One-pot synthesis of aminoenone via direct reaction of the chloroalkyl enone with NaN3: Rapid access to polycyclic alkaloids

Article abstract of DOI:10.1021/jo101226r

(Figure presented) A new one-pot procedure for the preparation of aminoenone from chloroalkyl enone and sodium azide was demonstrated. The structure of the presumed triazoline intermediate in this process was confirmed by X-ray analysis for the first time. As the application of this methodology, the synthesis of polycyclic alkaloid hexahydroapoerysopine (1a) was achieved through an efficient synthetic route.

Full text of DOI:10.1021/jo101226r

pubs.acs.org/joc
One-Pot Synthesis of Aminoenone via Direct Reaction of the Chloroalkyl
Enone with NaN3: Rapid Access to Polycyclic Alkaloids
Yu-Ming Zhao, Peiming Gu, Yong-Qiang Tu,* Hai-Jun Zhang,
Qing-Wei Zhang, and Chun-An Fan
State Key Laboratory of Applied Organic Chemistry, Department of Chemistry,
Lanzhou University, Lanzhou 730000, People’s Republic of China
tuyq@lzu.edu.cn
Received June 27, 2010
A new one-pot procedure for the preparation of aminoenone from chloroalkyl enone and sodium
azide was demonstrated. The structure of the presumed triazoline intermediate in this process was
confirmed by X-ray analysis for the first time. As the application of this methodology, the synthesis of
polycyclic alkaloid hexahydroapoerysopine (1a) was achieved through an efficient synthetic route.
Introduction
preparation of nitrogen heterocyclic compounds.3 As one part
of this pioneering research, the intramolecular reaction of alkyl
azide with enone has been investigated since the early 1980s,
with important contributions made by Schultz, Sha, and
Molander, among others.4 Much of the earlier research was
focused on mechanistic issues related to the breakdown of the
presumed triazoline intermediates. Although these investiga-
tions have greatly developed the azide chemistry, there still
remain some problems especially on the direct experimental
evidence of triazoline intermediate and mild condition of this
Aminoenone (including R-aminoenone and β-aminoenone)
as nitrogen-contained versatile building blocks are exhibiting
more and more utilities for preparation of many biologically
important organic molecules,1 and also, they are often endowed
with useful pharmacological properties.2 Several approaches
have been developed to achieve these units;1a,e however, more
efficient and practical approaches are still required. Rearrange-
ments related to azides have played an extensive role in the
ꢀ
transformation. In 2003, Aube and co-workers reported an
(1) (a) Greenhill, J. V. Chem. Soc. Rev. 1977, 6, 277–294. (b) Lue, P.;
Greenhill, J. V. Adv. Heterocycl. Chem. 1997, 67, 207–343. (c) Cimarelli, C.;
Palmieri, G. Recent Res. Dev. Org. Chem. 1997, 1, 179–189. (d) Michael, J. P.;
de Koning, C. B.; Gravestock, D.; Hosken, G. D.; Howard, A. S.; Jungmann,
C. M.; Krause, R. W. M.; Parsons, A. S.; Pelly, S. C.; Stanbury, T. V. Pure
Appl. Chem. 1999, 71, 979–988. (e) Elassara, A.-Z. A.; El-Khair, A. A.
Tetrahedron 2003, 59, 8463–8480. (f) Ferraz, H. M. C.; Goncalo, E. R. S.
Quim. Nova 2007, 30, 957–964.
elegant Lewis acid promoted intermolecular reaction of alkyl
azide with enone (Scheme 1a).5 In most cases, the products
obtained from the reaction were interesting β-aminoenones,
which might be formed via a [3þ2] cycloaddition-ring contrac-
tion process. According to this hypothesis, only β-aminoenone
(2) (a) Scott, K. R.; Rankin, G. O.; Stables, J. P.; Alexander, M. S.;
Edafiogho, I. O.; Farrar, V. A.; Kolen, K. R.; Moore, J. A.; Sims, L. D.;
Tonnu, A. D. J. Med. Chem. 1995, 38, 4033–4043. (b) Edafiogho, I. O.;
Alexander, M. S.; Moore, J. A.; Farrar, V. A.; Scott, K. R. Curr. Med. Chem.
1994, 1, 159–175. (c) Edafiogho, I. O.; Moore, J. A.; Alexander, M. S.; Scott,
K. R. J. Pharm. Sci. 1994, 83, 1155–1170. (d) Eddington, N. D.; Cox, D. S.;
Roberts, R. R.; Stables, J. P.; Powell, C. B.; Scott, K. R. Curr. Med. Chem.
2000, 7, 417–436. (e) Edafiogho, I. O.; Kombian, S. B.; Ananthalakshmi,
K. V. V.; Salama, N. N.; Eddington, N. D.; Wilson, T. L.; Alexander, M. S.;
Jackson, P. L.; Hanson, C. D.; Scott, K. R. J. Pharm. Sci. 2007, 96, 2509–
2531.
(4) (a) Schultz, A. G.; Ravichandran, R. J. Org. Chem. 1980, 45, 5008–
5009. (b) Schultz, A. G.; McMahon, W. G. J. Org. Chem. 1984, 49, 1676–
1678. (c) Sha, C. K.; Ouyang, S. L.; Hsieh, D. Y.; Hseu, T. H. J. Chem. Soc.,
Chem. Commun. 1984, 492–494. (d) Sha, C. K.; Yuang, J. J.; Ouyang, S. L.
Heterocycles 1984, 566. (e) Sha, C. K.; Ouyang, S. L.; Hsieh, D. Y.; Chang,
R. C.; Chang, S. C. J. Org. Chem. 1986, 51, 1490–1494. (f) Schultz, A. G. Adv.
Cycloaddit. 1988, 1, 53. (g) Molander, G. A.; Hiersemann, M. Tetrahedron
Lett. 1997, 38, 4347–4350. (h) Molander, G. A.; Christopher, T. B. Tetra-
hedron Lett. 2002, 43, 5385–5388.
(5) Reddy, D. S.; Judd, W. R.; Aube, J. Org. Lett. 2003, 5, 3899–3902.
Interestingly, acyclic enones gave different products under similar condi-
tions, see: Mahoney, J. M.; Smith, C. R.; Johnston, J. N. J. Am. Chem. Soc.
2005, 127, 1354–1355.
(3) Resent review see: (a) Lang, S.; Murphy, J. Chem. Soc. Rev. 2006, 35,
146–156. (b) Stefan, B.; Carmen, G.; Kerstin, K.; Viktor, Z. Angew. Chem.,
Int. Ed. 2005, 44, 5188–5240.
DOI: 10.1021/jo101226r
r
Published on Web 07/16/2010
J. Org. Chem. 2010, 75, 5289–5295 5289
2010 American Chemical Society

Zhao et al.
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SCHEME 1. Tandem [3þ2] Cycloaddtion/Rearrangement
SCHEME 2. Preparation of Arylazide Enone Substrate 7
could be formed. Inspired by this result, we envisioned that
the R-aminoenone could be formed (Scheme 1b, path b vs
path a) if the regioselectivity of the [3þ2] cycloaddition6 was
reversed.7 Herein, we present the designed tandem [3þ2]
cycloaddtion/rearrangement leading to R-aminoenone, toge-
ther with it is application to the synthesis of polycyclic
alkaloid.
and zwitterionic species be formed during the process?
(2) How could the regioselectivity of the 1,2-migration be
controlled in order to drive the rearrangement through
path b over path a. Because an electron-donating aromatic
ring has a stronger migratory aptitude over many other
groups,8 arylazide enone 7 was prepared for this envisage
as the model substrate.
As depicted in Scheme 2, reduction of Homoveratric acid 1
with LiAlH4 gave alcohol 2. Bromation and subsequent
chlorination of 2 afforded 4 in 78% overall yield. Treatment
Results and Discussion
Our strategy of constructing R-aminoenone relied on a
tandem regioselective [3þ2] cycloaddtion/1,2-migration.
For this approach to be successful, there were two central
issues to be addressed: (1) Could the triazoline intermediate
n
of 4 with BuLi and B(OMe)3 at -78 °C gave aryl boracic
acid 5 in 92% yield. The Suzuki-Kumada coupling of 5 and
2-iodocyclohexenone afforded enone 6 in 67% yield. We
tried to prepare substrate 7 by heating a mixture of chloride 6
and NaN3 (3.0 equiv) in dry DMF at 60 °C for 24 h. We found
that it directly gave the R-aminoenone 8 as the major product
along with a trace of 7 and the minor enamide-type product.9
(6) Such 1,3-cycloaddition of alkylazide enone to triazoline was presumed
in the literature, but chemists have never observed this intermediate up until
the present moment.
(7) For the decomposition of nonpolarized triazoline, see: (a) Wlad-
kowski, B. D.; Smith, R. H.; Michejda, C. J. J. Am. Chem. Soc. 1991, 113,
7893–7897. (b) Smith, R. H.; Wladkowski, B. D.; Taylor, J. E.; Thompson,
E. J.; Pruski, B.; Klose, J. R.; Andrews, A. W.; Michejda, C. J. J. Org. Chem.
1993, 58, 2097–2103. (c) Schmidt, B. F.; Snyder, E. J.; Carroll, R. M.;
Farnsworth, D. W.; Michejda, C. J.; Smith, R. H. J. Org. Chem. 1997, 62,
8660–8665. For the decomposition of polarized triazoline, see: Hong, K. B.;
Donahue, M. G.; Johnston, J. N. J. Am. Chem. Soc. 2008, 130, 2323–2328.
(8) Initially, we thought that the migration attitude between the aryl
group and acyl group would play an important role in the regioselectivity
during this process.
(9) Interestingly, Molander et al. had observed4h that, treatment of the
analogue of 7 in xylenes under reflux condition for 18-24 h gave enamides as
sole products.
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TABLE 1. One-Pot Strategy to R-Aminoenonea
aGeneral reaction condition: a mixture of chloroalkyl enone (0.2 mmol) and NaN3 (0.6 mmol) in DMF (3 mL) was stirred at 60 or 75 °C under argon
atmosphere until the corresponding alkylazide enone disappeared (determined by TLC analysis). bIsolated yield.
The structure of R-aminoenone 8 was assigned by comparation
of NMR spectra to the analogue 14, which was confirmed by
X-ray analysis (see further for details). Although the yield was
not excellent, this unexpected result indicated that the tandem
intramolecular [3þ2] cycloaddition-rearrangement was feasi-
ble for preparation of R-aminoenone. Further screening of
solvents revealed that it gave better results in polar aprotic
solvents such as DMF or DMSO, while only azide 7 could be
obtained when the reaction was performed in CH3CN or
nonpolar toluene. Additionally, this reaction was sensitive to
the temperature. We found that it gave aminoenone 8 in dra-
matically lower yield when the temperature was increased to
100 °C.
To our delight, all substrates were proved to be effective in
this reaction and the desired R-aminoenones were obtained
in moderate to good yields. Generally, five-membered sub-
strates gave better results than six-membered ones. Electron-
donating substitutions on the aryl rings only slightly affected
the yields. It should be noted that the five-membered sub-
strates always gave a relatively stable intermediate under the
reaction condition. The intermediates could be isolated and
converted to the final R-aminoenone products slowly in the
presence of water, while 2N aqueous HCl would accelerate
the process. We were pleased to observe that the triazoline
intermediate 1711 relevant to the R-aminoenone 1412 was
stable in basic medium. Initially, we tried our best to obtain
As shown in Table 1, several arylchloroalkyl enone analo-
gues10 were prepared to investigate the efficiency of the reaction.
(11) The crystallographic coordinates for 17 have been deposited with the
Cambridge Crystallographic Data Centre; deposition no. 742901. These data
can be obtained free of charge from the Cambridge Crystallographic Data
Centre, 12 Union Rd., Cambridge CB2 1EZ, UK or via www.ccdc.cam.ac.
uk/data_request/cif.
(10) For the syntheses of substrates see the Supporting Information for
details.
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FIGURE 1. X-ray crystallography of compounds 14 and 17.
produced by aryl and alkyl group migration. From our experi-
mental results, we thought that the migration difference between
these two types of substrates might be mainly caused by the
migratory aptitudes of the aryl and acyl groups. For arylchloro-
alkyl enone, the aryl group would migrate over the acyl group.
Additionally, the preference of an antiperiplannar fashion also
would be important to the regioselectivity of the 1,2-migration
process. The X-ray crystallographic analysis of triazoline 17
(Figure 1) agreed well with this presumption, which showed that
the dihedral angle (139.21°) of the acyl and the dinitrogen
groups was closer to a straight angle than that (92.01°) between
the aryl and the dinitrogen groups. However, the aryl migration
took place to give R-aminoenone as the sole product. For
nonarylchloroalkyl enone, the antiperiplannar migration rule
and the stability of the newly formed positive charge center
controlled the regioselectivity of this process, so the β-aminoe-
none formed as the major product. Currently, we are trying to
obtain more crystal structures of the triazoline intermediates.
We hope we can better understand the regioselectivity of the
migration from these intermediates. Additionally, we are also
trying to seek insight into this 1,2-migration process by means of
computational chemistry in our laboratory.
By the above results, some valuable information could be ob-
tained. First, the designed tandem [3þ2] cycloaddtion/1,2-migra-
tion rearrangement reaction to R-aminoenone was feasible when
arylchloroalkyl enones were employed as substrates. Second, the
reaction temperature was very important for this one-pot reac-
tion of both the arylchloroalkyl enone and nonarylchloroalkyl
enone substrates. Third, this reaction showed a high sovent effect.
We thought that polar aprotic solvents DMF or DMSO could
well promote the fragmentation of triazoline intermediate. Last,
this one-pot reaction could give some interesting aminoenones
which would be valuable for the syntheses of alkaloids.
FIGURE 2. Representative polycyclic alkaloids with [5,7] and [6,7]
ring-fused R-aminoenones.
the crystal of compound 17 in different solvents. After many
experiments, the crystalline form of 17 as yellow small needles
was obtained from a mixture of 5% triethylamine in DCM in
40-70% yield. The structure was confirmed by X-ray analysis
(Figure 1). To the best of our knowledge, this was the first time
the crystal structure of triazoline generated in the 1,3-cycload-
dition of alkyl azide and enone was obtained. These results
demonstrated this transformation was efficient to construct
[5,7] and [6,7] fused polycyclic R-aminoenones, which widely
existed in many important polycyclic alkaloids, such as hex-
ahydroapoerysopine (1a) and cephalotaxine (1b) (Figure 2).
Successively, our investigation of the substrate scope turned to
employing nonarylchloroalkyl enones. Thus, several such sub-
strates were synthesized and examined under the optimized con-
dition. However, these substrates afforded none of the desired
R-aminoenones, but only (Z)-β-aminoenones13 (Table 2). Both
cyclic and acyclic chloroalkyl enones were effective to give the
β-aminoenones. Some important nitrogen-contained units were
readily achieved in acceptable yields under this condition.
Compared with our designed strategy for R-aminoenone
(Scheme 1b), it was easy to find that all nonarylchloroalkyl
enone substrates gave the acyl group migration products (path a
favored over path b). The regioselectivity of the migration is
quite different because there are at least two factors that will
control the process, namely the inherent migratory aptitude of
the migrating group and stereoelectronic factors that generally
present as the antiperiplannar geometry between the migrating
group and the leaving group. Additionally, the stability of the
newly generating positive charge at the migration origin should
also be considered. For this process, the acyl group migration
would develop a more stable positive charge center than that
As a valuable demonstration of this strategy, a convergent
synthesis of 1a14 (Figure 2) was undertaken due to their unique
structures. As shown in Scheme 3, treatment of aminoenone 8
with acetyl chloride under basic condition gave amide 28 in 74%
yield. Aldol condensation of the amide 28 finished the last ring of
1a. Stereoselective hydrogenation of 29 delivered amide 30,
whose relative configuration was assigned by 2D-NMR. Sub-
sequent routine reduction of lactam 30 afforded the racemic
alkaloid 1a.15
(12) We do consider that compound 14 would be in the form of a solid. We
have tried to get it in the form of a solid, but failed. Fortunately the crystalline
product 14 (yellow solid, mp 153-154 °C) was obtained from the solution of
CDCl3 in a fridge at -6 °C after NMR experiment. The analogues of 14 were
all treated with the same operation in this work, unfortunately no crystallines
participated. The crystallographic coordinates for 14 have been deposited
with the Cambridge Crystallographic Data Centre; deposition no. 742900.
These data can be obtained free of charge from the Cambridge Crystal-
lographic Data Centre, 12 Union Rd., Cambridge CB2 1EZ, UK or via www.
ccdc.cam.ac.uk/data_request/cif; It should be noted that the earlier assigned
structure of 14 is now demonstrated to be erroneous, see: (a) Harding, T. T.;
Mariano, P. S. J. Org. Chem. 1982, 47, 482–485. (b) Brumfield, M. A.;
Mariano, P. S.; Yoon, U. C. Tetrahedron Lett. 1983, 24, 5567–5570.
(13) The geometry was assigned based on spectroscopic, see: Gilli, P.;
Bertolasi, V.; Pretto, L.; Lycka, A.; Gilli, G. J. Am. Chem. Soc. 2002, 124,
13554–13567.
(14) For the introduction of 1a, see: (a) Prelog, V; Wiesner, K; Khorana,
H. G; Kenner, G. W Helv. Chim. Acta 1949, 59, 453. (b) Warnhoff, E. W
In Molecular Rearrangements, Part 2; de Mayo, P., Ed.; Interscience:
New York, 1964; pp 846 and 847; (c) Boekelheide, V In The Alkaloids; Manske,
R. H. F., Ed.; Academic Press: London, UK, 1960; Vol. VII, pp 205. For the
synthesis of 1a, see: (d)Iida, H.;Takarai, T.;Kibayashi, C. Chem.Commun. 1977,
644. (e) Iida, H.; Takarai, T.; Kibayashi, C. J. Org. Chem. 1978, 43, 975–979.
(15) Kibayashi et al. had reported the synthesis of 1a. They only gave
some typical signals of 1H NMR in CDCl3 with JEOL JNM-PS-100 NMR
spectrometer. Our NMR spectra were obtained as solution in CD3COCD3,
and there were slight differences with 1H NMR spectra between their sample
and ours in the aromatic area (6.58 vs 6.59, and 6.65 vs 6.81). For details, see
ref 14e.
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TABLE 2. One-Pot Strategy to β-Aminoenonea
aReaction condition: a mixture of chloroalkyl enone (0.2 mmol) and NaN3 (0.6 mmol) in DMF (3 mL) was stirred at 75 °C under argon until the
corresponding alkylazide enone disappeared on TLC. bIsolated yields.
SCHEME 3. Total Synthesis of 1aa
of intermediate triazoline also played a very important
role during the 1,2-migration. Moreover, several notable
aminoenones were obtained and one of them was applied
to the total synthesis of hexahydroapoerysopine through
simple chemical transformations. Currently, extensive
applications of this methodology are underway in our
laboratory.
Experimental Section
aReagents and conditions: (a) 2,6-lutidine, DMAP (cat.), AcCl, THF,
rt, 74%; (b) NaOMe, THF, rt, 59%; (c) Pd(OH)2, H2 (1 atm), rt, 75%;
(d) LiAlH4, THF, reflux, 75%.
General Procedure for the Syntheses of Aminoenones. A
flame-dried Schlenk flask was charged with chloroalkyl en-
one (0.2 mmol) and NaN3 (0.6 mmol) in anhydrous DMF
(3 mL) under argon. The mixture was heated to the appro-
priate temperature and stirred until the alkylazide enone
disappeared (determined by TLC analysis). The mixture was
then cooled to room temperature, quenched with water (note:
Table 1, entries 3, 4, and 5 were quenched with 2 M HCl),
stirred for 5 min, and partitioned between water and CHCl3.
The collected organic layer was dried over MgSO4, concen-
trated, and purified by flash chromatography on silica gel
with ethyl acetate and heptanes as the eluent to give the
aminoenone products.
Conclusion
In conclusion, we have realized a practically useful
one-pot procedure for the syntheses of aminoenones
from the chloroalkyl enone and sodium azide. During this
process, the intramolecular distribution of alkylazide
and enone groups was crucial for the regioselectivity
of initial 1,3-dipolar cycloaddition and the conformation
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Data for 8: Rf 0.2, 2:1 hexane/ethyl acetate, colorless dense oil;
1H NMR (400 MHz, CDCl3) δ 1.86-1.92 (m, 2H), 2.37-2.41
(m, 2H), 2.82 (t, J = 6.4 Hz, 2H), 2.94 (t, J = 7 Hz, 2H), 3.37-
3.41 (m, 2H), 3.89 (s, 3H), 3.92 (s, 3H), 6.71 (s, 1H), 7.25 (s, 1H),
11.23 (br, 1H); 13C NMR (100.6 MHz, CDCl3) δ 21.9, 29.3, 31.3,
38.6, 38.9, 55.9, 56.1, 99.6, 110.7, 111.9, 122.3, 132.2, 147.0,
150.5, 153.1, 203.7; MS (EI) m/z 273, 244, 199, 186, 57; HRMS
(ESI) calcd for C16H20O3N (Mþ þ H) 274.1438, found 274.1435;
m/z287, 286, 165, 91; HRMS (ESI) calcd for C17H22O3N(Mþ þ H)
288.1594, found 288.1590; IR (neat) 1261, 1512, 1613, 2931 cm-1
Data for 25: Rf 0.15, 2:1 hexane/ethyl acetate, colorless dense
.
1
oil; H NMR (400 MHz, CDCl3) δ 1.60-2.10 (m, 5H), 2.25-
2.45 (m, 1H), 2.50-2.75 (m, 2H), 3.15-3.35 (m, 1H), 3.45-3.62
(m, 2H), 6.43-6.45 (q, J = 1.6 Hz, 1H), 6.78-6.80 (d, J = 3.6
Hz, 1H), 7.09 (br, 1H), 7.32-7.33 (d, J = 1.2 Hz, 1H); 13C NMR
(100.6 MHz, CDCl3) δ 21.5, 30.2, 30.9, 41.9, 42.8, 45.6, 100.7,
106.6, 111.3, 138.0, 152.5, 167.6, 196.6; MS (EI) m/z 217, 177,
149, 109, 81, 43; HRMS (ESI) calcd for C13H16O2N (Mþ þ H)
IR (neat) 1276, 1708, 2939 cm-1
.
Data for 10: Rf 0.4, 1:1 hexane/ethyl acetate, colorless dense
oil; 1H NMR (400 MHz, CDCl3) δ 1.84-1.91 (m, 2H), 2.39 (t,
J = 7.6 Hz, 2H), 2.80 (t, J = 6.4 Hz, 2H), 2.89 (t, J = 6.4 Hz,
2H), 3.38 (s, 2H), 6.01 (s, 2H), 6.70 (s, 1H), 7.18 (s, 1H), 11.23
(br, 1H); 13C NMR (100.6 MHz, CDCl3) δ 21.9, 30.0, 31.3, 38.5,
39.1, 101.5, 108.3, 108.6, 123.5, 133.9, 146.1, 148.9, 152.9, 204.1;
MS (EI) m/z 257, 229, 228, 151, 109, 83, 71, 57; HRMS (ESI)
calcd for C15H16O3N (Mþ þ H) 258.1125, found 258.1120; IR
218.1176, found 218.1180; IR (neat) 1545, 1580 cm-1
.
Data for 27: Rf 0.3, 4:1 hexane/ethyl acetate, colorless dense
oil; 1H NMR (400 MHz, CDCl3) δ 1.05 (s, 9H), 1.10-1.25 (m,
2H), 1.40-1.60 (m, 2H), 1.80-2.65 (m, 11H), 3.35-3.50 (m,
2H), 3.72 (t, J = 6.2 Hz, 2H), 7.30-7.45 (m, 6H), 7.60-7.75 (m,
4H), 9.41 (br, 1H); 13C NMR (100.6 MHz, CDCl3) δ 19.2, 23.5,
23.8, 26.8, 27.5, 27.7, 30.5, 34.6, 42.3, 45.4, 63.8, 97.0, 127.5,
129.4, 134.1, 135.6, 164.4, 198.3; MS (EI) m/z 447, 390, 312, 199,
165, 123; HRMS (ESI) calcd for C28H38O2NSi (Mþ þ H)
448.2666, found 448.2665; IR (neat) 704, 1108, 1546, 1634,
(neat) 1027, 1566, 2918 cm-1
.
Data for 12. Rf 0.6, 4:1 hexane/ethyl acetate, colorless dense
oil; 1H NMR (400 MHz, CDCl3) δ 2.49 (t, J = 4.8 Hz, 2H), 2.81
(t, J = 4.6 Hz, 2H), 2.98 (t, J = 4.4 Hz, 2H), 3.48 (t, J = 4.2 Hz,
2H), 4.66 (br, 1H), 7.02 (d, J = 7.2 Hz, 1H), 7.11 (dd, J = 7.2 Hz,
2859, 2932 cm-1
.
Detailed Procedure for Synthesis of the Triazoline 17. A flame-
dried 5 mL Schlenk flask was charged with five-membered
chloroalkyl enone 13 (0.2 mmol) and NaN3 (0.6 mmol) in
anhydrous DMF (3 mL) under argon atmosphere. The mixture
was heated to 60 °C and stirred until the alkylazide enone
disappeared (determined by TLC analysis), and then cooled to
room temperature. The mixture was diluted with CHCl3 and
Et3N (2 mmol). The organic layer was washed with cooled water
three times quickly, collected, dried over MgSO4, and concen-
trated. The solvent was removed under reduced pressure and the
residue was purified by flash chromatography on silica gel with
ethyl acetate, heptanes, and Et3N (10%, V/V) as the eluent. The
crude triazoline was recrystallized with a mixture of 5% triethy-
lamine in DCM several times, which gave pure triazoline 17 as a
small yellow needle in 40-70% yield. Noteworthy was that the
crystalline form of 17 began to melt at 96 °C, and completely
melted at 129 °C. In the melting process, we found that the
original yellow needle crystalline form of 17 was slowly changed
to a milk white solid along with the release of many bubbles. 1H
NMR (400 MHz, CD3COCD3) δ 1.70-1.85 (m, 1H), 2.50-2.85
(m, 6H), 3.40-3.60 (m, 1H), 4.35-4.45 (dd, J1 = 14 Hz, J2 =
5.2 Hz, 1H), 5.22-5.30 (dd, J1 = 8.4 Hz, J2 = 4.8 Hz, 1H),
5.92-5.95 (d, J = 1.6 Hz, 1H), 6.52 (s, 1H), 6.59 (s, 1H); 13C
NMR (100.6 MHz, CD3COCD3) δ 25.7, 28.5, 36.1, 43.6, 73.8,
89.9, 102.2, 106.7, 109.3, 126.0, 129.9, 148.1, 148.3, 206.3, 210.9;
IR (neat) 1035, 1240, 1387, 1481, 1503, 1584, 1697, 1742, 2095,
2919 cm-1; HRMS (ESI) calcd for C14H13O3N3Na (Mþ þ Na)
294.0849, found 294.0853.
Synthesis of 28. To a solution of the aminoenone 8 (42 mg,
0.15 mmol) in dry THF (4 mL) under argon atmosphere was
added 2,6-lutidine (36 μL, 2.0 equiv), acetyl chloride (22 μL,
2.0 equiv), and DMAP (4 mg, 0.2 equiv). The resulting mixture
was stirred for 40 min at room temperature. Then the mixture
was quenched with 3 mL of water and partitioned between water
and CH2Cl2. The organic layer was collected, dried over
MgSO4, filtered, concentrated, and chromatographed (Rf 0.1, 1:1
hexane/ethyl acetate) to afford 28 (36 mg, 74% yield, colorless dense
oil); 1H NMR (400 MHz, CDCl3) δ 1.90-2.20 (m, 5H), 2.25-2.50
(m, 3H), 2.90-3.10 (m, 3H), 3.80-4.00 (m, 8H), 6.69 (s, 1H), 6.98
(s, 1H);13CNMR(100.6MHz, CDCl3) δ20.1, 21.3, 27.6, 31.7, 39.2,
55.9, 56.0, 56.1, 56.2, 110.6, 111.5, 125.7, 127.4, 131.6, 146.6, 150.4,
170.0, 203.8; MS (EI) m/z 315, 287, 259, 244.
1H), 7.20 (dd, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H); 13
C
NMR (100.6 MHz, CDCl3) δ 25.4, 32.5, 39.2, 45.2, 125.9, 126.6,
127.2, 129.3, 130.0, 135.8, 140.9, 203.9; MS (EI) m/z 199, 198,
184, 170, 156, 141, 128, 115; HRMS (ESI) calcd for C13H14ON
(Mþ þ H) 200.1070, found 200.1074.
Data for 14: Rf 0.6, 2:1 hexane/ethyl acetate, colorless dense
1
oil; H NMR (400 MHz, CDCl3) δ 1.50-1.65 (m, 1H), 2.54-
2.57 (m, 2H), 2.80-2.83 (m, 2H), 2.96-2.99 (m, 1H), 3.54 (t, J =
4.4 Hz, 2H), 4.63 (br, 1H), 5.96-6.01 (m, 2H), 6.63 (s, 1H), 6.96
(s, 1H); 13C NMR (100.6 MHz, CDCl3) δ 25.8, 32.4, 38.9, 45.7,
101.2, 105.8, 110.3, 129.7, 135.7, 140.0, 146.4, 146.8, 203.6; MS
(EI) m/z 242, 228, 185, 172, 159, 132, 55, 43; HRMS (ESI) calcd
for C14H14O3N (Mþ þ H) 244.0968, found 244.0972; IR (neat)
1484, 1645, 1685, 2920 cm-1
.
Data for 16: Rf 0.7, 1:1 hexane/ethyl acetate, colorless dense
oil; 1H NMR (400 MHz, CDCl3) δ 2.55 (t, J = 4.6 Hz, 2H), 2.86
(t, J = 4.6 Hz, 2H), 3.00 (t, J = 4.4 Hz, 2H), 3.53 (t, J = 4.2 Hz,
2H), 3.89 (s, 3H), 3.91 (s, 3H), 4.63 (br, 1H), 6.63 (s, 1H), 6.96 (s,
1H); 13C NMR (100.6 MHz, CDCl3) δ 25.6, 32.4, 38.9, 45.3,
55.9, 56.1, 109.5, 113.5, 128.3, 130.0, 134.4, 140.2, 147.4, 148.2,
203.4; MS (EI) m/z 259, 244, 174, 115, 77, 63; HRMS (ESI) calcd
for C15H18O3N (Mþ þ H) 260.1281, found 260.1282; IR (neat)
1504, 1690, 3354 cm-1
.
Data for 19: Rf 0.15, 4:1 hexane/ethyl acetate, yellow dense
1
oil; H NMR (400 MHz, CDCl3) δ 1.05 (t, J = 7.6 Hz, 3H),
1.88-1.96 (m, 2H), 2.19-2.25 (m, 2H), 2.55 (t, J = 7.8 Hz, 2H),
3.51 (t, J = 7.0 Hz, 2H), 5.06 (s, 1H), 9.76 (br, 1H); 13C NMR
(100.6 MHz, CDCl3) δ 10.1, 21.3, 32.2, 34.6, 47.3, 88.4, 167.4,
198.8; MS (EI) m/z 139, 110, 80, 57; HRMS (ESI) calcd for
C8H14ON (Mþ þ H) 140.1070, found 140.1070; IR (neat) 1554,
1625 cm-1
.
Data for 21: Rf 0.1, 4:1 hexane/ethyl acetate, colorless dense
oil; 1H NMR (400 MHz, CDCl3) δ 1.61-1.73 (m, 4H),
1.94-2.02 (m, 2H), 2.28 (t, J = 6.4 Hz, 4H), 2.56 (t, J = 7.8
Hz, 2H), 3.58 (t, J = 7.2 Hz, 2H), 10.57 (br, 1H); 13C NMR
(100.6 MHz, CDCl3) δ 21.1, 23.8, 26.2, 29.6, 30.9, 37.5, 47.6,
97.4, 167.2, 194.7; MS (EI) m/z 165, 164, 136, 109; HRMS (ESI)
calcd for C10H16ON (Mþ þ H) 166.1226, found 166.1227; IR
(neat) 1519, 1610, 2928 cm-1
.
Data for 23. Rf 0.1, 1:1 hexane/ethyl acetate, colorless dense
oil; 1H NMR (400 MHz, CDCl3) δ 1.20-1.35 (m, 1H),
1.45-1.70 (m, 2H), 1.80-1.95 (m, 1H), 1.95-2.10 (m, 1H),
2.10-2.25 (m, 1H), 2.30-2.45 (m, 1H), 2.55-2.75 (m, 1H), 3.88
(s, 6H), 6.75-7.10 (m, 3H), 9.84 (br, 1H); 13C NMR (100.6
MHz, CDCl3) δ 23.8, 25.7, 27.4, 30.5, 42.6, 45.9, 55.8, 97.1,
110.0, 110.6, 119.8, 135.3, 148.4, 149.4, 167.5, 192.8; MS (EI)
Synthesis of 29. To a solution of 28 (152 mg, 0.48 mmol) in dry
THF (5 mL) under argon was added NaOMe (156 mg, 6.0 equiv).
The resulting mixture was stirred for 8 h at room temperature.
Then the mixture was quenched with 3 mL of water at 0°C and
partitioned between water and CH2Cl2. The organic layer was
5294 J. Org. Chem. Vol. 75, No. 15, 2010

Zhao et al.
JOCArticle
collected, dried over MgSO4, filtered, concentrated, and chroma-
tographed (Rf 0.1, ethyl acetate) to afford 29 (84 mg, 59% yield,
colorless dense oil); 1H NMR (400 MHz, CDCl3) δ 2.02-2.10 (m,
2H), 2.80-2.90 (m, 4H), 3.07 (t, J = 7 Hz, 2H), 3.93 (s, 3H), 3.95
(s, 3H), 4.25 (t, J = 6 Hz, 2H), 6.49 (s, 1H), 6.78 (s, 1H), 7.20
(s, 1H); 13C NMR (100.6 MHz,CDCl3) δ 26.2, 28.4, 32.8, 32.9,
39.8, 55.9, 56.1, 110.2, 111.1, 112.1, 119.2, 122.4, 130.8, 137.0,
147.2, 149.7, 159.1, 162.2; IR (neat) 1507, 1651 cm-1; MS (EI) m/z
297, 282, 205, 71, 57, 43; HRMS (ESI) calcd for C18H20O3N
(Mþ þ H) 298.1438, found 298.1443.
The resulting mixture was refluxed for 30 min, and then care-
fully quenched with 3 mL of water and partitioned between
water and CH2Cl2. The organic layer was collected, dried over
MgSO4, filtered, concentrated, and chromatographed (Rf 0.7,
100:3 ethyl acetate/Et3N) to afford 1a (17 mg, 75% yield, pale
yellow dense oil); 1H NMR (400 MHz, acetone-d6) δ 1.20-1.70
(m, 7H), 1.90-2.10 (m, 2H), 2.15-2.45 (m, 2H), 2.45-2.70 (m,
2H), 2.75-3.00 (m, 3H), 3.31 (s, 1H), 3.74-3.79 (d, 6H), 6.59 (s,
1H), 6.81 (s, 1H); 13C NMR (100.6 MHz, acetone-d6) δ 22.1,
23.6, 28.5, 32.6, 40.1, 44.6, 53.8, 56.0, 56.5, 57.4, 64.4, 110.4,
112.8, 128.4, 131.0, 148.6, 148.9; IR (neat) 1517, 2919 cm-1; MS
(EI) m/z 287, 286, 218, 205, 191, 190, 176; HRMS (ESI) calcd for
C18H26O2N (Mþ þ H) 288.1958, found 288.1962.
Synthesis of 30. A solution of 29 (92.7 mg, 0.312 mmol) in
ethyl acetate (6 mL) was treated with Pd(OH)2 (219 mg, 1.0
equiv) under hydrogen. The resulting mixture was stirred for
3 days at room temperature and then the mixture was concen-
trated and chromatographed (Rf 0.4, ethyl acetate) to afford 30
Acknowledgment. We gratefully acknowledge financial
support from the NSFC (Nos. 20732002, 20921120404, and
20972059), “973”program of MOST (2010CB833203), and
“111” program of MOE.
1
(70 mg, 75% yield, colorless dense oil); H NMR (400 MHz,
CDCl3) δ 0.90-1.40 (m, 4H), 1.40-1.60 (m, 1H), 1.80-2.00 (m,
1H), 2.30-3.00 (m, 7H), 3.83-3.84 (d, 6H), 4.48-4.66 (m, 2H),
6.59 (s, 1H), 6.61 (s, 1H); 13C NMR (100.6 MHz, CDCl3) δ 25.2,
27.9, 28.1, 34.3, 36.6, 37.8, 45.3, 55.7, 55.9, 56.1, 109.0, 111.0,
126.7, 127.4, 147.4, 147.9, 172.4; IR (neat) 1258, 1419, 1516,
1653, 2949 cm-1; MS (ESI) m/z 302 (M þ H), 603 (2M þ H).
Synthesis of 1a. To a solution of 30 (14 mg, 0.08 mmol) in dry
THF (4 mL) under argon was added LiAlH4 (6 mg, 2.0 equiv).
Supporting Information Available: Procedure for syntheses
of substrates and characterization date for some new com-
pounds including X-ray structures of 14 and 17. This material
is available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 15, 2010 5295