6
488 J . Org. Chem., Vol. 66, No. 19, 2001
Notes
Sch em e 3
chromatography was performed on Merck silica gel (60 Å, 230-
4
00 mesh). HRMS were recorded at the “Centre R e´ gional de
Mesures Physiques de l’Ouest”. Reagents were purchased from
Aldrich Chemical Co.
Syn th esis of Cyclop r op a n eca r bon itr iles 5a -e. Cyclopro-
panecarbonitriles 5a -c,e were prepared as previously de-
5
scribed. A procedure is given for the synthesis of cyclopropane-
carbonitrile 5d . At -10 °C (ice/salt bath) and under Ar, to a
solution of cyclopropanecarbonitrile 5a (0.098 g, 0.49 mmol, 1
equiv) in 10 mL of THF was added dropwise LDA (0.5 mL of a
2
M solution in THF/heptane/ethylbenzene, 2 equiv). The
mixture was stirred 30 min at -10 °C, and iodomethane (0.3
mL, 10 equiv) was then added. The mixture was allowed to warm
to room temperature. After 2 h, the reaction was quenched with
1
0% NH
with EtOAc. The combined organic layers were dried over Na
SO , filtered, and evaporated under reduced pressure. The crude
4
Cl and the aqueous layer was extracted three times
2
-
4
was purified on silica (hexane:EtOAc, 7:3) to afford cyclopro-
1
panecarbonitrile 5d (white powder, 0.048 g, 45%). H NMR
(
CDCl
6.7 Hz, 1H), 4.95 (s, 2H), 5.07 (m, 2H), 7.18-7.28 (m, 4H).
NMR (CDCl ): δ 15.9, 17.4, 71.0, 71.1, 94.8, 120.8, 127.1, 127.2,
27.6, 127.8, 137.0, 137.5. MS (CI/NH ): 216 (M + 1, 100). IR
(CN). HRMS: calcd for C13
15.0946; found, 215.0946.
Syn th esis of γ-Am in o Acid s 7a -d a n d 9 a n d Hyd r o-
3
): δ 1.21 (d, J ) 6.7 Hz, 1H), 1.51 (s, 3H), 1.75 (d, J )
13
situ within 24 h); for substrates 5b-d , more drastic
conditions (solvent, catalyst, and/or pressure) were neces-
sary to reduce the nitrile to the corresponding amine. The
two-step process, comprising ring opening and nitrile
reduction, thus provides rapid, high-yielding access to
γ-amino acid systems. The final example in Table 1 is
the aryl-substituted substrate 5e. Unfortunately, under
C
3
1
(
2
3
-
1
+
KBr): 2239 cm
2
H13NO (M) ,
gen olysis of 5e. A typical experimental procedure is given for
the synthesis of 4-aminobutyric acid (7a ). To a solution of
cyclopropanecarbonitrile 5a (0.030 g, 0.15 mmol, 1 equiv) in 3
mL of EtOAc was added 10 wt % Pd on C (0.031 g, 20 mol %).
The mixture was air evacuated and vigorously stirred under 1
2
the aforementioned conditions (H , Pd/C, EtOAc), 5e
spawned only the reduced cyclopropane 7e.
As the rearrangement of the cyclopropane ring pre-
sumably occurs with internal proton transfer, the incor-
poration of a deuterium label on the hydrate moiety
should afford selective â-labeling of the amino acid. The
method was therefore applied to cyclopropane 5b, which
2
bar of H for 24 h. The catalyst was filtered out and rinsed with
MeOH, and the solvents were removed under reduced pressure
to afford GABA 7a 8 as a white powder (0.014 g, 91%). 1H NMR
(D O): δ 1.84 (m, 2H), 2.23 (t, J ) 7.3 Hz, 2H), 2.94 (t, J ) 7.3
2
Hz, 2H). 13C NMR (D
O): δ 23.9, 34.7, 39.6, 181.8. MS (CI/
2
NH
3
): 104 (M + 1, 100).
was treated with D
2 2
instead of H in anhydrous EtOAc
4
-Am in o-2-eth ylbu tyr ic a cid (7b).9 7b was prepared as
(
Scheme 3). This afforded labeled 8 that was further
2
described for 7a by starting from cyclopropanecarbonitrile 5b
0.030 g, 0.13 mmol). After 24 h, the reaction was worked up as
reduced (Pd/C, AcOH) to give 3-[ H]-4-amino-2-ethyl-
butyric acid (9) in 93% yield and 79% isotopic enrichment.
A postulated reaction mechanism involves palladium
and its role in the key rearrangement step. Indeed, it has
recently been reported that Pd/C catalyzes the ring
(
described above. The crude was taken into 2 mL of AcOH, and
Pd/C (0.027 g, 20 mol %) was added. The mixture was air
evacuated and vigorously stirred under 1 bar of H for 72 h. The
2
catalyst was filtered out and rinsed with MeOH, and the solvents
7
were removed under reduced pressure to afford 7b as a white
opening of cyclopropanols. On the basis of this report,
powder (0.016 g, 93%). 1H NMR (D
O): δ 0.84 (t, J ) 7.4 Hz,
2
we suggest that a palladium alkoxide is formed by
oxidative addition of Pd(0) to the hydrate group. The
hydrate oxygen atoms then act as electron donors, and
the cyclopropane carbon atoms, as electron acceptors. The
relative stability of the indicated partial negative charge
directs the cyclopropane rearrangement. For example,
the regioselectivity of the rearrangement is governed by
the nitrile group that promotes stabilization of the partial
negative charge at the R-carbon atom. Subsequent ring
1
3
3
H), 1.49 (m, 2H), 1.77 (m, 2H), 2.21 (m, 1H), 2.93 (m, 2H).
C
2 3
NMR (D O): δ 13.2, 27.5, 31.7, 40.1, 48.6, 184.5. MS (CI/NH ):
1
32 (M + 1, 100).
4-Am in o-2,2-d im eth ylbu tyr ic a cid (7c).10 7c was prepared
as decribed for 7b by starting from cyclopropanecarbonitrile 5c
0.025 g, 0.11 mmol). The nitrile reduction step was performed
using a mixture of Pd/C (0.023 g, 20 mol %) and PdO (0.003 g,
0 mol %) under a pressure of 3 bar of H for 72 h. 7c was
(
2
2
1
obtained as a white powder (0.013 g, 91%). H NMR (D
1
2
O): δ
13
.14 (s, 6H), 1.82 (m, 2H), 2.98 (m, 2H). C NMR (D O): δ 25.6,
2
7
opening generates a σ-Pd complex that undergoes ex-
37.0, 37.9, 42.4, 185.5. MS (CI/NH ): 132 (M + 1, 100).
3
4-Am in o-3-m eth ylbu tyr ic a cid (7d ).11 7d was prepared as
decribed for 7c by starting from cyclopropanecarbonitrile 5d
clusive reductive elimination. Indeed, 9 (derived from 8)
was labeled only on the â-carbon atom.
(
0.024 g, 0.11 mmol). 7d was obtained as a white powder (0.012
In conclusion, we have shown that the rearrangement
of R-cyanocyclopropanone hydrates provides an easy
route to γ-amino acids. The approach developed here
permits the regioselective incorporation of isotopic label-
ing and is particularly well suited for the preparation of
radioactively labeled amino acids using, for example,
tritium gas.
1
g, 95%). H NMR (D
(
and 12.5 Hz, 1H). C NMR (D
MS (CI/NH ): 118 (M + 1, 100).
2
O): δ 1.02 (d, J ) 5.3 Hz, 3 H), 2.21-2.42
m, 3H), 2.87 (dd, J ) 6.4 and 12.5 Hz, 1H), 3.01 (dd, J ) 2.5
13
2
O): δ 17.0, 29.3, 41.1, 45.1, 179.4.
3
(7-Ben zyl-5,9-d ih yd r o-6,8-d ioxa ben zocycloh ep ten -7-yl)-
a ceton itr ile (7e). 7e was prepared as described for 7a by
starting from cyclopropanecarbonitrile 5e (0.030 g, 0.11 mmol).
7
1
e was obtained as a thick oil (0.029 g, 96%). H NMR (CDCl
3
):
Exp er im en ta l Section
(
8) Kohama, Y.; Matsumoto, S.; Mimura, T.; Tanabe, N.; Inada, A.;
Nakanishi, T. Chem. Pharm. Bull. 1987, 35, 2484-2489.
9) Azam, S.; D’Souza, A. A.; Wyatt, P. B. J . Chem. Soc., Perkin
Trans. 1 1996, 621-627.
10) Scheinmann, F.; Stachulski, A. V. J . Chem. Res., Synop. 1993,
1
13
2
Gen er a l Meth od s. H NMR, C NMR, and H NMR spectra
were recorded at 300, 75, and 46 MHz, respectively. Chemical
shifts are reported in ppm from TMS (0 ppm). Flash column
(
(
4
14-415.
(7) Okumoto, H.; J innai, T.; Shimizu, H.; Harada, Y.; Mishima, H.;
(11) Andruszkiewicz, R.; Barrett, A. G. M.; Silverman, R. B. Synth.
Suzuki, A. Synlett 2000, 629-630.
Commun. 1990, 159-166.