Synthesis, characterization, and nucleophilic ring opening reactions of cyclohexyl-substituted β-haloamines and aziridinium ions

Article abstract of DOI:10.1016/j.tetlet.2014.12.101

Cyclohexyl-substituted β-haloamines and aziridinium ions were prepared and characterized. Stereospecific ring opening of aziridinium ions was applied for efficient synthesis of vicinal amine, β-amino acid, and tetrahydroisoquinoline (THIQ) analogues. Nucleophilic ring opening reactions of aziridinium ions and N-protected aziridine analogues were for the first time comparatively studied. The result of nucleophilic reactions clearly indicates that aziridinium ions were significantly more reactive toward nucleophilic ring opening than the aziridine analogues.

Full text of DOI:10.1016/j.tetlet.2014.12.101

Tetrahedron Letters 56 (2015) 946–948
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis, characterization, and nucleophilic ring opening reactions
of cyclohexyl-substituted b-haloamines and aziridinium ions
⇑
Hyun-Soon Chong , Xiang Sun, Yunwei Chen, Meng Wang
Department of Biological and Chemical Sciences, Illinois Institute of Technology, Chicago, IL, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclohexyl-substituted b-haloamines and aziridinium ions were prepared and characterized. Stereospe-
cific ring opening of aziridinium ions was applied for efficient synthesis of vicinal amine, b-amino acid,
and tetrahydroisoquinoline (THIQ) analogues. Nucleophilic ring opening reactions of aziridinium ions
and N-protected aziridine analogues were for the first time comparatively studied. The result of nucleo-
philic reactions clearly indicates that aziridinium ions were significantly more reactive toward nucleo-
philic ring opening than the aziridine analogues.
Received 2 December 2014
Revised 15 December 2014
Accepted 17 December 2014
Available online 5 January 2015
Keywords:
Aziridinium ion
b-Haloamines
Ó 2014 Elsevier Ltd. All rights reserved.
Tetrahydroisoquinoline
Friedel–Crafts reaction
Strained ring
Aziridinium ions1 and aziridines2 as strained three membered
ring systems remain useful entities in asymmetric synthesis of
small organic molecules including vicinal amines, amino alcohols,
and amino acids. Aziridinium ion contains a positively charged
nitrogen and two electrophilic carbons and is expected to rapidly
react with various nucleophiles under mild conditions. Biological
application of the highly reactive aziridinium ions is well demon-
strated in the development of nitrogen mustards such as chloram-
bucil and mechlorethamine as anti-cancer agents.3 While
nucleophilic ring opening reactions of aziridinium ions and aziri-
dines are also described.
Synthesis of cyclohexyl-backboned b-haloamines 4 and aziridi-
nium ions 5 is shown in Scheme 1. trans-N,N-Dibenzyl-b-aminocy-
5
clohexanol 1 was used as a model system for the present study.
b-Amino alcohol trans-1 was reacted with one of the halogenating
reagents, diethylaminosulfur trifluoride (DAST), N-halosuccinimide
(NXS, X = Cl or Br), or I to provide trans-halocyclohexylamine 4a–d
2
as the exclusive product in 60–70% isolated yields. Conversion of
trans-1 to trans-4 was completed in 4 h at room temperature as
evidenced by TLC analysis during the reactions, and no byproduct
was formed during halogenation. However, b-haloamines 4 were
obtained in less than quantitative yield, mainly due to hydrolysis
of the products during column chromatographic purification. The
formation of trans-4 was rationalized based on the mechanism
wherein intramolecular rearrangement of phosphonium halide 2
to aziridinium ion 3 and subsequent ring opening of 3 by the halide
2
aziridines have been extensively utilized in organic synthesis,
chemistry of aziridinium ions and their applications as labile elec-
4
trophilic species for nucleophilic reactions are limitedly reported.
To the best of our knowledge, no comparative evaluation on ring
opening reactions of aziridinium ions and aziridine analogues has
been reported.
In this Letter, we report synthesis and characterization of
b-haloamines and aziridinium ions derived from trans-1,2-cyclo-
hexylamino alcohol. The cyclohexyl-backboned b-haloamines and
aziridinium ions were studied for nucleophilic ring opening reac-
tions for stereospecific synthesis of vicinal diamine, b-amino acid,
and tetrahydroisoquinoline (THIQ) analogues. Comparative
counter anion proceeded in
Bromocyclohexylamine 4c was prepared from reaction of 1 with
PPh and NBS for structural determination, and the retained
a
S
N
2
pathway. trans-b-
3
stereochemistry in 4c was unambiguously confirmed by X-ray
crystallography (Scheme 1) and proves the formation and ring
opening of aziridinium ion in a S
Aziridinium ions 5ca (X = BF ) and 5cb (X = OTf) were directly
prepared by treatment of trans-4c with a halosequestering silver
salt containing weakly nucleophilic counteranions, AgBF and
N
2 pathway.
4
⇑
Corresponding author at present address: Illinois Institute of Technology,
Chemistry Division, Biological, Chemical, and Physical Science Department, 3101 S.
Dearborn St., LS 182, Chicago, IL 60616, USA. Tel.: +1 312 567 3235; fax: +1 312 567
4
AgOTf, respectively (Scheme 1). Aziridinium ion 5ca containing
3
494.
E-mail address: Chong@iit.edu (H.-S. Chong).
tetrafluoroborate as a counter anion was rapidly formed from
http://dx.doi.org/10.1016/j.tetlet.2014.12.101
040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
0

H.-S. Chong et al. / Tetrahedron Letters 56 (2015) 946–948
947
droisoquinoline (THIQ) 6 in the respective isolated yields of 56%
and 76%. b-Fluoroamine 4a containing fluoride as a poor leaving
group was not an efficient substrate in producing 6 (24% isolated
yield). It appears that the FC reaction of 4c having bromide as a
better leaving group was more efficient than 4a–b containing chlo-
ride and fluoride. Interestingly, the reaction of 4d containing iodide
did not provide the desired THIQ product. Intermolecular nucleo-
philic reaction of aziridinium ion 3d with better nucleophilic
iodide seems to be favored over the FC reaction. The stereochemis-
try in 6 was confirmed by converting 6 to the known THIQ ana-
Dast, NXS, or I
PPh , CH CN
2
OPPh3
X
X
OH
3
3
N
Bn
0 oC to RT
NBn
2
NBn
2
Bn
5
h
3
1
2
4
4
4
4
a. X = F (70%)
b. X = Cl (71%)
c. X = Br (68%)
d. X = I (60%)
X
NBn
2
7
logue 7. Hydrogenolysis of cis-6 using ammonium formate and
10% Pd/C provided cis-7 in 53% isolated yield. Based on the stereo-
AgBF
or AgOTf
4
CDCl
3
chemistry observed, we propose that the intramolecular ring open-
Y
N
ing of aziridinium ion 3 by the N-aromatic ring occurred in a S i
8
a–d
pathway.
It is speculated that the intramolecular FC reaction
N
Bn
Bn
was promoted by the partial positive charge developed at C-1 or
C-2 carbon due to a loose C–N bond in the strained aziridinium
ion. The retained stereochemistry may be explained by stabiliza-
tion of the partial positive charge by one of the phenyl ring via cat-
5
5
4
ca (Y = BF )
cb (Y = OTf)
X-ray crystallographic structure of trans-4c
Scheme 1. Synthesis and characterization of cyclohexyl-substituted b-haloamines
and aziridinium ions.
ion–
p interaction followed by a front side attack of the other
8e,f
aromatic ring on the methine carbon in the aziridinium ion.
Ring opening reaction of aziridinium ions with nucleophiles
was further studied using b-bromoamine 4c (Scheme 3). Reaction
b-bromoamine 4c (13 min), while formation of aziridinium ion 5cb
1
13
containing triflate was complete in 2 h. H and C NMR spectra of
of trans-4c with NaCN and NaN
3
via formation of aziridinium ion
aziridinium ions 5ca or 5cb were clearly distinguished from those
3
c produced the respective ring opening product of trans-8 and
of b-bromoamine 4c (Supporting information). Aziridinium ions
trans-9 in excellent to good isolated yields (94% and 82%, respec-
tively). trans-b-Azidoamine 9 was also prepared by convenient
one-pot bromination and ring opening reaction of 1. The retained
stereochemistry in 8 and 9 was confirmed by preparing the known
1
5
ca and 5cb have very similar H NMR spectra. A slight difference
in coupling pattern and resonance frequency of the methylene pro-
tons in the cyclohexyl backbone of 5ca and 5cb was observed that
may be explained by the counter ion effect. The benzylic protons in
aziridinium ions resonate as two singlet signals at more deshielded
fields (d 4.2 and 4.4 ppm) than those in b-bromoamine 4c that
appeared as two doublets (d 3.5 and 3.9 ppm). The methine pro-
tons in b-bromoamine 4c (d 4.2 ppm) and aziridinium ions 5ca
and 5cb (d 4.1 ppm) have similar resonance frequency. Aziridinium
ions 5ca and 5cb with different counter ions produced the essen-
compounds, trans-c-amino acid 11 and trans-diamine 13 from 8
and 9, respectively. trans-8 was hydrolyzed using HCl (aq) to pro-
duce trans-11 which was subjected to hydrogenolysis to provide 12
in a quantitative yield. Hydrogenation of b-azidoamine 9 afforded
vicinal diamine 13 in 97% isolated yield. Interestingly, when
3
trans-4c was reacted with AgNO , the reaction provided b-amino
nitrate trans-10 in a quantitative yield. For confirmation of stereo-
chemistry in 10, trans-10 was converted to the known compound
trans-1 in 98% isolated yield by acidic hydrolysis of trans-11 under
reflux. The retained stereochemistry in C
formation and ring opening of aziridinium ion as the key interme-
diate in a S 2 pathway involving a double inversion of the stereo-
chemistry in The result indicates that ring opening of
aziridinium ions can be utilized for highly practical synthesis of
1
3
2
tially identical C NMR signals. The methine carbon (C ) in b-
bromoamine 4c (d 56 ppm) was shown to be more deshielded than
that of aziridinium 5ca or 5cb (d 49 ppm). The two phenyl rings in
aziridinium ions 5ca and 5cb were shown to be magnetically non-
2
of 8, 9, and 10 confirms
13
equivalent giving 8 different signals in C NMR.
N
Utility of cyclohexyl-backboned b-haloamines 4 and aziridini-
um ions 3 as electrophilic species for nucleophilic substitution
reactions was investigated. First, b-haloamines 4a–d were sub-
2
C .
c-aminoacids, vicinal diamines, and b-amino nitrate.
6
jected to intramolecular Friedel–Craft (FC) reaction (Scheme 2).
Aziridinium ion 3d containing iodide and N-protected aziridines
Lewis acid-promoted FC reaction of b-chloroamine 4b or b-bromo-
amine 4c produced cis-isomer of cyclohexyl-substituted tetrahy-
1
4a–b were compared for nucleophilic ring opening reactions with
cyanide and azide at room temperature (Scheme 4). N-Protected
aziridines 14a (X = Ts) and 14b (X = BOC) in the racemic form were
9
prepared as previously reported and reacted with NaCN and NaN
3
X
N
in a S 2 pathway to produce ring opening products 15a and 16a–b.
3
AlCl ,
X
Toluene
Among the substrates tested, aziridinium ion 3d formed from b-
iodoamine 4d was found to be most reactive with cyanide and
azide and provided ring opening products 8 and 9, respectively
N
Bn
(X = F, 24%)
(X = Cl, 56%)
0 oC 1.5 h
reflux 18 h
Bn
NBn
2
N
Bn
(
X = Br, 76%)
X = I, 0%)
4
a-d
3a-d
6
(
(
>94% isolated yield, 6 h). Aziridine analogues 14a–b were signifi-
cantly slower toward the nucleophilic reactions as compared to
HCO
2
NH
4
RT 5 min
aziridinium ions 3d formed from the corresponding b-haloamines
1
0% Pd/C reflux 10 min
9
4
d. Reaction of N-Ts protected aziridine 14a with cyanide and
MeOH
(
54%)
azide was completed in 5 days to provide the corresponding ring
1
0
11
opening products 15a and 16a in the respective isolated yields
9
of 77% and 95%. Compound 14b containing the N-BOC group was
sluggish in reaction with sodium azide to produce 16b12 in low iso-
lated yield (59%, 10 days). The results in Scheme 4 clearly indicate
that aziridinium ion 3d was significantly more reactive than N-pro-
tected aziridines 14a–b.
N
H
7
In conclusion, cyclohexyl-backboned b-haloamines and
aziridinium ions were prepared and characterized using NMR
Scheme 2. Ring opening of aziridinium ions: formation of tetrahydroisoquinoline 7
via intramolecular Friedel–Crafts reaction.

9
48
H.-S. Chong et al. / Tetrahedron Letters 56 (2015) 946–948
N
3
H
2
OH
i) NBS, PPh
NH
2
3
1
0% Pd/C
EtOH, 60 h
97%)
CH
ii) NaN
3
CN
, 0 oC, 2 h
3
NBn
N
Bn
2
NH2
(
(
59%)
1
9
13
Bn
NaN
2
CN/H O
3
RT, 11 h
6
M HCl (aq)
CH
3
(
82%)
reflux, 24 h
(98%)
NaCN
2
CH CN/H O
ONO
2
Br
X
AgNO
rt, 14 h
100%)
3
, EtOAc
3
N
Bn
14 h, rt
(94%)
NBn
2
N
Bn
Bn
(
1
0
3c
Bn
HCl (aq)
reflux, 48 h
8. X = CN (94%)
11. X = CO H (100%)
2
H
2
EtOH, 60 h
(100%)
Br
1
0% Pd/C
N
Bn
2
CO H
4
c
Bn
NH
2
1
2
Scheme 3. Stereospecific nucleophilic ring opening reactions of aziridinium ion 3c for synthesis of vicinal diamine and b-aminoacid.
References and notes
I
I
Nu
Bn
Bn
Nu
CH CN/H
N
3
2
O
NBn2
1. (a) Stankovi c´ , S.; D’hooghe, M.; Catak, S.; Eum, H.; Waroquier, M.; Van
Speybroeck, V.; De Kimpe, N.; Ha, H.-J. Chem. Soc. Rev. 2012, 41, 643–665; (b)
Métro, T.-X.; Duthion, B.; Pardo, D. G.; Cossy, J. Chem. Soc. Rev. 2010, 39, 89; (c)
Piotrowska, D. G.; Wróblewski, A. E. Tetrahedron 2009, 65, 4310; (d) Guan, H.;
Saddoughi, S. A.; Shaw, A. P.; Norton, J. R. Organometallics 2005, 24, 63582; (e)
Carter, C.; Fletcher, S.; Nelson, A. Tetrahedron: Asymmetry 2003, 14, 1995; (f)
Nagle, A. S.; Salvatore, R. N.; Chong, B. D.; Jung, K. W. Tetrahedron Lett. 2000, 41,
NBn
2
4
d
3d
8
9
(Nu = CN)
(Nu = N )
3
Nu
Nu
NX
CH
3
2
CN/H O
NHX
3011.
1
1
4a. X = Ts
15a (Nu = CN)
2. (a) Degennaro, L.; Trinchera, P.; Luisi, R. Chem. Rev. 2014, 114, 7881; (b) Zhu, Y.;
Wang, Q.; Cornwall, R. G.; Shi, Y. Chem. Rev. 2014, 114, 8199; (c) Wu, B.;
Parquette, J. R.; RajanBabu, T. V. Science 2009, 326, 1662; (d) Wu, B.; Gallucci, J.
C.; Parquette, J. R.; RajanBabu, T. V. Angew. Chem., Int. Ed. 2009, 48, 1126; (e)
Moss, T. A.; Fenwick, D. R.; Dixon, D. J. J. Am. Chem. Soc. 2008, 130, 10076; (f)
Rowland, E. B.; Rowland, G. B.; Rivera-Otero, E.; Antilla, J. C. J. Am. Chem. Soc.
2007, 129, 12084; (g) Yudin, A. K. Aziridines and Epoxides in Organic Synthesis;
Wiley-VCH: Weinheim, 2006; (h) Mit, T.; Fujimori, I.; Wada, R.; Wen, J.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 11252; (i) Lee, W.-Y.; Salvador, J.
M.; Kalavathi, B. Org. Lett. 2002, 2, 931; (j) Sabitha, G.; Babu, R. S.; Rajkumar, M.;
Yadav, J. S. Org. Lett. 2002, 4, 343.
4b. X = BOC
16a-b (Nu = N )
3
entry substrate
Nu
NaCN
NaN
NaCN
temp
reaction time
product
8
Yield (%)
2
3
4
5
6
4d
4d
rt
rt
rt
rt
rt
6 h
6 h
94
98
77
95
59
3
9
14a
14a
14b
5 d
15a
16a
16b
NaN
NaN
3
5 d
3
4
.
.
Noll, D. M.; Mason, T. M.; Miller, P. S. Chem. Rev. 2006, 106, 277.
3
10 d
(a) Oxenford, S. J.; Moore, S. P.; Carbone, G.; Barker, G.; O’Brien, P.; Shipton, M.
R.; Gilday, J.; Campos, K. R. Tetrahedron: Asymmetry 2010, 21, 1563; (b)
Hamilton, G. L.; Kanai, T.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 14984; (c)
Métro, T.-X.; Pardo, D. G.; Cossy, J. J. Org. Chem. 2007, 72, 6556–6561; (d)
Couturier, C.; Blanchet, J.; Schlama, T.; Zhu, J. Org. Lett. 2006, 8, 2183; (e)
Andrews, D. R.; Dahanukar, V. H.; Eckert, J. M.; Gala, D.; Lucas, B. S.;
Schumacher, D. P.; Zavialov, I. A. Tetrahedron Lett. 2002, 43, 6121; (f) Graham,
M. A.; Wadsworth, A. H.; Thornton-Pett, M.; Rayner, C. M. Chem. Commun. 2001,
Scheme 4. Nucleophilic ring opening reactions of aziridine and aziridinium
analogues.
and/or X-ray crystallography. We demonstrated utility of the
cyclohexyl-substituted aziridinium ions as precursor molecules
for highly practical stereospecific synthesis of vicinal diamine, b-
amino acid, b-amino nitrate, and THIQ analogues. Aziridinium ions
were found to be more sensitive toward nucleophilic ring opening
than the aziridine congeners. The result indicates that aziridinium
ions can be generated from the readily available b-aminoalcohols
and applied for stereospecific synthesis of various small organic
molecules.
9
66; (g) Weber, K; Kuklinski, S.; Gmeiner, P. Org. Lett. 2000, 2, 647; (h) Liu, Q.;
Marchington, A. P.; Boden, N.; Rayner, C. M. J. Chem. Soc., Perkin Trans. 1 1997,
11–526.
5
5. Miyano, S.; Lu, L. D. L.; Viti, S. M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 4350–
4360.
6
7
8
.
.
.
Yamashita, M.; Yamada, K.; Tomioka, K. J. Am. Chem. Soc. 2004, 126, 1954.
Chong, H.-S.; Chen, Y. Org. Lett. 2013, 15, 5912.
(a) Armaroli, S.; Cardillo, G.; Gentilucci, L.; Gianotti, M.; Tolomelli, A. Org. Lett.
2000, 2, 1105; (b) Davis, F. A.; Reddy, G. V. Tetrahedron Lett. 1996, 37, 4349; (c)
Hori, K.; Nishiguchi, T.; Nabeya, A. J. Org. Chem. 1997, 62, 3081; (d) Maas, H.;
Bensimon, C.; Alper, H. J. Org. Chem. 1998, 63, 17; (e) Yamada, S.; Fossey, J. S.
Org. Biomol. Chem. 2011, 9, 7275; (f) Catak, S.; D’hooghe, M.; De Kimpe, N.;
Waroquier, M.; Van Speybroeck, V. J. Org. Chem. 2010, 75, 885.
Mordini, A.; Russo, F.; Valacchi, M.; Zani, L.; Degl’Innocenti, A.; Reginato, G.
Tetrahedron 2002, 58, 7153.
Supplementary data
9
.
1
0. Minakata, S.; Okada, Y.; Oderaotoshi, Y.; Komatsu, M. Org. Lett. 2005, 7, 3509.
Supplementary data (experimental details on synthesis, charac-
1
13
11. Wang, Z.; Cui, Y.-T.; Xu, Z.-B.; Qu, J. J. Org. Chem. 2008, 73, 2270.
terization, and H and C NMR spectra of compounds) associated
with this article can be found, in the online version, at http://dx.
doi.org/10.1016/j.tetlet.2014.12.101.
1
2. Pendem, N.; Douat, C.; Claudon, P.; Laguerre, M.; Castano, S.; Desbat, B.;
Cavagnat, D.; Ennifar, E.; Kauffmann, B.; Guichard, G. J. Am. Chem. Soc. 2013,
135, 4884.