Cyclocondensation of amino-propargyl silanes

Article abstract of DOI:10.1021/ol300724c

Amino-propargyl silanes condense with carbonyl compounds to form imines and subsequently cyclize to form allenylidene tetrahydroquinolines. The cyclocondensations are catalyzed by a variety of Bronsted acids, among which phosphoric acids provide the highe

Full text of DOI:10.1021/ol300724c

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2308–2311
Cyclocondensation of Amino-propargyl
Silanes
Yizhong Wang and Joseph M. Ready*
Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines
Boulevard, Dallas, Texas 75390-9038, United States
Joseph.ready@utsouthwestern.edu
Received March 21, 2012
ABSTRACT
Amino-propargyl silanes condense with carbonyl compounds to form imines and subsequently cyclize to form allenylidene tetrahydroquinolines.
The cyclocondensations are catalyzed by a variety of Brønsted acids, among which phosphoric acids provide the highest yields. Subsequent
intramolecular and intermolecular additions to the allene moiety provide complex polycyclic amines.
The rapid generation of complex molecules from simple
precursors remains an important challenge in organic
synthesis.1 Strategies to create molecular diversity are
valuable in medicinal chemistry and the synthesis of small
molecule libraries. Among many approaches to this pro-
blem, we considered reaction sequences that would fulfill
two criteria (Scheme 1A). An initial transformation should
join two or more fragments to form new rings and/or
stereocenters. Second, the initial step should convert one
reactive functional group to an alternative functional
group that also displays high reactivity, but under conditions
orthogonal to those of the initial reactions. Thus, in a second
step, the new functional group could be used to promote
cyclization, fragment coupling, or conversion to stable
functionality.
electron-deficient olefins.2 As another example, cyclopro-
panation of enol ethers converts one high-energy material,
a diazo-carbonyl compound, to a different reactive sub-
stance, a donorꢀacceptor cyclopropane. In this example,
the first operation joins two fragments even as it prepares
the substrate for subsequent cycloaddition reactions.3 As a
final example, Schreiber and co-workers reported a
diversity-generating protocol in which an initial Petasis
three-component coupling facilitated formation of func-
tionalized enynes, which were then subject to a variety of
cyclization conditions.4
In this context, we considered the reactivity of propargyl
silanes.5 Specifically, we wondered if amino-propargyl
(3) Qi, X.; Ready, J. M. Angew. Chem., Int. Ed. 2008, 47, 7068.
(4) Kumagai, N.; Muncipinto, G.; Schreiber, S. L. Angew. Chem.,
Int. Ed. 2006, 45, 3635.
(5) Reviews:Blumenkopf, T. A.; Overman, L. E. Chem. Rev. 1986, 86,
857. Schinzer, D. Synthesis 1988, 263. Masse, C. E.; Panek, J. S. Chem.
Rev. 1995, 95, 1293.
(6) (a) Fustero, S.; Mateu, N.; Simon-Fuentes, A.; Acena, J. L. Org.
Lett. 2010, 12, 3014. (b) Schneider, U.; Sugiura, M.; Kobayashi, S. Adv.
Synth. Catal. 2006, 348, 323.
Several known reaction sequences fit these criteria. For
instance, Denmark’s tandem [4 þ 2]/[3 þ 2] sequence
involves an initial cycloaddition between a nitro olefin
and an electron-rich olefin. The cycloadduct, a cyclic
nitronate, participates in a second cycloaddition, but with
(7) Representative aza-Prins reactions: (a) Kim, C.; Bae, H. J.; Lee,
J. H.; Jeong, W.; Kim, H.; Sampath, V.; Rhee, Y. H. J. Am. Chem. Soc.
2009, 131, 14660. (b) Carballo, R. M.; Valdomir, G.; Purino, M.;
Martin, V. S.; Padron, J. I. Eur. J. Org. Chem. 2010, 2304. (c) Reddy,
B. V. S.; Borkar, P.; Yadav, J. S.; Sridhar, B.; Gree, R. J. Org. Chem.
2011, 76, 7677.
(1) Tan, D. S. In Chemical Biology; Schreiber, S. L., Kapoor, T. M.,
Wess, G., Eds.; Wiley-VCH Verlag GmbH: 2008; p 483. (b) Burke, M. D.;
Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46.
(2) Denmark, S. E.; Moon, Y. C.; Senanayake, C. B. W. J. Am. Chem.
Soc. 1990, 112, 311.
r
10.1021/ol300724c
Published on Web 04/16/2012
2012 American Chemical Society

silanes (1) would condense with carbonyl compounds and,
under acidic conditions, cyclize to generate allenes (3,
Scheme 1B).6,7 Allenes are subject to a wide range of
transformations, and we postulated that they could react
with a variety of nucleophiles to yield complex polycyclic
amines. Herein, we report the successful development of a
cyclocondensation to form allenylidene tetrahydroquino-
lines and preliminary exploration of derivatization strate-
gies. Since quinolines and their derivatives appear in a wide
range of natural products and pharmaceutical agents,8 this
approach may facilitate the discovery of novel biologically
active small molecules.
catalyst loadings characterized the reactions with substi-
tuted benzaldehydes. Thus, electron-rich and -poor alde-
hydes participated equally well. Protic functionality was
tolerated, including phenols (3f, 3g, 3h) and carboxylic acids
(3m). Steric hindrance was not problematic as demonstrated
by series of 2-substituted and 2,6-disubstituted benzalde-
hydes. Only the hindered and electron-rich 2,4,6-trimethoxy
benzaldehyde reacted in lower yield (3l). Thiophene and
furan carboxaldehydes were excellent substrates (3q, 3r, 3w),
but no product was obtained from pyrrole carboxyalde-
hyde (3s). Likewise, 3- and 4-pyridine carboxyaldehyde
reacted cleanly, but the 2-pyridyl analog was inactive.10
Both linear and branched aliphatic aldehydes were suitable
substrates (3y, 3z, 3aa), although an enal was unsuccessful
(3ab). Finally, whereas simple ketones like acetophenone
provided no product, certain classes of ketones worked
well. Thus, a series of isatins condensed in high yield
to form a quaternary carbon.11 Similarly, a β-keto-ester
reacted with high efficiency.
Scheme 1. Reaction Sequences To Rapidly Generate Molecular
Diversity
Table 1. Acid-Catalyzed Cyclocondensationa
catalyst
(mol %)
yield
(%)b
entry
solvent
1
CH3CO2H (15)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeOH
DCM
0
Initial experiments probed the reactivity of propargyl
silane 1a with aldehyde 2a (Table 1). Several Brønsted
acids catalyze the cyclocondensation in good yield. Acetic
acid was insufficient to promote cyclization, and imine
formation was observed. However, stronger carboxylic
acids (entry 2) and sulfonic acids (entries 3ꢀ5) formed
the cyclized product 3a in good yield. Diphenyl phosphate
emerged as the most efficient catalyst, and catalyst load-
ings as low as 1 mol % generated 1a in quantitative yields.
Faster reaction times were observed with 2 mol % catalyst,
and these conditions were adopted in subsequent experi-
ments. The cyclization required polar solvents, with both
acetonitrile (entry 6) and methanol (entry 8) supporting
product formation. Incontrast, only imine was observed in
less polar solvents (entries 9ꢀ12). Several Lewis acids
promoted cyclization as well.9 However, since these reac-
tions were inhibited by 2,6-di-tert-butylpyridine, we con-
cluded that Brønsted acids arising from hydrolysis of the
metal salts were responsible for catalysis.
2
CF3CO2H (15)
84
90
96
45
100
100
100
0
3
CSA (15)
4
TsOH (15)
5
Amberlyst (15)
6
(PhO)2P(O)OH (2)
(PhO)2P(O)OH (1)
(PhO)2P(O)OH (15)
(PhO)2P(O)OH (15)
(PhO)2P(O)OH (15)
(PhO)2P(O)OH (15)
(PhO)2P(O)OH (15)
7c
8
9
10
11
12
THF
0
Et2O
0
PhMe
0
a Reactions carried out on a 10 mg scale with [1a] = 0.045 under an
air atmosphere for 16 h unless otherwise noted. b NMR yield based on an
internal standard. c 24 h reaction time.
Several characteristics of the cyclocondensation deserve
comment. First, the reactions are relatively insensitive to
water and air and could be carried out using unpurified
solvents open to the atmosphere. Second, the reaction ap-
pears to scale well, as allene 3ai was prepared with equal
efficiency on 0.1 and 1 mmol scales. Finally, we never
Under optimized conditions, propargyl silane 1a was
condensed with a variety of aldehydes and ketones
(Scheme 2). Complete conversion, high yields, and low
(10) Hydrogen bonding of the protonated pyridine to the imine
nitrogen may deactivate this substrate.
(8) (a) Khan, M. T. H. Top. Heterocycl. Chem. 2007, 11, 213. (b)
Kaur, K.; Jain, M.; Reddy, R. P.; Jain, R. Eur. J. Med. Chem. 2010, 45,
3245. (c) Bongarzone, S.; Bolognesi, M. L. Expert Opin. Drug Discovery
2011, 6, 1. (d) Solomon, V. R.; Lee, H. Curr. Med. Chem. 2011, 18, 1488.
(9) For example, Sc(OTf)3, FeCl3, Zn(OTf)2, InCl3, Cu(OTf)2.
(11) (a) Castaldi, M. P.; Troast, D. M.; Porco, J. A. Org. Lett. 2009,
11, 3362. (b) Zhang, Y.; Panek, J. S. Org. Lett. 2009, 11, 3366. (c) Wang,
J.; Crane, E. A.; Scheidt, K. A. Org. Lett. 2011, 13, 3086.
(12) Crouch, I. T.; Dreier, T.; Frantz, D. E. Angew. Chem., Int. Ed.
2011, 50, 6128.
Org. Lett., Vol. 14, No. 9, 2012
2309

Scheme 2. Catalytic Synthesis of Alleneylidene Tetrahydroquinolinesa
a Reactions carried out on a 0.09 mmol scale with 2 mol % catalyst in 1 mL of CH3CH under an air atmosphere for 16 h unless otherwise noted.
Isolated yields of purified products indicated. b10 mol % catalyst. cFrom 2-carboxybenzaldehyde. d1.15 mmol scale.
observed isomerization of the allene to the conjugated
diene,12 demonstrating that these products are stable under
the acidic reaction conditions.
observed the formation of the tetracyclic benzofuran 4 in
91% yield (eq 1). Pd(0)-catalyzed cyclization of phenols
onto allenes has not been reported previously, although
cyclization of phenols and alcohols in the presence of elec-
trophilic metals is known.14,15 In this case, Pd(OAc)2 and
PdCl2 did not catalyze the formation of 4 at all, arguing
against an electrophilic activation of the allene. Rather,
this transformation may involve the formation of a
Pd(II)ꢀH species via protonation of Pd(0) with phenol.
Hydrometalation followed by reductive elimination
would yield the observed product (Scheme 3).16 Simi-
larly, carboxylic acid 3ai0 underwent arylation and
cyclization to form lactone 5 (eq 3). Here, aryl addition
to the allene likely generated a Pd(π-allyl) species that
was trapped by the carboxylate.17 Cyclization of both
the phenol and the carboxylic acid occurred with com-
plete control of relative stereochemistry to yield the cis-
fused 5,6-ring systems.
Substituted anilines participated in the cyclocondensa-
tion with variable results (Table 2). Methyl substituted
silane 1b condensed with aromatic and aliphatic aldehydes
and with isatin to generate the corresponding allenes in
high yield. In contrast, amide- or ester-substituted sub-
strates 1c and 1d only provided clean products with certain
aldehydes. Aliphatic aldehydes reacted cleanly (entries
4ꢀ5), but most aromatic aldehydes were converted into
unstable products. Thus, analysis of crude reaction mix-
tures indicated the formation of the expected heterocycle
(3), but attempts to isolate pure samples proved unsuccess-
ful because the products decomposed into complex mix-
tures.
With a high-yielding and general cyclocondensation
in hand, we sought conditions under which the allenes
might beconvertedtomorecomplex polycyclicproducts.13
Accordingly, we exposed allene 3g to Pd(PPh3)4 and
Finally, exposure of allene 3b to Pd(PPh3)4 and a series
of aryl iodides resulted in the formation of a mixture of
dihydroquinolines and quinolines (6, eq 3). Oxidation
of the crude reaction mixture yielded the arylated
quinolines (6) in uniformly high yield. The tandem
(13) (a) Painter, T. O.; Wang, L.; Majumder, S.; Xie, X.-Q.; Brummond,
K. M. ACS Comb. Sci. 2011, 13, 166. (b) Huryn, D. M.; Brodsky,
J. L.; Brummond, K. M.; Chambers, P. G.; Eyer, B.; Ireland, A. W.;
Kawasumi, M.; LaPorte, M. G.; Lloyd, K.; Manteau, B.; Nghiem, P.;
Quade, B.; Seguin, S. P.; Wipf, P. Proc. Natl. Acad. Sci. U.S.A. 2011,
108, 6757.
(15) Intermolecular addition of phenols to allene catalyzed by (a)
Pd(0): Grigg, R.; Kongkathip, N.; Kongkathip, B.; Luangkamin, S.;
Dondas, H. A. Tetrahedron 2001, 57, 7965. (b) Phosphine: Meng, X.;
Huang, Y.; Chen, R. Org. Lett. 2008, 11, 137. (c) DBU: Kumar, N. N. B.;
Reddy, M. N.; Swamy, K. C. K. J. Org. Chem. 2009, 74, 5395. (d)
Uncatalyzed: Nixon, N. S.; Scheinmann, F.; Suschitzky, J. L. Tetrahe-
dron Lett. 1983, 24, 597.
(16) (a) Trost, B. M.; Xie, J.; Sieber, J. D. J. Am. Chem. Soc. 2011,
133, 20611. (b) Kim, H.; Rhee, Y. H. J. Am. Chem. Soc. 2012, 134, 4011.
(17) (a) Saget, T.; Cramer, N. Angew. Chem., Int. Ed. 2010, 49, 8962.
(b) Ma, S.; Negishi, E.-i. J. Am. Chem. Soc. 1995, 117, 6345.
(14) (a) Wang, Y.-M.; Kuzniewski, C. N.; Rauniyar, V.; Hoong, C.;
Toste, F. D. J. Am. Chem. Soc. 2011, 133, 12972. (b) Zhang, Z.;
Widenhoefer, R. A. Org. Lett. 2008, 10, 2079. (b) Zhang, Z.; Liu, C.;
Kinder, R. E.; Han, X.; Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc.
2006, 128, 9066. (c) Bartolome, C.; Garcia-Cuadrado, D.; Ramiro, Z.;
Espinet, P. Organometallics 2010, 29, 3589. (d) Arbour, J. L.; Rzepa,
H. S.; White, A. J. P.; Hii, K. K. Chem. Commun. 2009, 7125. (e) Zhang,
Z.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2007, 46, 283. (f) Wang,
Z. J.; Brown, C. J.; Bergman, R. G.; Raymond, K. N.; Toste, F. D.
J. Am. Chem. Soc. 2011, 133, 7358. (g) Wang, Y.; Zheng, K.; Hong, R.
J. Am. Chem. Soc. 2012, 134, 4096.
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Org. Lett., Vol. 14, No. 9, 2012

Table 2. Cyclocondensation with Substituted Amino-propargyl
Silanesa
Scheme 3. Derivatization of Allenes
propargyl silane 1: X =
CH3
C(O)NMe2
CO2Et
(1b)
(1c)
(1d)
entry
2
b
b
b
b
b
b
b
1
2
3
4
PhCHO
90%
92%
96%
72%c
4-OH-C6H4-CHO
4-NO2-C6H4-CHO
2,4,6-(MeO)3-C6H2-
CHO
74%c
b
b
5
6
7
8
furfural
87%
94%
94%
94%
propionaldehyde
c-Hex-CHO
isatin
80%
71%
82%
84%
89%
b
a Reactions carried out on a 0.09 mmol scale in 1 mL of CH3CN under
an air atmosphere for 16 h unless otherwise noted. Isolated yields indicated.
b Product unstable to silica gel chromatography. c10 mol % catalyst used.
Heck reaction/oxidation tolerated electron-rich, -poor,
and -neutral aryl iodides.
Overall, the protocols described here outline an ap-
proach to transforming relatively simple starting materials
into complex polycyclic products. For instance, the exam-
ple in eq 2 merges three components, creating two new
rings and two adjacent quaternary stereocenters in two
operations. The key strategic element involves the conver-
sion of one reactive substructure, propargylic silanes, into
an alternative reactive functional group, an allene. We
anticipate that this design principle will have numerous
applications in organic synthesis.
Acknowledgment. Funding was provided by the NSF
(CAREER) and Welch Foundation (I1612).
Supporting Information Available. Complete charac-
terization data and experimental procedures. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 9, 2012
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