A novel approach for the one-pot preparation of α-amino amides by pd-catalyzed double carbohydroamination

Article abstract of DOI:10.1002/1521-3773(20010216)40:4<779::AID-ANIE7790>3.0.CO;2-1

A new domino reaction sequence, a palladium-catalyzed double carbohydroamination, which involves double carbonylation, amine condensation, and hydrogenation from an aryl iodide(1), a primary amine (2), and synthetic gas has been realized as a novel synthetic means for the one-pot synthesis of α-amino amides (3).

Full text of DOI:10.1002/1521-3773(20010216)40:4<779::AID-ANIE7790>3.0.CO;2-1

COMMUNICATIONS
The data in this report, in conjunction with the N-terminal
structure of the rapamycin PKS, allow us to identify 4 as the
true starter unit for the rapamycin PKS. The differing
stereospecificity of the enoyl reductions during the biosyn-
thesis of 1 for FK520, and by extrapolation for rapamycin, is
consistent with the use of the initiation module ER domain.[
The differences in stereochemical detail between the biosyn-
[4] J. Staunton, B. Wilkinson, Chem. Rev. 1997, 97, 2611 ± 2629.
[
5] T. Schwecke, J. F. Aparicio, I. Moln a r, A. König, L.-E. Khaw, S. F.
Haydock, M. Oliynyk, P. Caffrey, J. Cort e s, J. B. Lester, G. A. Böhm, J.
Staunton, P. F. Leadlay, Proc. Natl. Acad. Sci. USA 1995, 92, 7839 ±
7
843.
[6] N. L. Paiva, A. L. Demain, M. F. Roberts, J. Nat. Prod. 1991, 54, 167 ±
17]
177.
[
7] N. L. Pavia, M. F. Roberts, A. L. Demain, J. Ind. Microbiol. 1993, 12,
23 ± 428.
4
[
8]
[14, 15]
thesis of 1, and the biosynthesis of CHC
suggest that
[
8] K. K. Wallace, K. A. Reynolds, K. Koch, H. A. I. McArthur, M. S.
Brown, R. G. Wax, B. S. Moore, J. Am. Chem. Soc. 1994, 116, 11600 ±
11601.
[
18]
precursors of 4 occur as the free acids. By analogy to non-
[
19]
ribosomal peptide synthesis we suggest (Scheme 3) that the
[9] A. Shafiee, H. Motamedi, T. Chen, Eur. J. Biochem. 1994, 225, 755 ±
7
64.
A
[10] P. A. S. Lowden, G. A. Böhm, J. Staunton, P. F. Leadlay, Angew.
Chem. 1996, 108, 2395 ± 2397; Angew. Chem. Int. Ed. Engl. 1996, 35,
CO2H
CO-ACP
OH
CL domain
2
249 ± 2251.
4
[
[
11] a) H. Motamedi, S. J. Cai, A. Shafiee, K. O. Elliston, Eur. J. Biochem.
1
2
997, 244, 74 ± 80; b) H. Motamedi, A. Shafie, Eur. J. Biochem. 1998,
56, 528 ± 534.
HO
OH
CO-AMP HO
12] K. Wu, L. Chung, W. P. Revill, L. Katz, C. D. Reeves, Gene 2000, 251,
1 ± 90.
8
AMP
ATP
[13] K. A. Reynolds, K. K. Wallace, S. Handa, M. S. Brown, H. A. I.
PPi
HO
OH
McArthur, H. G. Floss, J. Antibiot. 1997, 50, 701 ± 703.
ACP
[
[
14] B. S. Moore, K. Poralla, H. G. Floss, J. Am. Chem. Soc. 1993, 115,
267 ± 5274.
5
15] B. S. Moore, H. Cho, R. Casati, E. Kennedy, K. A. Reynolds, U.
Mocek, J. M. Beale, H. G. Floss, J. Am. Chem. Soc. 1993, 115, 5254 ±
5266.
initiation
module
B
module 1
[16] S. Handa, H. G. Floss, Chem. Commun. 1997, 153 ± 154.
[
[
17] H. G. Floss, Nat. Prod. Rep. 1997, 14, 433 ± 452, and references therein.
18] K. A. Reynolds, K. A. Holland, Chem. Soc. Rev. 1997, 26, 337 ± 343,
and references therein.
CL ER ACP
KS AT DH ER KR ACP
S
S
S
[19] H. von Döhren, U. Keller, J. Vater, R. Zocher, Chem. Rev. 1997, 97,
675 ± 2705.
2
O
O
O
HO
OH HO
OH
HO
OH
Scheme 3. A) Proposed pathway for CL-catalyzed activation and subse-
A Novel Approach for the One-Pot
Preparation of a-Amino Amides by
Pd-Catalyzed Double Carbohydroamination**
quent attachment of 4 to the rapamycin PKS; B) translocation of ACP-
1
bound 4 involves reduction of the D bond by the initiation module ER
domain prior to chain elongation on module one of RAPS1, the N-terminus
of which is shown with a linear arrangement of the predicted catalytically
active domains. AMP ˆ adenosine monophosphate; Ppi ˆ inorganic phos-
phate; CL ˆ carboxylic acid ligase; ER ˆ enoyl reductase; ACP ˆ acyl
carrier protein; KS ˆ b-ketoacyl synthase; ATˆ acyl transferase; DH ˆ
dehydratase; KR ˆ b-ketoacyl reductase.
Yong-Shou Lin and Howard Alper*
Developing new synthetic methods for the preparation of
amino acids and their derivatives has attracted much attention
due to their applications to the fine chemical, agrochemical,
and pharmaceutical business sectors.[ Although a variety of
elegant routes has been discovered for the synthesis of amino
acids, amidocarbonylation (Wakamatsu reaction) is the only
method involving a transition metal complex catalyzed three-
component reaction of an aldehyde, an amide, and carbon
monoxide.[ Domino reactions, which include amidocarbony-
1]
CL domain catalyses formation of an AMP-activated form of
4
, which is subsequently transferred to the ACP domain.
Reduction by the ER domain is followed by transfer to the
KS1 domain of RAPS1 to initiate chain elongation. The
observation that 1 can also be directly incorporated points to a
broad substrate specificity in the CL domain which may allow
for its use for the production of analogues of rapamycin by
incorporation of a variety of alicyclic starter acids.
2]
[*] H. Alper, Y.-S. Lin
Center for Catalysis Research and Innovation
Department of Chemistry, University of Ottawa
Received: August 21, 2000 [Z15667]
1
0 Marie Curie, Ottawa, ON, K1N 6N5 (Canada)
Fax : (‡1)613-562-5871
[
[
[
1] a) R. R. Martel, J. Klicius, S. Galet, Can. J. Physiol. Pharmacol. 1977,
5, 48 ± 51; b) D. Latta, Hum. Exp. Toxicol. 2000, 19, 229.
2] A. B. Smith, S. M. Condon, J. A. McCauley, Acc. Chem. Res. 1998, 31,
1 ± 46, and references therein.
E-mail: halper@uottawa.ca
5
[
**] We are grateful to the Natural Sciences and Engineering Research
Council of Canada for support of this research.
3
3] F. J. Dumont, Q. X. Su, Life Sci. 1995, 58, 373 ± 395, and references
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
therein.
Angew. Chem. Int. Ed. 2001, 40, No. 4
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4004-0779 $ 17.50+.50/0
779

COMMUNICATIONS
lation, have proven effective for the one-pot synthesis of
organic compounds.[3]
amino acid derivatives, a previous case being Co- and Pd-
[2]
catalyzed amidocarbonylation. a-Amino amides, like a-
amino acids and their derivatives, are of medicinal value.[
9]
The first double carbonylation reaction, for introducing two
adjacent CO groups into an organic moiety, was found by
using cobalt carbonyl complexes as catalysts in converting
benzyl halides to the corresponding arylpyruvic acids.[
Development of the double carbonylation reaction has been
realized, for example, in the conversion of aryl and alkenyl
halides to the corresponding a-ketoamides and esters by using
The structure of the cyclohexylamino amide 2a was
1
13
established by H and C NMR spectroscopy, mass spec-
4]
[10]
trometry, as well as by elemental analysis. In addition to the
formation of 2a, cyclohexylamide (3a) was obtained as a by-
product, and traces to small amounts of a-N-cyclohexylimino
amide (4a) and N-benzylidenecyclohexylamine were also
detected in the reaction mixture. Various reaction conditions
were examined and the results are listed in Table 1. Addition
of triethylamine is essential for obtaining a higher proportion
of 2a over 3a (Table 1, entry 2). In the absence of 4Š
molecular sieves, some 4a was formed thus reducing the yield
of the amino amide (Table 1, entry 3). Reducing the reaction
temperature from 1208C to 1058C lowered the conversion of
iodobenzene to 2a (Table 1, entry 4). Increasing the hydrogen
[
5]
palladium complexes as catalysts, and in the synthesis of a-
ketolactones from epoxides by phase-transfer Co-catalyzed
[
6]
reactions. It is also known that a-keto acids are precursors of
[
7]
a-amino acids. Research in our laboratory has previously led
to useful methods for the hydrogenation of imines, a-
[
8]
ketoesters, and a-ketoamides. We now report a new domino
reaction, involving a sequence of double carbonylation, amine
condensation, and hydrogenation to produce a-amino amides.
Initial experiments were conducted by using iodobenzene,
cyclohexylamine (1a), carbon monoxide (800 psi; 1 psi ˆ
pressure from 100 to 400 psi afforded 5% of PhCH NHCy (by
2
hydrogenation of the other by-product PhCHˆNCy, Table 1,
6
894.76 Pa), hydrogen (100 psi), and Pd on charcoal as the
entry 6). In all of the reactions, an ammonium iodide
‡
�
[11]
RNH I was formed as a salt.
3
R
Primary amines other than cyclohexylamine can also be
used for the reaction. n-Butylamine (1b) gave the corre-
Pd/C, CO/H2
O
HN
NEt3, 4Å MS Ph CH C NH R
- RNH3+I–
O
PhI + RNH2
+
Ph C NH R
sponding a-amino amide (2b) in 67% yield together with
1
2
3
10]
2
9% of amide 3b (Table 1, entry 7).[ Using benzylamine
(1)
(
1c) gave 2c in only 24% yield, 3c in 34% yield, and several
R
N
C
O
other by-products (Table 1, entry 8).
The double carbohydroamination reaction is applicable to
various iodoarenes, giving the corresponding a-amino amides
+
Ph
C NH R
4
5
(
usually as the dominant products, together with amide 6
Table 2).[ Iodoarenes with electron-donating or electron-
10]
catalyst in the presence of triethylamine and 4Š molecular
sieves [Eq. (1); a: R ˆ cyclohexyl, b: R ˆ n-butyl, c: R ˆ
benzyl]. This reaction proceeded well to form a-cyclohexyl-
amino amide (2a, R ˆ cyclohexyl) as the major product (87%
yield, Table 1, entry 1). To our knowledge, this novel domino
reaction, double carbohydroamination, is unprecedented and
the first example of a one-pot preparation of a-amino amides
from the corresponding aryl halides. In addition, it is a rare
example of the transition metal catalyzed formation of a-
withdrawing substituents afforded a-amino amides in 60 to
8% yields (Table 2, entries 1 ± 5). Except for p-iodotrifluoro-
methylbenzene, the amides were formed in low yields.
8
Table 2. Pd-catalyzed double carbohydroamination of aromatic iodides.[a]
Cy
HN O
Pd/C, CO/H2
O
ArI
+
CyNH2
+
Ar C NH Cy
NEt3, 4Å, 120 °C Ar CH C NH Cy
6
CyNH3+I–
5
-
Table 1. Palladium-catalyzed double carbohydroamination of iodoben-
zene.
Yield[%][b]
Yield[%][b]
Entry
1[c]
ArI
5
6
[
a]
Entry
Amine
CO
psi]
H
[psi]
2
T
[8C]
Products [%][b]
Me
I
5a
88
6a
6
13
17
40
[
2
3
4
[
[
[
c]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1c
800
800
800
800
700
800
700
800
100
100
100
200
300
400
300
100
120
120
120
105
120
120
120
120
87
59
66
46
77
73
67
24
5
0
2[c,d]
MeO
Cl
I
5b
5c
5d
68
65
60
6b
6c
6d
d]
41
18
18
9
8
29
34
trace
10
18
trace
0
c,e]
3[c,d]
I
[
[
c]
f]
4
F3C
I
trace
5
[
g]
I
[
a] Reaction conditions: PhI (1 mmol), amine (10 mmol), Et
3
N (3 mL), 4 Š
5
[c,d]
5e
64
6e
18
MS (1 g), 10% of Pd/C (0.02 mmol), and CO/H
reactions for 24 h. [b] The yields were determined by H NMR spectro-
2
were employed in the
1
scopy. [c] A small amount of PhCHˆNCy (less than 5%) was obtained.
[a] Reaction conditions: Iodide (1 mmol), cyclohexylamine (10 mmol),
NEt (3 mL), 4Š molecular sieves (1 g), 10% of Pd/C (0.02 mmol), CO
(800 psi), and H
[
d] The reaction was carried out by using 1a (4 mL) as solvent instead of
3
Et
sieves. [f] PhCHˆNCy (5%) and PhCH
by-products. [g] PhCHˆNHCH
Ph (31%) and
PhCH NH were produced.
3
N. [e] The reaction was carried out in the absence of 4 Š molecular
NHCy (5%) were also formed as
small amount of
2
(100 psi) were employed at 1208C for 24 h. [b] Yields
were determined based on 1H NMR spctroscopy. [c] Trace amounts of
2
a
ArCHˆNCy were detected. [d] A small amount of a-imino amide (less
2
(
2
)
2
than 3%) was detected in the mixture.
780
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1433-7851/01/4004-0780 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2001, 40, No. 4

COMMUNICATIONS
A possible pathway for the formation of a-amino amides
Scheme 1) may involve the following sequence: double
carbonylation of the iodoarene to give the a-keto amide,
[1] a) G. C. Barrett, Chemistry and Biochemistry of Amino Acids, Chap-
man and Hall, London, 1985; b) I. Wagner, H. Musso, Angew. Chem.
(
1
983, 95, 827; Angew. Chem. Int. Ed. Engl. 1983, 22, 816.
[
2] a) M. Beller, M. Eckert, Angew. Chem. 2000, 39, 1026; Angew. Chem.
Int. Ed. 2000, 39, 1010; b) M. Beller, Med. Res. Rev. 1999, 19, 357; c) K.
Kühlein, H. Geissler in Transition Metals for Organic Synthesis:
Building Blocks and Fine Chemicals (Eds.: M. Beller, C. Bolm),
Willey-VCH, Weinheim, 1998, p. 79.
RNH2
Pd/C, CO
O
C
O
PhI + RNH2
NEt3
+ -
Ph
C NH R
- H2O
1
-
RNH3 I
[3] a) L. F. Tietze, Chem. Rev. 1996, 96, 115; b) L. F. Tietze, U. Beifuss,
Angew. Chem. 1993, 105, 137; Angew. Chem. Int. Ed. 1993, 32, 131.
[4] a) H. Alper, H. des Abbayes, J. Organomet. Chem. 1977, 134, C11;
b) H. des Abbayes, A. Buloup, J. Chem. Soc. Chem. Commun. 1978,
R
R
N
C
O
H2
Pd/C
HN O
1
090.
Ph
C NH R
Ph CH C NH R
[
5] a) F. Ozawa, H. Soyama, T. Yamamoto, A. Yamamoto, Tetrahedron
Lett. 1982, 23, 3383; b) T. Kobayashi, M. Tanaka, J. Organomet. Chem.
1982, 233, C64.
4
2
Scheme 1. Reaction pathway for the double carbohyroamination of
iodobenzene. a: R ˆ cyclohexyl, b: R ˆ n-butyl, c: R ˆ benzyl.
[6] H. Alper, H. Arzoumanian, J.-F. Petrignani, M. Saldana-Maldonado,
J. Chem. Soc. Chem. Commun. 1985, 340.
[
7] K. Harada, T. Munegumi in Comprehensive Organic Synthesis, Vol. 8
amine condensation with the a-keto group of the latter to
form an a-imino amide 4 as an intermediate, and hydro-
genation of the imino double bond of 4 to give the a-amino
amide 2. a-Keto amide formation in the double carbonylation
process can be considered to be related to that described by
Yamamoto and co-workers, via formation of an acylcarba-
moylpalladium intermediate followed by reductive elimina-
(
Eds.: B. M. Trost, I. Flemming), Pergamon Press, Oxford, 1991,
p. 139.
[8] a) R. Aldea, H. Alper, J. Org. Chem. 1998, 63, 9425; b) Z. Zhou, B. R.
James, H. Alper, Organometallics 1995, 14, 4209.
[
9] a) A. Gringauz, Introduction to Medicinal Chemistry: How Drugs Act
and Why, Wiley-VCH, New York, 1997; b) A. N. Collins, G. N.
Sheldrake, J. Crosby, Chirality in Industry: The Commercial Manu-
facture and Applications of Optically Active Compounds, Wiley,
[
12]
Chichester, 1992.
tion.
Palladium-catalyzed double carbonylation of aryl
1
[
10] For details on H and 13C NMR spectroscopy, mass spectrometry, IR
spectroscopy, and elemental analysis of a-amino amides 2 and 5, see
Supporting Information.
halides in the presence of a secondary amine to give a-keto
[
13]
amides has been extensively studied.
Using a primary
instead of a secondary amine in the double carbonylation
reaction has only been described in several papers.[
However, the double carbohydroamination reaction se-
quence, described herein can, for the first time, produce a-
amino amides in a one-pot manner. The formation of the
amide by-product results by monocarbonylation of iodoben-
zene. The formation of the by-product imine can be attributed
to competitive reactions of hydroformylation of iodobenzene
with subsequent amine condensation.
[11] It is noteworthy that using a catalyst other than Pd/C, such as the
5b, 12]
palladium(0) complex [Pd(PPh ) ] or palladium(ii) complex
3
4
[PdCl
2
(MeCN)
2
], together with Ph
2
MeP, gave rise to the formation
of 4a and oxamide CyNHCOCONHCy as major products, respec-
tively.
[12] F. Ozawa, H. Soyama, H. Yanagihara, I. Aoyama, H. Takino, K. Izawa,
T. Yamamoto, A. Yamamoto, J. Am. Chem. Soc. 1985, 107, 3235.
[13] A. Yamamoto, Bull. Chem. Soc. Jpn. 1995, 68, 433, and references
therein.
In conclusion, palladium-catalyzed double carbohydroami-
nation, consisting of double carbonylation, amine condensa-
tion, and hydrogenation, is a novel domino reaction for the
one-pot production of a-amino amides. The reaction is simple
in execution and workup, and is of considerable potential for
the synthesis of a-amino amides and other a-amino acid
derivatives.
A Neutral Three-Coordinate Alkylrhodium(i)
Complex: Stabilization of a 14-Electron Species
by g-C�H Agostic Interactions with a Saturated
Hydrocarbon Group**
Heiko Urtel, Claudia Meier, Frank Eisenträger,
Frank Rominger, Jens P. Joschek, and Peter Hofmann*
Experimental Section
Selective activation and functionalization of alkanes by
transition metals is a highly attractive goal[ which has led to
considerable efforts to understand hydrocarbon interactions
General procedure for the double carbohydroamination: A mixture of
iodobenzene (0.112 mL, 1 mmol), cyclohexylamine (1.14 mL, 10 mmol),
triethylamine (3 mL), Pd/C (10%, 0.0213 g, 0.02 mmol), and 4Š molecular
sieves (1 g) was placed in a 45-mL stainless steel autoclave equipped with a
glass liner and magnetic stirrer. The autoclave was purged three times with
1]
2
carbon monoxide and then pressurized with CO and H , respectively, to the
[
*] Prof. Dr. P. Hofmann, Dipl.-Chem. H. Urtel, Dr. C. Meier,
Dr. F. Eisenträger, Dr. F. Rominger, Dr. J. P. Joschek
Organisch-Chemisches Institut, Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
E-mail: ph@phindigo.oci.uni-heidelberg.de
desired level (see Tables 1 and 2). The reaction was carried out in an oil
bath for 24 h and the autoclave was cooled to room temperature and the gas
was released. The reaction mixture was filtered through Celite, washed
several times with CH Cl , and filtrate was evaporated to give a pale yellow
2 2
oily residue. Addition of ether gave a white precipitate, identified as
‡
�
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 247, Graduate College Fellowship to H.U.), by the BASF AG, by
the Degussa-Hüls AG, by the Fonds der Chemischen Industrie, and by
the EU.
CyNH
3
I . After filtration, the diethyl ether solution was evaporated and
1
the resulting oil was subjected to H NMR spectroscopy, and then to
preparative TLC, using hexane/ethyl acetate as eluant, affording the pure
a-amino amide.[
10]
Supporting information for this article is available on the WWW under
http://www.angewandte.com/ or from the author.
Received: October 18, 2000 [Z15967]
Angew. Chem. Int. Ed. 2001, 40, No. 4
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4004-0781 $ 17.50+.50/0
781