Copper-catalyzed anti-stereocontrolled ring-opening of azabicyclic alkenes with Grignard reagents

Article abstract of DOI:10.1021/ol0478133

(Chemical Equation Presented) The anti-stereocontrolled alkylative ring-opening reaction of azabicyclic alkenes is reported. N-(2-Pyridyl)sulfonyl azabenzonorbornadiene reacts with Grignard reagents in the presence of catalytic amounts of CuCN to afford,

Full text of DOI:10.1021/ol0478133

ORGANIC
LETTERS
2
005
Vol. 7, No. 2
19-221
Copper-Catalyzed Anti-Stereocontrolled
Ring-Opening of Azabicyclic Alkenes
with Grignard Reagents
2
Ram o´ n G o´ mez Array a´ s,* Silvia Cabrera, and Juan C. Carretero*
Departamento de Qu ´ı mica Org a´ nica, Facultad de Ciencias, UniVersidad Aut o´ noma de
Madrid, Cantoblanco, 28049 Madrid, Spain
juancarlos.carretero@uam.es; ramon.gomez@uam.es
Received October 25, 2004
ABSTRACT
The anti-stereocontrolled alkylative ring-opening reaction of azabicyclic alkenes is reported. N-(2-Pyridyl)sulfonyl azabenzonorbornadiene reacts
with Grignard reagents in the presence of catalytic amounts of CuCN to afford, in good yields and excellent anti selectivity, the corresponding
dihydronaphthalene-1-amines.
The transition metal-catalyzed ring-opening reaction of
heterobicyclic alkenes with nucleophiles is a powerful
carbon-carbon bond-forming method for the rapid construc-
that all precedents regarding the ring-opening addition of
carbon-based nucleophiles to azabicycles are described to
occur with syn stereoselectivity, resulting from exo attack
on the azabicyclic unit. These examples include the enantio-
selective Pd-catalyzed addition of arylboronic acids and
dimethylzinc to azabenzonorbornadienes, reported by Lautens
1
tion of stereochemically complex carbocyclic compounds.
Pioneering work in this area, including the development of
asymmetric variants, as well as the exploration of its synthetic
potential in natural product synthesis, has been reported by
4
et al., and the Pd- or Ni-catalyzed ring opening of azabenzo-
1
,2
Lautens et al.
In contrast to the widely studied ring-opening of oxa-
norbornadienes with organic halides or terminal acetylenes,
5,6
described by Cheng et al. To the best of our knowledge,
1,3
bridged bicyclic alkenes, there are few reports on stereo-
controlled ring-opening reactions of their azabicyclic
the only precedent of anti-stereocontrolled opening of an aza-
bicyclic alkene is the Rh-catalyzed reaction with nitrogen
2d,3b,4,5
analogues,
although the resulting 1-aminodihydronaph-
2d
nucleophiles. Recently, we have described the anti-stereo-
thalenes are useful scaffolds for the preparation of potentially
bioactive compounds. On the other hand, it must be noted
controlled copper-catalyzed alkylative ring-opening reaction
of benzo- and alkyl-substituted oxabicyclic alkenes using
Grignard reagents as widely available and versatile nucleo-
(
1) For reviews, see: (a) Lautens, M. Synthesis 1993, 177-185. (b) Chiu,
7
,8
P.; Lautens, M. Top. Curr. Chem. 1997, 190, 1-85. (c) Lautens, M.; Fagnou,
philes. Herein, we report the extension of this method to
the ring-opening reaction of the less reactive aza substrates
by means of using the (2-pyridyl)sulfonyl group as the key
K.; Hiebert, S. Acc. Chem. Res. 2003, 36, 48-58.
(2) For natural product synthesis, see: (a) Lautens, M.; Rovis, T. J. Org.
Chem. 1997, 62, 5246-5247. (b) Lautens, M.; Rovis, T. Tetrahedron 1999,
8
967-8976. (c) Lautens, M.; Colucci, J. T.; Hiebert, S.; Smith, N. D.;
Bouchain, G. Org. Lett. 2002, 4, 1879-1882. (d) Lautens, M.; Fagnou, K.;
Zunic, V. Org. Lett. 2002, 4, 3465-3468.
(4) (a) Lautens, M.; Hiebert, S.; Renaud, J.-L. Org. Lett. 2000, 2, 1971-
1973. (b) Lautens, M.; Dockendorff, C. Org. Lett. 2003, 5, 3695-3698.
(5) (a) Duan, J.-P.; Cheng, C.-H. Organometallics 1995, 14, 1608-1618.
(b) Feng, C.-C.; Nandi, M.; Sambaiah, T.; Cheng, C.-H. J. Org. Chem.
1999, 64, 3538-3543. (c) Rayabarapu, D. K.; Chiou, C.-F.; Cheng, C.-H.
Org. Lett. 2002, 4, 1679-1682.
(6) For the asymmetric reductive ring-opening of aza-benzonorborna-
dienes, see: Li, L.-P.; Rayabarapu, D. K.; Nandi, M.; Cheng, C.-H. Org.
Lett. 2003, 5, 1621-1624.
(3) For recent examples, see: (a) Lautens, M.; Hiebert, S. J. Am. Chem.
Soc. 2004, 126, 1437-1447. (b) Cabrera, S.; G o´ mez Array a´ s, R.; Carretero,
J. C. Angew. Chem., Int. Ed. 2004, 43, 3944-3947. (c) Lautens, M.; Fagnou,
K. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5455-5460. (d) Li, M.; Yan,
X.-X.; Hong, W.; Zhu, X.-Z.; Cao, B.-X.; Sun, J.; Hou, X.-L. Org. Lett.
2004, 6, 2833-2835. (e) Leong, P.; Lautens, M. J. Org. Chem. 2004, 69,
2194-2196. (f) Dotta, P.; Kumar, P. G. A.; Pregosin, P. S. Organometallics
2004, 23, 2295-2304.
1
0.1021/ol0478133 CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/24/2004

activating group at the nitrogen atom.9 This protocol
constitutes the first anti-stereocontrolled procedure of alkyl-
ative ring opening of azabicyclic alkenes.
The starting point of our research was to define the
appropriate protecting functionality at nitrogen and to identify
the optimal reaction conditions. To improve the leaving group
ability at nitrogen, we focused our attention on the carbamate
low12 (entries 2 and 3). On the other hand, the highly
electrophilic N-p-nosyl derivative 5 led to a sluggish reaction,
affording mainly decomposition products (entry 5). By far,
the best results were obtained from the (2-pyridyl)sulfonyl
derivative 4 (entry 4). Not only did this substrate show a
remarkable reactivity, but also the reaction occurred with
good anti stereocontrol.
1
and, especially, the sulfonamides 2-5 (Table 1). The
Having established the optimal protecting group for the
azabicyclic system, the effect of several commercially
available copper salts on the ring-opening reaction of 4 with
MeMgBr was surveyed (Table 2). The role of copper in this
Table 1. Screening of Different Activating Groups at Nitrogen
for the Ring-Opening Reaction of Azabenzonorbornadiene
Table 2. Ring Opening of Azabenzonorbornadiene 4 with
Methylmagnesium Bromide Catalyzed by Various Copper Salts
sub-
conversion
(%)a
anti/
product syna
entry
R group
stitution
1
2
3
4
5
Boc
Ts
1
2
3
4
5
0
20
20
85
b
6a
7a
8a
9a
71:29
62:38
90:10
entry
copper salt
conversion (%)a
t (h)
anti/syna
(2-thiophene)sulfonyl
(2-pyridyl)sulfonyl
p-nosyl
1
2
3
4
5
6
0
85
85
17
55
24
24
24
24
24
2
10a
CuCl
CuI
90:10
90:10
98:2
97:3
98:2
a
1
Determined by H NMR analysis of the crude reaction mixture (the
b
Cu(OTf)2
remaining product is starting material). Only decomposition products,
together with starting material, were detected.
b
CuTC
CuCN
100
a
1
b
Determined by H NMR analysis of the crude reaction mixture. CuTC
known sulfonamides 2 and 5 were synthesized by straight-
) copper thiophene-2-carboxylate (ref 13).
3
forward deprotection of carbamate 1 (TMSI/Et N), followed
2
d
by treatment with the corresponding sulfonyl chloride. On
the other hand, the heteroaryl sulfonamides 3 and 4 were
readily prepared in good yields by direct Diels-Alder
cycloaddition between benzyne, generated in situ from
anthranilic acid and isoamyl nitrite, and the corresponding
N-pyrrole derivative.
transformation seems to be essential since no reaction took
place in the absence of copper salt (entry 1). Additionally,
7
unlike the case of oxabicyclic alkenes, no other additive
1
4
was needed for this reaction. While most of the copper
sources evaluated led to incomplete reaction after prolonged
reaction time (24 h, entries 2-5), CuCN (entry 6) produced
a dramatic acceleration effect in the reactivity, the reaction
reaching completion in just 2 h, affording 9a in 90% yield
with virtually complete anti stereoselectivity.
As shown in Table 1, the outcome of the ring-opening
10
2 2
reaction of 1-5 with MeMgBr (CH Cl , rt) in the presence
of 10 mol % CuCl11 proved to be quite dependent on the
nature of the substitution at nitrogen. Thus, while no reaction
was observed in the case of the N-Boc carbamate 1 after 24
h, the starting material being recovered unaltered (entry 1),
the sulfonamides 2 and 3 provided the ring-opened products,
albeit both the reactivity and the stereoselectivity were very
The generality of the process was next investigated. Table
3
shows the results of the addition of a variety of Grignard
reagents to azabenzonorbornadiene 4 in the presence of
CuCN (10 mol %) in CH Cl at room temperature. Both alkyl
2
2
and aryl Grignard reagents were able to undergo ring-opening
addition, providing the corresponding 1-aminodihydronaph-
thalenes in good to excellent chemical yields and very high
(
7) G o´ mez Array a´ s, R.; Cabrera, S.; Carretero, J. C. Org. Lett. 2003, 5,
333-1336.
8) For other anti-stereoselective alkylative ring-opening reactions of
1
(
oxabicyclic alkenes, see: (a) Bertozzi, F.; Pineschi, M.; Macchia, F.; Arnold,
L. A.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2002, 4, 2703-2705. See
also: (b) Lautens, M.; Fagnou, K. J. Am. Chem. Soc. 2001, 123, 7170-
(12) Anti stereochemistry of the ring-opened products 6-9 was initially
assigned by 1H NMR, the signal of the olefinic proton at C-3 being of
great diagnostic value. For compounds with syn relative configuration, such
a proton appears 0.1-0.2 ppm more shielded compared to that of the anti
adducts. In addition, the coupling constant of H-3 with H-2 for anti products
is significantly higher (about 6.0 Hz) than that for syn compounds (roughly
3.0 Hz). The same tendency has also been observed in the coupling constants
of syn and anti ring-opened products from oxabicyclic alkenes (see refs 7
and 8a).
7
8
171. (c) Lautens, M.; Schmid, G. A.; Chau, A. J. Org. Chem. 2002, 67,
043-8053.
(9) For other successful applications of (2-pyridyl)sulfonyl group in
transition metal-catalyzed reactions, see: (a) Maule o´ n, P.; Carretero, J. C.
Org. Lett. 2004, 6, 3195-3198. (b) Han, H.; Bae, I.; Yoo, E. J.; Lee, J.;
Do, Y.; Chang, S. Org. Lett. 2004, 6, 4109-4112.
(10) 1,2-Dichloroethane (DCE) provided similar results, while decreased
solubility of compound 4 was found in toluene. More coordinating solvents
such as Et2O, THF, or DME proved to be much less efficient.
(13) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748-
2749.
(
11) CuCl was found to be the optimal copper catalyst in the case of
(14) Addition of Ph3P and other commonly used ligands for copper such
as BINAP or dimethyl ethylenediamine resulted in inhibition of the reaction.
oxabicyclic alkenes (see ref 7).
220
Org. Lett., Vol. 7, No. 2, 2005

Table 3. Cu-Catalyzed Ring Opening of
Azabenzonorbornadiene 4 with Grignard Reagents
Scheme 1. Deprotection of (2-Pyridyl)sulfonyl Group:
Synthesis of 2-Substituted 1,2-Dihydro- and
1,2,3,4-Tetrahydronaphthalene-1-amines
t
anti/
syna
entry
X
R
product (min)
yieldb
1
2
3
Br Me
Br TMSCH2
Cl Et
Cl PhCH2
Cl decyl
9a
9b
9c
9d
9e
9f
9g
9h
9i
120
95
98:2
93:7
89
73
c
20 >98:<2 65
20 >98:<2 53
20
4
c
hydronaphthalene 12 (a precursor in the synthesis of an
5
6
7
8
9
0
1
2
3
85:15
74
16
Br Ph
Cl tol
15 >98:<2 93
10 >98:<2 91
10 >98:<2 98
20 >98:<2 92
15 >98:<2 97
30 >98:<2 91
480 >98:<2 87
120 >98:<2 88
inhibitor of acyl CoA-cholesterol acyltransferase) by amine
deprotection and further alkene hydrogenation. This chemical
correlation led us to establish unambiguously the relative
anti configuration of the ring-opened products 9.
Cl (p-MeO)C6H4
Cl (p-F)C6H4
Br 3,5-[bis(CF3)]C6H4
Br 1-naphthyl
Br mesityl
Br 2-thienyl
1
1
1
1
9j
9k
9l
The high reactivity, coupled with the good anti stereo-
control featured by this catalytic system, suggests that the
(2-pyridyl)sulfonyl group could exert its influence on the
reactivity in the ring-opening reaction via an electron-
withdrawing inductive effect or/and through a coordination
d
e
9m
a
1
b
Determined by H NMR analysis of the crude reaction mixture. Yield
c
(
%) of anti adduct after chromatography. CuCl was used instead of CuCN.
Yield of converted product (30% of starting material was recovered).
Yield of converted product (25% of starting material was recovered).
d
17
effect. Investigation to gain insight into the mechanism of
e
this process is currently under way.
In conclusion, the combination of a (2-pyridyl)sulfonyl
moiety as an activating group at nitrogen, CuCN as a copper
catalyst, and Grignard reagents as nucleophiles results in a
novel and efficient anti-stereocontrolled copper-catalyzed
protocol for the ring-opening reaction of azabicyclic alkenes.
Each of these three elements proved to be essential for
achieving good yields and excellent regio- and stereocontrol
under mild reaction conditions. In addition, the process is
wide in scope, tolerating both aliphatic and aromatic Grignard
reagents. The enantioselective version of this method and
extension of this reaction to other types of substrates, such
as aziridines, is currently under investigation in our labs.
1
2
anti selectivity. Alkyl Grignard reagents with â-hydrogens
provided better results in the presence of CuCl rather than
CuCN (entries 3 and 5). Remarkably, aromatic reagents
displayed very high reactivity, regardless of their electronic
nature, affording ring-opened products with complete anti
stereocontrol (entries 6-12). It is also interesting to note
that the presence of ortho or meta substituents on the
aromatic ring does not have a detrimental effect on the
reactivity (entries 10 and 11), except for the very sterically
hindered ortho-disubstituted mesitylmagnesium bromide,
which led to incomplete reaction after 8 h (entry 12).
Although less reactive, heteroaryl Grignard reagents such
as 2-thienylmagnesium bromide also promoted the ring-
opening reaction, affording product 9j with good yield and
complete anti stereoselectivity (entry 13).
Acknowledgment. Financial support of this work by the
Ministerio de Ecucaci o´ n y Ciencia (Project BQU2003-0508)
is gratefully acknowledged. Dr. R.G.A. thanks the Ministerio
de Educaci o´ n y Ciencia for a Ram o´ n y Cajal contract. S.C.
thanks the Universidad Aut o´ noma de Madrid for a predoc-
toral fellowship.
To realize the full synthetic potential of this ring-opening
protocol in stereoselective amine synthesis, the deprotection
of the (2-pyridyl)sulfonamide group of products anti-9 was
readily achieved by treatment with magnesium under very
mild reaction conditions (MeOH/THF, 0 °C).15 Desulfonyl-
ation proceeded smoothly to afford cleanly the corresponding
primary amine within 2 h. Thus, compound anti-9f was easily
transformed into its Boc-derivative anti-6f in 83% overall
yield upon deprotection with Mg and subsequent treatment
of the free amine with di-tert-butyl carbonate at room
temperature (Scheme 1). It should be noted that the diastereo-
Supporting Information Available: Complete descrip-
tion of experimental procedures and characterization data for
all new compounds and copies of proton and carbon NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0478133
(15) Pak, C. S.; Lim, D. S. Synth. Commun. 2001, 2209-2214.
(16) Vaccaro, W.; Amore, C.; Berger, J.; Burrier, R.; Clader, J.; Davis,
H.; Domalski, M.; Fevig, T.; Salisbury, B.; Sher, R. J. Med. Chem. 1996,
4b
meric product syn-6f had been previously described, which
3
9, 1704-1719.
1
2
confirmed the anti relative setereochemistry of anti-6f. In
the same pursuit, compound anti-9h was converted into the
known anti-1-amino-2-[(p-methoxy)phenyl]-1,2,3,4-tetra-
(17) For Cu-catalyzed allylic substitution with Grignard reagents using
coordinating leaving groups, see: (a) Breit, B.; Demel, P.; Studte, C. Angew.
Chem., Int. Ed. 2004, 43, 3786-3789. (b) Breit, B.; Herber, C. Angew.
Chem., Int. Ed. 2004, 43, 3790-3792.
Org. Lett., Vol. 7, No. 2, 2005
221