Facile Installation of 2-Reverse Prenyl Functionality into Indoles by a Tandem N-Alkylation-Aza-Cope Rearrangement Reaction and Its Application in Synthesis

Article abstract of DOI:10.1002/chem.201503355

An unprecedented tandem N-alkylation-ionic aza-Cope (or Claisen) rearrangement-hydrolysis reaction of readily available indolyl bromides with enamines is described. Due to the complicated nature of the two processes, an operationally simple N-alkylation and subsequent microwave-irradiated ionic aza-Cope rearrangement-hydrolysis process has been uncovered. The tandem reaction serves as a powerful approach to the preparation of synthetically and biologically important, but challenging, 2-reverse quaternary-centered prenylated indoles with high efficiency. Notably, unusual nonaromatic 3-methylene-2,3-dihydro-1H-indole architectures, instead of aromatic indoles, are produced. Furthermore, the aza-Cope rearrangement reaction proceeds highly regioselectively to give the quaternary-centered reverse prenyl functionality, which often produces a mixture of two regioisomers by reported methods. The synthetic value of the resulting nonaromatic 3-methylene-2,3-dihydro-1Hindole architectures has been demonstrated as versatile building blocks in the efficient synthesis of structurally diverse 2-reverse prenylated indoles, such as indolines, indolefused sultams and lactams, and the natural product bruceolline D.

Full text of DOI:10.1002/chem.201503355

DOI: 10.1002/chem.201503355
Full Paper
&
Synthesis Design
Facile Installation of 2-Reverse Prenyl Functionality into Indoles
by a Tandem N-Alkylation–Aza-Cope Rearrangement Reaction and
Its Application in Synthesis
Xiaobei Chen,*[a, b] Huaqiang Fan,[a] Shilei Zhang,[b, c] Chenguang Yu,[b] and Wei Wang*[a, b]
Abstract: An unprecedented tandem N-alkylation–ionic aza-
Cope (or Claisen) rearrangement–hydrolysis reaction of read-
ily available indolyl bromides with enamines is described.
Due to the complicated nature of the two processes, an op-
erationally simple N-alkylation and subsequent microwave-ir-
radiated ionic aza-Cope rearrangement–hydrolysis process
has been uncovered. The tandem reaction serves as a power-
ful approach to the preparation of synthetically and biologi-
cally important, but challenging, 2-reverse quaternary-cen-
tered prenylated indoles with high efficiency. Notably, un-
usual nonaromatic 3-methylene-2,3-dihydro-1H-indole archi-
tectures, instead of aromatic indoles, are produced. Further-
more, the aza-Cope rearrangement reaction proceeds highly
regioselectively to give the quaternary-centered reverse
prenyl functionality, which often produces a mixture of two
regioisomers by reported methods. The synthetic value of
the resulting nonaromatic 3-methylene-2,3-dihydro-1H-
indole architectures has been demonstrated as versatile
building blocks in the efficient synthesis of structurally di-
verse 2-reverse prenylated indoles, such as indolines, indole-
fused sultams and lactams, and the natural product bruceol-
line D.
Introduction
theses make them attractive targets for synthesis and mecha-
nism-of-action studies.[3]
2-Reverse prenylated indole natural products are widely dis-
tributed in a number of terrestrial and marine fungi.[1] These
natural products display a broad spectrum of biological and
pharmacological activities, including cytotoxicity against
a number of cancer cell lines, antimicrobial and antiviral activi-
ties, and effects on the central nervous systems, which are dis-
tinct from the non-prenylated parent structures (Figure 1).[2]
Their intriguing biological properties underscore their potential
application as useful probes to elucidate the biological path-
ways and mechanisms and targets involved. They can also
serve as lead compounds for the development of new thera-
peutic agents. A combination of their activity, questions about
their modes of biological action, and challenges of their syn-
2-Reverse prenylated indole alkaloids are among the most
challenging class of natural products currently targeted by the
synthesis community. The structures of 2-reverse prenylated
indole alkaloids feature the same core unit of the 2-reverse
prenylated indole component (Figure 1). Therefore, construc-
tion of the challenging quaternary-centered reverse prenyl unit
in the indole scaffold is critical to their syntheses. The lack of
versatile, efficient synthetic methodologies is one of the major
bottlenecks in this field. More than a decade has passed, since
the only useful method developed by Danishefsky in 1999 was
reported [Scheme 1, Eq. (1)].[4] The strategy involves two steps:
in situ 3-chlorination of an indole by treatment with tBuOCl is
followed by a reaction with prenyl 9-BBN through a nucleophil-
ic substitution rearrangement to give the desired 2-reverse
prenylated indoles. The reaction has been successfully
used as a key step in the total synthesis of the indole alkaloids
gypsetin,[5] (+)-ambiguine H,[5] and asterriquinone B1.[6] An al-
ternative approach is the Cope rearrangement reaction
[Scheme 1, Eq. (2)].[7] Although the process looks more appeal-
ing because it uses readily accessible starting materials, the
poor reaction efficiency limits its synthetic application. Not
only was the yield (27%) far from satisfactory, two isomers
were also produced in the transformation studied by Sakamo-
to et al.[7c]
[a] Dr. X. Chen, H. Fan, Prof. Dr. W. Wang
School of Pharmacy, East China University of Science and Technology
130 Mei-Long Road, Shanghai 200237 (P. R. China)
E-mail: xiaobei@ecust.edu.cn
wwang@unm.edu
[b] Dr. X. Chen, Prof. Dr. S. Zhang, C. Yu, Prof. Dr. W. Wang
Department of Chemistry & Chemical Biology
University of New Mexico, MSC03 2060
Albuquerque, NM 87131-0001 (USA)
Fax: (+1)505-277-2609
E-mail: xiaobei@ecust.edu.cn
wwang@unm.edu
Herein, we report the results of an investigation that has led
to an unprecedented tandem N-alkylation–ionic aza-Cope rear-
rangement–hydrolysis reaction (Scheme 2).[8] The process
serves as a useful strategy for the facile installation of the chal-
lenging 2-reverse quaternary-centered prenyl functionality into
[c] Prof. Dr. S. Zhang
College of Pharmaceutical Sciences, Soochow University
199 Ren’ai Road, Suzhou 215123 (P.R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503355.
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Figure 1. Selected examples of 2-reverse prenylated indole alkaloids.
Scheme 1. Very limited methods available for the synthesis of 2-reverse prenylated indoles. Phth=phthaloyl, TEA=triethylamine, 9-BBN=9-borabicyclo[3.3.1]-
nonane, CSA=camphorsulfonic acid.
indoles with high regioselectivity and in good yields. Through
the careful screening of substrates and optimization of the re-
action conditions, we have identified readily available indolyl
bromides and enamines as effective reactants. Furthermore,
the two reactions require different reaction conditions. We
have managed to identify an operationally simple, sequential
N-alkylation, followed by microwave-irradiated ionic aza-Cope
rearrangement–hydrolysis processes. Notably, unusual, nonaro-
matic, synthetically even more useful 3-methylene-2,3-dihydro-
1H-indole architectures, instead of aromatic indoles, are pro-
duced under the reaction conditions. Moreover, the aza-Cope
rearrangement reaction gives a highly regioselective quaterna-
ry-centered reverse prenyl functionality, which often produces
a mixture of two regioisomers by previously reported meth-
ods.[7c] The synthetic utilities of the resulting nonaromatic 3-
methylene-2,3-dihydro-1H-indole architectures have been dem-
onstrated as versatile building blocks in the efficient synthesis
of structurally diverse 2-reverse prenylated indoles, such as in-
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Scheme 2. Design of the N-alkylation–aza-Cope rearrangement–hydrolysis cascade process for the synthesis of 2-reverse prenyl indoles.
dolines, indole-fused sultams and lactams, and the natural
product bruceolline D.
ity concerns for enamine 2a, an excess amount (5.0 equiv) was
used and the N-alkylation reaction was carried out in aprotic
CH3CN. Although, according to the theoretical studies of Jor-
gensen and Severance,[13] protic solvents offer favorable hydro-
gen-bonding interaction effects on the rate of pericyclic reac-
tions. Therefore, as a compromise, we carried out the two reac-
tions in two different media. Under these reaction conditions,
surprisingly, nonaromatic indoline 5a was formed exclusively.
Furthermore, to our delight, the N-alkylation reaction was com-
pleted within 9 h in CH3CN to give the desired more sterically
demanding 2-reverse prenyl regioisomer.
Results and Discussion
Design of N-alkylation–aza-Cope rearrangement tandem
processes
The Claisen and Cope rearrangements are known as viable syn-
thetic tools for the construction of CÀC bonds with tertiary
and quaternary carbon centers.[9] However, compared with the
classic Cope rearrangement reaction, the aza-Cope version re-
quires much harsher reaction conditions because more energy
is essential to bring the nitrogen atom into the chair topology
of the transition state.[10,11] Recent studies revealed that the
quaternized “N” molecules could dramatically reduce the
energy and enable the rearrangement to occur under milder
conditions.[8,12] As an intriguing extension of these protocols,
coupling of 3-substituted indoles 1 with nucleophilic N,N-dime-
thylisobutenylamine and its analogues 2 would in situ produce
essential quaternized N intermediates, which could undergo
a subsequent aza-Cope rearrangement. A class of compounds
composed of N,N-dimethylisobutenylamine and its analogues
2 are specifically designed for this purpose. It is expected that
the rearrangement products will contain the 2-reverse prenyl
precursor, which is a versatile gem-dimethyl aldehyde function-
ality that can be conveniently transformed into 2-reverse
prenyl group and its derivative through a Wittig reaction. It is
reasonably proposed that the more stable aromatic indole
products 6 may be produced dominantly. Nevertheless, nonar-
omatic 3-methylene-2,3-dihydro-1H-indole holds even more
broad synthetic utilities.
After removal of the solvent, a new protic medium was
added for the subsequent aza-Cope rearrangement process. It
appeared that the solvents had an important effect on the pro-
cess (Table 1). An accelerating effect of microwave irradiation
was observed with water as the solvent in an initial study
(Table 1, entry 3). Under regular heating, a long reaction time
was needed and the yield was low (Table 1, entries 1 and 2;
1008C, 3 and 12 h, 22 and 17% yield, respectively), whereas
with microwave irradiation, the reaction time was shortened
dramatically and the yield improved as well (Table 1, entry 3;
0.8 h, 26% yield). The addition of ethanol to water (EtOH/H2O
1:2) delivered a better yield (Table 1; entry 4, 31% yield). It was
also observed that the amount of EtOH played a role in gov-
erning the yield. A higher ratio of EtOH/H2O was beneficial,
presumably due to improved solubility of the reactants
(Table 1, entries 4–6). Nonetheless, interestingly, in pure etha-
nol, almost no desired product was formed (Table 1, entry 7).
This suggests that water is critical for the reaction, which is
consistent with the theoretical studies of Jorgensen and Sever-
ance.[12] Furthermore, water could also facilitate the hydrolysis
of the iminium ion 4a to give aldehyde 5a, which rendered
the process irreversible (Scheme 1). We then investigated the
rearrangement reaction time because the stability of in situ
generated iminium species 4a could also be affected by water
(Table 1, entries 6 and 8–10). Indeed, 1.5 h was suitable for ach-
ieving a much improved yield of 48%. Accordingly, 1.5 h was
chosen for further optimization. Among different solvent sys-
tems probed (Table 1, entries 8 and 11–14), a combination of
iPrOH/water (4:1) showed the best result with 51% yield
Exploration and optimization of the proposed tandem N-al-
kylation–aza-Cope rearrangement
We commenced our study by exploring the proposed tandem
N-alkylation–aza-Cope rearrangement, followed by hydrolysis,
by using N-acyl indolyl chloride (1a) and N,N-dimethylisobute-
nylamine 2a as starting materials (Table 1). As a result of stabil-
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Table 1. Exploration and optimization of aza-Cope rearrangement reaction.[a]
Entry
Solvent
Additive (2.0 equiv)
T2 [8C]
t2 [h]
Yield [%] (2 steps)[b]
1
2
3
4
5
6
7
8
H2O
H2O
H2O
EtOH/H2O (1/2)
EtOH/H2O (2/1)
EtOH/H2O (4/1)
EtOH
EtOH/H2O (4/1)
EtOH/H2O (4/1)
EtOH/H2O (4/1)
DMF/H2O (4/1)
CH3CN/H2O (4/1)
iPrOH/H2O (4/1)
tBuOH/H2O (4/1)
iPrOH/H2O (4/1)
iPrOH/H2O (4/1)
iPrOH/H2O (4/1)
–
–
–
–
–
–
–
–
–
–
–
–
–
–
100[c]
100[c]
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
3
12
22
17
26
31
36
39
<5
48
43
40
41
44
51
39
43
38
40
0.8
0.8
0.8
0.8
0.8
1.5
2.0
2.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
9
10
11
12
13
14
15
16
17
PhCO2H
[Bu4N][Br]
4 Š MS[d]
[a] Unless specified otherwise, the reactions were carried out on a 0.05 mmol scale of 1a and monitored by the appearance of 5a by TLC and 1H NMR
spectroscopy; see the Experimental Section and Supporting Information. [b] Yields of products isolated. [c] 1008C was achieved through regular heating,
instead of 100 W microwave irradiation. [d] 4 Š MS=4 Š molecular sieves.
(Table 1, entry 13). Nevertheless, there was no positive effect
observed when various additives were applied, including acid
(Table 1, entry 15), phase transfer catalyst (PTC) [Bu4N][Br]
(Table 1, entry 16), and 4 Š MS (Table 1, entry 17).
cess more efficient (Table 2, entries 8–14). When the first step
was carried out at room temperature for 12 min with bromide
1e and enamine 2b, a yield of 77% for the two-step reaction
was obtained (Table 2, entry 10). Longer or shorter reaction
times in the first step decreased the total yield (Table 2en-
tries 8, 9, 11, and 12). The reaction temperature in the first step
significantly affected the reaction yield (Table 2, entries 10, 13,
and 14).
Although the optimization reaction conditions for the
tandem N-alkylation–aza-Cope rearrangement process led to
significantly improved reaction efficiency, the yield of 51% is
far from satisfactory (Table 2, entry 1). Therefore, we turned on
our attention to further optimization by probing the structural
effects of both reactants 1 and 2 on the cascade process
(Table 2).
Scope
First, we focused on the optimization of the N-alkylation re-
action (Table 2). With respect to substrates 1, it is believed that
stronger electron-withdrawing groups (P) on the N atom and
a better leaving group X facilitate the process. Therefore, vari-
ous protecting groups, including Ac, Ms, Boc, and Tf, were ex-
amined (Table 2, entries 1–4). Under the same reaction condi-
tions, Ms-protected N-indole 1b gave an encouraging out-
come (Table 2, entry 2, 55% yield). Interestingly, Tf-protected
1d did not provide the desired product (Table 2, entry 4). How-
ever, switching the leaving group from chloride to bromide led
to a similar yield of product 5d, but the reaction proceeded
much faster (Table 2, entry 5; 2 h, 45% yield). Shorter reaction
times could further improved yields (Table 2, entries 6 and 7;
1 and 0.5 h, 67 and 58% yields, respectively). More stable pyr-
rolidine-derived enamine 2b could not only significantly
reduce the amount used (2.0 equiv), but also render the pro-
Having established an optimal procedure for the tandem N-al-
kylation–aza-Cope hydrolysis process, we probed the generali-
ty of the reaction (Table 3). The results show that the protocol
serves as a general strategy for the synthesis of structurally di-
verse indolines 5 containing the 2,2-dimethyl aldehyde moiety.
A variety of indole bromides, containing electron-neutral
(Table 3, entries 1–3), -donating (Table 3, entries 4 and 5), or
-withdrawing substituents (Table 3, entries 6–11), can efficiently
participate in the process to give good yields of products 5.
Although reasonable yields are obtained for the tandem N-
alkylation–aza-Cope rearrangement process in most cases, we
observed a small amount of compound 7 produced as side
product; this is an important factor that contributes to a reduc-
tion in the yield. It is believed that the compound is generated
from a nucleophilic carbon instead of N attack of indole bro-
mide (Scheme 3).
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Table 2. Optimization of reaction conditions for the first step of the N-alkylation reaction.[a]
Entry
1
2
T1 [8C]
t1
Yield [%] (2 steps)[b]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1e
1e
1e
1e
1e
1e
1e
1e
1e
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
50
0
9 h
9 h
9 h
9 h
2 h
1 h
0.5 h
0.5 h
15 min
12 min
10 min
5 min
12 min
12 min
51
55
35
no desired product
45
67
58[c]
67
72
77
73
56
58
33
9
10
11
12
13
14
1
[a] Unless specified otherwise, the reactions were carried out on a 0.05 mmol scale of 1 and monitored by the appearance of 5 by TLC and H NMR spec-
troscopy; see the Experimental Section. Ms=mesyl, Boc=tert-butyloxycarbonyl, Tf=trifluoromethanesulfonyl. [b] Yield of product isolated. [c] Some 1e re-
mained unreacted.
Table 3. Substrate scope of indole bromides.[a]
Entry
5
R
P
T1 [8C]
t1 [min]
Yield [%] (2 steps)[b]
1
2
3
4
5
6
7
8
5b
5a
5g
5h
5i
5j
5k
5l
–
–
–
Ms
Ac
Ts
RT
RT
RT
RT
RT
RT
50
50
RT
RT
50
12
15
20
15
5
45
15
15
35
80
15
77
37
48
71
73
72
66
64
66
61
85
5-CH3
5-OCH3
5-F
5-Cl
5-Br
6-Br
5-NO2
5-CO2Me
Ms
Ms
Ms
Ms
Ms
Ms
Ms
Ms
9
10
11
5m
5n
5o
1
[a] Unless specified otherwise, the reactions were carried out on a 0.05 mmol scale of 1 and monitored by the appearance of 5 by TLC and H NMR spec-
troscopy; see the Experimental Section. Ts=tosyl. [b] Yield of product isolated.
Synthetic applications
moiety in widely distributed 2-reverse prenylated indole alka-
loids. As demonstrated, the 2-reverse prenyl moiety can be
readily installed by treatment of 5b with methyltriphenylphos-
phonium bromide in the presence of nBuLi, through a Wittig
reaction, in quantitative yield (Scheme 4). Moreover, reverse
prenyl groups containing structurally different olefins, 9 and
The produced indoline compounds 5 are synthetically useful
building blocks, which can be conveniently elaborated for the
synthesis of valuable targets. In this context, the immediate
goal is to build the reverse prenyl group, which is an essential
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Scheme 3. Proposed mechanism for the formation of side product 7.
Scheme 4. The Wittig reactions of 5b for the synthesis of 2-reverse prenyl indolines.
10, can be also introduced successfully with the corresponding
Wittig reagents. This may offer an opportunity to generate un-
natural 2-reverse prenylated indole alkaloids.
yield).[23] In addition, compound 19 could serve as a key inter-
mediate for the syntheses of bruceollines E (20) and J (21), re-
ported by Lopchuk et al. recently.[23]
We found that indoline-fused diastereomeric sultams 11 a
and 11 b were formed efficiently through an interesting intra-
molecular aldol reaction when compound 5b was treated with
the base lithium hydroxide (Scheme 5).[14] The sultams (cyclic
sulfonamides) have emerged as “privileged” structures in drug
discovery.[15] They exhibit broad inhibitory properties against
a variety of enzymes, including cyclooxygenase-2 (COX-2),[16]
human immunodeficiency virus (HIV) integrase,[17] lipoxyge-
nase,[18] calpain I,[19] and matrix metalloproteinase-2 (MMP-2).[20]
In addition, tricyclic lactam 12 was also obtained quantitatively
from acetyl-protected indoline 5a when potassium carbonate
was employed as the base in the reaction.[21]
Conclusion
Driven by the limited number of methods available for the
construction of the synthetically challenging quaternary-cen-
tered reverse prenyl indole scaffold, we developed a new, ver-
satile, highly regioselective tandem N-alkylation–aza-Cope rear-
rangement–hydrolysis process for the facile installation of the
functionality into indoles. Notably, careful screening and opti-
mization of the reaction conditions led us to identify an opera-
tionally simple protocol for the difficult N-alkylation process,
which required mild reaction conditions and nonaqueous
medium, whereas the ionic aza-Cope rearrangement took
place under relatively harsh conditions in an aqueous medium.
Furthermore, the tandem process offered unusual nonaromatic
3-methylene-2,3-dihydro-1H-indole products. The versatile al-
dehyde structures could be conveniently elaborated for the
synthesis of structurally diverse 2-reverse prenylated indoles,
such as indolines, indole-fused sultams and lactams, and the
natural product bruceolline D. Further application of the meth-
odology in complex natural product syntheses is under investi-
gation and the results of these studies will be reported in due
course.
Furthermore, we found that, in the presence of TiCl4, the ex-
ternal olefin moiety in indoline 15, obtained in two-step reac-
tions, reduction of the aldehyde to an alcohol followed by acy-
lation, could undergo isomerization to give aromatic indole 16
in a high yield (Scheme 6). Finally, an intramolecular carbonyl–
ene reaction[22] of 5b through treatment with TiCl4 gave rise to
cyclopent[b]indole 17 in excellent yield. Compound 17 is an
important precursor for the synthesis of natural product bru-
ceolline D (19). Removal of the Ms protecting group by
MeONa was followed by an IBX-mediated oxidation, which led
to target 19. Notably, a high overall yield (62%) for the total
synthesis of 19 from compound 5b was impressively achieved.
This yield is higher than that reported previously (51% overall
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Scheme 5. Intramolecular aldol reactions of 5b and 5a; d.r.=diastereomeric ratio.
Scheme 6. Syntheses of rearomatized indole 16 and bruceolline D (19). DMAP=4-dimethylaminopyridine, IBX=1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide.
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2007; b) L. E. Overman, Tetrahedron 2009, 65, 6432–6446; c) L. E. Over-
man, P. G. Humphreys, G. S. Welmaker, Org. React. 2011, 75, 747–820.
[9] For reviews on Claisen and Cope rearrangements, see: a) H. Frauenrath,
in Houben-Weyl (Methods of Organic Chemistry), Stereoselective Syn-
thesis Vol. E21d, (Eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer, E.
Schaumann), Thieme, Stuttgart, 1995, 3301–3756; b) P. Metzner, Pure
Appl. Chem. 1996, 68, 863–868; c) D. Enders, M. Knopp, R. Schiffers, Tet-
rahedron: Asymmetry 1996, 7, 1847–1882; d) H. Ito, T. Taguchi, Chem.
Soc. Rev. 1999, 28, 43–50; e) U. Kazmaier, S. Maier, F. L. Zumpe, Synlett
2000, 1523–1535; f) S. M. Allin, R. D. Baird, Curr. Org. Chem. 2001, 5,
395–415; g) M. Hiersemann, L. Abraham, Eur. J. Org. Chem. 2002, 1461–
1471; h) Y. Chai, S.-P. Hong, H. A. Lindsay, C. McFarland, M. C. McIntosh,
Tetrahedron 2002, 58, 2905–2928.
[10] a) H. Kwart, C. M. Hackett, J. Am. Chem. Soc. 1962, 84, 1754–1755;
b) R. E. Ireland, J. P. Vevert, J. Org. Chem. 1980, 45, 4259–4260; c) T. Tsu-
noda, O. Sasaki, S. Ito, Tetrahedron Lett. 1990, 31, 727–730; d) S. E. Den-
mark, M. A. Harmata, J. Org. Chem. 1983, 48, 3369–3370; e) S. E. Den-
mark, M. A. Harmata, K. S. White, J. Am. Chem. Soc. 1989, 111, 8878–
8891; f) H. O. House, J. Lubinkowski, J. J. Good, J. Org. Chem. 1975, 40,
86–92.
Experimental Section
General procedure for the preparation of products 5
through the tandem N-Alkylation–aza-Cope rearrangement
reactions (5b as an example; Table 3)
Enamine 2b (0.1 mmol, 2 equiv) was added to a solution of 1e
(0.05 mmol, 1 equiv) in anhydrous CH3CN (0.5 mL). The reaction
was stirred at room temperature or 508C for the time listed in
Table 3. iPrOH (1.2 mL) and H2O (0.3 mL) were added to the reac-
tion mixture, and the resulting solution was subjected to micro-
wave irradiation (100 W, 1008C). After 90 min of microwave irradia-
tion, the reaction mixture was added to brine (10 mL) and extract-
ed with EtOAc (3”). The organic layers were combined and dried
over anhydrous Na2SO4. The solvent was removed under reduced
pressure and the residue was submitted to chromatography to
afford the corresponding product 5b (77% ). 1H NMR (300 MHz,
CDCl3): d=9.61 (s, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.44 (d, J=7.5 Hz,
1H), 7.31 (t, J=7.7 Hz, 1H), 7.19 (t, J=7.5 Hz, 1H), 5.66 (s, 1H), 5.17
(s, 1H), 4.95 (s, 1H), 2.62 (s, 3H), 1.09 (s, 3H), 1.04 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=203.8 (CH), 144.1 (C), 142.6 (C), 132.1
(C), 130.5 (CH), 126.3 (CH), 120.8 (CH), 118.6 (CH), 108.1 (CH2), 70.3
(CH), 51.9 (C), 35.2 (CH3), 18.6 (CH3), 17.5 ppm (CH3); HRMS (ESI+):
m/z calcd for C14H18NO3S+ [M+H]+: 280.1007; found: 280.1008.
[11] S. Marcinkiewicz, J. Green, P. Mamalis, Tetrahedron 1961, 14, 208–222.
[12] a) U. Nubbemeyer, Synthesis 2003, 961–1008; b) D. Fiedler, H. van Hal-
beek, R. G. Bergman, K. N. Raymond, J. Am. Chem. Soc. 2006, 128,
10240–10252.
[13] D. L. Severance, W. L. Jorgensen, J. Am. Chem. Soc. 1992, 114, 10966–
10968.
[14] For recent Adol reactions involving a sulfamide CH3 group, see: a) B.
Pete, G. Simig, L. Poszavacz, L. Toeke, Heterocycles 2003, 60, 2441–
2455; b) M. J. Tozer, I. M. Buck, T. Cooke, S. B. Kalindjian, M. J. Pether,
K. I. M. Steel, Bioorg. Med. Chem. 2001, 9, 425–432; c) H. Harada, J.-I.
Kazami, S. Watanuki, R. Tsuzuki, K. Sudoh, A. Fujimori, M. Sanagi, M.
Orita, H. Nakahara, J. Shimaya, S.-I. Tsukamoto, A. Tanaka, I. Yanagisawa,
Bioorg. Med. Chem. 2001, 9, 2955–2968.
Acknowledgements
Financial support for this research from the National Science
Foundation of China (no. 21372073), the Fundamental Re-
search Funds of East China University of Science & Technology,
East China University of Science & Technology, and the NSF
(CHE-1057569) is gratefully acknowledged.
[15] L. Levy, Drugs Future 1992, 17, 451–454.
[16] a) X. Rabasseda, S. J. Hopkins, Drugs Today 1994, 30, 557–561; b) M. Ina-
gaki, T. Tsuri, H. Jyoyama, T. Ono, K. Yamada, M. Kobayashi, Y. Hori, A.
Arimura, K. Yasui, K. Ohno, S. Kakudo, K. Koizumi, R. Suzuki, S. Kawai, M.
Kato, S. Matsumoto, J. Med. Chem. 2000, 43, 2040–2048.
[17] F. Brzozowski, F. Saczewski, N. Neamati, Bioorg. Med. Chem. Lett. 2006,
16, 5298–5302.
[18] Y. Misu, H. Togo, Org. Biomol. Chem. 2003, 1, 1342–1346.
[19] G. J. Wells, M. Tao, K. A. Josef, R. Bihovsky, J. Med. Chem. 2001, 44,
3488–3503.
[20] R. J. Cherney, R. Mo, D. T. Meyer, K. D. Hardman, R. Q. Liu, M. B. Coving-
ton, M. Qian, Z. R. Wasserman, D. D. Christ, J. M. Trzaskos, R. C. Newton,
C. P. Decicco, J. Med. Chem. 2004, 47, 2981–2983.
Keywords: alkaloids · domino reactions · natural products ·
rearrangement · synthesis design
[1] For recent reviews, see: a) R. M. Williams, E. M. Stocking, J. F. Sanz-Cer-
vera, Top. Curr. Chem. 2000, 209, 97–173; b) S. Li, Nat. Prod. Rep. 2010,
27, 57–78; c) J. M. Finefield, J. C. Frisvad, D. H. Sherman, R. M. Williams,
J. Nat. Prod. 2012, 75, 812–833.
[21] For recent Adol reactions involving an amide CH3 group, see: a) K. B.
Raju, B. N. Kumar, B. S. Kumar, K. Nagaiah, Helv. Chim. Acta 2015, 98,
386–399; b) J. E. Tungen, M. Aursnes, T. V. Hansen, Tetrahedron Lett.
2015, 56, 1843–1846; c) K. G. Primdahl, J. E. Tungen, M. Aursnes, T. V.
Hansen, A. Vik, Org. Biomol. Chem. 2015, 13, 5412–5417; d) Y. Li, G. J.
Dodge, W. D. Fiers, R. A. Fecik, J. L. Smith, C. C. Aldrich, J. Am. Chem.
Soc. 2015, 137, 7003–7006; e) T. A. Targel, J. N. Kumar, O. S. Shneidei, S.
Bar, N. Fridman, S. Maximonko, A. M. Szpilman, Org. Biomol. Chem.
2015, 13, 2546–2549; f) N. Takanashi, K. Tamura, T. Suzuki, A. Nakazaki,
S. Kobayashi, Tetrahedron Lett. 2015, 56, 327–330; g) J. G. Hubert, D. P.
Furkert, M. A. Brimble, J. Org. Chem. 2015, 80, 2715–2723; h) J. Ren, J.
Wang, R. Tong, Org. Lett. 2015, 17, 744–747.
[22] For recent intramolecular carbonyl–ene reactions, see: a) L. Liu, M.
Leutzsch, Y. Zheng, M. W. Alachraf, W. Thiel, B. List, J. Am. Chem. Soc.
2015, 137, 13268–13271; b) L. Butt, M. Hiersemann, Synthesis 2014, 46,
3110–3120; c) D. Tymann, A. Klueppel, W. Hiller, M. Hiersemann, Org.
Lett. 2014, 16, 4062–4065.
[2] a) A. G. Kozlovsky, N. G. Vinokurova, V. M. Adanin, G. Burchardt, H. M.
Dahse, J. Grafe, J. Nat. Prod. 2000, 63, 698–700; b) C. Shinohara, K.
Hasumi, Y. Takei, A. Endo, J. Antibiot. 1994, 47, 163–167; c) H. Hayashi,
K. Furutsuka, Y. Shiono, J. Nat. Prod. 1999, 62, 315–317; d) T. A. Smitka,
R. Bonjouklian, L. Doolin, N. D. Jones, J. B. Deeter, W. Y. Yoshida, M. R.
Prinsep, R. E. Moore, G. M. L. Patterson, J. Org. Chem. 1992, 57, 857–
861; e) J. F. Spilsbury, S. Wilkinson, J. Chem. Soc. 1961, 5, 2085–2091;
f) F.-H. Song, X.-R. Liu, H. Guo, B. Ren, C.-X. Chen, A. M. Piggott, K. Uy, H.
Cao, Q. Wang, M. Liu, X.-T. Liu, H. Q. Dai, L.-X. Zhang, R. J. Capon, Org.
Lett. 2012, 14, 4770–4773.
[3] a) K. A. Miller, R. M. Williams, Chem. Soc. Rev. 2009, 38, 3160–3174;
b) C. F. Nising, Chem. Soc. Rev. 2010, 39, 591–599; c) R. M. Williams, R. J.
Cox, Acc. Chem. Res. 2003, 36, 127–139.
[4] J. M. Schkeryantz, J. C. G. Woo, P. Siliphaivanh, K. M. Depew, S. J. Dani-
shefsky, J. Am. Chem. Soc. 1999, 121, 11964–11975.
[5] P. S. Baran, T. J. Maimone, J. M. Richter, Nature 2007, 446, 404–408.
[6] K. Tatsuta, H. Mukai, K. Mitsumoto, J. Antibiot. 2001, 54, 105–108.
[7] a) H. Plieninger, H. Sirowej, D. Raum, Chem. Ber. 1971, 104, 1863–1868;
b) L. V. Dunkerton, H. Chen, B. P. McKillican, Tetrahedron Lett. 1988, 29,
2539–2542; c) T. Kawasaki, K. Masuda, Y. Baba, K. Takada, M. Sakamoto,
Chem. Pharm. Bull. 1994, 42, 1974–1976.
[23] J. M. Lopchuk, I. L. Green, J. C. Badenock, G. W. Gribble, Org. Lett. 2013,
15, 4485–4487.
[8] For reviews on aza-Claisen and Cope rearrangements, see: a) U. Nubbe-
meyer, in The Claisen Rearrangement: Methods and Applications, (Eds.:
M. Hiersemann, U. Nubbemeyer), Wiley-VCH, Weinheim, Germany,
Received: August 24, 2015
Published online on November 20, 2015
Chem. Eur. J. 2016, 22, 716 – 723
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