Palladium-catalyzed synthesis of α-iminoamides from imidoyl chlorides and a carbamoylsilane

Article abstract of DOI:10.1021/jo050545h

A series of pure imidoyl chlorides were converted into α-iminoamides by treatment with a carbamoylsilane under catalysis by palladium(0) complexes.

Full text of DOI:10.1021/jo050545h

Palladium-Catalyzed Synthesis of
r-Iminoamides from Imidoyl Chlorides and
a Carbamoylsilane
1 are secondary amides, and among the most typical
reagents which have been employed for their conversion
5
to imidoyl chlorides are PCl , phosgene, thionyl chloride,
7
and triphenylphosphine-carbon tetrachloride. However,
for a given substitution pattern in 1, the use of any one
of these traditional preparative methods may give rise
to various coproducts which may seriously impact the
ability to isolate imidoyl chlorides in a pure state. Taken
together with their hydrolytic instability, these factors
have led in many instances to their preparation and use
without intervening isolation. For the present purpose,
imidoyl chlorides were required which were free of
protonic impurities, as 2 is subject to ready protonolysis.
We were thus drawn to a recently reported methodology
for their preparation (and in situ use) that employed
oxalyl chloride and 2,6-lutidine,8 as we believed that
removal of the attendant amine hydrochloride by filtra-
tion and subsequent distillation could afford pure imidoyl
chlorides. We find that imidoyl chlorides (1a-j) bearing
Robert F. Cunico* and Rajesh K. Pandey
Department of Chemistry and Biochemistry,
Northern Illinois University, DeKalb, Illinois 60115
rfc@marilyn.chem.niu.edu
Received March 17, 2005
,9
A series of pure imidoyl chlorides were converted into
R-iminoamides by treatment with a carbamoylsilane under
catalysis by palladium(0) complexes.
1
2
a fairly wide range of substitution patterns (R , R )
alkyl, aryl) may be prepared using this protocol and
easily isolated as analytically pure materials by vacuum
distillation. However, the imidoyl chlorides 1k-m could
R-Aminoamides are important synthetic targets, as
not be prepared by the oxalyl chloride method, and were
they represent the fundamental subunit of peptides and
10
obtained by the use of PCl
5
.
These results are shown
1
2
proteins. We and others have described methodologies
which access such structures by directly establishing
bond connectivity between the carbonyl and R-carbon
atoms. Another entry, however, would be a two-step
process in which similar establishment of connectivity
would be followed by reduction of an R-imine function to
generate the R-amino group. This approach would require
the availability of R-iminoamides which, to our knowl-
edge, have only been reported a few times in the chemical
in Table 1. Satisfactory analytical data were obtained for
1
k and 1l, but not for 1m, whose spectral data and
eventual conversion to 3m confirmed its structure.
A preliminary investigation of reaction parameters
for the conversion of 1e to 3e is given in Table 2. These
data suggested a standard reaction profile under the
mildest conditions which employed bis(tri-tert-butyl-
phosphine)palladium(0) as catalyst in THF solvent at 60
°
C. Positive results from exploring the full range of
3
literature. In both of these instances, the iminoamides
imidoyl chlorides prepared are summarized in Table 3.
Attempts to use N-phenyl, C-aliphatic imidoyl chlorides
bearing R-protons (1, R1 ) Me, nPr, iPr) led to the
isolation of small yields (12-20%) of what spectral data
indicated were impure imidoamides, possibly contami-
nated with the tautomeric enamines. When N-phenyl
were derived from previously extant carbon frameworks.
We have recently had success in assembling R-ketoam-
ides from the reaction of acid chlorides with a carbam-
4
oylsilane, and report here on the analogous use of
imidoyl chlorides (1) with a carbamoylsilane (2) to form
R-iminoamides (3).5
(
6) (a) Katritzky, A. R.; Hayden, A. E.; Kirichenko, K.; Pelphrey,
P.; Ji, Y. J. Org. Chem. 2004, 69, 5108-5111 and references therein.
b) Kantlehner, W.; Mergen, W. W. In Comprehensive Organic Func-
(
tional Group Transformations; Katritzky, A. R., Meth-Cohn, O., Rees,
C. W., Eds.; Pergamon: Oxford, UK, 1995; Vol. 5, pp 654-660. (c)
Kantlehner, W. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 6, pp 523-529.
(
d) Sustmann, R.; Korth, H. G. In Methoden der Organische Chemie;
Although the preparation and use of imidoyl chlorides
have been reported frequently, an examination of the
literature indicated that few of these species had actually
been isolated and characterized. Common precursors to
Thieme: Stuttgart, Germany, 1985; Vol. E5, pp 628-631. (e) Tennant,
G. In Comprehensive Organic Chemistry; Pergamon: Oxford, UK, 1979;
pp 469-487. (f) Bonnett, R. In The Chemistry of the Carbon-Nitrogen
Bond; Patai, S., Ed.; Interscience: London, UK, 1970; Chapter 13. (g)
Ulrich, H. The Chemistry of Imidoyl Halides; Plenum: New York, 1968.
6
(
7) (a) Appel, R.; Warning, K.; Ziehn, K.-D. Chem. Ber. 1973, 106,
(
1) (a) Chen, J.; Cunico, R. F. Tetrahedron Lett. 2003, 44, 8025-
3450-3454. (b) This method has also been used to form imidoyl
chlorides directly from mixtures of carboxylic acids and primary
amines: Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.;
Uneyama, K. J. Org. Chem. 1993, 58, 32-35.
8
8
027. (b) Chen, J.; Cunico, R. F. Tetrahedron Lett. 2002, 43, 8595-
597.
(
2) (a) Lin, Y.-S.; Alper, H. Angew. Chem., Int. Ed. 2001, 40, 779-
7
3
81. (b) D o¨ mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168-
(8) Manley, P. J.; Bilodeau, M. T. Org. Lett. 2002, 4, 3127-3129.
(9) The combination of oxalyl chloride and DMF has been used to
produce an imidoyl chloride: Zhong, Y.-L.; Lee, J.; Reamer, R. A.;
Askin, D. Org. Lett. 2004, 6, 929-931. The same reagents afford
amidinium salts (Vilsmeier reagents) from tertiary amides (cf. Bosshard,
H. H.; Zollinger, H. Helv. Chim. Acta 1959, 42, 1659-1671).
210.
(
3) (a) Masuda, K.; Adachi, J.; Nomura, K. J. Chem. Soc., Perkin 1
1
981, 1033-1036. (b) Lopatin, W.; Young, P. R., Jr.; Owen, T. C. J.
Am. Chem. Soc. 1979, 101, 960-969.
(4) Chen, J.; Cunico, R. F. J. Org. Chem. 2004, 69, 5509-5511.
5) All 3 prepared were monoisomeric and are arbitrarily shown as
(
(10) The use of PCl
5
for the preparation of 1 containing R ) alkyl
the Z isomer.
on the imide carbon atom did not afford pure imidoyl chlorides.
10.1021/jo050545h CCC: $30.25 © 2005 American Chemical Society
5344
J. Org. Chem. 2005, 70, 5344-5346
Published on Web 05/20/2005

TABLE 1. Imidoyl Chlorides Prepared with Oxalyl
SCHEME 1
Chloride (1a-j) and PCl5 (1k-m)
R1
R2
yield (%)
1
1
1
1
1
1
1
1
1
1
1
1
1
a
b
c
d
e
f
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH(Me)Ph
CH(Me)Ph
CH(Me)Ph
Ph
70
76
80
72
90
90
85
85
80
74
92
90
85
i
Pr
nPr
tBu
Ph
4-MeOPh
4-CNPh
nPr
g
h
i
tBu
Ph
2-furyl
2-thienyl
4-pyridyl
j
k
l
Ph
Ph
m
f O silyl group rearrangement within 2 is postulated.
Loss of TMSCl from 6 then affords 7, which undergoes
migration of the carbamoyl function and expulsion of
TABLE 2. Optimization of Reaction Conditions
PdL
2
to afford product 3.14
To demonstrate the utility of the product R-iminoam-
ides to afford R-aminoamides, reduction of a representa-
tive example was carried out with 3e and sodium
borohydride in methanol to give 96% of R-aminoamide
entrya catalystb temp (°C) time (h) solvent yield (%)
c
d
1
2
3
4
5
6
7
8
none
A
60
60
60
25
60
80
60
60
30
90
90
6
20
3
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
THF
0
33
14
trace
70
81
75
0
8
.
B
C
C
C
C
4
1
C
DMF
a
.5 mmol:0.6 mmol ratio of 1:2, 1 M. b 4 mol % of A, tetrakis-
0
(
triphenylphosphine)palladium(0); B, dichlorobis(triphenylphos-
phine)palladium(II); C, bis(tri-tert-butylphosphine)-palladium(0).
Experimental Section
c
To complete disappearance of 2. d Isolated yield.
Imidoyl Chlorides (Oxalyl Chloride Method). Under
TABLE 3. Preparation of 3 from 1 and 2 in THFa,b
imidoyl chloride 1
anhydrous conditions (Ar atmosphere), a mixture of amide (5.0
2 2
mmol) and 2,6-lutidine (8.3 mmol) in CH Cl (20 mL) was cooled
to 0 °C. To the stirred solution was added oxalyl chloride (5.0
mmol, 2 M solution in CH Cl diluted with 5 mL of CH Cl
dropwise over 5 min and the reaction mixture held at 0 °C for
0 min. Solvent was evaporated under vacuum and hexane (15
R1
R2
c
2
2
2
2
)
time (h)
yield of 3 (%)
1
1
1
1
1
1
1
d
e
g
i
k
l
m
tert-butyl
Ph
4-CNPh
tert-butyl
2-furanyl
2-thienyl
4-pyridyl
Ph
Ph
Ph
5
4
0.8
10
1
5
2
95
3
d
75 (83)
mL) was added. After the solution was stirred for 1 h, solids
were removed by glass frit filtration under Ar, and the filtrate
was concentrated and kugelrohr distilled.
94
77
95
88
93
e
CH(Me)Ph
Ph
Ph
Ph
Imidoyl Chlorides (PCl
amide and PCl were heated at 90 °C for 1 h. After the solution
was cooled to 25 °C, POCl was removed under vacuum and the
residue distilled. In the preparation of 1m, equimolar amounts
of amide and PCl (3.3 mmol) were refluxed in chloroform (15
5
Method). Equimolar amounts of
5
3
a
b
0
.5 mmol:0.6 mmol ratio of 1:2, 1 M. 4 mol % of bis(tri-tert-
butylphosphine)palladium(0). Isolated yield. d Yield from 9× scale-
c
5
up. e 1.5 equiv of 2 used.
mL) for 3 h. After the solution was cooled to 25 °C, 3.3 mmol of
triethylamine was added and the mixture was stirred for 1 h.
Solvent was removed under vacuum and diethyl ether was
added. After 3 h, solids were removed by filtration and the
solution evaporated. The solid product was very sensitive to
manipulation.
4-methoxybenzimidoyl chloride was used, total consump-
tion of 2 was observed within 1.5 h, but subsequent
chromatography only afforded 30% of N,N-dimethyl 2-(4-
methoxyphenyl)-2-oxo-ethanamide (4), the imine hy-
drolysis product of the expected iminoamide.
R-Iminoamides. A Schlenk tube fitted with a fused Teflon
vacuum stopcock and microstirbar was flame-heated under
The overall reaction may be understood by the se-
quence of events described in Scheme 1. Existing reports
on various coupling reactions involving imidoyl chlorides
and palladium catalysts suggest that the imidoylpalla-
dium species 5 may serve as a common initial intermedi-
ate.
between 5 and a nucleophilic carbene arising from a C
(
11) (a) Kobayashi, T.; Sakakura, T.; Tanaka, M. Tetrahedron Lett.
1985, 26, 3463-3466. (b) Tanaka, M.; Kobayashi, T. Synthesis 1985,
67-969.
9
(
12) Isolation of similar complexes, prepared by a different route,
has been reported: Vicente, J.; Abad, J.-A.; Martinez-Viviente, E.;
Jones, P. G. Organometallics 2003, 22, 1967-1978.
(13) Cunico, R. F.; Maity, B. C. Org. Lett. 2003, 5, 4947-4949.
(
11,12
Following previous arguments,13 ligand exchange
14) We do not exclude the possibility that imine to carbene-carbon
migration may precede TMSCl expulsion.
J. Org. Chem, Vol. 70, No. 13, 2005 5345

vacuum and refilled with Ar. Freshly prepared imidoyl chloride
0.5 mmol) and carbamoylsilane (0.6 mmol) were added and a
-fold evacuation-Ar refill was carried out. Catalyst (4 mol %
Acknowledgment. This work was supported by
National Institutes of Health grant R15 GM065864.
(
3
relative to imidoyl chloride) was then added, followed by dry
THF or toluene (0.5 mL). The sealed reaction mixture was stirred
at the indicated temperature and monitored by H NMR, using
periodic aliquots. After disappearance of starting material,
volatiles were removed under vacuum and the residue was
chromatographed on flash silica gel (15-25% EtOAc in hexane).
Supporting Information Available: Analytical and spec-
1
13
tral (IR, H, and C NMR) data for all imidoyl chlorides and
iminoamides; details of the preparation of 8. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
JO050545H
5346 J. Org. Chem., Vol. 70, No. 13, 2005