Intramolecular azide-alkene 1,3-dipolar cycloaddition/enamine addition(s) cascade reaction: Synthesis of nitrogen-containing heterocycles

Article abstract of DOI:10.1002/adsc.201200071

A cascade intramolecular azide-alkene 1,3-dipolar cycloaddition/1,2 enamine and/or 1,4 enamine addition reaction sequence has been developed, and provides access to a variety of nitrogen containing heterocycles from readily available ω-azido alkenes. Copy

Full text of DOI:10.1002/adsc.201200071

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DOI: 10.1002/adsc.201200071
Intramolecular Azide-Alkene 1,3-Dipolar Cycloaddition/Enamine
Addition(s) Cascade Reaction: Synthesis of Nitrogen-Containing
Heterocycles
Irene de Miguel,a Bernardo Herradꢀn,a and Enrique Manna,*
a
Instituto de Quꢁmica Orgꢂnica General, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
E-mail: mann@iqog.csic.es
Received: January 26, 2012; Published online: June 5, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200071.
Abstract: A cascade intramolecular azide-alkene
1,3-dipolar cycloaddition/1,2 enamine and/or 1,4 en-
amine addition reaction sequence has been devel-
oped, and provides access to a variety of nitrogen
containing heterocycles from readily available w-
azido alkenes.
Keywords: azides; conjugated addition; cycloaddi-
tion; enamines; ketimines
The development of new cascade processes is a topic
of major interest in organic synthesis.[1] These trans-
formations are generally accompanied by a rapid in-
crease in structural complexity. Furthermore, concepts
such as “atom economy”,[2] “steps economy”[3] or
“redox economy”[4] are inherent to them. In particu-
À
lar, cascade reactions involving the formation of C C
bonds in a stereoselective way are of special impor-
Scheme 1. IAOC/enamine addition cascade reaction.
tance due to the fundamental role of this transforma-
tion in the design of almost any synthetic plan.[5]
able w-azidoalkenes 3 (Scheme 1), after decomposi-
In connection with our interest in the stereoselec- tion of the resulting triazolines (4), could tautomerize
tive synthesis of nitrogen-containing heterocyclic to the corresponding exocyclic (6) and endocyclic (7)
compounds,[6] herein we report our preliminary find- enamines and react with a conveniently located elec-
ings on an efficient cascade reaction that is well- trophilic functionality to afford imines 8 or 9 in one
suited for the preparation of complex and diverse pyr- single synthetic operation. Thus, the success of this
rolidine- and piperidine-containing polycyclic hetero- approach relies on the intrinsic reactivity of the imine
cycles.[7]
functional group, and the correct position of the elec-
Under thermal conditions, azides react with olefins trophile group with respect to the enamine location.
through a 1,3-dipolar cycloaddition reaction to form Movassaghi and Chen recently reported an inter-
1,2,3-D2-triazolines (1)[8] that, unlike their aromatic molecular formal [3+3]cycloaddition of cyclic enam-
analogues, 1,2,3-triazoles, are in general not isolable ines and cyclic enones that provides tricyclic imino al-
and evolve after nitrogen loss to the corresponding cohols in a stereoselective way (Scheme 2).[10] This
imines (2) (Scheme 1). In particular, the intramolecu- methodology was successfully applied to the elegant
lar azide-olefin cycloaddition reaction (IAOC), has synthesis of galbulimima alkaloids GB-13[11] and hi-
found broad application in the synthesis of complex mandrine.[12] In order to test our working hypotheses,
molecules.[9] We envisioned that cyclic ketimines 5 we chose some members of that kind of tricyclic
generated from the IAOC reaction of readily avail- imino alcohols as model targets.
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Applying the optimized conditions for this cascade
reaction, we also prepared imino alcohols 12c–e, start-
ing from the correspondent w-azidoalkenes.[13] Forma-
tion of the corresponding aziridines resulting of de-
composition of the unstable triazoline intermediates
was not detected in any case. While related with the
methodology described by Movassaghi, our approach
is fundamentally different in the way that the enam-
Scheme 2. Movassaghiꢄs intermolecular [3+3]cycloaddition.
Initial studies were performed with w-azido alkenes ine group is introduced in the molecule and, since it is
10a and b (Scheme 3), synthesized in three steps from not only limited to the use of cyclic enones (vide
cyclopenten-2-one.[13] After screening different reac- infra), it allows an access to compounds of wide struc-
tion conditions it was found that the employment of tural diversity.
anhydrous dimethylformamide (DMF) as solvent was
We next turned our attention to the application of
critical for optimal results. We were pleased to find this methodology to more complex substrates. Due to
that heating a solution of w-azidoalkene 10a in DMF the presence of two non-equivalent nucleophilic posi-
in a sealed tube at 1208C for 14 h afforded tricyclic tions (Ca and Ca’) in the transient cyclic ketoimines
amino alcohol 12a as a single diastereomer in 64% generated after triazoline decomposition, we postulat-
yield. Gratifyingly, when the reaction was performed ed that sequential 1,4-addition/1,2-addition of these
under similar conditions but under microwave irradia- ketoimines to a conveniently located enone function-
tion, compound 12a was obtained in 71% yield in ality would afford the corresponding tetracyclic imino
only 3 h. On the other hand, when w-azidoalkene 10b alcohols in a single synthetic operation. As shown in
was subjected to the same protocol, only cyclic imino Scheme 4, Wittig reaction of readily available alde-
ketone 11b was isolated in 86% yield. Treatment of hyde 13[13] with known azidophosphonium salt 25[14]
11b with 1,8-diazabicycloACHTUNTRGNEUNG[5.4.0]undec-7-ene (DBU) in employing KHMDS as base, gave (Z)-w-azidoalkene
refluxing ethanol, as previously reported,[10] afforded 14 in good yield. When compound 14 was subjected
imino alcohol 12b in 77% yield as a single diastereo- to our optimized conditions described above, tetracy-
mer. Interestingly, we observed that just treating 10b clic imino alcohol 20 was obtained as a single diaste-
with DBU in a DMF/ethanol mixture under micro- reomer in 78% yield. Hypothetically, formation of 20
wave irradiation provided compound 12b in a single probably proceeds by an initial IAOC followed by tri-
synthetic operation in an excellent 81% yield, avoid- azoline decomposition that would afford the cyclic
ing the necessity of isolating the intermediate imino imine 16. Tautomerization of 16 to the corresponding
ketone 11b (Scheme 3).
exocyclic enamine 17 and subsequent conjugate addi-
Scheme 3. One-pot synthesis of compounds 12a–e.
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Intramolecular Azide-Alkene 1,3-Dipolar Cycloaddition/Enamine Addition(s) Cascade Reaction
Scheme 4. Synthesis of tetracyclic imino alcohols 20 and 23.
tion to the enone functionality would afford imino ence of dichloromethane as cosolvent (THF/CH2Cl2,
ketone 18, which might undergo a second tautomeri- 9:1) was critical for optimal results in the Wittig reac-
zation to the endocyclic enamine 19 and final addition tion. When compound 22 was subjected to the cycliza-
to the carbonyl group to give 20. Four stereogenic tion conditions, the stereoselective formation of tetra-
centers and three new rings are formed during this 1,3 cyclic imino alcohol 23 was observed. Due to the low
dipolar cycloaddition/1,4 addition/1,2 addition cascade stability of compound 23 towards air oxidation during
process. Finally, 20 was converted into 3-nitrobenzoyl isolation,[16] it was converted into the 3-nitrobenzoyl
derivative 21 and the relative stereochemistry of the derivative 24 for ease of isolation and characteriza-
six contiguous stereocenters present in this molecule tion (Scheme 4).
was confirmed by X-ray diffraction analysis.[15] For-
We also tested this IAOC/double enamine addition
mally, this transformation corresponds to the intramo- process in compounds 28 and 29 (Scheme 5). Since 28
lecular version of the Movassaghi formal [3+3]cyclo- and 29 are 3-substituted enones, a stereogenic quater-
addition reaction.
nary carbon center could be built after enamine con-
Employing azidophosphonium salt 26, (Z)-w-azi- jugate addition. Aldehyde 27 (prepared in two steps
doalkene 22 was prepared from aldehyde 13 in a simi- from commercially available 3-ethoxy-2-cyclohexen-
lar fashion. In this case, we observed that the pres-
one)[13] was converted into w-azidoalkenes 28 and 29
ACHTUNGTRENNUNG
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33. The relative sterochemistry of imino alcohol 30
was confirmed by X-ray crystallographic analysis of
the corresponding amido alcohol 32.[15]
There are interesting aspects to this cascade pro-
cess: as in compounds 20 and 23, (Scheme 4) four ste-
reogenic centers (two of them quaternary) and three
new cycles are created in a single synthetic operation,
but while in 20 and 23 the final stereochemistry is dic-
tated by the configuration of the stereogenic center
already present in the w-azidoalkenes 14 and 22, in
the case of imino alcohols 30 and 31 the cyclization
precursors (28 and 29) are achiral. This fact implies
the possibility of applying asymmetric synthesis meth-
odologies based on enone activation in order to
access to enantiomerically pure derivatives.[17]
Finally, the possibility of carrying out the IAOC/en-
amine addition sequence with acyclic substrates was
examined (Scheme 6). When a DMF solution of
linear w-azidoalkene 34[13] was heated at 1208C for
three hours under microwave irradiation, the bicyclic
imino ester 35 was obtained in 74% yield as a single
diastereomer. Imino ester 37 was prepared from w-
azidoalkene 36 in a similar way in 82% yield, but in
this case lower temperature (1008C) and shorter reac-
tion time (1 h) were required. In order to examine
the influence of the alkene geometry on the reaction
outcome, compound 38 was prepared and subjected
to our cyclization conditions. Treating a solution of
AHCTUNGTREGUN(NN E,E)-azidoalkene 38 in DMF under the same condi-
tions employed for its isomer 36, also furnished bicylic
imino ester 37 in a similar yield. This result indicates
that neither the efficiency nor the stereochemical out-
come of the process is affected by the geometry of
the employed starting w-azidoalkene.
Scheme 5. Synthesis of tetracyclic imino alcohols 30 and 31.
In summary, an efficient stereoselective intramolec-
ular azide-olefin cycloaddition/enamine addition(s)
using a Wittig reaction. Subsequent heating of these reaction cascade of w-azidoalkenes for the prepara-
compounds under optimized conditions afforded tet- tion of diverse complex polycyclic nitrogen-containing
racyclic imino alcohols 30 and 31 respectively, which structures has been developed. Further developments
were separately converted into amido alcohols 32 and of this methodology, including mechanistic insights
Scheme 6. IAOC/enamine addition cascade reaction with linear substrates.
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Intramolecular Azide-Alkene 1,3-Dipolar Cycloaddition/Enamine Addition(s) Cascade Reaction
1H), 1.64 (m, 2H), 1.58–1.51 (m, 5H), 1.36 (m, 1H), 1.24
and an enantioselective version as well as its applica-
tion to the total synthesis of different alkaloids are
currently in progress and will be reported in due
course.
(m, 1H); 13C NMR (100 MHz, CDCl3): d=172.9, 148.4,
139.2, 134.4, 129.8, 125.7, 123.6, 70.4, 59.9, 54.3, 49.9, 45.3,
39.7, 37.1, 35.4, 33.9, 30.8, 28.4, 27.0, 25.3, 18.1; FT-IR
(neat): nmax =3435, 2950, 1625, 1533, 1350 cmÀ1; HR-MS-
ESI: m/z=371.1964, calcd. for C21H27N2O4 [M+H]+:
371.1968.
Experimental Section
Caution: All organic azides should be treated as potential
explosion hazards.
Acknowledgements
rac-(1S,4S,8S,13S,15R)-10-Azatetracyclo-
We thank the Spanish Ministry of Economy and Competitivi-
ty (Project CTQ2010-19295) for financial support as well as
for the purchase of a QToF-HR-MS (Project CTQ2007-
28978-E). I.M. and E.M. thank the Spanish National Re-
search Council (CSIC) for a JAE-Predoc fellowship and I3P-
contract, respectively. We are grateful to Marina Velado for
technical assistance and Dr. Daniel Blanco for insightful dis-
cussions.
[6.5.2.04,15.09,13]pentadec-9-en-1-ol (20)
DBU (0.18 mL, 1.20 mmol) was added to a solution of com-
pound 14 (100 mg, 0.40 mmol) in DMF/ethanol (10 mL,
4:1). The mixture was heated in a microwave reactor at
1208C for 3 h. The dark brown solution was cooled to room
temperature and the solvent evaporated under reduced
pressure. The residue was purified by column chromatogra-
phy (silica gel, gradient from DCM to 97:3 DCM:MeOH) to
afford the desired imino alcohol 19 as a pale yellow viscous
oil; yield; 68 mg (78%). 1H NMR (400 MHz, CDCl3): d=
3.99 (m, 1H), 3.57 (m, 1H), 2.73 (app t, J=9.6 Hz, 1H),
2.41 (m, 2H), 2.16 (m, 1H), 2.08 (m, 1H), 1.94 (m, 1H),
1.82 (m, 2H), 1.76–1.71 (m, 2H), 1.52–1.42 (m, 4H), 1.30
(m, 4H); 13C NMR (100 MHz, CDCl3): d=179.9, 71.2, 59.1,
58.7, 44.8, 38.7, 38.5, 35.0, 34.7, 30.7, 26.5, 24.3, 23.2, 15.7;
FT-IR (neat): nmax =3330, 2950, 2860, 1649, 1460 cmÀ1; HR-
MS-ESI: m/z=220.1695, calcd. for C14H22NO [M+H]+:
220.1696.
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