Diastereoselective Ti-mediated preparation of bicyclic aminocyclopropanes from N-alkenyl amides

Article abstract of DOI:10.1016/j.tetlet.2009.07.031

Intramolecular Ti-mediated alkene-amide couplings of a range of N-alk-3-enyl amides fitted with a substituent at the homoallylic position are described. CF₃-substituted compounds are suitable substrates and bicyclic aminocyclopropanes bearing a

Full text of DOI:10.1016/j.tetlet.2009.07.031

Tetrahedron Letters 50 (2009) 5367–5371
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diastereoselective Ti-mediated preparation of bicyclic aminocyclopropanes
from N-alkenyl amides
b
Claire Madelaine a, Andrea K. Buzas a, Justyna A. Kowalska-Six a, Yvan Six a, , Benoît Crousse
*
a Institut de Chimie des Substances Naturelles, UPR 2301 du CNRS, Centre de Recherche de Gif-sur-Yvette, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
b Laboratoire BioCIS-CNRS, Faculté de Pharmacie, Université Paris-Sud 11, Rue Jean-Baptiste Clément, F-92296 Châtenay-Malabry, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Intramolecular Ti-mediated alkene–amide couplings of a range of N-alk-3-enyl amides fitted with a sub-
stituent at the homoallylic position are described. CF3-substituted compounds are suitable substrates and
bicyclic aminocyclopropanes bearing a CF3 group can be prepared in this way. Good diastereoselectivities
can be observed depending on the substitution pattern, and best results are obtained in diethyl ether
rather than in THF.
Received 15 June 2009
Revised 3 July 2009
Accepted 6 July 2009
Available online 10 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Dedicated to the memory of Professor
Charles Mioskowski
Keywords:
Kulinkovich-de Meijere reaction
Titanium
Cyclopropanes
Fluorine-substituted compounds
1. Introduction
diastereoselectivities of similar intramolecular Kulinkovich-de
Meijere reactions have been little documented.8
The titanium-mediated cyclopropanation of carboxylic amides
(Kulinkovich-de Meijere reaction) has become the method of
choice for the preparation of aminocyclopropanes.1,2 The ligand ex-
change variation of this reaction, especially efficient when pro-
moted by an intermediate titanacyclopropane (e.g., A) generated
from Ti(Oi-Pr)4 [or ClTi(Oi-Pr)3] and a cyclic Grignard reagent such
as cyclo-pentylmagnesium chloride or cyclo-hexylmagnesium chlo-
ride, allows alkene–amide coupling (Scheme 1).3
This process has triggered the development of new applications.
In particular, it has opened a practical possibility to perform intra-
molecular Kulinkovich-de Meijere reactions starting from carbox-
ylic amides fitted with an alkene moiety (Scheme 2).3–10 Various
transformations of the resulting bicyclic aminocyclopropanes have
been developed recently,6 highlighting their potential as useful
intermediates for the construction of polycyclic nitrogen-contain-
ing systems.10b–d In the context of this previous work, we became
interested in the study of intramolecular Kulinkovich-de Meijere
reactions of N-alk-3-enyl amides containing a chiral centre at the
XTi(Oi-Pr)3
(X = Cl or Oi-Pr)
c-C5H9MgCl (> 2 eq.)
R3
O
R3
R4
+
R4
N
N
R1 R2
R1 R2
OiPr
(alkene ligand exchange)
Ti
OiPr
R1
N
OiPr
Ti O
OiPr
A
R2
R3 R4
iPrO
Ti
iPrO
R3
O
R3
O
R1
R4
N
N
R4
R1 R2
R2
Ti
OiPr
iPrO
Scheme 1. Kulinkovich-de Meijere alkene–amide coupling.
R1
R1
O
N
homoallylic position,
a to the nitrogen atom. These raised an inter-
R2
N
R2
esting stereoselectivity issue: to the best of our knowledge, the
OiPr
Ti
OiPr
O
A
or
R2
R2
R1
N
R1
N
* Corresponding author. Tel.: +33 0 1 6982 3083; fax: +33 0 1 6907 7247.
E-mail address: yvan.six@icsn.cnrs-gif.fr (Y. Six).
Scheme 2. Intramolecular Kulinkovich-de Meijere reactions.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.031

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C. Madelaine et al. / Tetrahedron Letters 50 (2009) 5367–5371
acylation.11 For comparison purposes, non-chiral compounds 1b–H,
2. Results
1d–H and 1e–H were synthesised as well. The results of the transfor-
mations of these molecules under the conditions of Kulinkovich-de
Meijere alkene–amide coupling are presented in Table 1.12
In most cases, including with the CF3-substituted substrates, the
cyclisations proceeded efficiently, and the aminocyclopropane
Accordingly, a range of N-alk-3-enyl formamides and acetamides 1
fitted with a methyl, a trifluoromethyl or a phenyl group were prepared
by Barbier-type reactions of allyl bromide with the corresponding imi-
nes in the presence of Mg turnings or Zn coarse powder, followed by
Table 1
Intramolecular Kulinkovich-de Meijere reactions of N-alkenyl amides 1
1. Ti(Oi-Pr)4 (1.5 eq.)
c-C5H9MgCl (4.0 eq.)
solvent, 20°C
2. H2O
R3
R1
O
R3
*
N
1 N
R
*
R2
1
R2
2
Entry
1
N-Alkenyl amide 1
Solvent
THF
Aminocyclopropane 2a (yield)
drb
Other product (yield)
H
O
1a–Ph
N
2a–Ph (80%)c
54:46
N
Bn
Bn
Ph
Ph
H
O
N
N
2
3
1b–H
1b–H
THF
2b–H (42%)
2b–H (37%)
–
–
3b–H (32%)
N
n-BuO
MeO
n-BuO
MeO
n-BuO
MeO
Et2O
H
O
2c–Ph (30%)c
2c–Ph (49%)
52:48
62:38
3c–Ph (15%)c
N
N
4
5
1c–Ph
1c–Ph
THF
N
Ph
Ph
Ph
Et2O
O
6
7
1d–H
THF
THF
2d–H (75%)
–
N
N
N
Bn
Bn
Bn
O
O
1d–Me
2d–Me (55%)
58:42
N
Bn
N
8
N
N
1d–CF3
THF
2d–CF3 (67%)
60:40
Bn
Bn
Bn
CF3
O
CF3
9
1d–Ph
1d–Ph
THF
N
2d–Ph (54%)
2d–Ph (71%)
74:26
82:18
Bn
Ph
Ph
10
Et2O
O
N
N
11
12
1e–H
THF
2e–H (ꢀ100%)
2f–Me (71%)c
–
n-BuO
MeO
n-BuO
MeO
O
N
N
N
N
1f–Me
Et2O
89:11
O
13
14
1f–CF3
1f–CF3
THF
2f–CF3 (40%)
2f–CF3 (57%)
75:25
89:11
CF3
CF3
MeO
MeO
Et2O
O
N
N
15
1f–Ph
THF
2f–Ph (77%)
2f–Ph (80%)c
88:12
Ph
Ph
MeO
MeO
16
1f–Ph
Et2O
90:10
a
Only the major diastereoisomer is shown, when relevant. Unless otherwise stated, yields are given for the isolated products.
The diastereoisomeric ratios of compounds 2 were measured in the crude products by NMR spectroscopy (see Supplementary data).
Yield estimated by 1H NMR spectroscopy of the crude product (see Supplementary data).
b
c

C. Madelaine et al. / Tetrahedron Letters 50 (2009) 5367–5371
5369
products 2 were obtained in fair yields, even though they showed a
tendency to undergo partial decomposition during purification. For
instance, when the crude product of the experiment displayed in
entry 13 was purified by flash column chromatography on silica
gel, the oxidation product 4f–CF3 was isolated in significant
amounts.12 The mechanism leading to this type of peroxide has
been the subject of previous studies.10a,d
4 vs entry 15, and entry 5 vs entry 16). Moreover, significant
amounts of unexpected compounds 3b–H and 3c–Ph are produced
from formamides 1b–H and 1c–Ph,14 while the acetamide ana-
logues 1e–H and 1f–Ph cyclise without complication (entry 2 vs
entry 11, and entry 4 vs entry 15). However, and interestingly,
by-products 3b–H and 3c–Ph are no longer observed when the
transformations of 1b–H and 1c–Ph are carried out in diethyl ether
rather than in THF (entries 3 and 5).
The influence of the solvent is further evidenced by the diaste-
reoselectivities of the cyclisations of the chiral substrates. Indeed,
these are consistently and notably higher in diethyl ether than in
THF (entries 4–5, 9–10, 13–14 and 15–16).
Other reactions mediated by XTi(Oi-Pr)3 and Grignard reagents
can be found in the literature that are significantly influenced by
the nature of the solvent used.15–18 Notably, examples of Kulinko-
vich reactions17 and transformations of cyanoesters18 have been
reported to be more diastereoselective in THF than in diethyl ether,
thereby exhibiting an opposite behaviour to the presently de-
scribed cyclisations.
O
O
N
CF3
MeO
4f-CF3
2D NOESY NMR experiments were performed on the major diaste-
reoisomers of aminocyclopropanes 2f–Me and 2f–CF3, evidencing
trans relative configurations (Fig. 1).13 Moreover, the signal of the
proton borne by the tertiary centre at the
a-position relative to
Among the new bicyclic aminocyclopropanes synthesised, the
trifluoromethyl-substituted products are especially interesting.
The impact of the presence of the CF3 substituent on their reactiv-
ity is evidenced by the fact that compound trans-2f–CF3 is essen-
tially unaffected under conditions previously described for the
acetylation of structurally related substrates (Scheme 3).10b None-
theless, the isolation of peroxide 4f–CF3 shows that the CF3 group
does not preclude aerobic oxidation.19
the nitrogen atom has a chemical shift of 3.23 ppm in the case of
trans-2f–Me and of 3.94 ppm in the case of trans-2f–CF3, while they
lie around one ppm higher in the cases of the minor (cis)13 diaste-
reoisomers, with values of 4.33 and 4.79 ppm, respectively. This is
also consistent with the proposed stereochemical assignment: in
trans-2f–Me and trans-2f–CF3, a shielding effect might be exercised
by the cyclopropane ring on this proton.
The relative configurations of the major diastereoisomers of all
the other aminocyclopropane products 2 were also assigned as
trans by analogy with those of compounds 2f–Me and 2f–CF3.13
This is in full agreement with the chemical shifts of the protons
3. Mechanistic rationale
a
to the R2 substituents that were found to be lower than those
The origin of the diastereoselectivities of the presently de-
scribed reactions can be analysed as follows. After ligand exchange
of complex A with substrate 1, two diastereoisomeric titanacyclo-
propanes trans-B and cis-B can be formed, where the titanium cen-
tre is coordinated by the carbonyl oxygen atom (Scheme 4). As far
as we are aware of, the mechanism of this transformation—irre-
versible in this case—has not been clearly elucidated, and it is
therefore uneasy to predict which diastereoisomer would be fa-
voured. Nonetheless, it appears reasonable to suppose that diaste-
reochemical differentiation does not operate significantly at this
stage, and there is probably little energy difference between trans-
and cis-B.
of the minor diastereoisomers in every case (see Supplementary
data).
With respect to the influence of the substituents of the starting
alkenyl amides, all other parameters being equal, the diastereose-
lectivities of the reactions tended to be higher with N-aryl sub-
strates than with N-benzyl substrates (entry 13 vs entry 8, and
entry 15 vs entry 9; however, see entry 4 vs entry 1), and increased
with the nature of the R2 substituent at the homoallylic position in
the order Me < CF3 < Ph (entries 7–9, 13 vs 15, and to a minor
extent 12, 14 and 16). Substituent R3 has a dramatic effect on the
reaction: the diastereoselectivities of the cyclisations of forma-
mides 1a–Ph and 1c–Ph are much lower than those of the corre-
sponding acetamides 1d–Ph and 1f–Ph (entry 1 vs entry 9, entry
The next elementary step of the cyclisation process, the inser-
tion of the carbonyl group into a C–Ti bond, is thought to proceed
diastereospecifically following an SEi mechanism, giving the inter-
mediates trans- and cis-C via transition states trans-TS and cis-TS,
eventually yielding the corresponding aminocyclopropane diaste-
reoisomers 2, again diastereospecifically.
observed NOE correlations
Ar
N
In cis-TS, the R2 group adopts an endo position relative to the
developing oxatitanacyclopentane ring, while it is exo and pseu-
do-equatorial in trans-TS.20 cis-TS is therefore probably lying at a
higher energy than trans-TS, and trans-B is expected to cyclise
Me
H
H
Me
Ar
N
Me
H
H
Me
N
H
H
H
H
H
H
H
MeO
3.23 ppm
(dquint, J = 7.5, 6.0 Hz)
H
trans-2f-Me
[minor: 4.33 ppm
(quintd, J = 6.0, 3.0 Hz)]
no NOE correlation
O
O
Ac2O (10 eq.)
PhCl, reflux
14 h
observed NOE correlations
O
N
N
N
+
(23 : 77)
Ar
N
Me
H
79%
H
F3C
Ar
N
Me
H
PhO
MeO
PhO
PhO
H
F3C
N
H
H
H
H
Ac2O (10 eq.)
PhCl, reflux
16 h
H
CF3
H
H
MeO
3.94 ppm
H
trans-2f-CF3
(dqd, J = 8.5, 7.5, 2.0 Hz)
N
no reaction
[minor: 4.79 ppm
(dqd, J = 11.0, 8.0, 3.5 Hz)]
CF3
trans-2f-CF3
no NOE correlation
Figure 1. Evidence for the relative configurations of the major diastereoisomers of
2f–Me and 2f–CF3.
Scheme 3. The low reactivity of 2f–CF3 towards acylation.

5370
C. Madelaine et al. / Tetrahedron Letters 50 (2009) 5367–5371
R1
N
Supplementary data
R3
O
H
Method used for the evaluation of the yields and diastereoselec-
R2
tivities of the cyclopropanation reactions by analysis of the NMR
spectra of the crude products. Analytical data for compounds 2a–
Ph, 2c–Ph, 3c–Ph, 2d–Me, 2d–CF3, 2d–Ph, 2f–Me and 2f–Ph. Basic
molecular modelling of titanacyclopropane intermediates trans-
and cis-B. Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2009.07.031.
H
H
H
Ti(Oi-Pr)2
H
trans-TS
H
R3
O
R1
N
H
i-PrO Oi-Pr
R3
Ti
R2
H
O
fast
H
R3
R1 N
Ti(Oi-Pr)2
H
1 N
H
R2
R
References and notes
R2
trans-B
trans-C
trans-2
H
1. Chaplinski, V.; de Meijere, A. Angew. Chem. 1996, 108, 491–492. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 413–414.
A + 1
R1
R3
O
2. Reviews: (a) Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789–
2834; (b) de Meijere, A.; Kozhushkov, S. I.; Savchenko, A. I. In Titanium and
Zirconium in Organic Synthesis; Marek, I., Ed.; Wiley-VCH: Weinheim, 2002; pp
390–434; (c) Kulinkovich, O. G. Izv. Akad. Nauk. Ser. Khim. 2004, 1022–1043.
Russ. Chem. Bull., Int. Ed. 2004, 53, 1065–1086; (d) de Meijere, A.; Kozhushkov,
S. I.; Savchenko, A. I. J. Organomet. Chem. 2004, 689, 2033–2055.
3. Lee, J.; Cha, J. K. J. Org. Chem. 1997, 62, 1584–1585.
4. U, J. S.; Lee, J.; Cha, J. K. Tetrahedron Lett. 1997, 38, 5233–5236.
5. Cao, B.; Xiao, D.; Joullié, M. M. Org. Lett. 1999, 1, 1799–1801. Org. Lett. 2000, 2,
1009.
6. Lee, H. B.; Sung, M. J.; Blackstock, S. C.; Cha, J. K. J. Am. Chem. Soc. 2001, 123,
11322–11324.
7. Gensini, M.; Kozhushkov, S. I.; Yufit, D. S.; Howard, J. A. K.; Es-Sayed, M.; de
Meijere, A. Eur. J. Org. Chem. 2002, 2499–2507.
8. Tebben, G.-D.; Rauch, K.; Stratmann, C.; Williams, C. M.; de Meijere, A. Org. Lett.
2003, 5, 483–485.
9. Gensini, M.; de Meijere, A. Chem. Eur. J. 2004, 10, 785–790.
i-PrO Oi-Pr
N
H
R3
R1 N
H
Ti
O
R2
Ti(Oi-Pr)2
slow
R3
1 N
H
H
H
H
R2
R
R2
H
H
cis-B
cis-C
cis-2
R2
O
H
N
Ti(Oi-Pr)2
R3
H
R1
H
H
H
cis-TS
H
Scheme 4. Origin of the diastereoselectivity.
10. (a) Ouhamou, N.; Six, Y. Org. Biomol. Chem. 2003, 1, 3007–3009; (b) Larquetoux,
L.; Kowalska, J. A.; Six, Y. Eur. J. Org. Chem. 2004, 3517–3525; (c) Larquetoux, L.;
Ouhamou, N.; Chiaroni, A.; Six, Y. Eur. J. Org. Chem. 2005, 4654–4662; (d)
Madelaine, C.; Six, Y.; Buriez, O. Angew. Chem. 2007, 119, 8192–8195. Angew.
Chem., Int. Ed. 2007, 46, 8046–8049, and Supplementary data; (e) Madelaine,
C.; Ouhamou, N.; Chiaroni, A.; Vedrenne, E.; Grimaud, L.; Six, Y. Tetrahedron
2008, 64, 8878–8898.
faster than cis-B. This being stated, the preferential formation of
trans-2 can be readily understood by invoking the possibility of ra-
pid interconversion between cis-B and trans-B. This process could
operate by internal rearrangement or by ligand exchange with
residual substrate 1. This explanation is analogous to that formu-
lated by Cha et al. to explain the diastereoselectivities of Kulinko-
vich reactions of homoallyl alcohols.21 Moreover, it can readily
account for the lower diastereoselectivities observed with forma-
mides. Indeed, the rates of formation of cis-C and trans-C should in-
crease importantly in the case of these compounds, with rates of
interconversion between cis-B and trans-B comparable to those
met with acetamides, and diastereoselectivity would hence be
eroded.
11. For instance, compound 1f–CF3 was obtained by acetylating 4-methoxy-N-
(1,1,1-trifluoropent-4-en-2-yl)aniline, whose preparation has been described
previously: Legros, J.; Meyer, F.; Colibꢀuf, M.; Crousse, B.; Bonnet-Delpon, D.;
Bégué, J.-P. J. Org. Chem. 2003, 68, 6444–6446. N-(4-Methoxyphenyl)-N-(1,1,1-
trifluoropent-4-en-2-yl)acetamide (1f–CF3): To a solution of imine (E)-N-(2,2,2-
trifluoroethylidene)-4-methoxyaniline (1.00 equiv, 5.51 mmol, 1.12 g) in THF
(10 mL) were added allyl bromide (1.30 equiv, 7.15 mmol, 865 mg) and Zn
coarse powder (1.30 equiv, 7.15 mmol, 467 mg) followed by two drops of
Me3SiCl. The mixture was refluxed for 30 min, and then the solution was
hydrolysed with a saturated aqueous solution of NH4Cl (20 mL) and extracted
with Et2O (3 Â 20 mL). The combined organic layers were dried over MgSO4,
filtered and the solvents were removed. To the crude product were then added
Ac2O (6 mL) and a crystal of iodine, and the mixture was heated at reflux for
2 h. Then, the product was concentrated and finally purified by column
chromatography on silica gel (Et2O/petroleum ether 20%) to afford pure 1f–CF3
(1.26 g, 4.39 mmol, 80%). 1f–CF3: Bright yellow oil. IR (neat): 2960, 2935, 1672,
With respect to the solvent effect we observed, providing an
accurate explanation seems difficult at this stage, since it could
be caused by a number of factors.
1510, 1371, 1291, 1250, 1216, 1169, 1147, 1107, 1030, 920, 837 cmÀ1 1H NMR
.
(300 MHz, CDCl3): d 1.80 (s, 3H), 2.15–2.49 (m, 2H), 3.85 (s, 3H), 5.19 (dq,
J = 17.0, 1.5 Hz, 1H), 5.21 (dq, J = 10.5, 1.5 Hz, 1H), 5.68 (dqd, J = 11.0, 8.0,
4.0 Hz, 1H), 5.81 (dddd, J = 17.0, 10.5, 7.0, 5.0 Hz, 1H), 6.79–7.24 (m, 4H). 13C
NMR (75.5 MHz, CDCl3): d 22.9, 29.8, 53.6 (q, J = 29.5 Hz), 55.3, 114.3, 114.7,
118.1, 125.0 (q, J = 284 Hz), 130.4, 131.0, 132.7, 131.2, 159.8, 172.4. MS (ES+) m/
z 288 (MH+), 310 (MNa+). HRMS (ES+) m/z calcd for C14H17NO2 (MH+) 288.1211,
found 288.1221.
4. Summary and conclusion
In summary, the N-alk-3-enyl amides investigated, that bear a
methyl, a trifluoromethyl or a phenyl group at the homoallylic posi-
tion, undergo intramolecular Kulinkovich-de Meijere cyclopropana-
tioninmoderatetogood yieldswithupto90:10diastereoselectivity.
The influence of the solvent is noteworthy, with the cyclisation reac-
tions being consistently more diastereoselective in diethyl ether
than in THF. The syntheses of other CF3-containing bicyclic aminocy-
clopropanes, their oxidations to endoperoxides and the in vitro
activities of the latter against Plasmodium falciparum are under pro-
gress and will be reported in due course.
12. The following procedure is representative for the intramolecular
cyclopropanations of N-alkenyl amides 1. 2-(4-Methoxyphenyl)-1-methyl-3-
(trifluoromethyl)-2-azabicyclo[3.1.0]hexane
(2f–CF3):
Titanium(IV)
iso-
propoxide (1.50 equiv, 3.50 mmol, 1.04 mL) was added to a solution of N-
alkenyl amide 1f–CF3 (1.00 equiv, 2.33 mmol, 670 mg) in freshly distilled THF
(23.0 mL), followed by the addition of cyclopentylmagnesium chloride
(ꢀ2.32 M in Et2O, 4.00 equiv, 9.32 mmol, 4.02 mL) dropwise at 20 °C. After
30 min of stirring, water (1.00 mL) was added to the dark solution, which was
exposed to air, and stirring was continued until decolouration. The mixture
was then filtered through a 1-cm layer of Celite on a fritted-disc funnel that
was then rinsed with Et2O (2 Â 20 mL). The combined organic layers were
dried over sodium sulfate, filtered and concentrated under reduced pressure to
afford
spectroscopy, showing the near exclusive presence of aminocyclopropane 2f–
CF3 with 75:25 diastereoisomeric ratio. Purification by flash column
a brown oil (684 mg). The crude product was analysed by NMR
Acknowledgements
a
chromatography on silica gel (ethyl acetate/heptane, gradient from 0% to
We are grateful to the Centre National de la Recherche Scientif-
ique for financial support, and to the École Polytechnique for the
funding granted to A.K.B. We also warmly thank Dr. Julien Legros
for his valuable help during the preparation of this Letter.
10%) afforded analytically pure diastereoisomer trans-2f–CF3 (254 mg,
*
*
*
936
(trifluoromethyl)hexahydro-[1,2]dioxolo[3,4-b]pyrrole 4f–CF3 as
diastereoisomer (84.0 mg, 277 mol, 12%).
l
mol, 40%), and (3aS ,5S ,6aR )-6-(4-methoxyphenyl)-6a-methyl-5-
a
single
l

C. Madelaine et al. / Tetrahedron Letters 50 (2009) 5367–5371
5371
13. The cis or trans relative configurations of products 2 are defined by the relative
17. Kulinkovich, O. G.; Kananovich, D. G. Eur. J. Org. Chem. 2007, 2121–2132.
configurations, on the pyrrolidine ring, of the fused cyclopropane and the
18. Bertus, P.; Menant, C.; Tanguy, C.; Szymoniak, J. Org. Lett. 2008, 10, 777–780.
19. This is an interesting property because endoperoxides prepared by the
oxidation of similar bicyclic aminocyclopropanes have been found to exhibit
antimalarial activity. See Ref. 10d.
20. With the help of plastic molecular models or by performing molecular
mechanics calculations (see Supplementary data).
substituent R2 attached to the tertiary carbon at the
nitrogen atom.
a-position relative to the
14. The mechanism of formation of compound 3b–H has been discussed
previously in the Supplementary data provided with Ref. 10d.
Aminocyclopropane 3c–Ph is assumed to be produced according to a similar
pathway.
15. Suzuki, D.; Urabe, H.; Sato, F. Angew. Chem., Int. Ed. 2000, 39, 3290–3292.
16. Masalov, N.; Feng, W.; Cha, J. K. Org. Lett. 2004, 6, 2365–2368.
21. Quan, L. G.; Kim, S.-H.; Lee, J. C.; Cha, J. K. Angew. Chem. 2002, 114, 2264–2266.
Angew. Chem., Int. Ed. 2002, 41, 2160–2162.