Synthesis of 5,6,7,8-tetrahydro-1,6-naphthyridines and related heterocycles by cobalt-catalyzed [2 + 2 + 2] cyclizations

Article abstract of DOI:10.1021/ol0625280

Microwave-promoted, cobalt-catalyzed intramolecular [2 + 2 + 2] cyclizations of dialkynylnitriles successfully gave 5,6,7,8-tetrahydro-1, 6naphthyridines. The efficient synthesis of these relatively simple, yet rarely addressed heterocycles enabled the pr

Full text of DOI:10.1021/ol0625280

ORGANIC
LETTERS
2007
Vol. 9, No. 3
393-396
Synthesis of
5,6,7,8-Tetrahydro-1,6-naphthyridines
and Related Heterocycles by
Cobalt-Catalyzed [2
Cyclizations
+ 2 + 2]
Ya Zhou, John A. Porco, Jr., and John K. Snyder*
Department of Chemistry and the Center for Methodology and Library DeVelopment,
Boston UniVersity, Boston, Massachusetts 02215
jsnyder@chem.bu.edu
Received October 13, 2006
ABSTRACT
Microwave-promoted, cobalt-catalyzed intramolecular [2
+ 2 + 2] cyclizations of dialkynylnitriles successfully gave 5,6,7,8-tetrahydro-1,6-
naphthyridines. The efficient synthesis of these relatively simple, yet rarely addressed heterocycles enabled the preparation of a collection of
these compounds.
We recently reported the preparation of 1,2,3,4-tetrahydro-
1,5-naphthyridines 1a and pyrido[3,2-b]azepines 1b using
inverse electron demand Diels-Alder methodology.1 As
small, nitrogen-containing heterocycles, readily prepared with
various substituents, these heterocycles are attractive as
library core structures for diversification.2 To systematically
vary the structure, it was of interest to locate the ring
nitrogens in alternative positions. Thus, the analogous 5,6,7,8-
tetrahydro-1,6- (2), -1,7- (3), and -1,8-naphthyridines (4)
became targets, as did 1,2,3,4-tetrahydro-1,6- (5), -2,6- (6),
-2,7- (7), and -1,7-naphthyridines (8) (Figure 1). To gain
additional diversity, a second goal was to devise a procedure
that would allow easy variation of the size of the saturated
ring as accomplished with 1a and 1b.
Alder chemistry used to prepare 1a and 1b, so a different
approach was pursued. Transition metal-catalyzed [2 + 2 +
2] cyclizations have proven reliable for benzannulation since
Vollhardt,3 Bonneman,4 and Yamazaki5 reported the now
well-known cobalt(I)-catalyzed process in the 1970s.6 Mary-
anoff,7 Heller,8 and others9 have also shown that cobalt-
catalyzed [2 + 2 + 2] cyclizations of two alkynes and a
nitrile can produce pyridine rings in good yields, and cobalt-
catalyzed [2 + 2 + 2] chemistry is now prominent in organic
These additional naphthyridine targets (2-8) are not
readily accessible from the inverse electron demand Diels-
(1) (a) Lahue, B. R.; Lo, S. M.; Wan, J. K.; Woo, G. H. C.; Snyder, J.
K. J. Org. Chem. 2004, 69, 7171. (b) Woo, G. H. C. Ph.D. Dissertation,
Boston University, 2004.
(2) (a) Bemis, G. W.; Murcko, M. A. J. Med. Chem. 1996, 39, 2887. (b)
van de Waterbeemd, H.; Smith, D. A.; Beaumont, K.; Walker, D. K. J.
Med. Chem. 2001, 44, 1313.
Figure 1. Tetrahydronaphthyridine isomers.
10.1021/ol0625280 CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/03/2007

Table 1. Cobalt-Catalyzed Intermolecular [2 + 2 + 2] Cyclizations with Microwave Promotion
entry
aminonitrile
n
m
R1
R2
R3
catalysta
yields of 11b-d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
9a
9a
9a
9a
9a
9b
9b
9b
9c
9d
9a
9a
9a
9a
9a
9b
9a
9a
9a
9a
9a
1
1
1
1
1
1
1
1
1
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
1
1
1
1
1
1
1
1
1
1
1
1
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
CH2OH
CO2Me
CO2Me
Ph
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CpCo(CO)2
CpCo(COD)
InCo(COD)
11a, 69%
11a, 67%
11a, 67%
11a, 60%e
11a, 33%f
11b, 36%f
11b, 22%g
11b, 68%
11e, 53%
11f, 47%
11c, 43%
11d, 36%
no rxn
e
CpCo(CO)2
CpCo(CO)2
CpCo(CO)2
CpCo(CO)2
f
H
f
Me
Me
Me
H
H
H
H
H
H
H
Me
H
H
H
H
g
CpCo(CO)2
CpCo(CO)2
CpCo(CO)2
CpCo(COD)
CpCo(CO)2
CpCo(CO)2
CpCo(COD)
CpCo(CO)2
CpCo(CO)2
CpCo(CO)2
CpCo(CO)2
CpCo(CO)2
CpCo(CO)2
CpCo(CO)2
Ph
Ph
Et
CH2OH
CO2Me
CO2Me
COMe
TMS
TMS
Ph
TMS
TMS
Ph
no rxn
no rxn
no rxn
no rxn
H
Ph
Me
Me
no rxn
11g, (11h),h 32%
11i,h 21%
11j, 44%
H
a Catalyst load 20 mol % unless otherwise noted. b Isolated yields. c All the reactions were run under microwave irradiation, 300 W, 15 min, 150 °C
internal temperature, chlorobenzene as solvent unless otherwise noted. d See Figure 2 for product structures. e Catalyst load 10 mol %. f Reactions in refluxing
toluene, 12 h. g Reaction in toluene with hν activation, 6 h. h Minor regioisomers could be detected in trace amounts, and isolated only for 11h.
synthesis.10 Thus, it became apparent that [2 + 2 + 2]
pathways might prove to be a highly versatile strategy for
preparing naphthyridines 2-8 along with ring size variants
for added diversity (Scheme 1). Variation of “n” or “m”,
2] strategy for the preparation of tetrahydro-1,6-naph-
thyridines 2.
Intermolecular cyclization of propargylaminonitrile 9a,
easily prepared by conjugate addition of propargylamine to
acrylonitrile, with various alkynes was initially examined
(Scheme 2). The reaction was probed with numerous
Scheme 1
Scheme 2
while keeping “(n + m)” constant, would locate the nitrogen
at different positions in the A-ring, while the nitrogen
location in the pyridine ring would be varied by using
alkynylnitriles 9 and dialkynylamines 10. Expansion of the
A-ring would also be routine by increasing (n + m). We
now report the successful implementation of this [2 + 2 +
catalysts under a variety of conditions; best results were
obtained with 20 mol % CpCo(CO)2,7b CpCo(COD),11 or
InCo(COD)12 under microwave promotion (Table 1).
(8) (a) Heller, B.; Sundermann, B.; Fischer, C.; You, J. S.; Chen, W.
Q.; Drexler, H. J.; Knochel, P.; Bonrath, B.; Gutnov, A. J. Org. Chem.
2003, 68, 9221. (b) Gutnov, A.; Heller, B.; Fischer, C.; Drexler, H.-J.;
Spannenberg, A.; Sundermann, B.; Sundermann, C. Angew. Chem., Int. Ed.
2004, 43, 3795. (c) Gutnov, A.; Abaev, V.; Redkin, D.; Fischer, C.; Bonrath,
W.; Heller, B. Synlett 2005, 7, 1188.
(3) Vollhardt, K. P. C. Acc. Chem. Res. 1977, 10, 1.
(4) (a) Bo¨nnemann, H.; Brinkmann, R. Synthesis 1975, 9, 600. (b)
Bo¨nnemann, H. Angew. Chem., Int. Ed. Engl. 1978, 17, 505.
(5) Wakatsuki, Y.; Yamazaki, H. J. Chem. Soc., Chem. Commun. 1973,
280.
(6) For reviews: (a) Vollhardt, K. P. C. Angew. Chem., Int. Ed. 1984,
23, 539. (b) Varela, J. A.; Saa, C. Chem. ReV. 2003, 103, 3787. (c) Kotha,
S.; Brahmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741. (d) Candon,
V.; Aubert, C.; Malacria, M. J. Chem. Soc., Chem. Commun. 2006, 2209.
(7) (a) Moretto, A. F.; Zhang, H. C.; Maryanoff, B. E. J. Am. Chem.
Soc. 2002, 124, 6792. (b) Bon˜aga, L. V. R.; Zhang, H. Z.; Moretto, A. F.;
Ye, H.; Gauthier, D. A.; Li, J.; Leo, G. C.; Maryanoff, B. E. J. Am. Chem.
Soc. 2005, 127, 3473.
(9) (a) Varela, J. A.; Castedo, L.; Saa, C. J. Org. Chem. 1997, 62, 4189.
(b) Fatland, A. W.; Eaton, B. E. Org. Lett. 2000, 2, 3131.
(10) Examples: (a) Chouraqui, G.; Petit, M.; Aubert, C.; Malacria, M.
Org. Lett. 2004, 6, 1519. (b) Hoshi, T.; Katano, M.; Nozwawa, E.; Suzuki,
T.; Hagikawa, H. Tetrahedron Lett. 2004, 45, 3489. (c) Petit, M.; Aubert,
C.; Malacria, M. Org. Lett. 2004, 6, 3937. (d) Groth, U.; Richter, N.;
Kalogerakis, A. Synlett 2006, 905. (e) Chouraqui, G.; Petit, M.; Phansavath,
P.; Aubert, C.; Malacria, M. Eur. J. Org. Chem. 2006, 1413.
394
Org. Lett., Vol. 9, No. 3, 2007

Table 2. Synthesis of the 5-, 6-, 7-Membered 1,2,3,4-Tetrahydronaphthyridines by Intramolecular Pathway (Scheme 5)
a Isolated yields. b All reactions were run under microwave irradiation, 300 W, 15 min, 180 °C internal temperature, chlorobenzene as solvent. c See
Figure 2 for product structures. d 21k is not isolable. e The crude mixture of 21k was used for the [2 + 2 + 2] cyclization without further purification.
All three catalysts gave comparable yields in the reactions
of 9a with diphenylacetylene (67-69%, entries 1-3). The
use of CpCo(CO)2 was preferred, being more user-friendly
and stable to benchtop reaction conditions and storage, while
CpCo(COD) and InCo(COD) required a drybox environment.
Reduction of the catalyst load to 10 mol % resulted in a
slight drop in yield over the same reaction time period (60%,
entry 4). Thermal (33-36%, refluxing toluene) or photo-
chemical (22%) promotion of the cyclizations of 9a (and
9b) with diphenylacetylene using CpCo(CO)2 gave lower
yields (entries 5-7). Other intermolecular cyclizations pro-
ceeded in moderate yields, notably those with a phenyl ring
attached to the alkynes (entries 8-12). Secondary and tertiary
amines were tolerated (R1 ) H, Me), though alkynes with
carbonyl substituents (entries 13-15) and terminal alkynes
(entries 16-18) did not react. 5-Membered (entry 9, 53%)
and 7-membered (entry 10, 47%) annulated pyridines could
also be synthesized from aminonitriles with appropriately
lengthed tethers between the nitrile and alkyne groups,
though these cyclizations proceeded in lower yields than
those leading to the 6-membered annulated pyridines (com-
pare entries 1, 9, and 10). Cyclizations with unsymmetrical
alkynes gave only poor to modest yields (entries 19-21),
though with excellent regioselectivities; NOE studies on the
products showed the bulkier alkyne substituent preferred to
be adjacent to the ring nitrogen in the product (Scheme 3).
Given the modest yields of the intermolecular reactions,
intramolecular cyclizations were examined. Tosyl amide 12
was deprotonated, followed by addition of (R)-propylene
oxide to give homochiral secondary alcohol 13 (72%,
Scheme 4). Ether formation with propargyl bromide yielded
Scheme 4
Scheme 3
14, then deprotection and conjugate addition with acryloni-
trile gave cyclization precursor 16. Microwave irradiation
(11) Heller, B.; Oehme, G. J. Chem. Soc., Chem. Commun. 1995, 179.
(12) Gutnov, A.; Drexler, H.-J.; Spannenberg, A.; Oehme, G.; Heller,
B. Organometallics 2004, 23, 1002.
Org. Lett., Vol. 9, No. 3, 2007
395

of 16 with CpCoCO2 (20 mol %) produced tetrahydro-2,5-
naphthyridine 17 in 80% yield, validating the intramolecular
approach.
An alternative route to the cyclization precursors trans-
posed the oxygen and stereogenic center in the C-ring
(Scheme 5). Formation of dialkynyl ethers 19 by epoxide
Scheme 5
opening and propargylations of 18, followed by copper-
promoted Mannich reactions13 with aminonitriles 20 gave
cyclization precursors 21. Cyclizations proceeded smoothly
to give tetrahydronaphthyridines 22 (n ) 1) in excellent
yields (Table 2, 83-99%, Figure 2). Preparation of amino-
nitriles 20 from primary amines, by conjugate addition to
acrylonitrile or alkylation with bromoacetonitrile or 4-bro-
mobutyronitrile, enabled variation of the tether length
between the nitrile and amino groups, resulting in 6-, 5-, or
7-membered A-rings in the products, respectively. However,
formation of the dialkynylnitrile precursor 21j (n ) 0) by
the Mannich reaction proceeded in only 20-30% yield (entry
10). In addition, the cyclization precursor 21k, which leads
to a 7-membered A-ring, was difficult to purify. The
cyclization was thus performed without purification of 21k,
which may account for the low overall yield of 22k (25%,
2 steps).
In conclusion, we have demonstrated a new route to
5,6,7,8-tetrahydro-1,6-naphthyridines 11 and 22 and related
heterocycles using microwave-promoted, Co-catalyzed [2 +
2 + 2] cyclizations. Previous syntheses of these heterocycles
typically relied upon annulation of a pyridine ring onto a
4-piperidone or equivalent,14 or reductions or reductive
additions to the fully aromatized 1,6-naphthyridine sys-
Figure 2. 5,6,7,8-Tetrahydro-1,6-naphthyridines and related het-
erocycles prepared by [2 + 2 + 2] cyclizations.
tem.15,16 Fully aromatized naphthyridines were not detected
in any of the microwave-promoted reactions. Adaptation of
this chemistry for library synthesis and the use this approach
to access other naphthyridines 3-8 are underway.
Acknowledgment. This work was supported by the NIH
NIGMS CMLD Initiative (P50 GM067041). We thank CEM
Corp. for assistance with microwave instrumentation.
Supporting Information Available: Procedures and
characterization spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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