Phosphine-initiated general base catalysis: Facile access to benzannulated 1,3-diheteroatom five-membered rings via double-Michael reactions of allenes

Article abstract of DOI:10.1021/ol201730q

General base-catalyzed double-Michael reactions of allenes with various dinucleophiles are described. The reactions are facilitated most efficiently by a catalytic amount of trimethylphosphine, affording six types of C2-functionalized benzannulated five-m

Full text of DOI:10.1021/ol201730q

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5420–5423
Phosphine-Initiated General Base
Catalysis: Facile Access to Benzannulated
1,3-Diheteroatom Five-Membered Rings
via Double-Michael Reactions of Allenes
Judy Szeto, 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, United States
ohyun@chem.ucla.edu
Received June 27, 2011
ABSTRACT
General base-catalyzed double-Michael reactions of allenes with various dinucleophiles are described. The reactions are facilitated most
efficiently by a catalytic amount of trimethylphosphine, affording six types of C2-functionalized benzannulated five-membered heterocycles:
benzimidazolines, benzoxazolines, benzothiazolines, 1,3-benzodioxoles, 1,3-benzoxathioles, and 1,3-benzodithioles. This atom-economical
reaction is operationally simple and provides the product heterocycles in good to excellent yields. Careful mechanistic studies unveiled the
phosphine-triggered general base catalysis pathway. Furthermore, the double-Michael reaction can serve as an alternative method for the
selective monoketalization of β-diketones.
C2-Functionalized benzannulated 1,3-diheteroatom
five-membered rings are useful compounds for medicinal
purposes and in materials chemistry.1 For instance, some
1,3-benzodioxoles display endothelin antagonist, anti-in-
flammatory, antimicrobial, and antitumor activities.2 1,3-
Benzothiazolines are used as antioxidants to improve the
oxidative stability of rubbers, polymers, and plastics.3
These scaffolds are commonly synthesized through dehy-
drative condensation of 1,2-disubstituted benzenes with
aldehydes or ketones in the presence of acid catalysts.4 The
reaction conditions are, however, often harsh, employing
strong dehydrating agents (e.g., P2O5) or superstoichiometric
amounts of acid, requiring tedious workup.5 In addition,
no single set of conditions reported previously can be applied
to the preparation of all six benzannulated 1,3-diheteroa-
tom five-membered rings.
The Michael reaction is one of the most versatile pro-
cesses in organic synthesis.6 While intramolecular Michael
reactions of compounds featuring donor/acceptor groups
are valuable for forming functionalized cyclic compounds
from acyclic starting materials,7 intermolecular double-
Michael reactions are particularly powerful tools for assem-
bling complex cyclic products from simple acyclic starting
(5) (a) Iwagami, H.; Yatagai, M.; Nakazawa, M; Orita, H.; Honda,
Y.; Ohnuki, T.; Yukawa, T. Bull. Chem. Soc. Jpn. 1991, 64, 175. (b)
Chan, T. H.; Brook, M. A.; Chaly, T. Synthesis 1983, 203.
(6) (a) Michael, A. J. Prakt. Chem. 1887, 35, 349. (b) Jung, M. E. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Semmelhack,
M. F., Eds.; Pergamon: Oxford, 1991; Vol. 4, Chapter 1.1, pp 1ꢀ68. (c)
Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Else-
vier Science: New York, 1992.
(1) Boshta, N. M.; Bomkamp, M.; Waldvogel, S. R. Tetrahedron
2009, 65, 3773.
(2) (a) Jae, H.-S.; Winn, M.; von Geldern, T. W.; Sorensen, B. K.;
Chiou, W. J.; Nguyen, B.; Marsh, K. C.; Opgenorth, T. J. J. Med. Chem.
2001, 44, 3978. (b) Ullrich, T.; Baumann, K.; Welzenbach, K.; Schmutz,
S.; Camenisch, G.; Meingassner, J. G.; Weitz-Schmidt, G. Bioorg. Med.
Chem. Lett. 2004, 14, 2483. (c) Leite, A. C. L.; da Silva, K. P.; de Souza,
(7) (a) Ihara, M.; Fukumoto, K. Angew. Chem., Int. Ed. Engl. 1993,
32, 1010. (b) Parsons, P. J.; Stefinovic, M. Synlett 1993, 931.
ꢀ
I. A.; de Araujo, J. M.; Brondani, D. J. Eur. J. Med. Chem. 2004, 39,
1059.
€
(8) For a few prominent examples, see: (a) Enders, D.; Huttl,
(3) Robert, D. P.; Frank, A. H. U.S. Patent 4708810, 1987.
(4) Prakash, G. K. S.; Mathew, T.; Panja, C.; Vaghoo, H.; Venka-
taraman, K.; Olah, G. A. Org. Lett. 2007, 9, 179.
M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861. (b) Lu, Z.;
Chai, G.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 6045. (c) Zhang, X.;
Zhang, S.; Wang, W. Angew. Chem., Int. Ed. 2010, 49, 1481.
r
10.1021/ol201730q
Published on Web 09/20/2011
2011 American Chemical Society

materials. Among the intermolecular double-Michael re-
actions, the union of two olefins, functioning as both
acceptor and donor, is most common.8 Recently, we disclosed
the phosphine-catalyzed double-Michael reactions of dinu-
cleophiles with acetylenes as a powerful method for synthesiz-
DABCO, exhibiting efficiency comparable with that of
PMe3 (entries 2ꢀ5). Neither the basicity14 nor the
nucleophilicity15 of the amine base followed the same trend
as the reaction efficiency, hinting at a complex multistep
reaction mechanism (vide infra). The inorganic bases also
facilitated the reaction, albeit with much diminished effi-
ciency (entries 6ꢀ8). Focusing on the double-Michael reac-
tion with PMe3 and DMAP, we investigated a variety of
nucleophiles and allenes for the construction of benzannu-
lated 1,3-diheteroatom five-membered cycles.
ing heterocycles
A
(eq 1).9 Although, theoretically,
disubstituted acetylenes could be used to introduce a qua-
ternary center (as in B), we found that any additional
substituent at the β-carbon atom of the activated acetylene
prohibited its double-Michael reaction. Double-Michael re-
actions of dinucleophiles with allenes, which have the same
degree of unsaturation as acetylenes yet enhanced reactivity,
would conceivably also yield heterocycles B;10 it has been
reported, however, that allenes typically undergo tandem γ-
umpolung addition/Michael cyclization, forming heterocycles
C, in the presence of phosphines.11 Herein, we report a new
phosphine-triggered general base-catalyzed tandem double-
Michael reaction of dinucleophiles with allenes, affording,
under, simple and mild conditions, highly functionalized
heterocycles B featuring fully substituted carbon centers.
Table 1. Double-Michael Reactions of the Amidophenol 1a and
the Allene 2b Mediated by Different Basesa
entry
baseb
PMe3
pKa(H2O)c nucleophilicityd yield (%)e
1
2
3
4
5
6
7
8
8.7
11.3
9.9
15.49f
20.54g
86
26
54
77
82
35
16
53
quinuclidine
3-HQD
DABCO
DMAP
8.7
18.80g
9.2
15.80h (14.95)g
Na2CO3
NaHCO3
NaOAc
10.3
6.3
4.8
a Reactions were performed using 0.4 mmol of 1a and 1.1 equiv of 2b.
b For the complete list of bases tested, see the Supporting Information.
c Reference 14. d Reference 15. e Isolated yield. f The value is the nucleo-
philicity of PBu3 (in CH2Cl2). g Nucleophilicity in MeCN. h Nucleophi-
licity in CH2Cl2.
The tandem umpolung addition/Michael cyclization of
dinucleophiles and allenoates is typically facilitated by
PPh3.11 Indeed, treatment of N-tosyl-2-aminophenol (1a)12
and the allene 2a with PPh3 (10 mol %) provided the
benzomorpholine 3a in 88% yield (eq 2). Switching the
catalyst to PMe3, however, led to production of the double-
Michael product 4a in 92% yield.13 The addition of PMe3 to
allenoate 2a is speculated to form a phosphonium enolate
that acts as a general base and promote the formation of the
double-Michael product 4a (see mechanistic studies below).
To test this hypothesis, we also examined the double-Michael
reactions mediated by amines and inorganic bases.
The PMe3-mediated double-Michael reaction was gen-
erally applicable to a variety of ortho-substituted phenol,
aniline, and thiophenol dinucleophiles (Table 2). Under
the simple conditions of heating the dinucleophile at 90 °C
in MeCN in the presence of the allenoate 2a and PMe3 (10
mol %), 2-mercaptophenol provided the 1,3-benzox-
athiole 4c in 93% yield (entry 1).16 The 1,3-benzodioxole
4d and the 1,3-benzodithiole 4e were also formed readily in
good yields (entries 2 and 3). In contrast, N-tosyl-2-
(11) (a) Cristau, H. J.; Fonte, M.; Torreilles, E. Synthesis 1989, 301.
(b) Liu, B.; Davis, R.; Joshi, B.; Reynolds, D. W. J. Org. Chem. 2002, 67,
4595. (c) Lu, C.; Lu, X. Org. Lett. 2002, 4, 4677. (d) Lu, Z.; Zheng, S.;
Zhang, X.; Lu, X. Org. Lett. 2008, 10, 3267.
(12) Andersen, K. K.; Gowda, G.; Jewell, L.; McGraw, P.; Phillips,
B. T. J. Org. Chem. 1982, 47, 1884.
(13) The structures of 3b (5-chlorobenzene variant of 3a), 4b, and 5c
(5-chlorobenzene variant of 5a) were established unequivocally through
X-ray crystallographic analyses. See the Supporting Information for
details.
(14) (a) Streuli, C. A. Anal. Chem. 1960, 32, 985. (b) Ripin, D. H.;
Evans, D. A. Evans pKa Table. http://www2.lsdiv.harvard.edu/labs/evans/
index.html (accessed June 2011).
(15) (a) Ofial, A.; Mayr, H. Reactivity Scales. http://www.cup.uni-
muenchen.de/oc/mayr/CDpublika.html (accessed June 2011). (b) Brotzel, F.;
Kempf, B.; Singer, T.; Zipse, H.; Mayr, H. Chem.;Eur. J. 2007, 13, 336.
(16) Despite their acetal-like functionality, the heterocycles formed in
this study were stable to flash column chromatography over silica gel.
(17) Mizukami, S.; Kono, M. Chem. Pharm. Bull. 1965, 13, 33.
(18) Kato, T.; Masu, H.; Takayanagi, H.; Kaji, E.; Katagiri, K.;
Tominaga, M.; Azumaya, I. Tetrahedron 2006, 62, 8458.
N-Tosyl-2-aminophenol (1a) was reacted with allene 2b in
the presence of an amine (0.1 equiv) or an inorganic base (1.1
equiv) in MeCN at 90 °C (Table 1). While PMe3 provided
the double-Michael adduct 4b in 86% yield (entry 1), amine
bases displayed varying degrees of success. Among the
common nucleophilic amine bases, DMAP performed better
than quinuclidine, 3-hydroxyquinuclidine (3-HQD), and
(9) (a) Sriramurthy, V.; Barcan, G. A.; Kwon, O. J. Am. Chem. Soc.
2007, 129, 12928. (b) Sriramurthy, V.; Kwon, O. Org. Lett. 2010, 12,
1084.
(10) Cabiddu, S.; Cadoni, E.; Ciuffarin, E.; Fattuoni, C.; Floris, C. J.
Heterocycl. Chem. 1991, 28, 1573.
Org. Lett., Vol. 13, No. 20, 2011
5421

aminothiophenol17 and N,N0-ditosyl-1,2-diaminobenzene18
produced only their mono-Michael adducts at 90 °C; a
temperature of 120 °C was required to facilitate full con-
versions to their double-Michael products, the benzothiazo-
line 4f and the benzimidazoline 4g, respectively (entries 4
and 5). The presence of a chlorine substituent did not affect
the double-Michael reaction of 1g, giving the benzoxazoline
4h in 84% yield (entry 6). When DMAP (10 mol %) was
used, only moderate amounts of the benzothiazoline 4f and
the benzimidazoline 4g were obtained (entries 4 and 5).
general, DMAP was a less-efficient catalyst than PMe3, with
some exceptions (entries 2, 4, and 6). We observed a
particularly noteworthy improvement in the product yield
when DMAP was used for the reaction of the γ-benzyl
allenoate 2d (entries 2 and 6). The lower yield with PMe3 was
likely due to isomerization of the γ-benzyl allenoate 2d to the
corresponding diene.21 The generally superior performance
of PMe3 over DMAP might be due to the phosphonium
cation being better than the pyridinium ion at forming a
spectator countercation for the general bases.
Table 2. Double-Michael Annulations of Various Dinucleo-
philesa
Table 3. Double-Michael Annulations of Substituted Allenoa-
tesa
yield (%)b
yield (%)b
R1, R2
product
PMe3
DMAP
entry
X, Y
Z
product
PMe3
DMAP
entry
X, Y
1
O, S (1b)
H
H
H
H
H
Cl
4c
4d
4e
4f
93
80
74
68
79
84
1
O, NTs
O, NTs
O, NTs
O, S
Ph, H (2c)
Bn, H (2d)
t-Bu, H (2e)
Me, H
4i
83
61
69
74
86
65
58
70
77
89
82
89
86
80
2
O, O (1c)
2
4j
77
51
76
3
S, S (1d)
3
4k
4l
4c
5c
6
S, NTs (1e)
NTs, NTs (1f)
O, NTs (1g)
53
38
4
4g
4h
5
O, S
Ph, H
4m
4n
4o
4p
4q
4r
4s
4t
6
O, S
Bn, H
89
48
68
7
O, S
t-Bu, H
a Reactions were performed using 0.4 mmol of 1 and 1.1 equiv of 2a.
b Isolated yield after chromatography. c Reaction performed initially at
90 °C to obtain the mono-Michael adduct; the temperature was then
raised to 120 °C for full conversation to the double-Michael product.
8
O, O
O, O
O, O
O, O
O, O
O, O
O, O
Me, H
9
Ph, H
10
11
12
13
14
Bn, H
74
68
t-Bu, H
H, Me (2f)
H, Bn (2g)
H, CH2CO2Et
(2h)
4u
4v
To form fully substituted C2 centers decorated with
groups other than Me and CH2CO2Et units, we surveyed
the reactions of various R- and γ-substituted allenoates
(Table 3). Allenoates with γ-substituents19 of varying steric
and electronic demand were well suited to double-Michael
reactionswithN-tosyl-2-aminophenol, 2-mercaptophenol,
and catechol (entries 1ꢀ11). Furthermore, the reactions of
R-substituted allenoates20 with catechol provided the 1,3-
benzodioxoles 4tꢀv in excellent yields (entries 12ꢀ14).
With N-tosyl-2-aminophenol as the dinucleophile, R-substi-
tuted allenoates generated mixtures of diastereoisomers with
poor selectivity, albeit in excellent yields (entries 15ꢀ17). In
15c
16c
17c
O, NTs
O, NTs
O, NTs
H, Me
4w
4x
4y
81d
73d
84d
H, Bn
H, CH2CO2Et
a Reactions were performed using 0.4 mmol of 1 and 1.35 equiv of 2.
b Isolated yield. c NaOAc (50 mol %) was added. d Diastereoisomeric
ratio determined using 1H NMR spectroscopy. Diastereomeric ratios
1:1, 2:1, and 1.2:1 for 4w, 4x, and 4y, respectively.
We gleaned clues regarding the mechanism of this new
phosphine-mediated double-Michael reaction from the
isolation of the mono-Michael product 5a13 of N-tosyl-2-
aminophenol (1a) and the allenoate 2b (eq 3). Intriguingly,
when we heated 5a in MeCN in the presence of catalytic
PMe3, we obtained almost no cyclized product 4b. On the
other hand, exposure of 5a to catalytic PMe3 and the
allenoate 2b in MeCN at 90 °C provided the double-
Michael product 4b in 80% yield. Most interestingly,
treatment of 5a with catalytic PMe3 and 1.1 equiv of the
allenoate 2a also rendered formation of the benzoxazoline
4b. Notably, we detected no product 4a, arising from the
elimination of 1a from 5a and subsequent double-Michael
(19) Lang, R. W.; Hansen, H.-J. Org. Synth. 1984, 62, 202.
(20) Phosphine catalysis using R-substituted allenoates: (a) Kumar,
K.; Kapur, A.; Ishar, M. P. S. Org. Lett. 2000, 2, 787. (b) Zhu, X.-F.;
Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716. (c) Tran, Y. S.;
Kwon., O. Org. Lett. 2005, 7, 4289. (d) Zhao, G.-L.; Shi, M. Org. Biomol.
Chem. 2005, 3, 3686. (e) Castellano, S.; Fiji, H. D. G.; Kinderman, S. S.;
Watanabe, M.; de Leon, P.; Tamanoi, F.; Kwon, O. J. Am. Chem. Soc.
2007, 129, 5843. (f) Tran, Y. S.; Kwon, O. J. Am. Chem. Soc. 2007, 129,
12632. (g) Lu, K.; Kwon, O. Org. Synth. 2009, 86, 212. (h) Guo, H.; Xu,
Q.; Kwon, O. J. Am. Chem. Soc. 2009, 131, 6318. (i) Wang, T.; Ye, S.
Org. Lett. 2010, 12, 4168. (j) Zhang, Q.; Yang, L.; Tong, X. J. Am. Chem.
Soc. 2010, 132, 2550. (k) Wang, Z.; Castellano, S.; Kinderman, S. S.;
Argueta, C. E.; Beshir, A. B.; Fenteany, G.; Kwon, O. Chem.;Eur. J.
2011, 17, 649. (l) Guan, X.-Y.; Wei, Y.; Shi, M. Eur. J. Org. Chem. 2011,
2673. (m) Cruz, D.; Wang, Z.; Kibbie, J.; Modlin, R.; Kwon, O. Proc.
Natl. Acad. Sci. U.S.A. 2011, 108, 6769. (n) Baskar, B.; Dakas, P.-Y.;
Kumar, K. Org. Lett. 2011, 13, 1988. (o) Martin, T. J.; Vakhshori, V. G.;
Tran, Y. S.; Kwon, O. Org. Lett. 2011, 13, 2586.
(21) Xu, S.; Zhou, L.; Zeng, S.; Ma, R.; Wang, Z.; He, Z. Org. Lett.
2009, 11, 3498.
5422
Org. Lett., Vol. 13, No. 20, 2011

reaction of the allenoate 2a.
ketalization of asymmetric β-diketones. The ketalization
of the β-diketone 15 with catechol would produce a
mixture of the acetals 16 and 17. Conversely, the double-
Michael reaction of catechol with the allenone 1824 pro-
duced only the acetal 16 in 90% yield.
Scheme 2. Selective Synthesis of a β-Diketone Mono-acetal
Based on these insights, we propose the following me-
chanism for the double-Michael reaction (Scheme 1). Nu-
cleophilic addition of the phosphine to the allenoate 2results
in the phosphonium enolate 6. Protonation of 6 by the
pronucleophile 1 leads to the formation of a nucleophile/
phosphonium salt pair 7 8, which undergoes γ-umpolung
3
addition to yield the ylide 9 when PPh3 is employed as the
catalyst.11 In contrast, the more-electron-rich phosphine
PMe3 does not facilitate umpolung addition.22 As we had
observed for the double-Michael reactions of acetylenes, the
β,β-disubstituted enoate 10 did not undergo the Michael
reaction.9 Instead, the nucleophile 7 adds to the allenoate 2.
The resulting dienolate 11 undergoes γ-protonation to form
the R,β-unsaturated enoate 13, which is primed for a second
Michael addition. The cyclic enolate 14 can further facil-
itate the double-Michael reaction cycle by deprotonat-
ing the pronucleophile 1 (or mono-Michael product; e.
g., 5a in Scheme 1) to produce the product 4, supporting
the notion of general base catalysis.23 The observation
of no cyclized product derived from the allenoate 2a in
eq 3 also suggests that the second Michael addition is
facile and that the intermediate 11 does not revert back
to the allenoate 2 and the nucleophile 7.
In summary, we have developed a phosphine-triggered
general base-catalyzed double-Michael reaction that en-
ables the syntheses of six different C2-functionalized ben-
zannulated 1,3-diheteroatom five-membered rings from
dinucleophiles and allenes. The reported processes are
operationally simple and atom-economical, minimize the
generation of chemical waste, and employ mild reaction
conditions. Based on the results of experiments performed
using an isolated mono-Michael adduct, we have estab-
lished a general base catalysis mechanism for what appears
to be a phosphine catalysis reaction. Such mechanistic
insight introduces a new twist to the growing number of
phosphine-catalyzed annulation reactions25 and suggests
what might be a general role of phosphines in other annu-
lation processes. This highly efficient methodology also
circumvents the synthetic problem of nonselective ketali-
zation of β-diketones. Our focus is now on expanding the
scope of the pronucleophile, examining the diastereoselec-
tivity of the double-Michael reaction when using R-sub-
stituted allenes, and exploring the umpolung addition/
Michael reaction using 1,2-disubstituted benzenes.
Scheme 1. Mechanism of the Double-Michael Reactions of Allenes
Acknowledgment. This research was supported by the
NIH (R01GM071779, P41GM081282). O.K. thanks Profs.
Daniel A. Singleton (Texas A&M University) and Louis S.
Hegedus (Colorado State University) for helpful discussions.
Supporting Information Available.Representative experi-
mental procedures, characterization data, and copies of 1H
and 13C NMR spectra for all new compounds (PDF). Crystal-
lographic data for 3b, 4b, and 5c (CIF). This information is
available free of charge via the Internet at http://pubs.acs.org.
Scheme 2 demonstrates an additional application of this
double-Michael reaction: what amounts to the selective
(25) Reviews: (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34,
535. (b) Valentine, D. H., Jr.; Hillhouse, J. H. Synthesis 2003, 317. (c)
Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035. (d) Lu,
X.; Du, Y.; Lu, C. Pure Appl. Chem. 2005, 77, 1985. (e) Nair, V.; Menon,
R. S.; Sreekanth, A. R.; Abhilash, N.; Biju, A. T. Acc. Chem. Res. 2006,
39, 520. (f) Ye, L.-W.; Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37, 1140.
(g) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560.
(h) Kwong, C. K.-W.; Fu, M. Y.; Lam, C. S.-L.; Toy, P. H. Synthesis
2008, 2307. (i) Aroyan, C. E.; Dermenci, A.; Miller, S. J. Tetrahedron
2009, 65, 4069. (j) Cowen, B. J.; Miller, S. J. Chem. Soc. Rev. 2009, 38,
3102. (k) Marinetti, A.; Voituriez, A. Synlett 2010, 174. (l) Kolesinska, B.
Cent. Eur. J. Chem. 2010, 1147.
(22) Tricyclohexylphosphine, which is comparable in size to triphe-
nylphosphine, produced only the double-Michael product 4a (in yields
of 93%) when mixed with the allene 1a and the nucleophile 2a.
(23) (a) White, D. A.; Baizer, M. M. Tetrahedron Lett. 1973, 14, 3597.
(b) Yoshida, T.; Saito, S. Chem. Lett. 1982, 1587. (c) Gomez-Bengoa, E.;
Cuerva, J. M.; Mateo, C.; Echavarren, A. M. J. Am. Chem. Soc. 1996,
ꢀ
~
118, 8553. (d) Lumbierres, M.; Marchi, C.; Moreno-Manas, M.;
Sebastian, R. M.; Vallribera, A.; Lago, E.; Molins, E. Eur. J. Org.
ꢀ
Chem. 2001, 2321. (e) Stewart, I. C.; Bergman, R. G.; Toste, F. D. J. Am.
Chem. Soc. 2003, 125, 8696.
(24) Kumar, K.; Kaur, S.; Ishar, M. P. S. Synlett 1999, 1237.
Org. Lett., Vol. 13, No. 20, 2011
5423