DME, -35 to
25 °C.
chloride was achieved by treatment of trans-4-aminocyclo-
hexanol hydrochloride with tosyl chloride in the presence
of potassium hydroxide with a catalytic amount of triethyl-
amine in acetonitrile. This afforded the desired tosylamide
2 in nearly quantiative yield.14 The tosylamide 2 was then
subjected to Mitsunobu reaction conditions employing PPh3
(2.5 equiv) and DEAD (2.5 equiv) in THF at room temper-
ature.15 This effected the ring closure and generated the
7-azabicyclo[2.2.1]heptane 3 in 80% yield. It was determined
that excess PPh3 and DEAD were necessary to achieve high
yields of 3. For example, 1.2 equiv of PPh3 and DEAD gave
only a 66% yield of 3. In addition, other N-acyl groups (e.g.,
BOC, CBZ) proved to be less effective for ring closure under
these reaction conditions. This direct cyclization was a
significant improvement over existing methods which re-
quired additional protection and deprotection steps prior to
ring closure.12 In addition, the intramolecular cyclization
reaction does not appear to be limited by the reaction scale.
High yields have been obtained on either a milligram or
multigram scale.
entrya
Pd-ligand
time (h)
yield (%)b
1
2
3
4
5
6
7
Pd(OAc)2-PPh3
Pd(OAc)2-DPPP
Pd(OAc)2-DPPB
Pd2(dba)3-P(o-Tol)3
Pd2(dba)3-DPPFd
Pd2(dba)3-DiImes•HCl (5)
Pd2(dba)3-DiIpr•HCl (6)
42
40
40
36
36
36e
36e
37c
25c
11c
51
66
61
67
a Typical reaction conditions: 4 mol % of Pd, 4 mol % of ligand, 2.8
mmol of NaOtBu, 1 mmol of 2-bromopyridine, 1.2 mmol of 1, 5 mL of
dioxane, 100-110 °C. b Isolated yields. c 2-Bromopyridine was not com-
pletely consumed and Pd black was observed. d Pd/ligand ratio was 1:1.5.
e Reaction time after a 30 min catalyst activation period.
The N-tosyl group of 3 was removed with freshly prepared
sodium naphthalide in THF to furnish the desired 7-azabicyclo-
[2.2.1]heptane (1).16 Removal of the tosyl group was also
and P(o-tol)3 ligands exhibited low conversion and were
found to be less efficient than the two bisimidazolium salt
catalyst precursors, mesityl bisimidazolium salt 5 (DiImes‚
HCl, entry 6) and the 2,4,6-triisopropylphenyl bisimidazol-
ium salt 6 (DiIpr‚HCl, entry 7).17,18 Comparing the two
(12) Fraser, R. R.; Swingle, R. B. Can. J. Chem. 1970, 48, 2065-2074.
(13) Nelsen, S. F.; Ippoliti, J. T.; Frigo, T. B.; Petillo, P. A. J. Am. Chem.
Soc. 1989, 111, 1776-1781.
(14) Yoshida, Y.; Sakakura, Y.; Aso, N.; Okada, S.; Tanabe, Y.
Tetrahedron 1999, 55, 2183-22192.
(16) (a) Palmgren, A.; Larsson, A. L. E.; Ba¨ckvall, J. E.; Helquist, P. J.
Org. Chem. 1999, 64, 836-847. (b) Heathcock, C. H.; Blumenkopf, T. A.;
Smith, K. M. J. Org. Chem. 1989, 54, 1548-1562.
(15) Hughes, D. L. Org. React. 1992, 42, 335-656.
1372
Org. Lett., Vol. 3, No. 9, 2001

bisimidazolium salts, the catalyst precursor 6 gave a slightly
higher yield (entry 7) than 5 (entry 6). The higher perfor-
mance of the bisimidazolium salt 6 is thought to be due to
its better electron-donating ability and more steric hindrance.
Only the DPPF ligand gave a yield similar (entry 5) to that
of the bisimidazolium salt 6. However, this required a higher
Pd-ligand ratio (1:1.5) to furnish the optimized yield (66%).
In addition, when the amination reactions were attempted
with the Pd-bisimidazolium salt system, only tert-butyl aryl
ethers were isolated and no amination products were
observed.
71% yields, respectively. 4-Bromopyridine hydrochloride
also underwent the amination reaction and furnished 7b in
58% yield (4.2 equiv of NaOtBu employed). Conversely,
introduction of a methoxy group as electron donor on the
pyridine ring resulted in an incomplete reaction even after
long reaction times (41 h), and the yield of 7c was low (36%).
The quinoline and isoquinoline heterocyclic systems gave
results similar to those of the pyridine analogues and afforded
7e and 7f in good yields. However, longer reaction times
were needed to complete the cross-coupling reaction of
quinoline and isoquinoline heterocyclics relative to the
formation of 4. As a comparison, the tolyl bromide provided
7h in 66% yield.
The successful amination of 1 then prompted a further
investigation of the scope and limitations of the Pd2(dba)3-
bisimidazolium salt 6 catalyst system for general cross-
coupling amination reactions. As summarized in Table 2, a
As expected, the 2-chloro-5-iodopyridine gave a predomi-
nant coupling product at the 2-position (7d). However, a
small amount of 7-(2-chloro-5-pyridinyl)-7-azabicyclo-
[2.2.1]heptane (8) was isolated (5% yield) that resulted
from amination at the 5-iodo substituent. The regioselectivity
of this reaction is noteworthy since it has been shown that
the reaction of the polyfunctionalized heteroaromatic core
in the cross-coupling reaction gave a regioisomeric
mixture.19
Table 2. Pd-Bisimidazol-2-ylidene (6) Complex Catalyzed
Cross-Coupling Reactions of Aryl Halides and 1
In summary, application of the Pd-bisimidazolium salt
catalyzed cross-coupling amination methodology provides
a general and convenient route for the construction a wide
range of N-aryl-substituted-7-azabicyclo[2.2.1]heptane de-
rivatives. The synthetic utility of this catalyst system appears
to be broad and useful for the construction of N-arylamine
systems. The biological results and structure-activity rela-
tionships of the N-aryl-substituted-7-azabicyclo[2.2.1]heptane
(17) For recent examples of catalytic amination with modified phosphine
ligands, see: (a) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65,
1144-1157. (b) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35-37.
(c) Singer, R. A.; Buchwald, S. L.; Tetrahedron Lett. 1999, 40, 1095-
1098. (d) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38,
2413-2416. (e) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998,
120, 7369-7370. (f) Singer, R. A.; Sadighi, J. P.; Buchwald, S. L. J. Am.
Chem. Soc. 1998, 120, 213-214. (g) Old, D. W.; Wolfe, J. P.; Buchwald,
S. L. J. Am. Chem. Soc. 1998, 120, 9722-9723. (h) Wagaw, S.; Rennels,
R. A.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 8451-8458. (i) Louie,
J.; Hartwig, J. F.; Fry, A. J J. Am. Chem. Soc. 1997, 119, 11695-11696.
(j) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1997, 62, 6066-6068. (k)
Wolfe, J. P.; Buchwald, S. L. Tetrahedron Lett. 1997, 36, 6359-6362. (l)
Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 6054-6058.
(m) Marcoux, J.; Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1997, 62,
1568-1569.
a All products were characterized by NMR, IR, MS, and C, H, N analysis.
b Reaction time after a 30 min catalyst activation period. c Isolated yields.
d Pd(OAc)2 was used as the Pd source. e 4-Bromopyridine•HCl was
employed with 4.2 equiv of NaOtBu. f Yield based on recovered starting
material. g 7-(2-Chloro-5-pyridinyl)-7-azabicyclo[2.2.1]heptane (8) was also
isolated in 5% yield.
(18) The bisimidazolium salt 6 was made in a fashion similar to that of
the bisimidzolium salt 5 (ref 9). A mixture of 1,3-di(R-chloromethyl)-2,4,6-
trimethylbenzene (1.0 mmol) and N-(2,4,6-triisopropylphenyl)imidazole (2.0
mmol) was heated in xylene at 120 °C for 48 h and furnished 6 in 76%
yield.
(19) (a) Hama, Y.; Nobuhara, Y.; Aso, Y.; Otsubo, T.; Ogura, F. Bull.
Chem. Soc. Jpn. 1988, 61, 1683-1686. (b) Friesen, R. W.; Brideau, C.;
Chan, C. C.; Charleson, S.; Descheˆnes, D.; Dube´, D.; Ethier, D.; Fortin,
R.; Gauthier, J. Y.; Girard, Y.; Gordon, R.; Greig, G. M.; Riendeau, D.;
Savoie, C.; Wang, Z.; Wong, E.; Visco, D.; Xu, L. J.; Young, R. N. Bioorg.
Med. Chem. Lett. 1998, 8, 2777-2782.
number of structurally and electronically diverse aryl halides
were employed. Under the reaction conditions, 2- and
3-bromopyridines gave the corresponding N-pyridinyl-7-
azabicyclo[2.2.1]heptane derivatives (4 and 7a) in 67% and
Org. Lett., Vol. 3, No. 9, 2001
1373

derivatives are under further investigation and will be
reported in due course.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for the products. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We are grateful to the National
Institute on Drug Abuse for the financial support of this
research.
OL015746W
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Org. Lett., Vol. 3, No. 9, 2001