Tandem aziridination/rearrangement reaction of allylic alcohols: An efficient approach to 2-quaternary Mannich bases

Article abstract of DOI:10.1021/ol802005n

(Chemical Equation Presented) A novel tandem aziridination/rearrangement reaction of allylic alcohols has been discovered, in which the significant accelerating effect of silica gel has been identified. On the basis of this methodology, an efficient and highly stereoselective approach to various 2-quaternary Mannich bases has been put in place, readily providing an alternative route to the conventional vicinal amino-functionalization of alkenes.

Full text of DOI:10.1021/ol802005n

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4943-4946
Tandem Aziridination/Rearrangement
Reaction of Allylic Alcohols: An
Efficient Approach to 2-Quaternary
Mannich Bases
En Zhang, Yong-Qiang Tu,* Chun-An Fan, Xiong Zhao, Yi-Jun Jiang, and
Shu-Yu Zhang
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry,
Lanzhou UniVersity, Lanzhou 730000, P. R. China
tuyq@lzu.edu.cn
Received August 27, 2008
ABSTRACT
A novel tandem aziridination/rearrangement reaction of allylic alcohols has been discovered, in which the significant accelerating effect of
silica gel has been identified. On the basis of this methodology, an efficient and highly stereoselective approach to various 2-quaternary
Mannich bases has been put in place, readily providing an alternative route to the conventional vicinal amino-functionalization of alkenes.
3-Amino-aldehydes or ketones (Mannich bases) are regarded
as crucial building blocks1 for the synthesis of many
nitrogen-containing biologically important organic molecules.
In particular, Mannich bases bearing a quaternary carbon
center (e.g., anhydrolycodoline, kopsonoline, and holstiine2)
are of considerable synthetic importance. Generally, Mannich
bases without a quaternary center can be readily accessed
through aza-Michael addition,3 Mannich reaction, and its
modern variants.1 However, efficient synthesis of Mannich
bases with a quaternary stereocenter has proven to be
challenging,4 and the efficiency, regioselectivity, and ste-
reoselectivity required for designing this structural unit still
remains to be optimized.5
(1) For reviews, see: (a) Blicke, F. F. Org. React. 1942, 1, 303–341.
(b) Tramontini, M.; Angiolini, L. Tetrahedron 1990, 46, 1791–2230. (c)
Kleinman, E. F. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Heathcock, C. H., Eds.; Pergamon: Oxford, 1991; Vol. 2, pp 893-951.
(d) Heaney, H. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Heathcock, C. H., Eds.; Pergamon: Oxford, 1991; Vol. 2, pp 953-973.
(e) Overman, L. E.; Ricca, D. J. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon: Oxford, 1991; Vol.
2, pp 1007-1046. (f) Tramontini, M.; Angiolini, L. Mannich-Bases,
Chemistry and Uses; CRC: Boca Raton, FL, 1994. (g) Arend, M.;
Westermann, B.; Risch, N. Angew.Chem., Int. Ed. 1998, 37, 1044–1070.
(h) Co´rdova, A. Acc. Chem. Res. 2004, 37, 102–112. (i) Verkade, J. M. M.;
van Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Chem. Soc.
ReV. 2008, 37, 29–41.
In recent years, aziridines have been distinguished as
versatile synthetic intermediates and hence are well ex-
plored.6 The strained three-membered ring can undergo a
variety of reactions to give rise to amino-functionalized
products.6,7 In our previous investigation regarding construc-
tion of 2-quaternary-1,3-diheteroatom units,8 a novel semi-
pinacol rearrangement reaction of 2,3- aziridino alcohols was
discovered, yielding 2-quaternary Mannich bases via a Lewis
acid promoted ring-opening/rearrangement process with high
efficiency and stereoselectivity.8c However, this protocol
suffered from very low yields (20-30% yield) obtained for
the preparation of the aziridino alcohols from tertiary or
secondary allylic alcohols.9 The procedure developed by the
(2) (a) Morita, H.; Hirasawa, Y.; Kobayashi, J. J. Nat. Prod. 2005, 68,
1809–1812. (b) Lim, S.-H.; Sim, K.-M.; Abdullah, Z.; Hiraku, O.; Hayashi,
M.; Komiyama, K.; Kam, T.-S. J. Nat. Prod. 2007, 70, 1380–1383. (c)
Cherif, A.; Martin, G. J. Nat. Prod. 1990, 53, 793–802. (d) Kim, S.-W.;
Bando, Y.; Horii, Z.-i. Tetrahedron Lett. 1978, 26, 2293–2294.
10.1021/ol802005n CCC: $40.75
Published on Web 10/03/2008
2008 American Chemical Society

Sharpless group10 was found to be inefficient due to a
competitive bromonium-induced semipinacol rearrange-
ment.8e,9 Transition metal catalyzed aziridination11 also
proved to be inefficient, resulting in complicated reaction
mixtures.9 Hence, it has been our primary target to discover
a tandem sequence, directly from allylic alcohols, to ef-
fectively construct synthetically valuable 2-quaternary Man-
nich bases.
Intrigued by a novel nitrene equivalent for aziridination
of olefins described by Che and Yudin,12 we recently
developed an interesting tandem protocol based on the
combination of N-aminophthalimide (PhthNH2) and PhI(O-
Ac)2 in the presence of silica gel. Utilization of weakly acidic
silica gel was employed for the first time in such a reaction
system (Scheme 1).12 This tandem reaction provides a
Although stoichiometric amounts of HOAc are theoretically
formed in present reaction system, during the in situ
generation of nitrene donor by the reaction of PhthNH2 with
PhI(OAc)2,12 no further semipinacol rearrangement of the
above-mentioned intermediate 2a occurred in this case,
indicating that the protic acidity of HOAc cannot effectively
promote the 1,2-rearrangement transformation. To realize the
envisioned tandem aziridination/rearrangement sequence, we
then investigated the role of other additives in the optimiza-
tion of the existing reaction conditions. For the aziridination
of alkenes, it has been established that some basic additives
(e.g., K2CO3 and basic Al2O3) can improve the chemical
yields.12a Among the additives that we screened, however,
we found that the weakly acidic silica gel could significantly
promote the tandem two-step transformation,13 and the
desired Mannich base 3a could be isolated in 70% yield after
10 h (entry 2). Interestingly, the presence of silica gel not
only promoted the semipinacol rearrangement, it also ac-
celerated the initial aziridination significantly. In accordance,
the allylic alcohol 1a was observed to be consumed quickly
Scheme 1
.
Tandem Aziridination/Rearrangement of Allylic
Alcohols
(3) For recent reviews, see: (a) Vicario, J. L.; Bad´ıa, D.; Carrillo, L.
Synthesis 2007, n/a, 2065–2092. (b) Vicario, J. L.; Carrillo, L.; Etxebarria,
J.; Reyes, E.; Ruiz, N. Org. Prep. Proced. Int. 2005, 37, 513–538. (c) Xu,
L.-W.; Xia, C.-G. Eur. J. Org. Chem. 2005, n/a, 633–639.
(4) Marigo, M.; Kjærsgaard, A.; Juhl, K.; Gathergood, N.; Jørgensen,
K. A. Chem.-Eur. J. 2003, 9, 2359–2367, and references therein.
(5) (a) Saidi, M. R.; Heydari, A.; Ipaktschi, J. Chem. Ber. 1994, 127,
1761–1764. (b) Wrobleski, A.; Aube´, J. J. Org. Chem. 2001, 66, 886–889.
(6) (a) Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.;
Wiley-VCH: Weinheim, 2006. (b) Balkenhohl, F.; von dem Bussche-
Hunnefeld, C.; Lansky, A.; Zechel, C. Angew. Chem., Int. Ed. 1996, 35,
2288–2337. (c) Kissman, H. M.; Tarbell, D. S.; Williams, J. J. Am. Chem.
Soc. 1953, 75, 2959–2962. (d) Stamm, H. J. Prakt. Chem. 1999, 341, 319–
331.
convenient stereoselective access to the important 2-quater-
nary Mannich bases directly from allylic alcohols. The
synthetic utility of this reaction was highlighted by the ef-
fective amino-functionalization of allylic alcohols and the
stereoselective incorporation of two adjacent stereocenters
with one crucial quaternary carbon, providing an alternative
to the conventional vicinal aminofunctionalization of alk-
enes.7 Herein we report our progress toward the development
and optimization of this synthetic route.
(7) Block, E.; Schwan, A. L. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon: Oxford, 1991; Vol.
4, pp 329-362.
(8) (a) Tu, Y. Q.; Sun, L. D.; Wang, P. Z. J. Org. Chem. 1999, 64,
629–633. (b) Fan, C.-A.; Wang, B.-M.; Tu, Y.-Q.; Song, Z.-L. Angew.
Chem., Int. Ed. 2001, 40, 3877–3880. (c) Wang, B. M.; Song, Z. L.; Fan,
C. A.; Tu, Y. Q.; Shi, Y. Org. Lett. 2002, 4, 363–366. (d) Song, Z. L.;
Wang, B. M.; Tu, Y. Q.; Fan, C. A.; Zhang, S. Y. Org. Lett. 2003, 5, 2319–
2321. (e) Wang, B. M.; Song, Z. L.; Fan, C. A.; Tu, Y. Q.; Chen, W. M.
Synlett 2003, n/a, 1497. (f) Hu, X.-D.; Fan, C.-A.; Zhang, F.-M.; Tu, Y. Q.
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Y. Q.; Ma, Y.; Zhang, F. Org. Lett. 2006, 8, 5271–5273.
Allylic alcohol 1a was used as a typical substrate to
investigate the conventional aziridination conditions without
any additive (entry 1, Table 1). Under these conditions,
(9) Wang, B. M. In Studies on the Rearrangement Reactions of 2,3-
Heterocyclopropyl Alcohols and Allylic Alcohols, Doctoral Dissertation,
Lanzhou University, P. R. China, 2003; pp 51-52 and 91-92.
(10) Jeong, J. U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B.
J. Am. Chem. Soc. 1998, 120, 6844–6845.
Table 1. Optimization of Reaction Conditions
(11) For reviews, see: (a) Mu¨ller, P.; Fruit, C. Chem. ReV. 2003, 103,
2905–2919. (b) Dauban, P.; Dodd, R. H. Synlett 2003, 1571–1586. (c)
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Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, Germany, 2005;
Chapter 17, pp 379-416. (d) Halfen, J. A. Curr. Org. Chem. 2005, 9, 657–
669. (e) Jacobsen, E. N. In ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, 1999; Vol.
2, pp 607-618.
(12) (a) Li, J.; Liang, J.-L.; Chan, P. W. H.; Che, C.-M. Tetrahedron
Lett. 2004, 45, 2685–2688. (b) Krasnova, L. B.; Hili, R. M.; Chernoloz,
O. V.; Yudin, A. K. ARKIVOC 2005, 4, 26–38. (c) Krasnova, L. B.; Yudin,
A. K. Org. Lett. 2006, 8, 2011–2014. (d) Watson, I. D. G.; Yu, L.; Yudin,
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S.; Yu, Z.-X. Org. Lett. 2006, 8, 5877–5879.
entry
PhI(OAc)2/PhthNH2 (equiv)
additive
% yielda
1
2
3
4
5
2.5:2.5
2.5:2.5
3:3
2:2
1.5:1.5
0b
70
56
65
37
silica gel
silica gel
silica gel
silica gel
a Isolated yield. b Only aziridine intermediate 2a was detected after 12 h.
(13) (a) Banerjee, A. K.; Mimo´, M. S. L.; Vegas, W. J. V. Russ. Chem.
ReV. 2001, 70, 971–990. (b) Hudlicky, M. J. Org. Chem. 1974, 39, 3460–
3461. (c) Kotsuki, H.; Hayashida, K.; Shimanouchi, T.; Nishizawa, H. J.
Org. Chem. 1996, 61, 984–990. (d) Bobbit, J. M. J. Org. Chem. 1998, 63,
9367–9374. (e) Collins, J.; Drouin, M.; Sun, X.; Rinner, U.; Hudlicky, T.
Org. Lett. 2008, 10, 361–364, and references therein.
however, the desired product 3a could not be obtained.
Aziridino alcohol 2a was observed as an intermediate instead
with, after 12 h, the disappearance of starting material 1a.
4944
Org. Lett., Vol. 10, No. 21, 2008

(monitored by TLC) after the incorporation of silica gel in
the current tandem protocol. In addition, the effect of other
factors such as reagent ratios (entries 3-5) was also
examined. It was found that increasing or lowering the ratio
of PhI(OAc)2/PhthNH2 (e.g., 3:3, 2:2 or 1.5:1.5) did not have
any effect, and the yields were lower than that obtained by
using 2.5 equiv of both reagents.
Table 2. Tandem Aziridination/Rearrangement of Allylic
Alcohols
To probe the stereochemistry in the present tandem
reaction, X-ray diffraction analysis of 3a14 was carried out,
as shown in Figure 1; this clearly demonstrated the relative
Figure 1. X-ray structure of 3a.
anti configuration between PhthN and the migrating group
R2 (R2 ) Ph).
The generality of this tandem reaction was investigated
for a series of tertiary and secondary allylic alcohols 1b-1o
(Table 2) using the optimized reaction conditions (entry 2,
Table 1). The reaction was typically complete within 16 h
with the corresponding products all being obtained in good
to high yields (60-99%). From all of the examples inves-
tigated, except entries 13 and 15, only one diastereoisomer
was isolated, indicating excellent stereoselectivity for this
process. The structural diversity of 2-quaternary Mannich
bases described in Table 2 shows its synthetic utility for
accessing various nitrogen containing alkaloids.8d
For allylic alcohols involving a cyclohexene moiety
(1a-1f, entries 1-6 from Table 2), the tandem aziridination/
rearrangement provided a variety of 2-quaternary Mannich
bases 3a-3f, in which the migrating group was sp2-aryl
(entries 1-3 and 5), sp3-alkyl (entry 4), or sp-alkynyl (entry
6) during the second process. For the secondary allylic
alcohols (entries 5 and 6), longer reaction times (12-16 h)
were generally required.
Analogously, some tertiary allylic alcohols consisting of
cyclopentene or cycloheptene motifs were examined (entries
7-11 from Table 2), which afforded the desired 2-quaternary
Mannich bases with high stereoselectivity. The interesting
examples included several spirocyclic Mannich bases 3h, 3i,
a Isolated yield. b Five equivalents of propylene oxide were added.
c 1,2-Dichloroethane was used as solvent at 60 °C. d PhthNH2 (2.0 equiv)
and PhI(OAc)2 (2.0 equiv) were used. e PhthNH2 (1.1 equiv) and PhI(OAc)2
(1.1 equiv) were used.
(14) Crystallographic data for 3a have been deposited at the Cambridge
Crystallographic Data Centre (deposition no. CCDC-690341). Copies of
these data can be obtained free of charge www.ccdc.cam.ac.uk/data_request/
cif.
Org. Lett., Vol. 10, No. 21, 2008
4945

3k, as well as 3d, which could be potentially used to
synthesize a new category of ligands for asymmetric cataly-
sis.15
silica gel might have a crucial effect on this tandem reaction,
its exact role as a chemical promoter in the last rearrangement
still remains unclear.13
In conclusion, we have successfully developed a new
nitrene equivalent-mediated tandem aziridination/rearrange-
ment of allylic alcohols, which provides a highly stereose-
lective approach toward synthesis of 2-quaternary Mannich
bases under mild conditions. This tandem protocol not only
is highly efficient compared to the previous two-step reaction
starting from allylic alcohols but also provides an alternative
methodology to the conventional vicinal aminofunctional-
ization of alkenes. Further investigations on its asymmetric
version and synthetic applications of this methodology are
currently in progress.
Besides, some acyclic substrates consisting of trisubstituted
and gem-substituted olefin moiety (1l-1o, entries 12-15
from Table 2) were found to be useful in this particular
protocol. Indeed, the desired amino-functionalized products
with the quaternary carbon were obtained smoothly, further
demonstrating the broad scope of this protocol in choosing
the substrates.
The reaction yields and the reaction times were found to
be highly dependent upon the substrate structure and the
migration capability of R2 in 1. For example, aziridino
alcohol intermediates such as 2a could be detected for
substrates 1a-1 g and 1j-1o. However, 1h and 1i reacted
at comparatively higher rates, and no corresponding inter-
mediates could be observed. On the basis of the herein
described experimental details and our previous report,8c this
tandem protocol clearly consists of two chemical transforma-
tions, namely, aziridination and semipinacol rearrangement.
Although the acidic nature and surface catalytic activity of
Acknowledgment. We gratefully acknowledge financial
support from the NSFC (20621091, 20672048, and 20732002)
and the Chang Jiang Scholars Program.
Supporting Information Available: General experimental
procedures, characterization data for all products, and X-ray
crystallographic data for compounds 3a. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) Burke, M. J.; Allan, M. M.; Parvez, M.; Keay, B. A. Tetrahedron:
Asymmetry 2000, 11, 2733–2739.
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