Divergent amine-catalyzed [4+2] annulation of Morita-Baylis-Hillman allylic acetates with electron-deficient alkenes

Article abstract of DOI:10.1021/ol2032569

An amine-catalyzed [4 + 2] annulation of Morita-Baylis-Hillman allylic acetates 2 with electron-deficient alkenes or diazenes has been developed for efficient syntheses of highly functionalized cyclohexenes, tetrahydropyridazines, and important spirocycle

Full text of DOI:10.1021/ol2032569

ORGANIC
LETTERS
2012
Vol. 14, No. 4
996–999
Divergent Amine-Catalyzed [4 þ 2]
Annulation of MoritaꢀBaylisꢀHillman
Allylic Acetates with Electron-Deficient
Alkenes
Silong Xu, Rongshun Chen, Zifeng Qin, Guiping Wu, and Zhengjie He*
The State Key Laboratory of Elemento-Organic Chemistry and Department of
Chemistry, Nankai University, 94 Weijin Road, Tianjin 300071, P. R. China
zhengjiehe@nankai.edu.cn
Received December 8, 2011
ABSTRACT
An amine-catalyzed [4 þ 2] annulation of MoritaꢀBaylisꢀHillman allylic acetates 2 with electron-deficient alkenes or diazenes has been
developed for efficient syntheses of highly functionalized cyclohexenes, tetrahydropyridazines, and important spirocycles. This reaction unveils
a new reactivity pattern of the intensely studied allylic compounds 2 acting as a C4 synthon in Lewis base catalyzed annulation reactions and also
showcases divergent catalysis between tertiary amines and phosphines.
Lewis base catalysis1 using phosphines and amines as
catalysts is now established as a reliable platform for the
construction of complex molecular architectures, as well as
for diversity-oriented synthesis. In this context, phosphine-
catalyzed annulation reactions of allenoates with activated
alkenes, imines, or carbonyls provide a powerful synthetic
toolbox for a series of carbo- and heterocycles.2 For
example, Lu’s pioneering work3 unveiled that, under
the mediation of substoichiometric PPh3, unsubstituted
allenoates 1 (R = H) readily undergo [3 þ 2] cycloaddition
reactions with activated olefins or imines as a formal 1,
3-dipole to generate cyclopentenes or pyrrolines (Scheme 1,
top left). An innovative extension of this phosphineꢀallene
chemistry reported by Kwon4 disclosed that R-alkyl
allenoates 1 (R = CH2R0) undertake a distinct [4 þ 2]
annulation pattern as a formal 1,4-dipole with alkenes or
imines to provide cyclohexenes or tetrahydropyridines
(Scheme 1, top right). Owing to their high efficiency in
the organic synthesis of ring structures, these two types of
annulations have attracted intense research efforts.5
(5) For selected reports, see: (a) Cowen, B. J.; Miller, S. J. J. Am.
Chem. Soc. 2007, 129, 10988. (b) Fang, Y. Q.; Jacobsen, E. N. J. Am.
Chem. Soc. 2008, 130, 5660. (c) Voituriez, A.; Panossian, A.; Fleury-
Bregeot, N.; Retailleau, P.; Marinetti, A. J. Am. Chem. Soc. 2008, 130,
14030. (d) Sampath, M.; Loh, T.-P. Chem. Sci. 2010, 1, 739. (e) Xiao, H.;
Chai, Z.; Zheng, C.-W.; Yang, Y.-Q.; Liu, W.; Zhang, J.-K.; Zhao, G.
Angew. Chem., Int. Ed. 2010, 49, 4467. (f) Han, X.; Wang, Y.; Zhong, F.;
Lu, Y. J. Am. Chem. Soc. 2011, 133, 1726. (g) Wurz, R. P.; Fu, G. C.
J. Am. Chem. Soc. 2005, 127, 12234. (h) Tran, Y. S.; Martin, T. J.; Kwon,
O. Chem.;Asian J. 2011, 6, 2101. (i) Wilson, J. E.; Fu, G. C. Angew.
Chem., Int. Ed. 2006, 45, 1426. (j) Fujiwara, Y.; Fu, G. C. J. Am. Chem.
Soc. 2011, 133, 12293.
(6) In phosphine-catalyzed [3 þ 2] annulations as a C3 unit, see: (a)
Du, Y.; Lu, X.; Zhang, C. Angew. Chem., Int. Ed. 2003, 42, 1035. (b)
Zheng, S.; Lu, X. Org. Lett. 2008, 10, 4481. (c) Feng, J.; Lu, X.; Kong,
A.; Han, X. Tetrahedron 2007, 63, 6035. (d) Ye, L.-W.; Sun, X.-L.;
Wang, Q.-G.; Tang, Y. Angew. Chem., Int. Ed. 2007, 46, 5951. (e) Wang,
Q.-G.; Zhu, S.-F.; Ye, L.-W.; Zhou, C.-Y.; Sun, X.-L.; Tang, Y.; Zhou,
Q.-L. Adv. Synth. Catal. 2010, 352, 1914. (f) Zhou, R.; Wang, J.; Song,
H.; He, Z. Org. Lett. 2011, 13, 580. (g) Deng, H.-P.; Wei, Y.; Shi, M. Org.
Lett. 2011, 13, 3348. (h) Tan, B.; Candeias, N. R.; Barbas, C. F., III.
J. Am. Chem. Soc. 2011, 133, 4672. (i) Zhong, F.; Han, X.; Wang, Y.; Lu,
Y. Angew. Chem., Int. Ed. 2011, 50, 7837.
(1) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47,
1560.
(2) (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (b)
Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035. (c) Ma,
S. Chem. Rev. 2005, 105, 2829. (d) Ye, L.-W.; Zhou, J.; Tang, Y. Chem.
Soc. Rev. 2008, 37, 1140. (e) Cowen, B. J.; Miller, S. J. Chem. Soc. Rev.
2009, 38, 3102. (f) Marinetti, A.; Voituriez, A. Synlett 2010, 174.
(3) (a) Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906. (b) Xu, Z.; Lu,
X. Tetrahedron Lett. 1997, 38, 461. (c) Xu, Z.; Lu, X. J. Org. Chem. 1998,
63, 5031.
(4) (a) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125,
4716. (b) Tran, Y. S.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 12632.
r
10.1021/ol2032569
Published on Web 02/03/2012
2012 American Chemical Society

byproduct D1.10 Further surveys on catalysts revealed that
other nitrogen nucleophiles including NEt3, DMAP, DBU,
and imidazole all exclusively delivered 4a, but in inferior
yields. N-containing hexamethyl phosphorus triamide
(HMPT) and 1,3,5-triaza-7-phosphaadamantane (PTA)11
also effected the formation of 4a in moderate yields, whereas
PBu3 resulted in a complex mixture and trimethyl phosphite
was ineffective. In the absence of a catalyst, only a trace
amount of 4a was detected. Further optimizations on
conditions confirmed that toluene was still the best solvent
and a higher temperature was necessary for a fast transfor-
mation (for details, see Supporting Information).
Scheme 1. Similar Annulation Patterns of Allenoates 1 and
Allylic Compounds 2 under Lewis Base Catalysis
Recently, a class of generally formulated allylic com-
pounds 2 (Scheme 1, bottom), which could be conveniently
prepared from MoritaꢀBaylisꢀHillman adducts, have
also proven to be appealing and versatile substrates that
can be used as a C3 or C1 synthon in phosphine-catalyzed
[3 þ n] and [1 þ 4] annulations.6ꢀ8 Interestingly, in [3 þ 2]
annulation reactions with activated olefins or imines,
allylic compounds 2 act as a formal 1,3-dipole which
undertakes a similar reactivity to that of allenoates 1 to
furnish isomeric cyclopentenes or pyrrolines (Scheme 1,
bottom left).6 Intrigued by Kwon’s [4 þ 2] work,4 and by
the similar reactivity between allenoates 1 and allylic
compounds 2, we envisaged that allylic compounds 2 could
be employed as a C4 unit in Lewis base catalyzed [4 þ 2]
annulation reactions with activated alkenes if an alkyl
group (R = CH2R0) is introduced, thereby providing
new entries into six-membered ring structures (Scheme 1,
bottom right). Herein, we wish to report the first example
of a Lewis base catalyzed [4 þ 2] annulation reaction of
allylic compounds 2 bearing an extended alkyl group with
activated alkenes and also showcase an example of diver-
gent catalysis between amines and phosphines.
Due to its ease of preparation and equivalency in re-
activity, ethyl 2-bromomethyl-2-butenoate 2a0 was chosen
as an equivalent of allylic bromide 2a (R = Me, Y = Br).9
Our initial investigation started with the model reaction of
allylic bromide 2a0 (0.6 mmol) and N-phenyl maleimide
(0.5 mmol) with K2CO3 (0.75 mmol) in refluxing toluene
(Scheme 2). Under the catalysis of PPh3 (0.05 mmol), the
reaction, however, still proceeded in the well-established
[3þ 2] annulation mode,6a producing 3in 57% yield. Gratify-
ingly, by employing 1,4-diazabicyclo[2.2.2]octane (DABCO)
instead of PPh3 under otherwise identical conditions, the
reaction exclusively afforded the expected [4 þ 2] annulation
product 4a in 95% yield, with a small amount (5%) of
Scheme 2. Divergent Annulation Induced by PPh3 and DABCO
Under the optimized conditions, the scope of allylic
compounds 2 was investigated with N-phenyl maleimide
as a model substrate (Table 1). Allylic carbonate 2b readily
afforded4ain 69% yield in the absence ofK2CO3, since the
in situ generated tert-butoxide anion acted as a base in the
process6a (Table 1, entry 1). In the same manner, allylic
acetate 2c delivered 4a in almost quantitative yield within
24 h (entry 2). Allylic acetates bearing different electron-
withdrawing groups like tert-butoxycarbonyl (2d) and
acetyl (2e) also smoothly produced the corresponding
[4 þ 2] annulation products in good yields (entries 3, 4).
Impressively, allylic acetates (2fꢀi) with variable alkyl
groups were all effective, delivering products 4dꢀg in good
toexcellent yieldsandexclusivediastereoselectivity(entries
5ꢀ8). Regarding its high efficiency, broad scope, and
homogeneous reaction media, allylic acetate 2 (Y = OAc)
could be assessed as the preferred C4 component over its
carbonate and bromide analogues.
Various electron-deficient alkenes as C2 components
were also examined in DABCO-catalyzed [4 þ 2] annula-
tions with representative allylic acetates 2c, 2g, and 2h
(Table 2). Activated terminal alkenes were found to be
good candidates. For example, doubly activated alkene 5
and monoactivated methyl vinyl ketone 7 and acrylates 9
all delivered their cyclohexenes in good yields, albeit with
(7) In phosphine-catalyzed [3 þ n] annulations (n = 3, 4, 6) as a C3
unit, see: (a) Du, Y.; Feng, J.; Lu, X. Org. Lett. 2005, 7, 1987. (b) Zheng,
S.; Lu, X. Org. Lett. 2009, 11, 3978. (c) Zheng, S.; Lu, X. Tetrahedron
Lett. 2009, 50, 4532.
(8) In phosphine-catalyzed [4 þ 1] annulations as a C1 unit, see: (a)
Chen, Z.; Zhang, J. Chem.;Asian J. 2010, 5, 1542. (b) Xie, P.; Huang,
Y.; Chen, R. Org. Lett. 2010, 12, 3768. (c) Tian, J.; Zhou, R.; Sun, H.;
Song, H.; He, Z. J. Org. Chem. 2011, 76, 2374.
(10) Presumably, D1 resulted from dimerization of 2-carboethoxy-
1,3-diene which was derived from 2a0. (a) Spino, C.; Crawford, J.;
Gugelchuk, M.; Cui, Y. J. Chem. Soc., Perkin Trans. 2 1998, 1499. (b)
Spino, C.; Pesant, M.; Dory, Y. Angew. Chem., Int. Ed. 1998, 37, 3262.
(9) Bromination of MoritaꢀBaylisꢀHillman adduct ethyl 3-hydroxy-
2-methylenebutanoate with PBr3 exclusively produced allylic bormide
2a0 rather than 2a. In treatment with nucleophilic phosphines or amines,
both allylic bromides 2a and 2a0 gave the same allylic phosphonium
or ammonium salt and stood chemically equivalent. Also see
ref 6a.
(11) An air-stable and water-soluble cage-like phosphine, often used
as a nucleophilic trialkylphosphine. Tang, X.; Zhang, B.; He, Z.; Gao,
R.; He, Z. Adv. Synth. Catal. 2007, 349, 2007 and referencescited therein.
Org. Lett., Vol. 14, No. 4, 2012
997

Table 1. C4 Scope for the [4 þ 2] Annulation Reactiona
Table 2. C2 Scope for the [4 þ 2] Annulation Reactiona
time
yield
(%)b
entry
1
C4 units
(h)
4
2b: Y = OBoc;
E = CO2Et; R2 = H
2c: Y = OAc;
17
4a
69
99
86
53
77
78
96
93
2
3
4
5
6
7
8
24
10
17
5.5
4
4a
4b
4c
4d
4e
4f
E = CO2Et; R2 = H
2d: Y = OAc;
E = CO2 Bu; R2 = H
t
2e: Y = OAc;
E = COMe; R2 = H
2f: Y = OAc;
E = CO2Et; R2 = Me
2g: Y = OAc;
C4
C2
time
(h)
yield
(%)b
E = CO2Et; R2 = Et
2h: Y = OAc;
entry
1c
units
units
products
12
12
2c
5
6
6a: R3 = H,
major
64
E = CO2Et; R2 = iPr
2i: Y = OAc;
4g
2
3c
2h
2c
5
7
12
15
6b: R3 = iPr
8a: R4 = H,
major
76
88
E = CO2Et; R2 = nBu
a Typical conditions:
(0.5 mmol), and DABCO (0.05 mmol) was refluxed in toluene (3 mL)
under a N2 atmosphere. b Isolated yield based on maleimide.
a mixture of 2 (0.6 mmol), maleimide
4
2h
2c
7
15
15
8b: R4 = iPr
10a: R5 = Me,
major
51
83
5c
9a:
R5 = Me
9b:
6c
7c
8
2c
2c
2c
15
16
12
10b: R5 = tBu,
major
75
66
53
modest regioselectivity in some cases (entries 1ꢀ6). Cyclic
enones 11 and 13 also worked well in the cyclization with
allylic acetate 2c, efficiently constructing spirocycles in
moderate yields with good regioselectivity (>8:1) (entries
7ꢀ9). Spirooxindole scaffolds exist in a number of natural
products and biologically active compounds.12 Isatin-
derived alkene 15 proved to be effective in the [4 þ 2]
annulation reactions with allylic acetates 2c and 2h to
readily generate such complex structures. In a single step,
spirohexeneoxindoles 16 with two or three stereogenic
centers were formed stereoselectively and efficiently
(entries 10, 11).
R5 = tBu
11a:
n = 1
11b:
n = 2
13
12a: n = 1,
major
12b: n = 2
9
2c
2c
2h
2c
2g
2h
2c
24
12
7
14
49
79
76
83
92
94
43
10
11
12
13
14
15
15
16a: R6 = H
16b: R6 = iPr
18a: R7 = H
18b: R7 = Et
18c: R7 = iPr
20
15
17
12
13
12
12
17
17
19
a For details, see Supporting Information. b Isolated yield. c Product
The C2 scope could be further extended to heteroatom
double bonds. Diisopropyl azodicarboxylate 17 was found
to be an excellent partner in the annulations with all
selected allylic acetates, providing tetrahydropyridazines
18 in good to excellent yields (entries 12ꢀ14). Finally,
when 1,4-naphthaquinone 19 was tested, an interesting
cascade [4 þ 2] annulationꢀoxidation process occurred,
leading to the functional anthraquinone 2013 in one step
(entry 15). In the reaction, the naphthaquinone acts as
both an annulation partner and oxidant for the subsequent
aromatization.
was isolated as a regioisomeric mixture with a ratio of 2:1ꢀ8:1.
The above results indicate that this amine-catalyzed [4 þ 2]
annulation features a broad substrate scope with respect to
both the C4 and C2 components. Also, most of the reac-
tions were clean and afforded the cyclization products in
good to excellent yields with complete diastereocontrol
and good regioselectivity. These merits guarantee the
annulation reaction significant potential in the construc-
tion of six-membered carbo-, hetero-, and spirocycles. It is
worthy to mention that, under the catalysis of phosphines,
a series of structurally similar allylic compounds and
(12) (a) Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36, 127. (b)
Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748. (c)
Nandy, J. P.; Prakesch, M.; Khadem, S.; Reddy, P. T.; Sharma, U.;
Arya, P. Chem. Rev. 2009, 109, 1999.
(13) Anthraquinone 20 could provide easy access to some efficient
photoinitiators (“photonucleases”) for oxidative DNA cleavage. See:
(a) Armitage, B.; Yu, C.; Devadoss, C.; Schuster, G. B. J. Am. Chem.
Soc. 1994, 116, 9847. (b) Schuster, G. B. Acc. Chem. Res. 2000, 33, 253.
(14) Other important observations on divergent catalysis from
amines and phosphines were also reported. (a) Evans, C. A.; Miller, S. J.
J. Am. Chem. Soc. 2003, 125, 12394. (b) Shi, Y.-L.; Shi, M. Org. Lett.
2005, 7, 3057. (c) Saunders, L. B.; Miller, S. J. ACS Catal. 2011, 1, 1347.
998
Org. Lett., Vol. 14, No. 4, 2012

electron-deficient alkenes were previously reported by Lu
to undergo a distinct [3 þ 2] annulation.6aꢀc Hence this
study showcases a divergent catalytic reactivity between
tertiary amines and phosphines.14
Theoretically, the putative intermediate B could be fairly
stabilized by the right-positioned ester group. Such a
resonance-stabilized species B is well poised to undergo
1,2-elimination of the amine catalyst to produce a highly
reactive diene 24,10b which subsequently undergoes a Dielsꢀ
Alder reaction with alkenes to form the [4 þ 2] products
(Scheme 3, path a). From the outset, we are also aware that
the [4 þ 2] annulation might proceed via a stepwise mechan-
ism, in which B acts as a formal 1,4-dipole to couple with the
electrophilic alkene (path b). Formations of regioisomeric
[4þ 2] products in our experiments (Table 2, entries 1, 3, 5ꢀ7),
however, argue against such a stepwise scenario.17 Conver-
sely, the high diastereoselectivity observed in the [4 þ 2]
annulation is well in agreement with the endo stereochem-
istry of a DielsꢀAlder reaction.18
Scheme 3. Rationale for the Divergent Annulation Modes
Induced by Phosphines and Amines
In conclusion, we have developed a novel amine-catalyzed
[4þ 2] annulation reaction of MoritaꢀBaylisꢀHillman allylic
acetates 2 with electron-deficient alkenes, which provides
easy access to highly functionalized cyclohexenes, tetrahy-
dropyridazines, and important spirocycles from simple, read-
ily available starting materials. This reaction represents a new
reactivity pattern of the intensely studied allylic compounds 2
acting as a C4 unit in Lewis base catalyzed annulation
reactions. This amine-induced annulation mode is certainly
complementary to the previously well-established phosphine-
induced annulation modes as C3 and C1 units.6ꢀ8 Further-
more, this study showcases divergent catalysis between ter-
tiary amines and phosphines, which could be attributed to
their subtle difference in intrinsic properties such as the
stabilizing ability of ylides.14a,c Future efforts will focus on
exploring the application of the amine-induced reactivity
mode in the development of new synthetic reactions.
The different annulation modes of allylic acetates 2
induced by phosphines and amines are tentatively ratio-
nalized in Scheme 3 according to the stimulating work of
Aggarwal15 and Miller.14a As commonly proposed in
literatures,6ꢀ8 under the catalysis of phosphines, an allylic
P-ylide intermediate A16 is preferentially formed through
an additionꢀeliminationꢀdeprotonation process, which
serves as a surrogate of a 1,3-dipole to undergo the [3 þ 2]
cycloaddition with electron-deficient alkenes.6 This annu-
lation mode takes advantage of the decent ability of
phosphorus to stabilize an ylide structure.15 In sharp
contrast, the amine-catalyzed annulation of allylic com-
pounds 2 with alkenes could not adopt the same [3 þ 2]
mode since the N-atom lacks the suitable ability to stabilize
its corresponding N-ylide intermediate.15 Consequently, the
zwitterionic intermediate B is alternatively formed, presum-
ably by deprotonation at the δ-carbon of ammonium salt 23.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (Grant Nos.
20872063; 21072100; 21121002) is gratefully acknowledged.
Supporting Information Available. Experimental de-
tails, characterization data, and NMR spectra for new
compounds, as well as the X-ray crystallographic data
(CIF files) for 4d. This material is available free of charge
via the Internet at http://pubs.acs.org.
(17) Our preliminary attempt to explore an asymmetric version of the
[4 þ 2] annulation by using chiral amine catalysts (quinine, cinchonine,
O-methylated quinine) rendered no enantioselectivity. This result im-
plies that the amine catalyst might be eliminated before the annulation
and also supports the DielsꢀAlder pathway.
(15) Riches, S. L.; Saha, C.; Filgueira, N. F.; Grange, E.; McGarrigle,
E. M.; Aggarwal, V. K. J. Am. Chem. Soc. 2010, 132, 7626.
(16) P-ylide intermediates like A were observed by 31P NMR and
were successfully entrapped with aldehydes via a Wittig reaction in our
prior work. Zhou, R.; Wang, C.; Song, H.; He, Z. Org. Lett. 2010, 12,
976.
(18) (a) Diels, O.; Alder, K. Liebigs Ann. Chem. 1928, 460, 98. (b)
Pindur, U.; Lutz, G.; Otto, C. Chem. Rev. 1993, 93, 741.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
999