Addition reactions of iodomethyllithium to imines. A direct and efficient synthesis of aziridines and enantiopure amino aziridines

Article abstract of DOI:10.1021/ol801607r

(Chemical Equation Presented) An efficient and general synthesis of aziridines by the reaction of imines derived from p-toluenesulfonamides with in situ generated iodomethyllithium, with a simple and rapid experimental protocol, is reported for the first time. The reaction with the chiral aldimine derived from phenylalaninal allowed access to (2R,1′S)-2-(1′-aminoalkyl) aziridine with very high diastereoselectivity, in enantiopure form. A mechanism to explain this novel reaction is proposed.

Full text of DOI:10.1021/ol801607r

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4457-4460
Addition Reactions of Iodomethyllithium
to Imines. A Direct and Efficient
Synthesis of Aziridines and Enantiopure
Amino Aziridines
Jose´ M. Concello´n,* Humberto Rodr´ıguez-Solla, and Carmen Simal
Departamento de Qu´ımica Orga´nica e Inorga´nica, UniVersidad de OViedo, Julia´n
ClaVer´ıa 8, 33071 OViedo, Spain
jmcg@unioVi.es
Received July 15, 2008
ABSTRACT
An efficient and general synthesis of aziridines by the reaction of imines derived from p-toluenesulfonamides with in situ generated
iodomethyllithium, with a simple and rapid experimental protocol, is reported for the first time. The reaction with the chiral aldimine derived
from phenylalaninal allowed access to (2R,1′S)-2-(1′-aminoalkyl)aziridine with very high diastereoselectivity, in enantiopure form. A mechanism
to explain this novel reaction is proposed.
Organolithium reagents are probably the most popular orga-
nometallic compounds in contemporary organic synthesis.1
Moreover, functionalized organolithium compounds are espe-
cially useful to transfer functionality in a single synthetic
operation.2 However, some functionalized organolithium com-
pounds are unstable. For example, halomethyllithium com-
pounds decompose through an R-elimination process at tem-
peratures as low as -100 °C.3 To carry out the reaction of
halomethyllithium reagents with electrophiles, these anions must
be generated in situ, generally by treatment of dihalomethane
with methyllithium at -78 °C.4 In this way, reactions of
halomethyllithium with various electrophiles have been re-
ported.5 However, the in situ generated halomethyllithium
reagents did not react with poorly electrophilic reagents. Thus,
(4) (a) Barluenga, J.; Ferna´ndez-Simo´n, J. L.; Concello´n, J. M.; Yus,
M. J. Chem. Soc., Chem. Commun. 1986, 1665–1665. (b) Wallace, R. H.;
Battle, W. Synth. Commun. 1995, 25, 127–133.
(5) Reactions with aldehydes or ketones: (a) Barluenga, J.; Llavona, L.;
Bernad, P. L.; Concello´n, J. M. Tetrahedron Lett. 1993, 34, 3173–3176.
(b) Barluenga, J.; Baragan˜a, B.; Concello´n, J. M. J. Chem. Soc., Chem.
Commun. 1994, 969–970. (c) Barluenga, J.; Baragan˜a, B.; Concello´n, J. M.
J. Org. Chem. 1999, 64, 2843–2846. (d) Einhorn, C.; Allavena, C.; Luche,
J. L. J. Chem. Soc., Chem. Commun. 1999, 333–334. (e) Concello´n, J. M.;
Baragan˜a, B.; Riego, E. Tetrahedron Lett. 2000, 41, 4361–4362Reactions
with esters: (f) Barluenga, J.; Llavona, L.; Concello´n, J. M.; Yus, M. J. Chem.
Soc., Perkin Trans. 1 1991, 297–300. (g) Barluenga, J.; Llavona, L.; Yus,
M.; Concello´n, J. M. J. Chem. Soc., Perkin Trans. 1 1991, 2890–2890. (h)
Barluenga, J.; Baragan˜a, B.; Concello´n, J. M. J. Org. Chem. 1995, 60, 6696–
6699. (i) Concello´n, J. M.; Bernad, P. L.; Riego, E.; Garc´ıa-Granda, S.;
Force´n-Acebal, A. J. Org. Chem. 2001, 66, 2764–2768. Reactions with
carboxylic acid chlorides: (j) Barluenga, J.; Concello´n, J. M.; Ferna´ndez-
Simo´n, J. L.; Yus, M. J. Chem. Soc., Chem. Commun. 1988, 536–537. (k)
Barluenga, J.; Concello´n, J. M.; Ferna´ndez-Simo´n, J. L.; Yus, M. J. Chem.
Soc., Perkin Trans. 1 1989, 77–80. Reactions with boronic esters: (l)
Matteson, D. S.; Sadhu, K. M. Tetrahedron Lett. 1986, 27, 795–798. (m)
Matteson, D. S.; Sadhu, K. M.; Peterson, M. L. J. Am. Chem. Soc. 1986,
108, 810–819. (n) Brown, H. C.; Gupta, A. K.; Rangaishenvi, M. V.; Prasad,
J. V. N V. Heterocycles 1989, 28, 283–294. (o) Brown, H. C.; Phadke,
A. S.; Bhat, N. G. Tetrahedron Lett. 1993, 34, 7845–7848. (p) Soundarara-
jan, R.; Li, G.; Brown, H. C. Tetrahedron Lett. 1994, 35, 8957–8960. (q)
Soundararajan, R.; Li, G.; Brown, H. C. Tetrahedron Lett. 1994, 35, 8961–
8964. Reactions with N-protected 3-oxazolidin-5-ones: (r) Onishi, T.; Hirose,
N.; Takashi, N.; Masakazu, N.; Kunisuke, I. Tetrahedron Lett. 2001, 42,
5883–5885.
(1) (a) Wills, M. Contemp. Org. Synth. 1996, 3, 201. (b) Coldham, I.
Contemp. Org. Synth. 1997, 4, 136–163. (c) Gray, M.; Tinkl, M.; Snieckus,
V. In ComprehensiVe Organometallic Chemistry; Abel, E. W., Stone,
F. G. A., Wilkinson, G., McKillop, A., Eds.; Pergamon: Oxford, 1995; Vol
11, p 2.
(2) For reviews on the synthesis and synthetic applications of function-
alized organollithium compounds see: (a) Na´jera, C.; Yus, M. Trends Org.
Chem. 1991, 2, 155–181. (b) Na´jera, C.; Yus, M. Recent Res. DeV. Org.
Chem. 1997, 1, 67–96. (c) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel,
P. Angew. Chem., Int. Ed. 2000, 39, 4414–4435. (d) Yus, M.; Foubelo, F.
Targets Heterocycl. Syst. 2002, 6, 136–171. (e) Na´jera, C.; Yus, M. Curr.
Org. Chem. 2003, 7, 867–926. (f) Chinchilla, R.; Na´jera, C.; Yus, M.
Tetrahedron 2005, 61, 3139–3176.
(3) A synthesis of epoxides has been reported by reaction of iodom-
ethyllithium with aldehydes and ketones at 0 °C: Concello´n, J. M.; Cuervo,
H.; Ferna´ndez-Fano, R. Tetrahedron 2001, 57, 8983–8987.
10.1021/ol801607r CCC: $40.75
Published on Web 09/13/2008
2008 American Chemical Society

a general method for the addition of halomethyllithium to imines
has not been published to date, despite the fact that this reaction
would afford aziridines, which present important synthetic
applications6 and biological activity.7 Due to their important
applications, several methods to transform imines into aziridines
through methylene transfer using sulfur ylides8 or R-halogenated
organometallic reagents derived from other metals8g,9 have been
reported. In addition, aziridines could be also obtained by
the nucleophilic addition reaction of various nucleophiles
(hydride, cyanide, Grignard reagents, etc.) to R-chlor-
oimines.10 In general, the reported methods required long
reaction times, and in some cases, the yields were low.
In this context, to the best of our knowledge, only one
example of an aziridine ring has been reported through the
reaction of in situ generated chloromethyllithium and a specific
imine derived from 2-pyridinecarboxaldehyde. The authors
stated in their report that the presence of the 2-pyridineimine
moiety is a necessary requirement for the successful aziridina-
tion, and no reaction with other imines such as those derived
from benzaldehyde took place.11 In addition, the removal of
the N-substituent or the ring opening of this aziridine with
various nucleophiles could not be performed. Even more
important is the preparation of enantiopure aziridines. However,
the synthesis of aziridines in enantiopure form from chiral
aldimines and halomethyllithium has not been reported to date.
On these premises, the development of a general and novel
method to obtain a range of structurally diverse and enantiopure
aziridines, through the addition of halomethyllithium to imines,
would be desirable.
In this communication, we describe our preliminary results
concerning a novel and simple method to efficiently prepare
aziridines 2 by reaction of imines, derived from p-toluene-
sulfonamide, with in situ generated iodomethyllithium, in which
the experimental protocol is simple and rapid. The chiral version
has also been developed on the enantiopure R-dibenzylami-
noaldimine derived from phenylalaninal affording the corre-
sponding (2R,1′S)-2-(1′-aminoalkyl)aziridine 7 in enantiopure
form with high diastereoselectivity and in good yield.
Synthesis of Aziridines Derived from Sulfonamides
2. Initial attempts to prepare aziridines were performed on
imines derived from p-methoxyphenylamine and octanal or
benzaldehyde using conditions similar to those previously
described by Reetz;12 however, no addition of iodomethyl-
lithium took place under various reaction conditions, and the
starting imines were recovered unchanged.
This lack of reactivity could be overcome when using
imines with a more electrophilic CdN bond. Thus, we
prepared imines derived from p-toluenesulfonamide and
octanal or benzaldehyde (1a and 1e), following a method
previously reported.13 The reaction of 1a and 1e with
iodomethyllithium at low temperature (-78 °C) for 30 min
and additional stirring at room temperature for 30 min
afforded the corresponding aziridines 2a and 2e in 75 and
79% yield, respectively (Scheme 1).
(6) To see synthetic application of aziridines: (a) Kasai, M.; Kono, M.
Synlett 1992, 778–790. (b) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994,
33, 599–619. (c) Pearson, W. H.; Lian, B. W.; Bergmeier, S. C. In
ComprehensiVe Heterocyclic Chemistry II; Padwa, A., Ed.; Pergamon:
Oxford, 1996; Vol 1A, pp 1-60. (d) McCoull, W.; Davis, F. A. Synthesis
2000, 1347–1365. (e) Sweeney, J. B. Chem. Soc. ReV. 2002, 31, 247–258.
(f) Kumar, K. S. A.; Chaudhari, V. D.; Dhavale, D. D. Org. Biomol. Chem.
2008, 6, 703–711. (g) Kumar, K. S. A.; Chaudhari, V. D.; Puranik, V. G.;
Dhavale, D. D. Eur. J. Org. Chem. 2007, 489, 5–4901. (h) Trost, B. M.;
Dong, G. Org. Lett. 2007, 9, 2357–2359. (i) Caldwell, J. J.; Craig, D. Angew.
Chem., Int. Ed. 2007, 46, 2631–2634. (j) Crawley, S. L.; Funk, R. L. Org.
Lett. 2006, 8, 3995–3998. (k) Banwell, M. G.; Lupton, D. W. Org. Biomol.
Chem. 2005, 3, 213–215. (l) Smith, A. B., III; Kim, D. Org. Lett. 2004, 6,
1493–1495.
Scheme 1. Aziridination of Aldimines 1
(7) (a) Gerhart, F.; Higgins, W.; Tardif, C.; Ducep, J. J. Med. Chem.
1990, 33, 2157–2162. (b) Lefemine, D. V.; Dann, M.; Barbatschi, F.;
Hausmann, W. K.; Zbinovsky, V.; Monnikendam, P.; Adam, J.; Bohonos,
N. J. Am. Chem. Soc. 1962, 84, 3184–3185. (c) Han, I.; Kohn, H. J. Org.
Chem. 1991, 56, 4648–4653. (d) Skibo, E. B.; Islam, I.; Heileman, M. J.;
Schultz, W. G. J. Med. Chem. 1994, 37, 78–92.
The same reactions were performed utilizing chlorometh-
yllithium (generated from chloroiodomethane) instead of
iodomethyllithium, obtaining in this case the corresponding
aziridines in yields about 10% lower. On the basis of these
results and taking into account that diiodomethane is cheaper
than chloroiodomethane, further reactions were performed
employing iodomethyllithium. In addition, other reaction
conditions for the optimization of the aziridination reaction
were tested. The best results were obtained by treating a
solution of 1.5 equiv of diiodomethane and 1 equiv of the
imine in THF with 1.2 equiv of MeLi at 0 °C for 30 min
and further stirring at room temperature for an additional
30 min. Under these reaction conditions, the aziridines shown
in Table 1 were obtained.
(8) (a) Davis, F. A.; Zhou, P.; Liang, C. -H.; Reddy, R. E. Tetrahedron:
Asymmetry 1995, 6, 1511–1514. (b) Garc´ıa-Ruano, J. L.; Ferna´ndez, I.; del
Prado-Catalina, M.; Alcudia-Cruz, A. Tetrahedron: Asymmetry 1996, 7,
3407–3414. (c) Higashiyma, K.; Matsumura, M.; Shiogama, A.; Yamauchi,
T.; Ohmiya, S. Heterocycles 2002, 58, 85–88. (d) Corey, E. J.; Chaykovsky,
M. J. Am. Chem. Soc. 1965, 1353–1354. (e) Morton, D.; Pearson, D.; Field,
R. A.; Stockman, R. A. Synlett 2003, 1985–1988. (f) Miduka, W. H.
Tetrahedron Lett. 2007, 48, 3907–3910. (g) Aggarwal, V. K.; Stenson, R. A.;
Jones, R. V. H.; Fieldhouse, R.; Blacker, J. Tetrahedron Lett. 2001, 42,
1587–1589.
(9) tom Dieck, H.; Haupt, E. Chem. Ber. 1983, 116, 1540–1546
.
(10) (a) Singh, G. S.; D’hooghe, M.; De Kimpe, N. Chem. ReV. 2007,
107, 2080–2135. (b) De Kimpe, N.; Verhe´, R.; De Buyck, L.; Schamp, N.
Synth. Commun. 1975, 5, 269–274. (c) De Kimpe, N.; Schamp, N.; Verhe´,
R. Synth. Commun. 1975, 5, 403–408. (d) De Kimpe, N.; Verhe´, R.; De
Buyck, L.; Schamp, N. J. Org. Chem. 1980, 45, 5319–5325. (e) De Kimpe,
N.; Sulmon, P.; Verhe´, R.; De Buyck, L.; Schamp, N. J. Org. Chem. 1983,
48, 4320–4326. (f) De Kimpe, N.; Moens, L. Tetrahedron 1990, 46, 2965–
2974. (g) Denolf, B.; Mangelinckx, S.; To¨rnroos, K. W.; De Kimpe, N.
Org. Lett. 2006, 8, 3129–3132. (h) Denolf, B.; Leemans, E.; De Kimpe, N.
J. Org. Chem. 2007, 72, 3211–3217.
As can be observed in Table 1, the reaction seems to be
(12) Reetz, M. T.; Lee, W. K. Org. Lett. 2001, 3, 3119–3120.
(13) Wang, Y.; Song, J.; Hong, R.; Li, H.; Deng, L. J. Am. Chem. Soc.
2006, 128, 8156–8157.
(11) Savoia, D.; Alvaro, G.; Di Fabio, R.; Gualandi, A.; Fiorelli, C. J.
Org. Chem. 2006, 71, 9373–9381.
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Org. Lett., Vol. 10, No. 20, 2008

reported by the reaction of sulfur ylides with chiral amino
aldimines (from anisidine instead of p-toluenesulfonamide).12
The required aminoimine 6 was prepared by the Weinreb
procedure,17 but it could not be isolated due to its instability.
Therefore, the reaction with iodomethyllithium was carried
out on the crude aminoimine, rendering aminoaziridine 7 in
61% overall yield for the two transformations (from 5 to 7)
(Scheme 2). After testing several reaction conditions, the best
Table 1. Aziridination of Aldimines
entry
2
R
yield (%)a
1
2
3
4
5
2a
2b
2c
2d
2e
nC7H15
secBu
Cy
PhCH2
Ph
80
71b
87
58
88
Scheme 2. Synthesis of (2S,1′S)-2-(1-Aminoalkyl)aziridine 7
a Isolated yield after flash chromatography based on compound 1.
b Obtained as an inseparable mixture of diastereoisomers.
general, and linear, branched, and cyclic aliphatic or aromatic
aldimines could be used as the starting material, affording
the corresponding aziridines in good to high yields (>71%),
except when using the imine derived from the easily
enolizable phenylacetaldehyde. However, it is noteworthy
that, in general, organolithium compounds cannot be added
to phenylacetaldehyde or to its derivatives since the lithium
reagent is hydrolyzed under these conditions to give the
corresponding lithium enolate.The N-substituent on aziridines
2 could be easily removed by using lithium naphthalenide,
following a method previously reported, but with modifications
of the isolation and purification technique for the deprotected
aziridines14 since the previously described purification by
column chromatography afforded poor yields of deprotected
aziridines 3. These poor yields are in disagreement with the
good purity observed on the crude reaction, [1H (300 MHz)
and 13C (75 MHz) NMR]. Therefore, we tested other isolation
and purification methods. The best yields of pure compounds
3 were obtained performing an acid-base treatment of the crude
reaction products (Table 2).
result was obtained by treating a solution of crude ami-
noimine 6 in THF with 4.0 equiv of diiodomethane and 4.0
equiv of MeLi at -78 °C for 2 h.18 After hydrolysis and
usual workup, crude aminoaziridine 7 was obtained in 79%
yield. Purification by conventional column chromatography
afforded the expected pure aminoaziridine 7 in lower yield
(42% yield), which disagrees with the good purity observed
in the crude reaction material (1H and 13C NMR). The yield
of the pure aziridine 7 was increased by avoiding the
hydrolysis step and directly purifying the crude material by
column chromatography.
The high stereoselectivity of the addition reaction of
iodomethyllithium (dr 9/1, Scheme 2) was determined, on
1
the crude reaction products, by 300 MHz H NMR. It is
noteworthy that the previously reported synthesis of (2R,1′S)-
2-(1′-dibenzylamino-2′-phenylethyl)-1-(4-methoxypheny-
l)aziridine by reaction of the corresponding R-aminoaldimine
with dimethylsulfonium methylide took place with lower
stereoselectivity (dr 4/1).12
In general terms, it is noteworthy that this reported method
for the synthesis of aziridines 2 and 7 is experimentally
simple, the reaction time is short, and it takes place with
Table 2. Deprotection of N-Tosyl Aziridines
(14) Alonso, D. A.; Andersson, P. G. J. Org. Chem. 1998, 63, 9455–
9461.
entry
3
R
yield (%)a
(15) (a) Previously, we reported the synthesis of nonactivated enantiopure
syn-aminoalkyl aziridines by reduction of R-amino ketimines derived from
1-aminoalkyl chloromethyl ketones. See ref 5i. (b) Reetz et al reported the
synthesis of nonactivated enantiopure anti-aminoalkyl aziridines. See ref
12.
1
2
3
3a
3c
3d
nC7H15
Cy
PhCH2
62
65
75
a Isolated yield after column chromatography based on compound 2.
(16) (a) Concello´n, J. M.; Riego, E. J. Org. Chem. 2003, 68, 6407–
´
6410. (b) Concello´n, J. M.; Riego, E.; Alvarez, J. R. J. Org. Chem. 2003,
´
68, 9242–9246. (c) Concello´n, J. M.; Alvarez, J. R.; Garc´ıa-Granda, S.;
D´ıaz, M. R. Angew. Chem., Int. Ed. 2004, 43, 4333–4336. (d) Concello´n,
J. M.; Riego, E.; Rivero, I. A.; Ochoa, A. J. Org. Chem. 2004, 69, 6244–
6248. (e) Concello´n, J. M.; Riego, E.; Sua´rez, J. R.; Garc´ıa-Granda, S.;
D´ıaz, M. R. Org. Lett. 2004, 6, 4499–4501. (f) Concello´n; J. M.; Bernad,
P. L.; Sua´rez, J. R. Chem.-Eur. J. 2005, 11, 4492–4501. (g) Concello´n,
J. M.; Bernad, P. L.; Sua´rez, J. R.; Garc´ıa-Granda, S.; D´ıaz, M. R. J. Org.
Chem. 2005, 70, 9411–9416.
Synthesis of Enantiopure 2-(1-Dibenzylaminoalkyl)aziri-
dines.15 Given the synthetic utility of optically active syn-
aminoaziridines,5i,16 we performed the aziridination reaction
described above, utilizing enantiopure aldimine 6 derived
from N,N-dibenzyl phenylalaninal, with the goal of synthe-
sizing the anti-aminoaziridine (diastereoisomer of that previ-
ously reported by us).5i The synthesis of similar anti-
aminoaziridines with moderate diastereoselectivity has been
(17) Sisko, J.; Weinreb, S. M. J. Org. Chem. 1990, 55, 393–395.
(18) An excess of iodomethyllithium was necessary due to the presence
of N-tosylamine in the mixture reaction, as a consequence of the N-sulfinyl-
p-toluenesulfonamide required for the synthesis of aldimines 6, which is
purchased from TCI with a purity ∼70%.
Org. Lett., Vol. 10, No. 20, 2008
4459

high stereoselectivity. The structure and absolute configu-
ration of the aziridine ring was unambiguously established
through a deprotection/benzylation protocol of compound 7
(Scheme 3).
Scheme 4. Mechanism of the Aziridination Process
Scheme 3. Deprotection/Benzylation of Compound 7
established to explain the reduction of chloromethyl ketones5h
or chloromethyl ketimines.15a In addition, the stereochemistry
of aziridine 7 was also in agreement with the anti epoxides
obtained by treatment of R-aminoaldehydes 5 with iodom-
ethyllithium, previously described.5h
In conclusion, an efficient aziridination process by reaction
of imines derived from p-toluenesulfonamides with in situ
generated iodomethyllithium is reported. The reaction with
the aldimine derived from phenylalaninal afforded the
corresponding enantiopure (2R,1′S)-2-(1′-aminoalkyl)aziri-
dine with very high diastereoselectivity. Generalization of
this reaction and studies to fully delineate all the factors
involved in these transformations are currently under inves-
tigation in our laboratory.
1H and 13C NMR of the minor product 9 was consistent
with the aminoaziridine previously reported by us and
synthesized via the reduction and further heterocyclization
of the corresponding chloromethyl ketimine derived from
phenylalanine.5i Consequently, we deduced that the absolute
configuration of the major stereoisomer 8 was 2R. The
assigned structure for compound 8 was corroborated by its
spectroscopic data.
Finally, the enantiomeric purity of 7 was evaluated by
chiral HPLC. To carry out this analysis, a racemic mixture
of 7 was previously prepared from racemic phenylalaninal.
The chiral HPLC analysis of this racemic mixture allowed
the discovery of the best conditions to separate both
enantiomers. These conditions were used to analyze the
obtained aziridine 7 and showed an enantiomeric purity
>98%. This fact excluded a partial racemization of the
starting phenylalaninal 5 during its transformation into 7.
The synthesis of aziridines can be explained by assuming
the addition reaction of iodomethyllithium to the imine group
generating an iodated lithium amide 10 or 11, which
spontaneously undergoes a heterocyclization to afford the
corresponding aziridines 2 or 7, respectively (Scheme 4).
In this process, the addition of iodomethyllithium to
aminoimine 6 takes place under nonchelation control which
can be explained assuming that the energetically more
favored transition state has the larger substituent (N,N-
dibenzylamino group) anti to the attack of the iodomethyl-
lithium (Scheme 4). The same stereochemical course was
Acknowledgment. We acknowledge Ministerio de Edu-
cacio´n y Cultura (CTQ2007-61132) for financial support.
J.M.C. thanks his wife Carmen Ferna´ndez-Flo´rez for her
time. H.R.S. and C.S. thank MEC for a Ramo´n y Cajal
Contract (Fondo Social Europeo) and for a predoctoral
fellowship, respectively. Our thanks to Euan C. Goddard
(CRL, University of Oxford) for his revision of the English.
Supporting Information Available: General, general
1
procedures, and copies of H and 13C NMR spectra for all
new compounds 1-3 and 7-9. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL801607R
4460
Org. Lett., Vol. 10, No. 20, 2008