BH3-promoted stereoselective β-lithiation of N-alkyl-2-phenylaziridines

Article abstract of DOI:10.1021/jo102474u

BH₃ complexes of N-alkyl-2-phenylaziridines have been synthesized and their structure and stereochemistry proved with DFT calculations and NMR experiments. It has been demonstrated that the Lewis acid complexation is able to promote a regiosele

Full text of DOI:10.1021/jo102474u

NOTE
pubs.acs.org/joc
BH3-Promoted Stereoselective β-Lithiation of
N-Alkyl-2-phenylaziridines
Ugo Azzena,‡ Giovanna Dettori,‡ Luisa Pisano,*,‡ Biagia Musio,§ and Renzo Luisi*,§
‡Dipartimento di Chimica, Universitꢀa di Sassari, via Vienna 2, I-07100 Sassari, Italy
§Dipartimento Farmaco-Chimico, Universitꢀa degli Studi di Bari, Aldo Moro, Via E. Orabona 4, I-70125, Bari, Italy.
S Supporting Information
b
ABSTRACT: BH3 complexes of N-alkyl-2-phenylaziridines have been
synthesized and their structure and stereochemistry proved with DFT
calculations and NMR experiments. It has been demonstrated that the
Lewis acid complexation is able to promote a regioselective β-lithiation in
2-phenylaziridino-borane complexes. The lithiated intermediates were
configurationally stable, allowing an enantioselective preparation of cis-
2,3-disubstituted aziridines.
ziridines are widely used as versatile building blocks for the
synthesis of a variety of biologically and pharmaceutically
Table 1. Synthesis of the Aziridino-Borane Complexes 2a-c
A
important molecules.1 Several methods for the synthesis of
aziridines have been developed, and their use as chiral building
blocks has also emerged recently.2 In the past decade, much
interest has been devoted to the development of new methodol-
ogies for a regioselective lithiation and functionalization of such
substrates.3 Data from the literature indicate that N-alkyl-2-
phenylaziridines undergo smooth ortho-lithiation, thus showing
the ability of the aziridino group to act as a directing metalation
group (DMG).4 In contrast, trans-N-alkyl-2,3-diphenylaziridines
undergo exclusive R-lithiation with a stereochemistry strongly
depending on the coordinating ability of the solvents.5,6 These
results have been rationalized, taking into account the crucial role
of the aziridine nitrogen dynamics in controlling the R- versus
ortho-lithiation competition.7 Focusing on the deprotonation of
simple N-alkyl-substituted aziridines, Vedejs8 reported the lithia-
tion of a simple unsubstituted aziridine by using BH3 activation, a
procedure originally developed by Kessar9 to promote the R-
metalation of tertiary amines. A stereochemical analysis of the
reaction was consistent with a dominant aziridine lithiation syn to
the BH3 group.10 Starting from this evidence, and conscious that
N-alkyl-2-phenylaziridines undergo exclusive ortho-lithiation, we
decided to investigate the lithiation of the corresponding BH3
complexes lacking the nitrogen lone pair availability. We started
our investigation with a careful structural and stereochemical
analysis, by NMR and DTF calculations, on the BH3 complexes
of N-alkyl-2-phenylaziridines. 2-Phenylaziridines 1a-d were
prepared according to a known procedure11 and reacted with a
aziridine 1
R
borane complex 2
yielda (%)
1a
1b
1c
1d
t-Bu
2a
2b
2c
2d
>95
>95
92
Et
Ph(CH3)2C
(Ph3)3C
b
a Determined on pure isolated products. b The complex was not enough
stable for isolation.
Before evaluation of the structural analysis of the aziridino-
borane complexes, some stereochemical considerations are
needed. If one considers that N-alkyl-2-phenylaziridines could
undergo nitrogen inversion, two diastereoisomers should, in
principle, be expected in the reaction with BH3. Nevertheless,
previous reports demonstrated that, in N-alkylmonophenylazir-
idines, the main diastereoisomer is the one that sets the lone pair
on the same side of the phenyl ring (dr >98:2).4-7 With this
assumption in mind, the stereochemistry of BH3-coordinated N-
alkyl-2-phenylaziridines was assigned, taking into account the
results of NMR experiments and DFT calculations. Table 2
1
reports experimental, calculated, and scaled H and 13C NMR
1 M THF solution of BH3 THF complex (Table 1). The
chemical shifts (ppm) for complexes 2a and 2b bearing the
phenyl group and the BH3 group in a cis relationship. For
3
corresponding aziridino-borane complexes 2a-c were ob-
tained as single diastereoisomers in high yields, while attempts
to prepare the borane complex of the trityl aziridine 1d were
unsuccessful.12
Received: December 16, 2010
Published: March 02, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
NOTE
Table 2. Experimental, Calculated, and Scaled 1H and 13C NMR Chemical Shift (ppm)
2a
2b
inv-2b
a
b
c
a
b
c
c
atom
C1
δexp
δMPW1PW91
δB3LYP
δexp
δMPW1PW91
δB3LYP
δB3LYP
44.38
35.96
48.71 (44.94)
37.51 (35.26)
64.45 (60.94)
139.25 (132.25)
137.50 (130.58)
134.23 (127.47)
134.76 (127.97)
27.33 (25.56)
0.999
50.70 (46.03)
38.82 (34.64)
69.53 (64.08)
141.30 (132.8)
138.22 (129.94)
135.04 (126.89)
135.51 (127.34)
27.68 (23.95)
0.998
48.77
40.99
57.05 (53.65)
38.83 (36.31)
62.81 (59.14)
13.52 (12.20)
138.73 (131.45)
137.49 (130.27)
134.42 (127.34)
135.20 (128.09)
0.997
59.40 (54.64)
39.81 (35.98)
65.08 (60.05)
13.80 (11.21)
140.73 (132.10)
138.31 (129.79)
135.24 (125.92)
136.05 (127.64)
0.996
58.53 (53.30)
39.29 (35.35)
54.36 (49.41)
13.64 (11.42)
139.47 (128.80)
138.02 (127.44)
136.38 (125.92)
136.59 (126.11)
0.997
C2
C7
60.69
59.33
C8
132.01
129.96
127.90
128.29
26.27
11.85
C13
130.87
129.89
127.85
128.59
C14/C18
C15/C17
C16
R2
MAE
CMAE
H4
4.78
6.40
5.53
6.58
6.44
0.45
1.44
1.50
2.05
1.94
3.70
2.63
2.66
1.40
3.88 (3.79)
2.41 (2.61)
2.69 (2.69)
1.38 (1.48)
0.979
3.84 (3.79)
2.42 (2.46)
2.64 (2.67)
1.37 (1.48)
0.984
3.34
2.43
2.82
1.45
3.54 (3.50)
2.35 (2.40)
2.58 (2.62)
1.39 (1.52)
0.963
3.51 (3.49)
2.36 (2.42)
2.57 (2.62)
1.39 (1.51)
0.964
4.06 (3.62)
2.40 (2.41)
2.44 (2.44)
1.24 (1.56)
0.889
H5
H6
CH3
R2
MAE
0.10
0.10
0.14
0.14
0.34
CMAE
0.06
0.09
0.11
0.11
0.20
a Experimental values in CDCl3 at 298 K. b PCM/MPW1PW91/6-311þþG(d,p) calculation, scaled values in parentheses. c PCM/B3LYP/6-
311þþG(d,p) calculations, scaled values in parentheses.
2,3
Table 3. Experimental and Calculated SSCC
J
HH
2a
B3LYPb
2b
B3LYPb
inv-2b
SSCCa
exp
exp
B3LYPb
Jcis
7.8
6.3
2.1
7.7
4.9
1.9
7.5
6.3
2.1
7.3
5.1
2.1
6.5
4.9
2.0
Jtrans
Jgem
a Values in hertz. b At PCM/B3LYP/6-311þþG(d,p) level.
evaluate the quality of the theoretical prediction, and to dis-
criminate between the possible structures, are the last-squares
linear fitting parameter (R2) of the correlation plots between
computed (without scaling) and experimental data, the mean
absolute error (MAE), and the corrected mean absolute error
(CMAE).17,18 All of the calculated data are reported in Table 2,
and they are in good agreement with the experimental data of
complexes 2a and 2b. A better correlation, between experimental
and calculated chemical shifts, has been observed by using the
MPW1PW91 functional with respect to the B3LYP functional. In
addition, 13C chemical shifts calculated at the B3LYP/6-
311þþg(d,p) level of theory are unreliable to distinguish
between 2b and inv-2b.19 Nevertheless, a better fit with the
experimental chemical shifts of 2b was found by comparison of
calculated 1H chemical shifts of 2b with respect to inv-2b. In this
case, the results of calculations are more reliable to assign the
correct structure as clearly indicated by the corresponding R2,
MAE, and CMAE values. Furthermore, the geminal and vicinal
spin-spin coupling constants (SSCC) between the aziridinyl
protons of complexes 2a, 2b, and inv-2b have been calculated at
the B3LYP/6-311þþG(d,p) level (Table 3). In this case, a very
good correlation was found in the analysis of calculated and
experimental values, confirming the well-known trend observed
Figure 1. Equilibrium geometries (in CDCl3) at the PCM/B3LYP/6-
311þþG(d,p) level for complexes 2a, 2b, and inv-2b, experimental
main NOE interactions and 11B NMR (192 MHz) of complexes 2a,b.
comparison, the theoretical data of the diastereoisomeric com-
plex inv-2b, bearing the phenyl and the BH3 groups trans to each
other, were also evaluated. The equilibrium geometries at the
DFT-B3LYP/6-311þþG(d,p) level of complexes 2a, 2b, and
inv-2b are reported in Figure 1.
Chemical shift calculations were performed by employing the
gauge-invariant atomic orbital (GIAO) method implemented in
Gaussian 03 programs at the DFT-B3LYP/6-311þþG(d,p) and
DFT-MPW1PW91/6-311þþG(d,p).13,14 To take into account
the medium effect, we performed the calculations considering the
chloroform effect within the polarization continuum model (PCM).15
The NMR chemical shifts (δ) were calculated as the differences
of isotropic shielding constants (σ) with respect to the TMS
(tetramethylsilane) reference.16 The parameters employed to
for the aziridinyl ring: Jcis > Jtrans . Jgem
.
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NOTE
Table 4. Lithiation/Electrophile Trapping Sequence of
Aziridino-Borane Complexes 2a-c
Scheme 1. Attempts for Double Functionalization on Com-
plexes 2a,b
deuterium on the β-carbon was established. By assuming that
the reaction at the lithiated carbon occurs with retention of
configuration, this finding strongly suggests that metalation
occurred exclusively syn to the BH3 moiety as reported for other
aziridino-borane complexes.10
Comparable results were obtained when Et2O was used as the
reaction solvent, while no reaction was observed in hexane
(Table 4, entries 2 and 3, respectively).
As an extension, the lithiation/trapping sequence of 2a was
executed using several electrophiles. The reactions occurred with
high regio- and stereoselectivity furnishing, after removal of the
BH3 group, cis-2,3-disubstituted aziridines 4b-e (Table 4, en-
tries 4-7). The lithiation/electrophile trapping of borane com-
plexes 2b,c under the optimal reaction conditions (Table 4,
entries 8-14) furnished similar results. However, it is worth
noting that BH3 removal from N-ethyl-substituted aziridines 3f-j
proved to be more problematic, needing hot 28% aqueous NH3
for several hours (see the Supporting Information). In the case of
N-cumyl-substituted aziridines 3k-l, the BH3 removal was easily
achieved by addition of few drops of H2O at room temperature, a
procedure leading to an immediate and vigorous evolution of gas
from the reaction mixtures. These results strongly suggest that
steric demand of the aziridine nitrogen substituent could af-
fect the strength of N-B bond. The cis stereochemistry of the
aziridines 4a-l was easily ascertained by evaluating the 1H NMR 3J
coupling constants for the aziridinic protons (Jcis > Jtrans) and in
some cases confirmed by NOE experiments (see the Supporting
Information).
The possibility to perform the BH3-complexation/lithiation/
electrophile trapping/BH3 removal sequence under one pot
conditions was also pursued. Aziridines 1a,b were first converted
into the corresponding complexes 2a,b and reacted with s-BuLi
for 2 h and then with the electrophile (Scheme 1). The reaction
mixture was subjected to BH3 removal to obtain free aziridines
4b, 4d, and 4i (Table 4, entries 4, 6, and 11).21,22
When deuterated and methylated borane complexes 3a,b and
3f,g underwent lithiation with s-BuLi followed by the addition of
the electrophile and BH3 removal, only aziridines 4a,b and 4f,g
were recovered. Similar results were obtained by performing the
full sequence under one-pot conditions starting from complexes
2a,b (Scheme 1).
Moreover, in order to verify the configurational stability of this
kind of lithiated aziridino-borane complexes, of great impor-
tance for a stereoselective synthesis of aziridines and deriva-
tives,23 the enantioenriched complex (S,S)-2b was prepared (er
>95:5) and reacted with s-BuLi under the optimized reaction
conditions (Scheme 2).
entry
R
Eþ
aziridine 4
yielda (%)
1
2
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Et
D2O
D2O
D2O
CH3I
4a
4a
1a
4b
4c
4d
4e
4f
>95b,c
>95b,d
e
80b (78)f
>95b
73 (69)f
86g
3
4
5
(CH3)3SiCl
(CH3)2CO
(CH3)3CCHO
D2O
6
7
8
>95b
9
Et
CH3I
4g
4h
4i
60
10
11
12
13
14
Et
(CH3)3SiCl
(CH3)2CO
(CH3)3CCHO
D2O
72
Et
68 (63)f
48g
>95b
Et
4j
Ph(CH3)2C
4k
Ph(CH3)2C
CH3I
1
4l
56
a Isolated yields. b Ascertained by H NMR spectroscopy of the crude
reaction mixture. c Reaction performed in THF. d Reaction performed in
Et2O e Reaction performed in hexane. Only starting material was
recovered. f Yield obtained under one-pot reaction conditions. g A single
diastereoisomer was obtained (stereochemistry at the newly created
stereogenic center not assigned).
By this DFT analysis, we can conclude that on the basis of
calculated 1H chemical shifts and the predicted SSCC one could
be able to discriminate between very similar structures such as
diastereoisomers 2b and inv-2b. The computational results were
finally confirmed by 11B NMR and NOE experiments on borane
complexes 2a,b (see the Supporting Information). In the 11B
NMR the quartet was found, for the BH3 group, around -16.6
ppm (referenced to BF3 Et2O) as expected for tetracoordinated
3
boron.20 NOE experiments showed spatial correlations consis-
tent with a syn relationship between the phenyl ring and the BH3
group (Figure 1).
Once the structure of aziridino-borane complexes was estab-
lished, their reactivity with organolithiums was evaluated. Lithia-
tions were performed as reported in Table 4, and the optimal
reaction conditions were found using aziridino-borane complex
2a. When 2a was reacted with s-BuLi (1.2 equiv) in THF at
-50 °C for 2 h, the corresponding aziridinyllithium was gener-
ated as proved by its trapping with D2O to furnish complex 3a.
BH3 removal was easily achieved by adding a small amount of
H2O at room temperature.
After the workup, the corresponding 2-deuterated aziridine 4a
was recovered almost quantitatively and as a single stereoisomer
(Table 4, entry 1). By comparison of 1H NMR spectra of 1a and
4a, the syn relationship between the phenyl group and the
The corresponding aziridinyllithium reacted with retention of
configuration with D2O and Me3SiCl to furnish the correspond-
ing borane complexes (S,S,R)-3f and (R,S,R)-3h. Trapping with
benzophenone occurred again with retention of configuration,
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NOTE
Scheme 2. Evaluation of the Configurational Stability of
Lithiated Aziridino-Borane Complexes
Found: C, 66.84; H, 10.42; N, 6.08. Enantiomeric purity determined by
HPLC analysis (Cellulose LUX-2 chiral column, hexane-i-PrOH
99.95:0.005, 0.5 mL/min, 227 nm, for racemic 3h: t1 = 15.93 min,
t2 = 17.67 min; for (R,S,R)-3h major t = 16.05 min, minor t = 17.5 min.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details and anal-
b
ytical data for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: luisa@uniss.it; luisi@farmchim.uniba.it.
’ ACKNOWLEDGMENT
This work was supported by the University of Sassari (Fondo
di Ateneo per la Ricerca). This work was carried out under the
framework of the National Project “FIRB - Futuro in Ricerca”
(code CINECA RBFR083M5N) and supported by the Univer-
sity of Bari.
but the introduced hydroxyalkyl group likely promotes the BH3
removal to produce aziridine (S,S)-4m. However, all of the
products were found to be highly enantioenriched (er >95:5).24
The observed configurational stability is in accordance with the
results reported by Vedejs10a and Concellon10b,c and once more
proves the role of the BH3 group in promoting a syn lithiation,
likely by an electrostatic complex induced proximity effect
(CIPE).25 In conclusion, the preparation of new N-alkyl-2-
phenylaziridino-borane complexes has been accomplished, and
their structure and reactivity have been evaluated. By using DFT
analysis and NMR experiments, the structure and stereochem-
istry of the aziridino-borane complexes can be safely assessed
and the model for calculations can be useful for predictions in
similar systems. Concerning the reactivity of aziridino-borane
complexes, a regio- and stereoselective lithiation at the terminal
β-cis position, with respect to the R-benzylic position, has been
observed.26 It has been also demonstrated that the lithiated
aziridino-borane complex is configurationally stable allowing
the enantioselective synthesis of cis-2,3-disubstituted N-alkyla-
ziridines. A final evidence is the switch of the regioselectivity in
the lithiation of N-alkylmonophenylaziridines which are prefer-
entially ortho lithiated in the absence of the BH3 group.
’ DEDICATION
Dedicated to Prof. Saverio Florio on the occasion of his 70th
birthday.
’ REFERENCES
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’ EXPERIMENTAL SECTION
General Procedure for the Lithiation of Aziridino-Borane
Complexes. A solution of s-BuLi (1.2 equiv, 1.4 M in cyclohexane) was
added under inert atmosphere at -50 °C to a stirred solution of (S,S)-2b
(3.11 mmol) in dry THF (7 mL). The reaction mixture was stirred at
-50 °C for 2 h and then cooled at -78 °C before addition of Me3SiCl
(1.4 equiv, 4.35 mmol). The reaction mixture was then allowed to warm
to room temperature and stirred until substrate consumption (TLC
monitoring). The reaction mixture was poured into H2O and extracted
with CH2Cl2 (3ꢀ15 mL). The organic layers were dried under Na2SO4,
and the solvent was evaporated in vacuo. Aziridino-borane (S,R,R)-3h
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(R,S,R)-3h: 95%; white solid; mp 65-67 °C; 1H NMR (400 MHz,
CD3OD) δ 1.19 (s, 9 H), 1.46 (t, J = 7.1 Hz, 3 H), 1.63 (d, J = 9.6 Hz,
1 H), 2.84 (dq, J = 14.1, 7.1 Hz, 1 H), 2.94 (dq, J = 14.3, 7.1 Hz, 1 H),
3.54 (d, J = 9.6 Hz, 1 H), 7.31-7.35 (m, 3 H), 7.45-7.46 (m, 2 H); 13C
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2294
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NOTE
(12) Unstable borane complexes were obtained with sterically
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taken into consideration because their signals were difficult to assign
experimentally. Analogously, the diastereotopic methylenic protons of
complexes 2b and inv-2b (H9 and H10 in Figure 1) were not considered
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δscaled = (δcalc- intercept)/(slope).
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(21) Under these conditions, the use of freshly prepared BH3 THF
3
solutions is mandatory to recover the desired products in satisfactory
overall yields.
(22) Nevertheless, all attempts to perform a double functionalization
failed.
(23) Gawley, R. E. Overview of Carbanion Dynamics and Electro-
philic Substitutions in Chiral Organolithium Compounds. In Stereo-
chemical Aspects of Organolithium Compounds; Gawley, R. E., Ed.;
Helvetica Acta; Zurich, 2010; Vol. 26, Chapter 3, pp 93 -133.
(24) The enantiomeric ratios were established by HPLC analysis on
borane complexes 3f and 3h and aziridine 4m (see the Supporting
Information).
(25) (a) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew.
Chem., Int. Ed. 2004, 43, 2206–2225. (b) Strohmann, C.; Gessner, V. H.
Angew. Chem., Int. Ed. 2007, 46, 4566–4569.
(26) For another example of directed β-cis-lithiation, see: Luisi, R.;
Capriati, V.; Di Cunto, P.; Florio, S.; Mansueto, R. Org. Lett. 2007,
9, 3295–3298.
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