Synthesis of Tetrahydronaphthyridines from Aldehydes and HARP Reagents via Radical Pictet-Spengler Reactions

Article abstract of DOI:10.1021/acs.orglett.6b00523

The combination of aldehydes with newly designed HARP (halogen amine radical protocol) reagents gives access to α-substituted tetrahydronaphthyridines. By using different HARP reagents, various regioisomeric structures can be prepared in a single operation. These products, which are of high value in medicinal chemistry, are formed in a predictable manner via a formal Pictet-Spengler reaction of electron-poor pyridines that would not participate in the corresponding polar reactions.

Full text of DOI:10.1021/acs.orglett.6b00523

Letter
pubs.acs.org/OrgLett
Synthesis of Tetrahydronaphthyridines from Aldehydes and HARP
Reagents via Radical Pictet−Spengler Reactions
Moritz K. Jackl,† Imants Kreituss,† and Jeffrey W. Bode*
Laboratorium fur Organische Chemie, Department of Chemistry and Applied Biosciences, ETH-Zurich, 8093 Zurich, Switzerland
̈
̈
̈
S
* Supporting Information
ABSTRACT: The combination of aldehydes with newly designed
HARP (halogen amine radical protocol) reagents gives access to α-
substituted tetrahydronaphthyridines. By using different HARP
reagents, various regioisomeric structures can be prepared in a single
operation. These products, which are of high value in medicinal
chemistry, are formed in a predictable manner via a formal Pictet−
Spengler reaction of electron-poor pyridines that would not participate
in the corresponding polar reactions.
Scheme 1. SnAP and HARP Reagents
used aromatic/saturated N-heterocycles are important
Fscaffolds for biologically active pharmaceuticals and natural
products.1,2 While many widely used examples, including
tetrahydroisoquinolines and β-tetrahydrocarbinols, can be
accessed by established processes such as Pictet−Spengler3 or
Bischler−Napieralski4 reactions, these approaches are not well
suited for the preparation of electron-deficient systems such as
tetrahydronaphthyridines.5 The poor synthetic access to such
compounds is exemplified by recent work from Amgen, where
the target molecule synthesis relied on introduction of the
substituents in the very first step of a long synthetic sequence.6
While such an approach is suitable once a lead compound is
identified, it is not appealing in early stages where library
syntheses and structure−activity relationship studies are the
primary goal.
As part of a program aimed at establishing predictable, cross-
coupling approaches to saturated N-heterocycles from widely
available components, our group has developed SnAP (stannyl-
amine protocol) reagents,7 which enables the single-step
synthesis of diverse, saturated N-heterocycles from aldehydes
(Scheme 1). We sought to extend this concept to the
preparation of partially saturated bicyclic heterocycles, begin-
ning with otherwise difficult to access tetrahydronaphthyridines
in various regioisomeric forms. In this paper, we document our
successful development of a new class of reagents, HARP
(halogen amine radical protocol) reagents and conditions
suitable for this cross-coupling. Although the mechanism
involves radical additions to imines, the key step of the SnAP
chemistry, our solution to these product classes relies on a
different radical source and reaction conditions. The new
approach not only allows the assembly of fused saturated/
aromatic N-heterocycle scaffolds but also delivers the expected
products in a predictable manner, overcoming the inherent
Scheme 2. Synthesis of HARP Reagents
regioselectivity problems associated with the Pictet−Spengler
or Bischler−Napieralski reactions.
Received: February 24, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00523
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 3. Synthesis of 1,7-Tetrahydronaphthyridines
Scheme 4. 1,6- and 2,7-Tetrahydronaphthyridine Synthesis
a
Reaction conditions for imine formation: azido reagent (1.00 equiv),
aldehyde (0.95−1.00 equiv), polymer-bound triphenylphosphine (2.0
equiv), THF 55 °C, 12 h. Conditions for cyclization: imine (1.0
equiv), AIBN (0.2−1.0 equiv), (TMS)3SiH (1.5−2.0 equiv), toluene
100 °C. Yields refer to isolated amine products after purification by
column chromatography.
a
Reaction conditiona for imine formation: azido reagent (1.00 equiv),
aldehyde (0.95−1.00 equiv), polymer-bound triphenylphosphine (2.0
equiv), THF, 55 °C, 12 h. Conditions for cyclization: imine (1.0
equiv), AIBN (0.2 equiv), (TMS)3SiH (1.5−2.0 equiv), toluene, 100
°C. Yields refer to isolated amine products after purification by column
triphenylphosphine followed by an aza-Wittig reaction with the
corresponding aldehyde cleanly gave the requisite imines, which
were isolated by simple filtration from the resin.7d This
approach also allayed fears of intramolecular cyclization of the
amine to form an indoline. Using 4-(trifluoromethyl)-
benzaldehyde as a substrate for reaction optimization, we
tested several conditions for the radical generation and
b
chromatography. Alongside product 5m, the corresponding cyclic
imine was obtained in 24% yield (see the Supporting Information)
Although aryltin reagents could serve as the source of radicals
(Fg1 in Scheme 1), we sought to identify a starting material that
was both easier to prepare and avoided the use of organo-
stannes. We reasoned that the aromatic halides should be
sufficiently stable and would generate the corresponding sp2-
centered radical upon treatment with a radical initiator.8 We
therefore began our investigations with the preparation of 2-
bromopyridine reagent 3 from the corresponding aldehyde on a
multigram scale (Scheme 2).9
10
cyclization. The use of Et3B/O2 or AIBN/Bu3SnH11 led to
complex product mixtures, and iridium12 or organocatalytic
photoredox systems did not exhibit the desired reactivity. We
were, however, pleased to find that a catalytic amount of AIBN
in combination with (TMS)3SiH13 provided the cyclized
product, which was isolated in 84% yield after column
chromatography. Encouraged by these results, we continued
the investigation of the substrate scope. The imine formation
and cyclization proceeded equally well with both electron-poor
and electron-rich aldehydes and tolerated heterocyclic and
The azide could be reduced to the amine, but we found it to
be air and moisture insensitive and elected to use this reagent
for imine formation. Staudinger reduction with polymer-bound
B
DOI: 10.1021/acs.orglett.6b00523
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ortho-substituted substrates. Products derived from aliphatic
aldehydes could be isolated in acceptable yields. Surprisingly,
aromatic aldehydes containing halogen atoms (−Cl and −Br)
were suitable substrates, and we did not observe dehalogena-
tion during the cyclization. We attribute this to the kinetically
favored generation of the more stable 2-pyridyl radical.14
Given the key role of the 2-pyridyl halide for efficient radical
generation, it was unclear if our concept could be extended to
the construction of regioisomeric tetrahydronaphthyridines
(Scheme 3). The necessary reagents, also as the azides, could
be prepared by straightforward routes (see the Supporting
Information), and imine formation using the phosphine resin
proceeded equally well. As anticipated, the cyclization
conditions employed for the first reagent (3) gave only trace
amounts of the desired product. Lewis acidic additives such as
BF3·Et2O15 or the use of Brønsted acidic solvents such as
HFIP,16 which is crucial for cyclizations using SnAP reagents,
led to the decomposition of the imine intermediate.
By increasing the amount of AIBN, we could isolate the
cyclic amines in their N-unprotected form (Scheme 4). The
yields are considerably lower than for the 2-pyridyl halogen
reagents, and therefore a subject for further investigation, but
even at the current state of development HARP reagents
provide an attractive route to these products. We attribute the
lower yields and somewhat more restricted substrate scope to
the reduced stability of the aryl radical, which does not benefit
from stabilization from an adjacent heteroatom.17
CASAA) and the Swiss Federal Commission for Technology
and Innovation (CTI 15523.1).
REFERENCES
■
(1) (a) Taylor, R. D.; MacCoss, M.; Lawson, A. G. J. Med. Chem.
2014, 57, 5845−5859. (b) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J.
Med. Chem. 2014, 57, 10257−10274. (c) Xiong, B.; Li, Y.; Lv, W.; Tan,
Z.; Jiang, H.; Zhang, M. Org. Lett. 2015, 17, 4054−4057. (d) Basarab,
G. S.; Galullo, V.; DeGrace, N.; Hauck, S.; Joubran, C.; Wesolowski, S.
S. Org. Lett. 2014, 16, 6456−6459. (e) Palucki, M.; Hughes, D. L.;
Yasuda, N.; Yang, C.; Reider, P. J. Tetrahedron Lett. 2001, 42, 6811−
6814. (f) Hussenether, T.; Troschutz, R. J. Heterocycl. Chem. 2004, 41,
857−865.
(2) Murray, C. W.; Rees, D. C. Angew. Chem., Int. Ed. 2016, 55, 488−
492.
(3) (a) Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44,
2030−2036. (b) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen,
E. N. J. Am. Chem. Soc. 2007, 129, 13404−13405.
(4) Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279−1300.
(5) Davis, F. A.; Melamed, J. Y.; Sharik, S. S. J. Org. Chem. 2006, 71,
8761−8766.
(6) Horne, D. B.; Tamayo, N. A.; Bartberger, M. D.; Bo, Y.; Clarine,
J.; Davis, C. D.; Gore, V. K.; Kaller, M. R.; Lehto, S. G.; Ma, V. V.;
Nishimura, N.; Nguyen, T. T.; Tang, P.; Wang, W.; Youngblood, B.
D.; Zhang, M.; Gavva, N. R.; Monenschein, H.; Norman, M. H. J. Med.
Chem. 2014, 57, 2989−3004.
(7) (a) Vo, C. V.; Mikutis, G.; Bode, J. W. Angew. Chem., Int. Ed.
2013, 52, 1705−1708. (b) Vo, C. V.; Luescher, M. U.; Bode, J. W. Nat.
Chem. 2014, 6, 310−314. (c) Luescher, M. U.; Vo, C. V.; Bode, J. W.
Org. Lett. 2014, 16, 1236−1239. (d) Siau, W.-Y.; Bode, J. W. J. Am.
Chem. Soc. 2014, 136, 17726−17729. (e) Luescher, M. U.; Bode, J. W.
Angew. Chem., Int. Ed. 2015, 54, 10884−10888. (f) Geoghegan, K.;
Bode, J. W. Org. Lett. 2015, 17, 1934−1937.
This methodology serves as an expansion of our previous
established SnAP reagent based synthesis of saturated N-
heterocycles.
In summary, we have developed a new class of reagents to
access α-substituted tetrahydronaphthyridines and their
regioisomers via a formal Pictet−Spengler reaction in a
predictable manner. The requisite reagents are air and moisture
stable and can be prepared on a multigram scale in a few
synthetic steps from readily available starting materials.
Applications of this strategy to assemble other electron-poor
heterocyclic substrates are underway in our laboratories.
(8) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2016, 55, 58−
102.
(9) Heidelbaugh, T.; Chow, K.; Sinha, S.; Nguyen, P.; Fang, W.; Li,
L.; Taekuchi, J.; Bhat, S. Allergan, Inc. WO2009091760 (A1), 2009.
(10) Renaud, P.; Beauseigneur, A.; Brecht-Forster, A.; Becattini, B.;
Darmency, V.; Kandhasamy, S.; Montermini, F.; Ollivier, C.;
Panchaud, P.; Pozzi, D.; Scanlan, E. M.; Schaffner, A.-P.; Weber, V.
Pure Appl. Chem. 2007, 79, 223−233.
(11) The Bu3SnH/AIBN combination has been reported for
intramolecular cyclizations on imines: (a) Tomaszewski, M. J.;
Warkentin, J. Tetrahedron Lett. 1992, 33, 2123−2126. (b) Orito, K.;
Uchiito, S.; Satoh, Y.; Tatsuzawa, T.; Harada, R.; Tokuda, M. Org. Lett.
2000, 2, 307−310. (c) Johnston, J. N.; Plotkin, M. A.; Viswanathan, R.;
Prabhakaran, E. N. Org. Lett. 2001, 3, 1009−1011. (d) Viswanathan,
R.; Prabhakaran, E. N.; Plotkin, M.; Johnston, J. N. J. Am. Chem. Soc.
2003, 125, 163−168. (e) Viswanathan, R.; Mutnick, D.; Johnston, J. N.
J. Am. Chem. Soc. 2003, 125, 7266−7271.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00523.
Experimental procedures and analytical data of all new
compounds (PDF)
(12) Liu, D.; Liu, C.; Lei, A. Chem. - Asian J. 2015, 10, 2040−2054.
(13) (a) Chatgilialogu, C.; Timokhin, V. I. Silanes as Reducing
Agents in Radical Chemistry. In Encyclopedia of Radicals in Chemistry,
Biology and Materials; John Wiley & Sons, 2012, DOI: 10.1002/
9781119953678.rad074. (b) Chatgilialoglu, C.; Lalevee, J. Molecules
2012, 17, 527−555.
AUTHOR INFORMATION
■
Corresponding Author
(14) Lucas, M.; Minor, J.; Zhang, J.; Brazier, C. J. Phys. Chem. A
2013, 117, 12138−12145.
*E-mail: bode@org.chem.ethz.ch.
Author Contributions
(15) (a) Chen, Q.; Mollat du Jourdin, X.; Knochel, P. J. Am. Chem.
Soc. 2013, 135, 4958−4961. (b) Aubrecht, K. B.; Winemiller, M. D.;
Collum, D. B. J. Am. Chem. Soc. 2000, 122, 11084−11089.
(16) (a) Eberson, L.; Hartshorn, M. P.; Persson, O.; Radner, F.
Chem. Commun. 1996, 2105−2112. (b) Berkessel, A.; Adrio, J. A.;
Huttenhain, D.; Neudorfl, J. J. Am. Chem. Soc. 2006, 128, 8421−8426.
(17) Kikuchi, O.; Hondo, Y.; Morihashi, K.; Nakayama, M. Bull.
Chem. Soc. Jpn. 1988, 61, 291−292.
†M.K.J. and I.K. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Michael U. Luescher and Shen-Ying Hsieh (ETH)
for helpful discussions. This work was supported by the
European Research Council (ERC Starting Grant No. 306793-
C
DOI: 10.1021/acs.orglett.6b00523
Org. Lett. XXXX, XXX, XXX−XXX