Platinum-Catalyzed Selective Hydration of Hindered Nitriles and Nitriles with Acid- or Base-Sensitive Groups

Article abstract of DOI:10.1021/jo035487j

Hindered tertiary nitriles can be hydrolyzed under neutral and mild conditions to the corresponding amides using platinum(II) catalysts with dimethylphosphine oxide or other secondary phosphine oxides (SPOs, phosphinous acids) as ligands. We have found that this procedure also works well for nitriles with acid- or base-sensitive groups, which is unprecedented in terms of yield and selectivity. The catalyst loading can be as low as 0.5 mol %. Amides are isolated as the only product in high yield, and no further hydrolysis to the corresponding acids takes place. Reactions are carried out at 80 °C but take place even at room temperature. When enantiopure secondary phosphine oxide ligands are used in the hydrolysis of racemic nitriles, no kinetic resolution is observed, presumably due to racemization of the ligand during the reaction.

Full text of DOI:10.1021/jo035487j

P la tin u m -Ca ta lyzed Selective Hyd r a tion of Hin d er ed Nitr iles a n d
Nitr iles w ith Acid - or Ba se-Sen sitive Gr ou p s
Xiao-bin J iang,† Adriaan J . Minnaard,*,† Ben L. Feringa,*,† and J ohannes G. de Vries*,†,‡
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of Groningen,
Nijenborgh 4, 9747AG Groningen, The Netherlands, and DSM Pharma Chemicals, Advanced Synthesis,
Catalysis & Development, P. O. Box 18, 6160 MD Geleen, The Netherlands
hans-jg.vries-de@dsm.com
Received October 9, 2003
Hindered tertiary nitriles can be hydrolyzed under neutral and mild conditions to the corresponding
amides using platinum(II) catalysts with dimethylphosphine oxide or other secondary phosphine
oxides (SPOs, phosphinous acids) as ligands. We have found that this procedure also works well
for nitriles with acid- or base-sensitive groups, which is unprecedented in terms of yield and
selectivity. The catalyst loading can be as low as 0.5 mol %. Amides are isolated as the only product
in high yield, and no further hydrolysis to the corresponding acids takes place. Reactions are carried
out at 80 °C but take place even at room temperature. When enantiopure secondary phosphine
oxide ligands are used in the hydrolysis of racemic nitriles, no kinetic resolution is observed,
presumably due to racemization of the ligand during the reaction.
In tr od u ction
general, selective hydrolysis of nitriles to amides is
troublesome and yields are reasonable at best for two
reasons:
(1) It is difficult to stop the hydrolysis at the amide
stage and further hydrolysis to the carboxylic acid often
takes place, as the rate constant of amide hydrolysis is
usually larger than that for nitrile hydrolysis, especially
under basic conditions (Scheme 1).8
(2) Since the nitrile group is not very reactive, harsh
conditions using strong acids or bases are required, which
precludes the presence of acid- or base-sensitive func-
tional groups.
Tertiary nitriles are a special class as they are par-
ticularly resistant toward hydrolysis. There are only a
few successful examples known in the literature.5,9 Use
of 96% H2SO4 at 140 °C for 3 h yields tertiary amides
with yields ranging from 10% to 90% depending on the
substrate.5,9 Strong basic conditions have also been used,
but this leads to much lower yields. For instance,
tributylacetonitrile could be converted into tributylac-
etamide in 15% yield after 100 h of reflux with 50% KOH
in tert-butyl alcohol.9b Due to these difficulties, tertiary
amides are generally prepared from the corresponding
acid chloride and NH3.9c,10 Furthermore, the method of
The hydrolysis of nitriles to amides and carboxylic
acids is an important transformation in organic chemis-
try.1 Many industrial examples are known, such as the
hydrolysis of amino nitriles to amino acids,2 acrylonitrile
to acrylamide and acetone cyanohydrin to the corre-
sponding amide,3 en route to methyl methacrylate. Using
specific conditions, it is possible to stop at the amide
stage.4 Frequently used methods for nitrile hydrolysis to
amides are strong acid (96% H2SO4)5 or base (50% KOH/
t-BuOH).6 A simple and versatile method has been
reported by Katritzky and co-workers who used a com-
bination of 30% H2O2/K2CO3/DMSO at 0 °C for 5-10 min
to obtain high yields of pure amides.7 However, in
† University of Groningen.
‡ DSM Pharma Chemicals.
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10.1021/jo035487j CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/26/2004
J . Org. Chem. 2004, 69, 2327-2331
2327

J iang et al.
SCHEME 1. Nitr ile Hyd r olysis
(1) There is need for additional base or acid, which
precludes the hydrolysis of nitriles containing sensitive
functional groups.20a,b,22d,e
(2) Some catalysts are only effective for nitriles con-
taining an additional coordinating group.22f,24,27
(3) Some of the applied ligands are not easily synthe-
sized.22a-c
Katritzky and co-workers mentioned above does not work
for tertiary nitriles.11 No efficient method for the hy-
drolysis of tertiary nitriles has been reported so far.
To reduce salt formation in industrial nitrile hydroly-
sis, a number of methods based on the use of enzymes
and transition-metal catalysts have been developed.
Enzymatic hydrolysis takes place under exceptionally
mild conditions.12 A number of examples have been
reported, with some of them showing good enantioselec-
tivity in the kinetic resolution of racemic nitriles or in
the conversion of meso-dinitriles.13 A restriction, however,
is the low reactivity of the enzymes, although DeSantis
and co-workers have reported very high rates of hydroly-
sis with less hindered nitriles, such as mandelonitrile. 14
Transition-metal catalysts have also been successful
in the hydrolysis of nitriles to amides. Several classes of
heterogeneous catalysts15 have been used, such as sup-
ported metals (Cu, Ni, Ag, Pd),16 metal oxides17 (MnO2,
TiO2, SiO2, Al2O3), and zeolites18(NaY,18a Zn2+ exchanged
zeolites18b). Yields and selectivities generally are poor.
Homogeneous catalysts have been used, based on com-
plexes of Pd(II),19 Pt(II),20 Pt(0),21 Co(III),22 Cu(II),23,24a
Ni(II),24 Zn(II),24,25 Rh(I),26 Rh(III),27 Ru(II),28 Ru(III),26
Re(III),29 or Mo(I)30 and others.31 Limitations of these
catalysts are as follows:
The two reported catalysts that stand out in terms of
reactivity and selectivity are [PtH (PMe3)2(H2O)][OH]20b
and [PtH(PMe2OH) (PMe2O‚‚‚H‚‚‚OPMe2)]20c,d (1, Figure
3). In the hydrolysis of acetonitrile, the turnover frequen-
cies (TOF) of these two catalysts are 178 and 380 h-1
,
respectively. Both catalysts are surprisingly stable as
attested by their turnover numbers (TON) of 6 × 103 mol/
mol. Thus far, catalyst 1, developed by Parkins and co-
workers,20c,d has been shown to be the most active and
versatile one. In the hydrolysis of acetonitrile, with 0.015
mol % of 1, 91% isolated yield of acetamide was obtained
after 15.5 h of reflux in water. The applied secondary
phosphine oxide ligands are possibly involved in the
hydrolysis reaction by intramolecular nucleophilic attack
on the coordinated nitrile.20c,d The hydrolysis of tertiary
nitriles and acid- or base-sensitive nitriles using this
catalyst has not been reported, however.
Secondary phosphine oxide ligands (SPOs) have found
application in Pt-catalyzed hydroformylation,32 in Pt-
catalyzed hydrolytic amination of nitriles,33 and in Pd-
catalyzed aromatic substitution reactions.34 We recently
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2328 J . Org. Chem., Vol. 69, No. 7, 2004

Platinum-Catalyzed Selective Hydration of Hindered Nitriles
F IGURE 1. Structure of L1.
reported the preparation of enantiopure SPOs and their
application as ligands in the Ir(I)-catalyzed asymmetric
imine hydrogenation.35 The ligands are prepared by the
addition of a Grignard reagent to a solution of RPCl2 in
THF at -20 °C, followed by hydrolysis with water. They
are readily obtained enantiopure by preparative chiral
HPLC. In particular, t-BuPhPHO L1 (Figure 1) is easy
to separate by preparative chiral HPLC with a 4.3 min
retention time difference between the two enantiomers.35
Classical resolution has also been used to obtain enan-
tiopure SPOs.36
F IGURE 2. Perspective PLUTO drawing of catalyst 2.
More recently, this ligand has also been used by Dai
and co-workers in palladium-catalyzed allylic alkylation
reactions.37
In view of the above, we decided to further investigate
the hydrolysis of nitriles that are not easy to hydrolyze
by other means, such as tertiary nitriles and nitriles
containing acid- or base-sensitive groups. In addition, the
availability of the enantiopure L1 prompted us to inves-
tigate the possibility of kinetic resolution of racemic
nitriles.
F IGURE 3. Structures of preformed catalysts.
Me2PHO. Thus, a neutral Pt(II) complex is the net result.
Again, no well-defined complex could be obtained using
L1. It turned out, however, that in situ preparation of
the catalyst by using PtCl2 in combination with 3-4 equiv
of racemic or enantiopure L1 gave comparable results
in the hydrolysis reactions.
Resu lts a n d Discu ssion
Initially, acetonitrile and R-methylbenzyl cyanide 4k
(Scheme 3) were applied as model substrates in the
hydrolysis reactions. Catalysts 1-3 all gave full conver-
sion to the corresponding amide as the sole product, 1
being the most active catalyst. Their catalytic activities
decrease as follows: 1 > 3 > 2. With 0.5 mol % of 1, the
reaction took 3 h at 80 °C in EtOH/H2O (TOF 67 h-1),
Catalyst 1 has been prepared from Pt(PPh3)4 and 5
equiv of Me2PHO in toluene.20c,d The same procedure
could be used with Ph2PHO to form 3. Unfortunately,
with L1, this procedure failed to give the analogous
complex. For this reason, we explored the preparation of
complexes starting from PtCl2 instead of Pt(PPh3)4.
Gratifyingly, reaction of PtCl2 with 5 equiv of Me2PHO
in toluene gave a white solid, the structure of which was
determined by X-ray analysis after crystallization from
DCM/Et2O (Figure 2).
The structure of this complex (2), [PtCl (PMe2OH)-
(PMe2O‚‚‚H‚‚‚OPMe2)], is comparable to the structure of
1 (Figure 3). In particular, it shares with 1 the deproto-
nation of one of the hydroxyl groups of the Me2POH
ligands.38 The P-O- is hydrogen-bonded to the adjacent
whereas using 3, a reaction time of 20 h (TOF 10 h-1
)
was required. With 2 mol % of catalyst 2, 18 h was needed
for complete conversion (TOF 3 h-1). When 4k was used
as substrate, similar trends were found. The somewhat
reduced rate of 2 is due to the presence of chloride anion,
which can still compete with the nitrile for the binding
site. This can be remedied by the addition of AgBF4, as
shown by Parkins.20d This presumably creates the same
cationic complex as the one obtained by hydrolysis of 1.
To expand the scope of this reaction, a number of
sterically hindered tertiary nitriles and nitriles with acid
or base sensitive groups were hydrolyzed with the
catalysts mentioned above (Figures 4 and 5).
Using catalyst 1, all substrates were smoothly con-
verted to the corresponding amides in over 95% isolated
yield except for trimethylacetonitrile 4f. (Scheme 2, Table
1).
Catalyst 1 is more active than 2 and the in situ
complexes made from PtCl2 and ligand L1, especially
with the sterically hindered tertiary nitriles. With un-
hindered nitriles, the difference is less pronounced. All
nitriles (4a -j) except 4c were completely converted to
(34) (a) Li, G. Y.; Zheng, G.; Noonan, A. F. J . Org. Chem. 2001, 66,
8677-8681. (b) Li, G. Y.; Fagan, P. J .; Watson, P. L. Angew. Chem.,
Int. Ed. 2001, 40, 1513-1516. (c) Li, G. Y. US 6124462, US 6291722.
(d) Wolf, C.; Lerebours, R. J . Org. Chem. 2003, 68, 7077-7084.
(35) J iang, X.-B.; Minnaard, A. J .; Hessen, B.; Feringa, B. L.;
Duchateau, A. L. L.; Andrien, J . G. O.; Boogers, J . A. F.; de Vries, J .
G. Org. Lett. 2003, 5, 1503-1506.
(36) A three-step resolving procedure has been developed by
Haynes: (a) Freeman, R.; Haynes, R. K.; Loughlin, W. A.; Mitchell,
C.; Stokes, J . V.; Vonwiller, S. C. Pure Appl. Chem. 1993, 65, 647-
654. (b) Haynes, R. K.; Freeman, R. N.; Mitchell, C. R.; Vonwiller, S.
C. J . Org. Chem. 1994, 59, 2919-2921. (c) Haynes, R. K.; Au-Yeung,
T. L.; Chan, W. K.; Lam, W. L.; Li, Z. Y.; Yeung, L. L.; Chan, A. S. C.;
Li, P.; Koen, M.; Mitchell, C. R.; Vonwiller, S. C. Eur. J . Org. Chem.
2000, 3205-3216. Although the classical resolution of L1 has been
reported, this procedure was reported more recently by the same
authors to be not reproducible; see: Drabowicz, J .; Łyz˘ wa, P.; Om-
ela´nczuk, J .; Pietrusiewicz, K. M.; Mikołajcz, M. Tetrahedron: Asym-
metry 1999, 10, 2757-2763. Wang, F.; Polavarapu, P. L.; Drabowicz,
J .; Mikołajcz, M. J . Org. Chem. 2000, 65, 7561-7565.
(38) From the position of two oxygen atoms observed in X-ray, we
assume they share one hydrogen, as the catalyst itself is neutral. In
Figure 2, the distance of O1-O2 was 2.446(4) Å and angle between
O1-H12-O2 was 178°.
(37) Dai, W.-M.; Yeung, K. K. Y.; Leung, W. H.; Haynes, R. K.
Tetrahedron: Asymmetry 2003, 14, 2821-2826.
J . Org. Chem, Vol. 69, No. 7, 2004 2329

J iang et al.
SCHEME 3. Deu ter a tion Exp er im en t w ith
Ca ta lyst 1
under these conditions. Increasing the catalyst loading
to 2 mol % reduced the reaction time to 5-18 h.
Nitrile 4c remained unchanged with 0.5 mol % of 1
even after prolonged reaction time. Increasing the cata-
lyst loading to 3.5 mol %, however, did result in its
hydrolysis to amide 5c (entry 3). This sluggish reaction
might be due to the conformation of the substrate in
which the cyano group occupies an axial position were
its suffers severe steric hindrance (e.g., 1,3-diaxial in-
teraction).
F IGURE 4. Structures of tertiary nitriles.
The nitriles possessing acid- or base-sensitive groups
(4g-j) were all smoothly converted to the corresponding
amides without any side reactions (entries 7-10, 20, and
21). Even the sensitive D-amygdalin (4j) was converted
to the amide without racemization of any of the stereo-
genic centers in the sugar moieties in 98% yield. The
stereochemical integrity of the product was confirmed by
COSY and NOESY NMR experiments. All substrates
could even be hydrolyzed at room temperature, although
a long reaction time was needed (entries 13 and 21).
Because of the poor solubility of the catalysts in most
organic solvents, the products can be extracted with THF
or DCM after evaporation of the ethanol/water mixture.
The recycled catalysts could be used at least one more
time in subsequent reactions and were found to largely
retain their activity.
F IGURE 5. Structures of nitriles with acid- or base-sensitive
groups.
SCHEME 2. P la tin u m -Ca ta lyzed Nitr ile
Hyd r olysis
TABLE 1. P la tin u m -Ca ta lyzed Hyd r olysis of Nitr iles to
Am id es
There are very few reported examples of enantioselec-
tive hydration of nitriles, other than those catalyzed by
enzymes.39 With the enantiopure ligand L1, we at-
tempted a kinetic resolution of racemic nitriles. Using
the in situ formed complex of (R)-(+)-t-BuPhPHO (L1)
and PtCl2, nitrile 4k and sterically hindered tertiary
nitriles 4d ,e were hydrolyzed under the standard condi-
tions. The hydrolysis of 4d ,e did not go to completion
(55% conversion determined by GC). The ee’s of both the
remaining substrate and the product were determined
during the reaction by HPLC. However, in all cases (4k ,
4d ,e) both the nitrile and the product amide were found
to be racemic. To exclude the possibility of racemization
of the nitriles or amides an experiment was performed
using D2O instead of H2O. Upon D-NMR analysis only a
signal due to the ND2 group was observed and no
R-deuteration was found neither in the nitrile nor in the
amide (Scheme 3). These findings exclude racemization
of the substrates or products.
isolated
yield (%)
entry
nitrile
catalyst
T (°C) t (h) product
1
2
4a
4b
4c
4d
4e
4f
4g
4h
4i
1
1
1
1
1
1
1
1
1
1
2
2
1
1
1
80
80
80
80
80
80
80
80
80
80
80
80
25
45
45
80
80
80
80
80
25
5
12
48
25
35
41
5a
5b
5c
5d
5e
5f
5g
5h
5i
99
99
96
98
96
80
95
97
98
98
90
25
95
98
97
85
74
43
41
94
96
3b
4c
5c
6
7
8
9
3.5
3.5
3.5
4
10d
11e
12e
13e
14
15
16f
17f
18f
19f
20e
21e
4j
5j
4a
4d
4a
4a
4b
4a
4b
4d
4e
4g
4g
18
5a
5d
5a
5a
5b
5a
5b
5d
5e
5g
5g
18
90
27
59
21
33
48
48
20
20
PtCl2+ L1
PtCl2+ L1
PtCl2+ L1
PtCl2+ L1
PtCl2+ L1
1
After careful chiral HPLC-MS analysis of the hydroly-
sis samples, we discovered that the ligand L1 had largely
racemized during the reaction. This explains the disap-
pointing results in the kinetic resolution experiments.
a
General conditions: 0.5 mol % preformed catalyst, 5 mmol of
b
nitrile, 4 mL of EtOH, 2 mL of H2O, and heating to 80 °C. 3.5
mol % catalyst, 1 mmol of substrate. c 1 mol % catalyst. 1 mmol
d
of substrate, pure H2O as solvent. e 2 mol % catalyst. f 4 mol %
catalyst.
Con clu sion
the corresponding amides (5a -j) using only 0.5 mol % of
catalyst 1 in EtOH/H2O mixtures at 80 °C (Table 1). The
hydrolysis of unhindered nitriles (4g-j) is completed in
3-4 h but the sterically hindered tertiary nitriles (4a ,b,
4d -f) need reaction time up to 41 h to give full conversion
By broadening the scope of the nitrile hydrolysis
reaction reported by Parkins and co-workers, a catalytic
(39) J a¨hnisch, K.; Gru¨ndemann, E.; Kunnath, A.; Ramm, M. Liebigs
Ann. Chem. 1994, 881-883.
2330 J . Org. Chem., Vol. 69, No. 7, 2004

Platinum-Catalyzed Selective Hydration of Hindered Nitriles
2-F u r a m id e (5g)42 was isolated as an off-white solid: yield
95%; mp 140-142 °C (lit.42e,f mp 141-142 °C).
method has been developed for the hydrolysis of tertiary
nitriles and nitriles containing sensitive groups to their
corresponding amides. To the best of our knowledge, the
excellent yields and chemoselectivities of these hydration
reactions are unprecedented in the literature. An at-
tempted kinetic resolution failed and the ligand was
found to racemize during the reaction.
4-F or m ylben za m id e (5h )43 was isolated as a white solid:
yield 97%; mp 165-167 °C; 1H NMR (DMSO-d6) δ 7.61 (s, 1H),
7.95 (d, J ) 8.1 Hz, 2H), 8.04 (d, J ) 8.3 Hz, 2H), 8.20 (s, 1H),
10.04 (s, 1H); 13C NMR (DMSO-d6) δ 191.8, 166.0, 138.2, 136.7,
128.3, 127.1; MS (EI+) 149 (M, 100).
1,3-Ben zod ioxole-5-ca r boxa m id e (5i)44 was isolated as
an off-white solid: yield 98%; mp 167-168 °C (lit.44b mp 167-
168.5 °C); 1H NMR (DMSO-d6) δ 6.05 (s, 2H), 6.92 (d, J ) 8.3
Hz, 1H), 7.25 (s, 1H), 7.38-7.48 (m, 2H), 7.84 (s, 1H); 13C NMR
(DMSO-d6) δ 166.0, 148.6, 146.2, 127.2, 121.5, 106.7, 106.5,
100.5; MS (EI+) 165 (M, 50).
Exp er im en ta l Section
For general methods and details of experimental procedures,
see the Supporting Information.
Gen er a l P r oced u r e for Ca t a lyt ic Nit r ile Hyd r olysis
Rea ction . To a 25 mL round-bottom flask equipped with
magnetic stirrer were added preformed catalyst (0.011 g,
0.0256 mmol, 0.5 mol %), nitrile (5 mmol), EtOH (4 mL), and
H2O (2 mL), and the solution was heated to 80 °C (in air). After
the required reaction time (conversion was checked by TLC
and GC), the reaction was allowed to come to room tempera-
ture and the solvent was removed under vacuum. After
redissolution in DCM or THF, the solution was filtered, the
solvent was removed, and the solid product was dried over-
night under vacuum to yield the corresponding amides, gener-
ally pure enough for analysis. If further purification is needed,
the products were recrystallized from THF or DCM.
1-(4-Meth ylp h en yl)cyclop r op a n eca r boxa m id e (5a ) was
isolated as a white crystalline compound: yield 99%; mp 76-
77.5 °C; 1H NMR (CDCl3) δ 1.05 (t, J ) 3.4 Hz, 2H), 1.58 (t, J
) 3.7 Hz, 2H), 2.34 (s, 3H), 5.35 (br, 1H), 5.92 (br, 1H), 7.16
(d, J ) 7.3 Hz, 2H), 7.30 (d, J ) 7.6 Hz, 2H); 13C NMR (CDCl3)
δ 175.5, 136.2, 135.4, 129.2, 128.1, 28.1, 19.6, 14.5; HRMS (EI+)
m/z 175.1004, calcd for C11H13NO 175.0997. Anal. Calcd for
C11H13NO: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.51; H, 7.66;
N, 7.96.
2-P h en yl-2-{[(2S,3R,4S,5S,6R)-3,4,5-tr ih ydr oxy-6-({[(2R,
3R,4S,5S,6R)-3,4,5-tr ih yd r oxy-6-(h ydr oxym eth yl)tetr a h y-
d r o-2H -p yr a n -2-yl]oxy}m et h yl)t et r a h yd r o-2H -p yr a n -2-
yl]oxy}a cet a m id e (5j) was isolated as a white crystalline
compound: yield 98%; mp 57-59 °C; [R]D ) -125 (c ) 0.625,
H2O); 1H NMR (D2O) δ 3.19-3.24 (m, 2H), 3.26-3.40 (m, 6H),
3.58 (dd, J ) 5.4, 12.2 Hz, 1H), 3.73 (dd, J ) 5.4, 12.2 Hz,
1H), 3.78 (d, J ) 11.2 Hz, 1H), 4.06 (d, J ) 11.2 Hz, 1H), 4.15
(d, J ) 7.8 Hz, 1H), 4.39 (d, J ) 7.8 Hz, 1H), 5.25 (s, 1H),
7.32-7.36 (m, 5H); 13C NMR (D2O) δ 174.0, 133.5, 128.0, 127.5,
126.6, 101.3, 97.4, 77.0, 74.3, 74.1, 73.7, 73.4, 71.5, 71.2, 68.0,
67.7, 66.7, 59.1; MS (electro spray) 498 (M + Na+, 100). Anal.
Calcd for C20H29NO12‚H2O: C, 48.68; H, 6.33; N, 2.84. Found:
C, 48.69; H, 6.63; N, 2.83.
X-r a y Cr ysta llogr a p h ic Da ta of Ca ta lyst 2.45 See the
Supporting Information.
Ack n ow led gm en t. We thank Ms. T. Tiemersma for
GC and HPLC analysis and Dr. A. Meetsma for X-ray
analysis. Financial support from DSM and the Dutch
Ministry of Economic Affairs for a subsidy under the
EET scheme (Grant Nos. EETK97107 and EETK99104)
is gratefully acknowledged.
1-(4-Meth ylp h en yl)cyclop en ta n eca r boxa m id e (5b) was
isolated as a white crystalline compound: yield 99%; mp 110-
1
112 °C; H NMR (CDCl3) δ 1.69-1.74 (m, 2H), 1.75-1.81 (m,
Su p p or tin g In for m a tion Ava ila ble: General experimen-
2H), 1.92-2.12 (m, 2H), 2.33 (s, 3H), 2.36-2.52 (m, 2H), 5.20
(br, 1H), 5.48 (br, 1H), 7.15 (d, J ) 6.6 Hz, 2H), 7.26 (d, J )
6.4 Hz, 2H); 13C NMR (CDCl3) δ 177.8, 139.6, 135.1, 127.9,
125.1, 57.2, 35.3, 22.5, 19.4; HRMS (EI+) m/z 203.1354, calcd
for C13H17NO 203.1310. Anal. Calcd for C13H17NO: C, 76.81;
H, 8.43; N, 6.89. Found: C, 76.88; H, 8.61; N, 6.91.
1
tal procedure; H, 13C, 2D COSY, and NOESY NMR spectra
of 5j and 5a -c; selected X-ray data of catalyst 2. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O035487J
1-(4-Meth ylp h en yl)cycloh exa n eca r boxa m id e (5c) was
isolated as a white crystalline compound: yield 96%; mp 112-
(41) (a) Pala, W. C.; Susan, D.; Erich, M.; Satinder, B.; Pagni, R.
M.; Kabalka, G. W. Tetrahedron Lett. 1995, 36, 3469-3472. (b) Liu,
K.-T.; Shih, M.-H.; Huang, H.-W.; Hu, C.-J . Synthesis 1988, 9, 715-
717. (c) Merchant, K. J . Tetrahedron Lett. 2000, 41, 3747-3750. (d)
Whitmore, F. C.; Langlois, D. P. J . Am. Chem. Soc. 1932, 54, 3441-
3447. (e) Delseth, C.; Nguyen, T. T.-T.; Kintzinger, J .-P. Helv. Chim.
Acta 1980, 63, 498-503. (f) Lightner, D. A.; Pak, C.-S. J . Org. Chem.
1975, 40, 2724-2728.
1
114 °C; H NMR (CDCl3) δ 1.38-1.53 (m, 6H), 1.86-2.00 (m,
2H), 2.16-2.26 (m, 2H), 2.32 (s, 3H), 5.36 (br, 1H), 6.12 (br,
1H), 7.15 (d, J ) 8.3 Hz, 2H), 7.30 (d, J ) 8.3 Hz, 2H); 13C
NMR (CDCl3) δ 177.7, 138.8, 134.9, 128.0, 124.9, 48.9, 32.9,
24.3, 21.3, 19.4; HRMS (EI+) m/z 217.1456, calcd for C14H19
-
(42) (a) Frimer, A. A.; Aljadeff, G.; Ziv, J . J . Org. Chem. 1983, 48,
1700-1705. (b) Mauger, J .; Nagasawa, T.; Yamada, H. Tetrahedron
1989, 45, 1347-1354. (c) Otto, M.-C.; Wang, M.-X. Tetrahedron Lett.
1995, 36, 9561-9564. (d) Levin, J . I.; Turos, E.; Weinreb, S. M. Synth.
Commun. 1982, 12, 989-994. (e) Floyd, A. J .; Kinsman, R. G.; Yusuf,
R.-A.; Brown, D. W. Tetrahedron 1983, 39, 3881-3886. (f) Blanchette,
J . A.; Brown, E. V. J . Am. Chem. Soc. 1952, 74, 2098-2099.
(43) (a) Bergmann, E. D.; Pinchas, S. J . Org. Chem. 1950, 15, 1184-
1190. (b) Ramesha, A. R.; Bhat, S.; Chandrasekaran, S. J . Org. Chem.
1995, 60, 7682-7683. (c) Bendale, P. M.; Khadilkar, B. M. Synth.
Commun. 2000, 30, 1713-1718.
(44) (a) Rupe, H.; Majewski, S. Chem. Ber. 1900, 33, 3405-3406.
(b) Field, L.; Hughmark, P. B.; Shumaker, H. S.; Marshall, W. S. J .
Am. Chem. Soc. 1961, 83, 1983-1987. (c) Chattopadhyaya, J . B.; Rama
Rao, A. V. Tetrahedron 1974, 30, 2899-2900. (d) Beugelmans, R.;
Ginsburg, H.; Bois-Choussy, M. J . Chem. Soc., Perkin Trans. 1 1982,
1149-1152. (e) Naves, Y.-R.; Ardizio, P. Bull. Soc. Chim. Fr. 1957,
1053-1056. (f) Grotjahn, D. B.; Vollhardt, K.; Peter, C. Synthesis 1993,
6, 579-605.
NO 217.1467. Anal. Calcd for C14H19NO: C, 77.36; H, 8.81;
N, 6.45. Found: C, 77.61; H, 9.06; N, 6.41.
2-Meth yl-2-p h en ylp en ta n a m id e (5d )40a was isolated as
colorless oil: yield 98%; 1H NMR (CDCl3) δ 0.85 (t, J ) 7.1
Hz, 3H), 0.95-1.35 (m, 2H), 1.47 (s, 3H), 1.85-1.97 (m, 2H),
5.33 (br, 1H), 6.61 (br, 1H), 7.20-7.33 (m, 5H); 13C NMR
(CDCl3) δ 178.8, 142.7, 127.0, 125.3, 125.1, 48.8, 39.6, 22.1,
16.2, 13.1; MS(CI+) 209 (M + NH4+, 100).
2-Meth yl-2,3-d ip h en ylp r op a n a m id e (5e)40 was isolated
as a slight yellow crystalline compound: yield 96%; mp 126-
128 °C (lit.40a 133 °C); 1H NMR (CDCl3) δ 1.46 (s, 3H), 3.29
(dd, J ) 12.9, 13.2 Hz, 2H), 5.41 (br, 1H), 5.47 (br, 1H), 6.30-
6.81 (m, 2H), 7.11-7.12 (m, 3H), 7.21-7.29 (m, 5H); 13C NMR
(CDCl3) δ 178.1, 141.5, 135.9, 129.1, 127.0, 126.1, 125.8, 125.7,
124.8, 49.9, 43.5, 21.4; HRMS (EI+) m/z 239.1321, calcd for
C
16H17NO 239.1310.
2,2-Dim eth yl p r op a n a m id e (5f)41 was isolated as a white
(45) The crystallographic data for catalyst 2 in this paper have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC-213536. Copies of the data can
be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html
or from the Cambridge Crystallographic Data Centre (CCDC), 12
Union Road, Cambridge CB2 1EZ, UK [Fax: (int) +44-1223/336-033;
E-mail: deposit@ccdc.cam.ac.uk].
waxy-like compound: yield 80%; mp 155-156 °C (lit.41d mp
155-157 °C).
(40) (a) Levy, S.; Tabart, M. Bull. Soc. Chim. Fr. 1931, 1782-1786.
(b) Mentzer, L.; Chopin, S. Bull. Soc. Chim. Fr. 1948, 586-588.
J . Org. Chem, Vol. 69, No. 7, 2004 2331