Diphosphine-catalyzed mixed double-michael reaction: A unified synthesis of lndolines, Dihydropyrrolopyridines, Benzimidazolines, Tetrahydroquinolines, Tetrahydroisoquinolines, Dihydrobenzo-1,4-oxazines, and Dihydrobenzo-3,1- oxazines

Article abstract of DOI:10.1021/ol100078w

(Figure Presented) Seven different types of benzannulated N-heterocycles-indolines, dihydropyrrolopyridlnes, benzimidazolines, dihydrobenzo-3,1-oxazines, benzomorpholines, tetrahydroquinolines, and tetrahydroisoquinolines-can be obtained from simple dinuc

Full text of DOI:10.1021/ol100078w

ORGANIC
LETTERS
2010
Vol. 12, No. 5
1084-1087
Diphosphine-Catalyzed Mixed
Double-Michael Reaction: A Unified
Synthesis of Indolines,
Dihydropyrrolopyridines,
Benzimidazolines, Tetrahydroquinolines,
Tetrahydroisoquinolines,
Dihydrobenzo-1,4-oxazines, and
Dihydrobenzo-3,1-oxazines
Vardhineedi Sriramurthy and Ohyun Kwon*
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles, 607
Charles E. Young DriVe East, Los Angeles, California 90095-1569
ohyun@chem.ucla.edu
Received January 12, 2010
ABSTRACT
Seven different types of benzannulated N-heterocyclessindolines, dihydropyrrolopyridines, benzimidazolines, dihydrobenzo-3,1-oxazines,
benzomorpholines, tetrahydroquinolines, and tetrahydroisoquinolinesscan be obtained from simple dinucleophiles and electron-deficient
acetylenes in one synthetic step. This powerful methodology was made possible through the use of diphenylphosphinopropane (DPPP) as the
catalyst, with acetic acid and sodium acetate used as additives in some cases. The benzannulated N-heterocycles were isolated in excellent
yields under mild metal-free conditions; they were purified without the need for aqueous workups.
Functionalized saturated benzannulated N-heterocycles (e.g.,
indoline, dihydropyrrolopyridine, benzimidazoline, tetrahy-
droquinoline, tetrahydroisoquinoline, dihydrobenzo-1,4-ox-
azine, dihydrobenzo-3,1-oxazine) have been of interest to
chemists for over a century because of their seemingly
ubiquitous presence in natural products1 and pharmaceutical
drugs.2 Not surprisingly, several useful strategies are avail-
able for the synthesis of these heterocycles, with the majority
of them typically generating one or two of the compounds
mentioned above.3 Based on our recent finding of a diphos-
phine-catalyzed mixed double-Michael reaction that proceeds
through a [4 + 1] annulation, in this paper we report a unified
protocol for the synthesis of the title heterocycles under
robust metal-free reaction conditions (Scheme 1).4 Our
Scheme 1. Formation of Benzannulated Heterocycles
(1) Bonjoch, J.; Sole, D. Chem. ReV. 2000, 100, 3455.
10.1021/ol100078w  2010 American Chemical Society
Published on Web 02/09/2010

Table 1. Evaluation of Conditions for the Formation of Indoline 3aa
yield (%)c
with acid/base
b
entry
acid
pKa
conjugate base
with acid
1
2
3
4
5
6
7
8
9
none
CF3CO2H
H3PO4
2,4-dinitrophenol
CH3CO2H
bi(2-naphthol)
thiourea
NaHCO3
CF3CH2OH
urea
none
CF3CO2Na
N/A
79
0
0
N/D
0
N/D
N/D
99
94
68
87
93
-0.25d
2.1d
5.1
12.6
16.2
21.0
10.2d
23.5
26.9
31.4
N/A
0
CH3CO2Na
+ n-BuLi
+ n-BuLi
Na2CO3
CF3CH2ONa
+ n-BuLi
NaOH
92
81
57
80
91
82
67
10
11
85
75
H2O
a All reactions were performed using 1.0 mmol of 1a, 1.1 mmol of acetylacetylene (2a), 20 mol % of DPPP, and 0.50 mmol of the additive(s). b pKa in
DMSO. c Isolated yield. d pKa in H2O.
approach is highly modular and particularly well suited for
the preparation of substituted saturated benzannulated N-
heterocycles. The requisite dinucleophiles are readily as-
sembled from commercially available starting materials.5
Given the common occurrence of the title heterocycles in a
large number of bioactive molecules, this methodology
should provide new avenues toward the preparation of
compounds relevant to the development of human medicines.
to be compatible with nucleophilic phosphine catalysis.7 To
our delight, addition of 50 mol % of AcOH provided a
reaction efficiency comparable with that of aliphatic amine-
derived nucleophiles (entry 5; 92% yield).8 The combination
of a Brønsted acid and its conjugate base performed even
better; we obtained indoline 3a in 99% yield in the presence
of AcOH and NaOAc (50 mol % each).9 Indeed, for several
common Brønsted acid additives, pairs of acids and bases,
rather than the acids or bases alone, consistently provided
higher product yields (entries 5-11).10 Although there was
no clear correlation between the pKa of the Brønsted acid
and the reaction efficiency, additives of low pKa completely
shut down the reaction, presumably through quenching of
As a test case for the construction of aniline-containing
benzannulated heterocycles, we subjected the nucleophile 1a
and acetylacetylene (2a) to our previously reported mixed
double-Michael reaction conditions: i.e., 20 mol % of
diphenylphosphinopropane (DPPP) in CH3CN (Table 1, entry
1). The desired indoline 3a was obtained in 79% yield.6
Although this yield is acceptable synthetically, the reaction
efficiency was markedly poorer than that for pyrrolidine
formation from a corresponding aliphatic amine-derived
nucleophile (91% vs 79%). To improve the reaction ef-
ficiency, we tested Brønsted acid additives that are known
the reactive zwitterionic intermediates (entries 2-4).11
2-
Notably, one inorganic acid/base pair (NaHCO3/CO3
)
improved the reaction yield by 8%, whereas another (H2O/
NaOH) did not (entries 8 and 11).12 The added acid/base
pair presumably facilitated the proton transfer steps involved
in the double-Michael process.
The combination of DPPP catalyst and AcOH/NaOAc
(2) The Chemical Abstracts Service (CAS) database provided the
following numbers of references for each heterocycle: indoline, 3374 patents,
102 reviews; benzimidazoline, 1085 patents, 19 reviews; tetrahydroquinoline,
2020 patents, 38 reviews; tetrahydroisoquinoline, 2165 patents, 361 reviews;
dihydrobenzoxazines, 928 patents, 25 reviews.
(7) For selected examples, see: (a) Takashina, N.; Price, C. C. J. Am.
Chem. Soc. 1962, 84, 489. (b) Oda, R.; Kawabata, T.; Tanimoto, S.
Tetrahedron Lett. 1964, 5, 1653. (c) McClure, J. D. J. Org. Chem. 1970,
35, 3045. (d) Rychnovsky, S. D.; Kim, J. J. Org. Chem. 1994, 59, 2659.
(e) Thalji, R. K.; Roush, W. R. J. Am. Chem. Soc. 2005, 127, 16778. (f)
Xia, Y.; Liang, Y.; Chen, Y.; Wang, M.; Jiao, L.; Huang, F.; Liu, S.; Li,
Y.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 3470. (g) Mercier, E.; Fonovic,
B.; Henry, C.; Kwon, O.; Dudding, T. Tetrahedron Lett. 2007, 48, 3613.
(8) Trost, B. M.; Kazmaier, U. J. Am. Chem. Soc. 1992, 114, 7933.
(9) Trost, B. M.; Dake, G. R. J. Am. Chem. Soc. 1997, 119, 7595.
(10) See the Supporting Information for a list of all of the additives
tested.
(3) For reviews on their synthesis, see: (a) Katritzky, A. R.; Rachwal,
S.; Rachwal, B. Tetrahedron 1996, 52, 15031. (b) Achari, B.; Mandal, S. B.;
Dutta, P. K.; Chowdhury, C. Synlett 2004, 2449. (c) Ilas, J.; Anderluh, P. S.;
Dolenc, M. S.; Kikelj, D. Tetrahedron 2005, 61, 7325. (d) Chrzanowska,
M.; Rozwadowska, M. D. Chem. ReV. 2004, 104, 3341. For selected
examples, see: (e) Mei, T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009,
131, 10806. (f) Liu, X.-Y.; Che, C.-M. Angew. Chem., Int. Ed. 2009, 48,
2367.
(11) Virieux, D.; Guillouzic, A.-F.; Cristau, H.-J. Tetrahedron 2006,
62, 3710.
(4) Sriramurthy, V.; Barcan, G. A.; Kwon, O. J. Am. Chem. Soc. 2007,
129, 12928.
(12) For Brønsted acid/phosphine bifunctional catalysis, see: (a) Shi,
M.; Chen, L.-H.; Li, C.-Q. J. Am. Chem. Soc. 2005, 127, 3790. (b) Cowen,
B. J.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 10988. (c) Fang, Y.-Q.;
Jacobsen, E. J. Am. Chem. Soc. 2008, 130, 5660. (d) Meng, X.; Huang, Y.;
Chen, R. Org. Lett. 2009, 11, 3498, and references cited therein.
(5) See the Supporting Information for the preparation of the starting
materials.
(6) With 20 mol % of the monodentate tertiary phosphines PPh3 and
PEtPh2, we obtained 3a in 18 and 23% yields, respectively.
Org. Lett., Vol. 12, No. 5, 2010
1085

well as heteroaromatic rings were compatible with the
reaction. For instance, the pyridylmalonate 1d provided the
dihydropyrrolopyridines 3d and 3e in excellent yields at
elevated temperature (entries 3 and 4). The 1,2-benzenedi-
amine-derived nucleophile 1f also underwent the double-
Michael reaction to provide the benzimidazoline 3f (entry
5). This result is in stark contrast with Lu’s report of the
tandem umpolung addition/Michael reactions of 1,2-di(p-
toluenesulfonamido)ethane onto acetylenes.14 Benzimidazo-
lines are not only important biologicallysthey are used as
sources of organic hydrides and hydrogen storage materials.15
Next, we extended this chemistry to 1,5-dinucleophiles for
the synthesis of six-membered ring-fused benzannulated
heterocycles via [5 + 1] annulation. The benzyl alcohol 1g
reacted well under the optimized reaction conditions, provid-
ing the dihydrobenzo-3,1-oxazine 3g in 88% isolated yield
(entry 6). A notable extension of this methodology is
represented by the annulations of the related nitrogen-carbon
dinucleophile 1h to give the benzomorpholines 3h and 3i
(entries 7 and 8), which slowly decomposed in the presence
of AcOH and NaOAc in refluxing CH3CN; we found,
however, that catalytic DPPP alone provided slightly better
product yields.16 Dihydrobenzo-1,4- and -3,1-oxazines have
long been recognized for their wide range of medicinal
activities (e.g., antibacterial, neuroprotectant, cardiovascular,
antitumor).17
Table 2. Syntheses of Benzannulated N-Heterocyclesa
We further extended this [5 + 1] annulation to the
synthesis of tetrahydroquinolines and tetrahydroisoquinolines
(Table 2, entries 9-12). The benzylmalonate 1j, when mixed
with electron-deficient acetylenes and catalytic DPPP, gener-
ated the tetrahydroquinolines 3j and 3k in excellent yields
(entries 9 and 10). The tetrahydroisoquinolines 3l and 3m
were formed from the corresponding benzylamine-derived
pronucleophiles 1l and 1m (entries 11 and 12). Tetrahyd-
roquinolines and -isoquinolines are present in many natural
products and exhibit a wide range of pharmacological
activities.18
To summarize, seven different types of bicyclic
heterocyclessindoline, dihydropyrrolopyridine, benzimida-
zoline, dihydrobenzo-3,1-oxazine, dihydrobenzo-1,4-oxazine,
tetrahydroquinoline, and tetrahydroisoquinolinescan be syn-
thesized in one step, in excellent yields, from simple
dinucleophiles and electron-deficient acetylenes. The Michael
reaction is one of the most important fundamental organic
reactions; our study highlights the power of the Michael
reaction when applied to the right combination of starting
materials under suitable reaction conditions. This versatile
catalysis was mediated by DPPP with, in some cases, AcOH/
NaOAc additives. This DPPP-catalyzed mixed double-
a Performed using 1.0 mmol of the nucleophile, 1.1 mmol of the
acetylene, 20 mol % of DPPP, and 0.50 mmol of AcOH and NaOAc in
CH3CN at rt, unless otherwise noted. b Isolated yields after chromatographic
purification. c Reactions were performed under reflux. d Reactions were run
in the absence of AcOH/NaOAc in CH3CN under reflux. e In the absence
of AcOH/NaOAc in CH3CN at rt.
(14) Lu, C.; Lu, X. Org. Lett. 2002, 4, 4677.
(15) (a) Smith, J. G.; Ho, I. Tetrahedron Lett. 1971, 38, 3541. (b)
Prakash, G. K. S.; Mathew, T.; Panja, C.; Vaghoo, H.; Venkataraman, K.;
Olah, G. A. Org. Lett. 2007, 9, 179, and references therein.
(16) See the Supporting Information for details.
(17) (a) Gromachevskaya, E. V.; Kvitkovskii, F. V.; Kosulina, T. P.;
Kul’nevich, V. G. Chem. Heterocycl. Compd. 2003, 39, 137. (b) Liu, Z.;
Chen, Y. Tetrahedron Lett. 2009, 50, 3790, and references therein.
(18) (a) Balasubramanian, M.; Keay, J. G. In ComprehensiVe Hetero-
cyclic Chemistry II; McKillop, A., Ed.; Pergamon Press: Oxford, 1996; Vol.
5, Chapter 5, pp 245-300. (b) Scott, J. D.; Williams, R. M. Chem. ReV.
2002, 102, 1669.
additives provided a variety of aniline-containing hetero-
cycles efficiently (Table 2).13 With the phenylmalonate
nucleophile 1a, both benzoylacetylene and methyl propiolate
were suitable Michael acceptors (entries 1 and 2). A variety
of substituents on the benzene ring (cf. entries 6 and 12) as
(13) The structures of 3a,f-h,j,m were confirmed through X-ray
crystallographic analysis. See the Supporting Information for details.
1086
Org. Lett., Vol. 12, No. 5, 2010

Michael reaction should be further expandable to the
assembly of other heterocyclessone goal for our future
endeavors.
Supporting Information Available: Representative ex-
perimental procedures and spectral data for all new com-
pounds. Crystallographic data for 3a,f-h,j,m (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. Financial support was provided by the
NIH (R01GM071779 and P41GM081282). We thank Dr.
Saeed Khan (Department of Chemistry and Biochemistry,
UCLA) for performing the crystallographic analyses.
OL100078W
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