Friedel-Crafts α-aminoacylation of aromatic compounds with a chiral N- carboxy-α-amino acid anhydride (NCA); Part 2

Article abstract of DOI:10.1055/s-1999-3405

The N-carboxy-α-amino acid anhydrides (NCA) derived from L-Asp(OEt), L- Glu(OMe), L-Met, and L-Pro reacted with aromatic compounds (toluene or benzene) in the presence of AlCl₃ to afford the corresponding α-aminoalkyl aryl ketones as hydrochloride salts in moderate yields. The β- and γ-amino acid esters, which were obtained from the reaction of the aromatic compounds with L-Asp(OEt)- and L-Glu(OMe)-NCA, were hydrolyzed by hydrochloric acid to the corresponding β- and γ-amino acids as hydrochloride salts. L-Phe-NCA did not react with benzene in the presence of AlCl₃, instead an intramolecular acylation occurred to afford (S)-2-aminoin-danone hydrochloride. The chiralities of the original L-α-amino acids were most retained during these α-aminoacylation.

Full text of DOI:10.1055/s-1999-3405

PAPER
423
FriedelÐCrafts a-Aminoacylation of Aromatic Compounds with a Chiral
N-Carboxy-a-amino Acid Anhydride (NCA); Part 21
Osamu Itoh,* Akira Amano
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Sakyouku Kyoto 606-8501, Japan
Fax+81(75)7535697
Received 17 April 1998; revised 11 September 1998
Abstract: The N-carboxy-a-amino acid anhydrides (NCA) derived
from L-Asp(OEt), L-Glu(OMe), L-Met, and L-Pro reacted with ar-
omatic compounds (toluene or benzene) in the presence of AlCl3 to
afford the corresponding a-aminoalkyl aryl ketones as hydrochloride
salts in moderate yields. The b- and g-amino acid esters, which were
obtained from the reaction of the aromatic compounds with L-
Asp(OEt)- and L-Glu(OMe)-NCA, were hydrolyzed by hydrochloric
Scheme 2
acid to the corresponding b- and g-amino acids as hydrochloride
However, the reaction of a-AA NCAs with benzene did
salts. L-Phe-NCA did not react with benzene in the presence of AlCl3,
not give the corresponding a-aminoalkyl aryl ketones, but
instead resulted in two or three products in small yields
depending on the NCAs. On the other hand, toluene and
the other alkylbenzenes easily reacted with the a-AA
NCAs to form a-aminoalkyl aryl ketones. The reason why
both the reactions showed a different reactivity under the
same FriedelÐCrafts conditions, could not be explained
clearly. It might be related to (a) the stability of the NCAs
under the FriedelÐCrafts reaction condition, and (b) the
reactivity of the aromatic compounds with the acylating
species.
instead an intramolecular acylation occurred to afford (S)-2-aminoin-
danone hydrochloride. The chiralities of the original L-a-amino acids
were most retained during these a-aminoacylation.
Key words: FriedelÐCrafts acylation, a-aminoacylation, N-carb-
oxy-a-amino acid anhydride (NCA), a-aminoalkyl aryl ketone, op-
tically active b- and g-amino acids
In FriedelÐCrafts type a-aminoacylation with aromatic
compounds, N-protected amino acid chlorides were gen-
erally used to afford N-protected a-amino ketones.2 How-
ever, the deprotection of these N-protected a-aminoalkyl
aryl ketones is sometimes accompanied by considerable
racemization. Other methods to obtain N-unprotected
a-aminoalkyl aryl ketones were not found in the litera-
ture, except the one using N-carboxy-a-amino acid anhy-
dride (a-AA NCA).
We report here the use of N-carboxy anhydrides of a-ami-
no acids other than those of the A-group in the a-amino-
acylation of benzene. The NCAs derived from L-Met, L-
Asp(OEt), and L-Glu(OMe) (designated as the B-group)
reacted with benzene in the presence of AlCl3 to afford the
corresponding a-aminoalkyl phenyl ketones. This might
be because these NCAs are stable under the reaction con-
ditions.
The reaction of glycine N-carboxy-a-amino acetic acid
anhydride (Gly-NCA) with benzene in the presence of
AlCl3 was first reported in 1951.3 However, a-phenyl-
alanine NCA was found to undergo intramolecular a-ami-
noacylation in the presence of AlCl3 to form 2-
aminoindanone (Scheme 1).3
The NCAs were mainly prepared by the reaction of a-AAs
with phosgene4 or triphosgene (Scheme 3).5 The reaction of
L-N-methoxycarbonyl-a-amino acids with PBr3 also af-
forded the corresponding NCAs 2 and 46 (Scheme 3).
Scheme 1
We have reported earlier that the N-carboxy-a-amino acid
anhydrides (a-AA NCA) derived from L-Ala, L-Val, L-
Ile, L-Leu, and L-Phe (designated as the A-group) only re-
acted with alkylbenzenes in the presence of AlCl3 to af-
ford chiral a-aminoalkyl aryl ketones as free bases
without loss of chirality (Scheme 2).1
Scheme 3
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424
O. Itoh, A. Amano
PAPER
The L-Pro-NCA (5) was prepared in high yield by the re- ee values of the recrystallized 12-B-acid and 12-T-acid
1
ported method (Scheme 4).7
were estimated to be 98 and 84 %, respectively, by H
NMR analysis of their MTPA-amides.
The crude products 12-B and 12-T obtained from another
experiment were treated with MTPA-Cl and Et3N to af-
ford the respective MTPA-amides and analyzed by their
1H NMR spectra. The singlets due to CH3O-group of the
(R)-isomer at d = 3.48 in 12-B and 3.49 in 12-T were
found in less than 2 and 4% intensity, respectively. Ac-
cordingly, the ee values of the crude 12-B and 12-T were
estimated to be 96 and 92 %, respectively.
Scheme 4
NCA 3 reacted with benzene and toluene to give 13-B and
13-T (Scheme 5). The crude products 13-B and 13-T were
converted to the corresponding MTPA-amides by react-
ing with MTPA-Cl and Et3N and their ee values were de-
termined to be 88 and 94%, respectively.
The NCAs obtained (Schemes 3 and 4) are soluble in
CH2Cl2, and the small amount of insoluble material
formed can be separated out. The [a]D values of the NCAs
obtained by this simple purification were measured and
they were directly used in the next reaction.
The crude 13-B and 13-T were purified by crystallization
from a small amount of EtOH and the pure compounds
obtained in 9 and 27% yields had ee values of 93 and 98%,
respectively. The elemental analyses of 13-B was not co-
incident with the calculated values, however it gave a rea-
sonable HRMS analysis (see experimental).
NCA 1 reacted with benzene to afford 11-B (Scheme 5)
(the products are numbered in two digits with the alphabet
B denoting that the product is derived from benzene and
T, toluene), which was treated without purification with
a-methoxy-a-(trifluoromethyl)phenylacetyl
(MTPA-Cl) and Et3N to afford the MTPA-amide of 11-B.
The ee value of the MTPA-amide obtained from crude 11-
chloride
NCA 5 reacted with toluene to afford 15-T (Scheme 7),
and the ee value of this crude product could be determined
by the 1H NMR analysis of the MTPA-amide of 15-T. The
ee value of crude 15-T was estimated to be 96%, and the
[a]D25 value of the crude product was Ð106.39(c = 1.084,
H2O). The yield and [a]D22 of the recrystallized product
were 44% and Ð123.08(c = 1.096, H2O), respectively.
1
B was estimated to be 90.6% by H NMR analysis. The
crude 11-B was recrystallized from EtOH. The ee value of
the MTPA-amide from the recrystallized 11-B was found
to be 94% by 1H NMR analysis.
Scheme 7
Scheme 5
Furthermore, NCA 5 can probably react with benzene
NCA 2 reacted with benzene and toluene to afford 12-B and (Scheme 7). A FriedelÐCrafts reaction of L-proline acid
12-T, but neither of these products would crystallize. The chloride with benzene has already been reported,8 but the
crude products 12-B and 12-T were then hydrolized with [a]D of the product was not given. This reaction might be
aqueous 2 M hydrochloric acid at 50¡C to afford (S)-4-ami- a special case of an a-aminoacylation without racemiza-
no-4-phenylbutyric acid (12-B-acid, 23%) and (S)-4-ami- tion.
no-4-tolylbutyric acid (12-T-acid, 33%) (Scheme 6). The
The reaction of 4 with benzene in the presence of AlCl3
did not give (S)-2-amino-3-phenylpropiophenone hydro-
chloride (14-B). The major product was a brown solid that
was not soluble in any solvents, and its IR spectrum re-
vealed little information. However, a small amount of
white solid was obtained from the aqueous layer.
NCA 4 reacted with AlCl3 in CH2Cl2 without benzene to
afford the same compound as the above white solid isolat-
ed from the aqueous layer in a 25% yield . The white solid
was recrystallized from EtOH and was identified as (S)-2-
aminoindanone hydrochloride (14) by elemental analyses
and spectral data (Scheme 8). Although this reaction had
Scheme 6
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FriedelÐCrafts a-Aminoacylation of Aromatic Compounds
425
been reported earlier,3 use of optically active L-Phe-NCA ride with benzene in the presence of AlCl3 ([a]D25 +133.70
is reported here for the first time.
(c = 0.54, CHCl3), ee 98%.2b
The crude product 14 obtained by our method was treated
with ClCO2Me to afford N-methoxycarbonyl-(S)-2-ami-
noindanone (Scheme 8) ([a]D29 +133.80 (c = 1.012,
CHCl3)). The optical rotation of the N-CO2Me-compound
obtained from the recrystallized 14 was [a]D28 +133.80(c =
1.017, CHCl3)
A comparison of this value with that given above in the
literature2b showed both [a]Ds to be almost the same. The
ee values of both the crude and recrystallized product
were found to be the same (98%).
In all of the a-aminoacylation reactions shown in this ar-
ticle, the chiralities of the original L-a-amino acids were
considerably retained.
1
The important H NMR spectra of the MTPA-amides of
11-B, 12-B,12-T, 13-B, 13-T, 15-T are given in Table 2.
The ee values could be estimated from the integration of
the signals due to the methoxy hydrogens of the (S)- and
(R)-isomers.
Scheme 8
The reaction of dl-Pro-NCA with toluene was achieved
and the obtained crude dl-15-T was treated with MTPA-
Cl and Et3N to afford the MTPA-amide of dl-15-T. Two
singlets due to methoxy hydrogens were clearly identified
(ee 91.2%).
The analogous compound, N-methoxycarbonyl-(S)-2-a-
aminoindanone (Scheme 8) was synthesized by the reac-
tion of N-methoxycarbonyl-L-phenylalanine acid chlo-
Table 1 a-Aminoalkyl Aryl Ketones 11Ð15 Prepared
Sub-
strate
NCA
Product
Yield
(%)
Optical Rotation
[α]D Temp (¡C)
ee (%)a 1H NMR (D2O/PTS)
d, J (Hz)
(c, H2O)
1
1
11-Bb
11-Bc
43
30
Ð6.07
19
19
1.020
1.067
94
Ð
Ð5.56
+20.52
+23.62
Ð9.98
90.6
1.20 (t, 3 H, J = 7.0), 4.13 (q, 2 H, J = 7.0), 3.17 (d,
2 H, J= 5), 5.46 (t, 1 H, J = 6)d
2
2
3
3
12-B-acid
12-T-acid
13-B
23
33
9
30
31
Ð
1.072
1.091
1.044
1.077
98
84
93
98
2.1Ð2.7 (m, 4 H), 5.28 (t, 1 H, J = 6.0), 7.6Ð7.7 (m, 2
H), 7.75Ð7.85 (m, 1 H), 8.0Ð8.1 (m, 2 H)e
2.1Ð2.9 (m, 4 H), 2.49 (s, 3 H), 5.30 (t, 1 H, J = 6.0),
7.48 (d, 2 H, J = 8), 7.98 (d, 2 H, J = 8)
2.01 (s, 3 H), 2.1Ð2.4 (m, 2 H), 2.5Ð2.8 (m, 2 H),
5.3Ð5.4 (m, 1 H), 7.6Ð8.1 (m, 5 H)
13-T
27
Ð11.85
24
2.18 (s, 3 H), 2.20Ð2.45 (m, 2 H), 2.51 (s, 3 H), 2.65Ð
2.85 (m, 2 H), 5.43 (dd, 1 H, J = 4.4, 7.7), 7.50 (d, 2
H, J = 8), 8.02 (d, 2 H, J = 8)f
5
15-T
14
44
25
Ð123.08
+23.90
22
27
1.096
0.997
91.2
98
1.63Ð3.03 (m, 4 H), 2.47 (s, 3 H), 3.56 (t, 2 H, J = 7),
5.45 (t, 1 H, J = 6), 7.36 (d, 2 H, J = 8), 7.86 (d, 2 H,
J = 8)g
4
3.37 (dd, 1 H, J = 5.5, 8.1), 3.69 (dd, 1 H, J = 8.1,
16.8), 4.20 (dd, 1 H, J = 5.5, 8.1), 7.4Ð8.0 (m, 4 H)h
a
e
f
Enantiomeric excess was determined by 1H NMR analyses of the
MTPA-amides of the products for 11Ð13 and 15. For 14, the ee
value was determined from the [α]D value (Ð133.80) of its N-
methoxycarbonyl-2-aminoindanone (see Ref. 2b).
Method B. L-Asp(OMe)-NCA (1') was used.
13C NMR: d = 28.6 (t), 31.7 (t), 57.5 (d), 131.6, 132.0, 135.5,
138.2, 178.6, 200.0.
13C NMR: d = 16.7 (q), 23.7 (q), 31.3 (t), 32.9 (t), 57.4 (d), 131.7,
132.7, 132.8, 149.9, 199.5.
b
c
d
g
h
13C NMR: d = 21.8 (q), 24.2 (t), 30.4 (t), 46.5 (t), 62.9 (d), 129.5,
129.7, 129.9, 146.5, 193.5.
Method A. L-Asp(OEt)-NCA (1') was used.
13C NMR: d = 14.2 (q), 40.0, 61.0 (t), 52.7 (d), 128.5, 128.9,
133.5, 134.8, 171.3, 198.7.
13C NMR: d = 33.5, 56.4, 126.9, 129.5, 131.1, 135.6, 149.9,
154.3, 204.5.
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426
O. Itoh, A. Amano
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1
Table 2 ee Values and H NMR Spectra of MTPA-amides of a-
evaporated from the homogeneous solution to give N-chlorocarbo-
nyl-L-proline (N-COCl-L-Pro ) as an yellow oil. To a solution of N-
COCl-L-Pro (35.7 g, 150 mmol) in acetone (400 mL), were added
Ag2O (20.4 g, 88 mmol) and Norit A (4.5 g) and the mixture was
stirred for 1 d at r.t. The mixture was filtered from the black Norit
A and the THF was evaporated to afford 5; yield: 21.1 g (ca 100%);
mp 44.2Ð48.0¡C; [a]D25 Ð99.66 (c = 1.002, CHCl3); [a]D25 Ð101.23 (c
= 1.019, CH2Cl2).
1H NMR (270 MHz, CDCl3): d = 1.96 (1 H, m), 2.15 (1 H, m), 2.23
(1 H, m), 2.34 (1 H, m), 3.34 (1 H, m), 3.78 (1 H, m), 4.36 (1 H, dd,
J = 7.7, 9.2 Hz).
Aminoalkyl Aryl Ketones
Aryl
Ketones
ee (%)a ee (%)b 1H NMR (CDCl3), d
(crude) (recrys- CH3OÐCÐCF3
tallized)
11-B
Ð
94
Ð
98
Ð
84
Ð
93
Ð
3.33 (s)-97 % (S), 3.37 (s)-3% (R)
11-B
12-B-acid
12-B
12-T-acid
12-T
13-B
90.6
Ð
96
Ð
92
Ð
Ð
Ð
3.37 (s)-98% (S), 3.48 (s)-2% (R)
Ð
13C NMR (CDCl3): d = 26.9, 27.6, 46.6, 63.1, 154.9, 168.9.
3.37 (s)-92% (S), 3.49 (s)-4% (R)b
Ð
Ethyl (S)-3-Benzoyl-3-aminopropionateáHydrochloride (11-B)
Method A: To a cooled mixture of 1 (4.50 g, 24.0 mmol) in benzene
(11.5 mL, 128 mmol) was added AlCl3 (9.80 g, 73 mmol) portion-
wise over a period of 25 min with vigorous stirring. The mixture
was kept stirring at r.t. for 5 h, and then poured onto ice (70 g). To
the filtrate was added powdered NaHCO3 (22.0 g, 260 mmol) and
filtered. The filtrate was concentrated in vacuo and then extracted
with CHCl3 (3 – 40 mL). Removal of CHCl3 gave a yellow solid
(3.56 g) which was washed with Et2O (100 mL) to afford 11-B as a
white solid; yield: 2.99 g (48%); [a]D18 Ð5.19 (c = 1.010, H2O). A
portion of 11-B (303 mg) was treated with MTPA-Cl (310 mg) in
the presence of Et3N (220 mg). The corresponding MTPA-amide
was obtained in good yield and analyzed by 1H NMR spectroscopy;
ee 90.6 %.
13-B
13-T
88
Ð
3.38 (s)-94% (S), 3.40 (s)-6% (R)
Ð
98
Ð
13-T
15-T
94
91.2
3.38 (s)-97% (S), 3.48 (s)-3% (R)
3.70 (s)-95.6% (S), 3.95 (s)-4.4%
(R)
Ð
a
1
ee values were estimated by H NMR analyses of the product
MTPA-amides.
1H NMR: d = 1.81Ð1.91 (m, 1 H), 2.35Ð2.54 (m, 3 H), 2.42 (s, 3
H), 3.68 (s, 3 H), 5.69 (m, 1 H), 7.2Ð8.0 (m, 9 H).
b
L-Asp(OEt)¥HCl was prepared by the reported method9 in 46%
yield; [a]D25 +13.11 (c = 1.108, H2O). L-PheNCA (4) was synthe-
sized according to Ref. 1 (Scheme 3). L-Glu(OMe)¥HCl was pur-
chased from Aldrich.
The residual 11-B (2.32 g) was purified by recrystallization from
EtOH (3 mL) to afford a white solid; mp 129.8Ð131.4¡C; yield:
30%; [a]D19 Ð5.56 (c = 1.067, H2O).
(S)-4-Ethoxycarbonylmethyloxazolidin-2,5-dione [L-Asp(OEt)-
NCA, 1] and L-Asp(OMe)-NCA (1') were prepared according to
the reported method10 in 45% yield; [a]D26 Ð61.46 (c = 1.09, CHCl3).
1H NMR (270 MHz, CDCl3): d = 1.26 (3 H, t, J = 8 Hz), 2.97 (2 H,
d, J = 5 Hz), 4.17 (2 H, q, J = 8), 4.63 (1 H, t, J = 5), 7.24 (1 H, br s).
IR (neat): n = 3400 (br), 2800 (br), 1730, 1695, 1515, 1250, 1240,
1190, 1180, 760, 690 cmÐ1.
Anal. calcd for C12H16ClNO3: C, 55.93; H, 6.26; N, 5.43; Cl, 13.76.
Found: C, 55.83; H, 6.34; N, 5.37; Cl, 13.35.
Method B: The reaction of 1' (11.3 g, 60.4 mmol) with benzene
(23.6 g, 302 mmol) in the presence of AlCl3 (24.2 g, 181 mmol) was
carried out in order to prove the reproducibility. The reaction time
was prolonged to 8 h in order to improve the yield. By the similar
workup as given in method A above, a yellowish solid (9.20 g) was
obtained as the crude product (59%). This solid (9.10 g) was recrys-
tallized from EtOH (15 mL). The first crop amounted to 5.237 g;
[a]D Ð6.07 and the second 1.542 g; [a]D Ð5.67; total yield: 43%.
(S)-4-(2-Methoxycarbonylethyl)oxazolidine-2,5-dione (2)
Method A: To a suspension of L-Glu(OMe)¥HCl (24.3 g,
150 mmol) in THF (600 mL), was bubbled gaseous phosgene over
a period of 8 h at 40¡C. THF was then evaporated in vacuo at 40¡C.
The residue was dissolved in CH2Cl2 (100 mL) and an insoluble
solid was filtered. Removal of solvent gave a solid in 60% yield;
[a]D30 Ð24.86 (c = 1.034, DMSO) and used in the next reaction.
Method B: The reaction of N-methoxycarbonyl-L-Glu (OMe) with
(COCl)2 and a few drops of DMF at 50¡C gave L-Glu(OMe)-NCA
(2) in 70% yield; [a]D21 Ð25.24 (c = 1.07 , CHCl3) and [a]D20 Ð25.8 (c
= 1.0 , CH2Cl2).
A part of the first crop was treated with MTPA-Cl to afford the
1
MTPA-amide. By H NMR (270 MHz, CDCl3) analysis of the
MTPA-amide; ee 94%.
1H NMR (CDCl3): d = 1.66Ð2.33 (2 H, m), 2.33Ð2.80 (2 H, m), 3.63
(3 H, s), 4.36 (1 H, t, J = 6), 8.86 (1 H, br s).
11-B-acid
Acidic hydrolysis of 11-B with aq 2 N HCl often led to the forma-
tion of racemic 11-B acid. Care must be taken during this treatment
to avoid racemization. One of the hydrolysis experiment with 11-B
resulted in the formation of a solid in 9% yield, which was proved
L-Met-NCA (3)
To a cooled mixture of N-methoxycarbonyl-L-methionine (25.0 g,
120 mmol) and Et2O (45 mL) was added slowly a solution of PBr3
(13.3 g, 49.1 mmol) in Et2O (15 mL). The mixture was kept stirring
at r.t. for 2 h, and then poured onto hexane (180 mL). To the lower
layer separated from the mixture was added THF (100 mL). The
precipitated solid was filtered, and the THF was evaporated. L-Met-
NCA was obtained as a heavy yellow liquid; yield: 22.0 g (~100%);
[a]D29 Ð9.54 (c = 1.046, THF).
1
to be 11-B-acid by H NMR (270 MHz, D2O-PTS as a standard);
[a]D19 Ð10.20(c = 1.020, H2O) (see next section for the acidic hydrol-
ysis procedure). The ee value of 11-B-acid was not determined.
IR (neat): n = 3400, 1700, 1695, 760, 690 cmÐ1.
Anal. calcd for C10H12ClNO3: C, 52.26; H, 5.27; N, 6.10; Cl, 15.44.
Found C, 51.93; H, 5.24; N, 5.99; Cl, 14.96.
1H NMR (270 MHz, CDCl3): d = 1.9Ð2.4 (2 H, m), 2.1 (3 H, s), 2.5Ð
2.9 (2 H, m) 4.5 (1 H, t, J = 7 Hz), 7.0 (1 H, br s).
(S)-4-Benzoyl-4-aminobutyric Acid Hydrochloride (12-B-Acid
HCl)
To a cooled mixture of 2 (11.23 g, 60.0 mmol) and benzene
(23.6 g), was added portionwise AlCl3 (24.2 g, 181 mmol) over a
period of 50 min with vigorous stirring. The mixture was kept stir-
L-Pro-NCA (5)
To a mixture of L-Pro (17.25 g, 150 mmol) and THF (400 mL) was
bubbled gaseous phosgene over a period of 4 h at ca 30¡C. THF was
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FriedelÐCrafts a-Aminoacylation of Aromatic Compounds
427
ring at r.t. for 10 h, and then poured onto ice (150 g) and concd HCl
(5 mL). The mixture was washed with Et2O (3 × 50 mL). The aque-
ous layer was concentrated as much as possible on a rotary evapo-
rater and the residue was extracted with CHCl3 (3 × 30 mL). The
CHCl3 solution was dried (Na2SO4) and evaporated. The residue
was dissolved in Et2O (30 mL) and H2O (30 mL), and then neutral-
ized with an aq solution of 1 N Na2CO3 (30 mL) until the aqueous
layer reached pH 8. The mixture was extracted with Et2O (2 × 30
mL) and the extract was treated with a satd solution of gaseous HCl
in EtOH (50 mL). The solvent was evaporated to afford a red-brown
liquid (10.42 g) which did not crystallize. The above red-brown liq-
uid of 12-B (10.26 g) was treated with aq 2 N HCl (70 mL) at 50Ð
60¡C for 2 h, and the H2O was evaporated. Recrystallization of the
residue from hot water (20 mL) gave 12-B-acid in two crops; first
crop, 2.80 g; [a]D30 + 20.52 (c = 1.070, H2O); mp 200.9Ð202.2¡C;
and second crop, 0.66 g; [a]D30 + 19.72 (c = 1.029, H2O); total yield:
3.46 g (23% based on 2).
12-T:
1H NMR (270 MHz, CDCl3): d = 2.36 (m, 3 H), 2.40 (s, 3 H), 2.52
(m,1 H), 3.63 (s, 3 H), 5.51 (br d, 1 H), 7.19 (d, 2 H, J = 8 Hz), 7.89
(d, 2 H, J = 8 Hz), 8.8 (br s, 3 H).
HRMS (crude 12-T): m/z calcd for C13H18NO3: 236.1287, found
236.1286.
(S)-1-Benzoyl-3-methylthiopropylamine Hydrochloride (13-
B¥HCl)
To a cooled mixture of AlCl3 (29.8 g, 223 mmol) and benzene
(39.0 g, 499 mmol) was added portionwise 3 (17.6 g, 100 mmol)
over a period of 1 h. The mixture was kept stirring at 40¡C for 4 h,
and then poured onto ice (100 g). The aqueous layer was washed
with Et2O and then concentrated as much as possible on a rotary
evaporator. To the residue was added CHCl3 (30 mL) and the ex-
traction with CHCl3 was repeated (5 × 30 mL). The solvent was
evaporated to afford the crude product; yield: 6.21 g (25.3 mmol);
[a]D30 Ð7.43 (c = 1.078, H2O). A part of the crude product (3.46 g)
was recrystallized from EtOH (2.5 mL). The solid obtained was
washed with acetone (15 mL); yield: 1.16 g (9%); [a]D28 Ð9.98 (c =
1.044, H2O); mp 184.0Ð185.5¡C.
Anal. calcd for C11H14ClNO3: C, 54.22; H, 5.79; N, 5.75; Cl, 14.55.
Found C, 54.26; H, 5.99; N, 5.75; Cl, 14.32.
A part of the second crop was treated with MTPA-Cl and Et3N to
afford MTPA-amide of 12-B-acid; ee 98% (1H NMR, 270 MHz,
CDCl3).
IR (KBr): n = 3440, 1680, 1600 cmÐ1.
Anal. calcd for C11H16ClNOS: C, 53.76; H,6.56; N, 5.70; S, 13.05;
Cl, 14.43. Found C, 53.02; H, 6.61; N, 5.62; S,13.01; Cl, 14.18.
12-B and MTPA-Amide of the Crude 12-B
Another a-aminoacylation of benzene with 2 was carried out in a
1.0 mmol scale. A part of the crude product 12-B (170 mg) was
treated with MTPA-Cl before the acidic hydrolysis to afford the
corresponding MTPA-amide; ee 96% (1H NMR, 270 MHz, CDCl3).
HRMS: m/z calcd for C11H16ONS 210.0953, found 210.0954.
A part of the recrystallized 13-B (131 mg, 0.53 mmol) was treated
with MTPA-Cl (138 mg) and Et3N (119 mg) in CCl4 to afford
MTPA-amide of 13-B; ee 93% (1H NMR, 270 MHz, CDCl3).
12-B:
The crude 13-B obtained from the experiment in a 1.0 mmol scale
(257 mg) was treated with MTPA-Cl (263 mg) and Et3N (206 mg)
to afford the corresponding MTPA-amide. By its 1H NMR analysis,
the ee value was estimated to be 88%.
IR (neat): n = 3350 (br), 2980, 1725, 1690, 1230 (br), 680 cmÐ1.
1H NMR (270 MHz, CDCl3): d = 2.32 (m,1 H), 2.47 (m,1 H), 2.62
(m,1 H), 2.97 (m,1 H), 3.56 (s, 3 H), 5.60 (d,1 H), 7.39 (t, 2 H, J =
8 Hz), 7.55 (t, 1 H, J = 8 Hz), 8.00 (d, 2H, J = 8 Hz), 8.9 (br s, 3 H).
(S)-1-p-Toluoyl-3-methylthiopropylamine Hydrochloride (13-T)
To a cooled mixture of AlCl3 (17.9 g, 134 mmol) and toluene
(20.4 g, 220 mmol) was added portionwise 3 (7.77 g, 44.3 mmol)
with vigorous stirring over a period of 30 min. The temperature of
the mixture was raised to 50¡C and then came quickly down to r.t.
It was kept stirring for 4 h at r.t., and then poured onto ice-water
(200 g). The aqueous layer was concentrated as much as possible on
an evaporator. The residue was dissolved in CHCl3 (30 mL) and
dried (Na2SO4). The solvent was evaporated, and the yellow solid
HRMS of the crude 12-B: m/z calcd for C12H16NO3: 222.1130,
found 222.1134.
(S)-4-p-Toluoyl-4-aminobutyric Acid (12-T-acid)
To a cooled mixture of 2 (3.90 g, 20.8 mmol) and toluene (9.30 g,
101 mmol) was added portionwise AlCl3 (8.0 g, 60 mmol) over a
period of 15 min. The mixture was stirred for 4 h at r.t. and worked
up in the usual manner described above for 11-B; yield: 3.016 g
(37%); [a]D28 + 24.62(c = 1.063, H2O). The solid (2.916 g) was treat-
ed with aq 2 N HCl (30 mL) at 60Ð70¡C for 1 h, and the H2O was
evaporated. The greenish white solid residue (2.60 g, 10.1 mmol,
49%) was recrystallized from a mixture of acetone (20 mL) and
H2O (5 mL); first crop, 1.32 g (5.13 mmol, 25%); [a]D31 + 23.62 (c
= 1.091, H2O); mp 206.4Ð207.5¡C); second crop, 0.320 g
(1.25 mmol); third crop, 0.122 g (0.47 mmol); total yield: 33%
(6.85 mmol).
1
(4.99 g) obtained was characterized as 13-T by its H NMR spec-
trum. Recrystallization from EtOH gave 13-T in 27% yield; mp
192.4Ð193.2¡C; [a]D24 Ð11.85 (c = 1.007, H2O); ee 98% (1H NMR)
IR (KBr): n = 3430, 1680, 1600 cmÐ1.
Anal. calcd for C12H18ClNOS: C, 55.48; H, 6.98; N, 5.39; S, 12.34;
Cl, 13.65. Found: C, 55.39; H, 6.87; N, 5.34; S, 12.24; Cl, 13.53.
IR (neat): n = 3430, 3000, 1700, 1680 cmÐ1.
MTPA-Amide of the Crude 13-T
The crude 13-T obtained from the reaction of 3 with toluene in the
presence of AlCl3 in 1.0 mmol scale (176 mg) was treated with
MTPA-Cl (172 mg) and Et3N (136 mg) to afford the MTPA-amide
of the crude 13-T; ee: 94% (1H NMR).
Anal. calcd for C12H16ClNO3: C, 55.93; H, 6.26; N, 5.43; Cl, 13.76.
Found: C, 55.76; H, 6.30; N, 5.42; Cl, 13.58.
A part of the recrystallized product 12-T-acid (138 mg) was treated
with MTPA-Cl (157 mg) in the presence of Et3N (101 mg); ee 84%
(1H NMR, 270 MHz,CDCl3).
(S) 2-p-Toluoylpyrrolidine Hydrochloride [(S)-15-T]
To a cooled mixture of 5 (2.97 g, 20 mmol) and toluene (50 mL)
was added portionwise AlCl3 (6.20 g, 47.0 mmol) over a period of
1 h by keeping the temperature less than 3¡C. The mixture was kept
stirring at 2¡C for 2 h and poured onto ice (100 g) and concd HCl
(10 mL). The water layer was separated and concentrated. The res-
idue was extracted with CH2Cl2 (8 × 30 mL). The solvent was evap-
orated and the residue (3.80 g) was recrystallized from EtOH/Et2O
12-T and MTPA-Amide of the Crude 12-T
The crude product 12-T from the a-aminoacylation of toluene with
2 in a 1.0 mmol scale (178 mg) before acidic hydrolysis was treated
with MTPA-Cl (172 mg) and Et3N (136 mg) to afford the corre-
sponding MTPA-amide; ee 92% (1H NMR).
Synthesis 1999, No. 3, 423Ð428 ISSN 0039-7881 © Thieme Stuttgart · New York

428
O. Itoh, A. Amano
PAPER
to give yellow crystals; yield: 1.98 g (44%); [a]D22 Ð123.08 (c =
was filtered which was not analysed further. The aqueous layer was
separated and concentrated on a rotary evaporator. A white solid
[1.466 g, [a]D26 +23.82 (c = 1.003, H2O)] was filtered from the con-
centrated solution. Recrystallization of the white solid (500 mg)
from a small volume of EtOH afforded 14; yield: 219 mg (25%);
mp 220Ð221¡C; [a]D27 +23.90 (c = 0.997, H2O). Both [a]D values of
the crude and recrystallized 14 were almost identical.
1.096, H2O).
IR (KBr): n = 3440 (br), 3040,1680, 1600, 1250, 1180.
Anal. calcd for C12H16ClNO: C, 63.86; H, 7.14; N,6.21; Cl, 15.71.
Found: C, 63.76; H, 7.21; N, 5.98; Cl, 15.49.
MTPA-Amide of the Crude (S)-15-T
IR (KBr): n = 3550, 3500, 1725, 1610 cmÐ1.
Compound 5 (10 mmol) was reacted with toluene in the presence of
AlCl3 and the crude product (S) 15-T was obtained by solvent ex-
traction from the aqueous reaction mixture as described above
(1.70 g, [a]D25 Ð106.39). A part of the crude product (225 mg,
1 mmol) was treated with MTPA-Cl (252 mg) and Et3N (200 mg)
in CCl4 (10 mL); ee 91.2% (1H NMR).
Anal. calcd for C9H10ClNO: C, 58.87; H, 5.49; N,7.63; Cl, 19.31.
Found: C, 58.88; H, 5.37; N, 7.54; Cl, 19.26.
This recrystallized 14 was treated with ClCO2Me to afford N-
CO2Me-14 ([a]D28 +133.80 (c = 1.043, CHCl3)] and the [a]D value
was almost the same as the literature value, [a]D25 + 133.70 (c = 0.54,
CHCl3).2b Accordingly, both ee values of the recrystallized 14 and
the crude 14 were determined to be 98%.
HRMS of the MTPA-amide of the crude (S)-15-T: m/z calcd for
C22H22F3O3: 406.1630, found 406.1638 .
(dl)-2p-Toluoylpyrrolidine Hydrochloride [(dl)-15-T] and its
MTPA-Amide
References
dl-Proline-NCA was synthesized as an oily liquid and seemed to be
more unstable than L-Pro-NCA. The reaction of dl-Pro-NCA with
toluene in the presence of AlCl3 gave (dl)-15-T.
(1) Part 1: Itoh O.; Honnami, T.; Amano A.; Murata K.; Koichi
Y.; Sugita T. J. Org. Chem. 1992, 57, 7334.
(2) (a) Buckley T.F.; Rapoport H. J. Am. Chem. Soc. 1981, 103,
6157.
HRMS (crude product): m/z calcd for C12H16NO: 190.1232, found
190.1231.
(b) McClure D.E.; Arison B.H.; Jones J.H.; Baldwin J.J.
J.Org. Chem. 1985, 46, 2431.
(c) Nordlander J.E.; Njoroge, F.G.; Payne M.J.; Warman D.
The MTPA-amide of (dl)-15T was synthesized in the usual manner
from (dl)-15-T, MTPA-Cl and Et3N.
J. Org. Chem. 1985, 50, 3481.
(3) Statham F. S. J. Chem. Soc. 1951, 213.
HRMS: m/z calcd for C22H22F3NO3: 406.1632, found 406.1631.
(4) Leuchs H. Ber. Dtsch. Chem. Ges. 1906, 39, 857.
(5) Daly W.H.; Poche D. Tetrahedron Lett. 1988, 29, 5859.
(6) Ishai D.B.; Katchalski E. J. Am. Chem. Soc. 1952, 74, 3688.
(7) Kawasaki T.; Komai T. Polymer Journal (Tokyo) 1983, 743.
(8) Ookawa A.; Soai K. J. Chem. Soc., Perkin Trans. 1 1987,
1465.
1
In the H NMR spectrum of (dl)-15-T MTPA-amide, two singlets
due to methoxy hydrogens of (S) and (R)-15-T were clearly identi-
fied at 3.70 (S) and 3.95 (R), and thus the ee value of (S)-15-T was
estimated to be 91.2%.
2-Aminoindanone Hydrochloride (14)
(9) Goodman M.; Boardman F. J. Am. Chem. Soc. 1963, 85, 2483.
(10) Coleman D. J. Chem. Soc. 1951, 2294.
To a cooled solution of 4 (3.85 g, 20.1 mmol) in CH2Cl2 (70 mL)
was added portionwise AlCl3 (5.90 g, 44.2 mmol). The mixture was
kept stirring for 4 h in an ice-bath and then poured onto ice (150 g)
and aq 6 N HCl (20 mL). An insoluble brown solid (1.65 g) formed
Synthesis 1999, No. 3, 423Ð428 ISSN 0039-7881 © Thieme Stuttgart · New York