A practical regioselective ring-opening of activated aziridines with organoalanes

Article abstract of DOI:10.1016/j.tetlet.2009.05.081

The regioselective ring-opening of N-protected 2-phenylaziridines is accomplished by the addition of organoalanes in dichloromethane. With this simple method it is possible to introduce alkyl, alkenyl and alkynyl substituents at the benzylic position of t

Full text of DOI:10.1016/j.tetlet.2009.05.081

Tetrahedron Letters 50 (2009) 4515–4518
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Tetrahedron Letters
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A practical regioselective ring-opening of activated aziridines with organoalanes
a
a,
Ferruccio Bertolini a,b, Simon Woodward b, , Stefano Crotti , Mauro Pineschi
*
*
a Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy
b School of Chemistry, The University of Nottingham, Nottingham NG7 2RD, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 March 2009
Revised 8 May 2009
Accepted 22 May 2009
Available online 27 May 2009
The regioselective ring-opening of N-protected 2-phenylaziridines is accomplished by the addition of
organoalanes in dichloromethane. With this simple method it is possible to introduce alkyl, alkenyl
and alkynyl substituents at the benzylic position of the phenylaziridine to give the corresponding b-phe-
nyl-b-substituted amines, as useful precursors for intramolecular hydroaminations, in high yields.
Ó 2009 Elsevier Ltd. All rights reserved.
The ring-opening of aziridines with carbon nucleophiles repre-
sents a useful entry into substituted amines.1 Several organometal-
lic reagents have been used for this purpose, with the notable
exception of organoaluminium reagents. For example, organocup-
rates are particularly well suited for the ring-opening of N-tosyl
phenylaziridine, albeit with modest regioselectivity, and with pre-
dominant attack at the less-hindered position.2 More recently, a
completely reversed regioselectivity (1:5), favouring the benzylic
position was obtained with Me2CuLi in the ring-opening of 2-pyri-
dinesulfonamide-protected phenylaziridine, due to the chelating
properties of the protecting group.3 It should be noted that aziri-
dine ring-cleavage with metal acetylides to form homopropargylic
amines has scarcely been described,4 notwithstanding the syn-
thetic potential of these in the preparation of heterocycles by intra-
molecular amination,5 or ‘click chemistry’ manipulation of the
triple bond.6 Furthermore, when N-tosyl phenylaziridine was used,
a regioisomeric mixture, with predominant attack of the potassium
or lithium acetylide at the less-hindered position, was obtained.4
We report here a novel method for the ring-opening of aryl and
vinyl aziridines with alkyl, alkenyl and alkynyl organoaluminium
reagents to give the corresponding substituted amines with mod-
est to complete regioselectivity.
In preliminary experiments, we found that the reaction of a
variety of N-tosyl aziridines with AlMe3 under different reaction
conditions gave only trace amounts of alkylated products with very
low conversions (<10%) even with prolonged reaction times. Final-
ly, we found that the reaction between AlMe3 and N-tosyl pheny-
laziridine 1a was solvent dependent. A very low conversion
occurred when the reactions were carried out in THF and Et2O,
but when CH2Cl2 or toluene were used, complete conversion was
obtained in 1 h at 0 °C. To our delight, the ring-opening occurred
via completely selective attack of the methyl fragment at the ben-
zylic position (Table 1, entry 1). The use of AlEt3 afforded the cor-
responding adduct 3a, albeit with reduced regioselectivity (entry
2). When these reactions were carried out on enantiomerically
pure aziridine (R)-1a (>98% ee), the corresponding products 2a
and 3a were obtained with low enantioselectivity (14% ee).
However, it was possible to employ the Cbz-protected pheny-
laziridine 1b, even if a lower yield of the corresponding adduct
2b was obtained. Also in this case, when enantiomerically pure
(R)-1b was used, extensive racemization (25% ee) was observed.
The high extent of racemization, together with the selective attack
at the benzylic position, point to ring-opening under electronic
control. Probably, the high affinity of aluminium for oxygen allows
coordination of AlR3 to the oxygen lone-pairs of the protecting
group,8 thus creating a more reactive ‘ate complex’, which delivers
the methyl fragment intramolecularly onto the benzylic carbenium
ion (Fig. 1), with a substantial loss of stereochemical integrity of
the starting aziridine (57% inversion, 43% retention, as determined
by HPLC on a chiral stationary phase).
The reaction of vinyl aziridines with organometallic reagents
has often been promoted by copper salts and this usually results
in selective anti-SN20 reactions,9 even if particular steric bias can
induce a syn-stereoselective pathway.10 The uncatalyzed addition
of AlMe3 to 7-tosyl-7-azabicyclo[4.1.0]hept-2-ene (1c) proceeded
with full conversion in 1 h at 0 °C and with good regioselectivity
(SN2/SN20 = 93/7). Unfortunately, the product consisted of a mix-
ture of cis-6a (60%) and trans-7a (40%) diastereoisomers, which
was not separable by chromatographic purification (entry 6).
On the other hand, the uncatalyzed addition of AlMe3 to the
five-membered analogue 1d gave the cis-SN2 adduct 6a with
good stereo- and regioselectivity, in fair isolated yield (entry
7). The stereochemistry of adduct 8a was confirmed by 1H
NMR examination and by comparison with the data of the corre-
sponding trans adduct.11 The cis 1,2-opening is a mode of reac-
tion rarely observed with alkyl carbanions,12 and can be
explained via coordination of the organoalane to the aziridine-
protecting group with subsequent intramolecular transfer of
the R group from the same side.
* Corresponding authors. Tel.: +39 (0)502219668; fax: +39 (0)502219660 (M.P.).
E-mail address: pineschi@farm.unipi.it (M. Pineschi).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.081

4516
F. Bertolini et al. / Tetrahedron Letters 50 (2009) 4515–4518
Table 1
Ring-opening of aryl and vinyl aziridines with alkyl and alkenyl alanesa
Entry
1
Aziridine
AlR3 conditions
Regioselectivityb
>95/<5
Product yieldc (%)
AlMe3
1 h, 0 °C
Ts
Me
N
NHTs
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a, (92)
1a
2
3
4
AlEt3
1 h, 0 °C
88/12
Ts
Et
N
NHTs
3a, (70)
1a
AlMe3
1 h, 0 °C
>95/<5
>95/<5
Cbz
N
Me
NCbz
2b, (58)
1b
Ts
N
Ph
Ph
Al(i-Bu)2
1 h, r.t.
NHTs
1a
Ph
4a, (85)d
5
6
>95/<5
Ts
N
C5H11
C5H11
Al(i-Bu)2
1 h, r.t.
Ph
NHTs
1a
Ph
5a, (60)d
AlMe3
1 h, 0 °C
93/7
91/9
6a,7a
NTs
mixture
NHTs
NHTs
1c
Me
7
AlMe3
1 h, 0 °C
8a,
(62)
NTs
1d
Me
a
All reactions were carried out in CH2Cl2 in accordance with the typical procedures.7
Regioselectivity determined by 1H NMR examination of the crude mixture.
Isolated yield of pure product after chromatographic purification on silica gel.
The product was recovered contaminated (ca. 10%) with the corresponding alkynylated compound.
b
c
d
Me
Ar
PG
CH2Cl2
N
+
C4H9
AlMe2
C4H9
Ar
S
O
-
Al
O
d+
O
Me
0 °C, 1-3 h
NHPG
d-
Me
S
O
Me
Al
1e, PG = Ts
Me
Me
N
9a, (PG = Ts, 80%)
9b, (PG = Cbz, 70%)
N
1f, PG = Cbz
+
Ph
Ph
Scheme 1. Alkynylation of protected aziridines 1e and 1f.
Figure 1. A plausible mechanism for the ring-opening of N-tosyl phenylaziridine.
aziridines afforded only trace amounts of alkylated products.
Although it is not a normal procedure to carry out an alkyne depro-
tonation in CH2Cl2, the use of this solvent is mandatory here to ob-
tain high yields of alkynylated products. No evidence of competing
CH2Cl2 deprotonation was observed.
Alkynylaluminium reagents, which can be prepared from the
corresponding alkynyllithium and dialkylaluminium chlorides,13
have found widespread use in organic synthesis.
Interestingly, the increased reactivity of these reagents allowed
the reaction with protected aziridines 1e and 1f to occur at 0 °C in
CH2Cl2, togivegoodyieldsofhomopropargylamines 9a,b(Scheme1).
It should be noted that the reaction of AlMe3 with the same
We next examined the reaction of dimethyl(alkynyl)alanes with
aryl and vinyl aziridines, and the results are reported in Table 2.
Apart from the reaction of the organoalane derived from hep-
tyne (Table 2, entry 2), all the other reactions were complete in

F. Bertolini et al. / Tetrahedron Letters 50 (2009) 4515–4518
4517
Table 2
major product isolated in pure state by chromatographic purifica-
tion was the trans-homopropargyl amine 15 (entry 6). To our sur-
prise, the reaction with the five-membered analogue 1d exhibited
unusual cis-SN20 stereoselectivity, which might be ascribed to the
increased soft character of this reagent with respect to AlMe3 (en-
try 5). The 1,4-cis relationship of the substituents was deduced
from the large chemical shift difference (0.91 ppm) between the
two ring methylene protons and by their characteristic coupling
patterns.15 This stereoselective outcome nicely complements the
recently developed synthetic protocol for alkynylated 1,4-trans-
disubstituted cyclopentenes by desymmetrization of bicyclic
hydrazines.16
In conclusion, the ring-opening of aryl and vinyl aziridines with
organoalanes proceeds with high yields and regioselectivity in a
weakly coordinating non-ethereal solvent. This simple protocol al-
lows the introduction of alkyl, alkenyl and alkynyl substituents at
the benzylic position of the phenylaziridine to give the correspond-
ing b-phenyl-b-substituted amines in high yields. Of particular
interest is the practical synthesis of novel homopropargylic and
homoallylic amines which can be used for intramolecular
hydroaminations.
a
Ring-opening of aryl and vinyl aziridines with R-CCAlMe2
Entry
R
Conditions
Regio-
Product yieldc (%)
(Aziridine)
selectivityb
1
Ph
(1a)
1 h, 0 °C
>95/<5
Ph
NHTs
Ph
Ph
Ph
10, (85)
2
C5H11
(1a)
18 h, rt
>95/<5
C5H11
NHTs
11, (70)
3
C3H5
(1a)
1 h, 0 °C
>95/<5
Acknowledgements
NHTs
12, (88)
This work was supported by Ministero dell’ Istruzione, dell’Uni-
versità e della Ricerca (M.I.U.R. Rome, PRIN 2006) and by the Uni-
versity of Pisa. We also thank the Rotary Foundation for a post-doc
fellowship to F.B. S.W. is grateful to the European Union Coopera-
tion of Science and Technology (COST) programme D40 and to the
UK Engineering and Physical Sciences Research Council (EPSRC) for
co-support of D40.
4
Ph
(1b)
1 h, 0 °C
>95/<5
Ph
NHCbz
Ph
13, (60)
Supplementary data
5
Ph
(1d)
1 h, 0 °C
89/11
(SN20/SN2)
NHTs
Supplementary data (detailed experimental procedures and
characterization data for all new compounds) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.05.081.
14, (60)
Ph
References and notes
6
Ph
(1c)
1 h, 0 °C
7/93
1. For reviews, see: (a) Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247–258; (b) Hu, X.
E. Tetrahedron 2004, 60, 2701–2743; (c) Pineschi, M. Eur. J. Org. Chem. 2006,
4979–4988.
2. Kozikowski, A. P.; Ishida, H.; Isobe, K. J. Org. Chem. 1979, 44, 2788–2790.
3. Han, H.; Bae, I.; Yoo, E. J.; Lee, J.; Do, Y.; Chang, S. Org. Lett. 2004, 6, 4109–4112.
4. (a) Ding, C.-H.; Dai, L.-X.; Hou, X.-L. Tetrahedron 2005, 61, 9586–9593; (b) Ding,
C.-H.; Dai, L.-X.; Hou, X.-L. Synlett 2004, 1691–1694.
5. Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127–2198.
6. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004–
2021.
(SN20/SN2)
NHTs
15, (45)
Ph
a
7. Typical procedure for alkylation (entry 1, Table 1): AlMe3 (0.5 mmol, 0.25 mL of a
2 M solution in hexanes) was added at 0 °C under an argon atmosphere to a
solution of racemic or (R)-1a (68.3 mg, 0.25 mmol) in dichloromethane
(1.0 mL). The mixture was allowed to react at 0 °C for 1 h and then quenched
with 1 M hydrochloric acid (2.0 mL). The aqueous phase was extracted with
dichloromethane (5.0 mL) and diethyl ether (5.0 mL). The combined organic
fractions were dried over magnesium sulfate and filtered. Evaporation of the
organic solution afforded a crude residue which was purified by silica gel
column chromatography (hexane/EtOAc: 9/1), to give 4-methyl-N-(2-
phenylpropyl)benzenesulfonamide (2a) (66.5 mg, 92%).2,3 HPLC analysis of
All reactions were carried out in CH2Cl2 in accordance with the typical
procedure.14
Regioselectivity determined by 1H NMR examination of the crude mixture.
Isolated yield of pure product after chromatographic purification on silica gel.
b
c
1 h at 0 °C after the addition of the dimethyl(alkynyl)alane to the
aziridine. The regioselectivity of the ring-opening was excellent
in all cases for phenylaziridines 1a and 1b (entries 1–4), whereas
the use of cyclic vinyl aziridines 1d and 1c gave minor amounts
of regioisomeric products (entries 5 and 6). Moreover, the alkynyl
group of the reagent was found to have a significant influence on
the regio- and stereoselectivity of the ring-opening depending on
the substrate used. In fact, the reaction of the alkynyl alane derived
from phenylacetylene with the cyclohexene-derived aziridine 1c
proceeded with high SN2 regioselectivity. The 1,2-addition path
was not completely stereoselective (ca. 9:1 trans/cis), but the
Ò
the product was performed on a Chiralpak AD-H column, flow rate: 0.5 mL/
min, mobile phase: hexane/isopropanol 95/5, retention times (min): 49.0 (R,
minor stereoisomer); 54.1 (S, major stereoisomer). Typical procedure for
alkenylation (entry 4, Table 1): to
a solution of DIBAL-H in hexanes
(0.6 mmol, 0.6 mL of a 1 M solution in hexanes) was added phenylacetylene
(0.6 mmol, 3.0 equiv) dropwise. The solution was allowed to react at 55 °C for
3 h. At this point, the solution was cooled to room temperature and a solution
of aziridine 1a (54.6 mg, 0.2 mmol) in dichloromethane (0.6 mL) was added
dropwise at 0 °C. The mixture was allowed to react at room temperature for 1 h
and then quenched with 1 M hydrochloric acid (2.0 mL). The aqueous phase
was extracted with dichloromethane (5.0 mL) and diethyl ether (5.0 mL). The
combined organic fractions were dried over magnesium sulfate and filtered.

4518
Evaporation of the organic solution afforded
F. Bertolini et al. / Tetrahedron Letters 50 (2009) 4515–4518
crude residue which was 12. Xue, S.; Li, Y.; Han, K.; Yin, W.; Wang, M.; Guo, Q. Org. Lett. 2002, 4, 905–907.
a
purified by silica gel column chromatography (petroleum ether/EtOAc: 85/15)
to give 4a (64 mg, 85%) as a white solid (contaminated with 10% of 10).
Mp = 119–121 °C. 1H NMR (400 MHz, CDCl3): d = 2.45 (s, 3H, Ar-CH3); 3.22–
3.40 (m, 2H, CH2–NH); 3.55–3.66 (m, 1H, Ph-CH); 4.48 (br s, 1H, CH2–NH); 6.29
(dd, J1 = 17.7 Hz, J2 = 8.6 Hz, 1H, Ph-CH@CH–); 6.53 (d, J = 17.7 Hz, 1H, Ph-
CH@CH); 7.12–7.43 (m, 12H, Ar-H); 8.00 (d, J = 9.0 Hz, 2H, Ar-H). 13C NMR
(100 MHz, CDCl3): d = 21.6, 48.5, 48.7, 126.3, 127.2, 127.4, 127.7, 127.8, 128.6,
129.0, 129.8, 131.8, 132.3, 136.6, 137.0, 140.3, 143.5. ESIMS (+) m/z 400.1345
(M+Na).
13. Zweifel, G.; Miller, J. A. Org. React. 1984, 32, 375–517.
14. Typical Procedure for alkynylation (entry 1, Table 2): In a dry Schlenk tube, a
solution of BuLi (0.5 mmol, 0.3 mL of a 1.6 M solution in hexanes) was added
under an argon atmosphere at 0 °C to a solution of phenylacetylene (0.5 mmol)
in freshly distilled dichloromethane (1.0 mL). This mixture was allowed to
react for 15 min at 0 °C. To this solution, dimethylaluminium chloride
(0.5 mmol, 0.5 mL of a 1 M solution in hexanes) was then added dropwise at
0 °C. The resulting suspension was stirred for 25 min at room temperature and
added via cannula to
a solution of aziridine 1a (68.3 mg, 0.25 mmol) in
8. As the nitrogen of protected aziridines is very poorly basic, its direct interaction
with a Lewis acid is not likely. See also Ref. 1a.
dichloromethane (0.6 mL) at 0 °C. The mixture was allowed to react for 1 h at
0 °C. Column chromatography (petroleum ether/EtOAc: 9/1) afforded N-(2,4-
9. (a) Wipf, P.; Fritch, P. C. J. Org. Chem. 1994, 59, 4875–4886; (b) Ibuka, T.; Nakai,
K.; Habashita, H.; Hotta, Y.; Fujii, N.; Mimura, N.; Miwa, Y.; Taga, T.; Yamamoto,
Y. Angew. Chem., Int. Ed. Engl 1994, 33, 652; (c) Toda, A.; Aoyama, H.; Mimura,
N.; Ohno, H.; Fujii, N.; Ibuka, T. J. Org. Chem. 1998, 63, 7053–7061; (d) Penkett,
C. S.; Simpson, I. D. Tetrahedron Lett. 2001, 42, 1179–1181; (e) Gini, F.; Del
Moro, F.; Macchia, F.; Pineschi, M. Tetrahedron Lett. 2003, 44, 8559–8562; (f)
Cunha, R. L. O. R.; Diego, D. G.; Simonelli, F.; Comasseto, J. Tetrahedron Lett.
2005, 46, 2539–2542.
diphenylbut-3-ynyl)-4-methylbenzenesulfonamide (10), (80 mg, 85%) as
a
white solid. Mp = 122–123 °C. 1H NMR (400 MHz, CDCl3): d 2.45 (s, 3H, Ar-
CH3); 3.26–3.33 (m, 1H, CH2–NH); 3.36–3.43 (m, 1H, CH2–NH); 4.02 (dd, 1H,
J1 = 8.0 Hz, J2 = 6.4 Hz, Ph-CH); 4.80–4.84 (m, 1H, CH2–NH); 7.28–7.39 (m, 10H,
Ar-H); 7.41–7.48 (m, 2H, Ar-H); 7.76 (d, 2H, J = 8.0 Hz, Ar-H). 13C NMR
(100 MHz, CDCl3) d 21.5, 39.0, 49.3, 85.1, 87.5, 122.6, 127.0, 127.7 (2 carbons),
128.3, 128.4, 128.8, 129.7, 131.7, 137.0, 137.7, 143.5. ESIMS (+) m/z 398.1173
(M+Na).
10. Hudlicky, T.; Tian, X.; Königsberger, K.; Rouden, J. J. Org. Chem. 1994, 59, 4037–
4039.
11. Masse, C. E.; Dakin, L. A.; Knight, B. S.; Panek, J. S. J. Org. Chem. 1997, 62, 9335–9338.
15. Eisch, J. J.; Noels, A. F. J. Org. Chem. 1976, 41, 1461–1464.
16. Crotti, S.; Bertolini, F.; Macchia, F.; Pineschi, M. Chem. Commun. 2008, 3127–
3129.