Intramolecular trapping of amides by 1-lithio-1-bromocyclopropanes

Article abstract of DOI:10.1016/S0040-4020(00)01120-0

Reaction of 2-acylaminomethyl-1,1-dibromocyclopropanes with methyllithium at -90°C leads to selective bromine-lithium exchange and cyclisation to give a 1-bromo-3-azabicyclo[3.1.0]hexan-2-ol.

Full text of DOI:10.1016/S0040-4020(00)01120-0

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1593±1600
Intramolecular trapping of amides by
1-lithio-1-bromocyclopropanes
Mark S. Baird,a,p Florian A. M. Huber,a Viacheslav V. Tverezovskya,b and Ivan G. Bolesovb
aChemistry Department, University of Wales, Bangor, Gwynedd LL57 2UW, UK
bChemistry Department, Lomonosov Moscow State University, Vorobiovy Gory, Moscow 119899, Russia
Received 21 September 2000; revised 9 November 2000; accepted 23 November 2000
AbstractÐReaction of 2-acylaminomethyl-1,1-dibromocyclopropanes with methyllithium at 2908C leads to selective bromine-lithium
exchange and cyclisation to give a 1-bromo-3-azabicyclo[3.1.0]hexan-2-ol. q 2001 Elsevier Science Ltd. All rights reserved.
The reaction of 1,1-dibromocyclopropanes with methyl-
lithium is known to lead to a very rapid lithium-halogen
exchange, followed in most cases by formal elimination of
lithium bromide to produce a cyclopropylidene (or a
related carbenoid).1 If the reaction is carried out at low
temperature or, in some cases, if there is a co-ordinating
group present in the molecule, the organolithium may be
trapped in intermolecular processes by reaction with
electrophiles.1 There are many examples of intramolecular
trapping of the cyclopropylidene; thus insertion into CH
bonds is a characteristic reaction of carbenes and is of
considerable synthetic potential,2,3 e.g., in the presence of
monocyclic ethers,4 amines5 and sul®des6 of the general
structure (1) insertion occurs exclusively at the CH bond
adjacent to the heteroatom and 5,6-related to the carbenic
carbon (1,5-insertion) to give (4) (Scheme 1). This type of
insertion was the key step in a total synthesis of the natural
product 3,4-methanoproline.7
type of process, the reaction of the tetrabromide (5) with
methyllithium leads to the tetracyclic diketone (6) appar-
ently by a double intramolecular trapping of the derived
lithiobromides by the ester group in the adjacent cyclo-
propane ring.9 In a rather simpler system, methyl 3-(2,2-
dibromocycloprop-1-yl)propanoate is converted into
1-bromobicyclo[3.1.0]hexan-2-one by reaction with methyl-
lithium.10 We have recently reported that reaction of esters
of type (7) with MeLi leads to hemiacetals (9), apparently
derived by cyclisation of an intermediate lithiobromide
(8).11
We now report that reaction of the amide (11), and related
compounds with methyllithium also leads to the intra-
molecular trapping of a lithiobromocyclopropane with the
formation of a ®ve-membered ring.12
The amide (11) was obtained as shown in Scheme 3. Reac-
tion of the (S)-bromide (10)7 with (R)-a-phenylethylamine
gave the corresponding secondary amine; this was treated
with tri¯uoroacetic anhydride to give amide (11). This
compound showed the signals for two rotamers about the
There are fewer cases of similar intramolecular reactions of
the lithiobromides acting as nucleophiles; one such is the
1,3-elimination of BrCl from 1,1-dibromo-2-chloromethyl-
cyclopropanes on reaction with methyllithium.8 In another
1
amide bond by H and 13C NMR spectroscopy. The amide
Scheme 1.
p
Corresponding author. Tel.: 144-1248-382-374; fax: 144-1248-370-528; e-mail: chs028@bangor.ac.uk
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01120-0

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M. S. Baird et al. / Tetrahedron 57 (2001) 1593±1600
Scheme 2.
(11) gave a single product, hemiaminal (12), on reaction
with methyllithium (Scheme 3).
complex reaction when treated with methyllithium under
the same conditions. A mixture of three compounds was
obtained. The expected hemiaminal (16) was formed only
1
The stereochemistry at C-2 was assigned by analogy with
(9) and with that of a related azabicycle discussed later.
in 34% yield (Scheme 5). In the H NMR spectrum, this
exhibited a similar coupling behaviour to that with the
analogous hemiacetals. The vicinal coupling constant of
Hendo-4 was zero, thus the signal, which appeared at
2.94 ppm, showed only the geminal coupling constant
(9.0 Hz) from coupling with Hexo-4. In the 13C NMR spec-
trum, the carbon at the hemiaminal centre (C-2) appeared as
a quartet (Jˆ30.5 Hz) at 90.3 ppm due to CF coupling. The
tri¯uoromethyl group also gave a quartet (Jˆ289.0 Hz) at
Amide (13), derived from N-benzyl-N-(2,2-dibromo-1(R)-
methylcyclopropylmethyl)amine, behaved in a similar
manner (Scheme 4).
The corresponding racemic amide (15), without a methyl
group at the cyclopropane C-1 position showed a more
Scheme 3.
Scheme 4.
Scheme 5.

M. S. Baird et al. / Tetrahedron 57 (2001) 1593±1600
1595
Scheme 6.
124.1 ppm. Two other products were identi®ed as the keto-
amide (17) (22%) and hydrolysed amine (18) (20%). These
compounds are presumably derived from an intermolecular
reaction of the lithiocyclopropane derived from (15) with
another molecule of (15). It is not clear whether the ring
tri¯uoroacetyl group in (17) is cis or trans with regard to the
amide function. Compound (17) was again present as a
catalysed equilibrium was being established involving
traces of water in the solvent. The enamine decomposed
over several days at room temperature in CDCl3 to give
unidenti®ed products.
In the same way, the methyl-substituted analogue (22) gave
(23) and (24) (Scheme 7) and the corresponding benzoyl
derivative (25) led to (26) (Scheme 8).
1
mixture of two rotamers about the amide bond by H and
13C NMR. In the 13C NMR the two carbonyl groups
appeared as quartets (Jˆ39 Hz each); the major rotamer
of (17) gave a signal for the amide carbonyl at 157.8 ppm
and for the ketone at 184.7 ppm.
The stereochemistry of (26) was established by n.O.e.
experiments which showed that irradiation of the o-hydro-
gens of the 2-phenyl group caused a 4.5% enhancement in
the signal for the endo-cyclopropane proton. Indeed, in the
calculated endo-(26) structure (by HyperChem 5.0 with
AM1 method, until gradient became less then 0.1 kcal/
When the amide (19) was treated at low temperature
(2908C) with 1.3 mol.equiv. of methyllithium for 30 min,
two products were isolated in moderate yield (Scheme 6),
the enamine (20) and the aminal (21). The methylene group
Ê
(Amol)), these hydrogens are very close each to otherÐ
just 0.24 nm apart. Calculations on exo-(26) gave a structure
with these hydrogens far from each other (Fig. 1). The other
n.O.e. enhancements were consistent with the calculated
preferred conformation shown for endo-(26).
1
of the enamine showed two singlets in the H NMR spec-
trum at 3.82 ppm and 4.02 ppm and two 13C signals at 75.5
(CˆCH2) and 154.1 (C-2); these values are very close to
those reported for N-alkyl-2-methylenetetrahydropyrrole.13
If the mixture of (20) and (21) was heated in benzene and
water was removed by azeotropic distillation, the product
was (20). When (20) was dissolved in deuterochloroform
and the proton NMR spectrum run immediately, only the
signals corresponding to the enamine were detected.
However, if the solution was allowed to stand for some
hours, the signals corresponding to (21) were again
observed in addition to those for (20), suggesting an acid
The ester (27, XˆO, RˆH) has been shown to react with
methyllithium to produce compound (28) by initial hemi-
acetal formation, followed by ring-opening and addition of
the resulting alcohol to the b-position of the enone (Scheme
9).11 However, in the case of compound (27, XˆNCH2Ph,
RˆMe), the product was a white powder with a broad NMR
spectrum which was thought to be a polymer. Microanalysis
showed a carbon percentage slightly lower then that in the
Scheme 7.
Scheme 8.

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M. S. Baird et al. / Tetrahedron 57 (2001) 1593±1600
Figure 1.
Scheme 9.
starting material suggesting a reaction at the acylamide
group rather than the dibromide.
molybdic acid hydrate (2% solution in ethanol) followed by
heating to 1808C. Column chromatography was conducted
with Fisher Scienti®c silica gel 60 under medium pressure.
The potential applications of the enantiomerically pure
3-azabicyclo[3.1.0]hexane derivatives described in this
paper in the synthesis of natural products containing this
skeleton such as CC-1065 and adozelesin14 are currently
being examined.
Melting points are uncorrected. Infrared spectra were
obtained as KBr discs or as liquid ®lms on a Perkin±
Elmer 1600 FTIR spectrometer. Low resolution mass
spectra were obtained on a Finnigan 8430 spectrometer.
Accurate mass measurements refer to 79Br for mono-
bromides and to 79Br81Br for dibromides unless stated and
were obtained from the EPSRC Mass Spectrometry Service
in Swansea. Microanalyses were performed on a Carlo Erba
Model 1106 CHN analyser.
1. Experimental
1.1. General
NMR spectra were recorded in CDCl3 unless otherwise
stated on a Bruker AC250 at 250 MHz for protons and
62.9 MHz for carbon and in the latter case were broad-
band decoupled; DEPT spectra were also run and the
signs of signals (1 for CH, CH3; 2 for CH2) are indicated
on the data for the broad-band decoupled spectrum. Those
signals with no sign in such a spectrum are quaternary.
When a n.O.e difference spectrum was obtained conditions
were as follows: recorded on a Bruker 250 MHz spec-
trometer, a total of 576 scans per FID, interleaved in blocks
of 24 each with 4 `dummy scans', using Bruker program
N.O.EDIFF.AU; irradiation period: 8 s; 90 degree pulse,
FID acquisition time: 2 s; sample stationary. Data were
processed with 1 Hz line broadening.
Reagents were obtained from commercial suppliers
(Aldrich, Lancaster) and were used without further puri®-
cation unless otherwise stated. Solvents were puri®ed when
necessary using the methods suggested by Perrin et al.15
Dichloromethane was distilled over calcium hydride,
diethyl ether over sodium wire. Petroleum ether was of
boiling point 40±608C unless otherwise stated. Reactions
were performed using oven dried glassware (1608C) cooled
under a stream of dry nitrogen or argon; the experiments
were conducted under a positive atmosphere of one of these
gases. Organic solutions were dried over anhydrous mag-
nesium sulfate, and, unless stated, were evaporated at
14 mmHg. Yields quoted are for puri®ed compounds unless
otherwise stated. Any ratios given are calculated by com-
1
paring integrals of protons in the H NMR spectra unless
otherwise stated.
1.1.1. N-(R)-a-Phenylethyl-N-(2,2-dibromo-1(S)-methyl-
cyclopropylmethyl)-2,2,2-tri¯uoroacetamide (11). (a) A
solution of (R)-a-phenylethylamine (1.21 ml, 10 mmol)
and 1,1-dibromo-2(S)-bromomethyl-2-methylcyclopropane7
(1.53 g, 5.00 mmol) in dimethysulfoxide (5 ml) was stirred
at 608C over 4 h. Water (15 ml) and 5% sodium hydroxide
solution (5 ml, 6.5 mmol) were added and the product was
extracted with ether (2£15 ml). Chromatography on silica
All new compounds were homogenous by TLC or by GLC.
GLC was conducted using a Carlo Erba HRGC 5300 (F.I.D.,
on a capillary column). TLC was performed using Aldrich
silica plates coated with silica gel 60 (F254). Compounds
were visualised by examination under an ultraviolet source,
by exposure to iodine vapour or by contact with phospho-

M. S. Baird et al. / Tetrahedron 57 (2001) 1593±1600
1597
(petrol±ether, 3:1) gave N-(R)-a-phenylethyl-N-(2,2-di-
bromo-1(S)-methylcyclopropylmethyl)amine as a colourless
oil (1.59 g, 92%) (Found C 44.91, H 5.07, N 4.08. Calculated
for C13H17Br2N: C 44.99, H 4.94, N 4.04) which showed
anhydride (1 ml, 5 mmol) was added to N-benzyl-N-(2,2-
dibromo-1(R)-methylcyclopropylmethyl)-amine7 (1.20 g,
3.60 mmol) in dichloromethane (10 ml). After 2 h the
volatiles were removed and the residue was dissolved in
chloroform (20 ml). The organic layer was washed with
sat.aq. NaHCO3 (2£10 ml) and water (10 ml), dried and
the solvent was removed to give a colourless oil, N-benzyl-
N-(2,2-dibromo-1(R)-methylcyclopropylmethyl)-2,2,2-tri-
¯uoroacetamide (13) (1.55 g, 100%) as two rotamers
(67:33) (Found C 39.10, H 3.53, N 3.46. Calculated for
C14H14Br2F3NO: C 39.19, H 3.29, N 3.26) which showed
[a]D20±9.48 (c 1.138, CHCl3); nmax: 3371 w, 3066 m,
3032 m, 2935 m, 1693 br s, 1497 m, 1454 br s, 1367 s,
1292 s, 1250 s, 1210 s, 1142 s, 1090 s, 1029 s, 997 s,
960 s, 894 w, 844 w, 736 s, 698 s cm-1. The major rotamer
showed dH: 1.36 (1H, d, Jˆ8.0 Hz), 1.39 (3H, s), 1.56 (1H,
d, J8.0 Hz), 3.69 (1H, d, J14.5 Hz), 3.78 (1H, d, J14.5 Hz),
4.74 (1H, d, J16.5 Hz), 4.83 (1H, d, J16.5 Hz), 7.16±7.43
(5H, m); dC: 20.421, 27.51, 33.552, 35.10, 50.072 (q, JCF
4.0 Hz), 51.142, 116.40 (q, JCF 288.0 Hz), 126.281,
127.891, 128.801, 134.41, 157.91 (q, JCF 35.5 Hz). The
minor rotamer showed dH: 1.46 (1H, d, J8.0 Hz), 1.54
(3H, s), 1.64 (1H, d, J8.0 Hz), 3.50 (1H, d, J15.0 Hz),
3.91 (1H, d, J15.0 Hz), 4.57 (1H, d, J15.0 Hz), 4.94 (1H,
d, J15.0 Hz), 7.16±7.43 (5H, m); dC: 19.981, 26.35,
33.822, 34.20, 47.852, 52.322 (q, JCF 4.0 Hz), 116.36
(q, JCF 288.0 Hz), 127.191, 127.691, 128.681, 134.46,
157.50 (q, JCF 35.5 Hz).
20
[a]D 112.88 (c 1.396, CHCl3); dH: 1.37 (3H, d, Jˆ
6.5 Hz), 1.38 (1H, d, Jˆ7.5 Hz), 1.44 (1H, d, Jˆ7.5 Hz),
1.48 (3H, s), 1.55 (1H, s), 2.53 (1H, d, Jˆ12.5 Hz), 2.71
(1H, d, Jˆ12.5 Hz), 3.73 (1H, q, Jˆ6.5 Hz), 7.18±7.32
(5H, m); dC: 21.91, 24.31, 30.1, 33.52, 36.4, 55.92,
58.51, 126.61, 126.91, 128.41, 145.5; nmax: 3321 w,
3082 m, 3061 m, 3024 m, 2964 s, 2926 s, 2893 m, 2858 s,
1492 m, 1452 s, 1369 s, 1323 m, 1305 m, 1268 m, 1198 m,
1124 s, 1073 s, 1026 s, 760 s, 700 s cm21.
(b) Tri¯uoroacetic anhydride (1 ml, 5 mmol) was added to
N-(R)-a-phenylethyl-N-(2,2-dibromo-1(S)-methylcyclo-
propylmethyl)amine (294 mg, 0.85 mmol) in dichloro-
methane (5 ml). After 2 h the volatiles were removed and
the residue was dissolved in chloroform (5 ml). The organic
layer was washed with sat.aq. NaHCO3 (2£5 ml) and water
(5 ml), dried and the solvent was removed to give a colour-
less oil, N-(R)-a-phenylethyl-N-(2,2-dibromo-1(S)-methyl-
cyclopropylmethyl)-2,2,2-tri¯uoroacetamide (11) (357 mg,
95%) (Found C 40.79, H 3.80, N 3.08. Calculated for
C15H16Br2F3NO: C 40.66, H 3.64, N 3.16) which showed
[a]D20 116.08 (c 0.918, CHCl3); dH: 1.07 (1H, d, Jˆ8.5 Hz),
1.18 (1H, d, Jˆ8.5 Hz), 1.22 (3H, s), 1.75 (3H, d, Jˆ
7.0 Hz), 3.08 (1H, d, Jˆ14.5 Hz), 3.61 (1H, d, Jˆ
14.5 Hz), 5.40 (1H, q, Jˆ7.0 Hz), 7.27±7.40 (5H, m); dC:
17.21, 21.01, 27.0, 36.12, 37.1, 50.22, 55.31, 116.9 (q,
JCF 288.0 Hz), 127.41, 128.51, 128.91, 138.0, 158.0 (q,
JCF 35.5 Hz); nmax: 3372 br.w, 2986 w, 2940 w, 1694 s,
1450 m, 1219 s, 1192 s, 1143 s, 1087 m, 1027 m, 764 m,
1.1.4. (1S,2S,5R)-1-Bromo-2-tri¯uoromethyl-5-methyl-N-
benzyl-3-azabicyclo[3.1.0]hexan-2-ol (14). 1.27 M Methyl-
lithium in ether (0.87 ml, 1.10 mmol) was added to N-
benzyl-N-(2,2-dibromo-1(R)-methylcyclopropylmethyl)-2,
2,2-tri¯uoroacetamide (13) (430 mg, 1.00 mmol) in ether
(20 ml) at 2908C for 5 min. The solution was stirred for
30 min at 2908C then warmed to 08C for 30 min and
sat.aq. NH4Cl (10 ml) was added. The water layer was
extracted with ether (20 ml). The combined organic layers
were evaporated to give crude product (350 mg) which was
columned on silica (petrol:etherˆ1:4) to yield (1S,2S,5R)-
1-bromo-2-tri¯uoromethyl-5-methyl-N-benzyl-3-azabicy-
clo[3.1.0]hexan-2-ol (14), (183 mg, 52%), (Found C 48.21,
H 4.43, N 3.88. Calculated for C14H152B5 rF3NO: C 48.02, H
4.32, N 4.00), which showed [a]D 241.68 (c 0.972,
CHCl3), dH: 0.88 (1H, d, J6.0 Hz), 1.31 (3H, s), 1.82 (1H,
d, J6.0 Hz), 2.73 (1H, d, J9.0 Hz), 2.99 (1H, d, J9.0 Hz),
3.17 (1H, s), 3.51 (1H, d, J14.5 Hz), 4.43 (1H, d, J14.5 Hz),
7.20±7.36 (5H, m); dC: 17.191, 24.832 (q, JCF 2.0 Hz),
26.20, 46.32, 50.632 (q, JCF 3.0 Hz), 57.252, 90.98 (q,
JCF 29.5 Hz), 123.89 (q, JCF 290.0 Hz), 126.931,
127.881, 128.211, 138.36; nmax: 3541 br m, 3087 w,
3064 w, 3030 m, 2960 m, 2927 m, 2852 m, 1496 m,
1454 s, 1369 s, 1341 s, 1254 s, 1156 br. s, 1064 s, 983 s,
745 m, 698 m cm21
.
1.1.2. (1R,2R,5S)-1-Bromo-2-tri¯uoromethyl-5-methyl-N-
(R)-a-methylbenzyl-3-azabicyclo[3.1.0]hexan-2-ol (12).
1.5 M Methyllithium in ether (0.44 ml, 0.66 mmol) was
added to N-(R)-a-phenylethyl-N-(2,2-dibromo-1(S)-methyl-
cyclopropylmethyl)-2,2,2-tri¯uoroacetamide (11) (267 mg,
0.603 mmol) in ether (15 ml) at 2908C for 5 min. The solu-
tion was stirred for 30 min at 2908C then warmed to 08C for
30 min and sat.aq. NH4Cl (5 ml) was added. The water layer
was extracted with ether (10 ml). The combined organic
layers were evaporated to give crude (.85% pure by
NMR) product, half of which was columned on silica to
yield (1R,2R,5S)-1-bromo-2-tri¯uoromethyl-5-methyl-N-(R)-
a-methylbenzyl-3-azabicyclo[3.1.0]hexan-2-ol (12) (69 mg,
63%) (Found M1: 363.0446. C15H17BrF3NO requires:
363.0446) which showed [a]D25134.08 (c 1.00, CHCl3); dH:
0.95 (1H, d, Jˆ6.0 Hz), 1.20 (3H, s), 1.36 (3H, d, Jˆ7.0 Hz),
1.63 (1H, d, Jˆ6.0 Hz), 2.60 (1H, d, Jˆ8.5 Hz), 2.83 (1H, s),
2.99 (1H, d, Jˆ8.5 Hz), 4.60 (1H, q, Jˆ7.0 Hz), 7.22±7.38
(5H, m); dC: 17.521, 19.331, 24.712, 25.52, 46.08, 50.812,
52.651, 91.51 (q, JCF 29.55 Hz), 124.15 (q, JCF 289.5 Hz),
127.31, 128.31, 128.61, 141.1; nmax: 3548 m, 3350 br. w,
3031 m, 2977 s, 2931 s, 2850 m, 1693 m, 1495 m, 1454 s,
1388 m, 1166 br. s, 1068 s, 969 m, 762 m, 746 m, 700 s
cm21; m/z,%: 365, 3; 363, 3 (M1); 350, 17; 348, 22; 296,
18; 294, 18; 260, 10; 258, 10; 192, 12; 194, 12; 106, 17; 105, 100.
958 s, 743 s, 718 m, 699 s, 674 m cm21
.
1.1.5. N-Benzyl-N-(2,2-dibromocyclopropylmethyl)-2,2,2-
tri¯uoroacetamide (15). Tri¯uoroacetic anhydride
(0.34 ml, 2.4 mmol) was added to N-benzyl-(2,2-dibromo-
cyclopropylmethyl)amine7 (700 mg, 2.2 mmol) in dichloro-
methane (30 ml). After 30 min the volatiles were removed
and the residue was dissolved in ether (30 ml) and washed
with sat. aq. NaHCO3 (2£20 ml) and water (20 ml), dried
and evaporated to give a colourless oil, N-benzyl-N-(2,2-
1.1.3. N-Benzyl-N-(2,2-dibromo-1(R)-methylcyclopropyl-
methyl)-2,2,2-tri¯uoroacetamide (13). Tri¯uoroacetic

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M. S. Baird et al. / Tetrahedron 57 (2001) 1593±1600
dibromocyclopropylmethyl)-2,2,2-tri¯uoroacetamide (15)
m/z,%: 433, 10; 431, 8 (M1); 352, 10; 202, 18; 91, 100. The
(770 mg, 85%) as two rotamers (67:33) (Found M1:
analytical data of (18) were identical to those reported.7
414.9217. C13H12Br2F3NO requires: 414.9217); nmax
:
3032 w, 2936 w, 1694 s, 1452 s, 1386 w, 1362 w, 1205 s,
1144 s, 1001 m, 740 m, 702 m cm21; m/z,%: 417, 1; 415,
2; 413, 1 (M1); 229, 2; 202, 5; 91, 100; 65, 4. The major
rotamer showed dH: 1.25 (1H, t, J7.0 Hz), 1.76 (1H, dd,
J7.0, 10.5 Hz), 1.89 (1H, dddd, J5.0, 6.5, 7.0, 10.5 Hz),
3.45 (1H, dd, J6.5, 14.5 Hz), 3.62 (1H, dd, J5.0, 14.5 Hz),
4.74 (1H, d, J16.5 Hz), 4.87 (1H, d, J16.5 Hz), 7.22±7.45
(5H, m); dC: 25.5, 27.52, 28.41, 48.82, 51.22, 116.5 (q,
JCF 288 Hz), 127.21, 127.71, 129.11, 134.6, 157.5 (q, JCF
39 Hz). The minor rotamer showed dH: 1.35 (1H, t,
J7.0 Hz), 1.76 (1H, dd, J7.0, 10.5 Hz), 1.89 (1H, dddd,
J5.0, 6.5, 7.0, 10.5 Hz), 3.60 (1H, dd, J6.5, 14.5 Hz), 3.62
(1H, dd, J5.0, 14.5 Hz), 4.71 (1H, d, J15.0 Hz), 4.96 (1H, d,
J15.0 Hz), 7.22±7.45 (5H, m); dC: 24.9, 27.32, 29.61,
48.72, 49.52, 116.5 (q, JCF 288 Hz), 128.11, 128.41,
128.91, 135.0, 157.5 (q, JCF 39 Hz).
The reaction was repeated on a comparable scale and gave
the same three products with yields as follows: (16) 37%;
(17) 18% and (18) 28%.
1.1.7. (R)-N-Benzyl-N-(2,2-dibromocyclopropylmethyl)-
acetamide (19). Acetic anhydride (0.32 ml, 3.5 mmol)
was added to (R)-N-benzyl-(2,2-dibromocyclopropylmethyl)-
amine7 (1.03 g, 3.2 mmol) in dichloromethane (20 ml).
After 2 h the volatiles were removed and the residue
was dissolved in ether (30 ml) and washed with sat. aq.
NaHCO3 (2£20 ml) and water (20 ml). The organic layer
was dried and evaporated to give (R)-N-benzyl-N-(2,2-
dibromocyclopropylmethyl)acetamide (19) (1.11 g, 96%)
as a colourless viscous oil (Found: C 43.04, H 4.18, N
3.97. C13H15Br2NO requires: C 43.24, H 4.19, N 3.88)
20
which showed two rotamers (76:24) by NMR, [a]D
±
29.08 (c 1.175, CHCl3); nmax: 3029 w, 2929 w, 1638 s,
1467 s, 1437 s, 1414 s, 1381 s, 1363 s, 1252 s, 1207 s,
1105 m, 980 m, 962 m, 730 s, 684 m cm21; m/z,%: 363, 2;
361, 5; 359, 2 (M1); 188, 8; 175, 20; 174, 34; 146, 16; 120,
8; 106, 19; 91, 100, 65, 10.). The major rotamer showed dH:
1.32 (1H, t, J7.5 Hz), 1.79 (1H, dd, J7.5, 10.5 Hz), 1.89±
2.04 (1H, m, together with peaks for the minor isomer), 2.22
(3H, s), 3.28 (1H, dd, J7.0, 14.5 Hz), 3.93 (1H, dd, J5.5,
14.5 Hz), 4.77 (2H, s), 7.23±7.46 (5H, m); dC: 21.71, 27.1,
27.22, 29.71, 48.32, 52.42, 126.21, 127.71, 129.01,
136.6, 171.5. The minor rotamer showed dH: 1.32 (1H, t,
J7.5 Hz), 1.78±1.85 (1H, m, peaks underneath those of
major isomer), 1.89±2.04 (1H, m, together with peaks for
the major isomer), 2.31 (3H, s), 3.38 (1H, dd, J5.5, 15.5 Hz),
3.63 (1H, dd, J5.5, 15.5 Hz), 4.68 (1H, d, J15.0 Hz), 4.89
(1H, d, J15.0 Hz), 7.23±7.46 (5H, m); dC: 21.81, 25.6,
27.72, 29.71, 48.32, 49.92, 127.41, 127.81, 128.61,
137.5, 170.6.
1.1.6. 3-Benzyl-1-bromo-2-tri¯uoromethyl-3-azabicyclo-
[3.1.0]hexan-2-ol (16). Methyllithium in ether (0.46 ml,
0.62 mmol, 1.35 M) was added dropwise to N-benzyl-N-
(2,2-dibromocyclopropylmethyl)-2,2,2-tri¯uoroacetamide
(15) (200 mg, 0.48 mmol) in ether (10 ml) at 2908C. The
solution was stirred for 30 min at 2808C, then quenched
with a sat. aq. NH4Cl (5 ml). The aqueous layer was
extracted with ether (2£10 ml). The combined organic
layers were dried and evaporated. Chromatography on silica
(petrol±ether, 1:1) gave 3-benzyl-1-bromo-2-tri¯uoro-
methyl-3-azabicyclo[3.1.0]hexan-2-ol (16) (55 mg, 34%),
N-benzyl-N-[2-bromo-2-(2,2,2-tri¯uoroacetyl)cyclopropyl-
methyl]-2,2,2-tri¯uoroacetamide (17) (45 mg, 22%) and
N-benzyl-(2,2-dibromocyclopropylmethyl)amine (18)
(30 mg, 20%). Compound (16) (Found M1: 335.0133.
C13H13BrF3NO requires: 335.0133) showed dH: 1.38 (1H,
dd, J6.0, 9.0 Hz), 1.71 (1H, dd, J5.0, 6.0 Hz), 1.89 (1H, ddd,
J4.0, 5.0, 9.0 Hz), 2.94 (1H, d, J9.0 Hz), 3.02 (1H, dd, J4.0,
9.0 Hz), 3.27 (1H, s), 3.54 (1H, d, J14.5 Hz), 4.44 (1H, d,
J14.5 Hz), 7.24±7.39 (5H, m); dC: 19.62, 24.21, 38.2,
51.72, 52.12, 90.3 (q, JCF 30.5 Hz), 124.1 (q, JCF
289.0 Hz), 127.11, 128.01, 128.41, 138.4; nmax: 3544 br
s., 3030 w. 2920 w, 2851 m, 1682 w, 1455 m, 1364 m,
1182 s, 1150 s, 1076 m, 1035 m, 959 m, 742 m,
699 m cm21; m/z,%: 337, 1; 335, 1 (M1); 320, 1; 318, 1;
267, 22; 91, 100. Compound (17) (Found M1: 430.9956.
C15H12BrF6NO2 requires: 430.9956) showed a mixture of
rotamers (77:23) by NMR The major rotamer showed dH:
1.52 (1H, dd, J6.5, 9.5 Hz), 1.72 (1H, dd, J6.5, 8.5 Hz), 2.22
(1H, dddd, J6.5, 7.0, 8.5, 9.5 Hz), 3.05 (1H, dd, J6.5,
14.5 Hz), 3.49 (1H, dd, J7.0, 14.5 Hz), 4.49 (1H, d,
J16.0 Hz), 4.68 (1H, d, J16.0 Hz), 7.15±7.42 (5H, m); dC:
24.62, 28.4, 34.51, 44.42, 51.72, 115.5 (q, JCF 291 Hz),
116.4 (q, JCF 288 Hz), 127.51, 128.71, 129.21, 134.0,
157.8 (q, JCF 39 Hz), 184.7 (q, JCF 39 Hz). The minor
rotamer showed dH: 1.66 (1H, dd, J6.5, 9.5 Hz), 1.87 (1H,
dd, J6.5, 8.5 Hz), 2.22 (1H, m), 3.06 (1H, underneath the
peak for the major isomer), 3.63 (1H, dd, J4.5, 14.5 Hz),
4.66 (2H, s), 7.15±7.42 (5H, m); dC: 25.32, 29.9, 35.11,
44.12, 49.82, 115.5 (q, JCF 291 Hz), 116.4 (q, JCF 288 Hz),
127.81, 128.41, 129.11, 134.8, 157.8 (q, JCF 39 Hz), 184.8
(q, JCF 39 Hz); nmax: 3035 w, 1738 s, 1694 s, 1682 s, 1454 s,
1.1.8. (1S,5R)-3-Benzyl-1-bromo-2-methylene-3-azabicy-
clo[3.1.0]hexane (20). 1.37 M Methyllithium in ether
(0.95 ml, 1.3 mmol) was added dropwise to a solution of
(19) (361 mg, 1.00 mmol) in dry ether (20 ml) at 2908C.
After 15 min at 2908C the reaction mixture was warmed to
08C for 30 min and then was quenched with sat. aq. NH4Cl
(5 ml). The aqueous layer was extracted with ether
(2£10 ml). The combined organic layers were dried and
1
evaporated to yield crude product (254 mg). The H NMR
showed that it was a mixture, which contained two
main components, which were non-separable by column
chromatography, (20) and (21) in ratio 75:25; (1S,2S,5R)-
3-benzyl-1-bromo-2-methyl-3-azabicyclo[3.1.0]hexan-2-ol
(21) showed dH: 1.34 (1H, dd, J4.5, 5.0 Hz), 1.49 (3H, s),
1.53 (1H, peaks underneath peaks of (20)), 1.85 (1H, ddd,
J3.5, 4.5, 9.0 Hz), 2.76 (1H, d, J9.0 Hz), 2.88 (1H, dd, J3.5,
9.0 Hz), 3.57 (1H, d, J14.5 Hz), 4.17 (1H, d, J14.5 Hz),
7.20±7.40 (5H, m); dC: 19.42, 21.11, 23.41, 50.42,
50.52, 126.81, 128.01, 128.21, quaternary carbons
were not detected. To part of this mixture (120 mg), benzene
(3 ml) was added and distilled over 5 min at normal
pressure. Then more benzene (3 ml) was added and distilled
again. Chromatography of the residue on silica (petrol±
ether, 2:1, 3 drops of triethylamine per 100 ml of eluant)
gave (1S,5R)-3-benzyl-1-bromo-2-methylene-3-azabicyclo-
1245 s, 1210 s, 1149 s, 1072 m, 999 m, 743 m, 702 s cm21
;

M. S. Baird et al. / Tetrahedron 57 (2001) 1593±1600
1599
[3.1.0]hexane (20) (61 mg, 49%) (Found M1: 263.0310.
C13H14BrN requires: 263.0310) showed dH (benzene-d6):
0.97 (1H, dd, J5.5, 5.0 Hz), 1.27 (1H, dd, J9.0, 5.5 Hz),
1.57 (1H, ddd, J9.0, 5.0, 5.0 Hz), 2.47 (1H, d, J9.5 Hz),
2.78 (1H, dd, J9.5, 5.0 Hz), 3.66 (1H, d, J15.5 Hz), 3.89
(1H, d, J15.5 Hz), 3.99 (1H, broad s), 4.50 (1H, broad s),
7.05±7.30 (5H, m); dH: 1.19 (1H, t, J5.0 Hz), 1.53 (1H, dd,
J5.0, 9.0 Hz), 2.03 (1H, td, J5.0, 9.0 Hz), 3.04 (1H, d,
J9.0 Hz), 3.40 (1H, dd, J5.0, 9.0 Hz), 3.82 (1H, broad s),
4.06 (1H, d, J15.5 Hz), 4.07 (1H, broad s), 4.25 (1H, d,
J15.5 Hz), 7.20±7.40 (5H, m); dC: 23.42, 24.61, 34.2,
50.82, 52.12, 75.52, 127.01, 127.51, 128.51, 137.8,
154.1; nmax: 3568 w, 3085 m, 3062 m, 3028 s, 2999 m,
2875 s, 2838 s, 1948 w, 1877 w, 1810 w, 1644 s, 1604 m,
1495 s, 1453 s, 1356 s, 1301 s, 1217 m, 1180 s, 1129 s,
1080 m, 1039 m, 1010 m, 956 m, 912 m, 890 m, 735 s,
699 s cm21; m/z,%: 265, 14; 264, 39; 263, 19 (M1); 262,
19; 184, 20; 182, 11; 91, 100; 65, 30.
(5 ml). The aqueous layer was extracted with ether
(2£15 ml). The combined organic layers were dried and
evaporated to yield crude product (270 mg). Chroma-
tography of 50 mg of the crude material on silica (petrol±
ether, 7:3) gave (1S,5R)-3-benzyl-1-bromo-5-methyl-2-
methylene-3-azabicyclo[3.1.0]hexane (23) (33%). The
compound was not completely pure, the NMR also showing
signals of (1S,2S,5R)-3-benzyl-1-bromo-2,5-dimethyl-3-
azabicyclo[3.1.0]hexan-2-ol (24) (7%) [in total 20 mg,
ratio (23) to (24) 84:16]; nmax: 3382 br m, 3062 m,
2954 m, 2924 m, 2833 m, 1646 s, 1452 s, 1356 m,
1057 m, 734 s, 698 s cm21. Compound (23) showed dH:
1.19 (1H, d, J5.0 Hz), 1.34 (1H, d, J5.0 Hz), 1.36 (3H, s),
3.05 (1H, d, J9.0 Hz), 3.13 (1H, d, J9.0 Hz), 3.80 (1H, broad
s), 4.00 (1H, d, J15.5 Hz), 4.08 (1H, broad s), 4.27 (1H, d,
J15.5 Hz), 7.18±7.45 (5H, m); dC: 17,711, 27.13, 28.872,
42.64, 50.902, 57.752, 75.482, 127.051, 127.661,
128.461, 137.86, 155.18. Compound (24) showed dH:
0.86 (1H, d, J5.0), 1.33 (3H, s), 1.45 (1H, d, J5.0), 1.49
(3H, s), 2.14 (1H, br s), 2.64 (1H, d, J9.0 Hz), 2.80
(1H, dd, J9.0 Hz), 3.46 (1H, d, J14.5 Hz), 4.17 (1H,
d, J14.5 Hz), 7.18±7.45 (5H, m).
A solution of (20) (5 mg) in CDCl3 (1 ml) showed in 3 h a
mixture of (20) and (21) in ratio 75:25 by 1H NMR spectro-
scopy. In 8 h at room temperature it began to decompose
and after 3 days it had completely decomposed. Decompo-
sition of (20) in chloroform was detected by measuring the
1.1.11. N-Benzyl-N-(2,2-dibromo-1(R)-methylcyclopro-
pylmethyl)benzamide (25). Benzoyl chloride (0.38 ml,
3.3 mmol) was added to N-benzyl-(2,2-dibromo-1(R)-
methylcyclopropylmethyl)amine7 (1.00 g, 3.00 mmol) and
triethylamine (0.82 ml, 6 mmol) in benzene (20 ml) and
the mixture was re¯uxed for 1.5 h, then cooled to room
temperature and extracted with 5% HCl (2£30 ml). After
drying and evaporating the solvent, the crude product was
columned on silica (40 g, ether:petrolˆ1:1) to yield a
colourless oil, N-benzyl-N-(2,2-dibromo-1(R)-methylcyclo-
propylmethyl)benzamide (25) (1.15 g, 88%), which crystal-
lised in three days, m.p. 65±678C, (Found C 52.43, H 4.66,
N 3.16. Calculated for C19H19Br2NO: C 52.20, H 4.38, N
3.20) which showed [a]D20±35.68 (c 1.370, CHCl3); dH:
1.30 (1H, br s), 1.53 (4H, br s), 3.74 (1H, d, J14.0 Hz),
4.05 (1H, br d, J14.0 Hz), 4.68 (2H, br s), 7.15±7.45
(10H, m); dC: 13.831, 21.24, 26.452, 44.582, 45.072,
119.321 broad, 120.301, 121.431, 121.591, 122.551,
128.81, 129.46, 165.73; nmax (nujol): 3061 m, 3028 m,
2929 s, 2869 m, 1650 s, 1578 m, 1495 m, 1454 s, 1365 s,
1319 s, 1259 s, 1174 m, 1149 m, 1073 s, 1027 m, 989 m,
20
rotation angle (cˆ0.695). It showed [a]D 17.98 5 min
20
20
after dissolving, [a]D 13.58 in 15 min, [a]D 26.08 in
1.5 h, and [a]D20±15.78 in 16 h (became yellow solution).
The 1H NMR spectrum of the ®nal sample showed complete
decomposition.
1.1.9. N-Benzyl-N-(2,2-dibromo-1(R)-methylcyclopropyl-
methyl)acetamide (22). Acetic anhydride (0.50 ml,
5 mmol) was added to N-benzyl-(2,2-dibromo-1(R)-methyl-
cyclopropylmethyl)amine7 (1.00 g, 3.00 mmol) in dichloro-
methane (10 ml). After 2 h, the volatiles were removed and
the residue was dissolved in ether (30 ml) and washed with
sat. aq. NaHCO3 (2£10 ml) and water (10 ml), dried and
evaporated to give a colourless oil, N-benzyl-N-(2,2-
dibromo-1(R)-methylcyclopropylmethyl)acetamide
(22)
(1.09 g, 97%) as two rotamers (3.5:1) (Found C 44.52, H
4.64, N 3.77. Calculated for C14H17Br2NO: C 44.83, H 4.64,
N 3.73); [a]D20±20.58 (c 1.010, CHCl3); nmax: 3063 w,
3028 w, 2989 w, 2930 m, 1824 m, 1751 m, 1722 m,
1650 s, 1495 m, 1422 s, 1364 s, 1238 s, 1176 w, 1123 m,
1053 w, 1027 m, 986 m, 962 m, 896 m, 732 s, 695 s cm21
.
960 m, 788 m, 729 s, 697 s, 652 m cm21
.
The major rotamer showed dH: 1.39 (3H, s), 1.52 (2H, s),
2.16 (3H, s), 3.47 (1H, d, J14.5 Hz), 4.14 (1H, d, J14.5 Hz),
4.67 (1H, d, J17.5 Hz), 4.70 (1H, d, J17.5 Hz), 7.15±7.40
(5H, m); dC: 20.971, 21.561, 28.52, 33.212, 37.01,
50.512, 51.062, 125.871, 127.661, 128.961, 136.39,
172.05. The minor rotamer showed dH: 1.37 (3H, s), 1.53
(1H, d, J7.5 Hz), 1.59 (1H, d, J7.5 Hz), 2.29 (3H, s), 3.29
(1H, d, J15.0 Hz), 3.80 (1H, d, J15.0 Hz), 4.44 (1H, d,
J15.5 Hz), 4.92 (1H, d, J15.5 Hz), 7.15±7.40 (5H, m); dC:
20.791, 22.111, 27.17, 34.472, 34.68, 47.222, 54.062,
127.321, 127.541, 128.581, 136.74, 171.08.
1.1.12. (1S,2S,5R)-3-Benzyl-1-bromo-5-methyl-2-phenyl-
3-azabicyclo[3.1.0]hexan-2-ol (26). 1.27 M Methyllithium
in ether (1.15 ml, 1.46 mmol) was added dropwise to a solu-
tion of (25) (580 mg, 1.33 mmol) in ether (20 ml) at 2908C.
After 15 min at 2908C, the reaction mixture was warmed to
08C for 30 min and then quenched with sat. aq. NH4Cl
(5 ml). The aqueous layer was extracted with ether
(2£15 ml). The combined organic layers were dried and
evaporated to yield crude product (460 mg). Chroma-
tography of this crude material on silica (petrol±ether,
7:3) gave (1S,2S,5R)-3-benzyl-1-bromo-5-methyl-2-phen-
yl-3-azabicyclo[3.1.0]hexan-2-ol (26) (305 mg, 64%)
1.1.10. (1S,5R)-3-Benzyl-1-bromo-5-methyl-2-methylene-
3-azabicyclo[3.1.0]hexane (23). 1.27 M Methyllithium in
ether (0.87 ml, 1.1 mmol) was added dropwise to a solution
of (22) (375 mg, 1.00 mmol) in ether (20 ml) at 2908C.
After 15 min at 2908C the reaction mixture was warmed
to 08C for 30 min and then quenched with sat. aq. NH4Cl
(Found
C 64.00, H 5.80, N 3.76. Calculated for
C19H20BrNO: C 63.70, H 5.63, N 3.91), which showed
[a]D20±13.38 (c 0.645, CHCl3); dH: 0.85 (1H, d, J5.5 Hz),
1.39 (3H, s), 1.76 (1H, d, J5.5 Hz), 2.76 (1H, d, J9.0 Hz),
2.78 (1H, s), 3.02 (1H, d, J9.0 Hz), 3.46 (1H, d, J14.0 Hz),

1600
M. S. Baird et al. / Tetrahedron 57 (2001) 1593±1600
3.85 (1H, d, J14.0 Hz), 7.20±7.45 (8H, m), 7.76 (2H, dd,
J7.5, 1.0 Hz); dC: 17,611, 25.222, 26.90, 51.022, 54.47,
55.092, 94.77, 126.881, 127.231, 128.161, 128.191,
128.251, 128.291, 138.92, 139.94; nmax: 3562 s, 3085 w,
3061 m, 3027 m, 2954 s, 2923 s, 2811 s, 1604 w, 1494 s,
1446 s, 1364 s, 1330 s, 1207 s, 1170 s, 1059 s, 1028 s,
1015 s, 975 m, 948 s, 909 m, 866 w, 763 s, 731 s, 700 s,
dried and evaporated to yield 37 mg of a mixture of several
compounds (by H NMR). The powder (Found C 44.66, H
1
6.00, N 3.44. Calculated for C15H17Br2NO (compound (27)):
C 46.54, H 4.43, N 3.62), m.p. 187±1928C (decomp.)
showed dH: 0.8±1.7 (ca. 14H, br s), 4.2±4.7 (ca. 42H, br
s), 6.9±7.6 (ca. 44H, br s); nmax (nujol): 3416 br s, 2922 s,
2852 s, 1650 s, 1643 s, 1634 s, 1495 w, 1454 s, 1376 m,
1200 br w, 1076 w, 1028 w, 962 w, 846 w, 730 w, 698 w
666 s cm21
.
cm21
.
1.1.13. N-Benzyl-N-(2,2-dibromo-1(R)-methylcyclopro-
pylmethyl)acrylamide (27). Acryloyl chloride (0.29 ml,
3.6 mmol) was added to N-benzyl-(2,2-dibromo-1(R)-
methylcyclopropylmethyl)amine7 (1.00 g, 3.00 mmol) and
triethylamine (0.82 ml, 6 mmol) in benzene (20 ml) and
the mixture was re¯uxed for 1.5 h, then cooled to room
temperature and extracted with 5% HCl (2£30 ml). The
volatiles were removed and the residue was dissolved in
ether (30 ml) and washed with sat. aq. NaHCO3 (2£10 ml)
and water (10 ml), dried and evaporated to give a colour-
less oil, N-benzyl-N-(2,2-dibromo-1(R)-methylcyclopropyl-
methyl)acrylamide (27) (1.13 g, 97%), as two rotamers
(2.5:1) (Found C 46.30, H 4.65, N 3.48. Calculated for
C15H17Br2NO: C 46.54, H 4.43, N 3.62); which showed
[a]D20±33.38 (c 1.015, CHCl3); nmax: 3063 w, 3029 w,
2988 w, 2930 w, 1735 w, 1650 s, 1614 s, 1495 m, 1440 s,
1363 m, 1216 s, 1095 m, 1030 m, 961 m, 794 m, 733 s,
695 s cm21. The major rotamer showed dH: 1.40 (3H, s),
1.55 (2H, s), 3.53 (1H, d, J14.5 Hz), 4.19 (1H, d,
J14.5 Hz), 4.70 (1H, d, J17.5 Hz), 4.80 (1H, d, J17.5 Hz),
5.72 (1H, dd, J10.0, 2.5 Hz), 6.46 (1H, dd, J16.5, 2.5 Hz),
6.55 (1H, dd, J16.5, 10.0 Hz), 7.15±7.50 (5H, m); dC:
21.051, 28.66, 33.362, 37.09, 50.392, 51.162,
126.081, 127.341, 127.601, 128.901, 129.332, 136.59,
167.61. The minor rotamer showed dH: 1.34 (2H, br s), 1.54
(3H, s), 3.39 (1H, d, J15.5 Hz), 3.89 (1H, d, J15.5 Hz), 4.58
(1H, d, J15.0 Hz), 4.92 (1H, d, J15.0 Hz), 5.82 (1H, br d,
J10.5 Hz), 6.50 (1H, br d, J16.0 Hz), 6.53 (1H, dd, J16.0,
10.5 Hz), 7.15±7.50 (5H, m).
Acknowledgements
We wish to thank The Peboc Division of Eastman Ltd for
partial funding of F. A. M. H. and I. N. T. A. S. for the
support of V. V. T.
References
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10. Baird, M. S., unpublished results.
1.1.14. Reaction of N-benzyl-N-(2,2-dibromo-1(R)-cyclo-
propylmethyl)acrylamide (27) with methyllithium.
1.27 M Methyllithium in ether (0.87 ml, 1.10 mmol) was
added dropwise to a solution of (27) (390 mg, 1.00 mmol)
in ether (10 ml) at 2908C. After 15 min at 2908C, the
reaction mixture was warmed to 08C for 30 min (a white
precipitate was formed) and then was quenched with sat. aq.
NH4Cl (5 ml) and water (5 ml). The precipitate was ®ltered,
washed with water (2 ml), ether (2 ml) and dried to yield a
white powder (250 mg). The aqueous layer was extracted
with ether (2£15 ml). The combined organic layers were
11. Baird, M. S.; Huber, F. A. M.; Tverezovsky, V. V.; Bolesov,
I. G. Tetrahedron 2000, 56, 4799.
12. A preliminary account has already appeared: Baird, M. S.;
Huber, F. A. M.; Tverezovsky, V. V.; Bolesov, I. G.
Tetrahedron Lett. 1998, 39, 9081.
13. Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1996, 118, 9295.
14. Salaun, J.; Baird, M. S. Curr. Med. Chem. 1995, 2, 511.
15. Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. Puri®cation of
Laboratory Chemicals, 3rd ed; Pergamon Press: Oxford, 1988.