Novel photochemical hydrolysis of o-acetylphenylacetonitriles to amides

Article abstract of DOI:10.1021/jo952147s

Irradiation of o-acetylphenylacetonitriles 1a,b in methanol (λ >280 nm) leads to essentially quantitative photohydrolysis with formation of the corresponding ketal amides 3a,b. The mechanism proposed for this novel reaction is supported by the qualitatively different photochemical behavior of 1c and by a labeling experiment with 1a-L that confirms transfer of the carbonyl oxygen atom of 1a to the amide oxygen atom of 3a.

Full text of DOI:10.1021/jo952147s

J . Org. Chem. 1996, 61, 3729-3732
3729
Novel P h otoch em ica l Hyd r olysis of o-Acetylp h en yla ceton itr iles to
Am id es
Qingyi Lu, Pakorn Bovonsombat, and William C. Agosta*
Laboratories of The Rockefeller University, New York, New York 10021-6399
Received December 4, 1995X
Irradiation of o-acetylphenylacetonitriles 1a ,b in methanol (λ >280 nm) leads to essentially
quantitative photohydrolysis with formation of the corresponding ketal amides 3a ,b. The
mechanism proposed for this novel reaction is supported by the qualitatively different photochemical
behavior of 1c and by a labeling experiment with 1a -L that confirms transfer of the carbonyl oxygen
atom of 1a to the amide oxygen atom of 3a .
In the course of another study we had occasion to
irradiate o-acetylphenylacetonitrile (1a ) in methanol and
were surprised to isolate after chromoatographic purifi-
cation a good yield of the corresponding amide 2a . We
abstraction4 to biradical 5a , which relaxes to 6a .5 The
stereochemistry of the hydroxyl and cyano groups of 6a
permits cyclization to the corresponding iminolactone 7a ,
which then rearomatizes to 8a on 1,4 addition of metha-
nol. The aromatic iminolactone 8a can add another
molecule of methanol, probably by way of the highly
stabilized carbocation 9a formed on protonation and
heterolytic cleavage, finally furnishing the isolated ketal
amide 3a .
O
O
CN
CONH2
R R′
R R′
Several experiments support this mechanistic scheme.
As the mechanism permits, the methyl-substituted nitrile
1b behaves in an analogous fashion, furnishing ketal 3b
on irradiation and workup in the absence of acid and
ketone 2b, along with small amounts of isoquinoline 4b
and the related methyl ether 4c, in the presence of acid.
Intermediates 5b-9b readily account for this behavior.
As the mechanism also requires, neither phenylacetoni-
trile (10) nor p-acetylphenylacetonitrile (11) undergoes
hydrolysis under these conditions. Each is recovered
unchanged from the irradiation conditions.
1
2
OCH3
N
OCH3
CONH2
OR′
R
R R′
3
4
a, R = R′ = H; b, R = CH3, R′ = H; c, R = R′ = CH3
have now investigated the mechanism of this unexpected
hydrolysis and report our findings for 1a and the related
nitriles 1b,c below.1 Photochemical results are discussed
first, followed by presentation of the straightforward
synthesis of necessary compounds.
OH
R
CN
P h otoch em ica l Exp er im en ts. The first indication
of how hydrolysis of 1a occurs came with the observation
that 2a is not the direct product of the photochemical
reaction. If the reaction mixture is worked up after
irradiation without chromatography or use of acid, the
product obtained in essentially quantitative yield is
dimethyl ketal 3a . This ketal undergoes smooth hy-
drolysis to 2a on chromatography over silica gel or on
very mild treatment with acid. Further acid treatment
of 2a leads to the yellow 3-hydroxy-1-methylisoquinoline
(4a ),2 which was sometimes observed in minor amounts
on acid workup of the photochemical reaction.3
CN
10, R = H
11, R = CH3CO
12
O
OH
CN
CN
13
14
The mechanism in the scheme also implies that di-
methyl-substituted nitrile 1c cannot react as 1a ,b do. In
fact, we found that 1c behaves quite differently under
these conditions. Irradiation of 1c furnished a crude
reaction mixture whose infrared spectrum showed no sign
of amide absorption. Workup led to four isomeric pho-
tochemical products, all of which retain the nitrile
functionality. Two of these products are the two diaster-
eomeric hydroxy nitriles 12, which are formed in the ratio
83:17. The major isomer of 12 could be obtained pure
and has been fully characterized. The other two products
Isolation of 3a as the reaction product solves the initial
puzzle of how hydrolysis of a nitrile takes place in
methanol; more specifically, it suggests that conversion
of 1a into 3a follows the path shown in Scheme 1. Thus,
irradiation of 1a leads through unexceptional γ-hydrogen
X Abstract published in Advance ACS Abstracts, May 1, 1996.
(1) A preliminary communication has appeared: Lu, Q.; Bovonsom-
bat, P.; Agosta, W. C. Tetrahedron Lett. 1995, 36, 8941.
(2) This compound has been previously reported: Alpha, B.; Anklam,
E.; Deschenaux, R.; Lehn, J .-M. Helv. Chim. Acta 1988, 71, 1042. The
1H NMR spectrum of our sample of 4a was compatible with that on
record.
(3) Related cyclizations to 3-hydroxyisoquinolines have been stud-
ied: J ones, D. W. J . Chem. Soc. C 1969, 1729. For a relevant review,
see: Hazai, L. Adv. Heterocycl. Chem. 1991, 52, 155.
(4) Wagner, P. J . Pure Appl. Chem. 1977, 49, 259.
(5) Biradical 5a presumably also relaxes to geometric isomers of 6a ,
and these then revert to 1a . For information on the distribution of
enol isomers on γ-hydrogen abstraction in simple o-methylphenones,
see: Haag, R.; Wirz, J .; Wagner, P. J . Helv. Chem. Acta 1977, 60, 2595.
S0022-3263(95)02147-5 CCC: $12.00 © 1996 American Chemical Society

3730 J . Org. Chem., Vol. 61, No. 11, 1996
Lu et al.
Sch em e 1
OCH3
O
+
•
CH3OH
OCH3
OH
CN
OH
CN
O
hν
1a, b
3a, b
CH3OH
CONH2
NH
NH
•
R
H
R
H
R
R
R
5
6
7
8
9
a, R = H; b, R = CH3
confirmed in each case that this 18O atom is located at
the amide carbonyl group. These results thus fully
support the mechanistic requirement that the carbonyl
oxygen of 1a becomes the amide carbonyl oxygen of 2a
and 3a . We also measured the quantum yields for
reaction of 1a ,b using the concomitant formation of
acetophenone from γ-chlorobutyrophenone8 as an acti-
nometer and found them to be 0.1 (4.8% conversion) for
disappearance of 1a and 0.03 (1.5% conversion) for 1b.9
Sch em e 2
•
OH
•
OH
•
OH
1a
CN
•
CN
CN
15
16
17
18O
P r ep a r a tive Exp er im en ts. Cyano ketone 1a 10 was
prepared from the ethylene ketal of o-methylacetophe-
none (18a ) through benzylic bromination with N-bromo-
succinimide,11 followed by reaction with sodium cyanide12
and then deketalization of 18b. The para isomer 1113
was prepared in the same manner from p-methyl-
acetophenone. For 1b, ketal 18b was methylated using
sodium hydride and methyl iodide in dimethyl sulfoxide.14
The ketal of 1b was deketalized by treatment with
aqueous HCl in acetone. Dimethyl nitrile 1c was avail-
able through deprotonation of either 18b or the ketal of
1b with lithium diisopropylamide in tetrahydrofuran
containing hexamethylphosphoramide and treatment
with methyl iodide.15 Deketalization of the ketal of 1c
was most satisfactory using a three-phase system con-
sisting of aqueous oxalic acid, silica gel, and methylene
chloride.16 Labeled ketone 1a -L was also synthesized
from 18b through treatment with H218O in the presence
of camphorsulfonic acid in hot tetrahydrofuran.7 Mass
spectral analysis of the product 1a -L showed it to contain
55% of one atom of 18O.
O
CN
C
18O
NH2
O
1a-L
2a-L
OCH3
OCH3
O
CH2X
18
C
18O
NH2
a, X = H
b, X = CN
3a-L
are the rearranged keto nitrile 13 and the isomeric
unsaturated hydroxy nitrile 14. All of these photorear-
rangements of 1c can be accounted for by way of
abstraction of δ-hydrogen6 to yield 15. This biradical can
collapse to 12 or close to 16, as shown (Scheme 2). After
16 reopens to 17, both 13 and 14 can be formed through
appropriate 1,6 hydrogen transfers. Precedents for each
of these steps are available from earlier studies of δ
abstraction from the ortho position in aromatic ketones.6
For our present purposes, the behavior of 1c underscores
the necessity of a γ-hydrogen for hydrolysis of the nitrile.
Finally the mechanistic scheme requires that the
oxygen atom of the carbonyl group of 1a ,b becomes the
carbonyl oxygen of the product amide and that in
methanol as solvent this transfer of oxygen be clean and
complete. We investigated this prediction using 1a -L
containing 55% 18O in the carbonyl group, as indicated
by its mass spectrum. Irradiation of 1a -L under the
conditions used for 1a furnished 2a -L and 3a -L, the NMR
and mass spectra of which were examined. Earlier work
has shown that 18O-substitution induces a small upfield
shift in the carbonyl carbon signal in 13C-NMR spectra.7
This effect was apparent in 1a -L, which showed 13C-NMR
signals at δ 200.255 for the 18O-carbonyl carbon and δ
200.300 for the 16O-carbonyl carbon. The NMR spectrum
of 2a -L had two amide carbonyl signals of essentially
equal size, one at δ 171.809 and the other at δ 171.781,
and a single ketone carbonyl signal at δ 201.847. Mass
spectra of both 2a -L and 3a -L showed each to contain
53-55% of one atom of 18O; fragmentation patterns
Exp er im en ta l Section
Ma ter ia l a n d Equ ip m en t. Analytical GLC was carried
out on a HP-5890 temperature-programmable gas chromato-
graph using a capillary (30 m × 0.25 mm) column with a film
thickness of 0.25 µm. All NMR spectra were recorded at 300
MHz and are reported in ppm downfield from TMS employed
as an internal standard (δ). All spinning-disk chromato-
graphic separations were carried out on a Chromatotron
(Harrison Model-7924 T) using silica gel coated (1, 2, or 4 mm
thick) glass rotors. All reactions sensitive to moisture and air
were performed under argon. All organic solutions obtained
by workup of the reaction mixture were washed with brine
and dried over anhydrous MgSO4 prior to removal of solvent.
(8) For type II reaction of γ-chlorobutyrophenone, Φ is reported to
be 0.09: Wagner, P. J . Acc. Chem. Res. 1971, 4, 168.
(9) For a discussion of the factors that control hydrogen abstraction
and its reversion in o-alkylphenones, see: Wagner, P. J .; Chen, C-P.
J . Am. Chem. Soc. 1976, 98, 239. An additional limitation on the
efficiency of reaction of 1a ,b is the requirement that enol 6a ,b be
formed.
(10) Freerksen, R. W.; Pabst, W. E.; Raggio, M. L.; Sherman, S. A.;
Wroble, R. R.; Watt, D. S. J . Am. Chem. Soc. 1977, 99, 1536.
(11) Anzalone, L.; Hirsch, J . A. J . Org. Chem. 1985, 50, 2128.
(12) Friedman, L.; Schechter, H. J . Org. Chem. 1960, 25, 877.
(13) Kluiber, R. W. J . Org. Chem. 1966, 31, 1298.
(6) Wagner, P. J . Acc. Chem. Res. 1989, 22, 83, and references cited
therein.
(7) Risley, J . M.; DeFrees, S. A.; Van Etten, R. L. Org. Magn. Reson.
1983, 21, 28 and references cited therein.
(14) Bloomfield, J . J . J . Org. Chem. 1961, 26, 4112.
(15) MacPhee, J .-A.; Dubois, J .-E. Tetrahedron 1980, 36, 775.
(16) Huet, F.; Lechevallier, A.; Pellet, M.; Conia, J . M. Synthesis
1978, 63.

Hydrolysis of o-Acetylphenylacetonitriles to Amides
J . Org. Chem., Vol. 61, No. 11, 1996 3731
P r ep a r a tion of o-Acetylp h en yla ceton itr ile (1a ). o-
Acetylphenylacetonitrile was prepared from o-methylaceto-
phenone through the formation of the ethylene ketal, followed
by bromination with NBS, and reaction with NaCN to give
ketal 18b. The ketal 18b obtained in this way was used in
preparation of 1a -L and 1b after purification. Deketalization
of 18b with dilute HCl yielded 1a . Spectral data (1H NMR,
IR, MS) were identical with those reported:10 13C NMR (CDCl3,
75 MHz) δ 200.3, 135.3, 132.9, 130.9, 130.7, 130.6, 128.4, 118.0,
28.7, 23.1.
a signal at δ 200.300 for Cd16O. Mass spectral analysis
showed it to contain 55% of one atom of 18O.
P r ep a r a tive P h otoch em istr y. All preparative experi-
ments were carried out using a Hanovia 450-W medium-
pressure mercury arc lamp in Pyrex equipment (λ >280 nm).
Irradiations were carried out using toroidal Pyrex vessels in
degassed methanol.
A. o-Acetylp h en yla ceton itr ile (1a ). A solution (50 mL)
of 1a (120 mg, 0.75 mmol) containing H2O (20 mg, 1.1 mmol)
was irradiated for 8 h. Solvent was removed in vacuo to give
3a as a yellow oil. 1H NMR showed that 1a was converted
into 3a quantitatively. Purification by chromatography on
silica gel gave 2a as a white solid. For 3a : 1H NMR (CDCl3,
300 MHz) δ 7.56-7.52 (m, 1 H), 7.28-7.24 (m, 3 H), 6.24 (bs,
1 H), 5.82 (bs, 1 H), 3.77 (s, 2 H), 3.21 (s, 6 H), 1.53 (s, 3 H);
13C NMR (CDCl3, 75 MHz) δ 174.8, 140.7, 133.3, 132.5, 128.2,
127.9, 127.2, 102.9, 48.7, 41.8, 25.2; IR (CHCl3) 1679, 1590,
cm-1; MS m/ z 246.1119 [(M + Na)+, calcd for C12H17NO2Na
246.1106]. For 2a : mp 206-209 °C dec; 1H NMR (acetone-
d6, 300 MHz) δ 7.79 (dd, 1 H, J ) 7.5, 1.2 Hz), 7.46-7.31 (m,
3 H), 6.81 (bs, 1 H), 5.15 (bs, 1 H), 3.76 (s, 2 H), 2.55 (s, 3 H);
13C NMR (acetone-d6, 75 MHz) δ 201.8, 171.8, 139.0, 135.1,
131.8, 130.9, 128.7, 126.6, 40.0, 28.5; IR (CH3CN) 1690, 1630,
1600, cm-1; MS m/ z 177.0790 [M+, calcd for C10H11NO2-
177.0790].
P r ep a r a tion of 2-(o-Acetylp h en yl)p r op ion itr ile (1b).
To a stirred suspension of NaH (140 mg, 80% dispersion in
mineral oil) in DMSO (3 mL) was added a solution of ethylene
ketal 18b (580 mg, 2.8 mmol) and methyl iodide (513 mg, 3.6
mmol) in dry ether (3 mL). The reaction mixture was stirred
at rt for 2.25 h and then cooled in ice water. 2-Propanol (0.2
mL) was added dropwise, followed by the addition of water (5
mL). The aqueous layer was extracted three times with ether.
The combined ethereal layers were washed with dilute HCl,
water, and brine, then dried, and concentrated in vacuo. After
purification, the ketal obtained in this way was used in the
preparation of 1c described below. The crude reaction mixture
was then dissolved in acetone (7.5 mL), treated with HCl (6
N, 1.5 mL), and stirred at rt for 1.25 h. After removal of
solvent, the aqueous layer was extracted three times with
ether. The combined ethereal layer was washed with dilute
Na2CO3, water, and brine, then dried, and concentrated in
vacuo. The residue was purified by chromatography to give
1b (320 mg, 66%) as a colorless liquid: 1H NMR (CDCl3, 300
MHz) δ 7.83 (dd, 1 H, J ) 7.5, 1.5 Hz), 7.71 (dd, 1 H, J ) 7.8,
1.2 Hz), 7.58 (td, 1 H, J ) 7.5, 1.2 Hz), 7.46 (td, 1 H, J ) 7.5,
1.2 Hz), 4.96 (q, 1 H, J ) 6.9 Hz), 2.63 (s, 3 H), 1.61 (d, 3 H,
J ) 6.9 Hz); 13C NMR (CDCl3, 75 MHz) δ 200.8, 137.7, 135.1,
132.8, 130.4, 128.9, 127.9, 122.2, 29.2, 28.0, 21.6; IR (neat)
2241, 1684, 1600 cm-1; MS m/ z 174.0925 [(M + H)+, calcd for
C11H12NO 174.0919].
B. 2-(o-Acetylp h en yl)p r op ion itr ile (1b). A solution of
1b (70 mg, 0.40 mmol) and H2O (10 mg, 0.56 mmol) in
methanol (27 mL) was irradiated for 9 h. Solvent was removed
in vacuo. The residue was purified by chromatography to give
3b (43 mg, 45%), 4b (5 mg, 7%), and 4c (5 mg, 7%). For 3b:
1
mp 118-120 °C; H NMR (CDCl3, 300 MHz) δ 7.51 (dd, 1 H,
J ) 7.8, 1.8 Hz), 7.44 (dd, 1 H, J ) 7.8, 1.8 Hz), 7.32-7.20 (m,
2 H), 6.12 (bs, 1 H), 5.80 (bs, 1 H), 4.49 (q, 1 H, J ) 7.2), 3.37
(s, 3 H), 3.24 (s, 3 H), 1.61 (s, 3 H), 1.42 (d, 3 H, J ) 7.2 Hz);
13C NMR (CDCl3, 75 MHz) δ 177.2, 140.8, 139.2, 128.7, 128.5,
127.1, 126.5, 103.1, 49.5, 48.7, 40.6, 25.0, 18.5; IR (CHCl3)
1683, 1592, cm-1; MS m/z 260.1276 [(M + Na)+, calcd for
C13H19NO3Na 260.1263]. For 4b: mp 204-205 °C dec; 1H
NMR (CDCl3, 300 MHz) δ 7.87 (d, 1 H, J ) 8.4 Hz), 7.74 (d, 1
H, J ) 9.0 Hz), 7.54-7.49 (m, 1 H), 7.21-7.16 (m, 1 H), 2.95
(s, 3 H), 2.51 (s, 3 H); 13C NMR (CDCl3, 75 MHz) δ 159.4, 149.9,
140.0, 130.6, 126.3, 123.0, 122.0, 119.9, 109.8, 18.2, 10.4; IR
P r ep a r a tion of 2-(o-Acetylp h en yl)-2-m eth ylp r op ion i-
tr ile (1c). To a stirred solution of LDA (2.0 M, 1.0 mL, 2.0
mmol) in dry THF (1 mL) was added the ethylene ketal of 1b
(200 mg, 0.92 mmol) in THF (1 mL) slowly, followed by HMPA
(720 mg) at 0-2 °C. The reaction mixture was stirred at this
temperature for 0.5 h, and methyl iodide (230 mg, 3.7 mmol)
was then added. After being stirred for 0.5 h, the mixture was
allowed to warm to rt followed by pouring onto ice water. The
aqueous layer was extracted three times with ether. The
combined ethereal layer was washed with water and brine and
then dried and concentrated in vacuo. The residue was
purified by chromatography to give a mixture of ketal dimethyl
nitrile and unreacted starting material. The mixture in CH2-
Cl2 (1.0 mL) was then added at rt to a stirred suspension of
silica gel (680 mg), aqueous oxalic acid (10%, 68 mg), and CH2-
Cl2 (3.5 mL).16 The reaction was monitored by GC. After the
reaction was complete, Na2CO3 was added and the mixture
was stirred for 5 min. The mixture was filtered, and the
filtrate was concentrated in vacuo. The residue was purified
by chromatography to give 1c (76 mg, 44%) as a white solid:
(CHCl3): 1633 cm-1; MS m/ z 173.0837 [M+, calcd for C11H11
-
NO 173.0841]. For 4c (5 mg, 7%): 1H NMR (CDCl3, 300 MHz)
δ 8.03 (d, 1 H, J ) 8.4 Hz), 7.88 (d, 1 H, J ) 8.7 Hz), 7.60 (m,
1 H), 7.36 (m, 1 H), 4.08 (s, 3 H), 2.90 (s, 3 H), 2.48 (s, 3 H);
13C NMR (CDCl3, 75 MHz) δ 156.9, 154.0, 138.2, 129.2, 126.0,
123.4, 123.0, 122.9, 107.4, 53.7, 21.8, 10.0; IR (CHCl3) 1620,
1587, 1565, cm-1; MS m/z 187.0999 [M+, calcd for C12H13NO
187.0997 ].
C. 2-(o-Acetylp h en yl)-2-m eth ylp r op ion itr ile (1c).
A
solution of 1c (129 mg, 0.69 mmol) and H2O (20 mg, 1.1 mmol)
in methanol (46 mL) was irradiated for 1 h. Solvent was
removed in vacuo. The residue was purified by chromatog-
raphy to give four products, the two diasteromeric hydroxy
nitriles 12 (15 mg, 12%, ratio of two isomers is 83:17), 13 (44
mg, 34%), and 14 (25 mg, 19%). For major isomer of 12: mp
1
mp 88-89 °C; H NMR (CDCl3, 300 MHz) δ 7.48-7.39 (m, 4
1
71-73 °C; H NMR (CDCl3, 300 MHz) δ 7.40-7.22 (m, 4 H),
H), 2.70 (s, 3 H), 1.86 (s, 6 H); 13C NMR (CDCl3, 75 MHz) δ
204.7 140.8, 138.7, 130.6, 127.5, 126.0, 124.6, 36.5, 31.1, 29.5;
IR (CHCl3) 2237, 1696, 1598, cm-1; HRMS m/ z 188.1072
[(MH)+, calcd for C12H14NO 188.1075].
3.38 (d, 1 H, J ) 15.6), 3.07 (d, 1 H, J ) 15.9), 1.98 (s, 1 H),
1.74 (s, 3 H), 1.49 (s, 3 H); 13C NMR (CDCl3, 75 MHz) δ 145.0,
137.4, 129.1, 128.0, 125.2, 123.5, 123.0, 82.7, 47.6, 42.6, 25.3,
19.5; IR (CHCl3) 3442, 2238, cm-1; MS m/ z 187.0994 [M+, calcd
for C12H13NO 187.0997 ]. For 13: 1H NMR (CDCl3, 300 MHz)
δ 7.83 (d, 1 H, J ) 7.8 Hz), 7.51 (dt, 1 H, J ) 7.5, 1.5 Hz), 7.40
(t, 2 H, J ) 7.5 Hz), 3.24 (dd, 1 H, J ) 12.3, 4.8 Hz), 3.11-
3.04 (qm, 1 H, J 1 ) 6.9 Hz), 2.93 (dd, 1 H, J ) 12.3, 9.9 Hz),
2.62 (s, 3 H), 1.41 (d, 3 H, J ) 6.9 Hz); 13C NMR (CDCl3, 75
MHz) δ 201.2, 138.0, 136.6, 132.7, 132.3, 130.5, 127.5, 122.8,
38.9, 29.3, 27.6, 18.2; IR (neat) 2239, 1683, 1600, cm-1; MS
m/ z 188.1072 [(M + H)+, calcd for C12H14NO 188.1075]. For
14: 1H NMR (CDCl3, 300 MHz) δ 7.58 (dd, 1 H, J ) 7.8, 1.2
Hz), 7.43-7.26 (m, 2 H), 7.17 (d, 1 H, J ) 7.2), 5.95 (s, 1 H),
5.63 (t, 1 H, J ) 1.5 Hz), 5.09 (q, 1 H, J ) 6.3), 3.69 (d, 2 H,
J ) 1.5 Hz), 1.91 (s, 1 H), 1.51 (d, 3 H, J ) 6.3 Hz); 13C NMR
(CDCl3, 75 MHz) δ 143.9, 131.9, 131.0, 130.4, 128.2, 127.9,
P r ep a r a tion of p-Acetylp h en yla ceton itr ile (11). p-
Acetylphenylacetonitrile was prepared from p-meth-
ylacetophenone as described for 1a . Its spectral data (1H
NMR, IR) are identical with those reported:13 13C NMR (CDCl3,
75 MHz) δ 197.3, 136.7, 135.1, 129.0, 128.1, 117.2, 26.6, 23.5.
P r ep a r a t ion of [18O]-o-Acet ylp h en yla cet on it r ile (1a -
L). A mixture of ethylene ketal 18b (306 mg, 1.5 mmol), 10-
camphorsulfonic acid (34 mg, 0.15 mmol), and H218O (54 mg,
3 mmol) in dry THF (3 mL) was heated under reflux for 4 h,
following a known procedure.7 The mixture was allowed to
cool to rt and concentrated in vacuo. The residue was purified
by chromatography to give 1a -L (188 mg, 79%): 13C NMR
(CDCl3, 75 MHz) showed a signal at δ 200.255 for Cd18O and

3732 J . Org. Chem., Vol. 61, No. 11, 1996
Lu et al.
125.9, 122.6, 118.5, 66.6, 36.9, 24.5; IR (CHCl3) 3457, 2227
cm-1; MS m/ z 187.1242 [(M + NH4 - H2O)+, calcd for C12H15N2
187.1235].
Ack n ow led gm en t. This research was supported by
the National Science Foundation. NMR spectra were
determined on instruments purchased with funds from
the National Science Foundation, the National Insti-
tutes of Health, and the Keck Foundation.
D. [18O]- o-Acetylp h en yla ceton itr ile (1a -L). The pro-
cedure described for 1a was employed. 13C NMR (acetone-d6,
75 MHz) of 2a -L showed amide carbonyl signals at δ 171.809
and 171.781 and a single ketone carbonyl signal at δ 201.847.
Mass spectral analyses of 2a -L and 3a -L showed each to
contain 53-55% 18O; the fragmentation patterns indicated that
18O is located at the amide carbonyl.
Su p p or tin g In for m a tion Ava ila ble: 1H or 13C NMR
spectra for compounds 1b,c, 2a , 3a ,b, 4b,c, 12 (one diastere-
omer), 13, and 14 (10 pages). This material is contained in
libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
Qu a n tu m Yield Mea su r em en ts. All measurements were
made at λ ∼313 nm in wet methanol in a merry-go-round with
the concomitant formation of acetophenone from 4-chlorobu-
tyrophenone8 in benzene as the actinometer. Conversion was
limited to <5%. Results were Φ (for disappearance) 0.1 (1a )
and 0.03 (1b).
J O952147S