Non-cryogenic CeCl3-promoted double additions of methyllithium and n-butyllithium to unsaturated nitriles

Article abstract of DOI:10.1055/s-2006-950362

Subjection of methyl or n-butyllithium to a mixture of nitriles and activated cerium chloride in THF at -10 to 0 °C afforded the corresponding carbinamines, which were isolated as either the hydrochloride salts or acetamide or benzamide derivatives in 30-91% yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950362

PAPER
4143
Non-Cryogenic CeCl -Promoted Double Additions of Methyllithium and
3
n-Butyllithium to Unsaturated Nitriles
N
J
on-Cryo
o
genic MeLi
D
h
ouble
A
ddit
n
ions to Nitriles Limanto,* Benjamin Dorner, Paul N. Devine
Department of Process Research, Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, NJ 07065, USA
Fax +1(732)5941499; E-mail: john_limanto@merck.com
Received 18 August 2006
nocerium reagent (‘RCeCl ’) was then treated with the ni-
triles followed by warming to 0 °C to room temperature
2
Abstract: Subjection of methyl or n-butyllithium to a mixture of ni-
triles and activated cerium chloride in THF at –10 to 0 °C afforded
the corresponding carbinamines, which were isolated as either the
(
Scheme 1). Even though good yields of carbinamines
hydrochloride salts or acetamide or benzamide derivatives in 30– could be obtained using Ciganek’s procedure, the use of
9
1% yields.
cryogenic conditions and excess amount of CeCl (≥ 3 mol
3
equiv) are not feasible for large-scale processes. While
other ways for generating gem-dimethyl carbinamines are
available,10 we recently required access to this class of
compounds from their a,b-unsaturated nitrile precursors.
In this regard, we investigated the possibility of effecting
the same transformation by subjecting a mixture of acti-
Key words: carbinamines, carbinamides, organocerium reagents,
non-cryogenic conditions, reaction optimization
Addition of organolithium or Grignard reagents to nitriles
generally concludes at the ketimines (ketones) stage.1
vated CeCl and various nitriles to MeLi at higher temper-
Subsequent addition to the initially generated metal
ketimines usually requires the use of highly nucleophilic
organocerium reagent to afford the corresponding tertiary
3
ature, based on the notion that the potentially unstable
nucleophiles (‘RCeCl ’) would react with the substrate, as
2
11
2
soon as they are being formed (Scheme 1).
carbinamines. In few isolated cases, however, double ad-
ditions of Grignard or organolithium reagents have been Considering the availability and low price of anhydrous
3
12
observed with a-alkoxy nitriles or when allylmagnesium CeCl in bulk quantity, our studies were conducted with
3
4
halide was used as the nucleophile. In the case of a,b-un- commercial reagent, which typically contains £0.15 wt%
saturated nitriles, reaction with an organolithium or Grig- of water. While activation of CeCl in THF could be car-
3
nard reagent at low temperature could result in either 1,2- ried out at room temperature for 2–12 hours as mentioned
5
addition or 1,4-conjugated addition.
above, a more reproducible process involves heating the
solid (2 mol equiv) in 5–6 mL/g of THF at 40–45 °C for
three hours to afford active, crystalline, rod-shaped
1
,2-Double additions of pre-formed methylcerium re-
agent to various saturated nitriles and to a small set of6
1
3
CeCl ·THF complex. Gratifyingly, subsequent addition
a,b-unsaturated nitriles, have been reported by Ciganek.
3
of p-dimethylaminocinnamonitrile (1) (1 mol equiv) to
the slurry of the activated species, followed by subjecting
the resulting mixture to MeLi·LiBr (2.5 mol equiv) in
Et O at –10 to 0 °C, afforded the corresponding carbi-
namine 2 in 90% HPLC assay yield (Table 1). Upon ben-
The general procedure for the preparation of organoceri-
um reagents was initially developed by Imamoto et al.,7
involving pre-drying solid CeCl ·7H O under vacuum at
elevated temperature, followed by stirring the dried solid
in THF at room temperature for 2–12 hours and subject-
ing the suspension to the organolithium reagent at low
3
2
8
2
9
zoylation (BzCl, CH Cl /H O, K CO ), the allylic
2
2
2
2
3
benzamide derivative 3 was isolated by crystallization in
temperatures (£ –70 °C). The presumed generated orga-
7
5% yield.
Previous Approach: Cryogenic Conditions
R2
1
. 130–150 °C
CN
R2
R1
1
.
< 0.1 torr
R Li (3 mol equiv)
THF, <–70 °C
(1 mol equiv)
CeCl3 7H2O
3 mol equiv)
.
CeCl3 nTHF
active)
"R1CeCl2"
NH2
(
2. THF, r.t.
–70 °C r.t.
R1
(
2–12 h
4
9–77%
1
R = Me, n-Bu
2
R = Ph, c-Hex
Current Research: Non-Cryogenic Conditions
R2
1
.
R2
R1
NH2
THF, 40–45 °C
CN
2. R Li, –10 to 0 °C
anhydrous CeCl3
2 mol equiv)
CeCl .nTHF
3
1
(
(active)
R1
Scheme 1 Preparation of allylic carbinamines
SYNTHESIS 2006, No. 24, pp 4143–4150
x
x.
x
x
.
2
0
0
6
Advanced online publication: 14.11.2006
DOI: 10.1055/s-2006-950362; Art ID: M05406SS
Georg Thieme Verlag Stuttgart · New York
©

4
144
J. Limanto et al.
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Table 1 Reaction Profiling for CeCl -Promoted Double Additions of MeLi to Nitrile 1
3
NHR
CN
1. CeCl , THF
NHR
3
+
2. MeLi, Et2O
N
–10 to 0 °C
N
N
1
2 R = H
R = Bz
4 R = H
5 R = Bz
3
Entry
CeCl3
MeLi
(mol equiv)
Observed
producta
Yield (%)
HPLC
Isolated productb Yield (%)c
(
mol equiv)
1
2
3
4
5
6
7
2
2.5
2.0
2.5
2.5
2.5
2.5
2.5
1.2
2
2
90
83
–
3
75
ND
–
2
NDd
–
0
complex mixture
2e
0.3
1
complex mixture
trace
20
70
90
40
–
–
2
ND
3
ND
51
73
ND
2:4 = 5:1
2
3
3
8
2
2:1 = 1:1.2
ND
a
1
Ratio determined by H NMR spectroscopy.
BzCl, K CO , MTBE–CH Cl /H O.
b
c
d
e
2
3
2
2
2
Yield of isolated product 3, crystallized from CH Cl –MTBE.
2
2
Not determined.
No activation of commercial anhyd CeCl3.
Investigation of reaction stoichiometry was subsequently chlorocinnamonitrile afforded carbinamine 7, which was
performed, while keeping the reaction temperature be- isolated as its HCl salt in 68% yield (entry 2). Employing
tween –10 to 0 °C. A slightly lower assay yield of product excess amount of CeCl and MeLi (3 and 4 mol equiv, re-
3
was obtained when 2 molar equivalents of MeLi were spectively) resulted predominantly in the formation of
used (Table 1, entry 2). In the absence of CeCl (entry 3) over-alkylated product 8 (entry 2). Sterically encumbered
3
or when commercial anhydrous reagent was used without substrate, such as a-phenylcinnamonitrile (9), also under-
activation (entry 4), a complex mixture of products was went double addition to afford the carbinamine HCl salt
obtained, and only a trace amount of desired carbinamine 10, albeit in only 42% yield (entry 3).
was detected in the latter case. While reducing the amount
The studies were further extended to include cyclic and/or
aliphatic a,b-unsaturated nitriles. An example of the latter
class of substrates includes cyclohexenecarbonitrile 11,
which underwent the transformation smoothly to give the
corresponding amine HCl salt 12 in 74% yield (entry 4).
Additionally, the non-conjugated diene-nitrile 13 afford-
ed the corresponding amine-HCl 14 in 40% yield (entry
of CeCl to 30 mol% afforded 2 in only 20% assay yield
3
(
entry 5), performing the same reaction using equimolar
amount of CeCl gave a 5:1 mixture of 2 and over-alkylat-
3
ed product 4 in 70% combined yield (entry 6). On the oth-
er hand, increasing the amount of CeCl to 300 mol%,
3
while keeping the amount of MeLi constant, did not ap-
pear to favor the formation of amine 4 nor did it improve
formation of the desired carbinamine (entry 7). Using
MeLi as a limiting reagent (entry 8) afforded a 1:1.2 mix-
ture of product and unreacted starting material with no
trace of ketimine intermediate, suggesting that the rate of
the second addition is considerably faster.
5
). In terms of cyclic unsaturated nitriles, subjection of an
N-Boc-piperidine-indene 15 to the standard reaction con-
ditions also cleanly afforded the desired allylic carbi-
namine, which was isolated as its acetamide 16 in 73%
yield (entry 6).
On the other hand, the six-membered-ring variants, such
as dihydronaphthalene 17 or 19 gave predominantly [1,4-
The experimental results in Table 1 indicate that an effec-
tive reaction could be realized using 2 molar equivalents
1
6
,2] adducts 18 and 20, each as a single diastereomer, in
8% and 79% yields, respectively (entries 7,8). Reaction
of activated CeCl and 2.5 molar equivalents of MeLi. To
3
probe the scope and limitation of this non-cryogenic trans-
formation, further investigations were carried out using
other a,b-unsaturated nitriles and the results are summa-
rized in Table 2. The carbinamine products were isolated
as either the hydrochloride salt, acetamide or benzamide
derivatives. Under the conditions described above, p-
involving substrate 19 also afforded the desired carbin-
amine 21, which could be isolated as its HCl salt 21 in
1
3% yield. Incorporation of substituents at the g-position,
such as in substrate 22, strongly favored the [1,2]-double
addition, affording the carbinamide 23 in 83% yield
(
entry 9). Not surprisingly, the current non-cryogenic
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PAPER
Non-Cryogenic MeLi Double Additions to Nitriles
4145
a
Table 2 CeCl -Promoted Double Additions of MeLi to a,b-Unsaturated Nitriles
3
Entry
1
Substrate
Product(s)b
Yield (%)c
75
CN
NHBz
N
1
N
3
2
3
4
CN
7 68e
8
NH3Cl
NH Cl
3
42f
Cl
or
Cl
6d
Cl
7
8
42
74
CN
NH3Cl
9
1
2
0
CN
NH3Cl
11
1
5
6
40g
73
NH2
CN
13
1
4
NC
NHAc
NBoc
NBoc
1
7
5
1
8
6
7
8
CN
O
68g
1
1
g
CN
20 :21 = 79:13
O
NH3Cl
19
2
0
21
9
CN
83g
NHAc
NBoc
CN
22
NBoc
2
3
10
80
NH2
24
25
a
b
c
d
e
f
Typical conditions: activated [CeCl ] (2 mol equiv) = 6–8 mL/g THF, MeLi·LiBr (2.5 mol equiv), –10 to 0 °C, 1 h.
Amide or HCl salt formation was carried out using standard procedure. Unless otherwise noted, products were isolated by crystallization.
Overall isolated yields for the addition and amidation or salt formation.
3
Exists as an 85:15 E/Z mixture.
Three mol equiv of CeCl was used; 85:15 E/Z product mixture was isolated.
3
Four mol equiv of MeLi was used.
g
Isolated by SiO gel flash column chromatography.
2
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4
146
J. Limanto et al.
PAPER
conditions could also be applied to aromatic nitriles, such Table 4 CeCl -Promoted Double Addition of RLi to Saturated
3
as 4-phenylbenzonitrile (24), to generate the correspond- Nitriles
ing benzylic carbinamine HCl salt 25 in 80% isolated
yield (entry 10).
Entry
1
Substrate
Productsa
Yield (%)b
91
CN
While reactions between MeLi and a,b-unsaturated ni-
triles generate the corresponding carbinamines in moder-
ate to good yields as illustrated in Table 2, n-butyllithium,
on the other hand, adds to unsaturated nitriles less effi-
ciently as shown in Table 3. For example, under typical
reaction conditions, the g-disubstituted dihydronaphtha-
lene 22 afforded the corresponding benzamide derivative
NH3Cl
31
32
Bu
CN
NHBz
Bu
2
3
94
3
1
33
2
6 in only 46% yield (vs. 83% for MeLi addition, entry 9,
R
CN
NHBz
R
Table 2) (entry 1). Interestingly, a decyanation process
also took place to generate dihydronaphthalene 27 in 26%
yield (entry 1). Furthermore, the cinnamonitrile substrate
35a 68
35b 78
BocN
BocN
3
5a R = Me
3
4
1
reacted with n-BuLi in the presence of CeCl to give pre-
35b R = n-Bu
3
dominantly the [1,4-1,2]-adduct 28 in 58% yield, in addi-
tion to the desired carbinamine, isolated as its benzamide
derivative 29 in 22% yield (entry 2). On the other hand, a
cyclic aliphatic nitrile, such as substrate 11, underwent the
double addition smoothly to generate the desired carbin-
amine, which was benzoylated and isolated by crystalliza-
tion to give 30 in 78% overall yield (entry 3).
47 (85)c
4
CN
NH2
36
37
a
Isolated by either SiO gel chromatography or crystallization.
2
b
c
Overall two-step yields.
Yield under cryogenic conditions.
Additional substrate probing was carried out using satu-
rated nitriles and the results are summarized in Table 4.
Under standard conditions, cyclohexanecarbonitrile (31) Nonetheless, the desired carbinamide 37 could be isolated
underwent smooth double-additions with either MeLi or in 47% yield. When the same substrate was subjected to a
n-BuLi to afford HCl salt 32 or benzamide derivative 33 preformed methylcerium reagent (‘MeCeCl ’) at –70 °C,
2
in 91% or 94% yields, respectively (entries 1,2). Further- the transformation occurred smoothly to give carbinamide
more, similar treatment of N-Boc piperidine carbonitrile 37 after acetylation in 85% isolated yield.
3
4 with the organolithium reagents and CeCl also afford-
Mechanistically, based on the original report by Ciganek,6
it is likely that the current protocol also involves in situ
3
ed the corresponding carbinamine benzamides 35a and
5b in 68% and 78%, respectively. Substrates bearing a
3
generation of methylcerium reagents (‘MeCeCl ’), which
2
1
4
more acidic a-proton, such as a-phenylpropionitrile (en-
try 4), however, underwent only a 50% conversion, sug-
gesting that the a-deprotonation was a competing event.
immediately add to nitriles, affording the corresponding
carbinamines (Scheme 2). On the other hand, while the
Table 3 CeCl -Promoted Additions of n-BuLi to a,b-Unsaturated Nitriles
3
Entry
1
Substrate
Product(s)a
Yield (%)b
Bu
CN
Bu
NHBz
26:27 = 46:26
NBoc
NBoc
CN
NBoc
22
26
27
Bu
O
Bu
NHBz
Bu
2
Bu
28:29 = 58:22
N
N
N
1
28
29
Bu
CN
NHBz
Bu
3
78
11
3
0
a
Products were purified and isolated by either silica gel chromatography or crystallization.
Obtained for the two-step process.
b
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Non-Cryogenic MeLi Double Additions to Nitriles
4147
second addition certainly requires the use of an organoce- Double Additions of MeLi to a,b-Unsaturated Nitriles; Allylic
2
b,6
Acetamide 23; Typical Procedure
A suspension of commercial, anhyd CeCl (4.5 g, 18.25 mmol, 2
equiv) in anhyd THF (27 mL) was heated to 45 °C for 3 h and
checked under microscope to ensure complete formation of rod-
shaped crystalline materials. The slurry was cooled to r.t. and treat-
ed with solid nitrile 22 (2.96 g, 9.13 mmol, 1 equiv). After further
rium reagent, the initial addition might involve direct
3
attack of MeLi to activated RCN–CeCl complex, similar
to the previously reported reactions between Grignard re-
agents and ketone–CeCl complexes. In any events,
while in the absence of CeCl , reactions between MeLi
3
3
a
3
3
and a,b-unsaturated nitriles at –10 °C give a complex cooling to –10 °C, a 1.5 M solution of MeLi·LiBr in Et O (14.9 mL,
2
1
5
mixture of products (Table 1, entry 3), reactions involv- 22.38 mmol, 2.5 equiv) was added dropwise over 30 min to give a
brown slurry, which was aged for an additional 30 min. The reaction
ing saturated nitriles bearing acidic a-protons result in
partial conversions, due to competing deprotonation un-
was quenched by addition of concd NH OH (6 mL) over 30 min.
The yellow suspension obtained was allowed to warm to r.t., stirred
for 1 h, and then filtered. The wet cake was rinsed several times
4
der our reaction conditions.
with THF and the combined filtrates were then concentrated to al-
CeCl3
CeCl3
most dryness, diluted with MTBE (50 mL) and washed with H O
2
MeLi
LiCl
N
N
R
"
MeCeCl2"
(2 × 15 mL). To the crude carbinamine solution was added H O (15
2
–
R
R
mL) and K CO (3.78 g, 27.39 mmol, 3 equiv). The resulting bipha-
2
3
sic layers were cooled to 0 °C, treated with neat acetyl chloride
1.95 mL, 27.39 mmol, 3 equiv) and aged for 30 min at r.t. The or-
N
CeCl2
(
N
MeLi
LiCl
ganic layer was then separated, washed with brine (15 mL) and con-
–
R
centrated in vacuo. The crude oil was purified by SiO gel flash
2
column chromatography (8:1 to 1:1 hexanes–MTBE) to give pure
allylic acetamide 23 in 83% isolated yield; colorless foam.
MeCeCl2
CeCl2
Cl2Ce
IR (PTFE IR card): 3309, 3058, 2993, 2930, 2870, 1692, 1664,
N
–
1
1
647, 1531, 1425, 1366, 1097, 975, 769, 735 cm .
R
1
H NMR (500 MHz, CDCl ): d = 7.76 (1 H, dm, J = 7.5 Hz), 7.67
3
Scheme 2 Possible transformation pathways
(2 H, dm, J = 8.3 Hz), 7.45 (1 H, ddt, J = 8.3, 6.4, 1.2 Hz), 7.40–
7
.36 (2 H, m), 7.20–7.13 (3 H, m), 6.31 (1 H, s), 6.16 (1 H, s), 3.54
(
(
1
2 H, br m), 3.41 (2 H, ddd, J = 13.5, 8.4, 3.6 Hz), 2.73 (2 H, s), 1.86
6 H, s), 1.58 (2 H, m), 1.48 (9 H, s), 1.47 (1 H, m), 1.30 (1 H, m).
In summary, we have developed a non-cryogenic method
for accessing carbinamines via double additions of MeLi
and to some extent, n-BuLi, to various a,b-unsaturated
3
C NMR (125 MHz, CDCl ): d = 166.5, 155.1, 140.3, 136.6, 136.0,
3
1
5
33.2, 132.3, 131.2, 129.3, 128.7, 127.1, 126.8, 126.2, 125.3, 79.5,
and saturated nitriles in the presence of activated CeCl at
3
6.6, 40.7, 40.5 (br), 39.5 (br), 34.8, 33.0, 29.2, 28.2.
–
10 to 0 °C. The desired carbinamines are generally iso-
+
HRMS: m/z calcd for C H N O (MH ): 461.2804; found:
4
2
9
37
2
3
lated as either their HCl salts or amide derivatives in mod-
61.2811.
erated to good yields (40–94%). While the use of
anhydrous CeCl eliminates the tedious pre-drying pro-
3
HCl Salts; General Procedure
cess for the commonly used CeCl heptahydrate salt, pre- For formation of an HCl salt, the crude carbinamine solution in
3
generation of the organocerium reagent at low tempera- MTBE was cooled to 0 °C and treated with a 5 N solution of HCl in
propan-2-ol, followed by aging for 1 h and filtration. When neces-
ture (–70 °C) was no longer necessary. The current im-
proved protocol certainly offers major practicality and
convenience in both academic and large-scale industrial
sary, recrystallization can be carried out in either MeCN–H O or i-
2
PrOH–H O solvent system.
2
set-ups.
Benzamide 3
Colorless solid; mp 147–149 °C.
All reactions were conducted under N . Commercial reagents and
the following commercial solvents were used without further puri-
IR (KBr thin film): 3283 (br), 2967, 1636, 1610, 1524, 1489, 1359,
1312, 1187, 1169, 966, 949, 806, 711, 694 cm .
2
–
1
fication: anhyd THF (<100 ppm H O), HPLC-grade hexanes and
1
2
H NMR (400 MHz, CDCl ): d = 7.78 (2 H, d, J = 7.6 Hz), 7.45 (3
3
MTBE. HPLC analysis was performed using ACE 3C-18 (150 × 3
mm i.d.) column under the following assay conditions: 95% solvent
A (99% H O 1% buffer of 0.2 M NH CO H:0.2 M HCO H in H O)
H, m), 7.33 (2 H, d, J = 8.2 Hz), 6.70 (2 H, d, J = 8.2 Hz), 6.51 (1
H, d, J = 16.2 Hz), 6.40 (1 H, d, J = 16.2 Hz), 6.27 (1 H, br s), 2.96
(
2
,
4
2
2
2
6 H, s), 1.71 (6 H, s).
and 5% solvent B (90% MeCN, 9% H O, 1% buffer), ramped to
2
1
3
C NMR (100 MHz, CDCl ): d = 166.7, 150.1 135.8, 131.4, 131.1,
1
00% solvent B at 1 mL/min flow rate over 9.5 min and aged for 5
3
1
28.5, 127.4, 127.3, 126.9, 125.3, 112.5, 54.7, 40.5, 27.5.
additional min, measured at 210 nm and 35 °C column temperature.
1
H NMR spectra were measured on either a 400 MHz or 500 MHz
+
HRMS: m/z calcd for C H N O (MH ): 309.1961; found:
3
2
0
25
2
instrument and 13C NMR spectra on the corresponding 100 MHz or
09.1966.
1
25 MHz instrument. IR spectra were reported in wavenumbers and
measured with an FT-IR or ATR-IR spectrometer on either a KBr
salt or PTFE IR card. Melting points are uncorrected. HRMS mea-
surements were performed at Merck Research Laboratory, Rahway,
NJ.
Hydrochloride Salt 7
Colorless solid; mp 168–178 °C (85% trans- and 15% cis-isomeric
mixture).
IR (PTFE IR card): 3419, 2971, 2678, 2577, 2510, 2086, 1620,
1
7
522, 1491, 1392, 1376, 1306, 1296, 1088, 1012, 976, 858, 802,
57 cm .
–
1
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4
148
J. Limanto et al.
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1
13
H NMR (500 MHz, CDCl ): d (trans-isomer) = 7.30 (2 H, d,
C NMR (125 MHz, CDCl ): d = 135.8, 135.2, 135.0, 134.3, 131.8,
3
3
J = 8.3 Hz), 7.23 (2 H, d, J = 8.3 Hz), 6.08 (1 H, d, J = 16.3 Hz),
131.6, 124.4, 124.3, 50.7, 50.5, 41.6, 33.0, 32.7, 32.5, 27.1, 26.9,
6
.36 (1 H, d, J = 16.3 Hz), 1.62 (6 H, s).
25.9, 24.8, 17.9, 17.8, 17.2.
1
3
+
C NMR (125 MHz, CDCl ): d (trans-isomer) = 134.3, 134.2,
HRMS: m/z calcd for C H N (MH ): 182.1908; found: 182.1909.
3
12 24
1
30.9, 130.3, 128.9, 128.2.
1
Acetamide 16
Colorless solid; mp 177–179 °C (toluene–heptane).
H NMR (500 MHz, CDCl ): d (cis-isomer) = 7.30 (2 H, d, J = 8.3
3
Hz), 7.13 (2 H, d, J = 8.3 Hz), 6.49 (1 H, d, J = 12.7 Hz), 5.90 (1 H,
d, J = 12.7 Hz), 1.35 (6 H, s).
IR (KBr thin film): 3296 (br), 3067, 2980, 2937, 2863, 1692, 1550,
1424, 1364, 1243, 1161, 754, 733 cm .
–
1
1
3
C NMR (125 MHz, CDCl ): d (cis-isomer) = 135.3, 133.5, 133.3,
3
1
1
31.4, 129.9, 128.5.
H NMR (400 MHz, CDCl ): d = 7.51 (1 H, d, J = 7.0 Hz), 7.33 (1
3
+
H, d, J = 6.9 Hz), 7.23 (2 H, m), 6.64 (1 H, s), 5.88 (1 H, s), 4.19 (2
H, br s), 3.11 (2 H, t, J = 11.3 Hz), 2.00 (2 H, m), 1.92 (3 H, s), 1.73
HRMS: m/z calcd for C H ClN (M – Cl): 196.0893; found:
1
1
15
1
96.0896.
(
6 H, s), 1.51 (9 H, s), 1.34 (2 H, d, J = 12.9 Hz).
1
3
Hydrochloride Salt 8
Colorless solid; mp 223–224 °C.
C NMR (100 MHz, CDCl ): d = 169.1, 155.0, 153.3, 147.1, 140.6,
3
133.7, 126.6, 125.3, 122.0, 121.4, 79.5, 53.6, 49.7, 42.3 (br), 33.4,
2
8.4, 26.8, 24.1.
IR (ATR IR): 2972, 2875, 2048, 1626, 1506, 1395, 1277, 1173,
–
1
+
1
094, 1013, 851, 805, 661 cm .
HRMS: m/z calcd for C H N O (MH ): 385.2491; found:
2
3
33
2
3
1
385.2483.
H NMR (400 MHz, CDCl ): d = 8.60 (3 H, br s), 7.18 (2 H, d,
3
J = 8.4 Hz), 7.12 (2 H, d, J = 8.4 Hz), 3.12 (1 H, d, J = 12.6 Hz),
2
0
Ketone 18
Colorless oil.
.17 (1 H, t, J = 12.4 Hz), 2.07 (1 H, m), 1.44 (3 H, s), 1.43 (3 H, s),
.82 (3 H, d, J = 6.5 Hz).
1
3
IR (PTFE IR card): 3061, 3017, 2956, 2927, 1707, 1492, 1455,
C NMR (100 MHz, CDCl ): d = 138.1, 131.9, 130.4, 128.3, 58.3,
3
–1
1
435, 1380, 743, 554 cm .
4
3.4, 36.6, 24.4, 22.2, 13.4.
1H NMR (500 MHz, CDCl
): d = 7.21–7.12 (3 H, m), 6.95 (1 H, d,
+
3
HRMS: m/z calcd for C H ClN (M – Cl): 212.1206; found:
2
1
2
19
J = 7.6 Hz), 3.44 (1 H, d, J = 9.1 Hz), 2.95–2.82 (2 H, m), 2.10 (1
H, m), 2.04 (3 H, s), 1.98 (1 H, ddt, J = 13.1, 5.2, 3.4 Hz), 1.47 (1
H, ddt, J = 13.1, 10.9, 5.2 Hz), 1.10 (3 H, d, J = 6.8 Hz).
12.1198.
Hydrochloride Salt 10
Colorless solid; mp 236–241.
1
3
C NMR (125 MHz, CDCl ): d = 210.9, 137.0, 133.4, 129.7, 128.5,
3
1
27.0, 126.3, 62.9, 32.1, 30.1, 29.2, 26.9, 20.6.
IR (ATR IR): 2971, 2921, 2877, 2567, 1741, 1595, 1520, 1443,
1
–
1
+
374, 1175, 978, 767, 743, 665 cm .
HRMS: m/z calcd for C H O (MH ): 189.1279; found: 189.1281.
1
3
17
1
H NMR (400 MHz, CDCl ): d = 7.99 (3 H, br s), 7.35 (10 H, m),
3
Ketone 20
6
.68 (1 H, s), 1.52 (6 H, s).
Colorless oil.
1
3
C NMR (100 MHz, CDCl ): d = 144.3, 140.5, 136.9, 132.9, 129.1,
3
IR (PTFE IR card): 2959, 2925, 2876, 1700, 1612, 1578, 1481,
1
28.9, 128.3, 127.8, 127.6, 58.4, 28.1.
–1
1
455, 1380, 1353, 1033, 958, 858, 792, 565, 545, 511 cm .
+
HRMS: m/z calcd for C H N (M – Cl): 238.1596; found:
2
1
7
20
1
H NMR (500 MHz, CDCl ): d = 6.93 (1 H, s), 6.63 (1 H, s), 3.42
1 H, d, J = 9.5 Hz), 2.77 (1 H, dt, J = 17.1, 4.4 Hz), 2.65 (1 H, ddd,
3
38.1597.
(
J = 17.1, 10.7, 5.9 Hz), 2.27 (3 H, s), 2.26 (3 H, s), 2.10–1.99 (2 H,
m), 2.05 (3 H, s), 1.48 (1 H, ddt, J = 13.1, 10.8, 5.5 Hz), 1.09 (3 H,
d, J = 6.4 Hz).
Hydrochloride Salt 12
Colorless solid; mp 203–206 °C.
IR (KBr thin film): 3395 (br), 2937 (br), 2773, 2565, 2505, 2051
1
3
C NMR (125 MHz, CDCl ): d = 211.3, 136.8, 135.2, 133.0, 132.1,
3
(
5
br), 1597, 1511, 1446, 1394, 1372, 1295, 1169, 923, 845, 802, 737,
56 cm .
–1
129.5, 126.6, 63.1, 31.6, 30.0, 26.8, 26.0, 20.9, 20.3, 19.6.
+
1
HRMS: m/z calcd for C15
H
21O (MH ): 217.1592; found: 217.1597.
H NMR (400 MHz, CD OD): d = 5.79 (1 H, m), 2.11 (4 H, m), 1.70
2 H, m), 1.60 (2 H, m), 1.46 (6 H, s).
3
(
Hydrochloride Salt 21
Colorless solid; mp 232–235 °C.
1
3
C NMR (100 MHz, CD OD): d = 137.6, 122.3, 56.6, 24.7, 24.4,
3
2
3.5, 22.3, 21.4.
IR (KBr thin film): 3408 (br), 2941 (br), 2881 (br), 2561, 1606,
+
HRMS: m/z calcd for C H N (M – Cl): 140.1439; found:
–1
9
18
1511, 1476, 1394, 1377, 1286, 1269, 1152, 858, 737, 655 cm .
1
40.1432.
1
H NMR (400 MHz, CDCl ): d = 8.94 (3 H, br s), 7.13 (1 H, s), 7.13
3
(
1 H, s), 6.51 (1 H, t, J = 4.5 Hz), 2.59 (2 H, t, J = 7.4 Hz), 2.35 (3
Carbinamine 14
Pale yellow oil; a 1.3:1 mixture of olefin isomers,
H, s), 2.27 (3 H, s), 2.18 (2 H, m), 1.89 (6 H, s).
1
3
C NMR (100 MHz, CDCl ): d = 138.3, 134.8, 134.3, 133.7, 131.6,
3
IR (PTFE IR card): 3356 (br), 3287 (br), 2964, 2926, 2860, 2725,
1
29.8, 126.7, 123.1, 58.1, 27.4, 23.5, 23.0, 21.3, 20.1.
1
7
1
654, 1584, 1448, 1376, 1360, 1201, 1154, 1107, 1056, 985, 832,
73 cm .
–1
+
HRMS: m/z calcd for C H N (M – Cl): 216.1752; found:
1
5
22
216.1754.
H NMR (500 MHz, CDCl ): d = 5.31 (1 H, m), 5.29 (1 H, q, J = 1.2
3
Hz), 5.16 (1 H, tp, J = 7.2, 1.6 Hz), 5.10 (1 H, tp, J = 7.2, 1.6 Hz),
Biphenylamine 25
Colorless solid; mp 40–41 °C (MTBE–heptane).
2
.27 (2 H, m), 2.13 (2 H, m), 2.07 (2 H, m), 1.95 (2 H, m), 1.80 (3
H, d, J = 1.2 Hz), 1.71 (3 H, d, J = 1.6 Hz), 1.70 (3 H, d, J = 1.2 Hz),
.69 (3 H, d, J = 1.6 Hz), 1.63 (3 H, d, J = 1.2 Hz), 1.62 (3 H, d,
1
IR (NaCl thin film): 3376 (br), 2983, 2938, 1375, 1211, 1154, 1065,
–
1
J = 1.6 Hz), 1.55 (2 H, NH , br s), 1.29 (6 H, s), 1.28 (6 H, s).
877, 757 cm .
2
Synthesis 2006, No. 24, 4143–4150 © Thieme Stuttgart · New York

PAPER
Non-Cryogenic MeLi Double Additions to Nitriles
4149
1
13
H NMR (400 MHz, CDCl ): d = 7.63 (6 H, m), 7.48 (2 H, t, J = 7.6
C NMR (100 MHz, CDCl ): d = 166.4, 150.1, 136.0, 131.0, 130.5,
3
3
Hz), 7.38 (1 H, t, J = 7.3 Hz), 1.82 (2 H, br s), 1.58 (6 H, s).
1
128.5, 127.6, 127.2, 126.7, 125.3, 112.4, 60.6, 40.5, 37.4, 26.0,
23.0, 14.1.
3
C NMR (100 MHz, CDCl ): d = 149.3, 140.8, 139.0, 128.7, 127.1,
3
+
1
27.0, 126.9, 125.1, 52.2, 32.8.
HRMS: m/z calcd for C H N O (MH ): 393.2906; found:
2
6
37
2
+
393.2910.
HRMS: m/z calcd for C H N (MH ): 212.1439; found: 212.1434.
1
5
18
Benzamide 30
Colorless solid; mp 113–120 °C.
Benzamide 26
Colorless foam.
IR (KBr thin film): 3278 (br), 2950, 2924, 2859, 1640, 1541, 1303
cm .
IR (PTFE IR card): 3314, 3058, 2955, 2930, 2870, 1696, 1671,
–
1
1
7
1
650, 1525, 1481, 1425, 1365, 1277, 1176, 1097, 1027, 976, 865,
69, 735, 695 cm .
–
1
1
H NMR (400 MHz, CDCl ): d = 7.74 (2 H, d, J = 7.1 Hz), 7.44 (3
3
H, m), 5.94 (1 H, s), 5.62 (1 H, s), 2.14 (2 H, m), 2.00 (4 H, m), 1.81
H NMR (500 MHz, CDCl ): d = 7.74 (1 H, dm, J = 7.2 Hz), 7.65
3
(
2 H, m), 1.61 (4 H, m), 1.30 (4 H, q, J = 7.2 Hz), 1.15 (4 H, m),
(
2 H, m), 7.46 (1 H, ddt, J = 7.2, 6.8, 1.4 Hz), 7.39 (2 H, m), 7.15 (3
0
.88 (6 H, t, J = 7.3 Hz).
H, m), 6.14 (1 H, s), 6.05 (1 H, s), 3.61 (2 H, br m), 3.36 (2 H, ddd,
J = 13.5, 9.1, 4.0 Hz), 2.72 (2 H, s), 2.27 (4 H, m), 1.58 (2 H, m),
1
3
C NMR (100 MHz, CDCl ): d = 166.0, 138.5, 136.1, 130.9, 128.4,
3
1
.48 (9 H, s), 1.50–1.43 (1 H, m), 1.38–1.13 (9 H, m), 0.88 (6 H, t,
126.6, 121.4, 62.8, 34.3, 25.8, 25.4, 24.5, 23.1, 22.8, 22.2, 14.1.
J = 7.6 Hz).
+
HRMS: m/z calcd for C H NO (MH ): 328.2640; found:
328.2630.
2
2
34
1
3
C NMR (125 MHz, CDCl ): d = 166.1, 155.2, 136.8, 136.7, 136.2,
3
1
6
2
34.8, 132.8, 131.2, 129.3, 128.7, 127.0, 126.8, 126.1, 124.8, 79.5,
2.5, 41.2, 40.5 (br), 39.8 (br), 35.5, 34.9, 33.5, 32.1, 29.2, 28.7,
Hydrochloride Salt 32
Colorless solid; mp 259–262 °C.
6.5, 23.1, 14.3.
+
HRMS: m/z calcd for C H N O (MH ): 545.3743; found:
IR (KBr thin film): 3417 (br), 2933 (br), 2647, 2565, 2500, 2064
(br), 1606, 1511, 1450, 1394, 1377, 1195, 1165, 893, 461 cm .
3
5
49
2
3
–
1
5
45.3784.
1
H NMR (400 MHz, CDCl ): d = 8.24 (3 H, br s), 1.82 (4 H, m),
3
Dihydronaphthalene 27
1
.61 (2 H, m), 1.34 (6 H, s), 1.23 (2 H, m), 1.07 (3 H, m).
Pale yellow oil.
1
3
C NMR (100 MHz, CDCl ): d = 58.0, 46.1, 27.2, 26.2, 26.1, 23.5.
3
IR (PTFE IR card): 3015, 2975, 2928, 2865, 1700, 1684, 1476,
+
HRMS: m/z calcd for C H N (M – Cl): 142.1596; found:
142.1590.
1
7
1
452, 1419, 1364, 1246, 1161, 1120, 1092, 1066, 971, 905, 865,
93, 773, 705 cm .
9
20
–
1
H NMR (500 MHz, CDCl ): d = 7.20–7.10 (3 H, m), 7.06 (1 H, dd,
3
Benzamide 33
Colorless solid; mp 105–108 °C.
J = 7.2, 1.2 Hz), 6.47 (1 H, d, J = 9.9 Hz), 5.97 (1 H, d, J = 9.9 Hz),
3
1
.55 (2 H, m), 3.40 (2 H, ddd, J = 13.9, 8.3, 3.6 Hz), 2.77 (2 H, s),
.62–1.54 (2 H, m), 1.52–1.45 (2 H, m), 1.49 (9 H, s).
IR (KBr thin film): 3347 (br), 2954, 2928, 2855, 1645, 1532, 1489,
1
–
1
450, 1290, 711, 690 cm .
1
3
C NMR (125 MHz, CDCl ): d = 155.2, 135.7, 134.1, 133.6, 128.4,
3
1
H NMR (400 MHz, CDCl ): d = 7.71 (2 H, d, J = 7.4 Hz), 7.43 (3
1
27.4, 127.1, 126.8, 126.1, 79.6, 40.1, 39.8 (br), 35.3, 33.4, 28.7.
3
H, m), 5.65 (1 H, bs), 1.82 (10 H, m), 1.21 (14 H, m), 0.92 (6 H, t,
J = 6.8 Hz).
+
HRMS: m/z calcd for C H NO + Na (M + Na): 322.1753; found:
1
9
25
2
3
22.1826.
1
3
C NMR (100 MHz, CDCl ): d = 166.6, 136.5, 130.7, 128.4, 126.5,
3
6
1.7, 45.2, 34.5, 27.9, 27.0, 26.9, 26.6, 26.3, 23.3, 14.1.
Ketone 28
Yellow oil.
+
HRMS: m/z calcd for C H NO (MH ): 330.2797; found:
2
2
36
3
30.2806.
IR (PTFE IR card): 2928, 2859, 2799, 1715, 1615, 1520, 1456,
–
1
1
409, 1347, 1192, 1164, 1129, 1060, 947, 818, 734, 565 cm .
Benzamide 35a
Colorless solid; mp 153–155 °C.
1
H NMR (500 MHz, CDCl ): d = 7.07 (2 H, d, J = 8.7 Hz), 6.71 (2
3
H, d, J = 8.7 Hz), 3.05 (1 H, m), 2.94 (6 H, s), 2.68 (1 H, dd,
J = 15.5, 7.6 Hz), 2.64 (1 H, dd, J = 15.5, 7.2 Hz), 2.31 (1 H, dt,
J = 16.7, 7.6 Hz), 2.24 (1 H, dt, J = 16.7, 7.6 Hz), 1.58 (2 H, m),
IR (KBr thin film): 3326 (br), 2976, 2942, 2855, 1692, 1537, 1429,
1
–
1
364, 1295, 1243, 1161, 1040, 715 cm .
1
.47 (2 H, m), 1.35–1.10 (6 H, m), 0.86 (6 H, app q, J = 7.2 Hz).
1
H NMR (400 MHz, CD OD): d = 7.69 (2 H, d, J = 7.9 Hz), 7.45 (1
3
1
3
H, t, J = 7.3 Hz), 7.38 (2 H, dd, J = 7.9, 7.3 Hz), 5.91 (1 H, br s),
C NMR (125 MHz, CDCl ): d = 210.9, 149.3, 133.0, 128.2, 113.0,
3
4
.15 (2 H, d, J = 12.7 Hz), 2.65 (2 H, t, J = 12.3 Hz), 2.43 (1 H, tt,
5
0.6, 43.4, 40.9, 40.6, 36.4, 29.8, 25.8, 22.8, 22.4, 14.1, 14.0.
J = 12.3, 3.1 Hz), 1.66 (2 H, d, J = 12.6 Hz), 1.43 (9 H, s), 1.37 (6
H, s), 1.20 (2 H, dq, 2 H, t, J = 4.2, 12.6 Hz).
+
HRMS: m/z calcd for C H NO (MH ): 290.2484; found:
1
9
32
2
90.2504.
1
3
C NMR (100 MHz, CDCl ): d = 166.7, 154.6, 135.6, 131.1, 128.4,
26.6, 79.2, 56.5, 44.1, 42.4, 28.4, 26.9, 26.8, 24.3.
3
1
Benzamide 29
Colorless solid; mp 128–130 °C.
+
HRMS: m/z calcd for C H N O + Na (M + Na ): 369.2154;
2
0
30
2
3
found: 369.2145.
IR (KBr thin film): 3339 (br), 2954, 2928, 2868, 1640, 1610, 1524,
–
1
1
485, 1346, 1286, 1165, 962, 811, 715 cm .
Benzamide 35b
Colorless solid; mp 122–123 °C.
1
H NMR (400 MHz, CD OD): d = 7.81 (2 H, d, J = 7.1 Hz), 7.47 (3
3
H, m), 6.72 (2 H, d, J = 8.6), 6.40 (1 H, d, J = 16.4 Hz), 6.09 (2 H,
m), 2.98 (6 H, s), 2.28 (2 H, m), 1.88 (2 H, m), 0.92 (6 H, t, J = 6.7
Hz).
IR (KBr thin film): 2958, 2933, 2863, 1675, 1541, 1424, 1364,
–
1
1
243, 1165 cm .
Synthesis 2006, No. 24, 4143–4150 © Thieme Stuttgart · New York

4
150
J. Limanto et al.
PAPER
1
H NMR (400 MHz, CD OD): d = 7.69 (2 H, d, J = 7.7 Hz), 7.48 (1
D. J.; Davies, R. V.; Rafferty, P.; Twigger, H. L.; Whelan, H.
M. Tetrahedron Lett. 1997, 38, 1241.
(6) (a) Ciganek, E. J. Org. Chem. 1992, 57, 4521. (b) Ciganek,
E. US Patent 5306821, 1994; Chem. Abstr. 1994, 121,
508195. (c) For a subsequent example, see: Fadij, V.;
Lenoir, E. A. III; Suto, M. J.; Zeller, J. R.; Wemple, J.
Tetrahedron: Asymmetry 1994, 5, 1131.
3
H, t, J = 7.2 Hz), 7.42 (2 H, t, J = 7.3), 5.62 (1 H, bs), 4.17 (2 H, d,
J = 12.4 Hz), 2.64 (2 H, t, J = 12.4 Hz), 2.19 (1 H, tt, J = 12.2 Hz,
J = 2.8 Hz), 1.97 (2 H, m), 1.67 (4 H, m), 1.44 (9 H, s), 1.32 (10 H,
m), 0.92 (6 H, t, J = 6.9 Hz).
1
3
C NMR (100 MHz, CDCl ): d = 166.8, 154.7, 136.1, 131.0, 128.5,
3
1
26.5, 79.2, 61.2, 44.4, 43.6, 34.5, 28.3, 27.2, 26.2, 23.2, 14.0.
(
7) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392.
+
HRMS: m/z calcd for C H N O + Na (M + Na): 453.3093;
found: 453.3113.
2
6
42
2
3
(
8) Typical temperature is 130–150 °C. For modified drying
process, see: (a) Larkin, J. P.; Wehrey, C.; Boffelli, P.;
Lagraulet, H.; Lemaitre, G.; Nedelee, A.; Prat, D. Org. Proc.
Res. Dev. 2002, 6, 20. (b) Dimitrov, V.; Kostova, K.;
Genov, M. Tetrahedron Lett. 1996, 37, 6787. (c) For
identification of the species obtained post drying, see:
Evans, W. J.; Feldman, J. D.; Ziller, J. W. J. Am. Chem. Soc.
Acetamide 37
Colorless solid; mp 75–77 °C.
IR (KBr thin film): 3300 (br), 3084, 2971, 1653, 1558, 1459, 1372,
1
–
1
295, 1187, 1156, 772, 703 cm .
1
H NMR (400 MHz, CDCl ): d = 7.22 (5 H, m), 5.54 (1 H, bs), 3.68
3
1996, 118, 4581.
(
(
1
1 H, m), 1.83 (3 H, s), 1.37 (3 H, s), 1.26 (3 H, d, J = 7.1 Hz), 1.17
(
9) CeCl -nTHF complex was proposed to be the required
3
3 H, s).
species for successful generation of the corresponding
3
C NMR (100 MHz, CDCl ): d = 169.6, 143.2, 129.0, 127.7, 126.3,
organocerium reagent (‘RCeCl ’) (see ref. 7b). For
3
2
5
6.7, 44.5, 24.7, 24.3, 24.0, 15.4.
activation of CeCl via sonication, see: (a) Greeves, N.;
3
+
Lyford, L.; Pease, J. E. Tetrahedron Lett. 1994, 35, 285.
HRMS: m/z calcd for C H NO (MH ): 206.1545; found:
1
3
20
(
b) Greeves, N.; Lyford, L. Tetrahedron Lett. 1992, 33,
2
06.1543.
4759.
(
10) For representative examples, see: (a) Curtius
rearrangement: Shiori, Y. In Comprehensive Organic
Synthesis, Vol. 6; Trost, B. M.; Fleming, I., Eds.; Pergamon:
Oxford, 1991, 795. (b) Ritter reaction: Bishop, R. In
Comprehensive Organic Synthesis, Vol. 6; Trost, B. M.;
Fleming, I., Eds.; Pergamon: Oxford, 1991, 261.
Acknowledgment
We gratefully acknowledge Mr. Robert Reamer for his assistance
with NMR experiments and Ms. Theresa K. Natishan with the IR
experiments.
(
c) Addition to Ketimines, see ref. 2a and: Bloch, R. Chem.
Rev. 1998, 98, 1407. (d) Nitro reduction: Weis, C. D.;
Newkome, G. R. Synthesis 1995, 1053; and references cited
therein.
References
(1) Layer, R. W. Chem. Rev. 1963, 63, 489.
(
(
(
(
11) For a previous report on reaction between ketone–CeCl3
(
2) (a) Steinig, A. G.; Spero, D. M. Org. Prep. Proced. Int.
complexes and Grignard reagents at 0 °C, see ref. 3a.
2
000, 32, 205; and references cited therein. (b) Charette, A.
12) Anhyd CeCl for these studies was obtained from GFS
B.; Mellon C, Tetrahedron 1998, 54, 10525. (c) For a
review on organocerium compounds in organic syntheses,
see: Liu, H.-J.; Shia, K.-S.; Shang, X.; Zhu, B.-Y.
Tetrahedron 1999, 55, 3803.
3
Chemicals at $ 1.06/gram.
13) Conlon, D. A.; Kumke, D.; Moeder, C.; Hardiman, M.;
Hutson, G.; Sailer, L. Adv. Synth. Catal. 2004, 346, 1307.
14) For a review of the acidity strength of alkanenitrile, see:
Hibbert, F. In The Chemistry of Triple-Bonded Functional
Groups, Part I; Patai, S.; Rappoport, Z., Eds.; Wiley-
Interscience: Chichester, 1983, 699.
(3) (a) Amouroux, R.; Axiotis, G. P. Synthesis 1981, 270.
(
(
b) Chastrette, M.; Axiotis, G. P. Synthesis 1980, 889.
c) Henze, H. R.; Thompson, T. R. J. Am. Chem. Soc. 1943,
65, 1422. (d) Allen, B. B.; Henze, H. R. J. Am. Chem. Soc.
(
15) For generation of ketones via additions of organolithium
reagents to unsaturated nitriles at –78 °C, see for example:
1
939, 61, 1790.
(
4) (a) Grassberger, M. A.; Horvath, A.; Schulz, G. Tetrahedron
Lett. 1991, 32, 7393. (b) Henze, H. R.; Allen, B. B.; Leslie,
W. B. J. Am. Chem. Soc. 1943, 65, 87.
(a) Lashley, M. R.; Dicus, C. W.; Brown, K.; Nantz, M. H.
Org. Prep. Proced. Int. 2003, 35, 231. (b) Yoneda, R.;
Harusawa, S.; Kurihara, T. J. Chem. Soc., Perkin Trans. 1
(5) For examples, see: (a) Fleming, F. F.; Wang, Q. Chem. Rev.
1
988, 3163. (c) Fang, J. M.; Chang, H. T. J. Chem. Soc.,
2
003, 103, 2035. (b) Fleming, F. F.; Wang, Q.; Zhang, Z.;
Perkin Trans. 1 1988, 1945.
Steward, O. W. J. Org. Chem. 2002, 67, 5953. (c) Fleming,
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1
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