Rearrangements in the reduction of 3-iodobicyclo[1.1.1]pentyl azide with lithium aluminum hydride: Mechanistic evidence of intermediates

Full text of DOI:10.1021/jo001510e

J . Org. Chem. 2001, 66, 4409-4412
4409
Sch em e 1
Sch em e 2
Rea r r a n gem en ts in th e Red u ction of
3-Iod obicyclo[1.1.1]p en tyl Azid e w ith
Lith iu m Alu m in u m Hyd r id e: Mech a n istic
Evid en ce of In ter m ed ia tes
Md. T. Hossain and J ack W. Timberlake*
Department of Chemistry, University of New Orleans,
New Orleans, Louisiana 70148
jwtcm@uno.edu
Received October 23, 2000
Pseudohalogens add to olefins to afford R,â addition
products.1 Iodine azide, bromine azide, and iodine isocy-
anate provide R,â iodoazide, bromoazide, and iodoisocy-
anate, respectively. Because of the nitrogen functionality
these compounds play an important role in the synthesis
of amines, amino acids, aziridines, or other nitrogen
derivatives. [1.1.1]Propellane (1), the smallest tricyclic
bridgehead compound, possesses its highest electron
density at the bridgehead carbons and undergoes addi-
tion reactions at the 1,3 position.2 We have conducted
addition reactions of [1.1.1]propellane with pseudohalo-
gen iodine azide (IN3),3,4 which provided 3-iodobicyclo-
[1.1.1]pentyl azide in a 92% yield. It was hoped that
reduction of 2 would lead to 1-bicyclo[1.1.1]pentylamine
(3), a compound needed for other purposes.Attempts to
convert 3-iodobicyclo[1.1.1]pentyl azide to 1-bicyclo[1.1.1]-
pentylamine employed a wide variety of reducing agents.
The main concern was to keep the [1.1.1]pentyl skeleton
intact since this moiety is highly strained,5,6 and both the
iodine and azide are susceptible to reduction. Both azide
and iodine at bridgehead positions are not generally
known to be reduced although 3-chloroadamantyl azide
has been reduced to adamantylamine.7 1-Bicyclo[1.1.1]-
pentylamine has shown greater activity than a tert-butyl
group8 in the 1-position of quinilone against Gram-
positive and Gram-negative bacteria as well as anaerobic
organisms. The successful reduction of 3-iodobicyclo-
[1.1.1]pentyl azide to 1-bicyclo[1.1.1]pentylamine can
eliminate several steps in comparison with the synthesis
from 1-bicyclo[1.1.1]pentyl carboxylic acid.2,9 However, all
the efforts for reduction to afford 1-bicyclo[1.1.1]pen-
tylamine failed. We were surprised to obtain an unex-
pected open chain 3-chloro-3-methylbutylamine hydro-
chloride in up to 72% yield from reduction of 2 with
lithium aluminum hydride in THF.
Sch em e 3
Diborane is known to be a mild reducing agent and is
effective in partial reduction of o-bromobenzoic acid to
o-bromobenzyl alcohol.10 Other reducing agents such as
n-tributyltin hydride, triethylsilane, lithium in liquid
ammonia, sodium in ethanol, magnesium in methanol,
zinc and hydrochloric acid, samarium iodide, and alkaline
earth metal reductions are also effective for partial
reduction.11 However, reduction of 3-iodobicyclo[1.1.1]-
pentyl azide with these reagents afforded starting ma-
terials or unknown fragmentation products.In ether,
reduction with LAH under mild conditions and at a low
temperature afforded 3-methylenecyclobutylamine hy-
drochloride after hydrogen chloride workup in 82% yield.
3-Methylenecyclobutylamine hydrochloride with LAH in
THF under more vigorous conditions yielded 86% of
3-chloro-3-methylbutylamine hydrochloride.
Neither of the free amines of 4 and 5 could be isolated
directly due to their volatility. However, after the aque-
ous workup from the reduction with LAH in ether, the
amide from benzoyl chloride and pyridine was obtained
in a 74% yield.Reduction of 2 with diborane under mild
reaction conditions yielded 3-iodobicyclo[1.1.1]pentylamine
(7) and 3-iodobicyclopentylamine hydrochloride (8) with
hydrogen chloride. These are supported by IR, and H1
and C13 NMR, although the microanalysis of these
compounds were off. However, the reduction of 3-iodo-
bicyclo[1.1.1]pentylamine hydrochloride with LAH in
ether afforded 3-methylenecyclobutylamine hydrochloride
(4). Further reduction of 4 in THF under vigorous
(1) Flower, F. W.; Hassner, A.; Levy, L. A. J . Am. Chem. Soc. 1967,
89, 2077.
(2) Wiberg, K. B.; Waddell, S. T. J . Am. Chem. Soc. 1990, 112, 2194.
(3) Hassner, A.; Mathews, G. A.; Fowler, F. W. J . Am. Chem. Soc.
1969, 91, 5046.
(4) (a) Hassner, A.; Lorber, M. E.; Heathcock, C. J . Org. Chem. 1967,
32, 540. (b) Hassner, A.; Boerwinkle, F. P., Levy A. B. J . Am. Chem.
Soc. 1970, 92, 4879.
(5) Wiberg, K. B. Chem. Rev. 1989, 89, 975.
(6) (a) Politzer, P.; J ayasuria, K. J . Mol. Struct. 1986, 135, 245. (b)
Wiberg, K. B.; Waddell, S. T.; Laidig, K. Terahedron Lett. 1986, 27,
1553.
(7) Baruah, M.; Baruah, A.; Prajapati, D.; Sandhu, J . S. Tetrahedron
Lett. 1996, 26, 4559.
(8) Barbachyn, M. R.; Douglas, K. H.; Toops, D. S.; Reid, R. J .;
Zurenko, G. E.; Yagi, B. H.; Schaadt, R. D.; Allison, J . W. Biorg., Med.
Chem. Lett. 1993, 3, 671.
(10) Yoon, N. M.; Pak, C. S. J . Org. Chem. 1973, 38, 2786.
(11) (a) Leibner, J . E.; J acobus, J . J . Org. Chem. 1979, 44, 449. (b)
Doyle, M. P.; McOsker, C. C.; West, C. T. J . Org. Chem. 1976, 41, 1393.
(c) Niznik, W. J . Org. Chem. 1978, 43, 2396. (d) Berkowitz, D. B.
Synthesis 1990, 649. (e) Maiti, S. N.; Spevak, P.; Reddy, A. V. N. Synth.
Commun. 1988, 18, 1201. (f) Hanson, D. Angew. Chem., Int. Ed. Engl.
1968, 7, 247. (g) Benati, L.; Montevecchi, P. C.; Nanni, D.; Spagnolo,
P.; Volta, M. Tetrahedron Lett. 1995, 40, 7313.
(9) Wiberg, K. B.; William, V. Z., J r. J . Org. Chem. 1970, 35, 369.
10.1021/jo001510e CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/22/2001

4410 J . Org. Chem., Vol. 66, No. 12, 2001
Notes
Sch em e 4
Sch em e 5
(32-62, 60 A from ICN Biomedicals Gmbh, Germany). Elemental
analysis and HRMS were performed by Atlantic Microlab Inc.,
Norcross, GA, and Iowa State University of Science and Tech-
nology II.
condition and with hydrogen chloride provided 3-chloro-
3-methylbutylamine hydrochloride (5), implying that the
borane did reduce 3-iodobicyclo[1.1.1.]pentyl azide to
3-iodobicyclo[1.1.1]pentylamine.To understand the mech-
anism of formation of 3-chloro-3-methylbutylamine hy-
drochloride, we conducted the reduction of the 3-iodobi-
cyclo[1.1.1]pentyl azide with lithium alumunium deu-
teride (LAD) under identical conditions. In ether, the
reduction afforded 74% of 1-deutero-3-methylenecyclobu-
tylamine hydrochloride, and in THF, 71% of 3-chloro-1,1-
dideutero-3-methylbutylamine hydrochloride.
[1.1.1]P r op ella n e.2 [1.1.1]Propellane was prepared by the
Wiberg procedure2 incorporating the Lynch-Daily modification
for synthesis of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane.12
The yield of [1.1.1]propellane was estimated to be 60% by the
reaction with a solution of iodine in carbon tetrachloride.
Syn th esis of 3-Iod obicyclo[1.1.1.]p en tyl Azid e (2). To a
stirred slurry of 2.40 g (36.92 mmol) sodium azide in 30 mL of
acetonitrile in a salt-ice bath (temp -15 to -20 °C) was added
slowly 3.0 g (18.48 mmol) of iodine monochloride over a period
of 15 to 20 min under positive pressure of argon. A yellow-orange
color was formed within 10 min from the dark color of iodine
monochloride. The mixture was stirred for 10 min. An ethereal
solution of 18.52 mmol [1.1.1]propellane was then added slowly
with a syringe over a 15-20 min period. At the end of the
addition, the yellow-orange color turned to a pale yellow. The
salt-ice bath was removed, and the mixture was stirred at room
temperature for 18 h. The pale yellow slurry was poured into
100 mL water, and the mixture was extracted with ether (3 ×
25 mL). The combined ethereal solution was washed with 5%
sodium thiosulfate (100 mL), to remove unreacted iodine, and
water (500 mL) and dried with anhydrous magnesium sulfate.
Removal of the solvent under vacuum left a light orange liquid.
TLC in pentane indicated a mixture of two compounds. Separa-
tion was done under flash chromatography (silica gel) with
pentane as an eluent. The first eluent after evaporation afforded
a white solid. Recrystallization from n-pentane gave 0.4 g, 7%
1,3-diiodobicyclo[1.1.1]pentane, as white crystals, mp 145-146
°C (dec). 1H NMR (CDCl3) δ 2.67 (s, 6H); 13C NMR δ 68.1 (3CH2),
-1.8 (2C); HRMS calcd for C5H6I2: 319.85590; found 319.85542.
The second fraction, after vacuum evaporation of the eluent
at room temperature, gave an orange oil 4.01 g, 92%, 3-iodobi-
On the basis of these observations, we propose the
formation of 3-chloro-3-methylbutylamine hydrochloride
as shown in Scheme 5.
Exp er im en ta l Section
Gen er a l. THF and ether were distilled from sodium and
benzophenone. Acetonitrile was distilled from phosphorus pen-
toxide, pyridine from potassium hydroxide, and dichloromethane
from calcium sulfate. All the solvents after distillation were
preserved under either 4A molecular seive or potassium hydrox-
ide and used with a positive pressure of nitrogen. All other
reagents used were purchased from Aldrich Chemical Co.,
Milwaukee, WI.
IR spectra were recorded on Perkin-Elmer 1600 Seris FT-IR
1
and Magna-IR 550 instruments. H and 13C NMR spectra were
obtained on a Varian-Gemini 300 MHz or a Varian Unity 400
MHz (75 or 100 MHz for 13C, respectively) spectrometer where
chemical shifts are reported in parts per million referenced to
TMS (0.00 ppm) and chloroform (7.26 ppm 1H, 77.00 ppm 13C).
Melting points were determined in an open capillary tube on a
Unimelt or a Meltemp apparatus and are uncorrected. TLC was
performed using silica gel 60 F (E. Merck, Darmstadt, Germany),
and flash column chromatography was performed on ICN silica
(12) Lynch, K. M.; Dailey, W. P. J . Org. Chem. 1995, 60, 4666.

Notes
J . Org. Chem., Vol. 66, No. 12, 2001 4411
cyclo[1.1.1]pentyl azide (2). IR (neat) cm-1 2919 and 2109; 1H
NMR (CDCl3) δ 2.43 (s, 6H); 13C NMR δ 61.3 (CH2), 55.1 (CN3),
-2.9 (CI); HRMS calcd for C5H6NI: 206.95450; found 206.95456
(parent C5H6N3I - N2, as no parent ion was observed under EI
conditions).
mL of water, and dried over anhydrous magnesium sulfate.
Evaporation of the solvent gave a white powder. Recrystalliza-
tion from ethanol-water (50:50) gave white crystals of 6, 0.43
g, 74%, mp 142-143 °C. IR (K Br) cm-1 3310, 1636, 1540, 1491,
1345, 1304, 892;1H NMR (CDCl3) δ 7.40-7.82 (m 5H), 6.55 (s,
b, 1H), 4.88 (m, 2H), 4.61 (m, 1H), 3.16 (m, 2H), 2.71 (m, 2H);
13C NMR (CDCl3) δ 167.1, 142.1, 134.4, 131.4, 128.5, 126.9,
107.3, 41.3, 40.5. Anal. Calcd for C12H13NO; C, 76.96, H, 7.01,
N, 7.48. Found: C, 76.96, H, 6.97, N, 7.47.
Red u ction of 3-Iod obicyclo[1.1.1]p en tyl Azid e. (a ) With
lith iu m Alu m in u m Hyd r id e in Eth er . 3-Meth ylen ecy-
clobu tyla m in e Hyd r och lor id e (4). To a stirred slurry of 0.28
g (7.0 mmol) of lithium aluminum hydride in 15 mL of dry ether
under positive pressure of argon was added dropwise 0.718 g
(3.06 mmol) 3-iodobicyclo[1.1.1.]pentyl azide in 5 mL of dry ether.
The mixture was refluxed gently for 16 h and cooled to room
temperature. The unreacted hydride was taken up with 15 mL
of ice-cooled water. Ether (15 mL) was added to the solution,
and two layers separated. The aqueous layer was extracted with
ether (3 × 20 mL), and the combined ether was dried with
anhydrous magnesium sulfate overnight and filtered. Dry
hydrogen chloride gas was passed over the filtrate for 1 min.
Immediately, white amine salt formed. Evaporation of the
solvent provided a white solid which was recrystallized from
ethanol-ethyl acetate to give 0.30 g, 82%, of 3-methylenecy-
clobutylamine hydrochloride (4), mp 174-175 °C. IR (KBr) cm-1
Red u ction of 3-Meth ylen ecyclobu tyla m in e Hyd r och lo-
r id e. To stirred slurry of 0.1 g (2.63 mmol) of lithium aluminum
hydride in 15 mL of THF under positive pressure of argon was
added slowly 0.15 g (1.20 mmol) of solid 3-methylene cyclobu-
tylamine hydrochloride (4) for 20 min. The mixture was refluxed
for 48 h and cooled to room temperature. The unreacted lithium
aluminum hydride was taken up with ice-cooled water (10 mL),
and 10 mL ether was added. The two layers were separated,
and the aqueous layer was extracted with ether (3 × 15 mL).
The combined ether layers were dried over anhydrous magne-
sium sulfate and filtered. The salt precipitated when dry
hydrogen chloride gas was passed over the filtrate for 1 min.
The amine hydrochloride was recrystallized from ethanol-ethyl
acetate as white crystals 0.09 g, 51%, 3-chloro-3-methylbuty-
lamine hydrochloride (5), mp 194-195° C. Proton and carbon
spectra NMR confirmed the structure of the compound.
Red u ction of 3-Iod obicyclo[1.1.1]p en tyl Azid e. (a ) With
LAD in E t h er . 1-Deu t er o-3-m et h ylen ecyclob u t yla m in e
Hyd r och lor id e. To a stirred slurry of 0.450 g (10.72 mmol) of
lithium aluminum deuteride in 25 mL of dry ether under an
argon atmosphere was added slowly 0.91 g (3.86 mmol) of
3-iodobicyclo[1.1.1]pentyl azide in 5 mL of dry ether. The
reaction mixture was refluxed for 24 h and cooled to room
temperature. The mixture was taken up with 15 mL of ice-cooled
water. The organic layer was extracted with ether (3 × 15 mL),
dried overnight with anhydrous magnesium sulfate, and filtered.
Dry hydrogen chloride gas was passed over the filtrate for 1 min.
A white precipitate of salt formed immediately. Evaporation of
the ether gave a white salt which was recrystallized from ethanol
to give pure crystals, 0.34 g, 74%, 1-deutero-3-methylenecy-
clobutylamine hydrochloride, mp 191-193 °C. 1H NMR (D2O) δ
4.85 (m, 2H), 3.00 (d, 2H), 2.76 (d, 2H); 13C NMR (D2O) δ 135.5,
104.0, 36.9, 32.2.
1
3343, 3000, 2729; H NMR (D2O) δ 4.85 (b, s, dCH2), 3.76 (m,
CH), 2.99 (m, 2H), 2.78 (m, 2H); 13C NMR (D2O) δ 140.0, 108.6,
41.8, 36.8. Anal. Calcd for C5H9NCl: C, 50.20, H, 8.44, N, 11.71;
found: C, 50.19, H, 8.44, N, 11.63.
(b) With Lith iu m Alu m in u m Hyd r id e in THF . 3-Ch lor o-
3-m eth ylbu tyla m in e Hyd r och lor id e (5). To a 100 mL three-
neck flask equipped with a condenser, 20 mL addition funnel,
magnetic stirrer, and a stopper under positive pressure of argon
was added 0.37 g (9.75 mmol) of lithium aluminum hydride and
25 mL of dry THF. The reaction flask was cooled by an ice-
water bath, and 1.03 g (4.40 mmol) 3-iodobicyclo[1.1.1]pentyl
azide was added to the addition funnel in 10 mL of dry THF.
The 3-iodobicyclo[1.1.1]pentyl azide solution was added drop by
drop to the stirred slurry over 25 min. The ice-water bath was
removed, and it was stirred at room temperature for 6 h. The
reaction mixture was then refluxed gently for 24 h and cooled
to room temperature. The unreacted lithium aluminum hydride
was destroyed with ice-cold water (15 mL). Ether (15 mL) was
added to the solution, and two layers were separated. The
aqueous layer was extracted with ether (4 × 25 mL). The
combined ether layers were dried over anhydrous magnesium
sulfate and filtered. Dry hydrogen chloride gas was passed over
The addition of 2 to the slurry of LAD at -15 to 20 °C and
stirred at room temperature for 12 h in ether gave the same
compound.
the filtrate for
1 min. A white salt formed immediately.
Evaporation of the ether under vacuum gave 3-chloro-3-meth-
ylbutylamine hydrochloride (5), as a white powder. Recrystal-
lization from ethanol-ethyl acetate provided needlelike crystals,
0.60 g, 86%, mp 194-195 °C. 1H NMR (DMSO) δ 8.05 (b, 3H),
2.91 (t, 2H), 2.03 (t, 2H), 1.55 (s, 6H); 13C NMR (DMSO) δ 70.1,
42.3, 35.8, 32.3. Anal. Calcd for C5H13NCl2: C, 38.98, H, 8.31,
N, 8.86. Found: C, 38.77, H, 8.30, N, 8.88.
Red u ction a t Low Tem p er a tu r e. When the addition of
3-iodobicyclo[1.1.1.]pentyl azide was done at -15 to -20° C in
either ether or THF (reaction is not dependent on solvents at
this low temperature) and stirred at the same temperature for
2 h and 6h at room temperature, the same product, 3-methyl-
enecyclobutylamine hydrochloride (4). was obtained. The mp and
the spectroscopic data confirm the compound to be 4.
3-Meth ylen ecyclobu tylben za m id e (6). To a stirred slurry
of 0.28 g (7.37 mmol) of lithium aluminum hydride in 15 mL of
ether was added slowly 0.73 g (3.11 mmol) 3-iodobicyclo[1.1.1]-
pentyl azide in 5 mL of ether. The mixture was refluxed gently
for 24 h, cooled to room temperature, and treated with ice-cooled
water (15 mL). Ether (15 mL) was added, and two layers
separated. The aqueous layer was extracted with ether (3 × 20
mL), the combined ether was dried over anhydrous magnesium
sulfate and filtered. The filtrate was reduced to approximately
15 mL under flow of nitrogen gas and transferred to a 50 mL
three-neck flask equipped with a condenser, magnetic stirrer,
calcium chloride drying tube, and rubber septum. Pyridine (4.89
g, 61.82 mmol) was added to the solution via a syringe and
stirred for 10 min. Benzoyl chloride (0.51 g, 3.63 mmol) was
added slowly to the solution for 5 min and stirred for 7 h.
Evaporation of the solvent and excess pyridine under reduced
pressure gave a pale orange solid which was dissolved in 30 mL
of CHCl3, washed with 20% HCl (100 mL) and then with 100
(b) With LAD in THF . 3-Ch lor o-1,1-d id eu ter o-3-m eth yl-
bu tyla m in e Hyd r och lor id e (16). To a stirred slurry of 0.456
g (23.10 mmol) of lithium aluminum deuteride in 20 mL of THF
under argon atmosphere was added slowly 0.97 g (4.13 mmol)
of 3-iodobicyclo[1.1.1]pentyl azide. The reaction mixture was
refluxed for 48 h and cooled to room temperature. The lithium
aluminum deuteride was taken up with ice-cold water (15 mL),
and 15 mL of ether was added. The organic layer was extracted
with ether (3 × 20 mL), dried over anhydrous magnesium
sulfate, and filtered. Dry hydrogen chloride gas was passed over
the filtrate, and the amine hydrochloride precipitate formed. The
precipitate was separated by filtration and recrystallized from
ethanol-ethyl acetate to a pure white salt, 0.46 g, 71%, 3-chloro-
1,1-dideutero-3-methylbutylamine hydrochloride (16), mp 194-
196 °C. 1H NMR (D2O) δ 1.66 (s, 2H) and 1.08 (s, 6H).
Red u ction of 1-Deu ter o-3-m eth ylen ecyclobu tyla m in e
Hyd r och lor id e w ith LAD in THF . To a stirred slurry of 0.2
g (4.76 mmol) of lithium aluminum deuteride under argon
atmosphere in 15 mL of dry THF was added 0.20 g (1.65 mmol)
of 1-deutero-3-methylenecyclobutylamine hydrochloride slowly
over 10 min. The reaction mixture was refluxed for 24 h and
cooled to room temperature. The excess lithium aluminum
deuteride was taken up with ice-water and dried over anhy-
drous magnesium sulfate. The magnesium sulfate was separated
by filtration. Dry hydrogen chloride gas was passed over the
filtrate. The salt was filtered and purified by recrystallization
from ethanol-ethyl acetate to afford a pure amine salt 16, 0.17
g, 64%. Proton and carbon spectra confirmed that the salt was
3-chloro-1,1-dideutero-3-methylbutylamine hydrochloride (16).
Syn th esis of 3-Iod obicyclo[1.1.1]p en tyla m in e (7). To a
stirred solution of 0.55 g (2.34 mmol) of 3-iodobicyclo[1.1.1]pentyl
azide in 10 mL of dry THF equipped with a condenser and rubber

4412 J . Org. Chem., Vol. 66, No. 12, 2001
Notes
septum under positive pressure of argon was added 3 mL (3
mmol) of 1 M diborane-THF complex dropwise for 10 min. The
reaction mixture was stirred for 24 h and cooled in an ice-water
bath. Ice-cold water (5 mL) was added slowly to destroy excess
borane, and the reaction mixture was allowed to reach room
temperature. The aqueous layer was saturated with 2 g of
potassium carbonate. The organic layer was extracted with ether
(3 × 15 mL) and dried over anhydrous magnesium sulfate. TLC
in methylene chloride-n-pentane (1:1) indicated a mixture of
two compounds. Evaporation of solvent under reduced pressure
gave a white powder. The powder was dissolved in methylene
chloride (2 mL) and purified by silica gel flash chromatography
with dichloromethane/n-pentane (1:1) as an eluent. The first
fraction was collected as 0.06 g of a colorless oil which could not
be identified by proton NMR. The second fraction after evapora-
tion of eluent gave a white powder 0.34 g, 70%, 3-iodo-bicyclo-
[1.1.1]pentylamine (7), mp 104-106 °C. IR (KBr), cm-1, 3342,
3248 (d), 2907, 2401, 1443, 1184; 1H NMR (DMSO) δ 2.20 (s,
6H); 13C NMR (DMSO) δ 60.7 (CH2), 59.4 (CN), 1.6 (CI).
When dry hydrogen chloride gas was passed over the second
fraction of the eluent, a white precipitate of salt was formed.
Evaporation of the solvent gave the amine salt which was
purified by recrystallization from ethyl acetate to 0.36 g, 62%,
mp 139-140 °C, 3-iodobicyclo[1.1.1]pentylamine hydrochloride
(8). IR (KBr) cm-1, 3338, 3013, 2449, 1692, 1539, 1252, 1190,
967; 1H NMR (D2O) δ 2.40 (s, 6H); 13C NMR (D2O) δ 61.5 (3CH2),
49.0 (C-N), -2.6 (C-I).
Analytical analyses on 7 and 8 were unsatisfactory but
reduction of 8 with LAH gave 4 thus implying the correct
structure for 8.
J O001510E