Stereodefined homopropargyl amines by tandem nucleophilic addition/fragmentation of dihydropyridone triflates

Article abstract of DOI:10.1021/ol102760q

Dihydropyridone (DHPD) triflates undergo nucleophile-triggered fragmentation to provide homopropargyl amine derivatives, the stereochemistry of which is defined by starting from readily available β-amino esters.

Full text of DOI:10.1021/ol102760q

ORGANIC
LETTERS
2011
Vol. 13, No. 1
158-160
Stereodefined Homopropargyl Amines
by Tandem Nucleophilic Addition/
Fragmentation of Dihydropyridone
Triflates
Jumreang Tummatorn and Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State UniVersity, Tallahassee,
Florida 32306-4390, United States
gdudley@chem.fsu.edu
Received November 14, 2010
ABSTRACT
Dihydropyridone (DHPD) triflates undergo nucleophile-triggered fragmentation to provide homopropargyl amine derivatives, the stereochemistry
of which is defined by starting from readily available ꢀ-amino esters.
This work is focused on the synthesis of functionalized
homopropargyl amines. Conceptually, three strategic C-C
bond construction alternatives (A, B, and C, Figure 1) are
available. The first two, [A] propargyl addition to imines1,2
and [B] acetylide opening of aziridines,3 involve pre-existing
acetylenic substrates and often present unresolved stereo- and
regioselectivity issues. The third, [C] de noVo construction
of nonstereogenic alkynes, is largely unexplored.4,5 Strategy
[C] offers the advantage of starting from readily available
ꢀ-amino acid derivatives of prescribed stereochemistry6 but
requires installation of the Ct C triple bond. The nucleophile-
(1) Reviews: (a) Vilaivan, T.; Bhanthumnavin, W.; Sritana-Anant, Y.
Curr. Org. Chem. 2005, 9, 1315–1392. (b) Zhou, P.; Chen, B. C.; Davis,
F. A. Tetrahedron 2004, 60, 8003–8030. (c) Ellman, J. A.; Owens, T. D.;
Figure 1. Strategies for the assembly of functionalized homopro-
Tang, T. P. Acc. Chem. Res. 2002, 35, 984–995
.
pargyl amine derivatives. Strategies [A] and [B] make use of pre-
existing alkynes but pose stereo- and regiocontrol problems.
Strategy [C] exploits pre-existing stereochemistry but presents the
challenge of generating the Ct C triple bond.
(2) Recent examples: (a) Fandrick, D. R.; Johnson, C. S.; Fandrick, K. R.;
Reeves, J. T.; Tan, Z.; Lee, H.; Song, J. J.; Yee, N. K.; Senanayake, C. H.
Org. Lett. 2010, 12, 748–751. (b) Brawn, R. A.; Panek, J. S. Org. Lett.
2009, 11, 4362–4365. (c) Prajapati, D.; Laskar, D. D.; Gogoi, B. J.; Devi,
G. Tetrahedron Lett. 2003, 44, 6755–6757
.
(3) Ding, C.-H.; Dai, L.-X.; Hou, X.-L. Tetrahedron 2005, 61, 9586–
9593.
(4) (a) Larock, R. C. ComprehensiVe Organic Transformations, 2nd ed.;
Wiley & Sons: New York, 1999; pp 563-583. (d) Brandsma, L. PreparatiVe
triggered fragmentation of dihydropyridone (DHPD) triflates
described herein will enable development of strategy [C].
Acetylenic Chemistry, 2nd ed.; Elsevier: Amsterdam, 1988
.
10.1021/ol102760q  2011 American Chemical Society
Published on Web 11/24/2010

an excellent entry point into the synthesis of complex
alkaloids, have remained elusive until now.
Our hypothesis was that DHPD triflates derived from
ꢀ-amino esters (e.g., 1a, Scheme 1) would undergo nucleo-
Our laboratory has been investigating fragmentation7
reactions that deliver functionalized alkynes by means of
nucleophilic addition to vinylogous acyl triflates (VATs, eq
1).8 Note that most organic fragmentation processes produce
alkenes;7c “alkynogenic” fragmentations require a better
nucleofuge9 (typically triflate or molecular nitrogen; cf. eqs
1 and 2) than is needed to generate alkenyl carbonyls. Our
ongoing methodology is reminiscent of the classic Eschen-
moser-Tanabe alkynyl ketone synthesis (eq 2),10 but VAT
fragmentations deliver a wider array of products including
alkynyl ketones, alcohols, and ꢀ-keto phosphonates.11
Scheme 1. Synthesis of Dihydropyridone (DHPD) Triflate 1a
phile-triggered fragmentation to homopropargyl amine de-
rivatives. However, lactam carbonyls are less electrophilic
than lactones or ketones, and reaction conditions that had
proven optimal in our earlier studies8,11,12 were not applicable
in this new system.
Table 1 comprises illustrative data from a large body of
exploratory experiments aimed at establishing the appropriate
Table 1. Selected Experiments from the Optimization of
Nucleophile-Triggered Fragmentation of Dihydropyridone
(DHPD) Triflates (1)
Related methods deliver homopropargyl alcohols,12 allenyl
ketones,13 and alkynyl aldehydes.14 Homopropargyl amines,
(5) We found two examples of ethynylation of ꢀ-amino aldehydes (using
the Seyferth-Gilbert/Ohira-Bestmann and Corey-Fuchs homologation
protocols, respectively). The reagents involved are fundamentally one-carbon
synthons for making terminal alkynes; see: (a) Carballo, R. M.; Ram´ırez,
M. A.; Rodr´ıguez, M. L.; Mart´ın, V. S.; Padro´n, J. I. Org. Lett. 2006, 8,
3837–3840. (b) Kazuta, Y.; Tsujita, R.; Uchino, S.; Kamiyama, N.;
Mochizuki, D.; Yamashita, K.; Ohmori, Y.; Yamashita, A.; Yamamoto,
T.; Kohsaka, S.; Matsuda, A.; Shuto, S. J. Chem. Soc., Perkin Trans. 1
2002, 1199–1212.
entry
RN
Ph
R4-M
solvent
yield (%)
1
2
3
4
5
6
Ph-Lia
THF
56
Ph-Lia
toluene
toluene
THF
toluene
THF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
76
(6) EnantioselectiVe Synthesis of b-Amino Acids, 2nd ed.; Juaristi, E.,
Soloshonok, V. A., Eds.; Wiley-VCH: New York, 2005.
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bn
Octyl
Ph-MgBra
BnNH-Li
BnNH-Li
Me-Lic
sb
(7) Fragmentation reactions as defined by Grob: (a) Grob, C. A.; Schiess,
P. W. Angew. Chem., Int. Ed. Engl. 1967, 6, 1–15. Seminal paper: (b)
Eschenmoser, A.; Frey, A. HelV. Chim. Acta 1952, 35, 1660–1666. Recent
review: (c) Prantz, K.; Mulzer, J. Chem. ReV. 2010, 110, 3741–3766.
Leading references: (d) Ku¨rti, L.; Czako´, B. Grob Fragmentation. In
Strategic Applications of Named Reactions in Organic Synthesis; Elsevier:
New York, 2003; pp 190-191 and references cited. (e) Ku¨rti, L.; Czako´,
B. Wharton Fragmentation. In Strategic Applications of Named Reactions
in Organic Synthesis; Elsevier: New York, 2003; pp 480-481 and references
cited.
0
0
sb
7
Me-Lic
90 (2)
48 (3)
sb
8d
9
Me-Lic
Me-MgCle
n-Bu-Lif
t-Bu-Lig
t-Bu-Lig
n-Bu-Lif
n-Bu-Lif
10
11
12
13
14
97 (2)
38 (2)
64 (2)
46 (2)
54 (2)
(8) (a) Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2005, 127, 5028–
5029. (b) Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2006, 128, 6499–
6507.
(9) (a) Lepore, S. D.; Mondal, D. Tetrahedron 2007, 63, 5103–5122.
(b) Creary, X.; Burtch, E. A. J. Org. Chem. 2004, 69, 1227–1234. (c) Su,
T. M.; Sliwinski, W. F.; Schleyer, P. v. R. J. Am. Chem. Soc. 1969, 91,
5386–5388. (d) Streitwieser, A., Jr.; Wilkins, C. L.; Kiehlmann, E. J. Am.
Chem. Soc. 1968, 90, 1598–1601.
a 1.0 M in butyl ether. b Trace quantities of 2 and/or 3 observed in the
crude reaction mixture by H NMR spectroscopy. c 1.0 M in ether. d 2.0
1
equiv of MeLi, -78 to +80 °C. e 3.0 M in ether. f 2.4 M in hexanes. g 0.7
M in pentane.
(10) Seminal papers: (a) Eschenmoser, A.; Felix, D.; Ohloff, G. HelV.
Chim. Acta 1967, 50, 708–713. (b) Tanabe, M.; Crowe, D. F.; Dehn, R. L.
Tetrahedron Lett. 1967, 3943–3946. Leading references: (c) Ku¨rti, L.;
Czako´, B. Eschenmoser-Tanabe Fragmentation. In Strategic Applications
of Named Reactions in Organic Synthesis; Elsevier: New York, 2003; pp
158-159 and references cited.
combination of nitrogen substituent, external nucleophile,
solvent, and reaction temperature profile to provide control
(11) (a) Kamijo, S.; Dudley, G. B. Org. Lett. 2006, 8, 175–177. (b)
Jones, D. M.; Kamijo, S.; Dudley, G. B. Synlett 2006, 936–938. (c) Kamijo,
S.; Dudley, G. B. Tetrahedron Lett. 2006, 47, 5629–5632. (d) Jones, D. M.;
Dudley, G. B. Synlett 2010, 223–226. (e) Jones, D. M.; Lisboa, M. P.;
Kamijo, S.; Dudley, G. B. J. Org. Chem. 2010, 75, 3260–3267. (f) Jones,
D. M.; Dudley, G. B. Tetrahedron 2010, 60, 4860–4866.
(13) Kolakowski, R. V.; Manpadi, M.; Zhang, Y.; Emge, T. J.; Williams,
L. J. J. Am. Chem. Soc. 2009, 131, 12910–12911.
(14) (a) Draghici, C.; Brewer, M. J. Am. Chem. Soc. 2008, 130, 3766–
3767. (b) Draghici, C.; Huang, Q.; Brewer, M. J. Org. Chem. 2009, 74,
8410–8413. (c) Bayir, A.; Draghici, C.; Brewer, M. J. Org. Chem. 2010,
75, 296–302.
(12) Tummatorn, J.; Dudley, G. B. J. Am. Chem. Soc. 2008, 130, 5050–
5051.
Org. Lett., Vol. 13, No. 1, 2011
159

over the desired addition/fragmentation pathway. It is clear
from Table 1 that N-arylated DHPD triflates (RN ) Ph)
undergo optimal ring opening by the addition/fragmentation
pathway upon treatment with 1.0 equiv of alkyllithium
reagents in hydrocarbon solvents (entry 10). N-Alkyl DHPD
triflates (entries 13 and 14) were less effective, probably due
to greater electron density at the lactam nitrogen as compared
to the N-aryl substrates. Other organolithium nucleophiles
were suitable (entries 2, 7, and 12), but Grignard reagents
were not (entries 3 and 9). Toluene typically provides better
results than ethereal solvents (cf. entries 6 and 7).
Scheme 2
.
Synthesis of Functionalized Homopropargyl Amine
Derivatives from Diverse DHPD Triflates
The results in Table 1 are significant in that they enable
the synthesis of functionalized, internal homopropargyl amine
derivatives from nonacetylenic starting materials.5 Thus, we
turned our attention to other substituted DHPD triflates to
verify the generality of the method (Table 2). Variation in
Table 2. Preliminary Scope of the Tandem Addition/
Fragmentation of DHPD Triflates 1 to Homopropargyl Amines 2
entry
R2
R3
RN
yield (%)
1 (1a)
2 (1b)
3 (1c)
4 (1d)
5 (1e)
6a (1f)
H
H
H
H
H
Me
Me
Me
Me
i-Pr
Ph
Ph
97 (2a)
81 (2b)
88 (2c)
80 (2d)
77 (2e)
84 (2f)
p-MeO-C6H4
p-Cl-C6H4
Ph
Ph
Ph
in a reasonable yield. Finally, tricyclic DHPD triflate 12
underwent ring-opening fragmentation to yield propargylated
tetrahydroquinoline 13.
Ph
a 2.0 equiv of n-BuLi, 0 °C to rt.
In summary, we report the nucleophile-triggered fragmen-
tation of dihydropyridone (DHPD) triflates, which provides
multifunctional homopropargyl amine core structures of great
potential value in organic synthesis. The focus of this strategy
for the synthesis of homopropargyl amines is on the
formation of the nonstereogenic alkyne, which enables one
to avoid many of the synthetic challenges associated with
other approaches. Further development of this methodology,
including for application in the synthesis of complex
alkaloids from ꢀ-amino ester building blocks, is now
underway.
the N-aryl protecting group (entries 1-3) was tolerated, as
were branched alkyl (entry 4), aryl (entries 5-6), and
geminal dimethyl (entry 6) substituents, indicating that
changes in sterics and/or electronic features around the
periphery of the DHPD triflate are of minimal impact.
A diverse collection of DHPD triflates was assembled15
and examined next (Scheme 2), with each substrate designed
to probe a particular concept of interest to the methodology.
The first example (4 f 5) is notable because the cis-
cyclopentane stereochemistry would be difficult to access
by syn-selective imine cyclization or by (stereoretentive)
aziridine opening (cf. strategies A and B, Figure 1). The next
two examples illustrate the stereospecificity of the addition/
fragmentation process: cis-DHPD triflate 6 gives rise to syn-
homopropargyl amine 7, and the trans-DHPD triflate 8
provides anti-homopropargyl amine 9. Quinolone 10 presents
different stereoelectronic properties, but under slightly modi-
fied conditions the target o-alkynyl-aniline (11) was produced
Acknowledgment. This research is supported by a grant
from the National Science Foundation (NSF-CHE 0749918).
We thank Dr. Vithaya Ruangpornvisuti (Chulalongkorn
University, Thailand) for assisting J.T. with computational
analysis of DHPD triflates that helped guide her experimental
efforts.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) The DHPD triflates used in this methodology were prepared by
annulation of ꢀ-amino esters with carboxylic acid derivatives (cf. Scheme
1). See Supporting Information for details.
OL102760Q
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Org. Lett., Vol. 13, No. 1, 2011