Lactam synthesis via the intramolecular hydroamidation of alkynes catalyzed by palladium complexes

Article abstract of DOI:10.1021/jo060142x

The palladium complexes catalyzed intramolecular hydroamidation reaction of amidoalkynes gives the corresponding lactams in good to high yields. For example, in the presence of 10 mol % of Pd(PPh₃)₄ and 20 mol % of PhCOOH, the reacti

Full text of DOI:10.1021/jo060142x

various nitrogen heterocycles. However, an analogous trans-
formation involving the cyclization of activated C-C bonds with
tethered amides has not been achieved, perhaps due to the lower
nucleophilicity of amide nitrogen compared to amines.
Recently, we reported6 an entirely new method for the
hydroamination of alkynes using a Pd(PPh3)4/PhCOOH com-
bined catalyst system. In this process, acyclic amines (via
intermolecular hydroamination, eq 1) as well as cyclic amines
such as piperidines and pyrrolidines (via intramolecular hy-
droamination, eq 2) were obtained in excellent yields. If we
can extend this concept to hydroamidation, lactams can be
synthesized. With this in mind, we synthesized the substrate 1
and tested for the hydroamidation reaction. Our initial research
was focused on the study of solvents, concentration, and catalyst
loading. However, in all cases, isomerization via â-hydride
elimination mechanism7 occurred, giving the corresponding
diene 2 exclusively (eq 3). All attempts to suppress the â-hydride
elimination product 2 by using Pd2(dba)3‚CHCl3 catalyst in
combination with various ligands such as dppb, dppe, dppm,
and dppf failed. After a number of attempts, we found that the
N-tosylamides 3 undergo intramolecular hydroamidation in the
presence of Pd(PPh3)4/PhCOOH catalyst in 1,4-dioxane at 100
°C to give the desired lactams 4 in good to high yields (eq 4).
The key for this success was to use a tosyl group on amide
nitrogen.
Lactam Synthesis via the Intramolecular
Hydroamidation of Alkynes Catalyzed by
Palladium Complexes
Nitin T. Patil, Zhibao Huo, Gan B. Bajracharya, and
Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science,
Tohoku UniVersity, Sendai 980-8578, Japan
yoshi@mail.tains.tohoku.ac.jp
ReceiVed January 22, 2006
The palladium complexes catalyzed intramolecular hydro-
amidation reaction of amidoalkynes gives the corresponding
lactams in good to high yields. For example, in the presence
of 10 mol % of Pd(PPh3)4 and 20 mol % of PhCOOH, the
reaction of the amidoalkyne 3a in 1,4-dioxane at 100 °C
proceeded smoothly to give the corresponding lactam 4a in
92% yield.
The transition metal complex catalyzed addition of amines
to activated C-C bonds, generally known as hydroamination,1
has proven to be a valuable route for the formation of C-N
bonds. Particularly noteworthy is the intramolecular cyclization
of amines with tethered C-C bonds which leads to the formation
of a wide variety of nitrogen heterocycles. For example, the
hydroamination/cyclization of aminoalkenes,2 aminoallenes,3
aminodienes,4 and aminoalkynes5 using transition metal and
lanthanide complexes provides an efficient way for synthesizing
(1) For a review, see: (a) Muller, T. E.; Beller, M. Chem. ReV. 1998,
98, 675-703. (b) Pohlki, F.; Doye, S. Chem. Soc. ReV. 2003, 32, 104-
114. For a general review, see: (c) Nakamura, I.; Yamamoto, Y. Chem.
ReV. 2004, 104, 2127-2198.
(2) (a) Kim, Y. K.; Livinghouse, T.; Bercaw, J. E. Tetrahedron Lett.
2001, 42, 2933-2935. (b) Tian, S.; Arredondo, V. M.; Stern, C. L.; Marks,
T. J. Organometallics 1999, 18, 2568-2570. (c) Molander, G. A.; Dowdy,
E. D. J. Org. Chem. 1998, 63, 8983-8988. (d) Kim, J. Y.; Livinghouse, T.
Org. Lett. 2005, 7, 1737-1739. (e) Hultzsch, K. C. AdV. Synth. Catal. 2005,
347, 367-391.
(3) (a) Arredondo, V. M.; McDonald, F. E.; Marks, T. J. J. Am. Chem.
Soc. 1998, 120, 4871-4872. (b) Meguro, M.; Yamamoto, Y. Tetrahedron
Lett. 1998, 39, 5421-5424.
After finding the key role of tosyl group for obtaining the
lactams by suppressing the formation of the â-hydride elimina-
tion product, we screened various metal catalysts in order to
search the best one.8 The results are summarized in Table 1.
As anticipated, the reaction of 3a in the presence of 10 mol %
of Pd(PPh3)4 in benzene, without addition of carboxylic acids,
did not give the desired product at all (entry 1). After addition
of 20% benzoic acid,9 the reaction became facile, and 4a was
isolated in 91% yield as the E-isomer (entry 2). Similar to our
previous observations, no formation of the Z-isomer was
(4) (a) Hong, S.; Kawaoka, A. M.; Marks, T. J. J. Am. Chem. Soc. 2003,
125, 15878-15892. (b) Hong, S.; Marks, T. J. J. Am. Chem. Soc. 2002,
124, 7886-7887.
(5) (a) Ackermann, L.; Bergman, R. G.; Loy, R. N. J. Am. Chem. Soc.
2003, 125, 11956-11963. (b) Bytschkov, I.; Doye, S. Tetrahedron Lett.
2002, 43, 3715-3718. (c) Muller, T. E.; Grosche, M.; Herdtweck, E.; Pleier,
A.-K.; Walter, E.; Yan, Y.-K. Organometallics 2000, 19, 170-183. (e)
Fairfax, D.; Stein, M.; Livinghouse, T.; Jensen, M. Organometallics 1997,
16, 1523-1525. (f) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1996, 118, 9295-
9306. For a general review on organolanthanide-catalyzed hydroamination,
see: (g) Hong, S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673-686. For
a general review on group IV metal complex catalyzed hydroamination,
see: (h) Bytschkov, I.; Doye, S. Eur. J. Org. Chem. 2003, 935-946.
1
observed as judged by the H NMR spectrum of the crude
reaction mixture. The use of acetic acid, instead of benzoic acid,
10.1021/jo060142x CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/29/2006
3612
J. Org. Chem. 2006, 71, 3612-3614

TABLE 1. Catalyst Optimization for Hydroamidation of 3a
TABLE 2. Palladium-Catalyzed Hydroamidation of Various
Amidoalkynesa
yieldb
(%)
entry
catalyst
additive
solvent
1
2
3
4
5
10% Pd(PPh3)4
10% Pd(PPh3)4
10% Pd(PPh3)4
10% Pd(PPh3)4
10% Pd(PPh3)4
10% Pd(PPh3)4
benzene
benzene
20% CH3COOH benzene
0c
20% PhCOOH
93 (91)d
72
20% H2O
20% MeOH
10% PPh3
benzene
benzene
benzene
63
52
6
7
14e
10% Pd(PPh3)4 20% PhCOOH
1,4-dioxane 94 (92)d
8
9
10
11
12
10% Pd(PPh3)4
10% Pd(PPh3)4
10% Pd(PPh3)4
10% Pd(PPh3)4
5% Pd(PPh3)4
20% PhCOOH
20% PhCOOH
20% PhCOOH
20% PhCOOH
20% PhCOOH
toluene
THF
CH3CN
CH2Cl2
1,4-dioxane
45
46
76
84
61
a The reactions of 3a (0.3 mmol) in the presence of metal catalysts and
additives were carried out at 100 °C in benzene (0.2 M) for 12 h. b Yields
were determined by 1H NMR spectroscopy with dibromomethaneas in
internal standard. c The starting material was observed by TLC. d Isolated
yield is shown in parentheses. e The reaction mixture was heated for 100
h.
provided 4a in lower yield (entry 3). We then examined other
proton sources, H2O (63%) and MeOH (52%); however, the
yields were not superior to those obtained with carboxylic acid
additives (entries 4 and 5). Rather surprisingly, the use of PPh3
as an additive did not work well for the present reaction (entry
6).6c Various solvents such as 1,4-dioxane, toluene, THF,
acetonitrile, and CH2Cl2 were examined, but we found that 1,4-
dioxane (92%) gave the best result (entries 7-11). Decreasing
the amount of catalyst resulted in lower yields (entry 12).
With optimized conditions in hand, the hydroamidation was
explored using a variety of amidoalkynes 3 containing either
electron-donating or electron-withdrawing groups in the aromatic
ring. The results are summarized in Table 2. Treatment of 3b,
having a methyl group at the para position in the aromatic ring
(6) (a) Kadota, I.; Shibuya, A.; Lutete, M. L.; Yamamoto, Y. J. Org.
Chem. 1999, 64, 4570-4571. (b) Lutete, M. L.; Kadota, I.; Shibuya, A.;
Yamamoto, Y. Heterocycles 2002, 58, 347-357. (c) Bajracharya, G. B.;
Huo, Z.; Yamamoto, Y. J. Org. Chem. 2005, 70, 4883-4886. (d) Patil, N.
T.; Wu, H.; Kadota, I.; Yamamoto, Y. J. Org. Chem. 2004, 69, 8745-
8750. (e) Patil, N. T.; Pahadi, N. K.; Yamamoto, Y. Tetrahedron Lett. 2005,
46, 2101-2103. (f) Lutete, L. M.; Kadota, I.; Yamamoto, Y. J. Am. Chem.
Soc. 2004, 126, 1622-1623. For other references related to this chemistry,
see: (f) Kadota, I.; Shibuya, A.; Gyoung, Y. S.; Yamamoto, Y. J. Am.
Chem. Soc. 1998, 120, 10262-10263. (g) Patil, N. T.; Kadota, I.; Shibuya,
A.; Gyoung Y. S.; Yamamoto, Y. AdV. Synth. Catal. 2004, 346, 800-804.
(h) Patil, N. T.; Yamamoto, Y. J. Org. Chem. 2004, 19, 6478-6481. (i)
Patil, N. T.; Wu, H.; Kadota, I.; Yamamoto, Y. J. Org. Chem. 2004, 69,
8745-8750. (j) Kadota, I.; Lutete, M. L.; Shibuya, A.; Yamamoto, Y.
Tetrahedron Lett. 2001, 42, 6207-6210. (k) Patil, N. T.; Pahadi, N. K.;
Yamamoto, Y. Can. J. Chem. 2005, 83, 569-573. (l) Patil, N. T.; Khan,
N. F.; Yamamoto, Y. Tetrahedron Lett. 2004, 45, 8497-8499. (m) Zhang,
W.; Haight, A. R.; Hsu, M. C. Tetrahedron Lett. 2002, 43, 6575-6578.
(7) For the formation of 1,3-dienes from π-allylpalladium species, see:
(a) Takacs, J. M.; Lawson, E. C.; Clement, F. J. Am. Chem. Soc. 1997,
117, 55956-5957. (b) Trost, B. M.; Schmidt, T. J. Am. Chem. Soc. 1988,
110, 2301-2303.
a The reactions of 3 (0.3 mmol) in the presence of Pd(PPh3)4 (10 mol
%) and benzoic acid (20 mol %) were carried out at 100 °C in 1,4-dioxane
(0.2 M) for 12 h. b Isolated yields. c The starting material recovered.
with respect to alkyne, with Pd(PPh3)4 under the standard
conditions gave the corresponding hydroamidation product 4b
in 71% yield (entry 1). In a similar manner, the reaction of the
amidoalkynes 3c and 3d, having an electron-donating group at
the aromatic ring, also proceeded smoothly to afford the products
4c and 4d in 70 and 77% yields, respectively (entries 2 and 3).
The chloro group was tolerated under the present reaction
conditions, allowing us to use the substrate 3e which on
cyclization afforded 4e in 88% yield (entry 4). Substrates
containing electron-withdrawing groups at the aromatic nucleus
proved very good for the present reaction. Thus, the substrates
3f, 3g, and 3h, having -CF3, -COOMe, and -NO2 groups at
the para position in the aromatic ring, gave 4f, 4g, and 4h,
respectively, in excellent yields (entries 5-7). The five-
membered lactam 4i was not obtained from 3i under the present
reaction conditions (entry 8). We attempted various reaction
(8) This includes Pt(PPh3)4, Ni(PPh3)4, RhH(PPh3)4, RHCl(PPh3)3, Ni-
(CO)2(PPh3)2, RuHCl(CO)PPh3)2, and RuH2(CO)(PPh3)3. Only Pd(PPh3)4
was found to be effective.
(9) Enhancement of reaction rate by the use of a Pd(0)/carboxylic acid
combined catalytic system is also observed by others; see: (a) Trost, B.
M.; Rise, F. J. Am. Chem. Soc. 1987, 109, 3161-3163 (b) Trost, B. M.;
Jakel, C.; Plietker, B. J. Am. Chem. Soc. 2003, 125, 4438-4439. For a
review, see: (c) Trost, B. M. Chem. Eur. J. 1998, 4, 2405-2412.
J. Org. Chem, Vol. 71, No. 9, 2006 3613

conditions such as heating the reaction mixture without solvent
or increasing the amount of palladium catalyst and reaction time.
Unfortunately, none of the conditions gave the product 4i.
With success in developing the intramolecular hydroamidation
process, we next turned our attention toward the intermolecular
hydroamidation reaction. The reactions of 1-phenyl-1-propyne
6 with either of the amides 5a-d in the presence of 10 mol %
of Pd(PPh3)4 and 40 mol % of PhCOOH were examined under
the standard conditions. However, in all cases, the reactions did
not proceed to give product 7 (eq 5).
FIGURE 2. Explanation for the formation of diene 2.
The mechanism of the intramolecular hydroamidation reaction
is presumably similar to that of the hydroamination reaction
reported previously and is shown in Figure 1.6a Hydropallada-
tion10 of the alkyne 3a with the hydridopalladium species 9,
generated from Pd(0) and benzoic acid, produces the vinylpal-
ladium species 8, which gives the substituted phenylallene 10
on â-elimination.11 Subsequent hydropalladation of the allene
10 with 9 gives the π-allylpalladium species 11. Intramolecular
nucleophilic substitution in the π-allylpalladium complex 11
gives the product 4a along with the hydridopalladium species
9.
FIGURE 3. Explanation for the formation of the cyclic amide 4.
ladium group leading to the formation of diene 2.7 On the
contrary, 11 generated from 3 undergoes ligand exchange at
the palladium atom (path B) rather than â-hydride elimination
(path A) as the nitrogen of 11 becomes less basic due to the
presence of two electron-withdrawing groups (Figure 3). Perhaps
the nitrogen atom of 11 possesses nucleophilicity enough to
attack the palladium atom in the π-allyl complex 11, although
it is decreased by the presence of the two electron-withdrawing
groups.
In summary, we have developed the Pd(PPh3)4-catalyzed
intramolecular hydroamidation reaction of the amido alkynes
3. This process allows the facile and efficient construction of
six-membered lactams 4 in an atom-economical manner.
Although the reaction reported herein is limited for the synthesis
of six-membered lactams, we think that the absence of any other
comparable synthetic protocols for such transformations justifies
the importance of our findings.
Experimental Section
FIGURE 1. Plausible mechanism for the hydroamidation reaction.
General Procedure for Synthesis of Lactams. To a 5 mL
screw-capped vial equipped with a magnetic stirring bar were added
the amidoalkyne 3a (106 mg, 0.3 mmol), Pd(PPh3)4 (35 mg, 0.03
mmol), benzoic acid (7.5 mg, 0.06 mmol), and 1,4-dioxane (1.5
mL). After the mixture was stirred for 12 h at 100 °C, TLC was
taken in order to confirm whole disappearance of the starting
material. The solvent was removed under reduced pressure, and
the residue was purified by short silica gel column with eluent
(hexane/ethyl acetate, 9:1) to give 4a (98.0 mg) in 92% yield.
As mentioned above, the basicity of nitrogen atom is very
important for the amide cyclization reaction to proceed. The
amido alkyne 1 gave the diene 2, as shown in eq 3, instead of
giving the desired lactam. The reason for the formation of diene
can be well accounted for on the basis of the transition state
described in Figure 2. The π-allylpalladium complex 12 would
undergo â-hydride elimination due to the assistance of more
basic nitrogen, which abstracts a hydrogen â to the π-allylpal-
Supporting Information Available: Experimental details,
1
characterization data, and H NMR spectra of newly synthesized
(10) Trost, B. M.; Rise, F. J. Am. Chem. Soc. 1987, 109, 3161-3163.
(11) (a) Sheng, H.; Lin, S.; Huang, Y. Tetrahedron Lett. 1986, 27, 4893-
4894. (b) Lu, X.; Ji, J.; Ma, D.; Shen, W. J. Org. Chem. 1991, 56, 5774-
5778.
compounds 1, 2, 3a-i, and 4a-h. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO060142X
3614 J. Org. Chem., Vol. 71, No. 9, 2006