Efficient synthesis of α,β-unsaturated alkylimines performed with allyl cations and azides: Application to the synthesis of an ant venom alkaloid

Article abstract of DOI:10.1021/ol302608q

An efficient synthesis of α,β-unsaturated alkylimines at low temperature using azides has been developed. Carbocations generated from allyl alcohols helped achieve a rapid conversion under mild conditions with azides to afford reactive α,β-unsaturated imines. Hydroxy or alkoxy groups are essential for these transformations, and utilizing readily accessible allyl alcohols gave a wide extension of substrates. The efficiency of this novel method is demonstrated in the total synthesis of an iminium ant venom alkaloid.

Full text of DOI:10.1021/ol302608q

ORGANIC
LETTERS
2012
Vol. 14, No. 22
5728–5731
Efficient Synthesis of r,β-Unsaturated
Alkylimines Performed with Allyl Cations
and Azides: Application to the Synthesis
of an Ant Venom Alkaloid
Kyohei Hayashi, Hiroki Tanimoto,* Huan Zhang, Tsumoru Morimoto,
Yasuhiro Nishiyama, and Kiyomi Kakiuchi*
Graduate School of Materials Science, Nara Institute of Science and Technology
(NAIST), 8916-5 Takayama-cho, Ikoma, Nara 6300192, Japan
tanimoto@ms.naist.jp; kakiuchi@ms.naist.jp
Received October 4, 2012
ABSTRACT
An efficient synthesis of R,β-unsaturated alkylimines at low temperature using azides has been developed. Carbocations generated from allyl
alcohols helped achieve a rapid conversion under mild conditions with azides to afford reactive R,β-unsaturated imines. Hydroxy or alkoxy
groups are essential for these transformations, and utilizing readily accessible allyl alcohols gave a wide extension of substrates. The efficiency of
this novel method is demonstrated in the total synthesis of an iminium ant venom alkaloid.
R,β-Unsaturated imines (1-aza-1,3-butadienes, enimines)
provide more useful synthetic efficiency than saturated
imines, for example, as Michael acceptors, hetero-Dielsꢀ
Alder diene units, and dienophiles.1,2 Despite their useful-
ness and their simple structures, the preparation of R,β-
unsaturated imines, especially alkyl and cyclic enimines, is
problematic due to the tendency toward polymerizations
and hydrolysis by strong reactivity. Simple condensation
of R,β-unsaturated carbonyls and amines is often carried
out, but mostly to produce s-trans-fixed R,β-unsaturated
alkylimines.1e,f Thus, some elimination strategies have been
developed, but their heating conditions should be avoided
for the reactivity of products (Scheme 1a).
Furthermore, azides can also deliver saturated imines.4
The Schmidt reaction with alcohols or olefins and azides
(1) For recent examples, see: (a) Tanaka, K.; Siwu, E. R. O.;
Hirosaki, S.; Iwata, T.; Matsumoto, R.; Kitagawa, Y.; Pradipta,
A. R.; Okumura, M.; Fukase, K. Tetrahedron Lett. 2012, 53, 5899–
5902. (b) Hachiya, I.; Mizota, M.; Shimizu, M. Heterocycles 2012, 85,
993–1016. (c) Duttwyler, S.; Lu, C.; Rheingold, A. L.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2012, 134, 4064–4067. (d) Oberg, K. M.;
Rovis, T. J. Am. Chem. Soc. 2011, 133, 4785–4787. (e) Marcoux, D.;
(2) (a) Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099–
6138. (b) Fletcher, M. D.; Hurst, T. H.; Miles, T. J.; Moody, C. J.
Tetrahedron 2006, 62, 5454–5463. (c) Kobayashi, S.; Furuya, T.; Otani,
T.; Saito, T. Tetrahedron 2008, 64, 9705–9716. (d) Chen, W.-S.; Fowder,
F. W.; Lupo, A. T., Jr. J. Am .Chem. Soc. 1981, 103, 2090–2091. (e)
Franc-ois, D.; Maden, A.; Murray, W. V. Org. Lett. 2004, 6, 1931–1934.
(f) Gagnon, D.; Spino, C. J. Org. Chem. 2009, 74, 6035–6041. (g) Boger,
D. L.; Corbett, W. L.; Curran, T. T.; Kasper, A. M. J. Am. Chem. Soc.
1991, 113, 1713–1729.
€
Bindschadler, P.; Speed, A. W. H.; Chiu, A.; Pero, J. E.; Borg, G. A.;
Evans, D. A. Org. Lett. 2011, 13, 3758–3761. (f) Johannes, J. W.;
Wenglowsky, S.; Kishi, Y. Org. Lett. 2005, 7, 3997–4000. (g) Hong,
B.-C.; Wu, J.-L.; Gupta, A. K.; Hallur, M. S.; Liao, J.-H. Org. Lett.
2004, 6, 3453–3456.
(3) Schuster, E.; Hesse, C.; Schumann, D. Synlett 1991, 916–918 and
references therein.
r
10.1021/ol302608q
Published on Web 11/01/2012
2012 American Chemical Society

gives corresponding saturated imines via aminodiazonium
intermediates (Scheme 1b).5 However, this requires strong
acids and the substrates are limited to benzyl alcohols and
styrenes to generate carbocations.5d,e Although simple
olefins can also produce saturated imines with azide by
way of [3 þ 2] cyclization, high temperatures (>100 °C)
and long reaction times (from several hours to days) are
required.6 Moreover, direct transformation to “unsatu-
rated” imines through these procedures is quite limited.7,8
Thus, a more efficient method is required.
Our research plan is shown in Scheme 1c. To achieve a
rapidone-step transformation tounsaturatedimines under
mild conditions, we envisioned that allyl cations that are
easily accessible from allyl alcohols in the presence of
weakꢀmoderate acids could help our desired reactions to
produce R,β-unsaturated imines. Despite the reported
reactions of azides with oxyallylic and benzylic cations
that produce [3 þ 2] and [3 þ 3] reaction products,5fꢀh
unsaturated imine synthesis from allyl cations with azides
has not been reported. Focusing on these advantages of the
allylic carbocation, herein we report a fast, efficient in-
tramolecular transformation from azide-bearing allylic
alcohols to R,β-unsaturated imines under mild conditions
and its application to the total synthesis of an ant venom
alkaloid.
Scheme 1. Preparation of Imines and Our Plan
Since the desired unsaturated alkylimines were antici-
pated to be unstable due to hydrolysis or their ability as a
diene for the hetero DielsꢀAlder reaction, we commenced
our study with the cyclic substrate 1a which could afford a
rigid bicyclic unsaturated imine 1b, similar to the molecule
in the report from Pearson’s group.6e
Table 1. Screening of Reaction Conditions
T
yield
(%)b
entry
acida
TFA
(°C)
time
1
2
3c
4
5
6
7
reflux
60 min
30 min
20 min
2 days
40 min
10 min
60 min
trace
96
TsOH H2O
reflux
3
TFA
rt
69
TsOH H2O
rt
27
3
€
(4) (a) Brase, S.; Banert, K. Organic Azides, Syntheses and Applica-
MsOH
TMSOTf
none
0
58
tions; John Wiley & Sons: Ltd.: Chichester, 2010. (b) Wrobleski, A.;
Coombs, T. C.; Huh, C. W.; Li, S.-W.; Aube, J. Org. React. 2012, 78,
1–320. (c) Chiba, S. Synlett 2012, 23, 21–44. (d) Nair, V.; Suja, T. D.
Tetrahedron 2007, 63, 12247–12275. (e) Brase, S.; Gil, C.; Knepper, K.;
ꢀ
0
86
reflux
n.r.
€
Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5188–5240.
(5) (a) Banerjee, A.; Kumar, P. S.; Baskaran, S. Chem. Commun.
2011, 47, 12218–12220. (b) Pearson, W. H.; Fang, W. K. J. Org. Chem.
a 1.2 equiv of acid were used except for entry 3. b Isolation yield. c 22
equiv were used. TFA = trifuluoroacetic acid, TsOH = p-toluenesul-
fonic acid, MsOH = methanesulfonic acid, n.r. = no reaction.
ꢀ
2000, 65, 7158–7174. (c) Molina, P.; Alcantara, J.; Leonardo, L. Synlett
1995, 363–364. (d) Pearson, W. H.; Fang, W. K. J. Org. Chem. 1995, 60,
4960–4961. (e) Pearson, W. H.; Walavalkar, R.; Schkeryantz, J. M.;
Fang, W. K.; Blickendorf, J. D. J. Am. Chem. Soc. 1993, 115, 10183–
10194. For other examples of a reaction between azides and Oxy(or
amino)allyl cations including a cyclization reaction, see: (f) Scadeng, O.;
Ferguson, M. J.; West, F. G. Org. Lett. 2011, 13, 114–117. (g) Grecian,
Optimizations of acids and temperature conditions with
allyl alcohol 1a were attempted in dichloromethane (Table 1).
Although trifluoroacetic acid (pKa = 12.65 in CH3CN)9
produced a trace amount of 1b under reflux (entry 1),
p-toluenesulfonic acid (pKa = 8.45 in CH3CN) completed
the reaction in 30 min to afford desired 1b in excellent yield
(entry 2). It is noteworthy that the synthesis of this
unsaturated imine was accomplished with a moderate acid
at around 40 °C within 1 h, despite previous reports indicating
ꢀ
S.; Desai, P.; Mossman, C.; Poutsma, J. L.; Aube, J. J. Org. Chem. 2007,
72, 9439–9447. Pearson et al. also reported intramolecular [3 þ 2] and
[3 þ 3] cyclization with indolic tert-carbocations to give triazolines and
triazines rather than imines. See: (h) Pearson, W. H.; Fang, W. K.;
Kampf, J. W. J. Org. Chem. 1994, 59, 2682–2684. For an SN2-type
Schmidt reaction, see: (i) Kapat, A.; Nyfeler, E.; Giuffredi, G. T.;
Renaud, P. J. Am. Chem. Soc. 2009, 131, 17746–17747.
ꢀ
(6) (a) de Miguel, E.; Valedo, M.; Herradon, B.; Mann, E. Eur. J.
Org. Chem. 2012, 4347–4353. (b) Zhao, Y.-M.; Gu, P.; Tu, Y.-Q.;
Zhang, H.-J.; Zhang, Q.-W.; Fan, C.-A. J. Org. Chem. 2010, 75, 5289–
5295. (c) Zhou, Y.; Murphy, P. V. Org. Lett. 2008, 10, 3777–3780. (d)
Kim, S.; Lee, Y. M.; Lee, T.; Fu, Y.; Song, Y.; Cho, J.; Kim, D. J. Org.
Chem. 2007, 72, 4886–4891. (e) Schkeryantz, J.; Pearson, W. H. Tetra-
hedron 1996, 52, 3107–3116. (f) Hudlicky, T.; Luna, J. H.; Price, J. D.;
Rulin, F. J. Org. Chem. 1990, 55, 4683–4687. (g) Reddy, D. S.; Judd,
(8) (a) Chida, N. Keio University, personal communication, 2008.
Recently, Feldman et al. have developed allenyl azide cycloaddition chem-
istry which produces bicyclic unsaturated imines. See: (b) Feldman, K. S.;
Antoline, J. F. Org. Lett. 2012, 14, 934–937. (c) Feldman, K. S.; Iyer,
M. R. J. Am. Chem. Soc. 2006, 127, 4590–4591.
ꢀ
W. R.; Aube, J. Org. Lett. 2003, 5, 3899–3902.
€
(9) Eckert, F.; Leito, I.; Kaljurand, I.; Kutt, A.; Klamt, A.; Diedenhofen,
(7) Kozikowski, A.; Greco, M. N. J. Org. Chem. 1984, 49, 2310–2314.
M. J. Comput. Chem. 2009, 30, 799–810.
Org. Lett., Vol. 14, No. 22, 2012
5729

higher temperatures, much longer reaction times, and
strong acid conditions (TfOH in most case, pKa = 2.4 in
CH3CN).5 Thus, utilizing allylic alcohols as a carbocation
source is highly advantageous.
Table 2. Scope of the Reaction
To improve the reaction conditions, the reaction tem-
perature was cooled down to room temperature, but an
excess amount of acid was necessary for full conversion of
1a in 1 h (entry 3).10 Because TsOH was not well soluble at
room temperature (entry 4), a liquid methanesulfonic acid
(pKa = 9.97 in CH3CN) was used and could provide 1b in
58% yield in a 40 min reaction at 0 °C (entry 5). Finally,
trimethylsilyl trifluoromethanesulfonate (TMSOTf) was
found to be the best to carry out the reaction at 0 °C in
good yield (entry 6). With TMSOTf, the reaction was
accomplished in only 10 min.11 An additive-free reaction
(entry 7), other aprotic/protic solvents, or basic conditions
(not shown) did not afford the desired products. Addition-
ally, the introduction of leaving groups such as Ts, Ms, and
Tf or halogens on 1a for an SN20 type Schmidt reaction
under basic conditions destroyed the starting material, and
our desired R,β-unsaturated imines were not observed.5i,12
Scheme 2
With optimal conditions determined, our focus was
directed toward the substrate study and the reaction
mechanism of this transformation (Table 2). Acyclic com-
pound 2aa was delivered to 2b in good yield (entry 1). Not
only a protecting-group-free hydroxy group but also OH-
protected 2abꢀae could afford 2b in good yield (entries
2ꢀ5). From both (E)-olefin 3aa, 3ab and (Z)-olefin 4,
trans-conjugated imine 3b was obtained in a similar yield
regardless of the protection (entries 6ꢀ8). Interestingly, the
importance of the position of the hydroxy group was
revealed by substrate 5, which could give the same product
3b from 3aa but in a much lower yield than those of entries
6ꢀ8 and without reproducibility (entry 9). Probably, an
association of the SN2 reaction might have an effect in this
case.5i Compared to entry 6 in Table 1, 6, an epimer of 1a,
could also give 1b in a similar yield (entry 10). In contrast, 7a,
(10) Reaction with 1.2 equiv of TFA gave recovered starting
material.
(11) BF3 OEt2 also worked enough, but in a slightly lower yield (74%).
(12) Only in mesylation, a trace amount of unsaturated imine was
observed by using an excess of reagents (triethylamine, MsCl). But it
seemed to be generated by an acidic ammonium mesylate salt.
a Except for entries 14 and 16. b Isolation yield. c Lack of reproduci-
bility. d Reaction conditions: TFA (5 equiv), CH2Cl2, ꢀ50 °C, 10 min
3
(entry 14); TsOH H2O, CH2Cl2, reflux, 20 min (entry 16). e E/Z = 3/20.
n.r. = no reaction.
3
5730
Org. Lett., Vol. 14, No. 22, 2012

a deoxy compound of 1a, did not give any products, but
rather the recovered 7a (entry 11).13 The reaction with
primary alcohol 8a or 9a did not afford unsaturated imine
8b or 9b (entries 12ꢀ13, 8a: recovered, 9a: decomposed).
With tertiary alcohol 10a (entry 14), conversion to 10b was
achieved with the weaker acid TFA at the lower tempera-
ture ꢀ50 °C. With trisubstituted olefins, not only alcohol
11a but also epoxide 12a could be transformed to 11b and
12b in moderate yields (entries 15ꢀ16). Due to the in-
stability of 12aꢀb (entry 16), TsOH gave a better result
than that with TMSOTf (28% at 0 °C).
Scheme 3. Synthesis of Ant Venom Alkaloid
We also investigated intermolecular reactions (Scheme 2),14
and cinnamaldehyde 13b, a hydrolysis product of the re-
sulting aldimine, was generated from 13a in 39% yield. No
ketone or ketimine was observed.5h,15
In conclusion, we have demonstrated an efficient intra-
molecular transformation from substrates possessing azides
and allylic secondary/tertiary alcohols to R,β-unsaturated
alkylimines. Most reactions were performed with TMSOTf at
0 °C and were accomplished in 10 min. Allyl alcohols
and allyl epoxides of cyclic and acyclic compounds were
acceptable, and the use of readily accessible functional
groups gave us a wide extension of acceptable substrates
and improved reaction conditions to perform rapid trans-
formation and afford R,β-unsaturated imines at low tem-
peratures. The efficiency of this synthetic strategy was
demonstrated by the total synthesis of an ant venom
alkaloid. Further investigation of reaction mechanisms
and applications toward concise alkaloid synthesis is
currently underway.
To exclude reaction pathways,5h,i,6f we submitted three
possible intermediate compounds14ꢀ16,16 but none of the
three were converted to 1b. Considering these facts along
with the results of Table 2 (no [3 þ 3] or [3 þ 2] products
were observed),5h our reaction suggests a carbocation-
mediated SN20-type Schmidt reaction (Scheme 1b).17
With this established method, we demonstrated a total syn-
thesis of a conjugated pyrroline alkaloid from the venom of the
Costa Rican ant Megalomyrmex foreli.18 The MOM-masked
cyclization precursor 17 prepared from valeraldehyde19 was
treated with TMSOTf at 0 °C for 10 min, and the desired acid-
labile cyclic unsaturated iminium alkaloid 18 was synthesized
without a deprotection step (Scheme 3).20
(13) A thermal transformation of 7a into 7b via [3 þ 2] cyclization was
successful (toluene, reflux, 3h, 86%). See Supporting Information.
(14) (a) Barbero, M.; Cadamuro, S.; Dughera, S.; Venturello, P.
Synthesis 2008, 1379–1388. For a detailed mechanistic study, see: (b) Jia,
A. K.; Ottosson, H.; Zen, X.; Thibblin, A. J. Org. Chem. 2002, 67, 182–
187. (c) Goering, H. L.; Dilgren, R. E. J. Am. Chem. Soc. 1959, 81, 2556–
2561. (d) The reaction with trans-cinnamyl alcohol gave 14b in 20% yield
without ketones or ketimines.
(15) We confirmed that 14b and a promising unsaturated ketone
product were tolerable enough under the reaction conditions and that
14b was not produced in the absence of benzyl azide.
(16) Deposited crystallographic data for the bromobenzoate of 14, 16
and a synthetic intermediate of 1a with the Cambridge Crystallographic
Data Center are the following: CCDC 869959, 869960, and 869961.
(17) A cation-trapping experiment with 2aa also gave only 2b.
(18) Jones, T. H.; DeVries, P. J.; Escoubas, P. J. Chem. Ecol. 1991, 17,
2507–2518. The absolute stereochemistry or optical rotation value was
not provided in this paper.
Acknowledgment. This work was partly supported by
funding from NAIST for young scientists working on
photonanoscience. We are grateful to Prof. Noritaka
Chida of Keio University for fruitful discussions and sug-
gestions. We also thank Ms. Mika Yamamura, Ms. Yuriko
Nishiyama, Ms. Yoshiko Nishikawa (HRMS measurement),
and Mr. Shohei Katao (X-ray crystallographic analysis) of
NAIST.
Supporting Information Available. Reaction proce-
dures, preparations, and analytical data of all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) See Supporting Information.
(20) Alkaloid 18 was slightly sensitive to silica gel, and its volume was
halved after passing through silica gel. Use of triethylamine-containing
elution or alumina was not effective for purification.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 22, 2012
5731