Stereochemistry of the Deamination of Spiropentylamine

Article abstract of DOI:10.1021/jo990654u

The stereochemistry of the deamination of (-)-spiropentylamine in acetic acid has been studied, and it was found that one of the major products, (-)-spiropentyl acetate, was formed with essentially complete inversion of configuration. This suggests that it is formed via an S_N2 displacement on the spiropentyldiazonium ion. The stereochemistry was established by the conversion of (-)-spiropentanecarboxylic acid to (-)-spiropentylamine via a Curtius rearrangement that proceeds with retention of configuration. The (-) acid also was converted to spiropentyl methyl ketone with methyllithium and then to (+)-spiropentyl acetate via the Baeyer-Villiger reaction that also results in retention of configuration. The deamination of N-nitroso-N-spiropentyl urea was studied in methanol, and spiropentyl methyl ether was a major product. Similarly, the reaction in water led to spiropentanol. The latter reactions also lead to 2-methoxymethyl- or 2-hydroxymethyl-1,3-butadiene, respectively, corresponding to the alternative mode of reaction via a cyclopropyl cation-allyl cation rearrangement.

Full text of DOI:10.1021/jo990654u

J . Org. Chem. 1999, 64, 7763-7767
7763
Ster eoch em istr y of th e Dea m in a tion of Sp ir op en tyla m in e
Kenneth B. Wiberg* and Carmen O¨ sterle
Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107
Received April 20, 1999
The stereochemistry of the deamination of (-)-spiropentylamine in acetic acid has been studied,
and it was found that one of the major products, (-)-spiropentyl acetate, was formed with essentially
complete inversion of configuration. This suggests that it is formed via an SN2 displacement on the
spiropentyldiazonium ion. The stereochemistry was established by the conversion of (-)-spiropen-
tanecarboxylic acid to (-)-spiropentylamine via a Curtius rearrangement that proceeds with
retention of configuration. The (-) acid also was converted to spiropentyl methyl ketone with
methyllithium and then to (+)-spiropentyl acetate via the Baeyer-Villiger reaction that also results
in retention of configuration. The deamination of N-nitroso-N-spiropentyl urea was studied in
methanol, and spiropentyl methyl ether was a major product. Similarly, the reaction in water led
to spiropentanol. The latter reactions also lead to 2-methoxymethyl- or 2-hydroxymethyl-1,3-
butadiene, respectively, corresponding to the alternative mode of reaction via a cyclopropyl cation-
allyl cation rearrangement.
In tr od u ction
The formation of spiropentyl acetate is interesting in
that the loss of nitrogen from the intermediate diazonium
ion would lead to the spiropentyl cation, which would be
expected to quickly rearrange.5 Our calculations have
found the cation to be a transition state,6 and if this is
correct, the acetate could not be formed from the ion.
Another possibility would be an SN2 reaction with the
spiropentyldiazonium ion, which would lead to the ace-
tate with complete inversion of configuration. To examine
this question, we have carried out the deamination of
optically active spiropentylamine.
The spiropentyl cation is unusual in that it is both a
cyclopropyl cation and a cyclopropylcarbinyl cation. We
have been interested in the behavior of this ion, and we
have carried out both an experimental and a theoretical
study. The spiropentyl system has received previous
study. Applequist examined the solvolysis of spiropentyl
chloride (1) and found 2-methylenebut-3-en-1-ol as the
product.1 It corresponds to ring opening as a cyclopropyl
cation.
Resolu tion of Sp ir op en ta n eca r boxylic Acid
Monosubstituted spiropentyl derivatives have not pre-
viously been resolved. Spiropentanecarboxylic acid (3)
appeared to be the best compound for a resolution
because it could easily be converted to both spiropentyl-
amine (2) and spiropentyl acetate (4) by reactions that
are known to give complete retention of configuration.
It was conveniently prepared by the rhodium-catalyzed
addition of ethyl diazoacetate to methylenecyclopropane
followed by hydrolysis.7 An attempt to effect an enantio-
selective addition using a chiral rhodium catalyst8 was
unsuccessful.
Resolution of the acid by using brucine proceeded
rather slowly, and (-)-R-phenylethylamine proved to be
a superior resolving agent. The maximum rotation
achieved via fractional crystallization was [R]D ) -172.7°.
It was found that the two diastereomeric amides formed
from racemic 3 and the above amine had slightly different
GC retention times and gave two bands of equal inten-
sity. When resolved 3 with the above optical rotation was
converted to the amide, a GC analysis of the latter
without prior purification indicated that the enantiomeric
The nitrous acid deamination of spiropentylamine (2)
in aqueous solution was found to give 2- and 3-methyl-
enecyclobutanols in a 1:5 ratio.2 A later study confirmed
these results and also found a small amount of 1-vinyl-
cyclopropanol.3 When carried out in acetic acid solution,
the reaction has been reported to give spiropentyl acetate,
2-methylenecyclobutyl acetate, and 3-methylenecyclobu-
tyl acetate in a 5:1:5 ratio.4 The rearranged products are
formed via a cyclopropylcarbinyl-cyclobutyl rearrange-
ment.
(5) Compare Streitwieser, A. J . Org. Chem. 1957, 22, 861.
(6) Wiberg, K. B.; Shobe, D. J . Org. Chem. 1999, 64, 7768.
(7) de Meijere, A.; Kozhushkov, S. I.; Spaeth, T.; Zefirov, N. S. J .
Org. Chem. 1993, 58, 502.
(8) Doyle, M. P.; Protopopova, M.; Muller, P.; Ene, D.; Shapiro, E.
A. J . Am. Chem. Soc. 1994, 116, 8492.
(1) Applequist, D. E.; Bernett, W. A. Tetrahedron Lett. 1968, 3005.
Landgrebe, J . A.; Applequist, D. E. J . Am. Chem. Soc. 1964, 86, 1536.
(2) Applequist, D. E.; Fanta, G. F. J . Am. Chem. Soc. 1960, 82, 6393.
(3) Konzelman, L. M.; Conley, R. T. J . Org. Chem. 1968, 33, 3828.
(4) Gajewski, J . J .; Chang, M. J . J . Org. Chem. 1978, 43, 765.
10.1021/jo990654u CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/28/1999

7764 J . Org. Chem., Vol. 64, No. 21, 1999
Wiberg and O¨ sterle
Sch em e 1
methyl ketone using methyllithium, and the latter was
subjected to a Baeyer-Villiger oxidation using the urea-
hydrogen peroxide complex and trifluoroacetic anhy-
dride10 giving (4) having [R]25 ) +27.0° . This reaction
D
is known to proceed with retention of configuration.11
These data indicate that the (-)-(R) acid, the (-)-(R)
amine, and the (+)-(R) acetate have the same arrange-
ment of the groups about the stereocenters. The maxi-
mum rotations of (R)-3, (R)-2‚HCl, and (R)-4 are -190°,
-62.4°, and 45.3°, respectively.
F igu r e 1. ORTEP representation of (S)-R-methylbenzylam-
monium (R)-spiropentanecarboxylate.
Dea m in a tion of Sp ir op en tyla m in e in Acetic Acid
Solu tion
Treatment of the chiral amine hydrochloride with
nitrous acid in acetic acid led to a mixture of 2-methyl-
enecyclobutyl acetate, 3-methylenecyclobutyl acetate, and
spiropentyl acetate in a 1:3:2 ratio. Starting with an acid
having [R]D ) -116.2°, the acetate was isolated by
preparative GC, giving a mixture of spiropentyl acetate
(95.5%) and achiral 3-acetoxymethylenecyclobutene. When
corrected for the latter, it had a rotation of -26.1°, which
corresponds to 94% inversion of configuration. In view
of the difficulty in isolating pure 4 from the deamination
reaction, it is reasonable to conclude that the reaction
proceeded with complete inversion of configuration.12
Although nitrous acid deaminations of some chiral
amines do lead to inverted acetates as products, complete
inversion is not found,13 suggesting that in these cases
the acetate may be formed by reaction of the intermediate
carbocation with the solvent. In view of the computational
results that indicate the spiropentyl cation to be a
transition state and the observation of complete inversion
of configuration, it is reasonable to propose that the
acetate is formed by an SN2 displacement on the spiro-
pentyldiazonium ion.
F igu r e 2. Crystal structure of (S)-R-methylbenzylammonium
+
-
(R)-spiropentanecarboxylate showing the NH3 or CO2 hy-
drogen bond.
purity was 95.5%. Thus, the maximum rotation of 3 is
[R]D ) 190°.
The phenylethylamine salt (5) formed well-developed
crystals which were suitable for an X-ray crystallographic
study. The structure is shown in Figure 1. The amine
component has structurally similar methyl and am-
monium groups at the chiral center. The assignment
shown in the figure leads to the smaller R value, and
also has a short N‚‚‚O nonbonded distance characteristic
of a hydrogen bond (Figure 2). The (-) resolving agent
has the S configuration, and the structure indicates that
(-)-3 has the R configuration.
Dea m in a tion of Sp ir op en tyla m in e in Meth a n ol
Solu tion
Is the formation of spiropentyl acetate a consequence
of carrying out the deamination reaction in a medium
with a low dielectric constant, which forces all ions to
exist as ion pairs or higher aggregates? It is possible to
examine this question by studying the deamination of
The acid (3) was converted to 2 via the Curtius reaction
(Scheme 1), and it was isolated as the amine hydrochlo-
ride. The rearrangement is known to proceed via reten-
(10) Cooper, M. S.; Heaney, H.; Newbold, A. J .; Sanderson, W. R.
Synlett 1990, 533.
(11) Mislow, K.; Brenner, J . J . Am. Chem. Soc. 1953, 75, 2318.
(12) It is possible that some loss of configuration may result from
reversible deprotonation of the diazonium ion forming an achiral
diazoalkane: Kirmse, W.; Wa¨chterha¨user, G. Liebigs Ann. Chem. 1967,
707, 44.
(13) As an example, the deamination of (+)-2-butylamine in acetic
acid gave 30% inversion: Kirmse, W.; Banart, K.; Bunce, M.; Gassen,
K.-R.; Kurnianto, A. W. Recl. Trav. Chim. Pays Bas 1986, 195, 272.
tion of configuration.9 The (+) acid with [R]25 ) +64.2°
D
gave the amine hydrochloride with [R]25 ) +21.1° The
D
acid with [R]25 ) -113.3° also was converted to the
D
(9) J ones, L. W.; Wallis, E. S. J . Am. Chem. Soc. 1926, 48, 169.

Deamination of Spiropentylamine
J . Org. Chem., Vol. 64, No. 21, 1999 7765
measurements were performed with a gas chromatograph
connected to an integrator. The capillary column used was a
50 m × 0.2 µm i.d. column coated with a 0.33 µm layer of cross-
Sch em e 2
linked methyl silicone. Preparative gas chromatography was
1
performed using a 4 ft ×
/ in. column fitted with 20%
4
Carbowax 20M on Chromosorb P (80/100 mesh). Boiling and
melting points are uncorrected. Polarimetric analysis was
performed using a 1 dm cell.
Dea m in a tion of Sp ir op en tyla m in e Hyd r och lor id e. To
a 15 mL round-bottomed flask was added 0.31 g of spiropen-
tylamine hydrochloride4 (2.6 mmol) in 4 mL of glacial acetic
acid. Over a period of 45 min, 0.21 g of NaNO2 (3.1 mmol) was
added in small portions. Stirring was continued for another 2
h. The solution was extracted with pentane, and the combined
organic extracts were washed with saturated NaHCO3 until
the washings were basic. The organic extract was dried over
anhydrous Na2CO3 and concentrated in vacuo. Analysis of the
product mixture by analytical GC (T0 ) 40 °C, tinit ) 30 min,
r ) 15°/min, Tf ) 250 °C) showed the presence of three reaction
products. Since TLC analysis showed that column chromatog-
raphy would not separate the solution into its different
components, another approach was taken. The solution was
dissolved in 10 mL of CH2Cl2 and placed in a three-necked
round-bottomed flask equipped with gas inlet and magnetic
stirrer. The flask was placed in a dry ice/acetone bath, and
ozone was bubbled through the solution until the solution
turned light blue. The solution was purged with oxygen for
20 min, then 2 mL of dimethyl sulfide was added, and the
solution was stirred overnight. The dry ice/acetone bath was
not removed but was allowed to warm to room temperature
overnight. The solution was extracted with 20 mL of NaHSO3,
washed with water, and dried over anhydrous NaHCO3.
Concentration of the liquid in vacuo yielded a yellow oil. Two
of the compounds were isolated using microchromatography
on silica gel. The column was prerun with solvent (10% ethyl
acetate in pentane) before it was charged with the product
mixture. The first fraction isolated contained spiropentyl
acetate (Rf ) 0.74), and the second fraction was 3-acetoxy-1-
methylenecyclobutanone15 (Rf ) 0.015), which is the product
of the ozonolysis of 3-acetoxy-1-methylenecyclobutane. The
third component, 2-acetoxy-1-methylenecyclobutane, was iden-
tified by comparison of the GC trace with that of an authentic
sample. Spiropentyl acetate (tR ) 11.9 min, 32%), 3-acetoxy-
1-methylenecyclobutane (tR ) 12.3 min, 50%), and 2-acetoxy-
1-methylenecyclobutane (tR ) 12.4 min, 16%) were formed.
the corresponding nitrosourea in methanol by using base
catalysis. Here, the products from the N-nitroso-N-
spiropentyl urea (5) were spiropentyl methyl ether (41%),
3-methoxy-1-methylenecyclobutane (28%), and 2-meth-
oxymethyl-1,3-butadiene (31%) (Scheme 2). The forma-
tion of methoxymethylbutadiene indicates an interme-
diate position of this reaction between the solvolysis of
spiropentyl chloride and the deamination of spiropentyl-
amine hydrochloride in acetic acid.
The deamination also was carried out by heating 5 in
water. Here the products were spiropentanol (32%),
2-hydroxymethylbuta-1,3-diene (31%), and 3-hydroxy-1-
methylenecyclobutane (41%) (Scheme 2). The butadiene
derivatives formed in these reactions result from a
cyclopropyl cation type ring opening, which is the course
followed in the solvolysis of spiropentyl chloride.1
The stereochemistry of the reactions of the nitrosourea
was not studied because it is known that diazonium ions
and diazoalkanes are interconverted under basic condi-
tions,12 which would lead to racemization.
Su m m a r y
The deamination of spiropentylamine in acetic acid
solution leads to the formation of spiropentyl acetate with
essentially complete inversion of configuration. The
deamination of the corresponding N-nitrosourea in basic
methanol leads to spiropentyl methyl ether as a major
product, and the reaction in water leads to spiropentanol.
All of these reactions probably proceed via an SN2
displacement on spiropentyldiazonium ion. This indicates
that ion pairs are not necessary to obtain the displace-
ment reaction and also suggests that this diazonium ion
has a longer lifetime than most aliphatic diazonium ions
so that it has time to react via an SN2 pathway. It is also
interesting to note that, in addition to unrearranged
spiropentyl derivatives, the deamination in acetic acid
solution leads only to cyclopropylcarbinyl-cyclobutyl
cation type rearrangements, whereas the reaction in
methanol or water also leads to a cyclopropyl cation
rearrangement product. The latter product is also found
in the solvolysis of spiropentyl derivatives.1
Op tica l Resolu tion of Sp ir op en ta n eca r boxylic Acid
w ith (S)-(-)-r-Meth ylben zyla m in e. Spiropentanecarboxylic
acid (5.0 g, 44.6 mmol) was dissolved in 20 mL of ethyl acetate
in a 50 mL Erlenmeyer flask, and 5.4 g of (S)-(-)-R-methyl-
benzylamine (44.6 mmol) was added. The solution became
warm when the amine was added to the acid. The solution
was heated to boiling on a hot plate and was allowed to cool
to room temperature. Crystallization was achieved only after
cooling the solution to -60 °C and scratching the walls of the
Erlenmeyer flask with a spatula. The solution was allowed to
crystallize over a period of 10 h. The white crystals were
collected by removing the liquid by pipet. Fractional recrys-
tallization and acidic hydrolysis of the salt yielded optically
active spiropentanecarboxylic acid with [R]25 ) -172.7° (c )
D
0.035 g/mL, methanol), mp 120-121 °C. IR (KBr): 1650 cm-1
.
It should be noted that SN2 reactions at cyclopropane
rings have previously been observed. The reaction of
2-methylcyclopropyl trifluoromethanesulfonate with tribu-
tyl-hexadecylphosphonium azide in an aproptic solvent
was found to give complete inversion of configuration.14
However, an SN1 reaction leading to an allyl cation is
more commonly observed.5
1H NMR (C6D6): 0.6 (m, 2H, CH2), 0.83 (m, 2H, CH2), 0.97
(dd, 1H, J ) 7.5,3.3), 1.3 (d, 3H, J ) 6.6, CH3), 1.42 (m, 1H,
CH), 1.85 (dd, 1H, J ) 7.5,3.9, CHCO2), 3.92 (q, 1H, J ) 6.6,
CHCH3), 5.5 (bs, 3H, NH3), 7.0 (m, 1H, CH aromatic), 7.1 (m,
2H, aromatic), 7.2 (d, 2H, aromatic). 13C NMR (C6D6): 5.59(t),
6.56(t), 14.5(t), 17.64(s), 22.6(q), 22.66(d), 50.95(d), 126.7(d),
128.5(d), 142.5(s), 179.6(s). Anal. Calcd for C14H19NO2:
72.07, H 8.21, N 6.00. Found: C 71.95, H 8.33, N 6.04.
C
After 6-fold fractional recrystallization of the above salt, a
small sample of the crystals (approximately 0.2 g) was dis-
solved in 10 mL of ethyl acetate in a 15 mL Erlenmeyer flask,
Exp er im en ta l Section
Gen er a l In for m a tion . FT NMR spectra were taken in
CDCl3 and FT IR spectra were taken in CCl4. Analytical GC
(15) Tenud, L.; Meilmann, M.; Dallwigk, E. Helv. Chim. Acta 1977,
60, 975.
(14) Banert, K. Chem. Ber. 1985, 118, 1564.

7766 J . Org. Chem., Vol. 64, No. 21, 1999
Wiberg and O¨ sterle
heated to boiling for 5 min, and allowed to cool to room
temperature. The clear liquid was transferred to a small vial
and covered with perforated Parafilm. After a period of 36 h
rod-shaped clear crystals had formed which could be used for
the X-ray structure determination
The combined organic extracts were extracted with saturated
NaHCO3, dried over Na2SO4, and concentrated in vacuo to yield
a yellow oil (0.54 g, 56%). The acetate could be further purified
by flash column chromatography on silica gel (Rf ) 0.47; ether:
pentane 1:8). The NMR spectrum agreed with that reported
in the literature.4
Dea m in a tion of Ch ir a l Sp ir op en tyla m in e Hyd r och lo-
r id e. To a 15 mL round-bottomed flask was added 0.261 g of
chiral spiropentylamine hydrochloride (4.5 mmol) (derived
Syn th esis of Ch ir a l Sp ir op en tyl Aceta te. The conversion
of chiral 3 ([R]25D ) -113.3°) to the methyl ketone was carried
out as described above, and the latter was converted to the
acetate. The acetate could be further purified by flash column
chromatography on silica gel (Rf ) 0.47; ether:pentane 1:8),
from 3 having [R]25 ) -116.2°) in 4 mL of glacial acetic acid.
D
Over a period of 45 min, 0.31 g of NaNO2 (4.5 mmol) was added
in small portions. Stirring was continued for another 2 h. The
solution was extracted with pentane, and the combined organic
extracts were washed with saturated NaHCO3 until the
washings were basic. The organic extract was dried over
anhydrous Na2CO3 and concentrated in vacuo. Analysis of the
product mixture by analytical GC (T0 ) 40 °C, tinit ) 30 min,
r ) 15°/min, Tf ) 250 °C) showed that spiropentyl acetate,
3-acetoxy-1-methylenecyclobutane, and 2-acetoxy-1-methyl-
enecyclobutane were formed in a 1.6:2.8:1 ratio.
[R]25 ) +27.7° (c ) 0.02 g/ mL, methanol).
D
N -(S )-(-)-(r-M e t h y lb e n z y l)s p i r o p e n t a n e c a r b o x -
a m id e. To a 50 mL round-bottomed flask cooled in an ice bath
was added 0.3 mL of spiropentanecarboxylic acid (2.7 mmol)
in 10 mL CH2Cl2. Oxalyl chloride (0.3 mL, 3.5 mmol) was
added dropwise via syringe over a period of 30 min. After the
addition was complete the solution was stirred for another 0.5
h at 0 °C and 0.5 h at room temperature. The solution was
cooled to 0 °C, and 1.5 mL of (S)-(-)-R-methylbenzylamine
(11.6 mmol) dissolved in 2 mL CH2Cl2 was added slowly over
a period of 40 min. The solution was stirred for 2 h at room
temperature. After the addition of 30 mL of ether the solution
was washed with 20 mL of water, two 10 mL portions of 1 M
phosphoric acid, 10 mL of a saturated NaHCO3 solution, and
10 mL of brine. The organic layer was dried over anhydrous
Na2SO4 and concentrated in vacuo. Chromatography on silica
gel with 3:1 ether/pentane afforded 0.44 g of a white powder
(77% yield, Rf ) 0.44, mp 94-97 °C). IR (KBr): 1676(s), 1540-
For this run ozonolysis was not performed, because only a
small amount of amine was deaminated and loss of product
was to be avoided. Instead, preparative GC was used for the
separation of the liquid into its components (Tcol ) 110 °C, Tinj
) 120 °C, Tdet ) 140 °C). Two fractions were collected; one
containing a mixture of spiropentyl acetate (90.5%) and
3-acetoxy-1-methylenecyclobutane was collected after 8.15 min
and another fraction containing spiropentyl acetate (11%),
3-acetoxy-1-methylenecyclobutane (76%), and a third compo-
nent, 2-acetoxy-1-methylenecyclobutane (12%), was collected
after 8.40 min. 1H NMR spectra were recorded for two
fractions, and the integration of the peaks was compared with
the analytical GC data. GC assignments and NMR spectra
agreed well. The optical rotation measured for the first fraction
1
(m), 1494(s) cm-1. H NMR (C6D6): 0.56 (m, 2H, CH2), 0.76-
0.69 (m, 3H, CH2, CH), 1.15 (d, 3H, CH3), 1.39 (m, 1H, CH),
1.50 (t, 0.5H, CH, J ) 3.6), 1.54 (t, 0.5H, CH, J ) 3.6), 5.4 (bs,
1H, NH), 6.9-7.2 (m, 5H, C6H5) ppm. 13C NMR (C6D6): 5.25-
(t), 6.34(t), 13.4(t), 16.9(s), 21.7(q), 22.2(d), 48.3(d), 126.2(d),
126.3(d), 126.9(d), 127.7(s), 170.5(s). MS(CI): 216.2. HRMS-
(CI): calcd for C14H18NO (MH+) 216.1388, found 216.1386.
Anal. Calcd for C14H17NO: C 78.1, H 7.96, N 6.51. Found: C
77.01, H 7.97, N 6.39.
was [R]25 ) -23.46° (c ) 4.9 mg/mL, methanol). Because the
D
impurity was known and is achiral, this value could be
corrected, giving [R]25 ) -26.1°.
D
Sp ir op en tyl Meth yl Keton e. In a 100 mL three-neck
round-bottomed flask equipped with magnetic stirring bar
were placed 3.4 g of spiropentanecarboxylic acid (30 mmol) and
50 mL of anhydrous ether. The flask was placed in an ice/salt
bath at 0 °C, and methyllithium (1.4 M in ether, 42.7 mL, 59.9
mmol) was added slowly over a period of 1 h. A white
precipitate formed during this process. After the addition was
complete, the white slurry was stirred for an additional 1 h at
room temperature. The lithium salt was hydrolyzed by slowly
adding the slurry to a cold, vigorously stirred solution of dilute
HCl. The two layers were separated, and the aqueous layer
was extracted with three 10 mL portions of ether. The
combined ether extracts were washed with saturated NaHCO3
and saturated NaCl, dried over anhydrous Na2SO4, and
evaporated in vacuo to yield a yellow oil (2.9 g, 87%). The high-
resolution MS data showed a molecular ion peak at m/z
109.0651 instead of 110.0732. The analysis did not change
after isolating the compound by preparative GC, and no
obvious explanation can be given as to the origin of the
hydrogen atom loss. The low combustion analysis value for
carbon may be due to the presence of the quaternary spiro
carbon atom, which can lead to incomplete combustion. IR
Deter m in a tion of %ee by GC An a lysis of N-(S)-(-)-(r-
Meth ylben zyl)sp ir op en ta n eca r boxa m id e. Gas chromato-
graphic analysis of the racemic and chiral samples of N-(S)-
(-)-(R-methylbenzyl)spiropentanecarboxamide was performed
with analytical GC (Tinit ) 120 °C, Tf ) 250, t ) 15 min, r )
10 °/min). For the two diastereomers two peaks appeared in
the GC trace at tR ) 24.05 min and tR ) 24.25 min. For the
racemic sample the integrations of the two peaks indicated a
1:1 ratio. The integrations for the chiral sample ([R]25
)
D
-172.73°) were 2.96 and 62.95, respectively, indicating 95.5%
optical purity of the sample. With the X-ray structure it was
determined that negatively rotating acid has the (R) config-
uration, which leads to the assignment of N-(S)-(-)-R-meth-
ylbenzyl)-(R)-(-)-spiropentanecarboxamide for the chiral sample
(mp 129-131 °C). The maximum optical rotation of spiropen-
tanecarboxylic acid is determined to be [R]25 ) -190°.
D
N-Sp ir op en tyl Ur ea . Spiropentanecarboxylic acid (0.99 g,
8.8 mmol) was added to 10 mL of distilled water in a 50 mL
round-bottomed flask equipped with a pressure-equalizing
addition funnel and magnetic stirrer, and sufficient acetone
was added to dissolve the acid in the water. The flask was
placed in a 0 °C ice/salt bath, and 1.46 mL of triethylamine
(10.6 mmol) in 10 mL of acetone was added. After the addition
was completed 1.1 mL of ethyl chloroformate (13.6 mmol) in
10 mL acetone was added slowly over a period of 30 min.
Stirring continued for 30 min at 0 °C, after which a solution
of 0.88 g of sodium azide (15.8 mmol) in 10 mL of distilled
water was added dropwise. After stirring at 0 °C for 1 h, the
solution became cloudy and was poured into 100 mL of distilled
water. The solution was concentrated in vacuo, and the
aqueous solution was extracted with 3 × 10 mL of ether. The
combined ether extracts were washed with saturated NaHCO3
solution to eliminate any unreacted acid and dried over
anhydrous Na2SO4, and the solvent was carefully removed in
vacuo. The presence of the acyl azide was confirmed by IR
spectroscopy (ν ) 2130 and 1739 cm-1). The acyl azide was
used without further purification.
1
(CCl4): 1704(s) cm-1. H NMR: 0.8-1.10 (m, 4H, CH2), 1.42
(dd, 1H, J ) 7.5, 3.6), 1.53 (t, 1H, J ) 4.5, 3.6), 2.08 (s, 3H),
2.22 (dd, J ) 7.5, 4.5). 13C NMR: 5.46(t), 6.69(t), 16.58(t),
20.26(s), 28.28(d), 29.73(q), 208.56(s). HRMS(EI): calcd for
C7H9O 109.0653, found 109.0651. Anal. Calcd for C7H10O: C
76.33, H 9.15. Found: C 75.51, H 9.10.
Sp ir op en tyl Aceta te. In a 50 mL round-bottomed flask
were placed 0.85 g of spiropentyl methyl ketone (7.7 mmol),
7.6 g of urea‚H2O2 complex (15.4 mmol), 10 g of Na2HPO4 (70.4
mmol), and 30 mL of dry CH2Cl2. Trifluoroacetic anhydride (3
mL, 20 mmol) was added dropwise over a period of 30 min.
The reaction solution warmed during this period, and a reflux
condenser had to be attached. After the addition was com-
pleted, the solution was heated to reflux for another 3 h. The
solution was allowed to cool to room temperature, and 20 mL
of water was added. The layers were separated, and the
aqueous layer extracted with two 10 mL portions of CH2Cl2.

Deamination of Spiropentylamine
J . Org. Chem., Vol. 64, No. 21, 1999 7767
Spiropentanecarbonyl azide was added to 30 mL of dry
toluene in a 50 mL round-bottomed flask equipped with a
reflux condenser. The liquid was heated to reflux for 5 h until
the evolution of gas stopped. The solution then was cooled to
room temperature. IR spectroscopic analysis confirmed the
conversion to spiropentane isocyanate (ν ) 2200 cm-1). The
solution was cooled in an ice bath, and ammonia (gas) was
bubbled through the solution for 40 min. A white precipitate
formed. The solution was allowed to stand for an additional 1
h in the refrigerator, after which time the precipitate was
collected by vacuum filtration in a Buchner funnel. The solid
was washed with cold toluene, dried, recrystallized from ethyl
acetate, collected, and dried in vacuo to yield a white powder
(0.18 g, 16% yield, mp 149-151 °C). IR (KBr): 1661, 1538,
had been formed. The MS data of the three compounds
indicated the formation of three alcohol derivatives with
identical mass (m/z 84). Analysis of the mixture by H NMR
1
spectroscopy provided enough information to identify the
compounds as 3-hydroxy-1-methylenecyclobutane (δ 2.65 m,
2H, CH2; 3.0 m, 2H, CH2; 4.9 m, 1H, CHOH; 4.15 m, 2H, d
CH2), spiropentanol16 (δ 0.69-0.85, m, 4H, CH2; 1.0, t, 2H,
CH2; 3.85, dd, 1H, CHOH), and 2-hydroxymethyl-1,3-butadi-
ene17 (δ 4.4, s, 2H, CH2OH; 5.15-5.4, m, 4H, dCH2; 6.4, 1H,
dd, dCH). GC analysis (analytical GC, T0 ) 50 °C) showed
the product distribution to be 27% 2-hydroxymethyl-1,3-
butadiene (tR ) 15.6 min), 41% 3-hydroxy-1-methylenecyclobu-
tane (tR ) 16.1 min), and 32% spiropentanol (tR ) 16.3 min).
Deam in ation of N-n itr oso-N-spir open tyl Ur ea in Meth a-
n ol. To a solution of 0.79 g of NaHCO3 (9.5 mmol) in 2 mL of
methanol in a 5 mL round-bottomed flask was added a solution
of 0.74 g of N-nitroso-N-spiropentyl urea (4.8 mmol) in 2 mL
of methanol. The solution was stirred for 2 h during which
time the solution changed color from yellow to clear. The
solution was poured into 20 mL of water and extracted with 3
× 10 mL of CH2Cl2. The combined organic extracts were dried
over anhydrous Na2CO3 and concentrated to 2 mL by distil-
lation through a 20 cm steel-packed distillation column. The
concentrated solution was purified by preparative GC (column
A, Tinj ) 120 °C, Tdet ) 150 °C, Tcol ) 100 °C, tR ) 3.3 min).
NMR analysis of the collected sample shows three individual
compounds, 1-methoxyspiropentane, 1-methoxy-3-methylene-
cyclobutane,18 and 2-methoxymethyl-1,3-butadiene.19 GC analy-
sis (analytical GC, T0 ) 40 °C) showed the product distribution
to be 31% 2-methoxymethyl-1,3-buta-diene (tR ) 3.26 min),
41% 3-methoxy-1-methylenecyclobutane (tR ) 3.4 min), and
32% 1-methoxyspiropentane (tR ) 3.7 min).
1311 cm-1 1H NMR (CD3OD): 0.63 (m, 2H, CH2), 0.80 (m,
.
2H, CH2), 1.047 (t, 2H, J ) 5.5, CH2), 2.67 (m, 1H, J ) 3.5,
CHNH). 13C NMR (CD3OD): 3.45(t), 6.83(t), 15.09(t), 15.97-
(s), 28.68(d), 163(s). HRMS (CI): calc for C6H11NO2 (MH+)
127.0871, found 127.0871. Anal. Calcd for C6H10NO2: C 57.12,
H 7.99, N 22.21. Found: C 57.40, H 7.93, 22.01.
N-Nitr oso-N-sp ir op en tyl Ur ea . A 50 mL round-bottomed
flask was placed in an ice/salt bath and equipped with a
magnetic stirrer. To the flask were added 0.22 g of N-
(spiropentyl) urea (1.39 mmol) and 3 mL of a 7:3 mixture of
acetic acid and acetic anhydride. NaNO2 (0.15 g, 2.2 mmol)
was dissolved in 3 mL of water and added to the solution via
syringe pump over a period of 1 h. To the solution was added
30 mL of ice water, and the solution was stirred for an
additional 1 h in the ice bath. A yellow precipitate formed
during this time. The solution was placed in the refrigerator
overnight. The crystals were collected by vacuum filtration,
washed with ice water, and dried in vacuo. After recrystalli-
zation (ethyl acetate/petrol ether 1:1) 0.17 g of pure N-nitroso-
N-spiropentyl urea (81% yield) was collected (mp 87-89 °C,
Ack n ow led gm en t . This investigation was sup-
ported by a grant from the National Science Foundation.
We thank Prof. J ack Faller for his assistance in inter-
preting the X-ray data and Dr. Susan DeGala for
carrying out the X-ray crystallographic structure de-
termination.
dec). IR (KBr): 1715, 1507 cm-1 1H NMR (CD3OD): 0.64-
.
0.74 (m, 2H), 0.85 (m, 1H), 1.08 (m, 2H), 1.52 (t, 1H, J ) 6.6),
2.7 (dd, 1H, J ) 6.6, 7.8). 13C NMR (CD3OD): 3.97(t), 5.27(t),
13.35(t), 16.36(s), 29.4(d), 156.0(s). HRMS(CI): calcd for
C6H10N3O2 (MH+) 156.0773, found 156.0772. Anal. Calcd for
C6H9N3O2: C 46.45, H 5.85, N 27.08. Found: C 46.56, H 5.84,
N 27.01.
Dea m in a tion of N-Nitr oso-N-sp ir op en tyl Ur ea in Wa -
ter . A 10 mL round-bottomed flask equipped with magnetic
stirrer containing 4 mL of distilled water and 0.52 g of
N-nitroso-N-spiropentyl urea (3.4 mmol) was heated to 100 °C.
The decomposition of the nitrosourea was accompanied by
vigorous gas evolution (colorless gas). The solution was allowed
to cool to room temperature, the aqueous solution was ex-
tracted with 3 × 10 mL portions of CH2Cl2, and the combined
organic extracts were dried over anhydrous Na2SO4. The
solvent was removed in vacuo, and a GC/MS analysis was
performed. The analysis revealed that three major compounds
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data for (S)-R-phenylethylammonium (R)-spiropen-
tanecarboxylate, 5. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O990654U
(16) Applequist, D. E.; Nickel, G. W. J . Org. Chem. 1979, 44, 321.
(17) Bottini, A. T.; Christensen, J . E. Tetrahedron 1974, 30, 393.
(18) Kirmse, W.; Rhode, W. Chem. Ber. 1987, 120, 839.
(19) Mkryan, G. M. J . Org. Chem. USSR 1971, 6, 2135.